Method for recovery and utilization of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester crystallization mother liquor

Abstract

A method for recycling 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester crystallization mother liquor relates to the technical field of a cephalosporins drug intermediate. The method comprises: (1) distilling methanol-and-ethanol mixed alcohol crystallization mother liquor of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester to obtain a distilled fluid, the volume of which is 90+ / -2% of that of the mother liquor; (2) transferring the distilled fluid obtained in the step (1) to a dehydration kettle, detecting the water of the distilled fluid,adding a methanol solution of sodium methoxide and / or an ethanol solution of sodium ethoxide, and carrying out a reaction for 10-15 min; (3) adding ethyl acetate to the dehydration kettle, raising the temperature to 50+ / -2 DEG C, and carrying out a reaction for 2+ / -1 h; (4) after the reaction is over, performing normal-pressure distillation; (5) receiving the distilled fluid, detecting the waterand water content, and controlling the water content to be below 0.05 vt% for crystallization preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester. The method issimple to operate, high in reaction speed, low in cost, high in yield and low in device investment and is safe.

Description

technical field [0001] The invention relates to the technical field of cephalosporin drug intermediates, in particular to a method for recycling and utilizing 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester crystallization mother liquor. Background technique [0002] 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester, referred to as GCLE, is an important cephalosporin intermediate, and it is called the three major cephalosporin nuclei together with 7-ACA and 7-ADCA . [0003] The crystallization solvent recovery of GCLE is a key factor affecting product cost. DMF and ethyl acetate water system, DMF and methanol water system, methanol system, and methanol and ethanol mixed solvent crystallization system are the common crystallization systems currently used in GCLE industrial production. Among them, the solvent system of the DMF system is complex and the recycling cost is high, which affects the manufacturing cost of GCLE, ...

AI Technical Summary

Problems solved by technology

Among them, the solvent system of the DMF system is complex and the recycling cost is high, which affects the manufacturing cost of GCLE, and the related substances of GCLE products produced by the methanol system exceed the standard

The mixed solvent system of methanol and ethanol is a commonly used crystallization solvent system in production at present, but since the mixed crystallization system of methanol and ethanol also contains dioxane, it is difficult to recover, and the separation of methanol and ethanol requires rectification tower and extractive azeotropic distillation , the investment in rectification equipment is large, the operation is complicated, the energy consumption is large, the cost is high, and methanol and ethanol still cannot be completely separated

[0004] Chinese patent CN200810100620 reports that methanol, ethanol, toluene, dichloromethane or a mixture of any two solvents can be used as a crystallization solvent, but does not propose a method for recycling the solvent

[0005] Chinese patent CN201110210754 reports the one-step process route of chlorination closed-loop crystallization. The crystallization solvent uses methanol or ethanol alone, and a solvent is used for crystallization. The solvent recovery is simple and easy to operate, but the product quality is affected. Considering the cost and quality factors, methanol is used Crystallization with ethanol mixed solvent, and then choosing a suitable recovery method is the key to solve the cost and quality of GCLE production

[0006] Chinese patent CN201510982756 reports a method for removing moisture from the GCLE mixed alcohol crystallization mother liquor by using metal sodium and metal magnesium. The mixed alcohol steamed after dehydration is directly used in the GCLE crystallization process. The metal sodium used in this dehydration method is not easy Storage, flammability, severe dehydration reaction, and safety risks; metal magnesium has slow reaction speed, high energy consumption, poor dehydration effect, and it is difficult to remove the water content of mixed alcohols below 0.05vt%.