CH633290A5 - Process for preparing derivatives of 7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid - Google Patents

Description

The invention relates to a process for the preparation of 7-oxo-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid derivatives of the general formula I.

9 H H H R2-i -N =

65

NO

(I) CO OH

in the R2 one optionally by a C i _4-alkyl 1- or C i _4-

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Alkoxy radical, a trifluoromethyl, or hydroxyl group or a halogen atom substituted phenyl group, a phenoxymethyl group or a benzyl group optionally substituted on the benzene nucleus by a Ci-4-alkyl or Ci_4 alkoxy radical, a trifluoromethyl or hydroxyl group or a halogen atom, an a -Amino-benzyl, a-hydroxybenzyl or a-carboxy-benzyl group or a benzyloxy group, R3 denotes a hydrogen atom or an easily removable carboxyl protecting group and R4 denotes a Q_5-alkanoyl residue, a C2_5-Alkoxycar-bonyl residue, a haloacetyl or dihaloacetyl residue, optionally with a a C: _4-alkyl or C] _4-alkoxy radical, a trifluoromethyl group or a halogen atom substituted benzoyl group, one optionally on the benzene nucleus by a C | _4-alkyl or C (_4-alkoxy, a trifluoromethyl group or a halogen atom substituted phenylacetyl group, a methanesulfonyl, ethanesulfonyl, benzenesulfonyl, a-toluenesulfonyl or p-toluenesulfonyl group.

If the radical R3 is a hydrogen atom, the compounds can also be in the form of salts, for example as alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium salts, or as ammonium salts. The pharmacologically acceptable salts are preferred.

The term "easily removable carboxyl protecting group" has a certain meaning in the chemistry of penicillins, cephalosporins and peptides. Numerous such groups are known which are used to protect the carboxyl group during subsequent chemical reactions and which are split off again at a later stage by customary methods to form the free carboxylic acids. Examples of such known carboxyl protecting groups are 2,2,2 -Trichloräthylgruppe, C4_6-tert.-alkyl radicals, C5_7-tert.-alkenyl radicals, C5_7-tert.-alkynyl radicals, Ci_6-alkanoylmethyl radicals, the N-phthalimidomethyl, benzoylmethyl, naphthoylme-methyl, furoylmethyl, thoylmethyl Nitrobenzoylmethyl, 10 halobenzoylmethyl, methylbenzoylmethyl, methanesulfonylbenzoylmethyl, phenylbenzoylmethyl, benzyl, nitrobenzyl, methoxybenzyl, benzyloxymethyl, nitrophenyl, methoxyphenyl, benzhydryl, trimethylsilyl, tri-ethylsilyl . The type of carboxyl protecting group used depends, for example, on the type of subsequent reactions which the protecting group must withstand,

and the conditions under which the protective group is to be split off. The type of protective group used is of minor importance for the invention. 20 The compounds of general formula I and the starting compound of formula VIII are prepared in the manner described in Reaction Scheme A below. The radicals R2 and R4 have the meaning given above, R5 is an easily removable amino protective group, X is a halogen atom, 25 is preferably a chlorine atom, and R3 is an easily removable carboxyl protective group.

, co2ch3

N *

DMB

DMB = 2,4-DLmethoxybenzyl

Reaktlonsscheaa A

H H îAiw H H 5 H H tAju H H

^ co2CH3 rX; ^ CO2GH3 vH ^ H2at

->

CF "

-N

^ DMB

IX

K'y

-N

\

J) MB

III

"S

NÎ

IV

4T

r2conh-

H H

-f— CH2N3

VII

L-CH2NH2 R ^ CONH H H

H H

OHCCO2R

G '-H

VH-a ch2n3

. H H H H

R5NH- - - -rn-TJ- ° 5

VIII

VI-a vA

R CONH «

jl *

N \ H ^ C0:

R -X

SE

H H '

= -CH2N3 R3nh -; - ^ - cH2oa ^ - ^ a ^ <'

0 '' -H

VI

N-R 3

C02R '

l. "'-

s

\ r

Y-a '

R2 CONHl1?

N-R -Nv /

eo ^ H

According to reaction scheme A, methyl glyoxylate is reduced. The reaction of the tosylate generally condensed with 2,4-dimetoxybenzylamine and the product of formula V-a with an azide such as sodium azide provides the corresponding

the mixed anhydride of azidoacetic acid to form the azetidinone 60-corresponding azidomethyl compound of the general formula VI.

the general formula II implemented. The hydrogenation of this is then done by the amino protecting group, for example

Compound provides the corresponding amino compound, which cleaves off during treatment with trifluoroacetic acid and which

is protected in a manner known per se on the amino group. It tene amino compound of the general formula VI-a in itself, the compound of general formula III is obtained. In a known manner to connect the general formula VII

the reaction of this compound with potassium persulfate 65 is acylated. The reduction of this connection and the subsequent

Cleaved off dimethoxybenzyl group. There is the compound-sending reaction of the aminomethyl compound of the general formula IV obtained which, for example, with general formula VIII-a with a glyoxylic acid derivative (the

Sodium borohydride to connect the general formula V carboxyl group is replaced by an easily removable protective group

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protected) provides the compound of general formula VIII. The reaction of this compound with an acyl halide (RJ-X) gives the 1,3-diazabicyclo compound of general formula Ia, in which R3 represents an easily removable carboxyl protecting group. The splitting off of the carboxyl protecting group gives the compounds of general formula I.

The starting compounds used are either known or are prepared by known methods or in the manner described below.

Because of the asymmetric carbon atoms both in the bicyclic β-lactam ring system and in some of the acyl residues of the side chain acids, the compounds can also occur in stereoisomers (epimers). The invention encompasses all isomers and isomer mixtures.

The compounds of general formula I are valuable antibiotics or intermediates for the preparation thereof. In vitro experiments have shown that, for example, the 3-acetyl-7-oxo-6β-phenoxyacetylamino-1,3-diazabicyclo- [3.2.0] heptane-2-carboxylic acid exhibits antibiotic activity against Staphylococcus aureus, Bacillus subtilis and other bacteria.

For the production of medicaments, the compounds of the general formula I can be administered orally or parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of customary administration forms.

The examples illustrate the invention. The preparation of starting compounds is explained in the experiments.

Trial A

cis-3-Azido-l- (2,4-dimethoxybenzyl) -4-oxoazetidine-2-carbonic acid methyl ester

A mixture of 16.82 g (0.101 mol) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride is mixed at 25 ° C. with a solution of 10.05 g (0.114 mol) of methyl glyoxylate in 20 ml of methylene chloride. The mixture is stirred at room temperature for 15 h, then filtered and the filtrate evaporated under reduced pressure. The imine remains as a dark orange-colored smear.

A solution of 15.1 g (0.149 mol) of azidoacetic acid in 130 ml of anhydrous methyl chloride is added dropwise at 0 ° C in an ice bath with 21.0 ml (0.15 mol) of trifluoroacetic anhydride. The mixture is then stirred at 0 ° C. for 15 min and 20.8 ml (0.15 mol) of triethylamine are then added dropwise. The mixture is stirred for a further 45 min and then transferred under argon into a dropping funnel which is cooled from the outside with dry ice. The dropping funnel is placed on a flask containing the imine described above, 200 ml of anhydrous methylene chloride and 20.8 ml (0.15 mol) of triethylamine. The mixed anhydride solution is then added dropwise from the dropping funnel at 0 ° C to the imine solution. When the addition is complete, the mixture is stirred at 0 ° C. for 1 h. The dark colored reaction mixture is then transferred to a separatory funnel, washed with water, aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on 300 g of silica gel (60 to 210 n). A whitish solid is obtained which is digested with diethyl ether. The title compound falls as a white solid, which melts at 82 to 84 ° C. after recrystallization from a mixture of ethyl acetate and hexane. The compound has an Rr value of 0.64 in thin-layer chromatography in the benzene-ethyl acetate (1: 1) system on silica gel GF.

Experiment B cis-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylic acid methyl ester

A mixture of 10.0 g (0.0312 mol) of cis-3-azido-1- (2,4-dimethoxybenzyl) -4-oxoazetidine-2-carboxylic acid methyl ester, 1.0 g of 10% palladium-on-carbon as a catalyst and 200 ml of ethanol is hydrogenated in a hydrogen atmosphere at a pressure of 4.2 at 2 h at 40 to 45 ° C. The reaction mixture is then cooled to 25 ° C. and filtered through diatomaceous earth. The filtrate is evaporated under reduced pressure. The crude amine remains as a clear yellow smear. The product is taken up in 100 ml of anhydrous methylene chloride and the solution is cooled in an ice bath to 0 ° C. The solution is then mixed with 4.32 ml (0.0312 mol) of triethylamine and then slowly with a solution of 5.32 g (0 , 0312 mol) of phenoxyacetyl chloride are added to 40 ml of methylene chloride, the mixture is then stirred for 1 hour at 0 ° C. and then washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate Distilled off under reduced pressure. A yellow solid remains, which partially dissolves in diethyl ether. The solution is cooled to -25 ° C. and filtered. The cis-1- (2,4-dimethoxybenzyl) -4-oxo 3-phenoxyacetylaminoazetidine-2-carboxylic acid methyl ester obtained as a white solid After recrystallization from a mixture of ethyl acetate and hexane, the compound melts at 115.5 to 116.0 ° C. In thin layer chromatography in the benzene-ethyl acetate (1: 1) system on silica gel, the compound has an Rr value of 0.38.

900 ml of acetonitrile carefully degassed with argon are mixed with 30.0 g (0.070 mol) of cis-l- (2,4-dimethoxybenzyl) -4-oxo-3-phen-oxyacetylaminoazetidine-2-carboxylic acid methyl ester. The crystals are rinsed into the reaction vessel with a further 50 ml of degassed acetonitrile. The solution is then heated to 78 ° C. under argon and a degassed solution of 75.6 g (0.28 mol) of potassium persulfate and 37.5 g (0.14 mol) of sodium monohydrogenphosphate in 1400 ml of water is added. The aqueous solution is added in portions of 250 ml over a period of one hour, the outside temperature being set to 78 to 82 ° C. After the reaction mixture has cooled, the acetonitrile is distilled off. The concentrated reaction mixture is mixed with sodium chloride and extracted four times with ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate, filtered and evaporated to about 100 to 200 ml under reduced pressure. After adding about 300 ml of diethyl ether and cooling to -25 ° C, the title compound crystallizes out. The compound is filtered off and recrystallized from a mixture of ethyl acetate and hexane; F. 140 to 141 ° C. The compound has an Rr value of 0.44 in the ethyl acetate system in thin layer chromatography on silica gel GF and an Rr value of 0.21 in the ethyl acetate-benzene system (1: 1).

Attempt C

cis-2-hydroxymethyl-4-oxo-3-phenoxyacetylaminoazetidine

A solution of 13.5 g (0.049 mol) of cis-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylic acid methyl ester in 975 ml of tetrahydrofuran and 100 ml of water at 0 ° C. in an ice bath within a period of 10 min with a cold solution of 3.75 g (0.099 mol) of sodium borohydride in 250 ml of water. The solution is then stirred at 0 ° C. for 40 min and glacial acetic acid is then added until the evolution of hydrogen subsides. Then the reaction mixture is mixed with solid sodium bicarbonate and sodium chloride and extracted five times with 250 ml of ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in ethyl acetate and treated with activated carbon. The solution is then left to crystallize the title compound. After recrystallization from ethyl acetate, the compound melts at 153 to 154 ° C. In a thin-layer chromatogram on silica gel GF

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Ethyl acetate as eluent has an Rr value of 0.10.

Attempt D

cis-2-azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine

A solution of 4.30 g (0.022 mol) of 98% pure p-toluenesulfonyl chloride in 24 ml of anhydrous pyridine is mixed with 2.64 g (0.011 mol) of cis-2-hydroxymethyl-4-oxo- 3-phenoxyacetylaminoazetidine added all at once. The solution is stirred at 0 ° C for 3 h and then left at -25 ° C for 15 h. The solution is then warmed to 0 ° C., 1.0 ml of 85% lactic acid are added and the mixture is stirred for a further hour. The reaction mixture is poured into ethyl acetate and washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. After filtering, the filtrate is evaporated under reduced pressure. A yellow-colored solid residue remains, which is dissolved in 375 ml of hot ethyl acetate, clarified with activated carbon and mixed with 200 ml of hexane. The precipitated compound is filtered off and recrystallized. The cis-4-oxo-3-phenoxyacetylamino-2-p-toluenesulfonyloxymethylazetidine of mp 136 ° C (dec.) Is obtained. In thin-layer chromatography on silica gel GF with ethyl acetate as the eluent, the compound has an Rr value of 0.47.

A mixture of 1.131 g (2.8 mmol) of cis-4-oxo-3-phenoxy-acetylamino-2-p-toluenesulfonyloxymethylazetidine, 0.961 g (14.8 mmol) of sodium azide and 25 ml of anhydrous dimethylformamide is argon as a protective gas for 6 h warmed to 40 ° C and a further 24 h to room temperature. The reaction mixture is then poured into ethyl acetate and washed with water. The aqueous phases are combined and extracted once with ethyl acetate. Then the ethyl acetate extracts are combined and extracted with aqueous saline. Then the ethyl acetate solution is dried over magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. A yellow-colored semi-crystalline residue remains. The residue is slurried in methylene chloride and chromatographed on 25 g of silica gel (60 to 210 | i). A mixture of ethyl acetate and methylene chloride (1: 1) is used as the eluent. The eluate is evaporated. The title compound remains which, after recrystallization from a mixture of ethyl acetate and hexane, melts at 142 to 143 ° C. with decomposition. In thin layer chromatography on silica gel GF with ethyl acetate as the eluent, the compound has an Rr value of 0.38.

Tries

cis-2-azidomethyl-3-tert-butoxycarbonylamino-4-oxoazetidine

A mixture of 10.0 g (0.0312 mol) of cis-3-azido-1- (2,4-dimethoxybenzyl) -4-oxoazetidine-2-carboxylic acid methyl ester, 1.0 g of 10% palladium-on-carbon as The catalyst and 200 ml of ethanol are hydrogenated at 40 to 45 ° C. with a hydrogen of 4.2 at 2 h. The reaction mixture is then cooled to 25 ° C. and filtered through a filter aid. The filtrate is evaporated under reduced pressure. The cis-3-amino-1- (2,4-dimethoxybenzyl) -4-oxoazetidine-2-carboxylic acid remethyl ester remains.

A solution of 5.5 g (18.8 mmol) of the methyl ester obtained in 100 ml of anhydrous toluene is cooled to -78 ° C, mixed with 2.5 ml (18.8 mmol) of triethylamine and then quickly with 35 ml (42 mmol ) a 12% solution of phosgene in benzene. The mixture is stirred at -78 ° C for 15 min, at -45 ° C for 3 h in a mixture of acetonitrile and dry ice as a coolant, then warmed to room temperature and evaporated to half its volume under reduced pressure. The solution is then mixed with 50 ml of tert-butanol and stirred at room temperature for 15 h. After that

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the solvents are distilled off under reduced pressure, and the residue is diluted with ethyl acetate and filtered. The filtrate is transferred to a separatory funnel and washed with 5% aqueous sodium bicarbonate solution, 5% hydrochloric acid and aqueous saline solution, dried over magnesium sulfate and evaporated to dryness. »The crystalline crude product is recrystallized from diethyl ether. The cis - ^ - tert-butoxycarbonylamino-1- (2,4-dimethoxybenzyl) -4-oxoazetidine-2-carboxylic acid methyl ester of mp 134 to 135 ° C. is obtained.

A solution of 10.5 g (26.7 mmol) of the methyl ester obtained in 500 ml of acetonitrile is degassed with argon and heated to 80 ° C. A degassed solution of 15 g (55.5 mmol) of potassium persulfate and 7.5 g (28 mmol) of sodium monohydrogen phosphate in 150 ml of water is then added in 5 portions over a period of 1 h. The reaction mixture is heated to 80 to 85 ° C. under argon as a protective gas for 2 to 3 h and stirred until the reaction has ended. This is determined by thin layer chromatography. The reaction mixture is then cooled, evaporated under reduced pressure and shaken out in a mixture of ethyl acetate and water. The organic phase is washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with a mixture of benzene and ethyl acetate (1: 1) as the eluent. After recrystallization from a mixture of ethyl acetate and hexane, the pure cis-3-tert-butoxycar-bonylamino-4-oxoazetidine-2-carboxylic acid methyl ester of mp 140 ° to 144 ° C. is obtained.

The reduction of the methyl ester obtained according to experiment C with sodium borohydride and the subsequent conversion of the 2-hydroxymethylazetidine obtained into the corresponding p-toluenesulfonate (melting point 160 to 162 ° C. dec.) And the reaction of this compound with sodium azide according to experiment D yields the title compound.

Experiment F cis-3-amino-2-azidomethyl-4-oxoazetidine Iggis-2-azidomethyl-3-tert-butoxycarbonylamino-4-oxo-azetidine is dissolved in 2 ml of methylene chloride. The solution is cooled to 0 ° C. and treated with 0.5 ml of trifluoroacetic acid at 0 ° C. for 30 minutes. The solution is then washed with 5% aqueous sodium bicarbonate solution and extracted with dilute hydrochloric acid. The aqueous phase is neutralized and extracted with ethyl acetate. The ethyl acetate extract is evaporated. The title link remains.

Attempt G

cis-3-Amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine A degassed solution of 3.8 g (0.012 mol) of cis-3-azido-l- (2,4-dimethoxybenzyl) -4-oxoazetidine-2-carboxylic acid methyl ester is treated with potassium persulfate and sodium monohydrogen phosphate according to experiment B. The cis-3-azido-4-oxoaze-tidin-2-carboxylic acid methyl ester is obtained and is purified by chromatography on silica gel with a mixture of benzene and ethyl acetate as the eluent.

The cis-3-azido-4-oxoazetidine-2-carboxylic acid methyl ester is reduced with sodium borohydride according to experiment C. The product is purified chromatographically on silica gel using ethyl acetate as the eluent. The cis-3-azido-2-hydroxymethyl-4-oxoazetidine is obtained.

According to experiment D, the cis-3-azido-4-oxo-2-p-toluenesulfonyloxy-methylazetidine is prepared from the cis-3-azido-2-hydroxymethyl-4-oxoazetidine.

A solution of 5.0 g (0.011 mol) of cis-3-azido-4-oxo-2-p-toluenesulfonyloxymethylazetidine in 50 ml of 50% aqueous acetic acid is slowly and while cooling with 2.0 g (0.03 mol)

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Zinc dust added. The reaction mixture is stirred for 30 min and filtered. The filter residue is washed with water. The filtrate is saturated with hydrogen sulfide, filtered and evaporated almost to dryness. The residue is dissolved in a mixture of ethyl acetate and water and the pH is adjusted to 8.0 with sodium carbonate and sodium hydroxide solution. The layers are separated and the aqueous phase is extracted twice with ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated to dryness. The title link remains.

Attempt H

cis-2-Aminomethyl-4-oxo-3-mandeloylaminoazetidine cis-3-amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine is reacted with O-benzylmandeloyl chloride according to experiment B. The product obtained is then converted to the corresponding 2-azidomethyl compound, which is reduced with zinc and acetic acid according to Example 2. Ris-2-aminomethyl-3- (a-benzyloxyphenylacetylamino) -4-oxoazetidine is obtained.

A suspension of 14 mg of 10% palladium-on-carbon as a catalyst and 0.06 mol of cis-2-aminomethyl-3- (a-benzyloxyphenylacetylamino) -4-oxoazetidine in 2 ml of anhydrous ethyl acetate is hydrogenated at room temperature and atmospheric pressure . The reaction mixture is then filtered and the filtrate is evaporated to dryness. The title link remains.

Trial I

cis-3-Amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine is reacted with an acid halide of the optionally protected carboxylic acids listed below:

Benzoic acid,

p-toluic acid,

4-ethylbenzoic acid,

4-tert-butylbenzoic acid,

m-methoxybenzoic acid,

4-n-butoxybenzoic acid,

2-chlorobenzoic acid,

4-bromobenzoic acid,

4-hydroxybenzoic acid,

3-trifluoromethylbenzoic acid,

Phenylacetic acid,

a-aminophenylacetic acid,

a-carboxyphenylacetic acid,

4-fluorophenylacetic acid,

3-hydroxyphenylacetic acid and

4-trifluoromethylphenylacetic acid.

The reaction is carried out according to experiment B. Then the product obtained is converted according to experiment D to the 2-azidomethyl compound. After splitting off any protective groups that may be present, the following compounds are obtained: cis-2-azidomethyl-3-benzoylamino-4-oxoazetidine, cis-2-azidomethyl-4-oxo-3- (p-tolylamino) azetidine, cis-2-azidomethyl 3- (4-ethylbenzoylamino) -4-oxoazetidine, cis-2-azidomethyl-3- (4-tert-butylbenzoylamino) -4-oxoazetidine,

cis-3- (m-methoxybenzoylamino) -2-azidomethyl-4-oxoazetidine,

cis-2-azidomethyl-3- (4-n-butoxybenzoylamino) -4-oxoazetidine,

cis-2-azidomethyl-3- (2-chlorobenzoylamino) -4-oxoazetidine,

cis-2-azidomethyl-3- (4-bromobenzoylamino) -4-oxoazetidine,

cis-2-azidomethyl-3- (4-hydroxybenzoylamino) -4-oxoazetidine,

cis-2-azidomethyl-4-oxo-3- (3-trifluoromethylbenzoylamino) -

azetidine,

cis-2-azidomethyl-4-oxo-3-phenylacetylaminoazetidine,

cis-3- (a-aminophenylacetylamino) -2-azidomethyl-4-oxoaze-

tidin,

cis-2-azidomethyl-3- (a-carboxyphenylacetylamino) -4-oxoazetidine.

cis-2-azidomethyl-3- (4-fluorophenylacetylamino) -4-oxoazetidine, cis-2-azidomethyl-3- (3-hydroxyphenylacetyIamino) -4-oxoazeti-din and cis-2-azidomethyl-4-oxo-3- (4-trifluoromethylphenylacetyla-mino) azetidine.

Attempt K

cis-2-Aminomethyl-4-oxo-3-phenoxyacetylaminoazetidine A suspension of 0.499 g (1.81 mmol) of cis-2-azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% pal-ladium on carbon as The catalyst in 25 ml of anhydrous ethanol is hydrogenated at 40 ° C. for 1 h at atmospheric pressure. The mixture is then filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The title compound remains as a colorless grease.

Trial L

The reduction of the 2-azidomethyl-3-substituted-4-oxoazetidins listed in Experiment I according to Experiment H or K yields the following 2-aminomethyl compounds: cis-2-aminomethyl-3-benzoylamino-4-oxoazetidine, cis-2-aminomethyl-4 -oxo-3- (p-tolylamino) azetidine, cis-2-aminomethyl-3- (4-ethylbenzoylamino) -4-oxoazetidine, cis-2-aminomethyl I-3- (4-tert-butylbenzoylamino) -4- oxoaze-tidin,

cis-2-aminomethyl-3- (m-methoxybenzoylamino) -4-oxoaze-tidine,

cis-2-aminomethyl-3- (4-n-butoxybenzoylamino) -4-oxoazetidine,

cis-2-aminomethyl-3- (2-chlorobenzoylamino) -4-oxoazetidine,

cis-2-aminomethyl-3- (4-bromobenzoylamino) -4-oxoazetidine,

cis-2-aminomethyl-3- (4-hydroxybenzoylamino) -4-oxoazetidine,

cis-2-aminomethyl-4-oxo-3- (3-trifluoromethylbenzoylamino) -

azetidine,

cis-2-aminomethyl-4-oxo-3-phenylacetylaminoazetidine,

cis-2-aminomethyl-3- (a-aminophenylacetylamino) -4-oxoaze-

tidin,

cis-2-aminomethyl-3- (a-carboxyphenylacetylamino) -4-oxoaze-tidine,

cis-2-aminomethyl-3- (4-fluorophenylacetylamino) -4-oxoaze-tidine,

cis-2-aminomethyl-3- (3-hydroxyphenylacetylamino) -4-oxoazetidine and cis-2-aminomethyl-4-oxo-3- (4-trifluoromethylphenylacetylamino) azetidine.

Attempt M

cis-2-azidomethyl-3- (4,5-diphenyl-2-oxo-4-oxazolin-3-yl) -4-oxoazetidine

A mixture of 16.82 g (0.101 mol) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride is mixed at 25 ° C. with a solution of 10.05 g (0.114 mol) of methyl glyoxylate in 20 ml of methylene chloride. The reaction mixture is then stirred at room temperature for 15 h and then filtered. The filtrate is evaporated under reduced pressure. It leaves the N- (2,4-dimethoxy-benzyl) -iminoacetic acid methyl ester as a dark orange-colored smear.

A mixture of 2.1 g (7.1 mmol) of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid [cf. J. Org. Chem., Vol. 38 (1973), p. 3034], 5 ml of thionyl chloride and 20 ml of methylene chloride are heated under reflux for 2 / h. After cooling to room temperature, the solvent is distilled off under reduced pressure. The oily residue crystallizes on standing. The product is digested with a mixture of diethyl ether and hexane. The 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride of mp 104 to 112 ° C. is obtained.

1.43 g of methyl N- (2,4-dimethoxybenzyl) iminoacetate

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are dissolved in 13 ml of anhydrous methylene chloride, mixed with 1 ml of triethylamine and cooled in an ice bath. A solution of 2.0 g (6.4 mmol) of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride in 10 ml of methylene chloride is added within 10 minutes. After 1 h the mixture is washed with water and 5% aqueous sodium bicarbonate solution, then dried over magnesium sulfate and evaporated. A red-colored oil remains, which is chromatographed on silica gel. The cis-1- (2,4-dimethoxybenzyl) -3- (4,5-diphenyl-2-oxo-4-oxazolin-3-yl) -4-oxoazetidine-2-carboxylic acid methyl ester is obtained.

The carboxylic acid methyl ester is reacted with potassium persulfate and sodium monohydrogen phosphate according to test E. The methyl cis-3- (4,5-diphenyl-2-oxo-4-oxazolin-3-yl) -4-oxo-zetidine-2-carboxylate is obtained.

According to experiment C, the methyl ester is reduced with sodium borohydride, the 2-hydroxymethylazetidine compound obtained is converted into the p-toluenesulfonate and reacted with sodium azide according to experiment D to give the title compound.

Attempt N

When using p-methoxybenzyl alcohol, isoborneol, benzyl alcohol or 2,2,2-trichloroethanol instead of tert-butanol in experiment E, the cis-l- (2,4-dimethoxybenzyl) -3- (p-methoxybenzyloxycarbonylamino) -4 -oxoazetidine-2-carbonic acid methyl ester, cis-l- (2,4-dimethoxybenzyl) -3-isobornyloxy-carbonylamino-4-oxo-azetidine-2-carboxylic acid methyl ester, cis-3-benzyIoxycarbonyIamino-l- (2,4- dimethoxybenzyI) -4-oxoazeti-din-2-carboxylic acid methyl ester or the cis-l- (1,2-dimethoxy-benzyl) -4-oxo-3- (2,2,2-trichloroethoxycarbonylamino) -azetidine-

2-carboxylic acid methyl ester obtained. The 3-isobornyloxycarbonylamino-l- (2,4-dimethoxybenzyl) -

4-oxo-azetidine-2-carboxylic acid methyl ester can also be prepared by reacting the 3-amino compound with isobornyloxycarbonyl chloride in the presence of a base by the process described in Chem. Pharm. Bull., Vol. 20 (1972), p. 1017 .

The reaction of the abovementioned methyl esters with potassium persulfate and sodium monohydrogen phosphate according to test H provides the following compounds:

cis-3- (p-methoxybenzyloxycarbonylamino) -4-oxoazetidine-2-car-bonic acid methyl ester,

cis-3-isobornyloxycarbonylamino-4-oxoazetidine-2-carboxylic acid methyl ester,

cis-3-benzyloxycarbonylamino-4-oxoazetidine-2-carboxylic acid methyl ester and cis-4-oxo-3- (2,2,2-trichloroethoxycarbonylamino) -azetidine-2-carboxylic acid methyl ester.

The reduction of the aforementioned methyl esters with sodium borohydride according to experiment C, the conversion of the 2-hydroxymethylazetidines obtained into the corresponding p-toluenesulfonates and the reaction of these compounds with sodium azide according to experiment D yields the following azidomethyl compounds: cis-2-azidomethyl-3- (p methoxybenzyloxycarbonylamino) -4-oxoazetidine,

cis-2-azidomethyl-3-isobornyloxycarbonylamino-4-oxoazetidine,

cis-2-azidomethyl-3-benzyloxycarbonylamino-4-oxoazetidine and cis-2-azidomethyl-4-oxo-3- (2,2,2-trichloroethoxycarbonylamino) azetidine.

example 1

3-acetyl-7-oxo-6ß-phenoxyacetylamino-l, 3-diazabicyclo- [3.2.0] heptane-2-carboxylic acid

A suspension of 0.499 g (1.81 mmol) of cis-2-azidomethyl

4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% palladium-on-carbon in 25 ml of anhydrous ethanol is left for 1 h

633 290

hydrogenated at atmospheric pressure and 40 ° C. The mixture is then filtered through diatomaceous earth and the solvent is distilled off under reduced pressure. A colorless grease remains, which is dissolved in 15 ml of methylene chloride. Anhydrous magnesium sulfate is added to the solution, followed by a solution of 0.314 g (1.91 mmol) of benzyl glyoxylic acid in 10 ml of methylene chloride. The mixture is stirred under argon as protective gas 2'Ah at room temperature and then left to stand at 0 ° C. for 15 h. The reaction mixture is then filtered off and the filtrate is evaporated under reduced pressure. The semi-crystalline residue is recrystallized from a mixture of ethyl acetate and hexane. The benzyl N- (cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl) iminoacetate is obtained as a colorless solid.

A solution of 50 mg (0.13 mmol) of the benzyl ester in 1.8 ml of anhydrous methylene chloride is at 0 ° C under argon as a protective gas with 16 (xLiter (0.20 mmol) of anhydrous pyridine and then with 14 [iLiter (0, The mixture is stirred for 1 h at 0 ° C., then ethyl acetate is added and the mixture is rapidly filtered through a glass suction filter covered with 1.0 g of silica gel, and the filtrate is distilled off under reduced pressure yellow grease is recrystallized from a mixture of diethyl ether and methanol to give the 3-acetyl-7-oxo-6ß-phenoxyacetylamino-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid benzyl ester as a mixture of the C-2 epimers The compound melts at 148 to 150 ° C. In thin layer chromatography on silica gel GF with ethyl acetate as the eluent, the Rr value is 0.55.

A suspension of 14 mg of 10% palladium-on-carbon and 28 mg (0.064 mmol) of 3-acetyl-7-oxo-6β-phenoxyacetyl-amino-1,3-diazabicyclo [3.2.0] heptane-2- Benzyl carboxylate in 2 ml of anhydrous ethyl acetate is hydrogenated at room temperature and atmospheric pressure for 1 h. The reaction mixture is then filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The title compound remains, which has a Rr value of 0.31 in thin layer chromatography on silica gel GF with a mixture of methylene chloride, methanol and acetic acid (90: 8: 2).

Example 2

3-acetyl-6ß-benzyloxycarbonylamino-7-oxo-l, 3-diazabicyclo [3.2.0] heptane-2-carboxylic acid

According to experiment B, cis-3-amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine is reacted with benzyl chloroformate. The cis-3-benzyloxycarbonylamino-4-oxo-2-p-toluenesulfonyloxymethylacetidine is obtained.

According to experiment D, the cis-3-benzyloxycarbonylamino

4-oxo-2-p-toluenesulfonyloxymethylazetidin to cis-2-azidomethyl-3-benzyloxycarbonylamino-4-oxoazetidine implemented.

According to experiment G, the cis-2-azidomethyl-3-benzyloxy-carbonylamino-4-oxoazetidine is reduced with zinc dust in 50% aqueous acetic acid. The reaction of the crude product obtained with benzyl glyoxylate in methylene chloride according to Example 1 gives the benzyl N- (cis-3-benzyloxycarbonylamino-4-oxo-2-azetidinylmethyl) -iminoacetate, which according to Example 1 with acetyl chloride to give 3-acetyl-6ß-benzyloxy-carbonylamino -7-oxo-l, 3-diazabicyclo [3.2.0] heptane-2-carbonic acid benzyl ester.

According to Example 1, the benzyl ester obtained is converted to the title compound by hydrogenolysis.

Example 3

3-acetyl-6ß-mandeloylamino-7-oxo-l, 3-diazabicyclo- [3.2.0] heptane-2-carboxylic acid

In the manner described above, cis-2-aminomethyl-3- (a-benzyloxyphenylacetylamino) -4-oxoazetidine is reacted with benzyl glyoxylate and the product obtained with

7

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

633 290

8th

Acetyl chloride acetylated. The 3-acetyl-6ß- (a-benzyloxy-phenylacetylamino) -7-oxo-l, 3-diazabicyclo [3.2.0] heptan-2-carbenzoic acid benzyl ester is obtained, which gives the title compound after hydrogenolysis.

5

Example 4

According to Example 1, benzyl N- (cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl) -iminoacetate is reacted with propionyl chloride. The 7-oxo-6β-phenoxyacetylamino-3-propionyl-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid 10 rebenzyl ester is obtained.

Absorption spectrum: 5.57 u (β-lactam group), 5.7 [x (ester group), 6.00 | x (amide groups).

After the benzyl ester protecting group has been split off in the manner described above, the 7-oxo-6β-phenoxyacetyl-15 amino-3-propionyl-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid is obtained.

The 3-propionyl, 3-butyryl and 3-valeryl derivatives of 7-oxo-l, 3-diazabicyclo [3.2.0] heptane-2-car-bonic acid are prepared in the same way. 20th

Example 5

According to Example 1, N- (cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl) -iminoacetic acid benzyl ester is reacted with ethyl chloramate. The 3-ethoxycarbonyl-7-oxo-6β-phenoxyacetylamino-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid benzyl ester is obtained.

IR absorption spectrum: 5.56 u (β-lactam group), 5.66 | x (ester group), 5.85 and 5.90 u (amide groups and carbonate group).

After the benzyl ester protecting group has been split off in the manner described above, the 3-ethoxycarbonyl-7-oxo-6β-phenoxyacetylamino-1,3-diazabicyclo [3.2.0] heptane-2-car-bonic acid is obtained. 35

The 3-alkoxycarbonyl derivatives of other 7-oxo-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acids described above are prepared in the same way.

Example 6

According to Example 1, N- (cis-4-oxo-3-phenoxyacetylamino-

2-azetidinylmethyl) -iminoacetic acid benzyl ester reacted with p-toluic acid chloride or p-anisoyl chloride. The following connections are obtained:

7-Oxo-6ß-phenoxyacetylamino-3- (p-toluoyl) -l, 3-diazabicyclo- [3.2.0] heptane-2-carboxylic acid benzyl ester.

IR absorption spectrum: 5.58 u (β-lactam group, 5.70 | x (ester group), 5.90, 5.96 and 6.10 (x (amide groups).

3- (p-anisoyl) -7-oxo-6β-phenoxyacetylamino-1,3-diazabicyclo [3.2.0] benzyl heptane-2-carboxylate; F. 148 to 150 ° C.

After the benzyl ester protecting group has been split off in the manner described above or by other customary processes, the following compounds are obtained: 7-oxo-6β-phenoxyacetylamino-3- (p-toluoyl) -l, 3-diazabicyclo- [3.2.0] heptane 2-carboxylic acid and

3- (p-anisoyl) -7-oxo-6ß-phenoxyacetylamino-l, 3-diazabicyclo- [3.2.0] heptane-2-carboxylic acid.

In the same way, other 7-oxo-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid esters described above can be acylated with the acid chloride of a benzoic acid. The corresponding compounds of the invention are obtained.

Example 7

According to Example 1, methanesulfonyl chloride is reacted with N- (cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl) -iminoacetic acid rebenzyl ester. The 3-methanesulfonyl-7-oxo-6ß-phenoxyacetylamino-l, 3-diazabicyclo [3.2.0] heptane-2-carbenic acid benzyl ester of mp 117 to 120 ° C. is obtained.

After the benzyl ester protecting group has been split off in the manner described above or by other customary processes, the 3-methanesulfonyl-7-oxo-6β-phenoxyacetylamino-1,3-diazabicyclo [3.2.0] heptane-2-carboxylic acid is obtained.

The 3-substituted sulfonyl derivatives of the other 7-oxo-1,3-diazabi-cyclo [3.2.0] heptane-2-carboxylic acids described above can be prepared in the same way.

M

Claims (9)

633 290 PATENT CLAIMS 1. Process for the preparation of 7-oxo-1,3-diazabicyclo- [3.2.0] heptane-2-carboxylic acid derivatives of the general formula I. 10th (I) COOH in the R2 one optionally by a Q_4-alkyl or C | _4-alkoxy radical, a trifluoromethyl or hydroxyl group or a halogen atom substituted phenyl group, a phenoxymethyl or a benzyl group optionally substituted on the benzene nucleus by a C (_4-alkyl or Q_4-alkoxy radical, a trifluoromethyl or hydroxyl group or a halogen atom, an a -Amino-benzyl, a-hydroxybenzyl or a-carboxybenzyl group or a benzyloxy group, and R4 denotes a Q _5-alkanoyl residue, a Ci-s-alkoxycarbonyl residue, a halogenoacetyl or dihaloacetyl residue, optionally with a C | _4- Alkyl or Ci_4 alkoxy, a trifluoromethyl group or a halogen atom substituted benzoyl group, a phenylacetyl group optionally substituted on the benzene nucleus by a Ci_4 alkyl or C | _4 alkoxy group, a trifluoromethyl group or a halogen atom, a methanesulfonyl, ethanesulfonyl, benzenesulfonyl a-Toluenesulfonyl- or p-toluenesulfonyl group, and their salts with bases, characterized in that a compound of the general formula VIII 15 20th 6. The method according to claim 1, characterized in that one uses an acyl halide of the general formula R4-Hal, in which R4 is an acetyl, propionyl, ethoxycarbonyl, p-anisoyl, p-toluoyl or methanesulfonyl group. 7. The method according to claim 1, characterized in that one uses a compound of general formula VIII, in which R2 represents a phenoxymethyl group. 8. The method according to claim 1 for the preparation of 3-acetyl-7-oxo-6ß-phenoxyacetylamino-l, 3-diazabicyclo [3.2.0] heptane-2-carboxylic acid, characterized in that N- (cis-4-oxo -3-phenoxyacetylamino-2-azetidinylmethyl) -iminoacetic acid-benzyl ester is reacted with acetyl chloride and the carboxyl protecting group is then split off. 9. The method according to claim 1, characterized in that for the preparation of 3-acetyl-6ß-benzyloxycarbonyl-amino-7-oxo-l, 3-diazabicyclo [3.2.0] heptane-2-carboxylic acid, the N- (cis- 3-Benzyloxycarbonylamino-4-oxo-2-azetidinylmethyl) -iminoes-sigsäurebenzylester with acetyl chloride and then cleaves the carboxyl protecting group. 25th r2conh (VIII) 35 06R- in which R2 has the above meaning and R3 represents a hydrogen atom or an easily removable carboxyl protecting group, with an acyl halide of the general formula R4-Hal in which R4 has the meaning given above, is reacted and, if appropriate, the carboxyl protecting group is split off and, if appropriate, the free acid obtained is converted into a salt with a base. 2. The method according to claim 1, characterized in that one uses a compound of general formula VIII, in which R3 is an easily removable ester protecting group. 3. The method according to claim 1, characterized in that one uses a compound of general formula VIII in which R3 represents a hydrogen atom. 4. The method according to claim 1, characterized in that one uses a compound of general formula VIII, in which R3 is a 2,2,2-trichloroethyl, C4_6-tert.-alkyl, C5_7-tert.-alkenyl, C- _7-tert.-alkynyl, Ci_6-alkanoylmethyl, N-phthalimidomethyl, benzoylmethyl, naphthoylmethyl, furoylmethyl, thienoylmethyl, nitrobenzoylmethyl, halobenzoylmethyl, methylbenzoylmethyl, methanesulfon Phenylbenzoylmethyl, benzyl, nitrobenzyl, methoxybenzyl, benzyloxymethyl, nitrophenyl, methoxyphenyl, benzhydryl, trityl, trimethylsilyl or triethylsilyl group. 5. The method according to claim 1, characterized in that one uses a compound of general formula VIII, in which R3 is a 2,2,2-trichloroethyl, tert-butyl, benzyl, benzhydryl, benzyloxymethyl, p-nitrophenyl, p-methoxyphenyl, p-nitrobenzyl or p-methoxybenzyl group. 40 45 50 55 The basic structure of the penicillins is a 4-thia-l-azabicyclo- [3.2.0] heptan-7-one ring system with the following structure 4th 6 5 ^ S- 30th 60 Compounds with this structure have been the subject of intensive research over the past 20 years, which is reflected in numerous scientific publications and patents. Efforts to establish connections with analog ring systems have been underway for several years. Examples of these penicillin analogs are the l-azabicyclo [3.2.0] heptan-7-one compounds [cf. Mollu.Mitarb., Z. Natural science. (B), vol. 24 (1969), p. 942, E arie u. Mitarb., J. Chem. Soc. (C), 1969, p. 2093 and Lowe et al., J. Chem. Soc. Chem. Comm., 1973, p. 328], 4-oxa-l-azabicyclo [3.2.0] heptan-7-one compounds [cf. Deshpandeu. Mitarb., J. Chem. Soc. (C), 1966, p. 1241, Wolfe et al. Collaborator, Can. J. Chem., Vol. 50 (1972), p. 2902, Goldingu. Mitarb., J. Chem. Soc. Chem. Comm., 1973, p. 293, DT-OSen 2219 601.23 56862 and 2411856, JA-OS 90 07263 and NL-OS 73.13 896], 1,4-diazabicyclo [3.2.0] heptan-7-one -Connections [cf. Bose u. Mitarb., J. Org. Chem., Vol. 38 (1973), p. 3437 and DT-OS 2219601] and 3-thia-l-azabicyclo [3.2.0] heptan-7-one compounds [cf. Boseu. Mitarb., J. Chem. Soc. (C), 1971, p. 188].