KR840000948B1 - Process for the preparation of 9-deoxy-9a-methylene isosteres of pgi2 - Google Patents

Abstract

A wide range of 9-methylene carbaprostacyclin analogs and homologs, and intermediates for them (~250), were prepd. from appropriate bicyclic precursors; racemic and optically active compds. were prepd. Thus, 1.1g Na- borohydride was treated with 11.6g bicyclo [3,3,0 octane-3,7-dione in 100mL ethanol and 100mL CH2CL2 to give 9.1g 7-hydroxy-bicyclo[3.3.0 octane-3-one, 0.065 mol. of which were treated with 12.8g dimethyl-tertiary-butylcyllyl chloride and 8.85g imidazole to give 2.85g 7-oxo-hydroxy-bicyclo[3.3.0 -octane-3-one-dimethyl tertiary-butylcyllyl ether and 11.8g 7-endo-hydroxy-bicyclo-[3.3.0 -octane-3-one-7-dimethyl-tertiary-butylcyllyl ether. The latter compd. in Me2CO3 was treated with Na-hydride to give I.

Description

Method for producing 9-deoxy-9a-methylene iso-electron body of PGI2

The present invention relates to a method for producing 9-deoxy-9a-methylene iso-electron bodies of PGI ₂ .

The compound according to the present invention is represented by the following general formula (I).

In the above formula,

R is a) a free or esterified carboxy group;

b) —C (OR ′) ₃ , wherein each R ′ is independently C ₁ to C ₆ alkyl or phenyl;

c) —CH ₂ —R ″ wherein R ″ is hydroxy or C ₂ to C ₇ alkoxy;

(여기에서, R_a및 R_b는 독립적으로 수소, C₁내지 C₆알킬, C₂내지 C₆알카노일 및 페닐 중에서 선택된다) ;d)

Wherein R _a and R _b are independently selected from hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkanoyl and phenyl;

; g) -CHO; 또는e) -C≡N; f)

; g) -CHO; or

(여기에서, X'는 각각 독립적으로 -O- 또는 -S-이며, R_a' 및 R_b'는 같거나 다르며 C₁내지 C₆알킬을 나타내거나. 함께 직쇄 또는 측쇄 C₂내지 C₆알킬렌을 형성한다)이며 ;h)

Wherein X 'is each independently -O- or -S-, and R _a ' and R _b 'are the same or different and represent C ₁ to C ₆ alkyl, or together straight or branched C ₂ to C ₆ alkyl Forms a lene);

(시스)(트란스), -C≡C-,

-O-.-S-또는

(여기에서, R_c는 수소, C₁내지 C₆알킬 또는 C₂내지 C₆알카노일 일 수 있다)이고 ;D is

(Cis) (Trans), -C≡C-,

-O -.- S-or

Wherein R _c may be hydrogen, C ₁ to C ₆ alkyl or C ₂ to C ₆ alkanoyl;

One of R ₁ and R ₂ , and independently one of R ₃ and R ₄ is hydrogen, C ₁ to C ₆ alkyl or C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl-C ₁ To C ₆ alkyl, the other represents hydrogen, hydroxy, C ₁ to C ₆ alkoxy or aryl-C ₁ to C ₆ alkoxy, or R ₁ and R ₂ , and independently R ₃ and R ₄ together are oxo To form a group;

또는

기를 형성하고 ;R ₅ and R ₆ are the same or different and are each hydrogen, C ₁ to C ₆ -alkyl or halogen, preferably fluorine, or R ₅ , R ₆ and the carbon atoms to which they are attached together

or

To form a group;

(트란스),

(시스)(여기에서, Z는 수소 또는 할로겐이다), -NH-CO- 및 -NH-CH₂-중에서 선택되며 ;Y is -CH ₂ -CH _2- . -C≡C-,

(Trans),

(Cis) wherein Z is hydrogen or halogen, -NH-CO-, and -NH-CH _2- ;

(시스) ,

(트란스),-O-, -S- 및

(여기에서, R_c는 상기 정의한 바와 같다)중에서 선택되고 ;X is-(CH ₂ ) m _3- (wherein m ₃ is 0 or 1),

(Cis),

(Trans), -O-, -S- and

Wherein R _c is as defined above;

m ₁ , m ₂ , n ₁ and n ₂ may be the same or different and may be an integer of 0 or 0 to 12, provided that m ₁ + m ₂ and n ₁ + n ₂ are each 15 or less;

p and q are independently 0 or an integer of 1 to 3, provided that p + q must be an integer of 1 to 6;

R ₇ is a ') hydrogen; b ') C ₁ to C ₄ alkyl; c ') an alicyclic group unsubstituted or substituted with one or more C ₁ to C ₆ alkyl or C ₁ to C ₆ alkoxy; d ') an aryl group unsubstituted, unsubstituted or substituted with one or more halogen, halo-C ₁ to C ₆ -alkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy or phenyl; And e ') a saturated or unsaturated heterocycle ring unsubstituted or substituted with one or more halogen, halo-C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, phenyl or C ₁ to C ₆ alkyl.

The present invention also not only includes lacco derived from the compound of formula (I). Pharmaceutically or veterinary acceptable salts, optical colons and geometric isomers and diastereomers of the general formula (I) compounds and mixtures thereof.

)은 환상치환체가 β배위(즉, 치환체가 환의 평면위에 있는 것을 의미함), 비사이클로[(p＋q＋1).3.0] 알칸 치환체를 나타내는 것으로 환 치환체는 α 또는 β일 수 있고, 비사이크로알칸 치환체는 엔도 또는 엑소일 수 있으며 측쇄 치횐체는 R 또는 S일 수 있다.As used herein, the dashed line (……) means that the cyclic substituent is on the α coordination, ie below the plane of the ring, and also on a bicyclo [(p + q + 1) .3.0] alkane system (consisting of condensed rings A and B). Substituent means that the endo configuration, the substituent on the chain (chain) means that the S configuration. The wedge-shaped line (

) Represents a β configuration (ie, the substituent is on the plane of the ring), a bicyclo [(p + q + 1) .3.0] alkane substituent, and the ring substituent may be α or β, and the bicycloalkane substituent It may be an endo or exo and the side chain plaque may be R or S.

Compound (I) and derivatives thereof have a cis bond between the condensed rings A and B, and the hydrogen atoms bonded to the acyclic system at the bonding site are both dihedral angles formed by rings having intrinsic coordination. Is outside of.

The side chain (ω chain) on cyclopentane ring A is trans for ring B and exo for acyclic system.

The compounds according to the invention are formed by the coordination of exocycle double bonds to the B ring, ie the chain (chain α) bound to this double bond is the same group as the chain (chain o) on the cyclopentane ring A or the other side. There are two possible geometric isomers that are determined by cognition, and the exocycle double bond is defined as cis on the same side, and trans on the opposite side.

In the general formula (I) and the following general formulas, the -mark means both the geometric isomers and mixtures thereof included in the present invention. This labeling method is for natural compounds. However, enantiomers included in the present invention exhibit stereochemistry opposite to that found in natural compounds at all asymmetric sites. Therefore, they are mirror compounds of natural compounds and are prefixed with the name “ent” to indicate this precisely.

d, l mixtures contain equimolar amounts of natural compounds and the corresponding enantiomers.

Alkyl, alkenyl, alkynyl, alkoxy and alkanoyloxy groups may be straight or branched and may be unsubstituted or substituted with one or more halogens, C ₁ to C ₆ alkoxy and aryl, especially phenyl.

R is preferably a free or esterified carboxyl group or a derivative salt thereof.

The C ₁ to C ₆ alkyl group is preferably methyl, ethyl or propyl.

Preferred C ₂ to C ₇ acyloxy groups are C ₂ to C ₆ -alkanoyloxy, for example acetoxy, propionyloxy or benzoyloxy.

As the C ₂ to C ₆ alkanoyl group, acetyl or propionyl is preferable.

C ₂ to C ₆ alkylene are preferably ethylene or propylene.

As the C ₁ to C ₆ alkoxy group, methoxy, ethoxy or propoxy is preferred.

Benzyl is preferable as the aryl-C ₁ to C ₆ -alkyl group, and benzyloxy is preferable as the aryl-C ₁ to C ₆ -alkoxy group.

Preferred as C ₂ to C ₁₀ alkenyl groups are -CH≡CH-R ₈ , wherein R ₈ is hydrogen or branched C ₁ to C ₈ alkyl, with vinyl groups being particularly preferred.

Preferred for the C ₂ to C ₁₀ alkynyl group is —C≡CR ₈ , wherein R ₈ is as defined above, in particular an ethynyl group.

Preferred halo-C ₁ to C ₆ -alkyl groups are trihalo-C ₁ to C ₆ -alkyl, in particular trifuluromethyl.

When Z is halogen, chlorine or bromine is preferred.

R ₅ and R ₆ are independently selected from hydrogen, C ₁ to C ₆ alkyl and fluorine.

In the case where R ₇ is C ₁ to C ₄ alkyl, methyl is preferred.

Phenyl, α-naphthyl or β-naphthyl is preferred if R ₇ is aryl.

If R ₇ is an alicyclic group, it may be mono-, non- or tricycle. Preferred monocyclos are C ₃ to C ₉ -cycloalkyl or cycloalkenyl such as cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. In the case of bicycles, norbornyl is preferred, and tricycle is adamantyl.

In the case where R ₇ is an alicyclic group, mono-alicyclic groups as defined above are preferred.

When R ₇ is a heterocycle ring, it may be mono- or bicycle containing at least one N, S and O as a heteroatom. However, preferred heterocycles are monocycles as defined above, in particular tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidy Nyl or pyridazinyl is preferred.

When R is an esteroxy group, -COOR ₉ [wherein R ₉ is a C ₁ to C ₁₂ -alkyl group (particularly methyl, ethyl, propyl, heptyl) or C ₂ to C ₁₂ -alkenyl (particularly allyl ) Is desirable.

m ₁ , m ₂ , n ₁ and n ₂ are preferably 0,1,2 or 3 independently.

Pharmaceutically or veterinary-acceptable salts of compounds of formula (I) may be formed from inorganic and organic acids and bases.

Inorganic acids that are acceptable pharmaceutically or for veterinary use include hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids include citric acid, fumaric acid, tartaric acid, malic acid, maleic acid, methanesulfonic acid, and ethanesulfonic acid. Acceptable inorganic bases can be hydroxides of alkali or alkaline earth metals, zinc and aluminum. Acceptable organic bases include methylamine, diethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine dodecylamine, allylamine, crotylamine, cyclopentylamine, Amines such as dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine and other similar aliphatic, aromatic and heterocyclamines such as piperi As well as dean, morpholine, pyrrolidine and piperazine. Substituted derivatives such as 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and hydrophilic Derivatives, ie mono-, di- and triethanolamine, 2-amino-2-butanol, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl -1,3-propanediol, tris- (hydroxymethyl) -aminomethane, N-methylethanolamine, N- (p-tert-amylphenyl) -diethanolamine, ephedrine, procaine, and lysine There are α and β amino acids such as arginine.

Preferred salts according to the invention are compounds of formula (I), wherein R is -COOR _d , wherein R _d is a pharmaceutically or veterinary acceptable cation derived from one of the aforementioned bases.

In the present specification, the compound according to the present invention is referred to as a bicyclo [(p + q + 1) .0.3] alkane derivative, and preferably a compound having 20 carbon atoms of the following structural formula, ie, a derivative of prostacyclanoic acid.

(Here, the position of oxygen atom is called position 9a)

Therefore, compounds of formula (I) with p = q = 1 are bicyclo [3,3,0] octyl derivatives or preferably derivatives of 9a-deoxy-9a-methyleneprostacycloanoic acid, because methylene groups This is because it is substituted in place of the heteroatom at position 9a of the prostacyclanoic acid. A compound of formula (I) wherein p = 2 and p = 1 is a bicyclo [4,2,0] nonyl derivative or a hetero atom at the 9a position of prostacyclanoic acid substituted with two methylene groups Therefore it is a derivative of 9a-deoxy-9a, 9b-dimethyleneprostacyclanoic acid. Similarly, compounds of formula (I) wherein p is 3 and q is a bicyclo (5,3,0] dodecyl derivative, or preferably 9a-deoxy-9a, 9b, 9c-trimethylene prostar Derivatives of cyclanoic acid.

Similar prostacyclanoic acid derivatives with q or 2 are called “7a-homo” or “7a, 7b-dihomo”, respectively, and compounds of general formula (I) where p or q is 0 are referred to as “9a-nor -Methylene "or" 7-nor-methylene ".

The same nomenclature (homo, dihomo, nor, dino, etc.) is one (two) or more (electronic) or shortened (electron) in the α and ω chains as compared to the number of carbon atoms in prostacyclanoic acid ( Used to represent the latter). As an example of this nomenclature, the following two compounds (Ia) and (Ib) are fully named.

(Ia): 7-endo-hydroxy-6-exo- (3 ″ s-hydroxy-oct-1′-trans-1′-enyl) -bicyclo- [3,3,0] octyl-3 ( 5 ')-pent-5'-trans-enoic acid; Or 5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-procycline-5,13-dienoic acid;

(Ia): 8-endo-hydroxy-7-exo- (3 ″ R-hydroxy-4's-methyl-non-1'-yl) -bicyclo [4,3,0] -nonyl-3 (6 ') -Hex-6'-cis-enoic acid; Or 5c-11α, 15R-dihydroxy-16s, 2C-dimethyl-9a-deoxy-9a-methylene-7a, 2a-dihomo-procyclin-5-enoic acid.

Preferred compounds of formula (I) according to the invention are carboxy groups in which R forms free or salts, R ₇ is straight or branched C ₁ to C ₄ -alkyl, optionally substituted phenyl as described above, saturated Monoheterocycle (preferably tetrahydrofuryl or tetrahydrothienyl) or a C ₅ to C ₇ -monocycloalkyl group and the other substituents are compounds as defined above:

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl 5,13-dienoic acid;

5c, 13t-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-enoic acid and its 15R epimer;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid and its 15R epimer;

16S-methyl derivatives of the aforementioned acids;

20-methyl derivatives of the aforementioned acids;

5c, 13t-4-oxo-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid;

5c, 13t-4S, 11α, 15S-trihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid-1,4-γ-lactone, and 4R epimers thereof;

Sodium salt of 5c, 13t-4S, 11α, 15S-trihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid, and 4R epimer thereof;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17-cyclohexyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-17-phenyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17 (2 ')-tetrahydrofuryl-18,10,20-trinor-prostacycl-5-5,13-die Nosan;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16-m-trifluoromethylphenoxy-17,18,19,20-netlanor-prostacycl-5 , 13-dienoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16-methyl-16-butoxy-18,19,20-trinor-prostacycl-5-5,13-dienoic acid ;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-16R-fluor-prostacycle-5-ene-13-inoic acid;

5c, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid;

5c, 13t-11 alpha, 15R-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid;

5t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5-enoic acid and 15R epimer thereof;

5t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5-ene-13-inoic acid and 15R epimer thereof;

16S-methyl derivatives of the aforementioned acids;

20-methyl derivatives of the aforementioned acids;

5t, 13t-4-oxo-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid;

5t, 13t-4S, 11α, 15S-trihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid-1-4-y-lactone and its 4R epimer;

Sodium salt of 5t, 13t-4S, 11α, 15S-trihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid and its 4R epimer;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17-cyclohexyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5,13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17-phenyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17 (2 ')-tetrahydrofuryl-18,19,20-trinor-prostacycl-5-5,13-die Nosan;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prostacycl-5-5,13 -Dienoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16-methyl-16-butoxy-18,19,20-trinor-prostacycl-5-5,13-dienoic acid ;

5t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16R- pullouro-prostacycle-5-ene-13-ino acid;

5c, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-9a-nor-methylene-prostacycl-5-5,13-dienoic acid;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-13, 14-didehydro-prostacycl-5-ene-13-inoic acid;

5c, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-7-nor-methylene-prostacycl-5-5,13-dienoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-7-nor-methylene-17-phenyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5c-11α, 15S-dihydroxy-9a-deoxy-7-nor-methylene-16S-pullouro-13,14-didehydro-prostacycl-5-ene-13-inoic acid and its 16R -Pluoro isomer;

5c, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-5,13-dienoic acid;

5c-11α, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethyleneprostacycla-5-ene-13-inoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-5,13-dienoic acid;

5c, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-15-methyl-protacycl-5-5,13-dienoic acid;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16S-methyl-prostacycl-5-5,13-dienoic acid and its 16R-methyl isomer;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,18,19,20-tetranor-prostacycl-5-5,13 -Dienoic acid;

5c-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-ene-13-inoic acid;

5c, 13t-11-α, 15S-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-prostacycl-5-5,13-dienoic acid;

5t, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-9a-nor-methylene-prostacycl-5-5,13-dienoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-13,14-didehydro-prostacycl-5-ene-13-inoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-7-nor-methylene-prostacycl-5-5,13-dienoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-7-nor-methylene-17-phenyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid;

5t-11α, 15S-dihydroxy-9a-deoxy-7-nor-methylene-16S-fluor-13,14-didehydro-prostacycl-5-ene-13-inoic acid and its 16R-pullu Or isomer;

5t, 13t-11 alpha, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-5,13-dienoic acid;

5t-11α, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-5-ene-13-inoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid ;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-5,13-dienoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-15-methyl-prostacycl-5-5,13-dienoic acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16S-methyl-prostacycl-5-5,13 dienoic acid and its 16R-methyl isomer;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,18,19,20-terranonor-prostacycl-5-5,13 -Dienoic acid;

5t-11α, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-ene-13-ino acid;

5t, 13t-11α, 15S-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacycl-5,13-dienoic acid; As well as their 11-deoxy derivatives, 11-epimers, 15R-hydroxy isomers and all enantiomers, as well as their pharmaceutically and veterinary acceptable salts.

The compound of formula (I) according to the present invention, the compound of formula (II), followed by alkylation with a compound of formula (III), continues to remove the protecting group if desired, and optionally Y is CH = CZ Y is -CH ₂ -CH ₂ -and R ₃ and R after reduction of a compound of formula (I) in which-(trans), Z is hydrogen and R ₃ and R ₄ together form an oxo group To obtain a compound of formula (I) in which _tetravalent together form an oxo group, and / or optionally Y is -CH ₂ -CH ₂ -or CH = CZ- (trans) and Z is as defined above and R ₃ And Y is -CH ₂ -CH ₂ -or CH = CZ- (after the protective group is removed by nucleophilic addition reaction of free carbonyl on the ω chain of the compound of formula (I) wherein R ₄ together form an oxo group. trans) and Z were the same as defined above R ₃ and R ₄ one is hydroxy and the other is hydrogen, C ₁ to C ₆ Al , C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl -C ₁ to C ₆ - alkyl, in accordance with the general formula If (Ⅰ) to give the compound, and Y is -CH ₂ -CH ₂ Or -CH = CZ- (trans), Z is as defined above, one of R ₃ and R ₄ is hydroxy and the other is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ alkenyl, C Other hydroxyl groups which are ₂ to C ₁₀ -alkynyl, phenyl or aryl-C ₁ to C ₆ -alkyl which are present as described above may be prepared by ether derivatives from the protected general formula (I) compounds to remove the protecting group Y is —CH ₂ —CH ₂ — or —CH═CZ— (trans) and Z is as defined above and one of R ₃ and R ₄ is C ₁ to C ₆ alkoxy or allyl-C ₁ to C ₆ -alkoxy and the other is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ - alkyl screen of the general formula (ⅰ) - alkynyl, phenyl or aryl -C ₁ to C ₆ And to give a water and / or yield, to Y is -CH = CZ- (trans), as appropriate, wherein Z is halogen, R ₃ and R ₄ is one of hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ Alkenyl, C ₂ to C ₁₀ -alkynyl, phenyl or aryl-C ₁ to C ₆ -alkyl, the other being hydroxy, C ₁ to C ₆ -alkoxy or allyl-C ₁ to C ₆ -alkoxy or R _The hydroxy, oxo or carboxy group present when ₃ and R ₄ together form an oxo group is free or dehydrohalogenated to remove the protected compound of general formula (I) as described above and after removal of the protecting group, -C≡C- and one of R ₃ and R ₄ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl-C ₁ to C ₆ -alkyl and the other is hydroxy, C ₁ to C ₆ - alkyl, aryl or -C ₁ to C ₆ - alkoxy or an R ₃ and R ₄ to form an oxo group with Obtain and / or obtain a semi-formula (I) compound, optionally produce a lactone or salt derivative of a compound of formula (I), or optionally from a salt of a compound of formula (I) And / or preparations of free compounds of the compounds of the general formula (I).

Where

p, q, Y, n ₁ , n ₂ , X, R ₅ , R ₆ , R ₇ , D, m ₁ and m ₂ are as defined for general formula (I) above;

One of R ₁ ′ and R ₂ ′ and independently one of R ₃ ′ and R ₄ ′ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ -alkynyl, phenyl or Aryl-C ₁ to C ₆ -alkyl, the other being hydrogen, hydroxy, C ₁ to C ₆ alkoxy, allyl-C ₁ to C ₆ -alkoxy or a protecting group bound to the acyclic system or side chain with an ether bond Or

R ₁ ′ and R ₂ ′ and independently R ₃ ′ and R ₄ ′ together form a protecting group for a ketone group;

E is (C ₆ H ₅ ) ₃ P- or (ReO) ₂ P → (O) -group, wherein Re may each independently be C ₁ to C ₆ -alkyl or phenyl;

R ′ '' is a ″) carboxyl group in free, esterified or salt form,

b ″) -C (OR ') ₃ (where R' is as defined above)

c ″) —CH ₂ —R ^IV (here, R ^IV is a protecting group bonded to —CH ₂ — with a C ² to C ⁷ -acyloxy or ether bond,

(여기에서, R_a및 R_b는 상기 정의한 바와 같다.)d ″)

Wherein R _a and R _b are as defined above.

e ″) -C≡N,

및f ″)

And

(여기에서, X', Ra' 및 Rb'는 상기 정의한 바와 같다) 중에서 선택된다. 상술한 공정에서, 화합물에 대해 하나 이상의 치환체가 지정된다면 나머지는 모두 일반식(Ⅰ)에서 이미 정의한 것이다.g ″)

Wherein X ', Ra' and Rb 'are as defined above. In the above process, if one or more substituents are specified for the compound, all others are already defined in general formula (I).

For hydroxyl functional groups, protecting groups are ether or ester moieties that can be readily converted to hydroxyl groups under mild conditions such as acid hydrolysis. Preferred groups include silyl ethers such as trialkylsilyl ethers such as tramethyl, dimethyl tert-butyl, dimethyl-isopropyl or dimethylethylsilyl ether, and also tetrahydropyranyl ether, tetrahydrofuranyl ether, Dioxanyl ether, oxathanyl ether,

또는

or

Acetal and enolether moieties such as wherein Alk is C ₁ to C ₆ alkyl.

(여기에서, X', Ra' 및 Rb'는 상기 정의한 바와 같다)이다.Preferred carboxylate groups are ketal and thioketyl residues.

Wherein X ', Ra' and Rb 'are as defined above.

Alkylation of the compound of formula (II) by the compound of formula (III) is carried out using an excess of at least 1.1 molar equivalents of compound (III) per mole of compound (II). The reaction may be linear or cyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane), aliphatic or aromatic hydrocarbons (e.g. n-hexane, n-heptane, benzene or toluene), halogenated hydrocarbons (e.g. , Dichloromethane or carbon tetrachloride) and mixtures of these solvents.

Dimethyl sulfoxide, hexamethylphosphoramide and other aprotic solvents are particularly useful when E is (C ₆ H ₅ ) ₃ P- in the general formula (III) compound. Dimethyl sulfoxide reacts with alkali hydrides to produce dimethyl sulfinylcarbanion, which can then produce carbanion of the general formula (III) from the corresponding posuporan and posufonate, in which the solvent It is particularly preferable because carbanion (III) can be produced in the reaction system.

In the above alkylation reaction, the reaction temperature can vary between the freezing point and the boiling point of water, but room temperature is particularly preferred.

The reaction of the compound of formula (II) with compound (III) yields a mixture of geometric isomers, wherein the new exocyclic double bond formed by the reaction may be cis or trans. If desired, the individual geometric isomers can be separated by fractional crystallization from a suitable solvent or by chromatographic methods such as thin layer chromatography, column chromatography or low, medium or high pressure liquid-liquid chromatography. As the support, silica gel or magnesium silicate may be used, and a fluid such as cyclohexane, n-hexane, benzene, methylene chloride ethyl ether, isopropyl ether, ethyl acetate or methyl acetate may be used.

If necessary, the ether protecting group can be removed from the hydroxyl functional group by mild acid hydrolysis, which may be, for example, solvent (eg water, acetone, detrahydrofuran, dimethoxyethane or low molecular weight). Mono- or poly-carboxylic acids (eg, acetic acid, formic acid, citric acid, oxalic acid or tartaric acid) in alcohol) or sulfonic acids (eg, p-toluenesulfonic acid), or polystyrene in low molecular weight alcohols (eg, ethanol anhydride or methanol) -Using sulfonic acid resin. For example, 0.1 to 0.25 N polycarboxylic acids (eg oxalic acid or citric acid) are used with suitable low boiling solvents which are water miscible and can be easily removed under vacuum after the reaction has ended.

The silylether moiety can be selectively removed using F-ions in a solvent such as tetrahydrofuran and dimethylformamide in the presence of other protecting groups.

The ester protecting group can be removed by reaction with a representative soap.

Ketal and thioketal protecting groups for ketones are generally removed to acetal or thioacetal groups by mild acid hydrolysis as described above.

Thioketal and thioacetal are in the presence of other protecting groups, for example in the presence of alkaline earth metal carbonates such as calcium carbonate or magnesium carbonate. Mercury chloride in aqueous acetone or acetonitrile or mixtures thereof may be selectively removed.

Y is -CH = CZ- (trans) (wherein Z is hydrogen), and R ₃ and R ₄ are optionally reduced to remove the protecting group by the general formula (I) compound forming an oxo group, The reaction to obtain a compound of formula (I) wherein is CH ₂ -CH ₂ -and R ₃ and R ₄ together form an oxo group is carried out with a cosolvent (for example tert-butanol or 2-C ₁ to C ₄ Excess alkali or alkaline earth metals (e.g. lithium, sodium, potassium or calcium) in liquid ammonia, with or without aliphatic alcohols such as alkylpropan-2-ol or cyclic ethers such as tetrahydrofuran or dioxane Preference is given to using. At the end of the reaction, a weak acid such as ammonium chloride or ammonium sulfate or an aliphatic alcohol such as ethanol or propanol is used as the source of both. The reaction temperature may be between −70 ° C. and the reflux temperature of the solvent.

Y is -CH ₂ -CH ₂ -or -CH = CZ- (trans) and Z is as defined above and R ₃ and R ₄ together form a free carbo on the ω chain in the general formula (II) compound which together form an oxo group The nucleophilic addition reaction to the neyl group produces secondary or tertiary alcohols depending on the nucleophilic reagent.

Secondary alcohols are alkali or alkaline earth metals (e.g. sodium, lithium, calcium or magnesium) borohydride or zinc borohydride, where Y is -CH ₂ -CH ₂ -or -CH = CZ after removal of the protecting group. -(Trans), Z is as defined above and one of R ₃ and R ₄ is preferably hydrogen and the other is hydroxide to obtain a general formula (II) compound. The reducing agent is linear or cyclic (eg n-ethylether, tetrahydrofuran, dimethoxyethane or dioxane), aliphatic or aromatic hydrocarbons (eg n-heptane or benzene), halogenated hydrocarbons (eg methylene chloride) or hydride 0.5 to 6 moles per mole of carbonyl derivative (I) is used in aqueous or anhydrous solvents such as siloxane containing solvents (eg methyl, ethyl or isopropyl alcohol) as well as mixtures thereof. Reaction temperature is between -40 degreeC and a solvent, and -25 degreeC-+25 degreeC are preferable.

The tertiary alcohol is reacted with an organometallic derivative, after removal of the protecting group, Y is -CH ₂ -CH ₂ -or -CH = CZ- (trans) and Z is as defined above, R ₃ and R ₄ One of which is C ₁ to C ₆ alkyl, C ₂ to C ₁₀ -alkenyl, C ₂ to C ₁₀ -alkynyl, phenyl or aryl-C ₁ to C ₆ -alkyl and the other is hydroxy ) To obtain the compound. The organometallic derivative is a magnesium derivative such as R ₁₀ MgHal, wherein R ₁₀ is C ₁ to C ₆ alkyl, C ₂ to C ₁₀ -alkenyl, phenyl or allyl-C ₁ to C ₆ -alkyl, and Hal is halogen Preferably chlorine or bromine), lithium silicate such as R ₁₀ CuLi (wherein R ₁₀ is as above), organolithium derivatives such as R ₁₀ Li (here, R ₁₀ is as above), or Alkali or alkaline earth metal acetylides (R ₁₀ -C≡C-) _n -M ^{a +} where n is 1 or 2, R ₁₁ is hydrogen, straight or branched C ₁ to C ₈ alkyl, aryl-C ₁ to C ₆ alkyl or aryl, in particular phenyl, M is an alkali or alkaline earth metal). The reaction of a carbonyl compound with one of these organometallic derivatives can be carried out with an aprotic solvent (eg dimethylsulfoxide or hexamethylphosphoramide), type or cyclic ether (eg n-heptane, n-hexane, benzene). Or 1.05 mole (or slightly excess) of an organometallic derivative per mole of the compound in an anhydrous solvent such as toluene). The reaction temperature is about -70 ° C to the untested temperature of the solvent and is preferably -60 ° C to 20 ° C.

및

알콜(여기에서, R₁₂는 수소, C₁내지 C₈-알킬, C₂내지 C₁₀알케닐, C₂내지 C₁₀알키닐, 페닐 또는 아릴-C₁내지 C₆-알킬이다)은 원하는 바에 따라 상술한 바와같은 분별 결정법 및 크로마토그라피방법을 사용하여 분리할 수 있다.Whether the product of the nucleophilic addition reaction is a secondary or tertiary alcohol, this product is a mixture of epimer S and R alcohols. Individual

And

Alcohols wherein R ₁₂ is hydrogen, C ₁ to C ₈ -alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl-C ₁ to C ₆ -alkyl are as desired According to the above-described fractional determination method and chromatographic method.

From these secondary and tertiary alcohols, after removal of the protecting group, Y is —CH ₂ —CH ₂ — or —CH═CZ— (trans) and Z is as defined above and one of R ₃ and R ₄ is C ₁ To C ₆ alkoxy or aryl-C ₁ to C ₆ -alkoxy and the other is hydrogen, C ₁ to C ₈ -alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl-C ₁ Any ether preparation reaction to obtain a compound of formula (I), which is from C ₆ -alkyl, is optionally aryl-substituted diazoalkanes in the presence of a catalyst such as boric fluoride or borontrifluoride in an organic solvent such as dichloromethane. It can be carried out by reacting with secondary and tertiary alcohols. In addition, this preparation reaction may be carried out by reacting a hydroxyl group (in organic form or as a salt thereof) with an alkyl or arylalkyl halide in a solvent such as dimethylsulfoxide or dimethylformamide while the silver oxide is in the presence of a base. have.

, 디아자비사이클로운데센, 디아자비사이클로노넨 및 알칼리금속아미드 또는 알콜레이트중에서 바람직하게 선택된 탈하이드로할로겐화제를 사용하여 수행한다. 일반식(Ⅰ)화합물 1몰당 1내지 5몰(바람직하게는 1.5 내지 1.8몰)의 탈하이드로할로겐화제가 사용되며, 반응은 -60℃ 내지 물의 비점사이의 온도에서 디메틸설폭사이드, 디메틸포름아미드, 헥사메틸포스포르아미드, 상기한 바와 같은 선형 또는 사이클릭 에테르 또는 지방족 또는 방향족 탄화수소, 액체 암모니아 또는 이러한 용매들의 혼합물과 같은 불활성 용매중, 산소를 함유하지 않은 대기하에서 수행하는 것이 바람직하다. 암모니아 부재하에서는 실온이 바람직하다.Y is -CH = CZ- (trans), Z is halogen, R ₃ and R ₄ are hydroxy, C ₁ to C ₆ alkoxy or aryl-C ₁ to C ₆ -alkoxy and the other is hydrogen, C ₁ To C ₈ -alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl-C ₁ to C ₆ -alkyl or a general formula wherein R ₃ and R ₄ together form an oxo group ( I) optionally dehydrohalogenating the compound to yield the corresponding compound (I), wherein Y is -C≡C-, is CH ₃ -SO-CH ₂

, Diazabicycloundecene, diazabicyclononene, and a dehydrohalogenating agent, preferably selected from alkali metal amides or alcoholates. 1 to 5 moles (preferably 1.5 to 1.8 moles) of a dehydrohalogenating agent are used per mole of the compound of formula (I), and the reaction is carried out at temperatures between −60 ° C. and boiling point of water, dimethylsulfoxide, dimethylformamide, hexa Preference is given to performing in an inert solvent such as methylphosphoramide, linear or cyclic ethers or aliphatic or aromatic hydrocarbons as described above, liquid ammonia or mixtures of these solvents, under an oxygen free atmosphere. In the absence of ammonia, room temperature is preferred.

Any dehydrohalogenation reaction of the general (I) compound, wherein Y is -CH = CH- (trans) and Z is halogen, to prepare the corresponding derivatives where Y is -C≡C-, is a carbonyl nucleophilic reaction and This can be done prior to the subsequent ether preparation from the product alcohol.

All of the following reactions are carried out using standard procedures: any conversion of the compound of formula (I) to another compound, any reaction of lactone or salt preparation, from salts of the compound of formula (I) Preparation reaction of free compounds and separation of individual isomers from mixtures of isomers.

인 화합물로부터 제조할 수 있다.For example, a compound of formula (I) wherein R ₃ and R ₄ are both hydrogen can be prepared from compounds in which one of R ₃ and R ₄ is hydrogen and the other is hydroxy, e.g. Tosylate is prepared by treatment with tosyl chloride under reduced tosylate to NaBH ₄ or NaB (CN) H ₃ in water, aqueous alcohol or dimethylformamide, or ethyl at room temperature between the boiling point of the solvent Prepared by reduction with LiAlH ₄ in an anhydrous solvent such as ether or tetrahydrofuran. Similarly, compounds of formula (I) wherein R ₁ and R ₂ are both hydrogen can be prepared from compounds in which one of R ₁ and R ₂ is hydrogen and the other is hydroxy and D is -CH _2- (Ⅰ) is D

It can manufacture from a phosphorus compound.

Compounds of general formula (I), wherein R ₃ and R ₄ together form an oxo group, are compounds in which one of R ₃ and R ₄ is hydrogen and the other is hydroxy at room temperature, inert such as methylene chloride or chloroform, preferably Is optionally oxidized with excess activated MnO ₂ in a chlorinated solvent, or from 1.1 to 1.2 molar equivalents of dichlorodicyanobenzoquinone in an inert solvent such as dioxane, benzene or mixtures thereof at a temperature between 40 ° C. and the boiling point of the solvent. It can be prepared by selective oxidation.

인 일반식(Ⅰ)화합물은 D가

인 화합물로부터 제조할 수 있다.In a similar manner, compounds of formula (I) wherein R ₁ and R ₂ together form an oxo group can be prepared from a compound in which one of R ₁ and R ₂ is hydrogen and the other is hydroxy,

Phosphorus general formula (I) compounds

It can manufacture from a phosphorus compound.

If only one of several secondary alcohol functional groups is oxidized, the remaining functional groups must be protected as described above, after which the protecting group is removed after the reaction is over.

R ₁ and R ₂ is one of the C ₁ to C ₂ alkoxy or aryl -C ₁ to C ₆ - alkoxy formula (Ⅰ) compound is one of a hydroxy compound in the R ₁ and R _2, R ₃ and R It can be prepared by etherification in a manner similar to that described for the general formula (I) compound, wherein one of ₄ is hydroxy. In addition, if only one of several secondary alcohol functional groups reacts, the remaining functional groups must be protected, and such protecting groups are removed after the reaction has ended.

The compound of general formula (I) wherein R is a carboxylic ester group (e.g., C ₁ to C ₁₂ alkoxycarbonyl) is a compound rotor in which R is a free carboxylic group, by a standard procedure, for example, p- It can be prepared by reacting with a suitable alcohol such as C ₁ to C ₁₂ -aliphatic alcohol or treating with diazoalkane in the presence of an acid catalyst such as toluenesulfonic acid.

Any conversion reaction of a compound of formula (I) wherein R is an esterified carboxyl group (ie, C ₁ to C ₁₂ -alkoxycarbonyl) to a compound where R is a free carboxyl group, may be used in alkaline or alkaline earth metals in water or aqueous alcohols. It can be carried out using a standard saponification process which is acidified with hydroxides.

Any reaction which produces a compound of formula (I) wherein R is -CH ₂ -R " (R " is hydroxy) from a compound wherein R is a free or esterified carboxyl group can be carried out under reflux in ethyl ether or tetrahydrofuran. This can be done by reducing the ester with LiAlH ₄ .

(Ra 및 Rb는 상기 정의한 바와 같다)인 화합물로의 임의의 전환반응은 화합물을 카보디이미드(예, 디사이클로헥실카보디이미드)와 같은 축합제 존재하에서 아민 HNRaRb으로 처리하여 수행할 수 있다. R이 카복실릭에스테르인 일반식(Ⅰ)의 화합물은 환류하, 적합한 유기용매 중에서 2내지 3시간동안 아민 HNRaRb으로 처리하여 R이

인 화합물로 전환시킬 수 있다.R in the general formula (I) compound wherein R is a free carboxyl group

Any conversion to a compound wherein Ra and Rb are as defined above can be carried out by treating the compound with an amine HNRaRb in the presence of a condensing agent such as carbodiimide (eg, dicyclohexylcarbodiimide). The compound of formula (I) wherein R is a carboxylic ester is treated with amine HNRaRb for 2 to 3 hours in a suitable organic solvent under reflux, where R is

It can be converted into a phosphorus compound.

인 일반식(Ⅰ)화합물의 임의 제조공정은 R이 유리카복실그룹인 화합물로부터, 일차적으로 상응하는 아실할라이드(바람직하게는 클로라이드, 대체로 환류 디크로로에탄 또는 디옥산중의 티오닐 또는 옥살릴클로라이드와 반응시킨다)를 형성시킨 다음 아미드유도체를 생성시키고(예를들면 암모니아와의 반응으로), 계속해서 탈수시켜 니트릴을 수득하고(예를들어 90내지 100℃에서 피리딘중의 p-톨루엔설포닐클로라이드를 사용), 최종적으로 나트릴을 실온 내지 100℃에서 디메틸포름아미드중의 나트륨 아자이드 및 염화암모늄과 반응시켜 수행할 수 있다. 카복실그룹을 -CN 또는

로 전환시키는 반응은 출발물질에 대해 수행하는 것이 바람직하다.R is

Any process for the preparation of phosphorus general formula (I) compounds is carried out from compounds wherein R is a free carboxyl group, primarily with the corresponding acyl halides (preferably chloride, generally reflux dichloroethane or dioxane or thionyl or oxalyl chloride in dioxane). Reaction) to form an amide derivative (e.g. by reaction with ammonia), followed by dehydration to yield a nitrile (e.g., p-toluenesulfonylchloride in pyridine at 90 to 100 ° C). Finally, the natril can be carried out by reaction with sodium azide and ammonium chloride in dimethylformamide at room temperature to 100 ° C. Carboxyl group is -CN or

Reaction is preferably carried out on the starting material.

Formula (I) compounds in which R is a free or esterified carboxyl group can be carried out using standard procedures for any conversion to compounds in which R is -CHO, e.g. the corresponding chlorides from acids or esters. And continue to Org. Reactions, 4 362 (1948)] to perform the Rosenmund reaction.

Formula (I), wherein R is -C (OR ') ₃ (R' is as defined above), is a hydrochloride salt of the carboximide ester (prepared by a standard method) from a compound wherein R is a free or esterified carboxyl group. See, eg, J. Amer. Chem. Soc., 64,1827 (1942), can be prepared by reaction with a suitable alcohol.

(여기에서 X'는 산소이고, Ra' 및 Rb'는 상기 정의한 바와같다)인 일반식(Ⅰ)화합물의 임의 제조방법고 같은 아세탈화 반응은 p-톨루엔설폰산 또는 설폰산수지와 같은 촉매존재하, 용매중에서 알데히드와 알콜 또는 클리콜을 반응시키고 형성된 물은 공비증류시켜 제거하거나, 아세톤-디옥솔란을 사용하여 교환 반응시키고 형성된 아세톤을 제거하거나, 또는 오르토-에스테르와 반응시키고 형성된 알콜은 증류제거하여 수행한다. 아세탈은 또한, 교환촉매로써의 수은염(바람직하게는 HgCl₂) 및 알칼리토금속 탄산염 존재하, 불활성용매중에서 상응하는 티오아세탈을 적합한 알콜 또는 글리콜과 반응시켜 제조할 수도 있다.R is

Acetalization reactions such as any process for the preparation of compounds of general formula (I), wherein X 'is oxygen and Ra' and Rb 'are as defined above, include catalysts such as p-toluenesulfonic acid or sulfonic acid resins. Then, the aldehyde is reacted with alcohol or glycol in a solvent and the formed water is removed by azeotropic distillation, exchanged with acetone-dioxolane and the formed acetone is removed, or reacted with ortho-ester and the alcohol formed is distilled off. Do it. Acetals may also be prepared by reacting the corresponding thioacetals with a suitable alcohol or glycol in an inert solvent in the presence of mercury salts (preferably HgCl ₂ ) and alkaline earth metal carbonates as exchange catalysts.

(여기에서 X'는 황이며, Ra' 및 Rb'는 상기 정의한 바와같다)인 일반식(Ⅰ) 화합물의 임의의 제조반응은 불활성 용매, 바람직하게는 할로겐화 또는 방향족 탄화수소(메틸렌 클로라이드, 클로로포름, 벤젠, 톨루엔0중, 보론 트리플루오라이드 에테레이트와 같은 촉매 존재하에서, 메틸머캅탄, 에틸머캅탄, 디티오에틸렌글리콜 또는 디티오프로필렌글리콜 같은 모노-또는 디머캅탄과 반응시켜 바람직하게 수행한다.Thioacetalization reactions, for example, from compounds where R is -CHO,

Any reaction of the compound of formula (I) wherein X 'is sulfur and Ra' and Rb 'are as defined above is carried out in an inert solvent, preferably halogenated or aromatic hydrocarbons (methylene chloride, chloroform, benzene). In toluene, preferably in the presence of a catalyst such as boron trifluoride etherate, by reaction with a mono- or dimercaptan such as methylmercaptan, ethylmercaptan, dithioethylene glycol or dithiopropylene glycol.

Corresponding ketals and thioketals can be prepared from ketones following the process described above for acetals and thioacetals. The preparation of lactones and salts from compounds of formula (I) and the preparation of compounds of formula (I) from salts are carried out using standard procedures.

Individual isomers are separated from mixtures of isomeric compounds (I) using standard methods such as fractional crystallization and chromatography. Compounds of the general formula (III) wherein E is (ReO) ₂ P → (O)-, wherein Re is as defined above, may be prepared by the following formula (Al): Sodium, potassium, lithium or calcium hydride), alkali or alkaline earth metal alcoholates (e.g. sodium or potassium tert-butylate), alkali or alkaline earth metal amides (e.g. sodium amide), or alkaline or alkaline earth of carboxy amide Prepared by reaction with at least one molar equivalent of one of the bases, such as metal salts (e.g., N-sodioacetamide and N-sodiosuccinimide).

In the above formula,

Re, m ₁ , D, m ₂ and R ′ '' are as defined above.

Formula (III), wherein E is (C ₆ H ₅ ) P-, contains 1.1 to 1.3 moles of triphenylphosphine in an organic solvent such as benzene, acetonitrile, or diethyl ether. After reacting with an equivalent, the product phosphonium salt is prepared by treating with an equivalent amount of inorganic base such as NaOH, KOH, Na ₂ CO ₃ or NaHCO ₃ .

Hal-CH _2- (CH ₂ ) m ₁ -D- (CH ₂ ) m ₂ -R '''(Ⅷ)

Wherein m ₁ , D, m ₂ and R ′ '' are as defined above and Hal is halogen.

3247(1968) 및 88, 5654(1966)]에 기술된 방법과 같은 표준 방법을 사용하여 제조한다. 일반식(Ⅷ)의 화합물도 또한 표준 공정에 따라 제조된다.Compounds of general formula are described by Korey et al. In Corey et al., In

3247 (1968) and 88, 5654 (1966), using standard methods such as those described. Compounds of formula IV are also prepared according to standard procedures.

The compound of general formula (II) is a novel compound to which the manufacturing method is provided by this invention.

A compound of formula (II) wherein Y is -CH ₂ -CH _2- , -C≡C- or -CH = CZ- (trans), wherein Z is as defined above,

_a IV) reacting a compound of formula (XI) with a compound of formula (V) to form a compound of formula (XII);

_b IV) arbitrary conversion of the compound of the general formula (XII) to a compound of the general formula (VII);

_c IV) removing the protecting group of G from the product to give the compound of the following general formula (XIV);

_d IV) G ″ is hydroxy and, if present, another hydroxy group is prepared by a process of optionally oxidizing the protected compound of formula (XIV) as described above.

In the above formula

p, q, R ₁ ', R ₂ ', n ₁ , R ₅ , R ₆ , n ₂ , R ₇ , R ₃ ', R ₄ ', E and Z are as defined above;

(여기에서, G'는 실릴 에테르 또는 아세탈에테르 잔기 이다)이고 ;G is a protected carbonyl group or group

Wherein G 'is a silyl ether or acetal ether residue;

Y 'is -CH ₂ -CH _2- , -C≡C-, or -CH = CZ- (trans), wherein Z is as defined above;

또는

이다.G ″

or

to be.

A compound of formula (II) wherein Y is -NH-CH ₂ -reacts a compound of formula (XV) with an aldehyde of formula (XVI) in the presence of a reducing agent, followed by a protecting group of G and optionally, if present Prepared by removing other protecting groups.

In the above formula,

G, p, q, R ₃ ′, R ₄ ′, n ₁ , R ₃ , R ₆ , X, n ₂ and R ₇ are as defined above, R ₁ ′ and R ₂ ′ except hydroxy Is as defined above.

인 일반식(Ⅱ)의 화합물은 일반식(XV)의 화합물을 ;염기 존재하에서 다음 일반식(XⅦ)의 화합물과 반응시키고 계속해서 G에서의 보호그룹 및 임의로, 존재한다면 다른 보호 그룹을 제거하여 제조한다.Y is

The compound of formula (II) is reacted with a compound of formula (XV) with a compound of the following formula (X ') in the presence of a base and subsequently removing the protecting group at G and optionally, other protecting groups, if present Manufacture.

In the above formula,

Hal is halogen, preferably chlorine and R ₃ ′, R ₄ ′, n ₁ , R ₅ , R ₆ , x, n ₂ and R ₇ are as defined above.

Any conversion reaction of the general formula (XII) compound to the general formula (XIII) compound is carried out in the general formula (I), such as nucleophilic reaction to carbonyl on the ω chain, etherification of product alcohol, dehydrohalogenation and hydrogenation. A process for the preparation of the compound of general formula (I) from other compounds of

인 경우에, 보호 그룹 G'는 실릴 에테르 잔기(예를들어 트리메틸, 디메틸 3급-부틸, 디메틸이소프로필 또는 디메틸에틸실릴에테르와 같은 트리알킬 실릴 에테르, 바람직하게는 디메틸-3급 부틸 실릴 에테르) 또는 아세탈 에테르 잔기(예를들어 테트라하이드로피라닐에테르, 테트라하이드로푸리닐 에테르,디옥사닐 에테르, 옥사티아닐 에테르, 바람직하게는 테트라하이드로피라닐)일 수 있다.As mentioned above, G is a group

When protecting group G 'is a silyl ether moiety (e.g. trialkyl silyl ether such as trimethyl, dimethyl tert-butyl, dimethylisopropyl or dimethylethylsilyl ether, preferably dimethyl tert-butyl silyl ether) Or an acetal ether moiety (eg tetrahydropyranylether, tetrahydrofurinyl ether, dioxanyl ether, oxathanyl ether, preferably tetrahydropyranyl).

In the general formula (XIII) compounds the protecting group G 'is removed as described above, ie silyl ether is used F ^- and the acetal ether is selectively removed by acid hydrolysis. If the protecting group G 'must be removed in the presence of another labile ether group, this other group must be an acetal ether if -OG' is a silyl ether and a silyl ether if -OG 'is an acetal ether.

, 프로필렌디티오케탈

, 프로필렌디옥시케탈

, 에틸렌디티오케탈

, 바람직하게는 에틸렌디옥시케탈과 같은 케탈 또는 티오케탈로 보호되는 것이 바람직하다.If G is a protected carbonyl group, this group is dimethoxyacetal, diethoxyacetal, dimethylthioacetyl, diethylthioacetal, preferably with acetal or thioacetal, such as dimethoxyacetal, or ethylenedioxyketal

, Propylene Dithio Ketal

, Propylene deoxy ketal

Ethylenedithioketal

And preferably protected with ketals or thioketals, such as ethylenedioxyketal.

As well as the removal of the protecting groups in the general formula (XIII) compound. Any protection of the free hydroxy group in the general formula (XIV) compound (eg, with acetal ether or silyl ether) can be carried out as described above.

Any oxidation of compounds of formula (XIV), wherein G ″ is hydroxy, can be carried out using standard oxidation processes for secondary alcohols, for example alcohols in organic solvents such as acetone, chromic anhydride in sulfuric acid. The solution is carried out by treatment according to the general procedure.

The reductive amination reaction between the general formula (XV) compound and the general formula (XIV) aldehyde is preferably carried out under representative reaction conditions of this process using a mixed anhydride such as NaBH ₄ or LiAlH ₄ as the reducing agent.

The reaction between the general formula (XV) compound and the (XVII) compound is carried out under the general conditions of acylating the amine.

In addition, the compound of general formula (XI),

_a IV) converting the compound of formula (XXIA) or (XXIB) to the compound of formula (XXII);

Ⅳ _b) Formula (Compound Compound O = C (OR ₁₃ of XXⅡ)) ₂ [where, R ₁₃ is C ₁ to C ₆ alkyl or aryl -C ₁ to C ₆ - alkyl; and reacting the formula To obtain a compound of (XXIII);

_c IV) reducing the compound of formula (XXIII) to produce a compound of formula (XXIV);

_d IV) the compounds of formula (XXIV) are optionally separated into individual optical colons;

_e IV) optionally converting the compound of formula (XXIV) to the compound of formula (XXV);

_d IV) prepared by a process consisting of transforming a compound of formula (XXIV) or (XXV) to a compound of formula (XXIV):

In the above formula,

p, q, m, G, R ₁ ′ and R ₂ ′ are as defined above;

R ₁₃ is C ₁ to C ₆ alkyl or aryl-C ₁ to C ₆ -alkyl;

G '' 'is a protected carbonyl group as mentioned above.

(여기에서 G'는 상기 정의한 바와 같다)인 일반식(XXⅡ)의 화합물은 일반식(XXIA)의 화합물로부터 공지의 방법에 의해, 예를들어 염기의 존재하에서 실릴 할라이드, 실라잔 또는 실릴 트리플루오르아세트아미드와 반응시키거나, 공지의 공정에 따라 비닐 에테르

[여기에서 X″는 -O-,-S- 또는 -(CH₂)r (여기에서 r은 0 또는 1이다)이다]와 반응시켜 제조할 수 있다.G group

Compounds of formula (XXII), wherein G 'is as defined above, may be prepared by known methods from compounds of formula (XXIA), for example in the presence of a base such as silyl halide, silazane or silyl trifluor React with acetamide or vinyl ether according to a known process

Or wherein X ″ is —O—, —S— or — (CH ₂ ) r where r is 0 or 1).

Compounds of formula (XXII), wherein G is a protected carbonyl group, are oxidized to compounds of formula (XXIB) with an excess of pyridine-chromic anhydride complex in pyridine, or in the presence of pyridinium tripulouroacetate. In a mixture of benzene and dimethyl sulfoxide, dicyclohexylcarbodiimide can be used to oxidize according to the method of Moffatt.

The reaction of a compound of formula (XXII) with O = C (OR ₁₃ ) ₂ , wherein R ₁₃ is as defined above, preferably methyl, is in the presence of an inert solvent in the atmosphere that does not contain oxygen and water Or in the absence, in the presence of 2 to 4 moles of base such as sodium methoxide, sodium ethoxide, sodium or potassium hydride or potassium tert-butoxide using an excess of 6 to 12 moles of carboxylic acid diester per mole of ketone. . The reaction is carried out at a temperature of about 0 ° to 80 ° C. (preferably 60 to 80 ° C.) for 10 minutes to 1 hour. Yields vary from 5% to 90% depending on temperature, reaction time and concentration.

Compounds of general formula (XXIII) can be reduced with an alkaline or alkaline earth metal borohydride in an aqueous solution, preferably at pH 5.3 to 7.2, or refluxed with ethanolic NaBH ₄ in methylene chloride / ethanol at -20 ° C. have. In general, the reduction reaction is completed in 30 minutes and excess reagent is removed by addition of a readily reducible compound such as acetone and a quantum donor such as acetic acid.

The individual optical cognates of the general formula (XXIV) compound, as defined above by G, saponified esters using standard procedures, quinine, cinconine, ephedrine, 1-phenyl-1-aminoethane, dihydroabiethylamine, The diastereomeric salts formed by the formation of salts of the product acid with an optically active base such as amphetamine or arginine can be employed by, for example, separating by crystallization. The optically active phosphoric acid is then converted to the sodium salt and subsequently acidified to recover its aqueous solution to a pH that does not interfere with the protecting group at G.

Optionally, hydrolysis of the protecting group can be performed prior to the optical isolation step, after which the protecting group is regenerated. Optically active free acids prepared in this way are converted to optically active esters (XXIV) by standard processes such as treatment with suitable diazoalkanes.

로 형성시키고 그후 부리된 광학적으로 활성인 케토-에스테르를 통상적 방법으로 케탈화 도는 아세탈화하여 광학적 대장체(XXIV) 및 (XXV)로 전환시킬 수 있다.If desired, the same process can be used and the racemic mixture of compound (XXV) can be separated into individual optical colons. In addition, compounds of the general formulas (XXIV) and (XXV), wherein G is a protected carbonyl group, can be isolated into their optical counterparts which deprotected the carbonyl group at G, ie the compounds are arginine, lysine, alanine, 1 Reaction with an optically active primary amine such as -phenyl-1-ethylamine or 1-phenyl-1-propyl-amine to give the corresponding optically active diastereomeric Schiff base which is fractionated crystals or HPLC Separation by a known method such as hydrolysis of the imino group by a known method

The optically active keto-esters which are then formed and then beta may be converted to optical colons (XXIV) and (XXV) by ketalization or acetalization in a conventional manner.

Any conversion reaction of the general formula (XXIV) compound to the general formula (XXV) compound can be carried out on the racemic mixture or on the individual isomers isolated as described above. In this conversion process, the coordination of the cyclopentane cyclic free hydroxyls is reversed. Such a process is for example treated with 2 to 4 molar equivalents of triphenylphosphine and 2 to 4 molar equivalents of carboxylic acids such as acetic acid, benzoic acid or p-phenylbenzoic acid, or optionally halogenated aromatic hydrocarbons (eg benzene or chlorobenzene) or between Treatment with 2 to 4 molar equivalents of ethyl azo-bis-carboxylate in an inert solvent, such as a click ether (e.g. tetrahydrofuran), esterifies the hydroxyl, and subsequently formed ester functionalities are alkali carbonates, preferably K ₂ CO ₃ present. Performed by selective saponification by transesterification in inert alcohol R ₁₃ OH.

Compounds of formula (XXVI) are prepared from compounds (XXIV) or (XXV) using known methods. For example, the free hydroxy groups in compound (XXIV) or (XXV) may be formulated using C ₁ to C ₆ alkoxy, aryl-C ₁ to C, using the ether preparation methods already described for similar reactions of compounds of general formula (I). Conversion to C ₆ -alkoxy or labile ethers (eg, silyl or acetal ethers).

In the compounds of formula (XXIV) or (XXV) the free hydroxyl groups can be oxidized to oxo groups and the product canton is converted to ketal or thioketal according to the process already described for compounds of formula (I). A tertiary alcohol can be obtained.

The free hydroxyl groups in the general formula (XXIV) or (XXV) compounds are treated with sulfonic acid chlorides such as, for example, p-toluenesulfonyl, methinesulfonyl or benzenesulfonyl chloride and subsequently the product sulfonate is exemplified. For example, it may be reduced by using LiAlH ₄ in a standard manner and substituted with a hydrogen atom. In this case, the carboxylic ester group (-COOR ₃ ) can be reduced simultaneously with the primary alcohol (-CH ₂ OH) and then aldehyde hydrooxidized using a Morphet reagent.

The resulting compound of formula (XX ') can be converted to the corresponding compound of formula (XXVI) by reduction according to standard procedures, for example using diisobutylaluminum hydride or lithium diisobutylaluminum hydride. have.

In the above formula,

One of R ₁ ″ and R ₂ ″ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ -alkenyl, aryl or aryl-C ₁ to C ₆ -alkyl, and the other is hydroxy, C ₁ to C ₆ alkoxy, aryl-C ₁ to C ₆ -alkoxy or labile ether group,

R ₁ ″ and R ₂ ″ together form a ketone protecting group.

If the compound (XX ') is reduced using LiAlH ₄ according to a standard procedure, the product is the corresponding primary alcohol and this primary alcohol is also free acid by standard reduction reaction using BH ₃ in tetrahydrofuran. It can be manufactured from. Free acids are prepared by saponification of esters. This primary alcohol can then be oxidized to aldehyde using a mopatate reagent as described above.

The compound of formula (XV) is a general formula wherein the secondary alcohol functional group is protected with acetal ether if -OG 'is a silyl ether, or silyl ether if -OG' is an acetal ether. It is prepared according to a known method using the compound as a starting material. For example, the compound of general formula (XV) can be manufactured from the compound of general formula (XX ') according to the following co-authorization;

_a iii) optionally remove the protecting group of G;

로부터 유리된 유리 하이드록실 그룹은 예를들어, 죤즈 시약(Jones reagent)을 사용하여 케톤으로 산화하고; _b iii) optionally,

Free hydroxyl groups liberated from are oxidized to ketones using, for example, Jones reagent;

_{c iii} ) saponifying the ester to obtain an acid;

_d iii) the resulting acid is converted to a mixed anhydride by reaction with an acid chloride such as alkyl, benzyl or pivaloylchlorocarbonate in an inert anhydrous solvent such as acetone, tetrahydrofuran or methylene chloride;

_e iv) mixed anhydrides, for example, by treatment with an acetone solution of alkali metal azide to convert to azide;

_f iii) amine is prepared from azide by Curtius rearrangement reaction;

_g iii) finally the product amine of formula (xv) is optionally converted to another compound.

Compounds of formulas (XVI) and (XVII) are known compounds that can be obtained by known methods.

, 6347(1960)] 시키거나, 비사이클로-[3,3,0] 옥탄-3,7-디온-모노케탈을 환원[

2377(1974)] 시키거나, 계속해서 카보닐 작용기로부터 케탈을 제거하여 제조된다. 두 경우에 p=q=1인 생성물 하이드록시케톤 (XXI)은 엔도 유도체가 약 50%인 엔도-하이드록시 및 엑소-하이드록시 유도체의 혼합물이다. 2가지 이성체는, 상기에서 여러번 기술한 바와 같이 분별 결정법 또는 크로마토그라피방법에 의해 상응하는 라세미 실릴옥시 유도체를 사용하여 쉽게분리할 수 있다.Compounds of formulas (XXIA) and (XXIB) are prepared by known methods. For example, compound (XXIA) with p = q = 1 can be used to selectively reduce bicyclo- [3,3,0] octane-3,7-dione [

, 6347 (1960)] or reducing bicyclo- [3,3,0] octane-3,7-dione-monoketal [

2377 (1974) or by subsequently removing the ketal from the carbonyl functional group. In both cases the product hydroxyketone (XXI) with p = q = 1 is a mixture of endo-hydroxy and exo-hydroxy derivatives with an endo derivative of about 50%. The two isomers can be easily separated using the corresponding racemic silyloxy derivatives by fractional crystallization or chromatographic methods as described several times above.

Compounds of general formula (XXI) wherein p is 1 and q is 2, after standard hydroboration of double bonds (as described above) protecting ketones with ketals or thioketals, followed by ketone protecting groups as described above By a process consisting of removing them together, two rings are prepared from bicyclo- [4,3,0] non-7-en-2-ones (XX ') having cis bonds.

Compound (XXVII) can be synthesized, for example, by J. P. Vidal as described in the literature [JPVidalin “stereochimie et Selectivite 'Reactionelle en Serie Bicyclo [n.3.0] alcanique,” presented at the Universite de Sciences et Tecniques du Languedoc, Academie de Montpelier, n ^O d'orde CNRSAO 11257 (1975).

Compounds of the general formula (XXIA) wherein p is 1 and q is 2 (e.g., prepared as described above) are subjected to continuous ketylation or thioketalization, Vader-Billinger, using methods analogous to those described above. The reaction (Bayer-Wilinger) and product formulation can be performed to convert to other derivatives (XXI).

Compounds of the general formula (XXIB) in which p is 0 and q is 1 or p is 1 and q is 0 are known by bromidine 5-exo-bromo-6-endo-hydroxy-bicyclo [ 3.2.0] heptane-2-one [J. Chem. Soc., Perkin, 1, 1767 (1965)], for example, the bromidine can be converted to its acetal, thioacetal, ketal or thioketal and then known methods in organic chemistry using Compound (XXIB), for example, by reduction with chromic acid (III) salt or by catalytic hydrogenation in the presence of pd / CaCO ₃ or pd / c and in the presence of anhydrous halo acid acceptor or by reduction with tributyltin hydride Can be obtained.

Compounds of the general formula (XXIB) in which p is 2 and q is 1, or q is 2 and p is 1, for example, from the compound of formula (XX '), a carbonyl group is formed using LiAlH ₄ in ethyl ether Reduced to alcohol and the alcoholic group protected, for example with tetrahydropyranyl ether or silyl ether, usually hydroborated and oxidized to the olefinic double bond to deblock the protected hydroxy group, followed by acetal It can be prepared by the formation or the ketalization.

(여기에서, G'는 실릴 에테르의 잔기이다)이며, R₁' 및 R₂' 중의 하나가 수소이고 다른 하나가 하이드록시이면, 하이드록시는 바람직하게 아세탈 에테르 또는 에스테르로 보호되는 일반식(XI)화합물의 제조에 출발물질로 사용될 수도 있다.Compounds of the general formula (XXIB) with p = q = 2 are described, for example, in DK Banerjee and K. Sankara Ram. in Ind. J. of chem.vol. x, page 1 (1972). It can be prepared by a known method from 2-hydroxy-perhydro-azulen-6-one which can be obtained by the compound of general formula (XX ').

Wherein G 'is a residue of the silyl ether, and if one of R ₁ ′ and R ₂ ′ is hydrogen and the other is hydroxy, the hydroxy is preferably protected by acetal ether or ester (XI It can also be used as a starting material for the preparation of compounds.

As described above, by the known method, the compound (XX ') is converted to β-ketone ester (XXIX), and the compound (XXIX) is reduced to β-hydroxyester (XXX) in which the hydroxy group is protected with acetal ether. The obtained compound (XXXI) is hydroborated to an olefinic double bond in the usual manner to obtain alcohols (XXXIIa) and (XXXIIIa), which are then isolated by chromatography or fractional separation to give the corresponding silyl ether (XXXIIb). And (XXXIIIb) and finally reduced using diisobutylaluminum hydride in toluene according to a known method to transform into a general compound.

Compounds of general formula (I) exhibit the same pharmacological activity as natural prostacyclin or PGI ₂ , but the compounds included in the present invention have special stability with greater stability at pH 0 to 11, especially physiological pH, as compared to PGI ₂ There is an advantage, which results in a more persistent and more consistent biological activity. This greater safety is due to differences in the chemical structure of the compounds of the present invention compared to natural prostacyclins. Because the 2-oxa-bicyclo [3.3.0] octane system contains oxygen as a heteroatom, natural prostacyclin is an axocyclicenol ether and is very sensitive to acids. The reaction product with acid 6-keto-PGF shows little biological activity which is characteristic of natural prostacyclin. On the other hand, the compounds of the present invention are not enol ethers because they do not contain oxygen in the acyclic system. Since they do not have high instability unlike natural derivatives, they can be administered orally.

In addition, there are triple bonds at positions 13-14 of the ω-chain and adjacent to the hydroxyl at position 15 (R ₃ or R ₄ is hydroxy) (eg C ₁ to C ₆ alkyl group or fluorine) Compounds of formula (I) with electron acceptor groups, such as, are more resistant to enzyme-induced (eg 15-PG-dehydrogenase) metabolism than natural prostacyclins.

The pharmacological action of natural prostacyclin is known. Thus, for example, when inhaled in an asthmatic patient, prostacyclin prevents bronchial spasm even though it is induced (eg, by spraying water or mechanically induced) [S. Bianco et al, J. Res. Medical Science. 6, 256 (1978)], when injected into the human body shows blood pressure lowering action and bronchial dilation action and also platelet aggregation inhibition and separation properties [Szekely et al. pharm. Res. Comm. 10, 545 (1978)], also prostacyclin exhibits uterine stimulation in monkeys and women, prostacyclin exhibits progesterone inhibition in test animals, and also acetyl salicylic acid (ASA) and in test animals such as rats. Gastric lacquer can be protected from ulcers induced for nonsteroidal anti-inflammatory agents such as indomethacin.

However, in natural prostacyclin, these activities appear as marked chemical instability and are therefore not suitable for pharmaceutical use. As already described, the compounds of formula (I) exhibit similar pharmacological action as natural prostacyclins, but there is no unwanted chemical instability such as PCI _{2 in the} compounds of the present invention.

The following table shows the in vitro inhibitory effect on platelet aggregation induced by 10 μM ADP in platelet-rich plasma lines of the two compounds of the present invention and PCI ₂ and the hypotensive action on unanaesthetized rats.

(1) PGI ₂

(2) 5t, 13t-11α, 15s-dihydrocy-9a-deoxy-9a-methylene-prostacyclin-5,13-dienoic acid

(3) 5t, 13t-11α, 15s-dihydrocy-9a-deoxy-9a, 7a-homo-dimethylene-prostacyclin-5,13-dienoic acid

IC ₅₀ = 50% platelet aggregation inhibitory concentration

Comparing PGI ₂ with the mixture dl-5t, 13t-11α, 15s-dihydrocy-9a-deoxy-7-methylene-prostacyclin-5,13-dienoic acid, at an aggregation inhibitory dose exhibiting the same activity The latter antiulcer activity is 10 times greater than that of PGI ₂ .

Compared with PGI ₂ , in vitro progesterone inhibitory activity using hamsters at doses exhibiting the same aggregation inhibitory activity was dl-5t, 13t-11α, 15s-dihydrocy-9a-deoxy-9a, 9b-di. Methylene-17-cyclohexyl-18,19,20-trinor-prospacyclyl-5,13-dienoic acid and 5t, 13t-11α, 15s-dihydrocy-9a-deoxy-9a, 7a-homo -Dimethylene-16-phenoxy-17,18,19,20-tetranor-prostacyclin-5,13-dienoic acid are 5 and 8 times larger, respectively.

Since the compounds of the present invention exhibit prostacyclin- and prostacyclin-positive activity, they can be used as human and veterinary medicines in the areas where natural prostacyclin and prostaglandins are used for treatment. For example, these compounds are useful in the treatment of asthma because they exhibit obvious bronchodilating action. In this case, the compound may be administered by several routes, i.e. in the case of tablets, capsules, pills, or liquids (e.g., suppositories or syrups), rectally, or intravenously, intramuscularly or subcutaneously, with suppositories, Inhalation with aerosol or vaporization solution or blow off powder. A dose of about 0.01-4 mg / kg is administered 1 to 4 times per day, but the exact dose depends on the patient's age, weight and condition as well as the method of administration.

When using asthma therapies, the compounds of the present invention are used in combination with other asthma therapies, for example sympathetic stimulants such as isoproterenol, ephedrine, xanthine derivatives such as deophylline and aminophylline and corticosteroids such as prednisolone and ACTH can do.

Since the compound included in the present invention also has an accelerating action, it can be used in place of oxytocin to induce the release of a fetus or dead fetus for human and veterinary use. In this case, the compound is administered intravenously or orally at a dose of about 0.01 μg / kg until delivery.

The compounds according to the invention are also useful for regulating pregnancy because they exhibit progesterone suppression and they have the advantage of not stimulating smooth muscles so much that they do not show the side effects of natural prostaglandins such as vomiting and hari.

In addition, these compounds exhibit antiulcer activity and are therefore used to reduce or regulate excessive gastric secretion in mammals. In this action, the compounds of the present invention minimize or reduce the occurrence of ulcers in the gastrointestinal tract and promote the healing of ulcers already occurring in the gastrointestinal tract. In this case, the compound is administered by intravenous infusion, or by intravenous, subcutaneous or intramuscular injection, and the intravenous infusion is administered in the range of 0.1 μg to 500 μg / kilo / min. When administered by injection and infusion methods, the total daily dose ranges from 0.1 to 20 mg / kg, depending on the age, weight and condition of the patient or animal and the method of administration.

However, as with natural prostacyclins, the most important pharmacological properties of the compounds of the present invention are the effects of platelet aggregation inhibitor activity, that is, inhibiting platelet aggregation, reducing adhesion, preventing the formation of clots and dissolving freshly formed blood clots. Indicates. This platelet aggregation inhibitory activity also manifests as an extension of the coronary arteries. For this reason, the compounds of the present invention are useful for the prevention and treatment of myocardial infarction, and are generally useful for the prevention and treatment of thrombosis, atherosclerosis, atherosclerosis and more generally in the treatment of diseases such as hyperlipidemia.

In such cases, conventional methods of administration, ie intravenous, subcutaneous, intramuscular administration, are used. In an emergency, it is desirable to administer intravenously in a dosage range of 0.005 to 20 µg / kg / day, depending on the age, weight and condition of the patient and the method of administration.

As mentioned above, the compounds of the present invention are useful as therapeutic agents for human and veterinary medicine by various methods of administration. These compounds are administered orally in the form of tablets, capsules, suppositories or syrups, rectally with suppositories, parenterally in the form of solutions or suspensions administered subcutaneously or intramuscularly, or preferably intravenously in an emergency. Or inhaled with an aerosol or vaporization solution, sterilely implanted for continuous action, or vaginally administered in the form of a suppository.

Pharmaceutical compositions and veterinary compositions of the compounds of this invention may be prepared by conventional methods using conventional carriers and / or diluents. For example, sterile isotonic aqueous solutions are preferred for intravenous injection or infusion. For subcutaneous or intramuscular injection, sterile aqueous solutions or suspensions are used in aqueous or aqueous media. Sterile compresses or silicone rubber capsules containing or impregnated with the active ingredient can be used for sterile implantation.

Conventional carriers and diluents include water, gelatin, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium and magnesium stearate, glycol, starch, arribia rubber, adracant rubber , Alginic acid, alginate, lecithin, polysorbate, vegetable oil and the like.

The compounds of the present invention may be administered by spraying using an aqueous suspending agent or solution in its salt form, preferably in the sodium salt form. Alternatively, the compounds of the present invention may be suspended or dissolved in one of the conventional liquefied jetting agents, such as dichlorodifluoromethane or dichlorotetrafluoroethane and administered using a pressurized vessel such as an aerosol bomb. . If the compound does not dissolve in the ejector, cosolvents such as ethanol, dipropylene glycol and / or surfactants may be added to the pharmaceutical formulation.

In the following examples THP, DMTB, DIOX, THF, DMSO, DIBA and DMF are tetrahydropyranyl, dimethyl tert-butyl, 1, 4-diox-2-enyl, tetrahydrofuran, dimethylsulfoxide, Diisobutylaluminum hydride and dimethylformamide.

The following examples illustrate the invention in detail. It is not intended to limit the invention.

Example 1

To a solution of 11.6 g (8.4 × 10 ⁻² mol) of bicyclo [3.3.0] octane-3,7-dione in 100 ml of methylene chloride and 100 ml of ethanol, 1.1 g (0.029 mol) of sodium borohydride are added with stirring. After 45 minutes at the same temperature, 20 ml of acetone is slowly added to decompose the excess reagent. The mixture is then neutralized with 1.4 ml of acetic acid and evaporated in vacuo to give a residue which is dissolved in molar and methylene chloride. The organic phase is evaporated to dryness and filtered over silica gel (using 70:30 hexanes: ethyl ether as eluent) to yield 9.1 g of 7-hydroxy-bicyclo [3.3.0] octan-3-one. IR (Film) 3400, 1740 cm ^-1 .

A solution of the resulting compound (0.065 mol) in 27 ml of anhydrous dimethylformamide is treated with 12.8 g of dimethyl-3-tert-butylsilyl chloride and 8.85 g of imidazole. The resulting mixture is heated to 60 ° C. for 5 hours, cooled, diluted with twice the volume of water and extracted with ethyl ether (3 × 40 ml and 2 × 20 ml). The combined organic extracts are washed with 5% NaHCO ₃ and then water and evaporated to dryness until neutral to yield 15.8 g (95% yield) of the crude product. Purified on silica gel, 2.85 g of 7-oxo-hydroxy-bicyclo [3.3.0] -octan-2-one-dimethyl-tert-butylsilyl ether having a melting point of 40 to 42 ° C. and 7- of melting point of 51 to 52 ° C. 11.8 g of endo-hydroxy-bicyclo- [3.3.0] octan-3-one-7-dimethyl-tert-butyl silyl ether are obtained.

The solution of the latter compound (11.8 g, 4.63 × 10 ⁻² mol) dissolved in 295 ml of methyl carbonate (Me ₂ CO ₃ ) was stirred under an inert atmosphere, excluding water, and carefully treated with 6.95 g of 80% sodium hydride. do. When hydrogen evolution ceases, the reaction mixture is heated at 75 to 80 ° C. for 40 minutes. After cooling, the mixture is diluted with twice the amount of ethyl ether and carefully treated with 13 g of glacial acetic acid. The organic phase is then separated with buffer between pH 5.2 and 5.5 and the aqueous layer is extracted with ethyl ether. The combined organic extracts were dried over Na ₂ SO ₄ and evaporated to dryness to give d, l-7-endo-hydroxy-bicyclo [3.3.0] octan-3-one-2-carboxyketylester-7-dimethyl-3one. 12.82 g (14.49 g of theory; 85% yield) were obtained, which were purified on silica gel (45 g / g, using 97: 3hexane: ethyl ether as eluent) to obtain 10.81 g of pure product.

λ max = 254 mμε = 7,000.

The d, l-7-endo-hydroxy-bicyclo [3.3.0] octan-3-one-2-carboxymethylester-7-di-methyl-tert- Butyl silyl ether is obtained.

λ max = 254 mμε = 6.500.

Example 2

D, l-7-endo-hydroxy-bicyclo [3.3.0] octan-3-one-2-carboxymethylester-7-dimethyl-tert-butylsilylether-DMtB- in 75 ml of dichloromethine and 75 ml of ethanol 7.5 g of silylether) are cooled to -20 ° C and treated with 0.9 g of sodium borohydride while stirring. After stirring for 15 minutes, 12 ml of acetone are added to decompose excess reagents. The mixture is brought to 0 ° C., 20 ml of 20% KH ₂ PO ₄ is added, the solvent is evaporated in vacuo and the residue is extracted several times with ethyl ether. The combined organic extracts were washed with 5 ml of water and evaporated to dryness. The residue obtained was crystallized with n-hexane, and d, l-3.7-endo-dihydroxy-bicyclo [3.3.0] octane-2-, having a melting point of 68 to 70 ° C. 4.8 g of exo-carboxymethyl-ester-7-DMtB-silylether is obtained. The mother liquor is adsorbed onto 25 g of silica gel and eluted with 90:10 n-heptane: ethyl ether to give an additional 2 g of product which is pure enough to use on its own.

80:20 Methanol: A solution of 6 g of d, l-3,7-endo-dihydroxy-bicyclo [3.3.0] octane-2-exo-carboxymethylester-7-DMtB-silylether in 100 ml of water Treat with 2 g of potassium hydroxide and heat to reflux for 30 minutes. After concentration in vacuo, the mixture is acidified to pH 5.1 and extracted with ethyl acetate. The organic layer was evaporated to give 5.1 g of d, l-3,7-endo-dihydroxy-2-carboxy-bicyclo [3.3.0] octane-7-DMtB-silylether. Soluble in 150 ml of acetonitrile. The solution of compound is treated with 2.81 g of d-(+)-ephedrine. After 4 hours at room temperature, 2.9 g of lead are obtained which is crystallized twice with acetonitrile to give (+)-3,7-endo-dihydroxy-2-exo-carboxy-bicyclo [3.3.0] octane-7- 1.85 g of DMtB-silylether-d (+)-ephedrine salt are obtained ([α] _D = + 52 °). The mother liquors are combined and evaporated to dryness to obtain a residue, which is dissolved in water and treated with 0.68 g of sodium hydroxide in water. Extraction with benzene recovers d-(+)-ephedrine, the sodium salt solution is acidified to pH 5 and extracted with ethyl acetate. The residue obtained by evaporation to dryness of the organic phase was treated with 2.2 g of l-ephedrine and crystallized several times, followed by (-)-3,7-endo-dihydroxy-2-exo-carboxy-bicyclo [3.3.0] octane-7 2.3 g of -DMtB-silylether-L-ephedrine salt are obtained ([α] _D = -49 °).

Example 3

A solution of 6.28 g of d, l-3,7-endo-dihydroxy-bicyclo [3.3.0] octane-7-DMtB-silylether-2-exo-carboxymethyl ester in 30 ml of anhydrous ethylene chloride was prepared from 2, Treated with 2.19 g of 3-dihydropyran and 39 mg of P-toluenesulfonic acid. After 3 h at rt, the reaction mixture is washed with 5% NaHCO ₃ (2 × 5 ml). The organic phase was evaporated to dryness to give d, l-3,7-endo-dihydroxy-2-carboxy-bicyclo [3.3.0] octane-7-DMtB-silylether-3-THP-ether-2-carboxymethylmethyl ester After 8 g are obtained, it is dissolved in anhydrous benzene (2 x 15 ml), dried and evaporated to dryness. The product in 30 ml of anhydrous ethyl ether is added dropwise over 0.6 minutes of LiAlH _{4 in} 40 ml of anhydrous ethyl ether over 15 minutes of stirred suspension. After continuing stirring for 30 minutes, 5 ml of acetone are carefully added, followed by addition of water-saturated ethyl ether to decompose excess. Then 10 g of anhydrous sodium sulfate are added. The organic solution was filtered and evaporated to dryness to give d, l-3,7-endo-dihydroxy-2-exo-hydroxy-methyl-bicyclo [3.3.0] octane-7-DMtB-silylether-3-THP 7.2 g ether is obtained (M ⁺ 370).

In the method, the following compounds are prepared using optically active starting materials:

nat-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane-7-DMtB-silylether-3-THP-ether;

ent-3,7-endo-dihydroxy-2-exo-dihydroxymethyl-bicyclo [3.3.0] octane-7-DMtB-silylether-3-THP-ether.

If 1,4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 3 (2'-diox) -ether is obtained.

Example 4

A solution of 3.8 g of d, l-3,7-endo-dihydroxy-bicyclo [3.3.0] -octane-7-exo-carboxymethylester-7-DMtB-silylether in 40 ml of benzene was first added with 3.66 g of benzoic acid. And 7.9 g of triphenylphosphine, followed by 5.30 g of azo-bis-carboxylate in 15 ml of benzene with stirring. After stirring for 40 minutes, the organic phase is washed with 2N sulfuric acid (2 x 20 nl), then with sodium carbonate (3 x 15 ml) and with water until finally neutral. Evaporation to dryness d, l-3,7-exo-7-endo-dihydroxy-bicyclo [3.3.0] -octane-2-exo-carboxymethyl ester-7-DMtB-silylether-3-benzoate [NMR: 3 Endo (H, 5.8δm), 2 Endo (H, 3.32δd, d), CO ₂ CH ₃ (3H, 3.64δJ), 7 Endo (H, 4.4δ, m) and d, l- A mixture of 3,7-endo-hydroxy-bicyclo [3.3.0] -oct-3-ene-2-oxo-carboxymethylester-7-DMtB-silylether is obtained (M ⁺ 296).

The crude reaction product is dissolved in anhydrous methanol, stirred for 3 hours and treated with 0.5 g of anhydrous potassium carbonate. The residue obtained by evaporation to dryness is dissolved in ethyl acetate and saturated KH ₂ PO ₄ . The organic phase is washed until neutral and evaporated to dryness. The residue was adsorbed on silica gel and eluted with hexane and hexane: ethyl ether to afford the following compounds.

a) 1.01 g of d, l-7-endo-hydroxy-bicyclo [3.3.0] oct-3-ene-2-carboxymethyl ester-7-DMtB-silylether is obtained and dissolved in methanol; Treatment with 0.3 g of% pd / CaCO ₃ and hydrogenation at room temperature and pressure afforded d, l-7-endo-hydroxy-bicyclo [3.3.0] octane-2-carboxymethyl ester-7-DMtB-silylether (M ⁺ 298);

b) 2.01 g of d, l-3-exo-7-endo-dihydroxy-bicyclo [3.3.0] octane-2-carboxymethylester-7-DMtB-silylether was obtained to obtain 80:20 methanol. : Saponification as described in Example 2 using 5% potassium carbonate in water to give d, l-3-exo-7-endo-dihydroxy-bicyclo [3.3.0] -octane-2-exo- Carboxylic acid-7-DMtB-silylether is obtained (M ⁺ 300). These are then separated into individual optical objects using (+) and (−) amphetamines.

(+)-3-exo-7-endo-dihydroxy-bicyclo [3.3.0] Octane-2-exo-carboxylic acid-7-DMtB-silylether is reacted with etheric diazomethane to yield a methyl ester derivative. Switch. Subsequently, the reaction was performed with 2,3-dihydropyran and then rounded with LiAlH ₄ in ethyl ether to give (+)-3-oxo-7-endo-dihydroxy-2-exo-hydroxy-methyl-ratio. Cyclo [3.3.0] octane-7-DMtB-silylether is obtained (M ⁺ 370).

In a similar manner, a mixture of (-) enantiomers and racemics is obtained.

Example 5

5 g of d, l-7-endo-hydroxy-bicyclo [3.3.0] -octane-DMtB-silylether-3-exo-carboxymethyl ester in 100 ml of aqueous methanol are saponified with 2 g of KOH under reflux. After removing methanol under vacuum, an aqueous solution of potassium salt is extracted to remove neutral impurities, acidified and extracted with ethyl ether. The later extracts were combined and evaporated to dryness to afford 4.5 g of d, l acid, which was separated into the optical colon using (+) and (-) ephedrine.

1.32 g of (-)-7-endo-hydroxy-bicyclo [3.3.0] -octane-7-DMtB-silylether-2-exo-carboxylic acid is dissolved in 20 ml of THF and treated with 10 ml of 1M BH _{3 in} THF. do. After 4 hours at room temperature, 20 ml of 1.5 N NaOH is carefully added to decompose the excess reagent. Thereafter, THF is removed under vacuum and the aqueous phase is extracted with arylether. The combined organic extracts were washed until neutral and evaporated to dryness to afford 1.02 g of (-)-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane-7-DMtB-silylether Obtained (M ⁺ 270).

(+) Isomers and racemic mixtures are prepared in a similar manner.

Example 6

).Stir a solution of 0.74 g of d, l-2-exo-hydroxykenyl-3-exo-THF-oxy-7-endo-DMtB-silyl-oxy-bicyclo [3.3.0] -octane in 15 ml of anhydrous methylene chloride Then, a solution of 3.1 g of Collins' reagent (C ₅ H ₅ N ₂ ) ₂ .CrO _{3 in} 40 ml of anhydrous methylene chloride was added all at once while cooling to 0 to 5 ° C. After stirring for 15 minutes, filtering earth is added and the mixture is filtered to give an equivalent solution of the corresponding d, l-2-exo-formyl-derivative. After evaporation of the solvent under vacuum, the residue is taken up in anhydrous benzene and added to a solution of sodium dimethyl- (2-oxo-octyl) -phosphonate. The latter compound was added dropwise 0.59 g of (2-oxo-octyl) -dimethylphosphonate in 10 ml of benzene to a suspension of 0.07 g of 80% NaH in 20 ml of benzene and the resulting mixture was kept for about 1 hour until hydrogen evolution ceased. Prepared by stirring. The organic phase is then neutralized with excess 25% aqueous NaH ₂ PO ₄ and separated. After drying, the residue obtained by evaporation to dryness was purified on silica gel (using cyclohexane: ethyl ether as eluent) d, l-2-exo- [3'-oxo-non-1'-trans-1'-enyl 0.81 g of] -3-exo-THP-oxy-7-exo-DMtB-silyloxy-bicyclol [3.3.0] octane is obtained (

).

Example 7

A solution of 1.05 g of d, l-2-exo-hydroxymethyl-3-endo-THP-oxy-1-endo-DMtB-siloxy-bicyclo [3.3.0] octane in 8 ml of 75:25 benzene: DMSO Treated with 0.89 g of dicyclohexylcarbodiimide followed by 1.42 ml of pyridinium trifluor acetate solution with stirring. After stirring for 3 hours, 20 ml of benzene is added and excess carbodiimide is treated with 0.13 g of oxalic acid in 3.8 ml of water. The benzene phase is separated and washed until neutral and concentrated in vacuo to a solution of 2-exo-formal-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] -octane To give (not a separator compound).

Using this process, d, l-, nat- and enantio-formyl derivatives are prepared. In the same manner, 7-exo-hydroxy-bicyclo [3.3.0] octane-3-one-7-dimethyl-tert-butylsilyl ether is used in the process of Examples 1, 2 and 3, and 2-exo -Formyl-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo [3.3.0] -octane is obtained.

Example 8

A solution of 322 mg of (2-oxo-heptyl) -dimethyl phosphonate in 5 ml of benzene is added to a suspension of 4.5 mg of 80% NaH in 10 ml of benzene and the resulting mixture is stirred until hydrogen evolution stops. In the dark, 258 mg of fine N-bromosuccinimide is added and stirring is continued for an additional 5 minutes. Thereafter, 0.37 g of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane in 5 ml of benzene was added and the resulting mixture was added for 15 minutes. After stirring, the reaction mixture is partitioned between benzene and 15% NaH ₂ PO ₄ . The organic phase was dried, concentrated to taste and adsorbed onto silica gel, eluted with 80:20 cyclohexane: ethyl ether to 2-exo- [2'-bromo-3'-oxo-oct-1'-enyl] -3- 0.42 g of endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] -octane (λ max = 251 μm, ε = 9,250) is obtained.

)Using (2-oxo-3R-fluoro-heptyl) -dimethyl phosphonate, the corresponding 2-exo- [2'-bromo-3'-oxo-4'R-fluoro-oct-1'- Trans-enyl] -derivatives are obtained (

)

Example 9

A solution of 0.3 g of [2-oxo-4 (2 ')-tetrahydrofurylbutyl] -dimethyl phosphonate is added dropwise to a stirred suspension of 36 mg of 80% sodium hydride in 5 ml of benzene. Stirring was continued until hydrogen evolution ceased, then a solution of 0.37 g of 2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo [3.3.0] octane was added. do. After stirring for an additional 20 minutes, the mixture is dissolved in benzene and 20% aqueous monosodium phosphate. The organic phase was separated, concentrated in small amounts, adsorbed on silica gel and eluted with benzene: ethyl ether to elute with 2-exo- [3'-oxo-5 '(2' ')-tetrahydrofuryl-pent-1'-transcenyl]-. 0.35 g of 3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo [3.3.0] octane (λ max = 229 mM, ε = 8,800) is obtained.

Example 10

2-exo-formyl-7-exo-bicycloderivative used in the process of Example 9 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] Octane and the following phosphates (A) are used to prepare the following compounds (B):

A: (2-oxo-heptyl) -dimethyl phosphonate; (2-oxo-octyl) -dimethyl phosphonate; (2-oxo-3S-methyl-heptyl) -dimethyl phosphonate; (2-ox-4-cyclohexyl-butyl) -dimethyl phosphonate; (2-oxo-4-phenyl-butyl) -dimethyl phosphonate; (2-oxo-3-m-fluorouromethylenephenoxy-propyl) -dimethyl phosphonate; (2-oxo-3-methyl-3-butoxy-butyl) -dimethyl phosphonate.

B: 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-oct-1'-trans-1'-enyl) -bicyclo [3.3.0] octane (λ max = 228 mμ, ε = 8,700);

3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-non-1'-trans-1'-enyl) -bicyclo [3.3.0] octane (λmax = 228 mμ, ε = 8,950);

3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-4'S-methyl-oct-1'-trans-1'-enyl) -bicyclo [3.3.0 ] Octane (λ max = 228 mμ, ε = 8,400);

3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-5'-cyclohexyl-pent-1'-trans-1'-enyl) -bicyclo [3.3 .0] octane (λ max = 228 mμ, ε = 9,100);

3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl) -bicyclo [3.3. 0] octane (λ max = 227 mμ, ε = 14,250);

3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl) -Bicyclo [3.3.0] octane;

3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -Bicyclo [3.3.0] octane;

Example 11

=442,444m/e]0.11g 및 3'R에피머 0.1g을 수득한다.D, l-2-exo- (2'-bromo-3'-oxo-4'R-fluor-oct-1'-trans-1'-enyl) 3-endo-THP-oxy- in 10 ml of anhydrous ether A solution of 0.3 g of endo-DMtB-silyloxy-bicyclo [3.3.0] octane is added dropwise to a 0.1 M solution of zinc borohydride in ethyl ether (10 ml) over 15 minutes. After stirring for 2 hours, the reaction mixture is treated with saturated sodium chloride and 2N sulfuric acid. The ether layer is separated and washed successively with water, 5% NaHCO ₃ and water. Evaporation to dryness yields a mixture of 3'S and 3'R hydroxy, separated by liquid-liquid chromatography using isopropyl ether as solvent and d, l-2-exo- (2'-bromo-3'S-hydr Oxy-4'R-fluoro-oct-1'-trans-1'-enyl) -3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane [

= 442,444 m / e] 0.11 g and 0.1 g 3'R epimer.

Example 12

).2-exo- [3′-oxo-5 ′ (2 ″)-tetrahydrofuryl-pent-1′-trans-1′-enyl) -3-endo-THP-oxy-exo in 3 ml of methylene chloride and 3 ml of ethanol A solution of 0.3 g of -DMtB-silyloxy-bicyclo [3.3.0] octane is cooled to −10 ° to 15 ° C. and treated with 25 mg of NaBH ₄ . After stirring for 30 minutes, the reaction mixture is treated with ₁₅ ml of acetone and 3 ml of saturated NaH ₂ PO ₄ , evaporated under vacuum and then extracted with methylene chloride. Dried over organic phase Na ₂ SO ₄ and evaporated to dryness to afford a residue, which was purified on silica gel (hexane: ethyl ether as eluent) to 2-exo- [3'S-hydroxy-5 '(2 ″)-tetrahydrofuryl- 0.1 g of pent-1'-trans-1'-enyl] -3-endo-THP-oxy-7-DMtB-silyloxy-bicyclo [3.3.0] octane and 0.11 g of 3'R isomer are obtained (both are Compound all

).

Example 13

The processes of Examples 11 and 12 were carried out using one of the α, β-unsaturated ketones prepared in Examples 8,9 and 10 to prepare the following compounds:

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2- 2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-ethyl) -bicyclo [3.3 .0] octane ([M ⁺ -H ₂ 0 -102] 424,426 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -bicyclo [3.3.0] ([M ⁺ -H ₂ 0-102] 346;

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-ethyl) -bicyclo [3.3.0 ] Octane ([M ⁺ -H ₂ O-102] 360);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-non-1'-trans-1'-ethyl) -bicyclo [3.3.0] octane ([ M ⁺ -H ₂ 0-102] 360);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-cyclohexyl-pent-1'-trans-1'-ethyl) -bicyclo [3.3.0] Octane ([M ⁺ -H ₂ 0-102] 386);

3-Endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-ethyl) -bicyclo [3.3. 0] octane ([M ⁺ -H ₂ 0-102] 380 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-4'm-trifluoromethylphenoxy-but-1'-trans-1'-ethyl) -Bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 450 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-4'-methyl-4'butoxy-pent-1'-trans-1'-ethyl)- Bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 396 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (2'-bromo-3'R-hydroxy-oct-1'-trans-1'-ethyl) -bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 424,426 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-oct-1'-trans-1'-enyl) -bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 346);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -bicyclo [3.3 .0] octane ([M ⁺ -H ₂ 0-102] 360);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-non-1'-trans-1'-ethyl) -bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 360 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl) -bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 386);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -bicyclo [ 3.3.0] octane ([M ⁺ -H ₂ 0-102] 380);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-4'm-trifuluromethylphenoxy-but-1'-trans-1 ' -Enyl) -bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 450 m / e);

3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-3 ', 4'-hydroxy-4'-methyl-4'butoxy-pent-1'-trans-1'- Ethyl) -bicyclo [3.3.0] octane ([M ⁺ -H ₂ 0-102] 396);

Example 14

2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo- [3.3 in anhydrous ethylene chloride 12 ml .0] A solution of 1.17 g of octane is treated with 120 mg of 2,3-dihydropyran and 5 mg of p-toluene sulfonic acid. After 4 h at rt, the organic phase is washed successively with 5% NaHCO ₃ and water and evaporated to dryness to give 2-hydroxy (3'S-THP-oxy-oct-1'-trans-1'-enyl) -3-endo-THP- 1.45 g of oxy-7-endo-DMtB-silyloxy-bicyclo- [3.3.0] octane is obtained. This product is dissolved in 12 ml of THF and treated with 2 g of tetrabutyl ammonium fluoride. The resulting mixture was stirred at room temperature for 12 hours and concentrated in small amounts to obtain a residue that was purified on silica gel (using ethyl ether as eluent) to give 2-liquid (3'S-hydroxy-oct-1'-trans-1'-enyl). ) -3-endo-THP-oxy-7-endo-dihydroxy-bicyclo- [3. 3. 0] Octane-3, 3'-bis-THP-ether-920 mg is obtained [IR (film) 3400 cm ^-1 ].

Example 15

According to the process of Example 14 using the compound prepared according to Examples 11, 12 and 13, the following bicyclo [3.3.0] octane-3,3'-bis-THP-ether derivative was prepared.

2-exo- (2'-bromo-3'S-hydroxy-4'-fluoro-oct-1'-trans-1'-enyl) -3-endo-dihydrocy (IR film 3400 cm ^-1 ).

2-exo- (2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR Film 3400cm ^-1 );

2-exo- (3'S-hydroxy-5 '(2 ″)-tetrahydro-furyl-pent-1'-trans-1'-enyl) -3-endo-7-exo-dihydrocy (IR film 3400 cm ^-1 );

2-exo- (3'R-hydroxy-5 '(2 ″)-tetrahydrofuryl-pent-1'-trans-1'-enyl) -3-endo-7-exo-dihydrocy (IR film 3400, 1250 cm ⁻¹ );

2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR (film) 3400, 1250 cm ^-1) );

2-exo- (2'-bromo-3'R-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1) );

2-exo- (2'-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400 1250 cm ^-1 );

2-exo- (3'R-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'S-hydroxy-non-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'R-hydroxy-non-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250 cm ^-1 );

2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400,1250 cm ^-1 ) ;

2-exo- (3'S-hydroxy-4'-m-tripulifluorofluoromethylphenoxy-but-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400,1250 cm ^-1 );

2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR Film 3400, 1250 cm ⁻¹ );

2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy (IR film 3400, 1250cm ^-1 );

2-exo- (3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy.

Example 16

A solution of 0.4 g of chromic anhydride is added continuously to the pyridine 4 ml little by little while stirring. Once the complex is formed, this mixture is added to 2-exo- (3'R-hydroxy-5 '-(2'')-tetrahydrofurylpent-1'-trans-1'-enyl) -3-in 4 ml of pyridine. Endo-7-exo-dihydrocy-bicyclo [3.3.0] -octane-3,3'-bis-THP-ether is treated with 0.36 g. The reaction mixture was kept at room temperature overnight, diluted with benzene three times and reextracted, washed successively with water, NaHCO ₃ and water and evaporated to dryness to 2-exo- (3'S-hydroxy-5 '(2 ″)-tetra hydro 0.31 g of furyl pent-1'-trans-1'-enyl) -3-endo-hydrocy-bicyclo [3.3.0] octan-7-one-3,3'-bis-THP-ether is obtained ( IR film 1740,1220 cm ^-1 );

Example 17

2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydrocy-bicyclo [3.3.0] octane-3,3 in 20 ml of acetone A stirred, cooled (-10-6 ° C.) solution of 0.8 g of '-bis-THP-ether is treated with 1.6 ml of Jones' reagent over 15 minutes. After stirring for an additional 15 minutes, 80 ml of benzene are added. The organic phase was separated and washed with 15% aqueous (NH ₄ ) ₂ SO ₄ until neutral and dried by evaporation to dryness. 2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -endo- 0.371 g of hydroxy-bicyclo [3.3.0] octane-7-one-3,3'-bis-tetra hydropyranyl ether is obtained (IR film 1741 cm ^-1 );

Example 18

The triol of Example 15 was subjected to any of the oxidation processes described in Examples 16 and 17 to give the following 3-and-hydroxy-bicyclo [3.3.0] octane-7-one-3, Prepare 3'-bis-THP-ether:

2-exo- (2'-bromo--3'S-hydroxy-4'R-fluor-oct-l'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (2'-bromo--3'R-hydroxy-4'R-fluoro-oct-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3′S-hydroxy-5 ′ (2 ″)-tetrahydrofuryl-pent-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3′R-hydroxy-5 ′ (2 ″)-tetrahydrofuryl-pent-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (2'-bromo--3'S-hydroxy-oct-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (2'-bromo--3'R-hydroxy-oct-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3′R-hydroxy-oct-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl), IR film 1740 cm ^-1

2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3′S-hydroxy-non-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3′R-hydroxy-non-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3′S-hydroxy-5′-cyclohexyl-pent-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3′R-hydroxy-5′-cyclohexyl-pent-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3′S-hydroxy-4′-m-trifluoromethyl-phenoxy-but-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3′R-hydroxy-4′-m-trifluoromethyl-phenoxy-but-1′-trans-1′-enyl), IR film 1740 cm ⁻¹ ;

2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

2-exo- (3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl), IR film 1740 cm ^-1 ;

Example 19

d, l-2-exo- (3'-oxo-non1'-trans-1'-enyl) -3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] A solution of 2.1 g of octane (prepared according to Example 6) was reduced to 0.17 g of NaBH ₄ in methylene chloride: ethanol at -15 ° C. according to the procedure of Example 12 and then d, l-2-exo- (3 '( S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane 2.01 g is obtained do. Without separating the 3'S and 3'R alcohols, the product was reacted with 0.49 g of 2,3-dihydropyran in the presence of 25 mg of p-toluenesulfonic acid in 30 ml of methylene chloride to give the corresponding d, l-exo- (3 '(S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-hydroxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane-3,3'-bis -THP-ether is obtained. Without further purification of this product, treatment with 2.5 molar equivalents of tetrabutyl ammonium fluoride in THP removes the silyl ether.

The product d, l-2-exo- (3 '(S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-7-endo-dihydroxy-bicyclo [3.3.0] Octane-3,3'-bis-THP-ether (1.660 g) is oxidized to pyridine-chromic anhydride to give d, l-2-exo- (3 '(S, R) -hydroxy-non 1.25 g of -1'-trans-1'-enyl) -3-exo-hydroxy-bicyclo [3.3.0] octane-7-one-3,3'-bis-THP-ether is obtained (IR film) 1740 cm ^-1 )

Example 20

A solution of (2-oxo-5,5,5-trimethoxy-pentyl) -dimethyl phosphonate in 10 ml of THP is added dropwise to a stirred suspension of 68 mg of NaH (80%) in 10 ml of dry THF. Stirring was continued until hydrogen evolution ceased, followed by d, l-2-exo- (3 '(S, R) -hydroxy-non-1'-trans-1'-enyl)-in 5 ml of THF. A solution of 0.67 g of 3-exo-hydroxy-bicyclo [3.3.0] octane-7-one-3,3'-bis-THP-ether is added. After stirring for 6 h at 40 ° C. to 15 ° C., 20 ml of 20% NaH ₂ PO ₄ are added and the THF is removed under vacuum. The residue is extracted with ethyl ether and the organic extract is dried over Na ₂ SO ₄ and evaporated.

The residue was adsorbed on silica gel and cyclohexane; Eluted with ethyl ether to give d, l-5t, 13t-4-oxo-11β, 15 (S, R) -dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycl-5; 0.76 g of 13-dienoic acid-trimethylorthoester-11.15-bis-THP-ether is obtained.

The product solution in 15 ml of anhydrous methanol is treated with 6 mg of p-toluenesulfonic acid at room temperature for 5 hours. 0.1 ml of pyridine was added and the solution was evaporated to dryness, and the residue was purified on silica gel (isopropyl ether; ethyl ether as eluent) to give d, l-5t, 13t-4-oxo-11β, 15s-dihydroxy-20 -Methyl-9a-deoxy-9a-methylene-prostacycl-5, 13-dienoic acid-trimethyl-orthoester (IR film 1700,1690 cm ^-1 ; M ⁺ H ₂ O 420 m / e) 0.20 g and 15 R 0.21 g of epimer is obtained.

Example 21

The following trimethylorthoesters and 15R epimers were prepared following the process of Example 20 using the bicyclo [3.3.0] octane-7-ones prepared in Examples 16,17 and 18.

5,13t-4-oxo-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 406;

5,13t-4-oxo-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 420;

5,13t-4-oxo-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-17 (2 ')-tetrahydrofuryl-18,19,20-trinor-prostacycl-5 , 13-dienoic acid, M ⁺ -H ₂ O 434;

5,13t-4-oxo-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prostacy Cla-5,13-dienoic acid, M ⁺ -H ₂ O 150 m / e;

Each of the ortho-esters of Examples 20 and 21 were then refluxed in methanol (15 ml / g) with 2 ml of 0.2 N oxalic acid and the methanol was evaporated and extracted with ethyl ether to recover the product and convert to its methyl ester. Then saponification with 2% KHCO ₃ in 80% aqueous methanol to give the free acid.

Example 22

5,13t-4-oxo-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid-trimethylortho ester in 6ml methanol and 1.2ml 0.2N oxalic acid [lambda] max = 244 m [mu], [epsilon] = 9,850) A solution of 0.45 g was refluxed for 2 hours. The methanol was evaporated under vacuum and extracted with ethyl ether to obtain 0.42 g of the corresponding methyl ester.

A solution of the product dissolved in 6 ml of anhydrous ethyl ide was added dropwise to a 0.1 M solution of zinc borohydride (10 ml) over 10 minutes. After stirring for 1 hour at room temperature, the reaction mixture is treated with 2N sulfuric acid. The organic phase is separated, washed to neutrality and evaporated to dryness. 5,13t-4 (S, R), 11α, 15s-trihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13- 0.4 g of dienoic acid methyl ester are obtained. The product is chromatographed on silica gel (ethyl ether: ethyl acetate as eluent) to give 5, 13t-4s, 11α, 15s-trihydroxy-9a-deoxy-9a. Methylene-prostacycl-5-5,13-dienoic acid methyl ester [IR film 3400 cm ^-1 (broad); M ⁺ -2H ₂ 0 344 m / e] and 0.14 g of 4R-epimermethyl ester.

The solution of the latter compound dissolved in 5 ml of methanol was treated with 0.05 g of lithium hydrate and 0.3 ml of H ₂ O, followed by stirring at room temperature for 6 hours. Methanol was removed in vacuo to acidify to pH5.6 and quickly extracted with ethyl acetate to give 5,13t-4R, 11α, 15s-trihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13 -Dienoic acid-1,4-γ-lactone (M ⁺ -H ₂ O 406 330 m / e) is obtained quantitatively.

4S epimer- [gamma] -lactone is prepared by a similar method.

Example 23

In an inert gas atmosphere, 0.4 g of agitation suspension of NaH (75% mineral oil dispersion) in 13.5 ml of DMSO is heated to 60-65 ° C. for 4 hours. The mixture was cooled to room temperature and maintained at 20-22 ° C. while 2.6 g of 4-carboxy-butyl-triphenyl phosphonium bromide in 6 ml of DMSO, and 2-exo- (3′S-hydroxy-non-1′-trans-1 0.85 g of '-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octane-7-one-3,3'-bis-THP-ether is added successively. After stirring for 3 hours, the mixture is diluted with 35 ml of water and the aqueous phase is extracted with ethyl ether (5 x 12 ml) and ethyl ether: benzene (7 x 12 ml). Combine the organic extracts and re-extract with 0.5N NaOH (3x15ml), extract with water until neutral and discard. Combine the aqueous alkaline extracts and acidify to pH 5.3 and extract with 1: 1 ethylether: pentane. Wash until neutral and dry over NaSO ₄ to remove solvent to remove 5,13t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-5,13-die 0.86 g of nosane-11,15-bis-THP-ether is obtained. This product is then esterified by treatment with diazomethane and the pyranyl protecting group is removed in the following manner:

The methyl ester is dissolved in methanol anhydride and treated with ^10-2 molar equivalents of p-toluenesulfonic acid. After 4 hours ptoluenesulfonic acid is neutralized with pyridine and the mixture is evaporated to dryness. Purification on silica gel afforded 5,13t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycl-5-5,13-dienoic acid methyl ester (M ⁺ -H ₂ O = 360) is then separated into individual 5c, 13t and 5t, 13t isomers by liquid-liquid chromatography.

In a similar manner the following compounds are obtained: 5t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t), 4.00 (1 H, m), 4.40 (1 H, t), 5.30 (1 H, t)] and its 5c-isomer [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t), 4.00 (1 H, m), 4.00 (1 H, t), 5.27 (1 H, t); And 5t-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t) , 4.00 (1H, m), 4.39 (1H, t), 5.30 (1H, t)] and its 5c-isomer [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t), 4.00 (1H, m), 4.40 (1H, t), 5.28 (1H, t)].

Example 24

1.8 g of 4-carboxybutyl-triphenyl phosphonium bromide in 10 ml of DMSO and 5 ml of DMSO while stirring a solution of freshly sublimed potassium tert-butylate in 12 ml of anhydrous DMSO and cooling externally to maintain the reaction temperature at 20-22 ° C. 2-exo (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octane-7-one-3 Continuous treatment with 0.65 g of 3'-bis-THP-ether. After stirring for 8 hours at room temperature, the mixture is diluted with equal volume of water and acidified to pH 5 and extracted with 1: 1 ethylether: pentane. The acidic aqueous phase was discarded and the combined organic extracts were extracted with 0.8N NaOH (5 × 20 ml) and washed with water until neutral. Discard the organic phase and acidify the aqueous alkaline extract to pH 5 and extract with 1: 1 ethylether: pentane. The extracts are combined, dried over Na ₂ SO ₄ , filtered and treated with etheric diazomethane until yellow persists. Evaporation to dryness affords crude 11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inosanomethyl ester-11,15-bis-THP-ether. Remove the pyranyl protecting group and perform liquid-liquid chromatography by 5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid methyl ester (M ⁺ -H ₂ O 344, M ⁺ -H ₂ OC ₂ H ₄ O 300, M ⁺ -H ₂ OC ₅ H ₁₁ 237) and 5t geometric isomers are obtained.

In a similar manner the compound of Example 23 is obtained.

Example 25

The process of Examples 23 and 24 was carried out using bicyclo- [3.3.0] -octane-7-ene-3,3'-bis-THP-ether prepared according to Examples 16,17,18 and 19 When the methyl ester of the following acid is prepared:

5c, 13t-11β, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 346;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluoro-prostacycle-5-ene-13-inoic acid, M ⁺ -H ₂ O 362;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16S-luuro-prostacycle-5-ene-13-inoic acid M ⁺ -H ₂ O 362; m / e;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17 (2 ') tetrahydrofuryl-18,19,20-trinor-prostacycle-5-ene-13-inoic acid, M ⁺ -H ₂ O 386 m / e;

5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid, M ⁺ -H ₂ O 344 m / e;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5,13-dienoic acid, M ⁺ -H ₂ O 346 m / e;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16S-methylprostacyclo-5,13-dienoic acid M ⁺ -H ₂ O 360 m / e;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methylprostacyclo-5,13-dienoic acid M ⁺ -H ₂ O 360 m / e;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17-cyclohexyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid, M ⁺ - H ₂ O 372 m / e;

5c, 13t ⁺ -11α, 15S-dihydroxy-9a-deoxy-9a-methylene-17-phenyl-18,19,20-trinor-prostacycl-5-5,13-dienoic acid M ⁺ -H ₂ 0 380 m / e;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16-m-CF ₃ -phenoxy-17,18,19,20-tetranor-prostacycl-5-5,13 -Dienoic acid, M ⁺ -H ₂ O 450;

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16-methyl-16-butoxy-18,19,20-trinor-prostacycl 5,13-dienoic acid, M ⁺ 520 m / e (with bistrimethylsilylether); And their 5-trans-isomers, in particular 5t-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid methyl ester and their 15R epimers , In particular 5t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid methyl ester.

Thereafter, all the methyl esters are saponified, in particular to obtain the next free acid. 5t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t), 4.00 (1H, m), 4.40 (1H, broad), 5.28 (1H, broad)] and 5t-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid [ NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t), 4.00 (1H, m), 4.39 (1H, broad t), 5.29 (1H, broad t)].

Example 26

2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octane-7-one-3,3 in ethyl acetate A solution of 0.45 g of '-bis-THP-ether is hydrogenated at ambient temperature and pressure until 0.1 g equivalent of hydrogen is absorbed in the presence of 0.1 g of 5% Pd / CaCO ₃ . Filtration and evaporation to dryness afforded 2-exo- (3'S-hydroxy-oct-1'-yl) -3-endo-hydroxy-bicyclo [3.3.0] octane-7-one-3,3'-bis- 0.42 g of THP-ether is obtained. This was treated with a witting reagent prepared from 4-carboxy-butylphosphonium bromide according to Examples 23,24 and 25 to esterify with diazomethane and depyranylated to give 11α, 15S- 0.02 g of dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-enoic acid methyl ester (M366 m / e) are obtained. 5-cis and 5-trans geometric isomers are separated by liquid-liquid chromatography.

Example 27

(3-carboxy-propyl) -phosphonium bromide is used instead of (4-carboxy-butyl) -phosphonium bromide in the processes of Examples 25 and 26 to give the following acid.

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostacycle-5,13-dienoic acid, M ⁺ -N ₂ O 318, 5c-11α, 15S- Dihydroxy-9a-deoxy-9a-methylene-2-nor-prostacycle-5-enoic acid, M ⁺ 338; 5c-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostacycle-5-e-13-inoic acid, M ⁺ _-2 0 316

Example 28

5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-2a-homo-prostacycla using (5-carboxypentyl) -phosphonium bromide in the processes of Examples 25 and 26 -5,13-dienoic acid (M ⁺ 580, M ⁺ -CH ₃ 565; with tris-trimethylsilyl ether) and 5c, 13t-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20- Methyl-2a-homo-prostacycl-5-5,13-dienoic acid (M ⁺ 594, M-CH ₃ 579; with tris-trimethylsilylether) is prepared.

Example 29

A solution of 2.2 g of 3-endo-hydroxy-bicyclo [3.3.0] -octan-7-one in 100 ml of anhydrous benzene was treated with 4 ml of ethylene glycol and 0.2 g of p-toluene sulfonic acid monohydrate and refluxed for 12 hours. At this time, the water formed during the reaction is collected. 0.25 ml of pyridine is then added and the mixture is cooled. The organic phase was washed successively with water, NaHCO ₃ and water and evaporated to dryness to afford 2.32 g of 3-endo-hydroxy-bicyclo [3.3.0] octane-7-one 7,7-ethylenedioxide (IR film 3450 cm- ^{). 1} , no absorption at 1745 cm ^-1 ).

The solution in which the product was dissolved in 40 ml of acetone was cooled to −5 ° C. and treated with 4.1 ml of this temperature et Jones reagent. After 20 minutes at −5 ° C., the excess oxidant was treated with 4 ml of isopropyl alcohol. 150 ml of benzene are added and the Bezen phase is washed successively with 20% (NH ₄ ) ₂ SO ₄ , water 5% NaHCO ₃ and water. Evaporation to dryness yields 2.1 g of d, l-bicyclo [3.3.0] octane-3,7-dione-2-carboxymethylester-7,7-ethylenedioxide with a melting point of 40 to 42 ° C. This compound was reacted with methylcarbonate according to the method of Example 1 to obtain d, l-bicyclo [3.3.0] octane-3,7-dione-2-carboxy-methylester-7,7-ethylenedioxide. (λ max = 254 nm, ε = 7000).

According to the process of example 2, the product was dissolved in 20 ml of CH ₂ Cl ₂ and the solution was reduced to NaBH ₄ at −20 ° C. to d, l-3-endo-hydroxy-bicyclo [3.3.0] octane- 1.72 g of 7-one-2-exo-carboxymethyl ester-7,7-ethylenedioxide is obtained (IR film 3400 cm ^-1 , 1720 cm ^-1 ).

A solution of 1.57 g of the resulting compound dissolved in 3 ml of dimethylformamide was treated with 1.3 g of dimethyl tert-butyl-silyl chloride and 0.885 g of imidazole and then maintained at 0 ° C. for 5 hours. After cooling, water was added and conventionally treated to give d, l-3-endo-hydroxy-bicyclo [3.3.0] octan-7-one-2-exo-carboxymethyl ester-7,7-ethylene dioxide- 2.2 g of 3-dimethyl-tert-butylsilyl ether are obtained (IR film 1710 cm ^-1 ). Subsequently, as described in Example 3, reduction was carried out with LiAlH ₄ in anhydrous ethyl ether to give d, l-3-endo-hydroxy-3-exo-hydroxy-2-methyl-7,7-ethylenedioxy- Bicyclo [3.3.0] octane-7-one-3-dimethyl-tert-butylsilylether is obtained quantitatively (IR film 3400 cm ^-1 ).

Example 30

In the process of Example 29 dithioethylene glycol was used instead of ethylene glycol to prepare the corresponding 7,7-ethylenedithio homologues.

Example 31

d, l-3-endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo [3.3.0] -octane-7-one-3-dimethyl-tert-butylsilyl 1.8 g of ether was oxidized according to the process of Example 7 to obtain the corresponding 2-formyl derivative. The product was reacted with (2-oxo-heptyl) -dimethylphosphonate as in Example 9 to give d, l-3-endo-hydroxy-2-exo- (3'-oxo-oct-1'-trans -1'-enyl) -7,7-ethylenedioxy-bicyclo [3.3.0] -octane-7-one-3-dimethyl-tert-butylsilyl ether (λ max = 228 mμ, epsilon = 8980) 1.23 g To obtain. The product was reduced to zinc borohydride in ether according to the process of Example 11 to give d, l-2-endo-hydroxy-2-exo- (3 '(S, R) -hydroxy-oct-1'- 1.22 g of trans-1'-enyl) -7,7-ethylenedioxy-bicyclo [3.3.0] octane-7-one-3-dimethyl-tert-butylsilyl ether is obtained.

A solution of the resulting compound dissolved in 25 ml of methanol is treated with 10 ml of 1N H ₂ SO ₄ at reflux for 50 minutes. Methanol was evaporated in vacuo, cinnabar was extracted with ethyl ether and organic acid was evaporated to dryness to give crude product d, l-3-endo-hydroxy-2-exo- (3 '(S, R) -hydroxy-oct- 0.72 g of 1'-trans-1'-enyl) -bicyclo [3.3.0] octane-7-one are obtained. The individual isomers are separated by chromatography on silica gel using hexanes: ethyl ether as eluent and converted to tetrahydro pyranyl ether by treatment with 2,3-dihydropyran in methylene chloride as in Example 14. In this method, 2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo prepared in Example 17 from the 3'S-hydroisomer [3.3. 0] -octane-7-one-3,3'-bis-tetrahydropyranyl ethereo The same compound is prepared.

Similarly, following the process of Examples 29 and 31, all compounds prepared in Examples 16, 17 and 18 are obtained.

Example 32

4.8 g of d, l-3-endo-hydroxy-2-exo-carboxymethyl ester-7,7-ethylenedioxy-bicyclo [3.3.0] octan-7-one is refluxed for 80 minutes at 40 minutes; 20 Methanol: Saponified with 100 ml of 25% potassium carbonate in water, and then treated as described in Example 2 to give d, l-3-endo-hydroxy-2-exo-carboxybicyclo [3.3.0] octane- 4.02 g of 7-one-7,7-ethylenedioxide is obtained. The resulting compound was dissolved in 80 ml of anhydrous tetrahydrofuran, cooled to -10 ° C, and maintained at -10 ° C with 2.1 g of triethylamine in 12 ml of anhydrous tetrahydrofuran and 2.2 g of ethylchloro carbonate in 12 ml of anhydrous tetrahydrofuran. Add dropwise in succession. After stirring for 1 h at −10 ° C., 1.4 g of sodium azide in 12 ml of water is slowly added and stirring is continued for an additional 25 minutes. The reaction mixture is then concentrated in vacuo and diluted with water. Filtration separates the 2-exo-carboxy-azide from the regenerator and dried in vacuo.

A solution of 4.01 g of the resulting compound in 8 ml of pyridine was treated with 4 ml of anhydrous acetate, and maintained at 5-8 ° C. for 24 hours. The reaction mixture is then partitioned between ice water, ethyl ether and 2N sulfuric acid. The meat layer is separated, washed until neutral, dried and evaporated to dryness. 2-endo-hydroxy-2-exo-carboxycyanide bicyclo [3.3.0] octane-7-one-3-acetate-7,7- 4.1 g of ethylene dioxide (IR 2215 cm ^-1 ) are obtained.

The product is suspended in acetic acid (50 ml) and water (8 ml) and the mixture is heated to 40 ° C. Once the hydrochloric acid release is confirmed, the mixture is heated to 60-70 ° C. for 2 hours and then steam distilled to remove excess acetic acid. After cooling, the mixture was ethyl ether; Extract with ethyl acetate and the aqueous phase is brought to pH 9 by addition of sodium hydrate. The alkaline phase was washed with saturated salt solution and evaporated to dryness, followed by 3-endo-hydroxy-2-exo-amino-bicyclo- [3.3.0] -octane-7-one-3-acetate (-HCL melting points 111-113). 1.92 g) are obtained. The product was reacted with ethoxycarbonyl chloride and mixed anhydride from 2S-hydroxy-heptanoic acid-2-acetate to 3-endo-hydroxy-2-exo- (2'S-acetoxy-heptanoyl-amide)- Obtain bicyclo [3.3.0] octane-7-one-3-acetate (M ⁺ 367).

The product is then dissolved in anhydrous dimethylsulfoxide, reacted with lide obtained from 4-carboxy-butyl-triphenylphosphonium bromide and saponified before 5t-11α, 15S-polyhydroxy-9a-deoxy-9a-methylene To give -12-aza-14-oxo-prostacycle-5-enoic acid [M ⁺ 583 (as tris-trimethylsilyl ether); [NMR (free acid) CDCl ₃ , δ ppm: 0.89 (3H, t), 3.64 (1H, m), 3.97 (1H, m), 4.10 (1H, m), 5.33 (1H, broadt), 7.52 (1H , Broad t); IR knit ν (cm ⁻¹ ): 3360,3300,1705,1630,1545].

In a similar manner, a 15R-epimer analog is prepared from 2'R-hydroxy-heptanoic acid.

Example 33

Ethylene glycol (15 ml) and P-toluene sulfonic acid (0.9 g) were added to a solution of 2-exo-bromo-3-endo-hydroxy-bicyclo [3.3.0] -heptin-6-one in benzene, After the mixture was refluxed for 12 hours, water formed during the reaction was removed, and then pyridine (0.6 ml) was added to the mixture and cooled at room temperature.

The organic phase is washed with water, 2.5% aqueous NaHCO ₃ and water and dried. After partially removing benzene (100 ml) in vacuo, the mixture is treated with tributyltin-hydride (41 g) for 8 hours at 55 ° in N ₂ atmosphere. After cooling to room temperature, the organic phase is washed with saturated aqueous NaH ₂ PO ₄ , dried and evaporated to dryness. The resulting residue was purified over SiO ₂ (240 g) using benzene-ethyl ether as eluent to afford 14.9 g of 3-dodo-hydroxy-bicyclo [3.3.0] heptane-6-one-6,6-ethylenedioxide. To obtain [IR film 3460 cm ^-1 ; M ⁺ 242 (as trimethylsilylether)].

Example 34

A stirred solution of 3-endo-hydroxy-bicyclo [3.3.0] heptane-6-silver 6,6-ethylene dioxide (12.75 g) in benzene (340 ml) and DMSO (112 ml) was converted to dicyclohexylcarbodiimide ( 46.35 g), pyridine (5.9 g) and trifluoroacetic acid (5.4 g). After 6 hours the mixture was diluted with benzene (600 ml) and water (50 ml), dried over MgSO ₄ and evaporated to dryness to afford bicyclo [3.3.0] heptane-3,6, -dione-6,6-diethylenedioxide. (IR film 1742cm ^-1 ; M ⁺ 168)

The crude product thus obtained is dissolved in dimethyl carbonate (7 ml) and this solution is added to a suspension of sodium hydride (80% in mineral oil, 4 g). The mixture is stirred until H ₂ evolution stops and then warmed at 75 to 80 ° C. for 40 minutes.

After cooling, diluted with cooling (350 ml) and acetic acid (8.4 g), washed with water, dried and evaporated to dryness to give A mixture of ester-6,6-ethylenedioxide (p-1, q-0) (M ⁺ 226) is obtained, which is dissolved in SiO ₂ (Fe ⁺⁺ , Fe ⁺⁺⁺⁾ using hexane-hetylether as eluent. And chromatographically separate).

Example 35

In the process of Example 34, an oxidation reaction was carried out using 14.85 g of [4.3.0] nonan-7-one-7,7-ethylene dioxide as a 3-endo-hydroxy-bicycle to obtain a bicyclo [4,3, 0] 13.9 g of nonane-dione-3,7-dione-7,7-ethylenedioxide (IR film 1740 cm ^-1 ; M ⁺ 196 m / e) was obtained, which was subjected to carboxymethylation to give d, l-bicyclo [4.3.0] nonane-3,7-dione-2-carboxymethylester 7,7-ethylenedioxide (p = 1, q = 2) (M ⁺ 254 m / e) 4.2 g and d, l-bicyclo D, l-bicyclo [4.3.0] -nonane-, also referred to as [4.3.0] nonane-3,8-dione-2-carboxyketylester-8,8-ethylenedioxide (p = 2, q = 1) 4.8 g of 3,7-dione-4-carboxymethylester-7,7-ethylenedioxide (M ⁺ 257 m / e) is obtained.

Example 36

A solution of (2-oxo-heptyl) -dimethylphosphonate (0.33 g) in anhydrous benzene (5 ml) is added to a stirred suspension of NaH (80% dispersion in mineral oil, 43.5 g) in anhydrous benzene (10 ml). After 1 hour, N-bromosuccinimide (260 mg) was added and after 5 minutes bicyclo [4.3.0] nonan-3-endo, 8-dihydroxy-2-exo-formyl- in toluene (5 ml). A solution of 3-THP-ether, 8-DMtB-silyl ether (0.4 g) is added.

After continuing stirring for 15 minutes, the reaction mixture is washed with aqueous NaH ₂ PO ₄ , dried and evaporated in vacuo to give 2-exo- [2'-bromo-3'-oxo-oct-1'-trans-enyl ] -3-endo-THP-oxy-8-DMtB-silyloxy-bicyclo [4.3.0] -nonane (λ max 251 mμ, ε = 8,900).

Example 37

A solution of (2-phenoxy-2-oxo-propyl) dimethylphosphonate (2.85 g) in benzene (10 ml) is added to a stirred suspension of NaH (80% mineral oil dispersion, 10 ml) in benzene (50 ml). After continuing stirring for 45 minutes, 2-exo-formyl-2-3-endo-THF-oxy-7ζ-DMtB-silyloxy-bicyclo- [4.3.0] -nonane (3.82 g) in toluene Add a solution of After 20 minutes, the organic phase was washed with aq. 20% NaH ₂ PO ₄ and water, dried and evaporated to dryness, filtered over SiO ₂ (38 g) using benzene-ethylether as eluent and then 2-exo- [3′-oxo -4'-Penoxy-but-1'-trans-enyl] -3-endo-THF-oxy-7ζ-DMtB-silyloxy-bicyclo [4.3.0] nonane (3.97 g) is obtained (M ⁺ -102 412 m / e). In the above process, using (5-cyclohexyl-2-oxo-butyl) -dimethylphosphonate and the appropriate aldehyde as starting material, the following compounds are obtained. 2-exo- [3'-oxo-5'-cyclohexyl-pent-1'-trans-enyl] -3-endo-THF-oxy-7ζ-DMtB-silyloxy-bicyclo [4.3.0] nonane ( λ max = 228 mμ, ε = 9,300); 2-exo- [3'-oxo-5'-cyclohexyl-pent-1'-trans-enyl] -3-endo-THF-oxy-8ζ-DMtB-silyloxy-bicyclo [4.3.0] nonane ( λ max = 228.6 mμ, ε = 9,450).

Example 38

DMtB-silylether-α, β-unsaturated ketone obtained according to the procedure of Examples 36,37 is (a) reduced with allyl alcohol; (b) protecting the newly formed hydroxy group with THP-ether; Subsequently selectively removing (DM) DMtB-silyl ether protecting group to obtain a secondary alcohol; (d) oxidizing the secondary alcohol to form a ketone; Finally (e) after removing all remaining protecting groups, (f) HPLC-chromatography on SiO ₂ separates the epimeric allyl alcohol. The following process is carried out using 2.10 ^-2 moles.

a) Reduction: α, β-unsaturated ketone-DME-silyl ether (2.10) in methylene chloride-ethanol (1: 1) (180 ml) cooled to 1.10 ^-2 mol (0.32 g) of NaBH ₄ from -10 to -15 °. ^-2 ) add to moles of stirred solution. After 30 minutes, acetone (10 ml) and aqueous saturated NaH ₂ PO ₄ (25 ml) are added to decompose the residual hydride. The solvent is removed in vacuo and the residue is partitioned between water and methylenechloride. The organic layer is separated, dried and evaporated to dryness to afford a mixture of 3'S, 3'R-allylic alcohol-silyl ether (2.10 ^-2 moles).

b) Protection of allyl alcohol with THF-ether: Crude mixture (2.10 ^-2 moles) of 3'S, 3'R-allylic alcohol silyl ether is treated with methylene chloride and 2,3-dihydropyran (2 g) And a stirred solution of p-toluene sulfonic acid (0.038 g). After 2 hours the reaction is complete and stopped by addition of pyridine (0.5 ml) and the solvent is evaporated off in vacuo to yield a crude mixture of 3'S, 3'R-THP-ether-silylether.

c) Desilylation: The material obtained in b) is dissolved in dry THF (80 ml) and the solution is treated with dry tetrabutyl ammonium fluoride (14 g) for 12 hours at room temperature. After concentration in small amount in vacuo, the residue was adsorbed onto SiO ₂ (40 g) and eluted with ethyl ether to afford secondary alcohol-3 ′S, 3′R-THP-ether (about 2.10 ⁻² moles).

d) oxidation; 75:25 Dicyclohexylcarbodiimide (6.5 g), pyridine (1 ml) and trifluoroacetic acid (0.5) in a stirred solution of secondary alcohol-3'S, 3'R-THP-ether in 25 benzene-DMSO (60 ml) ml) is added continuously. After 4.5 hours, the reaction mixture is diluted with an aqueous solution of benzene (100 ml) and oxalic acid (3 g). The dicyclohexylurea formed is filtered and the organic layer is washed until neutral and dried and evaporated to dryness.

e, f) depyranylation and chromatographic separation methods; A solution of 3'S, 3'R-THP-ether-ketone in methanol (30 ml) is stirred with p-toluenesulfonic acid (0.18 g) at room temperature for 3 hours and pyridine (0.5 ml) is added followed by evaporation to dryness. The residue is dissolved in cyclohexane-ethyl acetate (80:20) and injected into an HPLC apparatus to give the following keto alcohol:

2-exo- [2'bromo-3'S-hydroxy-oct-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonin-8-one, M ⁺ -H ₂ O 340,342;

2-exo- [2'bromo-3'R-hydroxy-oct-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-8-one, M ⁺ -H ₂ 0 340,342;

2-exo- [3'S-hydroxy-4'-phenoxy-but-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-7-one, M ⁺ 460 (with bis-trimethyl silylether);

2-exo- [3'R-hydroxy-4'-phenoxy-but-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-7-one, M ⁺ 460 (as bis-trimethylsilyl ether);

2-exo- [3'S-hydroxy-5-cyclohexyl-pent-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-7-one, M ⁺ - H ₂ O 302;

2-exo- [3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-7-one, M ⁺ - H ₂ O 302 m / e;

2-exo- [3'S-hydroxy-5-cyclohexyl-pent-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-7-one, M ⁺ - H ₂ O 302 m / e;

2-exo- [3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonan-7-one, M ⁺ - H ₂ O 302 m / e;

Example 39

A suspension of NaH (80% dispersion in mineral oil, 2.1 g) in anhydrous DMSO (70 ml) is stirred for 4 h at 65 ° C. under N ₂ atmosphere. After cooling at 25 to 30 ° C., anhydrous 4-carboxyl-butyl-triphenyl phosphonium bromide (13 g) is added to give a dark red solution of the lide.

2-exo- [2'-bromo-3'S-hydroxy-oct-1'-trans-enyl] -3-endo-hydroxy-bicyclo- [4.3.0] nonan-8- in anhydrous DMSO (6 ml) After adding warm (1.79 g) of solution, the reaction mixture was stirred at 28 ° C. for 1 hour, then at 40 ° C. for 4 hours, then cooled to room temperature, diluted with water (80 ml) and 4N H ₂ SO ₄ Acidified to pH4.5, extracted with ethyl ether (4 x 50 ml, 2 x 25 ml). The aqueous layer is discarded and the combined organic phases are washed with water (this wash is discarded) and then washed with 1N NaOH (5 × 10 ml) and water until neutral. Combined alkaline extracts were acidified to pH5 and extracted with ethyl ether to give 5 (Z, E) -11α, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-5-ene-13 Inoic acid (a mixture of 5c- and 5t-isomers) is obtained. (M ⁺ 362, M ⁺ H ₂ O 344, M; -2H ₂ O 328, M; -H ₂ OO ₅ H ₁₁ 273).

Individual geometric isomers are obtained after chromatographic separation on acidic SiO (40 g / 1 g of acid) using cyclohexane-ethyl acetate as eluent.

Example 40

To the stirred solution of freshly sublimed potassium tert-butoxide (3.36 g) dissolved in anhydrous DMSO (36 ml) was added 6.5 g of 4-carboxyl-butyl-triphenyl phosphonium bromide under N ₂ atmosphere to give a dark red solution of the lide. Get 2-exo- [3'R-hydroxy-4'-phenoxy-but-1'-trans-enyl] -3-endo hydroxy-bicyclo- [4.3.0] nonane- in anhydrous DMSO (3 ml) After addition of a 7-one (0.8 g) solution, the reaction mixture is stirred at 42 ° C. for 5 hours, cooled, diluted with water (50 ml), acidified to pH 5 and extracted with ethyl ether (4 × 10 ml). Discard the aqueous phase, wash the combined etheric extracts with water (10 ml, discard this detergent), wash with 0.5 N NaOH (4 × 6 ml) and water until neutral. The alkaline extracts are combined and imaged to pH5 and extracted with ethyl ether.

The combined organic phases were dried and evaporated to dryness to give 5 (Z, E), 13t-11α, 15R-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17, 18, 19, 20-tetranor-prostar-5, 13-dienoic acid (a mixture of 5c and 5 ⁺ -geometric isomers) is obtained (M ⁺ 400, M ⁺ -H ₂ 0 382).

The product is chromatographed on acidic SiO ₂ (40 g / 1 g of acid) using cyclohexane-ethyl acetate as eluent to give the individual geometric isomers.

Example 41

Using the keto alcohol of Example 37 in the processes of Examples 38 and 40, the following prostar cycloanoic acid was prepared.

5c-11α, 15s-hydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-ene-13-inoic acid, M ⁺ 362 M ⁺ H ₂ OO ₅ H ₁₁ 273 m / e;

5c, 13t-11α, 15s-hydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17, 18, 19, 20-tetranor-prostacycl-5-5, 13- Dienoic acid, M ⁺ 400;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18, 19, 20-trinor-prostacycl-5, 13-dienoic acid, M ⁺ 404;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-17-cyclohexyl-18, 19, 20-trinor-prostacycl-5-5, 13-die Nosan, M ⁺ 404;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-ene-13-inoic acid, M ⁺ 362, M ⁺ -H ₂ OC ₅ H ₁₁ 273 m / e;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17, 18, 19, 20-tetranor-prostacycl-5-5, 13 -Dienoic acid, M ⁺ 400 m / e;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18, 19, 20-trinor-prostacycl-5, 13-dienoic acid, M ⁺ 404 m / e;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-17-cyclo-nucleus-18, 19, 20-trinor-prostacycl-5-5, 13- Dienoic acid, M ⁺ 404 m / e;

Example 42

Using the process of Example 33, 2-acetoxy-perhydroazulen-6-one [3-endo-hydroxy-bicyclo [5.3.0], decan-8- is also called acetate. Obtained according to DK Banerjee et al. Indian J. Chem. 10,1,1972] 30 g are converted to their ethylene dioxide (29.1 g). The compound is then saponified by treatment with 2% K ₂ CO ₃ in aqueous methol to give 3-endo-hydroxy-bicyclo [5. 3. 0] -decane-8-one-8, 8-ethylene dioxide was adsorbed and oxidized using the process of Example 34 and treated with dimethyl carbonate (see the process of Example 34).

d1-bicyclo [5. 3. 0] 21.2 g of decane-3,8-dione-2-carboxymethylester-8,8-dioxide (λ _max = 254 nm, ε = 7,000) are obtained.

Example 43

The bicyclo-β-keto ester ethylene dioxide obtained in Examples 34, 35 and 42 is reduced by the following process:

NaBH ₄ (0.9 g) was added little by little to a stirring solution of 1: 1 cyclone-keto ester-ethylene dioxide (2.5 × 10 ⁻² mol) of methylene chloride-ethanol (150 ml) and cooled at -20 ° C. After stirring for an additional 30 minutes at −20 ° C., the residual hydride is decomposed by addition of acetone (12 ml). The reaction mixture is allowed to warm to room temperature and treated with aqueous 20% KH ₂ PO ₄ , then the solvent is removed and diluted with water and extracted with methylene chloride. The combined organic phases are washed with water, dried and evaporated to dryness until thickened. The residue was equilibrated by treatment with anhydrous ethanol (12 ml) and sodium methoxide (0.54 g) for 12 hours at room temperature, acetic acid (0.59 g) was added, the solvent was evaporated and extracted with methylene chloride to give the following bicyclo-β- About 0.22 × 10 ⁻² moles of keto ester-ethylene dioxide are obtained:

d1-3-endo hydroxy-bicyclo [3. 2. 0] -heptan-6-one-2-exo carboxymethyl-ester-6, 6-ethylene dioxide, M + 300 (with trimethylsilyl ether);

d1-3-endohydroxy-bicyclo [3. 2. 0] -heptan-6-one-4-exo carboxymethyl-ester-6, 6-ethylene dioxide (d1-3-endo hydroxy-bicyclo [3. 2 0] -heptan-7-one- 2-exo carboxymethylester-7, also called 7-ethylene dioxide), M + 300 m / e (as trimethylsilylether);

d1-3-endo hydroxy-bicyclo [3. 2. 0] -nonan-7-one-2-exo carboxy-methylester-7, 7-ethylene dioxide, M + 328 (with trimethylsilylether);

d1-3-endo hydroxy-bicyclo [4. 3. 0] -nonan-8-one-2-exo carboxy-methylester-8, 8-ethylene dioxide, M + 328 (with trimethylsilylether);

d1-3-endo hydroxy-bicyclo [3. 2. 0] -decane-8-one-2-exo carboxymethyl-ester-8, 8-ethylene dioxide, M + 342 (with trimethylsilylether).

Subsequently, 25 ml of a 2 × 10 ⁻² mole solution of each of the compounds dissolved in anhydrous dimethylene chloride was added with 2, 3-dihydropyran (2 g) and p-toluene sulfonic acid (38 mg, 2 ×) for 2 hours at room temperature. 10 ^-4 mole). Pyridine (0.1 ml) is added to stop the reaction and the mixture is evaporated to dryness in vacuo to yield the corresponding 3-THP-ether, which is used without further purification.

Example 44

3-endo-hydroxy 2-exo-carboxymethyl ester and 3-THP-ether thereof obtained by the process of Example 43 were reduced according to the following procedure to obtain the corresponding 2-exo-hydroxymethyl derivative;

A solution of 2 × 10 ⁻² moles of β-ketoester (both alcohol and 3-THP ether) in anhydrous ethyl ether (25 ml) is added dropwise to a LiAlH ₄ (4.0 g) stirring suspension in anhydrous ethyl ether (50 ml). After stirring for an additional 30 minutes, ethyl ether saturated with acetone (5 ml) and water are added to decompose the residual hydride. After adding 12 g of anhydrous MgSO ₄ , the organic phase is filtered and evaporated to dryness.

3-Endohydroxy-2-exo-hydroxymethyl is obtained;

Bicyclo [3. 2. 0] -heptan-6-one-5, 6-ethylenedioxide, M ⁺ 342 m / e (with bis-trimethylsilylether);

Bicyclo [3. 2. 0] -heptan-7-one-7, 7-ethylenedioxide, M ⁺ 342 m / e (with bis-trimethylsilylether);

Bicyclo [4. 3. 0] -nonan-7-one-7, 7-ethylenedioxide, M ⁺ 370 m / e (with bis-trimethylsilylether);

Bicyclo [4. 3. 0] -nonan-8-one-8, 8-ethylenedioxide, M ⁺ 370 m / e (with bis-trimethylsilylether);

)Bicyclo [5. 3. 0] -decane-8-one-8, 8-ethylenedioxide, M ⁺ 384 m / e (with bis-trimethylsilylether); And their 3-endo-hydroxy-THP-ethers and the optically active materials produced in the optical isolation step described below, when used in the reduction process,

)

Example 45

Using the 2-exo-hydroxymethyl-THP-ether compound of Example 44 or 12β-hydroxymethyl-11-acetate as a starting material, the corresponding aldehyde was obtained according to the following oxidation process;

75:25 Dicyclohexylcarbodiimide (0.64 g), pyridine (0.1 ml) and trifluoroacetic acid (0.05) in a stirred solution of hydroxymethyl compound (2 × 10 ⁻³ mol) in benzene-DMSO (6 ml) ml) is added continuously. After 4.5 hours the reaction mixture is diluted with benzene (20 ml) and water (10 ml) and stirred again for 30 minutes. The dicyclohexyl urea was filtered off and the organic layer was washed with water until it became medium-west and concentrated to 10 ml to obtain anhydrous benzene solution of the following aldehyde:

3-endo-THP-oxy-2-exo-formyl-bicyclo- [3. 2. 0] heptane-6-one-6, 6-ethylenedioxide, M ⁺ -102 180 m / e;

3-endo-THP-oxy-2-exo-formyl-bicyclo- [3. 2. 0] heptane-7-one-7, 7-ethylenedioxide, M ⁺ -102 180 m / e;

3-endo-THP-oxy-2-exo-formyl-bicyclo- [4. 3. 0] Nonan-7-one-7, 7-ethylenedioxide, M ⁺ -102 208 m / e;

3-endo-THP-oxy-2-exo-formyl-bicyclo- [4. 3. 0] Nonan-8-one-8, 8-ethylenedioxide, M ⁺ -102 208 m / e;

3-endo-THP-oxy-2-exo-formyl-bicyclo- [5. 3. 0] decan-8-one-8, 8-ethylenedioxide, M ⁺ -102 222 m / e;

W (20 → 12) Octanonor-12β-formyl-11α-hydroxy-9a-deoxy-9a, 9b-7-homo-trimethylene-2-nor-prostacycl-5-5-enoic acid methyl ester -11-acetate (5 (Z, E); 5c; 5t), M ⁺ 322 m / e; W (20 → 12) Octa-nor-12β-formyl-11α-hydroxy-9a-deoxy-9a, 7a-7-homo-dimethylene-prostacycl-5-enoic acid-methylester-11 Acetate (5 (Z, E); 5c; 5t), M ⁺ 322 m / e;

These compounds are further purified and used for the next Wittig-Horner reaction.

Example 46

A solution of (2-oxo-heptyl) dimethylphosphonate (0.49 g) in benzene (6 ml) is added dropwise to a HaH (80% dispersion in mineral oil, 66 mg, 2.2 x 10 ^-3 mol) stirring suspension in benzene (15 ml). . After stirring for a further 45 seconds, 5t-W (20 → 12) -octanor-12β-formyl-11α-hydroxy-9a-deoxy-9a, 9b, 7a-homo-tree in benzene (10 ml) A 2 x 10 ^-3 molar solution of methylene-2-nor-prostacycl-5-enoic acid-methyl ester-11-acetate is added. After an additional hour, a solution of acetic acid (132 mg) in benzene (5 ml) is added to stop the reaction and the organic phase is washed with water until neutral and dried and evaporated.

1.2 g of the residue was adsorbed onto SiO ₂ (10 g) and eluted with cyclohexane-ethyl acetate to give 5t, 13t-11α-hydroxy-15-oxo-9a-deoxy-9a, 9b, 7a-homo-trimethylene 2-Nor-prostacycl-5, 13-dienoic acid-methyl ester-11-acetate (0.76 g, λ _max = 228 ***, ε = 9,800) is obtained (M ⁺ 418, M ⁺ −). CH ₃ CO ₂ H 358).

Use of other aldehydes of Example 45 in this process yields the following α, β-unsaturated ketones: 5c, 13t-11α-hydroxy-15-oxo-9a-deoxy-9a, 9b, 7a-homo A mixture of -trimethylene-2-norprostacyclo-5, 13-dienoic acid-methylester-11-acetate (λ _max = 228 ***, ε = 9,900) and its 5 (Z, E) isomer M ⁺ 418, M ⁺ -CH ₃ CO ₂ H 358;

5t, 13t-11α-hydroxy-15-oxo-9a-deoxy-9a, 7a-homo-dmethylene-prostacycl-5, 13-dienoic acid methyl ester-11-acetate (λ _max = 229 * **, ε = 10,000) and its 5t and 5 (Z, E) isomers, M ⁺ 418, M ⁺ -CH ₃ CO ₂ H 358; And

2-exo [3'-oxo-oct-1'-trans-enyl] -3-endo-hydroxy-THP-ether: bicyclo [3. 2. 0] heptane-6-one-6, 6-ethylenedioxide, M ⁺ -102 276 m / e;

Bicyclo [3. 2. 0] heptane-7-one-7, 7-ethylenedioxide, M ⁺ -102 276 m / e;

Bicyclo [4. 3. 0] Nonan-7-one-7, 7-ethylenedioxide, M ⁺ -102 304 m / e;

Bicyclo [4. 3. 0] Nonan-8-one-8, 8-ethylene dioxide, M ⁺ -102 304 m / e;

Bicyclo [5. 3. 0] decan-8-one-8, 8-ethylenedioxide, M ⁺ -102 318 m / e;

Example 47

In the process of Example 46, another dimethylphosphonate is used to prepare the α, β-unsaturated ketone as follows.

a) 3-endo-THP-oxy-2-exo-formyl-bicyclo [3. 2. 0] heptan-7-one-7, 7-ethylenedioxide (2 × 10 ^-3 moles) was added (2-oxo-3 (S, R) -fluoro-heptyl) dimethylphosphonate (0.54 g) Reacted with 3-endo-THP-oxy-2-exo- [3'-oxo-4 '(R, S) fluoro-oct-1'-trans-enyl] -bicyclo [3. 2. 0] Heptane-7-one-7, 7-ethylene dioxide (0.72 g; λ max = 229 nm, ε = 9,900, [α] _D = + 98 ° (CHC1 ₃ ) are obtained.

b) 3-endo-THP-oxy-2-exo by reacting heptane-6-one-6, 6-ethylenedioxide aldehyde (2x10 ^-3 mol) with (2-oxo-octyl) -dimethylphosphate -[3'-oxo-non-1'-trans-enyl] -bicyclo [3. 2. 0] Heptane-6-one-6, 6-ethylene dioxide (λ max = 228 nm, ε = 9,300) gives M ⁺ -102 290 m / e.

c) Reaction of heptane-7-one-7, 7-ethylenedioxide aldehyde with (2-oxo-4-phenyl-butyl) dimethylphosphate (0.565 g) to 3-endo-THP-oxy-2-exo- [ 3'-oxo-5'-phenyl-pent-1'-trans-enyl] -bicyclo [3. 2. 0] Heptane-7-one-7, 7-ethylenedioxide is obtained M ⁺ -102 310 m / e).

d) Nonane-7-one-7, 7-ethylenedioxide, (2-oxo-3s-methylheptyl) and 0.52 g of (2-oxo-3R-methylheptyl) dimethylsponate were reacted to obtain the following compounds, respectively.

3-Endo-THP-oxy-2-exo- [3'-oxo-4'S-methyl-oct-1'-trans-enyl] -bicyclo [4. 3. 0] Nonan-7-one-7, 7-ethylenedioxide, M ⁺ -102 318 m / e; 3-endo-THP-oxy-2-exo- [3'-oxo-4'R-methyl-oct-1'-trans-enyl] -bicyclo [4. 3. 0] Nonan-7-one-7, 7-ethylenedioxide, M ⁺ -102 318 m / e;

Example 48

Pyridine hydrobromide buffer bromide _{(. C 6 H 5 N. HBr} Br 2) 3- endo-2-exo -THP- of the 0.8g of anhydrous benzene (15ml) - [3'- oxo -4 '(R, S To a stirred solution of) -fluoro-oct-1'-trans-enyl] -bicyclo [3.2.0] heptane-7-one-7,7-ethylenedioxide. After stirring for an additional 4 hours at room temperature, the precipitate is filtered off and the organic eluate is partitioned between ice, 2N H ₂ SO ₄ and ethyl acetate. The organic layer was washed with cold 0.5NH ₂ SO ₄ , chlorine 1% sodium carbonate and water until neutral to yield 0.71 g of 2'-bromo-4 '(R, S) -fluoro compound, which was obtained in two parts. A mixture of stereoisomers 4'S and 4'R derivatives. Individual isomers were purified by HPLC-chromatography on SiO _{2 with} CH ₂ Cl ₂ -ethyl ether (85:15) as eluent.

3-endo-THP-oxy-2-exo [2'-bromo-3'-oxo-4'R-fluoro-oct-1'-trans-enyl] -bicyclo [3.2.0] heptane-7 0.22 and 0.19 g of 4'S-fluoro isomer (λmax = 251 nm, ε = 9.750) are obtained from -one-7,7-ethylene dioxide (λ max = 250 nm, ε = 9.830). (M ⁺ -102,372,374).

Other α, β-unsaturated ketones are used in this process to afford the following compounds.

3-endo-THP-oxy-2-exo [2'-bromo-3'-oxo-non-1'-trans-enyl] bicyclo [3.2.0] -heptan-6-one-6,6- Ethylene dioxide, M ⁺ -102,368,370 m / e; And 3-endo-THP-oxy-2-exo [2'-bromo-3'-oxo-oct--1'-trans-enyl] bicyclo [4.3.0] nonan-7-one-7,7 Ethylene-dioxide M ⁺ -102,382,384 m / e.

Example 49

Using the α, β-unsaturated ketones of Examples 46,47 and 48 as starting materials, secondary allylic alcohols are obtained according to the following procedure. An α, β-unsaturated ketone (2 × 10 ⁻³ mol) solution in anhydrous ethyl ether (20 ml) is added dropwise to a stirred crucible solution of 0.25 M hydrogen borohydride (48 ml) in anhydrous ethyl ether over 30 minutes. After stirring for an additional 2 hours, saturated NaCl is added to decompose the residual hydride. The organic layer is separated, washed until neutral, dried over Na ₂ SO ₄ and evaporated to dryness. Preparative HPLC-chromatography on SiO ₂ using methylene chloride / ethyl acetate as eluent affords the following compounds.

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacycl-5, 13-dienoic acid-ester-11-acetate (M ⁺ 420 m / e) and its 5 (Z, E) and 5t geometric isomers;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostar-cyclo-5,13-dienoic acid methyl ester-11-acetate (M ⁺ 420 m / e) ) And its 5 (Z, E) and 5c geometric isomers;

2-exo [3's-hydroxy-oct-1'-trans-enyl] 3-endo-THP-oxy: bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide (M ⁺ 380);

Bicyclo [3.2.0] heptane-7-silver-7,7-ethylenedioxide (M ⁺ 380);

Bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 408);

Bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide (M ⁺ 408);

3-endo-THP-oxy following:

2-exo [2'-bromo-3'S-hydroxy-4'R-fluoro-oct-1'-trans-enyl] bicyclo- [3.2.0] heptane-7-one-7,7-ethylene Dioxide (M ⁺ 476,478);

2-exo [2'-bromo-3'S-hydroxy-4'S-fluoro-oct-1'-trans-enyl] bicyclo- [3.2.0] heptan-7-one-7,7-ethylenedioxide ( M ⁺ 476,478);

2-exo [2'-bromo-3'S-hydroxy-non-1'-trans-enyl] bicyclo- [3.2.0] -heptan-6-one-6,6-ethylenedioxide (M ⁺ 472,474) ;

2-exo [3'S-hydroxy-non-1'-trans-enyl] bicyclo- [3.2.0] -heptan-6-one-6,6-ethylene-dioxide (M ⁺ 394);

2-exo [3'S-hydroxy-5'-phenyl-pent-1'-trans-enyl] bicyclo- [3.2.0] heptane-7-one-7,7-ethylenedioxide (M ⁺ 414);

2-exo [2'-bromo-3'S-hydroxy-oct-1'-trans-enyl] bicyclo- [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 48, 488 );

2-exo [3'S-hydroxy-4'S-methyl-oct-1'-trans-enyl] bicyclo- [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 422);

2-exo [3'S-hydroxy-4'R-methyl-oct-1'-trans-enyl] bicyclo- [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 422);

5c, 13t-11α, 15R-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacycl-5, 13-dienoic acid-ester-11-acetate (M ⁺ 420) and its 5 (Z, E) and 5t geometric isomers;

5t, 13t-11α, 15R-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-5,13-dienoic acid methyl ester-11-acetate (M ⁺ 420) and its 5 (Z, E) and 5c-isomers;

2-exo [3'R-hydroxy-oct-1'-trans-enyl] 3-endo-THP-oxy:

Bicyclo [3.2.0] heptane-6-one-6,6-ethylenedioxide (M ⁺ 380);

Bicyclo [3.2.0] heptane-7-silver-7,7-ethylenedioxide (M ⁺ 380);

Bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 408);

Bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide (M ⁺ 408); And

3-endo-THP-oxy following:

2-exo [2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-trans-enyl] bicyclo- [3.2.0] heptane-7-one-7,7 Ethylene dioxide (M ⁺ 476,478);

2-exo [2'-bromo-3'R-hydroxy-4'S-fluoro-oct-1'-trans-enyl] bicyclo [3.2.0] heptane-7-one-7,7-ethylenedioxide (M ⁺ 476,478);

2-exo [2'-bromo-3'R-hydroxy-non-1'-trans-enyl] bicyclo [3.2.0] -heptan-6-one-6,6-ethylenedioxide (M ⁺ 472,474 );

2-exo [3'R-hydroxy-non-1'-trans-enyl] bicyclo [3.2.0] heptane-6-one-6,6-ethylene-dioxide (M ⁺ 394);

2-exo [3'R-hydroxy-5'-phenyl-pent-1'-trans-enyl] bicyclo [3.2.0] -heptan-7-one-7,7-ethylenedioxide (M ⁺ 414) ;

2-exo [2'-bromo-3'R-hydroxy-oct-1'-trans-enyl] bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 486,488) ;

2-exo [3'R-hydroxy-4'S-methyl-oct-1'-trans-enyl] bicyclo [4.3.0] -nonan-7-one-7,7-ethylenedioxide (M ⁺ 422);

2-exo [3'R-hydroxy 4'R-methyl-oct-1'-trans-enyl] bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide (M ⁺ 422);

Example 50

Each of the bicyclo-THP-oxy-ethylenedioxide obtained by the process of Example 49 is converted to the corresponding prostacyclenoic acid according to the following process.

A 1.10 ^-3 molar solution of bicyclo-THP-oxy-ethylenedioxide in acetone (15 ml) is refluxed with 1N aqueous oxalic acid (10 ml) for 8 hours. Acetone is evaporated in vacuo and the aqueous phase is extracted with ethyl ether.

After conventional processing to the combined extracts were evaporated to dryness and water side by about 0.6 to 1.10 mole ^-3-hydroxy ketone. A solution of the resulting compound in anhydrous DMSO (2 ml) is added to a solution of illi obtained by Potassium tert-butoxide (1.35 g) was added to anhydrous DMSO (15 ml) in N ₂ atmosphere, and then 4-carboxy-butyl-triphenyl-phosphonium bromide (2.6 g) was added to give a dark red solution of the lide. do. After adding ketone, the reaction mixture is warmed to 40-42 ° C. for 6 hours, cooled, diluted with water (20 ml), acidified to pH5.1 and extracted with ethyl ether (5 × 25 ml).

The aqueous layer is discarded and the combined organic extracts are washed with water (5 ml discards the wash) and extracted with 0.5 N NaOH (6 × 6 ml) and water until neutral. Combine the alkaline extracts, acidify to pH5 and extract with ethyl ether.

The combined organic extracts were washed with water (2ml) and concentrated to dryness, it evaporated on NaSO ₄ to obtain a mixture of 5E and 5Z acid.

The individual geometric isomers are obtained by chromatographic separation using acidic SiO ₂ (F ⁺⁺ , Fe ⁺⁺⁺ not included) using CH ₂ Cl ₂ -ethyl acetate as eluent. (30 g SiO ₂ per 0.2 g acid).

In the same manner as described above to prepare the following compounds.

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-nor-methylene-prostacycl-5-5,13-dienoic acid, M ⁺ 522, M ⁺ -CH ₃ 537, M ⁺ -C ₅ H ₁₁ 481 (with tris-trimethylsilyl ether);

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-normethylene-20-methyl-prostacycl-5-5,13-dienoic acid, M ⁺ 566, M ⁺ -CH ₃ 551, M ⁺ -C ₅ H ₁₁ 481 (with trimethylsilyl ether);

5t-11α, 15s-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-prostacycl-5-ene-13-inoic acid, M ⁺ 564, M ⁺ -CH ₃ 549, M ⁺ -C ₅ H ₃ 479 m / e (with trimethylsilyl ether);

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-prostacycl-5-5,13 dienoic acid, M ⁺ 552 (as tris-trimethyl-silyl ether) ;

NMR (CDCl ₃ ) δ ppm: 0.89 (3H, t), 3.33 (1H, m) 4.05 (2H, m), 5315 (1H, m), 5.55 (2H, m);

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-5,13-dienoic acid, M ⁺ 364, M ⁺ -H ₂ O 346, M ⁺ -2H ₂ O 328, M + -H ₂ OC ₅ H ₁₁ 275 m / e;

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 346, M ⁺ -2H ₂ O 348;

5t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-16s-fluoro-prostacycl-5-5-ene-13-inoic acid, M ⁺ 352 m / e;

5t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-16R-fluoro-prostar-cyclo-5-ene-13-inoic acid, M ⁺ 352 m / e ;

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-17-phenyl-18,19,20-trinor-fluoro-prostacycl-5, 13-dienoic acid, M ⁺ 370 m / e;

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16s-methyl-prostar-cyclo-5,13-dienoic acid, M ⁺ 378, M ⁺ - H ₂ O 360;

5t, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16R-methyl-prosta-cyclo-5,13-dienoic acid, M ⁺ 378, M ⁺ - H ₂ O 360;

5t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-ene-13-inoic acid, M ⁺ 362;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-nor-methylene-prostacycl-5-5,13-dienoic acid, M ⁺ 336, M ⁺ -C ₅ H ₁₁ -H ₂ O 247 m / e;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-prostacycl-5-5,13-dienoic acid, M ⁺ 350;

5c-11α, 15s-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-prostacycl-5-ene-13-inoic acid, M ⁺ 348;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 318;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 364;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-5,13-dienoic acid, M ⁺ -H ₂ O 346;

5c-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-16s-fluoro-prostacycl-5-ene-13-inoic acid, M ⁺ 352;

5c-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-16R-fluoro-prostar-cyclo-5-ene-13-inoic acid, M ⁺ -H ₂ 0 334 m / e;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methylene-17-phenyl-18,19,20-trinor-prostacycl-5-5,13- Dietenoic acid, M ⁺ -H ₂ O 352;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16s-methyl-prostacycl-5-5,13-dienoic acid, M ⁺ 378;

5c, 13t-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16R-methylprostacycl-5-5,13-dienoic acid, M ⁺ 378 m / e;

5c-11α, 15s-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacycl-5-5-ene-13-inoic acid (M ⁺ 362) and their 15R-isomers;

Example 51

To a stirred solution of bicyclo [4.3.0] nonan-7-en--3-one (11.42 g) in ethanol (80 ml) is added sodium borohydride (2.5 g). After stirring for a further 2 hours, acetic acid (5 ml) is added and the mixture is evaporated to dryness. The residue is partitioned between water and CH ₂ Cl ₂ and the organic layer is evaporated to dryness. A solution of the resulting bicyclo [4.3.0] nonane-7-ene-3-hydroxy (11 g) in anhydrous DMF was dissolved in dimethyl-tert-butyl-silyl chloride (15.6 g) and imidazole (10.85 g). Continuous heating with, warmed at 60 ° C. for 6 hours, cooled and diluted with water (66 ml). After exhaust extraction with ethyl ether and treatment in a conventional manner, bicyclo- [4.3.0] nonane-7-ene-3-hydroxy-3-DMB-silyl-ether (19.1 g) is obtained. Anhydrous THF (100 ml) solution of the product cooled at 0 ° C. is treated with a THH (75 ml) solution of MBH ₃ solution (with stirring under N ₂ atmosphere). After 2 hours, 1N NaOH (25 ml) and 30% hydrogen peroxide (25 ml) are added while maintaining the temperature at 25 ° C. The mixture is heated at 60 ° C. for 2 hours, cooled and diluted with benzene (400 ml). The organic layer was washed successively with 1% Na 2 CO 3, saturated sodium sulfite and saturated NaCl, dried and evaporated to dryness. Bicyclo- [4.3.0] nonane-7 (8) one-3-dihydroxy-3-DMB-silylether (20.3 g) is obtained. The solution of the resulting alcohol in 75 / 25benzene-DMSO (150 ml) is successively treated with dicyclohexylcarbodiimide (16 g), pyridine (2 ml) and trifluoroacetic acid (1 ml).

After 5 hours, the mixture is diluted with a solution of oxalic acid (6 g) in benzene (400 ml), water (50 ml) and water (75 ml) and stirred for an additional 30 minutes before filtering. The organic phase was washed with water until neutral to give bicyclo- [4.3.0] nonane-7 (8) -one-3-hydroxy-DMB-silylether (18.25 g) which was dissolved in methanol (60 ml) treated with 1.8 g of p-toluenesulfonic acid. After 12 hours, the mixture is treated with pyridine (1.95 ml) and evaporated to dryness. The residue is filtered over SiO 2 (using ethyl ether-ethyl acetate as eluent) to afford bicyclo [4.3.0] nonan-7 (8) -one-3-hydroxy (10 g).

The solution obtained by dissolving the resulting compound in benzene (50 ml) is refluxed in the presence of anhydrous ethylene glycol (5.2 g) and p-toluene-sulfonic acid (0.62 g) while removing the water formed during the reaction. After 14 hours, pyridine (2 ml) is added and the organic phase is cooled and washed with water, 2% Na ₂ CO ₃ and saturated NaCl until neutral. The solvent is evaporated to yield bicyclo [4.3.0.] Nonane-7 (8) -one-hydroxy-7,7 (8,8) -ethylenedioxide. (Oil, IR film 3400 cm ^-1 , M ⁺ 109).

Example 52

Dl-3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one-8,8-diethylene dioxide-2-exo carboxy methyl ester (4.5 g) with 2% K2CO3 in 80% aqueous methanol Saponified to give free acid (4.2 g).

When d (+)-ephedrine (2.3 g) was added to a solution of free acid (4.2 g) in acetonitrile (120 ml), 2.8 g of salt crystallized after 4 hours at room temperature, which was further crystallized with acetonitrile to give a positive (+) ratio. 2.15 g of cyclo [4.3.0] nonane-8-one-8,8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid d (+)-ephedrineium salt are obtained. All the aqueous solutions were combined and evaporated to dryness and the residue dissolved in water and treated with 1N NaOH to an alkaline pH (12-13).

After extraction with ether to recover d (+)-ephedrine, the alkaline aqueous solution was acidified to pH 5, extracted with ethyl acetate, and the organic layers were combined and evaporated to dryness. The residue was diluted with acetonitrile and the process repeated using (-) ephedrine (-) bicyclo- [4.3.0] nonane-8-one-8,8-ethylene dioxide-3-endo-hydroxy- Obtain 2-exo-carboxylic acid l (-) epedinium salt. Each salt was dissolved in water / NaOH and extracted with ethyl ether to recover the optically active base, and the alkaline aqueous phase was acidified to pH 5 to 5.1 and extracted with ethyl acetate to extract (+) bisacrone [4.3.0] nonane- 8-one-8,8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid, and (-) bicyclo [4.3.0] nonane-8-one-8,8-ethylene-dioxide-3 Endo-hydroxy-2-exo-carboxylic acid is obtained, which is converted to methyl esters by diazomethane treatment.

Example 53

A solution of 26 g of dl-3-endo-hydroxy-bicyclo [4.3.0] -2-exo-carboxy-methylester-7-one-7,7-ethylenedioxide in acetone (100 ml) was added with 2N H ₂ SO _4. (20 ml) with reflux for 4 hours. Acetone is evaporated in vacuo and the aqueous phase is extracted with ethyl acetate. The combined organic extracts were washed until neutral, dried and evaporated to dl-3-endo-hydroxy-bicyclo [4. 3. 01.2-2-exo-carboxymethylester-7-one 21.2 g is obtained. To a solution of ketone in anhydrous acetonitrile (250 ml) is added d-1-phenyl-1-ethylamine (12.1 g) and the solvent is distilled off slowly to recover 50 ml for 30 minutes. The mixture was cooled slowly to room temperature and then filtered (+) to 3-endo-hydroxy-7,7- (1'-phenyl 1'-ethylidene amino) -2-exo-carboxy-methylester-bicyclo [ 4.3.0] 12.12g. The aqueous solution is further concentrated to give 6 g of racemic material. Finally, further concentrated to 80 ml (-) 3-endo-hydroxy-7,7- (1'-phenyl-1'-ethylideneimino) -2-exo-carboxy-methylester-bicyclo [4.3 .0] 11.42 g are obtained.

Separately, two Schiff bases are digested with 80:20 methanol / 2N H ₂ OR ₄ (200 ml) for 2 hours at reflux. The solvents were evaporated in vacuo, extracted with ethyl acetate, the combined organic phases were washed until neutral and dried and evaporated in vacuo to each (+) 3-endo-hydroxy-bicyclo [4.3.0] -2-exo-carboxy 7.2 g of methyl-ester-7-one are obtained.

Using this process, all bicyclo-β-hydroxy-carboxylic acid ester-ethylene dioxide of Example 43 is optically isolated to yield the following 3-endo-hydroxy alcohol.

(+) Bicyclo [3.2.0] heptane-6-one-2-exo-carboxy-methylester;

(+) Bicyclo [3.2.0] heptane-7-one-2-exo-carboxy-methylester;

(+) Bicyclo [4.3.0] nonane-7-one-2-exo-carboxy-methylester;

(+) Bicyclo [4.3.0] nonane-8-one-2-exo-carboxy-methylester;

(+) Bicyclo [5.3.0] decan-8-one-2-exo-carboxy-methylester;

(−) Bicyclo [3.2.0] heptane-6-one-2-exo-carboxy-methylester;

(−) Bicyclo [3.2.0] heptane-7-one-2-exo-carboxy-methylester;

(−) Bicyclo [4.3.0] heptane-7-one-2-exo-carboxy-methylester;

(-) Bicyclo [4.3.0] nonane-8-one-2-exo-carboxy-methylester;

(-) Bicyclo [5.3.0] decan-8-one-2-exo-carboxy-methylester;

Using the process of Example 42, these ketones are converted to their ethylene dioxide derivatives.

Example 54

A solution of freshly sublimed potassium tert-butoxide (3 g) in anhydrous DMSO (30 ml) was subjected to 2-exo in 4-carboxy-butyl-triphenylphosphonium bromide (5.4 g) and DMSO (5 ml) at room temperature under a nitrogen atmosphere. Continuous treatment with a solution of-(3'S-hydroxy-non-1'-ynyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one (600 ml). The reaction mixture is kept at room temperature under a nitrogen atmosphere for 15 hours and then poured into a 30% aqueous solution of NaH ₂ PO ₄ . The aqueous mixture is extracted with diethyl ether and the eder extracts are combined and extracted with aqueous 1N-NaOH.

The aqueous alkaline extract is then acidified to pH 5 and extracted again with diethyl ether. The organic phase is washed with water, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The residue oil was purified by silica gel column chromatography using diethyl ether (95.5)-acetic acid (0.5) as eluent, and 5c-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle- 5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.27 (1H, t)] 90 mg and 5t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.30 (1H, t)] 90 mg are obtained.

In a similar manner, using 2-exo- (3'R-hydroxy-non-1'-ynyl) -3-endo-hydroxy-bicyclo- [3.3.0] octan-7-one as starting material, 5c-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.28 (1H, t)] and 5t-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm : 0.90 (3H, t); 4.00 (1 H, m); 4.39 (1 H, t); 5.30 (1H, t)] and 2-exo- (3'S-hydroxy-oct-1'-ynyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one or a Using the 3'R-hydroxy isomer as starting material, the following compounds are respectively obtained:

5c-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 400 (1 H, m); 4.39 (1H, broad t); 5.29 (1H, broad t)] and 5t-11α, 15s-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 ( 3H, t); 4.00 (1 H, m); 4.40 (1H, broad t); 5.28 (1H, broad)], or 5c-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1H, broad t); 5.28 (1H, broad t)] and 5t-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-prostacycle-5-ene-13-inoic acid [NMR (CDCl ₃ ) δ ppm: 0.90 ( 3H, t); 4.00 (1 H, m); 4.39 (1H, broad t); 5.29 (1H, broad t)].

Example 55

2-exo-hydroxymethyl-3-endo-hydroxy-bicyclo [3.3.0] in a mixture of benzene / DMSO 75/25 (80 ml) with external cooling and stirring to maintain the reaction temperature at 20-22 ° C. To a solution of octane-7-one-7,7-ethylenedioxide-3-THP-ether (12 g) was added dicyclohexylcarbodiimide (12.7 g), pyridine (1.65 ml) and trifluoroacetic acid (0.83 ml). Apply in turn. The reaction mixture is diluted with benzene (50 ml), filtered, washed with water until neutral and dried over sodium sulfate.

The solvent was evaporated to a small amount (30 ml) and the solution was diluted with a solution of 2-oxo-octyl-dimethylphosphonate (10.8 g) in benzene (30 ml) of 80% sodium hydride (1.35 g) in benzene (125 ml). To the solution of sodium phosphonate prepared by addition to the suspension is added with stirring. After 15 minutes when the reaction is complete, the reaction mixture is heated with acetic acid (6 ml), washed with water until neutral and dried over sodium sulfate. The solvent is evaporated to dryness in vacuo and the residue is chromatographed on a SiO ₂ gel. Eluted with n-hexane-ethyl acetate (80:20) to give 2-exo (3'-oxo-non-1'-trans-1'-enyl) -3-endo-hydroxy-barcyclo [3.3] as a yellow oil. .0] octane-7-one-7,7-ethylenedioxide-3-THP-ether (12.7 g) is obtained.

IR (knit) ν cm ^-1 ; 2970, 1690, 1670, 1625: NMR (CDCl ₃ ) δ = 0.88 (3H, t), 3.2 to 4.2 (7H, m), 4.60 to 4.75 (1H, m); 6.18 to 6.20 (1H, m), 6.79 to 6.89 (1H, dd)

Pyridine-bromine-hydrobromic acid (24 g) is added to the solution of the resulting compound in anhydrous pyridine (100 ml) with stirring. After 1.30 h, the mixture is diluted with 30% aqueous solution of NaH ₂ PO ₄ (500 ml) and extracted with ethyl acetate. The organic extracts are combined, washed until neutral, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. The residue was purified on a SiO ₂ gel (eluent hexane-ethylether 80:20) 2-exo- (2'-bromo-3'-oxo-non-1'-trans-1'-enyl) -3- Endo-hydroxy-bicyclo- [3. 3. 0] Octane-7-one-7,7-ethylene dioxide-3-THP ether (13 g) is obtained. IR (knit) νcm ⁻¹ ; 2940, 1685, 1610.

The solution obtained by dissolving the obtained bromoketone (12.6 g) in methanol (32 ml) is added dropwise to a solution of NaBH ₄ (4.2 g) in methanol (65 ml) cooled to -20 ° C. The reduction reaction is completed in 1 hour, after which the reaction mixture is diluted with excess 30% NaH ₂ PO ₄ aqueous solution and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. The residue (12 g) was dissolved in acetone (100 ml) and then treated with IN aqueous oxalic acid solution (50 ml) at 40 ° C. for 12 hours. After removing acetone at 50 ° C. in vacuo, the aqueous suspension is extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na ₂ SO _4, the solvent was evaporated, the residue was eluted with silica gel column chromatography and eluted with n-hexane-ethyl acetate (50:50), followed by keto-alcohol as follows. To obtain.

2-exo (2'-bromo-3'R-hydroxy-non-1'-trans-1'-enyl) -3-endo-hydroxy-bacyclo [3.3.0] octan-7-one ( 3g) and 2-exo- (2'-bromo-3'S-hydroxy-non-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octane-7- On (4.2 g).

Under an inert gas (N ₂ ) atmosphere, 4-carboxybutyl-triphenylphosphonium bromide (32.4 g) was added to the urea of potassium tert-butoxide (18 g) in anhydrous DMSO (180 ml) to give a red solution of illid. do. Then a solution of 3'S alcohol (4.2 g) obtained above is added over 5 minutes. The reaction mixture is maintained by stirring for 15 hours at room temperature under an inert gas atmosphere. The reaction mixture is diluted with excess 30% NaH ₂ PO ₄ aqueous solution (about 350 ml) and extracted with ethyl acetate (5 × 50 ml). The ether extracts were combined, washed with brine (15 ml), extracted with 1N NaOH solution (5 × 15 ml) and washed with water until neutral. The basic extracts were combined and acidified until pH 5 and extracted with ethyl ether (3 × 30, 1 × 15, 1 × 10). The combined organic extracts are washed with brine and dried over Na ₂ SO _4, and the solvent is evaporated to dryness in vacuo. The residue was subjected to silica gel column chromatography using ethyl ether-acetic acid (100: 0.5) as the eluent to afford the following compounds:

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid (1.21 g),

NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.27 (1 H, t); And 5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid (1.84 g),

IR (knit) νcm ^-1 : 3350, 2115, 1705

NMR (CDCl ₃ ) δ = 0.9 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.30 (1 H, t); 6.38 (3 H, m).

In a similar manner, a Wittich reaction with 4'carboxybutyltriphenylphosphonium bromide was carried out using the 3'R alcohol obtained above as a starting material, and SiO₂ After chromatographic phase separation, the following compounds were obtained:

5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-ene-5-13-inoic acid (0.4 g),

NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.28 (1 H, t); And

5E-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycle-5-ene-13-inoic acid (0.8 g),

NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.39 (1 H, t); 5.20 (1 H, t).

Example 56

Using the process of Example 55, the following compounds are obtained from 2-oxo-nonyl-dimethylphosphonate instead of 2-oxo-octyl-dimethylphosphonate:

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-ethyl-prostacycle-ene-5-13-inoic acid m / e 358 (M ⁺ -H ₂ 0), 340 ( M ⁺ -2H ₂ 0);

NMR (CDCl ₃ ): 0.88 (3H, t); 2.37 (2H, t); 3.98 (1 H, m); 4.40 (1 H, t); 5.30 (1H, broad t); 5.98 (3H, Broad);

5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-ethyl-prostacycle-5-ene-13-inoic acid m / e 358 (M ⁺ -H ₂ 0), 340 ( M ⁺ -2H ₂ 0),

NMR (CDCl ₃ ): 0.88 (3H, t); 2.36 (2H, t); 3.98 (1 H, m); 4.39 (1 H, t); 5.30 (1H, broad t); 5.62 (3H, Broad), and 15R epimers thereof;

5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-ethyl-prostacycle-5-ene-13-inoic acid m / e 358 (M ⁺ -H ₂ 0), 340 ( M ⁺ -2H ₂ 0),

5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-ethyl-prostacycle-5-ene-13-inoic acid; m / e 358 (M ⁺ -H ₂ 0), 340 (M ⁺ -2H ₂ 0).

Example 57

According to the process of Example 55, 2-oxo-decyl-dimethylphosphonate, 2-oxo-isodecyl-dimethylphosphonate, 2-oxo-undecyl-dimethylphosphonate, or 2-oxo-isoound Phosphates such as sil-dimethylphosphonate are used to obtain the following compounds:

5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-n-propyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0) ,

NMR (CDCl ₃ ) δ ppm: 90.88 (3H, t); 4.37 (1 H, t); 5.26 (1 H, t); 7.21 (3H, Broad);

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-n-propyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0) ,

NMR (CDCl ₃ ) δ ppm: 0.88 (3H, t); 4.36 (1 H, t); 5.23 (1 H, t); 7.34 (3H, Broad);

5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d); 4.38 (1 H, t); 5.24 (1 H, t); 7.52 (3H, Broad);

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.85 (6H, d); 4.36 (1 H, t); 5.25 (1 H, t); 6.24 (3H, Broad);

5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-n-butyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ 0) ,

NMR (CDCl ₃ ) δ ppm: 0.89 (3H, t); 4.39 (1 H, t); 5.28 (1 H, t); 7.88 (3H, Broad);

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-n-butyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ 0) ,

NMR (CDCl ₃ ) δ ppm: 0.89 (3H, t); 4.39 (1 H, t); 5.23 (1 H, t); 6.70 (3H, Broad);

5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-isobutyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d); 4.34 (1 H, t); 5.26 (1 H, t); 7.32 (3H, Broad);

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-20-isobutyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d); 4.32 (1 H, t); 5.27 (1 H, t); 6.54 (3H, broad);

5E-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-propyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0) ,

NMR (CDCl ₃ ) δ ppm: 0.88 (3H, t); 4.38 (1 H, t); 5.26 (1 H, t); 6.26 (3H, Broad);

5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-propyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0) ,

NMR (CDCl ₃ ) δ ppm: 0.88 (3H, t); 4.38 (1 H, t); 5.24 (1 H, t); 6.02 (3H, Broad);

5E-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d); 4.37 (1 H, t); 5.27 (1 H, t); 6.58 (3H, Broad);

5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isopropyl-prostacycle-5-ene-13-inoic acid, m / e 372 (M ⁺ -H ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d); 4.36 (1 H, t); 5.27 (1 H, t); 6.63 (3H, Broad);

5E-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-butyl-prostacycle-5-ene-13-inoic acid, m / e 386 (MH ₂ 0),

NMR (CDCl ₃ ) δ ppm: 0.89 (3H, t); 4.39 (1 H, t); 5.26 (1 H, t); 6.40 (3H, Broad);

5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-butyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ 0) ,

NMR (CDC1 ₃ ) δ ppm: 0.89 (3H, t), 4.39 (1H, t), 5.25 (1H, t), 6.43 (3H, broad);

5E-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isobutyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ O),

NMR (CDC1 ₃ ) δ ppm: 0.86 (6H, d), 4.38 (1H, t), 5.25 (1H, t), 6.58 (3H, broad),

5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isobutyl-prostacycle-5-ene-13-inoic acid, m / e 386 (M ⁺ -H ₂ O),

NMR (CDC1 ₃ ) δ ppm: 0.87 (6H, d), 4.37 (1H, t), 5.25 (1H, t), 6.04 (3H, broad),

Example 58

According to the process of Example 55, 2-oxo-3R-methyl-heptyl-dimethylphosphonate and d, 1-2-exo-hydroxymethyl-3-endo-hybibicyclo- [3. 3. 0] Octane-7-one-7,7-ethylenedioxide-3-THP ether as starting material, brominated intermediates α, β-unsaturated ketones with pyridinium hydro tribromide, reduced with NaBH ₄ and protected The group was removed and then separated by chromatography to give d, 1-2-exo- (2'-bromo-3'S-hydroxy-4'R-methyl-oat-1'-trans-1'-enyl) -3-hydroxy-bicyclo [3. 3. 0] octane-7-one

NMR (CDC1 ₃ ) δ ppm: 0.76 (3H, d), 1.00 (3H, d), 3.73 (1H, d), 5.83 (1H, d), 8.85 (1H, d) and its 3 ′ R-epimer To obtain. The resulting intermediate is converted to the following compound using the process of Example 55:

d, 1-5 (Z, E) -11α, 15S-dihydroxy-9a-deoxy-9amethylene-16R-methyl-prot, tacycl-5-ene-13-inoic acid, and

d, 1-5 (Z, E) -11α, 15R-dihydroxy-9a-deoxy-9amethylene-16R-methyl-prot, tacycle-5-ene-13-inoic acid,

NMR (CDC1 ₃ ) δ ppm: 0.97 (3H, d), 4.27 (1H, broad), 5.25 (1H, broad).

Example 59

According to the process of Example 24, d, 1-3α-hydroxy-2β- [3'S-hydroxy-4 '-(R, S) fluoro-1'-trans-nonen-yl] -7-oxo- Bicyclo- [3. 3. 0] reacted with 320 mg of octane to give the title compound

d, 1-16 (R, S) fluoro-20-methyl-carboprostacycline and its 5Z-isomers d, 1-5Z, 13E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene 103 mg of -16 (R, S) fluoro-20-methyl-prostacycle-5, 13-dienoic acid and 15R-epimer of these two compounds are obtained. Thin layer chromatography (diethyl ether + 2% AcOH) of the title compound was carried out as follows.

NMR (CDC1 ₃ ) δ ppm: 0.86 (3H, t), 3.77 (1H, m), 4.0 to 4.3 (1.5H, m), 4.67 (0.5H, m) 5.27 (1H, t) H in C ₁₆ : J _Hf = -50 Hz

Example 60

Using the processes of Examples 23 and 24, suitable bicyclo [3. Prepared according to the processes of Examples 16, 17, 18 and 19]. 3. 0] The following methyl esters are obtained from octane-7-one-3, 3'-bis-THP-ether:

5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5Z-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16S-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5E-11α, 15S-dihydroxy-9a-deoxy-9a-methylene-16S-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-16R-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5Z-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-16S-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5E-11α, 15R-dihydroxy-9a-deoxy-9a-methylene-16R-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362; 5E-11α, 15R-Dihydroxy-9a-deoxy-9a-methylene-16S-fluoro-prostacycle-5-ene-13-inoic acid methyl ester, M ⁺ -H ₂ O 362.

The methyl ester is quilted to obtain free acid.

Claims (1)

Lactone derived from the compound of formula (I) and the compound of formula (I), characterized by the alkylation of the compound of formula (II) with the compound of formula (III) And methods of preparing their pharmaceutically or veterinary acceptable salts.

In the above formula, R is a) free or esterified carboxy group; b) —C (OR ′) ₃ , wherein each R ′ is independently C ₁ to C ₆ alkyl or phenyl; c) -CH ₂ -R ″, wherein R ″ is hydroxy or C ₂ or C ₇ alkoxy; d)

Wherein R _a and R _b are independently selected from hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkanoyl, and pentyl; e) -C≡N; f)

g) -CHO; or h)

Wherein X 'is each independently -O- or -S-, and R _a ' and R _b 'are the same or different and represent C ₁ to C ₆ -alkyl, or are together straight or branched C ₂ to C ₆ Forms alkylene); D is -CH _2- ,

(Cis),

(Trans), -C≡C-,

-O-, -S- or

Wherein R _C may be hydrogen, C ₁ to C ₆ alkyl or C ₂ to C ₆ alkanoyl; One of R ₁ and R ₂ , and independently one of R ₃ and R ₄ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl-C ₁ To C ₆ alkyl, the other represents hydrogen, hydroxy, C ₁ to C ₆ alkoxy or aryl-C ₁ to C ₆ alkoxy, or R ₁ and R ₂ , and independently R ₃ and R ₄ together are oxo To form a group; R ₅ and R ₆ are the same or different and each represents hydrogen, C ₁ to C ₆ alkyl or halogen, or R ₅ , R ₆ and the carbon atoms in which they are defective

or

Form a flag, Y is -CH ₂ CH _2- , -C≡C-,

(Trans),

(Cis) wherein Z is hydrogen or halogen, -NH-CO-, and -NH-CH _2- ; X is-(CH ₂ ) m ₃ (wherein m ₃ is 0 or 1),

(Cis)

(Trans), -O-, -S- and

Wherein R _c is as defined above; m ₁ , m ₂ , n ₁ and n ₂ may be the same or different and may be an integer of 0 or 1 to 12, provided that m ₁ + m ₂ and n ₁ + n ₂ are each 15 or less; p and q are independently 0 or an integer of 1 to 3, provided that p + q must be an integer of 1 to 6; R ₇ is a ') hydrogen; b ') C ₁ to C ₄ alkyl; c ') an alicyclic group unsubstituted or substituted with one or more C ₁ to C ₆ alkyl or C ₁ to C ₆ alkoxy; d ') arylgurup unsubstituted or substituted with one or more halogen, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or phenyl; And e ') a saturated or unsaturated heterocycle ring unsubstituted or substituted with one or more halogen, halo-C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, phenyl or C ₁ to C ₆ alkyl; One of R ₁ ′ and R ₂ ′ and independently one of R ₃ ′ and R ₄ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₁₀ -alkenyl, C ₂ to C ₁₀ alkynyl, phenyl or aryl -C ₁ to C ₆ alkyl, the other is soso, hydroxy, C ₁ to C ₆ alkoxy, aryl-C ₁ to C ₆ alkoxy or a protecting group bound to acyclic system or side chain with an ether bond, or R ₁ ′ and R ₂ ′ and independently R ₃ ′ and R ₄ together form a protecting group for a ketone group; E is (C ₆ H ₅ ) ₃ P- or (R _e O) ₂ P → (O) _-group , wherein R _e can each independently be C ₁ to C ₆ alkyl or phenyl; R ″ ′ is a ″) carboxyl group in free, esterified or salt form, b ″) -C (OR ') ₃ (where R' is as defined above), c ″) —CH ₂ —R ^IV , wherein R ^IV is a protecting group bonded to —CH ₂ — by C ₂ to C ₇ -acyloxy or ether linkage, d ″)

Wherein R _a and R _b are as defined above, e ″) -C≡N, f ″)

And g ″)

Wherein X ', R _a ' and R _b 'are as defined above.