Preparation methods of brinzolamide and an intermediate thereof

A technology of volume and ethylamine, applied in the field of preparation of brinzolamide and its intermediates, can solve the problems of improved reaction yield and purity, high reaction temperature, cumbersome reaction operation and the like

Active Publication Date: 2018-03-06
SHANGHAI VIWIT PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The technical problem to be solved by the present invention is aimed at the preparation method of existing brinzolamide, when compound B synthesizes brinzolamide, the reaction time of the amino protection step is long, the reaction temperature is high, the amount of reaction reagent is large, and the subsequent To deal with a series of problems such as large amount of reagents, excessive inorganic salt residues, reaction yield and purity to be further improved, cumbersome reaction operations, etc., a preparation method for synthesizing brinzolamide and its intermediates from compound B is provided , the reaction time of the amino protection step of the method is short, the reaction temperature is lower, the amount of reaction reagents is reduced, the amount of acid and alkali used in post-treatment is reduced, the residue on ignition of the product is reduced, the purity of the product is further improved, the operation is simplified, and it is more suitable for industrial production

Method used

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  • Preparation methods of brinzolamide and an intermediate thereof
  • Preparation methods of brinzolamide and an intermediate thereof
  • Preparation methods of brinzolamide and an intermediate thereof

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preparation example Construction

[0108] Preparation of reaction raw materials: Compound B(S)-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-thieno[3,2-e]-1,2-thiazine- 6-sulfonamide-1,1-dioxide was prepared by referring to the following synthetic route (reference: Organic Process Research and Development, 1999, 3(2), 114-120).

[0109]

[0110] Compound B NMR data: 1 H NMR (300MHz, DMSO) δ8.04(s, 2H), 7.60(s, 1H), 6.15(d, J=6.0Hz, 1H), 4.83(d, J=5.2Hz, 1H), 3.92(dd ,J=15.3,4.6Hz,1H),3.74(dd,J=15.3,5.6Hz,1H),3.34(dt,J=9.3,6.6Hz,4H),3.23(s,3H),1.83(t, J=6.5Hz, 2H).

Embodiment 1

[0112] Compound B (10.0g, 28.1mmol) was added to 90mL of acetonitrile, trimethyl orthoacetate (5.4g, 44.9mmol) and triethylamine (0.28g, 2.8mmol) were added under stirring, and the temperature was raised to 78°C after the addition was completed , stirred for 4h, and HPLC monitoring showed that the reaction was complete. Cool down to 40°C, distill under reduced pressure, and concentrate to the minimum volume to obtain the crude compound C.

[0113] Dissolve the crude compound C in 30mL tetrahydrofuran, cool to -10°C, slowly add triethylamine (6.2g, 61.7mmol) dropwise at a rate of 1d / s; after the addition, add 4- Tosyl chloride (10.7 g, 61.7 mmol) in 20 mL THF. After addition, stir at 5°C, and the reaction is complete in about 3 hours.

[0114] Under controlled temperature of 10°C, 70% ethylamine aqueous solution (72.2 g, 1.12 M) was slowly added dropwise at a rate of 3 d / s. After the addition is complete, the temperature is controlled at 20°C and stirred, and the reaction is...

Embodiment 2

[0120] Compound B (10.0g, 28.1mmol) was added to 90mL of acetonitrile, trimethyl orthoacetate (6.1g, 50.5mmol) and triethylamine (0.28g, 2.8mmol) were added under stirring, and the temperature was raised to 71°C after the addition was completed , stirred for 3h, HPLC monitoring showed that the reaction was complete. Cool down to 32°C, distill under reduced pressure, and concentrate to the minimum volume to obtain the crude compound C.

[0121] Dissolve the crude compound C in 30mL tetrahydrofuran, cool to 0°C, slowly add triethylamine (6.2g, 61.7mmol) dropwise at a rate of 1d / s; after the addition, add 4-toluene dropwise at a rate of 1d / s A solution of sulfonyl chloride (10.7 g, 61.7 mmol) in 20 mL of tetrahydrofuran. After the addition is completed, the temperature is controlled at -5°C and stirred, and the reaction is complete in about 3 hours.

[0122] At a controlled temperature of 5°C, a 70% ethylamine aqueous solution (72.2 g, 1.12 M) was slowly added dropwise at a rat...

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Abstract

The invention discloses preparation methods of brinzolamide and an intermediate thereof. The preparation method of the brinzolamide intermediate represented by a compound C comprises: carrying out a condensation reaction on a compound B and an orthoester-based compound at a temperature of 70-80 DEG C in an organic solvent in the presence of tertiary amine under an anhydrous condition, wherein theorthoester-based compound is one or a plurality of materials selected from trimethyl orthoacetate, triethyl orthoacetate and trimethyl orthobenzoate. According to the present invention, the condensation reaction is performed by using the tertiary amine as the catalyst, such that the reaction time for the amino protection is substantially shortened, the consumption of the protection reagent is reduced, the reaction temperature is reduced, the yield and the purity of the product are improved, the acid consumption and the alkali consumption during the post-treatment are reduced, the residue on ignition of the product is reduced, the operation is simplified, and the method is suitable for industrial production. The formulas B and C are defined in the specification.

Description

technical field [0001] The invention relates to a preparation method of brinzolamide and an intermediate thereof. Background technique [0002] Brinzolamide, chemical name: R-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2- e]-1,2-thiazine-6-sulfonamide-1,1-dioxide, the structure is shown in formula A. Brinzolamide is a pharmaceutical active ingredient used for the treatment of primary and secondary open-angle glaucoma and ocular hypertension, and for the prevention and treatment of elevated intraocular pressure after laser surgery. Brinzolamide can be used as a monotherapy in patients who are refractory to or have contraindications to β-blockers, or as a concomitant therapy with β-blockers. [0003] [0004] In 1995, Dean et al first disclosed the full preparation method of brinzolamide in the patent US5378703: starting from 3-acetylthiophene, after carbonyl protection, sulfonamide, deprotection, carbonyl α-hydrobromination, reduction-ring closure , N-a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04
CPCC07D513/04
Inventor 王健华何一刚魏彦君邢艳平赵天厂
Owner SHANGHAI VIWIT PHARMA CO LTD
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