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【结 构 式】 
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【分子编号】18468 【品名】(2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoic acid 【CA登记号】 |
【 分 子 式 】C16H23NO4 【 分 子 量 】293.36296 【元素组成】C 65.51% H 7.9% N 4.77% O 21.82% |
合成路线1
该中间体在本合成路线中的序号：(I)N-Boc-D-(3-phenylpropyl)glycine (I) was esterified to benzyl ester (II), and then, tert-butoxycarbonyl group was cleaved by acidic treatment to give amine (III). This was coupled with N-Boc-2-aminoisobutyric acid (IV) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to afford dipeptide ester (V), from which the benzyl ester group was removed by hydrogenolysis in the presence of Pd/C. The resulting acid (VI) was condensed with 1-(2-nitrophenyl)piperazine (VII) in the presence of EDC and HOBt to produce piperazide (VIII). Subsequent reduction of the nitro group by hydrogenation in the presence of Raney-Ni gave aniline (IX), which was treated with 2-propanesulfonyl chloride (X) to yield sulfonamide (XI). Finally, the tert-butoxycarbonyl protecting group was removed by treatment either with HCl in EtOAc or with trifluoroacetic acid to afford the target compound as the hydrochloride or the trifluoroacetate salt, respectively.
| 【1】 Barakat, K.J.; Cheng, K.; Chan, W.W.; Butler, B.S.; Jacks, T.M.; Schleim, K.D.; Hora, D.F. Jr.; Hickey, G.J.; Smith, R.G.; Patchett, A.A.; Nargund, R.P.; Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues. Bioorg Med Chem Lett 1998, 8, 11, 1431. |
| 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) | 18468 | (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoic acid | C16H23NO4 | 详情 | 详情 | |
| (II) | 18469 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoate | C23H29NO4 | 详情 | 详情 | |
| (III) | 18470 | benzyl (2R)-2-amino-5-phenylpentanoate | C18H21NO2 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 18472 | benzyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C27H36N2O5 | 详情 | 详情 | |
| (VI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (VII) | 18474 | 1-(2-nitrophenyl)piperazine | C10H13N3O2 | 详情 | 详情 | |
| (VIII) | 18475 | tert-butyl 1,1-dimethyl-2-[((1R)-1-[[4-(2-nitrophenyl)-1-piperazinyl]carbonyl]-4-phenylbutyl)amino]-2-oxoethylcarbamate | C30H41N5O6 | 详情 | 详情 | |
| (IX) | 18476 | tert-butyl 2-[((1R)-1-[[4-(2-aminophenyl)-1-piperazinyl]carbonyl]-4-phenylbutyl)amino]-1,1-dimethyl-2-oxoethylcarbamate | C30H43N5O4 | 详情 | 详情 | |
| (X) | 18477 | 2-propanesulfonyl chloride | 10147-37-2 | C3H7ClO2S | 详情 | 详情 |
| (XI) | 18478 | tert-butyl 2-([(1R)-1-[(4-[2-[(isopropylsulfonyl)amino]phenyl]-1-piperazinyl)carbonyl]-4-phenylbutyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C33H49N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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 |