|
【结 构 式】 
|
【分子编号】64728 【品名】ethyl 2-[8-(2-amino-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoate 【CA登记号】 |
【 分 子 式 】C26H32N2O3 【 分 子 量 】420.55176 【元素组成】C 74.26% H 7.67% N 6.66% O 11.41% |
合成路线1
该中间体在本合成路线中的序号：(XII)Demethylation of tropinone (I) by means of 1-chloroethyl chloroformate, followed by protection of the resultant secondary amine (II) with di-tert-butyl dicarbonate, leads to the N-Boc derivative (III). Treatment of the potassium enolate of (III) with N-phenyl trifluoromethanesulfonimide produces the vinyl triflate (IV), which is then converted to the stannyl derivative (V) upon treatment with hexamethylditin and palladium catalyst. Stille coupling of (V) with ethyl 2-bromobenzoate (VI) affords (VII). After catalytic double bond hydrogenation of (VII), the resultant mixture of diastereoisomers is separated by recrystallization from hexane/ethyl acetate to give (VIII). The N-Boc protecting group of (VIII) is cleaved with HCl in dioxane to yield amine (IX), which is then coupled with N-Boc-D-benzylalanine (X) to furnish amide (XI). Subsequent acidic Boc-group cleavage gives rise to the amine (XII).
| 【1】 Lu, Z.; Tata, J.R.; Cheng, K.; Wei, L.; Chan, W.W.-S.; Butler, B.; Schleim, K.D.; Jacks, T.M.; Hickey, G.; Patchett, A.A.; Substituted bridged phenyl piperidines: Orally active growth hormone secretagogues. Bioorg Med Chem Lett 2003, 13, 10, 1817. |
| 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) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (II) | 64720 | 8-azabicyclo[3.2.1]octan-3-one | C7H11NO | 详情 | 详情 | |
| (III) | 64721 | 1,1-dimethylethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate | C12H19NO3 | 详情 | 详情 | |
| (IV) | 64722 | 1,1-dimethylethyl 3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C13H18F3NO5S | 详情 | 详情 | |
| (V) | 64723 | 1,1-dimethylethyl 3-(trimethylstannanyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C15H27NO2Sn | 详情 | 详情 | |
| (VI) | 58367 | ethyl 2-bromobenzoate; 2-Bromobenzoic acid ethyl ester | 6091-64-1 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 64724 | 1,1-dimethylethyl 3-{2-[(ethyloxy)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C21H27NO4 | 详情 | 详情 | |
| (VIII) | 64725 | 1,1-dimethylethyl 3-{2-[(ethyloxy)carbonyl]phenyl}-8-azabicyclo[3.2.1]octane-8-carboxylate | C21H29NO4 | 详情 | 详情 | |
| (IX) | 64726 | ethyl 2-(8-azabicyclo[3.2.1]oct-3-yl)benzoate | C16H21NO2 | 详情 | 详情 | |
| (X) | 52886 | Boc-(-)-alpha-amino-4-phenylbutyric acid; Boc-D-Homophenylalanine | 82732-07-8 | C15H21NO4 | 详情 | 详情 |
| (XI) | 64727 | ethyl 2-{8-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-phenylbutanoyl]-8-azabicyclo[3.2.1]oct-3-yl}benzoate | C31H40N2O5 | 详情 | 详情 | |
| (XII) | 64728 | ethyl 2-[8-(2-amino-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoate | C26H32N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Coupling of the amine (XII) with N-Boc-2-aminoisobutyric acid (XIII) leads to the dipeptide amide (XIV). Alkaline hydrolysis of the ethyl ester group of (XIV) gives the benzoic acid (XV), which is then coupled to ethylamine to produce the amide (XVI). Finally, the N-Boc protecting group of (XVI) is cleaved by means of HCl in dioxane to furnish the target compound.
| 【1】 Lu, Z.; Tata, J.R.; Cheng, K.; Wei, L.; Chan, W.W.-S.; Butler, B.; Schleim, K.D.; Jacks, T.M.; Hickey, G.; Patchett, A.A.; Substituted bridged phenyl piperidines: Orally active growth hormone secretagogues. Bioorg Med Chem Lett 2003, 13, 10, 1817. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 64728 | ethyl 2-[8-(2-amino-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoate | C26H32N2O3 | 详情 | 详情 | |
| (XIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIV) | 64729 | ethyl 2-[8-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropanoyl]amino}-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoate | C35H47N3O6 | 详情 | 详情 | |
| (XV) | 64730 | 2-[8-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropanoyl]amino}-4-phenylbutanoyl)-8-azabicyclo[3.2.1]oct-3-yl]benzoic acid | C33H43N3O6 | 详情 | 详情 | |
| (XVI) | 64731 | 1,1-dimethylethyl 2-({1-[(3-{2-[(ethylamino)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-3-phenylpropyl}amino)-1,1-dimethyl-2-oxoethylcarbamate | C35H48N4O5 | 详情 | 详情 |