UK-294315

Chemical Name: 5-(4-Fluorophenyl)-6,7-dimethoxy-2-[4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepin-1-yl]quinolin-4-amine
项目整合开发状态: Phase I
项目研究机构: Pfizer (Originator)
合成路线: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).