tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】38231

【品名】tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate

【CA登记号】

【分子式】C₂₈H₃₈N₂O₃

【分子量】450.6214

【元素组成】C 74.63% H 8.5% N 6.22% O 10.65%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

The reductocondensation of 4-benzyloxyaniline (I) with 1-(tert-butoxycarbonyl)piperidin-4-one (II) by means of NaBH(OAc)2 in dichloromethane gives N-(4-benzyloxyphenyl)-N-[1-(tert-butoxycarbonyl)piperidin-4-yl]amine (III), which is alkylated with 3-methyl-2-butenyl bromide (IV) by means of DIEA in THF yielding the tertiary amine (V). The deprotection of (V) with TFA in dichloromethane affords the piperidine (VI), which is condensed with N-(tert-butoxycarbonyl)-L-leucine (VII) by means of HBTU and DIEA in DMF to provide the intermediate (VIII). Finally, (VIII) is deprotected with TFA in dichloromethane.

参考文献中间体

合成目标

【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. J Med Chem 1999, 42, 20, 4239.
【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 .

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)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(II)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(III)	38230	tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate		C₂₃H₃₀N₂O₃	详情	详情
(IV)	12989	4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene	870-63-3	C₅H₉Br	详情	详情
(V)	38231	tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate		C₂₈H₃₈N₂O₃	详情	详情
(VI)	38232	N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine		C₂₃H₃₀N₂O	详情	详情
(VII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(VIII)	38233	tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]carbonyl)-3-methylbutylcarbamate		C₃₄H₄₉N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).

参考文献中间体

合成目标

【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259.
【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 .

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)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(II)	40395	tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(III)	27058	tert-butyl (1S)-1-formyl-3-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(IV)	38232	N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine		C₂₃H₃₀N₂O	详情	详情
(V)	40394	tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate		C₃₄H₅₁N₃O₃	详情	详情
(VI)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(VII)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(VIII)	38230	tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate		C₂₃H₃₀N₂O₃	详情	详情
(IX)	12989	4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene	870-63-3	C₅H₉Br	详情	详情
(X)	38231	tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate		C₂₈H₃₈N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Reductive condensation of N-Boc-4-piperidone (I) with 4-(benzyloxy)aniline (II) in the presence of NaBH(OAc)3 produced the secondary amine (III), which was further alkylated with 4-bromo-2-methyl-2-butene (IV) to afford the tertiary amine (V). Subsequent acid cleavage of the Boc protecting group of (V) furnished the intermediate piperidine (VI).

参考文献中间体

合成目标

【1】 Ryder, T.R.; Rafferty, M.F.; Hu, L.-Y. (Pfizer Inc.); Heterocyclic substd. aniline calcium channel blockers. US 6251919; WO 9943658 .

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)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(II)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(III)	38230	tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate		C₂₃H₃₀N₂O₃	详情	详情
(IV)	12989	4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene	870-63-3	C₅H₉Br	详情	详情
(V)	38231	tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate		C₂₈H₃₈N₂O₃	详情	详情
(VI)	38232	N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine		C₂₃H₃₀N₂O	详情	详情

Extended Information