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【结 构 式】 
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【分子编号】28417 【品名】tert-butyl 4-[4-(4-fluorophenyl)-5-[2-(methylamino)-4-pyrimidinyl]-1H-imidazol-1-yl]-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C24H29FN6O2 【 分 子 量 】452.5319032 【元素组成】C 63.7% H 6.46% F 4.2% N 18.57% O 7.07% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimethyl acetal (II) afforded ketoenamine (III), which was condensed with N-methyl guanidine (IV) to give pyrimidine (V). Acid hydrolysis of the acetal function of (V) yielded pyrimidine carboxaldehyde (VI), which was converted to the imine (VIII) by treatment with 1-Boc-4-aminopiperidine (VII). Isonitrile (XII) was prepared by condensation of 4-fluorobenzaldehyde (IX) with formamide and p-thiocresol (X), followed by dehydration of the resulting formamide (XI) by means of POCl3 and Et3N. Reaction of isonitrile (XII) with imine (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) produced imidazole (XIII). Finally, acid deprotection of the Boc group of (XIII) provided the title compound.
| 【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 . |
| 【2】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 【3】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 . |
| 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) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (II) | 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 |
| (III) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (IV) | 28411 | N-Methylguanidine | 598-12-9 | C2H7N3 | 详情 | 详情 |
| (V) | 28412 | 4-(dimethoxymethyl)-N-methyl-2-pyrimidinamine | C8H13N3O2 | 详情 | 详情 | |
| (VI) | 28413 | 2-(methylamino)-4-pyrimidinecarbaldehyde | C6H7N3O | 详情 | 详情 | |
| (VII) | 28414 | 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine | 87120-72-7 | C10H20N2O2 | 详情 | 详情 |
| (VIII) | 28415 | tert-butyl 4-([(Z)-[2-(methylamino)-4-pyrimidinyl]methylidene]amino)-1-piperidinecarboxylate | C16H25N5O2 | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (X) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (XI) | 25438 | (4-fluorophenyl)[(4-methylphenyl)sulfanyl]methylformamide | C15H14FNOS | 详情 | 详情 | |
| (XII) | 28416 | 4-Fluoro-alpha-(4-methylphenylsulfanyl)benzyl isocyanide | C15H12FNS | 详情 | 详情 | |
| (XIII) | 28417 | tert-butyl 4-[4-(4-fluorophenyl)-5-[2-(methylamino)-4-pyrimidinyl]-1H-imidazol-1-yl]-1-piperidinecarboxylate | C24H29FN6O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)In a related procedure, condensation of 4-fluorobenzaldehyde (IX) with formamide and p-toluenesulfinic acid (XIV) produced the tosyl formamide (XV), which was dehydrated by means of POCl3 and Et3N to give isonitrile (XVI). Imidazole (XIII) was then obtained by reaction of this isonitrile with imine (VIII). Finally, the Boc protecting group of (XIII) was removed by acid treatment as above.
| 【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 . |
| 【2】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 【3】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 28415 | tert-butyl 4-([(Z)-[2-(methylamino)-4-pyrimidinyl]methylidene]amino)-1-piperidinecarboxylate | C16H25N5O2 | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (XIII) | 28417 | tert-butyl 4-[4-(4-fluorophenyl)-5-[2-(methylamino)-4-pyrimidinyl]-1H-imidazol-1-yl]-1-piperidinecarboxylate | C24H29FN6O2 | 详情 | 详情 | |
| (XIV) | 25593 | 4-methylbenzenesulfinic acid | C7H8O2S | 详情 | 详情 | |
| (XV) | 25594 | (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide | C15H14FNO3S | 详情 | 详情 | |
| (XVI) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 |