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【结 构 式】 
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【分子编号】23048 【品名】methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate 【CA登记号】 |
【 分 子 式 】C7H11N3O2 【 分 子 量 】169.18336 【元素组成】C 49.7% H 6.55% N 24.84% O 18.91% |
合成路线1
该中间体在本合成路线中的序号：(IV)By condensation of N-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionyl-L-histidine methyl ester (I) with isopropyl 3(S)-amino-4-cyclohexyl-2(R)-hydroxybutyrate (II) by means of diphenyl phosphoryl azide (DPA) in DMF. The starting products are prepared as follows: The condensation of 3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionic acid (III) and histidine methyl ester (IV) by means of DPA in DMF gives the substituted histidine ester (I). The hydrogenation of N-(tert-butoxycarbonyl)-L-phenylalanine (V) with H2 over Rh/Al2O3 gives N-(tert-butoxycarbonyl)-L-cyclohexylalanine (VI), which is reduced with borane to the corresponding alaninol (VII). Controlled oxidation of (VII) with SO3-pyridine in benzene-DMSO affords N-(tert-butoxycarbonyl)-L-cyclohexylalaninal (VIII), which by treatment with KCN followed by hydrolysis with concentrated HCl yields 3-amino-4-cyclohexyl-2-hydroxybutyric acid (IX). Finally, this compound is esterified with isopropanol and hydrochloric acid to the starting ester (II).
| 【1】 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 5e06 11-3. |
| 【2】 Khandewal, Y.; Rajgopalan, R.; Dohadwalla, A.N.; Rupp, R.H.; De Souza, N.J. (Aventis SA); 7-Acyloxy-6-aminoacyloxypolyoxylabdanes, process for their preparation and their use. DE 3623300; EP 0252482; JP 1988023878 . |
| 【3】 Castaner, J.; Prous, J.; KRI-1314. Drugs Fut 1988, 13, 12, 1042. |
| 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) | 23045 | methyl (2S)-3-(1H-imidazol-4-yl)-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (III) | 12864 | (2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (IV) | 23048 | methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate | C7H11N3O2 | 详情 | 详情 | |
| (V) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (VI) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (VII) | 23051 | tert-butyl (1S)-2-cyclohexyl-1-(hydroxymethyl)ethylcarbamate | C14H27NO3 | 详情 | 详情 | |
| (VIII) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (IX) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)L-Histidine methyl ester (I) was protected as the bis(tritylated) derivative (II) upon treatment with triphenylmethyl chloride and Et3N. Reduction of the ester function of (III) with LiAlH4 afforded alcohol (III), which was coupled with cyclohexylmethyl bromide (IV) in the presence of NaH in DMF, yielding the cyclohexylmethyl ether (V). Finally, cleavage of the trityl protecting groups of (V) with HCl in THF provided the title compound as the dihydrochloride salt.
| 【1】 Gynther, J.; Laitinen, J.T.; Kotisaari, S.; Tuomisto, L.; Mannistö, P.T.; Kovalainen, J.T.; Christiaans, A.M.; Synthesis and in vitro pharmacology of a series of new chiral histamine H3-receptor ligands: 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives. J Med Chem 1999, 42, 7, 1193. |
| 【2】 Kovalainen, J.T.; et al.; Investigation of the stereospecificity of the histamine H3-receptor with a series of new enantiomeric ligands. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.34. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 | |
| (I) | 23048 | methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate | C7H11N3O2 | 详情 | 详情 | |
| (II) | 34449 | methyl (2S)-2-(tritylamino)-3-(1-trityl-1H-imidazol-4-yl)propanoate | C45H39N3O2 | 详情 | 详情 | |
| (III) | 34450 | (2S)-2-(tritylamino)-3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C44H39N3O | 详情 | 详情 | |
| (IV) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (V) | 34451 | N-[(1S)-2-(cyclohexylmethoxy)-1-[(1-trityl-1H-imidazol-4-yl)methyl]ethyl]-N-tritylamine; (2S)-1-(cyclohexylmethoxy)-N-trityl-3-(1-trityl-1H-imidazol-4-yl)-2-propanamine | C51H51N3O | 详情 | 详情 |