CN103724238A - Preparation method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate - Google Patents
Preparation method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate Download PDFInfo
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- CN103724238A CN103724238A CN201310747473.3A CN201310747473A CN103724238A CN 103724238 A CN103724238 A CN 103724238A CN 201310747473 A CN201310747473 A CN 201310747473A CN 103724238 A CN103724238 A CN 103724238A
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Abstract
The invention belongs to the technical field of organic drug synthesis, and particularly relates to a synthesis method of (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate. According to the method, (1R, 2R)-1, 2-cyclohexanedimethanol is used as a raw material, under the action of an acid-binding agent, coupling reaction of (1R, 2R)-1, 2-cyclohexanedimethanol and aromatic sulfonyl chloride is produced in a hydrophobic solvent, and corresponding (1R, 2R)-1, 2-cyclohexanedimethanol diaryl sulphonate is obtained through washing, extraction, drying and distillation. The method is easy to operate, easy in obtaining of low-toxic raw materials, higher in yield, and suitable for mass production.
Description
Technical field
The invention belongs to organic drug synthesis technical field, the technique synthetic technology of be specifically related to (1R, 2R)-1,2-CHDM diaryl sulphonate.
Background technology
Asimadoline is a kind of κ-opioid receptor agonist, is the active drug for the treatment of irritable bowel syndrome (IBS), is at present the clinical study stage three phases.Clinical study shows can raise IBS patient's sensitivity threshold of Asimadoline, and tolerance is good, has a good application prospect.
Lurasidone is a kind of atypical antipsychotic of SUMITOMO CHEMICAL drugmaker exploitation, is a kind of novel antipsychotic drugs with dual function, and the insane positive and negative symptoms are all had to significant curative effect.(1R, 2R)-1,2-CHDM disulfonate is the important intermediate during Lurasidone synthesizes.
The synthetic method of existing (1R, 2R)-1,2-CHDM two methanesulfonates is:
Detailed process: by (1R, 2R)-1,2-cyclohexyl dimethanol is dissolved in acetonitrile or chloroform, adds triethylamine, slowly splashes into methylsulfonyl chloride under condition of ice bath, keeps ice bath room temperature reaction three hours after a hour, finishes system washing after reaction.Concentrated after organic phase is dry, concentrated solution adds diethyl ether and filters and can obtain target product (1R, 2R)-1,2-CHDM two methanesulfonates (EP0464846A) after crystallization.
This route has the following disadvantages: one, and raw materials used methylsulfonyl chloride is highly toxic product, it is bought with use and is subject to strict control, is not suitable for scale operation.Two, gained (1R, 2R)-1,2-CHDM disulfonate without uv-absorbing, does not have suitable HPLC method to detect under HPLC method.Three, yield is lower, less than 60%.
Summary of the invention
In order to overcome the defect existing in technique scheme, the present invention relates to a kind of synthetic (1R, the excellent process of 2R)-1,2-CHDM diaryl sulphonate, is used (1R, 2R)-1, in hydrophobic solvent, there is linked reaction in 2-cyclohexyl dimethanol and aromatic hydrocarbons SULPHURYL CHLORIDE, then obtain (1R after washing, extract, be dried, distill under the effect of acid binding agent, 2R)-1,2-cyclohexyl dimethanol diaryl sulphonate.
R of the present invention is straight chain hydrocarbon and the halogens such as methyl, ethyl, propyl group, sec.-propyl, preferably contraposition methyl, a position chlorine.
Solvent is selected the hydrophobic solvents such as methylene dichloride, chloroform, ethyl acetate or hexanaphthene, preferably methylene dichloride.
Acid binding agent is selected sodium carbonate, salt of wormwood, triethylamine, pyridine, preferably triethylamine.
Control temperature of reaction within the scope of-50 ℃～50 ℃, preferably-20 ℃～20 ℃.
Reactant feed ratio (1R, 2R)-1,2-CHDM: triethylamine: aromatic hydrocarbons SULPHURYL CHLORIDE is 1:1.3:1.9～1:4.1:4.7, preferably 1:1.5:1.9～1:3.8:3.9.
Great advantage of the present invention is: one, take aromatic hydrocarbons SULPHURYL CHLORIDE as raw material, toxicity reduces compared with methylsulfonyl chloride, buying is unrestricted, suitability for industrialized production processing safety improves.Two, gained target product is introduced ultraviolet absorption group, realizes quality HPLC monitoring operability.Three,, compared with former technique, yield of the present invention is higher.
Specific embodiments
With embodiment, further illustrate the present invention below, but the present invention is not limited.
Embodiment: (1R, 2R)-1,2-CHDM two p-toluenesulfonic esters synthetic
Embodiment 1
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds in 1500ml ethyl acetate ice bath to stir 1h together with pyridine 175.4g, keeps room temperature reaction to finishing after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 15h.The solution obtaining after reaction is finished successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation is removed a large amount of solvents and obtained white solid 158.8g, yield 50.6%.
HRMS:?C
22H
28O
6S
2?for?+,?calculated?452.58,?found?452.29
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 2
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds in 1500ml chloroform ice bath to stir 1h together with Anhydrous potassium carbonate 175.4g, keeps ice bath to react to finishing after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 15h.The solution obtaining after reaction is finished successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation is removed a large amount of solvents and obtained white solid 151.6g, yield 48.3%.
Embodiment 3
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds in 1500ml hexanaphthene ice bath to stir 1h together with triethylamine 175.4g, keeps-10 ℃ of reactions to finishing after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 15h.The solution obtaining after reaction is finished successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation is removed a large amount of solvents and obtained white solid 216.8g, yield 69.1%.
Embodiment 4
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds in 1500ml methylene dichloride ice bath to stir 30min together with triethylamine 77.2g, keeps-10 ℃ of reactions to finishing after adding 264.4g p-methyl benzene sulfonic chloride, coreaction 19h.The solution obtaining after reaction is finished successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation is removed a large amount of solvents and obtained white solid 269.0g, yield 85.7%.
Embodiment 5
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds in 1500ml methylene dichloride ice bath to stir 2.0h together with pyridine 280.7g, keeps-10 ℃ of reactions to finishing after adding 634.6g p-methyl benzene sulfonic chloride, coreaction 29.5h.The solution obtaining after reaction is finished successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation is removed a large amount of solvents and obtained white solid 191.5g, yield 61.0%.
Embodiment 6
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds in 1500ml methylene dichloride ice bath to stir 1.5min together with triethylamine 175.4g, keeps-10 ℃ of reactions to finishing after adding 370.2g p-methyl benzene sulfonic chloride, coreaction 21h.The solution obtaining after reaction is finished successively washs to water white transparency with water, saturated sodium bicarbonate solution and saturated brine, and underpressure distillation is removed a large amount of solvents and obtained white solid 234.8g, yield 74.8%.
Embodiment: two bromo-benzene sulfonic acid esters of (1R, 2R)-1,2-CHDM synthetic
Embodiment 7
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds ice bath in 1500ml hexanaphthene to stir 0.5h together with pyridine 77.2g, adds between 354.3g in batches and after bromobenzene sulfonyl chloride, keeps room temperature reaction to finishing, coreaction 26h.The solution obtaining after reaction is finished is successively with water, saturated sodium bicarbonate solution and saturated brine washing, and underpressure distillation is removed a large amount of solvents and obtained white solid 212.8g, yield 68.0%.
HRMS:?C
20H
22Br
2O
6S
2?for?+,?calculated?582.32,?found?582.37
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 8
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds ice bath in 1500ml ethyl acetate to stir 2.5h together with triethylamine 280.7g, adds between 529.0g in batches and after bromobenzene sulfonyl chloride, keeps ice bath to react to finishing coreaction 21h.The solution obtaining after reaction is finished is successively with water, saturated sodium bicarbonate solution and saturated brine washing, and underpressure distillation is removed a large amount of solvents and obtained white solid 243.6g, yield 62.3%.
Embodiment 9
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds ice bath in 1500ml methylene dichloride to stir 1.5h together with Anhydrous potassium carbonate 175.4g, adds between 496.0g in batches and after bromobenzene sulfonyl chloride, keeps ice bath to react to finishing coreaction 22h.The solution obtaining after reaction is finished is successively with water, saturated sodium bicarbonate solution and saturated brine washing, and underpressure distillation is removed a large amount of solvents and obtained white solid 287.1g, yield 73.3%.
Embodiment 10
By (1R, 2R)-1,2-cyclohexyl dimethanol 100.0g adds ice bath in 1500ml methylene dichloride to stir 1.5h together with anhydrous sodium carbonate 175.4g, adds between 496.0g in batches and after bromobenzene sulfonyl chloride, keeps-10 ℃ of reactions to finishing coreaction 22h.The solution obtaining after reaction is finished is successively with water, saturated sodium bicarbonate solution and saturated brine washing, and underpressure distillation is removed a large amount of solvents and obtained white solid 303.7g, yield 75.2%.
Claims (9)
1. the preparation method of class (1R, 2R)-1,2-CHDM diaryl sulphonate (I), with (1R, 2R)-1,2-cyclohexyl dimethanol is raw material, under the effect of acid binding agent, temperature of reaction is-50 ℃～50 ℃, reacts the formula of obtaining (I) in hydrophobic solvent with aromatic hydrocarbons SULPHURYL CHLORIDE
2. preparation method according to claim 1, is characterized in that R group is straight chain hydrocarbon or halogen.
3. preparation method according to claim 1, is characterized in that described R group is contraposition hydro carbons or a position halogen.
4. preparation method according to claim 3, is characterized in that described contraposition hydro carbons is methyl, and a position halogen is chlorine.
5. preparation method according to claim 1, is characterized in that acid binding agent is sodium carbonate, salt of wormwood, triethylamine, pyridine; Hydrophobic solvent is methylene dichloride, chloroform, ethyl acetate or hexanaphthene.
6. preparation method according to claim 5, is characterized in that described acid binding agent is triethylamine; Hydrophobic solvent is methylene dichloride.
7. preparation method according to claim 1, is characterized in that raw material ratio (1R, 2R)-1 used, 2-cyclohexyl dimethanol: triethylamine: aromatic hydrocarbons SULPHURYL CHLORIDE is 1:1.3:1.9～1:4.1:4.7.
8. preparation method according to claim 7, is characterized in that raw material ratio (1R, 2R)-1 used, 2-cyclohexyl dimethanol: triethylamine: aromatic hydrocarbons SULPHURYL CHLORIDE is 1:1.5:1.9～1:3.8:3.9.
9. preparation method according to claim 1, is characterized in that temperature of reaction is-20 ℃～20 ℃.
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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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012131606A1 (en) * | 2011-04-01 | 2012-10-04 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
| CN102827157A (en) * | 2012-09-20 | 2012-12-19 | 北京哈三联科技股份有限公司 | Method for preparing lurasidone |
| 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 |
-
2013
- 2013-12-31 CN CN201310747473.3A patent/CN103724238A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102827157A (en) * | 2012-09-20 | 2012-12-19 | 北京哈三联科技股份有限公司 | Method for preparing lurasidone |
Non-Patent Citations (1)
| Title |
|---|
| 张平: "盐酸鲁拉西酮的合成", 《化工时刊》, vol. 27, no. 5, 5 May 2013 (2013-05-05), pages 5 - 14 * |
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: 20140416 |