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【结 构 式】 
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【分子编号】33303 【品名】2-(bromomethyl)benzonitrile 【CA登记号】22115-41-9 |
【 分 子 式 】C8H6BrN 【 分 子 量 】196.04638 【元素组成】C 49.01% H 3.08% Br 40.76% N 7.14% |
合成路线1
该中间体在本合成路线中的序号：(B)It can be obtained in two different ways, both starting from ethyl alpha-(4-aminophenyl)propionate (I): 1) The condensation of the amino compound (I) with benzaldehyde (A), followed by reduction of the Schiff base with H2 over Pt in ethanol gives ethyl alpha-(benzylaminophenyl)propionate (II), which by reaction with phosgene in toluene affords ethyl alpha-[N-chlorocarbonyl-(4-benzylaminophenyl)]propionate (III); the cyclization of this compound with AlCl3 in CH2Cl2 yields ethyl alpha-[4-(1-oxo-2-iso-indolinyl)phenyl]propionate (IV), which is finally saponified with K2CO3 in ethanol - water. 2) The cyclization of the amino compound (I) with 2-cyanobenzyl bromide (B) in refluxing ethanol affords ethyl alpha-[4-(1-imino-2-iso-indolinyl)phenyl]propionate (V). which is finally hydrolyzed and saponified with K2CO3 as before. The starting aminoester (I) is obtained as follows: The nitration of alpha-phenylpropionitrile (VI) gives alpha-(4-nitrophenyl)propionitrile (VII), which is hydrolyzed with H2SO4 to alpha-(4-nitrophenyl)propionic acid (VIII). Esterification of this acid with ethanol and H2SO4 yields ethyl alpha-(4-nitrophenyl)propionate (IX), which is finally reduced with H2 over Pd/C in ethanol giving the aminoester (I), b.p.(0.5mm) 125 C.
| 【1】 Castaner, J.; Arrigoni, Martelli, E.; Indoprofen. Drugs Fut 1976, 1, 5, 242. |
| 【2】 Nanini, G.; et al.; New analgesic-anti-inflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch 1973, 23, Suppl. 3, 1090. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (B) | 33303 | 2-(bromomethyl)benzonitrile | 22115-41-9 | C8H6BrN | 详情 | 详情 |
| (I) | 33984 | ethyl 2-(4-aminophenyl)propanoate | C11H15NO2 | 详情 | 详情 | |
| (II) | 60734 | ethyl 2-[4-(benzylamino)phenyl]propanoate | C18H21NO2 | 详情 | 详情 | |
| (III) | 60737 | ethyl 2-{4-[benzyl(chlorocarbonyl)amino]phenyl}propanoate | C19H20ClNO3 | 详情 | 详情 | |
| (IV) | 60738 | ethyl 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]propanoate | C19H19NO3 | 详情 | 详情 | |
| (V) | 60739 | ethyl 2-[4-(1-imino-1,3-dihydro-2H-isoindol-2-yl)phenyl]propanoate | C19H20N2O2 | 详情 | 详情 | |
| (VI) | 60735 | hydratroponitrile | C9H9N | 详情 | 详情 | |
| (VII) | 60736 | 2-(4-nitrophenyl)propanenitrile | C9H8N2O2 | 详情 | 详情 | |
| (VIII) | 52520 | 2-(4-nitrophenyl)propanoic acid | C9H9NO4 | 详情 | 详情 | |
| (IX) | 33983 | ethyl 2-(4-nitrophenyl)propanoate | C11H13NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The cyclization of (XI) with o-cyanobenzyl bromide (XII) in refluxing ethanol gives 1-imino-2-[p-[(alpha-ethyl)carboxymethyl]phenyl]isoindoline (XIII), which is finally hydrolyzed with K2CO3 in refluxing ethanol water.
| 【1】 Giraldi, P.N.; et al.; Dérivés d'iso-indoline et procédé de leur préparation. DE 2154525; FR 2112480; JP 51068563; JP 52017463; NL 7115288 . |
| 【2】 Nannini, G.; et al.; New analgesic-antiinflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch Drug Res 1973, 23, 8, 1090. |
| 【3】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
合成路线3
该中间体在本合成路线中的序号：(II)6-Chlorouracil (I) is alkylated with 2-(bromomethyl)benzonitrile (II) in the presence of NaH and LiBr in DMF/DMSO to produce the N-benzyluracil derivative (III), which is further alkylated with iodomethane and NaH in DMF/THF to yield the 1,3-disubstituted uracil (IV) (1-3). Intermediate (IV) is alternatively obtained by alkylation of 6-chloro-3-methyluracil (V) with 2-(bromomethyl)benzonitrile (II) by means of diisopropylethylamine in hot NMP (3). Subsequent displacement of chlorouracil (IV) with 3(R)-aminopiperidine dihydrochloride (VI) in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (1-3), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol (3). Scheme 1.
| 【1】 Feng, J., Gwaltney, S.L., Stafford, J.A. et al. (Takeda San Diego, Inc.). Dipeptidyl peptidase inhibitors. EP 1586571, JP 2005263780, US2005261271, WO 2005095381. |
| 【2】 Feng, J., Zhang, Z., Wallace, M.B. et al. Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 2007, 50(10): 2297-300. |
| 【3】 Feng, J., Gwaltney, S.L., Stafford, J.A. et al. (Takeda Pharmaceutical Co., Ltd.). WO 2007035629. |
| 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) | 65543 | 6-Chloro-2,4-Pyrimidinediol | 107577-09-3 | C4H3ClN2O2 | 详情 | 详情 |
| (II) | 33303 | 2-(bromomethyl)benzonitrile | 22115-41-9 | C8H6BrN | 详情 | 详情 |
| (III) | 65544 | 2-((6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile | 865758-95-8 | C12H8ClN3O2 | 详情 | 详情 |
| (IV) | 65545 | 2-((6-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile | C13H10N3O2 | 详情 | 详情 | |
| (V) | 65546 | 6-Chloro-3-methyluracil; 3-Methyl-6-chlorouracil | 4318-56-3 | C5H5ClN2O2 | 详情 | 详情 |
| (VI) | 65547 | (R)-3-Aminopiperidine dihydrochloride | C5H12N2.2HCl | 详情 | 详情 |