Comparative Process for the Preparation of 9-Oxime Erythromycin A

Journal of Beijing Instute of Technology , 2004，Vol.13，No.1Comparative Process for the Preparation of 9-OximeErythromycin ASUN Jing-gud 孙京国)23，YAO Guo-we(姚国伟尸，0U Yu-xiang 欧育湘)( 1. School of Material Science and Engineering , Bejjng Institute of Technology , Beijing 100081 , China ;2. School of Life Science and Technology , Beijing Institute of Technology , Beijing 100081 , China ;3. Collge of Chemistry , Hebei Normal U niversity , Shijjazhuang , Hebei 050091 , China )Abstract : The comparative process for preparing 9-oxime erythromycin A( EMAO ) is investigated. EMAO wassynthesized and compared by the reaction of ery thromycin and hydroxylamine hydrochloride with various basessuch as sodium acetate , triethylamine , etc. A new synthetic method is established. The oximation is performedunder dynamic buffer system ; less degradation impurities are formed. The yield of EMAO reaches more than95% , HPLC analysis shows that the purity of EMAO is more than 90% , and the E/ Z isomeric ratio preponder-ates over 7:1.Key words : 9-oxime erythromycin A ; synthetie process ; comparisonCLC number :0621.3Document code :AArticle ID : 1004-0579 2004 )01-0076-049-oxime erythromycin A( EMAO)is a very im-making EMAO result in more degraded impurities .portant pharmaceutical intermediate in the synthesisParticularly , as aqueous hydrox ylamine is unstableof novel macrolide antibiotics such as roxithromycin ,and liable to explode ,it is difficult to carry out in in-clarithromycin , azithromycin , etc.' 1-31 As commondustrial scale production. Fortunately , we have foundtechniques, the synthetic method was paid most at-a new synthetic method and several new efficient ba-tention to in the last 10 years. The yield and purity ofsic reagents to improve the process of synthesis.EMAO have an important influence on the furtherHere , we show the results.synthesis. A variety of processes for preparing EMAOA new process for preparing EM AO directlyhas been described , by way of example , EMAO canfrom erythromycin( EM ) is contributed ;it results inbe made by reaction of erythromycin A of either hy-a high yield and minimized degradation impurities. Adrox ylamine hydrochloride under a base such as sodi-synthetic scheme is shown in Fig. 1. Here EM in-um acetate , triethylamine or 50% aqueous hydroxy-cludes major component EMA( R= OH ,R= CH3 ,lamine4-6]. However ，the mentioned methods of95% ), main impurities EMC( R=0H ,Ri= H ) andNOH,OHHQ在OHOHH*HOHsC"NH2OH-HCTHsCiQ-CH;EM中国煤化工Fig.1 Synthesis of 9-oxime ery.MYHCNMHGReceived 2003-03-20Sponsoredy the TechniquesInnovvationFoundation of State Economic & Trade Comission( 01 BK-009 )Biographies SUN Jing-guo( 1962 - ), in-service doctoral student ,sun_ jngguo@ 163. com ; YAO Guo-wei( 1942 - ), professor.一76-SUN Jing-gud(孙京国)et al. / Comparative Process for the Preparation of 9-0xime Erythromycin AEMB(R=H ,R|= CH3). The establishment of new1.4 Preparing EMAO in Dynamic Buffer Systemsynthetic process is not only significant in the investi-To a solution of EM ( 10.0 g) in an ethanolgation of new method , but also available and effective ( 95% , 60 ml ) was added hydroxy lamine hydrochlo-in the large-scale production.ride( mol eqv. 1 : 10 with EM ) and adjusted withbuffers to keep pH 6.5- 7.5 , and the mixture was1 Experimentalallowed to react at about 60 C until completion ，1.1 Instrument and Reagentswork-up as above. The dried extract solution wasInstrument : Bruker ARX 400 'H &I'C NMR ,concentrated and chloroform w as added to deposit theNicolet Magna IR 560 , VG ZAB-HS MS , Elementar .product. The solid was collected by filtration. m. p.Vario EL , HITACHI L-7100 HPLC system .is 156- 159 C. The yield is more than 95%. HPLC .Reagents: Erythromycin was purchased fromshowed the purity to be more than 90% .Xi' an Pharmaceutical Plant , other chemical materials1.5 Structure ldentificationwere analy tical grade and commercial available.The product was recrystallized from acetone-1.2 Preparing EMAO Using Triethylamine as awater to give pure EMAO-E isomer.BaseElemental analysi( calcd. for C37H68N2O13),% :Toa solution of EM ( 10.0 g) in an absoluteC58. 9759. 36), H9.179.09 ),N3.7l( 3.74 ).ethanol( 50.0 mL ) were added triethylamine( 19.4 mL)IR(KBr),σ,cm-1:3560,3400，2980,and hydroxylamine hydrochloride( 9.6 g), and then2950,1 460,1 390,1 165 ,1 110,1 085 ,1 050 ,acetic acid was added , and the mixture was stirred1 010.about 20 h at 50- 55 C. The reaction was monitoredH NMR( 400 MHz ,CDCl3 ),δ: 0.83 - 0.86by TLC until completion , the formed salt w as filtered(3H t ,15),1.04- 1.06(3H d),1.11- 1.26(2H，out from the reaction mixture and the filtrate wasm),1.26- 1.30(4H t),1.51(4H m ,6-CH3 ),1.53concentrated , then ethyl acetate was added，and the- 1.62( 3H ,m ,4'),1.67 - 1.71( 1H ,d), 1.90 -mixture was stirred while pH was adjusted to a value .2.04(2H ,m ,4 ,14)2.14( 1H s)3.32- 2.39( 8H，of no less then 11.0 by addition of 4 mol/L aqueoust ,N(CH3) ,2”)2.48( 1H m),2.69-2.70 1H q,sodium hydroxide. The extract w as separated and10),2.89- 2.94( 1H ,m ,2),2.99- 3.02( 1H ,d ),washed with water and saturated sodium hydrochlo-3.17 1H s)3.24-3.291H ,dd2' )3.32( 3H srride , and the organic layer was dried over anhydrous0-CH3 )3.47-3.52( 1H ,m 5' )3.58-3.60( 1H ,magnesium sulfate overnight. The solvent was evapo-d 5)3.70( 1H s,11)3.78-3.81( 1H ,m 8)4.02rated under vacuum and chloroform was added to de--4.06(2H q3 5" )4.42-4.43( 1H ,d ,1')4.55posit the product. m.p. is 156- 162 C. Product( 1H s)4.93-4.94( 1H ,d,1" )5.08-5.11( 1H ,yield is 88.0%. Purity is 87.9%.dd ,13 ).1.3 Preparing EMAO Using Other Basic ReagentsMS( EI):m/z 748 715 574 462 ,174 ,158.To a solution of EM ( 10.0 g ) in an absolute2 Results and Discussionsethanol( 50 ml ) were added basic reagents such assodium acetate( mol eqv. 1 : 10 with EM ) and hy-Many different reaction systems were studieddroxylamine hydrochloride( mol eqv.1:10 with EM ),such as dry methanol , anhydrous ethanol , 95% in-the reaction mixture was catalyzed by an acid. Thedustrial ethanol , isopropanol , ethyl acetate and recy-reaction was conducted at 50 - 55 C and monitoredcling中国煤化工f reaction temperatureby TLC until completion , work-up was performed as .and:MYHCN M H Gas investigated in de-above. m.p. is 156- 166 C. The yield is less thantail , and the procedure of isolation and purification90%. Purity is less than 85% .were also studied. Some conclusions can be recog-nized.一77-Journal of Beijing Instute of Technology , 2004，Vol.13，No.12.1 The Essentiality of Acidity of Reaction Systemthe more active species in the synthesis of novelWhen erythromycin A reacts with hydroxyl-macrolid antibiotics. The purity and E/Z isomer ra-amine , the addition of the acid increases the rate oftio were detected by HPLC. Oxime and relativeformation of 9-oxime erythromycin A. Nevertheless ,degradation impurities were purified by column withwhen more than a certain amount of the acid issilica gel or recrystallization and identified by elemen-added , a hemiacetal w hich formed by the reaction oftal analysis, IR , 'HNMR, I3CNMR and MSI3].the 9-carbonyl group with 6-hydroxyl group of ery-The yield and the E/Z isomer ratio obtained fromthromycin A is dehydrated to give the correspondingseveral methods were shown in Fig.2.enol-ether form. In order to obtain 9-oxime ery-120昌yetatiothromycin A in good yield ,it is necessary to prevent门EZ ratio100the formation of enol-ether form. Obviously , it is .very important to control the quantity of acid.In the reaction system , the relation bet ween the .quantities of acid and the products purity was stud-ied. Present basic systems have similar behavior with20the triethylamine systent 77. However , the reaction23467mixture acts as a dy namic buffer system ,the pH val-diferent methodsue ensures the minimum formation of impurities andFig.2 Comparison of yield and relative E/Z isomer ratiohigher yield ; the product w as pure.in different synthetic methods2.2 Comparison of Solvents and Basic Reagents1-triethylamine-anhydrous ethanol ; 2- -sodium acetate-anhydrousMethanol , ethanol and isopropanol were used asethanol; 3- -50% aqueous hydroxyl-amine- methanofl41; 4- -50%the reaction solvents in most of EMAO preparation.aqueous hydroxylamine-ethanotl4]; 5- -50% aqueous hydroxy-Basic reagents can be barium carbonate81 ,，pyri-lamine-isopropanot 4; 6- -a new basic reagent-anhydrous ethanol ;7- -a new basic reagent-recycling ethanoldine 61 , sodium carbonate 9]，imidazole 10]，sodiumacetatel1],, hydroxylamine 4] , triethylamine 12]」,etc.It reveals that our new synthetic process hasreached a better level of EM AO preparation. Further-In these methods , methanol is used as solvent in mostcases ,but it is toxic and unhealthy to the operators.more it has advantages such as a smoothly reactingcondition，easy purification ，green solvents and aMost of basic reagents are relatively expensive. Fur-thermore , the yields of some reaction systems are lessgood operational environment.than 85%. Even reaction needs to be free of water. .3 ConclusionsThe method using 50% hydroxylamine gives a higherFrom the above analyses and comparisons , someyield , but it is unstable and liable to explode. Ourconclusions can be summarized as follows :group has developed a new process by use of triethyl-①Degradation impurities are unavoidable in theamine and the yield reaches 88%[71. In an extendedsynthesis of EMAO because of reaction mechanics .research ,a dynamic buffer system was used and ledthe yield to be more than 95%，90% purity andWe could only expect the minima of impurities by im-proving process. .green reaction environment，even the hydrous opera-②For the safety problem of 50% hydroxyl-tion w as permitted. .2.3 Comparison and Analysis of the Productsamin中国煤化工-)roduction of EMAOneedsEMAO can exist in either of two isomeric formsTCHCNMH(affordsasmoothlyy Hicue ichod .relative to the 9-oxime moiety. 9- trans-oxime and 9-reaction condition ，short reaction time and simplecis-oxime are referred to as the E-isomer and Z-iso-procedure for isolation and purification. Inex pensivemer，respectively. It is well known that E isomer is一78一SUN Jing-gud孙京国)et al. / Comparative Process for the Preparation of 9-0xime Erythromycin Aand nontoxic reactants are commercial available , thetion of 9-deoxo-9 Z )-hydroxy-iminoerythromycin A[ P].solvent is recyclable and gives a favorable productionUSP :5912331 , 1999-06-15.[7] Shi Yan , Qian Guohua , Liang Jianhua ,et al. Synthesisenvironment.of erythromycin 9-oximC J ]. Chinese Journal of synthetic④The present method is to provide a process onChemistry ,2001 X2):172- 174.an industrial scale for preparing EMAO with safety[8] Slobodan D , Zrinka T. Erythromycin oxime and its 9-and good yield and purity.amino derivative[ P] BP : 1100504 , 1968-01-24.[9] Adachi T , Morimoto s , Matsunaga T ,et al. ProductionReferences :of oxime derivative of erythromyeir[ P]. JP : 62081399 ,[1] Clark R F ,MaZK , WangS Y ,et al. Synthesis and an-1987-04-14.tibacterial activity of novel 6- O-substituted erythromyein[10] Watanabe Y W , Morimoto S, Goi M ,et al. 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