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Synthesis method of brinzolamide key intermediate

A synthesis method and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of complicated synthesis route, low production efficiency, unfavorable industrialization and the like, and achieve the effects of easy reaction conditions, low production cost and reduction of reaction steps.

Active Publication Date: 2021-09-07
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

[0008] In 1995, Alcon Company reported another route to synthesize compound I. As shown below, the racemic compound I was first obtained, and then compound I was obtained through oxidation and chiral reduction. Although this method uses cheap vitriol The oxazoboridine chiral reducing agent has replaced the expensive diisopine pinocampyl chloride borane, but the synthesis route is cumbersome and unfavorable for industrialization
[0009] 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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  • Synthesis method of brinzolamide key intermediate
  • Synthesis method of brinzolamide key intermediate
  • Synthesis method of brinzolamide key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of Compound III: Dissolve 100 g (0.42 mol) of Compound II in 2 L of dimethyl sulfoxide, pour it into a 5 L three-necked round-bottomed flask, and add 115 g (0.83 mol) of potassium carbonate, 10 g (0.04 mol) benzyltriethylammonium chloride and 5 g (0.03 mol) potassium iodide, then heat the three-necked round-bottomed flask to 70-80 ° C, and then add 64 g (0.6 mol) 1-bromo-3 - Slowly drop methoxypropane into a three-necked round-bottomed flask, and lower the reaction temperature at 70-80°C until the reaction is completed; after the reaction is completed, transfer the product to a separatory funnel, add water and toluene to the separatory funnel, and extract. The upper toluene layer was taken, washed, dried, concentrated, and recrystallized by adding n-heptane to obtain 111.2 g of compound III, 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 (...

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 with 0.2 mol of copper bromide, p-toluenesulfonic acid was replaced with 0.01 mol of sulfuric acid (mass fraction 9...

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 0.57 mol; the reaction temperature was 80°C, and 104.6 g of compound III was obtained with a molar recovery of 86.1%. HPLC detection purity 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 was repl...

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a brinzolamide key intermediate. A compound II as an initial raw material and 1-bromo-3-methoxypropane are subjected to an alkylation reaction to synthesize a compound III, the compound III is subjected to a bromination reaction to synthesize a compound IV, and the compound IV is subjected to an intramolecular ring closing reaction to finally synthesize a brinzolamide key intermediate compound V. The specific reaction is shown in the specification. The synthesis method provided by the invention is simple in synthesis route, the whole process is easy to operate, and the obtained product is easy to purify, high in purity, high in yield and 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 Applications(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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