(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 -Drug Synthesis Database

【结构式】

【分子编号】16540

【品名】(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

【CA登记号】

【分子式】C₃₄H₃₆ClNO₃

【分子量】542.11748

【元素组成】C 75.33% H 6.69% Cl 6.54% N 2.58% O 8.85%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

参考文献中间体

合成目标

【1】 Magatti, C.V.; Villani, F.J.; Wong, J.; Poper, T.L.; Vashi, D.B.; N-substituted 11-(4-piperidylene)-5,6-dihydro-11H-. Arzneim-Forsch Drug Res 1986, 36, 9, 1311.
【2】 Magatti, C.V.; Vashi, D.B.; Wong, J.; Poper, T.L.; Villani, F.J.; Derivatives of 10,11-dihydro-5H-dibenzola[a,d]cycl. J Med Chem 1972, 15, 7, 750.
【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 .
【4】 Prous, J.; Castaner, J.; Loratadine. Drugs Fut 1987, 12, 6, 544.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(III)	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
(IV)	20645	chloro(1-methyl-4-piperidinyl)magnesium		C₆H₁₂ClMgN	详情	详情
(V)	23553	8-chloro-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol		C₂₀H₂₃ClN₂O	详情	详情
(VII)	20647	8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	38092-89-6	C₂₀H₂₁ClN₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

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

合成目标

【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

该中间体在本合成路线中的序号：(XVIII)

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

合成目标

【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