KR840000865B1 - Process for preparing -lactam-containing antibacterial agents - Google Patents

Abstract

Penems I (R=H, lower alkyl, 2,2,2-trichloroalkyl, benzyl, acetonyl, p-nitrobenzyl, p-methoxybenzyl, Ph, p-nitro-Ph, benzhydryl, acetoxymethyl, Me-CH-OCO2Et, CH2NHCOR2; R2=C1-C5 alkyl, aryl; Z=H, halo, OH, amino, carbamoyloxy, mercapto, pyridinium, OR3, OCOR3, NHCOR3, SR4; R3, R4 independently=lower alkyl, aryl, heterocyclic ring; n=0, 1) were prepd. Thus, 2.0g methylpenicillinate S-oxide in 40mL toluene and 2.8g butandiol diacetate were refluxed for 24 hrs. to give 1.4g 4β-vinylthio - [1,2-diacetoxymethyl - 1 - [methoxycarbonyl-2-methyl-2-propenyl - azetidine-2-on-S-oxide.

Description

Method for preparing β-lactam-containing antimicrobial agent

The present invention relates to a method for producing a β-lactam-containing compound having a broad antibacterial action and a β-lactamase inhibitory action, particularly a penem-carboxylic acid of the following general formula (I).

In the above formula

-니트로벤질,

-메톡시벤질, 페닐,

-니트로페닐 또는 벤즈히드릴, 생체내에서 대사적 활성화를 거쳐 유리한 약물동력학적 성질을 가지는 것으로 알려진 아세톡시메틸, 피발로일옥시메틸 또는 프탈리딜, 또는 일반식

또는 -CH₂NHCOR²(여기서 R²는 1내지 5개의 탄소원자를 가지는 알킬 또는 아릴이다)의 그룹이며,R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl,

Nitrobenzyl,

Methoxybenzyl, phenyl,

Nitrophenyl or benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl, known to have advantageous pharmacokinetic properties through metabolic activation in vivo, or a general formula

Or -CH ₂ NHCOR ² , wherein R ² is alkyl or aryl having 1 to 5 carbon atoms

Z is hydrogen or a halogen atom, hydroxy, amino, carbamoyloxy, mercapto, or pyridinium, or a general formula OR ₃ , OCOR ₃ , NHCOR ₃ and SR ⁴ , where R ³ and R ⁴ are lower alkyl, aryl Or hetero cyclic, each of which may be substituted or unsubstituted),

-니트로 벤질옥시카보닐 또는 디메틸-t-부틸-실릴이 바람직하고 n은 0 또는 1이다.R ¹ is a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl (preferably lower hydroxyalkyl), wherein the alcoholic functional group of the hydroxyalkyl is free or protected and

Nitro benzyloxycarbonyl or dimethyl-t-butyl-silyl are preferred and n is 0 or 1.

Substituents at the 6-position have α-configuration and β-configuration, with α-configuration being preferred.

및 -CH₂NHCOR²의 그룹이 포함된다.Examples of residues included in the definition of R known to have beneficial pharmacokinetic properties through metabolic activation in vivo include acetoxymethyl, pivalooxymethyl and phthalidyl and general formulas.

And a group of -CH ₂ NHCOR ² .

-니트로벤질옥시카보닐옥시)-에틸을 들 수 있다.Representative examples of R ¹ include methyl, ethyl, methoxy, 1-hydroxyethyl and -1- (

-Nitrobenzyloxycarbonyloxy) -ethyl is mentioned.

When R ³ and R ⁴ are heterocycles they are preferably 5- or 6-membered heterocycle ring moieties, for example 5-methyl-1,3,4-thiadiazol-2-yl, 1-methyl- Tetrazol-5-yl, 1,3,2-triazol-5-yl or pyrazinyl and the like.

These compounds have broad antibacterial activity and have β-lactamase inhibitory activity. The novel beta -lactam containing compounds and the stereochemistry at C ₅ in the intermediate for their preparation are identical to the naturally occurring penicillins and cephalosporins.

Preparation of Pharmaceutically Harmonic Salts of Compounds of Formula (I), Including Sodium, Calcium, Benzatin, Procaine Salts of Penem-Carboxylic Acid of Formula (I), and Salts with Common Penicillins and Cephalosporins It also falls within the scope of the present invention.

The following scheme illustrates the process for preparing the compound of general formula (I) according to the present invention.

2668 and EVRARD et al., Nature

1124)]. R¹이 저급알킬, 사이클로알킬 또는 하이드록시알킬인경우 R¹기는 디니노등의 방법에 따라 도입시킬 수 있다. [참조: Di Ninno et al., Journal of Organinc Chemistry,

2960(1977)]. R¹이 저급알콕시인경우 R¹는 저급알콕시인 경우 R¹기는 출발물질인 6-APA의 6위치에 하우스등의 방법 및 기딩등의 방법에 따라 도입시킬 수 있다. [참조 : Hauser et al., Helv. Chem. Acta,

1327(1967) and Giddings et al., Tetrahedron I etters, 11, 995(1978)].When R ¹ is hydrogen, the compound of formula (2) is prepared according to the well-known general method using (5R) 6-amino penicillic acid (6-APA) as the starting mole. [CINARELLA et al., Journal of Organnic Chemistry

2668 and EVRARD et al., Nature

1124)]. When R ¹ is lower alkyl, cycloalkyl or hydroxyalkyl, the R ¹ group can be introduced by methods such as diino. See Di Ninno et al., Journal of Organinc Chemistry,

2960 (1977). When R ¹ is lower alkoxy When R ¹ is lower alkoxy, the R ¹ group can be introduced at the 6-position of 6-APA, starting material, according to the method of house or the like. [Hauser et al., Helv. Chem. Acta,

1327 (1967) and Giddings et al., Tetrahedron I etters, 11, 995 (1978).

In addition, the compound of formula (2) wherein R ¹ is hydrogen may be prepared by introducing a substituent at the 6 position using a strong base, as described in the following examples, in which R ¹ is lower alkyl, cycloalkyl or hydroxyalkyl ( Can be converted to the compound of 2). Compounds of formula (2) wherein R ¹ is lower alkyl, cycloalkyl or hydroxyalkyl can be prepared starting with a suitable ester of penicsilane acid s-oxide as described in the following examples. The 6 position substitution reaction is performed stereospecifically to produce 6α derivatives.

CY [여기서, X'는 일반식 CH₂Z'(이때 Z'는 수소 또는 할로겐원자, 하이드록시, 아미노, 카바모일옥시거나 일반식 OR³, OCOR³또는NHCOR³(여기서 R³는 임의 치환된 저급알킬, 아릴 또는 헤테로사이클환이다)의 그룹이고, Y는 수소원자, 저급알킬, 시아노 또는 일반식 COOR⁵또는 CH₂Z'(여기서 R⁵및 Z'는 전술된 의미를 가진다)의 그룹이다.]의 적합한 아세틸렌 유도체와 함께 가열할 수 있다.The ester of peniclanic acid S-oxide of formula (2), wherein R ⁵ is an alkyl group and R ¹ has the aforementioned meanings, is generally of the general formula X'C in an inert solvent such as benzene or toluene at a temperature of

CY [where X 'is a general formula CH ₂ Z' wherein Z 'is hydrogen or a halogen atom, hydroxy, amino, carbamoyloxy or a general formula OR ³ , OCOR ³ or NHCOR ³ , wherein R ³ is optionally substituted Is a lower alkyl, aryl or heterocycle ring), Y is a hydrogen atom, lower alkyl, cyano or a group of the formula COOR ⁵ or CH ₂ Z ', wherein R ⁵ and Z' have the meanings set forth above Can be heated together with a suitable acetylene derivative.

In the compound of general formula (3), when X 'is different from X, a well-known substitution reaction, i.e., X' is used as a group X [where X is CH ₂ Z (where Z is as described above). The resulting compound of formula (3) can be isomerized to a compound of formula (4) using a base, and the compound of formula (4) is the final compound of formula (1) according to two different methods Can be converted to In the first method, selective ozonation on isopropenyl double bond of the compound of general formula (4) yields a compound of general formula (5) wherein n = 1 = which is phosphorus tribromide or sodium urine in acetyl chloride. Using a suitable reducing agent such as odaide, it can be reduced to the compound of formula (5) with n = 0 and subsequently hydrolyzed to the compound of formula (6) with n = 0 on relaxed base conditions or on silica gel. have. Condensation with a suitable ester of glyoxylic acid yields a compound of formula (7) with n-0, which yields a compound of formula (7) with n = 0 using chlorinating agents such as thionylchloride and pyridine. Chlorinating agents such as thionylchloride and pyridine can be used to convert to chloro derivatives of formula (8) with n = 0 and then to phosphoranes of formula (9) with n = 0. Furthermore, reactions of the same group may be carried out as starting materials with exceptional compounds of the general formula (6) with stable n = 1 when Y is not a strong leaving group. In the case of containing a compound of formula (9) with n = 0, the compound is selectively ozonated with a phosphonium salt under acidic conditions to give a compound of formula (11), which is only in an inert solvent such as toluene, 50 It can be ring-closed to the compound of the general formula (1) by simply heating at a temperature of 캜 to 140 캜.

In the case of the compound of formula (9), wherein n = 1, the compound is reduced to the compound of formula (10) and then selectively ozonated with the compound of formula (11) to give the compound of formula (1). .

In the second method, the compound of formula (4) is reduced under ordinary conditions to obtain a compound of formula (12), and then ozonated on both double bonds to obtain a compound of formula (13). Hydrolysis yields the compound of formula (14). Glyoxylation of the compound of formula (14) according to the same method as described above yields the compound of formula (15), which is converted to the chloro derivative of formula (16) and is then a common intermediate of the two methods. It can be converted into the phosphoran of formula (11).

When R ¹ is hydroxylalkyl, the reaction is preferably carried out by protecting the alcoholic functional groups. Compounds of formula (1) wherein R is hydrogen can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compound. The compound of the general formula (1) having n = 1 is easily prepared by using the compound of the general formula (1) having n = 0 as a starting material according to a well-known oxidation process. Advantageously peracids can be used, with m-chloroperbenzoic acid and peracetic acid being preferred. The processes described herein are included within the scope of the present invention.

(5R) acetoxymethyl-2-acetoxy methyl-2-phenem-3-carboxylate (experimental code FCE / 20077 / B40 / 341), (5R) acetoxymethyl-2-[(1'-methyl-1 'H-Tetrazol-5'-yl) -thiomethyl] -2-phenem-3-carboxylate (Compound A) and a series of in vitro to compare the activity of two control compounds (Ampicillin and Sepoxycitin) The test was performed. Table 1 below shows the test results as MIC (minimum inhibitory concentration).

TABLE 1

The following examples illustrate the invention but do not limit the invention.

Example 1

Reaction (2)-(3)

A solution of 2.0 g of methylphenicylinate S-oxide and 2.8 g of butynediol diacetate in 40 ml of toluene is heated at reflux for 24 hours. The title compound can be purified by column chromatography on silica gel with 96: 4 dichloromethane-ethyl acetate as eluent. 1.4 g of 4β-vinylthio [1,2-diacetoxymethyl] -1- [1-methoxycarbonyl-2-methyl-2-propenyl] -azetidin-2-one-S-oxide is obtained do.

Example 2

Reaction (3)-(4)

1.7 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-methoxycarbonyl-2-methyl-2-propenyl] -azetidin-2-one-S-oxide Dissolve in 80 ml of dichloromethane, add 0.5 ml of triethylamine and leave for several hours at room temperature. After evaporation of the solvent the title compound is obtained pure in quantitative yield.

Example 3

Reaction (4)-(5)

2.0 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-S-oxide It is dissolved in 150 ml of dichloromethane, cooled at -78 ° C, and the ozone in oxygen is passed through a cooled solution until a slightly blue color appears. The solution is allowed to warm to room temperature, shaken with aqueous Na ₂ S ₂ O ₅ solution and then dried over Na ₂ S ₂ O _{4 The} resulting organic layer is evaporated under vacuum to afford 1.4 g of the title compound.

Example 4

Reaction (5)

In a solution of 1.4 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1-methoxyoxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous dimethylformamide, After cooling at 25 ° C., 0.9 ml of phosphorus tribromide is added. After 10 minutes the mixture is diluted with ethyl acetate and washed twice with saturated NaHCO ₃ solution. Drying over Na ₂ SO _{4 and} then evaporating the solvent gave 0.9 g of the title compound.

Example 5

Reaction (5)-(6)

Dissolve 1.5 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1-methoxyoxaloyl-azetidin-2-one in 100 ml of methanol and add several grams of silica gel with stirring. . After 1 hour, the silica gel was filtered off and the methanolic solution was evaporated to yield 0.8 g of 4β-vinylthio- [1,2-diacetoxymethyl] -azetidin-2-one.

Example 6

Reaction (5)-(6)

0.8 g 4β-vinylthio [1,2-diacetoxymethyl) -1-1methoxyolsaloyl-azetidin-2-one-S-oxide was dissolved in 80 ml of methanol, followed by several g of silica gel. Add while stirring. After 1 hour, the silica gel was filtered off and the solvent was evaporated to yield 0.5 g of 4β-vinylthio- [1,2-diacetoxymethyl] -azetidin-2-one-S-oxide.

Example 7

Reaction (12)-(13)

0.8 g of 4β-vinylthio- [1,2-diacetoxymethyl-1- [1-acetoxymethyloxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one in 80 ml of dichloro Dissolve in methane and cool to −78 ° C. and allow the ozone in oxygen to pass through the cooled solution until a blue color appears. The solution was shaken with Na ₂ S ₂ O ₅ aqueous solution and dried over Na ₂ SO ₄ to afford 0.45 g of the title compound.

Example 8

Reaction (13)-(14)

0.6 g of 4β-acetylglycolylthio-1-methoxy oxaloyl-azetidin-2-one is dissolved in 100 ml of methanol, and then several g of silica gel is added while stirring the solution. After 1 hour, the silica gel is filtered off. The solvent in the resulting solution is then evaporated to yield 0.35 g of the title compound.

Example 9

(6)-(7)

0.7 g of acetoxymethyl-glyoxylate (freshly prepared by ozone decomposition of diacetoxymethylfumarate) is dissolved in 30 ml of benzene and the resulting solution is refluxed in a Dean-Stark apparatus for 20 minutes.

The resulting solution was cooled at 50 ° to 60 ° C. and 0.7 g of 4β-vinylthio- [1,2-diacetoxymethyl] -azetidin-2-one dissolved in 10 ml of benzene was added to reflux for 2 hours. Let's do it. The title compound is obtained in almost quantitative yield and can be used as a crude mixture in the next step. Pure samples for analysis are obtained by preparative TLC.

Example 10

************

Reaction (7)-(8)

0.6 g of 4β-vinylthio [1,2-diacetoxymethyl] -1- [acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one dissolved in 15 ml tetrahydrofuran was zero. After cooling at 占 폚, 0.115 ml of pyridine and 0.104 ml of thionylchloride are added and the resulting mixture is stirred for 10 minutes. The insoluble material is filtered off and the solution is evaporated at room temperature and vacuum to afford the title compound in high yield. Samples are purified on preparative TLC for analysis, but the crude mixture can be used in the next step without purification.

Example 11

Reaction (8)-(9)

0.430 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-in 5 ml of dioxane containing 5 ml of tetrahydrofuran, 0.520 g of triphenylphosphine and 0.08 ml of pyridine The solution in which acetoxymethyloxycarbonyl-1-chloromethyl] -azetidin-2-one is dissolved is stirred overnight at 50 ° C. The resulting phosphane was purified by column chromatography on silica gel with 70:30 dichloromethane-ethyl acetate as eluent to afford 0.400 g of the title compound.

Example 12

Reaction (10)-(11)

40 ml of 0.7 g of 4β-vinylthio- [1,2-diacetoxymethyl] -1- [1-acetoxymethyloxy carbonyl-1-triphenylphosphoranylidenemethyl] -azetidin-2-one In dichloromethane and then cooled to -20 ° C, then 50 ml of a 10% trifluoroacetic acid solution in dichloromethane is added. After a few minutes, oxygen in oxygen is passed through the solution at -20 ° C until it is slightly blue. At this time, the reaction is stopped and a few drops of trimethylphosphite are added. The organic solution is washed with saturated Na ₂ SO ₄ solution and dried over NaHCO ₃ to give 0.550 g of the title compound.

Example 13

Reaction (11)-(1)

0.7 g of 4β-acetylglycolylthio-1- [1-acetoxymethyloxycarbonyl-1-triphenylphosphoranilidenemethyl] -azetidin-2-one is dissolved in 30 ml of anhydrous toluene and then reflux temperature. Heat at for 2 hours. The reaction mixture consisting of the title compound and triphenylphosphine oxide was purified by single column chromatography on silica gel with 97: 3 dichloromethane-ethyl acetate as eluent to yield 0.250 g of acetoxymethyl-2-acetoxymethyl 2-penem-. 3-carboxylate is obtained.

Example 14

Reaction (6)-(7)

-니트로벤질푸마레이트를 가오존 분해하여 새로 제조한

-니트로벤질 글리옥실레이트를 사용하여 실시예 9와 동일한 방법에 따라 표제 화합물을 수득한다.

-Newly prepared by ozone decomposing nitrobenzyl fumarate

Nitrobenzyl glyoxylate is used to obtain the title compound following the same method as in Example 9.

Quantitative yield.

Example 15

Reaction (7)-(8)

The title compound is obtained according to the method described in Example 10.

Example 16

Reaction (8)-(9)

The title compound is obtained according to the method of Example 11.

Example 17

Reaction (9)-(11)

The title compound is obtained according to the method of Example 12.

Example 18

Reaction (11)-(1)

The title compound is obtained according to the method of Example 13.

Example 19

Reaction (1)

-니트로벤질-2-아세톡시메틸-2-페넴-3-카복실레이트를 12ml의 에틸아세테이트에 용해시킨다. 다음에 8ml의 0.2 M NaHCO₃용액 및 10% Pd/C 400mg을 가하여 생성된 2상 혼합물을 수소압하아에서 60분간 진탕시킨다. 촉매를 여과한 후 수층을 5%구연산용액 20ml로 산성화 한다음 메틸렌 클로라이드로 3회 추출한다. 유기층을 Na₂SO₄로 건조시킨다음 증발시켜 60mg의 표제화합물을 수득한다.200 mg of (5R)-prepared as described in Example 18.

Nitrobenzyl-2-acetoxymethyl-2-phenem-3-carboxylate is dissolved in 12 ml of ethyl acetate. Then, 8 ml of 0.2 M NaHCO ₃ solution and 400 mg of 10% Pd / C are added, and the resulting biphasic mixture is shaken under hydrogen pressure for 60 minutes. After filtering the catalyst, the aqueous layer was acidified with 20 ml of 5% citric acid solution and extracted three times with methylene chloride. The organic layer is dried over Na ₂ S0 ₄ and evaporated to afford 60 mg of the title compound.

IR (CHCl ₃ ): 1790 (β lactam), 1735 and 1700 cm ^-1

U.V (EtOH): 300nm

Example 20

Reaction (2)-(3)

4 g of peniclanic acid methyl ester s-oxide is dissolved in 15 ml of toluene and then refluxed with 15 ml of propazyl alcohol for 8 hours. After evaporation in vacuo, the residue is purified by single column chromatography on silica gel with dichloromethane-ethyl acetate 1: 1. 2.8 g of the title compound are obtained.

Example 21

Reaction (3)-(4)

3.0 g of 4β- (1-hydroxymethyl) -vinylthio-1- [methoxycarbonyl-2-methyl-2-propenyl] -azetidin-2-one-s-oxide in 100 ml of dichloromethane It is dissolved and left for several hours at room temperature. After evaporation of the solvent, a residue consisting of the pure title compound in quantitative yield is obtained.

Example 22

Reaction (4)-(12)

1.8 g of 4β- (1-hydroxymethyl) vinylthio-1- [1-methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-s-oxide in 40 ml of dimethylform It is dissolved in amide and then cooled at 20 ° C. 0.7 ml of pyridine and 3.0 ml of PBr3 are then added and the mixture is left for 15 minutes with stirring. Ethyl acetate was added and the organic layer was shaken with saturated NaHCO ₃ solution, washed with water, dried over Na ₂ SO ₄ and evaporated to give 1.6 g of the title compound.

Example 23

Reaction (12)

1.4 g of 4β- (1-bromomethyl) -vinylthio-1- [1-methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one are dissolved in 25 ml of tetrahydrofuran Then cooled to 0 ° C. 0.8 g of 1-methyl-5-thiol-tetrazole sodium salt is added and then stirred at room temperature for 3 hours. After filtering off the insolubles, the mixture was diluted with ethyl acetate, washed with water, dried over Na ₂ SO ₄ and evaporated. The residue consists of 2.0 g of pure title compound.

Example 24

Reaction (12)-(13)

1.8g 4β- [1- (1-methyl-1-H-tetrazol-5-yl) -thiomethyl] -vinylthio-1- [1-methoxycarbonyl-2-methyl-1-propenyl ] -Azetidin-2-one is dissolved in 200 ml of dichloromethane and cooled at -78 ° C.

Pass ozoneized oxygen through the solution until blue color appears. A drop of P (OCH ₃ ) ₃ was added followed by raising the temperature of the mixture to room temperature and evaporating to yield 1.3 g of the title compound.

Example 25

1.2 g of 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1-methoxyoxaloyl-azetidin-2-one 1: 1 ethylacetate / methane mixture It is dissolved in and then several g of silica gel is added with vigorous stirring.

After 1 hour the insolubles are filtered off and the solution is evaporated in vacuo. Crystallization from methanol-ethyl ether gives 0.6 g of the title compound.

Example 26

1.5 g of 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthioazetidin-2-one and 1.2 g of acetoxymethylglyoxylate (diacetoxymethylfumarate ozone And reflux in 50 ml of benzene with freshly prepared). After 3 hours the reaction is complete. The crude oil obtained by evaporating the solvent can be used without further purification in the next step. Spectroscopy data obtained samples are purified on TLC.

Example 27

Reaction (15)-(16)

Crude 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one The oil obtained in configured Example 26 was dissolved in anhydrous tetrahydrofuran (20 ml) and then treated with an equimolar amount of pyridine and thionyl chloride at 0 ° C. until the starting material disappeared.

After filtering the insoluble material, the filtrate is used directly in the next step.

Example 28

Reaction (16)-(11)

Crude 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one To the solution was added 800 mg of triphenylphosphine and 0.4 ml of pyridine to heat the resulting mixture at 60 ° to 70 ° C. for several hours. Phosphoran is purified by eluting with dichloromethane-ethyl acetate (1 :) on silica gel.

Example 29

Reaction (11)-(1)

0.500 g of 4β- (1-methyl-1-H-tetrazol-5-yl) -thioacetylthio-1- (1-acetoxymethyloxycarbonyl) -1-triphenylphosphoranylidenemethyl)- Azetidin-2-one is dissolved in 30 ml of toluene and then heated at 100 ° C. for 2 hours. The title compound is purified using eluent PPh ₃ O with dichloromethane-ethylacetate (8: 2) using a single column on silica gel.

Example 30

Reaction (1)

-니트로벤조일-2-(1-메틸-1-H-테트라졸-5-일)-티오메틸-2-페넴-3-카복실레이트는 전술된 실시예들어서 설명된 공정과 유사한 방법에 의해 수득된다.The title compound is obtained following the process described in Example 19. (5R)-

-Nitrobenzoyl-2- (1-methyl-1-H-tetrazol-5-yl) -thiomethyl-2-phenem-3-carboxylate is obtained by a method similar to the process described in the above-described examples. .

I.R. (CHCl 3): 1800 (β lactam), 1750 and 1720.

Example 31

Reaction (17)-(2)

A solution of 2.3 g of methylphenicylinate dissolved in 50 ml of anhydrous tetrahydrofuran is cooled at -78 ° C. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamid and 20 ml of 1.6M butyllilium hexane solution) dissolved in anhydrous tetrahydrofuran is added and the mixture is left at -78 ° C for 10 minutes. 5 ml of acetaldehyde is added continuously and the solution is stirred for 15 minutes. Subsequently, the reaction was quenched by addition of saturated aqueous NH ₄ Cl solution, extracted with ethyl acetate, washed twice with water, and dried over Na ₂ SO ₄ .

After evaporation of the solvent, the residue is quickly purified by column chromatography on silica gel with dichloromethane-ethylacetate (1: 1) as eluent. 1.5 g of product are obtained. The title compound consists of an apimer 2: 3 mixture for hydroxyl-containing carbon based on PMR, which has new C ₆ -C ₈ bonds only at the α-position due to the stereospecificity of the reaction under the conditions used. .

Example 32

Reaction (17)-(2)

To a solution of 2.2 g of methylphenicylinate dissolved in 30 ml of anhydrous tetrahydrofuran is added a slight excess of lithium diisopropylamide at -78 ° C under nitrogen atmosphere. Excess acetaldehyde is added and the mixture is stirred for 5 minutes, then the reaction is stopped with a small amount of acetic acid and added to the mixture in water to extract with methylene chloride. The organic layer is dried over Na ₂ SO ₄ and then evaporated in vacuo to yield 0.8 g of the title compound.

Example 33

Reaction (2)

-니트로벤질옥시카보닐클로라이드를 상기 혼합물에 가하고 -78℃에서 30분후 반응 혼합물을 실온에서 60분간 방치시켜 물속에 주가한 다음 메틸렌 클로라이드로 추출한다. Na₂SO₄로 건조시킨후 증발시켜 1.4g의 표제 화합물을 수득한다.1.2 g of methyl-6- [1-hydroxyethyl] -3-penicilanate are dissolved in 40 ml of tetrahydrofuran, cooled at -78 ° C and treated with 1 equivalent of butyllithium. 1.2 equivalents

Nitrobenzyloxycarbonylchloride was added to the mixture, and after 30 minutes at -78 ° C, the reaction mixture was left at room temperature for 60 minutes, added to water, and extracted with methylene chloride. Dry over Na ₂ S0 ₄ and evaporate to afford 1.4 g of the title compound.

Example 34

Reaction (17)-(2)

-니트로벤질옥시카보닐옥시에틸]-3-페니실라네이트를 50ml의메틸렌클로라이드에 용해시킨 다음 0℃에서 1.5당량의 m-클로로퍼벤조산으로 처리한다. 유기층을 NaHCO₃포화용액으로 진탕시켜 추출하고 Na₂SO₄로 건조시킨 다음 증발시키면 1.4g의 기대된 설폭사이드가 수득된다.1.8 g of methyl-6- [1-

Nitrobenzyloxycarbonyloxyethyl] -3-penicilanate is dissolved in 50 ml of methylene chloride and then treated with 1.5 equivalents of m-chloroperbenzoic acid at 0 < 0 > C. The organic layer was extracted by shaking with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and evaporated to yield 1.4 g of the expected sulfoxide.

Example 35

Reaction (2)-(3)

-니트로벤질옥시카보닐옥시에틸]-3-페니실라네이트-s-옥사이드 및 2.4g의 부틴디올 디아세테이트가 용해된 용액을 24시간동안 환류시킨다. 방취장치를 한 화합물을 9 : 1 디클로로메틴-에틸 아세테이트를 용출제로 실리카겔 칼럼 크로마토그라피에 의해 정제시킨다.2.0 g methyl-6- [1- in 50 ml toluene

-A solution of nitrobenzyloxycarbonyloxyethyl] -3-phenylanate-s-oxide and 2.4 g butynediol diacetate was refluxed for 24 hours. The deodorant compound is purified by silica gel column chromatography with 9: 1 dichloromethine-ethyl acetate as eluent.

1.1 g of the title compound are obtained.

Example 36

Reaction (3)-(4)

-니트로벤질옥시카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-2-프로페닐]-아제티딘-2-은-s-옥사이드를 80ml의 디클로로메탄중에 용해시키고 0.3ml의 트리에틸아민을 가한 다음 실온에서 2시간 동안 방치시킨다. 용매를 증발시킨 후 순수한 표제 화합물이 정략적으로 수득된다.1.3 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1-

Nitrobenzyloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-2-propenyl] -azetidine-2-silver-s-oxide in 80 ml of dichloromethane and 0.3 ml of tri Ethylamine is added and left for 2 hours at room temperature. Pure evaporation of the title compound is obtained after evaporation of the solvent.

Example 37

Reaction (4)-(5)

-니트로벤질옥시 카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온-s-옥사이드가 용해된 용액을 -78℃에서 냉각시킨다. 이 용액이 푸른색을 띨 때까지 산소 중 오존을 통해준다. 용액을 Na₂S₂O₅수용액과 함께 진탕시켜 Na₂SO₄로 건조시킨다. 증발시키면 0.5g의 표제화합물이 수득된다.1.1 g of 4β-vinylthio- [1,2-diacetoxymethyl) -3-1.1 g of 4β-vinylthio- [1,2-diacetoxymethyl) -3- [1- in 100 ml of dichloromethane

The solution in which nitrobenzyloxy carbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-s-oxide is dissolved is cooled at -78 deg. Give ozone in oxygen until the solution turns blue. The solution is shaken with an aqueous Na ₂ S ₂ O ₅ solution and dried over Na ₂ SO ₄ . Evaporation yields 0.5 g of the title compound.

Example 38

Reaction (5)

-니트로벤질옥시카보닐옥시에틸]-1-메톡시옥살로일-아제티딘-2-온 이 용해된 용액을 -20℃에서 냉각시킨 다음 0.6ml의 3브롬화인을 가한다. 10분후 반응물을 에틸아세테이트로 희석하고 NaHCO₃용액으로 2회 세척한다. 유기층을 Na₂SO₄로 건조시킨 다음 증발시켜 0.4g의 환원된 화합물을 수득한다.0.8 g 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- in 15 ml anhydrous dimethylformamide

-A solution of nitrobenzyloxycarbonyloxyethyl] -1-methoxyoxaloyl-azetidin-2-one is cooled at -20 ° C and then 0.6 ml of phosphorus tribromide is added. After 10 minutes the reaction is diluted with ethyl acetate and washed twice with NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ and then evaporated to yield 0.4 g of reduced compound.

Example 39

Reaction (5)-(6)

-니트로벤질옥시카보닐옥시에틸]-1-메톡시옥살로일-아제티딘-2-온을 메탄올중에 용해시킨 다음 2g의 실리카겔을 가한다. 60분 후 불용물을 여과하고 유기층을 증발시킨다. 단 칼럼크로마토그라피하면 0.4g의 표제 화합물이 수득된다.1.2 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1-

Nitrobenzyloxycarbonyloxyethyl] -1-methoxyoxaloyl-azetidin-2-one is dissolved in methanol and then 2 g of silica gel is added. After 60 minutes the insolubles are filtered off and the organic layer is evaporated. Column chromatography gives 0.4 g of the title compound.

Example 40

Reaction (6)-(7)

-니트로벤질옥시카보닐옥시에틸]-아제티딘-2-온 및 0.6g의 아세톡시메틸 글리옥실레이트(디아세톡시메틸 푸마레이트를 가오존분해시켜 새로 제조한 것)를 환류시킨다. 반응은 2시간후 완결된다. 축합 생성물은 더 정제하지 않고 다음 단계에 사용될 수 있다.0.6 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- dissolved in 30 ml of benzene

Nitrobenzyloxycarbonyloxyethyl] -azetidin-2-one and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozone decomposing diacetoxymethyl fumarate) are refluxed. The reaction is complete after 2 hours. The condensation product can be used in the next step without further purification.

Example 41

Reaction (7)-(8)

-니트로벤질옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온을 12ml의 무수 테트라하이드로푸란에 용해시킨 다음 0℃에서 냉각시킨 후 1.1당량의 피리딘 미치 1.1당량의 티오닐 클로라이드를 가한다. 혼합물을 10분간 교반시킨다. 불용성 물질을 여과하고 용액을 실온에서 증발시키면 포제호합물이 거의 정량적인 수율로 수득된다.0.5 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1-

-Nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one is dissolved in 12 ml of anhydrous tetrahydrofuran and cooled at 0 ° C. 1.1 equivalents of pyridine methion and 1.1 equivalents of thionyl chloride are then added. The mixture is stirred for 10 minutes. Filtration of the insoluble material and evaporation of the solution at room temperature gave the foam formulation in near quantitative yield.

The product can be used in the next step without further purification.

Example 42

Reaction (8)-(9)

-니트로벤조일옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온이 용해된용액을 2당량의 트리페닐 포스피 및 1.1 당량의 피리딘과 함께 +50℃에서 철야 교반한다. 포스포란은 70:30디클로로메탄-에틸아세테이트를 용출제로 실리카겔 칼럼크로마토그라피로 정제한다. 0.480g의 표제 화합물이 수득된다.0.760 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- in 10 ml of tetrahydrofuran and 10 ml of dioxane

2-nitrobenzoyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one in 2 equivalents of triphenyl phosphine and 1.1 equivalents It is stirred overnight at + 50 ° C with pyridine. Phosphoran is purified by silica gel column chromatography using 70:30 dichloromethane-ethyl acetate as eluent. 0.480 g of the title compound are obtained.

Example 43

Reaction (9)-(11)

-니트로벤질옥시에틸]-1-[아세톡시메틸옥시카보닐-1--트리페닐포스포라닐리덴메틸]-아제티딘-2-온을 50ml의 디클로로메탄에 용해시킨 다음 -20℃에서 냉각시킨 후, 디클로로메탄 중 트리플루오로아세트산 용액 30ml를 가한다. 수 분후 산소중 오존을 약간 푸른색이 나타날때가지 용액에 통해준다. 반응을 중단시키고 수적의 트리메틸포스파이트를 가한다. 유기층을 NaHCO₃의 포화용액으로 세척해서 Na₂SO₄로 건조시키면 0.26g의 표제 화합물이 수득된다.0.45 g of 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1-

-Nitrobenzyloxyethyl] -1- [acetoxymethyloxycarbonyl-1--triphenylphosphoranylidenemethyl] -azetidin-2-one was dissolved in 50 ml of dichloromethane and cooled at -20 ° C. Then 30 ml of trifluoroacetic acid solution in dichloromethane are added. After a few minutes, ozone in oxygen is passed through the solution until a little blue color appears. The reaction is stopped and a few drops of trimethylphosphite are added. The organic layer was washed with saturated solution of NaHCO ₃ and dried over Na ₂ SO ₄ to afford 0.26 g of the title compound.

Example 44

Reaction (4)-(12)

-니트로벤질옥시카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온-s-옥사이드를 10ml의 무수 디메틸포름아마이드에 용해시킨 다음 -20℃에서 냉각시켜 0.8ml의 3브롬화 인을 가한다. 혼합물을 10시간 동안 교반시켜 에틸아세테이트로 희석하고 NaHCO₃포화용액으로 2회 세척한다.유기층을 NaSO₄로 건조시켜 증발 시키면 1.1g의 표제 화합물이 수득된다.1.5 g of vinylthio- [1,2-diacetoxymethyl] -3- [1-

Nitrobenzyloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one-s-oxide in 10 ml of anhydrous dimethylformamide, and Cool at 20 ° C. and add 0.8 ml of phosphorus tribromide. The mixture is stirred for 10 hours, diluted with ethyl acetate and washed twice with saturated NaHCO ₃ solution. The organic layer is dried over NaSO ₄ and evaporated to give 1.1 g of the title compound.

Example 45

Reaction (12)-(13)

-니트로벤질옥시카보닐옥시에틸]-1-[메톡시카보닐-2-메틸-1-프로페닐]-아제티딘-2-온을 -78℃ㄹ까지 냉각시킨다. 다음에 오존함유 산소를 푸른색이 나타날때까지 용액에 통해준다. 이 용액을 Na₂S₂O₅의 수용액과 함께 진탕하고 Na₂SO₄로 건조시킨다. 용액을 증발시키면 0.8g의 표제 화합물이 수득된다.1.4 g 4β-vinylthio- [1,2-diacetoxymethyl] -3- [1- in 120 ml dichloromethane

Nitrobenzyloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl-1-propenyl] -azetidin-2-one is cooled to -78 ° C. Next, ozone-containing oxygen is passed through the solution until a blue color appears. This solution is shaken with an aqueous solution of Na ₂ S ₂ O ₅ and dried over Na ₂ SO ₄ . Evaporation of the solution yields 0.8 g of the title compound.

Example 46

Reaction (13)-(14)

-니트로벤질옥시카보닐옥시에틸 ]-1-메톡시옥살릴-아제티딘-2-온을 50ml의 메탄올에 용해시킨 다음 수 g의 실리카겔을 가한다. 혼합물을 실온에서 60분간 방치한다. 불용성물질을 여과하고 여액을 증발시키면 0.30g의 표제화합물이 수득된다.0.800 g of 4β-acetylglycolylthio-3- [1-

Nitrobenzyloxycarbonyloxyethyl] -1-methoxyoxalyl-azetidin-2-one is dissolved in 50 ml of methanol and then several grams of silica gel are added. The mixture is left at room temperature for 60 minutes. Filtration of the insolubles and evaporation of the filtrate gave 0.30 g of the title compound.

Example 47

Reaction (14)-(15)

0.5 g 4β-acetylglycolylthio-3- [1-p-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -agent in 30 ml of benzene Tidin-2-one and 0.5 g of acetoxymethylglyoxylate are refluxed until the reaction is complete (2 hours). The title compound obtained can be used in the next step without further purification.

Example 48

Reaction (15)-(16)

-니트로벤질옥시카보닐 옥시에틸] -1-[1-아세톡시메틸옥시카보닐-1-하이드록시메틸]-아제티딘-2-온을 0℃에서 10m l의 무수 테트라 하이드로푸란에 용해시킨다. 다음에 1.1당량의 피리딘과 1.1 당량의 티오닐클로라이드를 가한 다음 혼합물을 10분간 교반시킨다. 침전물을 여과하고 여액을 증발시키면 표제 화합물이 정량적인 수율로 수득된다. 조생성물은 다음 단계에서 그대로 사용된다.0.35 g of 4β-acetylglycolylthio-3- [1-

Nitrobenzyloxycarbonyl oxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-hydroxymethyl] -azetidin-2-one is dissolved in 10 ml of anhydrous tetrahydrofuran at 0 ° C. Then 1.1 equivalents of pyridine and 1.1 equivalents of thionylchloride are added and the mixture is stirred for 10 minutes. Filtration of the precipitate and evaporation of the filtrate gave the title compound in quantitative yield. The crude product is used as is in the next step.

Example 49

Reaction (16)-(11)

-니트로벤질옥시카보닐옥시에틸 ]-1-[1-아세톡시메틸옥시카보닐-1-클로로메틸]-아제티딘-2-온을 테트라하이드로푸란 및 디옥산(1: 1)의; 혼합물 20ml에 용해시킨다. 그후 2당량의 트리페닐포스핀과 1.1당량의 피리딘을 가하고 혼합물을 50℃에서 철야 교반시킨다. 표제 화합물을 70 : 30 디클로로메탄-에틸아세테이트를 용출제로하여 실리카겔 칼럼 크로마토그라피를 정제한다. 0.280g의 포스포란이 수득된다.0.400 g of 4β-acetylglycolylthio-3- [1-

-Nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-chloromethyl] -azetidin-2-one of tetrahydrofuran and dioxane (1: 1); Dissolve in 20 ml of the mixture. Then 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine are added and the mixture is stirred overnight at 50 ° C. The title compound was purified by silica gel column chromatography using 70:30 dichloromethane-ethyl acetate as the eluent. 0.280 g of phosphorane is obtained.

Example 50

Reaction (11)-(1)

-1-니트로벤질옥시카보닐옥시에틸]-1-[1-아세톡시메틸옥시카보닐-1-트리페닐포스포라닐리덴메틸]-아제티딘-2-온을 7ml의 톨루엔에 용해시킨 다음2시간동안 환류시킨다. 95:5 디클로로메탄-에틸아세테이트를 용출제로 단 칼럼크로마토그라피로 정제하면 0.05g의 표제 화합물이 수득된다.0.210 g of 4β-acetyl glycolylthio-3- [1-

-1-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl] -azetidin-2-one in 7 ml of toluene Reflux over time. Purification of 95: 5 dichloromethane-ethylacetate with eluent to sweet column chromatography afforded 0.05 g of the title compound.

Example 51

Reaction (1)

-니트로벤질옥시카보닐옥시에틸]-2-아세톡시메틸-2-페넴-4-카복실레이트를 물-에탄올-K₂HPO₄혼합물에 주가한 다음 % Pd/C로 가소분해시킨다. 실리카겔 칼럼크로마토그라피로 신속히 정제하면 0.015g의 표제 화합물이 수득된다.0.060 g of 5R-acetoxymethyl-6- [1-

Nitrobenzyloxycarbonyloxyethyl] -2-acetoxymethyl-2-penem-4-carboxylate is added to the water-ethanol-K ₂ HPO ₄ mixture and then plasticized to% Pd / C. Rapid purification with silica gel column chromatography yields 0.015 g of the title compound.

Manipulation as described in the above examples but with 5-methyl-2-thiol-1,3,4-thiadiazole, 5-thiol = 1,2,3- instead of 1-methyl-5-thiol-tetrazole When triazole or thiolpyrazine is used, (5R) -2-[(5'-methyl-1 ', 3,4'-thiadiazol-2'-yl) -thiomethyl] -2-phenem-3-carboxylic acid , (5R) -2-[(1 ', 2', 3'-triazol-5-yl) -thiomethyl] -2-phenem-3-carboxylic acid, (5R) -2- (pyrazinyl) -thio Methyl-2-phenem-3-carboxylic acid, (5R) -6- [1'-hydroxyethyl-2- [5′-methyl-1 ′, 3 ′, 4′-thiadiazol-2′-yl) Thiomethyl] 2-phenem-3-carboxylic acid, (5R) -6- [1'-hydroxyethyl] -2-[(1 ', 2', 3'-triazol-5'-yl) thiomethyl] 2-phenem-3-carboxylic acid, (5R) -6- [1'-hydroxyethyl] -2- (pyrazinyl) thiomethyl-2-phenem-3-carboxylic acid, is prepared, respectively.

Operation as described above, but reduction of methyl-6- [1'-hydroxyethyl] -3-phenylinate according to known methods yields the corresponding 6-ethyl-derivatives.

Claims (1)

A compound of Formula (2) Formula X'C ^- = CY reacted with an acetylene derivative of (where X 'and Y is as defined below), the basic compound of the obtained formula (3) Conditions Isomerization under to give a compound of formula (4) or to convert the resulting compound of formula (4) to a compound of formula (4a), the product is reduced ozonation and hydrolysis to prepare a compound of formula (14) This was followed by reaction with a glyoxylic acid ester of the general formula CHOCOOR (where R is as defined below), followed by chlorination of the compound of general formula (15) to obtain a chloro derivative of the general formula (16). And converting it into phospholane of formula (11) to cyclize the compound of formula (11), wherein the compound of formula (1) is prepared.

In the above formula R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl,

Nitrobenzyl,

Methoxy-benzyl, phenyl,

-Phenylnitrophenyl, benzhydryl, or residues that exhibit favorable pharmacokinetic properties through in vivo metabolic activation, R ¹ is a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl (alcohol functional groups of hydroxyalkyl are free or protected), Z is hydrogen or a halogen atom, hydroxy, amino, carbamoyloxy, mercapto, pyridinium or a general formula OR ² , OCOR ² , NHCOR ² or SR ³ (where R ² and R ³ are each substituted or unsubstituted) A lower alkyl, aryl or heterocyclic ring) R ⁵ represents an alkyl group, X 'is a general formula CH ₂ Z' wherein Z 'is a halogen or hydrogen atom, hydroxy, amino, carbamoyloxy or ylOR ² , OCOR ² or NHCOR ² , where R ² is lower alkyl, aryl or hetero Group represents a cycle ring), Y represents a hydrogen atom, lower alkyl, cyano or a general formula COOR ⁵ (where R ⁵ is lower alkyl) or a group of CH ₂ Z ′, X is a general formula CH ₂ Z wherein Z is as defined above Represents a group of ph represents phenyl.