Preparation method of tazobactam intermediate

A compound and selected technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of high cost, unsatisfactory yield, and unfavorable industrial production.

Active Publication Date: 2019-04-26
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route takes 6-APA (6-aminopenicillanic acid) as starting raw material, and after bromination and reoxidation, the yield of the two steps is only about 50%, and the yield is not ideal, resulting in high cost and unfavorable industrial production

Method used

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  • Preparation method of tazobactam intermediate
  • Preparation method of tazobactam intermediate
  • Preparation method of tazobactam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Add 750ml of water and 750ml of 1,4-dioxane to the reaction flask, add 6-APA (50g) to dissolve, add TEA (47g), dissolve and clear, add Boc anhydride (65.6g), control the temperature at 15-20°C, and keep warm for 12h , the conversion of raw materials is completed, and there is no need to concentrate and directly oxidize. Add sodium tungstate (0.5g) to the above reaction solution, add hydrogen peroxide (9.4g) dropwise at room temperature, react at room temperature for 2 hours, and the reaction monitoring ends. Post-treatment: Spin the aqueous solution to dry 1,4-dioxane, then lower the temperature to 0°C, keep warm to adjust the pH value to 3-4, precipitate solid, keep warm for 2 hours, and filter to obtain solid compound 1 (61.2g), two-step yield 80%.

[0056] Raw materials (50g), diphenylmethanol (27.7g), DMAP (1.8g), and DCE (350ml) were used as solvents, and the temperature was lowered to 5-10°C, and DCC (37g) / DCE (200ml) solution was slowly added, and kept warm afte...

Embodiment 2

[0059] Add 2000ml of water and 2000ml of 1,4-dioxane to the reaction flask, add 6-APA (200g) to dissolve, add TEA (186g), dissolve, add Boc anhydride (261g), control the temperature at 15-20°C, and keep it warm for 12h. After the conversion of raw materials is completed, direct oxidation without concentration is required. Add sodium tungstate (2g) to the above reaction solution, add hydrogen peroxide (37.5g) dropwise at room temperature, react at room temperature for 2 hours, and the reaction monitoring ends. Post-treatment: the aqueous solution was spin-dried with dioxane, then cooled to 0°C, and kept warm to adjust the pH value to 3-4. Solids were precipitated, kept warm for 2 hours, and filtered to obtain solid compound 1 (251 g). The two-step yield was 82%.

[0060] Raw material (100g), diphenylmethanol (55g), DMAP (3.7g), DCE (700ml) as solvent, lower the temperature to 5-10°C, start to add DCC (74g) / DCE (400ml) solution slowly, and keep warm for reaction After 2 to 3 ho...

Embodiment 3

[0063] Add 5000ml of water and 5000ml of 1,4-dioxane to the reaction bottle, add 6-APA (500g) to dissolve, add TEA (470g), dissolve and clear, add Boc anhydride (653g), control the temperature at 15-20°C, keep warm for 12h, After the conversion of raw materials is completed, direct oxidation without concentration is required. Sodium tungstate (5 g) was added to the above reaction solution, and hydrogen peroxide (94 g) was added dropwise at room temperature, and reacted at room temperature for 2 hours, and the reaction monitoring was completed. Post-treatment: the aqueous solution was spin-dried with dioxane, then cooled to 0°C, and kept warm to adjust the pH value to 3-4. Solids were precipitated, kept warm for 2 hours, and filtered to obtain solid compound 1 (627g). The two-step yield was 82%.

[0064] Raw material (500g), diphenylmethanol (277g), DMAP (183g), DCE (3500ml) as solvent, lower the temperature to 5-10°C, start to add DCC (371g) / DCE (2000ml) solution slowly, and k...

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Abstract

The invention provides a method for preparing a tazobactam intermediate. The method comprises the following steps: (1) introducing an amino-protecting group on an amino group of 6-APA (amino penicillanic acid) and performing oxidization with an oxidant, so as to obtain a compound 1, wherein the amino-protecting group is Boc preferably; (2) performing an esterification reaction on the compound 1 and an alcoholic compound, so as to obtain a compound 2, wherein the alcoholic compound is diphenyl carbinol preferably; (3) removing a Boc-NH-group from the compound 2, so as to obtain the tazobactam intermediate. According to the method, the amino group of 6-APA is protected by adopting protecting groups such as the Boc, so that a generated amino-protecting product is poor in water solubility andsteady in chemical properties; in addition, concentration is not needed in the first step, an oxidation reaction in the next step can be directly performed, and the total yield of the two steps reaches 80%.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an intermediate used as a beta-lactamase inhibitor tazobactam. Background technique [0002] The chemical name of tazobactam is 2α-methyl-2β-(1,2,3-triazol-1-yl)methylpenicillane sulfone-3α-carboxylic acid, and its structural formula is as follows: [0003] [0004] Tazobactam is a new type of penicillane sulfone β-lactamase inhibitor developed by Japan Dapeng Pharmaceutical Co. Low toxicity, strong enzyme inhibitory activity and so on. In 1992, the compound drug tazobactam / piperacillin (1:8) of tazobactam was first launched in France for the treatment of various bacterial infections. [0005] Taniguchi, M., etc. (EP 0031146, 1989) etc. used penicillane-3a carboxylate diphenylmethyl ester-1β-oxide as raw material through ring opening, chloromethylation, azidation, potassium permanganate oxidation, Synthesis of tazobactam by 1,3-dip...

Claims

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Application Information

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IPC IPC(8): C07D499/08C07D499/12C07D499/04C07D499/86C07D499/78
CPCC07D499/04C07D499/08C07D499/12C07D499/78C07D499/86Y02P20/55
Inventor李文森张文琦
OwnerHEADING NANJING PHARMTECH CO LTD