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【结 构 式】

【药物名称】UK-294315

【化学名称】5-(4-Fluorophenyl)-6,7-dimethoxy-2-[4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepin-1-yl]quinolin-4-amine

【CA登记号】

【 分 子 式 】C27H32FN5O4

【 分 子 量 】509.58559

【开发单位】Pfizer (Originator)

【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1-Adrenoceptor Antagonists

合成路线1

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
Extended Information