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368 GARBRECHT[CoxrmruuoN FRoM rsp Dpr"r. on Onc,lNrc Cnnurcer, DnvnlorMENT, En Lrli,r ,r.No Co. ]

vol,. 2l

Synthesis of Arnides of Lysergic AcidlWILLIAM L. GARBRECHT

ReceiuedSeptember 15, 1958Although interest in the chemistn' and pirarmacology of l1'sergic acid derivatives has remained high for man5' \rears,until recently onll' one useful method for converting lysergic acid into its amide derivatives has been recorded. This mcthodas described by A. Stollz consists of cieaving ergot alliaioids with h1'drazine. The resulting lysergic acid h.ydrazide on treat-ment with nitrous acid is converted into the azide u'hich may be used to prepare the desired amide by acl'lation of an appro-priate amine.

Roecrror{ft: l_i;Mixd.l lR_COil llt'

RCOCIDRCO:C(II CO:CqRCO,PC\RCOTSRCO,SItco,sc)qi

).R( rII

C,,Hu-N,C 'HsO- '

MARCH 1,Mostlthe gend

o A. St,(1943) .D(1937 ) .J. C. TalU. S.Pat 'Acta,34 ,J. Am. C|Cltem.9oI G. $r.( 1 9 5 2 ) ..77, 7067(1e55 ) . :Of ttr.

anirydrimost pr lin the oitotal anproceedsition olreactionture ancharact,and noThe amirnizatiorapidly IHo$'ebv thistheoreticounterterials. Iis affectthe ph1

CONHNH, CONs

HN INthough this procedure is frequently capableof producing amide product in gr-rod ields, certaininherent diffi.cuities reduce its practical value.Of these, he most important is that the necessar-r'reaction conditions for preparing lysergic acidhydrazide result in a racemized and isomerizedmaterial, nr,-isolysergic acid hydrazide. Further,the method leaves much to be desired in terms ofoperationai ease since the azide must be collectedin a relativeiy large volume of ether and several

hours are required to carry out the ac;'lation step.Because opticall5' active *-lysergic acid isreadily available through aqueous alkaline cleav-age of ergot alkaloids,3 a method u.hich utilizedthe free acid and caused no racemization \\rasdesired. Tlie classical methods for preparing amiclesby ac5'|a1ion f amines rvith estersor rcid chloridesfail when applied to lysergic acid. 'fhus, n'hilcthe methyls and ethyla esters of lysergic acid areknou'n, they fail to undergo aminolysis except inthe specialcasealread-vmentioned nvolving the useof hydrazine. On the other hand, attempts to( 1) I']resented in part before t,ire Divisiori of Organic

Chemistrl ', American Chemical Societ_r',Nerv York, N. Y. ,September, 1957.(2 ) A. Stol l an d A. I{ofrnar-n, Hclu. Clt int . Ackt,26,914( 1943) .7,131 W. A. Ju,cobsand L. C. Craig, J. RioI. C\rcru., LO4,( / .1934).,Srrr:.,.4.. Stoll arrd Th. I,ctrzilkz, IIclt:. Clrim. Ackr, l4O,( 5 ) : 9 5 3 ) .

ju,xNH,CON-R'| \R.fr\

\*-cH,I II

prepare lysergic acid chloride yield only decompo-sition products.Numerous ne\\ramide-forming techniques,chieflyarising from rvork in the peptide field, have ap-peared n the recent literature. \{any of t}resewereinvestigated with respect to l).sergic a,cid amides1'nthesis.A method to be suitable for this appli-cation must operate under mild non-acidic condi-tions because of the sensitive nature conferredupon lysergic acid derivatives by their indole con-taining structure.\'Iost of the ne\,\rermethods involve the appli-cation of certain mixed anhydrides. Such t'ech-niques frequently suffer from one or more of thefollowing disadvantages(o) The reaction faiis to go to compietion.(b) The reaction requires higher temperaturesthan are compatible with the stabilities of thesematerials.(c) The reacion s]'stem decornposes1'5s1*icacidor its amide product because f the acidic cha,racter.(d) The mixed anhydride undergoes dispro-portionation r.i'hich contributes to reaction in-completionand,/ornonspecificacylation :

(e) The mixed anhS'dride acylates in ^ non-specific manner, resulting in a mixture of ac5'latedproducts including esters,as weil a,satnides lvherepossible:O O C H Al t i t lR._C]__O-C__N,' + H,N-CH-CH,OI{ __1CH tIII-C_.N}I-CH-CHTOI{ 1.o cHsl r lIt'*C*NI{-CH-CI{2OH +CH t

Also, trvo nerv dehvdration reactions a,pplied opeptide bond formation have been described re-cently, rvherein an acid and an amine are causcdto condense under the influence of the pou.erfrtldehydration reagerrts, icl'slcihexylcerbodiimide ndcthoxl'acety'lene.G\

n-8-o-c''-3n-NHz * etc'

R : H , C H eRr CHzCoHs,CH,CH CH,) , ,CH(CHs)zRs: Rn: H, a lky l ,a ra lky l

I I

i, - \ -\l ' If 4 -'\) '3

L**S-H,,^.1

r _ ( \ . e L \L'\ ' - - \ \ - -..1 i q (\,t ,- \

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RCOCIDRCO:COCF,'R,COrCOrCrHr'RCOTPOzCoHE/n.COlSO?CoHnCHaoRCOTSOzCH.'IlCOrSOrt

1959I\{ost of the methods examined, together u'ithe generalresults obtained, are listed in Table I.

TABLE ISvsrnlrsAppupp ro Lvsnncrc Acrn Aurtr

bYNTFIESISA. \{ixed Anhvdride S1'stems

Mixed Anh-v-dride Value of S1's1srnR-CON.d (II) Poor. Requiredstarting mate-riai rvas racemized n prep-arationNone. Ll.sergic acid decom-posed

Good. Non-specific acr'lationdNone. Yielded ethl'l lvsergateI'oor. Lo*' f ield with decom-posit,ionNone. Decrornposed l1'sergicacidFair. N{oderat,c ).ield \f ithsome decompositionExccllent in ai l respcctsB. Deirydratiorr Systern-s

, l l t - ", u , /R'IiCOTH + II-N _____> RCONt.lr", Reagcnt \R,Il,eagent

CrH;-N:C:\r-CeH;/ None. Verl- poor .f el dCrHrO-C:CHe None. Verv poor f ieldoA . Stoll and A. Hofmann, Hclu. Chin. tlcla, 26, g+ 1D A. StoU an d A. Hofinann, Il . S. Pat. 2,090,430J. Bourne, S. H. Henry , C . t r . A{ . I ' a t l ow , andC. Tat lou', . - f . Ch,ent.Soc., 401.1 1952). d l i . 1 ' . Pi .rch,Pat. 2,736,728 (i956). e R. A. Boissortnas,Helu. Clt int .(1951) . / G. W. Anderson and R. W. Young,Am,. Chem. Soc.,74,5307 ( 1952). 4 J. H. Breu'ster, J . Ant..Soc.,77, 621-L 1955). n No previous leference found.G. \\r. Iienner an d R. J. Stedman, J. Chenr..Soc., 2069iJ . C. Sheehan an d G. P. Hess, J. Am.,Chem. Soc.,r J . F . A r - e n s ,R e c . t r a u . c h i n t . , 7 4 , 7 6 91955) .

Of the methods studied, the use of the mixedof sulfuric acid and lysergic acid pro\'edbecause lie diffictrlties iuherentthe other method \vere absent. Thus, ass a)'s oramide produced indicated that this reactiono compietion. There \vas no decomlro-observed u'hich could be ascriliecl to thesince t took place readiiy at lou'tenpera-altd at no time \\'a,s lie sJ/stem acidjc inDisproportionation wi.r,s ot encounteredd no evidence of esterification was observed.e amide products rvere obtained free from race-Ifurther, the process \\'as carried outand i,r'ithconsiderableexperimental e&se.Hou.ever, the f iclds of amide product isoletedthis method were ofterr considerabllr belorvas a consequence f the clifficultiesen-in the isolation of tfrese scnsiti\re ma-In addition, the yield of lysergic acid anideaffected by the e\,'erpresent equilibrium betu'eerre physioiogically active iysergic acid series and

AMIDES OF LYSERGIC ACID 369the inactive isolysergicacid series.This equilibriumis a consequence f the possiblechair conformationof ring D. Lysergic acid was deduced o possess nequatorial carbox;rl group and isolysergic acid anaxial carbox)4group.sFortunately, from a preparatir.'estandpoint, theamides of lysergic acid can usually be obtained ascrystaliine maleate or tartrate salts, r.r'hile theamides of isolysergic acid generally fail to formsuch cr1r51o11i,tealts and remain in the motherliquors. Also, the equiiibrium frequently favoredthe iysergic acid side and further amounts of it\\rere often obtained through re-equilibration ofthe iso-material in the mother liquors. Thus, inspite of the difficulties cited, it was possible toobtain first crop 5'ields of ergonovine maleate of6570,u'ith further amounts available through isom-erization of the iso amide rvhich remained in thernottrer iquor.The stoichiometry of the reaction and the con-ditiorrs lecessary or its successful pplication rverefound of considerable nterest. The best procedure\r'as to dissolve *lysergic acid monohydrate u'ithan equivalent amount of iithium hydroxide mono-hydrate in methanol. The methanol u'as removedin uacuo and the residue of lithium lysergate vi.asdissolved n dimeth)'lformamide. A suitable amountof dirnethylformamide was then distilled from thesolution under reduced pressure o ensure that itn'as anhydrous.The d.y lithium l1'sergate soiut,ion was thenchilled in an ice bath and a dimeth5'lforrnamidesolutiorr containing ts'o molar equivalents of sulfurtrioxide \\'as added quickly while mixirrg mechani-cally. Shortly thereafter, tire reaction mixture wastreated n'ith fir'e molar equivalents of the desiredamine and then ivithin a ferv minutes more a largeamount of ri'ater u'asadded and the amide product$'es solated by extraction.The successof the reaction depcnds verl' criti-cally on the degree of adherence to the correctstoichiomefr\'. It v'as for this reason that lithiurnh]'droxide nonoh)'drate was used, since it is non-h1'groscopic nd ma]'be weighed accuratel,\'.Otheralkali and alkaline earth hydroxides functionedas 'w-ellbut u'ere less convenient to handle. 'Iwomolar equivalcrrts of sulfur irioxide were requiredfor each mole of l-rrsergate nion, one forming themixcd auhydride and ttre other rea,ctingu'ith thepiperidine nitrogen. Smali deviatious from theinclicated ratio of sulfur trioxide to l5'ssloateanion

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370resulted in large decreases nproduct. Similarly, arnountsfour to five molar eouivalents

the yield of amideof amine less thanresuited n decreasedyield.Tu'o observations suggest that the piperidinenitrogen is compiexed by the sulfur trioxide pref-erentially to its involvement in mixed anhydrideformation: first, the stoichiometrical requirementalready described, and second, the fact that theamide product can be isolated from the reactionmixture only after adding u'ater which causes afairly exothermic reaction to take place. This latterreaction was, doubtlessly, the hydrolysis of the

sulfur trioxide complex of the tertiary nitrogen.The reaction sequence was carried out veryquickly since all three steps, anh5'dride forma-tion, acyiation, and hydrolysis, were virtually in-stantaneous. Reaction times from a few seconds oseveral hours did not materially affect the yield.Also, the reaction sequence ^ras ound to be littledependent upon temperature, proceeding well attemperatures from -20 to 35'.Since the present u'ork was aimed primarilytov'ards finding a method for making the lysergicacid amide of an amino alcohol. r,-2-amino-1-propanol, the fact that esters of l5'sergicacid u'erenot forined from the anhydride of lvsergic acid andsulfuric acid was unexpected. Not only could notrace of ester be found in this reaction, but treat-ment rn'ith simpie alcohols failed completely toJ'ieldestersof l5,ss1*icacid.The use of a suitable complex of sulfur trioxidewas lrecessary t,o masii the extremely reactivenature of this compound and provide a convenientmeans of handling, storing, and measuring thereagent. Similar compounds rvith tertiary amines,such as Ar-eth5'lmorpholine or triethS'lamine, \\rerefound to bind the sulfur trioxide so strongl5r as tomake it unavailable for reaction u'ith the lysergateanion. The less stable complex x'ith dioxtne pro-vided sulfur trioxicle for reaction but was more dif-ficult to prepareand use.The sulfur trioxide-dimeth.r'lformamide adductpossesses eariy ideal chara,cteristics. t readilypror.ides sulfur trioxide for mixed anhvdrideformation, its solutions in cxcess dirneth;'iform-amide are stable in the cold for months, a,nd di-methvlforma,rnide s the most useful solvent foundfor reactions nvolving lysergic acid. The adduct iszr, icely cr5r51o11'tte,orv melting soiid ivhich can beisolated and recr;'stallized from acetonitrile rn'ith-out decomposition.The reaction of free lysergic acid rvith sulfurtrioxide and subsequent treatment with excessamine gave poorer 5'ields of amide product tha,nthose obtaincd u'ith l5'sergateanion. Furthermore,the reaction follorl'ed a ciifferent course as rvas ndi-cated b.r' the stoichiornetr-v. Ihe free acid ga\rebetter 5'ields l'hen oniy one molar equir;ak:nt ofsulfur trioxide \\'ts emploved. Tire expllinat,iorr

probably may be found in the fact that lysergicacid, being a fairly t5'pical amino acid, exists tosome extent as the zwitterion. A representation ofthe reaction course s indicated belorv:COOH COOHt l- -fa ) sq'DMF) ^ so- R,NH, No amide-formingl l i r l l i , / " " r reac t , l on-\y'It-6r' -^--y'l\-^,,I ung I Uf te

GARBRECHT vor,.24 MARCHrvas addethorougbadded. lextractioTests n'jpletenesThe c,to a siru'tice to a-centraticThe lyline fornn'hich usolventlated cr1sa r5 ' t o t

Lyserg1.62 g .i n 2 5 mand cartsolutionquicklymmol. omin. an ,added. ,20/q sal'with ethdetermirgave onlThe cmagnesiuacuo, cThe resition mawith ethproduct,colorlescold meproduct

Thepurifiedcharactcm.p. 19Anal.\r , 9.97.Ergonacid dih'li1'drateThe sohpressurc400 tnl.of dimcthroughanhvdroamiclc uu'ith 50 .ru'asst,ir2-arninca,ndcooof watcrture vr':chlorofodimethl'80 g. ofwas tlrcmade btion. A_layer wportiorxhad be {reagent.

The ccold at75 nrl . ,I

t lcooeAI fl l l t - -^ so"'DMF-^YN-8H--

Although the earll' work rvas carried out usingfreshly prepared sulfur trioxide which \lras thendistilled tn'ice from phosphorus pentoxide, subse-quent experimentation indicated that commercialsulfur trioxide could be added to dry dimeth5'l-formamide to give a reagent of high quality suitablcfor this sJ'nthesis.EXPERIMENTAI,

Sulfur trioridc-ditnethylformamidc cotttplcr.o A carcfulll'dried. 22-liher, round bottomed flask, fitted u'ith an ice watercooling bath, condenser, dropping funnel, and mechanicalstirrer, was charged I'ith 10 to 11 l. of dimethl'Iforrnami de(freshiy distilled under reduced pressure). The condenserand dropping funnei rvere both protected from atmosphericmoisture. Two lb. of sulfur trioxideT w'ere then introd uceddropu'ise verl'cautiously u'ith stirring during 4 to 5 hr. Thctemperature was kept at 0-5o throughout the addition.After the addition u,as complete, the mixture was stirredfor 1-2 hr. until some separated, crl'sfalline sulfur trioxid e-dimeth5'lformamide complex had dissolved.The reagent was then transferred to a suitable stora,gcvessel, such as an automatic buret s1'stem u-ith an adequatereservoir, and liept in the cold. \\rhile the initially colorlessreagent gradually becomes first 5'ellow and then dark orangein color during storage, its efficac5' remains unimpaired forat least 3 to 4 months.The molaritv of the rcagcnt was estirnated b-u* itra,tion.An aliquot, first diluted rvith a little u'ater to convert tltcsulfur trioxide into sulfuric aci d, was titrated to a pirenol-phthalein endpoint u'ith standard aqueous allinli solution.Tire molarity ranged frorn 1.00 to 1.15.Th.epreparation of lysergic acid am,ides. Gcncrul proccdurc.A soiution of 7.15 g. of f-l l.sergic a,cid monoirvdrr,tc (2'.0mmol.) .r,rrd 1.06 g. of lithiunr hydroxide h1'drate (25.0mrnol) in 200 ml. of nrethzmol \l'a-sprcp&l'cd. Tirc solvcrnt u'asdisti i led on the st,ea,mbath unricr rcdueed prcssurc. 1'lrr:rcsidue of glass-li l ic l ithium l)'sergat,eu'as dissolvcd in 400nrl. of anhydrous dimethylforntamide. Aiiout 200 ml. ofdimetirylfonnamidc \r'as distilled at 15 rnm. prcssurctlrrough a l?-in. heliocs-packed column. The rcsultinganh5'd1ou. solution of lithium l]'sergate in dimethl'lfornr-amide s'as cooled to 0o and, n'ith stirring, treated rapidl5'with 50.0 ml. of SOr-DI\'{l ' solution (1.00 molar). The mix-ture'*'a,sstirred in the cold fo r 10 min. and then 125.0 mmol.of the desired amine s'as added. The stinirrg and coolingwere continued for 10 min. lonqer u'hen 400 ml. of water

(6 ) Tlte sulfur trioxide-dimethvlformamide compiex isIrcreinaftcr refcrred to es SO:-D\Iir.(7 ) Comrnercially available as "suifan B" from tireGenoral Cheniical Division, Allit:d Chemictr,l and I)1't:Oorp.

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1959added to decompose the reaction complex. After mixing200 ml. of saturated aqueous saline soiution r,r'asThe amide produgt rn'as then isolated by repeatedq'ith 500 mi. portions of ethylene dichloride.with \ran Urk reagent u'ere used to indicate com-of extraction.

Tlie combined extract n'as dried and then concentrateda sirup under reduced pressure. It u'zr,s suaily good prac-to avoid heating the extract or the sirup during the con-The lysergic acid amide u'as ordinaril5'isolated in a crrr,sll|-form from the sirup as a salt (maleate, tartrate, etc.),usualiv crystallized readilv from methanol-ethermixtures. Occasionally, the product could be iso-crystalline as the free base. Sometimes it was nece6-to resort to chromatographl..Lysergic acid-l{-benzyl am,ide acid nrzlealc. A solution ofg. of potassium f-lysergate monohl'drate (5 mmol.)25 ml. of anhl'drous dimeth-vformamide u'as preparedcarefullv protected fi'om contact witir moisture. Thewas chilled in an ice u'ater bath and then treatedrtith 7.7 ml. of SO3-D\,{F solution, providing 10.0of SOr. The mixture u:a-schilled s'ith sra'irling for 5and then 2.68 g. of benz5'lamine (25.0 mmol.) wasAfter 5 min. more cooling and swiriing, 100 m-1.ofadded. The mixture q'as extracteddichioride. Ttre completeness of extraction waswith Van Urk reagent. The fifth 150-ml. extractonl.v a slightl-v biue color s'ith the reagent.The c:ombined extracts u'ere dried brieflr. u'ith anhl'droussulfate and then concentrated to a sirup rnCare was taken to avoid heating the residual sirup.residue \r'as dissolved in 25 ml. of methanol, the solu-made slightiS- acid with maleic acid and then trea,tedether to a slight turbiditl'. After chilling for 4E hr., theq'hich had cn'stallized in rosettes of fine, nearll'needles, u'as coilected, u'ashed with a little fresh,methanol-ether mixture (1:1), an d dried. Th c crudeu'eighed 1.80 g.The {Jysergic acid-N-benz3'I amide acid maleete n'asb,v recrl'stallization from methanol and ether foras foilou's: [a]"D' +17.2o (c , L in methanol);193 ' (dec. ) .Anal. Calcd. fo r C:,rH:gN;O.CaHrOe:C, 68.48; H, 5.74;F o u n d : C , 0 8 . 4 5 ;H , 5 . 8 3 ; N , g . 0 9 .Ergortouhteac'id malealc. A solution of 7.60 g. f-)r'scrgicdihydrate (25.0 mmol.) and 1.06 g. of i ithium h1'droxide(25.0 mmol.) in 200 ml. of methanol u'as prepa,red.solvent u,as distilled on the stcam bath under reduced

The residue of lithium l1'sergate u..r,sdissoived inml. of anhydrous dimethl'lformamide. About 200 ml.dirnethylformamide s'as distilled at 15 mm. plessurca 12-inch helice-packed colurnn. Thc resultirrgsolutiorr of l ithium h'sergii i,c irr dimcthr.Ifornt-u'as coolccl to 0' ancl, u'ith st,irring, trea,t,ed lr,lr idly50.0 ml . of SOi-Il l\,11' solution ( 1.00moh,r.). irc rnixturcstirrc'd in thc cold for 10 mirr. a,rrd hen 9.40 g. of r(125 rnmol.) u'as arldcd. Thc stirrirrgcooling rvere continued lor 10 nrin. lorrgcr s'irerr 400 rnl.rvat,er u'as addecl to brea,li the rc.i,ct,ioncomltlcx. Tlic mix-was acidified rl ith tartu,ric acid lnd cxtracrtcd g'ith(thrcc 500-mi. portions) to remove most ofThe aqueous mixture u-as treatecl u'ithg. of sodium chloride and 200 ml . of cth:r,nol.Tire mixt,urehen lavered ".r'ith 500 ml. of e1,ir1.ls11sichloride andbasic u'ith concentrated ammonium hvdroxide soiu-After being mixed thoroughl5', the eth5'iene dicli loridel'as separated a,nd extraction continued u'ith freshdicii loride until :rl l t ire amide productl-reen extracted as inclicated b1' tests \a'ith \/an UrkTlre extrrict rvls conccntrated in uuctLo eeping the mixtuleat all tinres. l-hc re-"idue of sirun rvas oollected in 50 tcrnr l . of t r i t , t i r r t r r t . r l ,i l t , r , r 'cd, ,rrdaci , l i i ied r,r i i l r sol id nui l t , ic

AMIDES OF LYSEI iG iC ACI D

acid. The soiution r.l'as hen carefullv lal'ered rvith 50 ml. ofether. A-fter several minutes, cr1'stallizati on u'as well underi'r'ay. The mixture was treated r+'ith 200 ml. o f ether andrefrigerated for several hours. The crop of colorless, fineneedles was collected on a Buchner funnel, r'r'ashed rn'ith acold methanol-ether mixture (1:1), and dried. The ergon-ovine maleate thus obtained u'eighed 6.75 g. (6I.5/s) andu'as identical in all respects u'ith an authentic samille ofthe naturallr '-occurr'ng alkaloid.Aiternatively, thc free base as the stable, cr5'staliine addi-tion compound, ergonovine-chioroform,8 could be isolatedby triturating the residue from the ethl'lene dichlorideextract u'ith cold chloroform.The cr-r'staliization mother iiquor contained mainly theacid maleate of the isolysergic acid amide, ergonovinine.After removing the solvent under reduced pressure, theresidue rvas treated rvith 200 ml. of 10![ aqueous saline solu-tion arid excess coneentrated ammonium hydroxide soiution.The free base was extracted u,ith ethl'lene dichloride. Theextract \\'as evaporated under diminished pressure and theresidual sirup n'as treated u'ith 100 ml. of alcohol and 10 ml.of 4l / 1:1 aqueous alcoholic potassium h1'droxide. Thismixture n'a.s kspl at r6om t.emltcrat'ure for 1 to 2 hr. andthen neutralized u'ith solid carbon dioxide. A-fter adding 400mi. of ether, the mixture \^'as filtered and the filtrate wasconcent,rated. The sirup remaining u'as treated in the mannerpreviousiy indicated for the isolation of elgonovine maleate.The second crop rvcighed 0.91 g. (8.3%). Further cropsma}' be isolated b)' rec)'cling the iso-material through theallialine cquilibration procedure.Altemativeil', tire residual iso-matelial from the ethl-lenedichloride extract could be isola,ted as the cr1'stalline ergo-novinine nitrate.eN-Cyanontcthgl-f-Iysergic acid amide. The rnixed an-h.l'dride from 3.70 g. of ivsergic acid h1'drater, prcpared asfor ergonovine above, n-as treeted u'ith cxcess c1'anomethyl-amine. After dec omposing thrr complex with 400 ml. ofsaturatcd saline soiution, the ploduct s'as extract,ed u'ithtirree 500-ml. portions of chloroforn'r. The combinerd extractsu'ere dried (anh5'drou. magnesium sulfate) and then con-centla,ted undcr diminished prcssure. The residual sirup llasdissolved in 30 ml. of methanol, acidific'd u'itir solid maleicacid, trcated to turbidity u'ith ether, and refrigerated fo rseveral hours. The prec\ritate of colorless, soft needles wascollected, n'ashed u'it,h cold ethcr-methanol mixl,trle (2:1),and thcrr dried at 50o in uacuo. Tirc product u'eighed 2.52g. A portion of the niaterial ra'as ecrvstaliized florn metir:r,noland ether solvent mixture for arralvsis: [.] ',r ' {42.9" (c ,1 in rncthanol) ; rn.p. 194" (dec.) (corr.) .

Anal. Calcd. for CrrHrsNaO.CqHaOr.t fHzO: C, 61.17; H,5 .48 ;N, 12.97.Found: C, 61.25;H, 5 .70 ;N, 13.03.L31 cr c ac irl anilide. Potassium * -lvscrgat,e tnonoh J'drate(1.62 g.,5.0 rnmoi.) was dissolvcd in 25 nr i . of a,r th1'drousdimethvlfonn:r,rnidc. Tirc solutiol] \\ ' l :r,srelt,cci rvith E.20 ml .of S0;,.DX',IFsolttt ' iotr 1.21 nrolu,r)and t,hcrrr hil lerl iu arr iceu'lrt,er brth for 20 min. u'hcn 2.i-J0 . of nnil irrc (2 5 mtno..,u'u,s addeci. l ' l ic tl ixturer u'as su'irlcd lrriefl l ' anrl kept, coldfor 1 hr. Aftcr adding 100 mi . of 1016 aqueous salitte solu-tion, th c u,uridc product n'as cxtracted u'i '..,h t,lr l ' lerre di -cirlolirle rtnli l nc-r ti lther a,tnciunt, f \ran flrk-lrosil ivtr mate-ria,l coulrl )r e cxtracted. Thr: crornbincrd xtract \\ 'i t,scon(rclt-tra,ted unclcr rcduct,'d prcssurcr and tlie sirtt1r1, 'csidue u':l-"dissolved irr 20 ml. of mctha,nol, acidified rvith maleic acid,arid t,hcrr trcrted u'itir 200 rnl. of cthcr. After beirrg rcfriger-ated for several davs, the cr1'stals u'ere collectcld, u'asiteclfree of sirttpv material rrith l: 1 methanol-ether mixture,and air dried. The slightiy off-rvhite product 'lr'eighed 0.48g.The conrbined rnother liquor ancl u'asires l\ 'ere collcen-(8 ) A. Stoll arrd A. Hofrnartn, Z. plrysiol. Chern., I{oppe-Sev lc r 's ,251, 155 (1938 ) .(9 ) S .Sn r i t h and G. A{ . T imrn is , J . C l tem. Soc . , 1100( e36).

377

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trated to a sirup under reduced prcssure and th e residue ofsrrup r4'a.sreated q'ith I50 ml. of r.0.4f methanolic potassiumh1,droxide. After standing for 2 hr. at room temperature,the rnixture rl'as diluted *lith +00 mt. of r0lo aq.eJus;;il"solution and the Van Urk positive materiaj *,u. uitruJ"au'ith ethyiene dichloride. The residue ].om th e extract, after::5:Tfi to lfe aeidmaleate,.ietded0.80g. "il:,."rgi.

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ethanol).::t1-::111u_?.ldaleare-.,tortior,"i tn""""irlri;# ".*;:l,l:o9""t q'as recr],st1t]ized' rom methano), ;1 }/ruuuur, \4.4s recrl,stal. t tzecl trom methanol, vielding f inecolor less eedles;m.p. 200" (dec.); I"1,";-++b.'S;(.. '^3.b^i11

q'ith methanol-ether solvent mixture (1:l), and dried. Theneedles weighed 0,78 g,, m.p. 15&-tOb" (dec.;. necrystaf_lization from methanol an