Sythesis of optically active intermediate for the preparation of montelukast

A system and technology of ruthenium complexes, applied in the field of synthesis of optically active alcohols, can solve problems such as difficult preparation of ligands

Inactive Publication Date: 2012-07-11
DSM IP ASSETS BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, these ligands are often difficult to prepare

Method used

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  • Sythesis of optically active intermediate for the preparation of montelukast
  • Sythesis of optically active intermediate for the preparation of montelukast
  • Sythesis of optically active intermediate for the preparation of montelukast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-hydroxypropyl]benzoic acid methyl ester ((1), R= -C(O)OCH 3 ) Screening of catalysts in the preparation

[0033] According to the ratio given in Table 1, the ketone 2 (R=-C(O)OCH 3 ), sodium formate and surfactant (methyl trioctyl ammonium chloride) are added as solids into a Schlenk tube. The vessel is placed in an inert atmosphere after three vacuum / argon cycles. Degassed water and degassed dichloromethane were added in a ratio of water: dichloromethane=1:2. The catalyst was added in the proportions given in Table 1, and the reaction mixture was heated to 40°C. Timely, the conversion rate and enantiomeric excess were monitored by HPLC analysis at different times. The results are shown in Table 1.

[0034] Table 1 Screening of transfer hydrogenation catalyst

[0035]

[0036]

Embodiment 2

[0038] (E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-hydroxypropyl]benzoic acid methyl ester ((1), R= -C(O)OCH 3 ) Screening of hydrogen donors in the preparation

[0039] According to the ratio given in Table 2 ketone 2 (R = -C (O) OCH 3 ), hydrogen donor and surfactant (methyl trioctyl ammonium chloride) as a solid added to the Hiddink tube. The container is placed in an inert atmosphere after three vacuum / argon cycles. The solvent and catalyst were added in the proportions described in Table 2, and the reaction mixture was heated to 40°C. Timely, the conversion rate and enantiomeric excess were monitored by HPLC analysis at different times. The results are shown in Table 2.

[0040] Table 2 Screening of hydrogen donors

[0041]

[0042]

[0043] a) Dichloromethane: water

[0044] b) Dichloromethane

[0045] c) Tetrahydrofuran

[0046] TEAF: Triethylamine: HCO 2 H

Embodiment 3

[0048] (E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-hydroxypropyl]benzoic acid methyl ester ((1), R= -C(O)OCH 3 ) Screening of solvents in the preparation

[0049] According to the ratio given in Table 3, ketone 2 (R=-C(O)OCH 3 ), sodium formate, methyl trioctyl ammonium chloride (surfactant) as a solid added to the Hiddink tube. The container is placed in an inert atmosphere after three vacuum / argon cycles. (Mesitylene)-Ru-Ms-DPEN as a catalyst and a solvent were added in the ratio described in Table 3, and the reaction mixture was heated as shown. Timely, the conversion rate and enantiomeric excess were monitored by HPLC analysis at different times. The results are shown in Table 3.

[0050] Table 3 Screening of solvents

[0051]

[0052] a) Dichloromethane: water

[0053] d)Chlorobenzene: water

[0054] e) Toluene: water

[0055] f) Ethyl acetate: water

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Abstract

The present invention relates to the synthesis of optically active alcohols by means of enantioselective hydrogenation of ketones in biphasic systems. In particular the present invention relates to the synthesis of an optically active alcohol of general formula (1).

Description

Technical field [0001] The present invention relates to the synthesis of optically active alcohols, which are synthesized by enantioselective hydrogenation of ketones in a two-phase system. Background technique [0002] The enantioselective transfer hydrogenation of prochiral ketones was originally developed by Noyori et al. (J. Amer. Chem. Soc. 1995, 117, 7562), in which a chiral mono-N-tosylation vicinal was used Ruthenium complex of diamine ligand. The application of this technology is usually carried out in organic solvents, with good yield and enantiomeric excess (ee). In view of this, there is no immediate motivation to explore alternative solvents. Therefore, the Noyori technology can be extended to other systems in only a few ways, such as by using water-soluble ligands. Unfortunately, these ligands are often difficult to prepare. Alternatively, the use of surfactants has been reported (for example, Adv. Synth. Catal. 2002, 344, 239), and the use of aqueous micelles h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 劳伦特·莱福特
Owner DSM IP ASSETS BV
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