KR900005322B1 - Intermediates for beta-lactam antibiotics - Google Patents

Abstract

3-Beta-(4(S)-Aryloxazolidin-2-one-3-yl) azetidine-2-one derivs. of formula (I) are prepd. by reacting a cpd. of formual (II) with a cpd. of formula (III). In the formulas, Ar= phenyl, C1-4 alkylphenyl, halophenyl C1-4 alkoxyphenl, naphthyl, thienyl, furyl, benzotienyl or benzofuryl; R= phenyl, C1-4 alkylphenyl, C1-4 alkoxyphenyl or halophenyl; Y is -CH=CH- or -CH2-CH2-; R'= phenyl, C1-4 alkylphenyl, C1-4 alkoxyphenyl, halophenyl, furyl or naphthyl; X= Cl, Br, trifluoroacetoxy or -OP(=O)X2 (where X= halogen). (I) are intermediates for preparing beta-lactam antibiotics.

Description

Intermediates for the preparation of β-lactam antibiotics

The present invention relates to 3β- (4 (S) -aryloxazolidin-2-one-3- of general formula (1), which is useful for preparing 1-carba (1-dethia-3-cepam-4-carboxylic acid). (I) azetidin-2-one intermediate.

Wherein Ar is phenyl, C ₁ -C ₄ alkylphenyl, halophenyl, C ₁ -C ₄ , alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl; R 1 is phenyl, C ₁ -C ₄ alkalphenyl, C ₁ -C ₄ alkoxy phenyl or halophenyl; Y is —CH═CH—, or —CH ₂ —CH ₂ —; R 'is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl, halophenyl, furyl or naphthyl.

1-carba (1-dethia) -3-cepam-4-carboxylic acid (hereinafter 1-carbacephalophosphorine) has a 4,6-bicyclic ring system of the structure

In the above formula, the numbers according to the sefam nomenclature are as above for convenience.

The preparation of 1-carba-3cepam-4-carboxylic acid with anti-bioactivity is described in EP 14476. To date, 1-carbacephalosporin has not been obtained from natural sources, for example as a microbial metabolite. Thus, the overall synthesis method of the compound. There is a great need for methods that are particularly suitable for large scale manufacturing.

1-Substituted-3β- [4- (S) -arylosazolidin-2-one-3-yl] -4β- (2-arylvinyl) azetidin-2-one is 4 (S) -aryloxa The zolidin-2-one-3-ylacetyl helide is prepared by ring addition with imine formed from benzylamine and 3-aryl acrolein (e.g. cinnamic aldehyde). Preferred intermediates, 1-benzyl-3β- (4 (S) -phenyloxyzolidinin-2-one-3-yl) -4β- (3-methoxystyryl) azetidin-2-one are asymmetrically 1 It is converted to carbacephalosporin. The 4β- (3-methoxystyryl) substituted azetidine is first hydrogenated with the corresponding 4β- [2- (3-methoxyphenyl) ethyl] azetidione and reduced to lithium-ammonia in the presence of t-butyl alcohol. 3β-amino-4β- [2- (5-methoxycyclohex-1,4-dienyl) -ethyl] azetidinone is obtained. The 3-amino group of the reducing product was protected and then the diene was oxidized with ozone to beta-ketoester, methyl 5- [3β-protected amino] acetinin-2-one-4-yl] -3-oxopentano Forms an eight. Diazo transfer of β-ketoester to 4-iazo-3-oxo-pentanoic acid methyl ester and ring closure with rhodium (II) to 7β-protected amino-3-hydroxy-1-carbacephalo Obtained Sporin-4-carbacephalosporin-4-carboxylic acid methyl ester. Alternatively, the diazo β-ketone-methyl-esters are converted to esters which are more easily removed by transesterification with titanium tetraisopropoxide and benzyl alcohol, for example iazo β-ketobenzylester. Deprotect the 7-protected amino3-hydroxy 1-carbacephalosporin and nitrite with the desired carbolic acid followed by deesterification of the water with diazomethane to give the desired 7β-acylamino-3methoxy. Obtain 1-carbacephalosporin-4-carboxylic acid antibiotic.

Other 1-substituted 3β- (4 (S) -yloxazolidin-2-one-3-yl) -4β-substituted azetidin-2-ones are monocyclic β-lactam antibiotics such as monobactamic acid It is a useful intermediate for.

Preferred azetidinones are compounds of formula (1), wherein Ar and R are phenyl or substituted phenyl and R 'is phenyl, substituted phenyl or furyl. Examples of such preferred compounds are 1-benzyl-3B- [4 (S) -phenyloxazolidin-2-one-3-yl] -4β-styrylazetidin-2-one =-, 1-benzyl-3β -[4 (S) -phenyloxazolidin-2-one-3-yl] -4β- (3-methoxystyryl] azetidin-2-one, and 1-benzene-3β- [4 (S) -Phenylosazolidin-2-one-3-yl] -4β- [2- (2furyl) ethenyl] -azetidin-2-one.

Azzetinone of formula (1) is a cycloaddition reaction of 4 (S) -aryl oxazoladin-2-one-on-3-ylacetyl halide with imine formed from benzylamine and 3-aryl acrolein Obtained by. Acid halides are converted to the corresponding homochiral ketones using trialkalamines in situ. Cycloaddition of ketones and imines produces azetidinones. In contrast, ketene can be produced with oxazolidine as an anhydride of acetic acid and trifluoroacetic acid or with phosphoryl chloride or phosphoryl boromide. The ring addition reaction is the main step of the asymmetric method of the present invention for producing 1-carba- (1-dethia) cephalosphrine as described below.

4 (S) -aryloxazolidin-2-one-3-ylacetyl halide used for ring closure is prepared using L-arylglycine of the general formula (la).

In the above formula, Ar is the same as defined for the general formula (1). The preparation method is described in the following reaction scheme.

"Alk" in the above scheme is C ₁ -C ₄ , alkyl such as methyl, ethyl, n-phorophil and t-butyl; X is halogen, preferably chloro or bromo, and X 'is chloro, bromo, trifluoroaceoxy or OP-(= O) X ₂ , where X is halogen; Ar is the same as defined above.

In carrying out the preparation of 4-aryloxazolidine 4a, L-ylglycine is first converted to carbacate 2a. Arylglycine is coagulated to whiskers using only bases in amounts slightly above that required for soluble salt formation. The solution is cooled to a temperature of about 0 ° C. to about 100 ° C. and a non-stoichiometric amount of haloformate is added in portions with stirring. Additional base is added to redissolve the arylglycines and additional halopromate is added in portions with stirring. The process is repeated under cooling until more than the stoichiometric amount of haloformetine is applied and carbamenite formation is complete. The reaction is preferably carried out as soon as possible. Bases such as alkali metal hydrates such as sodium hydroxide and potassium hydroxide are preferred, preferably 3N sodium hydroxide. The L-carbamate derivative (2a) is dilute from the reaction mixture by extraction with acidified and precipitated water-immiscible solvents (halogenated hydrocarbon solvents such as dichloromethane).

L-carbamate 2a is reduced with borane-dimethylsulfide in tetrahydrofuran at a temperature of about 20 ° C. to about 40 ° C. to give L-alcohol 3a. Borane-dimethylsulfide reagent is added to a solution of carbamate acid in tetrahydrofuran cooled to about 0 ° C. and the mixture is stirred at this temperature range, typically at room temperature for about 10 to 20 hours. The mixture is cooled with water to destroy excess borane, the mixture is evaporated to concentration and the concentrate is diluted with water if necessary to recover (3a) and (3a) is extracted with a water-immiscible solvent such as methylene chloride. The recovered (3a) has sufficient purity for direct use in the ring closure reaction of (4a) but can be further purified by recrystallization before commercial use.

L-alcohol (3a) is cyclized to (S) -4-aryloxazolidin-2-one (4a) in an inert solvent using n-butyllithium or an alkali metal alkoxide (e.g. lithium or sodium anoxide). . n-butyllithium is the preferred base and is generally available in amounts less than stoichiometric amounts. The reaction is carried out at a temperature of about 25 ° C. to 65 ° C., preferably about 55 ° C. for 2 to 8 hours. Suitable inert solvents are tetrahydrofuran, 1,2-difetoxy ethane and compatible ethers. After ring closure is complete the reaction mixture is treated with acetic acid in an amount corresponding to the amount of base used and concentrated. Oxazolidin-2-one (4a) is recovered by extracting the concentrate with a suitable organic solvent such as methylene chloride, chloroform or trichloroethane.

(S) -4-aryloxazolindin-2-one (4a) is N-alkylated with haloacetic acid, deesterified esters and then the acid is converted to halide (5a).

Alkylation of (4a) with haloacetic acid esters is carried out with sodium hydride in dimethylformamide or tetrahydrofuran to give (S) -4-aryloxazolidin-2-one-3-alacetic acid ester. Haloacetic acid ether is represented by the general formula X-CH ₂ COOalk in which the reaction scheme is described above, wherein X is chloro or bromo and alk is C ₁ -C ₄ alkyl. Preferably, alk is t-butyl or acet. Examples of haloacetic acid esters are t-butyl bromoacetate, aryl bromoacetate, methyl chloroacetate, t-butylchloroacetate, methyl bromo acetate, isopropyl bromoacetate and similar esters. Preferred haloesters are t-butyl bromoacetate and ethyl bromoacetate.

Oxyzolidine is carried out by standard deesterification procedures in which the acetic acid ester is deesterified. For example, t-butyl ester groups can be removed by treating the ester with trifluoroacetic acid while other lower alkyl esters (eg ethyl esters) can be saponified.

Oxazolidine is converted to acetic acid as an acid halide (5a, X '= halogen), preferably an acid chloride, or tripuloacetic acid (X' = OCOCF ₃ ) or phosphoryl halide (X '= OP (O) = X ₂ ) converted to anhydride formed. Acid halides, preferably acid chlorides, are supplied with the desired ketene for use in subsequent ring addition reactions. Acid chlorides are water washed using oxalin chloride in an inert solvent such as, for example, benzene, toluene or xylene. Other conventional acid halide forming reagents can be used.

(S) -4-aryloxazolidin-2-one-3-ylacetylhalide or anhydride is azetidine of formula (1) is a derivative of the chiral auxiliary component used to form the β-lactam ring of the intermediate. Functionalized form.

Acetyl halide (5a) is reacted with an amine formed of benzylamine and 3-aryl acrolein to produce 1-benzene-3β- [. Small amounts of isomeric ring addition products are formed. The ring addition reaction is described in the following scheme.

In the above formula, R, R 'and Ar are the same as the definition of general formula (1).

The reaction can be carried out in an inert organic solvent such as methylene chloride, chloroform, toluene, or di- or trichloroethane in the presence of tri- (C ₁ -C ₄ alkyl) amine at a temperature of about -78 ° C to about 25 ° C. The reaction can be carried out by adding a solution of imine (6a) to (5a) solution in an inert solvent containing an excessive stoichiometric amount of tri- (C ₁ -C ₄ , alkyl) amine. Tri- (C ₁ -C ₄ , alkyl) amines should be added to the (5a) solution prior to the addition of imine (6a). The acid derivative 5a and the amine are preferably mixed at a temperature of about -80 ° C to about -50 ° C to form quetene in situ. Imine (6a) is added to azetidine to form (1). Typically, the solvent for imine is a solvent prepared as described below. Solvents such as benzene, toluene and xylene are suitable. The imine is added and then the reaction is preferably warmed and maintained at about 0 ° C. for 2-4 hours. The main isomer (formula 1) and minor isomer mixtures can be recovered from the reaction mixture as follows. The reaction mixture is diluted with a water-immiscible organic solvent such as methylene chloride or chloroform, first washed with a weak acid such as tartaric acid or citric acid and then with saturated aqueous alkali metal bicarbonate. The dried water, washed mixture is evaporated to dryness.

Most major isomers (1) can be crystallized from the residue from ethyl acetate-hexane (about 30% by volume hexane). Alternatively, the major isomers can be separated from the minor isomers by chromatography on silica using stepwise elution or specific elution. Stepwise elution of ethyl acetate-methylene chloride with a volume percentage of ethyl acetate of at least about 20% generally yields compound (1) and elutes minor components of increased polarity (about 40-50% by volume of ethyl acetate).

Imine (6a) used for ring addition is obtained by condensation of 3-arylacrolein with benzylamine or substituted benzylamine in a suitable solvent. The water produced during the reaction is removed using a desiccant or azeotropic distillation. Preference is given to using acrolein slightly above the stoichiometric amount. Desiccants or molecular sieves such as magnesium sulfate are suitable. Organic solvents such as diethyl ether or aromatic hydrocarbons (eg benzene or toluene) can be used.

Condensation reactions that produce imines proceed rapidly at temperatures of about 25 ° C. to 65 ° C. in the presence of a desiccant or during azeotropic removal of water.

Examples of 3-arylacrolein which may be used include the following general formula compounds.

Wherein R 'is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl, halophenyl, furyl or naphthyl. Examples of the aldehydes include cinnamic aldehyde, 4-methyl cinnamic aldehyde, 3-ethyl cinnamic aldehyde, 4-ethoxycinmanaldehyde, 3-methoxycinnamic aldehyde, 3-t-butyloxycinnamaldehyde, 3-ethoxycinnamaldehyde, 3-bromocinnamaldehyde, 2- (2-furyl) alcrolein, 2- (2-naphthyl) acrolein and similar aldehydes.

Examples of benzylamines useful for imine formation include benzylamine and C ₁ -C _4, alkyl, C ₁ -C _4, alkoxy, and 4-methylbenzylamine, 3-chlorobenzylamine, 3,4-dichlorobenzylamine, 4 -Methoxybenzylamine, 2-bromobenzylamine, 3-ethylbenzylamine, 3,4-dimethylbenzylamine, 2,4-dimethylbenzamine, 4-chloro-3-methylbenzylamine, 4-isopropylbenzyl Halo-substituted benzylamines such as amines, 4-t-butylbenzeneamine and the like.

The imine 6a can be used for the ring addition reaction without separating. For example, the reaction mixture in which the imine is prepared can be used directly in the ring addition reaction for producing the compound (1).

Acetidine of formula (1) wherein Y is -CH = CH- and R 'is an m-alcoholphenyl group is a valuable intermediate in the process of the present invention for the asymmetric preparation of 1-carbacephalosporin. to be. In particular, the present invention encompasses the preparation of 1-carba-3-idoxy-3-cepam-4-carboxylic acid esters.

In the above-described ring addition reaction of (S) -4-aryloxa-zolidin-2-one-3-ylatetyl halide (5a) according to the method of the present invention, benzylamine and m-alkoxycinnamaldehyde formed with The azetidine silver of the general formula (1) wherein Y is -CH = CH- and R 'is mC ₁ -C ₄ , an alkoxy phenyl group is prepared. Hydrogenation of azetidinone (1) yields the corresponding 4β-([2- (m-alkoxyphenyl) ethyl] azetidinone, which affects the reduction of the phenyl ring, the removal of the buchiral and 1-benzyl groups Reduction with lithium-almonia in the presence of t-butyl alcohol yields 3β-amino-4β- [2- (5-alkoxycyclohex-1,4-dienyl) ethyl] azetidinone. Protect the amino group with a conventional amino-protecting group and obtain 3β-protected-amino azetidinone The 3-amino group of azetidinone is protected with a conventional amino-protecting group and 3β-protected-amino Azeodinone is subjected to ozone degradation to give β-ketoester C ₁ -C ₄ alkyl 5- [3β- (protected amino) azetidin-2-one-4β-yl] -3-oxopentanoate.

The β-keto ester gazone degradation product is converted to an α-diazo derivative and the diazo derivative is closed with rhodium (II) to give 3-hydroxy-1-carbacephalosporin ester.

One particular aspect of the process of the invention is described in the following scheme. In the scheme “alk” is C ₁ -C ₄ alkyl.

Referring to the above scheme, it is clear that imine 6a is structurally selective for the present invention. Ozone decomposition of 5-alkoxycyclohexa-1,4-diene (8a) obtained by lithium reduction of (1) compound in which Y is -CH ₂ -CH ₂ -in lithium ammonium ultimately To give the alkyl β-ketoester (9a).

According to this method azetidinone (1) (Y = -CH = CH-) is hydrogenated on a palladium catalyst such as a supported palladium catalyst (eg 5% or 10% carbon steel palladium), barium carbonate or other suitable support. The reduction may be carried out at atmospheric temperature or at some elevated pressure in an inert solvent. Inert solvents such as methylene chloride, di or trichloroethane, tetrahydrofuran, methyl alcohol, or ethyl acetate can be used.

4β- [2 (m-alkoxyphenyl) ethyl] azetidinone was prepared using 3β-amino-4β- [2- (5-alcoholcyclohex-1, lithium) in liquid ammonia containing t-butyl alcohol. 4-dienyl) ethyl] azetidin-2-one (7a). The reduction is carried out at a temperature of about -30 ° C to about -90 ° C, preferably about -70 ° C to about -80 ° C. Power is performed by dissolving lithium in liquid ammonia and cooling the solution to about -50 ° C to -90 ° C. Excess t-butyl alcohol is added followed by the solution of azetidinone in an inert solvent. Azetidinone solutions may contain t-butyl alcohol as cosolvent. Suitable solvents for azetidinone are tetrahydrofuran, dimethoxyethane or similar solvents.

Azetidine is added to the solution and the reaction mixture is stirred for about 30 minutes to about 2 hours. In small laboratory reactions, the reaction is reduced by stirring for about 30 minutes in a cooled state, but in a large scale reduction, it may be required for some time to completely reduce the diene (7a) d.

Reduction (6a) removes the buchiral component introduced by the ring addition and leaves the 3-amino group. Reduction also removes 1-benzene or 1-substituted benzene groups.

3-aminoazetidinone (7a) can be separated from the reducing mixture and used in the next step after protecting the amino group as shown in the scheme. Alternatively, preferably (7a) is acylated in the same reaction vessel to obtain acylated aminoazetidinone (8a). Although the above scheme shows only acylations yielding acyl amino groups of the general formula R ₁ CONH-, _{one of} ordinary skill in the art finds that the 3β-amino functional group of the intermediate of structural (7a) is a conventional compound such as t-butoxycarbonyl. It can be seen that it can be protected with an amino protecting group. The intermediates of formulas (7a) and (8a) are novel and are therefore provided as compounds of formula (IV) in another aspect of the invention.

Wherein R ₅ is optionally amino protected by a conventional aminoprotecting group, or an acylamino group of the general formula R ₁ CONH, wherein R ₁ is as described above.

After reduction the reaction mixture is treated with a sufficient amount of benzene and the color of the mixture is decolorized. Amnonium acetate is added to the mixture and a large amount of ammonia is distilled off. The solvent and remaining ammonia are evaporated. The residue 7a is treated with a water-miscible organic solvent such as tetrahydrofuran and the mixture or solution is acidified to a pH of about 7 to about 9. The solution 7a is treated with an acylating agent to give 3β-acylamino-4β- [2- (5-alcoholcycylohex-1,4-dienyl) ethyl] azetidinone 8a. The 3β-amino group is protected so that it is preserved during the subsequent ozonolysis step.

Acylating agents may be formed with specific carboxylic acids and their acyl moieties are stable in subsequent ozonolysis steps. Carboxylic acids include, for example, alkylcarboxylic acids such as atetic acid, propionic acid, butyric acid and the like; Aryl carboxylic acids such as benzoic acid, naphthoic acid, which may be optionally substituted with lower alkyl, lower alkoxy or halogen; Or arylacetic acid, such as phenylacetic acid, phenoxyacetic acid, phenylthioacetic acid; And optionally substituted said acid. Preferred carboxylic acids for use in acylation are activities such as acid chlorides, acid anhydrides, or anhydrides formed with haloformates such as C ₁ -C ₄ alkyl chloroformates (e.g. ethylchloroformate, iso-butyl chloroformate). Converted to derivatives. The acylating agent may be an aryloxycarbonyl halide such as benzyloxycarbonyl chloride or p-nitrobenzyl to oxycarbonyl chloride.

Preferred acylating agents are the following general formula compounds.

Wherein R ₁ is C ₁ -C ₄ alkyl, phenyl group

의 그룹(여기서, Z는 산소 또는 황이고, m은 0또는 1이며, a 및 a'는 상술한 정의와 동일하다), 또는 RiO(여기서, Ri은 C₁-C₄알킬, 또는 일반식

(여기서, R₁은 상기 정의와 동일하다)의 무수물 형성그룹이다.Wherein a and a 'are independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halolene,

In which Z is oxygen or sulfur, m is 0 or 1, and a and a 'are the same as defined above, or RiO, wherein Ri is C ₁ -C ₄ alkyl, or

Wherein R ₁ is the same as defined above.

Examples of acyl halides represented by the above general formulas are ethyl chloride, acetyl bromide, butyryl chloride, propionyl chloride, benzoyl chloride, 4-chlorobenzoyl chloride, 4-methyl benzoyl chloride, phenoxyacetyl flora, 4-chlorophenoxy Cyacetyl chloride, phenyl-acetylchloride, 3-ethylphenylacetylbromide, phenyl-mercaptoacetyl chloride, 4-chlorophenylmercaptoacetyl chloride, benzyloxycarbonyl chloride, cyclohexyl-oxycarbonyl chloride, cyclopentyl Oxycarbonyl chloride, ethoxycarbonyl chloride and the like.

Examples of the anhydrides represented by the above general formulas include benzoic acid anhydride, phenoxyacetic anhydride, phenylacetic anhydride, p-chlorophenoxyacetic anhydride, phenylmergatoacetic anhydride, di-t-butyl dicarbonate, dibenzyl dicarbonate, Di- (p-nitrobenzyl) dicarbonate, di-ethyl dicarbonate, di-cyclohexyl dicarbonene and similar anhydrides.

The N-acylated reduction product 8a is recovered from the mixture by extraction and purified by chromatography on silica.

Unlike the single-vessel conversion of (1) (Y = -CH ₂ CH _2- ) compound as described above to (8a), compound (1) is reduced to lithium in liquid ammonia without addition of t-butylalkyl To obtain 3-amino-azetidinone of the following structural formula.

The 3β-amino group is acylated with the desired carboxylic acid or amino-protecting group and then reduced with lithium in liquid ammonia in the presence of excess t-butyl alcohol to give 5-alkoxycyclohex-1,4diene (8a).

The reduction reaction using lithium in ammonia as described above is preferably carried out using only about 3 equivalents rather than using an excessive amount of t-butyl alcohol. When the reaction is carried out with 3 equivalents of t-butyl alcohol over a short time, the aromatic phenyl ring remains intact while the buchiral and N-benzyl groups are removed. When reducing as described above without adding t-butyl alcohol, 1-benzene group and buchiral are incompletely removed.

The 3-acylaminoazetidinone (8a) obtained by another method is converted to β-ketoester (9a) by ozone decomposition. Ozone decomposition is preferably carried out at a temperature of from about −50 ° C. to about −80 ° C. in 50% methyl alcohol in dichloromethane or other suitable solvent mixture. Ozone is passed through a diene (8a) solution until the reaction is complete. Ozone is most commonly obtained from conventional ozone generators in the air stream.

Completion of ozone degradation can be measured using a diene indicator such as solvent red (Sudan III, Aldrich Chemical Company). After completion, the particular ozonide and excess ozone are destroyed in cold state using dimethyl sulfide or other suitable reducing agent (eg sulfite or inan salt) and product 9a is recovered from the mixture. For example, the reaction mixture is allowed to warm to room temperature, poured into brine and the product is extracted with a water-immiscible solvent such as methylene chloride. β-ketoester (9a) can be further purified by chromatography on silica.

β-ketoester (9a) passes through the diazo compound (10a) and 7-acylamino-1-carba (1-detia) by ring closing the diazo ester to 1-carbacephalosporin using rhodium (II). ) -3-hydroxy-3-cepemester (11-a).

β-ketoester (9a) is a P-toluenesulfonyl azide (tosyl azide) in the presence of an impaired tertiary amine (e.g. diisopropylethylamine) in an inert solvent such as acetonitrile, dichloromethane, trichloroethane and the like. It is converted into the diazo ester (10a) using. The reaction is usually carried out at room temperature. In general, tosyl azide is used in an amount exceeding the stoichiometric amount, while amine is used in an amount of about 1/4 of the stoichiometric amount. Diazo esters can be recovered by partitioning the mixture between a water immiscible solvent (eg, methylene chloride) and brine containing some tartaric or citric acid. Diazo esters are obtained in purified form from extracts by chromatography on silica and recrystallization.

The ester moiety " alk " of (10a) becomes an ester group of 1-carbacephalosporin (11a) upon ring closure as shown in the scheme. Ester groups, such as lower n-alkyl groups (eg methyl, ethyl), are less easy to remove from carboxyl groups than other groups. From a synthetic point of view, it may be desirable to form 1-carbacephalos 11a, which is a common carboxy-protective group in which ester groups are more easily removed than methyl or ethyl. Another aspect of the present invention provides a method for transesterifying an ester group (alk) of (10a) with a diazo ester (10b) as follows.

Wherein R ₁ and alk are as defined above and R ₂ is ethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, β-tri (C ₁ -C ₄ alkyl) Silal-ethyl, benzyl, C ₁ -C ₄ alkylbenzyl, C ₁ -C ₄ alkoxybenzyl, nitrobenzyl or chlorobenzyl. Other ester groups commonly used to protect the 4-carboxylic acid functional groups of cephalosporins can likewise be incorporated into the compound of formula (10b).

The process is carried out by mixing excess alcohol, R ₃ OH with Tifan terra isopropoxide and evaporating off isopropyl alcohol. Diazo ester 10a is added to the excess alcohol, and optionally Ti (OR ₂ ) ₄ , solution in an inert solvent, and the solution is maintained at a temperature of 25 ° C. to about 45 ° C. until the transesterification reaction is complete. .

Inert solvents that can be used are, for example, methylene chloride, di- or trichloroethane, chloroform, acetonitrile, tetrahydrofuran or dioxa. If benzyl alcohol is used in the R2 ester formation process, it may act as a solvent for the process.

Even when the 3β-amino functional groups of the intermediates of formulas (9a), (10a) and (10b) are shown to be protected by the general formula R1CO group, those skilled in the art will appreciate other conventional amino protection such as t-buroxycarbonyl. It will be appreciated that groups can be used similarly. According to another aspect of the present invention, the following general formula (V) compound is provided.

Wherein R ₆ is as defined by conventional amino protecting groups or is of the general formula R ₁ CO, wherein R ₁ is as defined above.

Diazo esters (10a) or diazo esters (10b) obtained by esterification exchange reactions are typically prepared using (11a) 1-carbacephalo using a rhodium (II) salt, preferably acetate, at reflux temperature in chloroform. It can be closed with sporin (or R ₂ derivative). The reaction can be carried out by heating for about 15 minutes to about 1 hour. Typical reaction temperatures may vary from 0 to 100 ° C. The 7-acylamino-3-hydroxy-1-carba (1-dethia) -3-cepam-carboxylic acid ester can be recovered from the reaction mixture or can be converted to a derivative which is subsequently separated off.

The reaction process only shows for the preparation of 3-hydroxycarbacepem derivatives in which the 7-amino group is substituted with R ₂ CO, clearly the 7-amino group can be protected by other conventional amino protecting groups. 3-hydroxy 1-carbacephalosporin ester can be recovered by first diluting the reaction mixture with water or brine and acidifying the mixture and then extracting it with a solvent such as ethyl acetate or methylene chloride. The extract is washed, dried and evaporated to yield the product. The product can be further purified by chromatography and crystallization.

The cis-enantiomers described above as (11a) are novel, and in one embodiment of the present invention there is provided a general formula (X) compound or a renal salt thereof.

의 페닐 그룹 (여기서, a 및 a'는 독립적으로 수소, C₁-C₄알킬, C₁-C₄알콕시 또는 할로게이다) ; 일반식

그룹(여기서, Z는 산소 또는 황이고, m은 0 또는 1이며, a 및 a'는 상술한 바와 같다) ; 또는 R₁ ^oO(여기서, R₁ ^oO은 C₁-C₄알킬, C₅-C₇사이클로알킬, 벤질, 니트로벤질, 메톡시벤질 도는 할로벤질이다)이다]이며 : R₂는 통상적인 카복시 보호 그룹이다.Wherein R ₆ is hydrogen; a typical amino protecting group; Or a general formula R ₁ CO group wherein R ₁ is C ₁ -C ₆ alkyl:

Phenyl group, wherein a and a 'are independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halo; General formula

A group wherein Z is oxygen or sulfur, m is 0 or 1 and a and a 'are as described above; Or R ₁ is ^o O (wherein, R ₁ ^o is O C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl, benzyl, nitrobenzyl, methoxybenzyl turning halo is benzyl) is: R ₂ is a conventional Carboxy protection group.

The chiral form described as (11a) above is particularly useful because it is the enantiomer, which can be converted to a pharmaceutically useful antibiotic alone in the form described in EP 14476. No. 761,647.

In a preferred embodiment of the process of the invention L-phenyl-glycine (1a, Ar = phenyl) is converted to ethyl carbamate by ethyl fluoroformate and carbamate is L-1-ethoxy by borane-dimethylsulfide. Carbonylamino-1-phenylethanol) (3a, alk = ethyl), and phenylethanol is ring-closed to (S) -4-phenyloxazolidin-2-one (4a) by n-butyllithium. (4a) is converted to (5a) by alkylation with ethyl bromoacetate and saponification followed by treatment of the acid with oxalyl chloride.

(S) -4-phenyloxazolidan-2-one-3-ylacetyl chlorrai is condensed with imine formed by benzylamine and m-methoxycinnamaldehyde (6a, alk = methyl, R = phenyl) To give azeditinone (1) (Ar = phenyl, alk = methyl).

(1) Compound reduction on 5% Pd-C (1) yielded compound (Y-CH ₂ -CH _2- ), which was reduced with lithium and t-butyl alcohol in liquid ammonia to 3-aminoase Tidinone (7a, alk = methyl) is obtained. 3-aminoazetidin-one is acylated with di- (t-butyl) dicarbonate without separation to yield 3-t-butyloxycarbonylaminoazididinone (8a, R ₁ = t-butyloxy, alk = methyl ). The 3-t-BOCamino protected diene product was warm zoned with 50% methyl alcohol in dichloromethane to afford β-ketomethylester 9a. β-ketomethylester is reacted with tosyl azide in the presence of isopropylethylamine in acetonitrile to form diazomethyl ester (10a, R ₁ = t-butyloxy, alk = methyl). The transesterification reaction of the corresponding benzyl ester of diazo methyl ester is carried out using titanium tetra-isopropoxide with heating to about 36 ° C. for 42 hours in excess benzyl alcohol. Benzyl 7β- (t-butyloxycarbonylamino) -3-hydroxy-1-carba (1-dethia) -3-cepem Obtain 4-carboxylate.

In one embodiment of the invention L-phenylglycine is 3β- (4- (S) -phenyloxazolidin-2-one-3-yl) -4β- [2- (m-methoxyphenyl) ethyl] -1 -Benzeneazetidin-2-one and reduced to lithium and t-butyl alcohol in liquid ammonia and then the reaction product 3β-Amano-4β- [2- (5-methoxycyclohex-1,4-diene Acylated with phenoxyacetic anhydride without separation of) ethyl] azetidin-2-one (7a, alk = methyl). 3β-phenoxyacetylaminoazetidinone was converted to benzyl 7β-phenoxyacetyl amino-3-hydroxy-1-carba (1-dethia)-as described above for t-BOC-amino-protected azetidinone. Convert to 3-cepam-4-carboxylate.

Azetidinone of formula (1), wherein Y is -CH = CH- and R 'is furyl, is also useful as an intermediate in the production of 1-carboxephalosporin. Thus, this intermediate is hydrogenated with the corresponding 3β- (2-furylethyl) azetidinone on 5% Pd / C in a suitable solvent. The hydrogenation product is converted to 1-carbacephalosporin as shown in the scheme below.

Wherein R ₂ is as defined above and is preferably "alk" and R ₇ is optionally substituted with C ₁ -C ₄ alkyl, benzyl, or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halo Phenyl.

The hydrogenated product was first reduced to lithium in ammonia in the presence of about 3 molar equivalents of t-butyl alcohol to prepare 3β-aminoazetidine (12) and the amino group to a conventional protecting group such as t-butoxycarbonyl group. To protect to give (13). (13) The compound represented by the general formula X-CH ₂ COOR ₂ reagent. Preferably, N-alkylation with alkyl haloacetate (e.g., t-butyl bromoacetate) is subjected to ozone degradation of (14) to prepare 2-carboxyethyl N-alkylated protected aminoazetidinone (15). The thio ester (15) is formed using an appropriate thiophenol or mercaptan and dicyclonucleosilcarbodiimide followed by 3-hydroxy-1-carbaferalosporin ester using lithium hexamethyl disalazine or similar impaired base. It is closed to (17). The disturbed base is a strong base that is nonnucleophilic to the β-lactam site.

Compound (16) is novel and forms an aspect of the zone invention. 3-Hydroxy-1-carbacerosolosporin ester (17) is treated to remove the amino-protecting group and the nuclear ester 7β-amino-3-hydroxy-1-carba (1-dethia) -3-sepam 4-carboxylic acid ester can be obtained. This is acylated with a desired carboxylic acid derivative (e.g., phenylacetyl chloride or phenoxyacetyl chloride) followed by treatment with diazomethane to 7β-amino-3-hydroxy-1-carba (1-dethia) -3- Sepem-4-carboxylic acid ester can be obtained. This is acylated with the desired carboxylic acid derivative (e.g., phenylsaacetylchloride or phenoxyacetyl chloride) and then treated with diazomethane to 7β-acylamino-3-methoxy-1-carba (1-dethia)- 3 cepam-4-carboxylic acid ester can be formed. Deesterification of the ester yields the free acid antibiotic.

Formulas (11a) and (17) are described in United States Patent Application No. 761. The method of 647 can also be used to convert to the corresponding 3-halo derivative. Azetidinone of formula (1), wherein Y is -CH = CH-, is useful as a monocyclic β-lactam antibiotic, described in US Pat. No. 4,502,994, as an intermediate in preparation. Azotidinone is ozone resolved to form the following 4β-formyl azetidione.

Reduction of 3β-formyl azetininone with subhydrochlorinated sodium gives the corresponding 3β-hydroxytenyl substituted azetidinone of the following general formula.

In the above formula, Ar, R 'and R are the same as the definitions for the general formula (1). The 3β-hydroxymethyl compound is reduced with lithium in liquid ammonia containing about 3 equivalents of t-butyl alcohol to give 3β-amino-4β-hydroxy-methylazetidin-2one of the formula

The amino group is protected with a conventional amino protecting group such as benzyloxycarbonyl group or t-butyloxycarbonyl group and the hydroxy group of the 4β-hydroxymethyl substituent is for example ethyl chloride, chloro attyl chloride or triclo It is protected by esterification with lower alkanoic acid chlorides such as roacetyl chloride. The double protected compound is reacted with SO ₃ in pyridine to form azetidinone of the general formula

Wherein P is typically an amino-protecting group, acy ¹ is an acyl moiety of lower alkanoic acid and M ⁺ is an alkali metal cation or tetraalkylammonium ion (eg tetrabutylammonium ion). Hydroxy-protected acyl groups are removed by basic hydrolysis and the product is reacted with isocyanates to afford the following general formula compounds.

Wherein P 'is an acyl group, for example trichloroacetyl or trituroracetyl. Aminoprotecting group P, carbamoyl N-protecting group P 'is removed and the 3β-amino group is 2- (2-protected-aminothiazol-4-yl) -2- (protected-carboxymethoxyimino) acetic acid Reacylated with carboxy active derivatives of yields double protected antibiotics. Removal of the protecting group yields a sulfazecin-related antibiotic of the structure

The 4β-formylazetidinone of the above structural formula can be converted to the corresponding 4β-carboxazetidinone using, for example, chromium oxide in acetone or by oxidation using acidic permanganate or other suitable reagent. The carboxy group can be esterified with C ₁ -C ₄ alkylesters and reduced with naborium borohydride or lithium aluminum hydride to give 4β-hydroxyazetidinone. 4β-carboxazetidinone in the lower alkyl ester form is epimerized with t-alkyl amine to give a 4α-carboxazetidinone ester which is reduced to 4α-hydroxymethyl azedidinone.

The epimeric 4-hydroxykenylazetidinones can each be converted to 4-halomethylazetidinone (e.g., bromomethyl or iodomethyl derivatives), which can be converted to the corresponding epimeric 4-methyl by using lithium aluminum hydride. Refactored to azetidione.

The 4-methylazetidinone obtained as described above may be lithium-reduced in amnonia using t-butyl alcohol to remove buchiral and 1-benzyl groups to obtain 3β-amino-4-methylazetidinone. have. This is converted into a monocyclic antibiotic, monobactam, of the following structural fabric by known methods.

In an aspect of the present invention there is provided a substituted azetidinone of the general formula:

Wherein R ₄ is formyl, carboxy, C ₁ -C ₄ alkoxycarbonyl, methyl, halomethyl or hydroxymethyl, Ar and R are as defined in formula (1), and R ₄ is formyl If not, a 4-position epimer of the compound is provided. Preferred groups of substituted azetidinones appear when Ar is phenyl or substituted phenyl, R is phenyl and R ₄ is formyl or hydroxymethyl. Preferred compounds are 1-benzene-3β-[(S) -4-phenyloxazoladin-2-one-3-yl] -4β-hydroxymethylazetidin-2-one. Another preferred compound is 1-benzene-3β-[(S) -4-phenyloxazolidinin) -2-one-3-yl] -4β-formylazetidin-2-one.

Intermediates useful for the asymmetric synthesis of azetidinone of formula (1) as described above are also part of the present invention. Buchiral-forming component when 4 (S) -aryloxazolinidin-2-one-3-ylacetic acid, ester and halide imine (6a) of general formula (5a) are cyclized to form azetidinone (1) It is useful as a process. Buchyral acts on the process so that the synthesis of the compound (1) is the desired stereo configuration. These acyl halides, anhydrides, and esters and their acid precursors are represented by the following general formulas.

Wherein Ar is the same as defined in formula (1) and R ₃ is hydroxy, C ₁ -C ₄ alkoxy, chloro, bromo, trifluoro acetoxy or —OP— (═O) × ₂ .

Examples of such intermediates are 4 (S) -phenyloxazolidin-2-one-3-yl- atesic acid, 4 (S)-(4-chlorophenyl) oxazolidin-2-one-3-yl-acetic acid , 4 (S)-(4-methylphenyl) oxazolidin-2-one-3-yl-acetic acid, 4 (S) -3-methoxyphenyloxazolidin-2-one-3-yl-acetic acid, 4 (S)-(2-naphthyl) -oxazolidin-2-one-3-yl-acetic acid, 4 (S)-(2-thienyl) oxazolidin-2-one-3-yl-acetic acid , 4 (S)-(benzothien-2-yl) oxazolidin-2-one-3-yl-acetic acid and C ₁ -C ₄ alkyl esters, acylchlorides and bromide and trifluoroacetic acid and their phosphoryls Halide derivatives. Preferred compounds are those wherein Ar is phenyl or substituted phenyl and R ₃ is t-butyl or chloro. Particularly preferred compounds are 4 (S) -phenyloxazolidin-2-one-3-yl-acetic acid, ethyl and t-butyl esters and acid chlorides thereof.

5-alkoxycyclohex-1,4-dienyl substituted azetindines (formulas 7a and 8a) are also novel intermediates and can be represented by the following formula.

Wherein R ₅ is amino or acylamino group R ₁ -CO-, wherein R ₁ is as defined for general formula (8a) and alk is C ₁ -C ₄ alkyl.

Where alk is preferably methyl.

Examples of R ₁ CO acyl groups where R ₁ is an alkoxy, cycloalkoxy or benzyloxy group are ethoxycarbonyl, t-butyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl and p Nitrobenzyloxycarbonyl and the like.

Examples of R ₁ CO acyl groups where R ₁ (formula 8a) is not R ₁ ^o are phenylacetyl, phenoxyacetyl, phenylmercapto acetyl, benzoyl, p-chlorobenzoyl, 2,6-dimethoxybenzoyl, 4- Chlorophenylmercaptoacetyl, 3,4-dimethylphenylacetyl, 4-methoxyphenylacetyl and 3-chlorophenoxyacetyl. The 3β-amino azetidinones of the above formula wherein R ₅ is amino may form salts with suitable inorganic and organic acids. Examples of such acids are hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and C ₁ -C ₄ alkylsulfur. Alkyl and aryl sulfonic acids such as phonic acid (eg, methanesulfonic acid and n-butylphonic acid); Arylsulfonic acids such as benzinesulfonic acid, p-toluenesulfonic acid, p-chlorophenylsulfonic acid, p-bromobenzenesulfonic acid and naphthalenesulfonic acid.

The following examples are intended to illustrate the invention in more detail. In the Examples, the number of the compound is the same as the compound number in the reaction scheme.

Preparation Example 1

(S) -4-phenyloxazolidin-2-one

To a stirred 0 ° C. solution of L-phenylglycine (25.3 g, 167.4 mmol) in 60 ml of 3N-aq. NaOH is added ethyl chloroprmate (8 ml) in various fractions. Additional 3N aqueous NaOH (35 ml) is added to dissolve the precipitated phenylglycine and then ethyl chloroformate (4 ml) is added. This process is continued over about 10 minutes using 3N aqueous NaOH (65 ml) and ethyl chloroformate (8 ml, 20 ml total, 209 mmol). After stirring for 1 h at 0 ° C. the solution is acidified with 6M H ₂ SO ₄ and the precipitated carbamate is extracted with 8% isopropanol in dichloromethane (2 × 300 ml). The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated to give 37.3 g of N-ethoxycarbonyl L-phenylglycine as a white solid. Carbamate is dissolved in 170 ml of THF, cooled to 0 ° C., treated with borane-dimethylsulfide (33.5 ml of 10M solution) and stirred at room temperature for 17 hours. Excess borane is carefully cooled with water (100 ml) and large amounts of THF are removed under reduced pressure. The white slurry is diluted with additional water (350 ml) and then extracted with dichloromethane (2x500 ml). The combined organic layers are washed with 100 ml of aqueous NaHCO ₃ containing, dried (Na ₂ SO ₄ ) and concentrated to give 27.4 g of (S) -2-ethoxycarbonylamino-2-phenyl ethanol as a white solid. It is dissolved in 200 ml of crude alcohol THF, cooled to 0 ° C. and treated with n-butyllithium (6 ml of 2M solution) in hexane. After heating at 55 ° C. for 6 hours, the solution is treated with acetic acid (1 ml) and concentrated. The residue is dissolved in dichloromethane (300 ml), washed with 100 ml brine, dried (Na ₂ SO ₄ ) and concentrated to give a white solid. Recrystallization from toluene yields 17.14 g (63%) of (S) -4-phenyl-oxazolidin-2-one: melting point 132 to 133 ° C; [α] _D ^{10 +} 49.5 ° (C = 2.1, CHCl ₃ );

Elemental Analysis of C ₉ H ₉ NO ₂

Calculated Value: C; 66.24, H: 5.56

Found: C; 66.16, H: 5.62

Production Example 2

(S) -4-phenyloxazolidin-2-one-3-ylacetic acid

To a stirred 0 ° C. solution of (S) -4-phenyloxazolidin-2-one (1.07 g, 6.54 mmol) in 15 ml of THF is added sodium hydride (0.32 g, 8.0 mmol) of 60% oil dispersion. When gas evolution has ceased (approximately 10 minutes) ethyl broroacetate (0.87 ml, 7.8 mmol) is added. After 2 h at 0 ° C. the mixture is treated with 50 ml of 2N-aq. NaOH and stirred rapidly at room temperature for 1 h and then partitioned between hexane (50 ml) and water (50 ml). The aqueous layer is separated, acidified with 6M aqueous H ₂ SO ₄ and extracted with dichloromethane (2x200 ml). The combined organic phases are dried (Na ₂ SO ₄ ), concentrated to give a thick oil which is dissolved in 4 ml of hot toluene, seeded and sun-crystallized. Filtration yields 1.33 g (92%) of (S) -4-phenyloxazolidin-2-one-3-ylacetic acid: melting point 106 to 108 ° C; [α] _D ^{22 +} 173 ° (C = 2.CHCl ₃ );

Elemental Analysis of C ₁₁ H ₁₁ NO ₄

Calculated Value: C; 59.72, H: 5.01

Found: C; 59.83, H: 5.00

Preparation Example 3

(S) -4-phenylotazolidin-2-one-3-ylacetylchloride:

In reflux cooling and a 250 ml round bottom flask equipped with a CaSO 4 dry tube is charged (S) -4-phenyloxazolidin-2-one-3-ylacetic acid (5.3 g, 23.96 mmol) and 60 ml of toluene. The suspension is treated with oxalin chloride (3.2 ml, 36.7 mmol) and stirred at 60 ° C. for 3 hours. At this point gas evolution stops and the reactants are homogeneous. The solvent is removed under reduced pressure to give the thick oily title acid chloride.

Production Example 4

Preparation of imines formed from benzylamine and 3-methoxycinnaaldehyde:

To a solution of 3-methoxycinnaaldehyde (4.27 g, 26.33 mmol) in 40 ml of toluene is added benzylamine (2.73 ml, 25.01 mmol). The solution is warmed to about 40 ° C. and cooled to turbid from the released water. Argon flashed 4A molecular sieves (18 g, freshly activated) are added and the mixture is left at room temperature for 16 hours. This imine solution is used directly for subsequent ring closure.

Example 1

1-benzyl-3β-[(S) -4-phenyloxazolidin-2-one-3-yl] 4β- (3-methoxystyryl) azetidin-2-one:

Oxazoladine is dissolved acid chloride in dichloromethane (70 ml), cooled to -78 ° C and treated with triethylamine (5.0 ml, 35.9 mmol). A fine amount of precipitate forms over 15 minutes. Toluene solution of imine prepared as described above is added to the mixture through a pipe. The sieve from the imine solution is washed with dichloromethane (2x10 ml) and each wash is added to the reaction. The cooling solution is removed and the reaction is allowed to warm up and held at 0 ° C. for 2 hours. The mixture is poured into 200 ml of trichloromethane and washed with 0.5 M tartaric acid and saturated aqueous NaHCO ₃ (50 ml each), then dried (Na ₂ SO ₄ ) and concentrated to give a reddish oil. Crystallization from about 150 ml of 30% hexane in ethyl acetate yields 6.87 g of the white needles of the title compound. Chromatograph the mother liquor on 170 g of silica using 20% ethyl acetate in dichloromethane to further obtain 1.9 g of azetidinone. (8.77 g total, 80%). The minor isomers are obtained by further eluting with 40% ethyl acetate in dichloromethane and then purified by chromatography on silica using 30% hexanes in ethyl acetate.

Main isomers, title compound: fusion | melting 142-143 degreeC; [α] _D ^{22 +} 46.3 ° (C = 1.0.CHCl ₃ );

Elemental Analysis of C ₂₂ H ₂₆ N ₂ O ₄

Calculated Value: C; 73.99, H: 5.77

Found: C; 74.06, H: 5.74

Example 2

1-benzyl-3β- [4 (S) using imine and 4 (S) -phenyloxazolidin-2-one-3-ylacetyl chloride prepared from benzylamine and cinnamic aldehyde by the method described in Example 1 ) -Phenoloxazolidin-2-one-3-yl] -4β-styrylazetidin-2-one is prepared: melting point 186.5-187.5 ° C .; [α] _D ²² = + 56.9 ° (C = 1.7, CHCl ₃ ),

Elemental Analysis of C ₂₇ H ₂₄ N ₂ O ₃

Calculated Value: C; 76.39, H: 5.70

Found: C; 76.53, H: 5.69

Example 3

Imine prepared from benzylamine and 3- (2-furyl) -acrolein using the method of Example 1 was condensed with 4 (S) -phenyloxazolidin-2-one-3-ylacetyl chloride 1-benzyl Prepare 3--3- [4- (S) -phenyloxazolidin-2-one-3-yl] -4β [2- (2-furyl) ethenyl] azetidin-2-one: melting point 181 to 182 ℃; [a] _D ² ° = +13.6 (C = 1.6, CHCl ₃ ) 3,

Elemental Analysis of C ₂₅ H ₂₂ N ₂ O ₄

Calculated Value: C; 72.44, H; 5.35

Found: C; 72.44, H; 5.41

Example 4

1-benzyl-3β-[(S) -4-phenyloxazolidin-2-one-3-yl] -4β- [2- (3-methoxystyryl) ethyl] azetidin-2-one: actual group 3-methoxy styryl substituted azetidinone (0.552 g, 1.22 mmol) prepared as described in Example 1 was hydrogenated in dichloromethane (20 ml) at 0.52 g on 5% Pd / C for 3 hours at room temperature. (Mechanical pressure). Filtration through celite and removal of the solvent under reduced pressure yielded 0.555 g (100%) of the corresponding 4β- [2- (3-methoxyphenyl) ethyl] azetidinone (Compound 8) on a white solid. Recrystallization from hexane-ethyl acetate gave a needle: melting point 134-135 ° C .; [α] _D ²³ +38.6。 (C = 2.2, CHCl ₃ ):

Elemental Analysis of C ₂₀ H ₂₄ N ₂ O ₆

Calculated Value: C; 73.66, H: 6.18

Found: C; 73.48, H: 6.11

Example 5

Methyl 5- [3β- (t-butyloxybarboylamino) azetidin-2-one-4β-yl] 3-oxopentanoate

Lithium wire (0.548 g, 79 mmol) was added to 55 ml of ammonia at -78 ° C and the mixture was warmed to a metal solution and then recooled to -78 ° C under constant argon pressure. The blue-blue solution is first treated with tert-butanol (12 ml). THF: 1-benzyl-3β- (4-phenyloxazolidin-2-one-3-yl) -4β- [2- (3-methoxyphenyl) in tert-butanol (24 ml of 3: 1 mixture) Ethyl] azetidin-2-one (2.36 g, 5.17 mmol) solution is added via duct over 5 minutes. After a further 30 minutes of stirring, anhydrous benzene (2 ml) is added. The blue color disappears after 1 minute. Ammonium acetate (6.08 g, 79 mmol) is added, the cold bath is removed and the ammonia mass is distilled off through a mercury bubbler. Solvent Residual ammonia is subtracted and removed at 40 ° C. The remaining white solid is suspended in 50 ml of THF: H ₂ O (1: 1), acidified to pH 8 with 3N HCl and treated with di-tert-butyl dicarbonate (1.8 ml, 7.8 mmol). The two phase mixture is stirred rapidly for 12 hours and then partitioned between dichloromethane (200 ml) and H ₂ O (50 ml). The aqueous phase is reextracted with dichloromethane (50 ml) and the combined organic phases are washed with 50 ml of saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. Partially purified dihydro aromatic 3β-t-butyloxycarbonylamino-4β- [2- (5-methoxy) as a waxy solid by chromatography of the residue on 110 g of silica using 40% hexane in ethyl acetate. 1.23 g of cyclonux-1,4-diene) ethyl] azetidin-2-one are obtained.

The diene product was dissolved in 25 ml of 50% methanol in dichloromethane and treated with 1 drop of pyridine and about 1 mg of Sudan III dye (Alderich Chemical Co.) and then ozone at -78 ° C. until no red color disappeared. Decompose Dimethyl sulfide (3 ml) is added and the cooling bath is removed and the reaction mixture is stirred at room temperature for 5 hours. The light red yellow solution is poured into 100 ml brine and extracted with dichloromethane (1 × 200 ml, 1 × 50 ml). The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The residue was chromatographed on 66 g of silica with 7% isopropanol in dichloromethane to give methyl 5- [3β- (t-butyloxycarbonylamino) azetidin-2-one-4β-yl] as a yellowish white solid. Oxopentanoate (0.97 g, 60% from 8) is obtained. Recrystallization from toluene to give a colorless needle: melting point 122 to 123 ° C; [α] _D ²⁰ +48.6。 (C = 1.4, CHCl ₃ ):

Elemental Analysis of C ₁₄ H ₂₂ N ₂ O ₆

Calculated Value: C; 53.49, H: 7.06

Found: C; 53.56, H: 7.11

The 3-t-Boc-aminoazetidine-β-keto ester prepared as described above is converted to 3-hydroxy-1-carba (1-dethia) -3-cepem ester by the method of Example 6 below. .

Example 6

Benzyl 7β- (t-butyloxycarbonylamino) -3-hydroxy-1-carba (1-dethia) -3-cepem-4-carboxylate

A. Diazo Metastasis

To 0 ° C. solution of β-keto ester (1.13 g, 3.6 mmol) in 10 ml of acetonitrile, p-toluenesulfonyl azide (3.6 ml of 1.5 M solution in dichloromethane) and diisopropyleththiamine (0.13 ml, 0.75 mmol) ) The reaction is covered with foil and stirred at room temperature for 2 hours and then partitioned between brine (50 ml) and dichloromethane (100 ml) containing 10 ml of 0.5 M tartaric acid. The aqueous layer is reextracted with dichloromethane (50 ml) and the combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The residue is chromatographed on 100 g of silica with 5% isopropanol in dichloromethane to give 1.15 g (94%) of diazo ketoester as white solid. Recrystallization from ethyl acetate-hexanes afforded needles: melting point 136-137 ° C .; [α] _D ^{20 +} 65.8 ° (C = 0.6, CHCl ₃ );

Elemental Analysis of C ₁₄ H ₂₀ N ₄ O ₆

Calculated Value: C; 49.40, H: 5.92

Found: C; 49.97, H: 5.93

B. Ester Exchange

A solution of benzyl alcohol (20 ml, 193 mmol) and titanium isopropoxide (0.78 ml, 2.62 mmol) is stirred under vacuum for 45 minutes to remove isopropanol. The flask is covered with foil, leaked into argon and diazo β-keto methylester (0.953 g, 2.80 mmol) is added. The solution is diluted with 60 ml of diethyl ether at 36 ° C. for 42 hours and then treated with saturated aqueous Na ₂ SO ₄ (3 ml). The mixture is stirred rapidly overnight and then filtered through celite. The ether is removed on a rotary evaporator and then distilled off using a benzyl alcohol Kugelrohr oven (15 millitorr, 50 ° C.). Chromatography of the residue on 100 g of silica gives the corresponding diazo beta-ketobenzyl ester (0.837 g, 72%) as a white solid: melting points 152 to 153 (decomposition); [α] _D ^{20 +} 55.6 ° (C = 0.7, CHCl ₃ );

Elemental Analysis of C ₂₀ H ₂₄ N ₄ O ₆

Calculated Value: C; 57.68, H: 5.81

Found: C; 57.57, H: 5.74

C. Rhodium (II) ring closure

A solution of diazo β-keto benzyl ester (0.12 g, 0.29 mmol) in 6 ml of alumina-filtered chloroform is heated to reflux and treated with rhodium (II) acetate dimer (1.5 mg, 0.0034 mmol). After heating for 20 minutes the title compound is obtained: ¹ H

Example 7

1-benzyl-3β- [4 (S) -phenyloxazolidin-2-one-3-yl] -4β-hydroxymethylazetidin-2-one

1-benzene-3β-[(S) -phenyl dissolved in 80 ml of 50% methanol in dichloromethane containing two drops of pyridine and several milligrams of Sudan III dye (Aldrich Chemical Co.) Oxazolidin-2-one-3-yl] -4β-styryl-azetidin-2-one (3.0 g, 7.06 mmol) solution is treated with a dilute mixture of ozone in oxygen at -78 ° C. When the dye disappears red, remove the ozone ingress and add 8 ml of dimethyl sulfide. The solution is heated at room temperature for 3 hours and then concentrated under reduced pressure. The oil is redissolved in 35 ml of ethanol, cooled at 0 ° C. and treated with sodium borohydride (0.40 g, 10.6 mmol). After about 15 minutes a large amount of precipitate is formed. Water (35 ml) is added and further stirred at room temperature for 30 minutes. Most of the ethanol is removed under reduced pressure and the remaining slurry is partitioned between dichloromethane and water (200 ml each). The organic layer is dried (Na ₂ SO ₄ ) and concentrated to give a white solid. Recrystallized from ethyl acetate-dichloromethane (first product, 1.187 g) and ethyl acetate-hexane (second product, 0.501 g) to give a white needle of 1-benzene-3β- [4 (S) -phenyloxazoladine- 2.388 g (96%) of 2-on-3-yl] -4β-hydroxymethyl-azetidin-2-one are obtained. Melting point 159.5-160.0 ° C .; ^{_{[α] D 23 +109.1 (C}} = 2.2, CHCl 3).;

Example 8

3β-benzyloxycarbonylamino-4β-hydroxymethyl azetidin-2-one

4 [beta] -hydroxymethylazetidinone (0.497 g, 1.41 mmol) was dissolved in 8 ml of 7: 1 THF: tert-butanol with heating, and -78 DEG C (0.87 g, 12.6 in 23 ml of anhydrous ammonia over 2 minutes). Millimolar) solution. After a further 2 minutes of stirring, the excess lithium is cooled to 2 ml of 50% tert-butanol in benzene. Powdered ammonium chloride (0.68 g, 12.7 mmol) is added and ammonia distilled off. The solvent and residual ammonia are removed under reduced pressure. The residue is dissolved in water (15 ml) and acidified to pH 3 with 1N modified NaHSO ₄ and then basified with 3N aqueous NaOH. Benzyl chloroformate (0.42 ml, 3.0 mmol) is added and the reaction is maintained at pH about 8 using aqueous sodium hydroxide while stirring at room temperature. After 3 hours excess benzyl chloroformate is decomposed using aqueous ammonia and the mixture is extracted with dichloromethane (1x150ml, 1x50ml). The organic layer is dried (Na ₂ SO ₄ ) and concentrated. Chromatography on 35 g of silica using 12% isopropanol in dichloromethane yields 0.219 g (62%) of 3β-benzyloxycarbonylamino-4β-hydroxymethyl-azetidin-2-one on a white solid. Recrystallization from hexane-ethyl acetate gave an analytical sample: melting point 128.5-129.5 ° C. [α] _D ^{23 +} 7.1 ° (C = 1.0, CHCl ₃ );

Example 9

1-benzyl-3β- (4 (S) -phenyloxazolidin-2-one-3-yl) -4β- [2- (2-furyl) ethyl) azetidin-2-one

The product (0.5 g) obtained as described in Example 3 is dissolved in 10 ml of methylene chloride and hydrogenated at 50 psi hydrogen pressure in the presence of 0.05 g of 5% Pd / C for 1 hour at room temperature. The reaction mixture is filtered and the filtrate is evaporated to afford the title compound on a white solid.

Example 10

3β-t-butyloxycarbonylamino-4β- [2- (2-furyl) ethyl) azetidin-2-one

A 500 ml five-necked flask equipped with a nitrogen inlet, ammonia inlet, agitator, thermometer, and drying tube is cooled to a temperature of about -70 ° C. in an acetone-anhydrous ice bath under nitrogen. When ammonia is introduced and the nitrogen flow is stopped, about 200 ml of ammonia is collected in the flask. Lithium (1.66 g, 240 mmol) is cut to small size from the lithium line, washed with benzene under argon and diethyl ether is added to ammonia.

1-benzene-3β- [4 (S) -phenyloxazolidin-2-one in 80 ml of tetrahydrofuran containing 3.85 ml (72 mmol) t-butyl alcohol over 4.5 minutes in a blue lithium-ammonia solution. A 10 g solution of 3-yl] -4β- [2- (2-furyl) ethyl] -azetidin-2-one is added dropwise. The temperature of the reaction mixture is raised to -46 ° C and the mixture is stirred for about 3 hours. The mixture is cooled to 18.9 ml of 1,2-dichloroethane and 3.14 ml of acetic acid. The ammonia is evaporated and THF is distilled off by warming the mixture to room temperature. THF is added again and distilled off to remove all ammonia. Aqueous THF is added to the residue of the product, then 11.58 ml (48 mmol) of di-t-butyl dicarbonate are added and the mixture is stirred overnight at room temperature.

The two-phase reaction mixture is extracted with methylene chloride and the extract is dried and evaporated to dryness. The residue is stirred with diethyl ether and the white solid is filtered to give 1.7 g of the product 3β-t-butyloxycarbonylamino-4β- [2- (2-furyl) ethyl] -azetidin-one on the white solid. . An additional 900 mg of product is obtained by grinding the mother liquor with ether.

Example 11

1-t-butyloxycarbonylmethyl-4β-t-butyloxycarbonylamino-4β- [2- (2-furyl) ethyl] azetidin-2-one

To a cooled (-30 ° C.) solution of 1.2 g (4.3 mmol) of 3β-t-butyloxycarbonylamino-4β- [2- (2-furyl) ethyl] azetidin-2-one in 15 ml of DMF was added to "Triton B "1.94 ml is added dropwise with stirring. The mixture is stirred at −30 ° C. for 15 minutes, warmed to 0 ° C. for 15 minutes and then recooled to −30 ° C. The solution of t-butyl bromoacetate in 3 ml of DMF is added dropwise and the mixture is stirred at −30 ° C. for 15 minutes, at 0 ° C. for 1 hour, and at room temperature for 2 hours. Cold water is added to the mixture and the precipitate is filtered off. The precipitate was washed with water, the DMF was removed and dried in vacuo to yield 1.2 g (71% yield) of the title compound as a white solid.

Example 12

1-t-butyloxycarbonylmethyl-3β-t-butyloxycarbonylamino-4β- (2-carboxoxyethyl] azetidin-2-one

In a 100 ml round bottom flask equipped with a magnetic stirrer, nitrogen inlet, ozone inlet, sodium bisulfite scrubber and thermometer, 1-t-butyloxycarbonylmethyl- in 30 ml of methylene chloride: methyl alcohol 1: 1 (v: v) 0.1 g solution of 3β-butyloxycarbonyl-amino-4β- [2- (2-furyl) ethyl] azetidin-2-one is charged and cooled to -78 ° C.

A small amount of means III red dye is added and the ozone in the air is bubbled into the solution until the red color disappears (about 40 minutes). Remove the cooling bath and add 1.56 ml of dimethylsulfide. The reaction mixture is allowed to warm to room temperature and stirred for about 5 hours. The mixture is poured into aqueous sodium bicarbonate and the mixture is washed with methylene chloride. The aqueous layer is acidified with hydrochloric acid and extracted with methylene chloride. The extract is washed with brine, dried over sodium sulfate and evaporated to afford 400 mg of the title compound on foam.

Example 13

1-t-butyloxycarbonylmethyl-3β-t-butyloxycarbonylamino-4β- (2-phenylthiocarbonylethyl] azetidin-2-one

Cooling of 350 mg of 1-t-butyloxycarbonylmethyl-3βb-t-butyloxycarbonylamino-4β- (2-carboxyethyl) azetidin-2-one in 6 ml of methylene chloride containing 1 ml of DMF maintained under nitrogen To the prepared (0 ° C.) solution, 26 mg of dimethylaminopyridine, 0.308 ml of thiophenol and 212 mg of dicyclohexyl carbodiimide (DCC) were added. The mixture is stirred for 10 minutes under cooling and for 1 hour at room temperature. Additional 45 mg of DCC was added followed by stirring for 2 hours. After standing overnight, the mixture is poured into 40 ml of methylene chloride and the mixture is washed with sodium bicarbonate (50% saturated solution), 0.1 N hydrochloric acid and saturated bicarbonate solution. The solution is dried over sodium sulphate and evaporated to dryness to afford the title compound in part crystalline oil. '

Example 14

t-butyl-7β-butyloxycarbonylamino-3-hydroxy-1-carba (1-dethia) -3-cepem-4-carboxylate

Azetidine prepared according to Example 14 in 100 ml of dry THF and maintained at −78 ° C. under argon was added 4.4 g (9.47 mmol) of phenylthio esters. After about 15 minutes, the mixture is poured into 750 ml of aqueous ammonium chloride (50% saturated solution) and the pH is adjusted to 3 with 1N hydrochloric acid. The acidified mixture is extracted three times with 50 ml of methylene chloride, the extracts are combined, washed with brine, dried over sodium sulfate and concentrated by evaporation. The concentrate is chromatographed on silica using a hexane-ethyl acetate about 3: 1 (v: v) mixture as eluent followed by the same solvent 1: 1 (v: v) mixture. The eluate is evaporated to dryness to afford the title compound.

Claims (3)

The compound of formula (I)

Wherein Ar is phenyl, C ₁ -C ₄ alkylphenyl, halophenyl, C ₁ -C ₄ alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl: R is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl or halophenyl; Y is -CH = CH- or -CH ₂ = CH _2- ; R 'is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl, halotenyl, furyl or naphthyl. When the compound of formula (III) and R ₄ is not formyl, its 4-position epimer,

Wherein Ar is phenyl, C ₁ -C ₄ alkylphenyl, halophenyl, C ₁ -C ₄ alkoxyphenyl, naphthyl, thienyl, furan, benzothienyl or benzofurylamine; R is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl or halophenyl; R ₄ is formal, carboxy, C ₁ -C ₄ alkoxycarbonyl, methyl, halomethyl, or hydroxymethyl. The following compound of formula (5a) is reacted with a compound of formula (6a) to produce a compound of formula (I), wherein Y is -CH = CH-, and the resulting compound is optionally hydrogenated so that Y is -CH ₂ -CH _{A process} for producing a compound of formula (I), characterized in that it produces a compound of formula (I), which is _2- .

Wherein Ar is phenyl, C ₁ -C ₄ alkylphenyl, halophenyl, C ₁ -C ₄ alkoxyphenyl, naphthyl, thienyl, furan, benzothienyl or benzofurylamine; R is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl or halophenyl; Y is -CH = CH- or -CH ₂ -CH _2- ; R 'is phenyl, C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl, halophenyl, furyl, or naphthyl; X 'is chloro, bromo, trifluoroacetoxy or -OP (= O) X ₂ , where X is halogen.