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【结 构 式】 
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【分子编号】29241 【品名】5-fluoro-2,4(1H,3H)-pyrimidinedione；5-fluorouracil；5-Fluoro-2,4-pyrimidinedione;5-Fluoropyrimidine-2,4-dione 【CA登记号】51-21-8 |
【 分 子 式 】C4H3FN2O2 【 分 子 量 】130.0785032 【元素组成】C 36.93% H 2.32% F 14.61% N 21.54% O 24.6% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of 5-fluorouracil (I) with n-hexylisocyanate (II) in dimethylacetamide at 50 C.
| 【1】 Ozaki, S.; Mizuno, H.; Mori, H.; Synthesis of 5-fluorouracil derivatives. JP 52078886 . |
| 【2】 Ozaki, S.; Mori, H. (Mitsui Chemicals, Inc.); 1-Carbamoyl-5-fluorouracil derivatives. BE 846956; DE 2639135; FR 2330401; GB 1524640; JP 52077073; US 4071519 . |
| 【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Woodman, R.J.; Carmofur. Drugs Fut 1982, 7, 4, 235. |
合成路线2
该中间体在本合成路线中的序号：(I)Atofluding can be prepared by several similar ways: a) Acylation of 5-fluorouracil (I) with acetic anhydride in refluxing pyridine gives 1-acetyl-5-fluorouracil (II), which is then acylated with 2-methylbenzoyl chloride (V) by means of either TEA in dioxane at room temperature or pyridine in dioxane at 80 C. b) Acylation of 5-fluorouracil (I) with 2-methylbenzoyl chloride (V) in pyridine at room temperature yields 5-fluoro-3-(2-methylbenzoyl)uracil (III), which is then acylated with acetic anhydride at 80 C or with acetic anhydride by means of TEA in cooled dioxane. c) Acylation of 5-fluorouracil (I) with acetyl chloride by means of TEA in dioxane at room temperature provides 1,3-diacetyl-5-fluorouracil (IV), which is then acytated with 2-methylbenzoyl chloride (V) by means of TEA in dioxane.
| 【1】 Kametani, T.; Hiiragi, M.; Kigasawa, K.; et al.; Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives. J Med Chem 1980, 23, 12, 1324. |
| 【2】 Castaner, J.; Zhang, Z.; Xu, W.; Atofluding. Drugs Fut 2001, 26, 10, 935. |
| 【3】 Okada, T.; Uracil derivs., process for preparing the same, and oncotic preparation thereof. JP 1979135782; WO 7900922 . |
| 【4】 Palleja Martinez, J.; Okada, T.; Process to obtain new 5-fluorouracil derivs., specifically N1-acyl-substd.-N3-ortho-toluyl-5-fluorouracils. ES 2015772 . |
| 【5】 Hoffer, M. (Hoffmann-La Roche, Inc.); Preparation of thymidine and deoxyfluorouridine, and intermediates therefor. US 2949451 . |
| 【6】 Okada, T.; Palleja Martinez, J.; Process to obtain a new 5-fluorouracil deriv.. ES 2015151 . |
| 【7】 Hoffer, M. (Hoffmann-La Roche, Inc.); Mercury salts of nitrogen heterocyclics and preparation thereof. US 3041335 . |
| 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) | 48658 | 1-acetyl-5-methyl-2,4(1H,3H)-pyrimidinedione | C7H8N2O3 | 详情 | 详情 | |
| (III) | 48659 | 5-fluoro-3-(2-methylbenzoyl)-2,4(1H,3H)-pyrimidinedione | C12H9FN2O3 | 详情 | 详情 | |
| (IV) | 48660 | 1,3-diacetyl-5-fluoro-2,4(1H,3H)-pyrimidinedione | C8H7FN2O4 | 详情 | 详情 | |
| (V) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)By reaction of 5-isopropoxy-1,4-dioxepane (I) with 5-fluorouracil (II) by means of SnCl4, hexamethyldisilazane (HMDS) and trimethylchlorosilane (TCS) in acetonitrile.
| 【1】 Gallo, M.A.; et al.; A facile synthetic method for pyrimidine acyclonucleoside analogues from alkoxy-1,4-diheterocycloheptanes. Synlett 1993, 6, 389. |
| 【2】 Campos, J.; et al.; Diheterocyclanes as synthons for the preparation of novel series of nucleoside and acyclonucleoside analogues. Farmaco 1997, 52, 5, 263. |
| 【3】 Campos Rosa, J.; Gallo Mezo, M.A.; Dominguez Senglar, J.F.; Entrena Guadix, A.; Pineda de las Infantas y Villatoro, M.J.; Camacho Quesada, E.; Espinosa Ubeda, A. (Universidad de Granada); New uracil derivs. having an anti-tumour activity and related cpds. (N-1 derivs. of 5-substd.-uracile). WO 9117147 . |
合成路线4
该中间体在本合成路线中的序号：(I)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 .
| 【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 |