Key intermediate of dorzolamide hydrochloride and synthesis method thereof

Abstract

The invention discloses a synthesis method of a key intermediate of dorzolamide hydrochloride. The method comprises the following steps: sequentially adding a compound II, acetamide, an acid binding agent and a phase transfer catalyst to an organic solvent, carrying out a reaction by stirring under the heating condition to obtain an initial product after the reaction is completed, filtering the initial product, concentrating the filtrate, performing recrystallization, performing filtering and drying to obtain the key intermediate of dorzolamide hydrochloride. The beneficial effects of the method are as follows: the method adopts the readily available compound II as the starting material, a SN2 nucleophilic substitution reaction with acetamide and the acid binding agent is carried out underthe action of the phase transfer catalyst, a compound I with high chiral purity is directly prepared by adjusting the molar ratio of the compound II, acetamide and the binding the acid agent and thereaction temperature, the yield is more than 80%, the chiral purity can reach to be 95% or more, the operation is simple and convenient, and the cost is low, so that the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of chemical industry, in particular to a key intermediate of dorzolamide hydrochloride and a synthesis method thereof. Background technique [0002] Dorzolamide Hydrochloride, chemical name (4S,6S)-4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran- 2-sulfonamide-7,7-dioxide hydrochloride, CAS No. 130693-82-2, the structure is as follows: [0003] [0004] Dorzolamide hydrochloride, trade name Trusopt, is a carbonic anhydrase inhibitor. It is an anti-glaucoma topical eye drops for the treatment and improvement of intraocular pressure, developed by Merck and approved by the FDA in 1994. For the synthesis of dorzolamide hydrochloride, there are many reports in relevant documents and patents, and there are many synthetic routes. Merck reported the total synthesis method of dorzolamide hydrochloride in detail in J.Org.Chem.1993,58,1672-1679 and patent US5688968, wherein compound I was prepared by ...

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Problems solved by technology

[0008] Among the many synthetic routes, most of the routes with practical production value need to use compound I, and the production methods of compound I that have been reported so far are all prepared by compound III through Ritter reaction, but this method has serious defects, namely The chiral selectivity of the reaction is poor, and the chiral purity of the obtained product is low, which creates great difficulties for subsequent product purification, reduces production efficiency, and will seriously increase production costs

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