lecture 10 classification of heterocyclic compounds on the basis of their chemical structure....
TRANSCRIPT
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!