Industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester

Abstract

The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester, characterized by: 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene benzhydryl ester and 40-300 mesh copper halide powder are subjected to a halogenation reaction in the presence of a phase transfer catalyst to obtain β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester. This method solves the problem of ineffective industrial scale-up during copper halide cyclization and halogenation during the preparation of β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester, an important intermediate of tazobactam, and simultaneously solves the pollution problems caused by the hydrohalic acid / sodium nitrite system and sulfuryl chloride halogenation.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a method for synthesizing tazobactam intermediate 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester. Background Art

[0002] Tazobactam (1), chemically named [2s-(2α,3α,5α)-3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-methyl)-4-thio-1-azabicyclo-[3,2,0]-heptane-2-carboxylic acid-4,4-dioxide, is a novel penicillin sulfone β-lactamase inhibitor developed by Taiho Pharmaceutical Co., Ltd., Japan. Tazobactam is currently the most promising β-lactamase inhibitor in clinical evaluation due to its excellent stability, low toxicity, and strong enzyme inhibitory activity. 2β-Halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is an important intermediate in the preparation of tazobactam. The current process for preparing 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester uses 3-methyl-{2-oxo-4-(2-benzothiazolyldisulfanyl)-1-azetidinyl}-3-butenoic acid benzhydryl ester as the raw material in a hydrohalic acid / sodium nitrite system to obtain 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester. The reaction scheme is as follows:

[0003]

[0004] The reaction process of preparing 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester by halogenation and cyclization reaction of compound 1 will produce a large amount of difficult-to-separate six-membered ring impurities and dimercaptothiazole by-products. The product needs to be separated and purified by column chromatography before the next reaction. The post-treatment process is complicated and tedious, which increases the production cost. At the same time, a large amount of three wastes is generated, which pollutes the environment and is not conducive to industrial production.

[0005] Deng Yong et al. (Deng Yong, Shen Yi, Zhong Yuguo, Tang Weigao. Synthesis of β-lactamase inhibitor - tazobactam acid [J]. Chinese Journal of Medicinal Chemistry, 2001.) reported that intermediate 6 was used as a raw material to react with sulfuryl chloride to obtain 2β-chloromethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester (7). Using SO2Cl2 as a chlorination cyclization reagent will produce a large amount of acidic waste gases such as SO2 and HCl, which is not friendly to the environment.

[0006] Although anhydrous copper chloride is used in the chlorination step in existing technologies, the reaction itself is a solid-liquid two-phase reaction. When the reaction is scaled up, commercially available copper chloride is relatively large and heavy, and tends to settle at the bottom of the reaction tank. No matter how fast the stirring speed is increased, it always settles at the bottom of the reaction flask, which is not conducive to the reaction. It causes a decrease in reaction speed, an increase in by-products, and a large amount of product remains after the reaction time is extended, making industrial production impossible. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for synthesizing 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester, an important intermediate in the synthesis of tazobactam, so as to solve the problems existing in existing halogenation conditions, such as the inability to scale up, long reaction time, low yield, high cost, many reaction impurities that are difficult to separate and purify, large amounts of three wastes generated, and serious environmental pollution. At the same time, the process of the present invention provides a simple process for separating and purifying halides, thereby preparing β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester with high purity, thereby ensuring the smooth progress of the subsequent preparation reaction of tazobactam.

[0008] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester, which is characterized by: 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene benzhydryl ester and 40-300 mesh copper halide powder are subjected to a halogenation reaction to obtain β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid benzhydryl ester.

[0009] The specific reaction formula is as follows:

[0010]

[0011] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0012] The above halogenation reaction is carried out under the action of a phase transfer catalyst.

[0013] The above-mentioned phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst, preferably tetrabutylammonium bromide.

[0014] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0015] The copper halide powder was added into the 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenylmethyl ester solution in portions.

[0016] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0017] The copper halide powder is selected from 80-100 mesh copper halide powder.

[0018] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is characterized in that the specific reaction process is as follows:

[0019] S1. In a dry environment, at room temperature, the copper halide is crushed and sieved to form a copper halide powder of a specified mesh size;

[0020] S2. 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenyl ester was dissolved in a solvent to prepare a 0.1-2Kg / 10L solution, and the solution was stirred at -10-5°C for 0.1-1 hour;

[0021] S3. The copper halide powder obtained in S1 is added in batches to the 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenyl ester solution in S2, a phase transfer catalyst is added, and the reaction is stirred for 1-5 hours. A high-purity product is obtained after post-treatment.

[0022] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0023] The mass ratio of the above-mentioned 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenylmethyl ester to the copper halide is 1:0.3-0.7.

[0024] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0025] The molar ratio of the copper halide to the phase transfer catalyst is 30-40:1.

[0026] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0027] The above post-treatment process includes: directly filtering the reaction liquid of S3, eluting the filter cake with an organic solvent, combining the filtrate and the washing liquid, washing with deionized water, sodium bicarbonate aqueous solution, and saturated brine in sequence, drying with anhydrous magnesium sulfate, filtering, and recovering the solvent under reduced pressure of the filtrate to obtain a crude product.

[0028] The present invention provides an industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which is further characterized by:

[0029] The post-treatment process includes: adding the crude product to a mixed solution of alcohol and ether, beating at room temperature for more than 1 hour, filtering, and drying to obtain β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester.

[0030] Function and effect of the present invention:

[0031] The present invention has found through research that the advantage of using copper halide to prepare halides by halogenation and cyclization is that the reaction almost does not produce six-membered ring impurities with a polarity similar to that of the product, and the reaction selectivity is high. However, the copper ions themselves can combine with the mercaptothiazole removed by the reaction to form a precipitate and leave the reaction system. When the feed is scaled up, when industrial-grade copper halide is directly used for the reaction in the traditional process, the mercaptothiazole copper salt generated in the reaction adheres to the surface of the copper halide particles, hindering the reaction from continuing, resulting in a low reaction conversion rate and a large number of impurities.

[0032] In the present invention, industrial-grade copper halide is made into copper halide with a mesh size of 40-300 and then added to the reaction, which can effectively overcome this problem. The raw materials can be fully converted. In particular, after the phase transfer catalyst is added, the reaction time is shortened, impurities are reduced, the product is easy to separate and purify, and the reaction is easier to scale up, making it suitable for large-scale industrial production.

[0033] It can be seen that this process solves the problem of ineffective industrial scale-up when using copper halide cyclization halogenation to prepare β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, an important intermediate of tazobactam, and also solves the pollution problem caused by the hydrohalic acid / sodium nitrite system and sulfuryl chloride halogenation. DETAILED DESCRIPTION

[0034] Example 1

[0035] 2 kg of 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfanyl)-1-azetidinyl]-3-butene diphenyl ester was dissolved in 20 L of dichloromethane, and the temperature was cooled at -10 to -5 ° C with stirring for 0.5 h. 80-100 mesh granules of copper chloride (0.758 kg, 5.638 mol) were added in batches. Tetrabutylammonium bromide (0.06 kg, 0.187 mol) was added. The temperature was kept stirring for 3 h, filtered, and 1 L* was added. The filter cake was washed with dichloromethane, and the filtrate and washings were combined. The dichloromethane feed solution was washed with 6 L of deionized water and 6 L of 10% sodium chloride aqueous solution in sequence. The obtained organic layer was concentrated under reduced pressure at 25-30°C to obtain 1.389 kg of an oily substance. 10 L of a mixed solvent of methanol and isopropyl ether was added and the mixture was slurried at room temperature for 1 hour. The mixture was filtered and dried to obtain 1.124 kg of a white solid powder with a yield of 74.6% and a purity of 99.1%. ESI (m / z) =

[0036] 424.1[M+23], melting point: 100-102℃.

[0037] Example 2

[0038] 2.2 kg of 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfanyl)-1-azetidinyl]-3-butene dibenzyl ester was dissolved in 22 L of a mixed solvent of toluene and acetone, and the mixture was stirred and cooled at -10 to -5 °C for 0.5 h. 80-100 mesh granules of copper chloride (0.834 kg, 6.2 mol) were added in batches. Tetrabutylammonium bromide (0.066 kg, 0.206 mol) was added. l), stirred at this temperature for 3 h, filtered, the filter cake was washed with 1.5 L*2 toluene, the filtrate and the washings were combined, the filtrate was washed with 6.5 L deionized water and 6 L 10% sodium chloride aqueous solution, and the obtained organic layer was concentrated under reduced pressure at 45-50 ° C to obtain 1.397 kg of an oily substance, 11 L of a mixed solvent of methanol and isopropyl ether was added, and the mixture was beaten at room temperature for 1 h, filtered, and dried to obtain 1.154 kg of a white solid powder, with a yield of 76.6%, a purity of 99.0%, ESI (m / z) = 424.1 [M+23], and a melting point of 100-102 ° C.

[0039] Example 3

[0040] 1.5kg 3-Methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene dibenzyl ester was dissolved in 15L of dichloromethane, stirred and cooled at -10 to -5°C for 0.5h, and copper bromide (0.944kg, 4.228mol) of 80-100 mesh particles was added in batches. Tetrabutylammonium bromide (0.045kg, 0.14mol) was added and stirred for 3h. The mixture was filtered and the filter cake was washed with 1L*2 dichloromethane. The filtrate and washings were combined. The dichloromethane feed liquid was washed with 5L of deionized water and 5L of 10% sodium chloride aqueous solution in turn. The obtained organic layer was concentrated under reduced pressure at 25-30°C to obtain 1.042kg of oil. 7.5L of a mixed solvent of methanol and isopropyl ether was added and slurried at room temperature for 1h. The mixture was filtered and dried to obtain 0.846kg of a white solid powder with a yield of 75.4% and a purity of 99.4%. 1 H NMR(400MHz,Chloroform-d)δ7.40–7.29(m,10H),6.94(s,1H),5.45(dd,J=4.0,2.0Hz,1H),5.20(s,1H) ), 3.62(dd,J=16.0,4.0Hz,1H),3.57(s,2H),3.14(dd,J=16.0,2.0Hz,0H),1.36(s,3H)., Melting point: 101-102℃.

[0041] Comparative Example 1

[0042] 1.0 kg of 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfanyl)-1-azetidinyl]-3-butene dibenzyl ester was dissolved in 10 L of dichloromethane and stirred at -10 to -5 ° C for 0.5 h. Commercially available industrial-grade copper chloride particles (0.379 kg, 2.82 mol) were added in batches and stirred for 6 h. The mixture was filtered and the filter cake was rinsed with 0.7 L * 2 dichloromethane. The filtrate and washings were combined, and the dichloromethane solution was washed with 3.2 L of deionized water and 3.5 L of 10% sodium chloride aqueous solution. The resulting organic layer was concentrated under reduced pressure at 25-30 ° C to obtain an oil. 5 L of a mixed solvent of methanol and isopropyl ether was added and the mixture was stirred at room temperature for 1 h. 0.726 kg of the precipitated oil accumulated at the bottom of the reactor. After the reaction, due to the mixing of multiple raw materials, the product and raw materials had similar polarity and were difficult to separate. According to the HPLC results, the yield was estimated to be 18%.

[0043] Comparative Example 2

[0044] 1.2kg 3-Methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butenediphenylmethyl was dissolved in 12 L of dichloromethane, stirred and cooled at -10 to -5 ° C for 0.5 h, 20% aqueous hydrogen bromide solution (9.11 kg, 22.52 mol) and tetrabutylammonium bromide (36.3 g, 0.123 mol) were added, and then a 2 mol / L aqueous sodium nitrite solution (310 g, 4.5 mol) was added. The reaction was kept warm for 1.5 h, filtered, and the filter cake was washed with 1.2 L * 2 dichloromethane. The filtrate and washings were combined and separated. The dichloromethane feed was washed with 5 L of deionized water and 8 L of 10% sodium chloride aqueous solution. The resulting organic layer was concentrated under reduced pressure at 25-30 ° C to obtain an oil. 6 L of a mixed solvent of methanol and isopropyl ether was added and slurried at room temperature for 1 h, filtered, and dried to obtain 523.3 g of a light yellow powder. Melting point: 92-106℃.

[0045] From the above comparative tests, it can be found that

[0046] In Comparative Example 1, industrial-grade copper chloride particles were used as feed material. After the reaction was scaled up, the amount of copper chloride added increased, and due to its weight and the tendency of the metal to agglomerate in a solvent environment, a large amount of copper chloride was deposited at the bottom of the reactor. As a result, the materials to be reacted were unable to fully contact each other, resulting in a difficult reaction. This resulted in a large amount of raw material remaining. Due to the similar structure and polarity of the raw material and the product, it was difficult to purify the product by post-processing in a relatively simple and industrially applicable manner, which limited the industrial production of this product.

[0047] In Comparative Example 2, although the bromide raw material prepared using the hydrobromic acid / sodium nitrite system can also react completely, the reaction contains many impurities and has a low yield. The product is difficult to be initially purified or completely purified by a simple solvent beating post-treatment. This is not conducive to promoting the effective progress of subsequent reactions in the preparation of tazobactam, thereby reducing product efficiency and is also not conducive to industrial production.

[0048] It can be found that the preparation of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester using the halogenation conditions in the prior art may produce a large amount of six-membered ring impurities. The crude product contains many impurities and the product is difficult to separate and purify, which has a great impact on the subsequent preparation of tazobactam. At the same time, there are problems such as harsh reaction conditions, long reaction time, low yield, large amounts of wastewater and waste gas generated, and significant environmental pollution. When industrial-grade copper halide anhydrous copper chloride or copper bromide is used and the feed amount is less than 100 grams, the reaction can be fully reacted by long-term vigorous stirring. However, during pilot-scale expansion, the copper halide particles will sink to the bottom of the reaction vessel, preventing full reaction, and the yield is far below the level of a small test.

[0049] However, referring to the examples of Examples 1 and 2 of the present invention, it can be found that the present invention overcomes the disadvantage that the existing non-highly refined anhydrous copper halide cannot be scaled up in the reaction of preparing 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester.

[0050] The use of 40-300 mesh anhydrous copper halide allows for uniform distribution throughout the system. The addition of a phase transfer catalyst, in particular, facilitates a more complete reaction, resolving the significant yield reduction associated with scaled-up production using existing technologies. It also addresses the difficulty in separating and purifying impurities in existing halide preparation processes. Therefore, this process is suitable for industrial scale-up production.

Claims

1. An industrial production process for 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, characterized by: 3-Methyl-[2-oxo-4-(2-benzothiazolyldisulfanyl)-1-azetidinyl]-3-butene diphenylmethyl ester is reacted with 80-100 mesh copper halide powder to obtain β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester; The halogenation reaction is carried out under the action of a phase transfer catalyst.

2. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 1, characterized in that: The phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst.

3. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 1, characterized in that: The phase transfer catalyst is preferably tetrabutylammonium bromide.

4. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 1, characterized in that: The copper halide powder is added into the 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenylmethyl ester solution in portions.

5. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester according to claim 1, characterized in that: The specific reaction process is as follows: S1. In a dry environment, at room temperature, the copper halide is crushed and sieved to form a copper halide powder of a specified mesh size; S2. 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenyl ester was dissolved in a solvent to prepare a 0.1-2Kg / 10L solution, and the solution was stirred at -10-5°C for 0.1-1 hour; S3. The copper halide powder obtained in S1 is added in batches to the 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenyl ester solution in S2, a phase transfer catalyst is added, and the reaction is stirred for 1-5 hours. A high-purity product is obtained after post-treatment.

6. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 5, characterized in that: The mass ratio of the 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butene diphenylmethyl ester to the copper halide is 1:0.3-0.

7.

7. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 5, characterized in that: The molar ratio of the copper halide to the phase transfer catalyst is 30-40:

1.

8. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 5, characterized in that: The post-treatment process includes: directly filtering the reaction liquid of S3, eluting the filter cake with an organic solvent, combining the filtrate and the washing liquid, washing with deionized water, sodium bicarbonate aqueous solution, and saturated brine in sequence, drying with anhydrous magnesium sulfate, filtering, and recovering the solvent under reduced pressure of the filtrate to obtain a crude product.

9. The industrial production process of 2β-halomethyl-2α-methyl-6,6-dihydropenicillanoic acid diphenylmethyl ester according to claim 8, characterized in that: The post-treatment process comprises: adding the crude product into a mixed solution of alcohol and ether, beating the mixture at room temperature for more than one hour, filtering, and drying to obtain beta-halomethyl-2alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester.

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