6-ethyl-5-fluoro-4-pyrimidinol -Drug Synthesis Database

【结构式】

【分子编号】45720

【品名】6-ethyl-5-fluoro-4-pyrimidinol

【CA登记号】

【分子式】C₆H₇FN₂O

【分子量】142.1328632

【元素组成】C 50.7% H 4.96% F 13.37% N 19.71% O 11.26%

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：(IV)

The fluorination of 3-oxopentanoic acid methyl ester with F2 gas gives 2-fluoro-3-oxopentanoic acid methyl ester (II), which is cyclized with formamidine (III) by means of NaOMe yielding 6-ethyl-5-fluoropyrimidin-4-ol (IV). Reaction of (IV) with POCl3 and TEA in dichloromethane affords 4-chloro-6-ethyl-5-fluoropyrimidine (V), which is brominated with NBS and AIBN in dichloromethane to provide 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (VI). Compound (VI) is condensed with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (VII) by means of I2 and Zn in THF furnishing a mixture of the diastereomeric racemates (2R*,3R*)- and (2R*,3S*)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (VIII) in a 1:10.3 molar ratio. The reductive dechlorination of (2R*,3S*)-(VIII) with H2 over Pd/C gives the (2R*,3S*)-racemate (IX), which is submitted to optical resolution by means of crystallization with (1R)-10-camphorsulfonic acid.

参考文献中间体

合成目标

【1】 Butters, M.; et al.; Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org Process Res Dev 2001, 5, 1, 28.

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)	15536	methyl 3-oxopentanoate	30414-53-0	C₆H₁₀O₃	详情	详情
(II)	45716	(E)-3-amino-2-chloro-2-propenal		C₃H₄ClNO	详情	详情
(III)	15369	Iminoformamide; Methanimidamide	463-52-5	CH₄N₂	详情	详情
(IV)	45720	6-ethyl-5-fluoro-4-pyrimidinol		C₆H₇FN₂O	详情	详情
(V)	15371	4-chloro-6-ethyl-5-fluoropyrimidine		C₆H₆ClFN₂	详情	详情
(VI)	45721	4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine	188416-28-6	C₆H₅BrClFN₂	详情	详情
(VII)	15372	1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone	863867-75-6	C₁₀H₇F₂N₃O	详情	详情
(VIII)	15373	(2R,3S)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₆H₁₃ClF₃N₅O	详情	详情
(IX)	15375	(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₆H₁₄F₃N₅O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Alternatively, 6-ethyl-5-fluoropyrimidin-4-ol (IV) can be obtained by reaction of 2,4-dichloro-5-fluoropyrimidine (X) with ethylmagnesium bromide in THF to give the dihydropyrimidine derivative (XI), which is aromatized by reaction with I2 and TEA in THF yielding 2,4-dichloro-6-ethyl-5-fluoropyrimidine (XII). The reaction of (XII) with NaOH and NH4Cl affords the aminooxy derivative (XIII) which is finally submitted to a reductive dechlorination and deamination with H2 over Pd/C in ethanol/water.

参考文献中间体

合成目标

【1】 Butters, M.; et al.; Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org Process Res Dev 2001, 5, 1, 28.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	45720	6-ethyl-5-fluoro-4-pyrimidinol	C₆H₇FN₂O	详情	详情
(X)	45722	2,4-dichloro-5-fluoropyrimidine；2,4-Dichloro-5-fluorouracil	C₄HCl₂FN₂	详情	详情
(XI)	45723	bromo[2,4-dichloro-6-ethyl-5-fluoro-1(6H)-pyrimidinyl]magnesium	C₆H₆BrCl₂FMgN₂	详情	详情
(XII)	45724	2,4-dichloro-6-ethyl-5-fluoropyrimidine	C₆H₅Cl₂FN₂	详情	详情
(XIII)	45725	4-(aminooxy)-2-chloro-6-ethyl-5-fluoropyrimidine; O-(2-chloro-6-ethyl-5-fluoro-4-pyrimidinyl)hydroxylamine	C₆H₇ClFN₃O	详情	详情

Extended Information