CN102952001A - Preparation method of chiral intermediate cyclohexane dimethanol - Google Patents
Preparation method of chiral intermediate cyclohexane dimethanol Download PDFInfo
- Publication number
- CN102952001A CN102952001A CN2011102381004A CN201110238100A CN102952001A CN 102952001 A CN102952001 A CN 102952001A CN 2011102381004 A CN2011102381004 A CN 2011102381004A CN 201110238100 A CN201110238100 A CN 201110238100A CN 102952001 A CN102952001 A CN 102952001A
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- CN
- China
- Prior art keywords
- preparation
- cyclohexanedimethanol
- cyclohexane dimethanol
- chiral intermediate
- cyclohexane cyclohexanedimethanodibasic
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- VEIOBOXBGYWJIT-UHFFFAOYSA-N cyclohexane;methanol Chemical compound OC.OC.C1CCCCC1 VEIOBOXBGYWJIT-UHFFFAOYSA-N 0.000 title 1
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 18
- 230000002829 reductive effect Effects 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims 1
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 abstract description 5
- 229960001432 lurasidone Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 230000003340 mental effect Effects 0.000 abstract description 2
- 208000024891 symptom Diseases 0.000 abstract description 2
- BXGYYDRIMBPOMN-UHFFFAOYSA-N 2-(hydroxymethoxy)ethoxymethanol Chemical compound OCOCCOCO BXGYYDRIMBPOMN-UHFFFAOYSA-N 0.000 abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 101150049660 DRD2 gene Proteins 0.000 description 1
- ORLQHILJRHBSAY-UHFFFAOYSA-N [1-(hydroxymethyl)cyclohexyl]methanol Chemical compound OCC1(CO)CCCCC1 ORLQHILJRHBSAY-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and specifically relates to a preparation method of a chiral intermediate 1R,2R-cyclohexane dimethanol. The chiral intermediate 1R,2R-cyclohexane dimethanol is an important intermediate of an antischizophrinic medicine lurasidone. Lurasidone has substantially treatment effects against both positive and negative symptoms of mental patients. A reduction agent adopted by the invention has low cost and stable property. The preparation method is suitable for industrialized productions.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of chiral medicinal intermediate 1R, the preparation method of 2R-cyclohexanedimethanol.
Background technology
Chipal compounds 1R, 2R-cyclohexanedimethanol (I) is the important intermediate of antischizophrinic Lurasidone (Lurasidone).Lurasidone is a kind of antipsychotic drug with dual function, and it all has high-affinity to 5-HT2 acceptor and d2 dopamine receptor, and mental patient's the positive and negative symptoms all had significant curative effect.
Japanese Patent JP2004-224764 has reported 1R, the preparation method of 2R-cyclohexanedimethanol: with 1R, the 2R-cyclohexane cyclohexanedimethanodibasic is raw material, adopting red aluminum solutions is that the reductive agent reduction obtains target compound, the red aluminium consumption of the method is large, the 1R of reduction 1g, and the 2R-cyclohexane cyclohexanedimethanodibasic approximately need be used the red aluminum solutions of 5g, cost is expensive, is unfavorable for suitability for industrialized production.
Summary of the invention
The invention provides a kind of 1R, the preparation method of 2R-cyclohexanedimethanol, the method are with 1R, and the 2R-cyclohexane cyclohexanedimethanodibasic is raw material, be dissolved in the organic solvent, then add reductive agent and boron trifluoride diethyl etherate, be incubated 10～70 ℃, reacted 2～15 hours, and got 1R, the 2R-cyclohexanedimethanol.
Used reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride.
Used 1R, the mole proportioning of 2R-cyclohexane cyclohexanedimethanodibasic, reductive agent and boron trifluoride diethyl etherate is 1: (1～10): (1～10).
Used solvent is tetrahydrofuran (THF), ether.
Beneficial effect: reductive agent low price of the present invention, stable in properties is fit to industrialization production requirements.
Description of drawings
Fig. 1 is 1R, the proton nmr spectra of 2R-cyclohexane cyclohexanedimethanodibasic
Fig. 2 is 1R, the proton nmr spectra of 2R-cyclohexanedimethanol
Embodiment
Starting raw material 1R among the embodiment, the 2R-cyclohexane cyclohexanedimethanodibasic prepares (nuclear magnetic spectrum is seen Fig. 1) according to Japanese Patent JP2004-224764, and all the other all reagent and raw material be commercially available getting all.
Embodiment 1:
With 1R, 2R-cyclohexane cyclohexanedimethanodibasic 17.2g (0.1mol) is dissolved in the 340ml tetrahydrofuran (THF), add successively sodium borohydride 3.8g (0.1mol), boron trifluoride diethyl etherate (content 47%) 14.5g (0.1mol), slowly be heated to 70 ℃ of back flow reaction 3 hours, reclaim under reduced pressure tetrahydrofuran (THF), basic evaporate to dryness, drip aqueous sodium hydroxide solution, transfer pH=11, filter, filtrate is used ethyl acetate extraction 3 times, merge ethyl ester solution, the salt washing, anhydrous magnesium sulfate drying filters, evaporate to dryness gets 1R, 2R-cyclohexanedimethanol 14g.
1H-NMR(CDCl
3)δ：0.95-1.32(m，6H)，1.57-1.74(m，4H)，3.38-3.59(m，6H)。(seeing Fig. 2)
Embodiment 2:
With 1R, 2R-cyclohexane cyclohexanedimethanodibasic 17.2g (0.1mol) is dissolved in the 680ml ether, add successively sodium borohydride 15.2g (0.4mol), boron trifluoride diethyl etherate (content 47%) 145g (1mol), room temperature reaction 10 hours, reclaim under reduced pressure tetrahydrofuran (THF), basic evaporate to dryness, drip aqueous sodium hydroxide solution, transfer pH=11, filter, filtrate is used ethyl acetate extraction 3 times, merge ethyl ester solution, the salt washing, anhydrous magnesium sulfate drying filters, evaporate to dryness gets 1R, 2R-cyclohexanedimethanol 13.5g.
1H-NMR(CDCl
3)δ：0.95-1.32(m，6H)，1.57-1.74(m，4H)，3.38-3.59(m，6H)。(seeing Fig. 2)
Embodiment 3:
With 1R, 2R-cyclohexane cyclohexanedimethanodibasic 17.2g (0.1mol) is dissolved in the 340ml tetrahydrofuran (THF), add successively POTASSIUM BOROHYDRIDE 54g (1mol), boron trifluoride diethyl etherate (content 47%) 72.5g (0.5mol), keep 10 ℃ of reactions 15 hours, reclaim under reduced pressure tetrahydrofuran (THF), basic evaporate to dryness, drip aqueous sodium hydroxide solution, transfer pH=11, filter, filtrate is used ethyl acetate extraction 3 times, merge ethyl ester solution, the salt washing, anhydrous magnesium sulfate drying filters, evaporate to dryness gets 1R, 2R-cyclohexanedimethanol 13.5g.
1H-NMR(CDCl
3)δ：0.95-1.32(m，6H)，1.57-1.74(m，4H)，3.38-3.59(m，6H)。(seeing Fig. 2)
Embodiment 4:
With 1R, 2R-cyclohexane cyclohexanedimethanodibasic 17.2g (0.1mol) is dissolved in the 680ml ether, add successively POTASSIUM BOROHYDRIDE 27g (0.5mol), boron trifluoride diethyl etherate (content 47%) 72.5g (0.5mol), kept room temperature reaction 10 hours, reclaim under reduced pressure tetrahydrofuran (THF), basic evaporate to dryness, drip aqueous sodium hydroxide solution, transfer pH=11, filter, filtrate is used ethyl acetate extraction 3 times, merge ethyl ester solution, the salt washing, anhydrous magnesium sulfate drying filters, evaporate to dryness gets 1R, 2R-cyclohexanedimethanol 14g.
1H-NMR(CDCl
3)δ：0.95-1.32(m，6H)，1.57-1.74(m，4H)，3.38-3.59(m，6H)。(seeing Fig. 2)
Embodiment 5:
With 1R, 2R-cyclohexane cyclohexanedimethanodibasic 17.2g (0.1mol) is dissolved in the 680ml tetrahydrofuran (THF), add successively sodium borohydride 38g (1mol), boron trifluoride diethyl etherate (content 47%) 145g (1mol), slowly be heated to 70 ℃ of back flow reaction 1 hour, reclaim under reduced pressure tetrahydrofuran (THF), basic evaporate to dryness, drip aqueous sodium hydroxide solution, transfer pH=11, filter, filtrate is used ethyl acetate extraction 3 times, merge ethyl ester solution, the salt washing, anhydrous magnesium sulfate drying filters, evaporate to dryness gets 1R, 2R-cyclohexanedimethanol 14g.
1H-NMR(CDCl
3)δ：0.95-1.32(m，6H)，1.57-1.74(m，4H)，3.38-3.59(m，6H)。(seeing Fig. 2)
Claims (5)
1. chiral intermediate 1R with formula I structure, the preparation method of 2R-cyclohexanedimethanol, it is characterized in that, comprise the steps: with 1R, the 2R-cyclohexane cyclohexanedimethanodibasic is raw material, is dissolved in the organic solvent, add reductive agent and boron trifluoride diethyl etherate, insulation reaction for some time gets 1R, the 2R-cyclohexanedimethanol
2. preparation method as claimed in claim 1 is characterized in that, described reductive agent is POTASSIUM BOROHYDRIDE, sodium borohydride.
3. preparation method as claimed in claim 1 is characterized in that, described holding temperature is 10～70 ℃, and described reaction for some time is 1～15 hour.
4. preparation method as claimed in claim 1 is characterized in that, described 1R, and the mole proportioning of 2R-cyclohexane cyclohexanedimethanodibasic, reductive agent and boron trifluoride diethyl etherate is 1: (1～10): (1～10).
5. preparation method as claimed in claim 1 is characterized in that, described organic solvent is tetrahydrofuran (THF), ether.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102381004A CN102952001A (en) | 2011-08-19 | 2011-08-19 | Preparation method of chiral intermediate cyclohexane dimethanol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102381004A CN102952001A (en) | 2011-08-19 | 2011-08-19 | Preparation method of chiral intermediate cyclohexane dimethanol |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105467028A (en) * | 2015-11-18 | 2016-04-06 | 北京万全德众医药生物技术有限公司 | A method of separating and measuring optical isomers of a lurasidone intermediate by gas chromatography |
| WO2016059649A1 (en) * | 2014-10-14 | 2016-04-21 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | An improved process for the preparation of lurasidone hydrochloride |
| CN107688069A (en) * | 2017-09-08 | 2018-02-13 | 安徽灵药业有限公司 | The detection method of the dimethanol of (1R, 2R) hexamethylene 1,2 |
| CN108993500A (en) * | 2018-07-02 | 2018-12-14 | 中国科学院兰州化学物理研究所苏州研究院 | Synthetic catalyst, its preparation method and the application of chiral cyclohexanedimethanol class compound |
| CN110668916A (en) * | 2019-10-23 | 2020-01-10 | 中国科学院兰州化学物理研究所 | Method for efficiently synthesizing 1R, 2R-cyclohexanedimethanol by gas-solid phase method |
-
2011
- 2011-08-19 CN CN2011102381004A patent/CN102952001A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| PAUL LE MAUX, ET AL.: "New optically active ruthenium porphyrin catalysts for asymmetric epoxidation of styrenes", 《JOURNAL OF MOLECULAR CATALYSIS A: CHEMICAL》 * |
| 陈升 等: "L-2-氨基丙醇的新合成方法研究", 《化工时刊》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016059649A1 (en) * | 2014-10-14 | 2016-04-21 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | An improved process for the preparation of lurasidone hydrochloride |
| US10426770B2 (en) | 2014-10-14 | 2019-10-01 | Jubilant Generics Limited | Process for the preparation of Lurasidone hydrochloride |
| CN105467028A (en) * | 2015-11-18 | 2016-04-06 | 北京万全德众医药生物技术有限公司 | A method of separating and measuring optical isomers of a lurasidone intermediate by gas chromatography |
| CN107688069A (en) * | 2017-09-08 | 2018-02-13 | 安徽灵药业有限公司 | The detection method of the dimethanol of (1R, 2R) hexamethylene 1,2 |
| CN107688069B (en) * | 2017-09-08 | 2020-11-03 | 顾世海 | Method for detecting (1R,2R) -cyclohexane-1, 2-dimethanol |
| CN108993500A (en) * | 2018-07-02 | 2018-12-14 | 中国科学院兰州化学物理研究所苏州研究院 | Synthetic catalyst, its preparation method and the application of chiral cyclohexanedimethanol class compound |
| CN108993500B (en) * | 2018-07-02 | 2021-06-15 | 中国科学院兰州化学物理研究所苏州研究院 | Synthesis catalyst of chiral cyclohexane dimethanol compound, its preparation method and application |
| CN110668916A (en) * | 2019-10-23 | 2020-01-10 | 中国科学院兰州化学物理研究所 | Method for efficiently synthesizing 1R, 2R-cyclohexanedimethanol by gas-solid phase method |
| CN110668916B (en) * | 2019-10-23 | 2020-12-11 | 中国科学院兰州化学物理研究所 | Method for efficiently synthesizing 1R, 2R-cyclohexanedimethanol by gas-solid phase method |
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Application publication date: 20130306 |