3,5-difluoro-N'-hydroxy-2-pyridinecarboximidamide -Drug Synthesis Database

【结构式】

【分子编号】55047

【品名】3,5-difluoro-N'-hydroxy-2-pyridinecarboximidamide

【CA登记号】

【分子式】C₆H₅F₂N₃O

【分子量】173.1221264

【元素组成】C 41.63% H 2.91% F 21.95% N 24.27% O 9.24%

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：(VII)

Preparation of 2-cyano-3,5-dichloropyridine (IV) has been reported by two alternative procedures: 3,5-Dichloropyridine (I) was converted to the corresponding N-oxide (II) by treatment with peracetic acid. Addition of cyanotrimethylsilane in the presence of dimethylcarbamoyl chloride gave rise to the cyanopyridine (IV). In a different method, displacement of the 2-chloro group of 2,3,5-trichloropyridine (III) with cuprous cyanide in refluxing diglyme led to the target nitrile (IV). Displacement of both chloro groups of pyridine (IV) by KF in hot DMSO furnished the difluoropyridine (V). The cyano group of (V) was then converted to the key amidine (VII) by two related routes. Addition of hydroxylamine to nitrile (V) provided the hydroxyamidine (VI), which was further reduced to amidine (VII) by catalytic hydrogenation. Alternatively, nitrile (V) was directly converted to (VII) by treatment with ammonium chloride and trimethylaluminium.

参考文献中间体

合成目标

【2】 Paessens, A.; Stoltefuss, J.; Goldmann, S.; Niewohner, U.; Kramer, T.; Schlemmer, K.-H.; Weber, O.; Graef, E.; Lottmann, S.; Stolting, J.; Deres, K. (Bayer AG); Dihydropyrimidines and their use in the treatment of hepatitis B. WO 0058302 .
【1】 Goldmann, S.; et al.; BAY 41-4109: A novel non-nucleosidic and highly potent inhibitor of human hepatitis B virus. Part 1: Synthesis and structure activity relationship (SAR). 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1664.

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)	35535	3,5-dichloropyridine	2457-47-8	C₅H₃Cl₂N	详情	详情
(II)	55042	3,5-dichloro-1-pyridiniumolate		C₅H₃Cl₂NO	详情	详情
(III)	55043	2,3,5-Trichloropyridine	16063-70-0	C₅H₂Cl₃N	详情	详情
(IV)	55044	3,5-dichloro-2-pyridinecarbonitrile		C₆H₂Cl₂N₂	详情	详情
(V)	55045	3,5-difluoro-2-pyridinecarbonitrile		C₆H₂F₂N₂	详情	详情
(VI)	55046	3,5-difluoro-2-pyridinecarboximidamide		C₆H₅F₂N₃	详情	详情
(VII)	55047	3,5-difluoro-N'-hydroxy-2-pyridinecarboximidamide		C₆H₅F₂N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Knoevenagel condensation of 2-chloro-4-fluorobenzaldehyde (VIII) with methyl acetoacetate (IX) in the presence of piperidine acetate afforded the benzylidene compound (X). Cyclocondensation of (X) with amidine (VII) provided the racemic dihydropyrimidine (XI). Resolution of (XI) was accomplished either by chiral HPLC or via conversion to the diastereoisomeric salts with (-)-camphanic acid.

参考文献中间体

合成目标

【2】 Paessens, A.; Stoltefuss, J.; Goldmann, S.; Niewohner, U.; Kramer, T.; Schlemmer, K.-H.; Weber, O.; Graef, E.; Lottmann, S.; Stolting, J.; Deres, K. (Bayer AG); Dihydropyrimidines and their use in the treatment of hepatitis B. WO 0058302 .
【1】 Goldmann, S.; et al.; BAY 41-4109: A novel non-nucleosidic and highly potent inhibitor of human hepatitis B virus. Part 1: Synthesis and structure activity relationship (SAR). 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1664.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	55047	3,5-difluoro-N'-hydroxy-2-pyridinecarboximidamide		C₆H₅F₂N₃O	详情	详情
(VIII)	55048	2-Chloro-4-fluorobenzaldehyde; 4-Fluoro-2-chlorobenzaldehyde	84194-36-5	C₇H₄ClFO	详情	详情
(IX)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情
(X)	55049	methyl (Z)-2-acetyl-3-(2-chloro-4-fluorophenyl)-2-propenoate		C₁₂H₁₀ClFO₃	详情	详情
(XI)	55050	methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate		C₁₈H₁₃ClF₃N₃O₂	详情	详情

Extended Information