CN101284789A - Novel method for Racemizing sertraline isomer - Google Patents
Novel method for Racemizing sertraline isomer Download PDFInfo
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- CN101284789A CN101284789A CNA2007100678965A CN200710067896A CN101284789A CN 101284789 A CN101284789 A CN 101284789A CN A2007100678965 A CNA2007100678965 A CN A2007100678965A CN 200710067896 A CN200710067896 A CN 200710067896A CN 101284789 A CN101284789 A CN 101284789A
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- sertraline
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- highly basic
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Abstract
The invention discloses a method for the racemization of sertraline isomer. The prior method has the disadvantages that the product recovery rate is low, the cost is high, different processing methods are adopted for different isomers, and the steps are complex. In the method, an organic solvent and a strong base are added into the sertraline isomer, racemization processing is performed after the sertraline isomer is heated to backflow, heat preservation is performed, distillation is performed to remove the solvent, water is added, the pH value of the solution is adjusted by acid, extraction is performed, and then the extract is dried by distillation to obtain the sertraline. The method can perform racemization processing to all sertraline isomers and can be completed in one process, the sertraline isomer is fully utilized, and the content of obtained sertraline is high.
Description
Technical field
The present invention relates to the method for Racemizing sertraline isomer.
Background technology
Sertraline hydrochloride (calling Sertraline in the following text), and chemical being called (1S, 4S)-4-(3, the 4-dichlorobenzene) 1,2,3,4-tetrahydrochysene-N methyl isophthalic acid-naphthylamine hydrochloride, has the following formula structure, Sertraline is up-to-date a kind of in the selective serotonin reuptake inhibitor, and it is by suppressing the re-uptake of 5-HT presynaptic membrane, and then improves the 5-HT concentration of synaptic cleft, reach antidepressant effect, be used for the treatment of dysthymia disorders, obsession and phobia.In the Sertraline product that the existing method of utilization prepares, contain three kinds of following isomer, the multiple racemization method that isomer is changed into Sertraline is now also arranged.
Sertraline isomer I isomer II isomer III
US 5082970 patent disclosures in organic solvent, use potassium alcoholate or sodium alkoxide to reflux to carry out the method for racemization, it was included in an alkali metal salt that uses potassium tert.-butoxide or C1～C4 alcohol among the THF (tetrahydrofuran (THF)) and sertraline isomer backflow more than 48 hours, and the product that obtains is about 2 to 1 the cis and the racemic mixture of trans diastereomer.This method need be used expensive an alkali metal salt, handles behind the salify again and causes yield to reduce the cost height; Adopt different treatment processs, complex steps at different isomer.
WO 0149638 patent disclosure realize the racemization method with the bromine oxidation, it comprised for two steps: at first, in the presence of methyl alcohol and NaOH, be oxidized to R-Sertraline imines with the liquid bromine; Imines salify subsequently gets cis racemize sertraline hydrochloride.This method need be used big bromine of contaminative and expensive sodium tert-butoxide.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, and a kind of novel method of a Racemizing sertraline isomer that the step finishes, production cost is low, pollution is few is provided.
For this reason, the present invention adopts following technical scheme: the novel method of Racemizing sertraline isomer, it adds organic solvent and highly basic in sertraline isomer, being heated to refluxes carries out the racemization processing, insulation afterwards, and distillation removes and desolvates then, add water, then with the pH value of acid-conditioning solution, extract, the evaporate to dryness extract gets Sertraline.The present invention can carry out that racemization is handled and a step finishes to all sertraline isomers, has made full use of sertraline isomer.
The novel method of described Racemizing sertraline isomer, its reflux temperature are at 40 ℃～110 ℃, and this temperature is decided according to the boiling point of different organic solvents.
The novel method of described Racemizing sertraline isomer, organic solvent is methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, Virahol, the trimethyl carbinol, propyl carbinol, acetone, the tertiary butyl-methyl ether, N, dinethylformamide, N, any of N-N,N-DIMETHYLACETAMIDE or the mixture more than two kinds, be preferably N, dinethylformamide (DMF) or N,N-dimethylacetamide, the Sertraline content height that utilizes it to obtain.
The novel method of described Racemizing sertraline isomer, highly basic is potassium hydride KH, sodium hydride, hydrolith, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, hydrated barta, be preferably potassium hydride KH, sodium hydride, hydrolith, the Sertraline content height that utilizes it to obtain.
The novel method of described Racemizing sertraline isomer, the mol ratio of highly basic and sertraline isomer is 1～10: 1, is preferably 2～3: 1, this ratio the most fully and not wastes raw material reaction.
The present invention has following beneficial effect: the reaction conditions gentleness, react more easy to control, and pollute and lack, production cost is low; The present invention can carry out that racemization is handled and a step finishes to all sertraline isomers, has made full use of the isomer of Sertraline, the Sertraline content height that obtains.
Embodiment
The isomer method of inspection: with CHIRALPAK AD-H chiral column is chromatographic column, is moving phase with normal hexane-ethanol-diethylamine, tests according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Embodiment 1: drop into sertraline isomer 10.00g in the reaction vessel, methyl alcohol 100ml adds potassium hydroxide 1.64g, is heated to 40 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.70g (wherein Sertraline content 11.2%).
Embodiment 2: drop into sertraline isomer 10.00g in the reaction vessel, ethanol 100ml adds potassium hydroxide 1.64g, is heated to 60 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.52g (wherein Sertraline content 16.8%).
Embodiment 3: drop into sertraline isomer 10.00g in the reaction vessel, propyl carbinol 100ml adds potassium hydroxide 1.64g, is heated to 60 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.60g (wherein Sertraline content 13.1%).
Embodiment 4: drop into sertraline isomer 10.00g in the reaction vessel, trimethyl carbinol 100ml adds potassium hydroxide 1.64g, is heated to 60 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.65g (wherein Sertraline content 13.6%).
Embodiment 5: drop into sertraline isomer 10.00g in the reaction vessel, Virahol 100ml adds potassium hydroxide 1.64g, is heated to 60 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.63g (wherein Sertraline content 10.3%).
Embodiment 6: drop into sertraline isomer 10.00g in the reaction vessel, methyl alcohol 100ml adds sodium hydroxide 1.17g, is heated to 60 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.72g (wherein Sertraline content 12.5%).
Embodiment 7: drop into sertraline isomer 10.00g in the reaction vessel, methyl alcohol 100ml adds potassium hydroxide 1.64g, is heated to backflow, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.79g (wherein Sertraline content 15.8%).
Embodiment 8: drop into sertraline isomer 10.00g in the reaction vessel, trimethyl carbinol 100ml adds potassium hydroxide 1.64g, is heated to backflow, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.69g (wherein Sertraline content 17.5%).
Embodiment 9: drop into sertraline isomer 10.00g in the reaction vessel, toluene 100ml adds potassium hydroxide 1.64g, is heated to backflow, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.51g (wherein Sertraline content 4.1%).
Embodiment 10: drop into sertraline isomer 10.00g in the reaction vessel, DMF100ml adds sodium hydride 1.64g, is heated to 80 ℃, insulation 24h, and reaction finishes, evaporated under reduced pressure.Add entry 10ml, the hydrochloric acid of 1N is transferred PH＜7.0, and chloroform extraction, evaporate to dryness get 9.51g (wherein Sertraline content 28.1%).
Protection scope of the present invention is not limited to the foregoing description, and all technology contents identical or close with the present invention all fall in its protection domain.
Claims (8)
1, the novel method of Racemizing sertraline isomer, it adds organic solvent and highly basic in sertraline isomer, and being heated to refluxes carries out the racemization processing, insulation afterwards, distillation removes and desolvates then, adds water, then with the pH value of acid-conditioning solution, extract, the evaporate to dryness extract gets Sertraline.
2, the novel method of Racemizing sertraline isomer according to claim 1, its reflux temperature is at 40 ℃～110 ℃.
3, according to the novel method of the described Racemizing sertraline isomer of claim 1 or 2, described organic solvent is methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, Virahol, the trimethyl carbinol, propyl carbinol, acetone, the tertiary butyl-methyl ether, N, any of dinethylformamide, N,N-dimethylacetamide or the mixture more than two kinds.
4, according to the novel method of the described Racemizing sertraline isomer of claim 3, described organic solvent is N, dinethylformamide or N,N-dimethylacetamide.
5, according to the novel method of the described Racemizing sertraline isomer of claim 3, described highly basic is potassium hydride KH, sodium hydride, hydrolith, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, hydrated barta.
6, according to the novel method of the described Racemizing sertraline isomer of claim 5, described highly basic is potassium hydride KH, sodium hydride, hydrolith.
7, according to the novel method of the described Racemizing sertraline isomer of claim 5, the mol ratio of described highly basic and sertraline isomer is 1～10: 1.
8, according to the novel method of the described Racemizing sertraline isomer of claim 7, the mol ratio of described highly basic and sertraline isomer is 2～3: 1.
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| CNA2007100678965A CN101284789A (en) | 2007-04-09 | 2007-04-09 | Novel method for Racemizing sertraline isomer |
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| CNA2007100678965A CN101284789A (en) | 2007-04-09 | 2007-04-09 | Novel method for Racemizing sertraline isomer |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016008285A1 (en) * | 2014-07-16 | 2016-01-21 | 雅本化学股份有限公司 | Method for recycling chiral 1-benzyl-3-hydroxypiperidine by racemization |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016008285A1 (en) * | 2014-07-16 | 2016-01-21 | 雅本化学股份有限公司 | Method for recycling chiral 1-benzyl-3-hydroxypiperidine by racemization |
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Open date: 20081015 |