乙拉西坦的合成

·484齐鲁药事 Qilu Pharmaceutical affairs2005vol.24,No8药物研究乙拉西坦的合成卢传广,王洪刚,王洪锋(鲁南制药集团股份有限公司临沂276005)摘要:目的合成乙拉西坦。方法2一吡咯烷酮絰N炕基化、解反应合成乙拉西坦。结果及结论总收率50.7%,乙拉西坦结构经H-NMR,C-NMR和IR确证。关词:乙拉西坦吡咯炕酮合成中图分类号:TQ460.31文獻标识码:A文章编号:1672-7738(2005)08-0484-02Synthesis of EtiracetamLu Chuan-guang, Wang Hong-gang, Wang Hong-feng(Lu'nan Pharmaceutical Share Limited company, Linyi, 276005)Abstract: Objective To synthesize Etiracetam Methods Etiracetam was synthesized from 2-pyrrolidone by N-alkylation andaminolysis, Results and conclusion The overall yield was 50.7% and the structure of Etiracetam was characterized by 'H-NMR, 3C-NMR and IRKey words: Etiracetam; pyrrolidone; synthesis乙拉西坦化学名;a-乙基-2-氧-1-吡咯烷乙酰胺,醇中,加入饱和氨水26m,32℃保温反应24h,用薄层色谱监它是比利时联合化学公司开发的促智药。文献以2-吡咯测反应终点,展开剂乙酸乙酯一二氯甲烷(4:1)。回收甲醇烷酮为原料,经N-烷基化氢解反应制得。本文对原工艺冷却得白色固体,用乙醇重结晶得16.2g,收率60.2%。加以改进。烷基化、氨解收率提高,效果显著。mp120~122℃(文献122℃);1H-NMR(CDCl3):890(t,3H,CH3),1.62~2.12(m,4H,CH2,吡咯环4-CH2),2.362.52(m,2H,吡咯环3-CH2),3.37~3.52(m,吡咯环5oCOOMeCH2),4.49(q,1H, NCHcO),6.03(br,1H,NH),6.63(br,1H,NH);13C-NMR(CDCl3):810.53(1C,CH3),18,14(1C,CH2),21.13(1C,吡咯环4-C),31.10(1C,吡咯环3-C)HNH」O43.83(1C,吡咯环5-C),55.99(1C,NCH),172.54(1C,C=IH2O),17607(1C,C=O);IR:03385,3204(N-H),2965,2872COOMe(CH3),1670(C=O)cm11实验部分2结果与讨论1.1仪器与试剂DF-101S集热式恒温加热搅拌器,Z7A2-吡咯烷与氢化钠反应较剧烈,并有氢气放出,应缓缓三用紫外分析仪,WRs-1B数字熔点仪,JA12002型电子天分批加入,根据试验结果列表得反应时间用加料情况对总收平,2-吡咯烷酮(工业级),其他为市售化学纯或分析纯试剂。率的影响。1.22-(2一氧一吡咯烷)丁酸甲酯的制备在250ml四口实验号t1(h)t2(h)总收率(%烧瓶中加人70ml甲苯和2-吡咯烷酮4.5g(53mmol),分四30,129.5批加入NaH2lg(53mmo)并通N2保护,室温搅拌2h后加入2-溴丁酸甲酯9.0g(50mmol),苄基三乙基氯化铵0.6g331,2445.7(26mmol),搅拌下加热至78℃反应4h,冷却,加人热水50.715ml,静置分层,水层用甲苯(3×15m)萃取,合并有机相,减44.8压蒸除溶剂得淡黄色液体,精制得78g,收率:84.2%。t1:加完氢化钠室温搅拌时间;t2:加热到78℃时的保温时间;t:加入氨水1.3乙拉西坦的合成将第一步淡黄色液体溶于100ml甲后保温反应时间;n加氢化钠的次数。TYH影化齐鲁药事· Qilu Pharmaceutical Affairs2005vol.24,No.84853结论步考文獻本文对乙拉西坦合成工艺进行了改进,用氨水代替氨[1]UGB( Union Chemische Bderijven). New N-substituted lactams.CGB气,将氢化钠分批加入收到较好效果。1309692,1973,(03):14.复方大青叶注射液生产工艺的研究沈兆军,刘铭传,潘春华(鲁南制药集团股份有限公司临沂27605)摘要:目的对复方大青叶注射液的生产工艺进行改进,降低毒、副作用,达到安全有效的目的。方法通过正交试验对加水量,提取时间,提取次数进行因亲考察,验证工艺路线的可行性。结果采用水提醇沉法提取,条件为加水10倍量、煎煮3次、每次为1.5h,在制剂中采用两步醇沉两步水沉,加入遁量活性炭,脱色。结论该工艺充分考虑经济性、可操作性,适用于复方大青叶注射液的大生产。关键词:复方大青叶注射液正交试验提取工艺生产工艺均匀设计中图分类号:TQ460.6文獻标识码:A文章编号:1672-7738(2005)08-0485-02Study on the productive process of Compound Folium Isatidis InjectionsShen Zhao-jun, Liu Ming-chuan, Pan Chun-huaLu'nan Pharmaceutical Share Limited Company, Linyi, 276005)Abstract: Objective To improve the process of Compound Folium Isatidis Injections, lower its poison and side effects, attain thesafe and operative goal. Methods The volume of water, extract time and the number of times of extract were studied to verify thepossibility of craft route by orthogonal design Results Using water-extraction and alcohol-precipitation to extract, 10 times water1.5 hours of three times needed. In the process of preparations, twice alcohols-precipitation and twice water-precipitation were adopted. It can make the color shallow by adding activity carbon. Conclusion This craft is considered on the economy and operation. Thisexperimental method is suitable to the productive preparation of Compound Folium Isatidis InjectionsKey words: Compound Folium Isatidis Injections; orthogonal design; extraction process; productive process uniform design复方大膏叶注射液具有清瘟、解毒之功效,用于急、慢性含量测定),所用试剂均为分析纯。肝炎,乙型脑炎,流行性感冒,腮腺炎等。它的临床应用非2实验方法与结果常广泛,是清热解毒类常用中成药。其成方已有几百年历2,1大黄素提取条件的优化试验以大黄素提取液含量(mg史,随着临床应用研究的发展,发现在越来越多其他病症的m1)为指标,选择L(34)正交试验表,对水提取工艺条件治疗功效,因此复方大青叶注射液被众多的厂家看好(2)。本进行筛选试验。选择因素和水平见表1试验结果见表2。试验在综合分析古今中医药文献资料的基础上,以大黄有效由表2中R值可知,RA,Rc较大,RD,RB较小,以最小的成分大黄素为指标,采用均匀设计优选复方大青叶提取工艺RD作误差估计,RA,Rc分别是RD,RB的近2倍,由此可知条件,从而达到提高活性成分含量和大黄药材利用率的目、C是影响提取的重要因素,DB则处于次要地位,再结合的,进一步对制剂工艺进行试验摸索,制定出符合工业化生各因子K值分析,A2>A1,B3>B1,C1>C2,D1>D2。因此,产的合格工艺3。提取的最佳条件是A2B3CD1,即加10倍量水,煎煮3次,每1仪锅与试药次1.5h4。1.1仪器1m3不锈钢提取罐,N-500不锈钢真空浓缩罐,提取试验因素、水平表500L不锈钢沉降槽,T-M-S-3板框压滤机,恒温加速器水平加水量(A)煎煮时间(B)煎煮次数(C)煎煮温度(D)GZ-200,CS-9301PC双波长薄层扫描仪(日本岛津)。0.751.2药材与试药大青叶、金银花、羌活、拳参、大黄(均自90制)大黄素(购于中国药品生物制品检定所,经检验可用于81.5