CS202058B2 - Process for preparing derivatives of 7-aminocephalosporanic acid - Google Patents

Abstract

Valuable antibiotics are obtained by reacting a compound of the formula <IMAGE> in which R<1> is acyl, or a salt or a readily hydrolysable ester thereof with 5-mercapto-1-tetrazoleacetic acid. The latter can be prepared by reacting sodium azide with an isocyanate of the formula ROOCCH2NCS and hydrolysing the resulting thiol ester.

Description

The present invention relates to a process for the preparation of 7-aminocephalosporanic acid derivatives of the general formula I,

H ₂ N-CH-S S - Y o = 6 -

COOR í

CH ₂ COOH where R is hydrogen or a residue of a readily hydrolysable moiety such as a pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacylic group, as well as the corresponding salts, characterized by treating or reacting with 7-aminocephalosporic acid or its Schiff base ester, or to the corresponding salt by a compound of formula ^{MS cis}

wherein the resulting compound of formula I, including the corresponding Schiff base, easily hydrolysable ester or corresponding salt, provided that if a salt, easily hydrolyzable ester or Schiff base of the compound of formula I is formed in the reaction, such a compound is converted using otherwise known methods to a compound of formula I.

Preferred intermediates are the 7-aminocephalosporanic acid derivatives of the formula Ia,

COOH

AND

COOH wherein ^R 'is hydrogen or an acyl group, as well as the corresponding ester, or non-toxic and pharmaceutically acceptable salts.

The esters of the compound of formula (Ia) include those containing a group of the formula

Z wherein W is hydrogen, Z is lower and lower, benzoyl, naphthyl, furyl, thebenzoyl, methylbenzoyl, halobenzoyl, phenylbenzoyl, N-phthalimiacuino, N-phthalimiacuino, N-phthalimiacuino, N-phthalimiacuino, N-phthalimiacuino, N-saccharide, lower N-alkylcarbamoyl, lower alkoxy, lower alkyl-urea, phenoxy, carbonylbenzyloxy, carbamoyl, benzyloxy, lower alkyl, cyclohexyl, alkoxy, butoxybenzylcarbonyl, cyclohexylbenzyl, cyclohexylbenzylcarbonyl, cyclohexylbenzylcarbonyl, cyclohexylbenzyl, is alkoxycarbonyl, Z is alkoxycarbonyl, and when W is phenyl, Z is benzyloxy or cyano, or W. and · Taken together! A 2-oxocycloalkyl group; 4 to 8 carbon atoms.

Preferred compounds of the present invention include alpha-alkylcyclohexyl ethers, acetoxymethyl esters, methoxyethyl ethers, acetonosteres, phenacylesters, o-nitrobenzyl esters, beta, beta, beta-tricycletyl ester, beta-adrenoic esters, or compounds of the formula I-5-esters or 5-esters.

As described in more detail below, the invention also relates to salts of said acid. Sterility of the acyclic nucleus corresponds to the stereochemistry! οefjlcsocridt C.

Acyl Sapina ^ ^R ^ includes the ujpení ^D, but uvedenýc ^h structures without their list exhausts ^ ICI:

(i) A moiety of the formula ## STR2 ## represents an aryl radical, which is a carbocyclic or heterocyclic group, a cycloalkyl group, a substituted aryl group or a substituted cyclic alkyl group, or a non-aromatic or meso-active ether group, n is 1 to 1; 4. · Examples of groups of this type are possible. mention may be made of phenyl or methyl, e.g., phenylphenylacetyl, nitrophenyl, acetyl, aminoCenylacetyl, beta- (c-aminomethylphenyl) acetyl, c-amino-methylphenylthiocetyl, o-, m-, m-, p-, m-, m- and p-methyl; -, and p-jminoIImehylfeIVlacetyloíOU, jcetcxyfe] nllacetylcícu, methoxy} χУ'eenУ.acetylovcu, meehylfenyljcetylovou or Уy (aro2χУeInl · ^ace tylcvcu further group Ν, Ν-bit- (2-cУlcretУyl) mlincfenylpropionovou, 2-and 3-thienyljcetlΓovou tyienylacetylovou, 4-iscxazolllacetllcíou optionally substituted 1-οyklcУexennlajetylovou 2-jninovetelyl 1-cylloУexeenlacetylcvou, 1, 4-cyklcУexadienyljcetylcíCU, 2-amino another ethyl-1, 4-οyklcУexadienylaοetllcíot, oУ ^г iayljcetylovou, tetrazclllacetyCoíct or other Уeterccyklicky substituovjné jcetylové groups of this type as described in U.S. Patent Nos. 3,819,623 and 3,516,997, or a synyl ion as described in U.S. Pat. U.S. Patent Nos. 3,681,328, 3,530,123 and 3,563,983.

The substituted 4-isopropyl group may be 3-aryl-5-methyl-5-methylsulfonyl-4-yl group, the aryl radical being, for example, phenyl or phenylphenyl, for example chlorophenyl or bromophenyl. An acyl group of this type is 3-o-cyclophenyl-5-methylnithoxy-4-yl-methyl, and another similar group is wherein the core is replaced by an internal core as described above. No. 3,551,440.

Other acyl groups of this type include the cyaracetyl group and the like as described in U.S. Pat. No. 3,719,673, hereinafter. 3,5,7-triaza-1-azonia-1-adamentylacetyl, as described in U.S. Pat. No. 3,720,666, and 9-amininopyyidinium acyl, as described in U.S. Patent 3,757,013; -, m- and β- (2'-mitethethetyl) fetylccetyl, as described in U.S. Pat. No. 3,759,905, 4,5-denethopyloxycarb-1,2, triazol-1-ylacetyl, or 4- (8,8) -diethyl-1-ylacetyl; 2,3,3-azazol-1-ylacetyl; as described in U.S. Patent 3,821. 206, imidazole-1-acetyl, as described in U.S. Pat. No. 3,632,810, p-amino-imidazolyl-acetyl, as described in U.S. Pat. This is described in U.S. Pat. No. 3,382,241, .beta.-amino-4'-.beta.-p-hydroxyoxyphetylcetyl, as described in U.S. Pat. No. 3,823,141, being α- (imino-methylphenyl) piperidine, as described in U.S. Pat. No. 3,813,391, alpha-quinopropane, 4,6-cyclohesylmethylationyl, as described in U.S. Pat. No. 3,539,562, and a lower alkoxycarbonylacetyl group, as described in U.S. Pat. No. 3,557,104. ....

(ii) Further, it may be a moiety of the formula wherein - is 1 to 7, the alkyl group may be straight or branched and, if necessary, may be interrupted by the introduction of an oxygen or sulfur atom, or may be substituted, for example cyano group. Examples of such groups include cyanoacetyl, hetoxyl, heptetyl, pktatoyl, butylthiocetyl, and the like. triftPimethylthioacetyPovpu;

(iii) Further, it may be a moiety of the formula ^С п ^Н 2о-1 ^С О "> where n is 2 to 7, the alkenyl group may be branched or straight and, if desired, may be interrupted by the introduction of an oxygen atom or sulfur. By way of example, the group cl111hhpoacelyPovpt.

(iv). It can also be a grouping of the general formula. R ^v

IR ^U OC-CO-

AND

R ^w where Ru has the meanings given in (i) above and may additionally be a benzyl group, and R ^v i Rw whose meanings are the same or different mean! hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such groups include the phetoxyacetyl group. 2-Fetyl-2-fetylpentyl, 2-phenoxypropiotyl, 2-phenoxybutylPVOU, benzyloxycarbonyl, 2-methylP-2-fetylpiperopiotylPvpu, p-kiesoxyactylpvpu and p-methoxytetyl. _in

K * и ¹

R ^U SC-CO- ·

Even RW (V) or may be grouped by the general formula wherein R has the meaning given above. (I) and in addition R may be a benzyl group, and ^R and Rw maj defined under (iv). Examples of such groups include S-Fetylhexylpiperidine, S-chlorophenylthiocyclyl, S-flupifethylthipacetyl, S -benzylthipacetyl, S-benzylthipacyl, paOnntPVém Patent 3,663,540, kyaomnthУ.thipccntyPpvpu _J as described in f Rinco ouusském patenopvém Patent 2,194,417, 4-pyindllthioacetylpvpu, as described in and RRI ^^ ^ c ^ k ^ e ^ m pcOenPpvém Patent 3,503,967 and a cyclo-subscribing mercapto-p-ethyl group as described in U.S. Pat. No. 3,627,760.

(vi) It may further be a moiety of the formula R ^C ^^^CO,, where R ^u má has the meanings given in (i), and may additionally be benzyl, ZZ is oxygen or sulfur and m is 2-5. An example of such a group is the 3-benzylthippropylpiperidine group.

202058 4 (vi ±) The grouping of the formula rUcO-, where R ^u has the meanings given in (i), is considered. Examples of such groups include benzoyl, optionally substituted, for example aminobenzoyl, 4-isoxazolylcarbonyl, optionally bath, cyclopentanecarbonyl, saturated carbboinyl, naphthoyl, optionally substituted, for example, 2-ethoxynaphthyl, quinoxalirylcarbonyl, optionally substituted, e.g. a 3-carboxy-2-quinoxalylcarbonyl group.

Other possible benzoyl substituents are alkyl, alkoxy, phenyl, optionally substituted with carboxyl, alkylimide, cycloalkyrmidide, allyamide, lower phenylalkyamide, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarboryl, tetahydropyridine, N-furfuryamide or their, or furfuryamide derivatives, or their derivatives. and these substituents may be in the 2-position or in the 2- and 6-positions.

Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylaminobenzoyl and 2-carboxybenzoyl. · If R ^u is substiu ^^^ ^ c ^ ou an isoxazolyl group, may be of such a substituent, the list mentioned in point (i). Examples of such substituted 4-isoxazal groups include 3-phen-1-methoxyl-oxazs-4-ylcarbonyl, N-chlorophenyl-4-methylisoxazol-4-ylcarbonyl and 3- (2,6-dichlorophenyl). -5-methylisoxazol-4-ylcrumboxyrl.

(vili) The grouping of the general formula is also possible

^For the R-CH-CO- or -CH-R C -CO

XX ^{wherein R} is as defined in (i) and X is the hydrazine, guanidine, ureide, thioureide, and thioureide substituted, as described in U.S. Patent 3,741,962, alloammide, as described in U.S. Patent 3,483,188, 3-gueyl-1-ureide, as described in U.S. Pat. No. 3,779,01, 1-anamide, as described in U.S. Pat. No. 3,796,709, an amino group optionally sub-labeled, for example acyl. Ldino or a group formed by the reaction of the amino and / or amino groups of the side chain at the -7- position with an aldehyde or ketone, for example, fojmaldehyde, acetaldehyde, butyraldehyde, acet, γ, α, α, α, α, α, methyl, acetoaceamide benzaldehyde, salicyalldehyde, acetone, methyl ethyl ketone or ethyl ester of acetoacetic acid, a hydroxyl group or a carboxylic acid group as described in U.S. Patents 3,282,926 and 3, respectively. 819 · 601, et al a fixed carbsxyl group as described in U.S. Pat. No. 3,635,961, a triazolyl, triazolyl, cyano, halogen, acyloxy group, such as an O 10 -O-1-group or the like. Whether an alkanoyloxy group or an esterified hydroxyl group. Examples of such acyl groups include alpha-4-inophenylacetyl, alpha-5-oxo-phenylacetyl, 2,2-dimethyl-5-oxo-4-olyl-1-imidazolidinyl, alpha-aminopiperolyl]] a .alpha.-amino-.beta.-amino-.beta.-acetoxyphenyl acetyl, .alpha.-hydroxy-phenylacetyl, and .alpha.-oxo-phen-acetyl or other acyl groups of said t-pu, as described above. See, for example, U.S. Pat. Nos. 3,812,116 and 3,821,017, and alpha-amino-3- or -3-thieryl acetyl, see U.S. Pat. No. 3,342,677, and alpha-mino-3-. or -4- or -5-18-thiaziazl-lacetyls, see U.S. Pat. No. 3,779-06, as well as other alpha-mino- and alpha-hydrox-heterocyclic-substituted acetyl groups, as described, for example, in U.S. Pat. 821 · 207.

(ix) Further, it may be a grouping of the formula rM-coti

202058 where phi ^x , _and r ² , which may have the same or different. denotes a lower alkyl group, a phenyl group optionally substituted. An example of a flow acyl group is the triphenylcarbonyl group.

(x) Further, it may be a grouping of the general formula

R ^u -NH-CH

Y ⁱⁿ which R has the meanings that are mentioned under (i) and may additionally be a hydrogen, lower alkyl or halogen, furthermore stbstituovεnюu lower alkyl group, and Y represents oxygen or sulfur. An example of such a group is Cl (CH ₂ ) ₂ NHCO.

(ii) Further, a group of formula

wherein X has the meanings given in paragraph (viii) hereinabove, and n represents a number from. An example of such a acyl group is 1-aminocyclohexanecarbonyl.

(xii) Aminoacyl groups, such as a group of the general formula, are further suitable

R ^w CH (NH ₂ ) - (CH ₂ ) _n -CO-, where a is from 1 to 10, or

HgN-Cn ^ nArCHg ^ CO, wherein m is 0 or a number from 1 to 10, and n is 0, 1 or. 2, R ^w represents a hydrogen atom or an alkyl, aralkyl or carboxyl group or group as defined in relation to R a above, and Ar represents an arylene group, for example a p-phenylene or 1,4-naphthylene group.

Examples of such groups are given in British Patent Specification No. 1,054,806. Such a group includes p-aminophenylacetyl, and other acyl groups include, for example, the delminoadipolyl group derived from naturally occurring αInclines, and derivatives thereof. , for example, 4-benzyl-delta-εminoadipoyl.

(xiii) Substituted glyoxyl groups of the general formula are further suitable

R3 is CO.CO-, wherein R3 is aliphatic, araliphatic or an aromatic group, for example a thienolyl group, further a phenyl group; optionally mono-, di- or tritubstituted, wherein the substituent may be one or more halogens, i.e. fluorine, chlorine, bromine or iodine, methoxy or methyl, or amino. or it may be a fused benzene ring as described, for example, in U.S. Pat. Nos. 3,546,219 and 3,573,294;

(xiv) Further, a grouping of the general formula is contemplated

HOOC-CH- (CH ₉ ) - Cl ^{2 3} 'II

NH O

I c = o

AND

OR wherein it is a lower alkyl group or an aralkyl group of formula

wherein n is 1 to 6 and R ¹⁷ and R ^1f are the same or different substituents and may be hydrogen, chloro, bromo, fluoro, nitro, lower alkyl or lower alkoxy.

(xv) In addition, a grouping of the skin pattern is possible

HOOO -CH- (CH ₀₎₎ - C | ² 3 II

NH O bo

AND

N

9 wherein R ¹ represents a lower alkyl group or a group of the formula

where n represents 0 to 6 and r '? i r ' ⁸ , which may have the same or different meanings! hydrogen, chloro, bromo, fluoro, nitro, lower alkyl or lower acetoxy.

(xvi) He continued to look soeen

HOCO-CH- (CH ₀ K-Cl 2 3 II

NH 0

R20 where Rp is an alpha-haoogeneno or 20 to 2 to 4 carbon atoms, or R is written in U.S. Pat.

-HN ^Z

\ ²²

The alpha, alpha-dihonyl group of the alkanoyl group of the N-isobenzyloxycarbonyl group as it is

619, or R is a group of formula or ^b- o-c- ^o - ^r23 .

wherein Rp ¹ or R 6 is hydrogen, lower alkyl, phenyl or halogen; X is oxygen or sulfur, and R is lower asyl, as described in U.S. Pat. No. 3,819,621, or R is hydrogen, which corresponds to Eephalosporin H. " (xvái) It may also be a grouping of the general formula

R ^u -CH = COI

NH l

Y = C

AND

H = N-C-Z

II

X wherein rU has the meanings as given in (i) above, X is oxygen or amino, Ϊ is oxygen or sulfur and Z is lower alkyl, cycloalkyl having 4, 5, 6 or 7 carbon atoms, a lower monhalogenated alkyl group, a dichloromethyl, a trichloromethyl group or a lower alkenyl group having 2 to 6 carbon atoms;

CH

енэ^kde. n stands for^and 0 to 3 a^toand^ždý from R symbols^P and⁺ means^and hydrogen ni.troslupi.ni, lower dial^toyl amino, lower alkanoyl-amino, lower alkanoyloxy, lower alkyl, including straight and branched chains, saturated with 1 to 6 carbon atoms, lower alkoxy, sulfonyl, chloro, iodo, bromo, fluoro, or trifluoromethyl. According to a preferred embodiment, rU is phenyl, p-hydroxyphenyl or 2- or 3-thienyl and Z is 2-fuoyl or phenyl.

Examples are given in U.S. Patents 3,687,949 and 3,646,024.

(xviii) A grouping of the general formula or

CHa-co-

or

Z-C-NH-CH2-COII

NH v

Ί

⁸ 202 058 ⁱⁿ which R has the meanings jak'byly mentioned under (i) and Z has the meanings as mentioned in (xvii); examples are described in U.S. Patent Nos. 3,626,024 and 3,692,779.

(xix)

R ^u -CH-CO ¹

SCR ²⁴ by II ⁱⁿ which R has the meanings ^kb yl ^y I mentioned under ⁽ⁱ⁾ and R ²⁴ represents ^a lower alkyl with ^the UPIN, cycloalkyl, aryl or any heterocyclic radicals. Examples are described in U.S. Pat. No. 3,778,436.

In a preferred embodiment of the present invention, a compound of formula I, ^w e ^r1 is the radical S-truXtury _{CH2 NH2}

Q- CHj — CO—

CH2MH ₂

HIM

CH2 "COCH2NH2 ^ {3- CH2COCH2NH2 ^<Q 4-CH ² -CO-

CH2NH2

CH2NH2 (j ^ H ^ CO--)

CH2NH2 <^ ~ У СН2СН2СОCH ^2-NH2 <^ Q4-CHjCH ODalším preferred embodiment of the present invention are compounds of formula I with a configuration · · ^ -D- strannllho chain ^of RET at position ^- 7 ~> wherein ^R 'is stouHurn

HOCH2

CH 3 CO-O-hQ-ch-CO 1 <1 N ₂

си, сн-со ² Ι

NH ₂ сн ₃ о

CH ₂ CH-CO ₂ H ₂

Qhch-cqnh ₂ nh ₂

Dedším preferred embodiment of the process according to the invention are compounds of formula 'I, kortfigurací -D- postrenního chain oloze -7- ^{p kd} e ^R1 is structurally hike

RJ-fH- ^"5 -OH wherein Ϊ represents hydrogen, chloro, bromo, fluoro, sku ^P inu trilluoraietlylovou, amino, a nitro group, a hydroxyl group or a lower alkyl or altoxylovou SKU ^p yne with 1 to 4 carbon _ atoms.

Another preferred embodiment of the present invention represent · a compound of formula ^d to e ^R1 is ^a a-structure bytek

CH ₂ NHCH 3 γ-CH 2 OCH 2 NHCH 3

HIM

CH2NHCH3

CH2MHCH3

QCOCH2NHCH3

CH2NHCH3 < y-CH2CH2CO202058

CH ₃ NHCH ₃ / Vch ₂ ch ₂ co-

СН _а МНСНз

CH ₂ CH ₂ CODalší preferred embodiment of the present invention relates to compounds of formula I, ^to de K ¹ st residue corresponding to ^A-ru-Ury

^ 2 ^ -O — CHiCO— QT ^CH2CO-

1 H -S-CH ₂ COCH ₂ COCN

co — nH2 _K or ° F7A O “N-CH2CO \ _N /

Another preferred embodiment of the present invention relates to compounds of formula I wherein: means useless ^{to the} structure

CH3NHCONHCCO-Z ^d «Ъ-со-

CH 2 NHCONHCO-Z ^H O- £ A- (H ₂ -CO ₂ NtCONHCO-Z

CH2COCH3NHCONHCO-Z

CH ² COjh ₂ nhconh <coz <fj / ~ ^S -CH ₂ COdCHoNHCONHCO-Z

CH ² CH ² Z + COCH2NHCONHCO-V-Z-CH2CH2COCH2NHCONHCO <^^ ^CH 2 ^CH 2 ^CO 'wherein Z is lower alkyl, cycloalkyl s'4, 5, 6 or 7, C atoms, a monohalogenated lower alkyl. a dichloroalkyl, trichloroethyl or lower alkenyl group having 2 to 6 carbon atoms, and a group of the formula

(CH ₂ ) n -

where n is ⁰ to 3 and each of ^R and ^{R is} hydrogen, nitro, lower dialkylamino, lower alkanoylEmino, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfmyl, chloro, iodo, bromo, fluoro or trilluomethyl . Most preferably, Z is phenyl, 2-thiyl,

3-thienyl, 2-fuoyl or 3- (1-yl) -2- (1: 0) -10%.

Deú.ší preferred embodiment of the present invention, · provides compounds of Formula I with D-IRAC koofi postřeného strings in ^p oloze -7 ^- přičmŽ ^R · has Lou ^ ^ ueu:

θ- ^ И-СОNH

AND

OC-NH-CO-Z

NH

AND

OC-NH-CO-Z

AND

OC-NH-CO-Z

(Усн-со- NH θ-CH 1 -CH-CO-T ^H OC-HH-CO-Z СНзО-ЛЛ-СН ₂ -СН-СО- | 0-CH-CO- N H ОС — NH — CO — Z OC-NH-CO-Z Q-CH-CO- NH AND в-r-CH-CO- ^and Οψ OC-NH-CO-Z

ОС — NH — CO — Z wherein Z denotes a lower alkyl group, a cycloalkyl group having 4, 5, 6 or 7 carbon atoms, a monohalogenated lower alkyl group, a dichloro-methyl group, a trichloro-methyl group or a lower alkenyl group having 2 to 6 carbon atoms , further

• э A where n stands for 0 to 3 and each. and the symbol · represents hydrogen гов о ^ ^ ^^ р Oiz ^br dialkylamino, lower alkanoyleminoskupinu · alkanoyloxyskupiou lower, lower alkylovou'nebo. lower alkeoyl group; a chlorine, iodine, boom, fluorine, or trillloryl group. According oe.jvýho (áoéjšíhc embodiment, Z is phenyl, Z-thierylovou J-TMEn-salicylic, 2-or 5-fuoylovcu oitrc-2-fl · orylovcu. ⁴

Another preferred embodiment of this invention relates to compounds of formula I for e ^d zolimen ^and the residue of general formula ^

Н00С-СН- (СНр) з-С1

I ^J

ΝΗ

I co

wherein R ¹ represents a lower alkyl ®. or an aralkyl group of formula

wherein m is 0-6 and both R ¹⁷ and R ¹⁸ have the same or different meanings. in otia. The cases may be hydrogen, chloro, bromo, fluoro, nitro, lower alkyl or lower alkoxy.

A further preferred embodiment relates to compounds of formula I wherein r 'is a radical of formula.

HQOC-CH- (CH ₂ ) ₃ -CO "

NH

I co

AND

NH '

Ř ”. with

Wherein R represents a lower alkyl group or a group of general formula

Wherein m is 0-6, and R 'and R' have the same or different meanings and are hydrogen, chloro, bromo, fluoro, nitro, lower alkyl or lower alkoxy.

A further preferred embodiment of the process of the present invention relates to compounds of formula I wherein R 6 is hydrogen, pivaloyloxymethyl, acetoxy, methoxymethyl, acetonyl, phenacyl, p-nitrobenzoyl or teta, teta, tetrichontonyl, and wherein r 'means the rest of the structure

CH ₂ CO-

<h, nhJLnh-Lz

Qh-hh ₂ co-JW ^o- f

CH ₂ -NH-NH-Z-I

QS-CH ₂

V. X

CH 3 NH-4-KM-4-Z 1 J-CH ₂ CH ₂ CO-

CH ₂ CH ₂ COch ₂ nh-1nh-β-Z ₂ -CH ₂ CH ₂ CO wherein X is oxygen or imino, Y is oxygen or sulfur and Z is amino, lower alkyl, cycloalkyl having 4, 5, 6 or 7 carbon atoms, monohalogenated alkyl, dichloromethyl, trichloromethyl, lower alkenyl of 2 to 6 carbon atoms, and the remainder of the formula

CL o гт V V "IN σ Q ^CH 3 1

wherein n is 0 to 3 and each of R ³ and R 6 may be hydrogen, nitro, lower dialkylamino, lower alkanoylamino, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chloro, iodo, bromo, fluoro or trifluoromethyl group.

Another preferred embodiment of the process of the present invention relates to compounds of the general formula

2 ее I wherein R ^J is hydrogen or methoxy, n is 1-9, R hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, aminobenzyl, acetonyl, phenacyl, p-nitrobenzyl or beta, beta, beta-trichloroethyl, and wherein side chain position -7 has the configuration -D-, while R ¹ has the structure

CH ^ CO-

15 '

Another preferred embodiment of the process of the present invention relates to compounds of formula (I) wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl. an acetonyl, phenacyl, p-nitrobenzyl or beta, beta, beta-trichloroethyl group, the side chain at the -7- position having the D- configuration, where R 1 represents the remainder of the structure

Q-CH ₂ CHCONH

Y = C-NH- (pZ

О "

NH

Y = C-NH-C-Z

CH ₃ O

with ₂ = Y = C-NH-CZ

Y = C-NH-C or

IQLch-coNH

AND

Y = C-NH-CZ wherein X is oxygen or imino, Y is oxygen or sulfur and Z is amino, lower alkyl, cycloalkyl having 4, 5, 6 or 7 carbon atoms, lower monohalogenated alkyl, dichloromethyl, trichloromethyl or lower alkenyl of 2 to 6 carbon atoms, hereinafter

wherein n is 0 to 3 and each of R _{6a is} hydrogen, nitro, lower dialkylamino, lower alkanoylamino, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chloro, iodo, bromo, fluoro or trifluoromethyl.

Another preferred embodiment of the process of the invention are compounds of formula I wherein R ⁵ has the D- configuration at the alpha-carbon atom and has the formula

NH

AND

AND

NH

AND

AND

C, XchcoNH

AND

Or

JQLch-coNH I A where A means

wherein Z is lower alkyl. alkyl, cycloalkyl having 4, 5, 6 or 7 carbon atoms, .monnhalogenovanou lower alkyl, dichloromethyl, trichloraethylovou, lower alkenyl having 2 to 6 carbon atoms, also a radical of formula or formula, ^'ХУ КН 21st ^-

AT- П ГТ NN CH ₃ TT in and v

t

^{СНз тт} '%> ^CH 3 wherein ⁿ is ^{A 0 and} 3, and each of ^b ecnýc ^{H, R} and ^R ^ is hydrogen Known slag ^ j-nu NIZW dillkyl · minosklpinl lower alkanoyl.aminoskupinu lower llklnoyluxysklpinu ·, lower alkyl , which may be branched and straight and contains up to 6 carbon atoms, a lower alkosyl group, a sulfimyl group, a chlorine, iodine, a bromine, a fluorine or a trilluoroaietyyrlovul.

Another preferred embodiment of the invention are compounds of formula I wherein R is hydrogen, pioeloyloxymethyl, acetoxymethyl, methomethyl, ethyl, ienacyl, p-nitro-benzyl or bet1, bet1, bet1-O1Co0o0oethyl and ^r1 . ^o is ^1- enylcetyloo ^, o-, m- or p -fluorophenylcetyl, o-, m- or p-rithiophenylacetylool, o- m- or p-acetoxyphenylacetyl, o-, m- or p-methoxyphenylacetyl, o-, m- or .beta.-methylene phenyl acetyl, o-, m- or .beta.-hydroxyferyl acetyl,

Ν, N ^- bis- (2-chloroethyl) ylthienylpropionyluuu, thiene-2-lcetyloouu, thien-3-lcetyluouu,

4-isoxazolyllcetylooou,

1- (1) -butyl-1-ethyl,

1,4-cyclehexadienyllcetyluoul, pyridyllcetyloouu, sydnonactyl,

3-o-Chloro-phenyl-3-methyl-ethyl-isoxyl-4-yl-ethyl, cyanacetyl,

3,5,7-Amino-1-isol-4-ylmethyl-ethyloacetyl, m-enylilino, o-, m- or p- (2'-aminoethoxy) phenyl-ethyl,

4,5-dimethoxycarbonyl-1,2,3 'toiazul-1-ylceetyl,

4-cyano-1,2,3-triazol-1-ylacetic acid,

1-: thiazoleacetyllool, m- and β-aminomethylphenylacetyl, alpha- lmino-2,4,6-C1-heptatoienyl acetyl, lower alkoxycarbonylacetyl, kylnacetylooul, hexanoylool, heptanilinoethyl, uctyl, thioacetyl, uctolyl, uctolyl, ethyl acetate, ucetyl, ethyl acetate, ucetyl, ethyl, ethyl, ethyl, ethyl methyl thioacetyl, 11-methyl, phenoxyacetyl,

2-phenoxy-2-phenylacetyl,

2-nono: for ^{R <n} ^ ions _verifies>

2-Nonexybeters Vouou, b-nylonecarbonel

2-tet2y2-2-nynopyyroyionic, p-kr-sonoac-Celovov, p-me-hyothiof-nonoac-Celov,

S, C, H, C,

S-ch.or2enolthiУacetylovyvJ

S-fluoro-nonthioactyl, pyridolthiyacetylyv,

S-benzyethiyaceColУVУU, p-aminometCh02-nylChioaceoOvУOUo ke.aø-hyththyac-Celova,

4-pyridolthioacetyl,

5-b-nylChiopropionel, benzoyl, aminobenzoyl,

4-isoxazolylcarbynel, cyclypocarbonol, sondornocarbonyl.

naftoelovou,

2-cyanone2Cyolonov, quinonalinolecarbonol,

1-carbones -? - quinoxaline-carbonel,

2,6-eiICh0ne: btbenzoyVovyu

2- 2t2oϊklkaУbonyVouou, .-

2-methyleuninobenooylyvyu,

2-carbonobenzoyl,

3- (2-methyl-5-methyl-isoxol-4-ylcarbonyl) -3- (2 *, 6'-dichlorophenyl) -S-eetholisynazol-4-ol .

The preferred embodiment of the process according to the invention is a compound of the general pattern where the remainder of the general pattern is ₂ cokd. Z is lower aminoalkel, lower N-alkenyl-alkanol (with both lower alkyl), n- or Ν, dial-dialkylminoalkyl with all lower alkyl, lower 2-amino-alkylalkyl, lower 2-non-alkylaminoalkyl ( With both alcohols (lower (lower)), a further substituted lower 2-non-alkynyl group or a 2-nonalkynyl alkenyl group having both lower alcol residues, the substituted phenyl group having the general formula

2 kd- X and X are the same or different and may be hydrogen, fluoro, chloro, bromo, lower appel, lower alkonel, nitro, amino, Cl 2 -fluoromethyl and phenyl, or R is о «-) у ^ - $ - ₂ сн соnebo ^R1 is wherein n is 1 or ^{R1 cording} ene ^and groupings of the general formula / N tCH2) _n CHjCO-

NH 2, with ^the UPIN ^b Proceed with the ^H of the formula _IB-CH2 -cokde Z represents a radical of the formula or

O wherein R represents lower alkyl, lower alkenyl or lower alkirylovou group, not a ^{b R1} - means ^{p s} --Oga OF ECN ^{b eh} of formula

^kd e R, ^R1 and ^R1 may represent ^Z, a ni ^ alk groups verifies lower al.ken ^y ^ verifies quick match 3, Ni ^Z, a lower alkynyl group or a cycloalkyl group and can also be hydrogen ^for, or ^R is ^the group in general ^oh o formulas

X

^to de X represents fluorine or chlorine, ^b not on ^R1 is ^a group of general formula ^

BCS-CH ₀ -CII ² II

X o where X is oxygen or sulfur,

B represents lower dialkylminoskupinu wherein alkyl-oic acid residues may be identical or different, · further group pipnridinozcu, meethypipericlinovou, dimentuУ-piperidinozou, pyгrclidinozou, pyrгceidinozcu, dimetluДpyIccolidinovou, moofolinovou, men. ^ UУmoo: CoOlnovou, dimetuyemoofolincvou lower Ν ^of -alkylpipnrazinczcu, lower N ^of -alkyl-methylpiperidine, lower N ^of -alkyld: methyl-piperidine, trimethyleneimino, hexane-ethyleneimino or a radical of formula

Ar- (CH) p NI R ⁷ wherein n is 0, 12 or 3 · R · represents a lower alkyl group and Ar is a radical of formula

R8

O r '

Wherein R6 and R6 may be hydrogen, fluoro, chloro, bromo, lower alkyl or lower alkoxy. ·

N ASI preferred embodiment of the present invention are compounds of formula 1 wherein ^{R b} is yte ^to otecné strukbu ^

R3

CH-CO

OH wherein ^R3 and ^R4 may represent hydrogen, chlorine, toom, ^{Fe UCC,} · ^{SAD, nitro,} lower alk ^y nominal or lower ae.kcxyeovou group, lower alkylthio, lower dialkylminoskupinu, lower alkanoylEminoskupinu lower alkanoyecvou or lower alkylsulfonyldvou group.

Another preferred embodiment of the process of the present invention are compounds of formula I wherein ^R 1 is a radical of the formula

II / P _X

CH ^{2 X} C ^H 3

NH, wherein Ar is a radical of formula

or

taking R? R® and may represent hydrogen, fluoro, chloro, methyl metlioxylovou group Neto SKU yne ^p and ^R3 are hydrogen ^and bromo · No ^b of clťLor.

A further preferred group of compounds of this invention are those compounds of formula (I) wherein ^R 'is

or ^R 'is unnecessary ^to otecnéto formula wherein ^R4 and · may be hydrogen and lower Neto ^LK yloiou Sapin, or ^R' represents a group

No ^{b R} a 'represents ^á Sapiną clad formula

CH ^ X is hydrogen -COkde ^b of not lower ^and a C ^ ^ no pin ^b of ^R4 is a ^{s b} ECN it formula

N == C-CH2 CON N ^«U or a group of formula

N is C-CH ₂ COor a group of formula or a group of formula _R 13-C = H

NM-CH ₂ -CO-

Wherein R 'is hydrogen or lower alkyl, ^R is hydrogen (chloro, bromo, iodo, fluoro, trifluoromethyl, lower alkyl, lower alkoxy, lower alkylthio, carboxymethoxy ₎ lower alkylsulfomyl, phenyl, benzyl, ieauxyfuvu or benzyluxyf and the radicals of the formula wherein ^R and R® may represent hydrogen, lower ^and al. C 3 -C 7, or together with the nitrogen atom = N- represent a heterocyclic ring selected from the group consisting of pyrrulidine, piperidine, moofoline, 1,2,5,6 "lower N-tetrlhlydrupyridinový ιaLkylpiperazinuvý and hexameetyleniminoskupina, AN is ^and 0 to 3j Neto ^R 'represents ^a moiety of formula otoc ^ him

R7

N NX ¹ or

N == N

Wherein R, R ^w and R are hydrogen, nitro, lower dialkylminustopine, lower alkanoylamino, lower alkenoyloxystopial, lower alkyl, lower altoxy, or sulf asylum, chloro, iodo, bromo, fluoro and trifluoromethyl, X and X which may MT meanings of "identical Neto znjmenají different H or ^R '= ^s u ^b sestopení nca ^eh in formula

AND

wherein R ¹⁰ and R 6 can be hydrogen, chloro, bromo, iodo and methyl.

Another preferred group of compounds of formula (I) of this invention are those wherein R ¹ is a moiety of formula

RS-C --- c-what—

where X is a divalent radical such as *

-SA -0- or R ^P and R are lower alkyl, chlorine, bromine or a radical of formula

Where R, R 'and R are hydrogen, fluoro, bromo and chloro, and R 6 is hydrogen, lower alkyl or a radical of formula

wherein R 1, R 10 and R 4 can be hydrogen, fluoro, bromo and chloro, and when bound together to form a fused benzo ring, R 6 and R 6 are vinyl, or R 6 is a hydrogen atom; represents any of the radicals of the general formula

? Wherein R and ^RJ are nitro, lower alkyl or lower alkoxy, lower alkanoylamino, chloro, bromo, iodo, fluoro, hydroxyl, lower alkylthio, cyclohexyl, cyclopentyl, cycloheptyl, lower alkoxycarbonyl. a mercapto group, a lower alkylsulfonyl group, a lower alkanoyl group, a lower alkanoyloxy group, and optionally 3 other radicals of the formulas

Po po 1 after where η 0 to 3> and R. ^v , R. ¹ and R .. hydrogen, fluorine, bromine, chlorine, iodine, trifluoromethyl, lower alkyl, lower alkoxy, hydroxyl, nitro or amino, hydrogen , a lower alkyl group or a radical of formula (I) having the meanings given hereinbefore, R8 'is hydrogen or lower

11 or any of the radicals R 'as defined hereinbefore, R''is lower alkoxy, chlorine, bromine, iodine, fluorine, wherein R ²⁰ , R ²⁸ and R ²² , R ¹⁶ hydrogen alkyl, cyclopentyl , cycloheptyl, or the following two samples zbytky.obecných alkyl and R ⁸⁸ lower cyklohexylo4

wherein n is 0-3, and R ^20, R ²¹ and R ²² bo substituent in a mixture ^ s ^ Lu of the R '' No ^b of ^R 'have the abovementioned meanings and R 8 represents hydrogen not yell it stated hereinabove , zněměná with oup ^to the ECN ^{b eh} of formula

wherein R 23, salicylic, phenylpropyl, furyl, thienyl, naphthyl or a radical of formula and ^{R 2} are 4-ni al verifies Sapin ^alkyl, lower altylthioškubnu, benzyltMosku ^ nu, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, styryl, fenylethy-

p £ p у PO where R., R.. and R. may be hydrogen, fluoro, chloro, bromo, iodo, trífuurraethylovou group, a lower alkyl, lower alkoxyl, nitro, 'meehylsulfonylovou group, a cyano group, a lower dialkylminoskupinu and metthylmerkaptoskupinu, or ^R' is unnecessary ^for the ECN ^{b eh} of formula

3 11 wherein R 8, R 8 and R '.Can means fluoro, methylsulfonyl group, and R ^J *.

hydrogen, chloro, bromo, iodo, trillurmeethyl, nitro, lower alkyl or lower alkoxy means lower alkyl, or R ¹ is α

or

O — R ³⁵ to

wherein R ^PP and ^P R ^ are hydrogen, chlorine, bromine, iodine, trifluoromethyl, and phi represents a lower alkyl or lower alkoxy lower alkyl.

Another preferred embodiment of the process of the present invention are compounds of formula I wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, asethoxylate, phenacyl, p-nitrobenzyl;

AND

CH ₂ N = CH->2y>

CH ₂ -CO or beta, beta, beta-trichloroethyl, wherein

A ch ₂ n = ch- ^} ^HO ~ ^ 3 ~ ^CH 2 ^_C ° -

A ch ₂ n = _C h - <H>

S-CH ₂ CO ₂ n = ch

CH ₂ CH ₂ COA

6CH ₂ №CH-CH ₂ CH ₂ COor

A ch ₂ n = ch CH ₂ CH ₂ CO where A represents hydrogen or a hydroxyl group.

CH ₂

N --- N

AND

C N

AND

CH ₂ COOH

Another preferred embodiment of the process of the invention relates to compounds of the general formula

R 1 -CHC = O

I i ..

N N-HCCH 'I

СНз ^XCH 3 J ^N _{Xc <F} ~ ^CH2 ~ ^{S O 1} 2-C-OR ² II o wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, p-nitrobenzyl or beta, beta, beta-trichloroethyl with in that the side chain at position -7- has the configuration D- and R 6 represents the remainder of the formula

HIM

A further preferred embodiment of the process of the invention are compounds of formula I wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, p-nitrobenzyl or beta, beta, beta-trichloroethyl having the -D- side chain configuration at the - 7-, wherein R ^ has the structure θ-fH-eoN

CH-CH3

H — what—

СНСНз

CH3COO

СНСНз

CHCH3

СНСНз

СНСНз

СНСНз

СО—

СНСНз

У-сн-соN

II снсн ₃

СН-СОN

II

СНСНз

Another preferred embodiment of the process of the present invention are compounds of the general formula

of formula 1 wherein R has the structure R ⁵ Ar-CH-CO- Ar-X-C-CO- Ar-CO- H ⁴ R ⁶

OR ⁷

Ar

CO-R ¹⁰

[* = ^# > »- СООН ^ чЛ-соAr — NH — CX—

Zl

Z ² - C - COR ^{71 -} NH - CX - wherein R ^{4 represents} hydrogen, amino, carbobenzoxyamino, phenyl, fluorine, chlorine, bromine, iodine, hydroxyl, lower alkanoyloxy and lower alkoxy, X oxygen or sulfur _and p6 is hydrogen, phenyl, benzyl or phenethyl or lower alkyl, R 'lower alkyl, R and R lower alkyl, lower alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, phenethyl, phenylpropyl, furyl, thienyl, naphthyl and Ar-; lower alkylamino, lower dialkylamino, C 3 -C 7 cycloalkylamino, allylamino, diallylamino, lower phenylalkylamino, morpholino, lower alkylamino-amino. oyrrolidine, lower alkylpyrrolidine, lower dialkylpyrrolidine, N, N-hexamethyleneimino, piperidine, lower alkylpiperidine, lower dialkylpiperidine, 1,2,5,6-tetrahydropyridine, lower ε-alkylpiperazine, lower N-alkylpiperazine N-phenylpiperazine, lower N-alkyl-alkylpiperazine, lower N-alkyl-dialkylpiperazine, furfurylamino, tetrahydrofupfurylamino, lower N-alkyl-N-furfurylamino, N-alkyl-N-aniline and lower alkoxyaniline; Z ² and Z ^P are lower alkyl, and Ar-, R 6 is lower alkyl, lower cycloalkyl, naphthyl, benzyl, phenethyl and the radical of formula

Ar-CO and Ar are a monovalent radical of formula

^R13 and R ·· can be hydrogen, chlorine, boom, iodo, triLU.uoraet ^ yLlovul ^wh e · ^R12 is phenyl, lower and lower alkyldvou alOuxylovul, but only one of R R may, Fe ^^ Vou group.

(AND)

The present invention also provides a process for the manufacture of antibacterially active compounds of the formula I, $ β '- ΝΗ — CH— (H ^ \ η ₂ NIN)

II-IIII

O == C - N 1 --CH ₂ --S - CN

II

COOH CH ₂ COOH wherein R 'represents an acyl group; the method being characterized in that a compound of formula II is treated

Г П xt-CH _{2 -} SC N

OH CHcOOHH (II) or a precipitating salt, easily hydrolysable ester or Schiff base, such as a reaction product with benzaldehyde or salicylaldehyde (including, but not limited to, the compounds described in U.S. Pat. Nos. 3,284,451 and 1,229,453, or any of the siahaesteoes described in U.S. Pat. No. 3,249,622 when used in desert with 7-aminopenic acid and as used in U.S. Patent No. 1,073,530, in particular, U.S. Pat. , · lcetuxhneehhhaeSee, metholcetu fhaeter ^ _J ^ y ^ female succinate, about ^_ nitoubenzyhaeSer, _J beta beta beta toiceluoethylester _J, 3-and 5-itlaidhlesteo i.ndιllyУestdr, chloriddm organic monoUarbo: χhLové acid or a functional equivalent of said acylating agent such as agent.

Functional periods include acid addition anhydrides, including mixtures thereof. mixed anhydrides and especially mixed anhydrides prepared using other acids such as lower aliphatic monohydric monohydric acid or alkyl esters or sulfonyl esters of sulfonic acids or diphosphonic acid. A particularly preferred anhydride is N-carboxyarniydride (also referred to as Leuchs anhydride, see U.S. Pat. Nos. 3,080,356 and 3,206,455, binding - but without any omme) - D-mandelic acid hydride (see U.S. Patent 3,167,549). and udpouVíalící slbstiluoíané klobuxylnhydridy mandelic acid. Furthermore, it may be an acid azide or an active ester or teiuester (for example, you-nitoofe ^^ ^ 2,4-dinitooienyheeter _J thiofenylester teiouctuíé or ester), or may působbt to the free acid compound of formula II after reacting said free acid with a first Ν N · ^У -dimethylchloiUolШl iminimcelooidem, see British Patent specification · 1,008,170, and further Novak · Weechet, Expoe0entil 21, 360 (1965), or may be enzymes or využžt condensing _Ν> N- ^O- cyclodiimidylzole or Ν, Ν ^/ -Olobonyonyadtoiazoll (see South African patent application 63 // 268 (6)), or reagents from Olobudiimidů groups, especially N, IN-dichOlueexylkarbodiimidu, Ν, Ν'-diiuoproohL 0lrbudiimidu-or N-cyclohexyl-N ^/ - (2-moofodinyldtehl) 0lobudiimidu see Schedhan and Hess, J. and NMR. Chem. Soc. 77, 1967 (1955), or an alkyl amine reagent, see R. Bule and HG Viehe, Angew. Chem., Intern. Ed. 6, 582 (1964), or a salt of the isuxlzium salt group, see BB Wouwald, RA01isun and H. Maaryr, J. Anmr.

Chem. Soc. 8J, 1010 (1961), or a ketenimine reagent, see C.L. Stevenc and MF Funk, J. Aner. Chem. Soc. 80, 4065 (1958), or aexaahaohccotrophosphatriazine or hexabromocyclotrifosphatriazine, see U.S. Pat. No. 3,651,505, or diphenyl sulphate azide, see J.A. Chem. Soc. · 24th 6203 (1972), or diethyliosforylkyanidu see Tetrahedron Letters .1973 (no. 18) 1Í595 or diienyliosfitu, see Tetrahedron 1972 tters L _e (Ref. 49) 5047th

Another equivalent of the acid chloride may be the corresponding azolid, i.e., the acid amide, wherein the nitrogen atom of the amide group is a member of a quasiaromatic five-membered cycle containing at least two nitrogen atoms, such as imidazole, pyrazole, triazoles. Examples of the general procedure for the preparation of azolides include the reaction of the Ν, N ^- carbosylalzazole with a carboxylic acid in a dihydroxide ratio at room temperature in tetralyarofurene, chloroform, dieetylformamide or a similar inert solvent. to give the carboxylic acid imidazole, which is formed in virtually quaternary yields to liberate the oxide of 1 mole of imidazole and from the dicarboxylic acid forms the aziazole. The by-product of the reaction, i.e. imidazole, is formed. precipitates and can be separated from the reaction form with the isolation of the imidazolide, but this Methods of carrying out these reactions to form cefaeosporin, as well as methods for isolating the cephalosporin thus prepared, are well known in the art.

There has already been mention of the offer of enzymes in the reaction of the free acid with the compound of formula II. These methods include the use of an ester, for example the melselster mentioned. free acids with the addition of enzymes produced by various microorganisms, as described, for example, by T. ТакгОгазЫ and spoV. · 3. Αγ ^ γ. Chem. Soc. 4, 4035 (1972) and T. Nara et al., 3. AZibiotics (Japan) 24, 321 (1971), and as described in U.S. Pat.

For the reaction of organic carbonic acids, including, but not limited to, optionally substituted acid (with optional alpha-hydroxy protecting group), with a compound of formula II as described above, or with a salt or, preferably, is readily with an hydrolyzable ester or a Schiff base, such as bddalddhya, can also be conveniently and effectively used as a phosphorous chloride trimmer (II) trimmer, see J. Org. Chem. 2979 (19668) or N-dhaoχ1111.29dahyldovhazzezu as described in J. Aimz. Chem. Soc. 22, 823 and 1652 (1968); The reaction is preferably carried out at a temperature of 30 to 35 ° C in benzene, ethanol or tetrahydrofuran using approximately two equivalents of all the three reactants, followed by conventional reactions. isolation, as well as any conventional protecting group, if present. .

A further process of the present invention involves the preparation of the compounds of this invention to replace the 3-acetoxyolyl group of 7-acelmino-phthalosporylic acid (prepared using 1-emethyletholeic acid instead of silyl-3-thio-7-ethylisocyloacylic acid). here, as discussed elsewhere herein) with a thiol of the formula

CH3COOH, with the removal of any optionally attached protecting group, such as in the case of alpha-hyaroxo acids, alpha-mizo acids, and the like, or a carboxy-functional protecting group or both. The replacement of the 3-acetyl group with thiol may be carried out in solution, for example in water or aqueous acetone, at a temperature of at least 20 ° C and preferably at a temperature in the range of about 50 to 100 ° C. The reaction product is isolated by careful acidification of the reaction mixture, followed by extraction into an aqueous solvent, with the aid of an excess of taivlu. It is sucking with water. In order to give some examples for a more detailed description and not to limit the scope of the invention, it is possible to prepare optionally substituted D-mineyeylanidocalphalosporanic acid using the procedures described above or as specifically described in J. Med. Chem. X, 34 (1974) with references cited therein. And, as described hereinabove, the preparation of numerous other 7-acylamidocephalosporenic acids is described in the patent and scientific literature, see, for example, U.S. Patent Papers 260-243 C.

If the organic carboxylic acid contains functional groups such as an amino or hydroxyl group, it is often desirable to first protect the amino or hydroxyl group with a capping function, then carry out the condensation reaction and then remove the capping group from the obtained condensation product.

In particular, the present invention encompasses antibacterially active agents which are prepared using the above acylation process using organic monocarboxylic acids or their corresponding chlorides or other periods previously used to acylate 6-aminoipetalic acid such as This is described, for example, in US

U.S. Pat . 2 ! 941 995 , 2 ’951 839; • 2 : 985 i 648, , 2,996,501 , 3,007,920. »3 1 025 290 3 028 379, 3 035 047, 3 040 033, 3 041 332, 3 041 333, 3 043 831, 3 053 831, 3 071 575, 3 071 576, 3 079 305, 3 079 306, 3 080 356, 3 082 204, 3 093 547, 3 093. 633, 3 t16 285, 3 117 119, 3 118 877, 3 120 512, 3 120 513, 3 130 514, 3 127 394, 3 140 282, 3 040 032, 3 142 673, 3 147 247, 3 174 964, 3 180 863, 3 198 804, 3 202 653, 3 202 654, 3 202 655, 3 210 337, 3 157 639, 3 134 767, 3 132 136, further v 'British No. 874,414

416,

1'10,

586,

785,

169,

066,

876

889

891

905

920

939

662,

066 938

778,

177,

708,

877

889

893

906

920

940

120 069 518 383 300 488

070,

247,

787,

513,

608,

877

889

894

914

922

944

531, 168, 460

419,

278,

417,

233,

231,

072 097

037,

880

890

899

916

925

042, 201, 199,

204,

281,

880

891

900

916

931

400,

174,

666,

205,

567,

882

891

902

916

932

335,

279,

703,

488,

644,

878

889

896

916

924 further in numerous Belgian patents

876

888

891

904

920

938, for example, 593 222, 595 171

877 323,

889

894

908

921

(+420) 943, (+420) 597 857, (+420) 602 494, (+420) 603 703, (+420) 609 039, (+420) 616 419, (+420) 617 187,

874

888

891

905

918

938, and in South African patent applications, for example 60, 2882, 60, 3057, 60, 3748, 61/1649, R61 / 2751, 62/54, 62, 4920, 63/1622 and 63/2423 .

The term lower alkyl as used herein means both straight and branched aliphatic hydrocarbon radicals having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isupropyl, butyl, isobityl, target, butyl, amyl, similarly, the term "lower," as used in the specification in conjunction with any other group, e.g., a lower alkoxy group, refers to the alkyl portion of such a group. to a lower alkyl lower group.

The process according to the invention also relates to a process for the preparation of antibacterially active compounds of the general formula I / S _{4 and} ¹ -NH-CH-CH ^X CH 3

II 1 ..

o = C-- _C-CH2-COOH, -SO

N — N

II II of N

HjCOOH C and the process is characterized by treating a compound of formula T-NH-CH-CH ₂ ^X

O = C-N-CH _and J -O-COCH ₃

Ύ cooh where R 1 represents an acyl group (counting in the cephalospoain C as such), a compound of the formula

N --- N li 1

HS — CN ch ₃ cooh

In the case of compounds containing an amino-substituted amino group in the -7- side chain, it is often desirable to first prepare a compound with an unsubstituted amino group (i.e., a primary) and then treat the product with a suitable reagent to produce the final product of the type above, with the acyl groups described in paragraphs viii, and χνΐϋ, as appropriate.

The process according to the invention also relates to a process for the production of a novel and valuable intermediate of the formula

H ₂ N - CH - CH ₂ --CH ₂ -

AND

COOH

NN

IIII

S — CN

I ch ₂ cooh

The method is characterized in that the side chain at position -7- is removed from the compound

of the general formula й'— NH — CH — CH CH ₂ NN II 1 'II II O = C — N X-CH ₂ -S-IN

COOH CH ₃ COOH wherein the acyl group r 'is any of those defined hereinbefore in xiv, xv and xvi, wherein the flowable substance, preferably in silylated form, is converted by reaction with the chloride chloride to the deoxidizing iminoechoride, followed by reaction with, for example, methanol to the iminoether and then hydrolysis, for example by treating the final product with water. Details of this process are described, for example, in U.S. Pat. Nos. 3,575,970, 3,573,295

573 296.. ‘

The process of the invention also relates to the production of novel and valuable structure intermediates

H ₂ N-CH-CH

I I I ·

O = C —- ^C-C ^SS f

COOH

AND

CH < ₂ COOH and characterized by treating 7-aminocephalosporanoic acid or its corresponding salt or a readily hydrotreatable ester or the corresponding Schiff base with a compound of the formula

CH2COOH

The replacement of the 3-actyloxy group with a thiol can be carried out in solution at a temperature of at least 20 ° C and preferably in a temperature range of about 50 to 100 ° C in the presence of a mild base such as hy (1). Sodium carbonate, for example in the region of near neutrality at a pH of about 6. The thiol is preferably used in excess The reaction product is isolated by carefully acidifying the reaction mixture, followed by extraction into an organic solvent mixed with water.

Suitable salts include nontoxic salts of carboxyl functions, including nontoxic metal salts such as sodium, potassium, calcium or aluminum, ammonium and nontoxic amine salts such as trialkylmines, e.g., procaine, dibenzylamine N-beta-bernýl fппп у ^! ^^ 1-efenímin, Ν, Ν'-dibnnУllntlllendiamin, dekydroabietylamin, Ν, Ν-dtlldrsabintllelhylendimin ^from -cis, lower N-alkyl derivatives pipej-di-nu, and other amines e.g. , which are usually used for the preparation of salts of enoyoyl. Non-toxic acid addition salts are also contemplated, for example, amine salts, which include mineral salts such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic and phosphoric acids, as well as organic acids, such as maaeinic acid. , acetic, lemon, oxial, amber, benzoic, tartaric, fumaric, cider, mesilic, ascorbic and the like.

Also included within the scope of the present invention are compounds (used either as intermediates or as meabolic starting materials) wherein the amino group is protected with substituents such as the 2-iodoethoxycarbonyl group, see British Patent 1,349,673, tert-butoxycarbonyl group, carbobenzyloxy group. a group of phimyl, s-nitrophenylsulfonyl, beta, beta, beta-trichloroethoxycarbonyl, 4-sxo-2-penten-3-llium, 1-methoxycarbonyl-1-propenyl and the like. These blocking groups include, in particular, ketones, especially acetone, and aldehydes, in particular formaldehyde and acetaldehyde, see, for example, U.S. Pat. Nos. 3,198,804 and 3,347,851; and esters of Oeta-inslyseliy and Oeta-diketsyy; 325,479, and further beta-ketoamides, see Japanese Patent 71/24714 (Farmdoc. 47,321 S).

Preferred esters of phthalosporside according to the invention include pivaloyloxymethyl ester, acetylene methyl ester, minor ethyl ether, acetonyl ester and phthacylate. All of these compounds are useful intermediates in the preparation of free carboxylic acid formulations, and the first 3 compounds are also of interest with respect to oral administration as they vary in the rate of absorption and the amount that is absorbed so that different concentrations of active α-thialtaltial can be achieved. blood and tissue agents.

As mentioned hereinabove, these 5 esters of 7-aminocephaline sporaye are prepared using known procedures. One excellent process is the process described in U.S. Pat. No. 3,284,451, wherein the sodium salt of cnfalstlinh is reacted with the corresponding active chlorinated ynone derivative, for example, phenylacylbnomide, chloroacetone, chloromethyl glycol ether, pivalomethyl siloxime, pivalomethyl siloxime. and acetosyl chloride, whereupon the side chain of thylyl acetic acid is cleaved by enzymes as described in the same patent, ynnn chemically as described in U.S. Pat. No. 3,575,970 and in Journ. ^ Aníbiotics 24. 767 (19 * 71). .

Another good procedure is to treat the 7-aminocephalosporonic acid salt with a tri-antimiline directly active halogenated compound, see for example British Patent Specification 1,229,453.

These 7-aminocephalosporic acid esters are then treated with a nucleophile, i.e. the aforementioned NSR ² compound, a compound of formula

CH 2 COOH in the same manner as described herein for 7-aminocephalosporic acid per se. The 3-thiol ester derived from 7-aminocephalosporanic acid is then condensed with an organic carboxylic acid such as D - (-) - 2-pherylglycine as previously described herein. Before or after removal of any protecting group, for example an amino or hydroxyl protecting group in the side chain at the -7- position, the cephalosporium ester thus obtained, if not used as a flowing, is converted to the free acid, attracting the zwitterion (and if desired, any salt) by removal of the ester group by a process such as aqueous or enzymatic hydrolysis (by treatment with human or animal serum), or by hydrolysis in an acidic or alkaline medium, or by treatment with iatril · icthicfeicsiiu, as evident from U.S. Pat

284,451, and in the penicillin series, see Sheehan et al., J. Org. Chem. 29, 2008 (1964).

In another alternative synthesis, 7-aminocephalosporancic acid is prepared with 3-thide-substituent as described herein, wherein the 7-amino group is acylated and then esterified, for example by reaction of a suitable alcohol with an acid chloride, prepared by, for example, reaction. of the final cephalospinin derivative with thiciyl chloride, or using another acid esterification procedure.

The present invention also relates to a process for the production of a novel and valuable structure intermediate

AND

CH 3 COOH, wherein the method is characterized in that a lithium and thiol derivative of the formula

and the resulting alcohol compound is treated with carbonic acid to produce a product which is hydrolyzed to give a compound of formula

N - N

HiJI N'W

CH3COOH

For the treatment of bacterial infections in humans, the compounds of this invention are administered parenterally or orally in an amount of about 5 to 200 mg / kg per day, and preferably in an amount of about 5 to 20 mg / kg per day in divided doses, i.e. They may be administered in unit doses containing, for example, 125, 250 or 500 mg of active ingredient with a suitable and physiologically acceptable carrier or diluent. Dosage units are usually in the form of liquid preparations such as solutions or sponges.

Starting materials

A. 1-Carboxymethyl-5-mercaptotetrazole

CH ₂ COOH

a) Recrystallization of 1-ethyl-5-mercaptotetrazole

Method:

1. Stir 110 g of 1-methyl-5-mercaptotetrazole in 350 ml of boiling chloroform; a clear solution is formed.

2. The hot solution at 50-60 ° C is quickly filtered using a vacuum heated Buchner funnel (11 cm, paper # 604; it also contains a compressed layer up to 0.8 to 0.6 cm Supercel filter aid). The filter was washed with 50 ml of chloroform heated to 50-60 ° C and added to the filtrate.

3. Cool the filtrate to about 0-6 ° C and hold at this temperature for 2 hours; the crystals formed are suction filtered with cooling to 0-6 ° C and washed with 60 ml of chloroform cooled to the same low temperature, and this chloroform is added to the filtrate. The crystals (Part A) were air dried at 37-45 ° C for 18 hours.

4. Concentrate the filtrate in a rotary evaporator (60 ° C bath) to approximately half the original volume. The suspension obtained is cooled to 0-6 ° C and held at this temperature for 2 hours. The crystals are suction filtered with cooling to 0-6 ° C, washed with 40 ml of chloroform cooled to 0-6 ° C and added to the filtrate. The crystals (Part B) were air dried at 37-45 ° C for 18 hours. Combining the proportions A and V yields the substance in a yield of approximately 65%.

5. After aspiration of the fraction В from step 4, the filtrate can be treated twice more as described in step 4; this gives an additional 15% yield ·

b) Preparation of 1-carboxymethyl-5-mercaptotetrazole disodium

Method:

1. Cool 500 ml of substantially dry and pure tetrahydrofuran in a 2 L three-necked flask with stirrer in a bath of salt, acetone and ice to approximately -10 ° C and dry nitrogen is introduced to the surface of the liquid.

2. 500 ml of a 15.06% (1.6 N) solution of butyllithium in hexane (Foote Mineral Co) is added over 10 minutes under dry nitrogen and with stirring to supercooled tetrahydrofuran. the clear solution is cooled to -5 to -10 ° C.

3. 46.4 g of 1-methyl-5-mercaptotetrazole, recrystallized as described above, are dissolved in 200 ml of substantially pure and dry tetrahydrofuran. The solution is filtered if cloudy, and then cooled to 5-10 ° C.

4. The cooled solution from step 3 is added to the butyllithium solution over 10 minutes with stirring and under dry nitrogen, maintaining the temperature between -5 ° C and not more than +10 ° C. A precipitate may form.

5. Stir the mixture under dry nitrogen and cool to 0 to + 10 ° C for 30 minutes.

6. Carbon dioxide gas is vigorously introduced into the reaction mixture with vigorous stirring for about 15 to 30 minutes at about room temperature (0 to 10 ° C), but not above +20 ° C.

7. Filter the white precipitate out in a low humidity area, wash the precipitate using approximately 75 mL of tetrahydrofuran.

8. Dissolve the precipitate in 250 ml of water (pH 8.5 to 9.5); a second tetrahydrofuran layer may be used and this may be distilled off on a rotary evaporator at a bath temperature of 0 ° C.

9. Adjust the aqueous solution to pH 1.6-2.0 by adding concentrated hydrochloric acid.

10. Extract the acidic aqueous solution twice with 250 ml of ethyl acetate each and extract each in ethyl acetate (250 ml) with 100 ml of water. Aqueous extracts are not required. The extracts in ethyl acetate (devoid of any aqueous fraction) were filtered and combined.

11. The combined extracts in ethyl acetate were concentrated to dryness on a vacuum rotary evaporator at a bath temperature of 60 ° C.

12. Heat the crystals in the flask with 300 ml of chloroform for about 2 minutes to boil, filter the hot suspension (50-60 ° C) under vacuum on a heated Buchner funnel (11 cm diameter, SS-604 filter paper) and wash the crystals. using about 75 ml of chloroform heated to 50 ° C. The crystals are dried in air at room temperature for about 3 hours and then crushed to a size of approximately 100-200 mesh.

13. Treat 100 to 200 mesh crystals using boiling chloroform exactly as described in step 12 (hot chloroform removes most unreacted 1-methyl-5-mercaptotetrazole). The yield is about 45 to 50 g crystalline

Of 1-carboxymethyl-5-mercaptotetrazole. These crystals may contain 0.02 to 0.05 moles of 1-methyl-5-mercaptotetrazole.

14. The crystals of step 13 are stirred into 250 ml of ethyl ether at room temperature for about 3 to 5 minutes, the mixture is filtered, insoluble matter (0.5 to 5%) may form a symmetrical mercaptotetrazolketone, perhaps a substance of this structure :

N - N NN

NN-CH ₂ -CO-CH ₂ -NN

Yγ

SHSH

Attention: this compound will explode at a temperature of approximately 205 to 210 ° C.

15. Evaporate the ether filtrate from step 14 to dryness using a vacuum rotary evaporator (50 ° C bath). 42 to 48 g of crystalline 1-carboxymethyl-5-mercaptotetrazole containing about 0.01 to 0.05 moles of 1-methyl-5-mercaptotetrazole are recovered.

16. Dissolve the crystals in 420 mL absolute ethanol (approximately 100 mg / mL) and heat the solution to 50-60 ° C.

17 310 ml of a 41% solution of sodium 2-ethylhexanoic acid in isopropyl alcohol are added to the hot solution of step 16 with vigorous stirring over 10 minutes. A crystalline precipitate is formed; the mixture is then stirred at 50-60 ° C for 20 minutes in suspension.

18. Filter the mixture while still hot (50-60 ° C) with a heated Buchner funnel (11 cm, paper # 604); the crystals were washed with 75 ml of ethanol heated to 50 ° C.

19. Stir the crystals from the ethanol suspension of step 18 into 200 to 300 ml of ethanol and sieve the suspension through a 200 mesh sieve. The suspension is heated at 50-60 ° C for 5 minutes with vigorous stirring (unreacted 1-methyl-5-mercaptotetrazole sodium is very soluble in hot ethanol).

20. Filter the crystals at 50-60 ° C on a heated 1 cm cm Buchner funnel using SS # 604 filter paper. Use 75-100 mL of ethanol, then vacuum dry the crystals obtained for 24-40 hours at Mp 50-60 ° C. The yield was 40-48 g of 1-carboxymethyl-5-mercaptotetrazole disodium salt (free of 1-methyl-5-mercaptotetrazole as shown by NMR spectra).

B. 7-Amino-3- (1-carboxymethyltetrazol-6-ylthiomethyl) -3-cephem-4-carboxylic acid

CH ₂ OCOCH ₃

COOH n-ch ₂ cooh

NaS - “--- N — CH ^ COONa

1. In a three-necked flask with stirrer, temperature control, thermometer and nitrogen tube, 18 g (0.066 mol) of 7-aminocephalosporanic acid and 300 ml of 0.1 M phosphate buffer pH 6.4 (20.7 g of monohydrate) are placed. sodium dihydrogen phosphate and 8.5 g of anhydrous sodium monohydrogen phosphate; make up to 2 liters with water).

2. While stirring the mixture described in (i), add 1.5 g of sodium bisulfite and 16 g (0.078 mol) of 1-carboxymethyl-5-mercaptotetrazole disodium.

3. Nitrogen is bubbled through the mixture for 10 minutes while stirring.

4. While stirring and introducing nitrogen, the suspension is heated to 56 ° C for 20 minutes; a total of 6.5 g of sodium bicarbonate is added in small portions during this period.

5. Maintain the solution at 56 ° C for 4 hours while stirring and introducing nitrogen; the pH of the solution should be maintained between 6.2 and 6.6.

6. Cool the reaction mixture further to 5 ° C in an ice bath.

* Add 50 ml of a 1: 1 solution of phosphoric acid in water or concentrated hydrochloric acid to pH 2.0 to 3.0.

8. The precipitated product is filtered off, the filter residue is washed with 20 ml of cold water and further washed with 200 ml of cold methanol.

9. Dry the solid in air to constant weight (typically 14.5 g of product). The color of the product obtained may vary from yellow to dark brown.

10. Pass the product through a 200 mesh stainless steel screen.

11. Suspend 10 g of the powdered product which has passed through a 200 mesh sieve in 200 ml of n-propyl alcohol with vigorous stirring.

12. After addition of 2.0 ml of concentrated hydrochloric acid, the reaction mixture is vigorously stirred for 30 minutes at room temperature.

The 13-suspension is filtered, the brown solid is washed with 20 ml of n-propyl alcohol and the wash is added to the filtrate (the filter portion is retained for the purpose of possibly recovering another portion of the product).

14. Add 1.5 g of activated carbon (Darco G-60) to the n-propanol filtrate of step 13, stir the suspension for 30 minutes, then filter the coal, wash with 20 ml of n-propyl alcohol and wash the washings. add to the filtrate.

15. With vigorous stirring, add triethylamine to the n-propyl alcohol filtrate until an apparent pH of 3.0 is reached. Crystals precipitated and the suspension was stirred for 10 minutes.

16. The white crystals were filtered off and washed with 30 ml of n-propyl alcohol, 50 ml of methanol, and then dried under vacuum at 40 ° C for 24 hours. In a yield of 4-8 g, 7-amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid is obtained.

17. An alternative procedure for purifying 7-amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid is as follows:

a) 10 g of the product of step 10, passed through a 200 mesh sieve, are slurried in 75 ml of 1 N hydrochloric acid and the suspension is stirred for 10 to 15 minutes at room temperature. The dark brown solids were removed by filtration.

b) Add 2.5 g of activated carbon ("Darco G-60") and stir the suspension for 0.5 hours.

c) The charcoal is filtered off, washed with 15 ml of water and the washings are added to the filtrate.

d) With vigorous stirring, add a concentrated ammonia solution to the filtrate until a pH of 2.5 to 3.0 is reached. White crystals formed.

e) The crystal suspension is stirred for 25 minutes, then the crystals are filtered off and washed with 30 ml of water, 50 ml of methanol, and dried at room temperature under vacuum. The yield was 4 to 7 g of off-white crystals.

Example A

7-Amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

To a stirred suspension of 1.0 g (0.0625 mol) of 1-carboxymethyl-5-mercaptotetrazole and 1.7 g (0.0625 mol) of 7-aminocephalosporanic acid in 50 ml of 0.1 M phosphate buffer pH 6.4 1.1 g of sodium bicarbonate were added in small portions under nitrogen at 55 ° C. The solution was stirred for 4 hours, then cooled to 5 ° C and acidified to pH 2.0 by addition of dilute phosphoric acid (1: 1). The precipitate formed is filtered off, washed with 50 ml of water, 50 ml of acetone and dried under vacuum over phosphorus pentoxide. 2.3 g of solids are obtained. These are then stirred into 25 ml of tetrahydrofuran and concentrated hydrochloric acid is added dropwise until the reaction mixture becomes clear. 100 mg of Darco KB active bottom was added to the solution, the occlusion mixture was filtered and concentrated at 30 ° C (15 Torr) to a volume of 10 ml to give a crystalline prodiAt which was filtered off and air dried overnight to give 560 mg. substances, bt above 170 ° C (dec.).

NR sppktrum (delta ppm limethySslžLflxilu _d g + DCl-D2 O): 3.8, s, 2H; 4.4, DOH; 5.1, quadruulet, 25; 5.35, singlet, 2H.

Ainlysa: for C 11 H 8 N 6 O 6 Sg. 1 / 2H ₂ 0: calculated: 34.63% C. H, 3.43; N, 22.04. Found:% C, 34.79;% H, 3.82;% N, 21.67.

^I n ^f r ^No erveoé s ^p e ^k trim ^(b perfluorooctyl bromide monopotassium ^ 1 ^{8 00} 1 ^{7 30} 1 ⁶ 20 cm ^- '.

Example B

Acidyl-3- (1-tert-ethyl-4-ylthiazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

To a mixture of 4.6 g (0.0286 mol) of 5-meerall-Cetol-zinc acid and 7.8 g (0.0286 mol) of 7-chloroforceic acid: 150 ml of 0.1 phosphate buffer at pH 6.4 is added stirring solid hS ^{<dгoggeoLhliČitao} sodium ^ REA until the mixture became clear (pH 7.5) · the resulting solution was heated under nitrogen for 4 hours at 55 ° C ckysseLí the addition of a solution of phosphoric acid (1 · 1) and the precipitate was It was filtered off, washed with water and then with a small volume of methanol.

The solid filtered is stirred into 150 ml of methanol and concentrated hydrochloric acid is added dropwise until the reaction mixture becomes clear. The solution is decolorized with charcoal and, after filtration, is neutralized by addition of concentrated ammonia solution to pH 4.5 by filtration. The solid is filtered and the methanol is passed through to give a mass of 5.0 g. Infrared and N ^ R ^ E ^ are consistent with the structure ascertained.

Example C '.

7-Amino-3- (1-trifluoromethyl-ethyl-tetrazo-5-yl-thiomethyl) -3-cephem-4-carboxylic acid

To a suspension of 22 g (0.0831 mol) of 7-aminocephalosylic acid in 350 ml of 0.1 M phosphate buffer at pH 6.4 is added 14.3 g (0.089 mol) of 1-cleanyl-ethyl-15-merctatol triazole and 1. 5 g of sodium hydrogen sulphide. The reaction mixture was heated to 55 ° C under nitrogen and solid sodium hydrogen chloride was added until the reaction mixture had cleared. (pH 7.5). The solution was heated for a further 3.5 hours, cooled to 10 ° C and adjusted to pH 2 by addition of 6 N hydrochloric acid solution. The precipitate was filtered, washed with chilled water, then with methanol, and air dried. 15.2 g of 7-amino-3- (1-chloroethyl ether-tetramethyl-5-methylmethyl) -3-carboxylic acid are isolated.

A sample of the obtained material was recrystallized from 100 ml of methanol dropwise with concentrated hydrochloric acid until the reaction mixture was clear, then the pH of the solution was adjusted to 5 by addition of concentrated ammonia solution, and the precipitate was filtered to yield 6.2 g. The IR spectrum and the infrared spectrum were consistent with this structure.

Other reagents that are used to prepare the compounds of the invention are synthesized either as described in the literature, see, for example, the previously cited patents and publications, or using similar procedures. N-α-α-α-acid is prepared by defeating the procedures described in U.S. Pat. Nos. 3,198,804, 3,342,677 or 3,634,418, or as described by Friis et al., Acta Chem. Scand. 17 2391 (196 (6) or Neims et al., £, 203 (196 (6)) or as described in other publications on this subject.

4!

In addition, some examples of similar syntheses of carboxylic acid preparations containing a free amino group which is protected by a tert-oxycartonyl group are given below.

C. To ^the linoleum 2- (terc.Uu0oxyaar0olyLlmlinoeetlhyl) - '1, 4-cyclohexadienylacetic

A solution of 16.5 g (0.1 mol) of o-aine-methylphenylacetic acid in 1.5 liters of liquid ammonia, from which any trace of moisture was previously removed by adding 50 mg of lithium, is slowly diluted by adding 500 ml of dry tert-butyl alcohol. ‘

3.4 g (0.5 atom) of lithium are added in small portions over 4 hours, and the mixture is then stirred for 16 hours at a temperature and distilling off the ammonia until exhausted, and finally dried to 40 ° C until dry. . The residue was dissolved in 500 ml of water. and the solution was chromatographed on an IR-120 column (in a hydrogen cycle, 700 m); eluting with 1% ammonia solution. The eluate fractions which react positively with ninhydrin are combined and concentrated to dryness. ,

The residue is washed with 4 portions of 50 ml of hot acetone and then washed with water. recrystallized from 500 mL of a 1: 1 mixture of ethanol and water; There was thus obtained 11.2 g (67%) of colorless needle crystals of 1- (2-aminoethyl-1H-cyclohexadienyl) acetic acid, m.p. 183 ° C.

Absorption spectrum in infračevnenée: Nu ^nu 3 1630, 1520, 1380, 1356 cm ''.

max

NR-sppetrum delta D ₂ O + К НСз _£ 2.72 (4H, s,. CO ₂ H, 3.01 (2H, s, ^ HH O), 3.20 (2H, s,

CH ₂ -N), 5.78 (22, s, HC =),

Ainlysa calculated for C ^ ^H ^NO NO: found:

64.65% H,

64.77% H,

7.84% 2,

8.06% H,

N, 8.38.

8.44% N.

Improved process for the preparation of o- (2-aminoethyl-1,4-cyclohexadeenyl) acetic acid

alcohol, tert-butyl alcohol

CH ₂ NH ₂ t - LiOH + (1 H 2 N 2

The procedure described in U.S. Pat. No. 3,720 has been modified. 665, cf. Example 1 therein, for the preparation of D-2-aminoalino (114-cycloadadiene) acetic acid. By adding 40 mg of lithium under argon, 830 ml of distilled liquid and dried under stirring are added and 11.0 g (0.07 mol) of 2-leinomethylphenylacetic acid and 340 ml of tert-butyl alcohol are added under stirring. while stirring vigorously, a total of 1.6 g (0.225 mol) of lithium is introduced over 3 hours, 35 g (0.215 mol) of triethylamine are added to the gray reaction mixture and the reaction mixture is stirred at room temperature for 18 hours overnight . Further, the tert-butyl alcohol was stirred in a vacuum of 15 ° C at 40 ° C to give a white residue, which was dried over phosphorus pentoxide under vacuum overnight.

The solid was then dissolved in 30 ml of 1: 1 methanol / water (1: 1) and the solution was added with stirring to 3.5 L of a 1: 1 mixture of chloroform and acetone at 5 ° C. The mixture was stirred for 20 minutes, after which the amino acid, alpha- (2-minomeecl-1,4-cyclohexadienyl) acetic acid was filtered off and dried for 16 hours under vacuum over phosphorus pentoxide. In yield

6.3 g (58%) gave 6.3 g of white crystals of m.p. 190 ° decomposition). The infrared spectrum and the NR-spectrum are consistent with this structure.

A solution of 19.31 g (0.135 mol) in 152 ml terc.buoxxykarbonylazidu tetrhydrofuranu was added to a stirred solution of 14> 89 g (0.09 mol) of _{2-aiinooithhl-1>} 4-cyklohl: · acetic xadilnyl

7.20 g (0.18 mol) of sodium hydroxide in 281 mL of water and the solution was stirred at 25 ° for 18 hours, filtered through a pad of diatomaceous earth (Supee-cel), then tetrithihydrofuran was collected at 40 ° C under vacuum. 15 Torr and the remaining solution was washed with two portions of 175 mL ether. The mixture, acidified by the addition of 6 N hydrochloric acid, was stirred in an ice bath and the precipitate was dried for 18 hours in vacuo over phosphoric acid at 25 ° under vacuum to give 17.3 g (72.6%) of 2 - (?). Butobutylcarbonyl (amino) -1,4-cyclohexadienylacetic acid in the form of a white powder. The IR and NMR spectra were consistent with the indicated structure.

D. Cyanide D - (-) - p-hydrooχ-al · fiaterc.butoxlcarboxamidoOenylacetic

In a mortar, triturate 5.65 g (0.14 mol) of magnesium oxide and 11.7 g (0.07 mol) of D - (-) - p -hydroxyphenylnyl glycine, add 177 ml · 50% dioxane and then grind tert-butoxycarbonylazide (20.0 g, 0.14 mol) was added to the vigorously stirred reaction roe, which was stirred at 45-50 ° C for 20 hours. The inert mixture was then diluted with 710 ml of ice-water and 177 ml of ethyl acetate, filtered, and the filtrate was separated into 2 phases. The organic phase is washed with three 50 ml portions of a 3% sodium thiosulfate solution. and three portions of 50 ml water each. All aqueous portions were combined and adjusted to pH 5.0 by cooling with concentrated hydrochloric acid. The product was extracted with 3 x 125 mL portions of ethyl acetate, and the solution in the solvent was washed with 2 x 50 mL portions of water, dried over anhydrous magnesium sulfate and concentrated at 35 ° C under a vacuum of 15 Torr to give an oil; This was triturated with petroleum ether to give D - (-) - p-hydroxyl-alpha-1-carboxylic acid as a white solid.

The product was filtered off and dried in vacuo over phosphorus pentoxide for 18 hours at 25 ° C; 13.5 g (72.2%) of an off-white powder are obtained. 102 °. The infrared spectrum and the N? PR? R? M are consistent with said etrpktprop.

E. Ky 'Hna D -' (() - α '- a-errc.butoykkrbOoxime miophenyl · acetic'

Repeat the above procedure for D - (() - p-tleroxy-alpha-errc.bPtoPkkkrbtoxymieo (flvlloctovop) to give 2 sample fractions of bt 82 ° C, yield 5.2 g (30%). PRPresp ^ m are consistent with this etrpktprop.

F. Kyyslina 2- (terc.PutxlykabbonylíminompettΊ) (1> 2 ^{^ 0 c} YKL hlxenyloctová, also known as alkyl salina 2- (N-tert. Bptoxykarbotnl ^ and ^[b ninčtmet TLL (-cyklohpχpn-1 -yioctová

(a) Alia- [2- (tert-butoxycarbonylamino) acetyl-1- (14-cyclohexoxdienyl) acetic acid

To a stirred solution of 8.0 g (0.048 mol) of alpha ((2-aminomethyl-1,4-cyclohlxadilnyl) acetic acid and 3.8 g · (0.086 mol) of sodium hydroxide in 150 ml of water is added a solution of 10, 3 g (0.072 mol) of tert-butyloxycarbonyl azide in 80 ml of tert-butyrophosphoric acid are added and the reaction mixture is stirred for 18 hours under reduced pressure. The tetrahydrofuran is separated off under reduced pressure and the remaining solution is washed with ether (2 x 100 ml). The combined extracts were washed with water (2 x 100 mL), saturated aqueous sodium chloride (100 mL) and dried over anhydrous sodium sulfate. zahnstí to dryness. the oily residue was tritprpjl n-hextrnem to give 10.5 g (82%) of colorless powder ^of mp __ 113 ° C. IR spe ^ rum ^j Nu 37 ^ ¹ ^ 5 ^{1 64} 0 1 ³⁰ 5 ¹ 2 ⁸ °, 1160 ^cm

Mur-spectrum: delta 1.45 (9H, s, (β ^ .- ^ Ι ιΙ alcohol), 2.73 (4H, (2H, s, _CH2 CO), 3.76 (2H, d, .. ........................

K-s, COOHH

Aialysis for

6H25, s, CH2 ₍ f = C), 3.16

CH ₂ N), 4.90 (1H, m), 5.66 (2H, s HC =), 10.6 (1H, broad ^c ) 4 ^h 2 N 2 ^O 4 calculated: found:

% C, 62.90;

% C, 63.13;% H, 8.21;

5.24% N;

5.26% N.

b) [2- (N-tert-Butoxycarbonylamino) methyl-cyclohexen-1-yl] acetic acid (2 ')

1.33 g (5 mmol) of 4- (1H-tert-butoxycarbonylamino) -ethyl-1,4'-cyclohexadien-1-yl-acetic acid (1) in 10 mL of 3% ammonium solution was hydrogenated to 0.2 g of 10% palladium on coal at a pressure of 2.8 at. The theoretical hydrogen is consumed in three hours, then the catalyst is filtered off and the filtrate is acidified to pH by addition of dilute hydrochloric acid, the acidified portion is extracted into two portions of 50 ml of ethyl acetate. The combined extracts were washed with water (20 mL) and dried over anhydrous under reduced pressure to give 1.34 g of an oil which solidified on standing from a mixture of n-hexane and ethyl acetate to give colorless prisms of m.p.

Sodium sulfate solution and concentrated for several days. Recrystallized 1.2 g (90%) of 2 in the form

118 až

Mp 119 ° C.

Infrared spectrum: nujol max

450, 1,730, 1,660,

510 cm -.

WR-S ^ ktrum ^D ELTA ppín ⁴³

1.90-2.20 (4H, m, methylene broad)

Hz, CH ₂ -N), 5.00 (1H, ^{1, 5, 8} (9H t ^ u ^ l ^ ^1, 5 ° and ^1.90 (4H, ^m,. - ^ ^{CH., -),} hydrogen allllsié 3.18 (2H, s-CH3-CO), 3.78 (2H, ds, NH), 8.98 (1H, broad-s, COOHH.

Analysis calculated for:

62.43% C,

62.12% C,

8.61

8.77% H,% H,

5.20% N;

5.37% N.

(c) Viburnum

2-tert-butoxycarbonylamino-4-hydroxyphenylacetic acid.

They are prepared, for example, by the process described in U.S. Pat

823

141

H. o- (tert-Butoxycarbonylamnomethyl) phenylthioacetic acid

They are prepared, for example, by the process of U.S. Pat. No. 3,813,390.

657

232, see Eq ^I. Kyneli on-beta- [o- ^(e erc.but0l ^was arbonylminomethy ^l-phenyl -poopiionová

They are prepared, for example, by the process described in U.S. Pat

813

391.

J. D- (-) - N-tert. buttxycsabboyl · ~ 2- (3'-oethyl-4-heptoxyphenyl) glycine

2- (3'-Ethyl-4'-hydrophenyl) glycine

A solution of 59.02 g (0.6 mol) of 75% glyoxylic acid in 100 ml of water is added to the suspension

54.6 g (0.5 mol) of 2-o-ethylphenol and 140 ml of concentrated aqueous ammonia solution in 400 ml of water are added. room temperature; the temperature of the reaction salt rises to 37 °. The reaction mixture was stirred at room temperature for 65 hours. The solution, initially pH 10.1, was acidified by adding 6 N hydrochloric acid to pH 6.8, thereby crystallizing the product. The product was filtered, washed with water and dried in vacuo over phosphorus pentoxide. It is obtained

3.1.5 g (34.8%) of 2- (3'-methyl-4'-hydroxyphenyl) glycine, decomposing at 196-199 ° C. The infrared and NMR spectra are consistent with this structure. Belgian patent 774 029 (1972, Fanndoc 27, 122 T) mentions m.p. 205-207 ° C.

H, 6.13; N, 7.73.

Found:% C, 57.68;% H, 23%;% N, 7.47;% H, 2.43;

found corrected for the indicated water content: C 59.06, H 6.12, N 7.67.

DL-N-Chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) glycine

The pH of the suspension of 20.2 g (0.112 mol) of DL-2- (3'-methyl-4'-hydroxyphenyl) glycine in 176 ml of water is adjusted to 10.3 by addition of 20% sodium hydroxide solution to effect dissolution. 38.2 g (0.224 mol) of chloroacetic anhydride are added to the solution cooled in an ice bath and the pH of the reaction mixture is maintained at 10 by addition of 20% sodium hydroxide solution until no pH change is detected. The reaction mixture was stirred for an additional 10 minutes under cooling, acidified to pH 2.0 by addition of 6 N hydrochloric acid solution to crystallize the product. The product was filtered off and air-dried after washing with water. Recrystallization from 200 ml of hot water gave 13.7 g (47.4%) of DL-N-chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) glycine. The infrared and NMR spectra are consistent with the structure of the compound.

H, 5.12; N, 5.08. Found: C, 37.92; H, 5.12; Found: C, 48.11, H, 5.16, N, 5.15.

D - (-) - N-Chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) glycine

Dissolve 5,0 g (0,0194 mol) of DL-N-chlorosyl-2- (3'-methyl-4'-hydroxyphenyl) glycine and 6,1 g of 0,0213 mol) of L-efenamine-acetic acid salt heating on a steam bath in 50 ml of isopropyl alcohol. By adding water and cooling, the salt of L-efenamine crystallizes, which is filtered off and air-dried.

This salt was suspended in 30 ml of water and 50 ml of methylene chloride and the pH of the reaction mixture was adjusted to 10.0 by addition of 20% sodium hydroxide solution. The two phases are separated and the aqueous phase is extracted twice more with methylene chloride.

The pH of the aqueous solution was adjusted to 2.0 by the addition of 6 N hydrochloric acid, thereby crystallizing the product, which was filtered off and dried in vacuo over phosphorus pentoxide. 0.9 g (36.1%) of D - (-) - N-chlorosyl-2- (3'-methyl-4'-hydroxyphenyl) glycine is obtained, m.p. M.p. 170-172 ° C, [α] D = 185.9 ° (95% C, OH, c = 1).

Infrared and NMR spectra were consistent with the structure of the prepared substance.

For C pro HH ^NO ^Cl requires: C, 51.27; H, 4.696; N, 5.44. Found: C 51.21, H 4.77, N 5.29.

2-Diphenyl-2-methylaminoethanol, commonly referred to as efenamine, has the structure

OH NH

AND

CH ₃ '202058

Said compound is also referred to as N-meetyl 11,2-diphenyl-2-hydroxyrethyllimium or alpha, beididolyl-bete-S-trrol, γ-N-ethyl-ethyl-ethylamine, optionally. 1,2-Phenyl-1,2-ethyl-imino-1-ethanol.

The present invention utilizes only left-handed nrythro-isoenr1. Methods for preparing this compound and reacting with pnaicilanee G are described in U.S. Patent Nos. 2,645,638 and 2,768,081. The foregoing summarizes the previous literature, as well as W. W. Weeaey et al., J. Org. Chem. 13, 1564 (1953). Shnnhaa et al., J. Aner. Chem. Soc. 81, 3089 (1959), use this substance to resolve racemic inaoχyenhelpenaccliau (see especially p. 3 091) ·

D- (-) -2- (3'-Menhel-4'-eyedroxyenyl) glycine

11.1 g (0.0431 mol) of D - (-) - N-chloroacetyl-2- (3'-ethyl-4-lyloxyphenylphenyl) lycin are mixed with 100 ml of a 2 N hydrochloric acid solution and the reaction mixture is heated The solution is then cooled and the pH of the solution is adjusted to 5.0 by the addition of 20% sodium hydroxide solution, so that the product is acidified and, after suctioning and washing with water, dried under vacuum over fossil dioxide. ^ nným 7.4 g (94.7 '%) of D - (-) - 2- (3'-Metta ^1' - Hydroxy ^{e s'} en ^{aS.) Gly} cial dec ^ ^ and orientations for is a temperature ^{from 205} to ²⁰ 9 ° C, FAL ^ j ^. = -152.6 ° (1N HC1), c = 1). The IR spectrum and the NMR spectrum were consistent with the structure of the product to be prepared.

Analysis for C 8 H 11 NO 3 calculated: 59.66% C, 6.13% H, 7.73% Ni; found: 58.62% C. 5419% H. 7.78% N. 1.46% Η ,, Ο; found after correction for water content: 59 _: H, 5.41; N, 7.84

D- (-) - N-tert. bltox karboonSl ^y · 2- (3 ^{out of} 4 -eeteyl hyíroxyienyl) glycine

To a suspension of 7.2 g (0.0397 mol) of D - (-) - 2- ^(3'-of-4 eethyl -eydroxyieayl) glycial and 3.2 g (0.08 mol) of powdered magnesium oxide with stirring for of t-butoxycarbonylazide (9.7 g, 0.068 mol) was added dropwise in 100 ml of 50% dioxy. The reaction mixture was further heated at 42-45 under nitrogen for 19 hours. ° C, further diluted with 100 ml of ice water, the solution is overlaid with eteyleptenee. acetic acid and filtration to remove some of the insoluble matter which has thus precipitated.

The aqueous fraction of the filtrate was separated and extracted twice more with ethyl acetate, then the pH of the aqueous solution was adjusted to 5.0 by the addition of 42% phosphoric acid and extracted five times with ethyl acetate. The combined organic extracts were washed three times with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oil; The latter is suspended in vacuo over the phosphorus pentachloride to give 10.6 g (95%) of D - (-) - N-tert-butoxycarbonyl-2- (3'-methyl-4'-hydroxyethyl) glycine. . The infrared spectrum is consistent with the intended structure of the prepared substance.

K. D - (-) - N-terc.BltoχskarboonlL-2 '(3 (4'--eeteoχs hyírox ^y Inn ^yl) glycine (3 (3' -Meehooxs- '-hydroxx-RNL) glycine

A solution of 59.2 g (0.6 mol) of 75% glyoxylic acid in 100 ml of water is added at room temperature to 62.07 g (0.5 mol) of 2-methoxyphenol and 140 ml of a concentrated solution; in 400 ml of water. The temperature of the reaction mixture rose to 35 ° C, after which the reaction mixture was stirred at room temperature for 65 hours.

The product which is acidified is filtered off, washed with water, then with acetone, and dried under vacuum over phosphorus pentoxide. There was obtained tkm 57.4 g (58.2%) of 2- (3'-methoxy-4'-dihydroxyphenyl) chloride which decomposes at 218-220 ° (literature 240 °). The IR spectra and the NM-sprons are consistent with the structure of the product obtained.

Aialysis for ^С 9 ^Н И ^И0 4 calculated: 54,82% С 5.62% H, 7.10 % N; found: · 53.77% C 5.91% H, 6.97 % N, 1.13 * HgO3 naleženo s correction for. water content: 54.38% С, 5.85% H, 7.05% N.

References: see B. Block, Houpee-eyler ^z with Z. Chem. 98, 226 (1917).

Cleavage of 2- (3 ' -methoxy-4 ^from -hyíroχlfenyl) glycine.

A. Meethyeeter 2- (3 ^Z- metho: χy-4 ^from -hydroxyphenyl) glycine ..... ·; ·· ·

To a cooled suspension of 94 g (0.476 · mol) of 2- (3-methoxy-4 ^{of from} -hlírro:> χlienУ-) 8 ¹ У ^ci · nl in 500 ml of absolute methanol is introduced swift rake TI 20 minutes gaseous hydrogen chloride.

First, a clear solution is formed, whereupon a crystalline product precipitates in the tint. After 20 hours, the methyl ester hydrochloride was filtered off and washed with a small amount of methanol; yield 99.6 g after air drying. The cooled hydrochloric acid solution in 800 ml of water is adjusted to pH about 8 by addition of sodium hydroxide solution, thereby eliminating the crystalline precipitate of the ester in the free base form. Yield: 81.3 g. considered structure.

Calcd: C 56.86%, H 6.00%, N 6.33%.

found: 56.46% С, 6228% H, 6.56% Ni, 0.59% HgO.

B. · D - (-) - 2- (3 ^from -methoxχl4 ^from -tydruзχrfernУ) sllcin

A mixture of 50 g (0.237 mole) metlhy ester 2- (3-methylbenzyl ^from <OXR-4 ^from -hydruxyfeIl·l) gllcinu, 19 mL (0.333 mol) acetic acid and L isupoopylaerohull heated to reflux · to become partially dissolution. With good stirring, 89.2 g (0.237 mol) of dibenzyl-d-tartaric acid monohydrate is then added and the reaction mixture is heated to reflux. Immediately the salt begins to crystallize. Heating is stopped in the greyhound and the flask containing the contents is allowed to cool slowly to room temperature. After cooling in an ice bath, the precipitated product is filtered off, the filtrate is concentrated to about a third of the initial volume to give a small fraction of the second salt fraction. The total yield of both crystal fractions is 54.1 g after air-drying: see solid subsection A below. '

The filtrate is freed from the solvent by distillation, 300 ml of a 1N hydrochloric acid solution are added to the viscous residue, and the reaction mixture is extracted with 400 ml of chloroform, the solution in chloroform is extracted twice using 100 ml of 1 N hydrochloric acid each. The combined hydrochloric acid extracts are somewhat thickened to remove chloroform residues, and then the acidic solution is heated under reflux for an hour. By concentrating the solution to a small volume, the amino acid salt and hydrochloric acid crystallize, the product obtained is filtered off and recrystallized from 50 ml of 1 N hydrochloric acid solution.

The product was then dissolved in 200 ml of water and the pH of the solution was adjusted to 4.5 by addition of sodium hydroxide solution. The reaction mixture was vylhřeje almost to boiling and then cooling the precipitated D - (-) - 2- (3 ^{out of} -methoχyl4 -hlíroxyfelnl) glycinate as chomáákru0tý! Ch jehličrooitých crystals. The reaction mixture is left to stand overnight, the product is then separated off, washed slightly with water and methanol and dried at 40 ° C. ·

The excavated ^8, 7 ^g · ^t and ^the iso ^ is ^ Units ser ^ C ^ rotation [al ^ ^{-1 24} = 36.5 DEG ^(c = ^{1, 1N} c ^hl orovo ^d i ^K b ^s acid ^. ^E

4Ί

Infrared spectra and NflR-spectra are consistent with the indicated structure.

H, 6.09; N, 6.51. Found: C, 50.43; H, 6.23; N, 6.51; HgO, 8.95.

C. L- (+) - 2- (3 ^Z -Methocэy4 ^/ -UydrocφУ'ennl) glycine

The solid A mentioned above in a weight of 54.1 g is suspended in 300 ml of 1 N hydrochloric acid solution and 500 ml of chloroform are added with good stirring. The salt does not disintegrate too well in this system, and therefore chloroform is separated as carefully as possible and 300 ml of MIBK is added with good stirring. . .

The water-insoluble phase is extracted using 200 ml of a 1N hydrochloric acid solution in three portions, the extracts are combined, filtered and the mixture is briefly suffused to precipitate the remainder of the solvents, after which the acidic mixture is heated under reflux for one hour (ester hydrolysis). The mother liquor is concentrated to a small volume and, after cooling in an ice bath, the hydrochloric acid salt of crystalline crystallizes out, which salt is filtered off, recrystallized from 75 ml of a 1 N hydrochloric acid solution, then sieved in 500 ml of water. and the pH of the filtrate is adjusted to 4.5 with sodium hydroxide solution after filtration. This will double the acid ion.

The reaction mixture is heated to boiling, filtered and, upon storage in the cold, a crystalline product, i.e., L - (+ -. + -. - &lt; / RTI &gt; The product was filtered, washed with a small amount of water and methanol, and then dried at 40 ° C to give 9.6 g of the product .alpha. @ + 127.2 DEG (c = 1.1 N hydrochloric acid). The infrared spectrum and the NRR spectrum are consistent with this structure.

Analysis for

C9H11N4O4H2O requires C, 50.23; 6.09%. H, 6.51%; N, 8.37% HgO;

Found: 50.53% C, 6.06% H, 6.22% N, 7.46% HgO.

² - (3'-Ethoxy-4 '(hydroxyphenyl) glycine)

A mixture of 8.6 g (0.04 mol) and - (-) - (2- (3 '(ethoxycarbonylphenyl) phenyl) glycine, 3.2 g (0.08 mol) of Magnesium Oxide, 9.7 g ( 0.068 moles of tert-butoxycarboxylic acid and 240 ml of a 1: 1 mixture of dioxane and water are stirred under heating at 45-50 ° C for 20 hours under nitrogen, and the cooled mother liquor is diluted by adding 240 ml of ice water, filtered and filtrate The aqueous phase was acidified to pH 2 * with 5 times more acetic acid, the combined extracts were concentrated in vacuo and dried in ethyl acetate, and ethyl acetate was distilled off to remove the product. Oil: 6.3 g.

I. α- (· () - N-trans-ethoxycarbonyl-22 (4-acetic / phenyl) glycine

This compound was prepared using the above procedure except that an equivalent amount of? - (-) - 2- (3 '(ethyl ⁾ (4'-cyclohexynyl) glyeine was used instead of? (-) (2- (4-aenthoxyphenyl) geycin, prepared as follows:

Preparation of α - (-) (2-Amino-2- (4 (acetoxyphenyl) acetic acid)

Procedure A (as a solvent in acetic acid):

A mixture of 203.5 g (1 mol) of α - (-) - β (U-pyrrolidinylglycine hydrochloride) in 800 ml of acetic acid and 314 g (4 mol) of acetic acid was stirred for 48 hours at a temperature of.

The mixture is then passed through 3 times with acetone each time using 2-0 m., Twice with ethanol each using 2-0 m., And the solid is dried at 40 °. In a yield of 210 g (Q5.4%), h-drochhoride is obtained, which is dissolved in 3.0 liters of water, the solution is cooled to + -10 ° C to 10 ° C and adjusted to pH By adding 20% ammonia solution. The suspension was stirred for one hour at - 0 ° C, the solid was filtered off, washed twice with water and acetone and dried at 40 ° C in a yield of 133 g (64%) to be sold, calculated on D - (-) - p-Hydroxy-4-ynyl. [.alpha ^ = -104 ° ^(c = 1, ⁰ · ¹ N extended ^to chlorovodtová ^ o ^ 1] ^ <^ 1 ^ ⁱ i).

Procedure B (in meetylencch-orUu):

A mixture of 4.07 g (0.02 mol) of D - (-) - p-hydroxy-ferrocycline hydrochloride, 30 mL of methylene chloride and 6.28 g (0.08 mol) of acetic acid is stirred for 48 hours. The mixture was washed twice with acetone and twice with ethanol. Yield 4.17 g (84%).

Analysis: Disconnected: 14.4%; found: 14.4% ·

Procedure C (in ^ ΟΓ ^ ο acetic acid):

1.67 g (0.01 mol) of D - (-) - p -droxy-frillil-tin was added with stirring to 10 mL of trifluoroacetic acid at room temperature and after dissolution, 1. -7 g (0.02 mol) was added. ) acel-Chloride. It undergoes a slight exotherm of the reaction and a solid product precipitates; The slurry was stirred at room temperature for 90 minutes, after which time the acid was removed in vacuo. The residual solid was washed with methylene chloride and ethanol. D (-) - 2-amino-2- (4-acetoxyphenyl) acid is identical to the product of procedures A or B. The yield is 1.9 g (7-%).

M. D - (R) - N-tert-Bttsx-carboryl-2- (1'-c-klerxenyl) gl-cii.

This compound was prepared using. of the above procedure by replacing the D - (-) - 2- (3-methyl-4 ^* - [beta] -sulfonyl) - gl-cin used therein by the equimolar team of D - (-) - 2- (1 ' Jgl-tin, prepared according to Belgian patent 773 773 (Оага ^ о 2 -, - 1- T) or african patent 3,824,237 ·

N. · D (-) - N-trrc.Sttsxyklrbsnil ---) 3 ^У -chL-r-4 ^from -eydro2χfyl) gl-cin

It is prepared, for example, using the procedure described in U.S. Pat. No. 3,489,7-1.

O. D - (-) - N-tert-butoxycarbonyl-2- (1 ', 4C-11kehexal-1-yl) This compound was prepared using the procedure described above by replacing it

D - (-) - 2- (3'-Methyl-4 * -h-dr-xyphenyl) gl-cin by equimolar team D - (-) - 2- (1 ^z ₎ 4'-cyl (neeadadil) gl-cint, which is also referred to as D-2-amino-2- (1,4-c-hexadidyl) acetic acid, and is prepared according to U.S. Pat. No. 3,488,819.

P. K-seina D - (-) - 2-tdrc.buSoJykarSoxamiilo-з) (1 _J 4) clyk-ohexadiene) ptopSonová

This compound was prepared using the above procedure by replacing the D ((-) - 2- (3 * -methyl-1 * 4 *) eyedoxyphenyl) g) used by the equimolar amount of -3- ( 1,4-Cyclohexene-1-propionic acid, prepared according to African Patent Specification No. 3 48-819.

Q. K-Seine D - (-) - 2-eerc.tuOo kkarOoxamido-3- ⁽⁴ '-methyl: χl-1 ^from 4 * -cykloedxadienyl) propionic acid

· This compound was prepared by substituting D) -) - 2) ^T3 -methlL ^from -H-4-lrsxyOrnyl) GL-tin Mon. No. 49202058 used in the above-described process, with a molar amount of acid. D-2-eаinooЗ- (4'-аeOhoxy-1> 4 ^"d ieoyl cyclohexanone) pijpionové prepared according to U.S. Patent 3,485,819 ·

R. Kyyelioc 2-tert-Butyl-BykeibonylcinnamomylpheenlLoctová

They are prepared, for example, according to U.S. Patent 3,766,173S. KisZioc N-teic.buOo: yrcarbooyl-1cmlinocyclohexcokaiboxyl

This compound was prepared using the above procedure by not replacing D - (-) - 2- (3'-methyl-4-hydroxy-hydroxy) -gemic acid with 1-amino-cyclohexylic acid.

T. KisZoc D - (-) - CLLaat-eerb.butxlyaiboxoximido-3-thietylacetic

They prepare examples using procedures. U.S. Patent Nos. 3,634,418 and 3,198,804 and references cited therein.

U. KyisZioa D - (-) - cfaa-eerb.butolyaibOxximido-2-thintLylacetic *

For example, they are prepared using the procedures described in U.S. Patent 3,634,418, with reference to those references.

V. KyisZioc beta ~ (2-nitro-tertyl) CbbOonyCm: O-methyl-1,4-cyclohexadiethyl) piopionic

a). KisZioa beOc- (2-lmiOjааeihУ · 1, 4`´cycleLohexadieoyl) -propioo

A solution of 10.74 g (60 mmol) of bet, α- (o-imiomeomethylphenyl) propioolic acid in 1000 ml of liquid ammonia (after preliminary addition of csi 50 mg of lithium to remove traces of water) was gently diluted by adding 300 ml of dry titanium dioxide. .butyl alcohol. To the solution was added in portions 2.08 g (0.3 etom) of lithium over 3 hours and the reaction mixture was stirred for one eye to evaporate the liquid mixture and evaporate to dryness.

The remainder of the sp span in 200 ml of water and the solution was filtered on an IR-120 column (high hydrogen cycle, 500 m.) Eluting continuously with 2000 ml of water. and csi 2,000 ml of a 5% ammonia solution. The tithydrite-positive fractions were pooled to dryness and the residue crystallized from 90% ethanol to give. colorless needles. The yield of .beta.- (1'-amino-4-cyclopentadienyl) -propionic acid was 9.68 g (89%), mp. Mp 228-229 ° C. 1 with ^p infrared ektrim Nu ^{2130, 1540,} 1st 3 ⁰⁰ cm ^-1

NI-specter deltc 2.68 (4H, s, CHgCHgCO), 2.74 (4H, s, methylet cycle groups), 3.68 (2H, s, CHgN), 5.79 (2H, s, vityl hydrogens in cycle).

Analysis for ^ θΗ ^) ^ calculated: 66.37% C, 8,34-. % H, 7.73% N; found: 66.25% C, 8.35 fc H, H, 8.52; N, 7.51. 7.71% N.

(b) KasUtc betc- (2-eicc.t) UtXlkerbOonyamiooettett. ”1,4-cyclOhexadieoyl) propionic

To a mixture of 1.40 g (7.7 mol) of beOe - ((2cMl: moаethy11,4-cyclohexadienyl) propixnové and 2.02 g (20 Mamo) Orieh] yrСmiou in 50% aqueous ^tetrťhy, drjf urea (20 m. A solution of 1.43 g (10 mmol) of azidic acid in 5 mL of tetrahydrofuran is added and the reaction mixture is stirred at room temperature for 2 hours. The mixture is washed twice with 20 mL of ether each time and the aqueous layer is washed twice. acidified to pH 2 by addition of dilute hydrochloric acid. The acidified solution is then extracted with chloroform four times using 30 ml each time, and the combined extracts are washed with water, then dried, and the extract is concentrated under reduced pressure to obtain beta acid. - (2-tert-butoxycarbonylaminomethyl-1,4-cyclohexadienyl) propionic acid as a colorless oil, yield 2.10 g (97%) ·

IR: Nu 1700, 1510, 1240, 1160 cm ¹

NMR Spectrum! delta _P ^ 3 1.47 (9H, a, t-Bu-H), 2.45 (4H, s, _{CH2 CH2),} 2.69 (4H, s, methylene groups in the ring), 3.80 (2H, d, 5 Hz, CH 3 N), 5.70 (2H, s, cyclic hydrogens).

W. Beta- (2-tert-butoxycarbonylaminomethyl-1-cyclohexenyl) propionic acid

0.92 g (3.2 mmol) of beta-2-tert-butoxycarbonylaminomethyl-1,4-cyclohexadienyl) propionic acid is dissolved in 20 ml of a 3% aqueous ammonia solution and the solution is hydrogenated at 2.1 atm using 0, 1 g of 10% palladium on carbon for 3 hours in a Parr apparatus. The reaction mixture is filtered, the filtrate is acidified to pH 2 by the addition of dilute hydrochloric acid and the acidified portion is extracted three times using 30 ml of ethyl acetate each time. The combined extracts were washed with a small amount of water and, after drying, distilling off the solvent under reduced pressure gave 0.84 g (91%) of .beta.- (2-tert-butoxycarbonylaminomethyl-1-cyclohexenyl) propionic acid.

Infrared Spectrum:? 341, 350 (NH), 3200 - 2400 (COOH), 1750 (CO), 1250,

165 BOC).

NMR: delta ® ^X ^ 3 1.48 (9H, s, t), 1.5 to 1.8 (4H, m, ^ CHgC)

1.8 - 2.2 (4H, m, CH allyl), 2.4 (4H, CH ₂ CH ₂ -C 0); 3. 72 (2H, s, N-CH _2).

X. D - (-) - N-terč.butoxykarbony1-2- ^(from 4-hydroxymethyl) glycine

This compound, also referred to as D- (~) -N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine, is prepared according to the process of South African Patent 73/4055; to simplify the situation, the entire workflow is further reproduced here.

To a solution of 50.0 g (0.373 mol) 1,4-benzenedicarboxaldehyde in 200 ml dry tetrahydrofuran was added dropwise under nitrogen and in an ice bath a solution of 104.0 g (0.410 mol) lithium tri- (tert-butoxy) aluminum in 500 ml dry tetrahydrofuran . The reaction mixture was stirred in an ice bath for 90 minutes, poured into 2 liters of ice-cold 2 N hydrochloric acid solution, extracted with four portions of ether (800 ml) and the combined ether extracts washed with ice-cold 5% 500 ml. sodium bicarbonate solution. After drying the solution, distilling off the ether under reduced pressure yielded 46 g of crude p-hydroxymethylbenzaldehyde. The crude product is chromatographed on 1 kg of neutral alumina and the ether eluted fractions are concentrated.

On cooling, p-hydroxymethylbenzaldehyde crystallized in a yield of 17.0 g (35%), mp. 44.5-46 ° C.

To a stirred solution of 10.0 g (0.0735 mol) of p-hydroxymethylbenzaldehyde and 17.1 g (0.15 mol) of ammonium carbonate in 110 ml of 60% ethanol was added dropwise a solution of 4.0 g (0.081) after heating to 50 ° C. mol) of sodium cyanide dissolved in 10 ml of water. The reaction mixture was stirred with heating at 55-60 ° C for 3 hours, then the temperature was raised to 85 ° C for 1 hour. After cooling in an ice bath, the pH of the solution is adjusted to 6 by addition of concentrated hydrochloric acid, the solid which precipitates by cooling overnight is filtered off, washed with cold water, and dried to give 11.0 g (72%) of 5- ( p-hydroxymethylphenyl) hydantoin o bt Mp 189-196 ° C (dec.). This material was used without any purification to prepare the corresponding amino acid.

A mixture of 10.9 g / 0.053 mol) of 5- (p-hydroxymethylphenyl) hydantoin and 2.5 g (0.081 mol) of barium hydroxide octahydrate in 125 ml of water was stirred and heated to reflux.

What for 18 hours. After cooling in an ice bath, the reaction mixture is diluted with 125 ml of water, acidified to pH 1 with concentrated sulfuric acid, filtered off and the pH of the filtrate is adjusted to 6 with lead carbonate. The lead sulphate is filtered off, the filtrate is saturated with hydrogen sulfide and the lead sulfide is filtered off.

The azeotropic distillation is then concentrated to a volume of 100 ml by azeotropic distillation under reduced pressure. 5.2 g (54%) of p-hydroxymethylphenylglycine, m.p. 228 DEG-229 DEG C. and crystallized from ethanol / water, m.p. Mp 230-231 ° C (dec.).

H, 6.12; N, 7.73. Found: C 59.46, H 6.24, N 7.93.

To a solution of 8.0 g (0.044 mol) of p-hydroxymethylphenylglycine and 8.8 g (0.087 mol) of triethylamine in 160 ml of water was added 6.95 g (0.049 mol) of tert-butoxycarbonylazide dissolved in 120 ml of tetrahydrofuran and the reaction mixture. is stirred overnight at room temperature. It is washed with two portions of 200 ml of ether each time, the aqueous layer is covered with ether and acidified in an ice bath to pH 3 - 3.5 by addition of 3 N hydrochloric acid solution.

The acidic solution is extracted three times with 200 ml of ether each time, the combined ether solutions are washed with saturated sodium chloride solution, dried and the ether is distilled off under reduced pressure. The resulting oil was triturated with chloroform-hexane, the precipitated solid was filtered off to give DL-N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine in a yield of 7.74 g (63%). The substance decomposes when heated to 139-141.5 ° C.

H, 6.81; N, 4.98. Found:% C, 59.67;% H, 6.76;% N, 4.69.

A mixture of 7.560 g (0.0269 mol) of DL-N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine and 10.199 g (0.0269 mol) of quinine is dissolved in 110 ml of boiling ethanol and the solution is cooled to room temperature. Crystallization overnight precipitated salt, which was filtered off, and such crystallization was repeated three times.

From 17.76 g of salt, m.p. 198 DEG-201 DEG, and with a specific rotation [.alpha.] D @ -149.8 DEG (e = 1, methanol), after three crystallizations, the cleaved salt was obtained in a yield of 4.6 g, m.p. 205 to 206 ° G,

will increase.

-163.4 ° (c-1, methanol). Further crystallization is no longer the value of the optical rotation of the non-rotatable salt of quinine and D - (-) - N-tert. The butoxycarbonyl-p-hydroxymethylphenylglycine is suspended in 75 ml of water and 175 ml of ether in an ice bath, and the pH is adjusted to 2.5 by addition of 3 N hydrochloric acid.

After separation of the ether layer, the aqueous portion is extracted into two portions of ether (100 ml each), the combined ethereal solutions are washed with 100 ml of saturated sodium chloride solution and, after drying, the ether is distilled off under reduced pressure. The residue was triturated with chloroform and hexane and filtered to give D - (-) - N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine in a yield of 1.68 g (98%), m.p. 111-115.5 ° (decomposition), specific rotation value = -136.5 ° (s = 1, methanol).

The use of an enamine protected group with a suitable side chain at position -7- containing a free amino group prior to acylation of the backbone, such as structure II, is well known in U.S. Patents 3,223,141, 3,813,390, 3,813,391, 3,834,141 and for the sake of Belgian patent specification 773 773.

2- [N- (1-ethoxycarbonylpropen-2-yl) quinomethyl] -1,4-cyclicexadienylacetic acid, sodium salt (4)

To the stirred solution 460. mg (0.02 moo) of sodium metal in 100 ml of absolute ethanol was added ^ with 3.34 g (0.02 mol) of 2-aminovethhl - CY-14 ^to L · chexadienyУoctcvé and 3.1 g (0.024 moo) ethyl acetate and acetic acid, then the reaction mixture is heated to reflux temperature. reflux. with stirring for 4 hours. The hot reaction mixture was filtered and the filtrate was collected overnight to give 2.0 g of colorless needles at 264 ° C. Da.Sd product in 3.3 g is obtained by concentrating the mother liquor to a boiling point of g (88%).

The total yield is 5.3

Infrared spectrum:

Nu ^nu * J 3300, ^{J υ max>} 1090 cm ''. 1 635, 1 600, 1,570, 1,300, 1,275, 1,170, delta ^D 2 ° 1.23 ppm (3H, t, 7Hz) , ch ₂ ch.j), 1.96 and 2.25 (3H, with C = (C-CH ₃ , cis and trans), 2.70 (4H, with HgK '),

3.04

4.07

5.76 (2H, (2H, (2H, s, CH ₂ CO)), 3.66 and 3.95 (2H, s, CH ₂ -N, q, 7 Hz, CH ₂ CH ₃ ), 4.45 and 4 56 (1H, s, -,

s.H cis and trans),

H = cis and trans),

Analysis for

^Ha oi ^ ^^ ^^ ^{At t}

calculated:

found:

59.76% C,

59.69% C,

6.69

6.76% H,% H,

4.64% N;

4.75% N.

Croscarmellose aminoCylsliny D - N- (2-πmthyoyklrac) nvnl1-1etlnУvivyll íjninncajfa--alpha (3 ^from 4--metУll -Уyarcxyfenyl ^Z) cοtcíé

To a stirred solution of 3.02 g (0.078 moo) of sodium hydroxide in 320 ml of methanol is added 0.08 mole of D - (-) - 2- (3'-metl'lyl ^from -4 · -hldrcxyfenyl) cllοint and the reaction mixture was heated to reflux while a solution of 9.6 ml (0.088 mol) of methacrylic acid meethyester in 80 ml methanol was added over 30 minutes. After heating the reaction mixture to boiling for an additional 30 minutes, methanol was distilled off while adding toluene at the same speed as methanol. The reaction mixture still has approximately the same internal volume. .

When the internal temperature of the reaction mixture reached 100 ° C, the solution was cooled in an ice bath, cooled there for 4 hours, the solid was filtered, washed well with toluene and air dried. the solid is further dried over phosphorus pentoxide to a constant molarity to give a solid sodium salt of DN- (2-methyl-1-methyl-1-thienyl) -1- (3-methyl-4-methyl) (3'-methyl-4 ^). -Уldrc: χ1phenyl) cctcíé.

Sodium salt of DN - (- ^r methycykaíbobo NL1 "Π-etnyУlivyn) - JLA-amnc) cajfa- (3 ^of -mstУcχl-4 -hydrcχlfeiyl) cctoíé

To a stirred solution of 3.02 g (0.078 mol) of sodium hydroxide in 320 mL of methanol was added 0.08 mol of D - (-) - 2- (3'-methoxy-4'-hydroxyphenyl) clyintine and the reaction mixture obtained was The mixture was heated to reflux while a solution of 9.6 ml (0.088 mol) of ethyl acetate was added. v. 80 ml of methanol in 30 minutes. The reaction mixture is further refluxed for 30 minutes, then methanol is distilled off while adding toluene at such a rate that the volume of the reaction mixture is maintained at approximately the same level. When the internal temperature reaches 100 ° C, the suspension is cooled in ice water for 4 hours, the solid is collected by filtration, washed well with toluene, air-dried, further under vacuum over phosphorus pentoxide until constant. as solid poddl DN ^ -methoXll: íabbvyl methyУlirχil-1) - JFA-j] einic-jfa- (зZ-methoэχl4 ^of -Уydrcχlfenyl) cctcíV acid, sodium salt.

S3

2020S8

With similar use of the proton-protected group to that of j-Comu in the case of acid chloride lysyl chloride, which is also well-known from LiCeraCuiy, proceed as follows:

D- (-) - 2- (3'-L-alkoxy-4'-lyloxy-2-oxo) chloride chloride is prepared in high purity and high efficiency in the following manner:

About 0.06 mol of D - (-) - 2- (3-chloro-4'-hydroxy-2-oyl) glohiourea is stirred in 100 ml of dionane and phosgene gas is introduced into the suspension while stirring. maintaining the C-ploCo slurry in the range of S0 to S8 ° C. A total of 20g-n was introduced over 3.5 hours to give a yellow solution. The excess phosgene is then purged with nitrogen and introduced into the solution for 2.5 hours with gaseous hydrogen chloride, then stirred with dilution by diluting a small amount of solution with crystals to obtain crystals to form a solution. - add as an eye to the main share. Remote-S- solution stirred for 16 hours at 20 C Ploc 2S ^ to C obtained suspo-ns krosCalhckélž of D - (-) - 2- ^(3/4 * -leChžxy -lydržxy2ero0.) - S- glOhylhllžridu filter, and collect the product.

The fraction of the filter with p-dioninium and ethyl chloride, followed by drying in a vacuum of 2 x 6-pentoxide, yields about 7 g of D (-) - 2 - (- (- ho ^ 0 - / - ^ (^ 0 ^ 02-100 ^ 10 ^ 0 ^)

Preparation of D - (-) - 2-Amino-2- (4-ahttonyltrino) -hydrochloride acid:

A mixture of 83.6 g (0.40 mol) of D - (-) - 2-ε-α-2- (4-ac-C2n-2-yl) -acetic acid and 1,2S of 1-b-induced e-CHenchClench is cooled to - After stirring at 0 ° C, 15 g of 2-magnesium-2-chloride chloride and 4 ml of ethyl formol are slowly added, and the mixture is stirred for 4 hours while cooling to 0 ° C. The first subclass was washed with b-aqueous ethyl ether and dried under vacuum at C-10 to give 61 g (S7, S%) of product.

Alialysis for chlorine calculated: 26.9% nal-z-oo: 27.2%.

Preparation of D-meaidylic acid carbonylamide:

COCI ^

C ₆ H ₅ CH — COOH

OH

D-msndelic acid carboxylate (2)

For 30 minutes, 2.0 g (0.013 mol) of D - (- mandelic acid) in dry CsCrlH2O was added to the solution, and the resulting solution was dried over a period of time. The resulting solution was heated at reflux for 10 minutes, and the solvent was removed by distillation under reduced pressure to provide the oil with the addition of 20 ml of 20 ml of 20 ml. The product was dried in vacuo over potassium hydroxide to give D-meaidic acid carbonyl hydride (2.3 g).

Io2rac-rsso sp-crm nuj 1889S, 1787S, 1780 cm -1.

¹ max

Among the more obvious substances of the invention, Cy compounds are found to be in the configuration of D-O and alpha-carbohydrate in the late-7-position, which are Cy, which they prepare from. D-2-2-silylglycine or D-mendlic acid o-bromine derivatives of D-2-2-oylglycine or D-meinddic acid as described above. Further, the configuration on two optional and α-active, asymmetric c-nCr-ch b-Ca-actomic s-groups is as general as

This is the case in cephalosporin C, which has been prepared by regeneration, and in 7-aminocephalosporaic acid, which has been prepared from these substances.

Further examples are appended to describe the process of the invention, but not to any limitation thereof. All temperatures are given in degrees Ceesia.

7-Aminocephalosporanic acid is shortened by 7 / ACAm where -ACA- is a structural group

so 7-aminocephalosportic acid -7-ACA can be expressed by the echo-formula

H-ACA-O-C-CH.

II 3

II o

Skeeiysolve B is the petroleum ether fraction o · b.v. 60-68 ° C consisting essentially of n-hexane.

The LA-1 resin is a mixture of secondary amines wherein each secondary amine has the formula

R ¹

CH ₃ (CH ₂ ) ₁₀ CH ₂ -NH-CR ²

Ř3

Wherein each of R ¹ , R ^{3 and} R ³ is a monovalent aliphatic hydrocarbon radical and wherein R ¹ , R ^{3 and} R ^{3 each} represent from 11 to 14 carbon atoms. This secondary amine mixture, sometimes referred to in the examples as the liquid amine mixture No. II, is a clear amber-colored liquid having the following physical properties: viscosity at 25 ° C: 70 cpd, specific gravity at 20 ° C is 0.826; refractive index at 25 ° C is 1.4554, distillation range under vacuum 10 Torr up to 170 ° C

170-220 ° C 220-230 ° C above 230 ° C

0,5.% «

%

6.5%

Ir α-120 is also referred to as Anberlite-120 and is a strong cation exchanger containing siphonic acid residues. It is a commercially available polystyrene siphonic acid cation exchanger, so it is a core sulfonated polystyrene resin crosslinked with benzene divisions, obtained by the procedure described in Kui et al., Hange Resins, second edition (19513). ; J. Wiley and Sons. Inc.,

USA, see, for example, pp. 84 and 87.

He did.

7- (2-AminobenzylphenyleneSacetic acid) -3- (1-carbonylcarbonyl-5-ylthiobetyl) -3-cefeb-4-carboxylic acid

CH ₂ NH ₂

CHjCONH

cooh

AND

CHjCOOH i

1. Charge 7.6 g (0.001 mol) of 7-amino-3- (1-carboxymtexultterazol-5-ylthiomethyl) acid to a three-necked flask containing 100 ml of ion-free water, equipped with a stirrer and thermometer. -3-ε-fem-4-carboxylic acid and 3.4 g (0.034 mol) of N-meetulmo-ro-in. The solution was cooled to 0 ° C with stirring in an ice bath and maintained at this temperature.

2. In another flask, also equipped with a stirrer, 9.6 g (0.03 mol) of sodium 2- (1-oethoxycarbonyl-1-propeo-2-l-aminomethoxy) -Oenyloct are added to 184 ml of tetrihydrofuran. The suspension was cooled to -30 ° C with a solid carbon dioxide bath and acetone with stirring. While stirring continuously at -30 DEG C., 20 drops of dimethylbenzyl amide and 4.4 g (0.03 moles) of culoboric acid isobutyl ester are added. the reaction mixture was stirred for 5 minutes.

3. The mixture from step 2 is added all at once with stirring to the solution prepared in step 1, the solution obtained is cooled to 3 ° C and kept under stirring for one hour.

4. Tetrotreated Ulydr-Oura is removed from the reaction mixture at 30 ° C using vacuum.

Tom.

5. Adjust the pH of the remaining solution in water to 4.0 with concentrated hydrochloric acid.

6. Add 2.5 g of activated carbon (Darco G-60) to the above solution and stir the color solution for 20 minutes; the coal is then filtered off.

7. Overlay the filtrate using 120 ml of ethyl acetate and reduce the pH to 3.8 by adding concentrated hydrochloric acid while stirring. Some of the brownish solids that may be precipitated are stripped off and retained for further processing and recovery.

8. Using a red bath, cool the filtrate to 5 ° C and reduce the pH to 2.5 to 5 ° C

2.8 by adding concentrated hydrochloric acid, maintaining the temperature at 5 ° C and stirring the reaction mixture for an hour. .

The product which precipitates is filtered off, washed according to the filter using 1 ml of cold and deionized water, followed by 5 ml of cold methanol.

10. The solid 7- (2-Amino-pyrrolidin-3-yl) -3- (1-carbonylethyl-etrazo-5-yl-trietho-ethano) -3-cyclo-4-carboxylic acid is dried in air to constant Umin-Si; in a typical experiment 4.1 g of product are obtained.

11. The product obtained in step 10 is passed through a 200 mesh stainless steel sieve.

12. 10 g of the product thus obtained are mixed into 100 ml of chloroform, 5 ml of triethylamine are added, the mixture is heated to 50 DEG C. with vigorous stirring and maintained at this temperature for 5 minutes with stirring. .

13. Filter the mixture hot; 7-Amino-3- (1-carbonyl-trifluoromethyl-5-ylmethyl) -methyl-carboxylic acid, pigments and other impurities are soluble in hot chloroform in the presence of triethylamine. chlvrof ^mL, oJmu and dried in air for two hours. Yield · 1-8 g of 7- (2-aminooithuSffenSysctamido) -3- (1-carbonyl> χy) ithylteerazol 5-yltUioietlhУ) -3-ce FEM -4 - carbv: ylyl.

14. The product obtained in step 13 is sieved through a 200 mesh sieve

15. 10 g of the product thus obtained are mixed into 75 ml of a 0.1 N solution of hydrochloric acid, stirred for 10 to 15 minutes, filtered and the filter is washed with 25 ml of water, 50 ml of methanol and air dry for 2 to 3 hours at room temperature. Yield up to 10 g.

16. 10 g of 7- (2-aminomethylsulfenylacetamido) -3- (1-carbonylphenylthiazol-5-ylmethyl) -1-cephem-4-carboxylic acid from step 15 are stirred into 65 ml of methanol.

(a) Add 2 ml of concentrated hydrochloric acid; a clear or almost clear solution is obtained and stirred for 5 minutes.

b) Mix vigorously with stirring. from step a) · add 130 m of water. A precipitate is immediately formed (entraining the largest proportion of dyes); a pH of 1.3 to 1.6 is required.

c) Stir the mixture for a minute, filter rapidly, retaining the solids for possible further processing and recovery.

d) The filtrate is seeded and mixed gently. Crystallization takes about 15 to 30 minutes.

e) The mixture was stirred at room temperature or 4 ° C for 2 hours after the start of crystallization.

f) The crystals are filtered off, firstly. using 25 ml of a mixture of 65% water and 35% methanol (v / v), 50 ml of methanol, and the solid is dried under vacuum at 50 ° C · 24 hours. Yield: up to 9 g of purified and white 7- (2-amino-sulfenesacetamido) -3- (1-carboxyethyl-tetramethyl-5-ylthiethyl) -3-cephal-4-carboxylic acid.

17- The following are 2 alternative methods of crystallizing 7- (2-aminomethyl-phenylacetyl (ii)) - 3- (1-carboxys] methylteerazol-5-ylthiomethyl) -3-methyl-4-carboxylate.

AND)

1. Stir 10 g of the product obtained from Stage 15 in 100 ml of methionol.

2. Add 2 ml of concentrated hydrochloric acid to obtain a clear or almost clear solution.

3. Add 1.5 g of active union (Darco G-60) and stir the vigorous mixture for 30 minutes.

4. Filter the activated carbon, wash with 20 mL of methanol and add the methanol portion of the wash to the filtrate.

5. Add 120 ml of water to the filtrate; it can cause small solids to precipitate. This subclass is filtered and retained for further processing or recovery.

6. With vigorous stirring of the solution from step 5, the pH is adjusted to 2.5-3.0 by the addition of 10% sodium hydroxide solution. Crystals are formed. 4

7. The mixture is stirred for 30 minutes, the crystals are dried (20 ml, 1: 1, v / v), 30 ml of methanol, and the crystals are dried under vacuum at 24 DEG C. for 24 hours. The yield is up to 9 g of purified 7- (2-aminomethylsulfonyl chloride) -1- (1-carbonylethyl) tetrazol-5-ylthiomethyl-4-cephem-4-carboxylic acid.

(B)

1. Stir 10 g of the product obtained in step 15 into 75 ml. water.

2. Add 10% sodium hydroxide solution to maintain pH at 6.8-7.2. This will dissolve or partially dissolve.

3. Add 1.5 g of activated carbon (Darco G-60) and stir the mixture for 30 minutes while maintaining a pH in the range of 6.8 to 7.2 by continuously adding 0.1 to 1 N solution. sodium hydroxide. .

4. Activated carbon is separated; Wash on the filter using 20 ml of water added to the filtrate. ,

5. The crystallization of the solution at pH 6.8-7.2 from step 4 can be carried out at pH 2.5-3.0 as described in steps 8 and 7 of process A above, above the pH value or beyond pH values of 1.2 to 1.5 (by addition of hydrochloric acid) and as described in steps d, e, f of step 16. In both cases, up to 9 g of crystalline 7- (2-amincmethylphenylacetamido) -3- ( This product is often obtained in the form of crystalline monohydrate, this compound is subcutaneously injected at a dose of 10 mg / kg of body weight of the mouse to achieve blood levels in 15 minutes.

19.7 mg / ml.

The protective dose for 50% of the animals given the title compound at a lethal intramuscular dose of Escherichia coli -A15119, K. pneumoniae A9977 and E. cloacae A21020 is 0.33-0.42, 1.5-25, 1- 3.2 mg / kg in which case, given for each type of microorganism. .

Example 2.

Dipotassium - 7- (D-alpha-Oxyacenylphenylacetamidyl) - (1-carboxyethylthetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid salt

COOK

CHjCOOK

DA).

7- (D-alpha-formyl) acetamido-3- (1-carbonyl-2-ethylsulfonyl-5-yl-hexyl) -4-carboxylic acid

To a suspension of 500 mg (0.0134 mole) of 7-aiinv-з ((-] krbbvχliteyllitrrzzV _{C-5-ylthiomethyl)} -3-cephem-4-carboxylic acid in 10 ml of water under cooling at O ° C was added under stirring 200 mg of sodium hydrogencarbonate Once the suspended substance is completely dissolved, a solution of 340 mg (0.0172 mol) of D - (-) - 2-phenyloxy-2-phenyloxyacetate in 10 ml of acetone is added in one portion and added to form a precipitate. solid sodium bicarbonate and the solution was stirred at pH 8 for 1 hour.

The acetone is distilled off at 30 ° C. ve. vacuum of 15 Torr, then the remaining solution is overcoated by addition of 20 ml of ethyl acetate and acidified by addition of dilute phosphoric acid (1: 1). After extraction into ethyl acetate, the reaction mixture is filtered, the organic layer is separated and the solvent is evaporated to give substantially pure 7- (D-alpha-aphoralyl-oxyphenyl acetyl) -3- (1-carbozxraietethLeerazoo-5-ylthi ometal) -3 product. -cephene-4-carboxylate.

B.

7- (D-alpha-Hydroxyphenylacetyl) -3- (1-carbonyl) -literter-5-ylthioethyl) -3-ethyl-4-carboxylic acid dibasic salt

The solid from Step A was dissolved in 5 ml of water with the addition of 5 drops of concentrated hydrochloric acid, the solution was decolourised with active carbon and heated for 3 minutes on a steam bath. The reaction mixture is then filtered, diluted with 15 ml of water, the gummy solid is triturated with cold water and then beige. ether. Left over. hard succumbed. Dissolve in 5 ml of acetone and add to the solution 50 mg of potassium 2-ethylllexanoic acid.

thus a 7- (D-alpha-hydroxyphenylacetamido) -3- (1-carboxyllithetetrahydro-5-yl-10-ethyl) -1-methyl-4-carboxylate is obtained as a white solid in a yield of 90 mg, bt. 175 ° (slow decomposition).

Analysis for C. gH, g ^ K ^ gNgOySg

H, 2.77; N, 14.42.

Found: 39.87% C. 3.50% H. 12.58% N ..

This compound was administered intramuscularly by injection at a dose of 10 µg / kg, calculated on body weight, to reach a blood level of 21.4 mg / ml in 15 minutes.

The protective dose for 50% of the animals protected by the title compound is 0.8 mg / kg for the E. coli A15119 at the intrinsic intramuscular dose.

Example 3

N- (D-.alpha.-aminophenylacetamido) -3- (1-carbonylthiylthiazol-5-ylthiomethyl) -3- (4-methylphenyl) carbonyl] -acetic acid

COOH

CH3COOH

A solution of 0.55 g (0.0022 mol) of D "(-) - εlLf - terb.bvto k ^г EabOoxmidof phenyl acetic acid and 0.22 g (0.0022 mol) in 17 ml tbiehhylmiil tetríhlyOrvfur · anus after Cool to 0 ° C vigorously with the addition of 0.300 g (0.0022 mml) of isobutyl ester by chloroformation. The reaction mixture was stirred for 30 minutes while cooling to 0 °, and then a solution of 7-amino-2- (1-carbonyl) -ethanol-5-yl-4-carboxylic acid (7-amino-2- (1-carbonyl)) - 3-ethyl-4-carboxylic acid (0.0022 mol) and 0.445 g. (0.0044 mol) triethylmiil in 6.8 ml of 50% tetrhydrofuran. The resulting solution was stirred for 2 hours at 25 ° C under 15 Tom vacuum to give an oily residue.

The oil is washed with two portions of ether (50 ml each), diluted with half of its own volume with water and acidified to pH 3.0 by addition of dilute hydrochloric acid. The reaction mixture is stirred for 1 hour in an ice bath, whereupon the product is extracted into 75 ml of ethyl acetate. ·.

The extract was washed with two 20 ml portions of water and two 50 ml portions of saturated sodium chloride solution. Ethyl acetate was separated in vacuo at 35 ° C. An oil remains, which is triturated with Sulfellsuid B to give 480 mg (35.3%) of 7- (D-11-tert-butyl) -hydrogenbuxamido-5-carboxylic acid --- (1-carboxylate-tetrazyl-tetrazol-5-ylmethyl) -3 cidem-4-Olrbuxluc. .

This sample was added to 1 mL of trifluoroacetic acid and the solution was stirred at 0 ° C for 1 hour, then diluted with 50 mL of ether. The salt was filtered, dissolved in 10 ml of water, and the pH of the solution was adjusted to 4.0 by addition of dilute ammonia solution. The precipitated product was filtered off, washed with water and acetone, and dried under vacuum over phosphorus pentoxide at temperature. 25 ° C for 18 hours yielded 150 mg (23.9%) of 7- (D-alpha-aminophenyl acetamido) -3- (1-carboxyethylthiazol-5-ylmethyl) -acetamide-4-carboxylic acid, bt above 180 ° C for slow decomposition. '

The infrared spectrum and NVIR-sppktnm are consistent with the structure.

An analysis for ^ 9 ^ 9 ^ 0 ^ 62. H, 4.16; N, 18.41. Found: 43.17% C · 4.12% H · 16.74% N.

Example 4

7- (2- ^ minumeehehL · 1,4-'ChexlueadadenyhacetlmidouЗ - '(1-Ocarbonyl-5-ethyl-hexyl) -5-nitro) -3-cephem-4-carbonic acid θ ^ 0Η3ΜΗ ₂ c

A solution of 0.80 g (0.003 mol) of 2-terc.buUoxykarbonhlamiiomeeheha · 1,4-cykaueexadidnylonové and 0.303 g (0.003 mol) trieehylmiiu in 19.2 ml of tetrahydrofuran is stirred under cooling ^{at 0,} followed by addition of 0.41 g (0.003 moo) isobutyldstdol ceaormic acid. The reaction mixture was stirred for 30 minutes at 0 ° C and added to a solution of 0.003 mol of 1-amino-L- (1-O-carbomethyl-hetetrazua-5-ylmethyl) -hydroxy-4-carboxylic acid. and 0.6 g (0.006 moa) of triethylamine in 9.2 m and 50% tetrMydrofuran.

The solution thus obtained is stirred at 25 DEG for 1.5 hours, the mixture is decanted at 30 DEG C. under a vacuum of 1.5 DEG C., the residue is washed with yellow portions of 30 and 30 ml of ether each time and diluted. with water. Furthermore, the solution of ^ 2 ^ ^£ ^ a ^ e ^ -t dilute hydrochloric acid to pH 3.5, the product was _oddiltolje) · dried in vacuo over kysaičnkkem fosfodčiým at 25 ° C for 18 hours to give the 1, 55 g (54.0%) of white powder.

To the above 7- (11-chloro-2-trifluoromethyl-1,4-chloro-oxadienyl) -ethoxy) -3- (1-clethoxy-ethyl-tetril-11-yl) -loyl} -yl- (2-trifluoromethyl-1,4-chloro-oxadienyl) -ethoxy-3- (4-chloro) -sulfyric acid was added. The reaction mixture was stirred at 0 ° H for 1 hour while cooling. The solution is then diluted with 150 ml of ether, the precipitate is filtered, the trifluoroacetic acid salt is suspended in 3.4 ml of water and the pH of the suspension is adjusted to 4.5 by addition of dilute ammonia solution.

The spherical residue is triturated with water, filtered off and washed with water and acetone. The product was dried under vacuum over phosphorus pentane for 18 hours. at 25 ° H to give 53 mg, (15.72%) of 7- (2-aminomethyl-114-cyclhexadiene-acetyl) --- (1-methylthiazol-5-ylthioethyl) -3-trifluoromethyl-4-chlorophenyl) bt above 160 ° H with slow decomposition.

Analysis H20H23 ^N ° 7 6S2 ^'1, 5 HgCl.

H, 4.55; N, 18.44. found: 45.46% C. 4.68% H- 17.09% N.

The infrared spectrum and the N? R? S? E? E? T? M are consistent with the proposed structure.

Example 5

7- (Alpholin-4-hydroxyphenyl-acetylide) -3- (1-quinolylthylmethylthalzol-5-ylthiomethyl) --- cefee-4-carboxylic acid

To a solution of 2.7 g (0.01 mol) of D - (-) - N-tert-butoxycyclyl-p-hydroxyphenyl-1-glycine in 92 ml of tetritrile-uranium is added 1.1 g (0.01 mol) of N-menylphiloline, the solution is The mixture is stirred at 0 DEG C. and 1.4 g (0.01 mol) of the isopropyl ester of the acid is added in one portion.

Stirring is continued for 10 minutes and the mixed anhydride solution is added to a solution of 3.7 g (0.01 mol) of 7-leino-3- (1-chloroethyltetrazo-5-ylthioethyl) -cefee-4. and 1.1 g (0.01 mol) of N-meethrmelfoline in 50 ml of water cooled to 0 ° H.

The prepared solution was stirred for an hour, then setetrl-ethylfuran was decanted at 30 ° H under 15 Torr vacuum to a total residue volume of 45 mL. This solution was acidified to pH 2 with dilute phosphoric acid (1: 1) and the acidic solution was extracted with ethyl acetate, the solution in this solvent was washed with water and then azeotropically stripped of the solvent to give a glassy solid (vacuum separation). 30 ° H and 15 Torr). The residue was triturated with ether to remove any optional starting acid and the product was then stripped.

The same is hygroscopic and is therefore immediately transferred to 5 ml of trifluoroacetic acid and the resulting reaction mixture is stirred for one hour at 27 °. The solution is diluted with 25 ml of ether, the precipitated product is filtered off and suspended in 5 ml of water, the pH is adjusted to 3 by the addition of a concentrated solution. The reaction mixture was then diluted with 10 ml of 1-propylpylalcohol.

The pale brown solid was filtered and dried in vacuo. vacuum over phosphorous after 24 hours. hours. This gave a total of 300 mg of 7- (.alpha.-Amino-4-thyroxyphenolcellyl) - (1-carboxymethyl-tetrazol-5-ylmethyl) -1,3-cyclohexyl-4-clyl. 175 ° (slow decomposition). .

202058 Analysis for C ^ HH ^ gNfOsOss iso iso — C3 C3 C3: C — C3H,7O: C, 42.78; H, 4.44; N, 17.32.

found: 42.86% C. 4.55% H. 15,: 39% N.

The infrared, the spectrum and the ikR -spectrum are consistent with the structure under consideration. The presence of 0.75 mol of isopropyl alcohol is not apparent from the NM-spectra. in the product

Example 6

KysHna 7 d ^{D-al f} -amino-al ^f a (- ^(p - ^{f Ty} roxy if ^c yl) -all ami ^e o ^{t t} - (3- (1-carboxy ^b t: ^χ lletlytleerazot 5- yl (ttiomet] TLL) (3 ^"c IFEMA (4-karboxlltvá ester of 7-alpha-id-e-rc.butOlkkubtonylímint-alpha- (ptlydroxlfenyl) -acetmieojcef aoosporanové '· followed by removal of protecting groups..'

A.. ’- '

7- [α] - [alpha] - ((4-Hydroxyphenyl) -α-D- (tert-butylcarbonylamin) acetamido] -3- (1-carbonyl-oxy-ethyl-thiazol-5-yl-thitmethyl) -3-cephem-4-carboxylic acid

0.27 g of sodium salt of 7- [alpha- (4-dihydroxyphenyl) -alpha-D- (lurc.PuOolcocarbonbutyl) -. The acetonitrile phosphate is suspended in 1000 ml of 0.1 M phosphate buffer, pH 6.4, and 0.31 is added to the buffer. mole of 1-cyano-4-hydroxy-5-methyl-10-azole isoisolate.

The solution was heated at 55 ° C under nitrogen for 5 hours; per hour, the pH is adjusted to 6.4 by adding a small amount! 40% phosphoric acid and at the end of the 5-hour heating period, the solution is cooled to 23 ° C, the pH is adjusted to 2 by addition of 3 N hydrochloric acid solution under a layer of ethyl acetate.

ProDuo t ^^ is extracted into ethyl ^ te-acetic acid in solution in this solvent is agitated for 15 minutes at 23 ° C with 2 g of charcoal, Darco KB odbarvtvacítt ", then the solution filtered through ičiPstriové hlirky ( '· Ceeitl ^И) and the oil is distilled off by distillation of the ethyl ether in acetic acid which is converted to a solid by trituration with ethyl ether, filtered off and dried. Phosphorous pentoxide under vacuum to give 7- [alpha- (4-hleroxyphenyl) -alpha-D-drrc .Pololocarbonylol-1-nitro] -acetamido-3- (1-carpoxymethylthltrazol-5-ylthtomethyl) (-) as a solid. clilmII (-4-carbonyl).

B.

7-CD-alpha-amino-alpha- (β-trifluoromethyl) -methyl-3- (1-carbonylmethyl-terazol-5-ylthiomethyl) -Зflef-4L-У-kbtXlloo

At 5 [deg.] C., 0.1 mol of 7- [alpha- (4-thyroxyphenyl) -alpha-D- (te: t-Butoyl-4-butylamino) acetamidet-3- (1- carboethyl ethyl terterazol-5-ylthtomethyl (-Zeil) (-4-carbonyl), the temperature of the solution was then allowed to rise to 23 ° C and the solution was stirred for an additional 30 minutes.

The solution obtained is poured slowly into 1000 ml / ml of water. under vigorous stirring, and the precipitate _{tčtfiltupjl>} for ^ is for pouUítí eilttlllttlrp 100 ml and dried over phosphorus pentoxide ^ dioxolan ^ m under vacuum for an hour. The precipitate is then dissolved in 75 ml of water and, after stirring the reaction mixture at 23 ° C for 30 minutes, the solids are filtered, 2 g of Darco® decolorizing charcoal are added to the filtrate, followed by stirring for 10 minutes. The filtrate was adjusted to pH 4 by addition of triethylamine, the solids were filtered, and the filtrate was concentrated under high vacuum to an oil which was taken up in acetonitrile. The product, i.e. 7- [D-alpha-amino-alpha- (β-thiertylphenyl) -altamethyl-3- (1-carbotyl-ethylthiomethyl) -3-cephem-4-carbonyl-oxoic acid, is separated with m.p. and dried in the air.

Example 7

When the sodium salt of 7- [alpha- (4-lycryloxyphepyl) -alpha-D-gerbutoxycarbamoyl-amino] -acetic acid was replaced in the procedure of Example 6, the amount of acid was replaced. cefalospoгdmove prepared, for example acylation of 7-αminocefalospoeemové usual manner pouužtí 2- (teic.UuCoykkabboayldmiacmeelh ^г S) -1,4-iykloheχαSieaylcitove acid - (-) - Ala - ters.bcto: kαarOoxmiScfeaylcctcve, acid, 2- ( terc.UuCoykearbonylιmiaobeeluS) -1,2-cyklcUexenylcctcve acid, 2-L4-teri.butoxykαrbonylαminombteluУ · hyjlsofeIarj ^oc 'World acid C- (terc.butcκskarbocmУLamnacbtnyl jfennSthiooctcvé acid betα- [o-eeic.UuCoykaabOonylιmiacbeehyS) -feayl] proρioaove - - (-) - N-t-t-butoxycarboca-2- (3 ^from -but-4-hydroxybutyl) glycol, D- (- bN-tert. ButcκУkrbscLaS-2- (3 ^from -bβУUc} qjy4 ^from -UySrc: χyf elmУ) - (g ⁾ -, - (-) - N-tert-butoxycarbonyl-2- (4-ethoxyphenyl) glycine,

- (-) - N-terbutylbutylcyclohexyl- (1'-cyclohexyl) glycine,

- (-) - N-tert-butoxycarbaminoL2 (3'-trifluoro-4-fluoropyloxy) glycol,.

(-) - N-tert. butyloxycarbonyl-2- (1 *, 4 * -cycloexediyl) glycine, - (-) - 2-eeic.UuCoycocarboxalbidocЗ- (1 ', 4'-cycloexylSieayl) propionic acid - (-) - 2-tert. UuCoylcarbonylbidocЗ- (4'-Bicyclo-1 ', 4 ^z -cyclohexylsilyl) propionic acid, 2-tertuocoylcarbamylbutylbutyl, N-terbutylcarbonyl-1-α, α-n-cyclohexylic acid. - (-) - elfe-terc.butcxykarboxεalidsoЗз-hiemjloctcvé,. Acid - (-) - .alpha.-Уeri.buУoκykarboxεшlbds 22-th.enylocУové acid Seta- (2-teri.butcxykarbcmyLαbinombehuУ1,4 oykloUexadinajl) peopionové acid beУα- (2-eeic.UuCoyk ^to ERCO ^ yΊmiacbeehhУ- 1-cyclchexemyl) piperione and - (-) - N-tert. buto: κrkkrb0CLaS-2- (4'-UySro: ynynbùhuУfenaenaenaУУL--gly gly gly gly gly gly gly gly,,,,,,,,, 7- 7-) yields 7- (2abincInbùhhУ--1,4-cyclobutadiene.aceУememids) -3- (1-carbonylcylbУe \myl-Cmmyl-icmmyl-icУ ylera) 3-4-cefeb karbcxylcvá acid, 7 - (- alfα-ebiaorem ^г lecetemido) -3- (1 -karboэχУbte] yltenrkzol 5-ylthiobetUyl) -3-cephem-4-kαeboxylcvá acid 7- (2-dminobbehuУl-, 2 ij ^to lchexenaУaecУ1anbds) --- (l-keeboxybbe hУУeteezcl-5-ylУUicmethyl) -3-4-cefβb kerboχylcvá _J 7- (2-h -'- αbinombУhhУl4 ^г dsoJφ'Уeceínmds) -3- (1 -carbobenzylamino-5-yl-benzoyl) -3-cephem-4-carboxylic acid 7- (c-aminobutelylphenylthioccetamides) 73- (1-carboxylic acid-5-ylidene-4-yl) - 3cephene -kartoκjlcvá _J 7- (beta "P · - · f ^ minobeУhyl eaylpropOontmido) -3- (1--kαrtoκynbetuУteteezcl 5 yltUicbβethУ) -3-4-cefeb _{karbcxylcvá>.}

acid 7 - C-.alpha.-eminac eL'a- ^{(3/4--bethjl /} -hySrcxyfeayl) -aceemiSo} -3- (1-kαřboχ; ynbehuУteteazcl 5-yltUiobethyl) -3-4-CθfΘb kαrbcxylcvá , *.

acid, 7-L - .alpha.methylbenzyl eminac-efa- (third ^from - · beУUc2χry4 ^of -hySecxyfenyl) -αcβamido] -3- (1-AZCL kartoκynbehuУtθte ¹ 5-yltUiobβthyl) -3-ce: EEB-4-carboxylic acid ^to Ysaline 7- [Da ^e f ^e eminac--alpha- ^(3-m αietcxyfeI У) -ecetamidsC-3- ⁽¹ - ^{χ to} erbC2 ymtelylУeeraezO 5-yltUiabetUy1) -3-4-iefnb kaeboχyLcvá acid. 7- Γ --- efα-ebiaac-efa- (1'-cycloexylyl) -acetyl] -3- (1-carbonyl) -ylteerazin-5-yl ^ 1 (611) -1) -3-cefeb-4 7- [--- efa-aniaac-efa- (3'-chloro-hydroxyhydroxyphenyl) -amino] -3- (1-carbonyl) -tetyl] -5-ylcarbonyl-4-carboxylic acid 7- (D (1 ', 4'-Cyclo-hexa-thienyl) -propicaamide C-3- (1-carboxylic acid) -3-cefeb-4-carboxylic acid, 7 [d- (4'-mellho-4-carboxylic acid)] ^ 1 ', 4 ^/ -cykloUexeSieayl) prcpionemiScJ -3- (1--keebcκylbУlзhlУterαzcl 5yLУUiobeУ]' hУ -) - 3-cefnb-4-kíaebo: · χyl CVA, 7- (2-ebiaoclbУe ulfenaУaecУ1amds ^.) - 3 - (1-Carbonyl) ethyl (5-ylethylbutyl) -3-cephem-4-cartoxylic acid 7- (1-abiocyclo-hexanecarboxoxide) -3- (1-carboxybutyl) -3- (1-carboxylic acid) -3- (1-carboxylic acid)

O-em-4-carboxylic acid 7 - ((-) - 10 - (- 1 - 1-enyl acetamido) -3- (1-carbo-methylthultetrazol-5-ylthioethyl) -3-chloro-4-cartoxylic acid) - (D-Al-a - + - Tluoyl-acetoido) -3- (1-carbonyl) -ethylthrazol-5-yl-thioacetyl-3-carboxylic acid-4-carboxylic acid, 7- (2-amino-amino-1-carboxylic acid) ^4-r l cyкlohexadeeIO-do-propynyl) -3- (1 -karboχ / ιο11 1 ^ '^ γ3ζχ1-5y1thiooetUyl) -3-cephem-4-carboxyphenyl xy1 acid,.

7- [beta- (amino-piperidin-1-cyclohexyl) -propen-3-yl] -3- (1-carbo-benzyltetxrazol-5-ylthioethyl) -3-cofeo-4-carboxylic acid and 7- [D - .alpha.-Amino-1? - (4 ' -hydroxy) -olinoacetyl] -3- (1- [beta] -benzyl) -3- (1- (8-chloro-5'-yl) -ethoxy) -11-caffeine-4-ol: arb-xylic acid.

Example '' 8 ''

NalualOnti was used in the procedure of the example. 5 D - (-) - N-tert. butoxycyclonyl-p-hydroxyphenylglycio by equimolar seed 2- (tert-glycarbonylaminoimido) -1,4-cyclohexadienylacetic acid seed, D - (-) - α1-tert-b-biphenylbenzoic acid, 2 - ( terc.žu-χyykrb onylmlnnooet1u ^г-l) -1,2-clk1ohexe: _nyloctové> acid 2-tert. butoχykarbonylaminxmoehhl 4-hydroxy-χyl'enyl -acetic acid 0- (1erc.butOJyгklrbooylloino-Thul) OenyLthi)) - c malate, acid beta-Eo "(terc.butoχlkar'bonylαmilnmothyl) -i ^e ϊnyl} -prΌpnonové, D- (-) -N-tert. buto: λУbb-ol12 '(3'-methyl ^-hydroxyphosphoryl) lycin, D - (-) - N -terbut-£bb-arbb-nУ-22 (3'-oethb> χl · 4 ^from -UyOr- D-(-) - N-tert-butyloxycarbonyl-2- (4-chloro-1-olefin) glycine,

D - (-) - N-tert-butoxycarbonyl-2- (1'-cycl-Uexeryl) glycine,

D - (-) - N ^ eirc. buto: χУcalbb-NL-2- (3 '- Cu1-r-4 hlydгoxy0eoyl ^Z) g1yciou,

D - (-) - N-tert-butylbutylbenzyl t2 · (11,4 -cyclo-oxalic acid), acid D - (-) t2tter.nu-x: lycarb-xloi (do-3- (1 (4 '- Cyclohexadienil) - (4'-oetho: χyanoic acid) - D - (-) - 2-tert-butoxy-3-carboxylic acid 1 ', 4'-cyk1-hexaOieoyl) propiooové acid, 2-terc.žutx: lkkaгbooylaminomet1u ^г У l10eln _l-acetic acid, N-tert. butorykarberyll1 INX -N ^ ^ j ^ JklOhexane Arbe L-X, of D - (· t) -aO.l - eerb.b-tblкaabOxx! Mie () - 3-1Uieoylxacetic acid D (-) - a0a - tec'bb-tXlкlaгOxx (mie - 2-tuneol acetic acid).

betal (2-tert-oxo-yloxycarbonylamino-amino) -11,4tCl-cyclohexa (ethylene) propionic acid,.

acid beta- (2-tert. butoxyкaгbol0l1amLnbmoehhl11 -cyklohexejnyl) propnonové, and D - (-) - N-terc.bžt xykarbxnol-2- (4 thydroχyIlothulfoeyl ^Z) · gllcnnu in any given case, a reaction takes place to give acid 7 · - (2-Amino-methyl-14-cyl-hexadecyl) acetylacetamide (b) -3- (1-carbomethoxymethyltetraz-1-5-1-thixoethyl) -3-cepeo-4-carboxylic acid 7- (D-alOi) -amine “phenylacetumdc)“ -3- (1-methylbutyl-4-methyl-5-ylthioethole) -3-oxo-4-carbonylbutyric acid 7- (2-1-1-methyl-4-carbonyl) -122-hexahydro-acetic acid 3- (1-methyl-4-ethyl-ethyl) -3- (4-carboxylic acid) -3-chloro-4-carboxylic acid 7- (2-amino-4-methyl-4-hydroxy) -t- (1-carbox-4-yl-ethyl) -15 3-Cephem-4-carboxylic acid, 7 - (- quino-10-methylphenylolodexacetyl): (d) -ZZ (1-carbonyl-4-ethyl-ethyl) -O-5-yl-thiol-3-carboxylic acid, 1-carbamic acid 7- (beta-oalminooethyl0enylpropionαniid) -l- (1--karbx χyothtUletralzO 5-ylthiooettul) · t3-cephem-4tkarboxylové _t 7- [l> -al: 0ι-ιο οαΙΟι- ^ (3 &apos; -methyl ^ '-hydroxiOenyl) icetimido) -3- (1-karboэχylothultttraz-lt5ty1hi) -oethyl) t3-4-ce0em karboχylové, ^selhn-1 7- [L-al ^f and-aminyo- ^and alpha- (3 -methyl ^{У e} hos ^χ y ^/ -hydros ^χl en ^{yУL 0} acetamido-3- ⁽¹ - ^k r ^{y b} ox ^e i ^h Me ^and r-tttraysl 5-1llhSometh1L ^ - cephem--karboxllové, 7- [D-alpha-amino-alpha- (3-acttox1feyyl) acttamidoS-3- (1-kar0oэχ1etnylУeetaay0-5- lthiomethyl ^yl) -3-4-cθfm karbox1loié, tyselin ¹ 7- ( ^D and -a ^f-aa aninos- ^{al (1'-C 1LL L} exeI ^{yy) 0} acttamido -3- ^(1-χ -karboэ yet ^{the cannula t} e ^r -5- taay ^of l- tlismetlhУ ^yl) -3-c. efnm 4-karbn:> χy ^and ew.,, kyseHiny 7- [Da ^y and f aminyoalf-a- (3'--cllsr 4 · ^'s -l1drox feyy ^yl) acetamide 3- (1 -karOoзQ1lethy ^and tteraУS ^and -5-1lthismet] hУ) -3-cephem-4-nm kar0oχy oic ^{y, y} KYSE ins 7- [D-AAFA-aminosulfonylphenyl-Ala- (1'-cyclohexane 4У olexadde ^yl] yУ.) acttamidoS 3 - (1-larbs: χ1lethy ^y tetraao ^y -

-5-1lthismetlhУ) --- Cefn-4-carboxy) _χylové> KYSE ^y ins 7- [D- ^(from 1, ^4'-yl cyclohexane slexadiery ^s) pnopnnnmido] -3- (1H-5 -karboxymeelhУ.tetraУol thSomethyl -y ^y) --- CTFE-4-oic karboэχy ^{y, y} KYSE ioy 7- [^ -methojxy DU-1 · '· 4 ^of -c1kloltxadienyl) prspioyamddO 3 - ^(1-y kkrbooχyeteLy teerazo ^y - 5-yl thSomttlyl ^yl) - 3-4-tfnem karboxyloié * 7 ins KYSE ^y '(2-aminomeehl1f enyУacetamids) -3- (L-5-кarOsχ1letttlltterazoOL yltlismeelhУ) -3-Cefn-4-carbo: Jχy ew ^{y, y} KYSE ioy · 7- (1 -amiyoc1klnhnxaykarboxami <to) -3- ^(1-y -karOoзQУlettll УetraayO 5-yltliometlhУ) -3-cephem--carboxyl-axis, ^y KYSE ioy 7- ^(Da fa -3-thia поу ^^ У amides) -3- ^(1-y -кfiar0oзχ1eУnylУetrazo ylУhiomttly ^{-5-yl) -3-cffem-4-yy} kar0sx OIE kyseiioy 7- (Da ^y fa-2-tlieo1laceУεmido) -3- (1 -lar0s: χyletttl ^tetrazo0-5-y y ^y tliometlhУ.) ^{-3-cephem-4-yl} kar0sχy OIE kyseiioy 7- (2-emiУO] melhУ-1,4-cyl ^y nhexadieny prspisnamido ^yl) -3- ^(1-y kar0oχyyleУhy Уetrazo -5- ^y. -yiyhoomeyhyl) -3-c.efem-4-carbo: xr ^y ew, acid Elina 7- [Oeta- (aminoolenhl1-1 -C1klolexeyyl) propioyamidoJ-3- (1 -larboяymetly tttrayo ^{y y} y ^y--5 - tliomethy ^{yl) -3-CTFE-4-yl} кarbsχy SIE and ^the YSE ^y O ^y 7- ^{[D-.alpha.-aminos- and} f a- ⁽⁴ '-h ^ f ^ ei roxymeet ^y y) ^T tes £ mido] -3- ^(1-χ -karOn yyeУhy Уttrazo ^{y y y} -5-1 l] In this case, i0ymeУlyl) -Зctenem-4-кar ^b sx1loié.

Example 9: ^{n (d y} O ^and are ^kyseld-1 7- ^{D - ^af a- ^{[- (2-fшn) yy} ttιri ^dn a] - ^d lУ DROXI ^yf it ^yl aceУami ^d oSct ^F and ^L ss ^p sraoové

6.4 mi (0.0454 mA ^and) trieUy-amine and 12.7 g (0.1039 · ^we) 2-fhrs1lisskyaoáth was added to ice. chilled suspeose 20.8 g (0.0415 mole) kjyseiioy 7- ^{(D-.alpha.-Amino-4-yl} l1droxyťeny aceУamido efalosporaoLové ^ (Sonata dimeyhylfomiamidu as water and ^y) in 175 ml dry dimethyl formamide ^y.

After a minute, the ice bath was removed and the reaction mixture was stirred for one hour, then the dark solution was diluted with 600 ml of water, layered with ⁿ tlyltstenem acid to ^y selioy and the aqueous pydíl Obselete to pH 2.5 by adding 42% phosphoric alkyl ^sel ioy The two phases were separated and the aqueous dimethylformamide phase was extracted four times with ethyl acetate.

The combined organic extracts were washed five times with water. After addition of pure ethyl acetate, 15.1 ml (0.0408 mol) of a solution of sodium 2-methylhexyl sodium in 1-butanol are slowly added to the stirred solution to crystallize the product. Thus 18.1 g (75.5%) of the substance are obtained. The infrared spectrum is consistent with this structure.

ISO ^{D d} O ^and ^ tysel salt of 7- ^[D-al and ^f - [- ^- (2ffurso ^yl) une ^dn o] l-4] -hydroxy ^{yd 1f} tn ¹ lacetamidoS-3- ⁽¹ - ^k arbo: χУlethyltterazsl- 5-ylmethyl-4-carboxy-4-carboxylic acid

A mixture of ^{4.0 g} (0.0069 mo ^ ¹ tyselíoi sodium salt of 7- ^{f D- A- ^[- (2-furoyl ^1L) to ^d ureido] 44 ^l y _r sχ _г d ^{y d} feo1lacttem dojctfalosporaУLOié, 1.83 g (0.00895 mol) of 5-menklatoo disodium acid ttra

2020-8 yellow and 200 mL of 0.1 M phosphate buffer pH 6.4 were heated at 7 ° C under nitrogen for 6 hours.

The reaction mixture is stored in a refrigerator overnight, then S (d1 is a small precipitate, the pH of the filtrate is adjusted to 2 by addition of 6 N acetic acid solution) and the mixture is extracted three times with acetic acid methyl ester. The mixture was filtered to remove a small amount of insoluble materials, combined in an extract, and the acetic k-bleach of 0000 ml was washed twice and dried over sodium sulphate and after filtration added to the filtrate 5.1 mL. (0.0138 mol, 2 equivalents) of the sodium salt of 2'-ethyl alcohol in Sutanslt, thereby eliminating the bulk product, some of the solvents were removed to remove water, stored in a refrigerator, then dissolved. The product was dried in vacuo over a tear filter. The infrared spectrum was determined by filtration and the gummy product was treated with acetone to give the title compound as an acetone. in accordance with the sertktte-t eoeoeo product.

Samples of the compounds prepared as described in Examples 1, 2, 3, 4, 14 and 14 after dissolution in water and dilution with nutrient mash were found to have the following minimum values: 0 ° C. (tg / ml against the following micetomes after incubation over hoc at 37 ° C and dilution in tubes).

Aimicrotal efficacy in vitro

Minimal ineSičií

Organism Example 1 (about 2-0 m &lt; 2 &gt; / ml as sodium salt)

Str. pndumonnae ⁺ (10O ³ ) ⁺⁺ A 9-8-0.13

Str. pyogenes ⁺ (10 ^-3 ) 960 9604'0.13

S. aureus Smith '(10 ^"4) A 9-371

A. aureus - 0% serum (10 ^-4 ) and 9-374

S. au ^ u BX1633 (10 ^-3 ) A 96061

S. · aureus 6Π633 <10 ~ ² ) A 96062

S. aureus Meth-Res (10 ^-3 ) A 150974

Hall. dnleritL11 (10 ^-4 ) A 95310,006

E. coli Juhl (10 ^-4 ) A, 151190, E. coli (10 ^-4 ), 967-16

K. · pnruooniad · (10 ^-4 ) A 99770,13

K. pndumoniad (10 ~ ⁴⁾ A 151 302

Ex. m / h press (10 ⁴ ) A 99000.13

Ex. motgεanni (10 “ ⁴ ) A 15153 above 125 concentration · in Ag / ml

2 3 4 5 6 0.6 0.6 0.06 0.13 0.25 0.6 0.6 0.13 0.13 1 13 2.5 0.5 over 1 over 1 16 32 over 0.5 nad 63 16 2.5 over 2,5 1.3 2 8 4 16 2.5 8 8 8 16 4 63 32 0.08 0.3 0.16 0.5 0.5 4 8 1.3 16 8 32 16 16 16 32 1 1 0.3 1 ’ 1 32 8 2 125 8 0.5 1 0.3 0.5 1 over · 12- over · 12- nad 12- 16 nad 12-

Organism

Example 1 (dissolves like sodium

250 mg / ml salt)

Ps. aeruginosa

<10 ⁴ ) nad 125 nad 125 nad 125 nad 125 16 nad 125 Ser. mu? (^ escens (10 ^-4 ) And 20019 nad 125 nad 125 nad 125 nad 125 nád 125 nad 125 Ent. cloacae (10 ^-4 ) A 9656 nad 125 nad 125 nad 125 nad 125 nad 125 nad 125 Ent. cloacae (10 " ⁴ ) And 9657 0.25 2 1 0.3 63 2 Ent. cloacae ' (10 ^-4 ) And 9659 32 nad 125 63 32 nad 125 125

* -

COO (H) (C) (Na)

CH2COO

ÍH.Na.K)

CH ₂ C ₆ H ₅ -CHOH

+ /% Of anti ioti ^ é ^ t ^ EST Ex ^{P y} Ar, 5 °% ^{fo in some AP} e ^y + 5% serum ^{++ / R and DE} of the raised ares ^ ^p res night

Example 10

Monosodium trihydrate salt of 7- (2-aminomietllfenylacetaoidt) -3-11-karboxymee (l ^_ (θ (^: ^ ι ^ ^ ο-55ι ^^ (^ 1 ^] ^ ^ ^ ο 611ι).) - 3-cefem44skeb0o2QlSsve

1. Suspend 10-g Seytaliic acid 7- (2-quinomethyl ether) acetamide (S) 3- (1-carboilithithetrazol-5-ylthtooethyl) -3-cyclo-4-carboxylic acid as described and prepared in Example 1, suspending in 50 ml of ion-free water.

2. With vigorous stirring, a 10% sodium hydroxide solution is slowly added so that the pH is maintained or is constant between 7.4 and 7.7. This will result in dissolution or an almost clear solution.

3. Add 2 g of active ingredient (Darco G-60 ") and stir for 30 minutes. Hoodiota pH is maintained between 7.4 and 7.7 by the addition of 1 N sodium hydroxide solution.

4. AAive. The mixture was separated, washed with water (10 ml) and added to the filtrate according to the purging procedure.

5. The solution of step 4, pH 7.4 to 7.7, is sterilized and pyrogen-free using appropriate atheetic filtration techniques.

The total time required to carry out steps 3, 4 and 5 does not exceed 5 hours at room temperature.

6. Using the sterile procedure, add approximately equal volume, i.e. 65 ml of sterile pyroget-free acetone, to the vigorously stirred solution of step 5. which takes 5 minutes.

7. Recalculated to the original volume of the aqueous supernatant, two additional volumes (120 ml) of sterile pyrogen-free ceteto were added from 15 to 20 minutes with vigorous stirring. This eliminates crystals with it. . .

8. Stir the reaction mixture. 10 minutes.

9. An additional 3 volumes (180 ml) of sterile ceto-ket are added over 15 minutes and mixed suspeose for 30 minutes.

10. Separate the crystals, wash. The mixture was dried in a vacuum oven at 45-50 ° C or in air at 50-56 ° C for 24 hours. 8.8 g.

In fact, the 7- (2-aminomethylleeyl-acetic acid) -3- (1-methylsulfonyl) tetrazol (1-5-ylthioacetyl) salt of 4- (4-carbonyl) -acetamide is the following:

%. HgO calculated 9.05%. found 9.2%;

% Na (flame photometers): calculated 3.86%, found 4.0%; 'water solubility = above 500 mg / ml;

in water: at least 24 hours at room temperature at a concentration of 250 mg / ml.

Preparation of products for injection preparations:

Preparation of 7- (2-ammonium methylphenylacetamide) -3- (1-carboxyacetyl) -3- (1-carboxyacetyl) -5- (4-ylthioacetyl) mono-sodium salt of 3-cepha-4-carbonyl salt:.

A) 2.5 g of 7 '- (2-quinonaphthylphenoacetenidyl) -3- (1-chlorobutyl-5-ylhexyl-5-yl-hexyl) 3' (Cefa-4-carbonyl) acid (in the form of the colony ion) was treated with Suspend in 8.5 mL of water with vigorous stirring and add sodium citrate, monosodium phosphate or sodium phosphate or other suitable base until dissolution is achieved, the pH should not be above 7.8. records.

B) Prepare a physical mixture of 2.5 g of 7- (2-cinnamomethyl-ethyl acetate) -dimethyl-3- (1-carboxymethyl-5-ylmethyl) -3-cepha-4-carboxylic acid as a solid base, if any. by the addition of water, various concentrations of itite prepared from the monosodium salt of 7- (2-amino-methacrylic acid) -3- (1-chloromethylleerazo-5-ylthio) acetic acid can be obtained. 3Cef is α-4-chlorobutyl.

This procedure can be very appropriate precisely because Orihldrao monosodium. acid salt of 7- (2-aаinomаehylfenylacetamidj) -3- (1--karbojχyаtnylleeoazoj 5 llthioаethyl) -3-4-cefeа kcrbjχylové ..zvýšených reading of the temperature as stable as the clearance kyselíte 7- ^{(2-aаinoImeOhll> e} (E-Acetamido) -3- (1-ketyl (3-chloroethylthioate-5-yl) ethyl) -3-cephem-4-carboxylic acid in the form of both.

With respect to the stability of the solutions of 7 '- (.beta.-hydroxymethylphentlacetylacetin-3' (1-ethyl-1,2,3,4-thiazol-5-ylthiomethyl) acid) at room temperature and from pH 10.3, is the lowest pH at which it can dissolve 150 mg / ml, with almost an almost 50% loss of bioactivity and a further 21% loss within the next 30 minutes.

In contrast, a solution containing 125.0 mg / ml of the monosodium salt trihydrate K ^was cast from 7- (2-amino-methylphenyl) acetonitrile) -3- (1-chloromethyl-5-yl-hexyl) -acetamide. The pH of 7.0 is stable over at least 24 hours to such an extent that there is no substantial loss of bioectivity at that time.

The compound referred to as 7- (c-iminoethylsulfonyl acetamilo) -3- (1-methyl-1,2,3,4-tolyl-5-syltliomethyl) zinc-carboxylic acid of Example 1 and point 2 of U.S. Pat. No. 3,765,175 is a very potent cephalosporium derivative and a very desirable spectrum of efficacy. especially for some gram-negative microorganisms. The unleash. with this duplex. ion is very small. solubility in water, and in particular in the bloodstream, meaning at or near pH 7.2. in other words, in the survey mentioned. solubility, a range of about 1.0 to 3.0 mg / ml was found in both the buffered aqueous medium and the urine of dogs at the temperature of the oss.

The pH of fresh dog urine is 7.6. This results in a number of toxic effects in humans when administering this zwitterion, because it is not. it should be assumed that the crystalline form is precipitated in the kidneys as this substance is precipitated here during excretion. And this is extremely undesirable in humans. .

Conventional attempts to solve this problem by using the usual forms of 7- (o-imino-methylsilyl) -1 ⁽ cetamido-3- (1-methyl-1,2,3,4-tetrazol-5-yl) acetyl) -3-tetramine The water-soluble, 4-carbonyl, or water-soluble derivatives were unsuccessful because the salt or derivative is converted into the form of both ions in the human body, and this is known to be a natural low fat content in both aqueous and blood environments.

It is one object of the present invention vyřeeit this problem without loss of valuable biological properties and účimnooti 7- (c-e ^and lminoolettylffen- there to to) - (1-Mete-1,2,3,4--6 traz1l 5- (diethyl) -3-methyl-4-methoxycarbonyl. After various failures the problem was solved by providing accordance with this invention, when the 7- (2-lminomtehhSfeϊnrSacetltido) -3- (1-karboxytethyS1etolzcl-5-s1thL ctetlcS ⁱ⁾ -3-4-cefet кarbcxy1cvá desired properties. More precisely, a sample of 7- (2-aminophthylpheoSaactin) -1C-3- (1-tetroxylthiyltetrazol-5-ylthioethyl) -3-cephem-4-carboxylic acid in a phosphate buffer of 7.0 has a solubility in m / g at 25 ° C above 15.3 and below 13.7, in which case there is no buffer, and the pH drops to 6.48, so 7- (2-aminomethylphenethyl acetamide) -3- (1- The cyclopropylmethyl tetrazol-5-ylthioththyl) -3-phthet-4-carbonyl salt of the present invention, even in the form of both ions, is too soluble in water and bloodstream to be able to excrete in the kidneys and as a result would be worried about toxic results, at least for some treated.

Further, as mentioned hereinbefore, otdlcDetermining water solubility posed a problem which was solved by the preparation of trity-wire. 7- (2-aminomethylphenoxyacetylmilc) -3- (1-carbonylmethylthetrazol-5-yl) cyclothyl] -3-tetram-4-carboxylic acid mono-sodium salt according to the present invention, said salt being said to have a pH value of about 8%. is suitable for injection purposes, as in the case of pH 7, and is still characterized by increasing solubility in the bloodstream and in the kidney fluids, even if the salt is converted into an acid-bivalent ion in the body. *

In accordance with what has been said hereinbefore, the advantage of the compounds of the present invention is their improved water solubility compared to other compounds known in the art, and the main advantage is generally the higher blood level of these compounds either by larenttoal administration or intramuphrolly administration.

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of 7'-aminocephleosporinic acid derivatives of the general formula I, h ₂ no = COOR (I) CH ₂ COOH wherein R is hydrogen or an easily hydrolysable moiety such as. pivaeoyloxyme Tulove group, acetoxymethyl Tulove · meta: χlnedta ^r lvvá, acetyl ^^ network zebo fenaclevíá and oapovídaaícíca salts, characterized in that it is treated under acid 7-aminocefleosporÉnovou or her. A Schiff base or an easily hydrolyzable ester or a salt thereof with a compound of the formula to form a compound of formula I or the corresponding Schiff base, a readily hydrolyzed ester or an opacifying salt, provided that if the reaction forms a salt, a readily hydrolyzable ester from a Schiff base of a compound of formula (I), such a compound is converted to a compound of formula (I) using otherwise known methods.