WO2019100544A1

WO2019100544A1 - METHOD FOR PREPARING TAZOBACTAM KEY INTERMEDIATE, 6α-BROMOPENICILLANIC SULFOXIDE ACID DIPHENYLMETHYL ESTER

Info

Publication number: WO2019100544A1
Application number: PCT/CN2018/000379
Authority: WO
Inventors: 高峰
Original assignee: 北京世纪润辉生物科技有限公司; 北京世纪迈劲生物科技有限公司
Priority date: 2017-11-23
Filing date: 2018-11-05
Publication date: 2019-05-31
Also published as: CN109824696A

Abstract

A novel method for preparing a key intermediate, a 6α-bromopenicillanic sulfoxide acid diphenylmethyl ester, in tazobactam analysis. The method comprises the following steps: dissolving a 6α-bromopenicillanic sulfoxide acid in an organic solvent, adding diphenyldiazomethane, evaporating the solvent under reduced pressure after complete reaction, performing extraction with the organic solvent, washing an organic layer with saturated brine, and after drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure to obtain a crude product. The crude product is recrystallized or washed by beating with the organic solvent, and thus a 6α-bromopenicillanic sulfoxide acid diphenylmethyl ester can be obtained. Compared with a conventional method for producing esters with a condensing agent, such as DCC, the method avoids the problem of a difficulty in removal of reaction by-products. Compared with using a benzophenone hydrazone/KI/peracetic acid system for esterification, the method simplifies operations, reduces by-products, improves the purity of final products, and is more conducive to industrial production.

Description

Preparation method of tazobactam key intermediate 6α-bromopenicillium sulfoxide diphenyl methyl ester

Technical field

The invention belongs to the technical field of organic and pharmaceutical synthesis, and particularly relates to a preparation method of tazobactam key intermediate 6α-bromopenicillin sulfoxide dibenzoate

Background technique

The structural formula of 6α-bromopentamidine sulfoxide dibenzoate is

6α-bromopenicillin diphenylmethyl sulfonate is an important intermediate for the synthesis of a novel β-lactamase inhibitor tazobactam, a broad-spectrum and highly efficient β-endo Amidase inhibitor, developed by Japan Dapeng Pharmaceutical Co., Ltd., was rated as the most promising at the 30th International Chemotherapy Conference due to its excellent application performance, small toxic and side effects, strong inhibitory activity and high stability. Beta-lactamase inhibitor.

Tazobactam, chemical name: 3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-methylene)-4-thia-1-nitrogen Heterobicyclo[3.2.0]heptane-2-carboxylic acid-4,4-dioxide, the structural formula is shown below. Its structure is to add a triazole ring to sulbactam to improve the inhibitory effect. It is the best clinically effective β-lactamase inhibitor with high stability, low activity and low toxicity. It has the characteristics of strong inhibition of enzyme activity. In 1992, tazobactam's combination drug tazobactam/piperacillin (1:8) was first marketed in France for the treatment of various bacterial infections.

The structural formula of tazobactam is as follows

According to the literature, the preparation of 6α-bromopenicillium sulfoxide dibenzoate from 6α-bromopenicillin sulfenic acid has the following two routes:

Bao Jianhua, Liu Yulin, Ma Jun et al. used the DCC/DMAP/diphenylmethanol method to prepare diphenylmethyl 6-bromopenicillin sulfoxide in the patent CN 101935324. The synthetic route is as follows:

Literature Micetich R G, Maiti S N, Spevak P, et al. Synthesis of 2β-azidomethylpenicillin-1, 1-dioxides and 3β-azido-3α-methylcepham-1, 1-dioxides [J]. Synthesis, 1986, 1986 ( 04): 292-296. Preparation of 6α-bromopenicillin sulfenic acid diphenylmethyl ester by reaction with benzophenone oxime in the presence of peracetic acid and KI. The synthetic route is as follows:

In the above method, in the first method, 6α-bromopenicillin sulfoxide and diphenylmethanol are condensed under the action of carbonyldiimidazole (DCC) to prepare diphenylmethanol ester, and the by-product N,N-dicyclohexylurea is not easily removed. Influencing the quality of the product; in the second method, 6α-bromopenicillin sulfoxide acid is reacted with diphenyl ketone oxime in the presence of 40% peroxyacetic acid and KI to esterify, 40% peroxyacetic acid is unstable and Unsafe to use, the reaction produces a large amount of acetic acid, and excess benzophenone oxime is not easily removed, which affects product quality.

Summary of the invention

In order to overcome the above defects such as difficulty in purchasing raw materials, difficulty in removing by-products, and difficulty in controlling product quality, the present invention provides a preparation method of 6α-bromopenicillin sulfenic acid diphenylmethyl ester, and the synthesis route thereof is as follows:

This includes the following steps:

The 6α-bromopenicane sulfoxide acid is dissolved in a solvent, and diphenyldiazomethane is added to keep the reaction. After the reaction is completed, the reaction solvent is evaporated to dryness, extracted with ethyl acetate or dichloromethane, and the organic phase is dried, filtered, and evaporated to dryness to give the crude product of 6?-bromopenic acid sulfonate diphenylmethyl ester; The solvent is beaten and washed, suction filtered, and the filter cake is dried to obtain 6α-bromopenicillin sulfoxide diphenylmethyl ester;

Further, the organic solvent for dissolving 6α-bromopenicillin sulfoxide may be selected from the group consisting of dichloromethane, ethyl acetate, acetone, methyl isobutyl ketone, ethanol, methanol, acetonitrile, N,N-dimethyl One or more of formamide and dimethyl sulfoxide are preferably a mixed solution of acetone, acetonitrile, dichloromethane/acetone; and the volume ratio of dichloromethane/acetone is preferably dichloromethane:acetone = 1:2.

Further, the molar ratio of diphenyldiazomethane to 6α-bromopenicillium sulfoxide is from 1:0.9 to 1:5, preferably from 1:0.9 to 1:1.5.

Further, the solvent used for the extraction is ethyl acetate, dichloromethane, chloroform, preferably ethyl acetate.

Further, the solvent used for recrystallization is one or more of dichloromethane, ethyl acetate, petroleum ether, n-hexane, acetone, methyl isobutyl ketone, acetonitrile, methanol, ethanol, isopropanol, and water, preferably It is a mixed solvent of ethyl acetate/petroleum ether.

Further, the solvent used for beating is one or more of dichloromethane, ethyl acetate, petroleum ether, n-hexane, acetone, methyl isobutyl ketone, acetonitrile, methanol, ethanol, isopropanol, and water, preferably Ethyl acetate / petroleum ether mixed solvent. The advantages of the method provided by the present invention are:

(1) The 6α-bromopenicillant sulfoxide dibenzoate prepared by the method of the invention effectively solves the problem that the reaction is incomplete when the acid system is ester-forming, and the excess benzophenone oxime affects the purity of the product. ;

(2) When an effective ester is formed by a DCC/diphenylmethanol system, the by-product N,N'-dicyclohexylurea which is produced is not easily removed, which affects the quality of the product.

(3) The 6α-bromopenicillium sulfoxide dibenzoate prepared by the method of the invention has a yield of 93.5% and a high-purity liquid purity of 99.578%.

DRAWINGS

1 is a high performance liquid chromatogram of 6α-bromopenicillin sulfoxide dibenzoate prepared by the operation described in Example 1;

2 is a high performance liquid chromatogram of 6α-bromopenicillant sulfoxide dibenzoate prepared by the operation described in Example 2;

Figure 3 is a 1H-NMR chart of 6α-bromopenicillium sulfoxide diphenylmethyl ester;

Figure 4 is a high performance liquid chromatogram of 6α-bromopenicillium sulfoxide dibenzoate prepared by the procedure described in Example 3 (refer to the patent CN 101935324);

Figure 5 is a high performance liquid chromatogram of 6?-bromopenicillium sulfoxide dibenzoate prepared by the procedure described in Example 4 (Reference Synthesis, 1986, 1986 (04): 292-296).

Detailed ways

The invention is described below by way of specific embodiments. Unless otherwise stated, the technical means used in the present invention are all methods known to those skilled in the art. Rather, the scope of the invention is to be construed as being limited by the scope of the invention. Various changes or modifications to the compositions and amounts of materials in these embodiments are also within the scope of the present invention, without departing from the spirit and scope of the invention. The materials and reagents used in the present invention are commercially available. Among them, diphenyldiazomethane was purchased and placed in Shanghai Zhixin Chemical Co., Ltd.;

6α-bromopenicillin sulfoxide acid was prepared by the company as follows: water, 400 g of hydrobromic acid, ethanol, and 400 g of 6-aminopenicillanic acid were added to the reaction vessel. The temperature control is less than 20 ° C, 200 g of sodium nitrite solution and 666 g of hydrobromic acid solution are added dropwise. After the dropwise addition, the reaction is kept at less than 20 ° C for 2 hours, the heat preservation is finished, the vacuum is applied for 30 to 60 minutes, and the mixture is extracted three times with dichloromethane. merge. Washing three times with water, the extraction and washing process requires a temperature of less than 20 °C. The organic layer is cooled to below zero, sodium tungstate is added, the temperature is less than 0 ° C, and hydrogen peroxide is added dropwise. After the dropwise addition, the reaction is kept at less than 10 ° C for 5 hours, washed twice with cold water, and the mother liquor is separated and distilled to obtain the sample 6α-bromo. Penicillin sulfoxide.

Example 1

Preparation of 6α-bromopentamidine sulfoxide dibenzoate

300g of 6α-bromopenicillin sulfoxide was added to 1.8L of acetonitrile, and diphenyldiazomethane in acetonitrile (256g of diphenyldiazomethane dissolved in 600mL of acetonitrile) was added dropwise at room temperature. The reaction is carried out for 0.5 to 3 hours. After the reaction is completed, the reaction solvent is evaporated to dryness, and extracted with 2 L of dichloromethane. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate, and then concentrated to give 6?-bromopenicane sulfonate diphenylmethyl ester The crude product was washed with ethyl acetate/n-hexane (1:5) mixed solvent, and then dried by air drying to obtain 438 g of 6α-bromopenicillin sulfoxide diphenylmethyl ester, melting point 150-154 ° C, yield 93.5%, HPLC purity 99.578% (see Figure 1);

Example 2

Preparation of 6α-bromopentamidine sulfoxide dibenzoate

300 g of 6α-bromopenicillin sulfoxide was added to a mixed solution of 1.8 L of dichloromethane and acetone (dichloromethane: acetone = 1:2, by volume), and diphenyldiazomethane was added dropwise at room temperature. The dichloromethane solution (256 g of diphenyldiazomethane dissolved in 600 mL of dichloromethane), after the completion of the dropwise addition, the reaction was continued for 0.5 to 3 hours. After the completion of the reaction, the reaction solvent was evaporated to dryness, and extracted with 2 L of dichloromethane, and the organic phase was saturated. After washing with brine and drying over anhydrous sodium sulfate, it is concentrated to give a crude product of 6α-bromopenicillin sulfoxide dibenzoate, and washed with a mixed solvent of ethyl acetate / n-hexane = 1:5 (volume ratio). After drying, 446 g of 6α-bromopenicillium sulfoxide dibenzoate was obtained, the melting point was 149-154 ° C, the yield was 95.3%, and the HPLC purity was 98.735% (see FIG. 2). ¹ H-NMR (600 MHz, CDCl ₃ ): 6 (ppm): 7.40 to 7.29 (m, 10H, Ar-H); 6.99 (s, 1H, (C ₆ H ₅ ) ₂ CH); 5.09 (d, 1H) , 5-H); 5.01 (d, 1H, 6-H); 4.65 (s, 1H, 2-H); 1.68 (s, 3H, -CH3); 0.94 (s, 3H, -CH3). ^{The 1} H-NMR spectrum is shown in Figure 3.

Example 3.

Add 0 ml of dichloromethane and 6α-bromopenicillin sulfoxide 30 g to a 1 L flask at 0 to 5 ° C, stir and dissolve, and add 20.0 g of diphenylmethanol and 1.0 g of DMAP at 0 to 5 ° C to continue stirring. Dissolve in the reaction system. DCC 23.0 g and dichloromethane (80 ml) were added at 0 to 5 ° C, and the mixture was diluted for about 5.0 h and kept for 1.0 h. After the completion of the reaction, the solution was filtered, and the filtrate was washed with 50 ml of water at 0 to 5 ° C, stirred for 10 min, and then allowed to stand for 20 min. The organic phase was added thereto, 80 ml of 8% sodium hydrogencarbonate was added thereto, stirred for 10 min, and then allowed to stand for 20 min. The layers were separated, and the organic phase was subjected to atmospheric distillation to recover dichloromethane. To the obtained white solid, 80 g of toluene was added, and the mixture was kept at 40 to 50 ° C for 1.0 h, cooled to -5 ° C for 4.0 h, filtered, rinsed with toluene, and dried by suction filtration to obtain 6α-bromopenicillin sulfoxide diphenyl. Methyl ester 42.5g, molar yield 90.7%, melting point 151 ~ 154 ° C, HPLC purity 96.772% (see Figure 4),

Example 4

To a 500 mL round bottom flask, 19.56 g (0.0698 mol) of 6α-bromopenicillin sulfoxide, 138 mL of chloroform and 69 mL of water were added, and the mixture was cooled to 0 ° C with stirring. To the mixture, 13.94 g (0.0733 mol) of 40% peroxyacetic acid was added dropwise over 30 minutes, stirring was continued for 30 minutes while maintaining 0 ° C, and 14.81 g (0.0755 mol) of benzophenone oxime and 4.6 mL of a 1% potassium iodide aqueous solution were added. Then, 15.93 g (0.0838 mol) of 40% peroxyacetic acid was added at 0 ° C for about 30 min, followed by dropwise addition of 5.5 mL of 10% sulfuric acid. The mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 h. The chloroform layer was separated and the aqueous layer was extracted with chloroform (2×50ml). The combined organic layers were washed with cold water (200 mL) andEtOAc. The chloroform layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered under suction, and the obtained filtrate was concentrated and washed with ethyl acetate / n-hexane = 1:5 (volume ratio) solvent mixture, and dried by suction filtration to give a pale yellow product, 28.2 g, yield 92.4%, melting point 149-153 ° C HPLC The purity was 98.648% (see Figure 5).

in conclusion:

The invention relates to a novel preparation method of a key intermediate 6α-bromopenicillium sulfoxide diphenylmethyl ester in the synthesis of tazobactam. The method comprises the steps of: dissolving 6α-bromopenicillin sulfoxide acid in an organic solvent, adding diphenyldiazomethane, and after the reaction is completed, the solvent is distilled off under reduced pressure, and extracted with an organic solvent, and the organic layer is saturated with salt. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a crude product. After the crude product is recrystallized or beaten with an organic solvent, 6α-bromopenicillium sulfoxide diphenylmethyl ester can be obtained. Compared with the conventional method of forming an ester by using a condensing agent such as DCC, the method avoids the problem that the reaction by-products are difficult to remove; compared with the esterification using a benzophenone oxime/KI/peracetic acid system, the operation is simplified. It reduces the formation of by-products, improves the purity of the final product, and is more conducive to industrial production.

Example 5

The β-lactamase inhibitor tazobactam prepared by the 6α-bromopenicillin sulfoxide dibenzoate intermediate prepared by the invention is subjected to a 6-step reaction (for the preparation method, see US2009012287A1; EP1813619A1). ; CN101048417B patent document), its physical and chemical properties are consistent with those reported in the above patent documents, which proves that the 6α-bromopenicillin sulfoxide dibenzoate prepared by the invention can be completely used for tazobactam. preparation.

Claims

A preparation method of tazobactam key intermediate 6α-bromopenicillium sulfoxide diphenyl methyl ester, which is characterized by the following steps:

(1) Dissolving 6α-bromopenicillin sulfoxide acid in an organic solvent, adding diphenyldiazomethane to the reaction system in batches at -20 ° C to 50 ° C, and reacting under magnetic stirring for 0.5 to 48 h. After the completion of the reaction, the solvent is evaporated under reduced pressure. The residue is purified eluting with methylene chloride or ethyl acetate. - a molar ratio of bromo penicillin sulfoxide to diphenyldiazomethane of 1:0.9 to 1:5;

(2) After the crude product is recrystallized or beaten with an organic solvent, 6α-bromopenicillin sulfenic acid diphenylmethyl ester can be obtained;

The organic solvent is a protic solvent such as ethanol or methanol or petroleum ether, n-hexane, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methyl isobutylene. One or more of aprotic solvents such as ketones;

The recrystallization solvent or beating solvent is ethyl acetate, n-hexane, cyclohexane, petroleum ether, ethanol, methanol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, water. One or several.
The process according to claim 1, wherein the molar ratio of said 6α-bromopenicill sulfoxide to diphenyldiazomethane is from 1:0.9 to 1:1.5.
The process according to claim 1, wherein the organic solvent for dissolving 6α-bromopenicillin sulfoxide is a mixture of ethyl acetate, dichloromethane, chloroform, ethyl acetate or dichloromethane/acetone. Solvent.
The process according to claim 3, wherein the recrystallization solvent or the beating solvent is a mixed solvent of dichloromethane/acetone in a volume ratio of dichloromethane:acetone = 1:2.
The process according to claim 1, wherein the recrystallization solvent or the beating solvent is a mixed solvent of ethyl acetate/n-hexane, dichloromethane/acetone, ethyl acetate/n-hexane or ethyl acetate/petroleum ether.
The preparation method according to claim 5, characterized in that the recrystallization solvent or the beating solvent is a mixture of ethyl acetate/n-hexane volume ratio of 1:5 mixed solvent or ethyl acetate/petroleum ether volume ratio of 1:4. Solvent.
Use of 6α-bromopenicillium sulfoxide dibenzoate prepared by the method of claim 1 for the preparation of a tazobactam acid drug for treating various bacterial infections.