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【结 构 式】 
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【分子编号】38645 【品名】methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate 【CA登记号】 |
【 分 子 式 】C19H20N2O5S 【 分 子 量 】388.44428 【元素组成】C 58.75% H 5.19% N 7.21% O 20.59% S 8.25% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected with HgCl2 and H2S in methanol to furnish the target ester.
| 【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011. |
| 【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 . |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (III) | 38643 | 2-methyl-5-nitro-1,1'-biphenyl | C13H11NO2 | 详情 | 详情 | |
| (IV) | 38644 | 5-nitro[1,1'-biphenyl]-2-carboxylic acid | C13H9NO4 | 详情 | 详情 | |
| (V) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VI) | 38645 | methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate | C19H20N2O5S | 详情 | 详情 | |
| (VII) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (VIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (IX) | 38647 | methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C46H51N3O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected and hydrolyzed first with LiOH and THF and then with TFA and Et3SiH in dichloromethane to furnish the target free acid.
| 【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011. |
| 【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 . |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (III) | 38643 | 2-methyl-5-nitro-1,1'-biphenyl | C13H11NO2 | 详情 | 详情 | |
| (IV) | 38644 | 5-nitro[1,1'-biphenyl]-2-carboxylic acid | C13H9NO4 | 详情 | 详情 | |
| (V) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VI) | 38645 | methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate | C19H20N2O5S | 详情 | 详情 | |
| (VII) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (VIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (IX) | 38647 | methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C46H51N3O5S2 | 详情 | 详情 |