·484齊魯藥事 Qilu Pharmaceutical affairs2005vol.24,No8藥物研究乙拉西坦的合成盧傳廣,王洪剛,王洪鋒(魯南制藥集團(tuán)股份有限公司臨沂276005)摘要:目的合成乙拉西坦。方法2一吡咯烷酮絰N炕基化、解反應(yīng)合成乙拉西坦。結(jié)果及結(jié)論總收率50.7%,乙拉西坦結(jié)構(gòu)經(jīng)H-NMR,C-NMR和IR確證。關(guān)詞:乙拉西坦吡咯炕酮合成中圖分類號:TQ460.31文獻(xiàn)標(biāo)識碼:A文章編號: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乙拉西坦化學(xué)名;a-乙基-2-氧-1-吡咯烷乙酰胺,醇中,加入飽和氨水26m,32℃保溫反應(yīng)24h,用薄層色譜監(jiān)它是比利時(shí)聯(lián)合化學(xué)公司開發(fā)的促智藥。文獻(xiàn)以2-吡咯測反應(yīng)終點(diǎn),展開劑乙酸乙酯一二氯甲烷(4:1)?；厥占状纪橥獮樵?經(jīng)N-烷基化氫解反應(yīng)制得。本文對原工藝?yán)鋮s得白色固體,用乙醇重結(jié)晶得16.2g,收率60.2%。加以改進(jìn)。烷基化、氨解收率提高,效果顯著。mp120~122℃(文獻(xiàn)122℃);1H-NMR(CDCl3):890(t,3H,CH3),1.62~2.12(m,4H,CH2,吡咯環(huán)4-CH2),2.362.52(m,2H,吡咯環(huán)3-CH2),3.37~3.52(m,吡咯環(huán)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,吡咯環(huán)4-C),31.10(1C,吡咯環(huán)3-C)HNH」O43.83(1C,吡咯環(huán)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實(shí)驗(yàn)部分2結(jié)果與討論1.1儀器與試劑DF-101S集熱式恒溫加熱攪拌器,Z7A2-吡咯烷與氫化鈉反應(yīng)較劇烈,并有氫氣放出,應(yīng)緩緩三用紫外分析儀,WRs-1B數(shù)字熔點(diǎn)儀,JA12002型電子天分批加入,根據(jù)試驗(yàn)結(jié)果列表得反應(yīng)時(shí)間用加料情況對總收平,2-吡咯烷酮(工業(yè)級),其他為市售化學(xué)純或分析純試劑。率的影響。1.22-(2一氧一吡咯烷)丁酸甲酯的制備在250ml四口實(shí)驗(yàn)號t1(h)t2(h)總收率(%燒瓶中加人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保護(hù),室溫?cái)嚢?h后加入2-溴丁酸甲酯9.0g(50mmol),芐基三乙基氯化銨0.6g331,2445.7(26mmol),攪拌下加熱至78℃反應(yīng)4h,冷卻,加人熱水50.715ml,靜置分層,水層用甲苯(3×15m)萃取,合并有機(jī)相,減44.8壓蒸除溶劑得淡黃色液體,精制得78g,收率:84.2%。t1:加完氫化鈉室溫?cái)嚢钑r(shí)間;t2:加熱到78℃時(shí)的保溫時(shí)間;t:加入氨水1.3乙拉西坦的合成將第一步淡黃色液體溶于100ml甲后保溫反應(yīng)時(shí)間;n加氫化鈉的次數(shù)。TYH影化齊魯藥事· Qilu Pharmaceutical Affairs2005vol.24,No.84853結(jié)論步考文獻(xiàn)本文對乙拉西坦合成工藝進(jìn)行了改進(jìn),用氨水代替氨[1]UGB( Union Chemische Bderijven). New N-substituted lactams.CGB氣,將氫化鈉分批加入收到較好效果。1309692,1973,(03):14.復(fù)方大青葉注射液生產(chǎn)工藝的研究沈兆軍,劉銘傳,潘春華(魯南制藥集團(tuán)股份有限公司臨沂27605)摘要:目的對復(fù)方大青葉注射液的生產(chǎn)工藝進(jìn)行改進(jìn),降低毒、副作用,達(dá)到安全有效的目的。方法通過正交試驗(yàn)對加水量,提取時(shí)間,提取次數(shù)進(jìn)行因親考察,驗(yàn)證工藝路線的可行性。結(jié)果采用水提醇沉法提取,條件為加水10倍量、煎煮3次、每次為1.5h,在制劑中采用兩步醇沉兩步水沉,加入遁量活性炭,脫色。結(jié)論該工藝充分考慮經(jīng)濟(jì)性、可操作性,適用于復(fù)方大青葉注射液的大生產(chǎn)。關(guān)鍵詞:復(fù)方大青葉注射液正交試驗(yàn)提取工藝生產(chǎn)工藝均勻設(shè)計(jì)中圖分類號:TQ460.6文獻(xiàn)標(biāo)識碼:A文章編號: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復(fù)方大膏葉注射液具有清瘟、解毒之功效,用于急、慢性含量測定),所用試劑均為分析純。肝炎,乙型腦炎,流行性感冒,腮腺炎等。它的臨床應(yīng)用非2實(shí)驗(yàn)方法與結(jié)果常廣泛,是清熱解毒類常用中成藥。其成方已有幾百年歷2,1大黃素提取條件的優(yōu)化試驗(yàn)以大黃素提取液含量(mg史,隨著臨床應(yīng)用研究的發(fā)展,發(fā)現(xiàn)在越來越多其他病癥的m1)為指標(biāo),選擇L(34)正交試驗(yàn)表,對水提取工藝條件治療功效,因此復(fù)方大青葉注射液被眾多的廠家看好(2)。本進(jìn)行篩選試驗(yàn)。選擇因素和水平見表1試驗(yàn)結(jié)果見表2。試驗(yàn)在綜合分析古今中醫(yī)藥文獻(xiàn)資料的基礎(chǔ)上,以大黃有效由表2中R值可知,RA,Rc較大,RD,RB較小,以最小的成分大黃素為指標(biāo),采用均勻設(shè)計(jì)優(yōu)選復(fù)方大青葉提取工藝RD作誤差估計(jì),RA,Rc分別是RD,RB的近2倍,由此可知條件,從而達(dá)到提高活性成分含量和大黃藥材利用率的目、C是影響提取的重要因素,DB則處于次要地位,再結(jié)合的,進(jìn)一步對制劑工藝進(jìn)行試驗(yàn)摸索,制定出符合工業(yè)化生各因子K值分析,A2>A1,B3>B1,C1>C2,D1>D2。因此,產(chǎn)的合格工藝3。提取的最佳條件是A2B3CD1,即加10倍量水,煎煮3次,每1儀鍋與試藥次1.5h4。1.1儀器1m3不銹鋼提取罐,N-500不銹鋼真空濃縮罐,提取試驗(yàn)因素、水平表500L不銹鋼沉降槽,T-M-S-3板框壓濾機(jī),恒溫加速器水平加水量(A)煎煮時(shí)間(B)煎煮次數(shù)(C)煎煮溫度(D)GZ-200,CS-9301PC雙波長薄層掃描儀(日本島津)。0.751.2藥材與試藥大青葉、金銀花、羌活、拳參、大黃(均自90制)大黃素(購于中國藥品生物制品檢定所,經(jīng)檢驗(yàn)可用于81.5