KR19990065726A - 3-substituted-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate compound and preparation method thereof - Google Patents

Abstract

The present invention provides a 3-substituted-7-oxo-1-azabicyclo [3,2,0] hept-2 of Formula 1, which can be used as an important intermediate for the preparation of a carbapenem antibiotic, a nonclassical beta-lactam antibiotic. -En-2-carboxylate compound and method for producing the same.

In the above formula,

R ₂ is hydrogen or lower alkyl,

R ₃ is a carboxy protector,

R ₄ and R ₅ are the same as or different from each other, and each independently represent lower alkyl.

Description

3-substituted-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate compound and preparation method thereof

The present invention provides a 3-substituted-7-oxo-1-azabicyclo [3,2,0] hept-2 of Formula 1, which can be used as an important intermediate for the preparation of a carbapenem antibiotic, a nonclassical beta-lactam antibiotic. -En-2-carboxylate compound and method for producing the same.

[Formula 1]

In the above formula,

R ₂ is hydrogen or lower alkyl,

R ₃ is a carboxy protector,

R ₄ and R ₅ are the same as or different from each other, and each independently represent lower alkyl.

The compound of Formula 1 may be usefully used as an intermediate in the preparation of a carbapenem antibiotic, which is a non-classical beta-lactam antibiotic represented by the following formula (2).

In the above formula,

R ₂ is hydrogen or a methyl group,

R ₆ is a pharmaceutically acceptable substituent,

X is hydrogen or a metal ion that forms a pharmaceutically acceptable salt such as sodium, potassium, calcium.

The compound of Formula 2 may be useful as an antibiotic for the treatment of bacterial infectious diseases in humans and animals as Staphylococcus aureus , Streptococcus pyogenes , Bacillus subtilis Gram-positive bacteria and Escherichia coli, Pseudomonas (Pseudomonas), Proteus know going (Proteus morganii), Serratia marcescens (Serratia), keulrep non-classical beta showing excellent antibacterial activity against Gram-positive bacteria such as Ella (Klebsiella), such as (Bacillus subtilis) It is a lactam antibiotic.

Here, the expression non-classical beta-lactam is a carbon source instead of sulfur in the 3 or 4 position of the chemical formula, unlike conventional penicillin and cephalosporin-based betalactam antibiotics, which can be represented by the following formulas (3) and (4), as shown in the structure of formula (2). It means that a person exists.

In the above formula,

R ₇ and R ₈ are substituted amides,

R ₉ is a pharmaceutically acceptable substituent,

Y is a metal ion that forms hydrogen or a pharmaceutically acceptable salt.

Unlike conventional penicillin and cephalosporin-based antibiotics represented by Formula 3 and Formula 4 can obtain and use intermediates having penicillin and cephalosporin nucleus through fermentation and purification of microorganisms, carbafe Nem-based antibiotics can obtain thienamycin with the carbapenem nucleus from the soil microorganism Streptomyces cattleya , but in the case of separation from the streptomyces cattleya, the fermentation yield is low for practical industrial purposes. Since it cannot be used as a raw material, it should be obtained through a synthetic method.

Until now, as an intermediate for the preparation of carbapenem, a compound represented by the following formula (5) has been used, and its manufacturing method known to date is Merck Co., Inc., which is described in US Pat. No. 4,994,568. It is only.

In the above formula,

R _a , R _b , R _c and R _d are each independently hydrogen, alkyl, aryl, aralkyl, and the like.

R _e represents a pharmaceutically acceptable ester moiety, a leaving protecting group, or a cation of an alkali or alkaline earth metal.

As described in U.S. Patent No. 4,994,568, the compound of Formula 5 is prepared by the method shown in the following scheme.

According to the method for preparing the compound of Formula 5 shown in Scheme 1, first, an acetyloxybutadiene derivative obtained by using β, β-dimethylglutaric acid or β-methylglutaric acid as a starting material is reacted with chlorosulfonyl isocyanate. The product is then hydrolyzed to give 4- (1-substituted-2-acetoxyvinyl) azetidin-2-one, and then the product is reduced to 4- (1-substituted-2-acetoxyethyl Azetidin-2-one was obtained and the product was hydrolyzed and then reacted with 2,2-dimethoxypropane in the presence of a catalyst such as borontrifluoride etherate to give a product having an azabicyclooctane structure. Next, the hydroxyethyl group is introduce | transduced here using n-butyllithium, acetaldehyde, etc. At this time, the stereochemically undesirable form is converted into a form having a stereochemical structure of the preferred form by using k-selectoride (potassium tri-butylborohydride), followed by several steps, Azetidinonic acid is obtained and 2-oxacarbapenem compound of the formula (5) is obtained by extending the chain and undergoing a diazo reaction according to the known Masamune method. The resulting 2-oxacarbapenem compound of formula 5 is reacted with chlorodiphenylphosphate to introduce a diphenylphosphoryl leaving group for use in the preparation of the carbapenem antibiotic of formula 2 to prepare a compound of formula 7 which is a carbapenem intermediate .

[Formula 5]

In the above, R _a , R _b , R _c , R _d and R _e are as defined above.

However, the above method has a disadvantage in that the process is very long, industrial use is impossible, operation of each reaction step is very difficult, and there are many isomers which cannot be used stereochemically, so that separation and purification thereof are difficult and yield is low. In particular, the compound of Formula 7, which is a major intermediate of the carbapenem antibiotic, has a low condensation yield because the reaction does not proceed when the reaction is condensed with a thiol derivative having a pharmaceutically effective group as a substituent in a subsequent reaction, and the diphenyl phosphate is released. Because of many side reactions with the polyyl group, the process needs to be purified using column chromatography using silica gel.

The present inventors have conducted extensive research over a long period of time to improve the problems described above and to develop a new carbapenem intermediate having a rational leaving group with high purity and high yield by a simple and short process. As a new and effective carbapenem intermediate meeting the same purpose, the compound of formula 1 was developed and the present invention was completed.

Accordingly, the present invention relates to a compound of formula 1 which can be used as an important intermediate for the preparation of a carbapenem antibiotic which is a nonclassical beta-lactam antibiotic.

[Formula 1]

In the above formula,

R ₂ is hydrogen or lower alkyl,

R ₃ is a carboxy protector,

R ₄ and R ₅ are the same as or different from each other, and each independently represent lower alkyl.

In the definitions for substituents used herein, the term loweralkyl generally means a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl and the like. The term hydroxy protecting group means a hydroxy protecting group commonly used in the field of carbapenem, preferably t-butyldimethylsilyl or triethylsilyl and the like, and the term carboxy protecting group refers to carboxy commonly used in the field of carbapenem. Protecting groups, preferably p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl, aryl and the like.

Preferred compounds of formula (1) according to the invention represent that R ₂ represents hydrogen or methyl, R ₃ represents p-nitrobenzyl, p-methoxybenzyl or aryl, and R ₄ and R ₅ are each methyl, ethyl, isopropyl Or a compound representing n-propyl.

Particularly preferred compounds of formula (1) according to the invention are compounds in which R ₂ represents methyl, R ₃ represents p-nitrobenzyl and R ₄ and R ₅ each represent methyl.

The present invention also relates to a process for preparing the compound of formula (I).

According to the method of the present invention, the compound of formula 1 may be prepared by reacting a compound of formula 12a with a triazine derivative of formula 13 below.

In the above formula

R ₂ , R ₃ , R ₄ and R ₅ are as defined above,

Hal represents a halogen atom such as chloro, bromo or iodo.

The process according to the invention can be represented by the following scheme 2.

As shown in Scheme 2, according to the method of the present invention, a compound of formula 12a is reacted with a triazine derivative of formula 13 to introduce various triazinyl groups as leaving groups to obtain the desired carbapenem intermediate compound of formula 1 . Triazine compounds of formula 13 that may be suitably used for the introduction of leaving groups in this reaction include, for example, 1-chloro-3,5-dimethoxy-2,4,6-triazine, 1-chloro-3 , 5-diethoxy-2,4,6-triazine, 1-bromo-3,5-dimethoxy-2,4,6-triazine, 1-chloro-3,5-diisopropoxy-2 , 4,6-triazine, 1-iodo-3,5-dimethoxy-2,4,6-triazine, 1-iodo-3,5-diethoxy-2,4,6-triazine, 1-bromo-3,5-dimethoxy-2,4,6-triazine and the like, particularly preferably 1-chloro-3,5-dimethoxy-2,4,6-triazine use. In this reaction, the triazine derivative of formula 13 is used in a ratio of 0.5 to 20 equivalents, more preferably 0.5 to 10 equivalents, most preferably 1 to 2 equivalents, relative to 1 equivalent of the compound of formula 12a.

This reaction can be carried out in the presence of a base. Examples of bases which can be preferably used for this purpose include triethylamine, diethylamine, diisopropylethylamine, pyridine, lutidine, DBU (1,8-diazabicyclo [5,4,0] undes- 7-ene), DBN (1,5-diazabicyclo [4,3,0] non-5-ene), N-methylmorpholine, morpholine, aniline or 4-methylaminopyridine, and the like. Even more preferably diisopropylethylamine, pyridine, triethylamine, morpholine or N-methylmorpholine, most preferably pyridine, morpholine or N-methylmorpholine is used. The base is used in this reaction in a ratio of 0.5 to 20 equivalents, more preferably 1 to 4 equivalents, relative to 1 equivalent of the compound of formula 12a.

The reaction is also generally carried out in the presence of a solvent. As the solvent that can be used for this purpose, any solvent that does not adversely affect the reaction can be used, preferably dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, tetramethylene sulfone, One or more solvents selected from the group consisting of hexamethylphosphoramide and the like are used, and even more preferably, acetonitrile, tetrahydrofuran or dimethylformamide is used alone or a mixed solvent thereof is used. This reaction is preferably carried out under anhydrous conditions.

The reaction temperature is not particularly limited, but is generally in the range of -50 ° C to 100 ° C, preferably -20 ° C to 50 ° C, even more preferably -20 ° C to 40 ° C, and most preferably 0 ° C to 15 ° C. The reaction is carried out at a temperature in the range. The reaction time is generally a few minutes to several tens of hours, preferably 0.5 to 30 hours, even more preferably 0.5 to 10 hours, most preferably 1 to 4 hours.

The compound of formula 12a used as a starting material in the process of the present invention is prepared by (a) reacting a compound of formula 8 with a malonic acid derivative of formula 15 to obtain a compound of formula 9, and (b) a compound of formula 9 From the hydroxy protecting group to give a compound of formula 10, (c) reacting the compound of formula 10 with an organic azide compound to obtain a compound of formula 11, and (d) It can manufacture by ring-closure reaction in presence of a catalyst.

[Formula 12a]

In the above formula

R ₂ and R ₃ are each as defined above,

R ₁ is a hydroxy protecting group.

The compound of formula 12a in keto form obtained in the reaction may exist in the enol form of formula 12b as a keto-enol tautomer. In the reaction of Scheme 2 according to the present invention, the obtained keto compound of Formula 12a and the enol compound of Formula 12b are used as they are without separation or separation.

The above method can be represented by the following scheme 3.

As shown in Scheme 3, first, in the first step reaction, the azetidinonic acid of formula (8) is converted to the malonic acid of formula (15) according to a method known as Masamune method (see Tetrahedron Letter, 30 (11), 1345, 1989). A derivative such as magnesium p-nitrobenzylmalonate [Mg (OCOCH ₂ CO ₂ PNB) ₂ ] was reacted to extend the side chain at the C-4 position of azetidinone to obtain a compound of formula 9. The azetidinonic acid of the formula (8) used as a starting material here can be purchased commercially as a known compound (Japan: Takasago company, soda company). This reaction is carried out in the presence of an activator capable of activating the acid group of the azetidinone carboxylic acid of formula 8 in the form of an activating ester, an acid halide, and the like. Activatable 1,1-carbonyldiimidazole, 1-hydroxybenzotriazole, 1-mercaptobenzothiazole, diphenylchlorophosphate, diethylchlorophosphate, diethylchlorothiophosphate, 1-chloro-3 , 5-dimethoxy-2,4,6-triazine and the like, or thionyl chloride, trichlorooxyphosphate, pentachlorophosphate and the like which are activated in the form of an acid halide may be used. As the activator, preferably 1,1-carbonyldiimidazole, diphenylchlorophosphate, diethylchlorophosphate, 1-chloro-3,5-dimethoxy-2,4,6-triazine and the like are used. More preferably 1,1-carbonyldiimidazole or 1-chloro-3,5-dimethoxy-2,4,6-triazine can be used. In the present reaction, the activator is used in a ratio of 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, even more preferably 0.5 to 2 equivalents, relative to 1 equivalent of the starting material of the formula (8).

The malonic acid derivative of the formula (15) used as a reactant in this reaction is a known compound, and may be prepared and used using a commercially available product or a method similar to the known method. For example, magnesium p-nitrobenzyl malonate can be used commercially (Tokyo Kasei Chemical Co., Ltd.), or can be manufactured and used by reaction of magnesium ethoxide and p-nitro benzyl malonate. The malonic acid derivative is used in a ratio of 0.1 to 30 equivalents, preferably 0.5 to 20 equivalents, and even more preferably 1 to 10 equivalents, relative to 1 equivalent of the starting material of the formula (8).

The reaction is carried out in the presence of a base, examples of bases which may be used for this purpose include triethylamine, diisopropylethylamine, pyridine, morpholine, N-methylmorpholine, 2,6-lutidine, collidine , Organic bases such as imidazole, DBU, DBN, or inorganic bases such as potassium-t-butoxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium carbonate, preferably imidazole, morpholine, N- Methylmorpholine, pyridine and the like are used. The base is used in a ratio of 0.5 to 10 equivalents, more preferably 0.8 to 2 equivalents, relative to 1 equivalent of the compound of formula 8. The reaction is also generally carried out in the presence of a solvent which does not adversely affect the reaction, and examples of solvents which may be used for this purpose include dichloromethane, chloroform, dichloroethane, tetrahydrofuran, acetonitrile, dioxane, nitromethane, dimethyl Formamide, dimethylacetamide, dimethylsulfoxide, tetramethylenesulfone, hexamethylphosphoramide and the like, even more preferably tetrahydrofuran, acetonitrile, dimethylformamide or dimethylacetamide.

The reaction is preferably carried out in the range of -30 ° C to 100 ° C, even more preferably in the range of -10 ° C to 60 ° C, most preferably in the range of 15 ° C to 30 ° C. The reaction time is generally from minutes to tens of hours, preferably from 3 minutes to 48 hours, even more preferably from 3 minutes to 24 hours, most preferably from 10 minutes to 20 hours.

The compound of formula 9 obtained in the reaction of the first step is hydrolyzed under acid conditions in the second step to remove the hydroxy protecting group to obtain the compound of formula 10. Acids that may be used in the reaction include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, and the like, preferably hydrochloric acid, sulfuric acid or acetic acid, and more preferably concentrated hydrochloric acid or dilute hydrochloric acid. do.

The second stage reaction is generally carried out in the presence of a solvent which does not adversely affect the reaction, and solvents which can be used for this purpose include methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacet Amide, water, and the like may be used alone, or a mixed solvent of two or more solvents thereof may be used. Preferably, water, acetone, methanol, tetrahydrofuran or acetonitrile, and more preferably water, methanol or tetrahydrofuran are used alone or in combination of two or more thereof.

The reaction is generally at a temperature of -50 ° C to 60 ° C, preferably at a temperature of -20 ° C to 50 ° C, even more preferably at a temperature of 0 ° C to 30 ° C, and most preferably at a temperature in the range of 15 ° C to 25 ° C. Perform on The reaction time is generally in the range of several tens of hours, preferably 10 minutes to 5 hours, even more preferably 30 minutes to 2 hours, and most preferably 30 minutes to 1.5 hours.

The compound of formula 10 obtained in the second stage reaction is prepared in the third stage reaction by reacting with a suitable organic azide compound to prepare a diazo compound of formula 11. The organic azide compound in this reaction is preferably p-toluenesulfonyl azide, p-carboxybenzenesulfonyl azide, methanesulfonyl azide, benzenesulfonyl azide, p-trifluoromethanesulfonyl azide, p-nitro Benzenesulfonyl azide and the like can be used, even more preferably p-toluenesulfonyl azide, p-trifluoromethanesulfonyl azide is used, and most preferably p-toluenesulfonyl azide is used. The organic azide compound is used in a ratio of 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, most preferably 1 to 2 equivalents, relative to 1 equivalent of the compound of formula 10.

The third stage reaction is carried out in the presence of a base. Bases that can be used for this purpose are preferably triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, lutidine, collidine, DBU, DBN, aniline, diethylamine and the like. More preferably, triethylamine, diisopropylethylamine, pyridine and the like are used. The amount of base used in this reaction is suitably in a ratio of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, and even more preferably 1 to 2 equivalents, based on 1 equivalent of the compound of formula 10.

The reaction is generally carried out in the presence of a solvent which does not adversely affect the reaction, and examples of the solvent which can be preferably used for this purpose include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, tetrahydrofuran, dioxane And the like, and even more preferably tetrahydrofuran, acetonitrile and the like are included. The solvent most preferably used in this reaction is acetonitrile. The reaction time is generally 0.5 to 20 hours, preferably 0.5 to 10 hours, even more preferably 1 to 4 hours. The reaction temperature is generally in the range of -20 ° C to 100 ° C, preferably -10 ° C to 50 ° C, and most preferably 15 ° C to 30 ° C.

The compound of formula 11 produced in the third step reaction can be subsequently cyclized in the presence of a metal catalyst in the fourth step to obtain the compound of formula 12a. Examples of metal catalysts that can be used for this purpose include bis (acetylaceto) copper (II) [Cu (acac) ₂ ], bis (acetylaceto) palladium (II) [Pd (acac) ₂ ], palladium chloride, palladium acetate , Rhodium acetate, copper powder and the like, and more preferably, bis (acetylaceto) palladium (II) [Pd (acac) ₂ ], palladium acetate or rhodium acetate, most preferably rhodium acetate. The amount of the catalyst used in this reaction is suitably in the range of 0.1 to 100 mol%, preferably 1 to 50 mol%, most preferably 5 to 10 mol% with respect to 1 equivalent of the compound of the formula (11). . The metal catalyst used in the reaction is removed using a Pyrex filter after the reaction.

This reaction is generally carried out in the presence of a solvent which does not adversely affect the reaction, and solvents which may be preferably used for this purpose include ethyl acetate, ether, tetrahydrofuran, dioxane, acetonitrile, pentane, hexane, heptane, There is one solvent selected from the group consisting of octane, chloroform, dichloromethane, benzene, toluene, or a mixed solvent of two or more, and more preferably acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, hexane Or heptane, each alone, or a mixed solvent of two or more thereof. The reaction temperature is generally suitable to be in the range of 20 ° C to 150 ° C, preferably 20 ° C to 100 ° C, even more preferably 50 ° C to 80 ° C. The reaction time is generally several minutes to several tens hours, preferably 10 minutes to 10 hours, even more preferably 10 minutes to 5 hours, most preferably 20 minutes to 2 hours.

The desired compound of formula 12a, which is a starting material for the preparation of compound 1, produced in this reaction, is a keto-enol tautomer as described above. Thus, in this reaction, the product coexists as a compound of formula 12a in keto form with a compound of formula 12b in enol form. The compound of Formula 12a and the compound of Formula 12b thus produced may be used in the preparation of the compound of Formula 1 shown in Scheme 2 without undergoing a separate separation process.

The desired carbapenem intermediate compound of formula 1 prepared according to the method of the present invention can be used for the preparation of the carbapenem compound of formula 2, which is a pharmacologically useful antibiotic as described above. That is, for example, the intermediate compound of formula (1) is condensed with a mercapto reagent of formula (16) having a pharmacologically effective functional group in the presence of a base to give a compound of formula (14), and a protecting group common to the resulting compound of formula (14) By carrying out the elimination reaction, it is possible to finally prepare the desired carbapenem antibiotic.

Wherein R ₂ , R ₃ and R ₆ are as described above.

The method as described above for preparing the carbapenem antibiotic of Formula 2 from the compound of Formula 1 can be represented by the following Scheme 4.

The reaction is described in detail as follows. That is, the compound of formula 1 is first reacted with a mercapto compound of formula 16 having substituent R ₆ , a pharmacologically useful functional group, to give a compound of formula 14. Examples of mercapto reagents (HSR ₆ ) that can be used for this purpose include N-protected N, N-dimethylcarbamoylmercaptopyrrolidine, N-protected carbamoylethylthiomethylmercaptopyrrolidine, N-protected Hydroxyethylthiomethylmercaptopyrrolidine, N-protected carbamoylmethylcarbamoylethylthiomethylmercaptopyrrolidine, and the like, wherein the N-protecting group of the pyrrolidine nucleus is p-nitrobenzyloxycarbo Neyl, p-methoxybenzyloxycarbonyl, aryloxycarbonyl, o-nitrobenzyloxycarbonyl and the like can be used.

This reaction is generally carried out in a solvent which does not adversely affect the reaction. Examples of solvents which may be preferably used for this purpose include chloroform, dichloromethane, tetrahydrofuran, acetonitrile, dioxane, ethyl acetate, diethylformamide , Diethylacetamide, dimethyl sulfoxide, tetramethylenesulfone, hexamethylphosphoramide, and the like, and more preferably acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, hexamethylphosphoramide, and the like. This is used. The reaction can also be carried out preferably in the presence of a base, and bases which can be used for this purpose include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, DBU, DBN, morpholine, N Organic bases such as methyl morpholine and inorganic bases such as potassium carbonate, sodium hydroxide, sodium bicarbonate and potassium hydroxide. Even more preferably, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like are used as the base. The amount of base used in this reaction is suitably in the ratio of 0.5 to 20 equivalents, preferably 0.5 to 10 equivalents, even more preferably 1 to 2 equivalents, to 1 equivalent of the compound of formula (1).

The reaction temperature is generally -50 ^o C to 100 ^o C, preferably -40 ^o C to 50 ^o C, even more preferably at a temperature range of -30 ^o C to 25 ^o C. The reaction time is suitably in the range of 0.5 to 40 hours, even more preferably 0.5 to 10 hours, most preferably 0.5 to 4 hours.

The compound of formula (14) produced in this reaction finally removes the carboxy protecting group to give the desired carbapenem derivative of formula (2). This reaction is carried out by conventional protecting group removal methods, for example by hydrolysis or hydrogenation. Preferably, when the carboxy protecting group is p-nitrobenzyl or p-nitrobenzyloxycarbonyl group, aryl or aryloxycarbonyl group, p-methoxybenzyl or p-methoxybenzyloxycarbonyl, 5-10% of palladium These protecting groups can be removed using a / carbon (Pd / C), palladium hydroxide (Pd (OH) ₂ ) catalyst. In the case of performing the hydrogenation reaction for the removal of the protecting group, the hydrogen pressure is suitably 3 to 5 atmospheres, the reaction time is 0.5 to 4 hours, the reaction temperature is preferably in the range of 0 ℃ to 30 ℃. This protecting group removal reaction is carried out in the presence of a solvent, solvents of which purpose are tetrahydrofuran-water, acetone-water, acetonitrile-water, dioxane-water, ethanol-water, isopropyl alcohol-water-tetrahydro Combinations of furan and the like can be used.

Compounds of formula (2) wherein X is hydrogen prepared by such a process can be converted to the form of a metal salt in which X represents an alkali metal or alkaline earth metal cation by conventional methods.

The invention described above is described in more detail by the following examples, but the invention is not limited in any way by these.

Example 1

(3S, 4R) -3-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxo Propyl] -azetidin-2-one

After adding 1.4 g of azetidinonic acid and 0.91 g of N, N-carbonyldiimidazole to 60 ml of anhydrous acetonitrile, and stirring at room temperature for 30 minutes, magnesium p- prepared in advance from magnesium ethoxide and p-nitrobenzylmalonate 2.23 g of nitrobenzyl malonate were added and stirred at 60 ° C. for 18 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, 30 ml of ethyl acetate was added to the oily product to dissolve, and the mixture was washed with 1.0 N HCl, distilled water, 10% K ₂ CO ₃ and brine, respectively. The combined organic layers were dried over MgSO ₄ , concentrated under reduced pressure and column chromatography using ethyl acetate as eluent to afford the title compound.

Yield: 2.1 g (95%)

Melting point: 73 to 77 ° C (document 76 to 78 ° C)

IR (New sol) cm ^-1 : 1750, 1680

NMR (CDCl ₃ , 400 MHz): δ 0.06 (s, 6H, (CH ₃ ) ₂ Si), 0.78 (s, 9H, (CH ₃ ) ₃ -C-Si), 1.10 (d, J = 6.8 Hz, 3H , CH ₃ CH), 1.23 (d, J = 7.5 Hz, 3H, CH ₃ CHOH), 2.92 (dd, J = 2.8 and 3.5 Hz, 1H), 2.93 (m, 1H, CH ₃ CH), 3.66 (s , 2H, CH ₂ CO ₂ ), 3.96 (dd, J = 2.8 and 4.5 Hz, 1H, C-4), 4.20 (m, 1H, CH ₃ CHO), 5,30 (s, 2H, OCH ₂ ), 5.92 (s, 1H, NH), 7.56 8.26 (d, J = 8.0 Hz, 2H, Ph)

Example 2

(3S, 4R) -3-[(1R) -1-Hydroxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxopropyl] -azetidine- Preparation of 2-one

12 g of the compound prepared in Example 1 was dissolved in 120 ml of methanol, 13 ml of 6N hydrochloric acid was slowly added dropwise with stirring at 0 ° C., stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 2 hours. 30 ml of 0.1 N Na ₂ HPO ₄ · 2H ₂ O solution and 57 ml of 10% K ₂ CO ₃ solution were added dropwise to the reaction solution to neutralize the reaction pH from 7.0 to 8.0, and ethyl acetate (200 mL × 2) was added and extracted. The combined organic layers were washed with distilled water and brine, the organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give an oily product. Isopropyl ether was added to the obtained product for crystallization, followed by filtration and drying under reduced pressure to obtain the title compound.

[α] ²⁰ _D : -8.0 ^o (C = 2.5, CH ₂ Cl ₂ )

Melting Point: 90-92 ° C (Literature Value: 94-96 ° C)

NMR (CDCl ₃ , 400 MHz): δ 1.25 (d, J = 7.0 Hz, 3H, CH ₃ CH), 1.30 (d, J = 6.4 Hz, 3H, CH ₃ CHOH), 2.90 (dd, J = 2.5 and 6.5 Hz, 1H, H-3), 2.94 (quintet, J = 7.0 Hz, 1H, CHCH ₃ ), 3.66 and 3.68 (ABq, J = 15 Hz, 2H, CH ₂ CO ₂ PNB), 3.84 (dd, J = 2.5 and 7.0 Hz, 1H, H-4), 4.14 (m, 1H, CHOH), 6.10 (s, 1H, NH), 7.55 and 8.25 (d, J = 7.0 Hz, 2H, Ph)

Example 3

(3S, 4R) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl ] -Azetidin-2-one

2.5 g of the compound prepared in Example 2 was added to 50 ml of anhydrous acetonitrile to dissolve it, 2.4 g of p-toluenesulfonyl azide and 1.6 ml of triethylamine were added thereto, stirred at room temperature for 3 hours, and the reaction solution was concentrated under reduced pressure. I was. The residue was purified by silica gel column chromatography using ethyl acetate as eluent to afford the title compound.

Yield: 2.54 g (95%)

IR (KBr) cm ^-1 : 2140, 1750, 1650

[α] ²⁰ _D : -50.4 ^o (C = 2.5, CH ₂ Cl ₂ )

NMR (CDCl ₃ , 400 MHz): δ 1.22 (d, J = 6.0 Hz, 3H, CH ₃ CH), 1.32 (d, J = 6.0 Hz, 3H, CH ₃ CHCO), 2.38 (d, J = 3.2 Hz, 1H, CH ₃ CH), 2.92 (dd, J = 2.5 Hz and 7.5 Hz, 1H, H-3), 3.77 (quintet, J = 6.0 Hz, 2H, CHCH ₃ ), 3.86 (dd, J = 2.5 and 6.0 Hz, 1H, H-4), 4.15 (m, 1H, CHOH), 5.38 (s, 2H, CO ₂ CH ₂ ), 5.90 (s, 1H, NH), 7.57 and 8.30 (d, J = 6.6 Hz , 2H, Ph)

Example 4

p-nitrobenzyl (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -4-methyl-3,7-dioxo-1-azabicyclo [3,2,0] heptane- Preparation of 2-carboxylate

5.0 g of the compound prepared in Example 3 was added to 30 ml of 75% anhydrous ethyl acetate-hexane, followed by stirring for 30 minutes. After stirring, 15 mg of rhodium acetate was added thereto under stirring, and the mixture was refluxed for 1 hour, cooled to room temperature, and then It was filtered using. The filtrate was concentrated to afford the title compound as an oily product which was used for the next reaction without further purification.

Yield: 4.6 g (quantitative)

IR (CHCl ₃ ) cm ^-1 : 1750, 1690

[α] ²³ _D : +89.2 ^o (C = 2.5, CH ₂ Cl ₂ )

NMR (CDCl ₃ , 400 MHz): δ 1.23 (d, J = 6.0 Hz, 3H, CH ₃ CH), 1.39 (d, J = 6.0 Hz, 3H, CH ₃ CHCO), 2.80 (quintet, J = 6.0 Hz , 1H, CHCH ₃ ), 3.30 (dd, J = 2.5 Hz and 6.0 Hz, 1H, H-4), 4.21 (m, 1H, CHOH), 4.78 (s, 1H, COCHCO ₂ PNB), 5.38 (s, 2H, CO ₂ CH ₂ ), 5.90 (s, 1H, NH), 7.57 and 8.30 (d, J = 6.5 Hz, 2H, Ph)

Example 5

4-nitrobenzyl (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -4-methyl-3- (3,5-dimethoxy-2,4,6-triazinyl)- Preparation of Oxy-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate

To a solution of 30 ml of anhydrous tetrahydrofuran and 30 ml of acetonitrile, 1.85 g of the compound prepared in Example 4 was added to dissolve and cooled to -30 DEG C, followed by 1-chloro-3,5-dimethoxy-2,4, 1.2 g of 6-triazine and 2.28 ml of N-methylmorpholine were added dropwise and stirred at the same temperature for 1 hour. The reaction solution was stirred for 1 hour at -10 ° C and 2 hours at 0 ° C to terminate the reaction. The reaction solution was concentrated under reduced pressure to remove the solvent, and then extracted with ethyl acetate (30 mL × 2) and distilled water. The combined organic layers were washed with 1N hydrochloric acid, saturated NaHCO ₃ , brine and distilled water, and then dried over MgSO ₄ and concentrated under reduced pressure to give a crude product. Ethyl acetate / hexane (1: 1, v / v) was added. Silica gel column chromatography using the eluent gave the title compound.

Yield: 2.25 g (88%)

IR (CHCl ₃ ) cm ^-1 : 1750, 1650

NMR (CDCl ₃ , 400 MHz): δ 1.27 (d, J = 6 Hz, 3H, CH ₃ CH), 1.87 (s, 3H, CH ₃ CH), 3.10 (dd, J = 3.5 and 4.5 Hz, 1H, CH ₃ CHOH), 4.09 (s, 6H, OCH ₃ ), 4.30 (s, 1H, C-5, H), 5.21 (dd, J = 7.0 and 7.5 Hz, CH ₂ , ph), 5.57 (d, J = 3.5 Hz, 1H, C-6, H), 7.25, and 8.20 (d, J = 6.50 Hz, 2H, Ph)

Example 6

4-nitrobenzyl (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -4-methyl-3- (3,5-dimethoxy-2,4,6-triazinyl)- Preparation of Oxy-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate

Except for using 1.6 g of 1-bromo-3,5-dimethoxy-2,4,6-triazine in place of 1-chloro-3,5-dimethoxy-2,4,6-triazine The reaction was carried out according to the same method as in Example 5, to obtain 2.4 g (90%) of the title compound.

Example 7

4-nitrobenzyl (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -4-methyl-3- (3,5-dimethoxy-2,4,6-triazinyl)- Preparation of Oxy-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate

Except that 1.8 g of 1-iodine-3,5-dimethoxy-2,4,6-triazine is used instead of 1-chloro-3,5-dimethoxy-2,4,6-triazine. The reaction was carried out according to the same method as Example 5 to obtain 2.21 g (89%) of the title compound.

Intermediate compounds of formula (1) provided according to the present invention as described above are useful intermediates which can prepare the carbapenem antibiotic of formula (2) in high yield and high purity by a simple method without side reactions that have been a problem in the prior art methods. Compound.

Claims (8)

3-Substituted-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate derivative represented by Formula 1 below: [Formula 1] In the above formula, R ₂ is hydrogen or lower alkyl, R ₃ is a carboxy protector, R ₄ and R ₅ are the same as or different from each other, and each independently represent lower alkyl. The compound of claim 1, wherein R ₂ represents hydrogen or methyl, R ₃ represents p-nitrobenzyl, p-methoxybenzyl or aryl, and R ₄ and R ₅ are each methyl, ethyl, isopropyl or n-propyl A compound of formula 1 representing _3. A compound of formula 1 according to claim 2, wherein R ₂ represents methyl, R ₃ represents p-nitrobenzyl and R ₄ and R ₅ each represent methyl. A process for preparing a compound of formula 1 characterized by reacting a compound of formula 12a with a triazine derivative of formula 13: [Formula 1] [Formula 12a] [Formula 13] In the above formula, R ₂ is hydrogen or lower alkyl, R ₃ is a carboxy protector, R ₄ and R ₅ are the same as or different from each other, and each independently represent lower alkyl, Hal represents a halogen atom. The method of claim 4 wherein the reaction is carried out in the presence of a base. 6. The process of claim 5, wherein the reaction is carried out using N-methylmorpholine, morpholine or pyridine as base. The reaction according to claim 4, wherein the reaction is carried out in one or two or more solvents selected from the group consisting of dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, tetramethylenesulfone and hexamethylphosphoramide Performing. The process according to claim 4, wherein the reaction is carried out in the temperature range of -50 ^o C to 100 ^o C.