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【结 构 式】 
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【分子编号】19493 【品名】2-aminobenzonitrile 【CA登记号】1885-29-6 |
【 分 子 式 】C7H6N2 【 分 子 量 】118.13812 【元素组成】C 71.17% H 5.12% N 23.71% |
合成路线1
该中间体在本合成路线中的序号：(I)By cyclocondensation of 2-aminobenzonitrile (I) with cyclohexanone (II) by means of ZnCl2 at high temperature.
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of anthranilonitrile (I) with cyclohexane-1,3-dione (II) in the presence of p-toluenesulfonic acid (removal of water) gives the enaminoketone (III). Cyclization of (III) in the presence of K2CO3 and CuCl yields the aminoketone (IV), which is then reduced with LiAlH4.
| 【1】 Shutske, G.M.; Pierrat, F.A. (Aventis Pharmaceuticals, Inc.); 9-Amino-1,2,3,4-tetrahydroacridin-1-ol and related cpds., a process for their preparation and their use as medicaments. AU 8549038; EP 0179383; ES 8701165; ES 8801213; ES 8802383; JP 1986148154; JP 1989125362; US 4631286; US 4839364 . |
| 【2】 Shutske, G.M.; VELNACRINE MALEATE < USAN >. Drugs Fut 1989, 14, 7, 643. |
合成路线3
该中间体在本合成路线中的序号：(II)The benzonaphthyridine system (III) was prepared by condensation of 1-Boc-4-piperidone (I) with 2-aminobenzonitrile (II) in the presence of ZnCl2. After acetylation of the 10-amino group of (III) with Ac2O in pyridine to afford (IV), the N-Boc protecting group was removed by treatment with HCl in dioxan-methanol, yielding 10-acetylamino-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine (V). The tricyclic amine (V) was then alkylated with the chiral sulfonate (VI), and the target compound was finally converted to the corresponding fumarate salt.
| 【1】 Honda, M.; Sato, Y.; Oka, H.; Iida, M. (Nippon Kayaku Co., Ltd.); Novel naphthyridine derivs. or salts thereof. EP 0997462; JP 2000038386; US 6294547; WO 9900388 . |
| 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) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (II) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
| (III) | 49140 | tert-butyl 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridine-2(1H)-carboxylate | C17H21N3O2 | 详情 | 详情 | |
| (IV) | 49141 | tert-butyl 10-(acetamido)-3,4-dihydrobenzo[b][1,6]naphthyridine-2(1H)-carboxylate | C19H23N3O3 | 详情 | 详情 | |
| (V) | 49142 | N-(1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridin-10-yl)acetamide | C14H15N3O | 详情 | 详情 | |
| (VI) | 49143 | (3S)-4-[benzoyl(methyl)amino]-3-(3,4-dichlorophenyl)butyl benzenesulfonate | C24H23Cl2NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Condensation of diketone (I) with the organocerium reagent derived from methylmagnesium bromide and CeCl3 afforded the oxaadamantanol (II), which was further converted to mesylate (III) upon reaction with methanesulfonyl chloride and Et3N. Subsequent fragmentation of (III) by treatment with silica gel in CH2Cl2 produced bicyclic enone (IV). This was condensed with 2-aminobenzonitrile (V) in the presence of AlCl3 in refluxing 1,2-dichloroethane to furnish the target tetracyclic derivative. Resolution was then achieved by chiral MPLC.
| 【1】 Awasthi, S.; Singhal, S.S.; Tetrahedron Asymmetry 1998, 9, 5, 835-849. |
| 【2】 Tetrahedron 1996, 51, 16, 5867-80. |
| 【3】 Muñoz-Torrero, D.; Gorbig, D.M.; Simon, M.; Contreras, J.; Camps, P.; Vivas, N.M.; Badia, A.; Banos, J.E.; Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease. Bioorg Med Chem 1998, 6, 4, 427-440. |
| 【4】 El Achad, R.; Görbig, D.M.; Camps, P.; et al.; Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine - Huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease. J Med Chem 1999, 42, 17, 3227. |
| 【5】 Contreras Lascorz, J.; El Achab, R.; Camps Garcia, P.; Baños Diez, J.E.; Muñoz-Torrero Lopez-Ibarra, D.; Badia Sancho, A.; Morral Cardoner, J.; Simon Fornell, M.; Görbig Romeu, M.; Vivas, N.M. (Medichem SA); Polycyclic aminopyridine cpds. which are acetylcholinesterase inhibitors, process for preparing them and their use. EP 0796849; ES 2100129; US 5965569; WO 9713754 . |
| 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) | 37697 | bicyclo[3.3.1]nonane-3,7-dione | C9H12O2 | 详情 | 详情 | |
| (II) | 37698 | 3-ethyl-2-oxatricyclo[3.3.1.1(3,7)]decan-1-ol | C11H18O2 | 详情 | 详情 | |
| (III) | 37699 | 3-ethyl-2-oxatricyclo[3.3.1.1(3,7)]dec-1-yl methanesulfonate | C12H20O4S | 详情 | 详情 | |
| (IV) | 37700 | 7-ethylbicyclo[3.3.1]non-6-en-3-one | C11H16O | 详情 | 详情 | |
| (V) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)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6
该中间体在本合成路线中的序号：(XV)2-Aminobenzonitrile (XV) was acylated with 2-bromoisobutyryl bromide (XVI) to afford the cyano amide (XVII). Halogen-metal exchange with ethylmagnesium bromide followed by intramolecular addition to the cyano group of (XVII) gave rise to the quinoline dione (XVIII). This was reduced to the tetrahydroquinoline (XIX) by means of LiAlH4 and AlCl3. Iodination of (XIX) with benzyltrimethylammonium iodine dichloride furnished (XX), which was coupled with ethyl acrylate (XXI) in the presence of palladium acetate, yielding the unsaturated ester (XXII). After catalytic hydrogenation of the olefin (XXII) to propionyl ester (XXIII), sulfonation and treatment with POCl3, intermediate sulfonyl chloride (XXIV) was obtained.
| 【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
| (XVI) | 19367 | 2-bromo-2-methylpropanoyl bromide | 20769-85-1 | C4H6Br2O | 详情 | 详情 |
| (XVII) | 43466 | 2-bromo-N-(2-cyanophenyl)-2-methylpropanamide | C11H11BrN2O | 详情 | 详情 | |
| (XVIII) | 43467 | 3,3-dimethyl-2,4(1H,3H)-quinolinedione | C11H11NO2 | 详情 | 详情 | |
| (XIX) | 43468 | 3,3-dimethyl-1,2,3,4-tetrahydroquinoline | C11H15N | 详情 | 详情 | |
| (XX) | 43469 | 6-iodo-3,3-dimethyl-1,2,3,4-tetrahydroquinoline | C11H14IN | 详情 | 详情 | |
| (XXI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XXII) | 43470 | ethyl (E)-3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-propenoate | C16H21NO2 | 详情 | 详情 | |
| (XXIII) | 43471 | ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate | C16H23NO2 | 详情 | 详情 | |
| (XXIV) | 43472 | ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate | C16H22ClNO4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)The cyclization of the phenylenediamine (I) with 3-ethoxy-3-iminopropionic acid ethyl ester (II) in refluxing ethanol gives the 2-(benzimidazol-2-yl)acetate (III), which is submitted to a new cyclization with 2-aminobenzonitrile (IV) by means of LiHMDS in THF to afford the target quinolinone.
| 【1】 Harris, A.; Renhowe, P.; Machajewski, T.; Shafer, C.; Wernette-Hammond, M.-E.; Pecchi, S.; Taylor, C.; McCrea, B.; McBride, C.; Jazan, E. (Chiron Corp.); Quinolinone derivs.. WO 0222598 . |
| 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) | 53573 | 2-amino-4-[(3S)-3-(dimethylamino)pyrrolidinyl]phenylamine; 4-[(3S)-3-(dimethylamino)pyrrolidinyl]-1,2-benzenediamine | n/a | C12H20N4 | 详情 | 详情 |
| (II) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
| (III) | 53574 | ethyl 2-{5-[(3S)-3-(dimethylamino)pyrrolidinyl]-1H-benzimidazol-2-yl}acetate | n/a | C17H24N4O2 | 详情 | 详情 |
| (IV) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)Treatment of 2-aminobenzonitrile (V) with N,N-dimethylacetamide dimethylacetal (VI) at 115 °C yields N’-(2-cyanophenyl)-N,N-dimethylacetamidine (VII), which by cyclization with 4-methoxyaniline (VIII) in AcOH/acetonitrile at 118 °C gives N-(4-methoxyphenyl)- 2-methylquinazolin-4-amine (IX). Finally, the secondary amine group in compound (IX) is methylated by means of NaH in DMF .
Intramolecular cyclization of the acetamidine (II) with 4-methoxy-N-methylaniline (IV) in the presence of AlCl3 in NMP at 200 °C (5).
| 【1】 Foucourt, A., Dubouilh-Benard, C., Chosson, E. et al. Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent. Tetrahedron 2010, 66(25): 4495. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 69159 | 4-methoxy-N-methylaniline hydrochloride | C8H11NO.HCl | 详情 | 详情 | |
| (V) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
| (VI) | 22915 | 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine | 18871-66-4 | C6H15NO2 | 详情 | 详情 |
| (VIII) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (IX) | 69161 | N-(4-methoxyphenyl)-2-methylquinazolin-4-amine | C16H15N3O | 详情 | 详情 |