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【结 构 式】

【分子编号】68374

【品名】6-amino-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione

【CA登记号】 

【 分 子 式 】C13H11FIN3O2

【 分 子 量 】387.152

【元素组成】C 40.33% H 2.86% F 4.91% I 32.78% N 10.85% O 8.27%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXIII)

Uracil intermediate (I) is obtained as follows. Condensation of 2-fluoro-4-iodophenyl isocyanate (XIII) with cyclopropylamine (XIV) in Et2O , or alternatively reaction of 2-fluoro-4-iodoaniline (XV) with CDI in the presence of Et3N in DMF, followed by condensation with cyclopropylamine (XIV) affords disubstituted urea (XVI). Cyclization of urea (XVI) is treated with malonic acid (XVII) in the presence of AcCl in Ac2O at 60 °C affords the pyrimidine trione (XVIII), which is chlorinated using POCl3 in the presence of PhNMe2 and a catalytic amount of H2O at 90 °C to provide a mixture of 6-chloropyrimidine (XIX) and the corresponding regioisomer. Finally, chloropyrimidine (XIX) is treated with methylamine (XX) in EtOH at 80 °C .
In an alternative procedure, acylation of urea (XVI) with cyanoacetic acid (XXI) by means of MsCl in DMF yields the N-(cyanoacetyl)urea (XXII), which cyclizes in aqueous NaOH at 80 °C to yield the amino-pyrimidine derivative (XXIII). Condensation of amine (XXIII) with dimethylformamide dimethylacetal (XXIV) in DMF affords formamidine (XXV), which is finally reduced using NaBH4 in EtOH/t-BuOH .

2 Sakai, T., Kawasaki, H., Abe, H. et al. (Japan Tobacco, Inc.). 5-Amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer. CN 101912400, EP 1761528, EP 1894932, EP 2298768, JP 2008201788, JP 2008501631, US 2006014768, US 7378423, US 2008312228, US 201024013, WO 2005121142.
1 Abe, H., Kikuchi, S., Hayakawa, K. et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-7407 DMSO solvate). ACS Med Chem Lett 2011, 2(4): 320.
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) 68359 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil;3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-(methylamino)pyrimidine-2,4(1H,3H)-dione C14H13FIN3O2 详情 详情
(XIII) 68369 2-fluoro-4-iodophenyl isocyanate   C7H3FINO 详情 详情
(XIV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XV) 63342 2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine 29632-74-4 C6H5FIN 详情 详情
(XVI) 68370 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea   C10H10FIN2O 详情 详情
(XVII) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(XVIII) 68371 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione   C13H10FIN2O3 详情 详情
(XIX) 68372 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione   C13H9ClFIN2O2 详情 详情
(XX) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(XXI) 12591 Cyanoacetic Acid; 2-Cyanoacetic acid 372-09-8 C3H3NO2 详情 详情
(XXII) 68373 2-cyano-N-cyclopropyl-N-((2-fluoro-4-iodophenyl)carbamoyl)acetamide   C13H11FIN3O2 详情 详情
(XXIII) 68374 6-amino-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione   C13H11FIN3O2 详情 详情
(XXIV) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(XXV) 68375 (E)-N'-(1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide   C16H16FIN4O2 详情 详情
Extended Information