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The crystallization separation method of nebivolol hydrochloride intermediate mixture

A technology for nebivolol hydrochloride and crystallization separation, which is applied in the field of crystallization separation of mixtures, can solve the problems of large production labor, low production efficiency and high production cost, and achieves the effects of reducing consumption, short preparation period and realizing industrialized production.

Active Publication Date: 2018-09-25
SHANGHAI SHYNDEC PHARMA HAIMEN CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, formula I and formula II are mainly separated by column chromatography, but this method has the following problems: 1, the production efficiency is low, and the production labor is large; 2, the amount of solvent used is large; 3, the yield Low rate, high production cost, etc.
Other separation methods of formula I and formula II are not yet available in relevant literature and patent reports

Method used

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  • The crystallization separation method of nebivolol hydrochloride intermediate mixture
  • The crystallization separation method of nebivolol hydrochloride intermediate mixture
  • The crystallization separation method of nebivolol hydrochloride intermediate mixture

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Put 50g of nebivolol hydrochloride intermediate mixture, 100mL cyclohexane and 20mL n-butanol into a 250mL four-necked bottle successively, dissolve at room temperature to form a clear solution, then cool down to -2°C to crystallize, keep warm for 20 hours, and filter Obtain 18.26gSS / RR type solid, product purity ≥ 97%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 5:1, the mother liquor after the above-mentioned crystallization filter is evaporated to dryness, add 10% mixed solvent ( Relative to the quality of the mother liquor after evaporation), the temperature was raised to dissolve into a clear solution, then cooled to 8°C to crystallize, kept for 20 hours, and 20.32g of RS / SR solid was obtained after filtration, with a product purity of ≥98%.

[0037] In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

[0038] The SS / RR type solid that above-mentioned implementation example...

Embodiment 2

[0040] Put 60g of nebivolol hydrochloride intermediate mixture, 100mL of n-heptane and 20mL of n-butanol into a 250mL four-neck bottle successively, dissolve at room temperature to form a clear solution, then cool down to -2°C to crystallize, keep warm for 20 hours, and filter Obtain 18.57gSS / RR type solid, product purity ≥ 95%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 5:1, the mother liquor after the above-mentioned crystallization filter is evaporated to dryness, add 10% mixed solvent ( Relative to the quality of the mother liquor after evaporation), the temperature was raised to dissolve into a clear solution, then cooled to 8°C to crystallize, kept for 20 hours, and 21.92g of RS / SR solid was obtained after filtration, with a product purity of ≥98%.

[0041] In this method, the single-pass yield of the formula I solid and the formula II solid is 68%.

Embodiment 3

[0043] Put 50g of nebivolol hydrochloride intermediate mixture, 10mL cyclohexane and 150mL n-butanol into a 250mL four-neck bottle successively, dissolve at room temperature to form a clear solution, then cool down to -5°C to crystallize, keep warm for 20 hours, and filter Obtain 15.61gSS / RR type solid, product purity ≥ 95%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 1:15, the mother liquor after the above-mentioned crystallization filter is spin-dried, add 15% mixed solvent ( Relative to the quality of the mother liquor after spin-drying), the temperature was raised to dissolve into a clear solution, and then the temperature was lowered to 5°C to crystallize, and the temperature was kept for 20 hours. After filtration, 22.51g of RS / SR solid was obtained, and the product purity was greater than or equal to 97%.

[0044] In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

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Abstract

Disclosed is a crystallization separation method for a nebivolol hydrochloride intermediate mixture, which comprises the following steps: step 1, adding an alcohol solvent or a mixed solvent of an alcohol and an alkane to a nebivolol hydrochloride intermediate mixture, dissolving same into a clear solution at normal temperature, then lowering the temperature and crystallizing same, and filtering same to obtain an SS / RR type solid; and step 2, concentrating a mother solution after crystallization and filtration in step 1 until dry, then adding the alcohol solvent or the mixed solvent of an alcohol and an alkane, raising the temperature and dissolving same into a clear solution, then lowering the temperature and crystallizing same, and filtering same to obtain an RS / SR type solid. The SS / RR type and RS / SR type diastereomers in the intermediate mixture are separated by using crystallization; the operation is simple, the preparation period is relatively short, at the same time, the solvent consumption is decreased, the production cost and the aftertreatment cost of the solvent are reduced, which are conducive to realizing industrial production, and a single-pass yield of a product obtained by the separation can reach 35%-70%.

Description

technical field [0001] The invention relates to a method for crystallization and separation of a mixture, in particular to a method for crystallization and separation of a mixture of nebivolol hydrochloride intermediate RS / SR type and SS / RR type. Background technique [0002] As a third-generation β-receptor antagonist, nebivolol hydrochloride is different from other β-receptor antagonists and has higher selectivity. It does not cause contraction of bronchial smooth muscle and vascular smooth muscle, and is suitable for mild to moderate high The treatment of blood pressure patients can also be used for the treatment of angina pectoris and congestive heart failure. [0003] [0004] Formula I [0005] [0006] Formula II [0007] RS / SR (formula I) and SS / RR (formula II) are two important intermediates for the synthesis of nebivolol hydrochloride, which are a pair of diastereoisomers. At present, formula I and formula II are mainly separated by column chromatography, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D407/04
CPCC07B57/00C07D311/20C07D407/04
Inventor 张东亚唐祁匀汤红叶于振鹏何康永李海峰邹凌燕
Owner SHANGHAI SHYNDEC PHARMA HAIMEN CO LTD