KR20070102254A - Process for the preparation of carbapenem intermediates - Google Patents

Abstract

A process for the preparation of carbapenem intermediates, 4-[3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivatives, is provided to improve preparation yield by using a titanium tetrachloride necessary to prepare the intermediates as different Lewis acid. A process for the preparation of carbapenem intermediates represented by the formula(3) comprises the steps of: reacting compounds represented by the formula(2) in the presence of silylation reagent, base and iodization reagent to form its silyl enolate; and reacting the silyl enolate of compounds represented by the formula(2) with compounds represented by the formula(1) in the presence of a catalyst amount of titanium tetrachloride at 5-10 deg.C for 5-7 hours, wherein R^1 is triethylsilyl, trimethylsilyl or t-butyldimethylsilyl; R^2 is H or CH3; R^3 is benzyl, allyl, C1-4 alkyl or p-nitrobenzyl. The silylation reagent is trimethylsilyl chloride, trimethylsilyl bromide or trimethylsilyl iodide, the base is triethylamine or pyridine and the iodization reagent is KI, NaI or I2.

Description

Process for the preparation of carbapenem intermediates

The present invention relates to a novel process for preparing intermediates for the preparation of carbapenem antibiotics, and more particularly to a process for preparing 4- [3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivatives. It is about.

Carbapenem antibiotics are one of the most attracting antibiotics because they show excellent antibacterial activity against a wide range of pathogens and their stability in vivo. Such carbapenems may be represented by the following Chemical Formula 5, specifically named as panipenem, imipenem, meropenem, thienamycin, and the like according to substituents of the following substituents R ² and thiol groups.

According to US Pat. No. 4,350,631, such carbapenem antibiotics can be prepared using intermediates of the compounds of formula (4), wherein the synthetic intermediate of carbapenems of formula (4) is 4- [3-carboxy-3-diazo- It can be prepared from 2-oxopropyl] azetidin-2-one derivative.

In the above formula, R ² is H or CH ₃ and R ³ is benzyl, allyl, C _1-4 alkyl, or p-nitrobenzyl.

Specifically, the compound of Chemical Formula 3 by dissolving the compound of Chemical Formula 3 and the catalytic amount of rhodium acetate polymer {Rh ₂ (OAc) ₄ } in methyl acetate, refluxing for about 1-3 hours, then concentrating and crystallizing under a non-polar solvent Can be prepared.

Various methods are known for preparing the 4- [3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivative of Formula 3, one of which is disclosed in US Patent 0078026. . According to the method, the compound of Formula 3 is prepared by reacting 4-acetoxyazetidinone derivative (1a) with trimethylsilylenolether derivative (2a) in the presence of Lewis acid as shown in Scheme 2 below.

In the above formula, R ¹ is t-butyldimethylsilyl, R ² is H or CH ₃ , and R ³ is benzyl, allyl, C _1-4 alkyl, or p-nitrobenzyl.

However, in this preparation method, a complicated preparation method of the trimethylsilylenol ether derivative (2a) must be performed separately. In order to overcome the drawbacks of this preparation method, US Pat. No. 4,841,042 introduced Lewis acid and Lewis acid, which can act simultaneously as silylating agents, specifically methanesulfonate as trimethylsilyltrifluoro.

However, in the two preparation methods, the yield of the produced compound of formula 3 remained below about 80%.

Therefore, the inventors of the present invention provide a method for preparing a 4- [3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivative of Formula 3, which is an intermediate for preparing a carbapenem antibiotic, in a higher yield. As a result of the study, the present inventors have found that the yield of the compound of formula 3 can be remarkably increased when a Lewis acid used in the preparation of the intermediate of formula 3 is prepared using a catalytic amount of titanium tetrachloride.

Accordingly, an object of the present invention is to provide a method for more efficiently preparing a 4- [3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivative which is an intermediate for preparing a carbapenem antibiotic. do.

In order to achieve the above object, the present invention

To form a silylenolate of a compound of formula (2) in the presence of a silylating agent, a base and an iodide, and then reacting it with a compound of formula (1) in the presence of a catalytic amount of titanium tetrachloride Provided is a process for preparing the compound of 3:

[Formula 3]

In the above formula,

R ¹ is triethylsilyl, trimethylsilyl, or t-butyldimethylsilyl,

R ² is H or CH ₃ ,

R ³ is benzyl, allyl, C _1-4 alkyl, or p-nitrobenzyl.

As the silylating agent, trimethylsilyl chloride, trimethylsilyl bromide or trimethylsilyl iodide may be used, but is not limited thereto.

The base may be a tertiary amine such as triethylamine, tributylamine or pyridine, but is not limited thereto.

The iodide may be selected from the group consisting of KI, NaI, and I ₂ , but is not limited thereto.

The reaction may be carried out in an aprotic solvent, and such an aprotic solvent may be selected from the group consisting of tetrahydrofuran, acetone, dimethylformamide, and acetonitrile, but is not limited thereto.

The reaction may be preferably performed at 5 to 10 ° C. for 5 to 7 hours.

Hereinafter, the present invention will be described in more detail.

The present invention provides a method for producing 4- [3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivatives used as intermediates for the preparation of conventional carbapenem antibiotics in higher yield. As a result of the study, it was found that the yield of the product is significantly higher than that of other Lewis acids specifically used in the past when catalytic amount of titanium tetrachloride is used as the Lewis acid which is essentially used in the preparation of the intermediate.

Therefore, the preparation method of the 4- [3-carboxy-3-diazo-2-oxopropyl] azetidin-2-one derivative of the general formula (3) provided by the present invention may be represented as in Scheme 1 below.

In Scheme 1,

R ¹ is triethylsilyl, trimethylsilyl, or t-butyldimethylsilyl,

R ² is H or CH ₃ ,

R ³ is benzyl, allyl, C _1-4 alkyl, or p-nitrobenzyl.

In the reaction, a silylating agent, a compound of formula (2), and a tertiary amine, which is a base, are added to an aprotic solvent to produce a solution of the compound of formula (2), and then the 4-acetoxy azetidinone derivative (1) is dissolved therein. It can be performed by adding a solution and adding catalytic amount of titanium tetrachloride which is a Lewis acid.

The aprotic solvent may be any solvent as long as it does not inhibit the reaction, and may be selected from the group consisting of tetrahydrofuran, acetone, dimethylformamide, and acetonitrile.

In the solution of the compound of Formula 2, the compound of Formula 2 may be converted to the silylenolate of the compound of Formula 2 by a silylating agent and a base. The silylating agent may stabilize the silylenolate of the compound of Formula 2 produced by the base to stably maintain the reactivity of Formula 2. As such silylating agent, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chloride, or trimethylsilyl bromide, trimethylsilyl iodide and the like can be used. The base may be a tertiary amine such as triethylamine, tributylamine or pyridine, but is not limited thereto.

The iodinating agent is to increase the reactivity of the compound of formula (2) with the 4-acetoxy azetidinone derivative of formula (1), it is possible to convert the compound of formula (2) to the silyl enolate type. Such iodinating agents may be selected from the group consisting of KI, NaI, and I ₂ , but any iodinating agent may be used so long as it enables silylenolate formation and does not cause other adverse reactions.

Dichloromethane, tetrahydrofuran, acetone, dimethylformamide, or acetonitrile may be used as the solvent used in the preparation of the solution of 4-acetoxy azetidinone derivative of Chemical Formula 1, preferably dichloromethane or Acetonitrile can be used.

After adding a solution of the compound of Formula 1 to the solution of the compound of Formula 2, a catalytic amount of titanium tetrachloride is added as Lewis acid, and the reaction proceeds. The reaction may be performed at 3 ° C. to about 25 ° C. for 3 to 10 hours, preferably at about 5 to 10 ° C. for 5 to 7 hours.

4-acetoxy azetidinone derivatives of Formula 1 are known and can be prepared by methods known in the literature (German Offenlegungsschrift No. 19 06 401; A. Oida et al., Chem. Pharm. Bull 29, 2899 (1981), M. Shiozaki et al., Tetrahedron 39, 2399 (1983), M. Shiozaki et al., Tetrahedron 39, 2399 (1983); M. Shiozaki et al. Tetrahedron 40, 1795 (1984 ), WJ Leanza et al., Tetrahedron 39, 2505 (1983), T. Kametani et al., J. Chem. Soc.Perkin I 1981, 2228; JL Roberts et al., Synthetic Communications 13, 797 (1983)) .

Compounds of Formula 2 are known and can be prepared by methods known in the literature (S. Julia et al., Compt. Rend. Acad. Sci. Paris, Section C 246, 1890 (1967), Europe Patent 52 299, R M. Kellogg et al., JCS Chem. Comm. (1977) 932.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrating the present invention, and the present invention is not limited by these examples.

Example 1

(3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitrobenzyloxycarbonylcarbonyl-3-diazo-2-oxopropyl) azetidin-2-one (3) Manufacture

11.9 g of p-nitrobenzyl 2-diazo-3-oxobutanoate, 15 g of KI, and 5.5 g of triethylamine were dissolved in 50 mL of acetonitrile, and 5 g of trimethylsilyl chloride was added dropwise. Here, (3R, 4R) -4-acetoxy-3-[(1R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one

10 g (manufactured by Kaneka, Japan) was dissolved in 50 mL of dichloromethane and added. 2.5 g of titanium tetrachloride was added to the solution, followed by stirring at 10 ° C. for 6 hours.

10% sodium bicarbonate was added to the reaction solution, diluted with 150 mL of dichloromethane, washed with 50 mL of saturated brine, and 50 mL of distilled water. The organic solvent layer was separated, filtered and concentrated under reduced pressure.

The residue was dissolved in 100 mL of methanol and 15 mL of 15% HCl was added dropwise at room temperature for 30 minutes, followed by stirring for 5 hours. After the reaction was completed, neutralized with a 10% sodium bicarbonate solution, 200 mL of water was slowly added to precipitate crystals, and then stirred at room temperature for 10 hours to increase the yield.

After the crystals were completely precipitated, filtered and dried under reduced pressure, the target compound was (3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitrobenzyloxycarbonylcarbonyl-3-diazo- 14.1 g of 2-oxopropyl) azetidin-2-one compound are obtained (yield: 91.3%).

Comparative Example 1

Preparation of (3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitrobenzyloxycarbonylcarbonyl-3-diazo-2-oxopropyl) azetidin-2-one

11.9 g of p-nitrobenzyl 2-diazo-3-oxobutanoate, 15 g of KI, and 5.5 g of triethylamine were dissolved in 50 mL of acetonitrile, and 5 g of trimethylsilyl chloride was added dropwise. 10 g of (3R, 4R) -4-acetoxy-3-[(1R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one (manufactured by Kaneka, Japan) was dissolved in 50 mL of dichloromethane. Added. 7.1 g of zinc chloride (ZnCl 2) was added to the solution, followed by stirring at room temperature for 6 hours.

The reaction solution was washed with 50 ml of sodium chloride 20% aqueous solution, washed with 50 mL of distilled water, and then, 100 mL of dichloromethane was added, the layers were separated, filtered, and concentrated under reduced pressure.

The residue was dissolved in 100 mL of methanol and 15 mL of 15% HCl was added dropwise at room temperature for 30 minutes, followed by stirring for 5 hours. After the reaction was completed, neutralized with a 10% sodium bicarbonate solution, 200 mL of water was slowly added to precipitate crystals, and then stirred at room temperature for 10 hours to increase the yield.

After the crystals were completely precipitated, filtered and dried under reduced pressure, the target compound was (3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitrobenzyloxycarbonylcarbonyl-3-diazo- 11.5 g of 2-oxopropyl) azetidin-2-one compound are obtained (yield: 74.5%).

Comparative Example 2

Preparation of (3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitrobenzyloxycarbonylcarbonyl-3-diazo-2-oxopropyl) azetidin-2-one

12 g of p-nitrobenzyl 2-diazo-3-oxobutanoate, 15 g of KI, and 5.5 g of triethylamine were dissolved in 50 mL of acetonitrile, and 5 g of trimethylsilyl chloride was added dropwise. Here, 10 g of (3R, 4R) -4-acetoxy-3-[(1R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one (manufactured by Kaneka, Japan) was dissolved in 50 mL of dichloromethane. Added. 11.1 g of trimethylsilyl trifluoromethanesulfonate (TMSOTf) was added to the solution, followed by stirring at 0 ° C for 10 hours.

The reaction solution was washed with 50 ml of sodium chloride 20% aqueous solution, washed with 50 mL of distilled water, and then, separated by layering with 100 mL of dichloromethane, filtered, and concentrated under reduced pressure.

The residue was dissolved in 100 mL of methanol and 15 mL of 15% HCl was added dropwise at room temperature for 30 minutes, followed by stirring for 5 hours. After the reaction was completed, neutralized with a 10% sodium bicarbonate solution, 200 mL of water was slowly added to precipitate crystals, and then stirred at room temperature for 10 hours to increase the yield.

After the crystals were completely precipitated, filtered and dried under reduced pressure, the target compound was (3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitrobenzyloxycarbonylcarbonyl-3-diazo- 12.6 g of 2-oxopropyl) azetidin-2-one compound are obtained (yield: 81.7%).

(3S, 4R) -3- (1-hydroxyethyl) -4- (3-p-nitro benzyloxycarbonylcarbonyl-3-diazo-2-oxopropyl) ase as in the above Examples and Comparative Examples As can be seen from the yield shown in the preparation method of thidin-2-one, when prepared using Lewis acids such as zinc chloride or trimethylsilyl trilomethanesulfonate used in the conventional manufacturing method, the Although yields were shown, in the present invention, the compound of formula 3 was obtained in a yield of more than 90% by using a catalytic amount of titanium tetrachloride as Lewis acid. From these results, it can be seen that the present invention can prepare carbapenem intermediates with remarkably high yield by selecting a Lewis acid different from the Lewis acid which has been used specifically in the prior art.

As described above, the present invention can produce the carbapenem intermediate in a significantly higher yield as a method for preparing a carbapenem intermediate using a catalytic amount of titanium tetrachloride.

Claims (6)

To form a silylenolate of a compound of formula (2) in the presence of a silylating agent, a base and an iodide, and then reacting it with a compound of formula (1) in the presence of a catalytic amount of titanium tetrachloride Preparation of the compound of 3: [Formula 1]

[Formula 2]

[Formula 3]

In the above formula, R ¹ is triethylsilyl, trimethylsilyl, or t-butyldimethylsilyl, R ² is H or CH ₃ , R ³ is benzyl, allyl, C _1-4 alkyl, or p-nitrobenzyl. The method of claim 1 wherein the silylating agent is trimethylsilyl chloride, trimethylsilyl bromide, or trimethylsilyl iodide. The method of claim 1 wherein the base is triethylamine or pyridine. The method of claim 1 wherein the iodide agent is selected from the group consisting of KI, NaI, and I ₂ . The method of claim 1, wherein the reaction is performed in a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, acetone, dimethylformamide, acetonitrile, or a combination thereof. The method of claim 1, wherein the reaction is performed at 5 to 10 ° C. for 5 to 7 hours.