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【结 构 式】 
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【药物名称】Org-37432 【化学名称】2-[N-(Carboxymethyl)-3-cyclohexyl-D-alanyl-L-prolyl-L-lysyl]thiazole 【CA登记号】190904-27-9 【 分 子 式 】C25H39N5O5S 【 分 子 量 】521.68408 |
【开发单位】Organon (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors |
合成路线1
Treatment of protected lysine (I) with N,O-dimethyl hydroxylamine and (benzotriazolyl)tetramethyluronium fluoborate afforded hydroxamate (II). This was condensed with organolithium reagent (IV) (prepared from 2-bromothiazole (III) and butyllithium), to yield thiazolyl ketone (V). Acid deprotection of the N-Boc group of (V) provided amine (VI), which was then coupled with the mixed anhydride obtained from dipeptide (VII) and isobutyl chloroformate. The resulting compound (VIII) was finally deprotected using TFA and thioanisole.
| 【1】 Rewinkel, J.B.M.; Smit, M.J.; Noach, A.B.J.; van Dinther, T.G.; Grootenhuis, P.D.J.; Peters, J.A.M.; Kelser, J.; Visser, A.; van Boeckel, C.A.A.; Vogel, G.M.T.; van Aelst, S.F.; Adang, A.E.P.; A polar pharmacophore for oral bioavailability in thrombin inhibitors. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.157. |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 23160 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-[methoxy(methyl)amino]-6-oxohexylcarbamate | C21H33N3O6 | 详情 | 详情 | |
| (III) | 23161 | 2-bromo-1,3-thiazole | 3034-53-5 | C3H2BrNS | 详情 | 详情 |
| (IV) | 23162 | 1,3-thiazol-2-yllithium | C3H2LiNS | 详情 | 详情 | |
| (V) | 23163 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1,3-thiazol-2-yl)hexylcarbamate | C22H29N3O5S | 详情 | 详情 | |
| (VI) | 23164 | benzyl (5S)-5-amino-6-oxo-6-(1,3-thiazol-2-yl)hexylcarbamate | C17H21N3O3S | 详情 | 详情 | |
| (VII) | 23165 | (2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid | C25H42N2O7 | 详情 | 详情 | |
| (VIII) | 23166 | tert-butyl 2-[[(1R)-2-[(2S)-2-([[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(1,3-thiazol-2-ylcarbonyl)pentyl]amino]carbonyl)pyrrolidinyl]-1-(cyclohexylmethyl)-2-oxoethyl](tert-butoxycarbonyl)amino]acetate | C42H61N5O9S | 详情 | 详情 |