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【结 构 式】 
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【分子编号】63321 【品名】methyl 4-[2-(tert-butylamino)acetyl]-7-hydroxy-1H-indole-2-carboxylate 【CA登记号】 |
【 分 子 式 】C16H20N2O4 【 分 子 量 】304.34588 【元素组成】C 63.14% H 6.62% N 9.2% O 21.03% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reaction of 3-benzyloxy-2-nitrotoluene (I) with diethyl oxalate and potassium ethoxide yields the potassium salt (II), which on reduction with iron in acetic acid atfords ethyl 7-benzyloxyindole-2-carboxylate (III). After hydrolysis of (III), 7-benzyloxyindole-2 carboxylic acid (IV) is formed, which by treatment with methanolic HCl is converted to methyl 7-benzyloxyindole-2-carboxylate (V). Debenzylation of (V) with H2 over Pd/C affords methyl 7-hydroxyindole-2-carboxylate (VI). Reaction of (VI) with tert-butylaminoacetonitrile hydrochloride in the presence of AlCl3/HCl and catalytic hdrogenation of the resulting aminoketone hydrochloride (VII) over Pd/C gives ZK-90055.
| 【1】 Loge, O.; Heindl, J.; Albrecht, R.; Beta2-Agonists containing metanolically labile groups. II. The influence of ester groups in the aryl system. Eur J Med Chem - Chim Ther 1985, 20, 57. |
| 【2】 Heindl, J; Loge, O. (Schering AG); Indole derivatives pharmaceutical preparations based thereon and beta -receptor stimulation therewith. DE 3115993; EP 0062919; GB 2098205; JP 58004765; US 4835175 . |
| 【3】 Loge, O.; heindl, J.; Albrecht, R.; Losert, W.; ZK-90055. Drugs Fut 1987, 12, 12, 1122. |
| 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) | 24147 | 1-(benzyloxy)-3-methyl-2-nitrobenzene | C14H13NO3 | 详情 | 详情 | |
| (II) | 24148 | (Z)-1-[3-(benzyloxy)-2-nitrophenyl]-3-ethoxy-3-oxo-1-propen-2-olate | C18H16NO6 | 详情 | 详情 | |
| (III) | 24149 | ethyl 7-(benzyloxy)-1H-indole-2-carboxylate | C18H17NO3 | 详情 | 详情 | |
| (IV) | 24150 | 7-(benzyloxy)-1H-indole-2-carboxylic acid | C16H13NO3 | 详情 | 详情 | |
| (V) | 24151 | methyl 7-(benzyloxy)-1H-indole-2-carboxylate | C17H15NO3 | 详情 | 详情 | |
| (VI) | 24152 | methyl 7-hydroxy-1H-indole-2-carboxylate | C10H9NO3 | 详情 | 详情 | |
| (VII) | 63321 | methyl 4-[2-(tert-butylamino)acetyl]-7-hydroxy-1H-indole-2-carboxylate | C16H20N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Alovudine can be obtained by several related ways: 1) The acylation of thymidine (I) with 4-chlorobenzoylchloride (II) in pyridine gives 5'-O-(4-chlorobenzoyl)thymidine (IX), which is then treated with diethylamino sulfur trifluoride in methylene chloride at -79 C, and finally with NaHCO3 in refluxing methanol. 2) By reaction of 2,3'-anhydro-1-(2'-deoxy-beta-D-xylofuranosyl)thymine (III) with AlF3 and 1% HF in anhydrous dioxan at 150-7 C. 3) By reaction of (III) with KHF2 or NH4F in diethylene glycol at 190C, or in ethanol at 150 C. 4) The reaction of 2,3'-anhydro-5'-O-(methylsufonyl)-1-(2'-deoxy-beta-D-xylofuranosyl) thymine (IV) with AlF3 and HF as before gives 3'-deoxy-3'-fluoro-5'-O-(methylsulfonyl)thymidine (V), which is then treated with NaOH in refluxing ethanol. 5) By reaction of 5'-O-(triphenylmethyl)thymidine (VI) with diethylamino sulfur trifluoride in THF, and then with aqueous, NaHCO3. 6) By reaction of 3'-O-(methylsulfonyl)thymidine (VII) with KHF2 or NH4F in diethylene glycol at 190 C. 7) By reaction of 2,3'-anhydro-5'-O-(triphenylmethyl)-1-(2'-deoxy-beta-D-xylofuranosyl) thymine (VIII) with 4-6% HF in anhydrous dioxan at 90 C.
| 【1】 Selway, J.W.T.; Beacham III, L.M.; Daluge, S.M.; Tuttle, J.V.; Krenitsky, T.A. (Glaxo Wellcome plc); 2,3-Dideoxy-3'-fluorothymidine and related cpds. for the treatment of adenovirus infections. AU 8821429; EP 0305117; EP 0479336; JP 1989068325; US 5070078 . |
| 【2】 Etzold, G.; Hintsche, R.; Langen, P. (Akademie der Wissenschaften der DDR); Cytostatically-active 2',3'-didesoxy-3'-fluoropyrimidine nucleosides. GB 1189973 . |
| 【3】 Castaner, J.; Hoshi, A.; Alovudine. Drugs Fut 1994, 19, 3, 221. |
| 【4】 Baba, M.; De Clercq, E.; Pauwels, R.; Herdewijn, P.; Balzarini, J.; Vanderhaeghe, H.; Broder, S.; 3'-Substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J Med Chem 1987, 30, 8, 1270-8. |
| 【5】 Kowollik, G.; Etzold, G.; Hintsche, R.; Langen, P.; Synthesis and reactivity of 3'-fluoro and 3'-chloro-3'-desoxy-thymidine. Tetrahedron 1971, 27, 2463-72. |
| 【6】 Langen, P.; Von Janta-Lipinski, M.; Gaertner, K.; Etzold, G.; Von Kowollik, G.; A novel access to 1-(2,3-didesoxy-3-fluoro-beta-D-ribofuranosyl)-pyrimidines. J Prakt Chem 1973, 315, 5, 895-900. |
| 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) | 12161 | Thymidine; 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 50-89-5 | C10H14N2O5 | 详情 | 详情 |
| (II) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (III) | 12163 | (1R,9R,10R)-10-(Hydroxymethyl)-4-methyl-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one | C10H12N2O4 | 详情 | 详情 | |
| (IV) | 12164 | [(1R,9R,10R)-4-methyl-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-10-yl]methyl methanesulfonate | C11H14N2O6S | 详情 | 详情 | |
| (V) | 12165 | [(2R,3S,5R)-3-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl methanesulfonate | C11H15FN2O6S | 详情 | 详情 | |
| (VI) | 12166 | 1-[(2R,4S,5R)-4-Hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C29H28N2O5 | 详情 | 详情 | |
| (VII) | 12167 | (2R,3S,5R)-2-(hydroxymethyl)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl methanesulfonate | C11H16N2O7S | 详情 | 详情 | |
| (VIII) | 12168 | (1R,9R,10R)-4-Methyl-10-[(trityloxy)methyl]-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one | C29H26N2O4 | 详情 | 详情 | |
| (IX) | 63321 | methyl 4-[2-(tert-butylamino)acetyl]-7-hydroxy-1H-indole-2-carboxylate | C16H20N2O4 | 详情 | 详情 |