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Synthetic process of dorzolamide Hydrochloride intermediate

A technology of dorzolamide hydrochloride and synthesis process, applied in the directions of organic chemistry, organic chemistry methods, etc., can solve the problems of harsh equipment performance and material requirements, unfriendly environment, difficult operation, etc., so as to reduce pollution and damage, and avoid operation hazards. Sex, damage reduction effects

Inactive Publication Date: 2020-06-05
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] As can be seen from the above-mentioned process route and reaction conditions: the reducing reagent used, such as borane dimethyl sulfide solution, the combination of boron trifluoride ether and sodium borohydride, and the combination of some other Lewis acids and sodium borohydride, all have obvious The disadvantages are not only highly toxic, unfriendly to the environment, but also difficult to operate, and have strict requirements on equipment performance and materials

Method used

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  • Synthetic process of dorzolamide Hydrochloride intermediate
  • Synthetic process of dorzolamide Hydrochloride intermediate
  • Synthetic process of dorzolamide Hydrochloride intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0067] 20 g of starting compound IIa (4-acetamido-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide ), 20g of zinc borohydride and 200ml of tetrahydrofuran were added to the reaction kettle, the temperature in the reaction kettle was heated to 70°C, and the reaction was stirred. After 2.5 hours of reaction, the reaction was tracked and monitored by TLC. After the complete reaction of the raw material compound IIa was detected, the When the temperature in the reaction kettle drops to 20°C, slowly add 300ml of 1M sulfuric acid into the reaction kettle dropwise. During the dropping process, control the temperature in the reaction kettle to 20°C. After reacting for 1h, the temperature in the reactor was lowered to room temperature, ethyl acetate was added for extraction twice, and 200ml of ethyl acetate was added for each extraction, and finally the organic phase obtained by extraction was concentrated to obtain 16.8g of white solid (Ia). 92%.

Embodiment 2

[0069] 20 g of starting compound IIa (4-acetamido-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide ), 16g of zinc borohydride and 150ml of dioxane were added to the reactor, the temperature inside the reactor was heated to 80°C, and the reaction was stirred. After 3 hours of reaction, the reaction was tracked and monitored by TLC. After the complete reaction of the raw material compound IIa was detected , when the temperature in the reactor is lowered to 25°C, slowly drop 250ml of 1M sulfuric acid into the reactor, and control the temperature in the reactor to 20°C during the dropping process, and then raise the temperature in the reactor to 85°C after the addition is completed , after stirring and reacting for 2 hours, the temperature in the reactor was lowered to room temperature, ethyl acetate was added for extraction twice, and 200 ml of ethyl acetate was added for each extraction, and finally the organic phase obtained by extraction was concentrated...

Embodiment 3

[0071] 20 g of starting compound IIa (4-acetamido-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide ), 12g of zinc borohydride and 100ml of acetic acid were added to the reactor, the temperature in the reactor was heated to 90°C, and the reaction was stirred. After 3 hours of reaction, TLC was used to track and monitor the reaction. After monitoring that the reaction of the raw material compound IIa was complete, the reaction When the temperature in the kettle drops to 30°C, slowly add 200ml of 1M sulfuric acid into the reaction kettle dropwise. During the dropping process, control the temperature in the reaction kettle to 30°C. After 2.5h, the temperature in the reactor was lowered to room temperature, ethyl acetate was added for extraction twice, and 200ml of ethyl acetate was added for each extraction, and finally the organic phase obtained by extraction was concentrated to obtain 16.5g of white solid (Ia). 89%.

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Abstract

The invention discloses a synthetic process of a dorzolamide Hydrochloride intermediate. According to the invention, mild zinc borohydride is adopted as a reducing agent; raw material compounds IIa 4-acetamido-5, 6-dihydro-6-methyl-4H-thieno [2, 3-b] thiopyran-2-sulfonamide-7, 7-dioxide and IIb ((4S, 6S)-4-acetamido-5, 6-dihydro-6-methyl-4H-thieno [2, 3-b] thiopyran-2-sulfonamide-7, 7-dioxide) arereduced at the temperature of 60-120 DEG C, acetamido is reduced into ethylamino, usage of a reducing agent which is highly toxic and high in operation danger coefficient is avoided, the whole reaction is easier to control, and the whole reaction process is milder and more environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis process of a dorzolamide hydrochloride intermediate. Background technique [0002] Dorzolamide hydrochloride, chemical name (4S,6R-trans)-4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b] Thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride, its chemical structure is as follows: [0003] [0004] Dorzolamide hydrochloride is a kind of ophthalmic solution suitable for treating high intraocular pressure or open-angle glaucoma patients developed by Merck & Co., Ltd. (MSD) of the United States. It has been approved by the FDA in 1994. [0005] Ia and Ib are key intermediates of dorzolamide hydrochloride. [0006] Among them, the chemical name of Ia is: 4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-di Oxide, its chemical structure is as follows: [0007] [0008] The chemical name of Ib is: (4S,6R-trans)-4-ethylamino-5,6-d...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07B2200/07C07D495/04
Inventor 张志峰刘传志翁飞杨宝娇朱毅杨波
Owner WUHAN WUYAO SCI & TECH
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