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Method for preparing montelukast nano chiral alcohol intermediate

A technology of intermediates and chiral alcohols, which is applied in the field of preparation of Montelus Turner chiral alcohol intermediates, can solve the complex operation of chiral oxazolidine and borane reducing agent, and the cost of chiral oxazolidine High, unfavorable industrial production and other issues, to achieve the effect of favorable industrial production, good commercial value, and low production cost

Inactive Publication Date: 2016-02-03
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method yield and stereoselectivity are all high, but the corresponding operation of chiral oxazolidine and borane reducing agent is complicated, and the cost of chiral oxazolidine is high, and borane reducing agent such as borane dimethyl sulfide etc. The methyl sulfide released during the reaction can also cause environmental pollution, which is not conducive to large-scale industrial production

Method used

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  • Method for preparing montelukast nano chiral alcohol intermediate
  • Method for preparing montelukast nano chiral alcohol intermediate
  • Method for preparing montelukast nano chiral alcohol intermediate

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preparation example Construction

[0030] The invention provides a kind of preparation method of Montelus Turner chiral alcohol intermediate, comprising the following steps:

[0031] Provide reaction raw material 2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]methyl benzoate (II);

[0032] Provide transition metal complexes as catalysts, with NH2-N(sp 2 ) or nitrogen phosphine transition metals formed by coordination of ligands with NH2-NH2 structure characteristics and transition metals. The general formula of the transition metal complex is MLnL'XY, wherein M is Ru, X is chlorine, bromine, iodine or hydrogen, and Y is chlorine, bromine, iodine or BH 4 , L, L' are R configuration, S configuration or racemate, n=1 or 2, when n=1, L is BINAP, MeO-BIPHEP, DIOP or SegPhos; when n=2, L is P(C 6 h 5 ) 3 or P(C 6 h 4 -4-CH 3 ) 3 , L' is DPEN, DAIPEN,

[0033] 1,2-Cyclohexanediamine, or L' has structure III:

[0034]

[0035] In the structure III, Z is NH or O, R 1 , R 2 It is hydrogen or a ...

Embodiment 1

[0044] The transition metal complex catalyst adopts structure IV; the base adopts alkoxy base, such as potassium tert-butoxide; the solvent adopts an aprotic solvent, such as toluene. Reaction materials 2-[3-[3-[2-(7-Chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]benzoic acid methyl ester (Ⅱ) and transition metal complexation The molar ratio of the substance is 20000. The reaction formula is as follows:

[0045]

[0046]

[0047]

[0048] In a 100L stainless steel autoclave, add 2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]methyl benzoate, toluene , at N 2 Under the atmosphere, add the catalyst [RuCl 2 ((S,S)-DIOP){(1H-benzo[d]imidazol-2-yl)ethanamine}] and potassium tert-butoxide; after hydrogen replacement, fill with H 2 To 5 atm, 100 ℃ of stirring reaction, when the hydrogen pressure is constant (about 4 hours), stop stirring, the H in the reactor 2 Empty, the reaction solution is sampled, carry out conventional post-treatment (filtration, centrifuga...

Embodiment 2

[0050] The transition metal complex catalyst adopts structure V; the base adopts triethylamine; the solvent adopts tetrahydrofuran. Reaction materials 2-[3-[3-[2-(7-Chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]benzoic acid methyl ester (Ⅱ) and transition metal complexation The molar ratio of the substance is 240000. The reaction formula is as follows:

[0051]

[0052]

[0053] In a 100L stainless steel autoclave, add 2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]methyl benzoate and tetrahydrofuran , at N 2 Under the atmosphere, add the catalyst [RuCl 2 ((S)-SegPhos){(1H-benzo[d]imidazol-2-yl)ethanamine}] and triethylamine; after replacing hydrogen, fill with H 2 To 10atm, 30 ℃ of stirring reaction, when the hydrogen pressure is constant (about 8 hours), stop stirring, the H in the reactor 2 The reaction solution was vented, and the reaction solution was sampled for conventional post-treatment to obtain a yellow solid product, which was detected by liquid...

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Abstract

The invention discloses a method for preparing a montelukast nano chiral alcohol intermediate. In alkali and solvent environment, 2-[3-[3-[2-(7-chloro-2-quinolyl) vinyl] phenyl]-3-oxo propyl] methyl benzoate (II) is subjected to catalytic hydrogenation reaction by using a transition metal complex as a catalyst to generating 2-[3-(S)-[3-[2-(7-chloro-2-quinolyl)-phenyl] vinyl]-3-hydroxy propyl methyl benzoate (I), wherein the transition metal complex has a general formula of MLnL'XY, and is a nitrogen phosphine transition metal formed by coordination of a ligand with NH2-N(sp2) or NH2-NH2 structural characteristic and a transition metal complex. The preparation method has the advantages of small catalyst amount, mild reaction conditions, stable process, conversion rate of more than 98%, less pollution, and high yield and high purity of obtained product, and has the very good value of industrialization.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, in particular to a preparation method of Montelustener chiral alcohol intermediates. Background technique [0002] Montelukast Sodium (Montelukast Sodium, MK-0476), the chemical name is 1-(((1-(R-(3-(2-(7-chloro-2-quinolyl)-vinyl)-phenyl )-3-(2-Hydroxy-1-methylethyl)-phenyl)propyl)mercapto)methyl)cyclopropyl sodium acetate is a highly efficient, low-toxic, safe A good anti-asthmatic anti-inflammatory and anti-allergic drug, trade name Singulair (Singular), was first launched in Mexico and Finland in 1998, and launched in China in 2002. As a new type of highly selective cysteinyl leukotriene LTD4 receptor antagonist, the drug can selectively bind to the leukotriene LTD receptor on the respiratory mucosa, block the action of allergic mediators, and improve respiratory inflammation , to make the airway unobstructed, it is clinically used to treat mild to modera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/55C07D213/30
CPCC07D213/55C07B2200/07C07D213/30
Inventor 徐亮李彦雄黄志鸿蒙发明毛波
Owner ENANTIOTECH CORP
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