Synthetic method of doxylamine succinate

Abstract

The invention discloses a synthetic method of doxylamine succinate. The synthetic method specifically comprises the following three reaction steps: (1) synthesizing 2-pyridylphenyl methyl methanol from acetophenone and 2-bromopyridine in the presence of butyl lithium; (2) reacting by virtue of 2-pyridylphenyl methyl methanol with 2-dimethylamino chloroethane under the action of organic alkali so as to generate doxylamine free alkali; and (3) carrying out salt formation reaction by virtue of doxylamine free alkali and succinic acid, so as to generate doxylamine succinate. The synthetic method has the beneficial effects that the raw materials are easily available, the yield is high, the cost is low, an acceptable product can be obtained without carrying out chromatographic column separation on the product of each step, the process is simple, the post-treatment is simple, the process is safe and reliable, and the synthetic method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical fields of medical technology and organic synthesis, and in particular relates to a synthesis method of doxylamine succinate, an ethanolamine antihistamine. Background technique [0002] Doxylamine succinate is a kind of ethanolamine drug, which has antihistamine effect, anticholinergic effect and significant sedative effect. It has strong activity and low gastrointestinal side effects, and is suitable for a variety of allergic skin diseases. Hay fever, allergic rhinitis, asthmatic bronchitis, etc., doxylamine succinate is a non-psychotropic, non-regulated over-the-counter drug. In October 1978, the FDA approved the marketing of doxylamine 25mg tablets from CHATTEM, which is used to help Relieve difficulty in falling asleep, became OTC in 1979, approved in September 1996 and approved the listing of generic drugs of LNK Company in August 2004. On April 8, 2013, the FDA approved Diclegis (doxylamine succinate and py...

AI Technical Summary

Problems solved by technology

Chinese patent CN102108059 discloses a Grignard reagent that uses 2-acetylpyridine as a starting material and reacts with bromobenzene to generate an important intermediate 2-pyridylphenylmethylcarbinol, which is then reacted with 2-dimethylamino Ethyl chloride generates doxylamine under the action of an organic base. This method: 1. Adopt high vacuum (129-134°C / 0.5mmHg) rectification to p-2-pyridylphenylmethyl which cannot be realized in large-scale industrial production Methanol is purified; 2, the final product doxylamine needs to be separated and purified by column chromatography, and this purification method is impossible to realize large-scale industrial production; 3, the yield is low; 4, the melting point is low as 101-103 ℃, can not meet the requirements of the United States Pharmacopoeia 103-108 ℃, obviously the purity is not enough, so that the melting point is low; 4, will produce toxic benzene by-products

[0005] The method announced by Chinese patent CN103524403 is basically the same as CN102108059, except that iodobenzene is used instead of bromobenzene, and the starting material is also 2-acetylpyridine. This method overcomes some of the shortcomings of the CN102108059 patent, and does not need high vacuum distillation to purify 2 -pyridylphenylmethylmethanol, but still can not meet the requirements of industrial production, 1, the preparation of 2-pyridylphenylmethylmethanol needs mixed solvent crystallization or column chromatography separation and purification, and no melting point data is given; 2 . The final product doxylamine needs to be purified by column chromatography; 3. It will produce toxic benzene by-products

[0008] Chinese patent CN105001149 has announced the synthetic method of preparing important intermediate 2-pyridylphenylmethyl carbinol with 2-benzoylpyridine and methyl bromide. Grignard reagent reaction is used to synthesize the important intermediate 2-pyridylphenylmethylcarbinol. The starting material 2-benzoylpyridine used in this process is not easy to obtain commercially, and the cost is high. In addition, methyl bromide is a gas at normal temperature, which is transported and stored. Harsh conditions, not suitable for industrialized mass production

[0010] In summary, there are many deficiencies in the current chemical synthesis technology for preparing doxylamine succinate such as low yield, cumbersome post-treatment, high cost, high toxicity, and inability to industrialized large-scale production. Therefore, research and development of a safe and reliable raw material Easy to obtain, high yield, low cost, and simple post-treatment, the process of doxylamine succinate suitable for large-scale industrial production is of great significance

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