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【结 构 式】 
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【分子编号】25595 【品名】4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide 【CA登记号】 |
【 分 子 式 】C15H12FNO2S 【 分 子 量 】289.3302232 【元素组成】C 62.27% H 4.18% F 6.57% N 4.84% O 11.06% S 11.08% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of p- fluorobenzaldehyde (I) with p-toluenesulfinic acid (II) in the presence of camphorsulfonic acid in formamide produced the tosylmethyl formamide (III). This was dehydrated to the required isocyanide (IV) using POCl3 and Et3N in cold dimethoxyethane.
| 【1】 Adams, J.L.; Garigipati, R.S. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0883402; WO 9725047 . |
| 【2】 Adams, J.L.; Garigipati, R.S.; Sorenson, M.E. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0889726; JP 2000503304; WO 9725048 . |
| 【3】 Boehm, J.C.; Garigipati, R.S.; Adams, J.L. (SmithKline Beecham Corp.); Novel cycloalkyl substd. imidazoles. EP 1019396; WO 9901452 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 25593 | 4-methylbenzenesulfinic acid | C7H8O2S | 详情 | 详情 | |
| (III) | 25594 | (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide | C15H14FNO3S | 详情 | 详情 | |
| (IV) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Condensation of pyruvic aldehyde dimethyl acetal (V) with dimethylformamide dimethyl acetal produced enamino ketone (VI). Cyclization of (VI) with thiourea (VII), followed by methylation with iodomethane furnished the (methylsulfanyl)pyrimidine (VIII). Acid hydrolysis of the dimethyl acetal gave rise to aldehyde (IX). Cyclohexanedione monoketal (X) was converted to oxime (XI) and then hydrogenated to give amine (XII). This was condensed with aldehyde (IX) yielding imine (XIII). Reaction of imine (XIII) with sulfonyl isocyanide (IV) gave rise to imidazole (XIV). The methylsulfanyl group of (XIV) was then oxidized to sulfone (XV) employing oxone®. Further displacement of the methylsulfonyl group of (XV) with NaOMe produced the methoxy pyrimidine (XVI). After ketal (XVI) hydrolysis, reduction of the resulting ketone (XVII) with NaBH4 furnished the title alcohol.
| 【1】 Adams, J.L.; Garigipati, R.S.; Sorenson, M.E. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0889726; JP 2000503304; WO 9725048 . |
| 【2】 Adams, J.L.; Garigipati, R.S. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0883402; WO 9725047 . |
| 【3】 Boehm, J.C.; Garigipati, R.S.; Adams, J.L. (SmithKline Beecham Corp.); Novel cycloalkyl substd. imidazoles. EP 1019396; WO 9901452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 | |
| (V) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (VI) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (VII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 41422 | methoxy[2-(methylsulfanyl)-4-pyrimidinyl]methyl methyl ether; 4-(dimethoxymethyl)-2-(methylsulfanyl)pyrimidine | C8H12N2O2S | 详情 | 详情 | |
| (IX) | 41423 | 2-(methylsulfanyl)-4-pyrimidinecarbaldehyde | C6H6N2OS | 详情 | 详情 | |
| (X) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (XI) | 41424 | 1,4-dioxaspiro[4.5]decan-8-one oxime | C8H13NO3 | 详情 | 详情 | |
| (XII) | 41425 | 1,4-dioxaspiro[4.5]dec-8-ylamine; 1,4-dioxaspiro[4.5]decan-8-amine | C8H15NO2 | 详情 | 详情 | |
| (XIII) | 41426 | N-(1,4-dioxaspiro[4.5]dec-8-yl)-N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]amine; N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]-1,4-dioxaspiro[4.5]decan-8-amine | C14H19N3O2S | 详情 | 详情 | |
| (XIV) | 41427 | 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfanyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfide | C22H23FN4O2S | 详情 | 详情 | |
| (XV) | 41428 | 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfonyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfone | C22H23FN4O4S | 详情 | 详情 | |
| (XVI) | 41429 | 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl ether; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-methoxypyrimidine | C22H23FN4O3 | 详情 | 详情 | |
| (XVII) | 41430 | 4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanone | C20H19FN4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVI)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 |
合成路线4
该中间体在本合成路线中的序号：(V)Two related syntheses have been reported for this compound. The intermediate alpha-tosyl-(4-fluorobenzyl)isonitrile (V) was prepared by condensation of 4-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide (III) in the presence of chlorotrimethylsilane (1-4), followed by dehydration of the resulting formamide derivative (IV) with POCl3 and triethylamine.
| 【1】 Sisko, J.; A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole: A potent inhibitor of P38 MAP kinase. J Org Chem 1998, 63, 13, 4529. |
| 【2】 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 . |
| 【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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 25593 | 4-methylbenzenesulfinic acid | C7H8O2S | 详情 | 详情 | |
| (IV) | 25594 | (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide | C15H14FNO3S | 详情 | 详情 | |
| (V) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)In the original procedure, pyruvic aldehyde dimethyl acetal (VI) was condensed with N,N-dimethylformamide dimethyl acetal to give enaminoketone (VII). Subsequent reaction of (VII) with guanidine (VIII) provided 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (IX), which was hydrolyzed to the corresponding aldehyde (X) with 3 N HCl at 48 C. This was condensed with 4-amino-2,2,6,6-tetramethylpiperidine (XI) to produce imine (XII). Finally, reaction between imine (XII) and tosyl isonitrile (V) in the presence of K2CO3 generated the target imidazole.
| 【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】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 . |
| 【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 | |
| (VI) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (VII) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (VIII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (IX) | 25435 | 4-(dimethoxymethyl)-2-pyrimidinylamine | C7H11N3O2 | 详情 | 详情 | |
| (X) | 25436 | 2-amino-4-pyrimidinecarbaldehyde | C5H5N3O | 详情 | 详情 | |
| (XI) | 25596 | 2,2,6,6-tetramethyl-4-piperidinamine | 36768-62-4 | C9H20N2 | 详情 | 详情 |
| (XII) | 25597 | 4-[[(2,2,6,6-tetramethyl-4-piperidinyl)imino]methyl]-2-pyrimidinamine | C14H23N5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)A new procedure, which avoided the unstable pyrimidine aldehye (X), started by condensing pyruvic aldehyde (XIII) with aminopiperidine (XI). The resulting imine (XIV) was reacted with tosyl isonitrile (V) to form the acetyl imidazole (XV). Subsequent treatment of (XV) with N,N-dimethylformamide dimethyl acetal gave enaminoketone (XVI), which was then condensed with guanidine (VIII) to produce the required pyrimidine ring.
| 【1】 Sisko, J.; A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole: A potent inhibitor of P38 MAP kinase. J Org Chem 1998, 63, 13, 4529. |
| 【2】 Sisko, J. (SmithKline Beecham plc); Novel synthesis. US 5917043; WO 9723479 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 | |
| (VIII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XI) | 25596 | 2,2,6,6-tetramethyl-4-piperidinamine | 36768-62-4 | C9H20N2 | 详情 | 详情 |
| (XIII) | 25598 | 2-oxopropanal | 78-98-8 | C3H4O2 | 详情 | 详情 |
| (XIV) | 25599 | 1-[(2,2,6,6-tetramethyl-4-piperidinyl)imino]acetone | C12H22N2O | 详情 | 详情 | |
| (XV) | 25600 | 1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-1-ethanone | C20H26FN3O | 详情 | 详情 | |
| (XVI) | 25601 | (E)-3-(dimethylamino)-1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-2-propen-1-one | C23H31FN4O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Condensation between p-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide in the presence of camphorsulfonic acid afforded 4-fluorophenyltosylmethyl formamide (III). Subsequent dehydration of (III) by means of POCl3 and Et3N produced isonitrile (IV). Imine (VII) was prepared by condensation of pyridine-4-carboxaldehyde (V) with 1-Boc-4-aminopiperidine (VI) using MgSO4 as the dehydrating reagent. Dipolar cycloaddition of this imine with the anion of tosyl isonitrile (IV) generated the trisubstituted imidazole (VIII). Finally, acid cleavage of the Boc protecting group furnished 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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16598 | Formamide | 75-12-7 | CH3NO | 详情 | 详情 | |
| (I) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 25593 | 4-methylbenzenesulfinic acid | C7H8O2S | 详情 | 详情 | |
| (III) | 25594 | (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide | C15H14FNO3S | 详情 | 详情 | |
| (IV) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 | |
| (V) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (VI) | 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 |
| (VII) | 34886 | tert-butyl 4-[[(Z)-4-pyridinylmethylidene]amino]-1-piperidinecarboxylate | C16H23N3O2 | 详情 | 详情 | |
| (VIII) | 34887 | tert-butyl 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]-1-piperidinecarboxylate | C24H27FN4O2 | 详情 | 详情 |