|
【结 构 式】 
|
【分子编号】54334 【品名】(2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile 【CA登记号】n/a |
【 分 子 式 】C7H9BrN2O 【 分 子 量 】217.06534 【元素组成】C 38.73% H 4.18% Br 36.81% N 12.91% O 7.37% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The deprotection of the resin (I) with piperidine in DMF gives the amino-resin (II), which is condensed with N-Fmoc-L-proline (III) by means of diisopropylcarbodiimide (DIC) in DMF to yield the anchored proline (IV). The deprotection of (IV) with piperidine in DMF affords compound (V) with a free NH group, which is condensed with 2-bromoacetic acid (VI) by means of DIC DMF to provide the bromoacetyl proline resin (VII). The condensation of (VII) with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in DMSO to give the resin anchored precursor (IX), which is finally cleaved by means of trifluoroacetic anhydride (TFAA) in THF to furnish the target pyrrolidine-carbonitrile. Alternatively, the acylation of L-prolinamide (X) with 2-bromoacetyl bromide (XI) by means of TEA and DMAP in dichloromethane gives the 1-(2-bromoacetyl)-L-prolinamide (XII), which is dehydrated by means of TFAA in dichloromethane to yield the pyrrolidine-carbonitrile (XIII). Finally, this compound is condensed with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in THF to furnish the target pyrrolidine-carbonitrile.
| 【1】 Mangold, B.L.; Mone, M.D.; Dunning, B.E.; Russell, M.E.; Brinkman, J.A.; Weldon, S.C.; Hughes, T.E.; Naderi, G.B.; Villhauer, E.B.; 1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidine-carbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2002, 45, 12, 2362. |
| 【2】 Villhauer, E.B. (Novartis AG); N-Substd. 2-cyanopyrrolidines. JP 2000511559; WO 9819998 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V),(X) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (VII),(XII) | 54331 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide | n/a | C7H11BrN2O2 | 详情 | 详情 |
| (I) | 28722 | 9H-fluoren-9-ylmethyl carbamate | 84418-43-9 | C15H13NO2 | 详情 | 详情 |
| (III) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (IV) | 42841 | 9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate | C20H20N2O3 | 详情 | 详情 | |
| (VI) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (VIII) | 54332 | 6-[(2-aminoethyl)amino]nicotinonitrile | n/a | C8H10N4 | 详情 | 详情 |
| (IX) | 54333 | (2S)-1-[2-({2-[(5-cyano-2-pyridinyl)amino]ethyl}amino)acetyl]-2-pyrrolidinecarboxamide | n/a | C15H20N6O2 | 详情 | 详情 |
| (XI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 54334 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile | n/a | C7H9BrN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of 6-chloropyridine-3-carbonitrile (I) with carbamate (II) by means of KHCO3 in hot DMF gives the adduct (III), which is treated with TFA in dichloromethane to yield 6-(2-aminoethylamino)pyridine-3-carbonitrile (IV). The cyclization of (IV) with formaldehyde affords 6-(1-imidazoldinyl)pyridine-3-carbonitrile (V), which is condensed with 1-(2-bromoacetyl)piperidine-2(S)-carbonitrile (VI) by means of TEA in THF to provide the adduct (VII). Finally, the cleavage of the imidazolidine ring of (VII) by means of TFA in water, or TFA and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin in dichloromethane, gives rise to the target pyridine-carbonitrile derivative.
| 【1】 Willand, N.; et al.; Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhihitor NVP-DPP728. Tetrahedron 2002, 58, 28, 5741. |
| 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) | 57164 | 2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile | 33252-28-7 | C6H3ClN2 | 详情 | 详情 |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 57165 | tert-butyl 2-[(5-cyano-2-pyridinyl)amino]ethylcarbamate | C13H18N4O2 | 详情 | 详情 | |
| (IV) | 54332 | 6-[(2-aminoethyl)amino]nicotinonitrile | n/a | C8H10N4 | 详情 | 详情 |
| (V) | 57166 | 6-(1-imidazolidinyl)nicotinonitrile | C9H10N4 | 详情 | 详情 | |
| (VI) | 54334 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile | n/a | C7H9BrN2O | 详情 | 详情 |
| (VII) | 57167 | 6-(3-{2-[(2S)-2-cyanopyrrolidinyl]-2-oxoethyl}-1-imidazolidinyl)nicotinonitrile | C16H18N6O | 详情 | 详情 |