|
【结 构 式】 
|
【分子编号】24175 【品名】N-[(2R)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide 【CA登记号】 |
【 分 子 式 】C16H21NO4 【 分 子 量 】291.34708 【元素组成】C 65.96% H 7.27% N 4.81% O 21.97% |
合成路线1
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (VI): 2) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is acetilated with acetic anhydride to give 2-acetylamino-1,2,3,4-tetrahydro-2-naphthoic acid (XV), which is submitted to optical resolution with I-alpha-phenylethylamine yielding the 2(R) isomer (XVI). Esterification of (XVI) with methanol-H2SO4 affords the corresponding methyl ester (XVII), which by reaction first with NaH and DMSO and then with Al-Hg in THF is converted into the acetyl derivative (VI).
| 【1】 Ishizumi, K.; Ohashi, N.; Tanno, N.; Sato, H.; Fukui, M.; Morisada, S. (Sumitomo Pharmaceuticals Co., Ltd.); Aminonaphthacene derivs.. EP 0107486; US 4673668 . |
| 【2】 Hoshi, A.; Prous, J.; Castaner, J.; SM-5887. Drugs Fut 1988, 13, 11, 962. |
| 【3】 Ishizumi, K.; et al.; Stereospecific total synthesis of 9-aminoanthracyclines: (+)-9-Amino-9-deoxydaunomycin and related compounds. J Org Chem 1987, 52, 20, 4477-85. |
| 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) | 24172 | 5,8-dimethoxy-3,4-dihydro-2(1H)-naphthalenone | C12H14O3 | 详情 | 详情 | |
| (II) | 24173 | 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid | C13H17NO4 | 详情 | 详情 | |
| (VI) | 24175 | N-[(2R)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C16H21NO4 | 详情 | 详情 | |
| (XV) | 24174 | 2-(acetamido)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid | C15H19NO5 | 详情 | 详情 | |
| (XVI) | 24177 | (2R)-2-(acetamido)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid | C15H19NO5 | 详情 | 详情 | |
| (XVII) | 24176 | methyl (2R)-2-(acetamido)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C16H21NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (VI): 1) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is esterified with methanol-HCl to the corresponding methyl ester (III). The optical resolution of (III) with D-(-)-mandelic acid affords the 2R isomer (IV), which by reaction first with NaH and DMSO and then with Zn and NaOH in water gives (R)-2-acetyl-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (V). The acetylation of (V) with acetic anhydride in pyridine yields (R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI).
| 【1】 Ishizumi, K.; Ohashi, N.; Tanno, N.; Sato, H.; Fukui, M.; Morisada, S. (Sumitomo Pharmaceuticals Co., Ltd.); Aminonaphthacene derivs.. EP 0107486; US 4673668 . |
| 【2】 Ishizumi, K.; et al.; Stereospecific total synthesis of 9-aminoanthracyclines: (+)-9-Amino-9-deoxydaunomycin and related compounds. J Org Chem 1987, 52, 20, 4477-85. |
| 【3】 Hoshi, A.; Prous, J.; Castaner, J.; SM-5887. Drugs Fut 1988, 13, 11, 962. |
| 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) | 24172 | 5,8-dimethoxy-3,4-dihydro-2(1H)-naphthalenone | C12H14O3 | 详情 | 详情 | |
| (II) | 24173 | 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid | C13H17NO4 | 详情 | 详情 | |
| (III) | 24180 | methyl 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 24181 | methyl (2R)-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C14H19NO4 | 详情 | 详情 | |
| (V) | 24182 | 1-[(2R)-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-1-ethanone | C14H19NO3 | 详情 | 详情 | |
| (VI) | 24175 | N-[(2R)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C16H21NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)(R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI) is submitted to a Friedel-Crafts cyclocondensation with phthalic anhydride (VII) by means of anhydrous AlCl3 at 135 C to afford (R)-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (VIII). The protection of the acetyl group of (VIII) with ethylene glycol and p-toluenesulfonic acid gives the corresponding ketal (IX), which by cyclization with 1,3-dibromo-5,5-dimethylhydantoin (DDH) yields the pentacyclic oxazine (X). The hydrolysis of (X) with hot H2SO4 affords 9-amino-4-demethoxy-9-deoxydaunomycinone (XI), which is condensed with 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranosyl bromide (XII) (obtained from acetyl 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranoside (XIII) and trimethylsilyl bromide) by means of tetramethylurea in chloroform to give the 3',4'- di-O-acetyl derivative (XIV) of the desired product. Finally, this compound is deprotected by hydrolysis with anhydrous K2CO3 in methanol - dichloroethane.
| 【1】 Ishizumi, K.; Ohashi, N.; Tanno, N.; Sato, H.; Fukui, M.; Morisada, S. (Sumitomo Pharmaceuticals Co., Ltd.); Aminonaphthacene derivs.. EP 0107486; US 4673668 . |
| 【2】 Ishizumi, K.; et al.; Stereospecific total synthesis of 9-aminoanthracyclines: (+)-9-Amino-9-deoxydaunomycin and related compounds. J Org Chem 1987, 52, 20, 4477-85. |
| 【3】 Hoshi, A.; Prous, J.; Castaner, J.; SM-5887. Drugs Fut 1988, 13, 11, 962. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 24175 | N-[(2R)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C16H21NO4 | 详情 | 详情 | |
| (VII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (VIII) | 24186 | N-[(2R)-2-acetyl-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl]acetamide | C22H19NO6 | 详情 | 详情 | |
| (IX) | 24187 | N-[(1R,2R)-5,12-dihydroxy-1-(2-methyl-1,3-dioxolan-2-yl)-6,11-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl]acetamide | C24H23NO7 | 详情 | 详情 | |
| (X) | 24188 | (1S,16R,17R)-3,14-dihydroxy-19-methyl-16-(2-methyl-1,3-dioxolan-2-yl)-20-oxa-18-azapentacyclo[15.3.1.0(2,15).0(4,13).0(6,11)]henicosa-2(15),3,6,8,10,13,18-heptaene-5,12-dione | C24H21NO7 | 详情 | 详情 | |
| (XI) | 24189 | (7S,9S)-9-acetyl-9-amino-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C20H17NO6 | 详情 | 详情 | |
| (XII) | 24190 | 2-bromo-5-(2-oxopropyl)tetrahydro-2H-pyran-4-yl acetate | C10H15BrO4 | 详情 | 详情 | |
| (XIII) | 24191 | 2-(acetoxy)-5-(2-oxopropyl)tetrahydro-2H-pyran-4-yl acetate | C12H18O6 | 详情 | 详情 | |
| (XIV) | 24192 | 2-[[(1S,3S)-3-acetyl-3-amino-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-5-(2-oxopropyl)tetrahydro-2H-pyran-4-yl acetate | C30H31NO10 | 详情 | 详情 |