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Intermediate compound for synthesizing montelukast and preparation method thereof

A technology for compounds and reactants, which is applied in the field of synthesizing intermediate compounds of montelukast and its preparation, can solve the problems of large environmental pollution, complicated operation, long β-pyruvate steps, etc., and achieves environmental friendliness and low cost. , the effect of simple steps

Active Publication Date: 2017-03-29
ZHEJIANG AUSUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] (1) The synthesis method of β-pyruvate 17 or 20 is not only long in steps and cumbersome in operation, but also uses some toxic reagents, such as Swern oxidation to produce unpleasant toxic gases, which has great environmental pollution
[0027] (2) The hydrolytic decarboxylation reaction of intermediate II is difficult, and it needs to be heated for a long time under the condition of strong acid (such as the mixture of glacial acetic acid and concentrated hydrochloric acid), which is corrosive to the production equipment
[0028] (3) The selectivity of hydrolysis reaction is bad, can make the methyl ester part hydrolysis on benzene ring, obtain the mixture of intermediate 23 and product 2, and also need this mixture further methyl esterification in order to obtain target product, thereby increased Cost of production

Method used

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  • Intermediate compound for synthesizing montelukast and preparation method thereof
  • Intermediate compound for synthesizing montelukast and preparation method thereof
  • Intermediate compound for synthesizing montelukast and preparation method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0089] The preparation of compound 18 of the present invention can refer to literature (McNamara, J.M.; Leazer, J.L.; Bhupathy, M.; Amato, J.S.; Reamer, R.A.; et al.Journal of Organic Chemistry, 1989, vol.54, #15p.3718 -3721) or similar methods.

[0090] Compound 4 can be purchased commercially or prepared according to known methods in literature or similar methods.

Embodiment 1

[0091] Example 1: tert-butyl 3-{3-[2(E)-(7-chloroquinolin-2-yl)vinyl]-phenyl}-3-oxopropionate (compound 3, wherein R' is Tertiary butyl, X is the preparation of Cl)

[0092]

[0093] Add 28ml (0.2mol) tert-butyl acetate to 200ml THF, cool to -78°C, add dropwise 200ml 1M LiN(TMS) 2 After the addition, stir at -78°C for 45min, then dropwise add 32.3g (0.1mol) of the raw material (compound 18, wherein R is methyl) in 180ml THF solution, after the addition, stir at -78°C for 1.5 hours, rise to room temperature and stir for 1.5 h, add about 30ml of acetic acid, add saturated NH 4 Cl400ml, the THF layer was separated, the aqueous layer was extracted with 100ml THF, the organic layers were combined, washed with saturated NaCl, anhydrous NaCl 2 SO 4 Dry, filter, and concentrate the filtrate to about 150ml under reduced pressure, add 300ml of water under stirring, precipitate crystals, filter, wash the filter cake with water, and dry to obtain 35g (86%) of light yellow (beige) so...

Embodiment 2

[0094] Example 2: tert-butyl 3-{3-[2(E)-(7-chloroquinolin-2-yl)vinyl]-phenyl}-3-oxopropionate (compound 3, wherein R' is Tertiary butyl, X is the preparation of Cl)

[0095]

[0096] Add 250ml THF to 42ml (0.31mol) tert-butyl acetate, cool to -78°C, add dropwise 136ml 2.2M NaN (TMS) 2After the addition, stir at -78°C for 60 minutes, then dropwise add 48g (0.15mol) of the raw material (compound 18, wherein R is methyl) in 500ml THF solution, after the addition, stir at -78°C for 1 hour, then rise to -20°C and stir After 1.5 hours, add 40ml of acetic acid, concentrate under reduced pressure to about 250ml, pour into 1 liter of ice water, precipitate crystals, filter, wash the filter cake with water, and dry to obtain 56g (93%) of light yellow (beige) solid.

[0097] 1 H NMR (300MHz, CDCl 3 )δ1.45(s,9H),3.95(s,2H),7.41-7.56(m,3H),7.62-7.65(d,J=8.7Hz,1H),7.72-7.75(m,2H),7.81 -7.88(m,2H),8.05-8.15(m,2H),8.21(s,1H)

[0098] HR-MS (ESI): calculated value C 24 h 23 ClNO 3 (...

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Abstract

The invention relates to a medicine intermediate and a preparation method thereof, and especially relates to an intermediate compound for synthesizing montelukast, and a preparation method thereof. The intermediate compound is represented by formula (2); and in the formula (2), R'' is a C1-4 alkyl group, and X is halogen.

Description

technical field [0001] The present invention relates to the synthesis of organic compounds. Specifically, the present invention relates to pharmaceutical intermediates and preparation methods thereof, such as intermediate compounds used in the synthesis of montelukast and preparation methods thereof. Background technique [0002] Montelukast is a highly selective leukotriene receptor antagonist developed by Merck, the structure of its sodium salt is shown in the following formula (1). The drug was launched abroad in 1998 and in China in 2002. It can be effectively used to treat bronchial asthma and allergies without obvious side effects. [0003] [0004] The intermediate compound of formula (2) is an important intermediate for the synthesis of montelukast (1), wherein R'' is C 1-4 Alkyl, X is halogen. [0005] [0006] The method for synthesizing this intermediate (2) in the prior art mainly contains following two kinds of approaches: [0007] 1. Heck coupling rea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/14
CPCC07D215/18
Inventor 郑志国
Owner ZHEJIANG AUSUN PHARMA