tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】35221

【品名】tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate

【CA登记号】

【分子式】C₁₁H₂₁NO₃

【分子量】215.29268

【元素组成】C 61.37% H 9.83% N 6.51% O 22.29%

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：(IV)

Racemic ethyl 3-piperidinecarboxylate (Ia, Ib) was resolved with D-(-)-tartaric acid in EtOH to afford the (S)-piperidine tartrate salt (II). After protection of (II) as the N-Boc derivative (III) by treatment with di-tert-butyl dicarbonate and NaOH, reduction of the carboxylate group of (III) by means of LiBH4 provided alcohol (IV). Subsequent coupling of (IV) with 4-bromo-2,6-dimethylphenol (V) under Mitsunobu conditions provided ether (VI). The N-Boc protecting group of (VI) was then cleaved employing trifluoroacetic acid to give piperidine (VII). Finally, Eschweiler-Clarke methylation using formaldehyde and formic acid furnished the corresponding N-methyl piperidine, which was isolated after conversion to the hydrochloride salt.

参考文献中间体

合成目标

【1】 Kojima, N.; Nishino, C. (Shiseido Co. Ltd.); Benzamide deriv., anti-ulcer drug, and antibacterial drug. EP 0869124; JP 1998279570; US 5891890 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ib)	12453	ethyl (3R)hexahydro-3-pyridinecarboxylate		C₈H₁₅NO₂	详情	详情
(Ia),(II)	35224	ethyl (3S)-3-piperidinecarboxylate		C₈H₁₅NO₂	详情	详情
(III)	35220	1-(tert-butyl) 3-ethyl (3S)-1,3-piperidinedicarboxylate		C₁₃H₂₃NO₄	详情	详情
(IV)	35221	tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(V)	31142	4-bromo-2,6-dimethylphenol	2374-05-2	C₈H₉BrO	详情	详情
(VI)	35222	tert-butyl (3S)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-piperidinecarboxylate		C₁₉H₂₈BrNO₃	详情	详情
(VII)	35223	(3S)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]piperidine; 4-bromo-2,6-dimethylphenyl (3S)piperidinylmethyl ether		C₁₄H₂₀BrNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII), which is further protected as the N-Boc derivative (IX) by using Boc2O. Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X). Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles, which are chromatographically separated after derivatization with trityl chloride. The desired isomer (XII) is then deprotected under acidic conditions, giving piperidine (XIII). Finally, EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.

参考文献中间体

合成目标

【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 .
【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	51595	(2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₂₆H₃₀ClN₃O₄	详情	详情
(VII)	12453	ethyl (3R)hexahydro-3-pyridinecarboxylate		C₈H₁₅NO₂	详情	详情
(VIII)	57427	(1S)-2,2-dimethylcyclopropanecarbonyl chloride		C₆H₉ClO	详情	详情
(IX)	35221	tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(X)	57428	ethyl 3-ethyl-2-pentenoate		C₉H₁₆O₂	详情	详情
(XI)	51586	4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole	822-36-6	C₄H₆N₂	详情	详情
(XII)	58429	tert-butyl (3S)-3-[(4-methyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxylate		C₁₅H₂₅N₃O₂	详情	详情
(XIII)	58430	(3R)-3-[(4-methyl-1H-imidazol-1-yl)methyl]piperidine		C₁₀H₁₇N₃	详情	详情

Extended Information