(rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】56455

【品名】(rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate

【CA登记号】

【分子式】C₁₄H₁₈FNO₂

【分子量】251.3008632

【元素组成】C 66.91% H 7.22% F 7.56% N 5.57% O 12.73%

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：(III)

The hydrogenation of 4-(4-fluorophenyl)-3-(ethoxycarbonyl)-1-methylpyridinium bromide (I) with H2 over PtO2 in toluene/ethanol gives racemic (cis)-4-(4-fluorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester (rac)-(II), which is isomerized with NaOMe in refluxing toluene to yield the trans-isomer (rac)-(III). The reduction of (rac)-(III) with LiAlH4 in toluene/THF affords the hydroxymethyl compound (rac)-(IV), which is submitted to optical resolution with L-(-)-di-p-toluoyltartaric acid to provide the chiral (3S,4R)-(V). Alternatively, the optical resolution of (cis)-(rac)-(II) with D-(+)-di-p-toluoyltartaric acid gives the ester (cis)-(3R,4R)-(VI), which is isomerized with NaOMe in refluxing toluene to yield ester (trans)-(3S,4R)-(VII). Finally, this compound is reduced with LiAlH4 in toluene/THF to afford the previously reported intermediate (3S,4R)-(V). The reaction of (3S,4R)-(V) with benzenesulfonyl chloride (VIII) and dimethylethylamine in toluene gives the corresponding sulfonate (3S,4R)-(IX), which is condensed with 5-hydroxy-1,3-benzodioxole (X) by means of NaOMe in hot DMF to yield the adduct (3S,4R)-(XI). Finally, this compound is demethylated by reaction with phenyl chloroformate (XII) to afford the cyclic carbamate (3S,4R)-(XIII), which is hydrolyzed with KOH in refluxing toluene.

参考文献中间体

合成目标

【1】 Borrett, G.T.; Ward, N.; Crowe, D.; Wells, A.S. (GlaxoSmithKline plc); Process for the preparation of paroxetine. WO 0129031 .

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)	56453	4-(4-fluorophenyl)-3-(methoxycarbonyl)-1-methylpyridinium bromide		C₁₄H₁₃BrFNO₂	详情	详情
(II)	56454	(rac)-methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate		C₁₄H₁₈FNO₂	详情	详情
(III)	56455	(rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate		C₁₄H₁₈FNO₂	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)	56458	[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol		C₁₃H₁₈FNO	详情	详情
(VI)	56456	methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate		C₁₄H₁₈FNO₂	详情	详情
(VII)	56457	methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate		C₁₄H₁₈FNO₂	详情	详情
(VIII)	14713	benzenesulfonyl chloride	98-09-9	C₆H₅ClO₂S	详情	详情
(IX)	10986	[(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl benzenesulfonate		C₁₉H₂₂FNO₃S	详情	详情
(X)	10985	1,3-Benzodioxol-5-ol; Sesamol	533-31-3	C₇H₆O₃	详情	详情
(XI)	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
(XII)	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(XIII)	43489	phenyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate		C₂₆H₂₄FNO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：rac-(IV)

The condensation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (I) with 4-fluorophenylmagnesium bromide (II) in toluene, ether/toluene or ether/dichloromethane gives 1-methyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid methyl ester (III) / (IV), which are an intermediates in the synthesis of paroxetine.(Scheme 10786008a).

参考文献中间体

合成目标

【1】 Ward, N. (GlaxoSmithKline plc); Process for making paroxetine. US 6172233 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
rac-(III)	56454	(rac)-methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate		C₁₄H₁₈FNO₂	详情	详情
rac-(IV)	56455	(rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate		C₁₄H₁₈FNO₂	详情	详情
(I)	38648	methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate		C₈H₁₃NO₂	详情	详情
(II)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情

Extended Information