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【结 构 式】 
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【药物名称】 【化学名称】2-[8-[2(R)-(2-Amino-2-methylpropionylamino)-5-phenylpentanoyl]-8-azabicyclo[3.2.1]oct-3exo-yl]-N-ethylbenzamide 【CA登记号】185099-60-9, 185099-56-3 (monoHCl) 【 分 子 式 】C31H42N4O3 【 分 子 量 】518.70539 |
【开发单位】Merck & Co. (Originator) 【药理作用】ENDOCRINE DRUGS, Pituitary Disorder Therapy, Treatment of Growth Hormone Deficiency, Treatment of Growth Hormone Secretion Disorders, Growth Hormone Secretagogues |
合成路线1
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
Alkaline hydrolysis of ethyl ester (XII) affords acid (XIII), which is further coupled to ethylamine, producing amide (XIV). Then, removal of the N-Boc group of (XIV) with HCl in EtOAc gives amine (XV). This is coupled to N-Boc-alpha-methylalanine (XVI) to furnish the dipeptide derivative (XVII). Finally, acidic Boc-group cleavage in (XVII) leads to the title compound.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XIII) | 58373 | 2-((1R,5S)-8-{(2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoyl}-8-azabicyclo[3.2.1]oct-3-yl)benzoic acid | C30H38N2O5 | 详情 | 详情 | |
| (XIV) | 58374 | tert-butyl (1R)-1-[((1R,5S)-3-{2-[(ethylamino)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-4-phenylbutylcarbamate | C32H43N3O4 | 详情 | 详情 | |
| (XV) | 58375 | 2-{(1R,5S)-8-[(2R)-2-amino-5-phenylpentanoyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-ethylbenzamide | C27H35N3O2 | 详情 | 详情 | |
| (XVI) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XVII) | 58376 | tert-butyl 2-({(1R)-1-[((1R,5S)-3-{2-[(ethylamino)carbonyl]phenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-4-phenylbutyl}amino)-1,1-dimethyl-2-oxoethylcarbamate | C36H50N4O5 | 详情 | 详情 |