Method for preparing and purifying olmesartan intermediate

Abstract

The invention relates to a method for preparing and purifying an olmesartan intermediate. The preparation method comprises the following steps of: chlorinating 4,5-dimethyl-1,3-dioxa-cyclopentene-2-ketone, distilling under reduced pressure to obtain 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-ketone, and performing rearrangement reaction to generate the olmesartan intermediate; reducing the temperature to be below 50 DEG C, concentrating until a solvent is removed completely to obtain a crude product; and recrystallizing and purifying the crude product at the temperature of between -20 and 0 DEG C for 1 to 48 hours, wherein a recrystallization solvent may be one or a mixed solvent of more of an alkane solvent and an ether solvent. The preparation method is low in production cost, mild in reaction condition and easy to operate, raw materials are wide in sources, and high-content 4-chloromethyl-5-methyl-1,3-dioxa-cyclopentene-2-ketone can be obtained directly, so the method is particularly suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method and purification method of olmesartan intermediate 4-chloromethyl-5-methyl-1,3-dioxol-2-one. Background technique [0002] Olmesartan (Olmesartan Medoxomil Tablets), the chemical name is 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(tetrazol-5-yl)phenyl]benzene Base] methylimidazole-5-carboxylic acid, the structural formula is as follows: [0003] [0004] Olmesartan is an angiotensin II receptor antagonist. In 1991, Olmesartan Medoxomil was successfully developed by Japan Sankyo Co., Ltd., and obtained patent protection in many countries. In April 2002, olmesartan medoxomil was approved by the US Food and Drug Administration (FDA), and it was first launched in the US in May of the same year. As of December 2005, olmesartan medoxomil has been listed in more than 20 countries in Europe and 8 countries and regions in Asia. Its over...

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Problems solved by technology

[0007] U.S. Patent No. 4,554,358 discloses a 4,5-dimethyl-1,3-dioxole-2-ketone chlorination, and vacuum distillation to obtain 4-chloro-4-methyl-5-methylidene Methyl-1,3-dioxolane-2-one, after rearrangement reaction at 90°C, then distilled under reduced pressure to obtain 4-chloromethyl-5-methyl-1 at 91-93°C (2mmHg) , 3-dioxol-2-one, but it is difficult to reach a vacuum of 2mmHg in industrial production; while 4-chloromethyl-5-methyl-1,3-dioxol- 2-ketone is easy to decompose and polymerize under high heat to deteriorate, and the vacuum distillation product decomposes at high temperature, the yield is low, and the energy consumption is large, and the production cost is high

[0008] At present, the purification method of compound (I) is operated by vacuum distillation in industrial production, and the total yield reported is usually between 45% and 55%, and the product GC detection purity after vacuum distillation reaches about 90% to 95%. , it is difficult to meet the high purity requirement of more than 98%

In addition, high vacuum (2mmHg) is required during distillation, which requires high equipment, and further amplification is limited, which seriously affects the production capacity of this intermediate

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