CN1358163A - 通过不对称转移氢化合成(r)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法 - Google Patents
通过不对称转移氢化合成(r)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法 Download PDFInfo
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- CN1358163A CN1358163A CN00809492A CN00809492A CN1358163A CN 1358163 A CN1358163 A CN 1358163A CN 00809492 A CN00809492 A CN 00809492A CN 00809492 A CN00809492 A CN 00809492A CN 1358163 A CN1358163 A CN 1358163A
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- Prior art keywords
- trifluoromethyl
- alcohol
- phenyl
- rhodium
- octane
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Links
- 238000000034 method Methods 0.000 title claims abstract description 43
- 230000008569 process Effects 0.000 title claims abstract description 15
- 238000009901 transfer hydrogenation reaction Methods 0.000 title abstract description 3
- MMSCIQKQJVBPIR-RXMQYKEDSA-N (1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol Chemical compound C[C@@H](O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MMSCIQKQJVBPIR-RXMQYKEDSA-N 0.000 title abstract 4
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims abstract description 20
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 15
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 14
- 239000010948 rhodium Substances 0.000 claims abstract description 14
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 53
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical group CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 6
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical compound CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims description 5
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 claims description 5
- -1 (trifluoromethyl)-phenyl Chemical group 0.000 claims description 2
- PKHAHMGOSZSDOV-UHFFFAOYSA-L C1(C=CC=C1)[Rh](Cl)Cl Chemical compound C1(C=CC=C1)[Rh](Cl)Cl PKHAHMGOSZSDOV-UHFFFAOYSA-L 0.000 claims description 2
- AGVSQJVNKWEDDW-UHFFFAOYSA-L C1(C=CC=C1)[Ru](Cl)Cl Chemical compound C1(C=CC=C1)[Ru](Cl)Cl AGVSQJVNKWEDDW-UHFFFAOYSA-L 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 14
- 239000003446 ligand Substances 0.000 abstract description 2
- LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 abstract 1
- MCYCSIKSZLARBD-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MCYCSIKSZLARBD-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000012973 diazabicyclooctane Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 8
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- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- RWXUNIMBRXGNEP-UHFFFAOYSA-N 1-bromo-2-(trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC=C1Br RWXUNIMBRXGNEP-UHFFFAOYSA-N 0.000 description 6
- 230000032683 aging Effects 0.000 description 6
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102100024304 Protachykinin-1 Human genes 0.000 description 3
- 101800003906 Substance P Proteins 0.000 description 3
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- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical class CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 2
- 229960003908 pseudoephedrine Drugs 0.000 description 2
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- 150000003283 rhodium Chemical class 0.000 description 2
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- GKSGSDYYIYURPD-PHDIDXHHSA-N 1,1,1-trifluoro-n-[(1r,2r)-2-(trifluoromethylsulfonylamino)cyclohexyl]methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N[C@@H]1CCCC[C@H]1NS(=O)(=O)C(F)(F)F GKSGSDYYIYURPD-PHDIDXHHSA-N 0.000 description 1
- FYDUUODXZQITBF-UHFFFAOYSA-N 1-[2-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC=C1C(F)(F)F FYDUUODXZQITBF-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- DNUJVGBNIXGTHC-UHFFFAOYSA-N 3,6-dihydro-2h-oxazine Chemical compound C1NOCC=C1 DNUJVGBNIXGTHC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
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- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
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- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
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- 230000037430 deletion Effects 0.000 description 1
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- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 208000030208 low-grade fever Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
-
- 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
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及在醇的存在下,使用一种铑或钌催化剂和一种配体,通过3,5-双(三氟甲基)乙酰苯的不对称转移氢化制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法。还要求保护的是(S,R)-1-氨基-2-羟基-二氢化茚与铑和钌的具体的络合物以及通过该络合物与1,4-二氮杂二环[2.2.2]辛烷接触的方式以及2∶1的(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇与1,4-二氮杂二环[2.2.2]辛烷络合物接触的方式来纯化(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇。
Description
背景技术
本发明涉及在制备某些治疗剂中用作中间体的(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的制备方法,尤其是,本发明提供了一种(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的制备方法,该化合物是一种药物化合物合成中的中间体,该药物化合物是指物质P(神经激肽-1)受体拮抗物。
在以下通式的(2R,2-α-R,3a)-2-[1-[3,5-双(三氟甲基)]乙氧基-3-(4-氟代苯基)-1,4-噁嗪的合成中可利用本发明所制备的(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇:该化合物在物质P(神经激肽-1)受体拮抗物这一药物化合物的合成中是一种已知的中间体。
本领域中所公开的制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的通用方法,所需产品的产率相对低且不稳定。与在先公知的方法相比,本发明提供了制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的有效工艺,且具有相对高的产率和对映体纯度。
应当理解的是,对于一组特别有用的治疗剂来说,(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇是一种重要的中间体。正因为如此,需要开发一种制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法,该方法能容易进行工艺放大,使用成本可行的、容易获得的试剂,从而在大规模的制造中能实际应用。
因此,本发明的目的是通过一种简单、简短且高效的合成来提供一种制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法。
发明概述
在合成具有药理活性化合物的过程中,该化合物是一种中间体。尤其是,这样的化合物是物质P(神经激肽-1)受体拮抗物,它在例如炎症、精神病和呕吐的治疗中是有用的。发明详述
本发明是涉及以下通式的(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的制备工艺:
制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的一种常用工艺的实施方案如下:
根据本发明的这一实施方案,在醇的存在下,用一种铑或一种钌催化剂和一种配体处理1-(3,5-双(三氟甲基)-苯基)乙-1-酮,得到(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇,与本领域所公开的方法相比,它具有较高的产率、较大的对映体纯度和是更有效的合成路线。
在另一实施方案中,本发明是涉及(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的制备工艺,它包括在醇的存在下,用一种铑或一种钌催化剂和一种配体处理1-(3,5-双(三氟甲基)-苯基)乙-1-酮,得到(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇。
本发明中,铑催化剂优选选自双((五甲基环戊二烯基)氯化铑)(即((五甲基环戊二烯基)RhCl2)2)和双((环戊二烯基)氯化铑)(即((环戊二烯基)RhCl2)2)。优选的铑催化剂是双((五甲基环戊二烯基)氯化铑)。铑催化剂优选以约0.1-1mol%的浓度存在,更优选约0.5mol%。
本发明中,钌催化剂优选选自双((4-异丙基-亚苄基)氯化钌)和双((环戊二烯基)氯化钌)。优选的钌催化剂是双((4-异丙基-亚苄基)氯化钌)[即双((对鏾花基)氯化钌))]。钌催化剂优选以约0.1-1mol%的浓度存在,更优选约0.3mol%。
为了使经费最小化,优选使用钌催化剂。
本发明中,配体优选选自(R,R)-环己烷二胺(R,R)CHXD、假麻黄碱、正假麻黄碱、麻黄碱、正麻黄碱和(S,R)-顺式-1-氨基-2-羟基-二氢化茚。本发明中,更优选的配体是(S,R)-顺式-1-氨基-2-羟基-二氢化茚。配体优选以约0.1-1mol%的浓度存在,更优选约0.5mol%。
为了方便起见,铑或钌催化剂和配体可就地结合在一起。本发明中,铑或钌催化剂和配体可任选地结合在一起以便在与(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇反应之前形成一种催化剂-配体络合物。
在另外的一个实施方案中,本发明是涉及下式的化合物:其中Cp*是五甲基环戊二烯基。
本发明中,醇优选选自甲醇、乙醇、异丙醇、异丁醇或正丁醇。最优选的醇是异丙醇。尽管也可存在其它溶剂,但为了方便起见,优选使用醇作为反应进行的溶剂。
本发明中,碱任选地与醇一起存在。碱可以是无机碱如选自氢氧化钠或氢氧化钾、碳酸钾或碳酸钠、碳酸氢钾或碳酸氢钠、钾或钠的醇盐等。醇盐可衍生于低级(C1-C5)或高级(>C6)伯、仲或叔醇。优选的碱是氢氧化钠。
根据本发明所获得的(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇可用作进一步直接反应的起始材料或随后纯化。
在另外的一个实施方案中,本发明是涉及(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的提纯或增加对映体纯度的方法,其包括:
在有机溶剂中使(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇与1,4-二氮杂二环[2.2.2]辛烷接触以形成双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷;
回收双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷;
和任选地从双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷中解离1,4-二氮杂二环[2.2.2]辛烷,得到(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇。
在该方法中,有机溶剂优选烷烃,更优选的有机溶剂选自己烷和庚烷,甚至更优选的有机溶剂是庚烷。
二氮杂二环[2.2.2]辛烷优选以0.5当量二氮杂二环[2.2.2]辛烷比1.0当量(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的量存在。
二氮杂二环[2.2.2]辛烷优选以约0.05-1mol%的浓度存在,更优选约0.5mol%。
任选地,在有机溶剂中使(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇与1,4-二氮杂二环[2.2.2]辛烷接触后,用双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷作为晶种接种该混合物,形成双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷的温度优选为约50℃-约-40℃,更优选约40℃-约-20℃,甚至更优选约0℃-约-20℃。
对于本领域的技术人员来说,应当理解的是,该替代的实施方案可用反复的方式进行重复,在每一循环之后会进一步提高(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的对映体纯度。
该替代的实施方案的一方面中,本发明涉及下式的化合物:
该替代的实施方案的另一方面涉及(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇,其中对映体纯度(对映体过量)大于90%,优选大于95%,更优选大于98%,尤其是大于99%和特别是大于99.5%(对映体过量)。
用于本方法中的起始材料和试剂或者是商购的,或者是文献中公知的,或者参照文献中所公开的类似化合物的方法来制备。进行反应和纯化所得到的反应产物所要求的技术是本领域的技术人员所公知的。纯化步骤包括结晶、蒸馏、正相或反相色谱。
提供下述实施例,仅用于进一步阐述的目的,而不是对所公开的发明的限制。
实施例13,5-双(三氟甲基)溴苯
材料 | Mw | 密度 | 用量 | Mmol | 当量数 |
1,3-双(三氟甲基)苯 | 214.1 | 1.38 | 107g | 500 | 1.0 |
96%硫酸 | 142ml | ||||
冰醋酸 | 22ml | 1.08(Br+) | |||
1,3-二溴代-5,5-二甲基乙内酰脲 | 285.93 | 77.25g | 270 | ||
5N氢氧化钠水溶液 | 75ml |
一次将(in one portion)浓硫酸(96%)(142ml)加入到在1L三颈圆底烧瓶(配有机械搅拌器、热电偶和加液漏斗)中冷却至15℃的冰醋酸(22.0ml)中,溶液放热使温度升至35℃,在冷至25℃后,加入1,3-双(三氟甲基)苯(107g,500mmol)。用酸性混合物快速搅拌的同时,在2分钟内加入1,3-二溴代-5,5-二甲基乙内酰脲(77.25g,270mmol),得到一多相混合物(固相和两个液相)。放热反应发生,使内部温度升高到~40℃(夹套冷却温度为15℃)。在反应温度开始下降之后(5分钟后)反应混合物在45℃下维持4.5小时。
溴化反应的速率和选择性高度取决于两相反应的搅拌。较慢的搅拌使双-溴化反应的量增加且使总的反应速率放慢。在整个反应过程中反应混合物保持非均相且当停止搅拌时有机相分离。反应后期,相分离变慢(溴化物的密度=1.699)。溴化反应的速率还取决于醋酸与硫酸之比。
通过GC分析来监控反应进程,如下所述:
样品:~50μl混合相用环己烷(1.5ml)稀释,用水(1ml),然后用2N NaOH(1ml)洗涤,分离并注射。
Resteck RTX-1701[60m×0.320mm]:100℃;升温速率:5℃/分到200℃;200℃下10分钟;流速1.15ml/分钟
Rt:1,3-双(三氟甲基)苯:7.0分钟
3,5-双(三氟甲基)溴苯:9.4分钟
联芳:19.2分钟
将混合物冷却到2℃并慢慢倾入到冷水(250ml)中。强烈搅拌混合物10分钟,静置并分离下层有机层,用5N NaOH(75ml)洗涤,得到145.1g透明、无色的有机层。
测定1,3-双(三氟甲基)溴苯的产率为93.7%(137.3g,469mmol),其中含有0.6%1,3-双(三氟甲基)苯,1.0%1,2-二溴代-3,5-双(三氟甲基)苯和0.3%1,4-二溴代-3,5-双(三氟甲基)苯。经GC测量总的异构体副产物为2.0mol%。
实施例21-(3,5-双(三氟甲基)-苯基)乙-1-酮
材料 | Mw | 密度 | 用量 | Mmol | 当量数 |
3,5-双(三氟甲基)溴苯 | 293.03 | 1.699g/l | 29.3g | 98.0 | 1.0 |
镁粒,20目 | 24.3 | 5.10g | 2.1 | ||
冰醋酸 | 102.1 | 1.08g/l | 40ml | 423 | 4.5 |
THF(KF=60μg/ml) | 260ml | ||||
MTBE | 650ml | ||||
水 | 300ml | ||||
50%Na0H | 40ml | ||||
产物 | |||||
3’,5’-双(三氟甲基)乙酰苯 | 256.14 | 20.3g | 79.0 | 82%产率 |
向配有滴液漏斗、氮气入口和特氟隆涂布的热电偶的500ml三颈圆底烧瓶中加入镁粒(5.10g,210mmol)和THF(200ml)。加热混合物使之回流。将3,5-双(三氟甲基)溴苯(29.3g,98mmol)溶解在30mlTHF中,在2分钟内将部分溴化物溶液(5ml)加入到轻微回流的含镁淤浆中以引发格利雅反应。格利雅引发可在0-20℃下进行以使溶剂损失最少。格利雅引发后,在1小时内加入剩余的溴化物。
通常允许5分钟起始的诱导期。若没有引发反应,则还要加入额外5%的溴化物;若加入10%溴化物之后仍未引发反应,则要加入100mg碘。若反应看起来太剧烈,则通过减缓或终止溴化物的滴加来控制反应放热。
在溴化物完全滴加完之后(~60分钟),在轻微回流之下再额外加热该暗褐色的溶液30分钟。
通过HPLC来监控反应(样品制备:100μl骤冷的样品放入3.5ml1∶1THF∶2N HCl中,然后在65∶35乙腈∶Ph为6的缓冲液中稀释),当溴化物含量低于1mol%时认为格利雅形成反应完成。
在水浴中冷却到环境温度之后,通过导管将混合物转移到1升滴液漏斗中,THF(10ml)用作漂洗剂。然后将该溶液于1小时内加入到在-15℃下保温的乙酸酐(40ml)的THF(40ml)溶液中。在水浴中将该暗褐色的混合物微热到10℃,并在3分钟之内加入水(300ml)。剧烈搅拌该两相混合物并同时在1小时之内逐步滴加50%NaOH,直到8.0的pH保持5分钟。加入MTBE(300ml),发生层分离,进一步用MTBE(3×150ml)萃取含水层。合并有机层并进行分析(22.4g酮),然后在32℃的浴温下真空浓缩(50-80torr)。接着在大气压下蒸馏该浓缩物,在150-189℃下收集到20.7g(82%产率,基于LC纯度)无色油状物,并在187-189℃下收集主体部分。
HPLC分析:97.7LCAP
方法:Luna C18,乙腈:0.1%含水H3PO4,75∶25-95∶5在20分钟之内;
保持5分钟。
Rt(分钟):
酚 5.2
酮 6.3
芳烃 7.3
溴化物 9.7
二聚体 13.3
GC分析:95.5GCAP
方法:Resteck RTX-1701[60m×0.320mm]
100℃-200℃@5℃/分;200℃10分钟;流速35cm/秒的恒定流速
Rt(分钟):
1,3-双(三氟甲基)苯 4.4
乙酸酐 5.6
甲酮 10.6
3,5-双(三氟甲基)溴苯 6.2
二聚体(bis adduct) 19.6
实施例3(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇1-(3,5-双(三氟甲基)-苯基) 256.15 3.9 1Kg乙-1-酮(Cp*RhCl2)2 618.08 0.01 6g(Cp*=五甲基环戊二烯基)(S,R)-顺式-氨基茚满醇 149.20 0.02 3.0gNaOH 5N(H2O) 0.05 9mlIPA 7LHCl 1N(H2O) 7L庚烷 7L1,4-二氮杂二环[2.2.2]辛烷 112.18 2.2 240g(DABCO)
在室温下将铑盐和配体加入到IPA中并陈化0.5小时,在陈化期间溶液通常会变成透明的桔红色,加入酮后接着加入碱,陈化反应直到通过HPLC观察反应完成(~3小时)。然后用1N盐酸使反应骤冷,并用庚烷(2×3.5升)萃取和用5升盐水洗涤。加入DABCO并浓缩溶液至~4ml/g醇的体积。此点上KF小于200和小于5%的IPA残留。若不满足这些标准,则用额外的庚烷冲洗。任选地,在40℃下用DABCO络合物作为反应的晶种接种和缓慢冷却反应到室温,迅速开始结晶,然后冷却反应到0℃并过滤,用冷的庚烷洗涤该滤饼。分离DABCO,其产率为~70%,对映体过量~99%。
实施例4(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇1-(3,5-双(三氟甲基)-苯基)乙 256.15 3.9 1Kg-1-酮(Cp*RhCl2)2 618.08 0.01 6g(Cp*=五甲基环戊二烯基)(R,R)-甲苯磺酰基环己烷二胺 268.38 0.02 5.2gNaOH 5N(H2O) 0.05 9mlIPA 7LHCl 1N(H2O) 7L庚烷 7L1,4-二氮杂二环[2.2.2]辛烷 112.18 2.2 240g(DABCO)
在室温下将铑盐和配体加入到IPA中并陈化0.5小时,在陈化期间溶液通常会变成透明的桔红色,加入酮后接着加入碱,陈化反应直到通过HPLC观察反应完成(~3小时)。然后用1N盐酸使反应骤冷,并用庚烷(2×3.5升)萃取和用5升盐水洗涤。加入DABCO并浓缩溶液至~4ml/g醇的体积。此点上KF小于200和小于5%的IPA残留。若不满足这些标准,则用额外的庚烷冲洗。任选地,在40℃下用DABCO络合物作为反应的晶种接种和缓慢冷却反应到室温,迅速开始结晶,然后冷却反应到0℃并过滤,用冷的庚烷洗涤该滤饼。分离DABCO,其产率为~75%,对映体过量~99.5%。通过使甲苯磺酰氯与(R,R)-二氨基环己烷反应以制备(R,R)-甲苯磺酰基环己烷二氨,分离产品,其产率为40~50%。
实施例5(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇材料 Mw Mol 用量1-(3,5-双(三氟甲基)-苯基)乙-1- 256.15 11.7 3Kg酮[RuCl2(对鏾花烃)]2 612.40 0.03 18.4g(Cym=对鏾花烃(4-异丙基甲苯)(S,R)-顺式-氨基茚满醇 149.20 0.06 9.0gNaOH 5N(H2O) 0.14 28mlIPA 21LHCl 1N(H2O) 21L庚烷 21L1,4-二氮杂二环[2.2.2]辛烷 112.18 ~6.6 ~740g(DABCO)
在室温下将钌盐[RuCl2(对鏾花烃)]2和(S,R)-顺式-氨基茚满醇加入到IPA中并陈化0.5小时,在陈化期间溶液通常会变成透明的桔黄色,加入1-(3,5-双(三氟甲基)-苯基)乙-1-酮和在真空下使反应脱气。然后加入碱以及陈化反应直到通过HPLC观察反应完成>98%(4-6小时)。然后倒入1N盐酸使反应骤冷,并用庚烷(2×10.5升)萃取和用15升盐水洗涤。加入1,4-二氮杂二环[2.2.2]辛烷(DABCO)并浓缩溶液至~4ml/g醇的体积。此点上KF小于200和小于5%的IPA残留。若不满足这些标准,则用额外的庚烷冲洗。任选地,在40℃下用DABCO络合物作为反应的晶种接种和缓慢冷却反应到室温,迅速开始结晶,然后冷却反应到0℃并过滤,用冷的庚烷洗涤该滤饼。分离DABCO络合物,其产率为75~80%,对映体过量>99%。
虽然用一些详细的实施方案公开并阐述了本发明,但本领域的技术人员会理解到在没有脱离本发明的精神和范围的情况下,可对各步骤和约定作出各种适应性修改、变化、改性、取代、删除或添加。例如,可应用此处所提出的详细反应条件之外的反应条件作为试剂或工艺变化而导致的一种结果来制备本发明上述工艺中所制备的化合物。同样地,起始材料的特定反应性可根据和取决于所存在的特定取代基或制造条件来变化,以及结果中的这种预期的变化或差异被认为是根据本发明的目的和实际操作而得到的。因此,认为随后的权利要求的范围所定义的本发明以及这些权利要求,其范围宽度是合理的。
Claims (20)
2.权利要求1的方法,其中催化剂是选自双((五甲基环戊二烯基)氯化铑)和双((环戊二烯基)氯化铑)的铑催化剂。
3.权利要求1的方法,其中催化剂是选自双((4-异丙基-亚苄基)氯化钌)和双((环戊二烯基)氯化钌)的钌催化剂。
4.权利要求1的方法,其中催化剂是一种铑催化剂,它是双((五甲基环戊二烯基)氯化铑)。
5.权利要求4的方法,其中铑催化剂以约0.1-1mol%的浓度存在。
6.权利要求1的方法,其中催化剂是一种钌催化剂,它是双((4-异丙基-亚苄基)氯化钌)。
7.权利要求1的方法,其中钌催化剂以约0.1-1mol%的浓度存在。
8.权利要求1的方法,其中配体是(S,R)-顺式-1-氨基-2-羟基-二氢化茚。
9.权利要求1的方法,其中配体以约0.1-1mol%的浓度存在。
10.权利要求1的方法,其中醇选自甲醇、乙醇、异丙醇、异丁醇或正丁醇。
11.权利要求1的方法,其中醇是异丙醇。
12.权利要求1的方法,其中氢氧化钠与醇一起存在。
13.一种制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法,该方法包括:
在异丙醇的存在下,用双((五甲基环戊二烯基)氯化铑)和(S,R)-顺式-1-氨基-2-羟基-二氢化茚处理1-(3,5-双(三氟甲基)-苯基)乙-1-酮,得到(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇。
14.一种制备(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法,该方法包括:
在异丙醇的存在下,用双((4-异丙基-亚苄基)氯化钌)和(S,R)-顺式-1-氨基-2-羟基-二氢化茚处理1-(3,5-双(三氟甲基)-苯基)乙-1-酮,得到(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇。
17.一种下式的化合物:
18.一种纯化(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇的方法,该方法包括:
在一种有机溶剂中使(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇与1,4-二氮杂二环[2.2.2]辛烷接触,形成双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷;
回收双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷;
和从双-((R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇)1,4-二氮杂二环[2.2.2]辛烷中解离1,4-二氮杂二环[2.2.2]辛烷,得到(R)-1-(3,5-双(三氟甲基)-苯基)乙-1-醇。
19.权利要求18的方法,其中有机溶剂选自己烷和庚烷。
20.权利要求18的方法,其中有机溶剂是庚烷。
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CN103232324A (zh) * | 2013-04-12 | 2013-08-07 | 广西新晶科技有限公司 | 一种(r)-3,5-双(三氟甲基)苯乙醇的制备方法 |
CN107602357A (zh) * | 2017-09-28 | 2018-01-19 | 万华化学集团股份有限公司 | 一种制备薄荷酮的方法 |
CN107641072A (zh) * | 2016-07-22 | 2018-01-30 | 江苏威凯尔医药科技有限公司 | 一种制备(s)‑2‑氯‑1‑(3,4‑二氟苯基)乙醇的方法 |
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IL146633A0 (en) * | 1999-07-01 | 2002-07-25 | Merck & Co Inc | Process for the synthesis of (r) -1-(3,5-bis(trifluoromethyl)-phenyl) ethan-1-ol by asymmetric transfer hydrogenation |
CA2431457A1 (en) | 2000-12-20 | 2002-06-27 | Merck & Co., Inc. | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one |
EP1448788A4 (en) * | 2001-11-19 | 2006-03-29 | Merck & Co Inc | SYNTHESIS PROCESS FOR (R) -1- (3,5-BIS (TRIFLUOROMETHYL) -PHENYL) ETHAN-1-OL AND ITS ESTER WITH DYNAMIC-KINETIC RESOLUTION |
WO2007147897A1 (de) * | 2006-06-23 | 2007-12-27 | Basf Se | Verfahren zur herstellung von optisch aktiven 2-halogen-1-phenylethanol-derivaten und folgeprodukten davon |
CN105085189A (zh) * | 2014-05-12 | 2015-11-25 | 中山奕安泰医药科技有限公司 | 不对称氢化法制备(r)- 3,5-双三氟甲基苯乙醇的方法 |
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DE3008671A1 (de) * | 1979-03-08 | 1980-09-11 | Montedison Spa | Verfahren zur katalytischen umwandlung von carbonylverbindungen bzw. hydroxylverbindungen |
DE69518497T2 (de) * | 1994-12-07 | 2001-04-19 | Nippon Kokan Kk | Verfahren zur Herstellung eines Alkohols |
EP1300381B1 (en) * | 1995-12-06 | 2006-03-08 | Japan Science and Technology Agency | Process for preparing optically active alcohols |
GB9706321D0 (en) * | 1997-03-26 | 1997-05-14 | Zeneca Ltd | Catalytic hydrogenation |
JPH11124350A (ja) * | 1997-10-21 | 1999-05-11 | Mitsubishi Chemical Corp | 光学活性アルコールの製造方法 |
IL146633A0 (en) * | 1999-07-01 | 2002-07-25 | Merck & Co Inc | Process for the synthesis of (r) -1-(3,5-bis(trifluoromethyl)-phenyl) ethan-1-ol by asymmetric transfer hydrogenation |
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Cited By (5)
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CN103232324A (zh) * | 2013-04-12 | 2013-08-07 | 广西新晶科技有限公司 | 一种(r)-3,5-双(三氟甲基)苯乙醇的制备方法 |
CN103232324B (zh) * | 2013-04-12 | 2016-03-16 | 广西新晶科技有限公司 | 一种(r)-3,5-双(三氟甲基)苯乙醇的制备方法 |
CN107641072A (zh) * | 2016-07-22 | 2018-01-30 | 江苏威凯尔医药科技有限公司 | 一种制备(s)‑2‑氯‑1‑(3,4‑二氟苯基)乙醇的方法 |
CN107641072B (zh) * | 2016-07-22 | 2020-07-21 | 江苏威凯尔医药科技有限公司 | 一种制备(s)-2-氯-1-(3,4-二氟苯基)乙醇的方法 |
CN107602357A (zh) * | 2017-09-28 | 2018-01-19 | 万华化学集团股份有限公司 | 一种制备薄荷酮的方法 |
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