CN115246844A

CN115246844A - Preparation method of tazobactam intermediate

Info

Publication number: CN115246844A
Application number: CN202110463942.3A
Authority: CN
Inventors: 张健; 唐磊; 欧洋; 王同强
Original assignee: SUZHOU LANXITE BIOTECHNOLOGY CO Ltd
Current assignee: SUZHOU LANXITE BIOTECHNOLOGY CO Ltd
Priority date: 2021-04-28
Filing date: 2021-04-28
Publication date: 2022-10-28

Abstract

The invention provides a preparation method of a tazobactam intermediate, which comprises the following steps: taking 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenyl methyl ester formula (I) and 1,2,3-triazole as reaction raw materials, taking a mixed solvent of acetone and water as a reaction solvent, adding an acid-binding agent A and a catalyst B, and carrying out condensation reaction at 20-30 ℃ to prepare an intermediate compound shown in formula (II); wherein A is basic resin or triethylamine, and the catalyst B is metal salt of magnesium or iron. The preparation method provided by the invention effectively reduces and eliminates the product of formula (III), the yield of the prepared intermediate compound shown in formula (II) can reach 90%, the production efficiency is greatly improved, and the preparation method is suitable for large-scale industrial production and has wide application prospect.

Description

Preparation method of tazobactam intermediate

Technical Field

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

Background

Tazobactam is a novel beta-lactamase inhibitor of the penicillanese sulfone type, is developed by the pharmaceutical company of Japan Roc, is used for treating various bacterial infections, and has the characteristics of high stability, low toxicity and strong enzyme inhibition activity, thus being one of the most promising beta-lactamase inhibitors for clinical evaluation at present. 2 alpha-methyl-2 beta- (1,2,3-triazole-1-yl) methyl penam-3 alpha-diphenylmethyl carboxylate is an important intermediate for synthesizing tazobactam, and the structural formula is shown as a formula (II).

The intermediate shown in the formula (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 which are used as reaction raw materials under the action of an acid binding agent, and is also called as a condensation product. In the prior art, besides condensation reaction, elimination reaction can also occur to obtain a byproduct, the structural formula of which is shown as formula (III), so that the yield and the quality of an intermediate are greatly influenced, and Deng Yong, shen Yihe Zhong Yuguo and the like refer to the reaction yield of 72 percent in the synthesis of beta-lactamase inhibitor-tazobactam acid.

The literature: deng Yong, shen Yi, zhong Yuguo, et al, synthesis of beta-lactamase inhibitor, tazobactam acid [ J ], china journal of pharmaceutical chemistry, 2001, 11 (2): 93-95.

The present inventors have made extensive studies to solve the above problems, and as a result, have found that in the presence of a specific metal salt, particularly a magnesium salt or an iron salt, the elimination product in the condensation reaction is greatly reduced, and the yield and quality of the condensation product are significantly improved.

Disclosure of Invention

The invention provides a synthetic method of a tazobactam intermediate, aiming at the problems of more byproducts and low yield in the synthesis of the tazobactam intermediate.

Taking 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester and 1,2,3-triazole as reaction raw materials, taking a mixed solvent of acetone and water as a reaction solvent, adding an acid binding agent A and a catalyst B, and carrying out condensation reaction at 20-30 ℃ to prepare an intermediate compound shown in a formula (II); wherein A is basic resin or triethylamine, and the catalyst B is metal salt of magnesium or iron. The preparation method provided by the invention effectively reduces and eliminates the product, has the yield of more than 90 percent, greatly improves the production efficiency, is suitable for large-scale industrial production, and has wide application prospect.

The technical scheme provided by the invention is as follows:

step one, putting the acetone solution of 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester into a reaction bottle, adding the catalyst B, stirring, and cooling to about 0 ℃.

And step two, adding an acid-binding agent A into the reaction kettle at the temperature of 0-5 ℃, slowly dripping a mixed solution of triazole and water, and slowly heating. The reaction was incubated for X hours and the resin was filtered to terminate the reaction.

And step three, filtering the reaction liquid. The filtrate was concentrated under reduced pressure in a water bath at 30 ℃. Adding dichloromethane, dissolving to clear, standing for layering, washing, and removing triazole. The aqueous layer was extracted with dichloromethane, and the dichloromethane layer was washed with water and separated.

And step four, combining dichloromethane layers, and concentrating to dryness. Ethyl acetate was added and dissolved to a clear solution. Stirring at 30-30 deg.C for crystallizing for 2 hr, maintaining the temperature at 30-30 deg.C for about 2 hr, cooling to 10-15 deg.C, maintaining the temperature overnight, and filtering to obtain solid.

Preferably, the molar ratio of the 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester to the 1,2,3-triazole is 1: 10-20

More preferably, the molar ratio of 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester to 1,2,3-triazole is 1: 15

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

More preferably, the catalyst in step one 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 the second step is an alkaline resin

Preferably, the reaction temperature in step two is 20-30 ℃.

Preferably, the reaction time in step two is 12 to 18 hours.

The technical effects are as follows:

in the presence of specific metal salt, especially magnesium salt or iron salt, the elimination products in the condensation reaction are greatly reduced, and the yield and quality of the condensation product are obviously improved.

Drawings

FIG. 1 shows 2 α -methyl-2 β - (1,2,3-triazol-1-yl) methylpenam-3 αOf diphenylmethyl carboxylates ¹ A HNMR map;

Detailed Description

In order that those skilled in the art may better understand the present invention, the following embodiments further illustrate the present invention. It should be understood that the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention.

Example 1:

adding 40.2 g (0.1no 1) of 2 beta-chloromethyl-2 alpha-methyl-6,6-dihydropenicillanic acid diphenylmethyl ester and acetone Yml into a reaction bottle, adding 0.95 g of magnesium chloride, stirring, and cooling to about 0 ℃. Adding 72g of alkaline resin into a reaction kettle at the temperature of 0-5 ℃, slowly dropwise adding a mixed solution of 138.2 g of triazole and 100g of water, and slowly heating after the addition is finished. Keeping the temperature at 20-30 ℃ for reaction for 12h, filtering the reaction feed liquid, and washing the solid with acetone. The washing filtrates were combined, concentrated under reduced pressure to remove acetone, added with 400ml of dichloromethane, dissolved until clear, and then allowed to stand for separation, and 120ml of water 4 was added to the dichloromethane layer, and washed four times. The dichloromethane layer was concentrated to dryness under reduced pressure in a water bath at 30 ℃ and 40ml of ethyl acetate was added and dissolved to be clear by stirring. Stirring for crystallization for 2 hours, slowly cooling to 10-15 ℃, and keeping the temperature overnight. The solid is obtained by filtration, and the solid is dried under reduced pressure at 30 ℃ to obtain 39.6 g, and the yield is 91.1%.

¹ HNMR：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 charge amount was changed to 40.2 g of 2 β -chloromethyl-2 α -methyl-6,6-dihydropenicillanic acid diphenylmethyl ester and 69.1 g of 1,2,3-triazole, and the rest was the same as in example 1, whereby 38.5 g was obtained, and the yield was 88.6%.

Example 3:

the catalyst was changed to 1.61 g of ferric chloride, and the same procedure was repeated as in example 1 to obtain 35.7 g of ferric chloride with a yield of 82.2%.

Example 4:

the acid-binding agent was changed to triethylamine in the same manner as in example 1 to obtain 37.1 g, and the yield was 85.4%.

Claims

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.