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A Study of Some Intermediates in the Preparation of New Derivatives of Barbituric Acid Cornelius Kennedy Cain University of Massachusetts Amherst

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A Study of Some Intermediates in the Preparation of New Derivatives of Barbituric Acid Cornelius Kennedy Cain University of Massachusetts Amherst University of Massachusetts Amherst ScholarWorks@UMass Amherst Masters Theses 1911 - February 2014 1937 A study of some intermediates in the preparation of new derivatives of barbituric acid Cornelius Kennedy Cain University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/theses Cain, Cornelius Kennedy, "A study of some intermediates in the preparation of new derivatives of barbituric acid" (1937). Masters Theses 1911 - February 2014. 1369. Retrieved from https://scholarworks.umass.edu/theses/1369 This thesis is brought to you for free and open access by ScholarWorks@UMass Amherst. It has been accepted for inclusion in Masters Theses 1911 - February 2014 by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. masq Arm TSF.TTS DATE DUE UNIVERSITY OF MASSACHUSETTS LIBRARY PHYS SCI LD 3234 M268 1937 Phys C135 :nce ' Hti> IS A STUDY OF SOME INTERMEDIATES IK THE PREPARATION OP NEW DERIVATIVES OP BARBITURIC ACID Cornelius K. Cain Thesis submitted for the degree of Hester of Science Massachusetts State College June 1937 TABLE OF CONTENTS Page Introduction 1 Theoretical Discussion and Review of Literature 3 Experimental Work 13 I The Condensation of Tertiaryamyl Chloride and Ethyl Chloroacetate by Means of the Wurtz Reaction 13 II The Condensation of Ethyl Chloroacetate and Tertiaryamyl Iodide by Means of the Grignard Reagent 14 III The Condensation of p-Bromoacetanillde and 5-Ethylbarbituric Acid 16 IV The Condensation of p-Bromoacetanillde and Ethyl Dihydroxymalonate 19 V The Preparation of 5-Ethyl-5-p-Nitro- phenoxybarbituric Acid 21 VI The Condensation of p-Acetaminophenol and 5-Ethyl-5-Bromobarbituric Acid .... 23 Conclusions 25 Bibliography 27 Acknowledgments 30 INTRODUCTION Barbituric acid is one of the cyclo-ureid group of compounds. It has the following constitution: •CO 4C0 Derivatives of it can be prepared in which one or both of the hydrogens in the 5- position are substituted by alkyl or aryl radicals. Although barbituric acid itself and its mono-substitution products have no pharmacological reaction, some of the disubstituted products are Important sedatives and hypnotics. The best known of these are "Veronal", or £ ,5- diethylbarbituric acid and "Luminal", or 5-ethyl- 5-phenylbarbituric acid. Since the exchange of one of the ethyl groups of Veronal by a phenyl group to form Luminal gave a product which had four times tho hypno- tic activity, a very large number of other derivatives have been prepared in attempts to obtain compounds of grea ter activity and of a wider range between the minimum effective dose and the minimum lethal dose. Also 3ince the yields of the products are not high in any of the syntheses employed, many attempts have been made to increase the yields by different methods of synthesis. In view of the fact that the yields obtained, although improvements over those from the original synthesis, are still not high; and because several derivatives have been prepared having more desirable properties than either Veronal or Luminal; the aim of the present investigation was two-fold: (1) To simplify further the synthesis or to improve the yields; and (2) To prepare new derivatives with properties superior to those of previously studied hypnotics. 3 THEORETICAL DISCUSSION AND REVIEW OF LITERATURE Substituted barbituric acids were first prepared by- condensing the corresponding malonic acid w ith urea, using 1 phosphorus oxychloride as the condensing agent. COOH HNH HN — CO CC + CO ». OC ZZ + 2H2 0 I 1* I I I R COOH HNH HN — CO Disubstituted Urea 5-5-Disubstituted malonic acid barbituric acid This method was later extended to include the esters, acid chlorides and amides of the disubstituted malonic acids. "Luminal" or 5-ethyl-5-phenylbarbituric acid was introduced by "Die Farbenfabricken vorm. Friedr. Bayer and Co., Elberfeld, Germany", who obtained a patent for its preparation by the condensation of urea with either of the three derivatives of 2 ethylphenylmalonic acid. Rising and Stieglitz^ studied the preparation of Luminal as a war measure in 1918. Their procedure may be summarized as follows: C 8H 8 CH a CN + CH 3 OH + HC1 + Ha 0 C 8H 5 CHaCOOCH 8 + NH*C1 Benzyl cyanide Methyl phenylacetate CH o 0Na 0 H (C0 CH )+2CH 0H C 8 H6 CH E COOCH 8 + (C0 2 CH 8 ) a ~- CH 8 2 CCOCH(C 8 8 ) 2 8 8 Dimethyl oxalate + CH 3 0 s CC0CH(C 6H 8 )(CO s CH8 )-^g_ C 8H8 CH(CO s CH8 ) . CO Dimethyl phenyl malonate CH ) + Nal C 8 H8 CH(CO a CH 0 ) 2 + C 8H8 I (C 8H 8 ) (C 2Hb)C(C0 2 8 s Dimethyl ethyl phenyl malonate b - HMH COOCH 8 HN — CO I I .C BHe CO OC C<f ! ^C H I e e I I C^Hb HNH COOCHa HN — CO Urea 5-Ethyl -5-phenyl barbituric acid Since the preparation of the ester of ethylphenylmalonic 4,5 acid was the most important step in the process, Rising and Zee studied other methods for its preparation. They succeeded in increasing the yield (based on the phenylacetonitrile) from 27.4JJ to 43.1$£. Nelson and Cretcher prepared the ester by slightly different means, but obtained only a 33.5$ yield. A number of other investigators modified the procedure by condensing substituted cyanoacetic esters with wjea. This procedure gave a 4-iminobarbituric acid tfiich could be easily hydrolyzed to form the 5-5-di substituted barbituric acid desired. In 1907, E. 7a. Merck obtained a patent for condensing diethylcyanoacetic esters with urea or acetyl urea to form 4-imlno-5-5diethylbarbituric acid, which was then hydrolysed to 6-5-diethylbarbituric acid. HNH COOR HN — CO !/C*H6 C sH8 0Na I I^C SH8 CO + C^ *- oc c<r XC«Hb I I CaH0 I I HNH CN HN — C = NH Urea Diethyl cyanoacetic ester 4-Imino-5-5-diethyl- barbituric acid HN — CO HN — CO .CaH, l/C aH8 I I HC1 I OC C^ + Ha 0 > OC CfX + NHbCI ^C H, I I C 8Hb I I 8 HN — C = NH HH CO 5-5-Piethyl- barbituric acid Nishikawa8 described a method for synthesizing Veronal by the same series of reactions but using <x-cyanobutyric esters as starting materials. - 9 Chamberlain, Chap, Doyle and Spaulding applied the general method to the synthesis of 5-5-alkyl- phenylbarbituric acids. Using phenylacetonitrile as the starting material, they synthesized the disubstituted acids as follows: N C eH 8 CH BCN + OC(OC 2H 8 )s ^S&^ C e H 6 CH(CN)COOCaH« + C 8H 8 ONa Phenyl ace to- Diethyl i-thyl cyanophenyl nitrile carbonate acetate CO0C 8H« COOCaH, H^2£aH^ CeH 'cH * IR b°* » NaI CN Alkyl CN hallde Lthyl alkyl- cyanophenylacetate HNH COOC eH 6 HN — CO C H | \ _.C 0H 8 I I ^ e 8 co + c C oc cc; R | I I^R | HNH CN HN — C = NH Urea 4-lraino-5- alkylphenyl- barbituric acid HN — CO HN — CO ^C H ^C«H 8 I I 6 8 wr1 ^Si». OC <X + Ha0 OC CC + NH4C1 R I I^R | | HN — C P NH HN — CO 5-5-Alkylphenyl- barblturic acid 6 the ethyl, Since this method wee successful in Introducing groups, it would iaopropyl, iaoamyl, n-hexyl end n-heptyl amy! group In Gils seem desirable to Introduce the tertiary 10 tertiaryalkylphenyl- way. rox end Bywater prepared several phenylmalonic barbiturie acids by alkylating the eater of They attributed acid and condensing the product with urea. of the tertiary amyl the very low yields <4.6g in the ease competing reaction in compound) to steric hindrance and to a condensed to form the wiich two moles of the alkyl hallde to prevent the hydrocarbon. Since the latter reaction seemed ethyl cyanophenyl- Introduction of the tertlaryamyl group Into hydrocarbon-like product on acetate (as evidenced by an oily, sought by which ethyl ter- attempted preparation), a means was indirect tlaryamylcyanophenylacetate could be prepared by was: methods. The first plan of reactions * 2SaC1 c,hx1ci sua i mmh Sftr*8fi22fi Ethyl Sthyl fertlaryaayl SSSSTacetate chloride ehloroaeetate aaeyl 2801 Ou<«*000*. 8C1. — ^iZf^S dichloracetate C«B xlCCl»COOC^e « Ben eJ0 Sthyl tertlaryamyl- phenylchloroacetate + C.Blt(O.H.)CClCOOC^ ~> _~^aSfiSMSS: phenylacetate reactions was essentially The second contemplated aeries of that the ethyl tertlaryamylacetate the same as the first except Orlgnard reagent as follows: was to be prepared using the ^ - C BH X1 I + Mg C BH xxMgI Tertiaryamyl Tertiaryaniyl iodide magnesium iodide C BH xxMgI + ClCH aCOOC aH B 1» C BH xxCHaC0OC aHB + MgClI Ethyl tertiaryamyl acetate Attention was next directed to the preparation of new derivatives of barbituric acid which might have more advanta- geous properties than those already known. The phenylacet- amlno compounds have been used for some time as medicinal substances. As examples of such compounds may be mentioned acetanillde or acetamlno benzene, commonly known as antifebrin, and acetphenetidlne or p-acetamlnophenetole, commonly known as phenacetln, which are widely used as antipyretics, analgesics, and sedatives. 12 Bosquet and Adams prepared 5-ethyl-5-p-acetaminophenyl- barbituric acid by nitrating the phenylethyl derivative, reduc- ing to the amino compound and acetylating. Their reactions may be summarized as follows: HN — CO HN — CO .C.H .C H*NO»(p) I | B | I e OC + HNO a —*- OC X + H20 H C 2H 5 |^C | | I 8 8 HN — CO HN CO 5-Ethyl-5-phenyl- 5-Ethyl 5-p-nitrophenyl- barbituric acid barbituric acid HN — CO HN — CO NH .C H4N0 | CeH (p) | | 6 8 (p) 4 8 OC Cf SHs — OC C^ + 2H a0 N X C H I | C aH» | | a B HN — CO HN — CO 5-Ethyl 6-p-aminophenyl- barbituric acid .
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