抗肿瘤药Dacomitinib的合成

Synthesis of Antitumor Drug Dacomitinib

7-氟-6-硝基-4(3H)-喹唑啉酮(2)经甲氧基化、氯化、与3-氯-4-氟苯胺进行亲核取代得7-甲氧基-6-硝基-4-(3-氯-4-氟苯胺基)喹唑啉,经硝基还原、4-溴-2-丁烯酰氯酰胺化制得(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基喹唑啉-6-基]-4-溴-2-丁烯酰胺,最后与哌啶经亲核取代反应制得抗肿瘤药dacomitinib,总收率约46%(以2计),纯度99.5%。

Dacomitinib, an antitumor drug, was synthesized from 7-fluoro-6-nitroquinazolin-4 （3/-/）- one （2） by methoxylation, chlorination and nucleophilic substitution to give 7-methoxy-6-nitro-4-（3-chloro-4- fluorophenylamino） quinazoline, which was subjected to reduction, amidation with 4-bromo-2-butenoyl chloride to afford （2E） -N- [4- [ （3-chloro-4-fluorophenyl） amino]-7-methoxyquinazolin-6-yl]-4-bromo-2-butenamide, followed by nucleophilic substitution with an overall yield of about 46 % （based on compound 2） and purity of 99.5 %.