Novel synthesizing method for dorzolamide HCL midbody

Abstract

The invention relates to a new synthetic method of a dorzolamide intermediate (S)-6-methyl-2-chlorosulfuryl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-carboxide, comprising the steps of synthesizing raceme 3-(thien-2-ylthio)butyric acid, performing chiral resolution to obtain stereoisomer thereof (S)-3-(thien-2-ylthio)butyric acid, and performing addition and ring-closing reactions to obtain (S)-6-methyl-2-chlorosulfuryl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-carboxide. The inventive method shortens conventional synthesis route, and performs chiral resolution of the intermediate raceme at the beginning of the synthesis route with a chiral resolution agent, so as to save a large amount of subsequent raw materials consumption. In addition, the synthetic method adopts 'one-pot' method, so as to reduce loss and the steps and cost of the subsequent operations, resulting in a more convenient, economical and effective synthesis route, compared with the known synthesis routes.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, in particular to (S)-6-methyl-2-sulfonyl chloride-5,6-dihydro-4H-thiophene[2,3b]thiopyran-4- A new preparation process of the carbonyl group, the compound can be used to prepare dorzolamide hydrochloride for treating glaucoma. technical background [0002] Glaucoma is an eye disorder caused by high pressure inside the eye, which can lead to vision loss and even blindness if left untreated. At present, many ophthalmologists believe that high eye pressure is an early symptom of glaucoma. It is generally believed that controlling the onset and development of glaucoma is accomplished by controlling the increase in intraocular pressure. [0003] Dorzolamide hydrochloride, the Chinese name is (4S,6S)-4-ethylamino-5,6-dihydro-6-methyl-4H-thiophene[2,3b]thiopyran-2-sulfonamide- 7,7-dioxyhydrochloride, the structure is as follows: [0004] [0005] Dorzolamide Hydrochlorid...

AI Technical Summary

Problems solved by technology

[0012] The biggest disadvantage of this type of route is: the intermediates are all racemates, and the resolution is carried out at the end. In the synthetic route, several times more reagents and reactants will be used to generate the racemates in order to obtain the target enantiomer, and finally Separation and removal of its enantiomers, which leads to a great increase in the cost of the final product

[0031] The disadvantages of the chiral synthesis of the above method are: (1) the chiral raw materials used in the reaction need to be synthesized additionally, which increases the complexity of the process and increases the cost; (2) a large amount of expensive and environmentally unfriendly heavy metal oxidation is used in the process. (3) There are many reaction steps, complex operation, large loss and time-consuming

[0034] In this method, the optical purity of the target isomer obtained by resolving the racemate has reached 97%. Although it has unique advantages in terms of productivity and saving the amount of mobile phase used compared with ordinary preparative chromatography, it is still in industrialization. The consumption of mobile phase in production is still not negligible, and in general, enantiomer separation is often carried out under nonlinear conditions, and it is very difficult to simulate the empirical optimization of moving bed multi-parameter nonlinear systems, such as mobile phase or extraction The change of liquid flow rate has a great influence on the purity of both enantiomers; the column characteristics are required to be as consistent as possible, otherwise there will be obvious loss of yield and purity

Therefore, there are obvious deficiencies in this method in industrialized production.

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