CN106279065A - A kind of hydrobromic acid irrigates the refined rotating crystal method for Xi Ting - Google Patents
A kind of hydrobromic acid irrigates the refined rotating crystal method for Xi Ting Download PDFInfo
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- CN106279065A CN106279065A CN201510237481.2A CN201510237481A CN106279065A CN 106279065 A CN106279065 A CN 106279065A CN 201510237481 A CN201510237481 A CN 201510237481A CN 106279065 A CN106279065 A CN 106279065A
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- hydrobromic acid
- mixed solvent
- ting
- water
- filter cake
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- 0 CC(C)=CC(C)=C(*)Sc1ccccc1N1CCNCC1 Chemical compound CC(C)=CC(C)=C(*)Sc1ccccc1N1CCNCC1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a kind of hydrobromic acid and irrigate the refined rotating crystal method for Xi Ting, belong to chemicals synthesis technical field.The present invention uses new recrystallization solvent system, obtains β type hydrobromic acid safely and efficiently fertile for Xi Ting.The inventive method solves the previously problem such as toluene solvant residual, inorganic salt residual present in technology, and the β type hydrobromic acid obtained is irrigated and met medicinal required chemical purity and crystal form purity for Xi Ting, is suitable for industrialization production.
Description
Invention field
The present invention relates to hydrobromic acid and irrigate the refined rotating crystal method for Xi Ting, belong to chemicals synthesis technical field.
Background of invention
Fertile is a kind of newly-developed antidepressant jointly developed by Denmark's spirit north pharmacy and Japan's force field drug company for Xi Ting (Vortioxetine).2013
Year, JIUYUE was by FDA (Food and Drug Adminstration) (FDA) approval listing, trade name Brintellix.This medicine is that 5-HT3,5-HT7,5-HT1D are subject to
Body antagonist, 5-HT1B acceptor portion agonist, 5-HT transporter inhibitors, play antidepressant effect by regulation 5-HT, press down for severe
The treatment of strongly fragrant disease (MDD) adult patient.Its medicinal forms is hydrobromate, for beta crystal.
Hydrobromic acid is fertile entitled for western spit of fland chemistry: 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine hydrobromide, and its chemical structural formula is:
At present, the document that report hydrobromic acid is irrigated for western spit of fland synthetic method is few, grinds spirit north pharmacy in addition to a series of patents that China applies for except former, state
The most also minority is had to be different from the former new synthetic method report grinding patent.But the hydrobromic acid that these techniques obtain is fertile can not meet high-quality for western spit of fland product
Pharmaceutical products required for purity, and use recrystallization solvent easily remain, cause unstable product quality.
Patent CN102617513A report synthesis hydrobromic acid is fertile for western spit of fland method is:
In this technique, the first step and second step all have employed toluene and make solvent；It is fertile for Xi Ting that 3rd step hydrobromic acid removing Boc protection group obtains hydrobromic acid
Crude product, crude product again with toluene and water refine further.Owing to toluene is two kind solvents, this route uses toluene solvant three times, easily causes finished product
Toluene solvant residual exceeds standard.
In order to improve purification efficiency further, Denmark's spirit north pharmacy discloses hydrobromic acid subsequently in patent CN1561340B and irrigates the refined side for Xi Ting
Method: first hydrobromic acid is fertile uses isopropanol, water weight mixed solvent recrystallization for western spit of fland crude product, obtains hydrobromic acid and irrigates the iso-propanol solvate for Xi Ting,
Then through toluene, water azeotropic distillation, turning crystalline substance, to obtain β type hydrobromic acid fertile for Xi Ting.Although the method can improve product purity through recrystallisation from isopropanol,
But generate hydrobromic acid and irrigate the iso-propanol solvate for Xi Ting, need to turn brilliant with toluene, easily cause finished product toluene solvant residual to exceed standard.
Therefore, seek to irrigate safely and efficiently for hydrobromic acid western spit of fland process for purification, reduce dissolvent residual risk, there is higher technology content and market price
Value.
Goal of the invention
It is an object of the invention to provide a kind of new hydrobromic acid and irrigate the refined rotating crystal method for Xi Ting.
Summary of the invention
1) present invention uses new recrystallization solvent system, the safe and efficient β type hydrobromic acid that obtains to irrigate for Xi Ting.It is molten that the inventive method solves toluene
The problems such as agent residual, inorganic salt residual, the β type hydrobromic acid obtained irrigates and meets medicinal required chemical purity and crystal form purity for Xi Ting,
It also is adapted for industrialization to produce.
2) hydrobromic acid that the present invention provides is fertile refines rotating crystal method for Xi Ting, comprises the following steps:
3) join in organic mixed solvent I by fertile for hydrobromic acid for western spit of fland crude product, backflow making beating two hours, filter, collect filter cake；
4) filter cake suspends in aqueous, pulls an oar 2 hours for 50-100 DEG C, is cooled to room temperature, continue stirring 2 hours, filter, collects filter cake,
Fertile more than 90% hydrobromic acid for Xi Ting to purity；
5) join in mixed solvent II by fertile for hydrobromic acid for Xi Ting, after backflow is dissolved, heat filtering, filtrate is cooled to room temperature, crystallize, filters,
Obtain purity fertile more than 99.5% hydrobromic acid for Xi Ting；
6) being placed in water azeotropic distillation, cooling crystallization by fertile for hydrobromic acid for Xi Ting, filter, the vacuum dried β type hydrobromic acid that obtains of filter cake is irrigated for west
Spit of fland.
Embodiment
Following embodiment, for the embodiment of claim is expanded on further, is not intended to the present invention.
Embodiment 1:(repeats the former embodiment grinding CN102617513A)
100g irrigates hydrobromic acid stir at 80 DEG C for western spit of fland crude product toluene (800mL) and water (80mL) mixed solvent (10: 1, V/V)
Mix dissolving, heat filtering；Filtrate is cooled to 9 DEG C, crystallize, filters；Filter cake toluene (50mLx2) washs, and 50 DEG C of vacuum is dried to constant weight,
75g white crystal, yield 75%, HPLC purity is 99.83%, maximum single the most miscellaneous only 0.1%, the most miscellaneous only 0.17%；Residue ＞ 0.1% does not conforms to
Lattice；GC detection toluene ＞ 0.15% is defective；XRD irrigates for western spit of fland beta crystal data consistent with the former hydrobromic acid grinding CN102617513A report.
Embodiment 2:
100g is irrigated hydrobromic acid and at 50 DEG C, pulls an oar 1 for western spit of fland crude product 200mL methyl tertiary butyl ether(MTBE) and alcohol mixed solvent (10: 1, V/V)
Hour, filter；Filter cake 200mL water is pulled an oar 1 hour at 50 DEG C, filters；Filter cake with the mixed solvent of 400mL n-butyl alcohol and water (10:
1, V/V) it is heated to backflow to dissolve, heat filtering, is cooled to 9 DEG C, crystallize, filters；Filter cake is azeotropic in 300mL water, distills out 150mL
Water, and this solution is slowly cooled to 9 DEG C, after standing 2 hours, crystallize filters, and filter cake use water (50mLx2) washs, 50 DEG C of vacuum be dried to
Constant weight, obtains 65g white crystal, yield 65%, and HPLC purity is 99.83%, and maximum single the most miscellaneous only 0.1%, the most miscellaneous only 0.17%；Residue
＜ 0.01% is qualified；GC detection n-butyl alcohol does not detects；XRD irrigates for western spit of fland beta crystal data one with the former hydrobromic acid grinding CN102617513A report
Cause.
Embodiment 3:
Pull an oar fertile for 100g hydrobromic acid at 50 DEG C for western spit of fland crude product 200mL methyl tertiary butyl ether(MTBE) and n-butanol mixed solvent (10: 1, V/V)
1 hour, filter；Filter cake 200mL water is pulled an oar 1 hour at 50 DEG C, filters；Filter cake with the mixed solvent of 400mL n-butyl alcohol and water (10:
1, V/V) it is heated to backflow to dissolve, heat filtering, is cooled to 9 DEG C, crystallize, filters；Filter cake is azeotropic in 300mL water, distills out 150mL
Water, and this solution is slowly cooled to 9 DEG C, after standing 2 hours, crystallize filters, and filter cake use water (50mLx2) washs, 50 DEG C of vacuum be dried to
Constant weight, obtains 74g white crystal, yield 74%, and HPLC purity is 99.93%, and maximum single the most miscellaneous only 0.03%, the most miscellaneous only 0.07%；Residue
＜ 0.01% is qualified；GC detection n-butyl alcohol does not detects；XRD irrigates for western spit of fland beta crystal data one with the former hydrobromic acid grinding CN102617513A report
Cause.
Embodiment 4:
Pull an oar fertile for 100g hydrobromic acid at 50 DEG C for western spit of fland crude product 400mL methyl tertiary butyl ether(MTBE) and n-butanol mixed solvent (10: 1, V/V)
1 hour, filter；Filter cake 200mL water is pulled an oar 1 hour at 50 DEG C, filters；Filter cake with the mixed solvent of 400mL n-butyl alcohol and water (10:
1, V/V) it is heated to backflow to dissolve, heat filtering, is cooled to 9 DEG C, crystallize, filters；Filter cake is azeotropic in 300mL water, distills out 150mL
Water, and this solution is slowly cooled to 9 DEG C, after standing 2 hours, crystallize filters, and filter cake use water (50mLx2) washs, 50 DEG C of vacuum be dried to
Constant weight, obtains 52g white crystal, yield 52%, and HPLC purity is 99.94%, and maximum single the most miscellaneous only 0.03%, the most miscellaneous only 0.06%；Residue
＜ 0.01% is qualified；GC detection n-butyl alcohol does not detects；XRD irrigates for western spit of fland beta crystal data one with the former hydrobromic acid grinding CN102617513A report
Cause.
Embodiment 5:
Pull an oar fertile for 100g hydrobromic acid at 50 DEG C for western spit of fland crude product 200mL methyl tertiary butyl ether(MTBE) and n-butanol mixed solvent (10: 1, V/V)
1 hour, filter；Filter cake 200mL water is pulled an oar 1 hour at 50 DEG C, filters；Filter cake with the mixed solvent of 400mL n-butyl alcohol and water (12:
1, V/V) it is heated to backflow to dissolve, heat filtering, is cooled to 9 DEG C, crystallize, filters；Filter cake is azeotropic in 300mL water, distills out 150mL
Water, and this solution is slowly cooled to 9 DEG C, after standing 2 hours, crystallize filters, and filter cake use water (50mLx2) washs, 50 DEG C of vacuum be dried to
Constant weight, obtains 67g white crystal, yield 67%, and HPLC purity is 99.91%, and maximum single the most miscellaneous only 0.03%, the most miscellaneous only 0.09%；Residue
＜ 0.01% is qualified；GC detection n-butyl alcohol does not detects；XRD irrigates for western spit of fland beta crystal data one with the former hydrobromic acid grinding CN102617513A report
Cause.
Claims (8)
1. a hydrobromic acid irrigates the refined rotating crystal method for Xi Ting, it is characterised in that the method comprises the following steps: hydrobromic acid is fertile to add for western spit of fland crude product
Organic mixed solvent I, making beating；After the making beating of filter cake use water, filter, filter cake mixed solvent II recrystallization；Then azeotrope with water turns brilliant.
Method the most according to claim 1, it is characterised in that organic solvent I is methyl tertiary butyl ether(MTBE), ethyl acetate, ethanol n-butyl alcohol, just
A kind of or the most several mixed solvent in amylalcohol, hexanol or isoamyl alcohol or isopropanol.
Method the most according to claim 2, it is characterised in that described organic solvent I is preferably methyl tertiary butyl ether(MTBE) and isoamyl alcohol mixed solvent.
Method the most according to claim 3, it is characterised in that described organic solvent I methyl tertiary butyl ether(MTBE): isobutanol=6-12: 1 (V: V),
It is preferably 10: 1.
Method the most according to claim 1, it is characterised in that described solvent II is n-butyl alcohol, n-amyl alcohol, hexanol or isoamyl alcohol, and water group
The mixed solvent become.
Method the most according to claim 5, it is characterised in that mixed solvent II is preferably the mixed solvent of n-butyl alcohol and water.
Method the most according to claim 6, it is characterised in that described mixed solvent II n-butyl alcohol: water=8-12: 1 (V: V), preferably 10: 1.
Method the most according to claim 1, it is characterised in that it is 1: 1-4 (WN) that hydrobromic acid irrigates the ratio for western spit of fland crude product Yu organic solvent I,
It is preferably 1: 2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510237481.2A CN106279065A (en) | 2015-05-12 | 2015-05-12 | A kind of hydrobromic acid irrigates the refined rotating crystal method for Xi Ting |
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| CN201510237481.2A CN106279065A (en) | 2015-05-12 | 2015-05-12 | A kind of hydrobromic acid irrigates the refined rotating crystal method for Xi Ting |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108929287A (en) * | 2017-05-26 | 2018-12-04 | 万全万特制药江苏有限公司 | The purification of Vortioxetine |
| CN112830906A (en) * | 2020-12-31 | 2021-05-25 | 江苏优仿医药科技有限公司 | Preparation method of vortioxetine hydrobromide alpha crystal form |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472906A (en) * | 2006-06-16 | 2009-07-01 | H.隆德贝克有限公司 | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
| WO2014128207A1 (en) * | 2013-02-22 | 2014-08-28 | H. Lundbeck A/S | Vortioxetine manufacturing process |
| CN104119298A (en) * | 2014-08-13 | 2014-10-29 | 北京蓝贝望生物医药科技股份有限公司 | Vortioxetine hydrobromide |
| WO2014177491A1 (en) * | 2013-04-29 | 2014-11-06 | Lek Pharmaceuticals D.D. | New solid form of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide |
| WO2015035802A1 (en) * | 2013-09-12 | 2015-03-19 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| CN104447622A (en) * | 2014-11-28 | 2015-03-25 | 郑州大明药物科技有限公司 | Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form |
-
2015
- 2015-05-12 CN CN201510237481.2A patent/CN106279065A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472906A (en) * | 2006-06-16 | 2009-07-01 | H.隆德贝克有限公司 | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
| WO2014128207A1 (en) * | 2013-02-22 | 2014-08-28 | H. Lundbeck A/S | Vortioxetine manufacturing process |
| WO2014177491A1 (en) * | 2013-04-29 | 2014-11-06 | Lek Pharmaceuticals D.D. | New solid form of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide |
| WO2015035802A1 (en) * | 2013-09-12 | 2015-03-19 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| CN104119298A (en) * | 2014-08-13 | 2014-10-29 | 北京蓝贝望生物医药科技股份有限公司 | Vortioxetine hydrobromide |
| CN104447622A (en) * | 2014-11-28 | 2015-03-25 | 郑州大明药物科技有限公司 | Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108929287A (en) * | 2017-05-26 | 2018-12-04 | 万全万特制药江苏有限公司 | The purification of Vortioxetine |
| CN112830906A (en) * | 2020-12-31 | 2021-05-25 | 江苏优仿医药科技有限公司 | Preparation method of vortioxetine hydrobromide alpha crystal form |
| CN112830906B (en) * | 2020-12-31 | 2022-05-13 | 微研优仿医药科技(江苏)有限公司 | Preparation method of vortioxetine hydrobromide alpha crystal form |
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Application publication date: 20170104 |