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Process for the synthesis (R)-1-(3.5-bis (trifluoromethyl)-phenyl) ethan-1-ol by asymmetric transfer hydrogenation

A technology of trifluoromethyl and phenyl, applied in the field of synthesizing (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol through asymmetric transfer hydrogenation, capable of Solve problems such as instability and low yield

Inactive Publication Date: 2002-07-10
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] General method for preparing (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol disclosed in the art, the yield of desired product is relatively low and unstable

Method used

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  • Process for the synthesis (R)-1-(3.5-bis (trifluoromethyl)-phenyl) ethan-1-ol by asymmetric transfer hydrogenation
  • Process for the synthesis (R)-1-(3.5-bis (trifluoromethyl)-phenyl) ethan-1-ol by asymmetric transfer hydrogenation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0073] Example 3 (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol 1-(3,5-bis(trifluoromethyl)-phenyl) 256.15 3.9 1Kg ethyl-1-one (Cp*RhCl 2 ) 2 618.08 0.01 6g (Cp*=pentamethylcyclopentadienyl)(S,R)-cis-aminoindanol 149.20 0.02 3.0gNaOH 5N(H 2 O) 0.05 9mlIPA 7LHCl 1N(H 2 O) 7L heptane 7L1,4-diazabicyclo[2.2.2]octane 112.18 2.2 240g (DABCO)

[0074] At room temperature, rhodium salt and ligand are added in the IPA and aged for 0.5 hour. During the aging, the solution usually turns into a transparent orange-red color. After adding the ketone, the alkali is added, and the aging reaction is completed until the reaction is observed by HPLC ( ~3 hours). The reaction was then quenched with 1N hydrochloric acid and extracted with heptane (2 x 3.5 L) and washed with 5 L of brine. DABCO was added and the solution was concentrated to a volume of ~4ml / g alcohol. At this point the KF is less than 200 and less than 5% IPA remains. If these crit...

Embodiment 4

[0075] Example 4 (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol 1-(3,5-bis(trifluoromethyl)-phenyl)ethane 256.15 3.9 1Kg-1-ketone (Cp*RhCl 2 ) 2 618.08 0.01 6g (Cp*=pentamethylcyclopentadienyl)(R,R)-tosylcyclohexanediamine 268.38 0.02 5.2gNaOH 5N(H 2 O) 0.05 9mlIPA 7LHCl 1N(H 2 O) 7L heptane 7L1,4-diazabicyclo[2.2.2]octane 112.18 2.2 240g (DABCO)

[0076]At room temperature, rhodium salt and ligand are added in the IPA and aged for 0.5 hour. During the aging, the solution usually turns into a transparent orange-red color. After adding the ketone, the alkali is added, and the aging reaction is completed until the reaction is observed by HPLC ( ~3 hours). The reaction was then quenched with 1N hydrochloric acid and extracted with heptane (2 x 3.5 L) and washed with 5 L of brine. DABCO was added and the solution was concentrated to a volume of ~4ml / g alcohol. At this point the KF is less than 200 and less than 5% IPA re...

Embodiment 5

[0077] Example 5 (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol Material Mw Mol dosage 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1- 256.15 11.7 3Kg ketone [RuCl 2 (paramene)] 2 612.40 0.03 18.4g (Cym=p-Cymene (4-isopropyltoluene) (S, R)-cis-aminoindanol 149.20 0.06 9.0gNaOH 5N(H 2 O) 0.14 28mlIPA 21LHCl 1N(H 2 O) 21L heptane 21L1,4-diazabicyclo[2.2.2]octane 112.18 ~6.6 ~740g (DABCO)

[0078] Ruthenium salt [RuCl 2 (paramene)] 2 and (S, R)-cis-aminoindanol were added to IPA and aged for 0.5 hours. During the aging, the solution usually turned into a transparent orange, and 1-(3,5-bis(trifluoro Methyl)-phenyl)ethan-1-one and degas the reaction under vacuum. Base was then added and the reaction was aged until >98% complete by HPLC (4-6 hours). The reaction was then quenched by pouring into 1N hydrochloric acid and extracted with heptane (2 x 10.5 L) and washed with 15 L of brine. 1,4-Diazabicyclo[2.2.2]octane (DABCO) was add...

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Abstract

The present invention is concerned with novel processes for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol. This compound is useful as an intermediate in the synthesis of compounds which possess pharmacological activity.

Description

Background technique [0001] The present invention relates to a process for the preparation of (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol which is useful as an intermediate in the preparation of certain therapeutic agents, in particular, the present The invention provides a method for preparing (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol, which is an intermediate in the synthesis of pharmaceutical compounds. By pharmaceutical compound is meant a substance P (neurokinin-1) receptor antagonist. [0002] (2R,2-α-R,3a)-2-[1-[3,5-bis(trifluoromethyl)]ethoxy-3-(4-fluorophenyl)- (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol prepared by the present invention can be utilized in the synthesis of 1,4-oxazine: This compound is a known intermediate in the synthesis of the pharmaceutical compound Substance P (neurokinin-1) receptor antagonist. [0003] The general methods for the preparation of (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol disclosed in the art give r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/32C07B53/00C07B61/00C07B63/02C07C13/15C07C17/12C07C29/143C07C29/145C07C29/74C07C29/88C07C33/46C07C45/00C07C211/42C07F15/00C07F17/02
CPCC07F15/0046C07B2200/07C07C33/46C07F17/02C07F15/0073C07C17/12C07C29/88C07C45/004C07C29/143A61P25/18C07C25/13C07C49/80
Inventor P·德维尼K·汉森
Owner MERCK & CO INC
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