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【结 构 式】 
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【分子编号】63342 【品名】2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine 【CA登记号】29632-74-4 |
【 分 子 式 】C6H5FIN 【 分 子 量 】237.0153132 【元素组成】C 30.41% H 2.13% F 8.02% I 53.54% N 5.91% |
合成路线1
该中间体在本合成路线中的序号：(I)Acylation of 2-fluoro-4-iodoaniline (I) with methanesulfonyl chloride affords the corresponding sulfonamide (II). Subsequent iodide displacement in (II) with zinc cyanide in the presence of palladium catalyst furnishes benzonitrile (III), which is further reduced to the benzylic amine (IV) by catalytic hydrogenation over Pd/C. Treatment of 4-(tert-butyl)benzylamine (V) with di-2-pyridyl thionocarbonate leads to the isothiocyanate (VI). This is finally condensed with amine (IV) to provide the target N,N'-dibenzyl thiourea derivative.
| 【1】 Lee, J.W.; Kim, J.K.; Choi, J.K.; Lee, Y.S.; Park, H.G.; Kim, S.Y.; Kim, H.D.; Park, Y.H.; Suh, Y.G.; Joo, Y.H.; Lim, K.M.; Moh, J.H.; Jeong, Y.S.; Yi, J.B.; Oh, U.T.; Park, O.H.; Koh, H.J.; Oh, Y.M. (AmorePacific Corp.); Novel thiourea derivs. and the pharmaceutical compsns. containing the same. EP 1303483; EP 1311478; US 2003212140; WO 0216318; WO 0216319 . |
| 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) | 63342 | 2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine | 29632-74-4 | C6H5FIN | 详情 | 详情 |
| (II) | 63343 | N-(2-fluoro-4-iodophenyl)methanesulfonamide | C7H7FINO2S | 详情 | 详情 | |
| (III) | 63344 | N-(4-cyano-2-fluorophenyl)methanesulfonamide | C8H7FN2O2S | 详情 | 详情 | |
| (IV) | 63345 | N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide | C8H11FN2O2S | 详情 | 详情 | |
| (V) | 47899 | 4-(tert-butyl)benzylamine; [4-(tert-butyl)phenyl]methanamine | 39895-55-1 | C11H17N | 详情 | 详情 |
| (VI) | 63346 | 1-(1,1-dimethylethyl)-4-(isothiocyanatomethyl)benzene; [4-(1,1-dimethylethyl)phenyl]methyl isothiocyanate | C12H15NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 1,2,3,5-tetrafluoro-4-nitrobenzene (I) with 2-fluoro-4-iodoaniline (II) by means of LiHMDS in THF gives diaryl amine (III),which undergoes selective fluoride substitution with NaOMe in THF to yield 5-methoxy-6-nitroaniline derivative (IV). Nitro group reduction in intermediate (IV) by means of Fe and NH4Cl in refluxing EtOH provides the corresponding diamine (V), which is then condensed with 1-allylcyclopropanesulfonyl chloride (VI) in the presence of pyridine at 40 °C to produce the sulfonamide (VII). Dihydroxylation of the allyl group of compound (VII) with OsO4 and NMMO in THF affords racemic refametinib, which is finally resolved using chiral HPLC .
In an alternative method, coupling of the primary amine (V) with the chiral sulfonyl chloride (VIII) in the presence of pyridine yields the corresponding sulfonamide (IX), which is finally hydrolyzed at the acetonide moiety with HCl in THF .
1-Allylcyclopropanesulfonyl chloride intermediate (VI) is prepared as follows. Treatment of 3-chloro-1-propanesulfonyl chloride (X) with BuOH affords butyl 3-chloro-1-propanesulfonate (XI), which cyclizes in the presence of BuLi to yield butyl cyclopropanesulfonate (XII),which can also be obtained by treatment of cyclopropanesulfonyl chloride (XIII) with BuOH in the presence of pyridine. Alkylation of butyl cyclopropanesulfonate (XII) with allyl iodide (XIV) using BuLi in THF at –78 °C yields butyl 1-allylcyclopropanesulfonate (XV), which is hydrolyzed by treatment with KSCN in DME/H2O at reflux producing potassium 1-allylcyclopropanesulfonate (XVI). Finally, the potassium sulfonate (XVI) is chlorinated with refluxing SOCl2 in the presence of a catalytic amount of DMF .
| 【1】 Maderna, A., Vernier, J., Barawkar, D., Chamakura, V., El Abdellaoui, H., Hong, Z. (Ardea Biosciences, Inc.). Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK. US 2008058340, US 8101799. |
| 【3】 Maderna, A., Vernier, J.-M. (Ardea Biosciences, Inc.). Preparation of (R)-and (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl)cyclopropane-1-sulfonamide and protected derivatives thereof. EP 2462111, JP 2013500242, KR 2012032536, WO 2011009541. |
| 【2】 Maderna, A., Vernier, J.-M., Barawkar, D., Chamakura, V., Abdellaoui, H.E., Hong, Z. (Ardea Biosciences, Inc.). N-(Arylamino)-sulfonamide inhibitors of MEK. EP 1912636, US 2012022076, WO 2007014011 |
| 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) | 67905 | 1,2,3,5-tetrafluoro-4-nitrobenzene | 314-41-0 | C6HF4NO2 | 详情 | 详情 |
| (II) | 63342 | 2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine | 29632-74-4 | C6H5FIN | 详情 | 详情 |
| (III) | 67906 | 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline | C12H5F4IN2O2 | 详情 | 详情 | |
| (IV) | 67907 | 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-5-methoxy-6-nitroaniline | C13H8F3IN2O3 | 详情 | 详情 | |
| (V) | 67908 | 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine | C13H10F3IN2O | 详情 | 详情 | |
| (VI) | 67909 | 1-allylcyclopropanesulfonyl chloride | 923032-59-1 | C6H9ClO2S | 详情 | 详情 |
| (VII) | 67910 | 1-allyl-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)cyclopropane-1-sulfonamide | C19H18F3IN2O3S | 详情 | 详情 | |
| (VIII) | 67911 | (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride | C10H17ClO3S | 详情 | 详情 | |
| (IX) | 67912 | (S)-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonamide | C22H24F3IN2O5S | 详情 | 详情 | |
| (X) | 39225 | g-Chloropropanesulfonyl chloride;3-Chloropropansulfonyl chloride;1-Chloro-3-propanesulfonylchloride;3-Chloropropanesulfonyl chloride;3-chloro-1-propanesulfonyl chloride;3-chloropropane-1-sulfonyl chloride | 1633-82-5 | C3H6Cl2O2S | 详情 | 详情 |
| (XI) | 67913 | butyl 3-chloro-1-propanesulfonate;3-Chloro-propane-1-sulfonic acid butyl ester | 146475-47-0 | C7H15ClO3S | 详情 | 详情 |
| (XII) | 67914 | butyl cyclopropanesulfonate | 83635-12-5 | C7H14O3S | 详情 | 详情 |
| (XIII) | 67915 | cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride | 139631-62-2 | C3H5ClO2S | 详情 | 详情 |
| (XIV) | 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 |
| (XV) | 67917 | butyl 1-allylcyclopropane-1-sulfonate | C10H18O3S | 详情 | 详情 | |
| (XVI) | 67916 | potassium 1-allylcyclopropanesulfonate | 923032-57-9 | C6H9KO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)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 |