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A kind of synthetic method of brinzolamide key intermediate

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve the problems of high production cost and low production efficiency, and achieve the effects of low production cost, reduced reaction steps and high yield

Active Publication Date: 2022-04-22
株洲壹诺生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The patent CN102056914B of PHF Company has reported a kind of method of synthesizing compound V, as follows, it is to use relatively high price raw material 3-(bromoacetyl)-5-chloro-2-thiophene sulfonamide as starting material, after carbonyl protection , ring closure, alkylation and deprotection four-step reaction to obtain compound Ⅴ, the synthesis method has low production efficiency and high production cost

Method used

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  • A kind of synthetic method of brinzolamide key intermediate
  • A kind of synthetic method of brinzolamide key intermediate
  • A kind of synthetic method of brinzolamide key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of Compound III: Dissolve Compound II 100g (0.42mol) in 2L dimethyl sulfoxide, pour it into a 5L three-necked round-bottomed flask, add 115g (0.83mol) potassium carbonate, 10g (0.04 mol) benzyltriethylammonium chloride and 5g (0.03mol) potassium iodide, then the three-neck round-bottomed flask was heated to 70-80°C, and then 64g (0.6mol) 1-bromo-3-methoxypropane was slowly Drop into a three-necked round-bottomed flask, and the reaction temperature is 70-80°C until the end of the reaction; after the end of the reaction, transfer the product to a separatory funnel, add water and toluene to the separatory funnel, extract, take the upper toluene layer, and pass through After washing, drying, concentration, and adding n-heptane for recrystallization, compound III 111.2 g was obtained, with a yield of 86% and a purity of 98.8% by HPLC.

[0037] HNMR data of compound III: HNMR (DMSO-d 6 ): 8.01 (t, 1H), 7.67 (s, 1H), 3.3-3.2 (m, 4H), 3.15 (s, 3H), 2.57 (s, 3H), 1....

Embodiment 2

[0046] According to the synthetic method in embodiment 1, difference is:

[0047] In the preparation of compound III, dimethyl sulfoxide was replaced by acetonitrile, potassium carbonate was replaced by cesium carbonate of the same molar mass, benzyltriethylammonium chloride was replaced by tetrabutylammonium chloride of the same molar mass, and potassium iodide was replaced by It is sodium iodide with the same molar mass; 1-bromo-3-methoxypropane is 0.5 mol, and the reaction temperature is 70°C to obtain 106.6 g of compound III with a molar recovery of 82.7% and a purity of 98.5% by HPLC.

[0048] HNMR data of compound III: HNMR (DMSO-d 6 ): 8.02(t, 1H), 7.65(s, 1H), 3.3-3.2(m, 4H), 3.13(s, 3H), 2.58(s, 3H), 1.78(m, 2H).

[0049] Mass spectral data of compound Ⅲ: ESI+[M+H] + =312.0

[0050] In the preparation of compound IV, dibromohydantoin was replaced by 0.2 mol of copper bromide, p-toluenesulfonic acid was replaced by 0.01 mol of sulfuric acid (mass fraction is 98%), m...

Embodiment 3

[0057] According to the synthetic method in embodiment 1, difference is:

[0058] In the preparation of compound III, dimethyl sulfoxide was replaced by dimethylformamide of the same volume, potassium carbonate was replaced by sodium methoxide of the same molar mass, and benzyltriethylammonium chloride was replaced by 18- Crown ether-6, potassium iodide was replaced by sodium iodide of the same molar mass, 1-bromo-3-methoxypropane was 0.57mol; the reaction temperature was 80°C, and 104.6g of compound III was obtained, with a molar recovery of 86.1%, HPLC The detection purity is 98.7%.

[0059] HNMR data of compound III: HNMR (DMSO-d 6 ): 8.01 (t, 1H), 7.65 (s, 1H), 3.36-3.21 (m, 4H), 3.13 (s, 3H), 2.57 (s, 3H), 1.78 (m, 2H).

[0060] Mass spectral data of compound Ⅲ: ESI+[M+H] + =312.0

[0061] In the preparation of compound IV, dibromohydantoin was replaced with 0.19 mol of N-bromosuccinimide, p-toluenesulfonic acid was replaced with 0.01 mol of acetic acid, and methanol ...

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a key intermediate of brinzolamide, which uses compound II as a starting material, and compounds II and 1-bromo-3-methoxypropane are synthesized by alkylation reaction Compound Ⅲ, compound Ⅲ is synthesized into compound Ⅳ through bromination reaction, and compound Ⅳ is finally synthesized into brinzolamide key intermediate compound Ⅴ through intramolecular ring-closing reaction, the specific reaction is as follows: The synthesis method provided by the invention has a simple synthesis route, easy operation in the whole process, and the obtained product is easy to purify, has high purity and high yield, and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for synthesizing a key intermediate of brinzolamide. Background technique [0002] Brinzolamide, the chemical name is (R)-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3, 2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide, CAS No. 138890-62-7, the structure is as follows: [0003] [0004] In 1998, the FDA approved Alcon's brinzolamide, trade name Azopt. Brinzolamide is a selective, high-affinity drug that significantly inhibits the activity of CAⅡ, which can reduce the formation of aqueous humor, thereby effectively reducing intraocular pressure. Small and well tolerated, it is suitable for patients with open-angle glaucoma, ocular hypertension and glaucoma patients who cannot tolerate β-blockers. [0005] Brinzolamide eye drops is currently a good drug for treating ocular hypertension and alleviating the elevated intraocular pressure in patients with...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04
CPCC07D513/04
Inventor 徐群杰于欢庆谢子刚杨国平王亚斌
Owner 株洲壹诺生物技术有限公司
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