DE2522142A1 - PROCESS FOR THE PRODUCTION OF CEPHALOSPORINES - Google Patents

Description

j jNAOHQEKEIOHTj

PATENTAf'WF.i-Tfc 1 Γ O J -j / y

. WIRTH - Dr. V. SCHMIED-KOWARZIK Dipi.4ng. G. DANNENBERG Dr. P. WElNHOLD Dr. D. GUDEL

28-34 6 FRANKFURT / M.

TELEPHONE (ΟβΠ) ^^^ _{GR ESCHENHE | MER STR} 39

Case; 331
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SOCIETA FARMACEUTICI ITALIA SpA 1/2 Largo Guido Donegani
I 20121 Milan
Italy

"Process for the production of cephalosporins"

509850/0970

The present invention relates to a method for producing cephalosporins. In particular, relates they focus on a new process for the preparation of cephalosporins from suitably substituted thiazolinazetidinones goes out.

The transformation of the penicillan skeleton into the cephalosporan skeleton was chemically for the first time by treating penicillin sulfoxides with acetic anhydride (R.R. Chauvette, J.Org.Chem. 36; 1971, page 1259) or with acid catalysts (BE-PS 747 119) achieved. Recently, the conversion of penicillin sulfoxides into cephalosporins was in attendance from azodicarboxylate (S. Terao, Chem. Comm. 1304, 1972) in low yields and in a mixture with other products reported.

According to the present invention, cephalosporins are to be obtained by a completely new method, such as shown schematically below:

Synthesis diagram

a) Opening of the thiazoline ring with an azo derivative

(D

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R-CONH

, (ID

wherein, apart from the other substituents , V is hydrogen or an aliphatic, aromatic, arylaliphatic or acyl group, in particular the group

CH-

oüer

COR

COR

COR ^M
can be,
b) closing of the intermediate product obtained

2 |!> - ThiohydrazoazetidinoiE with inorganic oxides or

Bases

NH R

R-CONH

(II ¹ )

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inorganic oxides

H H

or bases

COR ¹

where R is hydrogen, alkyl with 1 to 4 carbon atoms, cyanomethyl, thienylmethyl, Fury! methyl, naphthylmethyl, phenylmethyl, phenoxymethyl, phenylisopropyl, phenoxyisopropyl, pyridyl-4-thiomethyl or tetrazolyl-1-methyl, R is hydroxy, alkoxy with 1 to 4 carbon atoms, trichloroethoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy _r benzhydryloxy, triphenylmethoxy _t phenacyloxy or p-Halogenphenacyloxy, and Z represents hydrogen, hydroxy, -O-alkyl, -O-CO-alkyl, -Br, -I , -N ₃ , -NH ₃ , -0-CO-CH ₃ , O-CO-NH ₂ or an S-mononuclear heterocyclic nitrogen ring.

The compounds of the formula (I) can be obtained by heating the penicillin sulfoxide in the presence of trialkyl phosphite (NL-OS 70/08271). The process of the invention essentially consists in that the compound of formula (I) in a suitable solvent at a temperature of -20 to + 8O ⁰ C in the presence of an organic or inorganic aqueous acid with an azo derivative of the formula

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NR ²

I-R ³

2 3
wherein R and R are identical or different and are each lower alkyl, mononuclear aryl, CN, a mononuclear

4 4 4 heterocyclic ring, -COR, -COOR, -P- (OR) ₂ or

4 2 3

CONHR represent, or R and R together form the groups

0 0

Il Il

C y

T or T

v. 4 4

where T / CH ₂ or ^ NR and R are lower alkyl, mononuclear aryl, mononuclear heterocyclic ring or the like. The intermediate compound (II) is in a suitable solvent at a temperature of ^{-100 to +120 0} C with inorganic oxides, such as Al ₃ O ₃ , Fe ₂ O ₃ / ^Cr 2 ° 3 ' Si- ⁰ ?' ^{or with} inorganic and organic bases such as KOII, Na ₃ CO ₃ , NH ₄ OH, alkali metal alcoholates ^ aliphatic, aromatic and heterocyclic amines, alkylammonium bases and basic resins. In this way, the cephalosporin derivative of the formula (III) is obtained, which is isolated and purified in a manner known per se.

The following examples are intended to explain the present invention in greater detail without, however, imposing it on it should be limited.

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Example 1: Methyl 23-thiohydrazodicarboxymethyl-aisopropenyl-4-oxo-3β-phenoxyacetamido-1-azetidine acetate

⁰ "A

H-

00CH,

-OCBUCONH

NH-COOCH.

N-COOCH.

H H I

: 'js

^{! H} rT

COOCH.

A solution of 5 g of methyl-ot-isopropenyl-3-phenoxymethyl-la , 5a-4-thio-2,6-diaza-£ 3, 2 _/ ol ~ 2-hepten-6-acetate-7-one iii 200 ml of acetone containing 5 ml of methylazodxcarboxylate, 2.5 g of p-toluenesulfonic acid monohydrate and 2.5 ml of water was allowed to stand at room temperature for 6 to 8 hours. It was then ^{cooled to 0} ° C. and neutralized with a saturated NaIICO -, - solution.

The sodium salt of p-toluenesulfonic acid which precipitated out was filtered off, and after evaporation of the acetone at room temperature, the residue was dissolved in methylene chloride and washed with brine. The organic layer was _{dried over anhydrous Na 2} SO * and evaporated. The residue was chromatographed over silica, with

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15% benzene-ethyl acetate was eluted. That way were

6.2 g of methyl ^ ß-thiohydrazodicarboxymethyl-α-isopropenyl ^ -QXQ-3ß-phenoxyacetamido-1-azetidine acetate obtained, m.p. 133 bis

135 ° C.

IR (CHCl ₃ ): 3410 (NH), 1775 (C = O 0 -lactam)

1735 (C = O esters and carbamates)

1685 cm " ¹ (C = O amide)

NMR (CDCl ₃ ): 1.94 (singlet, 3H, CH ₃ -C =), 3.68, 3.73 and 3.81 (singlets 9H, three COOCH ₃ ), 4.56 (singlet, 2H, OCH ₂ CO), 4.90 (singlet, IH, N-CH-COOCH ₃ ), 5.07 and 5.16 (broadened singlets, 2H, = CH ₂ ), 5.3 to 5.7 (multiplet, 2H, CH B-lactam) and 6.9 to 8.0 6 (multiplet, 7H, aromatic H and NH).
Mass spectrum: m / e 510 (M) and 363 atomic mass units

NH-COOCH.

M -

N — COOCH.

Example 2: 2 ', 2', 2'-Trichloräthyl-2ß-thiohydrazodicarboxymethyl-a-isopropenyl ^ -oxo-Sß-phenoxyacetamido-

1-azetidine acetate

NH-COOCH.

H H j

N-COOCH.

CH ₂ CONH

0OCH ₂ CCl ₃

COOCH ₂ CCl ₃

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0.15 ml of water, 0.25 ml of methyl azodicarboxylate and 125 mg of p-toluenesulfonic acid monohydrate were added to a solution of 300 mg of 2 ', 2', 2: ^l -trichloroethyl-α-iΞopropenyl.3-phenoxymethyllα, 5a-4-thia -2,6-diaza - ([3, 2, oJ-2-hepten-6-acetate-7-one in 10 ml of acetone was added The mixture was allowed to stand at room temperature for 6 hours then was nit ^ a saturated NaHCO.. - , was added methylene chloride and shaken with brine. The organic layer was dried over anhydrous Na ₂ SO collected and evaporated. The residue eluting over silica gel _r with 85/15 V / V benzene-ethyl acetate neutralized solution. In this way, 320 mg of 2 ', 2' , 2 ^f -trichloroethyl-2ß-thiohydrazodicarboxymethy1-a-isopropeny1-4-oxo-3β-phenoxyacetamide-1-azetidine acetate were obtained in the form of an amorphous solid. IR (CHCl ₃ ): 3400 (NH) , 1770 (C = O β-lactam), 1740 (C = O esters and carbamates) and 16 90 cm " ¹ (C = O amide).

Example 3: Methyl-2ß-thiohydrazodicarboxyethyla-isopropylidene-4-oxo-3β-phenoxyacetamido-1-azetidine acetate

NHCOOC ₀ H ₁ -

OCH ₂ CONH

COOCH.

COOCH.

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5 ml of water, IO ml of ethyl azodicarboxylate and 10 g of p-toluenesulfonic acid monohydrate were added to a solution of 10 g of methyl-a-isopropylidene-S-phenoxyniethyl-lo ^ Sa-'l-thia-2,6-diaza-£ 3,2,0J-2-hepten-6-acetate-7-one added in 300 ml of acetone. The mixture was left to stand one night at room temperature and then with a saturated NaHCO., Solution neutralized. The precipitated insoluble sodium salt of p-toluenesulfonic acid was filtered off. Then were Salt water and methylene chloride added and shaken. The dried organic layer was covered over silica chromatographed, eluting first with benzene to to remove the unreacted azodicarboxylate, and then with benzene-ethyl acetate (80/20 v / v. In this way 10.8 g a white solid obtained by adding petroleum ether to a small volume solution of the product resulted in benzene.

NMR (CDCl ₃ ): 1.21 (triplet, 6H, 2CH ₃ , C (H ₃ )), 2.12 and 2.28 (two singlets, 6H, (CH ₃ J ₂ C =), 3.77 ( Singlet, 3H, COOCH ₃ ), 4.13 (quartet, 4H, 2CH ₂ -C (H ₃ )), 4.56 (singlet, 2H, 0-CH ₂ -CO), 5.14 (DD, IH, C (3) H), 5.86

(Doublet, IH, C (4) H) and 6.8 to 7.8 δ (multiplet, 7H, C ₆ H ₅ and amide 2NH).

IR (CHCl ₃ ): 3410 (NH), 1765 (C = Oβ-lactam), 1730 (C = O esters and carbamates), 1690 cm "(C = O amide).

Example 4: 2 ', 2', 2 '-Trichloräthyl ^ ß-thiohydrazodicarboxyethyl-a-isopropylidene ^ -oxo-Sß-phenoxyacetamido-l-aze- tidine acetate

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OOCH ₂ CCl ₃

OCH ₂ CONH

^{2 5}

COOCH ₂ CCl

A solution of 4.63 g of 2 ', 2', 2'-trichloroethyl-a-isopropylidene-3-phenoxymethyl-la, 5ot-4-thio-2,6-diaza- [j3, 2, 0 J-2- hepten-6-acetate-7-one in 200 ml of acetone, containing 3 ml of ethyl azodicarboxylate, 3 ml of water and 1.91 g of p-toluenesulfonic acid monohydrate, was left to stand for 24 hours at room temperature. It was neutralized with NaHCOn, CH ₀ Cl ₂ and brine were added and the organic layer was separated. Chromatograph over silica, eluting with benzene-ethyl acetate (95/5) v / v; the combined fractions gave 6 g of the desired product. NMR (CDCl ₃ ): 1.22 and 1.27 (two triplets, 6H, 2CH ₃ -C (H ₂ )), 2.22 and 2.37 (two singlets, 6H, (CH ₃ J ₂ C =) , 3.9 to 4.5 (multiplet, 4H, 2 CH ₃ C (H ₃ )), 4.58 (singlet, 2H, 0-CH ₂ -CO), 4.79 (DD, 2H, -0- CH ₂ -CCl ₃ ), 5.10 (singlet,

IH, CO) H), 5.98 (doublet, IH, C (4) H), 6.64 (singlet, 2H, 2NH) and 6.8 to 7.5 <S (multiplet, 5H, CgH ₅ ) . IR (CHCl ₃ ): 3410 (NH), 1760 (C = Oβ-lactam), 1730 (C = O ester and carbamate) and 1680 cm " ¹ (C = O amide).

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Example 5: Methyl-2ß-thiohydrazodicarlx> xymefehyl-a-l'-methoxyethylidene-phenoxyacetamido-l-azetidine acetate

BfHCOOCH.

NCOOCH ₀ ι 3

H H

OCH ₂ CONH

__ _H 0CH ₃

COOCH.

OCH,

COOCH.

A solution of 0.5 g of methyl-ot-l'-methoxyethylidene-3-phenoxymethyl-la, 5a-4-thio-2,6-diaza - [[3,2, o] r2-hepten-6-acetate- 7-one in 50 ml of acetone containing 0.5 ml of methyl azodicarboxylate, 3 ml of water and 50 mg of p-toluenesulfonic acid monohydrate was left to stand for 12 hours at room temperature. It was neutralized with the equivalent amount of NaHCO ₃ and extracted with methylene chloride. The residue was chromatographed over silica, eluting with benzene-ethyl acetate (85/15) v / v. In this way 320 mg of the desired product were obtained.
IR (CHCl ₃ ): 3420 (NH), 1770 (C = Oβ-lactam), 1730 (C = O ester

and carbamates), 1680 (C = O amide).

f NH-COOCH-, \

Dimensions

: m / e 378

M -

NH-COOCH.

NH-COOCH ₃ )

^{m / e 148} \ nh-cooch ₃

Example 6: Methyl 7 ^ phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

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MH-CCOCH ^

H H N-COOCH-ι -i

H H

, COHH

A solution of 1 g of methyl 2 & -thiohydrazodicarb-oxymetiiyl-a-isopropenyl-4-oxo-3g-phenoxyacetitido-1-azetidine acetate in 40 ntl of benzene was ^{stirred with an excess of al / CU at room temperature with a 111} magnetic stirrer. Complete conversion to the methyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate occurred after 60 minutes.

That

oOo

was filtered off and the residue off

Ethyl ether crystallized or chromatographed over silicon dioxide, eluting with 9:10 v / v benzene-ethyl acetate; 0.580 g of methyl ^ -phenoxyacetamido-S-methyl-S-cephem-4-carboxylate were thereby obtained, melting point 140 ° to 141 ° C. (crystallized from ethyl ether).

IR and NMR correspond to the literature (R.B.Morin: J.Am.Chem. Soc. 91, 1401 (1969)).

Example 7: Methyl T-phenoxyacetamido-S-methyl-S-cephem-4-carboxylate

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NH-COOCHo

H H I

I I

N-COOCH ₀

H H

OCH CONH-

O'

OCH CONH

COOCH.

COOCH.

A solution of 400 mg of methyl 2ß-thiohydrazodicarboxymethyl-α-isopropenyl-4-oxo-3ß-phenoxyacetamido-1-azetidine acetate in 30 ml of ethyl acetate was stirred in the presence of an excess of SiO 2 with a magnetic stirrer and 48

Heated at reflux for hours. The silicon dioxide was filtered off, evaporated and the residue crystallized or chromatographed on silica.

There was thus obtained 180 mg of methyl 7-phenoxyacetamido-3-methyl-3- ^ cephem-4-carboxylate obtained, m.p. 141-142 ° C. The IR and NMR data correspond to those given in the literature (R.B. Morin, J. Am. Chem. Soc. 91, 1969, p. 1401).

Example 8: Methyl T-phenoxyacetamido-S-methyl-S-cephem-4-carboxylate

NHCCOCH _n

NCOOCH

, CCNH

H H

OCH ₂ CONH

COOCH-

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0.8 ml of a 30% aqueous solution of KOH was added to a solution with magnetic stirring and at room temperature Solution of 510 mg of methyl 2ß-thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-33-phenoxyacetamido-1-azetidine acetate added in 20 ml of benzene. The mixture was stirred for 30 minutes after which the organic layer was separated with acidified water and then washed with water and finally dried. The residue was crystallized from ethyl ether, with 310 mg Methyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate were obtained, m.p. 141-142 ° C. The IR and NMR data correspond to those given in the literature (R.B. Morin, J.Am.Chem.Soc. 91, 1401 (1969)).

Example 9: 2 ', 2', 2'-Trichloroethyl-T-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

NHCOOCH.,

NCOOCH.

H ₂ CONH

COOCH ₂ CCl ₃

A solution of 250 mg of 2 ', 2', 2 '-trichloroethyl-23-thiohydrazodicarboxymethy1-a-isopropeny1-4-OXO-33-phenoxyacetamido-ls: etidine acetate in 15 ml of benzene was added in the presence of an Al ₂ O ₃ excess Room temperature stirred with a magnetic stirrer. The mixture was left to stand for 60 minutes, then filtered and finally poured over silicon

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Dioxide chromatographed, eluting with 93/7 v / v benzene-ethyl acetate. In this way, ISO mg of 2 ', 2', 2'-trichloroethyl-7-phenoxyacetamido-3-yneth.yl-3-cepiTiem-4-carboxylate, melting point 116 ° to 117 ° C., were obtained. The IR and NMR data correspond to those given in the literature (RRChauvette, J.Org.Chem. 36, No. 9, 1259 (1971)).

Example 10: Methyl ^ -phenoxyacetamido - ^ - methyl-3-cephem-4-carboxylate

Il

H ₂ CONH

COOCH-.

COOCH,

This example describes the procedure for transferring the compound (I) into the compound (III) without isolating the intermediate (II).

A solution of 500 mg methyl-a-isopropenyl-3-phenoxymethyl-1, 5a-4-thio-2,6-diaza- [3,2,0 J-2-hepten-6-acetate-7-one in 25 ml of acetone with 0.5 ml of methyl azodicarboxylate, 250 mg of p-toluenesulfonic acid monohydrate and 0.25 ml of water were left to stand at room temperature for 6 hours. It was ^{cooled to 0} ° C., the acid was neutralized with a saturated NaHCOg solution and extracted by shaking with benzene and salt water. The organic layer was dried _{over anhydrous Na 3} SO _4,

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Ak 2522U2

₃ O ₃ was added and stirred with a magnetic stirrer for 60 minutes at room temperature. It was filtered, the benzene evaporated and the residue crystallized from ethyl ether, 350 mg of methyl V-phenoxyacetamido-S-methyl-S-cephem-'icarboxylate were obtained, melting point 140 to 141 C.

The IR and NMR data correspond to those given in the literature (R.B. Morin, J. Am. Chem. Soc. 91, 1401 (1969)).

Example 11: Methyl T-phenoxyacetamido-S-methyl-S-cephem-4-carboxylate

COOCH ₃

A solution of 750 mg of methyl-a-isopropenyl-3-phenoxymethyl-1, 5a-4-thio-2,6-diaza- [3,2,0J-2-hepten-6-acetate-7-one in 35 ml Acetone with 0.75 ml of methyl azodicarboxylate, 375 mg of p-toluenesulfonic acid monohydrate and 0.375 ml of water was left to stand for 6 hours at room temperature. After cooling to ⁰ ° C., the mixture was _{neutralized with a saturated NaHCO 3} solution, water was added and the mixture was extracted with benzene. The organic layer was dried and 1.2 ml of a 30% KOH solution was added while stirring with a magnetic stirrer at room temperature. It was left for 30 minutes

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the organic layer separated, washed with acidified water and then with water and finally over anhydrous Na ₂ SO. dried. After evaporation, the residue was crystallized from ethyl ether, 540 mg of methyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate, melting point 141 ° to 142 ° C. being obtained.

The IR and NMR data correspond to those given in the literature (R.B. Morin, J. Am. Chem. Soc. 91, 1401 (1969)).

Example 12: p-Nitrobenzyl-7-LN-benzyloxycarbonyl-D-a-phenylglycine amido J-3-methyl-3-cephem-4-carboxylate

A solution of 600 mg of p-nitrobenzyl-a-isopropenyl-3-IN-benzyloxycarbonylbenzylamino3rl ^a r 5a-2,6-diaza- (_ 3,2,0 Jt-2-hepten-6-acetate-V-one, m.p. 141 to 143 ° C. in 20 ml of acetone containing 0.60 ml of methyl azodicarboxylate, 200 mg of p-toluenesulfonic acid monohydrate and 0.2 ml of water were left ^{to stand for 20 hours at room temperature, neutralized at 0} ° C. with NaHCO ₃ , and water and extracted with benzene _{, followed by drying over anhydrous Na 2} SO, and the solution

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30 minutes at room temperature with 0.2 ml of a 30% KOH solution stirred with a magnetic stirrer. Finally the organic layer was separated with acidified water and then washed with water and dried over anhydrous Na ^ SO. dried, a residue was obtained which, after crystallization from ether, 230 mg of p-nitrobenzyl-7- | _N-benzyloxycarbonyl-D-a-phenylglycine amido ^ J-3-cephem-4-carboxylate found m.p. 198 to 2O2 ° C.

The IR and NMR data correspond to the data obtained with a sample obtained by a different method.

"Example 13: In a manner analogous to the previous one described, the following compounds were obtained: 2 ', 2', i'-Trichloräthy! ester of V-phenylacetamido-S-methyl-S-cephem-4-carboxylic acid, Mp. 163 C,

p-methoxybenzyl ester of T-phenylacetamido-S-methyl-S-cephem-4-carboxylic acid, Mp. 151 to 152 ° C,

p-Chlorophenacyl ester of T-phenoxyacetamido-S-methyl-S-cephem-4-carboxylic acid, melting point 176 ° C,
Phenacyl ester of T-phenylacetamido-S-methyl-S-cephein ^ -carboxylic acid, m.p. 190 to 191 ° C-,

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49. 2522H2

- re -

p-Bromphenacrylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid, mp. 196-198 ⁰ C, t-butyl ester of V-phenylacetamido-S-methyl-S-cephem-'lcarbonsäure, mp. 122 ⁰ C, p-Nitrobenzyl ester of T-phenoxyacetamido-S-methyl-S-cephem-4-carboxylic acid, melting point 191 ° to 193 ° C., methyl ester of 7-phenylacetamido-3-methyl-3-cepheIn-4-carboxylic acid, melting point . 188-190 ⁰ C, p-nitrobenzyl ester of 7- (thiophen-2-acetamido) -3-methyl-3-cephem-4-carboxylic acid, mp. 217 ° C, p-methoxybenzyl ester of 7- (thiophen-2- acetamido) -3-methyl-3-cephem-4-carboxylic acid, mp. 160 ⁰ C.

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Claims (5)

Patent claims: 1. 'Process for the preparation of cephalosporins of the general formula H H 'S
R-CONH I. '. I " ,(in) 1 . COR ¹ where R is hydrogen, alkyl with 1 to 4 carbon atoms, cyanomethyl, thienylmethyl, Fury! methyl, naphthylmethyl, phenylmethyl, phenoxymethyl, phenylisopropyl, phenoxyisopropyl, pyridyl-4-thiomethyl or tetrazolyl-l-methyl, R is hydroxy, alkoxy with 1 to 4 carbon atoms, trichloroethoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, triphenylmethoxy, phenacyloxy or p-halophenacyloxy and Z represents hydrogen, hydroxy, -O-alkyl, -O-CO-alkyl, -Br, -J, - N ₃ , -NH ₃ , -0-CO-CH ₃ , "0-CO-NH ₂ or an S-mononuclear heterocyclic nitrogen ring, characterized in that a compound of the general formula 509850/0970 2522Η2 wherein R, R and Z are as defined above, at a temperature from -20 to +80 C in a suitable solvent in the presence of an organic or inorganic aqueous Acid with an azo derivative of the general formula .2 N- Il N- -R -R 2 3
wherein R and R are identical or different and are each lower alkyl, mononuclear aryl, CN, a mononuclear heterocyclic ring, -COR ⁴ , -COOR, -p- (OR) "or-CONHR 2 3 ® represent or R and R together form a group / ^c \ oaer CH. 4 4 or ^ IN-R jst and R lower alkyl, mono mean, where T nuclear aryl or a mononuclear heterocyclic ring is reacted, where a compound of the general formula NH-R ² R-CONH (II ¹ ) COR is obtained wherein R, R, R, R and Z are those given above 509850/0970 2522H2 Have meanings which are reacted in a suitable solvent at a temperature of ^{-100 to +120 0} C with a compound from the group of the inorganic basic or weakly acidic oxides, the inorganic and the organic bases, the compound of the formula (III) is obtained, which is isolated and purified in a manner known per se. 2. The method according to claim 1, characterized in that the inorganic basic or weakly acidic oxides for transferring of intermediate (II) into the compound of formula (III) aluminum, iron, chromium or silicon oxides, either alone or in admixture with other inorganic compounds. 3. The method according to claim 1, characterized in that as inorganic bases for transferring the intermediate product (II) into the compound of the formula (III) alkali metal and alkaline earth metal hydroxides, Ammonium hydroxide, alkali carbonates or alkali metal alcoholates are used. 4. The method according to claim 1, characterized in that the organic bases for transferring the intermediate product (II) aliphatic, aromatic and heterocyclic amines or basic exchange resins are used in the compound of the formula (III) will. 5. The method according to claim 1 for the preparation of a compound of the general formula 509850/0970 -TZ- NH R I _; R-COHN- • Ν where V is hydrogen, an aliphatic, aromatic, arylaliphatic or . Acyl group, in particular a group of the formula OR COR COR 12 3 wherein R, R, R, R and Z are those specified in claim 1 Have meaning and M denotes hydrogen or alkyl having 1 to carbon atoms, characterized in that one Compound of the general formula Η-H (D -N 609850/0970 IN THE 2522U2 in a suitable solvent at a temperature of -20 to + 8O ⁰ C in the presence of an organic or inorganic aqueous acid with an azo derivative of the general formula N- Ii N- -R is implemented.
6th 2 /!> - Thiohydrazoazetidinone of the general formula NH-R ² R-CONH- N-S 0 'V where V is hydrogen, an aliphatic ^, aromatic, is arylaliphatic or acyl group, in particular a group of the formula COR- CH. COR OM 3 or COR 509850/0970 2522H2 - atf - 12 3 and R, R, R, R, M and Z are those given in claim 1 · Have meaning. 509850/0970