|
【结 构 式】 
|
【分子编号】53597 【品名】methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate 【CA登记号】n/a |
【 分 子 式 】C26H28N2O4S 【 分 子 量 】464.5854 【元素组成】C 67.22% H 6.07% N 6.03% O 13.78% S 6.9% |
合成路线1
该中间体在本合成路线中的序号：(IV)The indole alkaloid catharanthine (I) is treated with m-chloroperbenzoic acid to provide the N-oxide (II). Condensation of (II) with the alkaloid vindoline (III) under Polonovski reaction conditions leads to the bis-indole adduct (IV), which is further reduced to the tetrahydropyridine compound (V). Catalytic hydrogenation of tetrahydropyridine (V) furnishes (VI). This is then oxidized to the N-oxide (VII) (3).
| 【1】 Mangeney, P.; Andriamialisoa, R.Z.; Langlois, N.; Langlois, Y.; Potier, P.; Preparation of vinblastine, vincristine, and leurosidine, antitumor alkaloids from Catharanthus spp. (Apocynaceae). J Am Chem Soc 1979, 101, 8, 2243. |
| 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) | 63594 | methyl 17-ethyl-3,13-diazapentacyclo[13.3.1.0~2,10~.0~4,9~.0~13,18~]nonadeca-2(10),4,6,8,16-pentaene-1-carboxylate | C21H24N2O2 | 详情 | 详情 | |
| (II) | 63595 | (1R,15R,18R)-17-ethyl-1-(methoxycarbonyl)-3-aza-13-azoniapentacyclo[13.3.1.0~2,10~.0~4,9~.0~13,18~]nonadeca-2(10),4,6,8,16-pentaen-13-olate | C21H24N2O3 | 详情 | 详情 | |
| (III) | 63596 | methyl 4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C25H32N2O6 | 详情 | 详情 | |
| (IV) | 53597 | methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate | n/a | C26H28N2O4S | 详情 | 详情 |
| (V) | 63598 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15R)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,16-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 | |
| (VI) | 63599 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S,17S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9-tetraen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H58N4O8 | 详情 | 详情 | |
| (VII) | 63600 | (13S,15S,17S)-13-[(3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9-tetraen-1-olate | C46H58N4O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reduction of 1-indanone (I) with NaBH4 in methanol gives 1-indanol (II), which is brominated with Tms-Br in chloroform to yield 1-bromoindane (III) (1). The condensation of (III) with triethyl phosphonoacetate (IV) and NaH in DMF affords 2-(diethoxyphosphoryl)-2-(1-indanyl)acetic acid ethyl ester (V), which is treated with paraformaldehyde and K2CO3 in refluxing THF to provide 2-(1-indanyl)acrylic acid ethyl ester (VI). The hydrolysis of (VI) with NaOH in acetone/water gives the corresponding acrylic acid (VII), which is condensed with thioacetic acid (VIII) in refluxing chloroform to yield 3-(acetylsulfanyl)-2-(1-indanyl)propionic acid ethyl ester (IX) as a mixture of the two (R,R)+(S,S) and (R,S)+(S,R) racemates. These two racemates are easily separated by HPLC affording the desired (R,R)+(S,S)-(X) racemate. The condensation of (X) with L-tryptophan methyl ester (XI) by means of EDC and HOBT in THF/chloroform to provide a diastereomeric mixture (R,R,S)+(S,S,S) of compounds that is separated by HPLC to provide the desired (R,R,S) diastereomer (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to furnish the target tryptophan derivative.
| 【1】 Inguimbert, N.; Roques, B.P.; Meudal, H.; Teffot, F.; Poras, H.; Fournié-Zaluski, M.-C.; Coric, P.; Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). J Med Chem 2002, 45, 7, 1477. |
| 【2】 Roques, B.P.; Renard, P.; Scalbert, E.; Bennejean, C.; Fournie-Lazuski, M.-C.; Inguimbert, N.; Poras, H. (ADIR et Cie.; INSERM (Institut National de la Sante et de la Recherche Medicale)); Amino acid derivs. and use thereof as NEP, ACE and ECE inhibitors. FR 2805259; WO 0160822 . |
| 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) | 23857 | 1-indanone | 83-33-0 | C9H8O | 详情 | 详情 |
| (II) | 53590 | 1-Hydroxyhydrindene; 1-Hydroxyindan; 1-Indanol | 6351-10-6 | C9H10O | 详情 | 详情 |
| (III) | 53591 | 1-bromoindane | n/a | C9H9Br | 详情 | 详情 |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 53592 | ethyl 2-(diethoxyphosphoryl)-2-(2,3-dihydro-1H-inden-1-yl)acetate | n/a | C17H25O5P | 详情 | 详情 |
| (VI) | 53593 | ethyl 2-(2,3-dihydro-1H-inden-1-yl)acrylate | n/a | C14H16O2 | 详情 | 详情 |
| (VII) | 53594 | 2-(2,3-dihydro-1H-inden-1-yl)acrylic acid | n/a | C12H12O2 | 详情 | 详情 |
| (VIII) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (IX) | 53595 | 3-(acetylsulfanyl)-2-(2,3-dihydro-1H-inden-1-yl)propanoic acid | n/a | C14H16O3S | 详情 | 详情 |
| (X) | 53596 | (2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoic acid | n/a | C14H16O3S | 详情 | 详情 |
| (XI) | 30387 | 2-amino-6-isopropyl-4-pyrimidinol | C7H11N3O | 详情 | 详情 | |
| (XII) | 53597 | methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate | n/a | C26H28N2O4S | 详情 | 详情 |