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【结 构 式】 
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【分子编号】14062 【品名】Nicotinonitrile; 3-Cyanopyridine 【CA登记号】100-54-9 |
【 分 子 式 】C6H4N2 【 分 子 量 】104.11124 【元素组成】C 69.22% H 3.87% N 26.91% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis used for the preparation of KRN2391 is as follows: The reaction of 3-cyanopyridine (I) with alcohol (ROH) in the presence of catalytic amount of alkoxide (NaOR) gives the imidate (II). The imidate (II) is converted to the cyanoimidate (III) by treatment with cyanamide in an aqueous phosphate buffer solution. The cyanoimidate (III) is coupled without further purification with nitroxyethylamine which is pre-prepared in situ from its hydrochloride (IV) and NaOH in water to provide the cyanoamidine (V). Finally, KRN2391 is obtained by salt formation of the cyanoamidine (V) with methanesulfonic acid.
| 【1】 Ogawa, N.; Izawa, T.; KRN2391. Drugs Fut 1994, 19, 6, 546. |
| 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) | 14062 | Nicotinonitrile; 3-Cyanopyridine | 100-54-9 | C6H4N2 | 详情 | 详情 |
| (II) | 14063 | methyl 3-pyridinecarboximidoate | C7H8N2O | 详情 | 详情 | |
| (III) | 14064 | methyl N-cyano-3-pyridinecarboximidoate | C8H7N3O | 详情 | 详情 | |
| (IV) | 14065 | N'-Cyano-N-[2-(nitrooxy)ethyl]-3-pyridinecarboximidamide | C9H9N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The methylation of 3-cyanopyridine (I) with methyl iodide in acetone gives 3-cyano-1-methylpyridinium iodide (II), which is reduced with NaBH4 in methanol/water yielding 1-methyl-1,2,5,6-tetrahydropyridine-3-carbonitrile (III). The reaction of (III) with ethyl chloroformate and K2CO3 in 1,1,1-trichloroethane affords 3-cyano-1,2,5,6-tetrahydropyridine-1-carboxylic acid ethyl ester (IV), which is cyclized with sodium azide by means of AlCl3 in refluxing THF giving tetrazole (V). Alkylation of (V) with ethyl iodide and NaOH in refluxing acetone, followed by column chromatography, yields 3-(2-ethyltetrazol-5-yl)-1,2,5,6-tetrahydropyridine-1-carboxylic acid ethyl ester (VI). The decarboxylation of (VI) with HBr in acetic acid affords 2-ethyl-5-(1,2,5,6-tetrahydropyridin-3-yl)tetrazole (VII), which is methylated with formaldehyde/formic acid or with methyl iodide to give 2-ethyl-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)tetrazole (VIII). Finally, this compound is treated with L-(+)-tartaric acid.
| 【1】 Pedersen, H.; Bogeso, K.P.; Moltzen, E.K.; et al.; Bioisosteres of arecoline: 1,2,3,6-Tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity. J Med Chem 1994, 37, 24, 4085-99. |
| 【2】 Castañer, J.; Mucke, H.A.M.; LU-25-109T. Drugs Fut 1998, 23, 8, 843-846. |
| 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) | 14062 | Nicotinonitrile; 3-Cyanopyridine | 100-54-9 | C6H4N2 | 详情 | 详情 |
| (II) | 17511 | 3-Cyano-1-methylpyridinium iodide | 1004-16-6 | C7H7IN2 | 详情 | 详情 |
| (III) | 17512 | 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarbonitrile | C7H10N2 | 详情 | 详情 | |
| (IV) | 17513 | ethyl 5-cyano-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H12N2O2 | 详情 | 详情 | |
| (V) | 17514 | ethyl 5-(2H-1,2,3,4-tetraazol-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H13N5O2 | 详情 | 详情 | |
| (VI) | 17515 | ethyl 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C11H17N5O2 | 详情 | 详情 | |
| (VII) | 17516 | 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-1,2,3,6-tetrahydropyridine | C8H13N5 | 详情 | 详情 | |
| (VIII) | 17517 | 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine | C9H15N5 | 详情 | 详情 | |
| (IX) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The amide anion obtained from 2-aminobenzonitrile (I) and NaH in THF was added to 3-cyanopyridine (II) yielding 2-(3-pyridyl)-4-aminoquinazoline (III). This was then condensed with 2-methoxyphenyl isocyanate (IV) to furnish the title urea.
| 【1】 Frijtag von Drabbe Künzel, J.; van Muijlwijk-Koezen, J.E.; de Groote, M.; van der Goot, H.; Menge, W.M.P.B.; Ijzerman, A.P.; Timmerman, H.; Isoquinoline and quinazoline urea analogues as antagonists for the human adenosine A3 receptor. J Med Chem 2000, 43, 11, 2227. |
| 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) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
| (II) | 14062 | Nicotinonitrile; 3-Cyanopyridine | 100-54-9 | C6H4N2 | 详情 | 详情 |
| (III) | 41952 | 2-(3-pyridinyl)-4-quinazolinamine; 2-(3-pyridinyl)-4-quinazolinylamine | C13H10N4 | 详情 | 详情 | |
| (IV) | 41953 | 1-isocyanato-2-methoxybenzene; 2-methoxyphenyl isocyanate | 700-87-8 | C8H7NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)3-Cyanopyridine (I) is converted into amidine (II), which is then condensed with 3-(trifluoromethyl)phenacyl bromide (III) to provide the target diaryl imidazole
| 【1】 Boyle, C.D.; et al.; 2,4-Diarylimidazoles as neuropeptide Y Y5 receptor antagonists. ACS Natl. Meet. 2002, Abst MEDI 335. |