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【结 构 式】 
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【分子编号】25859 【品名】6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether 【CA登记号】 |
【 分 子 式 】C11H15NO2 【 分 子 量 】193.24564 【元素组成】C 68.37% H 7.82% N 7.25% O 16.56% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-(4-nitrophenyl)ethyl bromide (I) with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (II) by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline (III), which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine (IV). Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) by means of DCC and HOBt in DMF to afford the target carboxamide. The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) has been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid (VI) with 2-bromobenzoic acid (VII) by means of K2CO3 and copper dust give the diphenylamine (VIII), which is cyclized to the target acridine (V) by means of POCl3 in refluxing acetonitrile.
| 【1】 Dodic, N.; et al.; Synthesis and activity against multidrug resistance in Chinese hamster ovary cells of new acridone-4-carboxamides. J Med Chem 1995, 38, 13, 2418. |
| 【2】 Dumaitre, B.A.; Dodic, N. (GlaxoSmithKline plc); Acridine derivs.. EP 0494623; EP 0569380; JP 1994506440; US 5604237; WO 9212132 . |
| 【3】 Sharp, M.J.; Mader, C.J.; Strachan, C. (GlaxoSmithKline plc); Synthesis of acridine deriv. multidrug-resistant inhibitors. WO 9852923 . |
| 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) | 19191 | 1-(2-bromoethyl)-4-nitrobenzene | 5339-26-4 | C8H8BrNO2 | 详情 | 详情 |
| (II) | 25859 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C11H15NO2 | 详情 | 详情 | |
| (III) | 19193 | 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C19H22N2O4 | 详情 | 详情 | |
| (IV) | 19194 | 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]aniline; 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]phenylamine | C19H24N2O2 | 详情 | 详情 | |
| (V) | 53881 | 5-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | n/a | C15H11NO4 | 详情 | 详情 |
| (VI) | 53879 | 2-Amino-3-methoxybenzoic acid; 2-Amino-m-anisic acid; 3-Methoxyanthranilic acid | 3177-80-8 | C8H9NO3 | 详情 | 详情 |
| (VII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
| (VIII) | 53880 | 2-(2-carboxyanilino)-3-methoxybenzoic acid | n/a | C15H13NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Condensation of 2-chloro-2-(3,4-dimethoxyphenyl)acetonitrile (I) with p-thiocresol (II) in the presence of K2CO3 gave thioether (III). Alternatively, thioether (III) was obtained by reaction of the anion of (3,4-dimethoxyphenyl)acetonitrile (IV) with p-tolyl disulfide (V). Subsequent alkylation of (III) with 1-bromo-5-chloropentane using NaH in DMSO produced the 5-chloropentyl derivative (VI). This was finally condensed with tetrahydroisoquinoline (VII) to yield the title compound.
| 【1】 Berger, D.; et al.; Novel multidrug resistance reversal agents. J Med Chem 1999, 42, 12, 2145. |
| 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) | 25855 | 2-chloro-2-(3,4-dimethoxyphenyl)acetonitrile | 7537-07-7 | C10H10ClNO2 | 详情 | 详情 |
| (III) | 25856 | 2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]acetonitrile | C17H17NO2S | 详情 | 详情 | |
| (IV) | 25857 | 2-(3,4-dimethoxyphenyl)acetonitrile | 93-17-4 | C10H11NO2 | 详情 | 详情 |
| (VI) | 25858 | 7-chloro-2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]heptanenitrile | C22H26ClNO2S | 详情 | 详情 | |
| (VII) | 25859 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C11H15NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Acylation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (I) with N-Boc-nipecotic acid (II) by means of EDC/HOBt gives amide (III). Subsequent acidic cleavage of the Boc protecting group yields amine (IV). 3,4-Methylenedioxyaniline (V) is acylated by acryloyl chloride in the presence of Et3N to produce the acrylanilide (VI). Then, Michael addition of piperidine (IV) to the acrylanilide (VI) in boiling toluene provides the title compound.
| 【1】 Kakefuda, A.; Okazaki, T.; Watanabe, T.; et al.; Structure-activity relationships of novel 1,2,3,4-tetrahydroisoquinolin derivatives as bradycardic agents. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Okazaki, T.; Watanabe, T.; Wada, K.; Kakefuda, A.; Masuda, N. (Yamanouchi Pharmaceutical Co., Ltd.); Novel isoquinoline derivs. or salts thereof. EP 1186601; WO 0075133 . |
| 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) | 25859 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C11H15NO2 | 详情 | 详情 | |
| (II) | 57078 | Boc-nipecotic acid | C11H19NO4 | 详情 | 详情 | |
| (III) | 58821 | tert-butyl 3-{[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]carbonyl}-1-piperidinecarboxylate | C22H32N2O5 | 详情 | 详情 | |
| (IV) | 58822 | [6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl](3-piperidinyl)methanone | C17H24N2O3 | 详情 | 详情 | |
| (V) | 10984 | 1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline | 14268-66-7 | C7H7NO2 | 详情 | 详情 |
| (VI) | 58823 | N-(1,3-benzodioxol-5-yl)acrylamide | C10H9NO3 | 详情 | 详情 |