2,2,6,6-tetramethyl-4-piperidinamine -Drug Synthesis Database

【结构式】

【分子编号】25596

【品名】2,2,6,6-tetramethyl-4-piperidinamine

【CA登记号】36768-62-4

【分子式】C₉H₂₀N₂

【分子量】156.27128

【元素组成】C 69.17% H 12.9% N 17.93%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XI)

In the original procedure, pyruvic aldehyde dimethyl acetal (VI) was condensed with N,N-dimethylformamide dimethyl acetal to give enaminoketone (VII). Subsequent reaction of (VII) with guanidine (VIII) provided 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (IX), which was hydrolyzed to the corresponding aldehyde (X) with 3 N HCl at 48 C. This was condensed with 4-amino-2,2,6,6-tetramethylpiperidine (XI) to produce imine (XII). Finally, reaction between imine (XII) and tosyl isonitrile (V) in the presence of K2CO3 generated the target imidazole.

参考文献中间体

合成目标

【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 .
【2】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 .
【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情
(VI)	25433	1,1-dimethoxyacetone	6342-56-9	C₅H₁₀O₃	详情	详情
(VII)	25434	(E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one		C₈H₁₅NO₃	详情	详情
(VIII)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(IX)	25435	4-(dimethoxymethyl)-2-pyrimidinylamine		C₇H₁₁N₃O₂	详情	详情
(X)	25436	2-amino-4-pyrimidinecarbaldehyde		C₅H₅N₃O	详情	详情
(XI)	25596	2,2,6,6-tetramethyl-4-piperidinamine	36768-62-4	C₉H₂₀N₂	详情	详情
(XII)	25597	4-[[(2,2,6,6-tetramethyl-4-piperidinyl)imino]methyl]-2-pyrimidinamine		C₁₄H₂₃N₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

A new procedure, which avoided the unstable pyrimidine aldehye (X), started by condensing pyruvic aldehyde (XIII) with aminopiperidine (XI). The resulting imine (XIV) was reacted with tosyl isonitrile (V) to form the acetyl imidazole (XV). Subsequent treatment of (XV) with N,N-dimethylformamide dimethyl acetal gave enaminoketone (XVI), which was then condensed with guanidine (VIII) to produce the required pyrimidine ring.

参考文献中间体

合成目标

【1】 Sisko, J.; A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole: A potent inhibitor of P38 MAP kinase. J Org Chem 1998, 63, 13, 4529.
【2】 Sisko, J. (SmithKline Beecham plc); Novel synthesis. US 5917043; WO 9723479 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情
(VIII)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(XI)	25596	2,2,6,6-tetramethyl-4-piperidinamine	36768-62-4	C₉H₂₀N₂	详情	详情
(XIII)	25598	2-oxopropanal	78-98-8	C₃H₄O₂	详情	详情
(XIV)	25599	1-[(2,2,6,6-tetramethyl-4-piperidinyl)imino]acetone		C₁₂H₂₂N₂O	详情	详情
(XV)	25600	1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-1-ethanone		C₂₀H₂₆FN₃O	详情	详情
(XVI)	25601	(E)-3-(dimethylamino)-1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-2-propen-1-one		C₂₃H₃₁FN₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Hydrogenation of 1-anilino-2-nitrobenzene derivative (I) over Pd/C affords the corresponding diphenylamine (II), which is oxidatively condensed by means of FeCl3 and HCl or AcOH in EtOH to form the iminophenazine derivative (III). Finally, the target compound can be obtained by reaction of (III) with substituted amine (IV) in refluxing dioxane.

参考文献中间体

合成目标

【1】 Medlen, C.E.; Anderson, R.; Huygens, F. (University of Pretoria); Use of riminophenazines as antimicrobial and antimalarial agents. WO 9745120 .
【2】 Anderson, R.; Medlen, C.E.; O'Sullivan, J.F. (Adcock Ingram Ltd.; University of Pretoria); Use of riminophenzine for treating MDR resistance. EP 0676201; US 5763443 .

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)	48838	2,4-dichloro-N-(2-nitrophenyl)aniline; N-(2,4-dichlorophenyl)-N-(2-nitrophenyl)amine		C₁₂H₈Cl₂N₂O₂	详情	详情
(II)	48839	N-(2-aminophenyl)-N-(2,4-dichlorophenyl)amine; N(1)-(2,4-dichlorophenyl)-1,2-benzenediamine		C₁₂H₁₀Cl₂N₂	详情	详情
(III)	48840	N,5-bis(2,4-dichlorophenyl)-3-imino-3,5,10,10a-tetrahydro-2-phenazinamine; N-(2,4-dichlorophenyl)-N-[5-(2,4-dichlorophenyl)-3-imino-3,5,10,10a-tetrahydro-2-phenazinyl]amine		C₂₄H₁₆Cl₄N₄	详情	详情
(IV)	25596	2,2,6,6-tetramethyl-4-piperidinamine	36768-62-4	C₉H₂₀N₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

N-Boc-O-(2,6-Dichlorobenzyl)-L-tyrosine (I) is coupled to 4-amino-2,2,6,6-tetramethylpiperidine (II) using BOP in DMF to provide amide (III). The N-Boc protecting group of (III) is then removed by trifluoroacetic acid, yielding amine (IV). This is finally acylated with pentafluorocinnamic acid (V) in the presence of BOP/i-Pr2NEt to furnish the title compound (1,2).

参考文献中间体

合成目标

【1】 Stewart, J.M.; et al.; Bradykinin-related compounds as new drugs for cancer and inflammation. Can J Physiol Pharmacol 2002, 80, 4, 275.
【2】 Stewart, J.M.; Gera, L.; Chan, D.C.F.; York, E.; Bunn, P.; Anti-cancer cpds. and methods related thereto. WO 0011022 .

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)	64526	(2S)-2-[(tert-butoxycarbonyl)amino]-3-{4-[(2,6-dichlorobenzyl)oxy]phenyl}propanoic acid		C₂₁H₂₃Cl₂NO₅	详情	详情
(II)	25596	2,2,6,6-tetramethyl-4-piperidinamine	36768-62-4	C₉H₂₀N₂	详情	详情
(III)	64527	tert-butyl (1S)-1-{4-[(2,6-dichlorobenzyl)oxy]benzyl}-2-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]ethylcarbamate		C₃₀H₄₁Cl₂N₃O₄	详情	详情
(IV)	64528	(2S)-2-amino-3-{4-[(2,6-dichlorobenzyl)oxy]phenyl}-N-(2,2,6,6-tetramethyl-4-piperidinyl)propanamide		C₂₅H₃₃Cl₂N₃O₂	详情	详情
(V)	64529	(E)-3-(2,3,4,5,6-pentafluorophenyl)-2-propenoic acid		C₉H₃F₅O₂	详情	详情

Extended Information