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【结 构 式】 
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【分子编号】49197 【品名】4-methyl-2-(methylsulfanyl)pyrimidine; methyl 4-methyl-2-pyrimidinyl sulfide 【CA登记号】 |
【 分 子 式 】C6H8N2S 【 分 子 量 】140.209 【元素组成】C 51.4% H 5.75% N 19.98% S 22.87% |
合成路线1
该中间体在本合成路线中的序号：(II)4-Methyl-2-(methylsulfanyl)pyrimidine (II) was prepared by methylation of mercaptopyrimidine (I) with dimethylformamide dimethylacetal (1). Condensation of the lithium anion of (II) with ethyl 4-fluorobenzoate (III) produced the diaryl ethanone (IV), which was further oxidized to diketone (V) by using HBr in DMSO. The target imidazole intermediate (VII) was then obtained by condensation of diketone (V) with glyoxal dimethylacetal (VI) in the presence of ammonium acetate.
| 【1】 Collis, A.J.; Wilsher, N.E.; Foster, M.L.; Redford, E.J.; McLay, I.M.; Page, K.M.; Maslen, C.; Halley, F.; Souness, J.E.; RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg Med Chem Lett 2001, 11, 5, 693. |
| 【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 . |
| 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) | 49196 | 4-methyl-2-pyrimidinylhydrosulfide; 4-methyl-2-pyrimidinethiol | C5H6N2S | 详情 | 详情 | |
| (II) | 49197 | 4-methyl-2-(methylsulfanyl)pyrimidine; methyl 4-methyl-2-pyrimidinyl sulfide | C6H8N2S | 详情 | 详情 | |
| (III) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (IV) | 49198 | 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)-4-pyrimidinyl]-1-ethanone | C13H11FN2OS | 详情 | 详情 | |
| (V) | 49199 | 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)-4-pyrimidinyl]-1,2-ethanedione | C13H9FN2O2S | 详情 | 详情 | |
| (VI) | 49200 | 2,2-dimethoxyacetaldehyde | C4H8O3 | 详情 | 详情 | |
| (VII) | 49201 | 4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazole-2-carbaldehyde | C15H11FN4OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Alkylation of 2-mercapto-4-methylpyrimidine (I) with iodomethane and NaOH affords 2-methylthio-4-methylpyrimidine (II). Condensation of (II) with methyl 4-fluorobenzoate (III) in the presence of sodium hexamethyldisilazide produces ketone (IV), which is further oxidized to dione (V) with DMSO/HBr. Ring closure of dione (V) with glyoxal dimethyl acetal (VI) in the presence of ammonium acetate leads to imidazole (VII). Acid-catalyzed transketalization of (VII) with the dihydroxy ester (VIII) yields the 1,3-dioxane derivative (IX) as a 3:2 mixture of cis- and trans- isomers. After chromatographic separation of the desired trans- isomer, oxidation of the methylthio group with mCPBA furnishes sulfone (X)
| 【1】 McKenna, J.M.; Halley, F.; Souness, J.E.; McLay, I.M.; Pickett, S.D.; Collis, A.J.; Page, K.; Ahmed, I.; An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J Med Chem 2002, 45, 11, 2173. |
| 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) | 49196 | 4-methyl-2-pyrimidinylhydrosulfide; 4-methyl-2-pyrimidinethiol | C5H6N2S | 详情 | 详情 | |
| (II) | 49197 | 4-methyl-2-(methylsulfanyl)pyrimidine; methyl 4-methyl-2-pyrimidinyl sulfide | C6H8N2S | 详情 | 详情 | |
| (III) | 62737 | methyl 4-fluorobenzoate | C8H7FO2 | 详情 | 详情 | |
| (IV) | 49198 | 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)-4-pyrimidinyl]-1-ethanone | C13H11FN2OS | 详情 | 详情 | |
| (V) | 49199 | 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)-4-pyrimidinyl]-1,2-ethanedione | C13H9FN2O2S | 详情 | 详情 | |
| (VI) | 49200 | 2,2-dimethoxyacetaldehyde | C4H8O3 | 详情 | 详情 | |
| (VII) | 62738 | 4-[2-(dimethoxymethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfanyl)pyrimidine; {4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl}(methoxy)methyl methyl ether | C17H17FN4O2S | 详情 | 详情 | |
| (VIII) | 33803 | methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate | C6H12O4 | 详情 | 详情 | |
| (IX) | 62739 | methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate | C21H21FN4O4S | 详情 | 详情 | |
| (X) | 62740 | methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate | C21H21FN4O6S | 详情 | 详情 |