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【结 构 式】 
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【分子编号】67537 【品名】4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine 【CA登记号】 |
【 分 子 式 】C13H14F3N3S 【 分 子 量 】301.336 【元素组成】C 51.82% H 4.68% F 18.91% N 13.94% S 10.64% |
合成路线1
该中间体在本合成路线中的序号：(X)Chlorination of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (I) using (COCl)2 in refluxing CHCl3 gives the corresponding acid chloride (II) , which by condensation with 4-methoxy-3-buten-2-one (III) by means of LiHMDS in THF at –78 °C affords the hepta-1,4-dien-3-one derivative (IV) . Cyclization of intermediate (IV) in the presence of TFA in toluene or benzene produces the pyranone (V) (1-5), which is treated with aqueous NH3 at 65 °C to provide pyridinone (VI). Bromination of compound (VI) with POBr3 in toluene at 80 °C or in dichloroethane at 85 °C leads to the 4-bromopyridine derivative (VII). Subsequent coupling of bromopyridine (VII) with 2-acetamido-4-methylthiazole (VIII) by means of Pd(OAc)2, t-Bu3P·HBF4 and Cs2CO3 in refluxing DMF yields the pyridylthiazole adduct (IX), which by deacetylation using HCl in refluxing EtOH affords the 2-aminothiazole derivative (X) . Acylation of amine (X) with phenyl chloroformate (XI), optionally in the presence of DIEA in THF gives the thiazolylcarbamate (XII), which is finally condensed with L-prolinamide (XIII), optionally in the presence of Et3N in H2O .
Similarly, reaction of amine (X) with carbonyldiimidazole (XIV) in refluxing CH2Cl2 gives the carbamoyl imidazolide (XV), which is finally coupled with L-prolinamide (XIII) in the presence of Et3N in DMF or in DMAc at 65°C .
| 【1】 Furet, P., Guagnano, V., Fairhurst, R.A. et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett 2013, 23(13): 3741-8. |
| 【2】 Caravatti, G., Fairhurst, R.A., Furet, P., Guagnano, V., Imbach, P. (Novartis AG). Organic compounds. kR 2011038737; US 2010105711; US 8710085; CN 102149711; US 2014005232; JP 2012502080; US 8476268; US 8227462; US 2014186469; EP 2331537; WO 2010029082; CA 2734819; US 2012263712. |
| 【3】 Caravatti, G., Guagnano, V., Fairhurst, R. et al. Discovery of a novel 2-aminothiazole derivative (NVP-BYL719) with potent and selective PI3Kalpha inhibitory activity. 22nd Int Symp Med Chem (September 2-6, Berlin) 2012, Abst L25. |
| 【4】 Gallou, I.S., Gauer, C., Stowasser, F. (Novartis AG). A crystalline form of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-(4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl)-amide and its use as PI3K inhibitor. WO 2012016970. |
| 【5】 Caravatti, G., Guagnano, V., Fairhurst, R. et al. 2-Aminothiazoles as potent and selective PI3Kalpha inhibitors: Discovery of NVP-BYL719 and structural basis for the isoform selectivity. 103rd Annu Meet Am Assoc Cancer Res (AACR) (March 31-April 4, Chicago) 2012, Abst 1922. |
| 【6】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071. |
| 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) | 67528 | 3,3,3-trifluoro-2,2-dimethylpropanoic acid | C5H7F3O2 | 详情 | 详情 | |
| (II) | 67529 | 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride | C5H6ClF3O | 详情 | 详情 | |
| (III) | 67530 | 4-methoxy-3-buten-2-one | 51731-17-0 | C5H8O2 | 详情 | 详情 |
| (IV) | 67531 | (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one | C10H13F3O3 | 详情 | 详情 | |
| (V) | 67532 | 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one | C9H9F3O2 | 详情 | 详情 | |
| (VI) | 67533 | 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one | C9H10F3NO | 详情 | 详情 | |
| (VII) | 67534 | 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydropyridine | C9H11BrF3N | 详情 | 详情 | |
| (VIII) | 67535 | 2-acetamido-4-methylthiazole | 7336-51-8 | C6H8N2OS | 详情 | 详情 |
| (IX) | 67536 | N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)acetamide | C15H16F3N3OS | 详情 | 详情 | |
| (X) | 67537 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine | C13H14F3N3S | 详情 | 详情 | |
| (XI) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (XII) | 67538 | phenyl (4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)carbamate | C20H18F3N3O2S | 详情 | 详情 | |
| (XIII) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (XIV) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XV) | 67539 | N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-1H-imidazole-1-carboxamide | C17H16F3N5OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Reaction of 2-acetyl-4-methylpyridine (XVI) with (trimethylsilyl)trifluoromethane (XVII) in the presence of NaOAc in DMSO produces the silylated tertiary alcohol (XVIII), which is further desilylated to alcohol (XIX) by treatment with k2CO3 in MeOH. Treatment of alcohol (XIX) with MsCl and NaH in THF, followed by substitution of the resultant mesylate (XX) with Me3Al in cyclohexane/hexane provides 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (XXI). Metalation of pyridine (XXI) with LDA (prepared from n-hexyllithium and didiisopropylamine in hexane) in THF, followed by condensation with Weinreb amide (XXII) at –15 °C, and subsequent quenching with H2SO4 in toluene leads to ketone (XXIII). Cyclization of crude ketone (XXIII) with thiourea (XXIV) in the presence of NBS in toluene/EtOH gives the hydrobromide salt 2-aminothiazole (XXV), which is finally converted to the free base intermediate (X) using pyridine in THF . Alternatively, intermediate (XXI) can be obtained by lithiation of 2,4-lutidine (XXVI) with BuLi in methyltetrahydrofuran at –30 °C, followed by condensation with diethyl carbonate (XXVII) in the same solvent, and subsequent dialkylation with MeI to produce the 2-pyridylisobutyrate (XXVIII). Finally, ethyl ester (XXVIII) is hydrolyzed with NaOH in EtOH at 78 °C, and the obtained sodium carboxylate (XXIX) subsequently fluorinated by using SF4 and HF .
| 【1】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 67537 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine | C13H14F3N3S | 详情 | 详情 | |
| (XVI) | 67540 | 2-acetyl-4-methylpyridine；1-(4-Methylpyridin-2-yl)ethanone | 59576-26-0 | C8H9NO | 详情 | 详情 |
| (XVII) | 67541 | trimethyl(trifluoromethyl)silane | C4H9F3Si | 详情 | 详情 | |
| (XVIII) | 67542 | 4-methyl-2-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)pyridine | C12H18F3NOSi | 详情 | 详情 | |
| (XIX) | 67543 | 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol | C9H10F3NO | 详情 | 详情 | |
| (XX) | 67544 | 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-yl methanesulfonate | C10H12F3NO3S | 详情 | 详情 | |
| (XXI) | 67545 | 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine | C10H12F3N | 详情 | 详情 | |
| (XXII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XXIII) | 67546 | 1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)propan-2-one | C12H14F3NO | 详情 | 详情 | |
| (XXIV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XXV) | 67547 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine hydrobromide | C13H14F3N3S.HBr | 详情 | 详情 | |
| (XXVI) | 67548 | 2,4-lutidine | 108-47-4 | C7H9N | 详情 | 详情 |
| (XXVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (XXVIII) | 67549 | ethyl 2-methyl-2-(4-methylpyridin-2-yl)propanoate | C12H17NO2 | 详情 | 详情 | |
| (XXIX) | 67550 | sodium 2-methyl-2-(4-methylpyridin-2-yl)propanoate | C10H12NaNO2 | 详情 | 详情 |