第25卷第1期河南大學(xué)學(xué)報(bào)(醫(yī)學(xué)版)Vol.25 No. 12006年2月Journal of Henan University ( Medical Science )Feb. 2006貝諾酯的合成王文靜,呂瑋,盧澤(河南省醫(yī)藥學(xué)校河南開(kāi)封475001 )摘要:目的探索貝諾酯具有工業(yè)生產(chǎn)價(jià)值新的合成路線。方法本合成法以撲熱息痛、阿司匹林為原料阿司匹林經(jīng)氯化撲熱息痛成鈉鹽二者以PEG6000為相轉(zhuǎn)移催化劑酯化而得貝諾酯。結(jié)果:總收率為92%產(chǎn)品質(zhì)量符合《中國(guó)藥典X 2000年版)標(biāo)準(zhǔn)。結(jié)論該路線使用PEG為相轉(zhuǎn)移催化劑,大大提高了收率降低成本,具有工業(yè)生產(chǎn)價(jià)值。關(guān)鍵詞:貝諾酯;PEG相轉(zhuǎn)移催化劑合成中圖分類號(hào):TQ460. 6.文獻(xiàn)標(biāo)識(shí)碼:A文章編號(hào):1672 - 7606( 2006 )01 -0039 -01Synthesis of BenoyilateWANG Wen- jing，LU Wei, LU Ze( Henan Pharmaceutical School, Kaifeng 475001，Henan, China)Abstract: Objective: To explore the new synthetic routh of Benorilate, which is of the value in the industrial production.Methods: Paracetamol and Aspirin was used as the raw material, Aspirin was chloridated by thiony chloride, paracetamotwas neutralized by sodium hydroxide. Benorilate was produced by the reaction of o - acetoxy benzogl chloride with sodiumpacetamido phenylate in the presence of PEG6000 phase transfer catalyst. Results:The total yield was 92%，and thequality of the products was according with ChP2000. Conclusion: This route is of high yield and low cost because of PEGphase transfer catalyst, so it is of the value in the industrial production.Key words: Benorilate, PEG, Phase transfer catalyzed reaction, Synthesis貝諾酯又名撲炎痛、苯樂(lè)萊、解熱安是非甾體了 阿司匹林用于抗炎引起胃痛、胃出血、胃潰瘍等缺.類解熱鎮(zhèn)痛藥環(huán)氧酶抑制劑。本品利用阿司匹林、點(diǎn)。臨床上主要用于治療風(fēng)濕及類風(fēng)濕性關(guān)節(jié)炎骨撲熱息痛經(jīng)化學(xué)法拼合制備而成。本晶經(jīng)口服進(jìn)入關(guān) 節(jié)炎、神經(jīng)痛、頭痛、感冒引起的中度鈍痛等。本合體內(nèi)后經(jīng)酯酶作用,釋放出阿司匹林和撲熱息痛而成法以撲熱息痛、阿司匹林為原料阿司匹林經(jīng)氯化，產(chǎn)年藥效。本品既有阿司匹林的解熱鎮(zhèn)痛抗炎作用，撲熱息痛成鈉鹽二者以PEG作為相轉(zhuǎn)移催化劑酯又保持了撲熱息痛的解熱作用。由于體內(nèi)分解不在化而得。 本法總收率為92%而且適用于工業(yè)生產(chǎn)。胃腸道，因而克服了阿司匹林對(duì)胃腸道的刺激克服,0COCH,,OCOCH,，0COCH-COOH-PEG_- NHCOCHCH,COHNOH_ NaOH >CH,COHN-ONa中國(guó)煤化工上端加裝氯化鈣干燥1實(shí)驗(yàn)管排Y片CNMHG的100ml三口燒瓶中,1.1乙酰水楊酸氯的制 備' I加入阿司匹林9g，(下轉(zhuǎn)第42頁(yè))收稿日期:2005-11-08作者簡(jiǎn)介:王文靜1966- )男河南開(kāi)封人,講師從事藥物化學(xué)的教學(xué)與科研工作。4河南大學(xué)學(xué)報(bào)(醫(yī)學(xué)版)2006年第25卷第1期抗腫瘤治療的新靶點(diǎn)"[6。參考文獻(xiàn):[ 1 ]TammI , Wang Y , Savsville E ,et al. LAP - family protein inhibits caspase activity and apoptosis induced by Fas( CD95 ), Bax ,caspases and anticancer drugs[ J]. Cancer Res ,1998 ,58( 23 ) 5315 - 5320.[2 ] Conway E M. Three dffentiallyl expressed survivin cDNA variants encode proteins with distinct antiapoptic functions[ J ]Blood , 2000 ,95( 4 ):1435 - 1442.[ 3 ] Dario C , Altieri , Carlo Marchisio. Survivin apoptosis : an interloper between cell death and cell proliferation in cancer[ J ] LabInvest ,1999 ,79( 11 ):1327 - 1333 .[4]僧靖靜張?jiān)茲h高冬玲. TRAIL Survivin mRAN表達(dá)與胃癌凋亡發(fā)生的關(guān)系J]河南大學(xué)學(xué)報(bào)(醫(yī)學(xué)版) 2005 24( 1):25 - 28.[ 5 ] Grabowski P. Prognostic value of nuclear survivin expression in esophageal squamovs cell carcinoma[ J] Br J Cancer 2003 ,88(1):115-119.[6]Olie RA Simoes - Wust AP ,Baumann B ,et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosisand sensitiaes lung cancer cells to chemotherapy[J] Cancer Res ,2000 60( 11 ) :2805 - 2809.[責(zé)任編輯姬荷](上接第39頁(yè))氯化亞砜5mL,滴入2滴吡啶,油浴緩緩加熱至版中國(guó)藥典標(biāo)準(zhǔn)。75%C維持70 ~ 75C反應(yīng)至無(wú)氣體放出冷卻,得2.2 化合物的性狀、 熔點(diǎn)及產(chǎn)率見(jiàn)表1。乙酰水楊酰氯。表1化合物的性狀、 熔點(diǎn)及產(chǎn)率1.2貝 諾酯的制備[2]性狀熔點(diǎn)(C)__產(chǎn)率(% )在裝有攪拌、滴液漏斗的100ml三口燒瓶中,加乙酰水楊酰氯 淡黃色液體98入撲熱息痛8. 6g ,加水50ml ,攪拌下緩緩加入貝諾酯白色結(jié)晶176- 178944. 5mol/L氫氧化鈉水溶液18ml。降溫至8C ~12C ,3討論加入20%PEG6000溶液5ml滴加上述乙酰水楊酰氯維持PH值為9~10。20°C ~25C攪拌反應(yīng)1 h。氯化一步加入吡啶作為有機(jī)堿起催化作用但不反應(yīng)完畢抽濾水洗至中性烘干得粗品。粗品以體宜加的太多 ,否則影響產(chǎn)。氯化時(shí)加入氯化亞砜兼做積分?jǐn)?shù)為95%的乙醇精制得精品。溶劑應(yīng)過(guò)量并注意回收利用。酯化一步加入PEG6000作為相轉(zhuǎn)移催化劑反應(yīng)時(shí)間由原來(lái)的2h縮短2結(jié)果為1h收率由44%提高至94%。本合成法具有工業(yè).2.1 應(yīng)用本合成法生產(chǎn)的貝諾酯質(zhì)量符合2000年 生產(chǎn)價(jià)值。[ 1 ]劉撫梅.藥物化學(xué)[ M ]北京:中國(guó)醫(yī)藥科技出版社2003 376 -378.[2]計(jì)志忠.化學(xué)制藥工藝學(xué)M]北京:中國(guó)醫(yī)藥科技出版社2003 88 - 89.[責(zé)任編輯李武營(yíng)]中國(guó)煤化工MHCNMHG