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
View PDF0 Cites 7 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07B53/00C07B61/00C07B63/02C07C13/15C07C17/12C07D265/32C07C29/143C07C29/145C07C29/74C07C29/88C07C33/46C07C45/00C07C211/42C07F15/00C07F17/02
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap