One-step green production process for preparing tazobactam diphenyl methyl ester

Abstract

The invention provides a green production process for preparing tazobactam diphenyl methyl ester by a one-step method, characterized in that: 3-methyl-[2-oxo-4-(2-benzothiazole disulfide)-1-azetidinyl]-3-butenoic acid diphenyl methyl ester is used as a raw material, and tazobactam diphenyl methyl ester is obtained by continuously undergoing a bromination ring-closing reaction, a nucleophilic substitution reaction with silver triazole, and an oxidation reaction. The process has safe production operation, low production cost, short production cycle, and low environmental pollution.

Description

Technical Field

[0001] The invention belongs to the field of green chemical pharmacy, and specifically relates to a synthetic method for preparing tazobactam diphenylmethyl ester. Background Art

[0002] Tazobactam, with the chemical name [2S-(2α,2β,5α)-3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-methyl)-4-thia-1-azabicyclo-[3,2,0]-heptane-2-carboxylic acid-4,4-dioxide. This drug is a new penicillin sulfone β-lactamase inhibitor developed by Taiho Pharmaceutical Co., Ltd. of Japan. It was first launched in France in 1992 as a combination drug of tazobactam / piperacillin (1:8) for the treatment of various bacterial infections. Tazobactam is currently recognized as the β-lactamase inhibitor with the broadest antibacterial spectrum, the best resistance and the most promising, with the characteristics of strong enzyme inhibition activity, high stability, low activity and low toxicity. The compound tazobactam diphenyl methyl ester is an upstream product for the synthesis of tazobactam. Since its synthesis yield is very low, the production process of tazobactam is greatly limited, so there is a lot of room for improvement in the synthesis process of tazobactam diphenyl methyl ester.

[0003] At present, the literature reports that there are several methods for synthesizing tazobactam diphenyl methyl ester:

[0004] Literature reports on the synthesis of tazobactam include two main preparation methods according to the different ways of introducing the triazole ring: synthesizing the five-membered triazole ring through the cycloaddition of an azide compound and directly adding a side chain triazole ring.

[0005] Cao Lin et al. disclosed a method for preparing tazobactam diphenylmethyl ester, the route of which is as follows:

[0006]

[0007] The azide compound cycloaddition preparation method uses penicillanic acid diphenylmethyl ester sulfoxide as a raw material, and undergoes thermal cracking ring opening, chlorination cyclization, substitution of azide groups, oxidation, and cycloaddition to obtain tazobactam diphenylmethyl ester. Although each step is relatively simple, most manufacturers on the market still use this route, but the use of acetylene cycloaddition reaction requires high temperature and high pressure conditions, and the use of highly dangerous sodium azide is prone to safety accidents. At the same time, a large amount of six-membered ring by-products are generated in the azidation reaction and are difficult to separate, the overall yield is low, and the production cost is high.

[0008] 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 a method for preparing tazobactam diphenylmethyl ester.

[0009]

[0010] Direct addition of triazole side chain is currently a hot topic in the research of synthesizing tazobactam; however, the use of sulfuryl chloride as a chlorination reagent generates a large amount of waste acid and waste gas in post-treatment, which increases the cost of post-treatment and causes serious environmental pollution; although a small amount of product is generated when the chlorinated material is directly reacted with triazole under alkaline conditions, almost all of the products obtained are six-membered ring impurities.

[0011] In order to avoid the formation of a six-membered ring as a byproduct, CN102020663A discloses that tazobactam diphenylmethyl sulfoxide is directly reacted with 2-trimethylsilyl-1,2,3-triazole without thermal cracking and ring opening, and triazole is added, and the route is as follows:

[0012]

[0013] This method has the shortest reaction steps, but the reaction conditions are very harsh. The reaction system must be strictly anhydrous, and the product needs to use benzene as an eluent for column chromatography separation. The use of benzene causes great harm to the operator. The preparation of 2-trimethylsilyl-1,2,3-triazole also requires strict anhydrous conditions, the reaction is difficult, high temperature and pressure are required, and high requirements are placed on equipment. In addition, trimethylsilyl-1,2,3-triazole is difficult to store, so it cannot be used in industrial production.

[0014] In addition, there are also documents that propose that when 3-methyl-[2-oxo-4-(2-benzothiazole disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester is used for the key CN coupling reaction with silver triazole, since a byproduct thiazole dimer insoluble in the reaction solvent is generated during the reaction, it will adhere to the surface of the silver triazole solid particles, hindering the contact between silver triazole and other raw materials. Therefore, it is difficult for the raw materials to fully participate in the reaction, making it difficult for the reaction to proceed smoothly, resulting in a low yield. In addition, the reaction also requires the use of easily sublimated iodine. When the reaction is amplified, it is easy to cause harm to the health of the operator, and there are very serious safety hazards. Summary of the invention

[0015] The present invention aims to provide a method for preparing tazobactam diphenylmethyl ester, which has the advantages of safe production operation, low production cost, short production cycle and small environmental pollution.

[0016] Specifically, the present invention provides a one-step green production process for preparing tazobactam diphenyl methyl ester, characterized in that: 3-methyl-[2-oxo-4-(2-benzothiazolyl disulfide)-1-azetidinyl]-3-butenoic acid diphenyl methyl ester is used as a raw material, and tazobactam diphenyl methyl ester is obtained by continuously undergoing a bromination ring-closing reaction, a nucleophilic substitution reaction with silver triazole, and an oxidation reaction;

[0017] Wherein, the 3-methyl-[2-oxo-4-(2-benzothiazolyl disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester is a compound shown in the following structure:

[0018]

[0019] The specific reaction equation is as follows:

[0020]

[0021] Furthermore, the present invention provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is also characterized by:

[0022] The reaction product of the bromination ring-closing reaction is: 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester;

[0023] The 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is a compound shown in the following structure:

[0024]

[0025] Furthermore, the present invention provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is also characterized by:

[0026] The reaction product of the nucleophilic substitution reaction is: 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester:

[0027] The 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is a compound shown in the following structure:

[0028]

[0029] Furthermore, the present invention provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is also characterized by:

[0030] The bromination ring-closing reaction is carried out using 3-methyl-[2-oxo-4-(2-benzothiazolyl disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester as a raw material in the presence of hydrobromic acid, sodium nitrite and a phase transfer catalyst.

[0031] Wherein, the molar ratio of 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester: hydrobromic acid: sodium nitrite: phase transfer catalyst is 1: 5-10: 1-2: 0.02-0.1;

[0032] The reaction temperature of the bromination ring-closing reaction is set to -10--5°C;

[0033] The reaction time of the bromination ring-closing reaction is 0.5-2 hours.

[0034] In the bromination ring-closing reaction process, copper bromide can actually be used as a bromine agent, but copper bromide is relatively expensive and will produce heavy metal residues.

[0035] Furthermore, the present invention provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is also characterized by:

[0036] In the nucleophilic substitution reaction, the molar ratio of 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester as a raw material to silver triazole is set to 1:1-2;

[0037] The reaction temperature of the nucleophilic substitution reaction is 20-25°C;

[0038] The reaction time of the nucleophilic substitution reaction is 1-5 hours.

[0039] In the present invention, the nucleophilic substitution reaction adopts the SN2 mechanism, which can avoid the use of iodine, thereby improving production safety. Moreover, due to the difference in mechanism, the generation of dimers can be avoided compared with the traditional reaction process, thereby improving the conversion rate, improving the reaction efficiency, and reducing the raw material cost.

[0040] Furthermore, the present invention provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is also characterized by:

[0041] The oxidation reaction uses 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester as a raw material, and oxidizes it with potassium permanganate and acetic acid to obtain tazobactam diphenylmethyl ester;

[0042] Wherein, the molar ratio of 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester: potassium permanganate: acetic acid is 1:1.5-2:15-20;

[0043] The reaction temperature of the oxidation reaction is 20-25°C;

[0044] The reaction time of the oxidation reaction is 1-5 hours.

[0045] Furthermore, the present invention provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is also characterized by:

[0046] The purification method of the tazobactam diphenyl methyl ester is as follows:

[0047] S1. After the reaction is completed, cool to 0-5 ° C and stir for 5-20 minutes;

[0048] S2. Add hydrogen peroxide dropwise until the purple-black color of the reaction solution just fades away;

[0049] S3. Keep warm and stir for 0.2-1 hours and filter;

[0050] S4. The filter cake is stirred and slurried with a mixed solvent of alcohol and ketone at 70-75°C for 0.5-2 hours, and then cooled to room temperature;

[0051] S5. After filtering, washing and drying, a purified product is obtained.

[0052] In addition, the present invention also provides a one-step green production process for preparing tazobactam diphenylmethyl ester, which is characterized by:

[0053] Using penicillanic acid diphenylmethyl sulfoxide as a raw material, tazobactam diphenylmethyl ester is obtained through a continuous ring-opening reaction, a bromination ring-closing reaction, a nucleophilic substitution reaction with silver triazole and an oxidation reaction.

[0054] Wherein, the penicillanic acid diphenylmethyl ester sulfoxide is a compound shown in the following structure:

[0055]

[0056] The reaction route is as follows:

[0057]

[0058] The green production process for preparing tazobactam diphenylmethyl ester by one-step method is also characterized in that:

[0059] The bromination ring-closing reaction is the same as above;

[0060] The silver triazole undergoes a nucleophilic substitution reaction as described above.

[0061] The green production process for preparing tazobactam diphenylmethyl ester by one-step method is also characterized in that:

[0062] The ring-opening reaction is to use penicillanic acid diphenylmethyl ester sulfoxide as a raw material and 2-mercaptobenzothiazole under the reaction conditions of reflux and water separation to prepare 3-methyl-[2-oxo-4-(2-benzothiazole disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester;

[0063] Wherein, the molar ratio of penicillanic acid diphenylmethyl ester sulfoxide to 2-mercaptobenzothiazole is 1:0.95-1.5.

[0064] In the present invention, the four-step reaction is completed by a one-step process, which can greatly shorten the production cycle and improve production efficiency. It is also simple to operate and easy to control. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 .Product mass spectrum;

[0066] Figure 2 .Product hydrogen spectrum;

[0067] Figure 3 .Mass spectrum of by-products;

[0068] Figure 4 . Hydrogen spectrum of by-products. DETAILED DESCRIPTION

[0069] The present invention is further described below through specific implementation cases, but the present invention is not limited to the scope of the following examples. The test methods without specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product instructions.

[0070] In this embodiment, the following reaction process is specifically adopted:

[0071]

[0072] In this embodiment, the reaction process from compound 1 to compound 2 was carried out using different ratios of penicillanic acid diphenylmethyl ester sulfoxide to 2-mercaptobenzothiazole, such as 1:0.95; 1:1; 1:1.2; 1:1.5.

[0073] In the reaction process from compound 2 to compound 3, different ratios of 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester: hydrobromic acid: sodium nitrite: tetrabutylammonium bromide were used for the reaction respectively; 1:5:1:0.02; 1:5:2:0.1; 1:10:2:0.1; 1:7:1.5:0.05; 1:8:1.8:0.07;

[0074] In the reaction process from compound 3 to compound 4, 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester was used as a raw material and the molar ratio of silver triazole was set to 1:1; 1:2 and other different ratios for reaction;

[0075] The reaction process from compound 4 to compound 5 was carried out using different ratios of 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester: potassium permanganate: acetic acid, such as 1:1.5:15; 1:2:20; 1:1.8:16; 1:1.7:19.

[0076] When the reaction is carried out according to the above reaction ratio, when the product purity is greater than 95%, the yield of the final product is basically between 55% and 69%.

[0077] Finally, the following Examples 1 and 2 were selected as the optimal reaction conditions.

[0078] Example 1

[0079] (1) Add 350 mL of toluene to a 500 mL three-necked flask, place the reaction flask in an oil bath and connect it to a water separator, heat up and reflux, collect the effluent, and after collecting about 50 mL, add penicillanic acid diphenylmethyl ester sulfoxide (30 g, 91%) and 2-mercaptobenzothiazole (13 g), continue to reflux and separate the water for 1 h, distill out about 50 mL of liquid, cool to room temperature, and obtain a toluene solution containing the thermal cracking ring-opening product, which is directly used for the next step reaction.

[0080] (2) Weigh the above toluene solution into a 1000 mL three-necked flask, add 300 mL toluene, stir and cool to -5°C, begin to dropwise add 20% hydrobromic acid aqueous solution (227.8 g), add tetrabutylammonium bromide (1.81 g), then dropwise add 2 mol / L NaNO2 (7.77 g) aqueous solution, after the dropwise addition, the reaction liquid is brown-black with foam, keep warm at -10 to -5°C for about 1 h, filter, wash, and dry to obtain a toluene solution of the bromine compound, which is directly used in the next step.

[0081] (3) The toluene solution containing the bromine compound in (2) was placed in a 1000 mL three-necked flask and stirred at 20°C. Silver trinitrate (15 g) was added at once and stirred for 3 h. After the raw materials were basically reacted, they were filtered, washed, and the solvent was evaporated under reduced pressure to obtain 40 g of a yellow oily substance, namely, methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which was directly used in the next step reaction.

[0082] (4) Dissolve the yellow oil in 400 mL of acetone, transfer to a 1000 mL three-necked flask, cool to 0-5°C and stir for 10 min, add 320 mL of ice water, add glacial acetic acid (67.6 g) in sequence, and add potassium permanganate (17.7 g) in batches over 20 min (in 4 batches), and then transfer to 20-25°C for reaction. The reaction is completed in about 3 h. The mixture was cooled to 0-5°C and stirred for 10 min, and 30% hydrogen peroxide was added dropwise until the purple-black color of the reaction solution just faded. The mixture was kept warm and stirred for 0.5 h, filtered, and the filter cake was added with 300 mL of a mixture of methanol and acetone (in a ratio of 1:1, 1:2, 1:3, etc.) and stirred and slurried at 70-75°C for 1 h. The mixture was cooled to room temperature, filtered, washed, and dried to obtain 25.20 g of a white solid powder, which was tazobactam diphenylmethyl ester. The four-step reaction yield was 69.02%, the HPLC purity was 95.03% (normalization method), the melting point was 202-204°C, and ESI-MS (m / z): 489.1 (M+Na). + . (See Appendix - Figure 1 )

[0083] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.96 (s, 1H, -CH=CH), 7.77 (s, 1H, -CH=CH), 7.27–7.55 (m, 10H, -Ph), 6.99 (s, 1H, -CHPh2), 5.22–5.36 (m, 3H, -CHCO2, -CH2N3, -CHS), 4.96 (d, J=15.4Hz, 1H, -CH2N3), 3.77 (dd, J=16.6, 4.5Hz, 1H, -CH2CON), 3.34–3.39 (m, 1H, -CH2CON), 1.12 (s, 3H, -CH3). (See Appendix - Figure 2 )

[0084] 2.56 g of white foam was separated from the mother liquor after post-treatment, ES I-MS (m / z): 467.1 (M+H) + . (See Appendix - Figure 3 )

[0085] 1H NMR(600MHz,CDC l3)δ(ppm):7.64(s,2H,-CH=CH),7.30–7.39(m,10H,-Ph),6.93(s,1H,-CHPh2),5.12(d,J=14.6Hz,1H,-CH2S),5.09(s,1H,-C HCO2), 4.95 (d, J=14.6Hz, 1H, -CH2S), 4.62 (dd, J=4.1, 2.1Hz, 1H, -CHS), 3.46–3.59 (m, 2H, -CH2CON), 1.05 (s, 3H, -CH3). (See Appendix - Figure 4 )

[0086] From the mass spectrum and hydrogen spectrum of tazobactam diphenylmethyl ester (5), it was inferred that the structure of the white solid was a six-membered ring isomer impurity.

[0087] Example 2

[0088] (1) Add 580 mL of toluene to a 1000 mL three-necked flask, place the reaction flask in an oil bath and connect it to a water separator, heat and reflux, and after about 80 mL of toluene is distilled out, add penicillanic acid diphenylmethyl ester sulfoxide (50 g, 91%) and 2-mercaptobenzothiazole (21.6 g) to the reaction flask, continue to reflux and separate water for 1 h, and accumulate about 100 mL of distilled liquid. Cool to room temperature to obtain a toluene solution containing the thermal cracking ring-opening product, which is directly used in the next step reaction.

[0089] (2) Weigh the toluene solution of the above-mentioned thermal cracking ring-opening product, put it into a 2000 mL three-necked flask, add 600 mL of toluene, stir at -10°C, start to drop 20% hydrobromic acid aqueous solution (528 g), add tetrabutylammonium bromide (2.1 g) directly after the dropwise addition, and add 2 mol / L NaNO2 (33.5 g) aqueous solution. After the dropwise addition, the reaction liquid is brown-black with foam. Keep the reaction at -10 to -5°C for about 1 h, filter, wash, and dry to obtain a toluene solution containing bromine compounds, which is directly used in the next step.

[0090] (3) The toluene solution containing the bromine compound in (2) was placed in a 1000 mL three-necked flask and stirred at 20°C. Silver trinitrate (24.6 g) was added at once and stirred for 4 h. After the raw materials were basically reacted, they were filtered, washed, and the solvent was removed by vacuum distillation to obtain 75 g of a yellow oily substance, namely, methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester, which was directly used in the next step reaction.

[0091] (4) Dissolve the yellow oil in 750 mL of acetone, transfer to a 2000 mL reaction bottle, cool to 0-5°C and stir for 10 min, add 600 mL of ice water, add glacial acetic acid (152 g), and add potassium permanganate (41.4 g) in batches over 20 min (in 4 batches), and then transfer to 20-25°C for reaction. The reaction is completed in about 3 h. The mixture was cooled to 0-5°C and stirred for 10 min, and 30% hydrogen peroxide was added dropwise until the purple-black color of the reaction solution just faded. The mixture was kept warm and stirred for 0.5 h, filtered, and the filter cake was added with 460 mL of a mixed solvent of methanol and acetone (1:2) and stirred and slurried at 70-75°C for 1 h. The mixture was cooled to room temperature, filtered, washed, and dried to obtain 41.78 g of a white solid powder, which was tazobactam diphenylmethyl ester, with a yield of 68.75%, HPLC purity of 95.15% (normalization method), and a melting point of 202-204°C (literature value = 202-205°C).

Claims

1. A production process for preparing tazobactam diphenyl methyl ester, characterized in that: Using 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester as a raw material, tazobactam diphenylmethyl ester is obtained by continuous bromination ring-closing reaction, nucleophilic substitution reaction with silver triazole and oxidation reaction. Wherein, the 3-methyl-[2-oxo-4-(2-benzothiazolyl disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester is a compound shown in the following structure: The reaction equation is as follows: The bromination ring-closing reaction is carried out using 3-methyl-[2-oxo-4-(2-benzothiazolyl disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester as a raw material in the presence of hydrobromic acid, sodium nitrite and a phase transfer catalyst. Wherein, the molar ratio of 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester: hydrobromic acid: sodium nitrite: phase transfer catalyst is 1: 5-10: 1-2: 0.02-0.1; the reaction temperature of the bromination ring-closing reaction is set at -10--5°C; The reaction time of the bromination ring-closing reaction is 0.5-2 hours; In the nucleophilic substitution reaction, the molar ratio of 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester as a raw material to silver triazole is set to 1:1-2; The reaction temperature of the nucleophilic substitution reaction is 20-25°C; The reaction time of the nucleophilic substitution reaction is 1-5 hours; The oxidation reaction uses 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester as a raw material, and oxidizes it with potassium permanganate and acetic acid to obtain tazobactam diphenylmethyl ester; Wherein, the molar ratio of 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester: potassium permanganate: acetic acid is 1:1.5-2:15-20; The reaction temperature of the oxidation reaction is 20-25°C; The reaction time of the oxidation reaction is 1-5 hours.

2. A production process for preparing tazobactam diphenylmethyl ester according to claim 1, characterized in that: The reaction product of the bromination ring-closing reaction is: 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester; The 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is a compound shown in the following structure:

3. A production process for preparing tazobactam diphenylmethyl ester according to claim 1, characterized in that: The reaction product of the nucleophilic substitution reaction is: 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester: The 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is a compound shown in the following structure:

4. A production process for preparing tazobactam diphenylmethyl ester according to claim 1, characterized in that: The purification method of the tazobactam diphenyl methyl ester is as follows: S1. After the reaction is completed, cool to 0-5 ° C and stir for 5-20 minutes; S2. Add hydrogen peroxide dropwise until the purple-black color of the reaction solution just fades away; S3. Keep warm and stir for 0.2-1 hours and filter; S4. The filter cake is stirred and slurried with a mixed solvent of alcohol and ketone at 70-75°C for 0.5-2 hours, and then cooled to room temperature; S5. After filtering, washing and drying, a purified product is obtained.

5. A production process for preparing tazobactam diphenyl methyl ester, characterized in that: Using penicillanic acid diphenylmethyl sulfoxide as a raw material, tazobactam diphenylmethyl ester is obtained through a continuous ring-opening reaction, a bromination ring-closing reaction, a nucleophilic substitution reaction with silver triazole and an oxidation reaction. Wherein, the penicillanic acid diphenylmethyl ester sulfoxide is a compound shown in the following structure:

6. A production process for preparing tazobactam diphenylmethyl ester according to claim 5, characterized in that: The reaction product of the bromination ring-closing reaction is: 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester; The 2β-bromomethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is a compound shown in the following structure: The silver triazole undergoes a nucleophilic substitution reaction: 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester: The 2α-methyl-2β-triazolylmethyl-2-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester is a compound shown in the following structure:

7. A production process for preparing tazobactam diphenylmethyl ester according to claim 5, characterized in that: The ring-opening reaction is to use penicillanic acid diphenylmethyl ester sulfoxide as a raw material and 2-mercaptobenzothiazole under the reaction conditions of reflux and water separation to prepare 3-methyl-[2-oxo-4-(2-benzothiazole disulfide)-1-azetidinyl]-3-butenoic acid diphenylmethyl ester; Wherein, the molar ratio of penicillanic acid diphenylmethyl ester sulfoxide to 2-mercaptobenzothiazole is 1:0.95-1.5.

Images