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Preparation method of brinzolamide intermediate

A technology of intermediates and compounds, applied in the field of brinzolamide intermediates and its preparation, can solve the problems of harsh reaction conditions, low reaction yield, high risk, etc., and achieve the effect of mild reaction conditions and simple operation

Active Publication Date: 2014-04-30
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Generally speaking, there are problems such as the need for chiral resolution, low reaction yield, n-butyl lithium metallization reagent, harsh reaction conditions and high risk in the prior art for the preparation of brinzolamide and its intermediates. To a certain extent, it limits the promotion and application of Brinzolamide in the market

Method used

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  • Preparation method of brinzolamide intermediate
  • Preparation method of brinzolamide intermediate
  • Preparation method of brinzolamide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of embodiment 1 compound 4

[0030] Add 20g (0.0837mol) of compound 1, 34.6g (0.251mol) of potassium carbonate, and 500ml of DMF solvent into a one-necked flask to dissolve, stir at 70°C for 0.5h, and then add 14.2g of 1-bromo-3-methoxypropane in batches ( 0.09mol), the reaction was continued at 70°C for 2h after the addition. After the reaction was finished, cool naturally, add the reaction solution to 1700ml saturated saline, extract with 2×700ml methyl tert-butyl ether, wash the organic layer with water, then wash with 1300ml sodium hydroxide solution (concentration: 1mol / l) alkali, and then Washed with 3×1.2L saturated brine, finally dried over anhydrous sodium sulfate, and spin-dried at room temperature to obtain 14.2 g of compound 4. 99.23% pure.

[0031] MS: 312.1 ([M+H] + ); 1 HNMR (DMSO) δ6.95(s, 1H), δ4.65(t, 1H), δ4.09(dd, 1H), δ3.80(dd, 1H), δ3.67-3.28(m, 6H) , δ3.25(s, 3H).

Embodiment 2

[0032] The preparation of embodiment 2 compound III

[0033] Weigh 24.2g of compound 4, 6g of palladium on carbon and 200mL of methanol into a single-necked bottle, vacuumize, pass in hydrogen gas to react at room temperature for 12h, after the reaction is completed, add 200ml of ethyl acetate and saturated saline to wash three times after the reaction is completed. Dried over anhydrous sodium sulfate and spin-dried to obtain 22 g of compound III with a purity of 99.68%. MS: 278.1 ([M+H] + ); 1 HNMR (DMSO): δ7.92(d, 1H), δ7.20(d, 1H), δ5.94(d, 1H), δ4.83(m, 1H), δ4.04(dd, 1H), δ3.73 (dd, 1H), δ3.38-3.24 (m, 6H), δ3.22 (s, 3H).

Embodiment 3

[0034] The preparation of embodiment 3 compound II

[0035] Add 22g (0.0794mol) of compound III, 17.6g (0.174mol) of triethylamine and 220ml of tetrahydrofuran into the reaction flask, stir and dissolve at 0°C, add 30.2g of p-toluenesulfonyl chloride (0.159mol), and raise the reaction solution to room temperature and stir After reacting for 18 hours, TLC detected that the reaction was complete, concentrated the reaction solution, added dichloromethane to dissolve, washed the organic phase with water and saturated sodium chloride, dried it with anhydrous sodium sulfate, and concentrated to obtain 27.3 g of compound II, which was directly put into the next experiment.

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Abstract

The invention relates to a preparation method of a brinzolamide intermediate I and an intermediate compound III. The preparation method is simple to operate, mild in reaction condition, high in efficiency and low in cost, and is suitable for industrial production.

Description

technical field [0001] This field belongs to the fields of medical technology and organic synthesis, and specifically relates to a brinzolamide intermediate and a preparation method thereof. Background technique [0002] Brinzolamide (Brinzolamide) is the pharmaceutical active ingredient of Azopt eye drops, which was developed by AlconLaboratories, Inc. and launched in the United States in 1998. It is suitable for reducing ocular hypertension, increased intraocular pressure in open-angle glaucoma, and It can be used as a monotherapy drug for patients who are ineffective or contraindicated to β-blockers, or as a co-therapy drug with β-blockers. Studies have shown that brinzolamide has less irritation to the eyes, is well tolerated and safe, and is a very valuable new anti-glaucoma drug. [0003] The chemical name of Brinzolamide is: R-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]- 1,2-thiazine-6-sulfonamide-1,1-dioxide, its structural formula is as follo...

Claims

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Application Information

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IPC IPC(8): C07D513/04
CPCC07D513/04
Inventor 包金远刘宝唐鲁蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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