Method for synthesizing montrlukast sodium chiral alcohol intermediate by means of catalysis of graphene palladium copper

The technology of montelukast sodium and alkene palladium copper is applied in the field of synthesis of montelukast sodium intermediates, which can solve the problem of low ee value of product alcohol, great influence of chiral impurity reaction, and great difficulty in synthesizing chiral ligands of catalysts. and other problems, to achieve the effect of good chiral selectivity, simple operation, easy separation, recovery and reuse.

Inactive Publication Date: 2017-07-07
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this catalyst requires high rhodium and chiral ligands. The synthesis cost of the catalyst and the difficulty in the synthesis of the chiral ligands are relatively large, and the ee value of the product alcohol is relatively low, which cannot meet the requirements for drug use. The presence of chiral impurities have a greater impact on subsequent reactions

Method used

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  • Method for synthesizing montrlukast sodium chiral alcohol intermediate by means of catalysis of graphene palladium copper
  • Method for synthesizing montrlukast sodium chiral alcohol intermediate by means of catalysis of graphene palladium copper
  • Method for synthesizing montrlukast sodium chiral alcohol intermediate by means of catalysis of graphene palladium copper

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment 1

[0018] Specific Example 1: [S-(E)]-2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-hydroxypropyl]benzoic acid Synthesis of methyl esters:

[0019] Take a dry 50 ml three-neck round bottom flask and add 590.1mg methyl (E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoate, 20mg Graphene loaded palladium-copper nanocapsules containing palladium 10% mass fraction, add 10 milliliters of anhydrous N under the protection of nitrogen, N-dimethylformamide, keep the N of the reaction system 2 Protection, under ice-water bath cooling, control the temperature of the reaction solution at -2~0 o C, Add ligand 11.4mg(1S,2S)-N to the reaction solution 1 ,N 2 -bis(1-(2-(di-4-methoxyphenylphosphanyl) phenyl) ethyl) cyclohexane-1,2-diamine, stirred for 20 minutes, then added 268mg α-pinene (alpha-pinene), and added 0.18mL BBr drop by syringe 3 , then dropwise add 0.22mL borane tetrahydrofuran solution, and raise the temperature to 35 o C, react for 3.5 hours until the com...

specific Embodiment 2

[0020] Specific Example 2: [S-(E)]-2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-hydroxypropyl]benzoic acid Synthesis of methyl esters:

[0021] Take a dry 50 ml three-necked round bottom flask and add 590.1 mg methyl (E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoate, 20mg of graphene-loaded palladium-copper nanocapsules containing 10% palladium by mass fraction, add 10 milliliters of anhydrous N under nitrogen protection, N-dimethylformamide, keep the N of the reaction system 2 Protection, under ice-water bath cooling, control the temperature of the reaction solution at -2~0 o C, add ligand 12.4mg (1S,2S)-N to the reaction solution 1 ,N 2 -bis(1-(2-(di-4-methoxyphenylphosphanyl) phenyl) ethyl)cyclohexane-1,2-diamine, stirred for 20 minutes, then added 278.2mg of α-pinene (alpha-pinene), dripped by syringe 0.26mL BBr 3 , then dropwise add 0.32mL borane tetrahydrofuran solution, and raise the temperature to 35 o C, react for 3.5 hours until the co...

specific Embodiment 3

[0022] Specific example 3, [S-(E)]-2-[3-[3-[2-(7-chloro-2-quinolyl) vinyl] phenyl]-3-hydroxypropyl] benzoic acid Synthesis of methyl esters:

[0023]Take a dry 100 ml three-neck round bottom flask and add 974.2 mg methyl (E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoate, 30mg of graphene-loaded palladium-copper nanocapsules containing palladium 10% mass fraction, add 30 milliliters of anhydrous N under the protection of nitrogen, N-dimethylformamide, keep the N of the reaction system 2 Protection, under ice-water bath cooling, control the temperature of the reaction solution at -2~0 o C, add ligand 19.2mg (1S,2S)-N to the reaction solution 1 ,N 2 -bis(1-(2-(di-4-methoxyphenylphosphanyl) phenyl) ethyl)cyclohexane-1,2-diamine, stirred for 20 minutes, then added 428.5mg α-pinene (alpha-pinene), dripped by syringe 0.31mL BBr 3 , then dropwise add 0.35mL borane tetrahydrofuran solution, and raise the temperature to 35 o C, react for 3.8 hours until the ...

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Abstract

The invention discloses a novel method for synthesizing a montrlukast sodium chiral alcohol intermediate-[S-(E)]-2-[3-[3-[2-(7-chlorine-2-quinolyl)vinyl]phenyl]-3-hydroxy propyl]methyl benzoate by means of compound catalysis of graphene palladium copper and a chiral diphosphine ligand. The method uses a composite catalyst prepared from the high-activity graphene palladium copper and the chiral diphosphine ligand to catalyze borane to reduce ketone carbonyl; the method is good in chiral selectivity and simple in operation; the catalyst is easy to separate and recover; after the method is adopted, the yield reaches up to 82.1%, and the best ee value is 99.5%; therefore, the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry synthesis, and in particular relates to a synthesis method of a Montelukast sodium intermediate. Background technique [0002] The chemical name of Montelukast Sodium is: 2-(1-((1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-vinyl) )phenyl)-3-(2-(2-hydroxy-2propyl)phenyl)-propylthio)methyl)cyclopropyl)sodium acetate, used as anti-asthma agent, anti-allergic agent, etc. It was first synthesized and developed by Canada Merk-Frosst Company. [0003] Investigating patents and journals found that in the synthesis of montelukast sodium, the synthesis of S-configuration chiral propanol intermediates is the most important work, whether through the control of chiral catalysts or through other methods The resolution of chiral reagents to obtain a single chiral product will have great limitations. In terms of chiral ligands and metal catalysts, chiral catalysts are mainly obtained by combining Ru, Rh, Ir, Pd wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18B01J23/89
CPCY02P20/584C07D215/18B01J23/8926
Inventor 郑庚修高令峰韩歆雨付凯王秋芬冯雪
Owner UNIV OF JINAN
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