CN103554097A - Impurity removing method of lurasidone - Google Patents
Impurity removing method of lurasidone Download PDFInfo
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- CN103554097A CN103554097A CN201310486519.0A CN201310486519A CN103554097A CN 103554097 A CN103554097 A CN 103554097A CN 201310486519 A CN201310486519 A CN 201310486519A CN 103554097 A CN103554097 A CN 103554097A
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- organic phase
- stir
- formula
- stirring
- filter cake
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Links
- 0 CC(*(cccc1)c1N)=* Chemical compound CC(*(cccc1)c1N)=* 0.000 description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N COC1CCCC1 Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an impurity removing method of lurasidone. The method comprises the following steps of mechanically stirring compounds of formula II and formula III, potassium carbonate and toluene, heating up until refluxing, adding water after reaction is finished, stirring, standing and layering, cooling an upper-layer organic phase, adjusting pH value of the organic layer by diluted hydrochloric acid to 2.0-7.0, and keeping the temperature between 30 DEG C and 70 DEG C; after stirring, standing and layering, collecting the upper-layer organic phase and adding 2.5% sodium chloride liquor to wash, standing and layering to collect the upper-layer organic phase after stirring again, adding isopropyl alcohol 3-15 times the amount of the liquor after drying the liquor by compressing and concentrating, heating up until refluxing, stirring and filtering after the isopropyl alcohol is completely dissolved, washing a filter cake by using frozen isopropyl alcohol, colleting the filter cake, compressing and drying under 85 DEG C-90 DEG C. The impurity removing method disclosed by the invention is simple and easy to implement, simple and convenient to operate, and suitable for scale type industrial production.
Description
Technical field
The present invention relates to a kind of impurity-removing method of pharmaceutical intermediate.Be specifically related to a kind of Lurasidone (3aR, 4S, 7R, 7aS)-2-[[(1R, 2R)-2-[[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl] six hydrogen-1H-4,7-methyl isoindole-1, the removal method of impurity in 3-diketone preparation process.
Background of invention
Lurasidone HCl (lurasidone HCI) belongs to atypical antipsychotic class, (the Dainipon Sumitomo Pharma Co. of Shi You SUMITOMO CHEMICAL drugmaker, Ltd.) a kind of antipsychotic drug with dual function of exploitation, belong to atypical antipsychotic class, it all has high-affinity to 5-HT2A acceptor and d2 dopamine receptor, and mental patient's the positive and negative symptoms are all had to significant curative effect.U.S. FDA approval listing on October 28th, 2010, for schizophreniac's treatment, its commodity are called Latuda, and recommended dose 1 tablet every day, for schizophreniac's first-line treatment.Its structural formula is as shown in the formula IX:
Lurasidone HCl trade(brand)name Latuda, belongs to chemical drug registration classification 3.1 classes, and the current domestic notice of import of only having, there is no producer and declare.US Patent No. expires for 5532372,2013 years, but does not see patent application at home.In US Patent No. 5532372, do not report concrete synthesis condition, do not report the removal of impurities of Lurasidone base and refining method yet.In the preparation of Lurasidone base, we have found to have following several impurity,
Summary of the invention
Technical problem to be solved by this invention is in the building-up process of Lurasidone HCl, provide that a kind of reaction conditions is simple, raw material is cheaply easy to get, cost is low except heterozygosis process for purification.
The removal of impurities and the process for purification that the invention provides a kind of Lurasidone HCl intermediate formula I, its chemical equation is as follows:
The method comprises the following steps: formula II and formula III (norborneol dicarboximide), salt of wormwood and toluene mechanical stirring, be warming up to backflow, keep backflow after 3.0-9.0 hour, be cooled to 40-100 ℃, then add a certain amount of water, stir after 30mins, stratification, collect upper organic phase, organic layer regulates pH value in 2.0-7.0 left and right with the dilute hydrochloric acid of 5% left and right, and maintains the temperature between 30-70 ℃.Stir after 30 minutes, stratification, collects upper organic phase and adds 2.5% sodium chloride solution washing, stir after 30 minutes stratification and collect upper organic phase, be evaporated to dry after, the Virahol that adds 3-15 doubly to measure, be warming up to backflow, after all dissolving, stir after 30 minutes, slow cooling is to 3-8 ℃ of cooling, insulated and stirred is filtered for 1.0 hours again, freezing washed with isopropyl alcohol for filter cake, collects filter cake drying under reduced pressure at 85-90 ℃, obtains intermediate I.
Embodiment
By following examples, the invention will be further elaborated.Embodiment: (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl] six hydrogen-1H-4,7-methyl isoindole-1, the preparation of 3-diketone (formula I):
150 grams of intermediate II, 42 grams of formula III (Suzhou Jingye Medicine & Chemical Co., Ltd. provides)), 57 grams of salt of wormwood and 500 grams of mechanical stirring of toluene, be warming up to backflow, after keeping refluxing 9.0 hours, be cooled to 40 ℃, add 200 grams of water, stir after 30mins, stratification, collect upper organic phase, organic layer regulates pH value in 4.5-5.0 left and right with the dilute hydrochloric acid of 5% left and right, and maintain the temperature at 30 ℃ of stirrings after 30 minutes, stratification, collect upper organic phase and add the sodium chloride solution of 100 gram 2.5% to wash, stir stratification after 30 minutes and collect upper organic phase, be evaporated to dry after, the Virahol that adds 10 times of amounts, be warming up to backflow, after all dissolving, stir after 30 minutes, slow cooling is to 3-8 ℃ of cooling, insulated and stirred is filtered for 1.0 hours again, freezing washed with isopropyl alcohol for filter cake, collect filter cake vacuum-drying at 85-90 ℃, obtain intermediate I, content 99.8%(content entrusts institute for drug control, Changzhou, Jiangsu Province to detect).IR：3066（=C-H),2936(-C-H),2258(-N-C=H),1761（-C=O）,1589(-C=C-),
1563 (C-N-), 1430 (C-H), 778 (=C-H) cm-1, MS (m/z): 493.68 (M
+), H-NMR spectrogram: (500MHz, CDCl
3) δ: 97(1H, m), 1.00(1H, m), 1.13(1H, m), 1.16(1H, m), 1.18(1H, m), 1.23(1H, m), 1.32(2H, m), 1.51(1H, m), 1.55(1H, m), 1.56(2H, m), 1.60(2H, m) 1.76(1H, m), 2.14(1H, m), 2.50(2H, m), 2.69(2H, m), 3.46(1H, m), 3.27(1H, m), 3.61(1H, m), 3.33(1H, m), 3.53(1H, m), 3.34(1H, m) and 3.57(1H, m), 3.61(1H, m), 3.64(1H, m), 3.75(1H, m), 4.05(2H, m), 7.48(1H, t), 7.59(1H, t), 8.10(1H, d), ultimate analysis (C
28h
37clN
4o
2s) theoretical value (measured value, %): C68.2(68.1), H7.3(7.4), N11.4 (11.4), all consistent with reference substance.
Claims (1)
1. an impurity-removing method for Lurasidone formula I, is characterized in that the method comprises the following steps:
Formula II, formula III compound, salt of wormwood and toluene mechanical stirring, be warming up to backflow, keep backflow after 3.0-9.0 hour, be cooled to 40-100 ℃, add a certain amount of water, stir after 30mins, stratification, collect upper organic phase, organic layer regulates pH value at 2.0-7.0 with dilute hydrochloric acid, and maintains the temperature between 30-70 ℃; Stir after 30 minutes, stratification, collects upper organic phase and adds 2.5% sodium chloride solution washing, stir after 30 minutes stratification and collect upper organic phase, be evaporated to dry after, the Virahol that adds 3-15 doubly to measure, be warming up to backflow, after all dissolving, stir after 30 minutes, slow cooling is to 3-8 ℃ of cooling, insulated and stirred is filtered for 1.0 hours again, freezing washed with isopropyl alcohol for filter cake, collects filter cake drying under reduced pressure at 85-90 ℃, obtains formula I compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310486519.0A CN103554097A (en) | 2013-10-17 | 2013-10-17 | Impurity removing method of lurasidone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310486519.0A CN103554097A (en) | 2013-10-17 | 2013-10-17 | Impurity removing method of lurasidone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103554097A true CN103554097A (en) | 2014-02-05 |
Family
ID=50008497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310486519.0A Pending CN103554097A (en) | 2013-10-17 | 2013-10-17 | Impurity removing method of lurasidone |
Country Status (1)
| Country | Link |
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| CN (1) | CN103554097A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860899A (en) * | 2014-02-24 | 2015-08-26 | 连云港恒运医药科技有限公司 | Lurasidone, or related substances of salt of lurasidone, and preparation method of lurasidone and related substances |
| CN116143771A (en) * | 2021-11-19 | 2023-05-23 | 北京阳光诺和药物研究股份有限公司 | Preparation method of high-purity lurasidone intermediate |
-
2013
- 2013-10-17 CN CN201310486519.0A patent/CN103554097A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860899A (en) * | 2014-02-24 | 2015-08-26 | 连云港恒运医药科技有限公司 | Lurasidone, or related substances of salt of lurasidone, and preparation method of lurasidone and related substances |
| CN104860899B (en) * | 2014-02-24 | 2019-02-22 | 连云港恒运药业有限公司 | Lurasidone or its salt related substances and preparation method thereof |
| CN116143771A (en) * | 2021-11-19 | 2023-05-23 | 北京阳光诺和药物研究股份有限公司 | Preparation method of high-purity lurasidone intermediate |
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Legal Events
| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| ASS | Succession or assignment of patent right |
Owner name: CHANGZHOU INSTITUTE OF ENGINEERING TECHNOLOGY Effective date: 20140110 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20140110 Address after: 213164 Jiangsu Province, Changzhou city Wujin District Gehu Lake Road No. 1 Applicant after: Changzhou University Applicant after: Changzhou Yinsheng Pharmaceutical Co.,Ltd. Address before: 213164 Jiangsu Province, Changzhou city Wujin District Gehu Lake Road No. 1 Applicant before: Changzhou University |
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| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140205 |