第8期曹春泉:奧氮平合成工藝研究舊出◆◆科研與開發(fā)奧氮平合成工藝研究曹春泉(菏澤學(xué)院制藥工程系,山東菏澤2740000摘要:2-甲基-10-(4-甲基-1-哌嗪)-4H-噻吩并[2,3-b][1,5]苯并二氮雜卓(即奧氮平)的合成過程中,4-氨基-2甲基-10H-噻吩并[2,3-b][1,5]苯并二氮雜·鹽酸鹽與N-甲基哌嗪縮合反應(yīng),所用溶劑為高沸點(diǎn)溶劑 DMso/Toluene,不易回收所得奧氮平不易提純,且污染環(huán)境,本論文首次以易于回收的乙醇為反應(yīng)溶劑,邐過加水?dāng)嚢栉鼍У?得到純度較高的奧氮平成品,避免了使用高沸點(diǎn)溶劑,且溶劑易于回收,縮短了反應(yīng)時(shí)間,大大提高了該產(chǎn)品的生產(chǎn)成本。關(guān)鍵詞:奧氮平;合成;反應(yīng)溶劑中圖分類號:B14.5;TQ463.5文獻(xiàn)標(biāo)識碼:A文章編號:1008-021X(2013)08-0001-02The Study on the Olanzapine SynthesisCAO Chun- quanHeze College of Pharmaceutical Engineering heze 274500, China)Abstract: 2 -methyl-10-(4piperazinyl )-4H- thiophene [2, 3-b][1, 5]benzodiazepine(called olanzapine). In the last step of synthesis process, the 4-amino-2- methyl10H-thiophene [2, 3-b][1, 5] benzodiazepine o hydrochloride and N-methyl - piperazincondensation process, the solvent is high boiling point solvents DMSO/Toluene, which is difficultrecover, not easy for purification, and pollution of the environment, the paper frist described using theeasily recyclable solvent ethanol as the reaction solvent, by adding water in the reaction mixture etc,obtain a high purity olanzapine product, avoiding the use of high boiling point solvent, and the solvent iseasy to recycle, to shorten the reaction time, greatly improving the commercial value of the procesKey words: olanzapine; synthesis; eaction solvent奧氮平,如圖1,即2-甲基-10-(4-甲基-1這幾種文獻(xiàn)中,最后一步縮合反應(yīng)均用高沸點(diǎn)混合哌嗪)-4H-噻吩并[2,3-b][1,5]苯并二氮雜溶劑即甲苯/二甲基亞砜,現(xiàn)實(shí)大生產(chǎn)操作中存在著卓,是第二代抗精神病的藥物。作為再普樂由美溶劑沸點(diǎn)高不易回收,溶劑價(jià)格昂貴,毒性較大,反國禮來公司銷售。它用于治療如精神分裂癥,躁郁應(yīng)時(shí)間長,反應(yīng)溫度過高等諸多缺點(diǎn),國外亦有相關(guān)癥精神病性抑郁癥,抽動穢語綜合征。此藥物作為文獻(xiàn)專利報(bào)道,文獻(xiàn)介紹了傳統(tǒng)的苯二氮卓類合拮抗劑拮抗羥色胺受體5-HT2以及D/D2多巴胺成方法,文獻(xiàn)6采用四氯化鈦為催化劑雖然提高了受體并表現(xiàn)出抗膽堿的屬性。文獻(xiàn)詳解了該藥收率與簡化了步驟但是但是四氯化鈦?zhàn)鳛橐环N毒性的幾種合成路線,文獻(xiàn)2-介紹了幾種合成奧氮平較大的化合物不亦作為工業(yè)化大生產(chǎn),文獻(xiàn)僅采的新方法,傳統(tǒng)奧氮平合成路線如圖2所示,但是在用二甲基亞砜作為單一溶劑參與最后一步縮合反收稿日期:2013-05-14中國煤化工作者簡介:曹舂泉(1983-)女,山東菏澤人,碩士,助教,研究方向;新型藥物HCNMHG山東化工SHANDONG CHEMICAL INDUSTRY2013年第42卷應(yīng),但是需要做酸、堿處理并且也面臨著不易回收,操作步驟繁瑣等缺點(diǎn),文獻(xiàn)。未采用溶劑僅采用加大N-甲基哌嗪用量,使其既做溶劑也做反應(yīng)原料但是存在著生成的奧氮平不易提純,且N-甲基哌N一CHb嗪也大大過量,進(jìn)一步增加了生產(chǎn)成本等缺點(diǎn),本文采用價(jià)格相對便宜,易于回收,污染較輕的乙醇為單反應(yīng)溶劑,通過控制反應(yīng)溫度與時(shí)間,反應(yīng)完畢后以純水處理等步驟得到了高純度的奧氮平成品,見圖3,而乙醇易于回收,大大降低了生產(chǎn)成本。圖1奧氮平結(jié)構(gòu)NO2CH CH CHO+H2NH HCIhSnChDMSO Toluenc圖2奧氪平傳統(tǒng)合成工藝路線-CH3NAhCCH:,OHH3CH3圖3奧氮平的合成原料與儀器濾得黃色固體約42g,收率為72%。熔點(diǎn):195乙醇分析純;N-甲基哌嗪分析純;4-氨基96℃與文獻(xiàn)一致,FSI-MS:313.4[M+1],1H2-甲基-10H-噻吩并[2,3-b][1,5]苯并二NMR,(CDCl3)8:2.25(s,3H,C-CH3),2.37(s,氮雜·鹽酸鹽,自制;純化水;WRS-1C型熔點(diǎn)測定3H,N-CH3),2.4(t,4H,(CH2)2N-CH3),3.49儀; Agilent G6460A型液質(zhì)聯(lián)用儀; Bruck400MHZ核(t,4H,C-N-(CH2)2),5.01(s,1l,NH),6.34(s磁共振儀。lH,S-C=CH-);6.60-7.06(m,4H,PhH)。2實(shí)驗(yàn)部分3小結(jié)1000mL四口瓶中加入4-氨基-2-甲基本工藝改進(jìn)中,首次嘗試以價(jià)格較低廉且易于10H-噻吩并[2,3-b][1,5]苯并二氮雜·鹽酸鹽回收處理的乙醇代替甲苯/DMSO體系,得到了純度50.0g(0.2mol),N-甲基哌嗪125mL,乙醇150mL,較高的奧氮平成品,經(jīng)過ES-Ms,H-NMR及熔氮?dú)獗Ｗo(hù)條件下緩慢加熱至回流約94℃左右,TC點(diǎn)檢測確證了結(jié)構(gòu),經(jīng)過工藝改進(jìn)后,收率達(dá)到了檢測反應(yīng)保溫?cái)嚢柽^夜,停止攪拌自然冷卻至72%,原料簡單易動聞尢十降低了奧氮50℃以下,加入水100mL,此時(shí)析出大量黃色固體,平生產(chǎn)成本,具抽濾,將該固體加入約50mL水中,常溫?cái)嚢?h,抽CNMH、轉(zhuǎn)第4頁)SHANDONG CHEMICAL INDUSTRY2013年第42卷Br何溶劑,40℃下直接反應(yīng)24h,可高純度,高收率得Br.得到1-溴-3,5-二甲基金剛烷,后處理簡單方「2便,可應(yīng)用于工業(yè)化生產(chǎn),降低了鹽酸美金剛的工藝成本參考文獻(xiàn)[1] Abdel-Aal Raafat A, Assi Abdel-Azim A, Kostandy1.3合成方法Botros B. 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