CN104513182A - Method for preparing (1R,2R)-1,2-cyclohexanedimethanol disulfonate - Google Patents
Method for preparing (1R,2R)-1,2-cyclohexanedimethanol disulfonate Download PDFInfo
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- CN104513182A CN104513182A CN201310468799.2A CN201310468799A CN104513182A CN 104513182 A CN104513182 A CN 104513182A CN 201310468799 A CN201310468799 A CN 201310468799A CN 104513182 A CN104513182 A CN 104513182A
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- triethylamine
- cyclohexane dimethanol
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Abstract
The invention relates to a synthetic method for (1R,2R) -1,2-cyclohexanedimethanol disulfonate of a general structure formula (I). In the present method, (1R,2R)-1,2-cyclohexanedimethanol is taken as a raw material and triethylamine is taken as an acid-binding agent. (1R,2R)-1,2-cyclohexanedimethanol disulfonate is obtained through a reaction of aromatic hydrocarbon sulfonyl chloride and (1R, 2R)-1,2-cyclohexanedimethanol in the presence of a hydrophobic solvent.
Description
Technical field
The present invention relates to important intermediate in a kind of antipsychotics Lurasidone HCl building-up process, i.e. the preparation method of (1R, 2R)-1,2-CHDM disulfonate.
Background technology
Lurasidone HCl is a kind of antipsychotic agent with dual function.1 important intermediate is had, i.e. (1R, 2R)-1,2-CHDM disulfonate in its building-up process.According to reported in literature, the synthetic method of this intermediate is: by (1R, 2R)-1,2-cyclohexane dimethanol is dissolved in triethylamine and acetonitrile, slowly instill methylsulfonyl chloride under condition of ice bath, keep ice bath room temperature reaction 3 hours after 1 hour, terminate system washing after reaction.Concentrated by gained solution, concentrated solution adds diethyl ether to filter after crystallization and can obtain (US5532372A, US5780632A, EP0464846A).
This route has the following disadvantages: one, and methylsulfonyl chloride used is highly toxic product, and it is bought and uses by strictly controlling, and is not suitable for scale operation.Two, products therefrom quality control is difficult to monitor with HPLC.
Between above deficiency, we have carried out new research to the synthetic method of this compound, obtain a new route, the raw materials used toxicity of this route lower and be easy to buying, reaction conditions is gentle, and product quality monitoring is convenient, substantially increases industrial security and feasibility.
Summary of the invention
The object of the present invention is to provide a kind of excellent process of producing above-mentioned (I), namely use (1R, 2R)-1,2-cyclohexane dimethanol and aromatic hydrocarbons SULPHURYL CHLORIDE are obtained by reacting in hydrophobic solvent.
1. the preferred R group of the present invention is contraposition hydrocarbon substituents, a position halogen substiuted.
2. preferred contraposition methyl in contraposition hydrocarbon substituents, between preferred in a position halogenic substituent, position bromine replaces.
3. select hydrophobic solvent, preferred methylene dichloride.
4. control temperature of reaction within the scope of-20 DEG C ~ 20 DEG C.
5. reactant feed molar ratio is (1R, 2R)-1,2-CHDM: triethylamine: aromatic hydrocarbons SULPHURYL CHLORIDE (bromine) (1:1.5:1.9 ~ 1:3.8:3.9).
6. the reaction times is 1 ~ 28h
Specific embodiments
Following embodiment is for describing the present invention in detail, and unrestricted the present invention
Embodiment 1
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add together with triethylamine 77.2g in 1500ml acetonitrile, stirring 30min under ice bath, keeping room temperature reaction to terminating after adding 158.8g methylsulfonyl chloride, coreaction 6h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains target product: white solid 178.5g, yield 85.7%.
Specific optical rotation :+18.5 °
(
1H-NMR(400MHz，DMSO)；δ(ppm)：δ3.89-3.79(m，8H)，δ2.53(s，δH)，δ1.59-1.48(t，6H)，δ1.08-1.04(t，4H))
Embodiment 2
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml acetonitrile stir 1.5h together with triethylamine 280.7g, keep ice bath to react to terminating after adding 381.1g methylsulfonyl chloride, coreaction 14.5h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 148.1g, yield 71.1%.
Embodiment 3
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml acetonitrile stir 1h together with triethylamine 175.4g, keep room temperature reaction to terminating after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 15h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 221.6g, yield 70.6%.
Specific optical rotation :+19.5 °
(
1H-NMR(400MHz，DMSO)；δ(ppm)：δ7.74-7.72(d，4H)，δ7.48-7.46(d，4H)，δ3.88-3.77(m，8H)，δ2.50(s，6H)，δ1.57-1.46(t，6H)，δ1.07-1.03(t，4H))
Embodiment 4
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml acetonitrile stir 1h together with triethylamine 175.4g, keep ice bath to react to terminating after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 15h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 251.7g, yield 80.2%.
Embodiment 5
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml acetonitrile stir 1h together with triethylamine 175.4g, keep-10 DEG C of reactions to terminating after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 15h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 248.2g, yield 79.1%.
Embodiment 6
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml methylene dichloride stir 30min together with triethylamine 77.2g, keep-10 DEG C of reactions to terminating after adding 264.4g p-methyl benzene sulfonic chloride, coreaction 19h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 168.2g, yield 53.6%.
Embodiment 7
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml methylene dichloride stir 2.0h together with triethylamine 280.7g, keep-10 DEG C of reactions to terminating after adding 634.6g p-methyl benzene sulfonic chloride, coreaction 29.5h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 160.1g, yield 51.0%.
Embodiment 8
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml methylene dichloride stir 1.5min together with triethylamine 175.4g, keep-10 DEG C of reactions to terminating after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 21h.The solution obtained after reaction being terminated successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 234.8g, yield 74.8%.
Embodiment 9
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml acetonitrile stir 0.5h together with triethylamine 77.2g, add between 354.3g in batches and after bromobenzene sulfonyl chloride, keep room temperature reaction to terminating, coreaction 26h.The solution obtained after reaction being terminated is successively with the washing of water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 277.8g, yield 71.0%.
Specific optical rotation :+19.0 °
(
1H-NMR(400MHz，DMSO)；δ(ppm)：δ8.13(d，2H)，δ7.79(d，2H)，δ7.88(d，2H)，δ7.49(d，2H)，δ3.89-3.78(m，8H)，δ2.50(s，6H)，δ1.57-1.46(t，6H)，δ1.11-1.07(t，4H))
Embodiment 10
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml acetonitrile stir 2.5h together with triethylamine 280.7g, add between 529.0g in batches and after bromobenzene sulfonyl chloride, keep ice bath to react to terminating coreaction 21h.The solution obtained after reaction being terminated is successively with the washing of water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 243.6g, yield 62.3%.
Embodiment 11
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml methylene dichloride stir 1.5h together with triethylamine 175.4g, add between 496.0g in batches and after bromobenzene sulfonyl chloride, keep ice bath to react to terminating coreaction 22h.The solution obtained after reaction being terminated is successively with the washing of water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 287.1g, yield 73.3%.
Embodiment 12
By (1R, 2R)-1,2-cyclohexane dimethanol 100.0g add ice bath in 1500ml methylene dichloride stir 1.5h together with triethylamine 175.4g, add between 496.0g in batches and after bromobenzene sulfonyl chloride, keep-10 DEG C of reactions to terminating coreaction 22h.The solution obtained after reaction being terminated is successively with the washing of water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation removes a large amount of solvent and obtains white solid 303.7g, yield 75.2%.
Claims (13)
1. a structural general formula is the preparation of (1R, 2R)-1,2-CHDM disulfonate of (I).
2., according to claim 1, it is characterized in that R group is hydro carbons, halogen.
3., according to claim 1 and 2, it is characterized in that middle R group used is contraposition hydro carbons or a position halogen.Wherein, may be methyl, ethyl, propyl group, sec.-propyl when R group is hydro carbons; For being Cl or Br during halogen.
4., according to claim 1, the method is: with (1R, 2R)-1,2-cyclohexane dimethanol for raw material, triethylamine is acid binding agent, is obtained by reacting in hydrophobic solvent with SULPHURYL CHLORIDE.
5., according to claim 4, it is characterized in that reaction environment is anhydrous condition.
6., according to claim 4, it is characterized in that reaction solvent is hydrophobic solvent.
7., according to claim 4, it is characterized in that hydrophobic solvent is methylene dichloride.
8. method according to claim 4, is characterized in that raw material ratio used is for (1R, 2R)-1,2-cyclohexane dimethanol: triethylamine: aromatic hydrocarbons SULPHURYL CHLORIDE (1:1.3:1.9 ~ 1:4.1:4.7).
9. method according to claim 4, is characterized in that raw material ratio used is for (1R, 2R)-1,2-cyclohexane dimethanol: triethylamine: aromatic hydrocarbons SULPHURYL CHLORIDE (1:1.5:1.9 ~ 1:3.8:3.9).
10. method according to claim 4, is characterized in that temperature of reaction is at-50 DEG C ~ 50 DEG C.
11. methods according to claim 4, is characterized in that temperature of reaction is at-20 DEG C ~ 20 DEG C.
12. methods according to claim 4, is characterized in that reaction segmentation is carried out, first will (1R, 2R)-1,2-cyclohexane dimethanol and triethylamine in hydrophobic solvent, react 1 ~ 2h, then add SULPHURYL CHLORIDE and react to terminating.
13. methods according to claim 4, is characterized in that the reaction times is 1 ~ 28.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106518729A (en) * | 2016-09-21 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Lurasidone hydrochloride intermediate preparation method |
| CN106632358A (en) * | 2016-10-31 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | Method for preparing lurasidone hydrochloride intermediate |
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| JPS51132190A (en) * | 1975-03-04 | 1976-11-17 | Agency Of Ind Science & Technol | Complex catalist for asymmetric reaction |
| US5780632A (en) * | 1990-06-07 | 1998-07-14 | Sumitomo Pharmaceuticals Company, Limited | Imide derivatives and their production and use |
| JP2006282527A (en) * | 2005-03-31 | 2006-10-19 | Sumitomo Chemical Co Ltd | Cyclohexane derivative and method for producing the same |
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| WO2012131606A1 (en) * | 2011-04-01 | 2012-10-04 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
| WO2013121440A1 (en) * | 2012-02-13 | 2013-08-22 | Cadila Healthcare Limited | Process for preparing benzisothiazol-3-yl-peperazin-l-yl-methyl-cyclo hexyl-methanisoindol-1,3-dione and its intermediates |
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| JPS51132190A (en) * | 1975-03-04 | 1976-11-17 | Agency Of Ind Science & Technol | Complex catalist for asymmetric reaction |
| US5780632A (en) * | 1990-06-07 | 1998-07-14 | Sumitomo Pharmaceuticals Company, Limited | Imide derivatives and their production and use |
| JP2006282527A (en) * | 2005-03-31 | 2006-10-19 | Sumitomo Chemical Co Ltd | Cyclohexane derivative and method for producing the same |
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| WO2012131606A1 (en) * | 2011-04-01 | 2012-10-04 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106518729A (en) * | 2016-09-21 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Lurasidone hydrochloride intermediate preparation method |
| CN106632358A (en) * | 2016-10-31 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | Method for preparing lurasidone hydrochloride intermediate |
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Application publication date: 20150415 |