索法酮的合成

第22卷第6期沈阳药科大学学报Vol.22No.62005年11月Journal of Shenyang Pharmaceutical UniversityNov.2005 p.417文章编号: 1006 -2858( 2005 )06 -0417. 03索法酮的合成王绍杰,郑洪伟,赵存良，陈欣(沈阳药科大学制药工程学院,辽宁沈阳110016)摘要:目的研究抗溃疡药索法酮( I )的合成工艺。方法以2’A'-二羟基苯乙酮为原料经两步烃化反应得中间体[2-乙酰基-5<(3-甲基-2-丁烯基)氧基]苯氧基乙酸乙酯( II );对羟基苯甲醛与溴代异戊烯反应得4(3-甲基-2-丁烯基)氧基苯甲醛( II )( II )与( I )缩合得到了目标化合物。结果以2' A'-二羟基苯乙酮计三步反应总收率为44.4% ,目 标化合物结构经核磁共振氢谱、质谱确证。结论该法原料易得、操作简便、反应条件温和，有-定的工业生产应用价值。关键词: 索法酮;抗溃疡作用;药物合成中图分类号:R914文献标识码: A索法酮sofalcone )化学名为[5(3-甲基-2- 丁抑制作用,并能抑制菌体对胃黏膜的黏附。因此,烯基氧基-2-[3[4 (3-甲基-2-丁烯基)氧基]苯本品具有较好的临床应用价值12]。文献[ 3 ]报基-1-氧代-2-丙烯基苯氧基]乙酸，为一种胃黏膜道了索法酮的合成方法:以对羟基苯甲醛为原料,保护剂和组织修复剂，可用于胃溃疡、急慢性胃炎通过与溴代异戊烯烃化得到4-(3-甲基-2-丁烯的治疗,由日本大正制药公司研制开发,1984 年基)氧基苯甲醛再以2' A-二羟基苯乙酮为原料,3月在日本上市。本品通过扩张胃黏膜血管,增分别与溴代异戊烯和溴乙酸乙酯烃化合成[ 2-乙加胃黏膜血流量和胃组织耗氧量,抑制前列腺素酰基-5(3-甲基-2-丁烯基)氧基]苯氧基乙酸乙分解酶从而增加胃内前列腺素含量等药理作用,酯二者缩合得到目标产物总收率为41.2%。作发挥出较强的抗溃疡、胃黏膜保护和促进胃黏膜者采用此路线,并对合成工艺进行改进得到索法修复作用。另外,本品对幽门螺旋杆菌有较强的酮总收率为44.4%合成路线见图1。COCH30HOCHCOOC2HsK2CO3 , acetoneBrCH2COOC2Hs，KOH+ BrCH2CH=C(CH)2acetone .OHOCHCH=C(CH)2.OCH2CH=C(CH)2IICHO+ BrCH2CH=C(CH)2 KxCO3, actoKOH, ethanol6CH2CH=C(CH)2IIICOCH=CH-O-0CH2CH=C(CH)2HO0OCH2CO中国煤化工》MHCNMHGFig.1 The synthetic route of the target compound收稿日期2005-02-28作者简仿数綱( 1968- )男(汉族)辽宁大连人副教授主要从事新药设计与研究开发,Tel. 024-23986421 ,E-mailsjwang-99 @ yahoo . com. cn。418沈阳药科大学学报第22卷盐酸调至pH=1用乙醚( 20 mLx3 )萃取,水洗有1仪器与材料机层将乙醚蒸干,所得固体用无水乙醇重结晶。熔点测定毛细管(自制),ARX-300核磁共振得到黄色固体11.06 g ,收率为75.2% ,mp 142~仪(美国Bruker 公司),1100四极杆液相色谱-质146 C(文献[3 ]:收率74% )。'H-NMR( CDC]3 )δ :谱联用仪(美国Agilent 公司)。1.73(d 6H,一OCH2CH=C ( CH3 )λ1.84(d ,6H ,溴代异戊烯和2' A-二羟基苯乙酮(工业级市-OCH2CH=C(CH3))4.57(t，4H，售)其他试剂分析纯,市售)。OCH2CH=dCH3) x 2 ) 4.79 ( s, 2H,-0CH2C0OH入5.48( m 2H ,- 0CH2CH- =CCH3) x2方法与结果2)6.55(d ,1H , - COCH=CH入6.67( dd ,1H ,2.1 4(3-甲基2-丁烯基)氧基苯甲醛的合成ArH入6.94(d,2H，ArH)7.24(d,1H,将10 g(0.040 mol )对羟基苯甲醛和13.2 g-COCH=CH ) 7.58( d ,2H ,ArH ) 7.73(d ,H ,(0.048 mol )无水碳酸钾溶于10 mL丙酮中，室 温ArH)7.78(d,H ,ArH)。MS m/z :451[M+ H]+。下搅拌30 min后滴入11 g(0.037 mol )溴代异戊烯搅拌5h。抽滤,减压蒸出丙酮加入50 mL乙3讨论酸乙酯,用质量分数为10%的氢氧化钾溶液洗涤，文献3在合成4-(3-甲基-2-丁烯基)氧基苯水洗乙酸乙酯层，无水硫酸钠干燥过夜。过滤,减甲醛时对羟基苯甲醛与溴代异戊烯等摩尔反应,压蒸出乙酸乙酯,得到淡红色液体5.6 g ,收率为反应结束后减压蒸出产品。作者通过改变反应物80%(文献[3]:bp 92~94 C/6.75x 10-3Pa ,收率配比使对羟基苯甲醛稍过量反应结束后用质量84% )分数为10%的氢氧化钾水溶液洗涤将过量的对羟2.22- 羟基4'-3甲基丁烯基-氧基苯乙酮的合成基苯甲醛成盐洗去,不需减压蒸馏即可得到纯品。将10g0.066 mol )2' A4-二羟基苯乙酮和11 g合成24羟基-4(3-甲基-丁烯基)氧基苯乙酮时(0.080mol)无水碳酸钾溶于120mL干燥的丙酮文献3采用将反应物-次性加入到反应瓶中进行中室温下搅拌0.5h后滴入13 g0.088 mol )溴代反应的方法,反应结束后用乙醚、石油醚的混合溶异戊烯25~30 C搅拌3h蒸干丙酮放冷得到Q剂重结晶得到纯品。由于合成2-羟基- 4(3-甲基淡红色固体用石油醚洗涤得到淡粉色固体10.34.丁烯基氧基苯乙酮时先生成钾盐作者采用先使g收率为71.2% mp 46.47 C ,可直接进行下步反应2'A'二羟基苯乙酮生成钾盐再滴入溴代异戊烯的方(文献3]mp 46.47 C收率76% )法此操作可使反应充分进行无需重结晶直接进行2.3 [2-乙酰基5-(3-甲基-2-丁烯基)氧基苯氧下步反应。合成2-乙酰基5(3-甲基- 2-丁烯基)基乙酸乙酯的合成氧基苯氧基乙酸乙酯时,文献[3]也采用将反应将10g0.045 mol )2'羟基-4'(3-甲基-丁烯物一次性加入到反应瓶中进行反应的方法,反应基)氧基苯乙酮和3.05 ( 0.055 mol )氫氧化钾溶结束后用石油醚重结晶得到纯品。作者采用先使于67 mL干燥丙酮中搅拌20 min滴入8 g( 0.0482-羟基-4(3-甲基-丁烯基)氧基苯乙酮生成钾盐mol)溴乙酸乙酯室温搅拌3h,抽滤减压蒸出丙再滴入溴乙酸乙酯的方法,反应结束后用石油醚酮放冷得浅红色晶体。用石油醚洗涤所得晶体，洗涤即得纯品。通过以上改进可使操作简化、收干燥得白色固体11.53 g收率为82.9% ,mp 63、率提高到44.4%，更适于工业化生产。64 C( 文献3]imp63、64 C收率68.3% )参考文献:2.4索法酮的合 成取14g氢氧化钾配成质量分数为50%的水.[ 11 Parmar N S Parmar s Anti-nlrer potential of flavonoid[ J ].溶液,加入到120 mL无水乙醇中,放冷备用。将中国煤化工8 4X3)343- 351.10g0.0326 mol[2-乙酰基-5-(3-甲基-2-丁烯HCNMHGlcone[J].NipponRinsho,2002 60( S2 ) .704- 709.基)氧基苯氧基乙酸乙酯加入其中。室温搅拌下[3 ] Kazuaki K , Katsuo H. Anti-ulcer efect of isoprenyl滴入6.2 60.0326 mol)4-(3-甲基-2-丁烯基)氧基flavonoids II synthesis and anti-ulcer activity of new chal-苯甲醛搅拌5 h ,减压蒸出乙醇加水20 mL滴加cones related to sophoradin[ J ]. Chem Pharm Bull ,1979 27( 12) 2943 - 2953.第6期王绍杰等:索法酮的合成419Synthesis of sofalconeWANG Shao-jie , ZHENG Hong-wei , ZHAO Cun- liang , CHEN Xin( School of Pharmaceutical Engineering ,Shenyang Pharmaceutical University , Shernyang 110016 , China )Abstract : Objective To investigate the synthetic process for the anti-ulcer drug sofalcone(I ). Methods Startingfrom 2' A'-dihydroxyacetophenone ethy[ 2-acetyl-5{ 3-methyl-2-butenyloxy )phenoxy ]acetate( I ) was obtained via twosteps of alkylation ;4( 3-methy1-2- butenyloxy ) benzaldehyde( II ) was prepared by the reaction of 4-hydroxyben-zaldehyde with 1-bromo-3-methyl-2-butene .Thus the target compound was obtained through the condensation of II andII. Results Starting from 2' A-dihydroxyacetophenone ,the target compound was synthesized through a three-step pro-cedure in a total yield of 44.4% ,and its structure was confirmned by 'H-NMR and MS . Conclusions The processshould has certain value for industrial application with respect to its availability of the raw materials simple operatingprocedure and mild reacting condition .Key words : sofalcone ; anti-ulcer activity ; drug synthesis(上接第408页)Preparation of sustained-release poly( D ,L-lactide-co -glycolide ) microspheres (containing bupivacaineand the evaluation of drug release in vitroLIU Xiao-rui' , DING Ping-tian' , ZHANG Jin2 , JIANG Jing- jing2( 1. School of Pharmacy , Shenyang Pharmaceutical University ，Shenyang 110016，China ; 2. Department QAnaesthesia ,Second Clinical Hospital ,China Medical Universily , Shengyang 110001 , China )Abstract : Objective To prepare sustained-release poly( D ,L-lactide- co-glycolide X PLGA )microspheres containingbupivacaine and study drug release in vitro . Methods Ultraviole( UV )spectrophotomatry method was used for deter-mination of the drug loading percent and drug entrapment efficiency of PLGA microspheres containing bupivacaine .High-performance liquid chromatography method with UV detector was applied to detect drug release of the prepara-tion in vitro . The orthogonal design was used to optimize the preparation technology of the microspheres . The micro-spheres containing bupivacaine were prepared by the emulsification-solvent evaporation method using PLGA as carri-ers and their release characteristics were measured in vitro . Results The analytical methods for determination of thedrug loading percent ,drug entrapment efficiency and drug release of microspheres in vitro were proved to be sensi-tive ,precise and reliable. PLGA microspheres containing bupivacaine were globular and had porous surface likehoneycomb" .The yield of microspheres with diameter between 50- 100 pμm was more than 80% . The in vitro re-lease profiles could be expressed by Ritger- Peppas equation with t1/2 = 242.05 h. Conclusions The emulsification-solvent evaporation method is applicable for the preparation of PLGA microspheres containing bupivacaine.It is .shown that the microspheres containing bupivacaine have good appearance and significant in vitro sustained- releasecharacteristics. .中国煤化工Key words : bupivacaine ; microspheres ; poly( D ,L-lactide-ccYHCNMHGrvitro