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Simple and easy synthetic method for key intermediate of dorzolamide hydrochloride

A technology of dorzolamide hydrochloride and a synthesis method, which is applied in the chemical field, can solve the problems of many by-products, long reaction steps and low product purity, and achieves the effects of improving utilization rate, simple synthesis method and high product purity

Inactive Publication Date: 2019-08-16
株洲壹诺生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, compound I is produced by this method, the reaction steps are long, and there are many by-products, and the product purity is not high

Method used

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  • Simple and easy synthetic method for key intermediate of dorzolamide hydrochloride
  • Simple and easy synthetic method for key intermediate of dorzolamide hydrochloride
  • Simple and easy synthetic method for key intermediate of dorzolamide hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] A kind of simple and easy synthetic method of dorzolamide hydrochloride key intermediate, comprises the following steps:

[0026] The structural formula of the dorzolamide hydrochloride key intermediate is:

[0027]

[0028] The synthetic method of the key intermediate compound I of dorzolamide hydrochloride comprises the following steps:

[0029] (1) Compound II undergoes an intramolecular ring-closing reaction under the action of an acidic catalyst to generate the primary product;

[0030] The structural formula of the compound II is:

[0031]

[0032] (2) Quenching is carried out to the first product, and then extracted and concentrated to obtain the crude product;

[0033] (3) The crude product is recrystallized, filtered, and dried to obtain the key intermediate of dorzolamide hydrochloride.

Embodiment 2

[0035] A kind of simple and easy synthetic method of dorzolamide hydrochloride key intermediate, comprises the following steps:

[0036] The structural formula of the dorzolamide hydrochloride key intermediate is:

[0037]

[0038] The synthetic method of the key intermediate compound I of dorzolamide hydrochloride comprises the following steps:

[0039] (1) Preparation of compound II: Add 60 g of 3-(4-toluenesulfonyloxy) butyric acid methyl ester, 28 g of 2-mercaptothiophene and tetrahydrofuran into the reaction flask, stir and cool down to 0°C, then add three Ethylamine 26.8g, raised to 25°C after dropwise to complete the reaction; add ethyl acetate 200mL and water 200mL, stir and extract, the obtained ethyl acetate phase was dried, filtered and concentrated to obtain 50.3g of oily product Compound II, yield 90% . 1HNMR (CDCl 3 )7.41(m, 1H), 7.17(m, 1H), 7.02(m, 1H), 3.69(s, 3H), 3.39(m, 1H), 2.67(dd, J=15.7, J=6.4,1H) , 2.42 (dd, J=15.7, J=8.2, 1H), 1.32 (d, J=6.9, 3...

Embodiment 3

[0048] A kind of simple and easy synthetic method of dorzolamide hydrochloride key intermediate, comprises the following steps:

[0049] The structural formula of the dorzolamide hydrochloride key intermediate is:

[0050]

[0051] The synthetic method of the key intermediate compound I of dorzolamide hydrochloride comprises the following steps:

[0052] (1) Preparation of compound II: Add 65 g of 3-(4-toluenesulfonyloxy) methyl butyrate, 30 g of 2-mercaptothiophene and tetrahydrofuran into a reaction flask, stir and cool down to 0° C., then add three Ethylamine 28.5g, raised to 25°C after dropwise to complete the reaction; add 200mL of ethyl acetate and 200mL of water, stir and extract, the obtained ethyl acetate phase was dried, filtered and concentrated to obtain 51.8g of oily product Compound II, yield 88.9% . 1HNMR (CDCl 3 )7.41(m, 1H), 7.17(m, 1H), 7.02(m, 1H), 3.69(s, 3H), 3.39(m, 1H), 2.67(dd, J=15.7, J=6.4,1H) , 2.42 (dd, J=15.7, J=8.2, 1H), 1.32 (d, J=6.9, 3H)...

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Abstract

The invention discloses a simple and easy synthetic method for a key intermediate of dorzolamide hydrochloride. The simple and easy synthetic method for the key intermediate of the dorzolamide hydrochloride comprises the following steps: performing an intramolecular ring-closing reaction on a compound II under the action of an acidic catalyst to form an initial product; performing quenching treatment on the initial product, performing extraction, and performing concentration on an organic phase to obtain a crude product; and performing recrystallization on the crude product, performing filtration, and performing drying to obtain the key intermediate of the dorzolamide hydrochloride. The method provided by the invention has the beneficial effects that the synthetic method for the key intermediate of the dorzolamide hydrochloride is relatively simple, the key intermediate is synthesized in one step, the yield of the product compound I is relatively high, and the product purity is relatively high; and compared with a traditional synthetic method, the synthetic method for the key intermediate of the dorzolamide hydrochloride provided by the invention saves raw material costs, has higher purity of the produced product, and improves a utilization rate of the product.

Description

technical field [0001] The invention relates to the technical field of chemical industry, in particular to a simple synthesis method of a key intermediate of dorzolamide hydrochloride. 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, and the specific synthetic route is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 徐群杰于欢庆丁磊谢子刚
Owner 株洲壹诺生物技术有限公司