LECTURE 10LECTURE 10Classification of heterocyclic Classification of heterocyclic

compounds on the basis of their compounds on the basis of their chemical structure. Derivatives of chemical structure. Derivatives of

5-nitrofuran as antimicrobial 5-nitrofuran as antimicrobial agentsagents

associate profassociate prof. . Mosula L.M.Mosula L.M.

The planThe plan

1. Concept about heterocyclic 1. Concept about heterocyclic compounds and their classification.compounds and their classification.

2. Derivatives of 5-nitrofuran as 2. Derivatives of 5-nitrofuran as antimicrobial agents: Nitrofurazone, antimicrobial agents: Nitrofurazone, NitrofurantoinNitrofurantoin, Furazolidone., Furazolidone.

Concept about heterocyclic compounds and Concept about heterocyclic compounds and their typestheir types

Heterocyclic compoundsHeterocyclic compounds are compounds, which are compounds, which

contain contain cycles withcycles with atoms Carbon and other atoms Carbon and other elements – elements – heteroatoms heteroatoms (more often (more often ООxygenxygen, , NitrogenNitrogen, , SulphurSulphur). Such compounds widespread in ). Such compounds widespread in the nature (vitamins, antibiotics, enzymes, alkaloid) the nature (vitamins, antibiotics, enzymes, alkaloid) also can be easily synthesized. Heterocyclic also can be easily synthesized. Heterocyclic compounds can contain cycles from three to six and compounds can contain cycles from three to six and more atoms and to contain odes of one to four more atoms and to contain odes of one to four heteroatoms, but the greatest practical value have heteroatoms, but the greatest practical value have five-and hexatomic heterocycles.five-and hexatomic heterocycles.

O.. 1

2

34

5 S.. 1

2

34

5

HN ..1

2

34

5

Trimonial heterocycles: Ethylene imine (aziridine) Ethylene oxide

furan pyrol thiophene

N H

Pentatomic heterocycles with one heteroatom:

O

HN

N

1

2

34

5

HN

N

1

2

34

5S

N

1

2

34

5SH

NH

1

2

34

5O

N

1

2

34

5

Pentatomic heterocycles with two heteroatoms:

pyrazol imidazole 1,3-thiazole 1,3-thiazolidin 1,3-oxazole

ON

N

1

2

34

5

N

SN

12

34

5

N

HN

N

N

1

2

34

5

N

HN

N

1

2

34

5

N

S

N

1

2

34

5

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

O 1

2

34

5

6

7 HN

N

12

34

5

6

7 HN

1

2

34

5

67

N

N

N

NH

Condensed derivatives with pentatomic heterocycles:

benzofuran benzimidazole indole

purine

Feature of structure and chemical properties of Feature of structure and chemical properties of pentatomic heterocyclespentatomic heterocycles

Furan is pentatomic heterocycle with one Furan is pentatomic heterocycle with one heteroatom heteroatom – – atom Oxygen:atom Oxygen:

Pentatomic heterocycles with one heteroatomPentatomic heterocycles with one heteroatom ((furanfuran, , pyrolpyrol, , thiophenethiophene) ) have properties of have properties of aromatic compoundsaromatic compounds. . --Position is most reactivePosition is most reactive. . For its compounds characteristic For its compounds characteristic are reactions of are reactions of halogenation, alkylation, acylation, sulphonation, halogenation, alkylation, acylation, sulphonation, nitration.nitration.

O 1

2

34

5

Drugs –derivatives of furan

In medical practice use derivatives of 5-nitrofuran

OO2N

1

2

34

5

OCH NRO2N

1

2

34

5

Syntetical derivatives of 5-nitrofurfurol, which has substituens in position 2.

It is general formula of 5-nitroderivatives of furan series with bactericidal action.

NitrofurazoneNitrofurazone (Nitrofural, Ph Eur monograph 1135)(Nitrofural, Ph Eur monograph 1135) NitrofuralumNitrofuralum FuracilinumFuracilinum

C6H6N4O4C6H6N4O4     198.1 198.1     59-87-059-87-0 DEFINITIONDEFINITION Nitrofural contains not less than 97.0 per cent and not Nitrofural contains not less than 97.0 per cent and not

more than the equivalent of 103.0 per cent of more than the equivalent of 103.0 per cent of 2-[(5-2-[(5-nitrofuran-2-yl)methylene]diazanecarboxamidenitrofuran-2-yl)methylene]diazanecarboxamide, , calculated with reference to the dried substance.calculated with reference to the dried substance.

OO2NHC N N

HC NH2

O

SynthesisSynthesis Synthesis nitrofurazone (furacilinum) from furfurol (Synthesis nitrofurazone (furacilinum) from furfurol (--

furilaldehyde):furilaldehyde): 1. Furfurol nitration1. Furfurol nitration

OC

O

H

H

OOCHHONO2

(CH3CO)2OO2N O2N C

O

O

C

C

O

CH3

O

CH3

H2SO4

HOH-2 CH3COOH

O

H

furfurol 5-nitrofurfuroldiacetate 5-nitrofurfurol

OC

O

H

O

OCH(CH3CO)2O

O2N C

O

O

C

C

O

CH3

O

CH3

CH3COONO2

HNO3 + C5H5N

O

H

OCH

O

O

C

C

O

CH3

O

CH3

O2N

H2O, H2SO4

-2CH3COOH

H3C C

O

OH

+ HO-NO2 H3C C

O

O NO2-H2O

*Acetylnitrate –is anhydride СН3СООН and HNO3:

2. Condensation 5-nitrofurfurol with semicarbazide hydrochloride.

OO2N C

O

H

+ H2N-NH-C-NH2 HCl.=

OO

O2N CH N NH C

O

NH2 + H2O + HCl

5-nitrofurfurol semicarbazide hydrochloride semicarbazone 5-nitrofurfurol (nitrofural)

CHARACTERS

A yellow or brownish-yellow, crystalline powder, very slightly soluble in water, slightly soluble in alcohol.

IDENTIFICATION First identification B. Second identification A, C, D. A. UV-spectroscopy. B. Examine by infrared (IR) absorption spectrophotometry.B. Examine by infrared (IR) absorption spectrophotometry. C. Examine by thin-layer chromatographyC. Examine by thin-layer chromatography.. D.D. Dissolve about 1 mg in 1 ml of Dissolve about 1 mg in 1 ml of dimethylformamide dimethylformamide RR and add 0.1 ml of and add 0.1 ml of

alcoholic potassium hydroxide solutionalcoholic potassium hydroxide solution R R. A . A violet-red colourviolet-red colour is is

produced.produced.

ON+HC N N C NH2

O

-O

O-

ON+HC N N

HC NH2

O

O

O-

+ N C

H3C

H3C

O

H

N+ C

H3C

H3C

O

HH*

Other reactions:Other reactions: 1. With alkali solution.1. With alkali solution. Some crystals of drug add in flask, dissolutions in mix of 5 ml Some crystals of drug add in flask, dissolutions in mix of 5 ml

waterwater R R and 5 ml and 5 ml 10 %10 % solution NaOH - solution NaOH - orange-red colourorange-red colour are are formed:formed:

ON+HC N N

HC NH2

O

O

O-

NaOH ON+HC N N C NH2

O

+Na-O

O-

+ H2O

salt of nitronic acid (orange-red colour)

Other nitrofurans with alkali solutions yields too coloured products.

At heating of salt of nitronic acid (product) allocated ammonia NH3 (smell and wet litmus paper becames blue colour in steam of boiling solution):

OO2NHC N N

HC NH2

O

2NaOH H2O

OO2N C O

H

NH3 Na2CO3 H2N NH2+ + ++ +t

2. Melting point (230 С to 236 С).3. Other colored reactions:

№ Reagents Result

1. 95 % ethanol, 10 % solution CuSO4, 10

% solution NaOH

Dark-red solution and precipitate

2. Perhydrol (30 % solution Н2О2), 30 %

solution NaOH

Light-yellow colour

3. 95 % ethanol, 5 % solution sodium nitroprusside Na2[Fe(CN)5NO]

Red solution and precipitate

4. Nesler reagent (solution K2[HgI4] in

KOH)

Red-brown colour

TESTSTESTS pH pH (2.2.3)(2.2.3) To 1.0 g add 100 ml of To 1.0 g add 100 ml of carbon dioxide-free water Rcarbon dioxide-free water R. Shake . Shake

and filter. The pH of the filtrate is 5.0 to 7.0.and filter. The pH of the filtrate is 5.0 to 7.0.

Loss on drying Loss on drying (2.2.32)(2.2.32) Not more than 0.5 per cent, determined on 1.000 g by drying Not more than 0.5 per cent, determined on 1.000 g by drying

in an oven at 100-105 °C. in an oven at 100-105 °C. Sulphated ash Sulphated ash (2.4.14)(2.4.14) Not more than 0.1 per cent, determined on 1.0 g. Not more than 0.1 per cent, determined on 1.0 g.

ASSAYASSAY

1. UV-spectrophotometry.1. UV-spectrophotometry. 2. 2. IodometryIodometry, , back titration (back titration (In the alkaline medium)In the alkaline medium) . .

Еm = М. м./4

OO2NHC N N

HC NH2

O

2I2

OO2NHC N N

HC NH2

O

I I

2HI+ + ;

I2 + 2NaOH → NaI + NaIO + H2O;NaIO + NaI + H2SO4 → I2 + Na2SO4 + H2O,

I2 + 2Na2S2O3 → 2NaI + Na2S4O6.Еm = М. м./4STORAGE

Store protected from light (list of strong substance!). Action and use

Antibacterial, topical antiprotozoan. Ph Eur

NitrofurantoinNitrofurantoin General NoticesGeneral Notices (Ph Eur monograph 0101)(Ph Eur monograph 0101)

FuradoninumFuradoninum FuradantinFuradantin ChemiofuranChemiofuran

OO2N CH N N NH

O

O

1

2

34

5 1

2 3

45. H2O

C8H6N4O5   238.2   67-20-9 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.

SynthesisSynthesis

Synthesis of Nitrofurantoin (Furadoninum) from 5-nitrofurfurol:

CHARACTERS

A yellow, crystalline powder or yellow crystals, odourless or almost odourless, very slightly soluble in water and in

alcohol, soluble in dimethylformamide.

OO2N C

O

H

OO2N CH N N NH

O

O

+

N

NH

O

O

NH2

1

2

34

5NaOH

- H2O

5-nitrofurfurol 1-aminohydantoin Nitrofurantoin

IDENTIFICATIONA. 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:

OO2N CH N

N

NH

O

O

ON CH

O

NaO

+

_

N N CH2C

O

ONa

+ Na2CO3 + NH3 + H2O

4 NaOH

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.

ASSAYASSAY 1.1. UV-spectrophotometry.UV-spectrophotometry. 2. Alkalimetry, non-aqueous titration2. Alkalimetry, non-aqueous titration Exact shot of drug dissolves in protophilic dissolvent (DMF, Exact shot of drug dissolves in protophilic dissolvent (DMF,

pyridine, butylamine) and pyridine, butylamine) and titrate withtitrate with standard solution of standard solution of sodiumsodium methylatemethylate CH CH33ONaONa (or (or sodiumsodium methoxidemethoxide, lithium , lithium methoxidemethoxide – International Pharmacopoeia) in the presents – International Pharmacopoeia) in the presents DMF and dioxane (indicator – thymol dark blue).DMF and dioxane (indicator – thymol dark blue).

ЕЕmm = М. м. = М. м.

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

FurazolidoneGeneral Notices Furazolidonum Diafurone Furoxon

OO2N CH N N O

O

1

2

34

51

23

4 5

C8H7N3O5  225.2  67-45-8

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.

Synthesis Synthesis furazolidone from 5-nitrofurfurol by means of

reaction condensation with 3-aminooxazolidone-2:

OO2N C H2N N O

O

+

O

H- H2O

OO2N CH N N O

O

CHARACTERISTICS

A yellow, crystalline powder.

Very slightly soluble in water and in ethanol (96%); practically insoluble in ether .

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 colour is produced.

ON CH

OO2N CH N N O

O

O

NaO

_

+N N CH2CH2OH + Na2CO3 + H2O3 NaOH

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%

STORAGESTORAGE

Furazolidone should be protected from light (list of Furazolidone should be protected from light (list of strong substance!). strong substance!).

Action and use Action and use

Antibacterial; antifungal; antiprotozoal.Antibacterial; antifungal; antiprotozoal.

Thanks for attention!