|
【结 构 式】 
|
【分子编号】54956 【品名】N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine 【CA登记号】162012-67-1 |
【 分 子 式 】C14H7ClF2N4O2 【 分 子 量 】336.6848464 【元素组成】C 49.94% H 2.1% Cl 10.53% F 11.29% N 16.64% O 9.5% |
合成路线1
该中间体在本合成路线中的序号：(VII)The aminoquinazoline precursor (I) is prepared by condensation of 4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinazoline (VII) with 3(R)-hydroxytetrahydrofuran (VIII) by means of potassium tert-butoxide in DMF to yield the tetrahydrofuranyloxyquinazoline (IX), which is then reduced at the nitro group by catalytic hydrogenation over PtO2 (1). Scheme 2.
| 【1】 Himmelsbach, F., Langkopf, E., Solca, F., Jung, B., Baum, A., Blech, S. (Boehringer Ingelheim Pharma GmbH & Co., KG). Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof. DE 10063435, EP 1345910, JP 2004516283, US 2002173509, US 2006100223, US 7019012, WO 0250043. |
| 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) | 65710 | N4-(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4,6-quinazolinediamine | 314771-76-1 | C18H16ClFN4O2 | 详情 | 详情 |
| (VII) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 65714 | N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4-quinazolinamine | 314771-88-5 | C18H14ClFN4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)4-Chloro-7-fluoro-6-nitroquinazoline (I) was condensed with 3-chloro-4-fluoroaniline (II) to afford the 4-anilino quinazoline (III). Displacement of the activated fluorine of (III) with the potassium alkoxide of morpholinopropanol (IV) gave the morpholinopropyl ether (V). Subsequent reduction of the nitro group of (V), either using iron dust and acetic acid or catalytic hydrogenation over Raney-Ni, furnished aminoquinazoline (VI). This was finally condensed with acrylic acid (VII), via activation as the mixed anhydride with isobutyl chloroformate or using EDC as the coupling reagent, to provide the title acrylamide.
| 【1】 Loo, J.A.; Rewcastle, G.W.; Smaill, J.B.; et al.; Tyrosine kinase inhibitors.17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides baring additional solubilizing functions. J Med Chem 2000, 43, 7, 1380. |
| 【2】 Bridges, A.J.; Klohs, W.D.; Driscoll, D. (Pfizer Inc.); N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases. EP 1131304; US 6344455; WO 0031048 . |
| 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) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (II) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (III) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |
| (IV) | 54957 | 3-(4-morpholinyl)-1-propanol | C7H15NO2 | 详情 | 详情 | |
| (V) | 54958 | N-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-{7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinyl}amine | C21H21ClFN5O4 | 详情 | 详情 | |
| (VI) | 54959 | N-{6-amino-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl}-N-(3-chloro-4-fluorophenyl)amine; N~4~-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-4,6-quinazolinediamine | C21H23ClFN5O2 | 详情 | 详情 | |
| (VII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XX)The 7-methoxy-6-nitroquinazoline derivative (I) can be prepared by cyclization of 2-amino-4-fluorobenzoic acid (XIV) with formamidine acetate (XV) in 2-methoxyethanol to yield 7-fluoroquinazolin-4(3H)-one (XVI), which is then nitrated with HNO3 and H2SO4 to give 7-fluoro-6-nitroquinazolin-4(3H)-one (XVII) (1). Chlorination of quinazolinone (XVII) with SOCl2 at reflux provides 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) , which is then coupled with 3-chloro-4-fluoroaniline (XIX) by means of Et3N or PhNMe2 in i-PrOH to produce the diarylamine (XX). Finally, fluoroquinazoline (XX) is treated with MeOH and NaH in .
| 【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758. |
| 【3】 Bridges, A.J., Klohs, W.D., Driscoll, D. (Pfizer, Inc.). N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases. EP 1131304, JP 2002530386, US 6344455, WO 2000031048. |
| 【4】 Smaill, J.B., Rewcastle, G.W., Loo, J.A. et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino) quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solublizing functions. J Med Chem 2000, 43(7): 1380-97. |
| 【2】 Bridges, A.J., Horne, N.M., Jacks, T.E. et al. (Pfizer, Inc.). Preparation of substituted quinazolines. JP 2006517959, US 2004158065, WO 2004069791. |
| 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) | 68469 | N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine | C15H10ClFN4O3 | 详情 | 详情 | |
| (XIV) | 10805 | 2-Amino-4-fluorobenzoic acid | 446-32-2 | C7H6FNO2 | 详情 | 详情 |
| (XV) | 67709 | formamidine acetate | 3473-63-0 | CH4N2.C2H4O2 | 详情 | 详情 |
| (XVI) | 19140 | 7-fluoro-4(3H)-quinazolinone | C8H5FN2O | 详情 | 详情 | |
| (XVII) | 19141 | 7-fluoro-6-nitro-4(3H)-quinazolinone | C8H4FN3O3 | 详情 | 详情 | |
| (XVIII) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (XIX) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (XX) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |