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Process for preparing cefathiamidine

A technology of cefathiamidine and diisopropylthiourea, which is applied in the fields of organic chemistry and antibacterial drugs, can solve the problems that chlorine is not as active as bromine, the reaction difficulty is increased, and the reaction time is long, so as to facilitate storage and transportation , more stable quality and shorter steps

Active Publication Date: 2009-07-22
GUANGZHOU BAIYUNSHAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chloroacetyl chloride is the congener of bromoacetyl bromide, and the price of chloroacetyl chloride is one-sixth of that of bromoacetyl bromide, but because the activity of chlorine is not as good as that of bromine, the reaction is more difficult, especially the intermediate chloroacetyl 7- The reaction of ACA and thiourea to generate cefathiamidine is more difficult. Therefore, in the preparation of cefathiamidine, the preparation method using chloroacetyl chloride as a raw material has complex processes, long reaction times, low yield, and poor quality. moot
Therefore, no producer has used chloroacetyl chloride to prepare cefathiamidine so far, and there are no related literature reports

Method used

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  • Process for preparing cefathiamidine
  • Process for preparing cefathiamidine
  • Process for preparing cefathiamidine

Examples

Experimental program
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Effect test

Embodiment 1

[0024] The preparation of embodiment 1 chloroacetyl 7-ACA

[0025] Add 600 milliliters of acetone and 100 milliliters of water into the reaction vessel, add 100 grams of 7-ACA and 40 grams of triethylamine at 0-5 ° C, after dissolving, add 50 milliliters of chloroacetyl chloride dropwise, and then add 70 grams of triethylamine dropwise , heat up to 15-25°C, and react for 1 hour; then, add 500 ml of water to the reaction solution, adjust the pH to 4-4.5 with 6N hydrochloric acid, control the internal temperature at about 20°C, and distill acetone under reduced pressure; Continue to adjust the pH to 1 with 6N hydrochloric acid at 5°C, filter, and wash the product twice with water. Vacuum-dried to obtain white solid chloroacetyl 7-ACA with a yield of 84-87%, and the content of chloroacetyl 7-ACA measured by HPLC was greater than 95%.

Embodiment 2

[0026] The preparation of embodiment 2 chloroacetyl 7-ACA

[0027] Add 300ml of ethanol and 900ml of water into the reaction vessel, add 100g of 7-ACA at 1-5°C, stir, add 150g of sodium bicarbonate to dissolve 7-ACA, then slowly add 70ml of chloroacetyl chloride dropwise , heated to 25-30°C, and reacted for 0.5 hours; then, 6N hydrochloric acid was added dropwise to the reaction liquid to adjust the pH of the solution to 1, stirred for 1 hour, filtered, and the product was washed twice with water. Vacuum-dried to obtain white solid chloroacetyl 7-ACA, the yield is 76-80%, and the content measured by HPLC method is greater than 92%.

Embodiment 3

[0028] Example 3 Preparation of Cefathiamidine

[0029] Add 50 ml of THF and 50 ml of DMA solvent into the reaction vessel, add 100 g of chloroacetyl 7-ACA, 50 g of diisopropylthiourea and 2 g of sodium iodide. React at 30-35°C for 2 hours, add 200 ml of dichloromethane dropwise at 10-15°C, stir for 0.5 hours, add 1000 ml of acetone dropwise at 0-5°C, and the crude cefathiamidine is precipitated with a yield of 103-108 %. Recrystallize and refine with 95% ethanol to obtain a qualified product, the refined yield is 74-78%, and the average total yield is 80%. The content of cefathiamidine measured by HPLC method is greater than 97%, and the color is measured by colorimetry. Lower than the No. 2 yellow standard control solution, and other indicators all meet the quality standards of cefathiamidine on page 156 of the Chinese Pharmacopoeia of the 2005 edition. The nuclear magnetic resonance spectrum of the refined cefathiamidine is as follows figure 1 shown.

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Abstract

The invention relates to the field of the synthesis of chemical medicaments and discloses a preparation method of cefathiamidine; the method takes chloracetyl chloride as a raw material and comprises the following steps: (1) on the condition of the presence of a solvent, alkali is added so as to cause 7-ACA to be dissolved, and then the chloracetyl chloride is added for a condensation reaction; after the condensation reaction is finished, chloracetyl 7-ACA crystals are separated out with an acid; and (2) on the condition of the presence of both the solvent and a catalyst of a catalyzing amount, the chloracetyl 7-ACA reacts with N, N-di-isopropyl thiourea to produce the cefathiamidine. Besides the advantages of bromoacetyl-bromide preparation method of cefathiamidine, the technology of adopting chloracetyl chloride as the raw material to produce the cefathiamidine also has the advantages that: as no alkali is added into the reaction between the chloracetyl 7-ACA and the N, N-di-isopropyl thiourea, the produced cefathiamidine has lighter color, and better and more stable quality, is more beneficial to store and transport, improves the overall yield, lowers the cost and has broader prospects; and the price of the chloracetyl chloride is one sixth of that of the bromoacetyl bromide, which significantly reduce the cost.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, in particular to a new method for synthesizing cefathiamidine using chloroacetyl chloride as a raw material. Background technique [0002] Cefathiamidine (cefathiamidine) has another name called cephalosporin 18, and its structural formula is as follows: [0003] [0004] Cefathiamidine is the first-generation cephalosporin and the first and only self-innovated broad-spectrum cephalosporin injection preparation in my country. It has a strong killing effect on most Gram-positive bacteria and some Gram-negative bacteria. In particular, the effect on enterococcus exceeds all cephalosporin antibiotics in clinical use, and it has the characteristics of high blood concentration and good clinical curative effect. It has definite curative effect on respiratory tract infection, urinary tract infection, skin and soft tissue infection, ear, nose and throat infection, sepsis, biliary tract infectio...

Claims

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Application Information

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IPC IPC(8): C07D501/28A61P31/04
Inventor 傅海燕田美如
Owner GUANGZHOU BAIYUNSHAN PHARM CO LTD
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