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【结 构 式】 
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【分子编号】25780 【品名】3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine 【CA登记号】10272-07-8 |
【 分 子 式 】C8H11NO2 【 分 子 量 】153.18088 【元素组成】C 62.73% H 7.24% N 9.14% O 20.89% |
合成路线1
该中间体在本合成路线中的序号：(II)Ullman reaction of 2,4-dichloro-5-nitrobenzoic acid (I) with 3,5-dimethoxyaniline (II) in the presence of cupric acetate gave the diphenylamine carboxylic acid (III), which was cyclized with polyphosphoric acid at 110 C to afford acridone (IV). This was N-alkylated with 2-(diethylamino)ethyl chloride in the presence of 18-crown-6 to provide (V). The nitro group of (V) was then reduced to amine (VI) using SnCl2 and HCl. Finally, O-demethylation with boiling 48% HBr yielded the target monodemethylated compound along with the dihydroxyl analogue, which were separated by chromatography.
| 【1】 Fravolini, A.; Tabarrini, O.; Sissi, C.; Sabatini, S.; Nocentini, G.; Barzi, A.; Cecchetti, V.; Miao, H.; Design and synthesis of modified quinolones as antitumoral acridones1. J Med Chem 1999, 42, 12, 2136. |
| 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) | 25779 | 2,4-dichloro-5-nitrobenzoic acid | C7H3Cl2NO4 | 详情 | 详情 | |
| (II) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (III) | 25781 | 4-chloro-2-(3,5-dimethoxyanilino)-5-nitrobenzoic acid | C15H13ClN2O6 | 详情 | 详情 | |
| (IV) | 25782 | 6-chloro-1,3-dimethoxy-7-nitro-9(10H)-acridinone | C15H11ClN2O5 | 详情 | 详情 | |
| (V) | 25783 | 6-chloro-10-[2-(diethylamino)ethyl]-1,3-dimethoxy-7-nitro-9(10H)-acridinone | C21H24ClN3O5 | 详情 | 详情 | |
| (VI) | 25784 | 7-amino-6-chloro-10-[2-(diethylamino)ethyl]-1,3-dimethoxy-9(10H)-acridinone | C21H26ClN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Quinoline (IV) was prepared by condensation of 3,5-dimethoxyaniline (I), pyruvic acid (II) and o-tolualdehyde (III) in refluxing EtOH. After activation of (IV) as the acid chloride (V) by means of SOCl2 in benzene, its condensation with guanidine (VI) in DMF yielded the corresponding acyl guanidine.
| 【1】 Fujiwara, J.; Mori, H.; Yamashita, H.; Kitamori, T.; Hosoya, J.; Banno, H. (Mitsui Chemicals, Inc.); Quinoline-4-carbonylguanidine derivates, process for producing the same and pharmaceutical compsns. containing the cpds.. EP 0726254; JP 1996277269; US 5627193 . |
| 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) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 27085 | 2-methylbenzaldehyde | 529-20-4 | C8H8O | 详情 | 详情 |
| (IV) | 27086 | 5,7-dimethoxy-2-(2-methylphenyl)-4-quinolinecarboxylic acid | C19H17NO4 | 详情 | 详情 | |
| (V) | 27087 | 5,7-dimethoxy-2-(2-methylphenyl)-4-quinolinecarbonyl chloride | C19H16ClNO3 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Ullman reaction of 2,4-dichloro-5-nitrobenzoic acid (I) with 3,5-dimethoxyaniline (II) in the presence of cupric acetate gave the diphenylamine carboxylic acid (III), which was cyclized with polyphosphoric acid at 110 C to afford acridone (IV). This was N-alkylated with 2-(diethylamino)ethyl chloride in the presence of 18-crown-6 to provide (V). The nitro group of (V) was then reduced to amine (VI) using SnCl2 and HCl. Finally, O-demethylation with boiling 48% HBr yielded the target dihydroxy compound along with the monodemethylated analogue, which were separated by chromatography.
| 【1】 Fravolini, A.; Tabarrini, O.; Sissi, C.; Sabatini, S.; Nocentini, G.; Barzi, A.; Cecchetti, V.; Miao, H.; Design and synthesis of modified quinolones as antitumoral acridones1. J Med Chem 1999, 42, 12, 2136. |
| 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) | 25779 | 2,4-dichloro-5-nitrobenzoic acid | C7H3Cl2NO4 | 详情 | 详情 | |
| (II) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (III) | 25781 | 4-chloro-2-(3,5-dimethoxyanilino)-5-nitrobenzoic acid | C15H13ClN2O6 | 详情 | 详情 | |
| (IV) | 25782 | 6-chloro-1,3-dimethoxy-7-nitro-9(10H)-acridinone | C15H11ClN2O5 | 详情 | 详情 | |
| (V) | 25783 | 6-chloro-10-[2-(diethylamino)ethyl]-1,3-dimethoxy-7-nitro-9(10H)-acridinone | C21H24ClN3O5 | 详情 | 详情 | |
| (VI) | 25784 | 7-amino-6-chloro-10-[2-(diethylamino)ethyl]-1,3-dimethoxy-9(10H)-acridinone | C21H26ClN3O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVI)Carboxylic acid (XV) was coupled with 3,5-dimethoxyaniline (XVI) using EDC and HOBt to produce amide (XVII), which was cyclized to the fused pyrazinone derivative (XVIII) by treatment with pyridinium p-toluenesulfonate in toluene. The benzyloxycarbonyl group of (XVIII) was then removed by catalytic hydrogenation to give amine (XIX). This was finally coupled with (3,4,5-trimethoxyphenyl)glyoxylic acid (XX) to yield the title amide.
| 【1】 Reich, S.; Guo, C.X.; Villafranca, E.; Showalter, R.; Dong, L.; A concise synthesis of AG5473/5507 utilizing N-acyliminium ion chemistry. Tetrahedron Lett 2000, 41, 28, 5307. |
| 【2】 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 . |
| 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) | 43303 | 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid | C20H26N2O7 | 详情 | 详情 | |
| (XVI) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (XVII) | 43304 | benzyl 3-[2-(3,5-dimethoxyanilino)-2-oxoethyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C28H35N3O8 | 详情 | 详情 | |
| (XVIII) | 43305 | benzyl 4-(3,5-dimethoxyphenyl)-5,8-dioxo-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-13-carboxylate | C26H27N3O6 | 详情 | 详情 | |
| (XIX) | 43306 | 4-(3,5-dimethoxyphenyl)-4,7,13-triazatricyclo[7.3.1.0(2,7)]tridec-2-ene-5,8-dione | C18H21N3O4 | 详情 | 详情 | |
| (XX) | 30046 | 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid | C11H12O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Acylation of 3,5-dimethoxyaniline (I) with 4-methoxyphenylacetyl chloride (II) afforded amide (III). Treatment of (III) with Vilsmeier reagent gave rise to 2-chloroquinoline derivative (IV), which was hydrolyzed to quinolinone (V) using aqueous HOAc. Conjugate addition to (V) of acrylonitrile (VI) produced the cyanoethyl quinolinone (VII). The title tetrazole was then obtained by reaction of nitrile (VII) with tributyltin azide in hot toluene.
| 【1】 Guillaumet, G.; Darro, F.; Frydman, A.; Joseph, B.; Kiss, R. (Laboratoires L. Lafon); Pharmaceutical compsns. comprising 2-quinolones. EP 1097138; FR 2781218; WO 0003990 . |
| 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) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (II) | 26758 | 2-(4-methoxyphenyl)acetyl chloride | 4693-91-8 | C9H9ClO2 | 详情 | 详情 |
| (III) | 46380 | N-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)acetamide | C17H19NO4 | 详情 | 详情 | |
| (IV) | 46381 | 2-chloro-5,7-dimethoxy-3-(4-methoxyphenyl)quinoline; 4-(2-chloro-5,7-dimethoxy-3-quinolinyl)phenyl methyl ether | C18H16ClNO3 | 详情 | 详情 | |
| (V) | 46382 | 5,7-dimethoxy-3-(4-methoxyphenyl)-2(1H)-quinolinone | C18H17NO4 | 详情 | 详情 | |
| (VI) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (VII) | 46383 | 3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1(2H)-quinolinyl]propanenitrile | C21H20N2O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The cyclization of 3,5-dimethoxyaniline (I) with 2-formyl-2-(4-methoxyphenyl)acetic acid ethyl ester (II) by means of polyphosphoric acid trimethylsilyl ester (PPSE) by heating at 110 C gives the quinolone (III), which is alkylated with vinyl cyanide (IV) by means of Triton B in DMF to yield the propionitrile derivative (V). Finally, the cyano group of (V) is converted into the target tetrazolyl derivative by cyclization with tri-tert-butylstannyl azide in refluxing toluene.
| 【1】 Joseph, B.; et al.; 3-Aryl-2-quinolone derivatives: Synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration. J Med Chem 2002, 45, 12, 2543. |
| 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) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (II) | 48551 | ethyl 2-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (III) | 46382 | 5,7-dimethoxy-3-(4-methoxyphenyl)-2(1H)-quinolinone | C18H17NO4 | 详情 | 详情 | |
| (IV) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (V) | 46383 | 3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1(2H)-quinolinyl]propanenitrile | C21H20N2O4 | 详情 | 详情 |