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SYNTHESIS of BARBITURIC ACID DERIVATIVES a THESIS Presented

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SYNTHESIS OF BARBITURIC ACID DERIVATIVES A THESIS Presented to The Faculty of the Graduate Division hy John James Walker In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry Georgia Institute of Technology May, 1973 ii ACKNOWLEDGEMENTS "For the lord grants wisdom.' His every word is a treasure of knowledge and understanding." (Proverbs 2:6). The author gratefully and humbly acknowledges his Creator and Redeemer who gave the talents to complete this course of study and research. The author acknowledges the assistance, counsel, and encourage­ ment of Dr. James A. Stanfield for his invaluable direction and super­ vision during this work. Appreciation is expressed to Dr. Erling Grovenstein, Jr. and Dr. Charles L. Liotta for serving on the reading committee and to Mr. Larry Abbey and Mr. George Turner for obtaining the mass spectral data herein reported. For the two years of part-time instructorships and three years of Graduate Assistantships, the author is very grateful to Dr. William M. Spicer, Chairman of the School of Chemistry. He is especially thankful for the encouragement of an under­ standing wife and children. The unending thoughtfulness and devotion of a discerning wife was a prodigious asset during his graduate studies. iii LIST OF TABLES Table Page 1. Derivatives of 5-Ethylbarbituric Acid 19 2. Derivatives of 5-Phenylbarbituric Acid 21 3. Wavelengths and Extinction Coefficients of Derivatives of 5-Ethylbarbituric Acid 29 k. Wavelengths and Extinction Coefficients of Derivatives of 5-Phenylbarbituric Acid 32 5. NMR Shift Values for Derivatives of 5-Ethylbarbituric Acid J+O 6. NMR Shift Values for Derivatives of 5-Phenylbarbituric Acid 45 iv TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ii LIST OF TABLES iii LIST OF ILLUSTRATIONS vii SUMMARY xi CHAPTER I. INTRODUCTION 1 II. DISCUSSION OF EXPERIMENTAL INVESTIGATIONS 10 III. EXPERIMENTAL. 68 Preparation of 5-Ethylbarbituric Acid 68 Preparation of 5-Bromo-5-ethylbarbituric Acid.... 70 Synthesis of 5-Ethyl-5-[N-benzylamino)]- barbituric Acid 70 Synthesis of 5-Ethyl-5-[N-(^-benzylpiperidino)]- barbituric Acid 71 Synthesis of 5-Ethyl-5-[N-(morpholino)]- barbituric Acid 72 Synthesis of 5-Ethyl-5-[N-(ethylisonipecotato)]- barbituric Acid 73 Synthesis of 5-Ethyl-5-[N-(il-methylpiperazino)]- barbituric Acid fk Synthesis of 5-Ethyl-5-[N-(^-p-hyroxyethyl- piperazino) ]-barb it uric Acid 75 Synthesis of 5-Ethyl-5-[N-(ethyl-Nl- piperazinocarboxylato)]-barbituric Acid 76 Synthesis of 5-Ethyl-5-[N-(N,-3(ami.nopropyl)- 2-pyrrolidinono)]-barbituric Acid 77 V Page Synthesis of 5-Ethyl-5-[W-(l,2,3,^-tetra- hydroisoquinolino) ]-barbituric Acid 77 Synthesis of 5-Ethyl-5-[N-(U-aminoanti- pyreno)]-barbituric Acid 78 Preparation of 5-Phenylbarbituric Acid 79 Preparation of 5-Bromo~5-phenylbarbituric Acid* 80 Synthesis of 5-Phenyl-5-[n-(n-propylamino)]- barbituric Acid 8l Attempted Preparation of 5-Phenyl-5-[N- (l-ephedrine)]-barbituric Acid 82 Synthesis of 5-Phenyl-5-[N-(2-methoxy- ethylamino) ] -barb it uric Acid 83 Synthes:i s of 5-Phenyl-5- [M- (allylamino) ]- barbituric Acid 83 Attempted Preparation of 5-Phenyl-5-"N- (benzimidazole)1-barbituric Acid Synthesis of 5-Phenyl-5-[N-(benzylamino)1- barbituric Acid 85 Synthesis of 5-Phenyl-5-[!".-(3-amino-l- propanol) ]-barb it uric Acid 86 Synthes is of 5-Phenyl-5- [n- (l_-amphetamino) ] - barbituric Acid 87 Synthesis of 5-Phenyl-5-[K-(d_-amphetamino)]- barbituric Acid 88 Synthesis of 5-Phenyl-5-[N-(p-phenetidino,) ]- barbituric Acid 89 Synthesis of 5-Phenyl-5-[N-(U-benzylpiperidino)]- barbituric Acid 90 vi Page Attempted Preparation of 5-Phenyl-5-[N-(2,2,6,6- tetramethylpiperidino)]-barbituric Acid 91 Synthesis of 5-Phenyl-5»-[N-(morpholino)]- barbituric Acid , 92 Synthesis of 5-Hienyl-5-[N-(Nt-methyl- piperazino)]-barbituric Acid 93 Attempted Preparation of 5-Phenyl-5-(N- (anilino)]-barbituric Acid $h Synthesis of 5-Phenyl-5-[N-(N1-p-hydroxyethyl- piperazino) ]-barb it uric Acid 94 Attempted Preparation of 5-Phenyl-5-[N- (L-a-methylbenzylamino)]-barbituric Acid 95 Synthesis of 5-Phenyl-5-[N-(l,2,3,6- tetrahydropyridino)]-barbituric Acid 95 Synthesis of 5-Phenyl-5-[N-( 1,2,3,1»- tetrahydroisoquinolino) ]-barb it uric Acid 97 Synthesis of 5-Phenyl-5-[N-(ethyl-Nt- piperazinocarboxylato) ]-barbituric Acid 98 Synthesis of Salt of 5-Phenyl-5-[N-(2- aminopryimidino) ]-barbituric Acid 99 Synthesis of 5-Phenyl-5-[K-CN1-3-(amino- propyl ) -2-pyrrolidinono)] -barb it uric Acid 99 Synthesis of 5-Phenyl-5-[N-(h-amino- antipyreno) ]-barb it uric Acid 100 IV. CONCLUSIONS •••• 10^ V. RECOMMENDATIONS 106 APPENDIX A 108 APPENDIX B 12K APPENDIX C 128 APPENDIX D 13^ BIBLIOGRAPHY.. 236 VITA IKI vii LIST OF ILLUSTRATIONS Figure Page 1. Barbiturates 2 2. Pentothal, Sodium 3 3. Suggested Compounds 5 k. Uramil 6 5« Uramil Derivatives 8 6. Reaction Sequence to be Studied 9 7« Mechanism of Levina and Velichko 11 8. Possible Mechanisms for Formation of Salt or 5-Phenyl­ barbituric Acid 1^ 9. Hydrazine Type Structure 15 10. 5-Ethyl-l-[N-(anilino)]-barbituric Acid 15 11. Product of Rearrangement 16 12. Possible Zwitterionic Form 17 13. Simplified Scheme for Barbiturate Hydrolysis 25 ih, Amido-imidol Tautomerism 27 15. Solvent Effects ' 39 16. Tautomerism 39 17. 5-Phenyl-5-[N-(2-aminopyrimidino)]-barbituric Acid 57 18. m/e 1CJ+ and m/e 103 59 19. Molecules Having Base Peak at m/e l6k 59 20. m/e 225 60 21. m/e 20h 61 viii Bage 22. m/e l^k 6l 23- m/e 132 62 2^. m/e 118 and m/e 117 63 25. m/e 56 and m/e 55 63 26. m/e 156 6k 27. Cleavage of a Methyl Radical 65 28. m/e 128 65 29. m/e 98, m/e 85, and m/e 83 66 30. Infrared Spectrum of 5-Ethyl-5-[N- (benzylamino) ]-barbituric 'Acid 109 31. Infrared Spectrum of 5-Ethyl-5-[N- (^-benzylpiperidino)]-barbituric Acid 109 32. Infrared Spectrum of 5-Ethyl-5-[N- (morpholino) ]-barbituric Acid 110 33. Infrared Spectrum of 5-Ethyl-5-[N- (ethylisonipecotato)]-barbituric Acid 110 3^. Infrared Spectrum of 5-Ethyl-5-[N- (^-methylpiperazino) ]-barbituric Acid Ill 35. Infrared Spectrum of 5-Ethyl-5-[N- (^-p-hydroxyethylpiperazino)]-barbituric Acid Ill 36. Infrared Spectrum of 5-Ethyl-5-[N- (Ethyl-N^piperazinocarboxylato)]-barbituric Acid 112 37. Infrared Spectrum of 5-Ethyl-5-[N- (N'-3- aminopropylj-barbituric Acid 112 38. Infrared Spectrum of 5-Ethyl-5-[N- (1,2,3,^-tetrahydroisoquinolino)]-barbituric Acid 113 39. Infrared Spectrum of 5-Ethyl-5-[N- (^-aminoantipyreno)]-barbituric Acid 113 ho. Infrared Spectrum of 5-Phenyl-5-[N- (n- propylamine)]-barbituric Acid 11^ ix Page hi. Infrared Spectrum of 5-Phenyl-5-[N- (2-methoxyethylamino)]-barbituric Acid 11^ h2. Infrared Spectrum of 5-Phenyl-5-[N- (allylamino) ]-barbituric Acid 115 h$. Infrared Spectrum of 5-Phenyl-5-[N- (benzylamino)]-barbituric Acid 115 hh. Infrared Spectrum of 5-Phenyl-5-[N- (3-amino-1-propanol)]-barbituric Acid 116 ^5. Infrared Spectrum of 5-Phenyl-5-[TT- (l-amphetamino) ]-barb it uric Acid H6 h6. Infrared Spectrum of 5-Phenyl-5-[N- (d-amphetamino) ]-barbituric Acid HT ^7. Infrared Spectrum of 5-Phenyl-5-[N- (g-phenetidino)]-barbituric Acid H7 hQ. Infrared Spectrum of 5-Phenyl-5-[N- (^-benzylpiperidino)]-barbituric Acid 118 h$. Infrared Spectrum of Salt of 5-Phenyl- [N- (2,2,6,6-tetramethylpiperidino)]-barbituric Acid •••• 50. Infrared Spectrum of 5-Phenyl-5-[N- (morpholino) ]-barbituric Acid 51. Infrared Spectrum of 5-Phenyl-5-[N- (ir-methylpiperazino) ]-barbituric Acid 52. Infrared Spectrum of 5-Phenyl-5-[N- (N'-p-hydroxyethylpiperazino)]-barbituric Acid 120 53- Infrared Spectrum of 5-Phenyl-5-[N- (1,2,3,6-tetrahydropyridino)]-barbituric Acid 120 5h. Infrared Spectrum of 5-Phenyl-5-[N- (l,2,3,^-tetrahydroisoquinolino)]-barbituric Acid •• 121 55. Infrared Spectrum of 5-Phenyl-5-[N- (ethyl-N'-piperazinocarboxylato)]-barbituric Acid 121 56. Infrared Spectrum of Salt of 5-Phenyl-5-[N- (2-aminopyrimidino)]-barbituric Acid » • 122 X Page 57. Infrared Spectrum OF 5-Hienyl-5-[N- (N'-SCAMINOPROPYLJ^-PYRROLIDINONO) ]-BARBITURIC Acid 122 58. Infrared Spectrum OF 5-Phenyl-5-[N- (k-AMINOANTIPYRENO) ]-BARBITURIC Acid 123 xi SUMMARY The purpose of this research was to develop a simple method for synthesis of 5-ethylbarbituric acid and 5-phenylbarbituric acid derivatives in which the hydrogen at the 5 position is replaced by an amine function. Due to reports of synergism of numerous drugs with barbiturates, it was considered that such compounds could have thera­ peutic value. The 5,5-dialkyl barbituric acids are a class of compounds known to possess pronounced hypnotic activity. The 5-ethylbarbituric acid or 5-phenylbarbituric acid was pre­ pared by condensing the appropriately substituted malonic ester with urea in dry absolute ethanol utilizing sodium ethoxide as the base. The 5-ethylbarbituric acid was then brominated with liquid bromine follow­ ing dissolution of the barbiturate in hot water. The bromination of the 5-phenylbarbituric acid was accomplished in 0.6 N aqueous sodium hydroxide with bromine water. Replacement of the bromine atom with various amines was accomplished in methanol and the resultant uramil derivative could usually be isolated either following evaporation of the solvent or adjusting carefully the pH of the solution. Twenty-nine new barbituric acids have been prepared by this method. Hydrolytic stabilities of barbiturates may often be correlated with their hypnotic properties. For this reason the stability of each of these compounds was determined in 95 per cent ethanol made 0.3 N in sodium hydroxide. It was found that each compound prepared was rel­ atively stable to the base described on mixing and after being heated xii in a constant temperature bath for two hours.
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    E/NL. 1977/26-28 20 March 1979 UNITED NATIONS ENGLISH AND SPANISH ONLY LAWS AND REGULATIONS PROMULGATED TO GIVE EFFECT TO THE PROVISIONS OF THE INTERNATIONAL TREATIES ON NARCOTIC DRUGS AND PSYCHOTROPIC SUBSTANCES CHILE Communicated by the Government of Chile NOTE BY THE SECRETARY GENERAL - In accordance with the relevant Articles of the International Treaties on Narcotic Drugs and Psychotropic Substances, the Secretary-General has the honour to communicate the following legislative texts. INDEX Page E/NL.1977/26 Regulation No. 4 on Dependence-producing Pharmaceutical Products, 2 January 1970 E/NTJ.1977/27 Order No. 90 of 4 February 1970 - Schedule of products subject to control under the Regulations on Dependence-producing Pharmaceutical Products. 5 E/NLol977/28 Order No. 92 of 19 January 1976 13 Official Gazette No. 27.554 E/NL,1977/26 24 January 1970 Recovery of Health Division Pharmaceutical Section REGULATION NO. 4 ON DEPENDENCE-PRODUCING PHARMACEUTICAL PRODUCTS Santiago, 2 January 1970 Considering the information furnished by the National Health Service in Circular No. 19.892 of 1 October 1969; the reports, recommendations and agreement of the United Nations specialized agencies concerning the harmful effects of abuse of dependence- producing drugs; the provisions of articles 2 and 107 of the Health Code; and the authority conferred on the undersigned by article 72 (2) of the Constitution of Chile, IT IS HEREBY DECREED AS FOLLOWS: The "REGULATIONS ON DEPENDENCE PRODUCING PHARMACEUTICAL PRODUCTS" set out below are adopted: Article 1. The production, manufacture, extraction, preparation, import, export, distribution, possession or ownership, removal for whatever reason, transit, transport and use of hypnotic agents, amphetamines and other stimulants of the central nervous system, meprobamates and all other dependence-producing drugs, shall be subject to the norms contained in these Regulations.
  • List of Controlled Drugs and Permitted Quantities)

    List of Controlled Drugs and Permitted Quantities)

    1.6 Open General Licence List (List of controlled drugs and permitted quantities) The following are the maximum quantities which may be carried by patients without requiring a licence, provided they carry with them a covering letter from their prescribing doctor. Alphapropine 3600mgs Amphetamine 300mgs Amphetamine Phosphate 225mgs Amphetamine Sulphate 225mgs Anhydrous Morphine 360mgs Anileridine 900mgs Anileridine Hydrochloride 900mgs Anileridine Phosphate 900mgs Benzphetamine 2250mgs Benzitramine 450mgs Buprenorphine (as hydrochloride) Temgesic 24mg Buprenorphine (as hydrochloride) Subutex 140mg Chlorphentermine Hydrochloride 975mgs Cocaine Hydrochloride, Nitrate, or ) 20ml at 4% 4mlSulphate Eyedrops ) maximum strength Cocaine Hydrochloride, Nitrate, or Sulphate ) as active ingredient in a mixture being used ) 500mgs by a patient who is terminally ill. ) Dexamphetamine 300mgs Dexamphetamine Phosphate 150mgs Dexamphetamine Sulphate 900mgs Dextromoramide Tartrate 900mgs Diamorphine Hydrochloride as an ingredient 500mgs ) Permission in a mixture or linctus ) will be needed ) from relevant ) Ministry of Diamorphine Hydrochloride Tablets 450mgs ) Health as Diamorphine Hydrochloride Ampoules 1350mgs ) Diamorphine Diamorphine Hydrochloride Elixir 500mgs ) is illegal in )most of the )world. Diazepam (and all drugs falling within Schedule 4 Part II) 900mgs Diethylpropion Hydrochloride 1125mgs 1 Dihydrocodeine Tartrate 3600mgs ) Not controlled Dihydrcodeine O-carboxymethyloxine 150mgs ) if not injectable ) or tablet strength <100mg Dipipanone 600mgs