Method for preparation of brinzolamide and intermediates thereof

Abstract

The invention discloses a method for preparation of a compound shown in formula (II). The method mainly includes two steps: an amination reaction and introduction of an amino protection group. The invention also discloses a method for preparation of brinzolamide through the compound in formula (II), and the method mainly consists of: sulfamation of the compound in formula (II) and amino protection group removal of the sulfamation product. According to the method, a protection group is first introduced at site C-3, then a sulfonamide group is introduced at site C-6, and finally the protection group at site C-3 is removed, so that the synthesis operations of brinzolamide become easier, the security risk and the cost are lower, and the total yield of brinzolamide is significantly enhanced. Therefore, the feasibility of large-scale industrial production and the competitive advantage of the product in the market are improved.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing brinzolamide and its intermediates. Background technique [0002] Brinzolamide (Brinzolamide) is the pharmaceutical active ingredient of Azopt eye drops. It was developed by Alcon Laboratories, Inc. and launched in the United States in 1998. It is suitable for reducing ocular hypertension and increased intraocular pressure in open-angle glaucoma. And it can be used as a single treatment drug for patients who are ineffective or have contraindications to β-blockers, or as a co-treatment 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: [0004] R-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6- Sulfa-1,1-dioxide [0005] The structural formula is: [0006] ...

AI Technical Summary

Problems solved by technology

[0011] 1. The price of raw material 3-acetyl-2,5-dichlorothiophene (1-1) and the raw material 1-bromo-3-methoxypropane to be adopted when synthesizing intermediate (1-6) is more expensive, Not conducive to industrial cost control;

[0012] 2. When the intermediate (1-7) is synthesized, the yield is low (less than 70%), and when the sulfonyl group is introduced at the C-6 position, more than 2.0 equivalents of organolithium will be used, which increases the risk and cost of production;

[0013] 3. Lower yield

[0018] 1. The raw material 3-acetylthiophene (2-1) is relatively expensive, which is not conducive to industrial cost control;

[0019] 2. High security risk

When synthesizing intermediate (2-4), the introduction of sulfonyl at the C-2 position requires the use of more expensive and dangerous organolithium reagents; during the synthesis of intermediate (2-9), the introduction of sulfonyl at the C-6 position The sulfonyl group needs an alkyllithium reagent with more than 2.0 molar equivalents, and the dosage is too much, which increases the cost and danger

[0020] 3. Low yield

[0024] 3. When synthesizing the intermediate (3-9), the introduction of methoxyl yield is low (only 78%), which increases the cost of raw materials and production;

[0025] 4. Low yield

[0027] 1. Raw materials (4-1) are relatively expensive;

[0028] 2. When using L-di-p-toluyl tartaric acid to split the racemate (4-5) to synthesize the intermediate (4-6), the yield is only 33%, and the low yield increases the cost;

[0029] 3. When synthesizing the intermediate (4-2), the introduction of the methoxypropyl group requires the use of raw material 3-methoxy-1-propylamine, which is relatively expensive and unfavorable for industrial cost control;

[0035] On the whole, the above-mentioned synthetic routes all have problems such as high cost, difficult production operation and low safety, and low total yield from raw materials to final product brinzolamide. Therefore, to a certain extent, brinzolamide is limited in Promoted applications in the market

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