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【结 构 式】 
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【分子编号】31962 【品名】2-Nitro-5-fluorobenzoic acid; 5-Fluoro-2-nitrobenzoic acid 【CA登记号】320-98-9 |
【 分 子 式 】C7H4FNO4 【 分 子 量 】185.1115032 【元素组成】C 45.42% H 2.18% F 10.26% N 7.57% O 34.57% |
合成路线1
该中间体在本合成路线中的序号：(II)The oxidation of 2-nitro-5-fluorotoluene (I) with KMnO4 in water gives 2-nitro-5-fluorobenzoic acid (II), which by reduction with H2 over Pd/C in methanol - aqueous HCl yields 2-amino-5-fluorobenzoic acid (III). The reaction of (III) with phosgene in THF aqueous HCl affords 5-fluoroisatoic acid anhydride (IV), which by cyclization with N-methylglycine (V) in OMS at 100 C affords 7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (VI). Finally, this compound is cyclized again with ethyl isocyanacetate (VII) by means of potassium tert-butylate and diethyl chlorophosphate in DMF.
| 【1】 Haefely, W.; Hunkeler, W.; Kyburz, E.; Mohler, H.; Pieri, L.; Polc, P.; Gerecke, M. (F. Hoffmann-La Roche AG); Imidazodiazepine derivatives. EP 0027214; GB 2060632; JP 1156968; US 4316839; US 4346033 . |
| 【2】 Blancafort, P.; Castaner, J.; Hillier, K.; Serradell, M.N.; RO-15-1788. Drugs Fut 1982, 7, 6, 402. |
| 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) | 20612 | 4-Fluoro-2-methyl-1-nitrobenzene; 2-Nitro-5-fluorotoluene | 446-33-3 | C7H6FNO2 | 详情 | 详情 |
| (II) | 31962 | 2-Nitro-5-fluorobenzoic acid; 5-Fluoro-2-nitrobenzoic acid | 320-98-9 | C7H4FNO4 | 详情 | 详情 |
| (III) | 31963 | 2-Amino-5-fluorobenzoic acid | 446-08-2 | C7H6FNO2 | 详情 | 详情 |
| (IV) | 31964 | 6-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione; 5-Fluoroisatoic acid anhydride | C8H4FNO3 | 详情 | 详情 | |
| (V) | 10429 | N-Methylglycine; Sarcosine; 2-(Methylamino)acetic acid | 107-97-1 | C3H7NO2 | 详情 | 详情 |
| (VI) | 31965 | 7-Fluoro-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione; 7-Fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione | C10H9FN2O2 | 详情 | 详情 | |
| (VII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Hydrogenation of 2-nitro-5-fluorobenzoic acid (I), followed by in situ condensation with acetic anhydride produced benzoxazinone (II). Subsequent reaction of (III) with 2-chloroaniline (III) in refluxing AcOH furnished quinazolinone (IV). Treatment of (IV) with 2,6-pyridinedicarboxaldehyde (V) in the presence of ZnCl2 and Ac2O gave rise to the pyridinylvinyl derivative (VI). The title amine was finally obtained by reductive amination of aldehyde (VI) with diethylamine using NaBH(OAc)3). The two atropisomers were separated by means of preparative chiral HPLC.
| 【1】 Ewing, F.E.; Welch, W.M.; Huang, J.; et al.; Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-ethyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Bioorg Med Chem Lett 2001, 11, 2, 177. |
| 【2】 Elliott, M.L.; Welch, W.M. Jr. (Pfizer Inc.); Novel 2,3 disubstd.-4(3H)-quinazolinones. EP 0901487; JP 1999514663; WO 9743276 . |
| 【3】 Welch, W.M. Jr.; DeVries, K.M. (Pfizer Inc.); Atropisomers of 3-aryl-4(3H)-quinazolinones and their use as AMPA-receptor antagonists. EP 0968194; JP 2000509731; WO 9838173 . |
| 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) | 31962 | 2-Nitro-5-fluorobenzoic acid; 5-Fluoro-2-nitrobenzoic acid | 320-98-9 | C7H4FNO4 | 详情 | 详情 |
| (II) | 38462 | 6-fluoro-2-methyl-4H-3,1-benzoxazin-4-one | C9H6FNO2 | 详情 | 详情 | |
| (III) | 35804 | 2-chloroaniline; 2-chlorophenylamine | 95-51-2 | C6H6ClN | 详情 | 详情 |
| (IV) | 38463 | 3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3H)-quinazolinone | C15H10ClFN2O | 详情 | 详情 | |
| (V) | 38464 | 2,6-pyridinedicarbaldehyde | 5431-44-7 | C7H5NO2 | 详情 | 详情 |
| (VI) | 38465 | 6-[(E)-2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydro-2-quinazolinyl]ethenyl]-2-pyridinecarbaldehyde | C22H13ClFN3O2 | 详情 | 详情 |