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【结 构 式】 
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【分子编号】16011 【品名】(2R)-2-bromo-4-methylpentanoic acid 【CA登记号】 |
【 分 子 式 】C6H11BrO2 【 分 子 量 】195.05614 【元素组成】C 36.95% H 5.68% Br 40.96% O 16.4% |
合成路线1
该中间体在本合成路线中的序号：(II)The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.
| 【1】 Ngo, J.; Graul, A.; Castaner, J.; Batimastat. Drugs Fut 1996, 21, 12, 1215. |
| 【2】 Campion, C.; Davidson, A.H.; Dickens, J.P.; Crimmin, M.J. (British Biotech plc); Hydroxamic acid based collagenase inhibitors. US 5240958; US 5310763; WO 9005719 . |
| 【3】 Beckett, R.P.; Crimmin, M.J.; Galloway, W.A.; Matrix metalloproteinase inhibitors in the treatment of rheumatoid arthritis and cancer. 205th ACS Natl Meet (March 28-April 2, Denver) 1993, Abst MEDI 147. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 | |
| (I) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (II) | 16011 | (2R)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
| (III) | 16012 | tert-butyl (2R)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
| (IV) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
| (V) | 16014 | 1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate | C27H34O6 | 详情 | 详情 | |
| (VI) | 16015 | (2S)-2-amino-N-methyl-3-phenylpropanamide | C10H14N2O | 详情 | 详情 | |
| (VII) | 16016 | dibenzyl 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonate | C33H38N2O6 | 详情 | 详情 | |
| (VIII) | 16017 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonic acid | C19H26N2O6 | 详情 | 详情 | |
| (IX) | 16018 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]acrylic acid | C19H26N2O4 | 详情 | 详情 | |
| (X) | 16019 | 2-Thienylhydrosulfide; 2-Thiophenethiol | 7774-74-5 | C4H4S2 | 详情 | 详情 |
| (XI) | 16020 | (2S,3R)-3-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methyl-2-[(2-thienylsulfanyl)methyl]hexanoic acid | C23H30N2O4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Diazotization of D-asparagine (I) in the presence of KCl afforded (R)-2-chlorosuccinamic acid (II) with retention of the configuration. Subsequent displacement of the chlorine atom of (II) with tert-butyl mercaptan provided thioether (III). Reduction of the carboxyl group of (III) by means of borane in THF gave alcohol (IV), which was converted to thioester (V) by esterification with thioacetic acid under Mitsunobu conditions. The chiral bromo acid (VII) (prepared by diazotization of L-leucine (VIII) in the presence of KBr) was then condensed with the thiol liberated from thioacetate (V) in the presence of NaOEt, yielding the corresponding thioether (VIII). Coupling of N-methyl-L-phenylalaninamide (IX) with carboxylic acid (VIII) using DCC and HOBt gave rise to amide (X). The S-tert-butyl group of (X) was then removed by means of 2-nitrobenzenesulfenyl chloride (XI) in HOAc, generating the disulfide (XII). Finally, the disulfide bond of (XII) was reductively cleaved with 2-mercaptoethanol to furnish the title thiol.
| 【1】 Schwartz, M.A.; Wart, H.V. (Florida State University); Mercaptosulfide metalloproteinase inhibitors. WO 9509833 . |
| 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) | 28237 | R-(-)-Asparagine; S-(-)-2-Aminosuccinamic acid; D-asparagine | 5794-13-8 | C4H8N2O3 | 详情 | 详情 |
| (II) | 45637 | (2R)-4-amino-2-chloro-4-oxobutyric acid | C4H6ClNO3 | 详情 | 详情 | |
| (III) | 45638 | (2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyric acid | C8H15NO3S | 详情 | 详情 | |
| (IV) | 45639 | (3S)-3-(tert-butylsulfanyl)-4-hydroxybutanamide | C8H17NO2S | 详情 | 详情 | |
| (V) | 45640 | S-[(2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyl] ethanethioate | C10H19NO2S2 | 详情 | 详情 | |
| (VI) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (VII) | 16011 | (2R)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
| (VIII) | 45641 | (2R)-2-[[(2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyl]sulfanyl]-4-methylpentanoic acid | C14H27NO3S2 | 详情 | 详情 | |
| (IX) | 16015 | (2S)-2-amino-N-methyl-3-phenylpropanamide | C10H14N2O | 详情 | 详情 | |
| (X) | 45642 | (2R)-2-[[(2S)-4-amino-2-(tert-butylsulfanyl)-4-oxobutyl]sulfanyl]-N-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-4-methylpentanamide | C24H39N3O3S2 | 详情 | 详情 | |
| (XI) | 45643 | O-Nitrobenzenesulfenyl chloride; 2-nitrobenzenesulfenyl chloride; 2-nitrophenylsulfenyl chloride | 7669-54-7 | C6H4ClNO2S | 详情 | 详情 |
| (XII) | 45644 | (2R)-2-([(2S)-4-amino-2-[(2-nitrophenyl)disulfanyl]-4-oxobutyl]sulfanyl)-N-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-4-methylpentanamide | C26H34N4O5S3 | 详情 | 详情 |