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A high-purity selective preparation and purification method of aminothioxamic acid dimer

A technology of aminothiaxamic acid dimer and purification method, which is applied in the direction of organic chemistry, can solve the problem of no dimer being found, achieve the effect of improving product purity, simplifying the process flow, and realizing selective preparation

Active Publication Date: 2021-07-20
河北合佳医药科技集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] At present, there is no literature report on the preparation of the dimer by means of chemical synthesis and purification at home and abroad.

Method used

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  • A high-purity selective preparation and purification method of aminothioxamic acid dimer
  • A high-purity selective preparation and purification method of aminothioxamic acid dimer
  • A high-purity selective preparation and purification method of aminothioxamic acid dimer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add 100ml of dichloromethane into a 250ml four-necked bottle, add 20.8g of athioxamic acid, cool down to 0°C, add 8.4g of diethylamine, control the temperature at 0-2°C, and stir for 60 minutes until it dissolves. In another 500ml four-neck bottle, add 150ml of dichloromethane, 21g of athioxamic acid, cool down to 0°C, add 11g of triethylamine, control the temperature at 0-2°C, stir for 60min until dissolved, cool down to -35°C, add 13.2g of pivaloyl chloride , N-methylmorpholine 0.83g, react at -20°C for 60min under temperature control.

[0042] Add the solution to the mixed anhydride solution, add 1g of DCC, control the temperature at -20°C, add triethylamine dropwise during the process to control the pH=7.5, and react for 5 hours to obtain a light yellow suspension. Suction filtration, the filtrate is at 30°C, -0.08Mpa Distill under vacuum until no distillate flows out. Add 100ml of water dropwise over 1.5h to precipitate a light yellow solid, filter and wash the fil...

Embodiment 2

[0044] Add 80ml of acetonitrile to a 250ml four-necked flask, add 20.8g of acetioxamic acid, cool down to 0°C, add 9.4g of tetramethylguanidine, control the temperature at 5°C, and stir for 60 minutes until it dissolves. Another 500ml four-neck bottle was added with 180ml of acetonitrile, 21g of aminothioxamic acid, cooled to 0°C, added 10g of diethylamine, controlled temperature at 5°C, stirred for 60min until dissolved, cooled to -30°C, added 13.2g of pivaloyl chloride, N-formazol 0.83 g of morpholine was reacted at -15°C for 60 minutes.

[0045]Add the solution to the mixed anhydride solution, add 1.5g of BSA, control the temperature at -15°C, add diethylamine dropwise during the process to control the pH=8.0, and react for 3 hours to obtain a light yellow suspension. Suction filtration, the filtrate is at 50°C, - Distill under vacuum condition of 0.08Mpa until no distillate flows out, add 200ml of water dropwise in 2 hours, precipitate a light yellow solid, filter, wash th...

Embodiment 3

[0047] Add 120ml of ethyl acetate to a 250ml four-necked bottle, add 20.8g of aminothiaxamic acid, cool down to 0°C, add 7.8g of triethylamine, control the temperature at 5°C, and stir for 60 minutes until dissolved. In another 500ml four-necked bottle, add 180ml of ethyl acetate, 21g of aminothiaxamic acid and cool down to 0°C, add 10g of diethylamine, control the temperature at 5°C, stir for 60min until it dissolves, cool down to -40°C, add 13.2g of pivaloyl chloride, N - 0.83 g of methylmorpholine, reacted at -10°C for 60 min at a controlled temperature.

[0048] Add the solution to the mixed anhydride solution, add 3g of anhydrous sodium sulfate, control the temperature at -10°C, add diethylamine dropwise during the process to control the pH=8.5 and react for 2.5 hours to obtain a light yellow suspension, filter with suction, and the filtrate is at 40 ℃, distilled under -0.09Mpa vacuum condition until no distillate flowed out, then 240ml of water was added dropwise in 2 ho...

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Abstract

The invention discloses a high-purity selective preparation and purification method of aminothioxamic acid dimer, comprising the following steps: A, adding aminothioxamic acid and an organic base into a low-boiling point solvent, stirring to dissolve; B, preparing mixed anhydride; C, selecting Sexual condensation: add the aminothiaxamic acid solution obtained in step A to the mixed anhydride liquid system obtained in step B, add a catalyst, reduce the generation of trans-aminothiaxamic acid dimer through the control of process conditions, and realize selective condensation to prepare high-purity aminothiaxamic acid dimer; D. Product purification. The method for preparing and purifying dimers of aminothioxamic acid provided by the invention greatly reduces the generation of trans isomers through selective condensation reaction, and the yield and purity of products are obviously improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation process of aminothiaxamic acid dimer with simple process and high product yield and purity. Background technique [0002] Aminothioxamic acid, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (cis) English name 2-(2-Aminothiazole-4-yl-2-methoxyiminoacetic acid (ATMIA), the structural formula is [0003] [0004] Amthioxamic acid is the raw material for the synthesis of the third and fourth generation cephalosporins. The cephalosporins synthesized by using aminothiaxamic acid compounds as antibiotic side chains mainly include: cefixime, cefpodoxime, cefotaxime, cefepime, cefteren, Cefazolin, cefodizime, cefpirome, ceftriaxone, and cefotaxime. Therefore, aminothiaxamic acid is an important pharmaceutical intermediate. [0005] Amthioxamic acid will produce dimers during the production process, and this impurity cannot be avoided during the production proc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/593
CPCC07D277/593
Inventor 刘振强姜鹏鹏徐鑫林梁丙辰刘新元
Owner 河北合佳医药科技集团股份有限公司
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