Process for preparing montelukast and precursors thereof
AssigneeChemagis Ltd.
InventorsJingshan Shen, Yiru Dai, Joseph Kaspi
Life of this patent
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Abstract
The present invention provides a process for stereoselectively reducing 2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]-phenyl]-3-oxopropyyl]benzoic-acid methyl ester, to produce to produce methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate, and a process for producing montelukast or a salt thereof. The present invention further provides a process for purifying methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate. The reduction process of the present invention uses a chiral reagent and can produce the desired reduction product in high enantiomeric excess (ee).
Claims25
A process for producing montelukast or a salt thereof, the process comprising:
- stereoselectively reducing 2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]-phenyl]-3-oxopropyl]benzoic acid methyl ester 2 in the presence of a catalytic amount of a chiral reduction catalyst comprising (R)-methyl oxazaborolidine (MeCBS) 6, (−)-B-bromodiisopinocamphenylborane, trans-RuH(η1BH4)[(R)-2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthyl][(R,R)-1,2-diphenyl-ethylenediamine, trans-RuCl2[(R)-2,2′-bis(di-3,5-dimethylphenylphosphino)]-1,1′-binaphthyl][(R,R)-1,2-diphenylethylenediamine], or [[N(S),N′(S), 1R, 2R]-N,N′-bis-[[2-(diphenylphosphino)-phenyl]methyl]1,2-cyclohexanediamine-N,N′,P,P′]-dichloro-ruthenium, to produce methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate 5;
- and
- converting the methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate 5 into montelukast or a salt thereof.
A process for purifying methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate 5, the process comprising:
- dissolving crude methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate 5 in a polar organic solvent;
- adding a non-polar solvent and water;
- optionally adding another portion of the non-polar solvent cooling sufficiently to produce crystals of methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate 5;
- isolating the crystals by filtration;
- and
- optionally washing and drying the crystals.
A process for producing methyl 2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-hydroxypropyl]benzoate 5, the process comprising stereoselectively reducing 2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]-phenyl]-3-oxopropyl]benzoic acid methyl ester 2 in the presence of a catalytic amount of a chiral reduction catalyst comprising (R)-methyl oxazaborolidine (MeCBS) 6, (−)-B-bromodiisopinocamphenylborane, trans-RuH(η1BH4)[(R)-2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthyl][(R,R)-1,2-diphenyl-ethylenediamine, trans-RuCl2 [(R)-2,2′-bis(di-3,5-dimethylphenylphosphino)]-1,1′-binaphthyl][(R,R)-1,2-diphenylethylenediamine], or [[N(S),N′(S), 1R, 2R]-N,N′-bis-[[2-(diphenylphosphino)-phenyl]methyl]1,2-cyclohexanediamine-N,N′,P,P′]-dichloro-ruthenium.
Dependencies are inferred from the claim text.