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【结 构 式】 
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【药物名称】 【化学名称】N-[2,2-Dimethyl-1(S)-(N-methylcarbamoyl)propyl]-2(R)-isobutyl-4(R)-hydroxy-5-sulfanylpentanamide 【CA登记号】 【 分 子 式 】C16H32N2O3S 【 分 子 量 】332.50904 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Collagenase Inhibitors |
合成路线1
The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound.
| 【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
| (I) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 26985 | (2R)-2-isobutyl-4-pentenoic acid | C9H16O2 | 详情 | 详情 | |
| (IV) | 27021 | (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone | C9H15IO2 | 详情 | 详情 | |
| (V) | 27022 | (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone | C28H30O2S | 详情 | 详情 | |
| (VI) | 27023 | (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid | C34H46O3SSi | 详情 | 详情 | |
| (VII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (VIII) | 27024 | (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide | C35H46N2O3S | 详情 | 详情 |