4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine -Drug Synthesis Database

【结构式】

【分子编号】19349

【品名】4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine

【CA登记号】7144-05-0

【分子式】C₆H₁₄N₂

【分子量】114.19064

【元素组成】C 63.11% H 12.36% N 24.53%

与该中间体有关的原料药合成路线共 6 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5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(I)

4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI) to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).

参考文献中间体

合成目标

【1】 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 .

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)	19349	4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine	7144-05-0	C₆H₁₄N₂	详情	详情
(II)	19352	4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate	144222-22-0	C₁₁H₂₂N₂O₂	详情	详情
(III)	29971	4-chloro-3-nitropyridine		C₅H₃ClN₂O₂	详情	详情
(IV)	59460	tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate		C₁₆H₂₄N₄O₄	详情	详情
(V)	59461	tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate		C₁₆H₂₆N₄O₂	详情	详情
(VI)	12831	ethyl ethanimidoate	1000-84-6	C₄H₉NO	详情	详情
(VII)	59462	tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate		C₁₈H₂₆N₄O₂	详情	详情
(VIII)	59463	2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine		C₁₃H₁₈N₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound.

参考文献中间体

合成目标

【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.

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)	19349	4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine	7144-05-0	C₆H₁₄N₂	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	19351	N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine		C₁₃H₁₈N₂	详情	详情
(IV)	19352	4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate	144222-22-0	C₁₁H₂₂N₂O₂	详情	详情
(V)	12419	4-Amino-5-chloro-2-methoxybenzoic acid	7206-70-4	C₈H₈ClNO₃	详情	详情
(VI)	19354	tert-butyl 4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]-1-piperidinecarboxylate		C₁₉H₂₈ClN₃O₄	详情	详情
(VII)	19355	4-amino-5-chloro-2-methoxy-N-(4-piperidinylmethyl)benzamide		C₁₄H₂₀ClN₃O₂	详情	详情
(VIII)	19356	benzyl 4-chlorobutyl sulfone; benzyl(4-chlorobutyl)dioxo-lambda(6)-sulfane	14633-43-3	C₁₁H₁₅ClO₂S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(A)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(I)	19349	4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine	7144-05-0	C₆H₁₄N₂	详情	详情
(II)	19351	N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine		C₁₃H₁₈N₂	详情	详情
(III)	21110	benzylhydrosulfide; phenylmethanethiol	100-53-8	C₇H₈S	详情	详情
(IV)	21111	benzyl(3-chloropropyl)dioxo-lambda(6)-sulfane; benzyl 3-chloropropyl sulfone		C₁₀H₁₃ClO₂S	详情	详情
(V)	21112	[1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methylamine; [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methanamine		C₁₆H₂₆N₂O₂S	详情	详情
(VI)	12419	4-Amino-5-chloro-2-methoxybenzoic acid	7206-70-4	C₈H₈ClNO₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI), to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).

参考文献中间体

合成目标

【1】 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 .

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)	19349	4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine	7144-05-0	C₆H₁₄N₂	详情	详情
(II)	19352	4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate	144222-22-0	C₁₁H₂₂N₂O₂	详情	详情
(III)	29971	4-chloro-3-nitropyridine		C₅H₃ClN₂O₂	详情	详情
(IV)	59460	tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate		C₁₆H₂₄N₄O₄	详情	详情
(V)	59461	tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate		C₁₆H₂₆N₄O₂	详情	详情
(VI)	12831	ethyl ethanimidoate	1000-84-6	C₄H₉NO	详情	详情
(VII)	59462	tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate		C₁₈H₂₆N₄O₂	详情	详情
(VIII)	59463	2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine		C₁₃H₁₈N₄	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

Selective protection of the secondary amino group of 4-(aminomethyl)piperidine (I) was achieved via conversion to imine (III) upon condensation with benzaldehyde (II), followed by treatment with di-tert-butyl dicarbonate to afford carbamate (IV). Subsequent acid hydrolysis of the imine function of (IV) furnished the mono-protected diamine (V). Coupling of amine (V) with 3-methoxy-4-(3-o-tolylureido)phenylacetic acid (VI) using HATU furnished amide (VII). Acidic cleavage of the N-Boc protecting group of (VII) gave piperidine (VIII). Aziridine (X) was prepared from ethyl 2,3-dibromopropionate (IX) by treatment with ammonia in acetonitrile. Condensation of (X) with N-(benzyloxycarbonyloxy)succinimide produced the benzyl carbamate (XI). Regioselective ring opening of the aziridine (XI) with piperidine (VIII) yielded adduct (XII). The ethyl ester group of (XII) was finally hydrolyzed to the target carboxylic acid under basic conditions.

参考文献中间体

合成目标

【1】 Astles, P.C.; et al.; Diamine containing VLA-4 antagonists. Bioorg Med Chem 2001, 9, 8, 2195.
【2】 McCarthy, C.; Morley, A.D.; Harris, N.V. (Rhone-Poulenc Rorer Ltd.); Substd. diamines and their use as cell adhesion inhibitors. WO 9954321 .

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)	19349	4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine	7144-05-0	C₆H₁₄N₂	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	19351	N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine		C₁₃H₁₈N₂	详情	详情
(IV)	49958	tert-butyl 4-([[(E)-benzylidene]amino]methyl)-1-piperidinecarboxylate		C₁₈H₂₆N₂O₂	详情	详情
(V)	19352	4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate	144222-22-0	C₁₁H₂₂N₂O₂	详情	详情
(VI)	39718	2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid		C₁₇H₁₈N₂O₄	详情	详情
(VII)	49959	tert-butyl 4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinecarboxylate		C₂₈H₃₈N₄O₅	详情	详情
(VIII)	49960	2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]-N-(4-piperidinylmethyl)acetamide		C₂₃H₃₀N₄O₃	详情	详情
(IX)	18341	ethyl 2,3-dibromopropanoate	3674-13-3	C₅H₈Br₂O₂	详情	详情
(X)	49961	ethyl 2-aziridinecarboxylate		C₅H₉NO₂	详情	详情
(XI)	49962	1-benzyl 2-ethyl 1,2-aziridinedicarboxylate		C₁₃H₁₅NO₄	详情	详情
(XII)	49963	ethyl 2-[[(benzyloxy)carbonyl]amino]-3-(4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinyl)propanoate		C₃₆H₄₅N₅O₇	详情	详情

合成路线6

该中间体在本合成路线中的序号：(I)

The primary amino group of 4-(aminomethyl)piperidine (I) was protected by conversion to the phthalimide (III) upon heating with phthalic anhydride (II). After coupling of piperidine (III) with 1-naphthylacetic acid (IV) to give amide (V), hydrazinolysis of the phthalimido group of (V) liberated the primary amine (VI). Alkylation of (VI) with N-(4-bromobutyl)phthalimide (VII) furnished the secondary amine (VIII), which was further protected with a tert-butoxycarbonyl group to provide (IX). The phthaloyl group of (IX) was then removed by hydrazinolysis, yielding amine (X). This was subjected to reductive alkylation with cyclohexanecarboxaldehyde (XI) in the presence of NaBH4 to afford the cyclohexylmethyl amine (XII). After purification as the di-Boc derivative, acid cleavage of the tert-butyl carbamate groups provided the title compound.

参考文献中间体

合成目标

【1】 Yoneda, Y.; et al.; Synthesis of diaminobutane derivatives as potent Ca2+-permeable AMPA receptor antagonists. Bioorg Med Chem Lett 2001, 11, 19, 2663.
【2】 Ito, M.; Yoneda, Y.; Kawagoe, K.; Yasukouchi, T.; Kito, F.; Mimura, T.; Kawajiri, S.; Sugimura, M.; Saito, M.; Tatematu, T.; Discovery of diaminobutane derivatives as Ca2+ -permeable AMPA receptor antagonists. Bioorg Med Chem 2002, 10, 5, 1347.

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)	19349	4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine	7144-05-0	C₆H₁₄N₂	详情	详情
(II)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(III)	51132	2-(4-piperidinylmethyl)-1H-isoindole-1,3(2H)-dione		C₁₄H₁₆N₂O₂	详情	详情
(IV)	51133	Planofix; alpha-Naphthylacetic acid; 1-Naphthaleneacetic acid; 1-Naphthylacetic acid; alpha-Naphthaleneacetic acid; Naphthalene-1-acetic acid	86-87-3	C₁₂H₁₀O₂	详情	详情
(V)	51134	2-([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)-1H-isoindole-1,3(2H)-dione		C₂₆H₂₄N₂O₃	详情	详情
(VI)	51135	1-[4-(aminomethyl)-1-piperidinyl]-2-(1-naphthyl)-1-ethanone		C₁₈H₂₂N₂O	详情	详情
(VII)	17163	N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione	5394-18-3	C₁₂H₁₂BrNO₂	详情	详情
(VIII)	51136	2-[4-[([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)amino]butyl]-1H-isoindole-1,3(2H)-dione		C₃₀H₃₃N₃O₃	详情	详情
(IX)	51137	tert-butyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)carbamate		C₃₅H₄₁N₃O₅	详情	详情
(X)	51138	tert-butyl 4-aminobutyl([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)carbamate		C₂₇H₃₉N₃O₃	详情	详情
(XI)	33694	cyclohexanecarbaldehyde	2043-61-0	C₇H₁₂O	详情	详情
(XII)	51139	tert-butyl 4-[(cyclohexylmethyl)amino]butyl([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)carbamate		C₃₄H₅₁N₃O₃	详情	详情

Extended Information