JPH072764A - Beta-lactam compound - Google Patents

Abstract

PURPOSE:To obtain a new beta-lactam compound having an alkylthio or arylthio group at 4 position and useful as an inexpensive synthetic intermediate capable of industrially providing in large amounts and used for beta-lactam-based antibiotics having strong antimicrobial action. CONSTITUTION:A carboxylic acid of formula I [R1 is H, lower alkyl, (protected) hydroxyl-lower alkyl or (substituted) amino; R2 is (substituted) lower alkyl, aryl, etc.] are treated with a halogenating agent to afford a beta-halogenated carboxylic acid and then, this compound a carboxylic acid group of which has been activated with thionyl chloride, etc., is successively made to react with the formula R3-NH2 (R3 is H, aryl, substituted aryl, aralkyl, acyl, lower alkoxycarbonyl, etc.) to give an azide compound of formula III. Then, the azide compound is subjected to cyclization reaction in the presence of a deacidifying agent such as triethylamine to provide the objective beta-lactam compound expressed by the formula IV and used as an intermediate, etc., for beta-lactam- based antibiotics.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to β-lactam compounds.

[0002]

2. Description of the Related Art Recently, thienamycin (JP-A-51-73)
191), PS-5 (JP-A-53-121702).
Carbapenem-type antibiotics such as the above have been discovered from nature and have been reported to have a strong antibacterial action. However, the yield by the fermentation method is extremely low, and the production method by total synthesis for large-scale synthesis has been actively studied.

On the other hand, it has been reported that a penem compound having a similar structure to thienamycin has a similar strong antibacterial activity [JA
m. Chem. Soc., 102 , 2039 (1980); J. Antimicrobial Chemoth
erapy 9 , Suppl.C.1-5 (1982)], but the penem compound cannot be obtained from nature, so the method by total synthesis must be relied upon. As a typical example, recently, a method of deriving from 6-aminopenicillanic acid [Tetrahedron, 39 , 2505]
(1983)], a method of deriving from L-threonine [Tetrahed
ron Letters, 22 , 5205 (1981), Tetrahedron Letters, 24 , 1
037 (1983)] and the like have been reported.

However, since the synthetic raw materials are expensive, the number of steps is long, and a large number of by-products are generated in the middle to cause complicated separation, it cannot be said that the method is an industrially satisfactory method.

[0005]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made earnest studies on a method for industrially and economically producing a β-lactam compound, and as a result, found an extremely advantageous intermediate, and completed the present invention.

[0006]

The present invention relates to a β-lactam compound represented by the general formula (I), which is an important synthetic intermediate for β-lactam antibiotics.

[0007]

[Chemical 2]

(In the formula, R ₁ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group which may have a protecting group or an amino group which may have a substituent. R ₂ represents a lower alkyl group or a substituted group. A lower alkyl group, an aryl group or a heterocyclic group, wherein R ₃ is a hydrogen atom, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group or the general formula —O—R ₄ (wherein R ₄ is a hydrogen atom). , A lower alkyl group, a substituted lower alkyl group (the substituent on the lower alkyl group is a phenyl group, a substituted phenyl group, a heterocyclic group, a substituted heterocyclic group, a tri-lower alkylsilyl group or a sulfo group)). Group, acyl group, lower alkoxycarbonyl group, substituted lower alkoxycarbonyl group, aryloxycarbonyl group or sulfo group.)

The present invention also has the general formula (I) in which the configuration and substituents at the 3- and 4-positions are 3S-[(R) -1-hydroxy (or substituted hydroxy) ethyl] -4S-substituted thio. The present invention relates to a β-lactam compound represented by

The method for producing the β-lactam compound of the present invention will be described below.

In order to produce the β-lactam compound of the present invention, as shown in the figure below, the compound of general formula (VII) is halogenated to give compound (VI), and then the reactive derivative of the carboxylic acid ( III), which is a compound of the general formula H ₂ N—O—R ₄ (IV) (wherein R ₄ is the same as above) or a compound of the general formula H ₂ N—R ₅ (V) (formula Wherein R ₅ is a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a benzhydryl group, a substituted benzhydryl group or a group represented by —SO ₃ ⁻ M ⁺ (M ⁺ is a quaternary ammonium ion or a metal ion). It means that the compound (II) is condensed with the compound (II), and finally the compound is ring-closed in the presence of a deoxidizing agent to give the desired compound (I). Continuously identical without refining Is intended also possible to perform the reaction in vessel, it is extremely industrially advantageous method.

[0012]

[Chemical 3]

(In the formula, R ₁ , R ₂ and R ₃ are the same as above.
X means a halogen atom. A represents a halogen atom, a reactive ester residue of carboxylic acid, an acid anhydride residue or an acid azide residue. )

The details of the method for producing the β-lactam compound of the present invention will be described below.

First, the substituents used here will be described in detail.

R ₁ : hydrogen atom, methyl group, ethyl group, n
-Lower alkyl groups such as propyl group, isopropyl group, and n-butyl group, and hydroxy lower alkyl groups which may have a protecting group (as a protecting group of hydroxyl group, trimethylsilyl group, tributylbutylsilyl group such as tert-butyldimethylsilyl group). Lower alkylsilyl group, lower alkoxycarbonyl group such as tertiary butyloxycarbonyl, aralkyloxycarbonyl group such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl , 2-ethyloxycarbonyl iodide, 2,
A halogeno lower alkoxycarbonyl group such as a 2,2-trichloroethoxycarbonyl group, an aliphatic acyl group such as an acetyl group, an aromatic acyl group such as a benzoyl group, a benzhydryl group, an aralkyl group such as a benzyl group, and methoxymethyl. Group, such as a lower alkoxyalkyl group, a 2-tetrahydropyranyl group, etc.) or an amino group which may have a substituent.

R ₂ : a lower alkyl group such as methyl, ethyl and tertiary butyl, a substituted lower alkyl group such as triphenylmethyl, a phenyl group, an aryl group such as a substituted phenyl group, a pyridyl group and a substituted pyridyl group, A heterocyclic group such as a thienyl group, a substituted thienyl group, a thiazolyl group, an aryl group or a benzothiazolyl group is meant, and in the definition of R ₂ , a substituent on the group is a lower alkyl group such as methyl or ethyl, fluorine, There are halogen such as chlorine and bromine, a sulfonamide group, a lower alkoxy group, a nitro group, a cyano group, an alkoxycarbonyl group, a carbamoyl group, and the like, and these substituents are the same or different and are combined to one to three.
It may be replaced individually.

R _{3 is} an aryl group or a substituted aryl group such as a hydrogen atom, a phenyl group, a naphthyl group, a substituted phenyl group or a substituted naphthyl group, a benzyl group, a substituted benzyl group, a benzhydryl group or an aralkyl group such as a substituted benzhydryl group. Or a substituted aralkyl group, a general formula -O-
Group represented by R ₄ (R ₄ is a hydrogen atom, phenyl methyl, ethyl, lower alkyl group or a substituted lower alkyl group (substituents of isopropyl etc., nitrophenyl, methoxyphenyl, dimethoxyphenyl, 4-hydroxy-3, An aryl group such as 5-di-tertiary butylphenyl, etc. These substituents may be the same or different and may be substituted by 1 or 2), or a heterocyclic group such as pyridyl, furyl or thienyl, or Substituted heterocyclic group (lower alkyl group, lower alkoxy group as a substituent), trimethylsilyl, tri-lower alkylsilyl group such as tert-butyldimethylsilyl, or sulfo group), fat such as acetyl group, benzoyl group Group or aromatic acyl group, lower alkoxy such as methoxycarbonyl, ethoxycarbonyl Carbonyl group, benzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2,
It means a substituted lower alkoxycarbonyl group such as 2,2-trichloroethoxycarbonyl, an aryloxycarbonyl group such as phenoxycarbonyl, or a sulfo group. In the definition of R ₃ , a substituent such as a substituted phenyl group, a substituted naphthyl group, a substituted benzyl group, a substituted benzhydryl group and a substituted lower alkoxycarbonyl group is a lower alkyl group such as methyl and ethyl, a lower alkoxy such as methoxy and ethoxy. Groups, lower alkylthio groups such as methylthio and ethylthio, halogen atoms such as fluorine, chlorine and bromine,
There are a hydroxyl group, a nitro group, a cyano group, an amino group, a methanesulfonyl group, a p-toluenesulfonyl group, an alkoxycarbonyl group, a carbamoyl group, a sulfonamide group and the like, and these substituents are the same or different and are combined to form 1 Or 3 to 3 may be substituted.

R ₅ : an aryl group or a substituted aryl group such as phenyl or substituted phenyl, an aralkyl group or a substituted aralkyl group such as benzyl, substituted benzyl, benzhydryl or substituted benzhydryl (these substituents include methyl, ethyl and the like). There are lower alkyl groups, halogens such as fluorine, chlorine, bromine, etc., lower alkoxy groups, sulfonamide groups, nitro groups, cyano groups, alkoxycarbonyl groups, carbamoyl groups, etc. You may replace 3)
Or _-SO ³ - group represented by ^{M + (M +} is tetra -n
-Quaternary ammonium ion such as butylammonium, metal ion such as Na ⁺ , K ⁺ , 1 / 2Ca ⁺⁺ ).

A: Activated by an acid chloride method, a mixed acid anhydride method, an active ester method, an azide method, a dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) method, and a carbonyldiimidazole method which are used in general peptide synthesis methods. Means a residue of a reactive derivative of a carboxylic acid, for example, a halogen such as chlorine, a tertiary butyryloxy group,
Isoamyloxycarbonyloxy group, paranitrophenyloxy group, succinimideoxy group, benzotriazolyloxy group, azido group, imidazolyl group and DC
C ₆ H ₁₁ N = C (C ₆ H ₁₁ NH) O derived from C
Examples thereof include a group represented by-.

Each step will be described below.

First step: Halogenation 1) Halogenating agent: N-chlorosuccinimide (hereinafter abbreviated as NCS) N-bromosuccinimide (hereinafter abbreviated as NBS) Sulfuryl chloride Chlorine, bromine, 3-iodoviridine chlorine Adducts 2) Reaction solvent: Halogenated hydrocarbons such as chloroform and dichloromethane Ethers such as diethyl ether Aromatic hydrocarbons such as benzene and toluene 3) Reaction time: 2 minutes to 1 hour, usually 3 minutes to 20 Min 4) Reaction temperature: 0-50 ° C, preferably 10-30 ° C

Second step: Activation of carboxylic acid 1) Activation method (reagent): DCC method Acid chloride method (thionyl chloride, phosphorus oxychloride, phosphorus pentachloride) Acid anhydride method (isobutyl chloroformate, pivalo) Iloxycarbonyl chloride, triethylamine as deoxidizing agent, N-methylmorpholine) Active ester method (p-nitrophenol, N-oxysuccinimide, 1-oxybenzotriazole, DCC as condensing agent) 2) Reaction solvent: first step 3) Reaction time: 10 minutes to 2 hours, usually about 30 minutes 4) Reaction temperature: 0 to 25 ° C, preferably 5 to 15 ° C

Third step: (H ₂ N—O—R ₄ or H ₂
Reaction with NR ₅ ) 1) Reaction reagent (deoxidizing agent): triethylamine (hereinafter, referred to as T
2) Reaction solvent: same as in the first step 3) Reaction time: 10 minutes to 2 hours, 20 minutes to 40 minutes are often sufficient 4) Reaction temperature: 0 to 40 ° C., preferably 5 ~ 35 ° C

Fourth step: ring-closing reaction 1) Reagent (deoxidizing agent): tri-lower alkylamines such as triethylamine and diisopropylethylamine, alkali metal hydroxide, silver oxide, silver nitrate, copper powder 2) Reaction solvent: first Same as step 3) Reaction time: 5 minutes to 3 hours, usually 10 minutes to 1 hour 4) Reaction temperature: 0 to 40 ° C, preferably 5 to 35 ° C

Specific examples will be described below with reference to examples and reference examples. However, the scope of the present invention is not limited by these. The following abbreviations are used.

Ph: Phenyl SiBMM: Tertiary butyldimethylsilyl PNB: Paranitrobenzyl

[0028]

【Example】

Example 1 (3S, 4S) -3-[(R)
-1- (tert-Butyldimethylsilyloxy) ethyl]
-1- (4-nitrobenzyloxy) -4-phenylthio-2-azetidinone

[0030]

[Chemical 4]

140 mg of (2S, 3R) -threo-3-tert-butyldimethylsilyloxy-2-phenylthiomethylbutyric acid was dissolved in 1.4 ml of chloroform (purified through an alumina column) at room temperature to obtain NCS of 66 mg.
Is gradually added and stirred for 7 minutes. The reaction solution is ice-cooled and O-4-
A solution of 69 mg of nitrobenzylhydroxylamine in 0.14 ml of chloroform and then a solution of 85 mg of DCC in 0.14 ml of chloroform are added, and the mixture is stirred at room temperature for 20 minutes. Then TEA 0.06 ml chloroform 0.1
Add 4 ml solution and stir at the same temperature for 20 minutes. 5 ml of water is added to the reaction solution, extracted with chloroform, and dried over sodium sulfate. The residue obtained by evaporation of the solvent was subjected to column chromatography on 3 g of silica gel, and the benzene eluate was concentrated under reduced pressure to give 30 mg of the title compound as an oil.

[0032]

[Table 1]

Example 2 (3S, 4S) -3-[(R)
-1- (tert-Butyldimethylsilyloxy) ethyl]
-1-hydroxy-4-phenylthio-2-azetidinone

[0034]

[Chemical 5]

30 mg of the compound obtained in Example 1 was dissolved in 5 ml of methanol, and 30 mg of 10% palladium-supported carbon was dissolved.
Is added and catalytic reduction is carried out under normal pressure for 3 hours and 40 minutes. Further, 30 mg of the above catalyst is added, and catalytic reduction is carried out at normal pressure for 1 hour. The catalyst was removed using Celite, and the solvent was evaporated under reduced pressure to give the title compound (16 mg) as colorless crystals. Melting point 132-13
5 ° C.

[0036]

[Table 2]

Example 3 (3S, 4S) -3-[(R)
-1- (tert-Butyldimethylsilyloxy) ethyl]
-4-phenylthio-2-azetidinone

[0038]

[Chemical 6]

15 mg of the compound obtained in Example 2 was dissolved in 1.2 ml of methanol and 0.5 ml of water, and this was dissolved at room temperature for 2 hours.
Add 75 μl of 5% titanium trichloride solution with 1N sodium hydroxide while keeping the pH around 7. After stirring at the same temperature for 30 minutes, 5 ml of water is added, extracted with ethyl acetate, and dried over magnesium sulfate. The residue obtained by distilling off the solvent is subjected to preparative thin layer chromatography (20 × 20 × 0.5).
cm) using chloroform-methanol (93: 7)
13 mg of the title compound was obtained.

[0040]

[Table 3]

[0041]

[Reference example]

Reference Example 1 (2S, 3R) -threo- and (2R, 3R) -erythro-3-hydroxy-2-phenylthiomethylbutyric acid methyl ester

Dry tetrahydrofuran (THF) 200
30 ml of isopropylamine was dissolved in ml, and the internal temperature was cooled to −60 ° C. under an argon stream, and 132.5 ml of n-butyllithium (15% hexane solution) was added to the internal temperature of −5.
Add dropwise so that the temperature does not exceed 0 ° C. Next, the temperature was raised to -30 ° C over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes, and then -6 again.
Cool to 0 ° C. To this, a solution of 12.5 g of methyl (-)-(R) -3-hydroxybutyrate in 20 ml of dry THF was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 26.6 g of iodomethylphenyl sulfide in 20 ml of hexamethylphosphoric amide was added dropwise, and the mixture was stirred at the same temperature for 30 minutes and at -40 ° C. for 10 minutes, 400 ml of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated and the obtained residue was subjected to column chromatography on 100 g of silica gel to obtain 9.5 g of the title compound as a mixture of erythro-threo (4: 1) from the chloroform eluate. This product was used in the next reaction without separation as a mixture.

Reference Example 2 (3R) -3-hydroxy-2
-Methylidene butyric acid methyl ester

15.57 g of (2S, 3R) -threo-3-tert-butyldimethylsilyloxy-2-phenylthiomethylbutyric acid was dissolved in 450 ml of methylene chloride, and 13.4 g of metachloroperbenzoic acid was added little by little under ice cooling. Add and then stir at room temperature for 1 hour. The reaction solution is washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate, and then the solvent is distilled off to obtain 16.66 g of an oily substance. This product is immediately dissolved in 160 ml of toluene without purification and heated at 120 ° C for 1 hour. The solvent was distilled off, and the residue was subjected to column chromatography on 50 g of silica gel to remove the portion first eluted with benzene, and the portions eluted with chloroform were collected and concentrated under reduced pressure to obtain 6.5 g of the title compound.

[0046]

[Table 4]

Reference Example 3 (2S, 3R) -Threo- and (2R, 3R) -Erythro-3-hydroxy-2-phenylthiomethylbutyric acid methyl ester

4.5 g of the compound obtained in Reference Example 2 was dissolved in 95 ml of chloroform, and thiophenol 4.58 was added under ice cooling.
ml and triethylamine (TEA) 1.87 g are added, followed by stirring at room temperature for 21 hours. The reaction solution is washed with a cooled 5% aqueous sodium hydroxide solution, further washed with water and dried over sodium sulfate. The solvent was evaporated, the obtained residue was subjected to column chromatography on 30 g of silica gel, and the chloroform eluate was concentrated under reduced pressure to give 6.7 g of the title compound as an oil as a mixture of erythro-threo (3: 7).

[0049]

[Table 5]

Reference Example 4 (2S, 3R) -threo- and (2S, 3R) -erythro-3-hydroxy-2-phenylthiomethylbutyric acid

5.64 g of the compound obtained in Reference Example 3 was dissolved in 55 ml of carbon tetrachloride, 4.1 ml of iodotrimethylsilane was added, and the mixture was heated in a sealed tube at 50 ° C. for 15 hours. After cooling, 10 ml of water is added and the mixture is stirred at room temperature for 6 hours.
Carbon tetrachloride is distilled off, saturated aqueous sodium hydrogen carbonate solution is added, and the mixture is washed with ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether. Wash the ether layer with aqueous sodium thiosulfate,
Dry with sodium sulfate. The solvent was distilled off, and the residue was subjected to column chromatography on 20 g of silica gel to give the title compound 4.13 as an oily mixture as a mixture of erythro-threo (3: 7).
g was obtained.

[0052]

[Table 6]

Reference Example 5 (2S, 3R) -Threo-3-
Hydroxy-2-phenylthiomethyl butyric acid

4.13 g of the compound obtained in Reference Example 4 was dissolved in 100 ml of ethanol, and dicyclohexylamine 4.
5 ml is added, and after standing, ethanol is distilled off. The residue was washed with ether, and the obtained crystal (1.3 g) was recrystallized from benzene to obtain a colorless crystal of dicyclohexylamine salt. Melting point 145-149 [deg.] C. [Α] _D −21.80 °
(C = 4.0 CHCl _3).

520 mg of this dicyclohexylamine salt
2 ml of 1N hydrochloric acid is added to and extracted with ether. After drying the ether layer with magnesium sulfate, the solvent was distilled off to obtain 230 mg of the title compound as an oil.

[0056]

[Table 7]

Reference Example 6 (2S, 3R) -threo-3-
Tert-Butyldimethylsilyloxy-2-phenylthiomethylbutyric acid

230 mg of the compound obtained in Reference Example 5 is dissolved in 5 ml of dimethylformamide (DMF), 290 mg of imidazole and 365 mg of tert-butyldimethylchlorosilane are added, and the mixture is stirred at room temperature for 14 hours. Water (15 ml) and methanol (30 ml) are added to the reaction solution, and the mixture is stirred at room temperature for 3 hours. The reaction solution was benzene-ethyl acetate (1:
Extract with the mixed solvent of 1) and dry with magnesium sulfate.
The residue obtained by distilling off the solvent was subjected to column chromatography on 5 g of silica gel, and the eluate of benzene was concentrated under reduced pressure to obtain 100 mg of the title compound as an oil. Melting point 63-67 [deg.] C.

[0059]

[Table 8]

The manufacturing steps from Reference Example 1 to Reference Example 6 will be illustrated below.

[0061]

[Chemical 7]

Reference Example 7 (±) -Erythro and (±)
-Tert-butyl threo-3-hydroxy-2-phenylthiomethylbutyrate

63 g of sodium acetate was dissolved in 350 ml of methanol at room temperature, and 59 g of 37% formalin was dissolved therein.
55 g of thiophenol and 79 g of tert-butyl acetoacetate are sequentially added, and the mixture is stirred at the same temperature for 1 hour. The reaction solution is ice-cooled, 9 g of sodium borohydride is added little by little, and the mixture is stirred at the same temperature for 2 hours. The solvent is distilled off and the residue is n
-Hexane was added and the insoluble matter was filtered off, and then n-hexane was distilled off to obtain 71 g of an oily matter. From NMR, this compound was a mixture of the erythro body and the threo body (4: 1).

[0064]

[Table 9]

Reference Example 8 (±) -Threo and (±)-
Erythro-3-hydroxy-2-phenylthiomethylbutyric acid

20 g of the compound obtained in Reference Example 7 is dissolved in 50 ml of anisole and 100 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. After the solvent is distilled off, the residue is dissolved in saturated aqueous sodium hydrogen carbonate solution and washed with ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether. After drying over sodium sulfate, the solvent is concentrated under reduced pressure to obtain 15 g of colorless crystals. From NMR, this compound was a mixture of the erythro body and the threo body (4: 1). Further recrystallization with benzene was performed (±) -erythro-3-hydroxy-
2-Phenylthiomethylbutyric acid was obtained. Melting point 79-80
° C.

[0067]

[Table 10]

Dicyclohexylamine was added to the filtrate for crystallization, and recrystallization from ethanol was performed to obtain a colorless crystalline dicyclohexylamine salt. Melting point 155-157 [deg.] C.

The dicyclohexylamine salt is acidified with 1N hydrochloric acid and extracted with ether. After drying over sodium sulfate, the solvent was distilled off to obtain oily (±) -threo-3-hydroxy-2-phenylthiomethylbutyric acid.

[0070]

[Table 11]

Reference Example 9 (±) -Erythro-3-tert-butyldimethylsilyloxy-2-phenylthiomethylbutyric acid

Using the (±) -erythro compound obtained in Reference Example 8 and performing the same reaction and post-treatment as in Reference Example 6, the title compound was obtained as colorless crystals. Melting point 91-92 [deg.] C.

[0073]

[Table 12]

Reference Example 10 (±) -threo-3-tert-butyldimethylsilyloxy-2-phenylthiomethylbutyric acid

The (±) -threo compound obtained in Reference Example 9 was used for the same reaction and post-treatment as in Reference Example 6 to obtain the title compound as colorless crystals. Melting point 93-94 [deg.] C.

[0076]

[Table 13]

Reference Example 11 Methyl (±) -erythro and (±) -threo-3-hydroxy-2-phenylthiomethylbutyrate

Using methyl acetoacetate as a raw material, the same reaction as in Reference Example 7 was carried out to obtain a mixture of the erythro form (4: 1).

[0079]

[Table 14]

[0080]

The β-lactam compound of the present invention is a penem,
It is an important compound as a synthetic intermediate for 1-carbapenem and other β-lactam antibiotics. In particular, 3S-[(R) -hydroxyethyl] -azetidine- in which R ₁ of general formula (I) has the same configuration as the side chain [(R) -hydroxyethyl group] at the 6-position of natural thienamycin.
The 2-one derivative or the compound (Ib) in which the hydroxyl group thereof is protected by a protecting group is a derivative of the natural product thienamycin or (5R, 6S, 8R) -of the thienamycin analogs.
It is a very important compound for the synthesis of 6- (hydroxyethyl) penem-3-carboxylic acid derivative. Upon induction into these compounds, the substitution reaction of the leaving group (Ro) of (Ib) with the nucleophile (Nu) produces (Ic) in the middle,
It is known that a nucleophile (Nu) reacts with this to produce (Id) [Can. J. Chem., 61 , 1899 (1983); Organic Synthetic Chemistry, Vol. 41, No. 1, page 63 (1983). )], And thus (I
The configuration of the 4-position Ro in b) may be either the R configuration or the S configuration.

[0081]

[Chemical 8]

(In the formula, R ₁₁ means a protecting group for a hydrogen atom or a hydroxyl group, and Ro means a leaving group.)

The 4-position substituent —S—R ₂ of the β-lactam compound (I) of the present invention can be easily converted into a leaving group having higher activity. Therefore, penem, 1-carbapenem and other β-lactam antibiotics can be used. It is a very useful compound as a synthetic intermediate of a substance.

The leaving group is a group which can be easily removed in the nucleophilic substitution reaction to substitute the nucleophilic reagent residue, and typical examples thereof include a halogen atom, an acetoxy group, a benzenesulfonyl group and the like. Can be mentioned.

Further, the 1-position of the compound of the present invention can be changed. That is, when R ₃ is a protecting group, it can be eliminated if desired. The desorption method reductive degradation by hydrogenation, sodium amalgam, aluminum amalgam, ammonia in metallic _{sodium, (NH 4) 2 Ce (} NO 3) 6, K 2 S 2 O 8,
Examples of the method include decomposition using TiCl ₃ or another reducing agent, hydrolysis using an acid or a base, and oxidative decomposition using ozone.

More specifically, 1) R ₃ is —O—
When R ₄ is a compound such as benzyl group, p-nitrobenzyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and benzhydryl group, R ₄ is palladium-supported carbon, platinum oxide, or other known metal Deprotection by catalytic reduction using a catalyst gives the general formula

[0087]

[Chemical 9]

(In the formula, R ₁ and R ₂ are the same as above.)

The N-hydroxy-2-azetidinone derivative can be used. As a reaction solvent, methanol, ethanol, dioxane, tetrahydrofuran (TH
F), preferably in methanol, under a hydrogen pressure of 1-4 atm,
The desired product can be obtained by reacting at 0 to 50 ° C., preferably 10 to 30 ° C. for 30 minutes to 10 hours, usually 1 to 5 hours. The product can be isolated by usual extraction and recrystallization.

Further, the above N-hydroxy-2-azetidinone derivative is reduced with a reducing agent such as titanium trichloride to give a compound of the general formula

[0091]

[Chemical 10]

(In the formula, R ₁ and R ₂ are the same as above.)

It is possible to derive the 2-azetidinone derivative of. As the reaction solvent, use methanol, ethanol, dioxane, THF, or a water buffer solution (including mixed solvents).
At 0 to 50 ° C., preferably at 15 to 30 ° C. in water-containing methanol, an aqueous solution of TiCl ₃ is added while neutralizing with an aqueous sodium hydroxide solution and reacted for 20 minutes to 5 hours, preferably 30 minutes to 2 hours, ethyl acetate, The target product can be obtained by extraction with an organic solvent such as benzene or chloroform.

As described above, in the 2-azetidinone derivative, the compound in which R ₃ is —O—R ₄ is reduced with metallic sodium in liquid ammonia without isolating the N-hydroxy-2-azetidinone derivative in the middle. Can be obtained directly by The 2-azetidinone derivative as a raw material may be directly added to the liquid ammonia solution of sodium metal,
When the raw material is poorly soluble, good results can be obtained by dissolving the raw material in a small amount of THF and adding it little by little. Reaction is -50 to -30
The reaction is carried out at 5 ° C for 1 minute to 1 hour, and after the reaction, ammonium chloride is added, an extraction solvent such as CH ₂ Cl _{2 is} further added, and ammonia is driven out with nitrogen gas, and then the desired product can be obtained by a normal extraction operation. .

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group which may have a protecting group or an amino group which may have a substituent. R ₂ represents a lower alkyl group, a substituted lower alkyl group R ₃ represents a hydrogen atom, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group or the general formula —O—R ₄ (wherein R ₄ is a hydrogen atom or a lower alkyl group). A group, an acyl group represented by a substituted lower alkyl group (the substituent on the lower alkyl group is a phenyl group, a substituted phenyl group, a heterocyclic group, a substituted heterocyclic group, a tri-lower alkylsilyl group or a sulfo group), acyl Group, a lower alkoxycarbonyl group, a substituted lower alkoxycarbonyl group, an aryloxycarbonyl group or a sulfo group). Compound 2. The configuration and substituents at the 3- and 4-positions are 3S-.
[(R) -1-hydroxy (or substituted hydroxy)
The β-lactam compound according to claim 1, which is ethyl] -4S-substituted thio.