JPH032869B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivative having the following formula, a pharmacologically acceptable salt thereof, and a method for producing the same. In the above formula, R ¹ represents an alkyl group having a hydroxyl group as a substituent, R ² represents an alkyl group having an amino group as a substituent, and R ³ represents a hydrogen atom or a carboxyl group that is eliminated under physiological conditions. Indicates a protecting group. Since the discovery of thienamycin, an antibiotic with extremely strong natural antibacterial activity (Japanese Patent Application Laid-open No. 51-73191)
No.) Research on this family of compounds has been actively conducted. However, this type of compound is known to be quite unstable (The Journal of Antibiotics, Vol. 32, p. 1).
1979). Therefore, the present inventors searched for compounds that would increase the stability of thienamycins without reducing their antibacterial activity.
The present invention has now been completed. In the general formula (), R ¹ preferably represents methyl, ethyl, n-, which has a hydroxyl group as a substituent.
A linear or branched alkyl group such as propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, and R ² is methyl, ethyl, etc. having an amino group as a substituent, n-propyl, isopropyl, n-
It is a lower alkyl group such as butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, and R ³ is a hydrogen atom or acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, n-butyryl. oxymethyl,
lower alkanoyloxymethyl groups such as isobutyryloxymethyl, pivaloyloxymethyl,
Physiological conditions such as 1-lower alkoxycarbonyloxyethyl group or phthalidyl group such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl It is a protecting group for the carboxyl group that is removed in . In addition, in the compound having the general formula (), there are optical isomers and stereoisomers based on the asymmetric carbon atom, and all of these isomers are shown by a single formula. The scope of the description of the present invention is not limited. However, it is preferable to select a compound in which the carbon atom at position 5 has the same coordination as that of penicillins, that is, the R coordination. Furthermore, in the general formula (), the carboxylic acid compound in which R ³ is a hydrogen atom can be made into a pharmacologically acceptable salt form, if necessary. Examples of such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, preferably sodium salts. salt and potassium salt. Examples of the compound having the general formula () obtained by the present invention include the compounds described below.

【table】 /
_CH3 ｜
OH
8 -CH ₂ CH ₂ NH ₂
As mentioned above, this exemplified compound has stereoisomers, and among these isomers, preferred are (5R, 6S) coordination and (5R, 6S) coordination.
6R) Compounds with coordination and α of the 6-position substituent
Compounds having a substituent such as a hydroxyl group, an acetoxy group, an amino group, or an acetamido group at the position thereof are R-coordinated. The novel compound () according to the present invention can be produced by the method shown below. In the above formula, R ¹ , R ² , R ³ , X and Y have the same meanings as described above, R ¹ ' represents an alkyl group having a hydroxyl group which may be protected as a substituent, and R ² ' represents an alkyl group having a protected amino group as a substituent, R ³ ' represents a protecting group for a carbonyl group, R ⁷ represents an alkyl group or an aryl group, and Z represents a halogen atom. In the above formula, R ¹ ' and R ² ' correspond to the corresponding groups in R ¹ and R ² described above, and the protected hydroxyl groups contained therein include benzyloxycarbonyloxy,
an aralkyloxycarbonyloxy group such as p-nitrobenzyloxycarbonyloxy or
Examples of protected amino groups include tri-lower alkylsilyloxy groups such as tert-butyldimethylsilyloxy, and aralkyloxycarbonylamino groups such as benzyloxycarbonylamino and p-nitrobenzyloxycarbonylamino. The protected carboxyl group of R ³ ' includes lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-
an aralkyloxycarbonyl group such as methoxybenzyloxycarbonyl, a benzhydryloxycarbonyl group, a halogeno lower alkoxycarbonyl group such as 2,2-dibromoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, or phenacyloxycarbonyl; Mention may be made of substituted or unsubstituted phenacyloxycarbonyl groups such as p-bromophenacyloxycarbonyl, and of protecting groups for carboxyl groups which are eliminated under physiological conditions in ^R3 . R ⁷
Examples of the alkyl group of Z include n-butyl group or n-octyl group, examples of the aryl group include phenyl group or tolyl group, and examples of the halogen atom of Z include chlorine, bromine or iodine atom. The 4-(γ-halogeno-β-oxopropyl)azetidinone compound having the general formula (), which is a raw material compound in the method for producing the compound of the present invention, is
It can be synthesized by the method described in Japanese Patent Application No. 53-80641 (Japanese Unexamined Patent Publication No. 55-7251). The first step is a step of producing a compound having the general formula (). (In the formula, R ² ' has the same meaning as defined above.) This is a process in which a nucleophilic reagent having the following or a reactive derivative thereof is reacted in a solvent. Reactive derivatives of the nucleophilic reagents used in this reaction include alkali metal salts or alkaline earth metal salts such as salts with lithium, sodium, potassium or calcium, magnesium, and triethylamine, N-methylmorpholine, etc. Examples include salts with organic bases. Examples of solvents used in the reaction include halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene and toluene. Examples include inert solvents such as fatty acid amides such as dimethylformamide and dimethylacetamide. The reaction temperature is not particularly limited, and is usually -30 to 50°C, and the reaction time is about 1 to 24 hours, although it varies depending on the types of raw material compounds and bases, reaction temperature, etc. After the reaction is completed, the target compound () of this step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is extracted with an organic solvent, the organic solvent layer is washed with dilute hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, the solvent is distilled off, and the residue is subjected to recrystallization or column chromatography. It can be obtained by purification with The second step is a step of producing a compound having the general formula (), in which the compound having the general formula () has the general formula OHC-COOR ³ ′ () (wherein R ³ ′ has the same meaning as above). ) or its hemiacetal derivative in a solvent. When the glyoxylic acid ester () used in this reaction is a hemiacetal derivative, hemiacetal with a lower alkanol such as methanol or ethanol is suitable. Examples of the solvent used in the reaction include fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, and aromatic hydrocarbons such as benzene, toluene and xylene. The reaction temperature is not particularly limited, but it is preferably 25°C to around the reflux temperature of the solvent used, and is usually carried out in a nitrogen or argon atmosphere to avoid side reactions. The reaction time varies depending on the reaction temperature, etc., but is about 2 to 10 hours. In addition, when using the hydrate of glyoxylic acid ester (),
If necessary, water may be removed by azeotropic distillation or dehydration using a molecular sieve. After the reaction is completed, the target compound () of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the organic solvent from the reaction mixture and purifying the residue by recrystallization, reprecipitation, or column chromatography. The third step is a step of producing a compound having the general formula (), and is a step of halogenating the compound having the general formula () in a solvent. The halogenating agent used in this reaction is not particularly limited as long as it is a reagent that halogenates hydroxy compounds, but phosphorus trihalides such as phosphorus trichloride and phosphorus tribromide, phosphorus pentachloride, and Examples include phosphorus pentahalides such as phosphorus chloride, phosphorus oxychloride, phosphorus oxyhalides such as phosphorus oxybromide, and thionyl halides such as thionyl chloride and thionyl bromide. The reaction is preferably carried out in the presence of an acid binder, and the acid binder used is preferably an organic base such as triethylamine, pyridine, lutidine, or collidine. Examples of the solvent used in the reaction include inert solvents such as ethers such as ethyl ether, tetrahydrofuran and dioxane, and halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is -40 to 40°C, and the reaction time is 15 minutes to 5 hours, although it varies depending on the halogen agent and reaction temperature. After the reaction is completed, the target compound () of this step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is diluted with an inert organic solvent, the generated hydrohalide of the organic base is separated, the solvent is distilled off from the solution, and the residue is purified by recrystallization or reprecipitation. However, the halogenating agent and organic solvent may be distilled off from the reaction mixture under reduced pressure, and the residue may be used as it is in the next reaction step. The fourth step is a step of producing a compound having the general formula (), in which the compound having the general formula () is converted to the general formula P(R ⁷ ) ₃ () (wherein R ⁷ is the one described above) in the presence of a base. This is a process in which a phosphine compound having the same meaning as ) is reacted in a solvent. This reaction is a part of the so-called Wittig reaction, and is used to produce a phosphorus-ylide compound (2), and the most suitable phosphine (2) used is triphenylphosphine. The base used in the reaction is not particularly limited, but includes, for example, organic bases such as triethylamine, pyridine, lutidine, and collidine, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Examples of solvents used in the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as methylene chloride and chloroform, dimethylformamide, and dimethyl. Examples include fatty acid dialkylamides such as acetamide, and inert solvents such as dimethyl sulfoxide. The reaction temperature is not particularly limited, but -30
The temperature is from 120°C to 120°C, and the reaction time varies depending on the reaction temperature, etc., but is usually from 0.5 to 10 hours. In this reaction, if necessary, a catalytic amount of an antioxidant such as hydroquinone can be added to prevent the oxidation reaction. After the reaction is completed, the target compound () of this step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is diluted with an organic solvent that is immiscible with water, washed with water, dried, the solvent is distilled off, and the residue is subjected to a recrystallization method.
It can be obtained by purification by reprecipitation method or column chromatography. The fifth step is a step of producing a compound having the general formula (a) that also includes the target compound of the present invention, and is a step of heating the compound having the general formula () in a solvent to cause a ring-closing reaction. Examples of solvents used in the reaction include ethers such as tetrahydrofuran and dioxane;
Examples include inert solvents such as halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, and mixed solvents of these solvents. The heating reaction temperature ranges from 30 to 200°C,
The reaction time varies depending on the reaction temperature, etc., but is usually 1 to 40 hours. In this reaction, in order to prevent side reactions due to heating, it is preferable to carry out the reaction in a stream of inert gas such as argon or nitrogen, if necessary, and to prevent oxidation reactions, a catalytic amount of hydroquinone, etc. Antioxidants can also be added. The main ring-closing reaction by heating may proceed in the phosphorus-ylide synthesis reaction of the fourth step described above to produce the target compound (a) of this step. After the reaction is completed, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture and purifying the residue by recrystallization, reprecipitation, or column chromatography. The sixth step is a step for producing a 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivative having the general formula (), which is the target compound of the present invention. Using the compound (a) obtained in the fifth step, a reaction for removing the carboxyl group protecting group R ³ ' and removing the protecting groups of the corresponding substituents from the substituents contained in R ¹ ' and R ² ', respectively. This is a step of restoring hydroxyl groups and amino groups. In other words, the reaction for producing a carboxylic acid compound in which the substituent R ³ is a hydrogen atom in the compound having the general formula () involves removing the protecting group R ³ ' of the carboxyl group of the compound having the general formula (a). This is achieved by doing. Removal of the protecting group R ³ ′ differs depending on the type, but
It is generally removed by methods known in the art. Preferably, the reaction is carried out according to the general formula (
This is achieved by contacting a compound having a) in which the substituent R ³ ' is a protective group that can be removed by reduction treatment, such as a halogenoalkyl group, an aralkyl group, or a benzhydryl group, with a reducing agent. . As the reducing agent used in this reaction, zinc and acetic acid are preferred when the protecting group for the carboxyl group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl. , hydrogen and palladium when the protecting group is, for example, an aralkyl group such as benzyl, p-nitrobenzyl, or a benzhydryl group.
Catalytic reduction catalysts such as carbon or aralite metal sulfides such as sodium or potassium sulfide are preferred. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and acetic acid are used. A mixed solvent of a fatty acid such as and an organic solvent thereof and water or a phosphate buffer (PH7.0) is suitable. The reaction temperature is usually around 0°C to room temperature,
The reaction time varies depending on the raw material compound and the type of reducing agent, but is usually 1 minute to 1 hour. In addition, in the reduction reaction of this step, the compound (
When the substituent R ¹ ' and/or R ² ' in a) has a hydroxyl group, amino group, etc. protected by an aralkyloxycarbonyl group, those aralkyloxycarbonyl protecting groups are simultaneously protected. Can be removed. After completion of the reaction, the target compound of the reaction for removing the carboxyl protecting group R ³ ' is collected from the reaction mixture according to a conventional method. For example, after removing insoluble matter precipitated from the reaction mixture, the organic solvent layer is washed with water, dried, and the solvent is distilled off. If necessary, conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. It can be purified by e.g. In addition, when the target compound is water-soluble, after removing the precipitated insoluble matter from the reaction mixture and concentrating the liquid under reduced pressure if necessary, the diamond ion
It can be obtained by subjecting it to column chromatography using a porous adsorption resin such as HP20AG (manufactured by Mitsubishi Kasei Corporation), separating the portion from which the target compound is eluted, and freeze-drying it. The reaction for producing a compound in which the substituent R ¹ is an alkyl group having a hydroxyl group among the compounds having the general formula () is carried out using the reaction in the substituent included in R ¹ ' in the compound having the general formula (a). This is accomplished by removing the trialkylsilyl protecting group of the hydroxyl group from a compound in which the protected hydroxyl group represents a trialkylsilyloxy group. When the protected hydroxyl group contained in R ¹ ' is an aralkyloxycarbonyloxy group such as benzyloxycarbonyloxy or p-nitrobenzyloxycarbonyloxy, the reaction is carried out by contacting the corresponding compound (a) with a reducing agent. This can be done by letting The type of reducing agent and reaction conditions used in this reaction are the same as those for removing the aralkyl group, which is the carboxyl group-protecting group R ³ ', described above.
R ³ ' can also be removed at the same time. Furthermore, when the protected hydroxyl group in the substituent included in the above substituent R ¹ ' is a tri-lower alkylsilyloxy group such as tert-butyldimethylsilyloxy, the reaction can be carried out using the corresponding compound (
This can be carried out by treating a) with tetrabutylammonium fluoride. The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction is suitably carried out by treating at around room temperature for 1 to 18 hours. Among the compounds having the above general formula (), the reaction for producing a compound in which the substituent R ² is a group having amino is the protection of the substituent contained in R ² ' of the compound having the general formula (a). This is achieved by removing the substituted aralkyloxycarbonyl protecting group of the amino group from a compound in which the amino group represents an aralkyloxycarbonylamino group. When the protected amino group in the substituent contained in R ² ' is an aralkyloxycarbonylamino group such as benzyloxycarbonylamino or p-nitrobenzyloxycarbonylamino, the reaction is performed using the corresponding compound (
a) can be carried out by contacting with a reducing agent. The type of reducing agent and reaction conditions used in this reaction are the same as those for removing the aralkyl group, which is the protecting group R ³ ′ for the carboxyl group, as described above, and therefore the protecting group R ³ ′ for the carboxyl group is also removed at the same time. You can also. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, if the liquid nature of the reaction mixture is near neutral, then the diamond ion
Subject it to column chromatography using a porous adsorption resin such as HP20AG (manufactured by Mitsubishi Kasei Corporation), separate the portion where the target compound is eluted, freeze-dry it, and if necessary use a conventional method such as recrystallization. It can be obtained by further purification by reprecipitation method or the like. The 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivative of the present invention having the general formula () is a compound that exhibits excellent antibacterial activity. When measured by the dilution method, for example, Staphylococcus aureus,
Gram-positive bacteria such as Bacillus subtilis, Escherichia coli, Shigella,
It showed activity against a wide range of pathogenic bacteria, including Gram-negative bacteria such as Klebsiella pneumoniae, M. aeruginosa, and Pseudomonas aeruginosa. Such compounds are therefore useful as antibacterial agents to treat bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration via intravenous injection, intramuscular injection, etc. The dosage varies depending on age, body weight, symptoms, etc., as well as the mode of administration and frequency of administration, but the usual dose for adults is about 250 to 3000 mg per day, once or divided into several doses. Next, the present invention will be explained in more detail with reference to Examples. Example 1 (a) (3S,4R)-3-[(1'R)-1'-t-butyldimethylsilyloxy]ethyl-4-[3'-(p-
Nitrobenzyloxycarbonylaminoacetoxy)-2'-oxo]propyl-azetidine-
2-on (2) Iodomethylketone compound (1) (1g, 2.43
mmol) of dry dimethylformamide (20 ml)
N-p-nitrobenzyloxycarbonylglycine (0.68 g, 2.67 mmol) and triethylamine (0.27 g, 2.67 mmol) were added to the solution at room temperature (20° C.) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (500 ml), water (twice) and sodium bicarbonate aqueous solution (two times).
The mixture was washed with saline (1 time) and brine (1 time), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residual oil was subjected to rabbit chromatography on silica gel (90 g) eluting with ethyl acetate. As a result, 0.78 g (59
%) was obtained. NMR δppm (CDCl ₃ ) 0.05 (6H, s, Dimethy1) 0.86 (9H, s, t・Buty1) 1.20 (3H, d, J=6.0Hz, CH ₃ ) 2.6-2.95 (3H, m, 3-H,
CH ₂ COCH ₂ OCO) 4.10 (1H, d, J=6.0Hz, CH ₂ NH) 3.8~4.4 (2H, m, 4-H, CH ₃ CH-) 4.72 (2H, s, CH ₂ COCH ₂ OCO) 5.20(2H,s,

[Formula]) 5.80 (1H, t, J=6.0Hz, CH ₂ NH) 6.40 (1H, bs,

[Formula]) 4.48 (2H, d, J=9.0Hz,

[Formula]) 8.18 (2H, d, J = 9.0Hz,

[Formula]) (b) (3S,4R)-3-[(1'R)-1'-t-butyldimethylsilyloxy]ethyl-1-(1'-hydroxy-1'-p-nitrobenzyloxy carbonyl)methyl-4-[3'-(p-nitrobenzyloxycarbonylaminoacetoxy)-2'-oxo]propylazetidin-2-one (3) p-Nitrobenzylglyoxylate hydrate (0.65 g, 2.88 mmol) in dry benzene (200
ml) The solution was refluxed using a dehydration tube (Dean-Stark apparatus) and simultaneously concentrated until the benzene amount was about 15 ml. Next, a solution of aminoacetoxy compound (2) (0.78 g, 1.44 mmol) in dry benzene (1 ml) was added to this solution, and the mixture was refluxed overnight (16 hours). The solvent was evaporated from the reaction mixture under reduced pressure, and the residual oil was subjected to rabbit chromatography using silica gel (150 g) to extract p-nitrobenzylglyoxy with a mixture of isopropyl ether-ethyl acetate (2-1). rate was eluted. The solvent was then converted to ethyl acetate to obtain 0.86 g (80%) of the desired hydroxy compound (3). NMR δppm (CDCl ₃ ) 0.05 (6H, s, Dimethy1) 0.84 (9H, s, t-Buty1) 1.20 (3H, d, J=5.0Hz, CH ₃ CH-) 2.8-3.1 (3H, m, 3- H,
CH ₂ COCH ₂ OCO) 3.9 to 4.5 (4H, m, CH ₃ CH−, 4−H,
COCH ₂ NH) 4.74 (2H, bs, CH ₂ COCH ₂ OCO) 5.15~5.7 (6H, m,

【formula】

【formula】

【formula】) 7.4~7.7 (4H, m,

[Formula]) 8.25 (4H, d, J = 8.0Hz,

[Formula]) (c) (3S,4R)-3-[(1'R)-1'-t-butyldimethylsilyloxy]ethyl-4-[3'-(p-
Nitrobenzyloxycarbonylaminoacetoxy)-2'-oxo]propyl-1-(1'-p-
Nitrobenzyloxycarbonyl-1-triphenylphosphonylidene)methyl-azetidine-
2-on (4) In a solution of hydroxy compound (3) (0.86 g, 1.15 mmol) in dry tetrahydrofuran (19 ml),
Cool to -15℃ under argon atmosphere and add 2,6
- adding lutidine (0.37 g, 3.44 mmol);
Then, a solution of thionyl chloride (0.41 g, 3.44 mmol) in dry tetrahydrofuran was added, and the mixture was stirred at the same temperature for 20 minutes. After diluting the reaction mixture with dry benzene (50 ml), the insoluble portion was removed using Celite, and the Celite was washed twice with a small amount of benzene. The liquid reaction mixture was then evaporated under reduced pressure at room temperature.
Azeotroping twice with dry benzene (5 ml) removed tetrahydrofuran, thionyl chloride and 2,6-lutidine to give a crude mixture of chloro compounds. This evaporation residue was added to dry tetrahydrofuran (13
ml), triphenylphosphine (0.6 g, 2.3 mmol) and 2,6-lutidine (0.25 g, 2.3 mmol) were added, and the solution was heated under an argon atmosphere at a bath temperature of 45°C.
Stir for hours. The reaction mixture was diluted with ethyl acetate (120ml) and
Washed with brine and dried over magnesium sulfate. The solvent and 2,6-lutidine were evaporated under reduced pressure at a bath temperature of 30°C, and the residual oil was subjected to rabbit chromatography using silica gel (115 g) and eluted with benzene-acetone (75-25). . As a result, the target phosphoranylidene compound (4) was 0.75
g (66%) was obtained. At this time, a carbapenem compound (4') (0.11 g, 13%) in which the phosphoranylidene compound underwent a thermal cyclization reaction was also obtained. (d) (3S,4R)-3-[(1′R)-1′-hydroxy]
Ethyl-4-[3'-(p-nitrobenzyloxycarbonylaminoacetoxy)-2'-oxo]
Propyl-1-(1'-p-nitrobenzyloxycarbonyl-1'-triphenylphosphonylidene)methyl-azetidin-2-one (5) To a solution of phosphoranylidene compound (4) (0.75 g) in methanol (78 ml) was added 10% hydrochloric acid (31
ml), stirred at the same temperature for 30 minutes, and then heated to room temperature (23 ml).
℃) for 11 hours. Add ethyl acetate (50 ml) to the reaction mixture, add saturated sodium bicarbonate (190 ml, (2 eq)) under ice cooling to bring the pH to around -8, then extract with ethyl acetate (3 times) and wash with brine. After that, it was dried over magnesium sulfate. The solvent was evaporated under reduced pressure at a bath temperature of 35 DEG C. and the residual oil was subjected to rapid chromatography on silica gel (63 g), eluting with cyclohexane-acetone (35-65). As a result, 0.54 g (81%) of the desired hydroxyethyl compound (5) was obtained. IR, ν _nax (CHCl ₃ ): 1740, 1630, 1608, 1520 cm ^-1 NMR δppm (CDCl ₃ ) 1.04 (3H, d, J=6.0Hz, CH ₃ ) 2.3-3.4 (4H, m, CH ₂ COCH ₂ OCO, 3-
H, OH) 3.7-4.3 (4H, m, OCOCH ₂ NH, 4-H,
CH ₃ CH−) 4.6 to 4.9 (2H, m, CH ₂ COCH ₂ OCO) 5.22 (2H, be,

[Formula]) 6.7 (1H, d, J = 8Hz, NH) 7.58 (15H, bs, = PPh ₃ ) 7.85 (4H, d, J = 8.0Hz,

[Formula]) 8.22 (4H, d, J = 8.0Hz,

[Formula]) (e) p-nitrobenzyl (5R, 6S)-3-(p-
Nitrobenzyloxycarbonylaminoacetoxy)methyl-6-[(1′R)-1′-hydroxy]ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6) Dry benzene (250 ml) was refluxed using a dehydration tube and concentrated to about 180 ml. A catalytic amount of hydroquinone (1 mg) and a solution of hydroxyethylphosphoranylidene compound (5) (0.54 g) in dry tetrahydrofuran (2 ml) was added to the mixture, and the mixture was refluxed for 2.5 hours under an argon atmosphere. The benzene was evaporated from the reaction mixture under reduced pressure at room temperature and the residual oil was subjected to rapid chromatography on silica gel (81 g) and eluted with cyclohexane-acetone (4-6). As a result, 0.28g of the target carbapenem compound (6) was obtained.
(77%) obtained. IR ν _nax (CHCl ₃ ) 1780, 1730, 1605, 1520 cm ^-1 NMR δppm (CDCl ₃ ) 1.30 (3H, d, J=6.0Hz, CH ₃ ) 2.6-3.4 (4H, m, 4-H ₂ , 6 -H, OH) 3.9 to 4.5 (4H, m, CH ₂ OCOCH ₂ NH, 5-
H, CH ₃ CH−) 5.0 to 5.7 (6H, m,

【formula】

【formula】

[Formula]) 7.65 (4H, d, J=8.0Hz,

[Formula]) 7.4~7.6 (1H, m, NH) 8.25 (4H, d, J=8.0Hz,

[Formula]) (f) (5R,6S)-3-aminoacetoxymethyl-
6-[(1′R)-1′-hydroxy]ethyl-7-oxo-1-azabicyclo[3.2.0]hepta-2
-ene-2-carboxylic acid (7) To a solution of carbapenem compound (6) (0.185 g) in tetrahydrofuran (14 ml) were added phosphate buffer (14 ml) of PH-7.0 and 10% Pd-C catalyst (0.092 g), and the mixture was heated at room temperature (15° to 15°) in a hydrogen atmosphere. The mixture was stirred for 4 minutes at 20°C. Paldium-carbon was removed from the reaction mixture using Celite, and the Celite was washed with phosphate buffer (20 ml) of pH 7.0.Then, the solution was washed three times with ethyl ether and diluted in half. Concentrated. This concentrate is used as a polymer (CHP20P: Mitsubishi Kasei)
The mixture was subjected to chromatography (wet 80ml) and eluted with water, and the ninhydrin-positive components were collected and lyophilized. As a result, 0.041 g of the desired carbapenem compound (7) was obtained as a pale yellow powder. At this time, a methyl compound (8) in which the 3-position was hydrogenolyzed was also obtained. NMR δppm (D ₂ O) DSS 1.36 (3H, d, J = 6Hz, CH ₃ ) 2.8 ~ 3.2 (2H, m, 4-H ₂ ) 3.3 ~ 3.7 (1H, m, 6-H) 4.0 ~ 4.5 ( 4H, m, CH ₂ NH ₃ ⁺ , 5-H,
CH ₃ CH−) 5.05, 5.45 (2H, AB−q, J=
CH ₂ OCOCH ₂ ) Example 2 (a) (3S,4R)-3-[(1′R)-1′-tert-butyldimethylsilyloxy]ethyl-4-〓3′-
[β-(p-nitrobenzyloxycarbonylamino)propionyloxy]-2'-oxopropyl-azetidin-2-one (9) By reacting iodomethyl ketone (1) with N-p-nitrobenzyloxycarbonyl-β-alanine in exactly the same manner as in Example 1(a), 67%
The desired product (9) was obtained in a yield of . NMR δ (CDCl ₃ ) 0.07 (6H, s) 0.88 (9H, s) 1.41 (3H, d, J=6Hz) 2.7~3.1 (5H, m, C ₃ −H, C ₄ −CH ₂ CO,
OCOCH ₂ ) 3.5-4.0 (2H, m, CH ₂ NHCO ₂ Ar) 4.0-4.6 (2H, m, C ₄ -H, C ₃ -CH) 4.88 (2H, s, COCH ₂ OCO) 5.37 (2H, s ，

[Formula]) 5.75 (1H, broad, CH ₂ NHCO ₂ Ar) 6.33 (1H, bs, NH) 7.66 (2H, d, J = 9Hz) 8.37 (2H, d, J = 9Hz) (b) (3S, 4R)-3-[(1′R)-1′-tert-butyldimethylsilyloxy]ethyl-1-(1′-hydroxy-1′-p-nitrobenzyloxycarbonyl)methyl-4-〓3′- [β-(p-nitrobenzyloxycarbonylamino)propionyloxy]-2'-oxopropyl-azetidin-2-one (10) By treating the compound (9) obtained above in exactly the same manner as in Example 1(b), the desired compound (10) was obtained with a yield of 42%. (c) (3S,4R)-3-[(1′R)-1′-tert-butyldimethylsilyloxy]ethyl-4-〓3′-
[β-(p-nitrobenzyloxycarbonylamino)propionyloxy]-2'-oxopropyl-1-(1'-p-nitrobenzyloxycarbonyl-1'-triphenylphosphonylidene)methyl-azetidine-2 −On (11) By treating the above compound (10) in exactly the same manner as in Example 1(c), the desired compound (11) was obtained with a yield of 57.5%. (d) (3S,4R)-3-[(1′R)-1′-hydroxy]
Ethyl-4-〓3'-[β-(p-nitrobenzyloxycarbonylamino)propionyloxy]-2'-oxo〓propyl-1-(1'-p-nitrobenzyloxycarbonyl-1'-triphenylphospho nylidene) methyl-azetidine-2
−On (12) By treating the above compound (11) in exactly the same manner as in Example 1(d), the target compound (12) was obtained in good yield. (e) p-Nitrobenzyl (5R, 6S)-6-[(1′R)
-1'-hydroxy]ethyl-3-[β-(p-
Nitrobenzyloxycarbonylamino)propylyloxy]mer-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (13) By treating the compound (12) in exactly the same manner as in Example 1(e), the target compound (13) was obtained from compound (11) in a yield of 78% in two steps. IR (Nujol) ν _nax 1775, 1745, 1715, 1694 cm ^-1 NMR δ (CD ₃ COCD ₃ ) 1.25 (3H, d, J = 6Hz) 2.5 ~ 3.8 (7H, m) 3.9 ~ 4.5 (2H + 1H, m) 5.05 (1H, m) 5.17 (2H, s) 5.24, 5.52 (2H, AB-q, J = 14Hz) 6.55 (1H, bs, NH) 7.50~8.27 (8H, m) (f) (5R, 6S) - 6-[(1′R)-1′-hydroxy]ethyl-3-(β-aminopropionyloxy)methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (14) By treating the compound (13) in exactly the same manner as in Example 1(f), the target compound (14) was obtained at 26
% yield. At this time, compound (8) in which the 3-position was hydrogenolyzed and became a methyl group was similarly produced as a by-product. Physical constants of (14) NMR δ (D ₂ O) 1.50 (3H, d, J = 6.5Hz) 2.8 to 3.35 (4H, m) 3.35 to 3.8 (3H, m) 3.9 to 4.7 (2H, m) 5.0 Physical constants of ~5.7 (2H, m) (8) NMR δ (D ₂ O) 1.36 (3H, d, J = 6Hz) 2.08 (3H, t, J = 1Hz) 2.8 ~ 3.1 (2H, dq, C ₃ −H ₂ ) 2.2 to 2.3 (1H, m) 3.9 to 4.5 (2H, m)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents an alkyl group having a hydroxyl group as a substituent, R ² represents an alkyl group having an amino group as a substituent, and R ³ represents a hydrogen atom or a carboxyl group that is eliminated under physiological conditions. 7-oxo-1-azabicyclo [3.2.0] with
Hept-2-ene-2-carboxylic acid derivatives and pharmacologically acceptable salts thereof. 2 General formula (In the formula, R ¹ ′ represents an alkyl group having an optionally protected hydroxyl group as a substituent, R ² ′ represents an alkyl group having a protected amino group as a substituent, and R ³ ′ represents a carboxyl group. indicates the protecting group of
R ⁷ represents an alkyl group or an aryl group. ) by heating a phosphorus-ylide compound having the general formula (In the formula, R ¹ ′, R ² ′ and R ³ ′ have the same meaning as described above.) Then, if desired, the obtained compound is treated with a carboxyl group protecting group R ³ ′ and the corresponding protecting groups contained in R ¹ ′ and R ² ′ are removed to restore the hydroxyl group and the amino group. (In the formula, R ¹ represents an alkyl group having a hydroxyl group as a substituent, R ² represents an alkyl group having an amino group as a substituent, and R ³ represents a hydrogen atom or a carboxyl group that is eliminated under physiological conditions. 7-oxo-1-azabicyclo [3.2.0] with
A method for producing a hept-2-ene-2-carboxylic acid derivative and a pharmacologically acceptable salt thereof.