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LECTURE № 1 4

LECTURE № 1 4 Theme: Derivatives of barbituric acid: properties, analysis, storage, action and use. Primidone as structural analog of barbiturates Associate prof . Mosula L.M. The plan

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LECTURE № 1 4

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  1. LECTURE № 14 Theme: Derivatives of barbituric acid: properties, analysis, storage, action and use. Primidone as structural analog of barbiturates Associate prof. Mosula L.M.

  2. The plan • Medical preparations from group of derivatives of barbituric acid:barbital, barbital sodium, phenobarbital, phenobarbital sodium, benzonal, hexenal, thiopental sodium. • Primidoneas structural analog of barbiturates.

  3. Derivatives of pyrimidine • In structure of many natural and synthetic drugs is pyrimidine – hexatomic heterocycle with two atoms of Nitrogene, which are in the position 1,3: Completely hydrogenated cycle of pyrimidine names hexahydropyrimidine:

  4. In medical practice the synthetic preparations, which contains hexahydropyrimidinecyclewith three hydroxy-groups -С=О in the position 2,4,6 – derivatives of barbituric acid are widely applied: Barbituric acid– is hexahydropyrimidine-2,4,6-trione. Barbituric acidis cyclic ureide – product of condensation of carbamide (urea) and dibasic malonic acid (propane diacid):

  5. Derivatives of barbituric acidareproducts of condensation of carbamide (urea) and derivatives of malonic acid:

  6. Barbituratesare cyclic imides used as hypnotics and (in the case of phenobarbital) as anticonvulsants. They are derivatives of barbituric acid (which is not pharmacologically active) and differ only in their substituents on the 5-position of the ring. The hypnagogue action of barbiturates was revealed in the early ХХ-thcentury byFisherand Mering. In the 1904 Fisher was synthesized barbital, after that were synthesized many barbiturates and was fixed relationship between structure and action. 1. The hypnagogue action is characteristic for derivatives of barbituric acid, which have in the position 5,5 alkyl, aryl or other radicals. 2. The impact surface and valid time of barbiturates are increased at increase of lenght of hydrocarbonic chain in the alkyl substitute in the position 5,5 until 5-6 atoms of Carbon.Then lenght of hydrocarbonic chain in the barbiturates is more? Such drugs have stimulant action. 3. The pharmacological effect at hydrocarbonic chain branching, presence of unsaturated bonds, alkoholic hydroxyl –ОН, atom of halogen (especially Br) is intensified.

  7. 4. Then action of barbiturates is more intensified the hypnagogue effect is shot. 5. With one phenyl radical(C6H5)on the 5-position of the ringto intensifyaction, not change duration of action, but then second phenyl radicalon the 5-position is presents the hypnagogue action is decreased. 6. Then alkyl radical is on the 1- or 3-position (nearly imide group)valid time of drugs is abbreviated. 7. The change of hydrogen on the 1-position on the rest of aromatic acid (for example, benzoic acid) add to drug antiepileptic action (benzonal). 8. Thenatoms of hydrogen of imide groups (1- and 3-positions of the ring) are substituted such drug can make convulsions. 9. Derivatives of thiobarbituric acid (atom of sulphur on the 2-position of the ring ) have more intensive and short-time action unlike oxygen analogue of barbiturates.

  8. Chemical properties of barbituric acid and barbiturates Barbiturates contain nitrogen atoms, but the lone pair on the nitrogen is not available for reaction with protons, so barbiturates are not basic. Barbituric acidand derivatives have the acid nature. Thus barbituric acid in 5–6 times is stronger then acetic acid. 5-Monosubstituted ofbarbituric acid (for example, 5-ethylbarbituric acid) – enough strong acids, and 5,5-disubstituted ofbarbituric acid (for example, 5,5-diethylbarbituric acid) – very weak acid. Acid properties of these compounds are caused keto-enol tautomerism ofbarbituric acid – at the expense of Hydrogene atoms of methylene groups –СН2–.

  9. Besides, at the expense of Hydrogene atoms of imide groups-NH - it is possible imido-imidolnic tautomerism: For barbiturates, which Hydrogene atoms of methylene groups are substituted on radicals, is possible only imido-imidolnictautomerism(lactam-lactimtautomerism).

  10. Thus it is necessary to notice, that unlike barbituric acids derivatives of barbituric acid in water solutions almost not dissociates; at presence of ions ОН–– they are dissociated as acids also are capable to give salts with metals: Barbituric acid and its salts do not have medical properties and consequently are not drugs.

  11. General formula of barbiturates(imide form): General formula of Na-salts (imidol-form):

  12. Synthesis of barbiturates • Derivatives of barbituric acid are synthezed by condensation of urea and corresponding esters of malonic acid. Therefore synthesis consists of two stages. 1. Synthesis corresponding esters of malonic acid: 2. Condensation of ester and urea in the presence of Na-alcoholate in the solution of absolute alcohol. For example, synthesis of barbital:

  13. Chemical structure and properties of derivatives of barbituric acid Barbital General Notices (Ph Eur monograph 0170) Barbitalum C8H12N2O3184.257-44-3 DEFINITION Barbital contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione, calculated with reference to the dried substance. CHARACTERS A white, crystalline powder or colourless crystals, slightly soluble in water, soluble in boiling water and in alcohol. It forms water-soluble compounds with alkali hydroxides and carbonates and with ammonia.

  14. Phenobarbital General Notices (Ph Eur monograph 0201) Phenobarbitalum C12H12N2O3 DEFINITION Phenobarbital contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione, calculated with reference to the dried substance. CHARACTERS A white, crystalline powder or colourless crystals, very slightly soluble in water, freely soluble in alcohol. It forms water-soluble compounds with alkali hydroxides and carbonates and with ammonia.

  15. Benzonal Benzonalum 1-benzoyl-5-ethyl-5-phenyl-barbituric acid CHARACTERS A white, crystalline powder, melting point 134-137 С;very slightly soluble in water, partly soluble in alcohol, freely soluble in chloroform, soluble in ether.

  16. Barbital sodium Barbitalum-Natricum sodium 5,5-diethyl-barbiturate CHARACTERS A white, crystalline powder without smell, bitter taste. Water solution has alkaline reaction; freelysoluble in water, slightly soluble in alcohol, practically insoluble in ether.

  17. Hexenal Hexenalum Hexobarbitalum sodium 1,5-dimethyl-5-(cyclohex-1-enyl)-1Н,3Н,5Н-pyrimidine-2,4,6-trion CHARACTERS A white foamy consistence, at action CO2(on the air) decomposes. Hygroscopic. very soluble in water and alcohol, practically insoluble in ether and chloroform.

  18. Barbamyl Barbamylum sodium 5-ethyl-5-isoamyl-1Н,3Н,5Н-pyrimidine-2,4,6-trion CHARACTERS A white fine-crystalline powder without smell, hygroscopic; freelysoluble in water, practically insoluble in ether.

  19. Thiopental sodium (Thiopental Sodium and Sodium Carbonate, Ph Eur monograph 0212) Thiopentalum-Natriсum (mix with anhydrousNa2CO3) DEFINITION Thiopental sodium and sodium carbonate is a mixture of the sodium derivative of 5-ethyl-5-[(1RS)-1-methylbutyl]-2-thioxo-2,3-dihydropyrimidine-4,6(1H,5H)-dione (C11H17N2NaO2S; Mr 264.3) and anhydrous sodium carbonate, containing the equivalent of not less than 84.0 per cent and not more than 87.0 per cent of thiopental and not less than 10.2 per cent and not more than 11.2 per cent of Na, both calculated with reference to the dried substance. CHARACTERS A yellowish-white powder, hygroscopic, freely soluble in water, partly soluble in ethanol.

  20. Identification • 1. Formation of the painted complexes (various colours for different barbiturates) with salts of heavy metals (Co (NO3) 2 in the presence of CaCl2, CuSO4 in the presence of КНСО3 and К2СО3, CuSO4 in neutral medium (that not are formed precipitates Me(OH)n). • This is group reaction.

  21. 2. Fusion with alkalis Molecules of barbiturates are break up to ammonia NH3andsodium carbonateNa2CO3. Then product of reaction dilute in water and add dilute hydrochloric acidHCl, gasCO2 is allocated and is present characteristic smell of conforming disubstituted acid (for example, diethylacetic acid – smell of rancid butter, 2-phenylpentanoic acid – smell of acacia)

  22. 3. Reactions of condensation with aldehydes and the concentrated sulphatic acid • At heating with formaldehydeНСНО and concentrated sulphatic acid H2SO4 (the Mark reactant) the products painted in various colour are formed: phenobarbital and benzonal – pink colouring (for phenylacetic acid); hexenal – dark red colouring with green fluorescence. • From steam-dimethylaminobenzaldehyde and concentrated H2SO4:

  23. 4. Interaction with solution of chloride acid(for sodium salts of barbiturates – barbital-sodium, hexenal, barbamyl). At interaction of test solution with HCl there is a reaction of neutralisation with formation of precipitate (barbiturates). The precipitate of barbiturate filter, wash out water, dry and identify on fusion temperature, and in a filtrate find out Sodium ions..

  24. Reactions for definition of functional group (on position 1 and 5,5) 1. Reaction nitration (for phenyl radical C6H5)(phenobarbital and benzonal) At heating of test substance, which contain in a molecule benzoic cycle, with concentrated sulphatic acid H2SO4 and solution of sodium nitrate NaNO3 (or a mix conc. HNO3 and H2SO4) occurs nitration in meta-position with formation of nitroderivative of yellow colour.

  25. 2. Reaction for benzoate-ion after alkaline hydrolysis of preparation (benzonal) • SPU. To 1 ml of test solution add 0,5 ml solution of iron(ІІІ) chloride R1; the pale yellow precipitate, soluble in ether R is formed: 3. Reaction for double bound(hexenal) – decolouration solution of potassium permanganate KMnO4 or bromic water Br2.

  26. 4. Reactions for revealing of Sulphur(thiopental sodium) • a) At heating of test substance in the presence of sodium hydroxide NaOH and lead acetate (CH3COO) 2Pb a black precipitate is formed (lead sulphide PbS). black precipitate b) At mineralization of preparation with mix for sintering (mix Na2CO3 and NaNO3) Sulphur passes in anions SO42 - which reveals by means of solution BaCl2: SO42– + Ba2+ → BaSO4↓ white precipitate

  27. 5. Reaction with silver nitrate AgNO3 in the medium of soda Na2CO3 • At interaction with ions Ag + are formed one-substituted (soluble in water) and two- substituted (insoluble in water) silver salts. In the presence of Na2CO3 at first Na-salt, and then Ag-salt in positions 4 and 6are formed

  28. Tests • Specific impurities – products of semisynthesis • 1. Barbital – ethylbarbituric acid • 2. Phenobarbital – phenylbarbituric acid • 3. Barbamyl, thyopental sodium, hexenal – methanol

  29. Assay of barbiturates • For quantitative definition of barbiturates various methods are used: • 1. Titrimetric: • a) acid- base titration in water, aqueous-alcoholic and non-aqueous mediums; • b) argentometry; • c) bromatometry; • d) iodo-chlorometry (for barbiturates with nonsaturated bonds, for example, hexenal). • 2. Gravimetry. • 3. Photocolorimetry.

  30. 1. Alkalimetry, non-aqueous titration This method is applied to quantitative definition of barbital, phenobarbital, benzonal. Medium – mixture of DMF and benzene (1:3), preliminarily neutralized by thymol blue in the DMF (protophilic solvent, which can intensify acid properties of barbiturates). Standard solution – solution of sodium methylate CH3ONa or sodium hydroxide NaOH in the mixture of methanol CH3OH and benzene C6H6to blue colour. This method is based on ability of barbiturates to tautomeric transformations and formation imidolic or the acid-form, which have acid character:

  31. а)Titrant – solution of sodium methylateCH3ONa: Em = М. m. b) Titrant – solution of sodium hydroxideNaOH: Em = М. m.

  32. 2. Alkalimetry, non-aqueous substitute titration (phenobarbital, etc.) 0,100 g substance dissolve in 5 ml pyridine R, add 0,5 ml of thymolphthaleine solution R, 10 ml 87 g/l silver nitrate AgNO3 in pyridine R and titrate with 0,1 M sodium hydroxide NaOH in the ethanol before not disappearing blue colour. Em = М. m.

  33. 3. Alkalimetry in the aqueous-alcoholic medium • This method can be used for quantitative definition of all barbitrate, which have acid character. • Titrant - solution sodium hydroxide NaOH. • Indicator – thymolphthaleine. • Shot of preparation dissolve in neutralised on thymolphthaleine alcoholС2Н5ОН (for solubility improvement of barbiturates and preventions of hydrolysis formed sodium salt). • Em = М. m.

  34. 4. Acidimetry in the water medium This method can be used for quantitative definition of sodium salts of barbiturates, which have basic character (barbital-sodium, barbamyl, hexenal). Titrant - hydrochloric acid HCl. Indicator – methyl orange or methyl red. Na-salts of barbiturates are hydrolyzed in water solutions with formation alkaline medium (рН 77) and therefore their can titrate with acids, for example, with hydrochloric acid HCl in the presence of methyl orange or methyl red as indicator (to pink colour). Em = М. м. The free alkaly (NaOH), which is formed at hydrolysis of sodium salts of barbiturates, titrate with acid too:

  35. Therefore the maintenance of Na-salt of barbitutates (Х, %) calculate by means of formula: , Where: % NaOH – the maintenance of free alkali in substance, in %; K – coefficient (factor), which calculate as a parity between molar weights of salt and sodium hydroxide NaOH. At quantitative definition of thiopental sodium by means of acidimetry define the total maintenance of Sodium (titrate with sulphatic acid H2SO4 in the presence of methyl red as indicator). 5. Argentometry 1. Method of Fialkov and employees(benzonal) Shot of test substance (the acid or salt form) dissolve in 5 % anhydrous solution of sodium carbonate Na2CO3 and titrate with nitrate AgNO3 without the indicator to occurrences of not disappearing dregs (the two-substituted Ag-salt).

  36. Proceeding processes it is possible explanes so. At first barbiturate it is dissolved in sodium carbonate Na2CO3 with formation one- substituted Na-salt, which reacts with silver nitrate AgNO3 with formation soluble one- substituted Ag-salt. Then soluble Na-Ag-salt is formed. In equivalence point excess of titrant AgNO3 destroys Na-Ag-salt and the insoluble two- substituted Ag-salt is formed, that specifies in the titration end.

  37. 6. Bromatometry, back titration, with iodometric finishing The method is used for quantitative definition of barbiturates with nonsaturated bound, for example, hexenal. This method is based on bromination substance in a place of double bound. KBrO3 + 5KBr + 6HCl = 3Br2 + 6KCl + 3H2O Br2 + 2KI = I2+ 2KBr I2 + 2Na2S2O3 = 2NaI + Na2S4O6 Carry out the control test. Еm(hexenal) = М. m./2

  38. 7. Iodo-chlorometry, back titration This method is used for quantitative definition of barbiturate with nonsaturated bound(for example, hexenal). (Iodochloride ICl reacts with hexenal in a place of double bound in cyclohexenyl group): ICl + KI = I2 + KCl I2 + Na2S2O3 = 2NaI + Na2S4O6 Carry out the control test. Еm(hexenal) = М. m./2

  39. 8. Gravimetry Gravimetric method usually is used for quantitative definitions of Na-saltsof barbiturates(for example, thiopental sodium), and also at the analysis of medicinal mixtures. To water solution of preparation add diluted chloride acid HCl. The received acid form (thiopental-acid) extract by means of chloroform (5 times in the small portions). All chloroformic extraction connect, chloroform distillates, and the rest dry at 70C to constant mass and weigh.

  40. Storage Group of strong preparations. In the dense corked container. Hygroscopic preparations – in the dry, cool place, protected from light. Phenobarbital and benzonal – in the banks of dark glass, in the place protected from light. Hexenal and thiopental sodium – in glass bottles on 0,5–1,0 g, which are hermetically closed by rubber stoppers, are fitted by aluminium caps; in the dry, cool place protected from light. As the stabilizer to hexenal add 0,05–0,25 % sodium hydroxide NaOH, to thiopental sodium – 5–6 % of sodium carbonate Na2CO3. Water solutions of barbiturates Na-salts easily hydrolyze, therefore them prepare on a physiological solution in aseptic conditions directly ahead of the use (ex tempore).

  41. Action and use Sedative and hypnagogue: a) Long action – barbital, phenobarbital, barbital sodium; b) Average duration – barbamyl; c) Shot-term action – hexenal, thiopental sodium. Protiepileptic (anticonvulsant) means: phenobarbital and benzonal (hypnagogue action has not). For intravenous narcosis: hexenal and thiopental sodium. At long application and high doses of barbiturates can be a poisoning, therefore their application should be supervised by the doctor. In case of barbiturates poisoning applied stimulators of the central nervous system – strychnine, corasole, etc. Subsequently it has been established, that the antagonist of barbiturates is bemegride.

  42. Primidone Hexamidinum Primidonum C12H14N2O2 218.3 DEFINITION 5-Ethyl-5-phenyldihydropyrimidine-4,6(1H,5H)-dione. The chemical structure of primidine is analogue of barbiturates, but unlike phenobarbital, primidone do not have hydroxy-group =С= О on the 2-position in the ring.

  43. Content. 98.0 per cent to 102.0 per cent (dried substance). Synthesys Primidone is synthezed from phenylethylmalonic ester: водного шару. CHARACTERS Appearance White or almost white, crystalline powder. Solubility Very slightly soluble in water, slightly soluble in ethanol (96 per cent). It dissolves in alkaline solutions.

  44. IDENTIFICATION • (BrPh). Measure of ratio of the absorbance. • (BrPh). Infrared absorption spectrophotometry. • D. (BrPh, SP X).Melting with anhydrous sodium carbonate (BrPh) or alkalis (SP X).Mix 0.2 g and 0.2 g of anhydrous sodium carbonate R. Heat until the mixture melts. Ammonia is evolved which is detectable by its alkaline reaction • (molecules of primidine are destroys). • Then alloy dilute with water and acidified by H2SO4, -phenylpentanoic acid with characteristic smell is formed: • The gas CO2is allocated too: • Na2CO3 + H2SO4 = Na2SO4 + H2O + CO2 • The formaldehyde can be identified by reaction C. 2. Гравіметрія 2. Гравіметрія 2. Гравіметрія

  45. C. (BrPh, SP Х).Reaction with sodium salt of chromotropic acid and concentrated sulphuric acid at heating (for formaldehyde) Dissolve 0.1 g in 5 ml of a 5 g/l solution of chromotropic acid, sodium salt R in a mixture of 4 volumes of water R and 9 volumes of sulphuric acid R. A pinkish-blue colour develops on heating.

  46. TESTS IMPURITIES Specified impuritiesA, B, C, D, E, F. A. R1 = NH2, R2 = CO-NH2: 2-ethyl-2-phenylpropanediamide (ethylphenylmalonamide),  C. R1 = NH2, R2 = H: (2RS)-2-phenylbutanamide, D. R1 = NH2, R2 = CN: (2RS)-2-cyano-2-phenylbutanamide, E. R1 = OH, R2 = H: (2RS)-2-phenylbutanoic acid,  B. phenobarbital, F. 5-ethyl-5-phenyl-2-[(1RS)-1-phenylpropyl]dihydropyrimidine-4,6(1H,5H)-dione. Ph Eur

  47. ASSAY • (BpPh). Dissolve 60.0 mg with heating in 70 ml of ethanol (96 per cent) R, cool and dilute to 100.0 ml with the same solvent. Prepare a reference solution in the same manner using 60.0 mg of primidone CRS. Measure the absorbance (2.2.25) of the 2 solutions at the absorption maximum at 257 nm. • Calculate the content of C12H14N2O2 from the absorbances measured and the concentrations of the solutions. • Other method – Keldal method (defenition of total Nitrogen after mineralization. The test substance mineralize by boiling with K2SO4, CuSO4and concentratedH2SO4. Nitrogen is passed to ammonium hydrosulphate NH4HSO4, which react with 30 % solution ofNaOHand ammonia gas NH3 is formed : • NH4HSO4 + 2NaOH  NH3 + Na2SO4 + 2H2O • Obtaned ammonia distil off to flask with HCl: • NH3 + HCl  NH4Cl • Ammonia chloride titrate with 0,1 М solution of NaOH: • NH4Cl + NaOH  NH4OH + NaCl • Em = М. m./2

  48. Storage List of strong preparations. In the dense corked container. Action and use Anticonvulsant. Preparations Primidone Oral Suspension Primidone Tablets Ph Eur

  49. Thanks for attention!

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