(2,3-dimethoxyphenyl)(4-piperidinyl)methanone -Drug Synthesis Database

【结构式】

【分子编号】17408

【品名】(2,3-dimethoxyphenyl)(4-piperidinyl)methanone

【CA登记号】

【分子式】C₁₄H₁₉NO₃

【分子量】249.3098

【元素组成】C 67.45% H 7.68% N 5.62% O 19.25%

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：(XVI)

2) Racemic MDL-100907 (VII) can also be obtained by reaction of piperidine-4-carboxylic acid (X) with di-tert-butyl dicarbonate (XI) by means of NaOH in tert-butanol/ water, giving piperidine-1,4-dicarboxylic acid 1-mono-tert-butyl ester (XII), which is treated with N,O-dimethylhydroxylamine (XIII) and carbonyldiimidazole (CDI) in dichloromethane to afford the methoxy(methyl)amide (XIV). The condensation of (XIV) with veratrole (VI) by means of BuLi in THF gives 4-(2,3-dimethoxybenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (XV), which is decarboxylated by means of trifluoroacetic acid, yielding ketone (XVI). The condensation of (XVI) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in DMF affords 1-(2,3-dimethoxyphenyl)-1-[1-[2-(4-fluorophenyl)-ethyl]piperidin-4-yl]methanone (XVII). Finally, this compound is reduced with NaBH4 in methanol

参考文献中间体

合成目标

【1】 Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; MDL-100907. Drugs Fut 1998, 23, 9, 955.
【2】 Carr, A.A.; Kane, J.M.; Hay, D.A. (Merrell Pharmaceuticals, Inc.); (+)-*-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. EP 0531410; JP 1993507482; US 5134149; WO 9118602 .

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)	17394	1-(2-bromoethyl)-4-fluorobenzene		C₈H₈BrF	详情	详情
(VI)	17398	2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene	91-16-7	C₈H₁₀O₂	详情	详情
(VII)	17399	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol		C₂₂H₂₈FNO₃	详情	详情
(X)	17402	4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid	498-94-2	C₆H₁₁NO₂	详情	详情
(XI)	13214	Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate	24424-99-5	C₁₀H₁₈O₅	详情	详情
(XII)	17404	1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid	84358-13-4	C₁₁H₁₉NO₄	详情	详情
(XIII)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XIV)	17406	tert-butyl 4-[[methoxy(methyl)amino]carbonyl]tetrahydro-1(2H)-pyridinecarboxylate		C₁₃H₂₄N₂O₄	详情	详情
(XV)	17407	tert-butyl 4-(2,3-dimethoxybenzoyl)tetrahydro-1(2H)-pyridinecarboxylate		C₁₉H₂₇NO₅	详情	详情
(XVI)	17408	(2,3-dimethoxyphenyl)(4-piperidinyl)methanone		C₁₄H₁₉NO₃	详情	详情
(XVII)	17409	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone		C₂₂H₂₆FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The condensation of 1,2-dimethoxybenzene (I) with 1-(tert-butoxcarbonyl)-N-methoxy-N-methylpiperidine-4-carboxamide (II) by means of BuLi in THF gives the protected benzoylpiperidine (III), which is deprotected by means of TFA to yield the deprotected piperidine (IV). The reduction of the carbonyl group of (IV) by means of NaBH4 in methanol affords the racemic carbinol (V), which is submitted to optical resolution with (+)-di-O,O'-p-toluyltartaric acid, providing the (+)-(R)-carbinol (VI). Finally, this compound is condensed with 2-(4-fluorophenyl)ethyl bromide (VIII) by means of NaHCO3 in hot DMF.

参考文献中间体

合成目标

【1】 Ullrich, T.; Rice, K.C.; A practical synthesis of the serotonin 5-HT2A receptor antagonist MDL-100907, its enantiomer and their 3-phenolic derivatives as precursors for [11C]labeled PET ligands. Bioorg Med Chem 2000, 8, 10, 2427.

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)	17398	2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene	91-16-7	C₈H₁₀O₂	详情	详情
(II)	17406	tert-butyl 4-[[methoxy(methyl)amino]carbonyl]tetrahydro-1(2H)-pyridinecarboxylate		C₁₃H₂₄N₂O₄	详情	详情
(III)	17407	tert-butyl 4-(2,3-dimethoxybenzoyl)tetrahydro-1(2H)-pyridinecarboxylate		C₁₉H₂₇NO₅	详情	详情
(IV)	17408	(2,3-dimethoxyphenyl)(4-piperidinyl)methanone		C₁₄H₁₉NO₃	详情	详情
(V)	52803	(2,3-dimethoxyphenyl)(4-piperidinyl)methanol		C₁₄H₂₁NO₃	详情	详情
(VI)	52804	(R)-(2,3-dimethoxyphenyl)(4-piperidinyl)methanol		C₁₄H₂₁NO₃	详情	详情
(VII)	17394	1-(2-bromoethyl)-4-fluorobenzene		C₈H₈BrF	详情	详情

Extended Information