精細(xì)石油化工2004年1月第1期SPECIALITY PETROCHEMICALS聚乙二醇催化合成6,6-二溴青霉烷酸李士杰朱領(lǐng)地°章文軍張麗萍閆紅霞高訓(xùn)章(河北工業(yè)大學(xué)化工學(xué)院應(yīng)用化學(xué)系,天津300130)摘要:以6-氨基青霉烷酸(6-APA)為原料,以二氯甲烷為溶劑,在聚乙二醇(PEG-400)催化劑的存在下，經(jīng)重氮化、溴代合成了6.6-二溴青霉烷酸。通過(guò)正交實(shí)驗(yàn)得到最佳反應(yīng)條件為;m(NaNO2) : n(6-APA)=2 : 1;m(PEG-400) : m(6-APA)=0.08: l; n(Br2) : n(6-APA)=2.0t 1;反應(yīng)溫度8~12 C;反應(yīng)時(shí)間4h。在此條件下,6,6-二溴青霉烷酸的產(chǎn)率為95% ,純度97% ,并對(duì)聚乙二醇的催化機(jī)理進(jìn)行了初步探討。關(guān)鍵詞:6氨基青霉烷酸6,6-二溴青霉烷酸 聚乙二醇合成中圍分類(lèi)號(hào):TQ465. 1文獻(xiàn)標(biāo)識(shí)碼:A6,6-二溴青霉烷酸是合成亞硫胺霉素[1、青COOH霉烯類(lèi)抗生素的中間體,文獻(xiàn)[2]采用將6-氨基CHs青霉烷酸(6-APA)溶于稀硫酸,在水溶液中進(jìn)行BCHz重氮化,溴化的方法,但收率低。文獻(xiàn)[3]在非均(6.6-二溴青霉烷酸)相反應(yīng)體系中使重氮化,溴化同時(shí)完成,產(chǎn)率較筆者采用聚乙二醇(PEG-400)為相轉(zhuǎn)移催化高,但是純度較差。6-APA 及6,6-二溴青霉烷酸劑-步法合成6,6-二溴青霉烷酸,通過(guò)適當(dāng)降低的分子結(jié)構(gòu)如下:溫度和調(diào)整液溴與原料比,使生成的重氮鹽在相CO0H0、CHa收稿日期:2003 -05-08;修改稿收到日期:2003- 12- 27.作者簡(jiǎn)介:李士杰(1976-),男，在讀研究生。H2N基全項(xiàng)目:河北省博士基金資助項(xiàng)目(230020509)。*通訊聯(lián)系人。(6-APA)PREPARATION AND CHARACTERIZATION OFSOLID SUPERBASE Na-Na2CO3/ y-Al2O3Ding Yuansheng' , Luo Zhichen'，Wang Xun' and Han Xiaoyan2(1. Department of Pharmacy and Applied Chemistry, J inlin Institute of Chemical Technology ,Jilin 132022 ,China; 2. Environment Monitoring Station, Lishu 136500，Jilin, China)Abstract: The preparation method for the solid superbase catalyst consisting of Na-Na2CO3/r-Al2O3was studied, and its base strength, basicity and structure were analysed. The results showed that itsbase strength is higher than H_ =43, and its basicity (H_≥35) is 9. 00 mmol/g. The results of itsare surface layer structure analysis by XRD and IR showed that r Al2O3 has reacted with Na2CO3 toform sodium metaaluminate on the supporter surface, when Na was added, the electrons of Na wastransferred, so that negative charge density of O~- incre中國(guó)煤化工th base site on thesolid base surface are formed. This catalyst was used inNB, the conversionand selectivity are both almost 100%.TYHCNMHGKey words: solid superbase; catalyst; base strength; basicity第1期李士杰等.聚乙二醇催化合成6,6-二溴青霉烷酸35轉(zhuǎn)移催化劑的作用下,很快的接觸到有機(jī)相中的用0.45μm濾膜抽吸過(guò)濾。液溴,不但可以提高產(chǎn)率和純度,而且縮短反應(yīng)時(shí)1.2實(shí)驗(yàn)方法間。該類(lèi)相轉(zhuǎn)移催化劑具有化學(xué)穩(wěn)定性高、毒性在帶電動(dòng)攪拌的三口瓶中加入二氯甲烷和液低、來(lái)源方便、價(jià)格低廉.使用簡(jiǎn)便等優(yōu)點(diǎn),適合于溴,在冰鹽水中冷卻到0 C ,然后加入相轉(zhuǎn)移催化工業(yè)化生產(chǎn),該工藝末見(jiàn)文獻(xiàn)報(bào)道。劑PEG-400,攪拌使溫度為0~5 C。依次加入硫1實(shí)驗(yàn)部分酸、亞硝酸鈉。然后,分批加人6-APA,并保持反.1.1 試劑與儀器應(yīng)溫度在--5~0C.此時(shí)反應(yīng)液顏色為黑紅色。二氯甲烷、亞硝酸鈉、溴素、濃硫酸、PEG-在0C攪拌45min后，于室溫再攪拌3h。反應(yīng)400、硫酸鎂、氯化鈉均為分析純;6-APA,工業(yè)品，完后滴加亞硫酸氫鈉溶液脫溴,并且溫度保持在華北制藥倍達(dá)公司。5~15 C。當(dāng)溴色被除去后,進(jìn)行分離,水相用WC-1顯微熔點(diǎn)測(cè)試儀，四川大學(xué)科儀廠;(2X20 mL)二氯甲烷萃取,有機(jī)相用飽和的食鹽WZZ 2S數(shù)字式自動(dòng)旋光儀,上海精密科學(xué)儀器水(2X20 mL)洗滌,無(wú)水硫酸鎂干燥，減壓蒸餾有限公司;IR-435型紅外光譜儀,日本島津; LC得到淡黃色固體。 通過(guò)液相色譜進(jìn)行了檢測(cè)純10AT反相高效液相色譜儀，色譜條件:色譜柱度。Sperisorbcl8 (250 mmX46 mm,內(nèi)徑10 μm)不2結(jié)果與討論銹鋼柱;檢測(cè)波長(zhǎng)UV 220 nm,流動(dòng)相為V(甲6,6-二溴青霉烷酸合成反應(yīng)的正交實(shí)驗(yàn)因素醇) : V(雙蒸水)=80 : 20,流速為0. 8 mL/min.安排見(jiàn)表1,結(jié)果及分析見(jiàn)表2。表1合成反應(yīng)正交實(shí)驗(yàn) 因素水平表因素水平A(時(shí)間/h) B(反應(yīng)溫度/C) C[V(Br2) : V(CH2Cl2)]D[Cn(Brz): n(6-APA)] E[m(PEG-400) : m(6-APA)]2~8, 031.53. 58~120. 042.00.044.012~150, 052.20. 064. 515~200.062.50.08表2正交實(shí)驗(yàn)結(jié)果及分析由重氮化反應(yīng)動(dòng)力學(xué)["1可知反應(yīng)速率與亞硝.實(shí)驗(yàn)號(hào)ACDE產(chǎn)率.% .酸濃度的平方成正比。兩個(gè)亞硝酸相互作用生成一個(gè)中間產(chǎn)物亞硝酸酐(N2O3),N2Os與HBr反.7679應(yīng)生成ON-Br重氮化活潑質(zhì)點(diǎn),N2O3與75ON- Br均為親電質(zhì)點(diǎn),并進(jìn)攻6-APA分子生成78.534重氮鹽。82根據(jù)動(dòng)力學(xué)方程,通過(guò)單一因素實(shí)驗(yàn)確定重8130氮化反應(yīng)中n(NaNO2) ; n(6-APA) = 2:1。當(dāng)39比值小于2時(shí),反應(yīng)不完全,產(chǎn)率低。比值大于20°)5時(shí),過(guò)量的NaNO2促進(jìn)重氮鹽分解,不僅降低收19012率而且浪費(fèi)原料。386從表2極差分析中可看出,5個(gè)影響因素中4B431反應(yīng)時(shí)間影響最大。反應(yīng)時(shí)間為4 h時(shí),產(chǎn)率較1680好。反應(yīng)時(shí)間過(guò)短,物料反應(yīng)不完全,產(chǎn)物干燥過(guò)K 308.5 335 32833032K2 327 340 333335 329程中中國(guó)煤化工鹽在中性條件下，363327 32833332發(fā)生i低。溫度在8~K, 331 327.5 340.5330.5336.5R_ 54.5 13_ 12.5_57.52d0HCNMHG低.反應(yīng)速率緩注:n(NaNO2) : n(6-APA) = 2: 1.慢,4 h內(nèi)反應(yīng)進(jìn)行不完全;溫度過(guò)高，易造成液36精細(xì)石油化工2004年溴揮發(fā)和亞硝酸的分解,并使6-APA增多。其他溴青棕烷酸的產(chǎn)率為95%(文獻(xiàn)值田為80%),純最優(yōu)條件為:V (Br2) : V (CH2Cl2) = 0.06,度為97%(雜質(zhì)為6-溴青霉烷酸),粗產(chǎn)品的熔程n(Br2) ; n(6- APA)=2.0。為136~138C,經(jīng)重結(jié)晶得到的產(chǎn)物熔點(diǎn)為1453催化機(jī)理 初步探討C(文獻(xiàn)值[E]為144~ 146 C); IR(KBr) v:6-APA與HNO2和Br2 在( PEG-400)- 2 600~3 700，1 799，1 775 cm-1,與文獻(xiàn)相符。CH2Cl2體系中，進(jìn)行重氮化和a氫的取代反應(yīng)，得高產(chǎn)率、高純度的產(chǎn)品。PEG-400 可作為相轉(zhuǎn)移催化劑(PTC) ,是由于在無(wú)水情況下, PEG-400參考文獻(xiàn)呈鋸齒狀;在水存在下,呈曲鏈狀[門(mén),曲鏈狀的1劉液,屈傳星,王燕云 等.亞硫胺霉素的合成[J].中國(guó)新藥雜PEG-400具有絡(luò)合正離子的能力5],其催化機(jī)理志,1997 ,6(6) :467~469可能是:Volkmann R A,Carroll R D,Drolet R B.et al. Efficient prep-1) PEG-400激活亞硝酰溴有利于ON+的形aration of 6, 6-dihalopenicillanic acids. Syathesis of penicllan-成。使重氮化反應(yīng)能平穩(wěn)進(jìn)行,得到高產(chǎn)率的重ic acid s, S-dioxde ( sulbactam). J Org Chem, 1982， 47 ;氮鹽"°3];3 344~3 3452)作相轉(zhuǎn)催化劑,使反應(yīng)體系由非均相體系3 ClaytonJ P. The Chemistry of Penicillanic acid. Part I.6.6-dibromo and 6,6 diodo derivatives. J Chem Soc (C), 1969;變?yōu)榫囿w系;2. 123~2 1273)PEG400的存在能極化有機(jī)相的溴形成唐坍輦.精細(xì)有機(jī)合成化學(xué)及工藝學(xué)[M] .天津:天津大學(xué)出極性分子[] ,進(jìn)行a取代。版社.1993.11~184結(jié)論章亞?wèn)|.高曉蕾等， 聚乙二醇相轉(zhuǎn)移催化合成對(duì)硝基苯甲醚綜上所述,實(shí)驗(yàn)較優(yōu)條件為:n(NaNO2) :工藝[J].鄭州大學(xué)學(xué)報(bào)( T.學(xué)版) ,2002 ,23(2):23~26李懷剛. 芳香伯胺重氮化的特殊反應(yīng)條件[J].淮海工學(xué)院學(xué)n(6-APA)=2 : 1; m(PEG-400) : m(6-APA)=報(bào)，2000,S1:4~50.08: 1; n(Br2) : n(6-APA)=2.0: 1;反應(yīng)溫劉增勛.相轉(zhuǎn)移催化劑在有機(jī)化學(xué)和農(nóng)藥合成中的應(yīng)用[M].度8~12 C;反應(yīng)時(shí)間4 h。在此條件下,6,6-二北京:科學(xué)出版社,1987.12~16SYNTHESIS OF 6,6-DIBROMOPENICILLANIC ACID ONPOLYETHYLENE GLYCOLLi Shijie, Zhu Lingdi, Zhang Wenjun, Zhang Liping，Yan Hongxia and Gao Xunzhang(School of Chemical Engineering and Technology, Hebei University of Technology，Tianjin 300130, China)Abstract: 6,6-Dibromopenicillanic acid was synthesis from 6-aminopenicillanic acid (6-APA) by bro-minated on the polyethylene glycol (PEG-400) as phase-transfer catalyst in methylene chloride as sol-vent. The optimal conditions was obtained by orthogonal experiment as follows: n(NaNO2) : n(6-APA)=2: 1, m(PEG-400) : m(6-APA)=0.08: 1, n(Br2) : n(6-APA)=2.0: 1, reaction tempera-ture 8~12 C, reaction time 4 h with the yield up to 95% and purity 97%. The mechanism of the ca-talysis was discussed.Key words: 6-aminopenicillanic acid; 6, 6- dibromopenicillanic acid; phase transfer catalyst; synthesize中國(guó)煤化工HCNMHG