ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】13489

【品名】ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate

【CA登记号】

【分子式】C₁₃H₂₀BrNO₃

【分子量】318.21074

【元素组成】C 49.07% H 6.34% Br 25.11% N 4.4% O 15.08%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IX)

The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II), which is submitted to optical resolution with (-)-dibenzoyltartaric acid, yielding the 3(S)-enantiomer (III). The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV), which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V). The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) , which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX). Finally, the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene. Alternatively, the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI), which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group. Alternatively, the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII), which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.

参考文献中间体

合成目标

【1】 Lynch, I.R.; Richardson, J.E.; Buxton, P.C.; Curzons, A.D.; Wood-Kaezmar, M.W.; Barnes, R.D. (Ferrosan A/S; SmithKline Beecham plc); Piperidine derivs., their preparation and their use as medicaments. EP 0223403; JP 1987129280; US 4721723 .
【2】 Sato, F.; Amano, T.; Kameo, K.; Tanami, T.; Muto, K.; Ono, N.; Goto, J. (Taisho Pharmaceutical Co., Ltd.); Prostaglandin derivs.. JP 1997286775 .
【3】 Lucas, E. (SmithKline Beecham plc); Process for the preparation of paroxetine and structurally related cpds.. WO 0078753 .
【4】 Christensen, J.A.; Squires, R.F. (Ferrosan A/S); 4-Phenylpiperidine compounds. DE 2404113; ES 422734; FR 2215233; GB 1422263; JP 58174363; US 3912743 .
【5】 Lemmens, J.M.; Peters, T.H.A.; Picha, F. (Synthon BV); Process to produce paroxetine. WO 0266466 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10989	4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine		C₁₂H₁₄FN	详情	详情
(II)	10990	[4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol		C₁₃H₁₆FNO	详情	详情
(III)	43486	[(3S)-4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol		C₁₃H₁₆FNO	详情	详情
(IV)	43487	[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol	105812-81-5	C₁₃H₁₈FNO	详情	详情
(V)	43488	(3S,4R)-3-(chloromethyl)-4-(4-fluorophenyl)-1-methylpiperidine		C₁₃H₁₇ClFN	详情	详情
(VI)	10985	1,3-Benzodioxol-5-ol; Sesamol	533-31-3	C₇H₆O₃	详情	详情
(VII)	10987	(3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether		C₂₀H₂₂FNO₃	详情	详情
(VIII)	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(IX)	13489	ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate		C₁₃H₂₀BrNO₃	详情	详情
(X)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(XI)	43490	ethyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate		C₂₂H₂₄FNO₅	详情	详情
(XII)	28068	1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate	5130-24-5	C₃H₃ClO₂	详情	详情
(XIII)	43491	vinyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate		C₂₂H₂₂FNO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

YM-796 can be obtained by two different ways: 1) The Wittig condensation of 1-methylpiperidin-4-one (I) with 2-(diethoxyphosphoryl)acetic acid ethyl ester (II) by means of NaH in dimethoxyethane gives 2-(1-methylpiperidin-4-ylidene) acetic acid ethyl ester (III), which is cyclized with ethyl lactate (IV) by means of NaH in DMSO yielding 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylic acid ethyl ester (V). The decarboxylation of (V) with refluxing aqueous 1N HCl affords 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (VI), which is submitted to a new Wittig condensation with methyltriphenylphosphonium iodide (or bromide) (VII) by means of NaH in DMSO to give racemic 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (VIII). Finally, this compound is submitted to optical resolution with L-tartaric acid or with di-p-toluoyl-D-tartaric acid. 2) The Wittig condensation of 4-oxopiperidine-1-carboxylic acid ethyl ester (IX) with phosphorane (VII) as before gives the corresponding methylene derivative (X), which is submitted to alkoxybromination with N-bromosuccinimide (NBS) and (S)-3-butyn-2-ol (XI) yielding (S)-4-(bromomethyl)-4-(1-methyl-2-propynyloxy)piperidine-1-carboxylic acid ethyl ester (XII). The radical cyclization of (XII) with NaBH4 catalyzed by bis(dimethylglyoximato)(pyridine)cobalt(III) chloride [chlorocobaloxime(III)] affords (S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (XIII), which is finally reduced with sodium bis(2-methoxyethoxy)aluminum hydride (vitride) in toluene and treated with fumaric acid to obtain the sesquifumarate salt.

参考文献中间体

合成目标

【1】 Ngo, J.; Martel, A.M.; Castaner, J.; YM-796. Drugs Fut 1997, 22, 2, 144.
【2】 Tsukamoto, S.; Kondo, Y.; Igarashi, S.; An efficient synthesis of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane by cobaloxime(I)-mediated radical cyclization. Heterocycles 1995, 41, 8, 1771-1778.
【3】 Tsukamoto, S.; Fujii, M.; Yasunaga, T.; Matsuda, K.; Wanibuchi, F.; Hidaka, K.; Furuya, T.; Tamura, T.; Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists. Chem Pharm Bull 1995, 43, 5, 842-852.
【4】 Tsukamoto, S.-I.; Nagaoka, H.; Usuda, S.; Harada, M.; Tamura, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic spiro cpds. and their preparation. AU 8823449; EP 0311313; JP 1990036183; US 4996210 .
【5】 Tsukamoto, S.; Kohinata, T.; Fujii, M.; Tomisawa, S. (Yamanouchi Pharmaceutical Co., Ltd.); (-)-(S)-2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate. EP 0590150; JP 1993508699; WO 9220683 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10919	1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one	1445-73-4	C₆H₁₁NO	详情	详情
(II)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(III)	13480	ethyl 2-(1-methyl-4-piperidinylidene)acetate		C₁₀H₁₇NO₂	详情	详情
(IV)	13481	ethyl lactate; ethyl 2-hydroxypropanoate	97-64-3	C₅H₁₀O₃	详情	详情
(V)	13482	ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylate		C₁₃H₂₁NO₄	详情	详情
(VI)	13483	2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one		C₁₀H₁₇NO₂	详情	详情
(VII)	13484	Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide	2065-66-9	C₁₉H₁₈IP	详情	详情
(VIII)	13485	2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane		C₁₁H₁₉NO	详情	详情
(IX)	13486	Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone	29976-53-2	C₈H₁₃NO₃	详情	详情
(X)	13487	ethyl 4-methylene-1-piperidinecarboxylate		C₉H₁₅NO₂	详情	详情
(XI)	13488	(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol	2914-69-4	C₄H₆O	详情	详情
(XII)	13489	ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate		C₁₃H₂₀BrNO₃	详情	详情
(XIII)	13490	ethyl (2S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylate		C₁₃H₂₁NO₃	详情	详情

Extended Information