|
【结 构 式】 
|
【分子编号】23165 【品名】(2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C25H42N2O7 【 分 子 量 】482.61776 【元素组成】C 62.22% H 8.77% N 5.8% O 23.21% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |
合成路线2
该中间体在本合成路线中的序号：(IX)Synthesis of the dipeptide intermediate (IX): The esterification of D-cyclohexylalanine (I) by means of SOCl2 and methanol gives the methyl ester (II), which is condensed with tert-butyl bromoacetate (III) by means of DIEA in acetonitrile to yield the N-substituted cyclohexylalanine (IV). The reaction of (IV) with Boc2O and DIEA in DMF affords the N-protected compound (V), which is hydrolyzed with NaOH in dioxane/water to provide the free N-substituted cyclohexylalanine (VI). The condensation of (VI) with L-proline benzyl ester (VII) by means of HOBT and DCC in DMF gives the dipeptide (VIII), which is finally debenzylated by means of H2 over Pd/C in methanol to yield the target dipeptide intermediate (IX).
| 【1】 Adang, A.E.P.; De Man, A.P.A.; Vogel, G.M.T.; Grootenhuis, P.D.J.; Smit, M.J.; Peters, C.A.M.; Visser, A.; Rewinkel, J.B.M.; van Dinther, T; Lucas, H.; Kelder, J.; van Aelst, S.; Meuleman, D.G.; van Boeckel, C.A.A.; Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem 2002, 45, 20, 4419. |
| 【2】 Adang, A.E.P.; Peters, J.A.M.; Van Boeckel, C.A.A.; Rewinkel, J.B.M. (Akzo Nobel N.V.); Thrombin inhibitors. WO 9807308 . |
| 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) | 39357 | (2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine | 27527-05-5 | C9H17NO2 | 详情 | 详情 |
| (II) | 60226 | methyl 2-amino-3-cyclohexylpropanoate | C10H19NO2 | 详情 | 详情 | |
| (III) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (IV) | 60227 | methyl 3-cyclohexyl-2-({2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate | C16H29NO4 | 详情 | 详情 | |
| (V) | 60228 | methyl 3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate | C21H37NO6 | 详情 | 详情 | |
| (VI) | 60229 | 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}alanine | C20H35NO6 | 详情 | 详情 | |
| (VII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
| (VIII) | 60230 | phenylmethyl 1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinecarboxylate | C32H48N2O7 | 详情 | 详情 | |
| (IX) | 23165 | (2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid | C25H42N2O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The esterification of N2-(benzyloxycarbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (X) by means of BTU in dichloromethane/methanol gives the methyl ester (XI), which is reduced with iBu2AlH in dichloromethane to yield the corresponding aldehyde (XII). The reaction of (XII) with NaCN and Ac2O affords the acetylated cyanohydrin (XIII), which is hydrolyzed with HCl in ethyl ether/methanol to provide the alpha-hydroxyester (XIV). The trans-esterification of (XIV) with isopropanol and HCl gives the isopropyl ester (XV), which is N2 deprotected by means of H2 over Pd/C in DMF to yield the primary amine (XVI). The condensation of the lysine derivative (XVI) with the dipeptide intermediate (IX) by means of HOBT and DCC in DMF affords the tripeptide derivative (XVII), which is oxidized by means of DMP in dichloromethane to provide the alpha-oxo ester (XVIII). Finally, this compound is Boc-deprotected by means of TFA in dichloromethane to obtain the target alpha-oxo-tripeptide derivative.
| 【1】 Adang, A.E.P.; De Man, A.P.A.; Vogel, G.M.T.; Grootenhuis, P.D.J.; Smit, M.J.; Peters, C.A.M.; Visser, A.; Rewinkel, J.B.M.; van Dinther, T; Lucas, H.; Kelder, J.; van Aelst, S.; Meuleman, D.G.; van Boeckel, C.A.A.; Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem 2002, 45, 20, 4419. |
| 【2】 Adang, A.E.P.; Peters, J.A.M.; Van Boeckel, C.A.A.; Rewinkel, J.B.M. (Akzo Nobel N.V.); Thrombin inhibitors. WO 9807308 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 23165 | (2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid | C25H42N2O7 | 详情 | 详情 | |
| (X) | 39273 | (2S)-2-[[(benzyloxy)carbonyl]amino]-6-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (XI) | 60218 | methyl 6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-({[(phenylmethyl)oxy]carbonyl}amino)hexanoate | C20H30N2O6 | 详情 | 详情 | |
| (XII) | 60219 | benzyl (1S)-5-[(tert-butoxycarbonyl)amino]-1-formylpentylcarbamate | C19H28N2O5 | 详情 | 详情 | |
| (XIII) | 60220 | 1-cyano-6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-({[(phenylmethyl)oxy]carbonyl}amino)hexyl acetate | C22H31N3O6 | 详情 | 详情 | |
| (XIV) | 60221 | methyl 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxy-3-({[(phenylmethyl)oxy]carbonyl}amino)heptanoate | C21H32N2O7 | 详情 | 详情 | |
| (XV) | 60222 | 1-methylethyl 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxy-3-({[(phenylmethyl)oxy]carbonyl}amino)heptanoate | C23H36N2O7 | 详情 | 详情 | |
| (XVI) | 60223 | 1-methylethyl 3-amino-7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxyheptanoate | C15H30N2O5 | 详情 | 详情 | |
| (XVII) | 60224 | 1-methylethyl 3-[({1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinyl}carbonyl)amino]-7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxyheptanoate | C40H70N4O11 | 详情 | 详情 | |
| (XVIII) | 60225 | 1-methylethyl 3-[({1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinyl}carbonyl)amino]-7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-oxoheptanoate | C40H68N4O11 | 详情 | 详情 |