CN115246844A - Preparation method of tazobactam intermediate - Google Patents

Abstract

The invention provides a preparation method of a tazobactam intermediate, comprising the following steps: using 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl formula (I) and 1,2,3-triazole is used as a reaction raw material, a mixed solvent of acetone and water is used as a reaction solvent, an acid binding agent A and a catalyst B are added, and at 20-30° C., a condensation reaction is performed to obtain the formula shown in formula (II) The intermediate compound; wherein, the A is a basic resin or triethylamine, and the catalyst B is a metal salt of magnesium or iron. The preparation method provided by the invention can effectively reduce the elimination of the product formula (III), obtain the intermediate compound represented by the formula (II) in a yield of up to 90%, greatly improve the production efficiency, and is suitable for large-scale industrial production. Broad application prospects.

Description

A kind of preparation method of tazobactam intermediate

technical field

The invention belongs to the technical field of medicine, and relates to a preparation method of a tazobactam intermediate.

Background technique

Tazobactam is a new penicillane sulfone β-lactamase inhibitor developed by Japan's Dapeng Pharmaceutical Company for the treatment of various bacterial infections. It has high stability, low toxicity and strong enzyme inhibitory activity. Characterized by one of the most promising beta-lactamase inhibitors currently in clinical evaluation. 2α-methyl-2β-(1,2,3-triazol-1-yl) methyl penicillane-3α-carboxylate diphenylmethyl is an important intermediate in the synthesis of tazobactam, and its structural formula is shown in the formula ( II).

The intermediate shown in formula (II) is composed of 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl as shown in formula (I) and 1,2,3- Triazole is obtained by condensation of reaction raw material under the action of acid binding agent, so it is also called condensation product. In the existing technology, except that condensation reaction occurs, elimination reaction can also occur, and its structural formula of by-product is obtained such as formula (III), which greatly affects the yield and the quality of the intermediate. Deng Yong, Shen Yi and Zhong Yuguo etc. - Synthesis of Lactamase Inhibitor - Tazobactam Acid" mentioned that the yield of this reaction was 72%.

Literature: Deng Yong, Shen Yi, Zhong Yuguo, etc., Synthesis of β-lactamase inhibitor - tazobactam acid [J], Chinese Journal of Medicinal Chemistry, 2001, 11(2): 93-95.

In order to solve the above problems, the inventors have carried out repeated and in-depth research, and found that in the presence of specific metal salts, especially magnesium salts or iron salts, the elimination products in the condensation reaction are greatly reduced, and the yield of condensation products is significantly improved. and quality.

SUMMARY OF THE INVENTION

Aiming at the problems of many by-products and low yields in the synthesis of tazobactam intermediates, the present invention provides a method for synthesizing tazobactam intermediates.

Take 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl and 1,2,3-triazole as the reaction raw materials, and use the mixed solvent of acetone and water as the reaction solvent , adding acid binding agent A and catalyst B, at 20-30 ° C, through a condensation reaction to prepare the intermediate compound shown in formula (II); wherein, the A is a basic resin or triethylamine, and the catalyst B is magnesium. or iron metal salts. The preparation method provided by the invention can effectively reduce the elimination products, the yield is over 90%, the production efficiency is greatly improved, it is suitable for large-scale industrial production, and has broad application prospects.

The technical scheme provided by the present invention is:

Step 1. Put the acetone solution of 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl into the reaction flask, add catalyst B, stir, and cool down to about 0°C.

Step 2: Add acid binding agent A to the reaction kettle at 0-5°C, slowly drop a mixture of triazole and water, and slowly heat up. The reaction was incubated for X hours, and the reaction was terminated by filtering the resin.

Step 3: Filtration of the reaction feed liquid. The filtrate was concentrated under reduced pressure in a water bath at 30°C. Dichloromethane was added, dissolved until clear, left to stand for layers, washed to remove triazole. The aqueous layer was extracted with dichloromethane, the dichloromethane layer was washed with water, and the layers were separated.

Step 4. Combine the dichloromethane layers and concentrate to dryness. Ethyl acetate was added and dissolved until clear. 30-30°C, stirring and crystallization for 2 hours, keeping at 30-30°C for about 2 hours, cooling to 10-15°C, keeping the temperature overnight, and filtering to obtain a solid.

Preferably, the molar ratio of the 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl to 1,2,3-triazole is 1:10-20

More preferably, the molar ratio of 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl and 1,2,3-triazole is 1:15

Preferably, in step 1, the catalyst is magnesium chloride or ferric chloride

More preferably, in step 1, catalyst is magnesium chloride

Preferably, the acid binding agent in the second step is an organic amine such as basic resin and triethylamine.

More preferably, the acid binding agent in step 2 is basic resin

Preferably, the reaction temperature in step 2 is 20-30°C.

Preferably, the reaction time in step 2 is 12-18 hours.

Technical effect:

In the presence of specific metal salts, especially magnesium salts or iron salts, the elimination products in the condensation reaction are greatly reduced, and the yield and quality of the condensation products are significantly improved.

Description of drawings

Accompanying drawing 1 is the ¹ HNMR chart of 2α-methyl-2β-(1,2,3-triazol-1-yl)methylpenicillane-3α-carboxylate diphenylmethyl;

Detailed ways

In order to enable those skilled in the art to better understand the present invention, the technical solutions of the present invention are further described below through specific embodiments. It should be understood that the following embodiments are only given to better illustrate the present invention, and are not intended to limit the content of the present invention.

Example 1:

2β-Chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl 40.2g (0.1no1) and acetone Yml into the reaction flask, add 0.95g of magnesium chloride, stir, cool down to 0 ℃ or so. Add 72 g of basic resin to the reaction kettle at 0-5° C., slowly add a mixture of 138.2 g of triazole and 100 g of water dropwise, and slowly heat up after the addition is completed. The reaction was incubated at 20-30 °C for 12 h, the reaction solution was filtered, and the solid was washed with acetone. Combine and wash the filtrates, concentrate under reduced pressure to remove acetone, add 400 ml of dichloromethane, dissolve until clear, leave to stand for layers, add 120 ml*4 of water to the dichloromethane layer, and wash four times. The dichloromethane layer was concentrated to dryness under reduced pressure under a water bath at 30°C, 40 ml of ethyl acetate was added, and the mixture was stirred and dissolved until it became clear. Stir and crystallize for 2 hours, slowly lower the temperature to 10-15°C, and keep the temperature overnight. The solid was filtered and dried under reduced pressure at 30°C to obtain about 39.6 g, with a yield of 91.1%.

¹ H NMR: 7.74(2H), 7.32(10H), 6.91(1H), 5.42(1H), 4.87(1H), 4.59(2H), 3.67(1H), 3.18(1H), 1.22(3H)

Example 2:

The feeding amount is changed to 40.2 g of 2β-chloromethyl-2α-methyl-6,6-dihydropenicillic acid diphenylmethyl, 1,2,3-triazole 69.1 g, and the rest are the same as in Example 1 , 38.5 grams were obtained, the yield was 88.6%.

Example 3:

The catalyst was changed to 1.61 g of ferric chloride, and the rest were the same as in Example 1, yielding 35.7 g, a yield of 82.2%.

Example 4:

The acid binding agent was changed to triethylamine, and the rest were the same as those in Example 1, yielding 37.1 g, a yield of 85.4%.

Claims (7)

1. A preparation method of a tazobactam intermediate is characterized by comprising the following steps:

the intermediate compound shown in (II) is prepared by condensing 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester shown in the formula (I) and 1,2,3-triazole serving as reaction raw materials under the action of an acid-binding agent and metal salts such as magnesium, iron and the like.

2. The process as claimed in claim 1, wherein the molar ratio of 2 β -chloromethyl-2 α -methyl-6,6-dihydropenicillanic acid diphenylmethyl ester to 1,2,3-triazole is 1: 10-20.

3. The molar ratio of 2 β -chloromethyl-2 α -methyl-6,6-dihydropenicillanic acid diphenylmethyl ester and 1,2,3-triazole as claimed in claim 1 is 1: 15.

4. The catalyst of claim 1, which is magnesium chloride or ferric chloride.

5. The catalyst of claim 1 which is magnesium chloride.

6. The reaction temperature of claim 1 is 20 to 30 ℃.

7. The reaction time of claim 1 is 12-18h.

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