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Synthesis and purification method of t-butyloxycarboryl cefcapene diisopropylammonium

A technology of carpine acid diisopropylamine salt and tert-butoxycarbonyl head, which is applied in the field of medicine and chemical industry, can solve the problems of extended production cycle, cumbersome operation, and a large number of by-products, and achieve energy saving and environmental protection. Growth of ester impurities, effects of avoiding production cycles

Active Publication Date: 2016-12-14
青岛睿森生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the need to prepare acid anhydrides or acid chlorides separately, the production cycle is prolonged and the operation is cumbersome; during the post-treatment, there may be no purification process, resulting in the generation of a large number of by-products; Improper purification methods lead to unstable mass production of products with high yield, less impurities, and meeting the requirements of pharmaceutical intermediates

Method used

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  • Synthesis and purification method of t-butyloxycarboryl cefcapene diisopropylammonium
  • Synthesis and purification method of t-butyloxycarboryl cefcapene diisopropylammonium
  • Synthesis and purification method of t-butyloxycarboryl cefcapene diisopropylammonium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] (1)(6R,7R)-7-[(2Z)-(2-tert-butoxycarbonylamino-thiazol-4-yl)pent-2-enamido)-3-hydroxymethyl-8-oxo Synthesis and Purification of -5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Compound Ⅰ)

[0046] Into a 5L reaction flask, add 1500mL of acetonitrile, 76g (0.33mol) of D-7ACA, 107.4g (0.36mol) of side chain acid, cool to -15°C, add 133.6g (1.32mol) of triethylamine dropwise, continue to drop after dropping Add 55.2g (0.36mol) of phosphorus oxychloride, after dripping, the material solution is heated to 0℃ to react for 2h, add 3000mL of dichloromethane, 1000mL of purified water, separate, collect the organic phase, and wash the organic phase twice with 1000mL of purified water , Add 50g of anhydrous magnesium sulfate, stir and dry for 1h, filter with suction to obtain the filtrate, refrigerate for later use;

[0047] (2) Synthesis and purification of tert-butyloxycarbonyl cefcapene acid diisopropylamine salt

[0048] Put the filtrate in step (1) into a 5L reaction flask...

Embodiment 2

[0050] (1)(6R,7R)-7-[(2Z)-(2-tert-butoxycarbonylamino-thiazol-4-yl)pent-2-enamido)-3-hydroxymethyl-8-oxo Synthesis and purification of -5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (compound Ⅰ)

[0051] Into a 5L reaction flask, add 1500mL of acetone, 76g (0.33mol) of D-7ACA, 119.3g (0.40mol) of side chain acid, reduce the temperature to -12°C, add 202.4g (2.0mol) of triethylamine dropwise, control the temperature -3 Continue to add phosphorus oxychloride (0.50mol) dropwise at ℃, keep the temperature at -3℃ for 2h, add 3000mL of dichloromethane, 1000mL of purified water, separate, collect the organic phase, wash the organic phase twice with 1000mL of purified water, add 50g anhydrous magnesium sulfate, stir and dry for 1h, filter with suction to obtain the filtrate, refrigerate for later use;

[0052] (2) Synthesis and purification of tert-butoxycarbonyl cefcapinic acid diisopropylamine salt

[0053] Put the filtrate in step (1) in a 5L reaction flask, lower the temperatur...

Embodiment 3

[0055] (1)(6R,7R)-7-[(2Z)-(2-tert-butoxycarbonylamino-thiazol-4-yl)pent-2-enamido)-3-hydroxymethyl-8-oxo -5-

[0056] Synthesis and Purification of Sulfur-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Compound Ⅰ)

[0057] Into a 5L reaction flask, add 1500mL of acetonitrile, 76g (0.33mol) of D-7ACA, 107.4g (0.36mol) of side chain acid, cool to -13°C, add 267.1g (2.64mol) of triethylamine dropwise, continue to drop after dropping Add 76.7g (0.50mol) of phosphorus oxychloride, after dripping, the material solution is heated to -5℃ and react for 2h, add 3000mL of dichloromethane, 1000mL of purified water, separate, collect the organic phase, and wash the organic phase with 1000mL of purified water 2 Add 50g of anhydrous magnesium sulfate, stir and dry for 1 hour, filter with suction to obtain the filtrate, refrigerate for later use;

[0058] (2) Synthesis and purification of tert-butyloxycarbonyl cefcapene acid diisopropylamine salt

[0059] Put the filtrate in step (1) in a 5L react...

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Abstract

The invention belongs to the field of chemical synthesis of antibiotics, and in particular discloses a synthesis and purification method of t-butyloxycarboryl cefcapene diisopropylammonium which is used as a key intermediate of cefcapene pivoxil hydrochloride hydrate. The method comprises the following steps: carrying out an acylation reaction on D-7ACA and side chain acid under the actions of triethylamine and phosphorus oxychloride, purifying to obtain an acylation reaction feed liquid to be directly reacted with chlorosulfonyl isocyanate, carrying out water washing, drying and dropwise adding diisopropylamine to form salt and concentrating after the reaction is quenched, and performing crystallization by using a poor solvent of a target product to ensure that the pH of the feed liquid is weak acidic or neutral in the whole post-processing process so as to improve the stability of the feed liquid, thereby solving the problem of impurity increase caused by the prolonged subsequent processing time in large-scale production, and further improve the yield, thereby being especially suitable for industrialized mass production.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry. In detail, it is a method for synthesizing and purifying diisopropylamine salt of cefcapene pivoxil hydrochloride key intermediate tert-butoxycarbonyl cefcapene acid. Background technique [0002] Cefcapene Pivoxil Hydrochloride Hydrate was developed by Shionoyoshi Pharmaceutical Co., Ltd., and its chemical name is 2,2-Dimethylpropionyloxymethyl-(6R,7R)-7-[(2Z) -(2-Amino-thiazol-4-yl)pent-2-enamido]-3-(carbamoyloxymethyl)-8-oxo-5-thio-1-azabicyclo[4.2.0 ] Oct-2-ene-2-carboxylate hydrochloride monohydrate, the structural formula is shown below, [0003] [0004] This product is a third-generation cephalosporin, a broad-spectrum antibiotic drug. Compared with other oral antibiotics, it has strong antibacterial activity against gram-positive bacteria and gram-negative bacteria, and against Staphylococcus aureus It also shows strong antibacterial activity and has a strong clinical application...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04C07D501/12
CPCC07D501/04C07D501/12C07D501/34
Inventor 张颖史长丽郑钧飞
Owner 青岛睿森生物科技有限公司
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