NO772752L - PROCEDURE FOR THE PREPARATION OF 1,5-DISUBSTITUTED 2-PYRROLIDIONS - Google Patents

Description

This invention relates to a new series of 1,5-disubstituted 2-pyrrolidones which are prostaglandin-like in chemical structure and biological character, methods for producing these 2-pyrrolidones and synthetic intermediates used in these methods.

DeC20 unsaturated fatty acids, known as prostaglandins, form a large family of naturally occurring compounds.

These molecules can have as many as five asymmetric centers and are present in and elicit responses from a variety of biological tissues. An example of a particular species of the prostaglandin E family is PGE2, which is pictured below.

prostaglandin E2

According to the notation system commonly used to describe the stereochemistry of prostaglandins!, a thick, unbroken line means the /3-configuration ion, which is defined as a bond coming out of the plane of the paper and up toward the reader. Similarly, a dotted or broken line signifies the a-configuration, which is defined as a bond that goes behind the plane of the paper and away from the reader. Thus, in the configuration of prostaglandin E2 depicted above, a is at carbon 8 and j3 is at carbon 12. [P. Bergstrom et al., Acta. Chem. Scand., 16, 501 (1962)]..

"-. By the same terminology, a wavy line means a mixture of the two forms a and j3. Thus etJ means 2-pyrrolidone with the structure:

a mixture of the epimers and ,';;.■•.,,."'■,.

By reference to the pyrrolidone of structure B and prostaglandin Ej, shown above, a stereochemical comparison can be made between the two sets of compounds. The stereochemistry at positions 12 and 15 is the same in both types, but at position 8 it is different. That is, the configuration of the C8-C7 bond in prostaglandin E is a, but that of the N8-C7 bond is in the paper plane as represented in the drawing above. Another way of presenting the above two examples that will give a better appreciation of this difference in configuration is the edge-state diagram below:

where A' and B mean the two side chains in the examples. Here, the illustration shows the eclipse of the A-C8 bond by the Cl2-H bond

and the eclipsing of the Cl2-B bond by the C8-H bond in the case of prostaglandin E, and the halving of the A-N8 bond with respect to the dihedral angle formed with B-C12-H in the case of the pyrrolidone. This difference in conformation is a result of the planarity developed by the amide moiety in the pyrrolidone. ["Basic Principles of Organic Chemistry", J.D. Roberts and M.C. Caserio, W.A. Benjamin, New York, 1965, p. 674].

A systematic name for a 1,5-disubstituted 2-pyrrb-lidone of structure

is 1-(6'-carboxyhexyl)-5/3-(3"Q!-hydroxyoct-1"-enyl)-2-pyrrolidone and it can also be called a derivative of 11-deoxyprostaglandin E^, that is say 8-aza-11-deoxy-PGE^.

The corresponding 8-aza-11-deoxy-PGE2 compound has the structure: where the single bond between C2' and C3' is replaced by a double bond. The corresponding 8-aza-11-deoxy-PGEQ compound has the structure

where the double bond between Cl" and C2" is replaced by a single bond.

The above-mentioned pyrrolidones have several asymmetric centers, and can exist in the racemic (optically inactive) form and in each of the two enantiomeric (optically active) forms, i.e. the dextrorotatory (D) and levorotatory (L) forms. As drawn above, each pyrrolidone structure signifies the particular optically active form or enantiomer that can be partially evolved from D-glutamic acid. The mirror image or the optical antipode

to each of the above structures means the other enantiomer

to that pyrrolidone and can be partially evolved from L-glutamic acid.

For example, the optical antipode to -.1-(6'-.carboxyhexyl)-5/S-(3"a-hydroxyoct-1"-enyl)-2-pyrrolidone is drawn in this way t

and is named 1-(6'-carboxyhexyl)-5α-(3"H-hydroxyoct-1"-enyl)-2-pyrrolidone.

The racemic form of the above pyrrolidone contains

equal number of a particular enantiomer and its mirror image. When reference is made to the crude matemate of a compound contained herein, the symbol "rac" will precede the compound name. This expression will then mean and is a correct angi<y>élse of an equimolar mixture of D and L or enantiomeric forms.

A pair of optical isomers that are optical antipodes

or enantiomers are relative to each other by inversion of the absolute configuration at all their centers of asymmetry■.

In contrast, when the ratio is an inversion of the absolute configuration at one or more but not all a centers of symmetry, the pair of isomers are epimers or diastereomers. For example, 1-(6'-carboxyhexyl)-5/3-(3"of-hydroxyoct-1"-enyl)-2-pyrrolidone and 1-(6'-carboxyhexyl)-5a-(3"a-hydroxyoct -1"-enyl)-2-pyrrolidone diastereomers which are in relation to each other by an inversion of configuration around the C5 atom, and can be shown as respectively s

Chemical experimentation on each individual of one enantiomeric pair or on one mixture of the two actually gives the same and identical results.

As previously pointed out, the insertion of a nitrogen atom in place of the carbon atom at C8 causes a drastic change in the three-dimensional conformation of the resulting prostaglandin. Due to the fact that the structure has a connection with biological activity and that a fundamental change in structure such as a conformational change will often have a profound effect on the biological activity, such molecular modifications of prostaglandins by substitution of heteroatoms have been explored

lately. Most compounds have been explored with respect to heteroatom substitutions at the C9 and C11 prostaglandin positions, and include such examples as the 9-oxaprostaglandins [I. Vlattas, Tetrahedron Let., 4455 (1974)], 11-oxaprostaglandins [A. Fougerousse, Tetrahedron Let., 3983 (1974)] and S. Hanessian

et al., Tetrahedron Let., 3983 (1974) and 9-thiaprostaglandins [I. Vlattas. Tetrahedron Let., 4459 (1974)]. Two 8-aza-ll-deoxy-prostaglandin' E 'err with natural fej side chain; that is, compounds with aza substitution at C8 <:> in ri-deoxy-prostaglandin E^^ and E2, have also been discussed in the literature tG. Bolliger and J.M. Muchowski, Tetrahedron Let.,

2931 (1975). (Aug. 1975) and J. W. Bruin et al., Tetrahedron Let.,

4599 (1975)]. These examples of pyrrolidone compounds lie outside the scope of the present invention, which provides a higher order of complexity and molecular variation at the Cl-prostaglandin position and in the side chain. Relatively little biological activity is mentioned for these literature examples, and those

can form a contradiction in form and molecular complexity to the new compounds according to the present invention.

The natural prostaglandins and many of their derivatives, such as esters, acylates and pharmaceutically acceptable salts, are extremely powerful inducers of various biological responses [Di,E. Wilson, Are. Intern. Med., 133 (29) (1974)] in Tissues composed of smooth muscles, such as those in the cardiovascular, pulmonary, gastrointestinal and reproductive systems, in cellular tissues, such as those in the central nervous system and in hematological, reproductive, gastrointestinal, pulmonary, nephritic, epidermal, cardiovascular and adipose systems, and also act as mediators in the homeostasis process. With such a wide response range, the prostaglandins are apparently involved in basic biological processes in the cells. This fundamental involvement of prostaglandins is really supported by the fact that they can be found in the cell-vew of almost all kinds of animal organisms.

In such cells, the effect of closely related natural prostaglandins can often be the opposite. The effect of PGE2 on blood lamellae in humans is, for example, an increase of aggregation, while the effect of PGE^ is inhibitory of aggregation.

Such contrast effects Jéan are also observed in the tissue. For example, the in vivo effect of PGÉ2 on the cardiovascular system in mammals is manifested by causing hypotension, while the in vivo effect of PGE2q is hypertension [J. B. Lee, Arch. Intern. Med., 133 56 (1974)]. However, the ability to predict the biological effect of prostaglandin groups based on such observations is very illusory today. Although, for example, the cardiovascular effects of PGE2 and PG^a are opposite"as *le~ written above, their action^in vivo or in vitro on mammalian uterine smooth muscle is the same and it is stimulatory (causes contraction) [ H. R. Behrman et al., Arch. Intern. Med., 133, 77 (1974)].

Among the main objectives in the manufacture of synthetic pharmaceuticals is the development of compounds which are highly selective in their pharmacological activity and which have an increased duration of activity compared to their related naturally occurring compounds. In the case of a series of compounds similar to the naturally occurring prostaglandins, an increased selectivity for a single compound usually leads to an increase in one prostaglandin-like physiological effect and a decrease in the others. By increasing the selectivity, the serious side effects that are often observed after administration of the natural

similar prostaglandins, for example such gastrointestinal side effects as diarrhea and emesis or cardiovascular side effects when bronchodilator effects are desired. Recent research aimed at an increase in biological selectivity includes the 11-deoxy-prostaglandins [N. H. Anderson, Arch. Intern. Med., 133, 30 (1974) Review] , 2-decarboxy-2-(tetrazol-5-yl)-11-deoxy-15-substituted-ul-pentanor-prostaglandins (M. R. Johnson et al., U.S. pat. 3,932,389) where it is mentioned that certain modifications produce selective vasodilatory, anti-ulcerative, anti-inflammatory, bronchodilator and antihypertensive properties, 16-phenoxy-

16-(»)-tetranor prostaglandins reported to have anti-fertility activity (British Pat. 1,350,971), and 1-imide and 1-sulfonamide prostaglandins (U.S. Pat. 3,954,741).

The present invention relates to new prostaglandin-like compounds which have selective and powerful biological activity and which have the structure:

and the C5 epimer thereof, where: Q is selected from the group consisting of

, tetrazol-5-yl

A is one single or cis double bond,

B is a single or triple-double bond, UerflA OH or H0^"<»>H,

R 2 is selected from the group consisting of α-thienyl, phenyl,

phenoxy, monosubstituted phenyl and monosubstituted phenoxy, said substituents being selected from the group consisting of chlorine, fluorine, phenyl, methoxy,'' trifluoromethyl and alkyl with from one to three carbon atoms,

R.j is selected from the group consisting of hydrogen, alkyl having from one to five carbon atoms, phenyl and p-biphenyl,

R A is selected from the group consisting of

and -SO 2 R 5 , said R 5 being selected from the group consisting of phenyl and alkyl having from one to five carbon atoms, and alkali, alkaline earth and ammonium salts of such compounds having a carboxylate or tetrazol-5-yl group. In addition, the present invention includes intermediate products which can be used for the production of the final products above, and which have the structures:

and the C5 epimer thereof, wherein W is selected from the group consisting of

0

-COR3/ tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl with from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazolr-5-yl and N-(tetrahydropyran-2-yl) tetrazol-5-yl, and A, B, R2 and R3 are each as defined above,

and the C5 epimer thereof, wherein W and A are as above, and

and the C5 epimer thereof.

Of interest as agents such as hair.selective prostaglandin-like biological activity, is the series of pyrrolidones with the structure:

where A, B, U, R 2 and: are as above, and the C5 epimer thereof. Also of interest in this connection is the series of pyrrolidones with the structures; :• . ■ - ■ ■'"•»■ ■ . .'■:■.■''*■■■': where A, B, U, R2 and R^ are as indicated above, bg the C5 epimeres thereof. .Of special interest in the above compound is the series of compounds represented by that of the structure

where A, B, U and R2 are as above, and the C5 epimer thereof.

Another particularly interesting series of compounds having selective biological activity is represented by the structure:

where A, B, U and Rj are as above, and the C5 epimer thereof.

Particularly preferred because of their selective biological activity are: 1-(6'-carboxyhexyl)-5/3-(3"G"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone and the methyl ester and the 5a-epimer thereof,

1-(6'-carboxy-hex-2;-enyl)-5/3-(3"o-hydroxy-4"-phenylbut-1"-enyl)-<2>i-pyrrolidone and its 5a-epimer, -

1-(6'-carboxyhexyl)-519~ (3"a-hydroxy-4'1-phenylbutanyl)-2-pyrrolidone and its Sa-epimer,

1-(6'-carboxyhexyl)-5/3-(3"O!-hydroxy-4"-phenoxybut-1"-enyl)-2-pyrrolidone and its 5a-epimer,

1-(6'-carboxyhex-2'-enyl)-5,3-(3"α-hydroxy-4:'-phenoxy-but-1"-enyl)-2-pyrrolidone and its 5α-epimer,

1^-(6'-carboxyhexyl)-5/3-(3"o!-hydroxy-4"-phenoxybutanyl)-2-pyrrolidine and its 5a-epimer,

the compounds where 6'-(tetrazol-5-yl) replaces the 6'-carboxy group in each of the above particularly preferred compounds, and

the compounds where a 3"j3-hydroxy group replaces the 3"d-hydroxy group in each of the above-mentioned 6•-carboxy- and 6'-(tetrazol-5-yl)-compounds.

The pyrrolidone compounds according to the present prostamimetic invention are prepared in an optically active form by a sequence of six steps which links the two side chains, the a-, or top side chain and the - or bottom 3-ide chain, to the pyrrolide backbone, and it begins with a cleaved amino acid, D- or L-glutamic acid. It is noted that the choice of route starting from D- or L-glutamic acid establishes the absolute configuration for C5 on the 2-pyrrolidone ring and accommodates the need to cleave this position at the end of the synthesis. In this example and in the discussion that follows, the b configuration is shown. The L-configuration is produced with the same sequence from L-glutamic acid. The synthetic sequence" shown in schematic representation A illustrates the methods by which the α-chain is attached to the 2-pyrrolidone nucleus. It will be noted that the methods in each case form a pyrrolidone intermediate.19 which differs only at C2 the '-C3' bond. The final products of the present invention are then synthesized from intermediate 19 according to the methods set forth in schematic representations B, C and D.

SCHEMATIC PREPARATION A - a-CHAIN CONNECTION

A brief summary of the steps in schematic representation A is given in the following" The first step, labeled (a), illustrates the cyclization of D-glutaric acid to methyl-D-pyroglutamate, and the reduction of the pyroglutamate to 5-D-hydroxy-2- pyrrolidone is known [V. Bruckner et al., Acta. Chim. Hung. Thomas, 21, 106 (1959)]. The second step (bj) is the protection of the hydroxymethyl group with the protecting agent T, which can be any group suitable for the protection of hydroxyl against alkylation, for example benzyl, dimethyl-t-butylsilyl, acetyl, 1-ethoxyethyl or especially tetrahydropyranyl Steps (c) and (e) illustrate the alkylation of the sodium or lithium saltate of pyrrolidone JL with alkylating agents of the formula

or XCH2CH(0Y)2, respectively, where X is Cl, I or especially Br, W is CO2R3v N-acyloxymethyl)tetrazol-5-yi with. from two to

five carbon atoms in the acyloxy group, N-(phthalidyl) tetrazol^-5-yl-i

N-(tetrahydropyran-2-yl)-tetrazol-5-yl or tetrazol-5-yl, Y is alkyl having from one to three carbon atoms, and A and R are as above. Step (d) is deprotection of T, and the method for this will depend on the identity of T. Step (f) is deprotection of the pyrrolidone compound 18 to form in situ 1-(ethan-2'-al) -5-hydroxymethyl-r-2-pyrrolidine which can exist in intimate equilibrium with the hemiacetal compound 5_. Step (g) is a Wittig reaction between the equilibrium mixture containing bicyclo[4,3 i0]nonan-5-one 5_ and a phosphorane of the structure Ph2P=CH(CH2)3W where W, indicated above, is unprotected, to form the corresponding to 2-pyrrolidone compound 19 where A is a double bond.

The reactions which are necessary to form the products according to the invention are arranged so that this should not happen

some epimerization of the optically active center at C5 takes place. Therefore, by proceeding from one of the two enarithiomers of glutamic acid, the same configuration at the asymmetric centers is preserved in the products. Also starting from racemic glutamic acid, racemic or rac products are formed.

The C5 position in the intermediates and products according to the present invention will be drawn in the j8 configuration, but the a configuration at the C5 position is also applicable, .-f . •

provided that the starting glutamic acid has the correct configuration.

The first two steps of the reaction sequence are the condensation and esterification of D-glutamic acid to form the corresponding D-methyl-pyroglutamate with the structure:

[E. Hardegger et al., Heiv. Chem. Acta., 38, 312 (1955) : E. Segel, . J. Am. Chéra. Soc., 74, 851 (1952)J.

The third known step of the sequence shown in schematic representation A as step (a) is the reduction of the 5-carboxymethyl group in the D-methylpyroglutamate to form 5-D-hydroxymethyl-2-pyrrolidone. This conversion is most conveniently performed using a variation of the method discussed by V. Bruckner et al., [Acta. Chem. Hung. Thomas, 21, 106 (1959)]. The D-methyl pyroglutamate is stirred with lithium borohydride in dry tetrahydrofuran or other ethereal solvent until the reduction is essentially complete. Isolation of the product in the indicated manner gives 5-D-hydroxymethyl-2-pyrrolidone with the structure:

In order to alkylate the amide nitrogen in the 5-D-hydroxymethyl-2-pyrrolidone, it is appropriate to protect the labile 5-hydroxymethyl hydrogen with the known tetrahydropyranyl group. This protection (Scheme A, step (b)) is most conveniently carried out by contacting 5-D-hydroxymethyl-2-pyrrolidone with dihydropyran in the presence of an organic acid, such as p-toluenesulfonic acid, and i. an inert solvent, such as methylene chloride, chloroform, tetrahydrofuran or diethoxyethane. The appropriate temperature range for this turnover is from ice bath-. temperature to the reflux temperature of the solvent, and preferably at ambient temperature. After the formation of 5-D-(tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone_1 is substantially complete, usually overnight, this is isolated by first removing the organic acid by basic extraction and removing the solvent and any excess of . dihydropyran by vacuum evaporation techniques. The product will be . mostly purified by column chromatography.

Other protecting agents that can be used just as easily include any that will protect the hydroxyl from alkylation. Some examples are benzyl, acetyl, dimethyl-t-butylsilyl and 1-ethoxyethyl. These protective agents are readily available because they can be attached to the 5-hydroxymethyl group by known methods. Their choice for synthetic purposes depends on the protecting group at C7'. If, for example, it is desired to use N-tetrahydropyran-2-yl as a protecting group for the acid

hydrogen at C7' tetrazol-5-yl (W), suitable 03" hydroxyl protecting groups (T) will be acetyl or dimethyl-t-butylsilyl. Part-(alkylated)-2-pyrrolidone compounds (17 and 18 in schematic representation A) is prepared by a combination of two reactions carried out on 5-D-(tetrahydropyran-2'-yloxymethyl)-2-pyrrblidone 1 on any of its T-group analogs. First, sodium- or the lithium salt of pyrroli-dinone^ prepared by contacting a solution of compound JL in an inert organic solvent, such as tetrahydrofuran, dioxyethane, or dipxane, with a base, such as n-butyl lithium, phenyl- lithium or especially sodium hydride. The suitable temperature range for this salt formation is from ambient temperature to the reflux temperature of the solvent pg preferably at ambient temperature. All bases must be

reacted before the alkylation begins, because this usually takes 1 to 4 hours. Then the desired 1^(alkylated)-2-pyrrolidone compounds 17 and 18, respectively, are formed by contacting the above-prepared lithium or sodium salt of 2-pyrrolidone compound 1 with an alkylating agent of the structure

or XCH 2 CH(OY) 2

where X is Cl, I and especially Br,

t'7 and A are each as indicated above and Y is alkyl of from one to three carbon atoms. Dehné

the second part of the alkylation process is usually carried out by adding either a mixture of the alkylating agent in an inert organic solvent, as previously defined, or in particular by adding a mixture of the alkylating agent in a polar aprotic organic solvent, such as dimethylformamide or dimethylacetamide, to the above formed mixture of sodium

or the lithium salt of pyrrolidone JL in an inert organic solvent, and then keeping the mixture of alkylating agent 1 and the 2-pyrrolidone sodium or lithium salt in contact at a temperature between the temperature of the surroundings and the reflux temperature of the solvent until the alkylation is complete .lt substantially complete, usually overnight.

Of course, the alkylated 2-pyrrolidone resulting from the use of XCHjCHfOY^ can also be prepared by using XCI^CC^Et as the alkylating agent, followed by selective conversion of the ester group in the resulting 1-(2'-ethyl acetate)-5-) substituted)-2-pyrrolidone to aldehyde.

When there is the possibility of having an acidic hydrogen atom present in W, the alkylation process is most conveniently carried out by protecting or otherwise removing the acidic hydrogen atom. For example, in the case where R is hydcogen, the best method is to use an ester derivative which can then be removed by alkaline hydrolysis at the end of the synthesis sequence. In the case where W

is tetrazol-5-yl, the best method is to replace the acidic hydrogen atom with an acyloxymethyl group, as indicated above, a phthalidyl group [W. v. Daehne, J. Med. Chem., 13, 60? (1970); I. Isaka et al., Chem. Pharm. Bull., 24, 162 (1976)] or a tetrahydropyran-2-yl group. The first two groups for tetrazol-5-yl protection can also be removed by alkaline hydrolysis at the end of the synthesis (schematic representation B) but the THP group can be removed by acid hydrolysis. It is assumed in the following description that the acidic hydrogen atom in the W group is protected unless otherwise stated.

The nature of the C2\-C3' bond in 2-pyrrolidone compound 17 obtained from the alkylation step is determined by the nature of A in the alkylating agent

The choice of A will thus determine the unsaturated or saturated character of the a-side chain in the final synthesis product, i.e. whether the final product will be an 8-aza-ll-deoxy-PGE^ or an 8-aza-deoxy- PGE2.

Obviously, the choice of A causes only a difference in the character of the C2'-C3' bond in the α-side chain, and in reality conversion from pyrrolidone compounds where A

is one double bond to those where A is a single bond in the synthesis step for the pyrrolidone compound 17. For example, the 2-pyrrolidone compound _17_ with a double bond at A can be converted into the 2-pyrrolidone compound 17 with a single bond at A by hydrogenation over a noble metal catalyst, such as palladium-on-carbon, at ambient temperature until 1 equivalent of hydrogen is absorbed.

Compound 17. A = double- Compound JL7 A = single-bond bond

In each case, the protecting group T is removed (step d, schematic representation A) by methods known to those skilled in the art, such as anticipating the formation of the CU side chain. The resulting 2-pyrrolidone compounds have the structure:

Connection 19

where W and A are as indicated above, are then carried through the schematic representations B, C and D to form the new final products according to the present invention.

The above 2-pyrrolidone compound _19 can also be prepared by bringing the hydrolyzed form of the 2-pyrrolidone of the structure: where Y and T are as above into contact with a phosphorane of the structure:

where W, as indicated above, is unprotected, for example GO 2 H or tetrazol-5-yl. The synthesis of the tetrazol-5-yl-phosphorane will be found in the U.S. pat. 3,953,466.

This reaction sequence, illustrated by steps (f) and (g) in the schematic representation A, can be carried out in the following way. If the preferred protecting group T, tetrahydropyran-2-yl, is used in compound 18, acid hydrolysis of compound 18 according to the usual method of acetal removal, such as by acetic acid in water at approx. 40°C, cleave both the tetrahydropyran-2-yl and the acetal to form 1-(ethan-2'-al)-5/3-hydroxymethyl-2-pyrrolidone which can exist in intimate equilibrium with 4-aza-2-hydroxy -1-oxa-bicyclo[4,3,0]nonan-5-one j>.

The equilibrium mixture containing hemiacetal 5_ can then be converted with approx. 2 equivalents of phosphorane, as indicated above, in a polar aprotic solvent, such as dimethylsulfoxide, or a mixture of an ethereal and a polar aprotic solvent, such as tetrahydrofuran and dimethylsulfoxide, at temperatures of 0 to 60°, usually overnight, for to form 2-pyrrolidone 19 where A is a double bond. It should be noted that the acidic hydrogen atom or group W can then be protected as an ester in the case of the carboxylic acid, or as an N-acyloxymethyl, N-phthalidyl or N-tetrahydropyran-2-yl group in the case of

themselves. about tetrazol-5-T-yl. This 2-pyrrolidone 19 with A as a double bond can, if desired, be converted into 2-pyrrolidone JL9 where A is a single bond by the hydrogenation method described above. Several of the final products according to the present invention, 2-pyrrolidone compounds 22, carb. and tight. , is prepared by oxidation of the 5/3-hydroxymethyl group in 2-pyrrolidone 19 and Horner-Wittig reaction of the thus formed 5/3-rformyl-2-pyrrolidone compound 20 with the sodium or lithium salt of a phosphonate with the structure (MeO)

where R 2 is as indicated above, followed by reduction of the thus formed 5-(4"-substituted-but-1"-en-3"-onyl) part of 2-pyrrolidone 21.

The schematic representation B illustrates this outlined process, which method associates the u> chain.

The aldehyde 20 is obtained from the 5/3-hydroxymethyl-2-pyrrolidone compound 19 by a modification of the Pfitzner-Moffatt oxidation [K. E. Pfitzner and M.E. Moffatt, J. Am. Chem. Soc. , 87, 5661 (1965)] whereby contact between the 5/3-formyl compound 20 and water is avoided. For example, stirring a slurry of 1-(7N-methylheptanoate)-5/3-hydroxymethyl-2-pyrrolidone or other suitable 5?-hydroxymethyl-2-pyrrolidone in an inert hydrocarbon solvent, such as toluene, xylene or especially benzene, together with dimethylsulfoxide., a weak acid such as acetic acid or especially pyridine trifluoroacetate And a water-soluble diimide such as diethylcarbodiimide or especially dimethylarainopropylethylcarbodiimide or if desired its hydrochloride salt, at a temperature from 0°C to ambient temperature for 1 to 4 hours, oxidizing the primary alcohol 19 to aldehyde 20. Alternative methods for achieving oxidation include the usual Pfitzner-Moffatt reaction and oxidation with chromium trioxide pyridine complex [R. Ratcliffe et al., J. Org. Chem.. 35_, 4000 (1970)] even bm the chosen method is the above-described reaction. The 5/3-(4"-substituted but-1"-en-3"-onyl)-2-pyrrolidone compound 21 is prepared by contacting the 5/3-form 1-2-pyrrolidone compound 20 with sodium or lithium, the salt of a phosphonate with the structural

where R 2 is as indicated above, in a solution or slurry

with an ethereal solvent, such as tetrahydrofuran, dimethoxyethane or dioxane, at a temperature of from 0 to 50°C until the reaction is substantially complete, as determined by

reaction monitoring methods. The isolation of the product from

this Horner-Wittig reaction, the method of which is known to those skilled in the art, is carried out conventionally by chromatography. Other methods include liquid chromatography at high pressure and

in some cases fractional recrystallization. The method for producing the phosphonates can be found in U.S. Pat. pat. 3,932,389.

Reduction and, if desired, alkaline or acidic hydrolysis of 2-pyrrolidone compound 21 produces several of the final products according to the invention where Q is CO2R3 or tetrazol-5-yl. The reagent of choice to carry out the reduction is lithium triethylborohydride, but other selective reducing agents which will reduce the ketone but no other groups, for example zinc borohydride or sodium borohydride, can be used just as easily. The solvents usually used are ethereal in nature, such as tetrahydrofuran and diethyl ether. The temperature which. chosen will be based on the activity of the reducing agent, and in most cases it is convenient to use a dry ice/acetone bath.

Under the usual reaction conditions, the reduction of the but-1"-en-3"-onyl portion of the pyrrolidone 21 will in fact form two 2-pyrrolidone compounds 22, which are diastereomers.

3"a-hydroxy compound 22a 3"/3-hydroxy compound 22b

These two compounds, which can be separated by common isolation techniques, such as liquid chromatography at high pressure, are thus both prepared in the manner described, and it is assumed that both are shown until even the pm æ isomer is consistently shown. If the two diastereomers have not been separated, the result is a mixture of the two compounds, and is stated as:

and it is believed that this means a mixture of the α-epimer and the β-epimer.

After isolation of the product from the above reduction reaction in the usual manner, if desired, the protecting group at the acidic position of the C7 group W can be removed using conditions customary for the removal of such groups. If for example

an alkyl ester is chosen as W and the acid is desired, simple alkaline hydrolysis with an equivalent base at ambient temperature to the reflux temperature of the solvent will,

usually overnight, after neutralization give the carboxylic acid.

In a similar way, the phthalidyl and acyloxymethyl groups can be removed, but the tetrahydropyrah-2-yl (THP) group will be removed with acid, such as acetic acid in water or p-toluenesulfonic acid in methanol, at ambient temperature to 50°C, usually overnight above. The products according to the present invention where A and B are each single bonds, for example compound 23. carb. and tight. , is prepared by catalytic reduction of the 3"-tetrahydropyran-2"'-yloxy derivative of 2-i-pyrrolidori ^22 where A is a single bond. This sequence is outlined in the schematic representation C.

■ Alternatively, the pyrrolidone compounds 23 can be prepared by catalytic reduction of the 3'"-tetrahydropyr ah-2-yloxy derivative of 2-pyrrolidone 22. where A is a double bond. In this case A and B will be reduced to single bonds simultaneously.

SCHEMATIC DRAWING C

The tetrahydropyran-2"'-yloxy derivative of compound 22 where A is a single bond is formed in the same way as described for 5-D-(tetrahydropyran-2-yloxymethyl)-2-pyrrolidone 1. Thus, hydrogenation over noble metal catalysts, such as palladium-on-carbon or platinum oxide, in solvents such as ethyl acetate, methanol or ethanol, at ambient temperature to

the reflux temperature until 1 equivalent of hydrogen is absorbed, followed by removal of the tetrahydropyran-2"'-yl group and, if desired,

protecting the Ises group for W by usual methods, lead to the production of S^azar-ll-deoxy-prostagiandin Eq compounds 23.

The products according to the present invention where

P.

ii

Q is CNHR^ is prepared from tetrahydropyran-2"'-yl ox sy-de r in water of compounds 22. and 23, which have a CO 2 H* group at W" This synthetic sequence is outlined in the schematic representation D where Rjj is as indicated above. These acid derivatives, compounds 24 and 25, are formed according to well-known methods described for the formation of irides and sulfonimides from carboxylic acids. The preferred method is that according to

the method of Spesiale and Hurd where the acyl or sulfonyl isocyanate is brought into contact with the above-cited

derivatives of the compounds 22/and 2^3. in an inert solvent,

such as ether or tetrahydrofuran, at temperatures from ambient to the reflux temperature of the solvent, usually overnight. See the following [A. J. Speziale et al., Jo Org. Chem., 30, 4306 (1965), C.D. Hiird and A.G. Prapas, J. Org. Chem.., 24, 388 (1959)? reactions of isocyanates with carboxylic acids in "Survey of Organic Synthesis", C. A. Beuhler, D. E. Pearson, Wiley Interscience, New York, 1970, N-acylation

of amides and. imides, J. March, - "Advanced Organic Chemistry's Reactions, Mechanism and Structure", McGraw-Hill, Nev/York, 1968, p. 340].

There are also several other methods for preparing the products according to the present invention where Q is CONHR^. The first alternative route involves treatment of the 5-(4"-substituted but-i"-en-3"-onyl)-2-pyrrolidone compound 21 where W is COOH with an acyl or sulfonyl isocyanate under the above conditions '-written conditions for the process of Speziale and Hurd. The C-15-keto group in the resulting aminated or sulfonaminated pyrrolidone intermediate is then reduced to a hydroxyl group using the procedure described for the reduction of pyrrolidone compound Ise 21 to pyrrolidone compound 22.

The second alternative route involves the condensation of nonanone compound Ise 5_ with a phosphorane of the structure Ph^P^H-(CK^)3-CONHR^ using the procedure described for the analogous preparation of pyrrolidone 19. from nonanone 5. After

possible hydrogenation of the resulting C5-C6 double bond, a pyrrolidone intermediate with the structure is produced by this route:

The above pyrrolidone carboxamide intermediate is analogous to pyrrolidone compound Ise 17.°9 can be carried through the subsequent steps illustrated in schematic representation B to form the compounds of the present invention where Q is CONHR 4 .

The ester products according to the present invention where Q is carbo- alkoxy, carbophenoxy and carbo-para-biphenoxy can be prepared from the corresponding acid products according to the present invention where Q is COOH by well-known esterification methods, including reaction with diazoalkanes with from one to five carbon atoms, and reaction of phenol or p-biphenol with the acid and dicyclohexylcarbodiimide.

In addition to forming the 8-aza-prostaglandins as described in the schematic representations A to C, they can be synthesized from intermediate 18 by initially attaching the bottom side chain and then forming the top side chain. The reactions used for this synthetic sequence are shown in schematic representation E. They have previously been described in detail in schematic representations A to C. Reaction 1 is cleavage of the protecting group dimethyl-t-butyl1-silyl, annotated as T in the schematic presentation, and is described on pages 16, 22 and 41. Reaction 2 is oxidation of the primary alcohol group to an aldehyde group which forms the agent for the attachment of the bottom side chain. This reaction is described on page 26, lines 1 to 14. Reaction 3 is the Honer-Wittig reaction described on page 26, lines 15 to 25. It uses the same type of phosphonate as is used throughout the main synthesis. Reaction 4-1 is the reduction of the enone part in the Buhn side chain to an allyl part. This is described on page 27, lines 1 to 20. Reaction 4-2. is protection aV.hydroxyl function in the allyl-ah part formed In reaction 4-1, It is described on page.19. Reaction 5 is the removal and protection of the acetal group which forms a hinge before the top aide chain. This is a simple hydrolysis and is described on page 40, Reaction 6 is the usual Wittig reaction used to form the top side chain of prostaglandins and is described on page 23, lines 8 to 12, and on page 42. Reaction 7 is again deprotection of the hydroxyl group and is analogous to reaction 1. The symbols Y, T, Rg and Q have the meanings given above.

SCHEMATIC PREPARATION D - IMID AND SULFONIMIDE DERIVATIVES

SCHEMATIC PREPARATION E

Alternative reaction core for 8-aza-prostaglandin synthesis

In numerous tests in vivo and in vitro, it has been shown that the new prostaglandin analogues have physiological activities with greater selectivity, potency and duration of action than those exhibited by the natural prostaglandins". These tests include, inter alia, tests with regard to efficacy on isolated smooth muscle from guinea pig uterus, inhibition of histamine^-induced brochospasm in guinea pigs, effect on blood pressure in dogs, inhibition of stress-induced ulceration1 in rats, diarrhea effect in mice and inhibition of stimulated stomach acid -secretion in rats and dogs.

The physiological responses observed in these tests are useful for determining the usefulness of a test substance in the treatment of various natural and pathological conditions. Such specific uses include: vasodilator activity, antihypertensive activity, bronchodilator activity, antifertility activity and antiulcer activity.

The new 8-aza-11-deoxy-prostaglandins according to the present invention have highly selective activity profiles compared to the corresponding naturally occurring prostaglandins, and in many cases exhibit a longer duration of action. The new prostamimetic pyrrolidones according to the present invention which have substitutions of aryl (including phenyl, substituted phenyl and α-thienyl) at R2 and carboxylic acid, carboxylic acid ester or tetrazol-5-yl at Q,

for example, has useful vasodilatory activity. The main examples of the therapeutic importance of these pyrrolidone compounds are the efficacies of 1-(6'-carboxyhexyl)-5/3-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone and l -(6'-carboxyhexyl)-5a-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone, which exhibit hypotensive activity of a similar potency to PGE2 when administered intravenously to anesthetized dogs according to the method in the U.S. pat. 3,956,284. At the same time, other activities, such as bronchodilation and antiulceration, are greatly reduced compared to PGE2, measured by the method described in U.S. Pat. pat. 3,956,284.

Another outstanding example of the therapeutic importance of the pyrrolidones according to the present invention is the selective antiulcerative activity of the compounds having substitutions of aryloxy (including phenoxy and substituted phenoxy) by and carboxylic acid, carboxylic acid ester or imide,

in

tetrazol-5-yl or sulfonamide at Q. For example, 1-(6'-carboxyhexyl)-5/3-(3"-hydroxy-4"-phenoxy-but-1"-enyl)-2-pyrrolidone exhibits excellent and selective antisecretory activity by oral administration to dogs.

The new compounds according to the invention can be used in a number of pharmaceutical preparations containing a compound or a pharmaceutically acceptable salt thereof. They can administer in a variety of ways that will depend on the type of ailment and the condition of the person being treated.

The 8-aza-11-desox<y>-16-ar<y>1-tu-tetranorprostaglandin compounds of the present invention and their epimers are useful vasodilator agents. For the treatment of hypertension, these drugs can be conveniently administered as an intravenous injection with doses of approx. 0.5-10 mg/kg or preferably in the form of capsules or tablets in doses of 0.005 to 0.5 mg/kg/day.

The 8-aza-11-deoxy-16-aryloxy-n-tetranor-prostaglandin compounds of the present invention and their epimers are useful anti-ulcer agents. For the treatment of peptic ulcer, these drugs can be administered in the form of capsules or tablets with doses of 0.005 to 0.5 mg/kg/day.

Pharmacologically acceptable salts useful for the purposes described above are those having pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are those derived from the alkali metals, for example lithium, sodium and potassium, and from the alkaline earth metals, for example magnesium and calcium, although cationic forms of other metals, for example aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methyl 1-hexylaminedecylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, Ø-phenylethylamine, ethylenediamine, diethylenetriamine and other aliphatic, cycloaliphatic and araliphatic amines containing up to and including approx. 18 carbon atoms, and also heterocyclic amines, for example piperlidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives thereof, for example 1-methyl-pyrrolidine, 1,4-dimethylpiperaziri, 2-methylpiperidine and the like, and also amines containing water- solubilizing or hydrophilic groups, for example mono-, di- and triethanolamine, ethyldiethanolamine, N-butyl-ethaholarain, 2-amino-1-butanol, 2-araino-2-ethyl-1,3-propanediol,

2-amino-2-methyl-l-propanol, tris (hydroxymethyl)-aminomethane., N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephedrine, epiriephrine , procaine and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

To produce any of the numerous possible compositions, different reaction inerts can be used

fortifying agents, inert shaping agents or carriers.

Such substances include, for example, water, ethanol, gel

thinners, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for drugs. About. if desired, these pharmaceutical preparations can contain auxiliary substances, such as preservatives, wetting agents, stabilizing agents - or other therapeutic agents such as antibiotic substances.

The following examples are illustrative only and not in any way limiting the scope of the subsequent claims. The spektrai data were obtained on a Varian T-60 or an A-60 NMR, a Perkin-Elmer Grating Infrared Spectrometerbg an LKB-9000 Mass Spectrometer... The infrared data are given in reciprocal centimeters and the NMR data are given. in parts per million using TMS as a standard.

Generally, the temperatures of the described reactions in the examples, when these are unspecified, will be at the ambient temperature or room temperature, which varies from 15 to 30°C.

The time required for the reactions described in the examples was, unless otherwise stated, determined by monitoring with thin layer chromatography (TLC). The usual TLC system was silica gel on glass (E. Merck silica gel plates, E. Merck Dormstadt,

B.R.D.) with benzene/ether or methanol/chloroform as eluents and. vanilla/ethanol or iodine as developers. ["Intro-duction to Chromatography" J. M. Bobbitt, A. E. Schwarting, R. J. Gritter, Van Nostrand-Reinhold, N;.Y; 1968]. As a general rule, the reaction in question was judged to be complete when the TLC spot representing the critical starting material had disappeared or had completely changed.

EXAMPLE 1

5/ ?- (tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone L

Into a flame-dried flask under a nitrogen atmosphere was introduced 2.54 g (22.1 mmol).5-D-hydroxymethylene-2-pyrrolidone, prepared according to the method of V. Brucknér et al., Acta. Chim. Hung. Tomus , 21, 106 (1959) ,. and 50 ml me ty le hk lor id. To this solution at 0 to 5°C were then added 3.72 g (44.2 mmol) of redistilled dihydropyran and 0.2 g of p-toluenesulfonic (tosic) acid. The solution was then allowed to warm to room temperature and stirred overnight. After diluting the reaction mixture with 20 ral of ethyl acetate, the solution was extracted with 2 x 5 ml saturated sodium bicarbonate solution and 1 x 10 ml saturated saline solution. The organic layer was dried with magnesium sulfate, filtered

to remove the desiccant and the solvent was. removed in vacuo to give 4.1 g of a yellow oil. This oil was chromatographed

50 g of Merck silica gel packed in chloroform were added to a column.

Elution with 1 liter of chloroform removed less polar contaminants. Elution with 2% methanol in chloroform and collection of 10 ml fractions separated and purified the product. Combination of product fractionation and removal of solvent in vacuo gave 3.95 g of the title compound Isen 1^ as a yellow oil, and. the yield was 90%. NMR T-60(DCCl3) b.s., 06.60 ppm (1H) , m. ^4.60 ppm (1H) , m. é4.05 - 63.25 ppm (5H), m. $2.50 - 62, 10 ppm, m. o2.00- &L.40 ppm (10H).

IR(CHCl3^ solution) 3425, 2980, 2930, 2850, 1680, 1250-1200, 1025 cm"<1>. Also, the protecting group dimethyl-t-butylsilyl can be used instead of the tetrahydropyran-2-yl grouph upon application

by the method of E. J. Corey et al. , J. Am. Chiem. Soc. , 94,

6190 (1974) on 5-b-hydroxymethylene-2-pyrrolidone..

. EXAMPLE 2

1-(7'-(ethylheptanato)-5/3-(tetrahydropyran-2"-yloxymethyl)-2-pyrrolidone 2^

Into a flame-dried flask containing a nitrogen atmosphere was introduced 0.725 g (18.7 mmol) of a 62%-in. q. sodium hydride dispensjoh in mineral oil and 10 ml of dry THF. To this mechanically stirred slurry, 3.74 g (18.7 mmol) of 5-D-(tetrahydropyrari-2-yloxymethyl)-2-pyrrolidone 1L in 10 ml of dry THF were then added slowly and dropwise. After the addition was complete, the thick slurry was stirred for 30 minutes until all hydrogeh evolution had ceased.

The alkylation of the sodium salt was then carried out.

5.34 g (22.5 mmol) of ethyl 7-bromoheptanoate was then added dropwise to this slurry at room temperature in 15

ml dry DMF. At the end of the addition, after approx. 15 minutes, the slurry had dissolved and sodium bromide slowly began to precipitate from the solution. The reaction mixture was stirred overnight,

was then filtered and the solvent was removed in vacuo from the filtrate. 100 ml of ethyl acetate was then added to the residue and this organic solution was extracted with 2 x 20 ml of water. After drying the organic layer with magnesium sulfate and filtering to remove the drying agent, the solvent was removed in vacuo from the filtrate to give a yellow oil which was chromatographed on a column of 120 g Merck silica gel packed in chloroform. Elution with: (a) 250 ml chloroform, (b) 500 ml 5% ethyl acetate in chloroform, (c) 1 liter 10% ethyl acetate in chloroform, and automatically

collection of fractions of 10 ml gave rise to the separation and purification of the product. The product fractions were combined and stripped of solvent to give the title compound Isen 2

as a colorless oil, 3.39 g, 51% yield. NMR T-60 (DCC13): M £4.60 ppm (1H), q. Å4.17 ppm jy = 8 hz.,

m, i4»00~2.70 ppm (9H), m, ^2.6 -.1.4 ppm, t. i1.3 ppm = 8 hz.

(23H);

IR (HCC13) solution) 2975, 2915, 2840, 1720, 1665, 1450, 1250-1200, 1125, 1025 cm""1. r

MS heated inlet (m/e-%) 356-1%, 355-3%, 310-17%, 240-100%, .194-83 .%.

The preceding procedure can be adapted to the preparation of pyrrolidones with the structure below by substituting a passing alkylating agent for ethyl 7-bromoheptanoate and optionally, by using the dimethyl-t-butyl-sily analogue of pyrrolidone 1-

- co2æ3 N-(tetrahydropyran-2-yl)tetrazol-5-yl N-(acetyloxymethyl)tetrazol-5-yl A:- single or cis-double bond

T = THP or dimethyl 1-t-butyl-rsilyl

As indicated, 1-(substituted)-5/3^(tetrahydropyran-2"-yloxymethyl or dimethyl-t-butylsiloxymethyl)-2-pyrrolidones can be prepared by substitution of the appropriate alkylating agents for the ethyl 7-bromoheptanoate. for example 1-(6'-carboxymethylhex-2'-enyl)-5i8-'(tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone is to be prepared, the alkylating agent will be methyl 7-bromohept-5-enoate.

If 1-(6'-1"-acetyloxymethyltetrazol-5"'-ylhexyl)-5/3-(tetra-hydropyran-2"-yloxymethyl)-2-pyrrolidone is to be prepared, the alkylating agent will be 6-bromo-1- (1'-acetyloxymethyltetrazol-5'-yl)-n-hexane.

1-(2,2-diethoxyethyl)-5/3-(tetrahydropyran-2"-yloxymethyl)-2-pyrrolidone can also be prepared by the same method

using 2-bromo-acetaldehyde-diethyl acetal as alkylating agent.

The preparation of 6-bromo-1-tetrazol-5'-yl-n-hexane can be carried out in the following way.

, A mixture of 2.98 g (23.5 mmol) 7-hydroxyheptanenitrile, 1.60 g (30.0 mmol) ammonium chloride, 0.032 g (0.76 mmol) lithium chloride, 1.91 g'. (29.3 mmol) of sodium azide and 50 ml of dimethylformamide

can be heated to 120° under nitrogen with stirring for 18 hours or until the reaction is substantially complete. The dimethylformamide can then be removed in vacuo and the resulting residue can then be purified by one of several methods, such as chromatography

or extraction.. This product, 6-hydroxy-1-(tetrazol-5-yl)-hexane, can then be treated with phosphorus tribromide under appropriate conditions to form 6-bromo-1-(tetrazol-5-yl)-hexane. The N'-acetyloxy-methyl 1 group can be attached using the method of W. V. Daehne et al. Opt. one. , while the N-tetrahydropyran-2-y1 group

can be connected according to the method in example 1.

Treatment of 7-(tetrahydropyran-2'-yloxy)hept-5-yn-nitrile in the same way as above will give rise to the production of 6-(tetrahydropyran-2'-yloxy)-1-(tetrazbl-5' -yl)hex-4-yno This material can then be converted to 6-bromo-1-(tetrazol-5'-yl)-hex-4-ene according to the procedure in B.R.D. official document no.

2,121,361 (CA. 76:24712d). Of course, the starting compound Isen, hept-5-yn-nitrile, can also be hydrogenated to an olefin before conversion of

the nitrile to tetrazole, by essentially following the same procedure. Again, the protecting groups for the acidic hydrogen on tetrazol-5-yl can be attached by the methods above.

EXAMPLE 3

1-(7'-methylheptanato)-5/3-hydroxyethyl-2-pyrrlidone 4

To a solution of 200 ml of methanol and 3.99 g of THP-pyrrolidone 2 was added 79 mg of p-toluene-sulfonic (tosic) acid. and the solution

was refluxed overnight. After work-up, as described above, an NMR spectrum of the reaction mixture showed

presence of a small amount of the starting ethyl ester. The reaction mixture was therefore redissolved in 160 ml of methanol, 0.080 g of tonic acid was added and the reaction mixture was again refluxed overnight. Removal of the solvent in vacuo from the reaction mixture gave a yellow oil which was dissolved in ethyl acetate and extracted with 1 x 10 ml of a 1:2 mixture of saturated sodium bicarbonate and semi-saturated Rochelle's salt solution.

The organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated to give titre1-fprbindeIsen4 as a clear yellow oil. 2.528 g (38%).

NMR A-60 (DCCl^) p. 63.86 ppm, m. Å 4.00-3.33 ppm, m. £3.20 é2'7°PPm (13H), m. £2.50 -02 .00 ppm, m. ,£l.90 -©1.20 ppm (10H), partial spectrum.

IR (HCCl3 solution) 3550-3100, 2980, 2910, 2840, 1720, 1650, 1450, 1425, 1410, 1250-1190 cm"<1>.

MS, LKB 9000, solids inlet (m/e-%) 70eV 226-26 '%, .194-19.8%, 74-100%, 13eV 257-3.3%, 226-100 [%, 168- 24.6%.

Alternatively, the tetrahydropyran-2"'-y1 group can be removed by hydrolysis in a 65:35 mixture of glacial acetic acid:water for about 18 hours in total essentially according to the method in example 14.

In this case, the ethyl ester group in pyrrolidone 2 will be kept intact.

The preceding hydrolysis process with acetic acid and water can also be used to remove the tetrahydropyranyl protecting group from the other pyrrolidone products in example 2, which will then form the corresponding 1-(substituted)-5/3-hydroxymethyl 1-2 -pyrrolidones. If, however, the protecting group for tetrazol-5-yl is tetrahydropyran-2-yl, then it will be appropriate to use the dimethyl-t-butyl silyl group as T. This silyl group can be selectively removed with tetra-n-butyl ammonium fluoride according to the method of Corey, opt. one.

.Using acetic acid to prepare 1-(2>2-diethoxyethyl)-5-(tetrahydropyran-2"-yloxymethyl)-2-pyrrolidone 3^

from Example 2, removal of the tetrahydropyrany1 group will be

followed by cleavage of the acetal and ring closure, to give as product an equilibrium mixture of the open form and 4-aza-2-hydroxy-1-oxa-bicyclo[3,4,0]nonan-5-one 5_.

The equilibrium mixture containing compound 5_ can be converted to 1-(substituted)-5β-hydroxymethyl-2-pyrrolidone by the following procedure.

To a solution of 23.04 g (52.0 mmoi). 5-triphenylphosphino-pentanoic acid (bromide salt) in 46 ml of dry dimethylsulfoxide, 49.3 ml (98.6 mmol) of a 2.0 N solution of sodium methylsuiphenylmetld in dimethylsulfoxide can be added dropwise. 3.27 g can then be added to the resulting red solution within 1 hour

(20.8 mmol) with 4-aza-2T-hydroxy-1-oxa-bicyclo[3,4,0]nonan-5-pn 5_, in dry dimethylsulfoxide (63 ml). After stirring for a further half an hour or until the reaction is essentially complete, the reaction mixture is poured into 600 ml of ice-water and can then be extracted with 2 x 300 ml of ethyl acetate. The cold

aqueous layers can then be covered with ethyl acetate and acidified to

pH/v 3 with 10% hydrochloric acid, after which the aqueous layer can be extracted with 2 x 200 ml of ethyl acetate. The combined organic extracts are washed with water, followed by brine, and the organic layer can be dried over anhydrous sodium sulfate. Concent- :

trituration of the filtered organic layer will give impure 1-(6'-carboxyhex-2'-enyl)-5,3-hydroxymethyl-2-pyrrolidone which can be chromatographed. The acid can then be esterified with diazomethane. This method can also be used to prepare 1-(substituted)T5j3-hydroxymethyl-2-pyrrolidone with the structure

where X is the same as in Example 2, by substituting an appropriate phosphonium salt in place of 5-triphenylphosphonopentanoic acid,

and then protecting the acidic hydrogen with an N-acyloxymethyl group according to the procedure described by W. V. Daehne et al., op. one. ,' with an N-tetrahydropyran-2-yl group according to the method in example 1 or - by esterification when it concerns the carboxylic acid.

EXAMPLE 4

1-(7,-methylheptanato)-5,3-pyrimyl-2-pyrrolidone €>

To a flame-dried flask containing a nitrogen atmosphere was added 0.1286 g (0.5 mmol) with 1-(7'-methylheptanato)-5/3-hydroxymethyl-2-pyrrolidone 4 15 ml of dry benzene. To this solution was added 0.1286 g (1.5 mmol) of dimethylaminopropylethylcarbodiimide hydrochloride (DAPC) and 0.142 ml (2 mmol) of dimethyl sulfoxide followed, after five minutes, by 0.108 g (0. 55 mmol) with pyridine trifluoroacetate. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 3/4 hours, then the benzene was decanted and the viscous second phase which had formed at the bottom of

flask, was washed with 3x5 ral benzene. The benzene solutions were combined and the solvent was removed in vacuo to give 0.152 g of the title compound Isen 6 as a clear yellow oil. The crude product was used immediately and without further purification in the next reaction.

NMR T-60 (DCC13), d.

(3H). partial spectrum

The preceding method can also be used to oxidize the other 1-(substituted)-5/3-hydroxymethyl-2-pyrrolidones from example 3 to the corresponding 1-(substituted)-5/3-formy 1-2-pyrrolidones.

EXAMPLE 5

1-( 7 '- methylheptanato)- 5ff-( 4"- phenylbut- 1"- en- 3"- onyl)- 2- pyrrolidones 2

Into a flame-dried flask containing a nitrogen atmosphere was placed 0.1188 g (2.97 mm<p>l) of a 60% sodium hydride

mineral oil dispersion and 5 ml of THF. To this slurry became

a solution of 0.7815 g (3.24 mmol) of dimethyl(3-phenyl-propan-2-onyl)phosphonate in 5 ml of THF was added. After the development of

hydrogen had ceased, a white suspension appeared which remained

stirred for 15 minutes. To this suspension was added 0.6894 g (2.70 mmol) of 1-(7'-methylheptanato)-5/3-formyi-2-pyrrolidone 6.

in 10 mL of THF, over 1 minute, within five minutes the reaction mixture became a clear yellow solution and it was stirred for another two. hours. The reaction mixture was then quenched with glacial acetic acid to a pH of 5... The solvent was removed in vacuo and the residue was taken up in 100 ml of ethyl acetate. / The organic solution was extracted with 2 x 10 ml saturated aqueous sodium bicarbonate, 3 x 10 ml

water and 1 x 10 ml saturated salt solution. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give 1.141 g of a yellow oil. This crude product was chromatographed on a column of 35 g E. Merck silica gel packed in ethyl acetate. Elution with ethyl acetate and automatic collection of fractions of 10 ml allowed the product to be purified. The product fractions were combined and the solvent removed in vacuo to give 0.614 g of the "title compound Isen T_" as a colorless oil (61% yield, from the starting alcohol).

NMR T-60 (DCC13) p. ^7.33 ppm (5H) / dofd. $6.73 ppm

Jj=7 hz J2=16. hz, d. ^5.60. ppm J2=16 n'z (2H) , m. 64.27 ppm center (1H) , Si <£3.93 (2H)i, p. 6 3.73 ppm (3H) . partial spectrum.

IR (CHC13 solution) 2980, 2900/2840, 1725, 1685 (sh), 1675,. 1625, 1250-1200 cnT<1>.

MS,LKB 9000 (m/e%) 70eV 372-20%, 371-82%, 252^96%, 226-24%, 194-35%, 12eV 372-18%, 371-100%, 252^24 %, 226-39%.

The others. The 1^ (substituted)-5/3-formyl-2-pyrrolidone compounds of Example 4 can be used in the preceding procedure in place of pyrrolidone 6_ to form! the corresponding 1-(substituted )-5/3-(4"-phenylbut-1"en-3"-onyl)-2-pyrrolidone compounds. Dessrr. ' without can phos f ona ts with the struc turen:

Z = -C6H4CH3(m)

-α-thienyl

-C6H4OCH3(£)

<-c>6<H>4<-c>s<H>5<<a>>-C6H4CF3<£>

-C6H4C1 (o)

are used instead of dimethyl (3-phenylpropan-2-onyl)phosphonate to form the corresponding 1-(substituted)-5/3-(4"-substituted but-1"-en-3"-onyl)-2- pyrrolidone compounds Hereinafter, all pyrrolidones, including the 4"-phenyl compounds, will be called 1-(substituted)-5/3-(4"-substituted but-1"-en-3"-onyl)-2-pyrrolidones.

EXAMPLE 6

1-(7'-methylheptanato)-5/3-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-

, pyrrolidone Q

To a flame-dried flask fitted with a magnetic stir bar, thermometer and containing a nitrogen atmosphere was added 0.5784 g (1.56 mmol) of 1-(7'-methylheptanato)-5/3-(4" -phenylbut-1"-en-3"-onyl)-2-pyrrolidone 7_ in 20 ral of dry THF. The clear colorless solution was cooled to -78°C and 1.56 mL (1.56 mmol) of lithium -triethylborohydride was added dropwise via syringe, needle, and serum hyster 4 over 15 minutes.After 1 hour, one TLC examination showed the absence of the starting Ises enone so that the reaction was quenched

with glacial acetic acid to a pH of 5, and this was followed by removal of the solvent in vacuo. The residue was dissolved in 50 ml of ethyl acetate

and this organic solution was then extracted with 1 x 10 ml semi-saturated aqueous sodium bicarbonate, 4 x 10 ml water and 1 x 10 ml saturated saline. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo

to give 700 mg of impure product. This product was chromatographed on a column of 9 g silica gel packed in ethyl acetate. Elution with ethyl acetate and automatic collection of fractions

of 5 ml separated the product from impurities, combining the product fractions and removing the solvent in vacuo gave 0.289 g of the title compound Isen 8 as a colorless oil (51% yield).

KMR T-60 (DCCl3) p. 67.37 ppm (5H), d. ^5.72 ppm jy = 7 hz, d. ^5.62 = 7 hz (2H), m. $4.67 - 64, 33 ppm, m. 64.30 - 63.83 ppm (2H), s. $3.73 ppm (3H), d. $ 2.90 ppm J2 = 6 hz (2H). partial spectrum.

IR (HCC13 solution) 3450-3200, 2975, 2900, 2830, 1725, 1665, 1250-1200 cm"<1>.

The other 1-(substituted)-5/3-(4"-substituted but-1"-en-3-oyl)-2-pyrrolidone compounds from Example 5 can be used by the preceding method to prepare the corresponding 1- (substituted)-5/3-(4"-substituted-3"-hydroxybut-1"-enyl)-pyrrolidone compounds.

EXAMPLE 7

1-(6;-carboxyhexyl)-5/3-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone 9

0.185 ml ( 0.185 meq.) with 1 N sodium hydroxide. The reaction solution was then refluxed overnight and was then neutralized to a pH of 4 by addition of glacial acetic acid." The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate. The organic solution was extracted with 2 x 2 ral water and 1 x 2 ml saturated salt solution, dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give the title compound 9 as a yellow oil, 59.4 mg, 89% yield.

NMR, T-60 DCCl 3 , p 67.33 ppm (5H), b.p. fe,30ppm center (1H), d. 65.73 ppm jy = 7 hz, d. 65.6 ppmJ±= 7 hs (2H), m. 64.6 -

63.2 ppm (4H), d. 62.93 ppmJ2=7 hz (2H). (partial spectrum).

IR (HCC13 solution) 3500-3100 , 2980, 2920, 1700<,>1600 , 1250-1200 cm"<1>.

Use of the other 1-(substituted)-5/3-hydroxybutenyl-2-pyrrolidones from example 6 instead of pyrrolidone:^ by the

the preceding procedure will allow cleavage of the methyl ester

or the acyloxymethyl-protecting groups and will allow the production of the following 8-aza-11-deshydroxy-prostaglaridin E^ and

..No connections. The N-tetrahydropyran-2-yl protecting group can, if one was used, be removed by the method in example 3 or 14.

• X = -COaH Z = -C,H.CH, .

2,643

-tetrazol-5~yl - -a-thienyl y.-:C f" -<e>6<H>4<0CH>3

"<C>6<H>4"<C>6H5

"C6H4CF3

v<y>; -<c>6<h>5

EXAMPLE 8

1-(7'-methylheptanato)-5/9-(4"-phenoxybut-1"~en-3"-onyl)-2-

' . pyrrolidone 10

In a flame-dried flask containing a nitrogen atmosphere, 22 mg (0.55 mmol) of a sodium hydride dispersion was placed

in mineral oil and 5 ml THF. For this slurry it was put

a solution of 0.1549 g (0.6 mmol) of dimethyl 1-(3-phenoxypropan-2-onyl)-phosphonate in 5 ml of THF. After the evolution of hydrogen had ceased, there was a clear/light yellow solution which was stirred for 15 minutes. To this solution was added 0.1277 g (0.5 mmol) of 1-(7'-methylheptanatb)-5^-formyl-2-pyrrolidoh 6_ in 5 ml of THF

1 over the course of I minute, within five minutes the reaction mixture had become a clear, yellow solution and it was stirred for a further two

hours. The reaction mixture was quenched with glacial acetic acid to a pH of

5. The solvent: was removed in vacuo and the residue was taken up

in. 50 ml ethyl acetate.. The organic solution bee extracted with

2 x 5 ml saturated, aqueous sodium bicarbonate ,\ 2 x 5 ml water and f ''•. 1 x 5 ral saturated sa It solution. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to yield 0>231 g of a yellow oil. This uncleaned product

was chronatographed on a column of 25 g E. Merck silica gel<:>packed in cyclohexane. Elution with 50% chloroform in cyclohexane and automatic collection of fractions of 10 ml enabled the purification of the product. The product fractions were combined and the solvent was removed in vacuo to give 53.6 mg of the title compound; connect Isen 10 (28% of the starting alcohol).

NMR T-60 (DCC1-), m; /S 7.40-6.70 ppm. (5H) , m. $6.7-^6.33 ppm (2H) p. 04.67 ppm (2H), m. $4.40-3.97 ppm (1H), p. 03.67 ppm. (3H). partial spectrum.

The other 1-(substituted)-5/3-formyl 1-2-pyrrolidone compounds from Example 4 can be used in the preceding procedure in place of pyrrolidone 6_ to form the corresponding 1-(substituted)-5/3-( 4"-phenok"s<y>but-<l>"-ene-<3>"<->bnyl)-2-pyrrolidone compounds. In addition, phosphonates with the structure can:

is used instead of dimethyl (3-phenoxypropan-2-onyl)phosphonate to form the corresponding 2-pyrrolidone compounds.

EXAMPLE 9

i-(7'-methylheptanato)-5/3-(3"-hydroxy-4"-phenoxybut-1-enyl)-2-pyrrolidone 11

To a flame-dried flask fitted with a magnetic stir bar, thermometer and containing a nitrogen atmosphere was added 0.1046 g (0.27 mmol) of 1-(7'-methylheptanato)-5-(4"- phenoxybut-1"-erythr-3"-onyl)-2-pyrrolidone 10 in 5 mL of dry THF. The clear, colorless solution was cooled to -78°C and: 0.27 mL (0.27 mmol) of lithium triethylborohydride was added dropwise via a syringe, needle and one serum hyster within 15 minutes.After 1 hour a TLC examination showed the absence of the starting enone as

The reaction mixture was quenched with glacial acetic acid to a pH of 5, followed by removal of solvent in vacuo. The residue was dissolved in 25 ml of ethyl acetate and this organic solution was then extracted with 1 x 5 ml of half-saturated aqueous sodium bicarbonate, 1x 10 ml of water and 1x 10 ml of saturated saline. The organic magnesium sulfate was filtered and the solvent was removed in vacuo to give 101 mg of crude product. This product was chromatographed on a column of 25 g silica gel packed in benzene. Elution with ethyl acetate and automatic collection of fractions of 5 ml separated the product from the

impurities but did not separate the two epimers. Combining the product fractions and removing the solvent in vacuo gave 85.6 mg of the title compound 11 (82% yield).

NMR T-60 (DCC13) m. ^7.54-6.82 ppm (5H), m. 65 , 94-5 , 73 ppm (2H), m. 64.79-4.43 ppm (1H), m. 6 4.33-3.94 ppm (3H), p. 63.70 ppm (3H). partial spectrum.

IR (CHCl3 solution) 3600-3100, 2980, 2920, 1730, 1670,

1600, 1200-1250 cm"<1>.

The other 1-(substituted)-5/3-(phenoxybutenoyl)-2-pyrrolidone compounds from Example 8 can be used instead of

pyrrolidone 10 by the preceding method and will form the corresponding 1-(substituted)-5/3r-(4"-phenoxy-3"-hydroxybut-1"-enyl)-2-pyrrolidone compounds.

EXAMPLE 10

1-(6'-carboxyhexyl)-5/3-(3"-hydroxy-4'-phenoxybut-1"-enyl)-2-pyrrolidone 12

To a solution of 50 mg (0.128 mmol) of 1-(7'-methylheptanato)-5/3-(3"-hydroxy-4"-phenoxybut-1"-enyl)-2-pyrrolidone 11 in 3 mL of methanol was added 0.128 ml (0.128 mmol) were added with 1 N'

sodium hydroxide. The reaction mixture was refluxed overnight and then neutralized to a pH of 4 by the addition of glacial acetic acid. The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate. The organic solution was extracted with 2 x 2 ml of water and 1 x 2 ml of saturated saline, dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give the title compound 12 as a yellow oil. 48.0 mg (99% yield).

NMR T-60 (DCC13) m. 67.40-6.82 ppm (5H), m. ^6.73-6.17 ppm (2H), m. 65.87-5.70 ppm (2H), m. 64.7-4.4 ppm (1H), m. 64.23-3.88 ppm (3H). partial spectrum.

IR (HCC13 solution) 3600-2900, 2920, 1700, 1670, 1600, 1200, 1250 cm"1.

Use of the other I-(substituted)-5/3-(hydroxy-phenoxybutenyl)-2-pyrrolidone compounds from Example 9 instead of pyrrolidone 11 in the preceding procedure will allow

cleavage of the methyl ester or acyloxymethyl groups and allow the preparation of the following 8-aza-11-des-hydroxy-prostaglandin E 1 and E 2 compounds. The N-THP protecting group can be cleaved according to the procedure in Example 14.

EXAMPLE 11 1-(7'-Methylheptanato)-5-(<3>-(<3>"-tetrahydropyran-2"'<y>lox<y>-<4>"-phenylbut-1-enyl)-2- pyrrolidone 13. In a flame-dried flask under a nitrogen atmosphere was placed 128 mg (0.342 mmol) of 1-(7'-methylheptanato)-5/3-(3"-hydroxy-4"phenylbut-1-enyl)- 2-pyrrolidone 9 and 5 ml of methylene chloride. To this solution at 0 to 5° C. was then added 0.062 ml (0.684 mmol) of redistilled dihydropyran and 3 mg of tosic acid. The solution was then allowed to warm to room temperature and was stirred overnight. The reaction mixture was worked up by diluting with 10 mL of ethyl acetate, extracting with 2 x 2 mL of saturated sodium bicarbonate solution and 1 x 5 mL of saturated brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give 0.135 g of a yellow oil. This was chromatographed on a column of 15 g Merck silica gel packed in chloroform. Elution with 1 liter of chloroform removed less polar impurities. Elution with 2% methanol in chloroform and au automatic collection of fractions of 10 ml separated and purified product,. Combining the product fractions and removing the solvent in vacuo gave 0.1756 g of the title compound 13 as a yellow oil.

NMR T-60 (DCC13) p. &6.34 ppm (5H) , m. 5.77-5.37 ppm (2H), m. £5.13-4.80 ppm (1H), p. $ 3 , 7 ppm (3H). partial spectrum.

In addition, the 1-(substituted)-5j8-(4"-substituted-3"-hydroxybut-1"-enyl)-2-pyrrolidones from examples 6, 7, 9 and 10 can be used by this method to prepare the corresponding THP -defivate.

EXAMPLE 12

1-(7'-methylheptanato)-5/3-(3"-tetrahydropyran-2"'-yloxy-4"-phenylbutanyl)-2-pyrrolidone 14

To a solution of 156.5 mg (0.342 mmol) of 1-(7'-methylheptanato)-5/3-(3"-tetrahydropyran-2"'-yloxy-4"-phenylbut-1-enyl)- 2- pyrrolidone 13 in 10 ml ethyl acetate was added 31 mg with 10%

palladium on charcoal and the whole mixture was placed in a Parr hydrogen reduction apparatus and shaken under a pressure of 22.68 kg of hydrogen for 4 hours. The slurry was then filtered through celite to remove the catalyst and the solvent was removed from the filtrate to give 158.2 mg of the title compound 14.

NMR T-60 (DCC13) p. é7.33 ppm (5H), m. §5.13-4.67 ppm (1H), m. ©4.5 7-4.33 ppm (1H), p. 03.73 ppm (3H). partial spectrum.

In addition, the other THP derivatives from example 11 where A is a single bond can be used in this method to prepare the corresponding hydrogenated derivatives.

EXAMPLE 13

1-(6'-carboxyhexyl)-5/3-(3"-tetrahydropyran-2"'-yloxy-phenyl-butanyl)-2-pyrrolidone 15

To a solution of 1582 mg (0.342 mmol) of 1-(7'-methylheptanato)-5/3-^(3"-tetrahydropyran-2"'-yloxy-4"-phenylbutanyl)-2-pyrrolidone 14 in 5 ml methanol, 0.342 mL (0.342 mmol) of 1N sodium hydroxide was added. The reaction solution was refluxed overnight and then neutralized to a pH of 4 by addition of glacial acetic acid. The solvent was removed in vacuo and the oily residue was dissolved in 15 mL of ethyl acetate. The organic solution was extracted with 2 x 2 mL water and 1 x 2 mL saturated brine, dried over magnesium sulfate, and filtered. The solvent was removed in vacuo to give the title compound 15 as a yellow oil. 134.2 mg (89% yield).

NMR T-60 (DCCl3) p. 57.37 ppm (5H), m. é4.4-3.2 ppm, m. 62.92 (2H). partial spectrum.

In addition, the other hydrogenated derivatives from example 12 can be used in this method to prepare the corresponding 6'-carboxylic acid and 6'-tetrazol-5-yl compounds.

EXAMPLE 14

1-(6'-carboxyhexyl)-5j3-(3"-hydroxy-4-phenylbutanyl)-2-pyrrolidone 16(8-aza-11-deshydroxy-16-phenyl 1-16-a"-tetranor-PGEQ 16)

A solution of 134.2 mg (0.3 mmol) of compound 15 was stirred in 5 mL of a 65:35 mixture of acetic acid:water overnight under nitrogen at ambient temperature. The solvent was then removed by vacuum evaporation using an oil vacuum pump, and the residue was azeotropically treated with benzene.

The crude product was then chromatographed on 15 g of ARCC7 silica gel eluting with 2% methanol in chloroform to give 82 mg of the title compound 16.

NMR T-60 (DCC13) p. $ 1.17 ppm (5H), m. 53.2-4.0 ppm (3H), d. 62.77 ppm, JH = 7 hz (2H). partial spectrum.

IR (HCC13 solution) 3600-3100, 2930, 2860, 1700, 1660, 1250, 1200, 710 cm"<1.>

In addition, this method can be used to remove the THP-protecting group from the 6'-carboxylic acid and 6'-tetrazol-5-yl derivatives from example 13 and the hydrogenated derivatives from example 12.

EXAMPLE 15

1-(6,-N-phenylimidohexyl)-5/3-(3"-hydroxy-4"-phenylbut-1"-enyl)-2-pyrrolidone To a solution of 64 mg (0.171 mmol) of 1-(6 '-carboxyhexyl)-5/3-(4"-phenyl-3"-tetrahydropyran-2'"-yloxybut-1"-enyl)-2-pyrrolidone, prepared according to the procedure in example 11)

in 10 ml of dry tetrahydrofuran, 25.16 mg (0.171 mmol) of benzoisocyanate, prepared according to the method of A. J. Speziale, J. Org. Chem., 27, 3742 (1962), in 5 ml of dry THF. After refluxing overnight, the solvent can be removed in vacuo and the reaction medium can be deprotected (THP group removed) according to the procedure in Example 14 to give the title compound.

In a similar manner, the following imide derivatives can be prepared by substituting the other suitably protected carboxylic acids from Examples 7, 10 and 14.

Z is defined in example 7

V is defined in example 10

A is a single or cis double bond B is a single or trans double bond EXAMPLE 16

1-(6'-N-methylsulfonimidohexyl)-5/5-(3"-hydroxy-4"-phenylbut-1"-enyl)-2- pyrrolidone

To a solution of 64 mg (0.171 mmol) of 1-(6'-carboxyhexyl-SØ^-phenyl-S^tetrahydropyran^'"-yloxybut-1"-enyl)-2-pyrrolidone, prepared according to the procedure in Example 11, in 10 ral of dry benzene, 20.7 mg (0.171 mmol) of methylsulfonyl isocyanate (A.J. Speziale, see example 16) can be placed in 5 ml of dry benzene at ambient temperature. After refluxing overnight, the solvent can then be removed in vacuo and the resulting residue deprotected (THP group removed) according to the procedure in Example 14 to give the title compound.

By using phenylsulfonyl isocyanate instead of methanesulfonyl isocyanate in this method, the corresponding phenylsulfoxyarid derivatives can also be prepared.

Additionally, the following sulfonimides can be prepared by substituting the other appropriately protected carboxylic acids from Examples 7, 10, and 14.

Suf NHS02CH3 •'•

V is defined in example 10.

Z is defined in example 7

A is a single or cis double bond B is a single or trans double bond

Claims (18)

1. Process for producing a pyrrolidone compound, characterized in that a compound with the formula: where W is , tetrazol-5-yl or tetrazol-5-yl substituted with N-(acyloxymethyl) having from two to five carbon atoms in the acyloxy group, N-phthalidyl or N(tetrahydropyran-2-yl), A is a single or cis double bond, B is a single or trans double bond, U is or 1 R, is selected from the group consisting of α-thienyl, phenyl, phenoxy, monosubstituted phenyl and monosubstituted phenoxy, said substituents being selected from the group consisting of chlorine, fluorine, phenyl, methoxy, trifluoromethyl and alkyl with from one to three carbon atoms, is selected from the group consisting of hydrogen, alkyl having from one to five carbon atoms, phenyl and p-biphenyl, R^ is selected from the group consisting of wherein R,, is selected from the group consisting of phenyl and. alkyl having from one to five carbon atoms, and the alkali, alkaline earth and ammonium salts of such compounds having a carboxylate or tetrazoyl-5-yl group, is prepared from a pyrrolidone of the formula where T is any group suitable for protecting the hydroxyl group against alkylation, by a reaction sequence whereby the amido group is reacted with either a compound of the formula where X is chlorine, bromine or iodine and W is.CO^Rj # N-acyloxymethyl-tetrazol-5-yl with from two to five carbon atoms in the acyloxy group, N-^phthalidyDtetrazol-S-yl, N- (t. tetrahydropyran-2-yl)tetrazol-5-yl or tetrazol-5-y1, or with a compound of the formula XCHjCH (OYjj where X is as indicated above and Y is alkyl having from one to three carbon atoms and A and R^ are as stated above, and in the event that the turnover is carried out with a connection with the formula first the protecting group T is removed and the alcohol thus formed is oxidized to an aldehyde and then it is added second side chain by reaction of the aldehyde with a phosphonate with the structure where alk is an alkyl group of 1 to 3 carbon atoms, and in the case that the first turnover was with the compound with the formula performed in any order A) removing the protecting group Y to release the aldehyde and reacting this with Ph3 P=C (CH2 )3 W to add the upper side chain, and B) removal of the protecting group Tog, oxidation of the product so that the alcohol formed is converted into the corresponding aldehyde, and reaction of the product with a compound of the formula to add the laveré side chain, and if desired, the following reactions known in and for eeg are carried out for the production of the desired product with formula I. 2. Process for the production of a pyrrlidone compound, characterized in that one compound with the structure and the C5 epilayer thereof, where: Q is selected from the group consisting of -COOR 3 , tetrazol-5-yl and -CGNHR^ , A is a single or cis double bond, B is a single or crane double bond, :' in U is or R2 is selected from the group consisting of α-thienyl, phenyl, phenoxy, rao-substituted phenyl' and monosubstituted phenoxy, said substituents being selected from the group consisting of chlorine, fluorine, phenyl, methoxy, trifluoromethyl * and alkyl with from one to three carbon atoms, R 3 is selected from the group consisting of hydrogen, alkyl having from one to five carbon atoms, phenyl and p-biphenyl. R4 is selected from the group consisting of -COR^ and -SC^R^, where Rg is selected from the group consisting of phenyl and alkyl with from one to five carbon atoms, and the alkali, alkaline earth and ammonium salts of such compounds which have a carboxylate* or tetra-201-5,-yl group, is produced by reducing the C15-keto group in et pyrrolidone intermediate with the structure where A, B, Q, R,2 and Rg are as indicated above. 3. Process for the preparation of a pyrrolidone compound with the structure I as stated in claim 1, where Q is. -C0NHR4, characterized in that it comprises: to form a C-15-tetrahydropyran-2-yloxy derivative of a pyrrolidone compound of the structure I as set forth in claim 18, wherein Q is -COOH, treating said tetrahydropyran-2-yloxy derivative with a reagent of the formula RgCONCO or R5 SO2 NCO where R, is as set forth in claim 18, and removing the C-15-tetrahydropyran-2-yl grouph to form a C-15- hydroxyl group. 4. Method for preparing a pyrrolidone compound with the structure and the C5 epimer thereof, wherein: G is selected from the group consisting of ay -CQOR3, tetrazol-5-yi, N-(acyloxymétyi)tetrazol-5-yl with from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl, N -(tetrahydropyran-2-yl)tetrazOl-5-yl and -CONHR4 , Å is a single or cis double bond, B is a single or trans double bond, 1*2 is selected from the group consisting of α-thienyl, phenyl, phenoxy, monosubstituted phenyl and monosubstituted phenoxy, said substituents being selected from the group consisting of chlorine, fluorine, phenyl, methyl, trifluoromethyl and alkyl with from one to three carbon atoms, Rj is selected from the group consisting of hydrogen, alkyl with from one to five carbon atoms, phenyl and p-biphenyl, R4 is selected from the group consisting of -COR^ and -SO^Rjj , where R'j. is selected from the group consisting of phenyl and alkyl with from one to five carbon atoms, characterized in that it includes: condensation of a pyrrolidone intermediate with the structure where G and A are as defined above, with a lithium, sodium or potassium salt of a phosphonate having the structure where R 2 is as indicated above and alk is an alkyl group with from 1 to 3 carbon atoms. 5. Process for the preparation of a pyrrolidone compound with the structure III as stated in claim 4, where Q is -CONHR^ , which comprises treating a pyrrolidone compound of structure III as set forth in claim 4, where Q is -COOH, with a reagent of the formula RgCONCO or RgSC^NCO where R5 is as set forth in claim 4. 6. Process for the preparation of a pyrrolidone compound with the structure I as stated in claim 2, where Q is -COOH, characterized in that it comprises hydrolyzing a pyrrolidone compound with the structure I as stated in claim 2, where Q is -carboalkoxy, carbophenoxy or carbo-p-biphenoxy. 7. Method according to any one of claims 1 and 2 for preparing a pyrrolidone compound with the structure I as stated in claim 2, where Q is -carboalkpoxy, carbophenoxy or carbo-p-biphenoxy, characterized in that it comprises esterifying a pyrrolidone compound of structure I as set forth in claim 2, wherein Q is -COOH. 8. Method according to claim 2, characterized in that it is phenyl or phenoxy. 9. Process according to claim 8, where Q is -COOR^ or tetrazol-5-y1. 10. Method according to claim 9, where A is a single bond, B is a trans-double bond, Q is -COOH and U is and the configuration at C5 is a. 11. The C5r epimer of the compound prepared according to claim 10. 12. Method according to claim 9, where A is a single bond, B is a single bond, Q is -COOH, u is and the configuration at C5 is. a. 13. The C5 epimer of compound produced according to claim 12. 14. Compound, characterized in that it has the structure: pg the C5 epimer thereof, where: W is selected from the group consisting of , tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl with from two to five carbon atoms in the acylbxy group, N-(phthalidyl)tetrazol-5-yl and N-(tetrahydropyran-2-yl)tetrazol- 5-yl, A is a single or cis double bond> B is a single or trans double bond, R 2 is selected from the group consisting of α-thienyl, phenyl, phenoxy, monosubstituted phenyl and monosubstituted phenoxy, said substituents being selected from the group consisting of chlorine, fluorine, phenyl, methoxy, trifluoromethyl and alkyl with from one to three carbon atoms, is selected from the group consisting of hydrogen, alkyl having from one to five carbon atoms; phenyl and p-biphenyl, and the alkali, alkaline earth and ammonium salts of such compounds having a carboxylate or tetrazol-5-yl group. 15. Compound, characterized in that it has the structure and the C5rrepimer thereof, where: A is a single or cis double bond, W is selected from the group consisting of , tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl with from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl and N-(tetrahydropyran-2-yl)tetrazol-5- the y1 group, N-(phthalidyl)tetrazol-5-yl and Nr(tetrahydrpyran-2-yl)tetrazol-5-yl, and is selected from the group consisting of hydrogen, alkyl having from one to five carbon atoms, phenyl and p-biphenyl. 16. Connection according to claim 15, k a r acts in - sert in that W is 17. Compound according to claim 15, character i-S e r t e d that W is tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl or N-(tetrahydropyran-2-yl)tetrazol-5-yl. 18. Compound, characterized by the structure and the C5 epimer thereof.