[1-(4-pyridinyl)-4-piperidinyl]methanol -Drug Synthesis Database

【结构式】

【分子编号】45860

【品名】[1-(4-pyridinyl)-4-piperidinyl]methanol

【CA登记号】

【分子式】C₁₁H₁₆N₂O

【分子量】192.26092

【元素组成】C 68.72% H 8.39% N 14.57% O 8.32%

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：(I)

Swern oxidation of 1-(4-pyridinyl)-4-piperidinemethanol (I) affords aldehyde (II). Reductive amination of (II) with the (R)-diaminopropionic acid derivative (III) in the presence of NaBH(OAc)3 yields (IV). Subsequent acylation of (IV) with bromoacetyl chloride (V) provides bromoacetamide (VI). Acidic cleavage of the N-Boc group of (VI), followed by cyclization in the presence of triethylamine leads to piperazinone (VII). Sulfonylation of amine (VII) with 6-chloro-2-naphthalenesulfonyl chloride (VIII) gives (IX). Finally, the target carboxylic acid is obtained by hydrolysis of ethyl ester (IX) under acidic conditions.

参考文献中间体

合成目标

【1】 Nishida, H.; Miyazaki, Y.; Mukaihira, T.; Saitoh, F.; Fukui, M.; Harada, K.; Itoh, M.; Muraoka, A.; Matsusue, T.; Okamoto, A.; Hosaka, Y.; Matsumoto, M.; Ohnishi, S.; Mochizuki, H.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities. Chem Pharm Bull 2002, 50, 9, 1187.
【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 .

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)	45860	[1-(4-pyridinyl)-4-piperidinyl]methanol		C₁₁H₁₆N₂O	详情	详情
(II)	52205	1-(4-pyridinyl)-4-piperidinecarbaldehyde		C₁₁H₁₄N₂O	详情	详情
(III)	45862	ethyl (2R)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate		C₁₀H₂₀N₂O₄	详情	详情
(IV)	45863	ethyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-([[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)propanoate		C₂₁H₃₄N₄O₄	详情	详情
(V)	27903	2-Bromoacetyl chloride	22118-09-8	C₂H₂BrClO	详情	详情
(VI)	45864	ethyl (2R)-2-((2-bromoacetyl)[[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)-3-[(tert-butoxycarbonyl)amino]propanoate		C₂₃H₃₅BrN₄O₅	详情	详情
(VII)	61247	ethyl (2R)-6-oxo-1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinecarboxylate		C₁₈H₂₆N₄O₃	详情	详情
(VIII)	45865	6-chloro-2-naphthalenesulfonyl chloride		C₁₀H₆Cl₂O₂S	详情	详情
(IX)	45866	ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate		C₂₈H₃₁ClN₄O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Oxidation of 1-(4-pyridyl)piperidin-4-yl methanol (I) with oxalyl chloride and DMSO in dichloromethane provides carbaldehyde (II), which is then subjected to a reductive amination with amino acid (III) by means of HOAc and triacetoxyborohydride (Na(OAc)3BH) in dichloromethane to provide compound (IV). Condensation of (IV) with bromoacetyl chloride (V) in dichloromethane in the presence of Et3N furnishes derivative (VI), which is converted into compound (VIII) by first removal of the Boc group with HCl in MeOH followed by condensation with 6-chloronaphthalen-2-ylsulfonyl chloride (VII) in dichloromethane/DMF in the presence of Et3N. Finally, the target compound is obtained by treatment of (VIII) with methanesulfonic acid (CH3SO3H) in MeOH.

参考文献中间体

合成目标

【1】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 .

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)	45860	[1-(4-pyridinyl)-4-piperidinyl]methanol		C₁₁H₁₆N₂O	详情	详情
(II)	45861	1-(4-pyridinyl)-4-piperidinecarboxylic acid		C₁₁H₁₄N₂O₂	详情	详情
(III)	45862	ethyl (2R)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate		C₁₀H₂₀N₂O₄	详情	详情
(IV)	45863	ethyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-([[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)propanoate		C₂₁H₃₄N₄O₄	详情	详情
(V)	27903	2-Bromoacetyl chloride	22118-09-8	C₂H₂BrClO	详情	详情
(VI)	45864	ethyl (2R)-2-((2-bromoacetyl)[[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)-3-[(tert-butoxycarbonyl)amino]propanoate		C₂₃H₃₅BrN₄O₅	详情	详情
(VII)	45865	6-chloro-2-naphthalenesulfonyl chloride		C₁₀H₆Cl₂O₂S	详情	详情
(VIII)	45866	ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate		C₂₈H₃₁ClN₄O₅S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The condensation of 4-piperidinylmethanol (I) with 4-chloropyridine (II) gives 1-(4-pyridyl)piperidin-4-ylmethanol (III), which is oxidized with (COCl)2 and TEA in DMSO to yield the carbaldehyde (IV). The reductocondensation of (IV) with N-(tert-butoxycarbonyl)ethylene-1,2-diamine (V) by means of sodium triacetoxyborohydride and acetic acid affords the corresponding adduct as the borane complex (VI), which is acylated with bromoacetyl chloride (VII) and TEA in dichloromethane, providing the bromoacetamide (VIII). The cleavage of the boron complex and the Boc protecting group of (VIII) with TFA and anisole in ethyl ether gives the precursor (IX), which is cyclized to the piperazinone (X) by means of TEA in DMF. Finally, compound (X) is condensed with 6-chloronaphthalene-2-sulfonyl chloride by means of TEA in dichloromethane to yield the target sulfonamide.

参考文献中间体

合成目标

【1】 Nishida, H.; et al.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor. Chem Pharm Bull 2001, 49, 10, 1237.
【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 .

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)	32954	4-piperidinylmethanol		C₆H₁₃NO	详情	详情
(II)	32889	4-chloropyridine	7379-35-3	C₅H₄ClN	详情	详情
(III)	45860	[1-(4-pyridinyl)-4-piperidinyl]methanol		C₁₁H₁₆N₂O	详情	详情
(IV)	52205	1-(4-pyridinyl)-4-piperidinecarbaldehyde		C₁₁H₁₄N₂O	详情	详情
(V)	13241	N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate	57260-73-8	C₇H₁₆N₂O₂	详情	详情
(VI)	52206			C₂₂H₃₇BN₄O₇	详情	详情
(VII)	27903	2-Bromoacetyl chloride	22118-09-8	C₂H₂BrClO	详情	详情
(VIII)	52207			C₂₄H₃₈BBrN₄O₈	详情	详情
(IX)	52208	N-(2-aminoethyl)-2-bromo-N-{[1-(4-pyridinyl)-4-piperidinyl]methyl}acetamide		C₁₅H₂₃BrN₄O	详情	详情
(X)	52209	1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinone		C₁₅H₂₂N₄O	详情	详情
(XI)	45865	6-chloro-2-naphthalenesulfonyl chloride		C₁₀H₆Cl₂O₂S	详情	详情

Extended Information