LECTURE 10

1. LECTURE 10 Classification of heterocyclic compounds on the basis of their chemical structure. Derivatives of 5-nitrofuran as antimicrobial agents associate prof. Mosula L.M.

2. The plan • 1. Concept about heterocyclic compounds and their classification. • 2. Derivatives of 5-nitrofuran as antimicrobial agents: Nitrofurazone, Nitrofurantoin, Furazolidone.

3. Concept about heterocyclic compounds and their types • Heterocyclic compounds are compounds, which contain cycles with atoms Carbon and other elements – heteroatoms (more often Оxygen, Nitrogen, Sulphur). Such compounds widespread in the nature (vitamins, antibiotics, enzymes, alkaloid) also can be easily synthesized. Heterocyclic compounds can contain cycles from three to six and more atoms and to contain odes of one to four heteroatoms, but the greatest practical value have five-and hexatomic heterocycles.

4. Trimonial heterocycles: Ethylene imine (aziridine) Ethylene oxide Pentatomic heterocycles with one heteroatom: furanpyrolthiophene

5. Pentatomic heterocycles with two heteroatoms: pyrazol imidazole 1,3-thiazole 1,3-thiazolidin 1,3-oxazole

6. Pentatomic heterocycles with three and four heteroatoms: 1,2,3-oxadiazole 1,3,4-thiadiazole 1,2,4- thiadiazole 1,3,4-triazole 1,2,3,4-tetrazole

7. Condensed derivatives with pentatomic heterocycles: benzofuran benzimidazole indole purine

8. Feature of structure and chemical properties of pentatomic heterocycles • Furan is pentatomic heterocycle with one heteroatom – atom Oxygen: • Pentatomic heterocycles with one heteroatom (furan, pyrol, thiophene) have properties of aromatic compounds. -Position is most reactive. For its compounds characteristic are reactions of halogenation, alkylation, acylation, sulphonation, nitration.

9. Drugs –derivatives of furan In medical practice use derivatives of 5-nitrofuran Syntetical derivatives of 5-nitrofurfurol, which has substituens in position 2. It is general formula of 5-nitroderivatives of furan series with bactericidal action.

10. Nitrofurazone • (Nitrofural, Ph Eur monograph 1135) • Nitrofuralum • Furacilinum • C6H6N4O4 198.159-87-0 • DEFINITION • Nitrofural contains not less than 97.0 per cent and not more than the equivalent of 103.0 per cent of 2-[(5-nitrofuran-2-yl)methylene]diazanecarboxamide, calculated with reference to the dried substance.

11. Synthesis • Synthesis nitrofurazone (furacilinum) from furfurol (-furilaldehyde): • 1. Furfurol nitration furfurol 5-nitrofurfuroldiacetate 5-nitrofurfurol

12. *Acetylnitrate –is anhydride СН3СООН and HNO3: 2. Condensation 5-nitrofurfurol with semicarbazide hydrochloride. 5-nitrofurfurol semicarbazide hydrochloride semicarbazone5-nitrofurfurol (nitrofural) CHARACTERS A yellow or brownish-yellow, crystalline powder, very slightly soluble in water, slightly soluble in alcohol.

13. IDENTIFICATION • First identificationB. • Second identificationA, C, D. • A. UV-spectroscopy. • B. Examine by infrared (IR) absorption spectrophotometry. • C. Examine by thin-layer chromatography. • D. Dissolve about 1 mg in 1 ml ofdimethylformamide R and add 0.1 ml of alcoholic potassium hydroxide solution R. A violet-red colour is produced.

14. Other reactions: • 1. With alkali solution. • Some crystals of drug add in flask, dissolutions in mix of 5 ml water R and 5 ml 10 % solution NaOH - orange-red colour are formed: salt of nitronic acid (orange-red colour) Other nitrofuranswith alkali solutions yields too coloured products.

15. At heating of salt of nitronic acid (product) allocated ammonia NH3 (smell and wet litmus paper becames blue colour in steam of boiling solution): 2. Melting point (230 С to 236 С). 3. Other colored reactions:

16. TESTS • pH (2.2.3) • To 1.0 g add 100 ml of carbon dioxide-free water R. Shake and filter. The pH of the filtrate is 5.0 to 7.0. • Loss on drying (2.2.32) • Not more than 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105 °C. • Sulphated ash (2.4.14) • Not more than 0.1 per cent, determined on 1.0 g.

17. ASSAY • 1. UV-spectrophotometry. • 2. Iodometry, back titration (In the alkaline medium). I2 + 2NaOH → NaI + NaIO + H2O; NaIO + NaI + H2SO4 → I2+ Na2SO4 + H2O, I2 + 2Na2S2O3 → 2NaI + Na2S4O6. Еm = М. м./4 STORAGE Store protected from light (list of strong substance!). Action and use Antibacterial, topical antiprotozoan. Ph Eur Еm = М. м./4

18. Nitrofurantoin • General Notices • (Ph Eur monograph 0101) • Furadoninum • Furadantin • Chemiofuran C8H6N4O5 238.267-20-9 DEFINITION Nitrofurantoin contains not less than 98.0 per cent and not more than the equivalent of 102.0 per cent of 1-[[(5-nitrofuran-2-yl)methylene]amino]imidazolidine-2,4-dione, calculated with reference to the dried substance.

19. Synthesis Synthesis of Nitrofurantoin (Furadoninum) from 5-nitrofurfurol: 5-nitrofurfurol 1-aminohydantoinNitrofurantoin CHARACTERS A yellow, crystalline powder or yellow crystals, odourless or almost odourless, very slightly soluble in water and in alcohol, soluble in dimethylformamide.

20. IDENTIFICATION A. UV-spectroscopy. B. Reaction with alcoholic solution of alkali.Dissolve about 10 mg in 10 ml of dimethylformamide R. To 1 ml of the solution add 0.1 ml of 0.5 M alcoholic potassium hydroxide. A brown colour develops. • Other reaction: • 1. SP Х. Reaction with water solution of alkali. • Some crystals of drug add in flask, dissolutions in mix of 5 ml water R and 5 ml 30 % solution NaOH - dark-red colour develops:

21. TESTS • Loss on drying(2.2.32) • Not more than 1.0 per cent, determined on 1.00 g by drying in an oven at 100 °C to 105 °C. • Sulphated ash(2.4.14) • Not more than 0.1 per cent, determined on 1.0 g. • ASSAY • 1.UV-spectrophotometry. • 2. Alkalimetry, non-aqueous titration • Exact shot of drug dissolves in protophilic dissolvent (DMF, pyridine, butylamine) and titrate with standard solution of sodiummethylate CH3ONa (or sodiummethoxide, lithium methoxide – International Pharmacopoeia) in the presents DMF and dioxane (indicator – thymol dark blue). • Еm = М. м.

22. STORAGE Store protected from light, at a temperature below 25 °C (list of strong substance!). Ph Eur Action and use Antibacterial. Preparations Nitrofurantoin Oral Suspension Nitrofurantoin Tablets Ph Eur

23. Furazolidone General Notices Furazolidonum Diafurone Furoxon C8H7N3O5225.267-45-8 DEFINITION Furazolidone is 3-(5-nitrofurfurylideneamino)oxazolidin-2-one. It contains not less than 97.0% and not more than 103.0% of C8H7N3O5, calculated with reference to the dried substance.

24. Synthesis Synthesis furazolidone from 5-nitrofurfurol by means of reaction condensation with 3-aminooxazolidone-2: CHARACTERISTICS A yellow, crystalline powder. Very slightly soluble in water and in ethanol (96%); practically insoluble in ether .

25. IDENTIFICATION A. The infrared absorption spectrum. B. With alcoholic solution of alkali. Dissolve 1 mg in 1 ml of dimethylformamide and add 0.05 ml of 1M ethanolic potassium hydroxide. A deep blue colour is produced. Other reaction: 1. SP Х. With water solution of alkali. Some crystals of drug add in flask, dissolutions in mix of 20 ml water R and 5 ml 30 % solution NaOH and heating - brown colouris produced.

26. TESTS Acidity or alkalinity Shake 1 g for 15 minutes with 100 ml of carbon dioxide-free water and filter. The pH of the filtrate is 4.5 to 7.0, Nitrofurfural diacetate Carry out in subdued light the method for thin-layer chromatography. Any spot corresponding to nitrofurfural diacetate in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (2). Loss on drying When dried to constant weight at 105°, loses not more than 0.5% of its weight. Use 1 g. Sulphated ash Not more than 0.1%

27. STORAGE Furazolidone should be protected from light (list of strong substance!). Action and use Antibacterial; antifungal; antiprotozoal.

28. Thanks for attention!