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【结 构 式】 
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【分子编号】13439 【品名】3,4-Dimethoxybenzoic acid 【CA登记号】93-07-2 |
【 分 子 式 】C9H10O4 【 分 子 量 】182.176 【元素组成】C 59.34% H 5.53% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(VII)The condensation of 4-hydroxybenzaldehyde (I) with 2-(dimethylamino)ethyl chloride (II) by means of K2CO3 in hot isopropyl ether yields 4-[2-(dimethylamino)ethoxy]benzaldehyde (III), which is treated with hydroxylamine hydrochloride in refluxing ethanol to afford the corresponding oxime (IV). The hydrogenation of (IV) with H2 over RaNi in methanolic ammonia yields 4-[2-(dimethylamino)ethoxy]benzylamine (V), which is finally condensed with 3,4-dimethoxybenzoyl chloride (VI) (obtain303ed from the corresponding acid (VII) with SOCl2) in toluene.
| 【1】 Castaner, J.; Mealy, N.; Itopride Hydrochloride. Drugs Fut 1995, 20, 12, 1220. |
| 【2】 Ogawa, N.; Yasuda, S.; Kato, H.; Sakaguchi, J.; Iwanaga, Y.; Ito, Y.; Nishino, H.; Synthesis, gastrointestinal prokinetic activity and structure-activity relationships of novel N-[[2-(dialkylamino)ethoxy]benzyl]benzamide derivatives. Chem Pharm Bull 1992, 40, 1, 202-11. |
| 【3】 Itoh, Y.; Kato, H.; Koshinaka, E.; Ogawa, N.; Nishino, H.; Sakaguchi, J. (Hokuriku Seiyaku Co., Ltd.); Amide cpds., process for preparing the same, and compsn. for activating gastric motor function containing the same. AU 8821862; EP 0306827; JP 1989066153; JP 1989079144; JP 1989085960; JP 1989093568; US 4983633 . |
| 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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (III) | 13435 | 4-[2-(Dimethylamino)ethoxy]benzaldehyde | C11H15NO2 | 详情 | 详情 | |
| (IV) | 13436 | 4-[2-(Dimethylamino)ethoxy]benzaldehyde oxime | C11H16N2O2 | 详情 | 详情 | |
| (V) | 13437 | 2-[4-(Aminomethyl)phenoxy]-N,N-dimethyl-1-ethanamine; N-[2-[4-(Aminomethyl)phenoxy]ethyl]-N,N-dimethylamine | C11H18N2O | 详情 | 详情 | |
| (VI) | 13438 | 3,4-Dimethoxybenzoyl chloride | 3535-37-3 | C9H9ClO3 | 详情 | 详情 |
| (VII) | 13439 | 3,4-Dimethoxybenzoic acid | 93-07-2 | C9H10O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3,4-Dimethoxybenzoic acid (I) is converted into oxazoline (II) by known methods. This compound is treated with BuLi and I2 in ethyl ether to yield the 2-iodo derivative (III), which is treated with POCl3 in hot pyridine to afford 2-iodo-3,4-dimethoxybenzonitrile (IV). The nitration of (IV) by means of nitronium tetrafluoroborate in acetonitrile provides 2-iodo-3,4-dimethoxy-6-nitrobenzonitrile (V), which is condensed with 4-fluorophenylboronic acid (VI) by means of Pd(PPh3)4 in toluene/ethanol to give the biphenyl derivative (VII). The reduction of the nitro group of (VII) by means of sodium dithionite in DMF/water yields the corresponding amino derivative (VIII), which is condensed with 1-acetyl-4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepine (IX) by means of POCl3 in dichloromethane to afford the adduct (X). Finally, this compound is cyclized by means of LDA in THF to provide the target quinoline derivative. The intermediate 1-acetyl-4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepine (IX) has been obtained as follows: The reaction of perhydro-1,4-diazepine (XI) with Boc2O in dichloromethane gives the monoprotected diazepine (XII), which is condensed with morpholin-4-yl-carbonyl chloride (XIII) by means of TEA in dichloromethane to yield the acylated diazepine (XIV). The deprotection of (XIV) by means of HCl in dichloromethane/methanol affords the deprotected diazepine (XV), which is finally acylated with acetic anhydride and TEA in dichloromethane to provide the target intermediate (IX).
| 【1】 Collis, A.J.; Fox, D.N.A.; Newman, J. (Pfizer Inc.); Quinoline and quinazoline cpds. useful in therapy. EP 0877734; JP 1999501668; US 6103738; WO 9723462 . |
| 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) | 13439 | 3,4-Dimethoxybenzoic acid | 93-07-2 | C9H10O4 | 详情 | 详情 |
| (II) | 54071 | 2-(3,4-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-methoxyphenyl methyl ether | n/a | C13H17NO3 | 详情 | 详情 |
| (III) | 54072 | 2-(2-iodo-3,4-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-iodo-6-methoxyphenyl methyl ether | n/a | C13H16INO3 | 详情 | 详情 |
| (IV) | 54073 | 2-iodo-3,4-dimethoxybenzonitrile | n/a | C9H8INO2 | 详情 | 详情 |
| (V) | 54074 | 2-iodo-3,4-dimethoxy-6-nitrobenzonitrile | n/a | C9H7IN2O4 | 详情 | 详情 |
| (VI) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (VII) | 54075 | 4'-fluoro-5,6-dimethoxy-3-nitro[1,1'-biphenyl]-2-carbonitrile | n/a | C15H11FN2O4 | 详情 | 详情 |
| (VIII) | 54076 | 3-amino-4'-fluoro-5,6-dimethoxy[1,1'-biphenyl]-2-carbonitrile | n/a | C15H13FN2O2 | 详情 | 详情 |
| (IX) | 54077 | 1-[4-(4-morpholinylcarbonyl)-1,4-diazepan-1-yl]-1-ethanone | n/a | C12H21N3O3 | 详情 | 详情 |
| (X) | 54078 | 4'-fluoro-5,6-dimethoxy-3-({(E)-1-[4-(4-morpholinylcarbonyl)-1,4-diazepan-1-yl]ethylidene}amino)[1,1'-biphenyl]-2-carbonitrile | n/a | C27H32FN5O4 | 详情 | 详情 |
| (XI) | 25030 | 1,4-diazepane | 505-66-8 | C5H12N2 | 详情 | 详情 |
| (XII) | 54079 | tert-Butyl 1-homopiperazine carboxylate | n/a | C10H20N2O2 | 详情 | 详情 |
| (XIII) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (XIV) | 54080 | tert-butyl 4-(4-morpholinylcarbonyl)-1,4-diazepane-1-carboxylate | n/a | C15H27N3O4 | 详情 | 详情 |
| (XV) | 54081 | 1,4-diazepan-1-yl(4-morpholinyl)methanone | n/a | C10H19N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)
| 【1】 Zhu CQ, Chi YS, Deng, YL,et aL 2006.Process for preparation of 4-(3’-chloro-4'-fluoroanilino)-7-methoxy6-(3-morpholinopropoxy) quinazoline.发明专利申请公开说明书，CN 1733738 |