|
【结 构 式】 
|
【分子编号】10445 【品名】N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine 【CA登记号】1142-20-7 |
【 分 子 式 】C11H13NO4 【 分 子 量 】223.22856 【元素组成】C 59.19% H 5.87% N 6.27% O 28.67% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of methyl 1-aminocyclopentane-1-carboxylate (I) with N-benzyloxycarbonyl-alanine (II) by the mixed anhydride method gives methyl 1-(benzyloxycarbonyl-alanyl)aminocyclopentane-1-carboxylate (III). Debenzylation of (III) by hydrogenation with H2 over Pd/C in methanol followed by a cyclization reaction in refluxing toluene yields alaptide.
| 【1】 Kasafirek, E.; Vanzura, J.; Krejci, I.; Krepelka, J.; Dlabac, A.; Valchar, M. (SPOFA - United Pharmaceutical Works); 2,5-Piperazinedione derivs. CS 231227; GB 2127807 . |
| 【2】 Rádl, S.; Kasafírek, E.; Krejcí, I.; ALAPTIDE. Drugs Fut 1990, 15, 5, 445. |
| 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) | 10444 | methyl 1-aminocyclopentanecarboxylate | C7H13NO2 | 详情 | 详情 | |
| (II) | 10445 | N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine | 1142-20-7 | C11H13NO4 | 详情 | 详情 |
| (III) | 10446 | methyl 1-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)amino]cyclopentanecarboxylate | C18H24N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Diol (I) was protected as the isopropylidene ketal (III) by reaction with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid. Then, the N-carbobenzoxy groups of (III) were eliminated by hydrogenolysis on Pd/C to give the diamine (IV), and this was coupled with N-carbobenzoxy-valine (V) using O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (HBTU) to afford (VI). A new sequence of hydrogenolytic Cbz deprotection to give diamine (VII) and coupling with N-carbobenzoxy-alanine (VIII) and HBTU provided (IX). Finally, the target compound was obtained by hydrolysis of the isopropylidene ketal in methanol containing p-toluenesulfonic acid.
| 【1】 Lee, T.; et al.; Analysis of the S3 and S3' subsite specificities of feline immunodeficiency virus (FIV) protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo. Proc Natl Acad Sci USA 1998, 95, 3, 939-944. |
| 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) | 16587 | benzyl (1S,2R,3R,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 18090 | benzyl (1S)-1-[(4R,5R)-5-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylcarbamate | C37H40N2O6 | 详情 | 详情 | |
| (IV) | 18091 | (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine | C21H28N2O2 | 详情 | 详情 | |
| (V) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (VI) | 18093 | benzyl (1S)-1-([[(1S)-1-((4R,5R)-5-[(1S)-1-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2-phenylethyl]amino]carbonyl)-2-methylpropylcarbamate | C47H58N4O8 | 详情 | 详情 | |
| (VII) | 18094 | (2S)-2-amino-N-[(1S)-1-[(4R,5R)-5-((1S)-1-[[(2S)-2-amino-3-methylbutanoyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethyl]-3-methylbutanamide | C31H46N4O4 | 详情 | 详情 | |
| (VIII) | 10445 | N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine | 1142-20-7 | C11H13NO4 | 详情 | 详情 |
| (IX) | 18095 | benzyl (1S)-2-[((1S)-1-[[((1S)-1-[(4R,5R)-5-[(1S,4S,7S)-1-benzyl-4-isopropyl-7-methyl-3,6,9-trioxo-11-phenyl-10-oxa-2,5,8-triazaundec-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethyl)amino]carbonyl]-2-methylpropyl)amino]-1-methyl-2-oxoethylcarbam | C53H68N6O10 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Deprotection of the 6-benzyloxypyrrolotriazine (I) by transfer hydrogenation with ammonium formate and Pd/C in DMF provides alcohol (II) , which is condensed with (R)-propylene oxide (III) in the presence of triethylamine , and optionally LiCl , in ethanol at 70 °C to give the hydroxypropyl derivative brivanib (IV) . Subsequent coupling of alcohol (IV) with N-Cbz-L-alanine (V) by means of HATU in the presence of DIEA and DMAP in DMF or THF gives the N-protected alanine ester (VI), which is finally deprotected by treatment with ammonium formate and Pd/C in DMF . Alcohol intermediate (II) is alternatively obtained by addition of methylmagnesium bromide to the 6-(ethoxycarbonyl)pyrrolotriazine derivative (VII) in THF to afford the tertiary alcohol (VIII), which undergoes oxidative cleavage to the key 6-hydroxypyrrolotriazine (II) in the presence of H2O2 and BF3·Et2O in dichloromethane .
| 【1】 Bhide, R.S., Cai, Z.W., Zhang, Y.Z. et al. Discovery and preclinical studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem 2006, 49(7): 2143-6. |
| 【2】 Cai, Z.-W., Qian, L., Bhide, R., Barbosa, A. (Bristol-Myers Squibb Co.).Novel inhibitors of kinases. EP 1434290, JP 2005538989, US 2004072832, US 6869952, WO 2004009784. |
| 【3】 Cai, Z.W., Zhang, Y.Z., Borzilleri, R.M. et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008, 51(6):1976-80. |
| 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) | 69463 | 6-(benzyloxy)-4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine | C23H19FN4O2 | 详情 | 详情 | |
| (II) | 69464 | 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol | C16H13FN4O2 | 详情 | 详情 | |
| (III) | 62110 | (R)-(+)-PROPYLENE OXIDE; 1,2-Epoxypropane; R(+)-Propylene oxide; R(+)-Methyloxirane; (R)-propylene oxide; [(R-(+)-1,2-EPOXYPROPANE]; (R)-(+)-1,2-Propylene oxide; (R)-(+)-1,2-Epoxypropane | 15448-47-2 | C3H6O | 详情 | 详情 |
| (IV) | 69465 | (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol | C19H19FN4O3 | 详情 | 详情 | |
| (V) | 10445 | N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine | 1142-20-7 | C11H13NO4 | 详情 | 详情 |
| (VI) | 69466 | (R)-(S)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-(((benzyloxy)carbonyl)amino)propanoate | C30H30FN5O6 | 详情 | 详情 | |
| (VII) | 69467 | ethyl 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate | C19H17FN4O3 | 详情 | 详情 | |
| (VIII) | 69468 | 2-(4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)propan-2-ol | C19H19FN4O2 | 详情 | 详情 |