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Crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl

A technique for bromosartan biphenyl and crude sartan biphenyl, which is applied in the field of crystallization for preparing high-purity bromosartan biphenyl, and can solve the problem that the mass yield is not more than 75%, the purity is lower than 99%, and it is difficult to Obtaining yield and other issues, to achieve the effect of reducing side reactions, high yield per pass, and uniform particle size distribution

Active Publication Date: 2014-03-12
TIANJIN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the determination of the solubility data of bromosartan biphenyl in various solvents by the applicant, at 5°C, bromosartan biphenyl still has a relatively high solubility in its good solvent (0.01-0.04mol / mol) , it is difficult to obtain higher yields only by cooling
In industrial production, the economic benefit of a single cooling crystallization method is relatively low
[0008] At present, the bromosartan biphenyl crystal product obtained in industrial production has a small particle size, the main particle size is about 20 μm, and the single-pass mass yield of the crystallization process does not exceed 75%, and the purity is lower than 99%.

Method used

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  • Crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl
  • Crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl
  • Crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl

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Experimental program
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Effect test

Embodiment 1

[0027] Add 40.00g of the bromosartan biphenyl crude product with a chromatographic purity of 90% into 100mL of DMF and dissolve it with continuous stirring at 60°C. Cool down to 20°C at a cooling rate of 10°C / hr; add 10mL water and 30mL ethanol mixed eluent at a rate of 16mL / hr after constant temperature for 30min; filter the crystal slurry with suction, wash with water, and dry the crystal at 50°C for 5hr; 34.89 g of bromosartan biphenyl crystals were obtained. The purity of bromosartan biphenyl detected by HPLC was 99.6%, the product quality yield was 96.9%, and the primary particle size was 98 μm.

Embodiment 2

[0029] Add 64.29g of bromosartan biphenyl crude product with a chromatographic purity of 70% to 100mL of tetrahydrofuran, stir and dissolve at 50°C, and connect the reflux tube to the top of the crystallizer to prevent solvent volatilization; carry out the cooling and crystallization process under stirring, at 8°C / hr cooling rate to 10°C; after constant temperature for 60min, add 5mL water and 45mL isopropanol mixed eluent at a rate of 25mL / hr; suction filter the crystal slurry, wash with water, and dry the crystal at 35°C for 6hr; Bromosartan biphenyl crystal 43.35g. The purity of bromosartan biphenyl was detected by HPLC: 99.5%, the product quality yield: 96.34%, and the main particle size was 102 μm.

Embodiment 3

[0031] Add 64.10g of bromosartan biphenyl crude product with a chromatographic purity of 76% to 100mL of toluene, stir and dissolve at 55°C, and connect the reflux tube to the top of the crystallizer to prevent solvent volatilization; carry out cooling and crystallization process under stirring, at 10°C / hr The cooling rate was lowered to 10°C; after a constant temperature of 45min, 100mL of methanol eluent was added at a rate of 30mL / hr; the crystal slurry was filtered with suction, washed with a mixed solution of water and ethanol, and the crystal was dried at 55°C for 7hr; bromosand was obtained 47.40 g of tansbiphenyl crystals. The purity of bromosartan biphenyl was detected by HPLC: 99.7%, the product quality yield: 97.30%, and the main particle size was 95 μm.

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Abstract

The invention relates to a crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl. The crystallizing method comprises the following steps: adding a 4-bromomethyl-2-cyanobiphenyl crude product in a solvent according to 0.4-0.65 g / mL of the solution concentration, stirring and dissolving the crude product at 40-60 DEG C, carrying out cooling and sterilization, reducing the temperature to 5-20 DEG C, keeping the temperature constant for 30-60 minutes, adding an elution agent to carry out solvent dilution crystallization, filtering, washing and drying the crystal mush to obtain the 4-bromomethyl-2-cyanobiphenyl product. The product color is purely white; the high performance liquid chromatography purity is up to 99.5%; the crystal granularity is large, the main granularity is about 100 microns, and the granularity distribution is uniform. During crystallization, the once through yield is high, so that the post treatment cost is saved. The method can provide the high-quality raw material for follow-up synthesis of sartan drug products, reduces unnecessary side reaction during the synthetic process, improves the quality indexes such as impurity and yield of the sartan drug products, and has good industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of chemical engineering crystallization, in particular to a crystallization method for preparing high-purity bromosartan biphenyl. Background technique [0002] Hypertension is a major risk factor for cardiovascular and renal vascular diseases. Currently, there are many types of antihypertensive drugs clinically, but most of them have side effects other than the antihypertensive effect. Sartan drugs, also known as angiotensin II (Ang II) receptor (AT1) antagonists, can effectively intervene in the renin-angiotensin-aldosterone system (RAAS), and are important drugs for the treatment of hypertension. Sartan drugs can be used to treat all kinds of mild and moderate hypertension, and their antihypertensive effect is not inferior to that of various existing antihypertensive drugs, especially for patients who are intolerant to AngⅡ receptor blockers. A new generation of oral potent antihypertensive drugs with gr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/50C07C253/34
Inventor 王永莉杨景翔郝红勋侯宝红鲍颖谢闯王静康尹秋响龚俊波张美景
Owner TIANJIN UNIV
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