CN104744389A - Method for recycling valsartan methyl ester from valsartan crystallization mother solution - Google Patents
Method for recycling valsartan methyl ester from valsartan crystallization mother solution Download PDFInfo
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- CN104744389A CN104744389A CN201510108609.5A CN201510108609A CN104744389A CN 104744389 A CN104744389 A CN 104744389A CN 201510108609 A CN201510108609 A CN 201510108609A CN 104744389 A CN104744389 A CN 104744389A
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- valsartan
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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Abstract
The invention relates to a method for recycling valsartan methyl ester from valsartan crystallization mother solution. The method comprises the following steps of: washing the valsartan crystallization mother solution by using acid aqueous solution, drying, dehydrating, and filtering; distilling filtrate, recycling ethyl acetate in the valsartan crystallization mother solution, dissolving distillation residues by using a solvent I, adding methanol and a catalyst, keeping the temperature, and reacting; washing by using water after keeping the temperature; extracting by using sodium hydroxide solution; adjusting alkaline extraction liquid to acidity, and extracting by using a solvent II; and drying and dehydrating the extraction liquid, dropping in a solvent III, crystallizing, and separating out valsartan methyl ester solids. The method disclosed by the invention has the beneficial effects that: the cost of a raw valsartan material can be effectively reduced; and the method is simple and convenient to operate, and is applied to large-scale industrial production.
Description
Technical field
The present invention relates to chemosynthesis technical field, especially valsartan in valsartan mother liquid is prepared into the method for valsartan methyl esters solid.
Background technology
Valsartan is Angiotensin Ⅱ receptor antagonist of new generation, there is high selectivity and special direct effect, can effective antagonism AT1 acceptor, its transformation period is about 9 hours, efficacy of antihypertensive treatment can maintain more than 24 hours, and has good Trough to peak ratio, possesses therapeutic action widely, patient's better tolerance is the hypertensive first-line drug for the treatment of.
The valsartan production technique adopted at present extensively first prepares valsartan methyl esters, then obtains valsartan through hydrolysis reaction, and can generating portion racemization in hydrolysis reaction, generates valsartan chiral isomer.In order to reduce the content of chiral isomer in valsartan, needing strict crystallization control condition, thus causing the reduction of valsartan yield, namely contain more valsartan and chiral isomer thereof in valsartan crystallization mother liquor.If valsartan crystallization mother liquor is not recycled, valsartan raw materials cost can be caused to rise, be also unfavorable for emissions reduction, therefore the recycling of valsartan mother liquid not only produces economic benefit, also has good social benefit simultaneously.
Ideal way of recycling directly reclaims valsartan from valsartan crystallization mother liquor, but owing to wherein containing chiral isomer in more valsartan, reclaim valsartan to need just can conform to quality requirements through repeatedly recrystallization process, reclaim the valsartan obtained simultaneously and how to meet GMP specification, also there is certain management difficulty.And the valsartan in valsartan crystallization mother liquor is reacted into again valsartan methyl esters, then preferably resolve above problem.
The valsartan crystallization solvent extensively adopted at present is ethyl acetate, and namely valsartan crystallization mother liquor is the ethyl acetate solution of valsartan and chiral isomer thereof.Valsartan in valsartan crystallization mother liquor is prepared into valsartan methyl esters solid by the present invention, can re-start hydrolysis reaction and obtain valsartan after qualified after testing.Reaction formula valsartan being prepared into valsartan methyl esters is as follows:
Summary of the invention
The technical problem to be solved in the present invention is: based on the problems referred to above, the invention provides a kind of method reclaiming valsartan methyl esters from valsartan crystallization mother liquor.
The present invention solves the technical scheme that its technical problem adopts: a kind of method reclaiming valsartan methyl esters from valsartan crystallization mother liquor, comprises the following steps:
(1) valsartan crystallization mother liquor acidic aqueous solution washs, drying and dehydrating, filters;
(2) diafiltration liquid distillation, reclaim the ethyl acetate in valsartan crystallization mother liquor, distillation leftover solvent I dissolves, and adds methyl alcohol and catalyzer, insulation reaction;
(3), after insulation terminates, wash with water;
(4) extract with sodium hydroxide solution;
(5) alkaline extraction liquid is adjusted to acidity, extracts with solvent II;
(6) extraction liquid drying and dehydrating, is added drop-wise in solvent III, crystallization valsartan methyl esters solid.
Further, in step (1), acidic aqueous solution is the aqueous hydrochloric acid of the aqueous hydrochloric acid of pH=2 ~ 5, preferred pH=3 ~ 4, and washing times is 2 ~ 4 times, preferably 3 times, and drying and dehydrating agent is anhydrous sodium sulphate.
Further, in step (2), solvent I is toluene or dimethylbenzene, and preferred toluene, catalyzer is the vitriol oil, and insulation reaction temperature is 70 ~ 90 DEG C, preferably 75 ~ 85 DEG C.
Further, in step (3), the terminal of insulation reaction is determined by thin-layer chromatography method.
Further, concentration of sodium hydroxide solution is 1 ~ 3% in step (4), preferably 2%.
Further, in step (5), acidity refers to pH=1 ~ 3, preferred pH=1.5 ~ 2.5, and solvent II is methyl tertiary butyl ether or isopropyl ether, preferable methyl tertbutyl ether.
Further, step (6) solvent III is normal hexane, normal heptane, hexanaphthene or sherwood oil, preferred hexanaphthene, and Tc is 0 ~ 15 DEG C, preferably 5 ~ 10 DEG C.
The invention has the beneficial effects as follows: the method reclaiming valsartan methyl esters solid from valsartan crystallization mother liquor can effectively reduce valsartan raw materials cost, easy and simple to handle, is suitable for large-scale industrial production.
Embodiment
The invention will be further described in conjunction with specific embodiments now, and following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment 1
Get the valsartan ethyl acetate crystalline mother solution 200ml in theory containing 10g valsartan, wash 3 times with the aqueous hydrochloric acid of pH=3 ~ 4, each 100ml, then dewater 30 minutes with anhydrous sodium sulfate drying.Filter, washing filtrate merges, concentrating under reduced pressure, and distillation leftover toluene 100ml dissolves, and adds 20ml methyl alcohol and vitriol oil 1ml after dissolving, 75 ~ 85 DEG C of insulation reaction, and TLC follows the tracks of reaction to valsartan spot and disappears.Be cooled to room temperature, wash 2 times with water, each 30ml, then extracts 2 times with the sodium hydroxide solution of 2%, each 50ml below 10 DEG C, merge buck phase, below 10 DEG C, adjust pH=1.5 ~ 2.5 with hydrochloric acid, extract 2 times with methyl tertiary butyl ether, each 40ml, combining extraction liquid, dewaters 30 minutes with anhydrous sodium sulfate drying.Filter, washing filtrate merges, and 5 ~ 10 DEG C are added drop-wise in 80ml hexanaphthene, separates out solid, filters, and dry, obtain valsartan methyl esters 7.1g, chemical purity more than 99%, chiral photo-isomerisation body burden is about 1.5%.
Embodiment 2
Get the valsartan ethyl acetate crystalline mother solution 200ml in theory containing 10g valsartan, wash 3 times with the aqueous hydrochloric acid of pH=3 ~ 4, each 100ml, then dewater 30 minutes with anhydrous sodium sulfate drying.Filter, washing filtrate merges, concentrating under reduced pressure, and distillation leftover toluene 100ml dissolves, and adds 20ml methyl alcohol and vitriol oil 1ml after dissolving, 75 ~ 85 DEG C of insulation reaction, and TLC follows the tracks of reaction to valsartan spot and disappears.Be cooled to room temperature, wash 2 times with water, each 30ml, then extracts 2 times with the sodium hydroxide solution of 2%, each 50ml below 10 DEG C, merge buck phase, below 10 DEG C, adjust pH=1.5 ~ 2.5 with hydrochloric acid, extract 2 times with isopropyl ether, each 60ml, combining extraction liquid, dewaters 30 minutes with anhydrous sodium sulfate drying.Filter, washing filtrate merges, and 5 ~ 10 DEG C are added drop-wise in 80ml hexanaphthene, separates out solid, filters, and dry, obtain valsartan methyl esters 7.1g, chemical purity more than 99%, chiral photo-isomerisation body burden is about 1.5%.
Embodiment 3
Get the valsartan ethyl acetate crystalline mother solution 200ml in theory containing 10g valsartan, wash 3 times with the aqueous hydrochloric acid of pH=2 ~ 3, each 100ml, then dewater 30 minutes with anhydrous sodium sulfate drying.Filter, washing filtrate merges, concentrating under reduced pressure, and distillation leftover toluene 100ml dissolves, and adds 20ml methyl alcohol and vitriol oil 1ml after dissolving, 75 ~ 85 DEG C of insulation reaction, and TLC follows the tracks of reaction to valsartan spot and disappears.Be cooled to room temperature, wash 2 times with water, each 30ml, then extracts 2 times with the sodium hydroxide solution of 2%, each 50ml below 10 DEG C, merge buck phase, below 10 DEG C, adjust pH=1.5 ~ 2.5 with hydrochloric acid, extract 2 times with methyl tertiary butyl ether, each 40ml, combining extraction liquid, dewaters 30 minutes with anhydrous sodium sulfate drying.Filter, washing filtrate merges, and 5 ~ 10 DEG C are added drop-wise in 80ml hexanaphthene, separates out solid, filters, and dry, obtain valsartan methyl esters 7.1g, chemical purity more than 99%, chiral photo-isomerisation body burden is about 1.8%.
Claims (7)
1. from valsartan crystallization mother liquor, reclaim a method for valsartan methyl esters, it is characterized in that: comprise the following steps:
(1) valsartan crystallization mother liquor acidic aqueous solution washs, drying and dehydrating, filters;
(2) diafiltration liquid distillation, reclaim the ethyl acetate in valsartan crystallization mother liquor, distillation leftover solvent I dissolves, and adds methyl alcohol and catalyzer, insulation reaction;
(3), after insulation terminates, wash with water;
(4) extract with sodium hydroxide solution;
(5) alkaline extraction liquid is adjusted to acidity, extracts with solvent II;
(6) extraction liquid drying and dehydrating, is added drop-wise in solvent III, crystallization valsartan methyl esters solid.
2. the method reclaiming valsartan methyl esters from valsartan crystallization mother liquor according to claim 1, it is characterized in that: in described step (1), acidic aqueous solution is the aqueous hydrochloric acid of pH=2 ~ 5, washing times is 2 ~ 4 times, and drying and dehydrating agent is anhydrous sodium sulphate.
3. the method reclaiming valsartan methyl esters from valsartan crystallization mother liquor according to claim 1, is characterized in that: in described step (2), solvent I is toluene or dimethylbenzene, and catalyzer is the vitriol oil, and insulation reaction temperature is 70 ~ 90 DEG C.
4. the method reclaiming valsartan methyl esters from valsartan crystallization mother liquor according to claim 1, is characterized in that: in described step (3), the terminal of insulation reaction is determined by thin-layer chromatography method.
5. the method reclaiming valsartan methyl esters from valsartan crystallization mother liquor according to claim 1, is characterized in that: in described step (4), concentration of sodium hydroxide solution is 1 ~ 3%.
6. the method reclaiming valsartan methyl esters from valsartan crystallization mother liquor according to claim 1, is characterized in that: in described step (5), acidity refers to pH=1 ~ 3, and solvent II is methyl tertiary butyl ether or isopropyl ether.
7. the method reclaiming valsartan methyl esters from valsartan crystallization mother liquor according to claim 1, is characterized in that: described step (6) solvent III is normal hexane, normal heptane, hexanaphthene or sherwood oil, and Tc is 0 ~ 15 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457266A (en) * | 2020-12-24 | 2021-03-09 | 江苏新瑞药业有限公司 | Valsartan mother liquor recovery method |
| CN113773267A (en) * | 2021-09-06 | 2021-12-10 | 安徽美诺华药物化学有限公司 | Method for recovering methyl ester from valsartan mother liquor |
| CN115160246A (en) * | 2022-08-04 | 2022-10-11 | 江苏新瑞药业有限公司 | Process for recovering valsartan from valsartan mother liquor |
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|---|---|---|---|---|
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| CN101367772A (en) * | 2008-10-06 | 2009-02-18 | 北京赛科药业有限责任公司 | Control method for diovan foreign matter |
| CN102060797A (en) * | 2010-12-31 | 2011-05-18 | 江苏江神药物化学有限公司 | High-purity valsartanmethyl ester crystal production process |
| CN102329276A (en) * | 2011-09-30 | 2012-01-25 | 浙江新赛科药业有限公司 | Method for recovering valsartan mother liquid |
| CN102351804A (en) * | 2011-09-30 | 2012-02-15 | 浙江新赛科药业有限公司 | Method for recovering valsartan racemate |
| CN104402838A (en) * | 2014-11-04 | 2015-03-11 | 常州康丽制药有限公司 | Valsartan refining method |
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2015
- 2015-03-12 CN CN201510108609.5A patent/CN104744389B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| CN101367772A (en) * | 2008-10-06 | 2009-02-18 | 北京赛科药业有限责任公司 | Control method for diovan foreign matter |
| CN102060797A (en) * | 2010-12-31 | 2011-05-18 | 江苏江神药物化学有限公司 | High-purity valsartanmethyl ester crystal production process |
| CN102329276A (en) * | 2011-09-30 | 2012-01-25 | 浙江新赛科药业有限公司 | Method for recovering valsartan mother liquid |
| CN102351804A (en) * | 2011-09-30 | 2012-02-15 | 浙江新赛科药业有限公司 | Method for recovering valsartan racemate |
| CN104402838A (en) * | 2014-11-04 | 2015-03-11 | 常州康丽制药有限公司 | Valsartan refining method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457266A (en) * | 2020-12-24 | 2021-03-09 | 江苏新瑞药业有限公司 | Valsartan mother liquor recovery method |
| CN113773267A (en) * | 2021-09-06 | 2021-12-10 | 安徽美诺华药物化学有限公司 | Method for recovering methyl ester from valsartan mother liquor |
| CN115160246A (en) * | 2022-08-04 | 2022-10-11 | 江苏新瑞药业有限公司 | Process for recovering valsartan from valsartan mother liquor |
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Address after: 213105 Changzhou, Wujin District, Luoyang City, Dai Dai Street Applicant after: Kang Li (Changzhou) Medicine Pharmaceutical Co. Ltd. Address before: 213105 Changzhou, Wujin District, Luoyang City, Dai Dai Street Applicant before: Changzhou Kangli Pharmaceutical Co., Ltd. |
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