tert-butyl (2R)-2-(hydroxymethyl)-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】26747

【品名】tert-butyl (2R)-2-(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：(XIX)

The reduction of piperidine-2(R)-carboxylic acid (XVII) with BH3/Me2S and BF3/Et2O in THF gives the carbinol (XVIII), which is treated with Boc2O and NaOH in THF yielding the carbamate (XIX). The silylation of the carbinol group of (XIX) with TBDMS-Cl and imidazole in DMF affords the silyl ether (XX), which is methylated with BuLi and methyl iodide providing the 2-methyl derivative (XXI). The desilylation of (XXI) with TBAF in THF affords the free carbinol (XXII), which is oxidized to the corresponding aldehyde (XXIII) with RuO4NPr4. The condensation of aldehyde (XXII) with the tricyclic sulfone intermediate (XVI) by means of BuLi in DME and sodium amalgam in methanol yields the vinylpiperidine intermediate (XVII), which is oxidized at the lactol group with Jones reagent (CrO3, H2SO4) giving the tricyclic lactone (XVIII). The deprotection of the piperidine ring of (XVIII) with TFA in dichloromethane yields the intermediate (XIX), which is finally methylated with formaldehyde and sodium cyanoborohydride in acetonitrile/water.

参考文献中间体

合成目标

【1】 Wu, W.-L.; Hart, D.J.; Li, J.; Applications of Organosulfur Chemistry to Organic Synthesis: Total Synthesis of (+)-Himbeline and (-)-Himbacine. J Org Chem 1997, 62, 5023.
【2】 Hart, D.J.and Wu, W.-L.; Total syntheses of (+)-Himbacine and (-)-Himbeline. J Am Chem Soc 1995, 117, 9369.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVI)	33193	[(1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl phenyl sulfone; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfonyl)methyl]dodecahydronaphtho[2,3-c]furan	C₂₁H₃₀O₄S	详情	详情
(XVII)	26751	(2R)-2-piperidinecarboxylic acid	C₆H₁₁NO₂	详情	详情
(XVII)	33198	tert-butyl (2R,6S)-2-[(E)-2-[(1S,3S,3aR,4S,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]ethenyl]-6-methyl-1-piperidinecarboxylate	C₂₇H₄₅NO₄	详情	详情
(XVIII)	26746	(2R)-piperidinylmethanol	C₆H₁₃NO	详情	详情
(XVIII)	33199	tert-butyl (2R,6S)-2-[(E)-2-[(3S,3aR,4S,4aS,8aR,9aS)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-yl]ethenyl]-6-methyl-1-piperidinecarboxylate	C₂₆H₄₁NO₄	详情	详情
(XIX)	26747	tert-butyl (2R)-2-(hydroxymethyl)-1-piperidinecarboxylate	C₁₁H₂₁NO₃	详情	详情
(XIX)	33200	(3S,3aR,4S,4aS,8aR,9aS)-3-methyl-4-[(E)-2-[(2R,6S)-6-methylpiperidinyl]ethenyl]decahydronaphtho[2,3-c]furan-1(3H)-one	C₂₁H₃₃NO₂	详情	详情
(XX)	33194	tert-butyl (2R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-piperidinecarboxylate	C₁₇H₃₅NO₃Si	详情	详情
(XXI)	33195	tert-butyl (2R,6S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6-methyl-1-piperidinecarboxylate	C₁₈H₃₇NO₃Si	详情	详情
(XXII)	33196	tert-butyl (2R,6S)-2-(hydroxymethyl)-6-methyl-1-piperidinecarboxylate	C₁₂H₂₃NO₃	详情	详情
(XXIII)	33197	tert-butyl (2R,6S)-2-formyl-6-methyl-1-piperidinecarboxylate	C₁₂H₂₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

Vinylpiperidine (IV): The reduction of (R)-piperidine-2-carboxylic acid (XIII) with BH3-THF gives the carbinol (XIV), which is protected at the NH group with tert-butoxycarbonyl anhydride yielding the N-protected carbinol (XV). The Swern oxidation of (XV) affords the corresponding aldehyde (XVI), which is finally condensed with trimethylphenylphosphonium bromide and potassium hexamethyldisylazane (KHMDS) in THF to provide the target intermediate (IV).

参考文献中间体

合成目标

【1】 Brosius, A.D.; et al.; Total synthesis of (+)-aloperine. Use of a nitrogen-bound silicon tether in a intramolecular diels - Alder reaction. J Am Chem Soc 1999, 121, 4, 700.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	26737	tert-butyl (2R)-2-vinyl-1-piperidinecarboxylate	C₁₂H₂₁NO₂	详情	详情
(XIII)	26751	(2R)-2-piperidinecarboxylic acid	C₆H₁₁NO₂	详情	详情
(XIV)	26746	(2R)-piperidinylmethanol	C₆H₁₃NO	详情	详情
(XV)	26747	tert-butyl (2R)-2-(hydroxymethyl)-1-piperidinecarboxylate	C₁₁H₂₁NO₃	详情	详情
(XVI)	26748	tert-butyl (2R)-2-formyl-1-piperidinecarboxylate	C₁₁H₁₉NO₃	详情	详情

Extended Information