Montelukast sodium, L-706631, MK-0476, MK-476, Kipres, Singulair, -Drug Synthesis Database

【结构式】

【药物名称】Montelukast sodium, L-706631, MK-0476, MK-476, Kipres, Singulair

【化学名称】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

【CA登记号】151767-02-1, 142522-81-4 ([R, (E/Z)]-isomer), 158966-92-8 (free acid), 142522-28-9 (free acid, [R,(E/Z)-isomer])

【分子式】C₃₅H₃₅ClNNaO₃S

【分子量】608.1809

【开发单位】Banyu (Originator), Merck & Co. (Originator), Merck Frosst (Originator), Merck Sharp & Dohme (Originator), Kyorin (Codevelopment)

【药理作用】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

合成路线1 合成路线2 合成路线3

合成路线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).

参考文献中间体

【1】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103.
【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 .
【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 .
【4】 King, S.; Pipik, B.; Conlon, D.A. (Merck & Co., Inc.); Process for the preparation of 1-(thiomethyl)-cyclopropaneacetic acid. US 5523477 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	27347	N,N-dicyclohexylamine	101-83-7	C₁₂H₂₃N	详情	详情
(I)	16523	3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde		C₁₈H₁₂ClNO	详情	详情
(II)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(III)	16525	1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-2-propen-1-ol		C₂₀H₁₆ClNO	详情	详情
(IV)	15938	methyl 2-bromobenzoate	610-94-6	C₈H₇BrO₂	详情	详情
(V)	16527	methyl 2-(3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-oxopropyl)benzoate		C₂₈H₂₂ClNO₃	详情	详情
(VI)	16528	methyl 2-((3S)-3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxypropyl)benzoate		C₂₈H₂₄ClNO₃	详情	详情
(VII)	16529	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-1-propanol		C₂₉H₂₈ClNO₂	详情	详情
(VIII)	16530	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl methanesulfonate		C₃₀H₃₀ClNO₄S	详情	详情
(IX)	16531	2-[1-(sulfanylmethyl)cyclopropyl]acetic acid; 1-(mercaptomethyl)cyclopropane acetic acid		C₆H₁₀O₂S	详情	详情
(X)	16532	2-[1-[1(R)-[3-[2(E)-(7-Chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]acetic acid dicyclohexylamine salt		C₄₇H₅₉ClN₂O₃S	详情	详情
(XI)	16533	[1-(hydroxymethyl)cyclopropyl]methanol		C₅H₁₀O₂	详情	详情
(XII)	16534	5,7-dioxa-6lambda(4)-thiaspiro[2.5]octan-6-one		C₅H₈O₃S	详情	详情
(XIII)	16535	2-[1-(hydroxymethyl)cyclopropyl]acetonitrile		C₆H₉NO	详情	详情
(XIV)	16536	[1-(cyanomethyl)cyclopropyl]methyl methanesulfonate		C₇H₁₁NO₃S	详情	详情
(XV)	16537	S-[[1-(cyanomethyl)cyclopropyl]methyl] ethanethioate		C₈H₁₁NOS	详情	详情

合成路线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).

参考文献中间体

【1】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103.
【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.
【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 .
【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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	16533	[1-(hydroxymethyl)cyclopropyl]methanol		C₅H₁₀O₂	详情	详情
(XVIII)	16540	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-1-propanol		C₃₄H₃₆ClNO₃	详情	详情
(XIX)	16541	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl methanesulfonate		C₃₅H₃₈ClNO₅S	详情	详情
(XX)	16542	methyl 2-[1-[(acetylsulfanyl)methyl]cyclopropyl]acetate		C₉H₁₄O₃S	详情	详情
(XXI)	16543	methyl 2-(1-[[((1R)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl)sulfanyl]methyl]cyclopropyl)acetate		C₄₁H₄₆ClNO₄S	详情	详情
(XXII)	16544	diethyl 1,1-cyclopropanedicarboxylate	1559-02-0	C₉H₁₄O₄	详情	详情
(XXIII)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XXIV)	16546	[1-(hydroxymethyl)cyclopropyl]methyl benzoate		C₁₂H₁₄O₃	详情	详情
(XXV)	16547	(1-[[(methylsulfonyl)oxy]methyl]cyclopropyl)methyl benzoate		C₁₃H₁₆O₅S	详情	详情
(XXVI)	16548	[1-(cyanomethyl)cyclopropyl]methyl benzoate		C₁₃H₁₃NO₂	详情	详情
(XXVII)	16549	methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate		C₇H₁₂O₃	详情	详情

合成路线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).

参考文献中间体

【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.
【2】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103.
【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 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	16529	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-1-propanol	C₂₉H₂₈ClNO₂	详情	详情
(XVI)	16538	2-[2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]propyl)phenyl]-2-propanol	C₃₅H₄₂ClNO₂Si	详情	详情
(XVII)	16539	tert-butyl(dimethyl)silyl (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl ether; 2-[(E)-2-[3-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl)phenyl]ethenyl]-7-chloroquinoline	C₄₀H₅₀ClNO₃Si	详情	详情
(XVIII)	16540	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]-1-propanol	C₃₄H₃₆ClNO₃	详情	详情
(XIX)	16541	(1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl]propyl methanesulfonate	C₃₅H₃₈ClNO₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)