2,4-dichloro-5-fluoropyrimidine；2,4-Dichloro-5-fluorouracil -Drug Synthesis Database

【结构式】

【分子编号】45722

【品名】2,4-dichloro-5-fluoropyrimidine；2,4-Dichloro-5-fluorouracil

【CA登记号】

【分子式】C₄HCl₂FN₂

【分子量】166.9692232

【元素组成】C 28.77% H 0.6% Cl 42.47% F 11.38% N 16.78%

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：(X)

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

合成路线2

该中间体在本合成路线中的序号：(II)

Chlorination of 5-fluorouracil (I) by means of POCl3 gives 2,4-dichloro-5-fluoropyrimidine (II), which is condensed with the pyrido-[3,2-b][1,4]oxazin-3-one derivative (III) to afford the secondary amine (IV). Then, subsequent displacement of the remaining chlorine of pyrimidine (IV) with 3,4,5-trimethoxyaniline (V) yields the substituted pyrimidine-2,4-diamine (VI) . Condensation of pyridooxazinone derivative (VI) with di-tert-butyl chloromethyl phosphate (VII) prepared by chlorination of potassium di-tert-butylphosphate (VIII) with ClSO3CH2Cl by means of Bu4NHSO4 in CH2Cl2/H2O – in the presence of Cs2CO3 in acetone or DMF gives a mixture of three N-substituted regioisomers, which are then subjected to either column chromatography or crystallization on MTBE to provide the major N-substituted oxazinone (IX). Hydrolysis of the t-butyl ester groups of (IX) by means of AcOH in H2O or TFA in CH2Cl2 affords free acid (X) , which is finally treated with aqueous or IPA/H2O NaOH .
Alternatively, condensation of pyridooxazinone (VI) and chloromethyl phosphate (VII) with Cs2CO3 in DMAC at 40 °C affords the N-substituted oxazinone (IX), which is directly hydrolyzed by means of AcOH in H2O, and the phosphoric acid (X) is submitted to purification by crystallization on DMF .

参考文献中间体

合成目标

【1】 Singh, R., Atuegbu, A., Ramphal, J. et al. (Rigel Pharmaceuticals, Inc.).Pyrimidinediamine kinase inhibitors. US 2010179134, WO 2010078369.
【2】 Felfer, U., Giselbrecht, K.-H., Wolberg, M. (Rigel Pharmaceuticals, Inc.). Synthesis of N4-(2,2-dimethyl-4-[dihydrogen phosphonoxy]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine disodium salt. US 2011003986, WO 2011002999.
【3】 Bhamidipati, S., Singh, R., Sun, T., Masuda, E. (Rigel Pharmaceuticals, Inc.). Prodrug salts of 2,4-pyrimidinediamine compounds and their uses. EP 2078026, JP 2010510322, WO 2008064274.
【4】 Singh, R., Bhamidipati, S., Masuda, E., Stella, V.J., Sun, T. (Rigel Pharmaceuticals, Inc.). Prodrugs of 2,4-pyrimidinediamine compounds and their uses. CA 2591948, EP 1856135, EP 2161275, JP 2008527048, US 2006211657, US 7449458, WO 2006078846.
【5】 Singh, R., Bhamidipati, S., Stella, V.J., Sun, T. (Rigel Pharmaceuticals, Inc.). Prodrugs of 2,4-pyrimidinediamine compounds and their uses. US 7563892.

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)	29241	5-fluoro-2,4(1H,3H)-pyrimidinedione；5-fluorouracil；5-Fluoro-2,4-pyrimidinedione;5-Fluoropyrimidine-2,4-dione	51-21-8	C₄H₃FN₂O₂	详情	详情
(II)	45722	2,4-dichloro-5-fluoropyrimidine；2,4-Dichloro-5-fluorouracil		C₄HCl₂FN₂	详情	详情
(III)	68776	6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one	1002726-62-6	C₉H₁₁N₃O₂	详情	详情
(IV)	68777	6-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one		C₁₃H₁₁ClFN₅O₂	详情	详情
(V)	31545	3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine	24313-88-0	C₉H₁₃NO₃	详情	详情
(VI)	68778	6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one		C₂₂H₂₃FN₆O₅	详情	详情
(VII)	42239	di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate；PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER	229625-50-7	C₉H₂₀ClO₄P	详情	详情
(VIII)	68779	potassium di-tert-butyl phosphate		C₈H₁₈KO₄P	详情	详情
(IX)	68780	di-tert-butyl ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl) phosphate		C₃₁H₄₂FN₆O₉P	详情	详情
(X)	68781	(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl dihydrogen phosphate		C₂₃H₂₆FN₆O₉P	详情	详情

Extended Information