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药物详细合成路线

Name Montelukast sodium;L-706631;MK-0476;MK-476;Kipres;Singulair
Chemical Name 2-[1-[1(R)-[3-[2(E)-(7-Chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]acetic acid sodium salt
CAS 151767-02-1
Related CAS 142522-81-4 ([R, (E/Z)]-isomer), 158966-92-8 (free acid), 142522-28-9 (free acid, [R, (E/Z)-isomer]
Formula C35H35ClNNaO3S
Structure
Formula Weight 608.1809
Stage 上市-1997
Company Banyu (Originator), Merck & Co. (Originator), Merck Frosst (Originator), Merck Sharp & Dohme (Originator), Kyorin (Codevelopment)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Antiallergy/Antiasthmatic Drugs, Antimigraine Drugs, Asthma Therapy, Atopic Dermatitis, Agents for, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, Migraine, Prophylactic Treatment of, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Leukotriene CysLT1 (LTD4) Antagonists
Syn. Route 3
Route 1
montelukast can be obtained by two related ways:1) the grignard reaction of 3-[2(e)-(7-chloroquinolin-2-yl)vinyl]benzaldehyde (i) with vinylmagnesium bromide (ii) in toluene/thf gives the expected secondary alcohol (iii), which is condensed with methyl 2-bromobenzoate (iv) by means of palladium acetate and lithium acetate in dmf to yield methyl 2-[3-[3-[2(e)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-oxopropyl]benzoate (v). the enantioselective reduction of the keto group of (v) with (-)-b-chlorodiisopinocampheylborane in thf affords methyl 2-[3-[3-[2(e)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3(s)-hydroxypropyl] benzoate (vi), which is reacted with methylmagnesium bromide in toluene/thf or methylmagnesium chloride/cecl3 in thf to give the expected tertiary diol (vii). the selective esterification of (vii) with mesyl chloride and diisopropylethylamine in toluene/acetonitrile yields the expected secondary mesylate (viii), which is condensed with 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (ix) by means of butyllithium in thf to afford the corresponding condensation product as free acid that is separated by addition of dicyclohexylamine and precipitates the corresponding salt (x). finally, this dicyclohexylamine salt (x) is treated with naoh in toluene/water.2) the 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (ix) has been obtained as follows: the reaction of 1,1-cyclopropanedimethanol (xi) with socl2 or diisopropyl sulfite in dichloromethane gives 1,1-cyclopropanedimethanol cyclic sulfite (xii), which is treated with nacn in dichloromethane yielding 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile (xiii). the reaction of (xiii) with mesyl chloride and triethylamine affords the corresponding mesylate (xiv), which is treated with potassium thioacetate in isopropyl acetate giving 2-[1-(acetylsulfanyl)cyclopropyl]acetonitrile (xv). finally, this compound is hydrolyzed with naoh in toluene/water to afford (ix).
List of intermediates No.
diethyl benzylphosphonate (iv)
benzhydryl (6r,7r)-7-amino-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i)
benzhydryl (6r,7r)-7-[((2r,3s)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (ii)
benzhydryl (6r,7s)-7-[((2r,3s)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-7-methoxy-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
benzyl 4-ethyl-3,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carboxylate (v)
benzyl 1,4-diethyl-1,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carboxylate (vi)
benzyl 3,4-diethyl-3,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carboxylate (vii)
1,4-diethyl-4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine (viii)
3,4-diethyl-4,5,6,7-tetrahydro-3h-imidazo[4,5-c]pyridine (ix)
2-isothiocyanatopropane (x)
1,4-diethyl-n-isopropyl-1,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carbothioamide (xi)
3,4-diethyl-n-isopropyl-3,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carbothioamide (xii)
3-chloro-6-hydrazinopyridazine (xiii)
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one n-(6-chloro-3-pyridazinyl)hydrazone (xiv)
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one n-[6-(4-morpholinyl)-3-pyridazinyl]hydrazone (xv)
4-(3-methoxyphenyl)-4-oxo-2-phenylbutanenitrile
Reference 1:
    graul, a.; martín, l.; casta?er, j.; montelukast sodium. drugs fut 1997, 22, 10, 1103.
Reference 2:
    belley, m.l.; leger, s.; roy, p.; xiang, y.b.; labelle, m.; guay, d. (merck frosst canada inc.); unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. ep 0480717; jp 1993105665 .
Reference 3:
    bhupathy, m.; mcnamara, j.m.; sidler, d.r.; volante, r.p.; bergan, j.j. (merck & co., inc.); process for the preparation of leukotriene antagonists. wo 9518107 .
Reference 4:
    king, s.; pipik, b.; conlon, d.a. (merck & co., inc.); process for the preparation of 1-(thiomethyl)-cyclopropaneacetic acid. us 5523477 .

Route 2
compound (xix) is condensed with 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (xx) by means of cs2co3 in acetonitrile yielding the expected condensation product (xxi). finally, this compound is treated successively with pyridine and p-toluenesulfonic acid to eliminate the tetrahydropyranyl protecting group, and with naoh to hydrolyzed the acetate ester group of (xxi).4) the 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (xx) has been obtained as follows: the reduction of diethyl cyclopropane-1,1-dicarboxylate (xxii) with lialh4 in thf gives 1,1-cyclopropanedimethanol (xi), which is monobenzoylated with benzoyl chloride (xxiii) and pyridine in dichloromethane yielding benzoic acid 1-(hydroxymethyl)cyclopropylmethyl ester (xxiv). the mesylation of (xxiv) as usual affords the mesylate (xxv), which is treated with nacn in dmso to give 2-[1-(benzoyloxymethyl)cyclopropyl]acetonitrile (xxvi). the hydrolysis of (xxvi) with koh in refluxing ethanol, followed by methylation with diazomethane, yields methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (xxvii), which is mesylated as usual affording the mesylate (xxiii). finally, this compound is treated with cesium thiocetate in dichloromethane to give (xx).
List of intermediates No.
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (xxiii)
1,4-diethyl-n-isopropyl-1,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carbothioamide (xi)
tert-butyl 3-[(amino[[(benzyloxy)carbonyl]imino]methyl)amino]propylcarbamate (xviii)
4-methylmorpholine (xix)
benzyl (e)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate (xx)
tert-butyl (1r)-2-[(2s)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate (xxi)
tert-butyl (1r)-2-[(2s)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-hydroxy-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate (xxii)
tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate (xxiv)
3-methyl-4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-4-oxobutyric acid (xxv)
1-nitroso-2-naphthol (xxvi)
n-isopropyl-1-nitroso-2-naphthalenamine (xxvii)
Reference 1:
    graul, a.; martín, l.; casta?er, j.; montelukast sodium. drugs fut 1997, 22, 10, 1103.
Reference 2:
    labelle, m.; belley, m.; gareau, y.; et al.; discovery of mk-0476, a potent and orally active leukotriene d4 receptor antagonist devoid of peroxisomal enzyme induction. bioorg med chem lett 1995, 5, 3, 283-8.
Reference 3:
    belley, m.l.; leger, s.; roy, p.; xiang, y.b.; labelle, m.; guay, d. (merck frosst canada inc.); unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. ep 0480717; jp 1993105665 .
Reference 4:
    bhupathy, m.; mcnamara, j.m.; sidler, d.r.; volante, r.p.; bergan, j.j. (merck & co., inc.); process for the preparation of leukotriene antagonists. wo 9518107 .

Route 3
the selective silylation of the diol (vii) with tert-butyldimethylsilyl chloride (tbdms-cl)/dimethylaminopyridine (dmap) and imidazole in dichloromethane gives the monosilylated compound (xvi), which is treated with dihydropyran and triphenylphosphonium bromide to yield (xvii) with the tertiary alcohol protected as its tetrahydropyranyl ether. the desilylation of (xvii) with tetrabutylammonium fluoride (tbaf) in thf affords the secondary alcohol (xviii), which is mesylated as usual giving the mesylate (xix).
List of intermediates No.
benzyl 3,4-diethyl-3,4,6,7-tetrahydro-5h-imidazo[4,5-c]pyridine-5-carboxylate (vii)
tert-butyl propiolate (xvi)
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (xvii)
tert-butyl 3-[(amino[[(benzyloxy)carbonyl]imino]methyl)amino]propylcarbamate (xviii)
4-methylmorpholine (xix)
Reference 1:
    labelle, m.; belley, m.; gareau, y.; et al.; discovery of mk-0476, a potent and orally active leukotriene d4 receptor antagonist devoid of peroxisomal enzyme induction. bioorg med chem lett 1995, 5, 3, 283-8.
Reference 2:
    graul, a.; martín, l.; casta?er, j.; montelukast sodium. drugs fut 1997, 22, 10, 1103.
Reference 3:
    bhupathy, m.; mcnamara, j.m.; sidler, d.r.; volante, r.p.; bergan, j.j. (merck & co., inc.); process for the preparation of leukotriene antagonists. wo 9518107 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名孟鲁司特钠;英文名Montelukast sodium;L-706631;MK-0476;MK-476;Kipres;Singulair;CAS[151767-02-1]

 
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