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【结 构 式】 
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【分子编号】25437 【品名】4-methylphenylhydrosulfide 【CA登记号】106-45-6 |
【 分 子 式 】C7H8S 【 分 子 量 】124.20652 【元素组成】C 67.69% H 6.49% S 25.82% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(VI)Condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimehylacetal provided ketoenamine (II). This was cyclized with guanidine to afford aminopyrimidine (III). Then, hydrolysis of the dimethyl acetal of (III) with 3 M HCl yielded aldehyde (IV). 4-Fluorobenzaldehyde (V) was condensed with thiocresol (VI) and formamide in refluxing toluene to give 4-fluorophenyl-tolylthiomethyl formamide (VII), which was dehydrated to isocyanide (VIII) with POCl3 and Et3N at -30 C. Finally, imine (X), (obtained from pyrimidine aldehyde (IV) and 4-(3-aminopropyl)morpholine (IX)), was condensed with isocyanide (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene to furnish the title imidazole.
| 【1】 Adams, J.L.; Boehm, J.C.; Kassis, S.; Gorycki, P.D.; Webb, E.F.; Hall, R.; Sorenson, M.; Lee, J.C.; Ayrton, A.; Griswold, D.E.; Gallagher, T.F.; Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes. Bioorg Med Chem Lett 1998, 8, 22, 3111. |
| 【2】 Adams, J.L.; Sheldrake, P.W.; Gallagher, T.F.; Garigipati, R.S.; Bender, P.E.; Boehm, J.C. (SmithKline Beecham plc); Tri-substd. imidazoles having multiple therapeutic properties. EP 0708768; WO 9502591 . |
| 【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 【4】 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) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (III) | 25435 | 4-(dimethoxymethyl)-2-pyrimidinylamine | C7H11N3O2 | 详情 | 详情 | |
| (IV) | 25436 | 2-amino-4-pyrimidinecarbaldehyde | C5H5N3O | 详情 | 详情 | |
| (V) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (VI) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (VII) | 25438 | (4-fluorophenyl)[(4-methylphenyl)sulfanyl]methylformamide | C15H14FNOS | 详情 | 详情 | |
| (VIII) | 25439 | 4-Fluoro-alpha-(4-methylphenylsulfanyl)benzyl isocyanide | C15H12FNS | 详情 | 详情 | |
| (IX) | 25440 | 3-(4-morpholinyl)-1-propanamine | 123-00-2 | C7H16N2O | 详情 | 详情 |
| (X) | 25441 | 4-([[3-(4-morpholinyl)propyl]imino]methyl)-2-pyrimidinamine | C12H19N5O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The formylation of 3,5-dichloropyridine (I) with methyl formate by means of lithium diisopropylamide (LDA) in THF gives 3,5-dichloropyridine-4-carbaldehyde (II), which is condensed with p-thiocresol (III) by means of K2CO3 in DMF (or t-BuOK in THF) yielding 3-chloro-5-(4-methylphenylsulfanyl)pyridine-4-carbaldehyde (IV). The cyclization of (IV) with methylthioglycolate (V) by means of K2CO3 in DMF affords 4-(4-methylphenylsulfanyl)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally treated with ammonia in methanol to obtain the target amide. Alternatively, The hydrolysis of the methyl ester (VI) with LiOH in hot isopropanol/water gives the corresponding free acid (VII), which is treated with oxalyl chloride in dichloromethane to obtain the acyl chloride (VIII). Finally, this compound is treated with NH4OH in THF/water to afford the target amide.
| 【1】 Boyd, S.A.; Stewart, A.O.; Bhatia, P.A.; et al.; Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells: Selective inhibition of ICAM-1 and E-selectin expression. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 73. |
| 【2】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 . |
| 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) | 35535 | 3,5-dichloropyridine | 2457-47-8 | C5H3Cl2N | 详情 | 详情 |
| (II) | 35536 | 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde | 136590-83-5 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (IV) | 35537 | 3-chloro-5-[(4-methylphenyl)sulfanyl]isonicotinaldehyde | C13H10ClNOS | 详情 | 详情 | |
| (V) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 35538 | methyl 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylate | C16H13NO2S2 | 详情 | 详情 | |
| (VII) | 35539 | 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylic acid | C15H11NO2S2 | 详情 | 详情 | |
| (VIII) | 35540 | 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carbonyl chloride | C15H10ClNOS2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The formylation of 3,5-dichloropyridine (I) with methyl formate by means of lithium diisopropylamide (LDA) in THF gives 3,5-dichloropyridine-4-carbaldehyde (II), which is condensed with p-thiocresol (III) by means of K2CO3 in DMF (or t-BuOK in THF) yielding 3-chloro-5-(4-methylphenylsulfanyl)pyridine-4-carbaldehyde (IV). The cyclization of (IV) with methyl thioglycolate (V) by means of K2CO3 in DMF affords 4-(4-methylphenylsulfanyl)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally condensed with 2,3-dihydroxypropylamine (VII) by means of NaH in DMF to obtain the target amide. Alternatively, The hydrolysis of the methyl ester (VI) with LiOH in hot isopropanol/water gives the corresponding free acid (VIII), which is treated with N-hydroxysuccinimide (IX) and DCC in dichloromethane to obtain the activated ester (X). Finally, this compound is treated with 2,3-dihydroxypropylamine (VII) in dioxane/methanol to afford the target amide. The activation of the acid (VIII) can also be performed with oxalyl chloride or EDC and HOBT.
| 【1】 Patel, S.A.; Staeger, M.A.; McCarty, C.M.; et al.; Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells: Selective inhibition of ICAM-1 and E-selectin expression. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 74. |
| 【2】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 . |
| 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) | 35535 | 3,5-dichloropyridine | 2457-47-8 | C5H3Cl2N | 详情 | 详情 |
| (II) | 35536 | 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde | 136590-83-5 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (IV) | 35537 | 3-chloro-5-[(4-methylphenyl)sulfanyl]isonicotinaldehyde | C13H10ClNOS | 详情 | 详情 | |
| (V) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 35538 | methyl 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylate | C16H13NO2S2 | 详情 | 详情 | |
| (VII) | 35539 | 4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridine-2-carboxylic acid | C15H11NO2S2 | 详情 | 详情 | |
| (VIII) | 35544 | 1-[([4-[(4-methylphenyl)sulfanyl]thieno[2,3-c]pyridin-2-yl]carbonyl)oxy]-2,5-pyrrolidinedione | C19H14N2O4S2 | 详情 | 详情 |