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【结 构 式】 
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【药物名称】GSK-1120212B;JTP-74057;Trametinib Dimethyl Sulfoxide 【化学名称】N-[3-[3-Cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,6,7-hexahydropyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide dimethyl sulfoxide solvate 【CA登记号】1187431-43-1;871700-17-3 (free base);871702-06-6 (sodium salt);871702-07-7 (monoacetate salt) 【 分 子 式 】C26H23FIN5O4.C2H6OS 【 分 子 量 】693.528 |
【开发单位】Japan Tobacco, Inc. (JP); licensed to GlaxoSmithKline (UK) 【药理作用】MAP Kinase Kinase 1 and 2 (MEK 1/2) Inhibitor;Oncolytic |
合成路线1
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 |
合成路线2
Cyclization of 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil (I) (optionally containing some 1-cyclopropyl regioisomer) with either diethyl 2-methylmalonate (II) in Ph2O at 220 °C or with 2-methylmalonic acid (III) in Ac2O at 100 °C yields the 5-hydroxypyrido[2,3-d]pyrimidine-2,4,7-trione derivative (IV) , which can be separated from its regioisomeric byproduct by crystallization from acetone . Treatment of compound (IV) with Tf2O in the presence of 2,6-lutidine in CHCl3 gives the corresponding triflate (V) . Similarly, reaction of (IV) with p-TsCl in the presence of Et3N and Me3N·HCl in acetonitrile produces tosylate (VI) . The condensation of triflate (V) with 3-nitroaniline (VII) at 130 °C furnishes the 5-(arylamino)pyrido[2,3-d]pyrimidine derivative (VIII), which undergoes rearrangement to the isomeric pyrido[4,3-d]pyrimidine (IX) in the presence of K2CO3 in MeOH/THF at 80 °C. Reduction of nitro compound (IX) by means of Na2S2O4 in DMF/H2O at 90 °C, followed by acetylation of the resulting amine with Ac2O in pyridine/CHCl3, leads to trametinib (X). Finally, crystallization of (X) from DMSO produces trametinib dimethyl sulfoxide solvate .
In an alternative procedure, condensation of either triflate (V) or tosylate (VI) with N-(3-aminophenyl)acetamide (XI) by means of 2,6-lutidine in DMA at 130 °C affords intermediate (XII), which upon rearrangement in the presence of NaOMe in THF/MeOH gives rise to the pyrido[4,3-d]pyrimidine compound (IX) .
| 【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. |
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68368 | N-(3-aminophenyl)acetamide；3'-Aminoacetanilide | C8H10N2O | 详情 | 详情 | |
| (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 | |
| (II) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
| (III) | 68360 | 2-methylmalonic acid | 516-05-2 | C4H6O4 | 详情 | 详情 |
| (IV) | 68361 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione | C18H15FIN3O4 | 详情 | 详情 | |
| (V) | 68362 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate | C19H14F4IN3O6S | 详情 | 详情 | |
| (VI) | 68363 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate | C25H21FIN3O6S | 详情 | 详情 | |
| (VII) | 57781 | 1-Amino-3-Nitrobenzene; 3-Nitroaniline; m-Nitroaniline | 99-09-2 | C6H6N2O2 | 详情 | 详情 |
| (VIII) | 68364 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-5-((3-nitrophenyl)amino)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione | C24H19FIN5O5 | 详情 | 详情 | |
| (IX) | 68365 | 3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-nitrophenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione | C24H19FIN5O5 | 详情 | 详情 | |
| (X) | 68366 | N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide | C26H23FIN5O4 | 详情 | 详情 | |
| (XII) | 68367 | N-(3-((3-cyclopropyl-1-(3-fluoro-5-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)acetamide | C26H23FIN5O4 | 详情 | 详情 |