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【结 构 式】 
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【分子编号】58367 【品名】ethyl 2-bromobenzoate; 2-Bromobenzoic acid ethyl ester 【CA登记号】6091-64-1 |
【 分 子 式 】C9H9BrO2 【 分 子 量 】229.07326 【元素组成】C 47.19% H 3.96% Br 34.88% O 13.97% |
合成路线1
该中间体在本合成路线中的序号：(VI)Tropinone (I) is demethylated by treatment with 1-chloroethyl chloroformate, followed by decomposition of the intermediate carbamate in refluxing MeOH. The resultant N-nortropinone (II) is then protected with Boc2O to produce (III). Treatment of N-Boc-nortropinone (III) with N-phenyl trifluoromethanesulfonimide in the presence of potassium bis(trimethylsilyl)amide gives rise to the vinyl triflate (IV), which is further converted to the stannyl derivative (V) with hexamethylditin in the presence of palladium catalyst. Stille coupling of the stannyl compound (V) with ethyl 2-bromobenzoate (VI) produces the aryl tropane derivative (VII). Catalytic hydrogenation of the double bond of (VII) gives rise to a mixture of cis (VIII) and trans (IX) saturated isomers, which are separated by either chromatography or by recrystallization. The desired isomer (VIII) is then deprotected under acidic conditions to furnish the secondary amine (X). Coupling of (X) with (R)-N-Boc-2-amino-5-phenylpentanoic acid (XI) yields amide (XII).
| 【1】 Brinkmann, V.; Hesise, C.E.; Davis, M.D.; et al.; FTY720, a novel therapeutic for transplantation and autoimmunity, targets G-protein-coupled receptors for sphingosine-1-phosphate. 19th Int Congr Transplant Soc (Aug 25 2002, Miami) 2002, Abst 0116. |
| 【2】 Patchett, A.A.; Tata, J.R.; Lu, Z. (Merck & Co., Inc.); Bridged piperidines promote release of growth hormone. US 5731317 . |
| 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) | 58363 | (1R,5S)-8-azabicyclo[3.2.1]octan-3-one | C7H11NO | 详情 | 详情 | |
| (III) | 58364 | tert-butyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate | C12H19NO3 | 详情 | 详情 | |
| (IV) | 58365 | tert-butyl (1S,5R)-3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C13H18F3NO5S | 详情 | 详情 | |
| (V) | 58366 | tert-butyl (1S,5R)-3-(trimethylstannyl)-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) | 58368 | tert-butyl (1S,5R)-3-[2-(ethoxycarbonyl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate | C21H27NO4 | 详情 | 详情 | |
| (VIII) | 58369 | tert-butyl (1R,5S)-3-[2-(ethoxycarbonyl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylate | C21H29NO4 | 详情 | 详情 | |
| (IX) | 58370 | tert-butyl (1R,5S)-3-[2-(ethoxycarbonyl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylate | C21H29NO4 | 详情 | 详情 | |
| (X) | 58371 | ethyl 2-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]benzoate | C16H21NO2 | 详情 | 详情 | |
| (XI) | 18468 | (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoic acid | C16H23NO4 | 详情 | 详情 | |
| (XII) | 58372 | ethyl 2-((1R,5S)-8-{(2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoyl}-8-azabicyclo[3.2.1]oct-3-yl)benzoate | C32H42N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |