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Cephalosporins medicine intermediate crystal and method for preparing same

A technology for intermediates and crystals, applied in the field of pharmaceutical synthesis, can solve problems such as being unsuitable for commercial storage, and achieve the effects of no degradation of decomposition point, good crystallinity and high purity

Active Publication Date: 2005-07-06
TIANJIN INSTITUTE OF PHARMA RESEARCH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

According to this method, the compound shown in the prepared formula (I) is an amorphous powdery solid, which is only suitable for the next step reaction requirements of the CN1338459A patent, and is not suitable for commercial storage

Method used

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  • Cephalosporins medicine intermediate crystal and method for preparing same
  • Cephalosporins medicine intermediate crystal and method for preparing same
  • Cephalosporins medicine intermediate crystal and method for preparing same

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Experimental program
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Effect test

preparation example Construction

[0034] Preparation of the amorphous substance of compound (I):

[0035] PCl 5 (20.7g, 0.099mol), dichloromethane (180mL) in a 500mL reaction flask, stirred and dissolved at room temperature, added dropwise 8mL of pyridine at 5°C, reacted for 30 minutes, added compound (II) (20g, 0.041mol), in At this temperature, react for 4 hours, then cool down to -25°C, add methanol, react for 2 hours, dropwise add normal water (180mL), and hydrolyze at 0°C for 1 hour to obtain 15.3g of an amorphous solid of compound (I). : 91%.

[0036] X-ray powder diffraction pattern see figure 2 , the measurement conditions are the same as those in Figure 1.

Embodiment 1

[0038] Take 50 g of the amorphous solid of Compound (I), add 150 ml of tetrahydrofuran, stir in an ice bath, add triethylamine dropwise at a temperature below 10°C until pH = 7.0, stir and react for 0.5 hours, then filter, add 600 ml of acetone to the filtrate, and add dropwise under stirring 20ml of concentrated HCl precipitated white crystals, filtered after cooling, and washed with an appropriate amount of acetone to obtain 45g of a white crystalline solid of compound (I), that is, 7-amino-3-chloromethyl-3-cephalosporanic acid-4-carboxylic acid p- Crystal of methoxybenzyl ester hydrochloride (I), yield 90%, melting point 148°C-150°C (decomposition point).

[0039] The infrared spectrum data are as follows:

[0040] IR (KCl, cm -1 ): 2899, 2835, 2765, 2602, 1786, 1723

[0041] Elemental Analysis: C 16 h 17 ClN 2 o 4 S·HCl

[0042] Found (%) C, 47.26; H, 4.41; N, 6.87; S 7.80; Cl 17.46

[0043] Theoretical value (%) C, 47.35; H, 4.44; N, 6.91; S 7.89; Cl 17.51

[004...

Embodiment 2

[0054] Take 50 g of the amorphous solid of Compound (I), add 300 ml of tetrahydrofuran, stir in an ice bath, add tert-butylamine dropwise at a temperature below 2°C until pH = 7.0, and filter after stirring for 0.5 hours, add 1,000 ml of butanone to the filtrate, and add concentrated 20ml of HCl precipitated white crystals, cooled and filtered, and washed with an appropriate amount of acetone to obtain 43g of white crystalline solids, which were the crystals of the compound shown in formula (I), with a yield of 86% and a melting point of 148°C-150°C (decomposition point).

[0055] The measurement conditions and measurement data of infrared spectrum, proton nuclear magnetic resonance spectrum, elemental analysis data and X-ray powder diffraction pattern are the same as embodiment 1.

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Abstract

The invention relates to a crystal of cephalosporin intermediate 7-amino-3-chloromethane-3-aminocephalosporanic acid-4-carboxylic acid pair methoxyl benzyl ester hydrochlorate (1) and a method for preparing the same. The method comprises the steps of: liberating the amorphous solid of said compound by alkali, dissolving it in an organic solvent, salifying it with hydrochloric acid, and separating by crystallization in another organic solvent. The obtained crystal of cephalosporin (1) has high purity and steady quality, and it is applicable to synthesis of multiple cephalosporin antibiotics and derivatives.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to the synthesis of cephalosporin crystals, more specifically, the cephalosporin intermediate 7-amino-3-chloromethyl-3-cephalosporanic acid-4-carboxylic acid p-methoxy Benzyl ester hydrochloride crystal (I) and its preparation method. Background technique [0002] by the following formula [0003] [0004] It represents important intermediate compounds known to be used in the synthesis of various cephalosporin antibiotics and their derivatives such as cefepime (CN1392149A) and cefazolin (CN1338459A). [0005] The present invention is the continuation of our previous work, previous work has been disclosed by CN1338459A, in CN1338459A patent, what the inventor discloses is by the preparation of the cephalosporin intermediate compound shown in formula (I), and it is based on compound ( II) as raw material, take dichloromethane as solvent through and PCL 5 , Pyridine, and alcohol are o...

Claims

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Application Information

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IPC IPC(8): C07D501/18
Inventor 孟红赵平
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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