LECTURE 11- 12LECTURE 11- 12

Derivatives of pyrrolidine, Derivatives of pyrrolidine, pyrazolone and pyrazolidindione: pyrazolone and pyrazolidindione: its properties, analysis, storage, its properties, analysis, storage,

action and use. action and use. Derivatives Derivatives of of imidazoleimidazole, , imidazolineimidazoline, , triazoletriazole

Associate profAssociate prof. . Mosula L.MMosula L.M..

The planThe plan1.1. Derivatives of Derivatives of pirolidinepirolidine as drugs as drugs: : piracetam piracetam

(Nootropilum), polyvinylpyrrolidone(Nootropilum), polyvinylpyrrolidone ..

2.2. Derivatives of Derivatives of pyrazolone-5pyrazolone-5 as drugs as drugs: : phenazone phenazone (antipyrine), dipyrone (metamizole sodium), (antipyrine), dipyrone (metamizole sodium), budirol (propiphenazonum)budirol (propiphenazonum)..

3.3. Derivatives of Derivatives of pyrazolidine-3,5-dionepyrazolidine-3,5-dione as drugsas drugs: : phenylbutazonephenylbutazone, , tribuzonumtribuzonum, , kebuzonekebuzone..

4.4. Derivatives of Derivatives of imidazoleimidazole as drugsas drugs :: thiamazolethiamazole ((mercazolilmercazolil), ), metronidazolemetronidazole. .

5.5. Derivatives of Derivatives of imidazolineimidazoline as drugs: naphazoline as drugs: naphazoline nitratenitrate, hylometazoline hydrochloride (halazolin), clonidine hydrochloride.

6.6. Derivatives of Derivatives of triazole triazole as drugs:as drugs: thiotriazolinumthiotriazolinum..

A heterocycle or heterocyclic compoundA heterocycle or heterocyclic compound is an is an organic compound in which the carbon ring includes at least one organic compound in which the carbon ring includes at least one atom in addition to carbon (S, O, N, etc.).atom in addition to carbon (S, O, N, etc.).

Derivatives of pirolidine as drugsDerivatives of pirolidine as drugsPyrrole Pyrrole – not satureted pentatomic heterocycle with one – not satureted pentatomic heterocycle with one

heteroatom of Nitrogene:heteroatom of Nitrogene:

PyrrolidinePyrrolidine – – satureted satureted pentatomic heterocycle with pentatomic heterocycle with

one heteroatom of Nitrogeneone heteroatom of Nitrogene::

As drugs most often are used derivatives of As drugs most often are used derivatives of 2-oxopyrrolidine (2-2-oxopyrrolidine (2-pyrrolidone)pyrrolidone) ::

Like drugsLike drugs: : piracetam, piracetam,

polyvinylpyrrolidone and its combined preparationspolyvinylpyrrolidone and its combined preparations ..

NH

NH

NH

O

1

2

34

5

PiracetamPiracetam General NoticesGeneral Notices

(Ph Eur monograph 1733)(Ph Eur monograph 1733)

PyracetamumPyracetamum

NootropilumNootropilumN

O

CH2 C

O

NH2

C6H10N2O2  142.2

DEFINITION 2-(2-Oxopyrrolidin-1-yl)acetamide.

Content 98.0 per cent to 102.0 per cent (dried substance).

CHARACTERS Appearance. White or almost white, powder. Solubility. Freely soluble in water, soluble in ethanol (96 per

cent). It shows polymorphism.

IDENTIFICATION 1. (PhBr). Infrared absorption

spectrophotometry. 2. (not pharmacopoeial reaction). Reaction with

solution of alkaly at heating; ammonia gas are formed, which identificated by waited red litmus paper – paper becames blue.

TESTSInadmisible impurities not present in the test substance.

ASSAY 1. (BrPh). Liquid chromatography.2. Modificated Keldal”s method. Test substance

hydrolyzed by alkaly; Nitrogen deformed in the ammonia.

STORAGE

Protected from light.

Action and use

Central nervous system stimulant.

Ph Eur

N

O

CH CH2 n

Polyvinylpyrrolidone

It is polymer of N-vinyl-2-oxopyrrolidine or N-vinyl-pyrrolidone.

O

O

NH3

-H2ON

O

H

N

O

CH CH2 n

Synthesis from γ-butyrolactone

Action and use

Detoxic agent, plasma substitute.

It is a part of such preparations:1.Haemodesum.

2. Neohaemodesum

Pyrazole (1,2-diazole) is pentatomic heterocycles with two heteroatoms of Nitrogene in the positions 1, 2:

NH

NH

1

2

34

5

Pyrazoline is a partially hydrogenated cycle of pyrazole:

NN

H

4

51

2

3

Completely hydrogenated cycle (saturated compound) of pyrazole names pyrazolidine:

NH

NH

1

2

34

5

NH

NH

1

2

34

5

O

In the medical practice as antiseptic, anti-inflammatory and febrifuges agents are used derivatives of pirazolone-5 (pyrazyl ketone) (pyrazoline, containing in the position 5 ketogroup С=О): phenazone, metamizol sodium (analginum), propiphenazone.

NH

NH

1

2

34

5

O

O

To derivatives of pyrazolidine-3,5-dione concerns drugs: phenylbutazone, tribuzonum, kebuzon.

Derivatives of pirazolone-5 (pyrazyl ketone)

NN

O

CH3

CH3

C6H5

R

For phenylbutazone, dipyrone (metamizole sodium), propiphenazone is characteristic the general formula:

PhenazoneGeneral Notices (Ph Eur monograph 0421)

Antipyrine Phenazonum Antipyrinum Analgesin Sedatin

C11H12N2O   188.2  DEFINITION

Phenazone contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, calculated with reference to the dried substance.

NN

O

CH3

CH3

H3C C

O

O C2H5 + C C

H

H

H

O

O C2H5

C2H5ONaH3C C

O

CH2 C

O

O C2H5C2H5OH_

SynthesisSynthesis of Phenazone (antipyrine) from

phenylhydrazine and acetacetic ester*

* Acetacetic ester are synthesed by means of Klyaizen reaction: condensation two molecules of ethylacetate СН3СООС2Н5 at heating in the presents of sodium ethylate С2Н5ОNa:

Acetacetic ester

CH2

C

C CH3O

O

O

C2H5

HN

NH2

CH2

C

C CH3O

O

N

C2H5 HN-H2O100 0C

-C2H5OH

H2C

CN

N

C CH3

O

Synthesis of Phenazone consists of three stages.

1. Interaction Acetacetic ester with phenylhydrazine and formation phenylhydrazone acetacetic ester, and then 1-

phenyl-3-methylpyrazolone-5:

2. Methylation the received product by means of methyliodide CH3I or methyl ester of benzene sulphonic acid C6H5–SO2–O–CH3 with formation of intermediate product – salts of quarternary base:

H2C

CN

N

C CH3

O

SO2OCH3

+

HC

CN

N

C CH3

OH

CH3

+

SO3

_

3. Formation of Phenazone at action of alkali NaOH on the received salt quarternary base:

HC

CN

N

C CH3

OH

CH3

+

SO3

_

+ NaOH

HC

CN

N

C CH3

O CH3

SO3Na

+

CHARACTERS

A white or almost white, crystalline powder or colourless crystals, very soluble in water, in alcohol

and in methylene chloride.

IDENTIFICATION First identification A, B. Second identification A, C, D.  A. Melting point (2.2.14): 109 °C to 113 °C.  B. Examine by infrared absorption spectrophotometry

(2.2.24), comparing with the spectrum obtained with phenazone CRS. Examine the substances prepared as discs using potassium bromide R.

 C. Reaction with sodium nitrite in the acid medium. To 1 ml of solution S (see Tests) add 4 ml of water R and 0.25 ml of dilute sulphuric acid R. Add 1 ml of sodium nitrite solution R. A green colour develops.

NN

H3C

C6H5

O

H3C

NN

H3C

C6H5

O

H3C N ONaNO2

H2SO4

TESTSInadmisible impurities not presents in the test substance

ASSAYIodometry, back titration. Dissolve 0.150 g in 20 ml of water R. Add 2 g of sodium acetate

R and 25.0 ml of 0.05 M iodine. Allow to stand protected from light for 30 min. Add 25 ml of methylene chloride R and shake until the precipitate dissolves. Titrate with 0.1 M sodium thiosulphate, using 1 ml of starch solution R, added towards the end of the titration, as indicator. Carry out a blank titration.

1 ml of 0.05 M iodine is equivalent to 0,009411 g of C11H12N2O.

NN

H3C

C6H5

O

H3C

I2N

NH3C

C6H5

O

H3C I

HI;+ +

The formed precipitate of 4-iodoantipyrine (iodopyrine) can adsorb a quantity of iodine I2 on the surface, therefore for precipitate dissolution add methylene chloride (chloroform) (shake until the precipitate dissolves).

Sodium acetate CH3COONa add for fixation formed iodide acid HI:

HI + CH3COONa NаI + CH3COOH;I2 + 2Na2S2O3 2NaI + Na2S4O6.

Еm = М. м./2

STORAGE Store protected from light (list of strong means!).

Action and use

Anaesthetic, antipyretic, resolvent.Release forms: a powder and tablets - 0,25 g.

DipyroneGeneral Notices

(Metamizole Sodium, Ph Eur monograph 1346)

Metamizolum natricumAnalginum Analgetin

C13H16N3NaO4S,H2O  351.4

DEFINITION Metamizole sodium contains not less than 99.0 and not more than the equivalent of 100.5 per cent of sodium [(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N-methylamino]methanesulphonate, calculated with reference to the dried substance.

SynthesisSynthesis from 4-aminoantipyrine

Synthesis consists of 3 stages.1. Interaction 4-aminoantipyrine with benzaldehyde

С6Н5СНО with formation benzylidenaminoantipyrine:

NN

O

CH3

CH3

C6H5

H2N

NN

O

CH3

CH3

C6H5

NC6H5CHO HCC6H5

2. Methylation benzylidenaminoantipyrine by means of dimethylsulphate (СН3)2SO4 with formation 4-methylaminoantipyrine:

NN

O

CH3

CH3

C6H5

NHCC6H5 (CH3)SO4

NN

O

CH3

CH3

C6H5

N

H

H3C

H C

O

H

+ NaHSO3 HO-CH2-SO3Na

3. Interaction 4-methylaminoantipyrine with a mix of solutions of formaldehyde НСНО and sodium hydrogensulphyde NaHSO3 (differently НО–СН2–SO3Na):

NN

O

CH3

CH3

C6H5

N

H3C

NaO3SH2C

NN

O

CH3

CH3

C6H5

N

H

H3C HO-CH2-SO3Na+H2O_

CHARACTERS A white or almost white, crystalline powder, very soluble in water,

soluble in alcohol.

IDENTIFICATIONFirst identification A, D. Second identification B, C, D.  A. Examine by infrared absorption

spectrophotometry (2.2.24), comparing with the spectrum obtained with metamizole sodium CRS.

 B. Oxidation of preparation by means of strong

hydrogen peroxide solutionDissolve 50 mg in 1 ml of strong hydrogen peroxide solution R. A

blue colour is produced which fades rapidly and turns to intense red in a few minutes.

Mechanism of oxidationInteraction of dipyrone with differents oxidaizers (chloramine,

chlorinated lime, solution of iron(ІІІ) chloride, hydrogen peroxide and other) is bused on formation not stability colored tetraoxiderivative of pirazolone-5, which change the colour after same minutes, then dioxiderivative is formed:

NN

O

CH3

CH3

C6H5

N

H3C

NaO-O2S-H2C[O],HCl

NaCl_ SO2 + H CO

H+

C

C

N

H

H3CO

N

C6H5

N

C CH3

CH3

HO OHHO OH

_

C

C

N

H

H3CO

N

C6H5

N

C CH3

CH3

O O

2H2O

C. Oxidation of preparation by means of potassium iodate with the next revealing of oxidation products (see mechanism of reaction B)

Identification of oxidation products (SO2 и HCHO):5SO2 + 2KIO3 I2 + 4SO3 + K2SO4

HO

HO

SO3Na

SO3Na

H H

NaO3S

NaO3S

OH

OHH C H

O

H2O

HO

HO

SO3H

SO3H

CH2

HO3S

HO3S

OH

OH

+ H2SO4(conc)_

[O]

[O]

H2O_

HO

HO

SO3H

SO3H

CH

HO3S

HO3S

O

OH

D. 0.5 ml of solution S (see Tests) gives reaction (a) of sodium (2.3.1):

.Na+ + [Sb(OH)6]– → Na[Sb(OH)6] ↓ white precipitate

TESTSThe inadmisible impurities are not presents in the test substance

ASSAY

Iodometry, direct titration Dissolve 0.200 g in 10 ml of 0.01 M hydrochloric acid previously

cooled in iced water and titrate immediately, dropwise, with 0.05 M iodine. Before each addition of 0.05 M iodine dissolve the precipitate by swirling. At the end of the titration add 2 ml of starch solution R and titrate until the blue colour of the solution persists for at least 2 min. The temperature of the solution during the titration must not exceed 10 °C.

1 ml of 0.05 M iodine is equivalent to 16.67 mg of C13H16N3NaO4S.

NN

O

CH3

CH3

C6H5

N

H3C

NaO-O2S-H2C+ J2 + 2H2O

NN

O

CH3

CH3

C6H5

N+

. J_

+ NaHSO4 + HJ + HCHO

H3C

HH

IV VI

Еm (C13H16N3NaO4S, H2O) = М m./2

STORAGEStore protected from light.

Action and use Analgesic.

Ph Eur

Propiphenazonum (latin name) (not pharmacopoeial drug)

Budirol

NN

O

CH3

CH3

1

2

34

5

CHH3C

H3C Causytin

The chemical name: 1-phenyl-2,3-dimethyl-4-isopropyl-pyrazolone-5 (4-isopropylantipyrine).

CHARACTERS Appearance. White or slightly yellowish crystal powder without a smell, bitter taste. Solubility. Slightly soluble in water, freely soluble in alcohol, methylenchloride, chloroform and ether.

Chemical propertiesUnlike antipyrine propiophenazonum shows the expressed

reducing properties, because it is derivative partially hydrogenated pyrazoline and is presence alkyl radical at С4, interfering reactions, characteristic for antipyrine.

Like analginum propiophenazonum is oxidised even slight oxidizers.

Identification

1.IR-spectroscopy.

2. UV-spectroscopy.

3. Reaction with solution of silver nitrate At action on solution of substance of solution silver nitrate

AgNO3 there is a violet colour, and then precipitate of grayish-brown colour (precipitate of metal silver).

NN

O

CH3

CH3

C6H5

CH

H3C

H3CC

C

CH

H3C

H3CO

N

C6H5

N

C CH3

CH3

HO OHHO OH

2H2O_

C

C

CH

H3C

H3CO

N

C6H5

N

C CH3

CH3

O O

+ 4AgNO3+ 4H2O 4Ag + 4HNO3 +

+ 4Ag + 4HNO3

NN

O

CH3

CH3

C6H5

CH

H3C

H3CC

C

CH

H3C

H3CO

N

C6H5

N

C CH3

CH3

HO OHHO OH

2H2O_

C

C

CH

H3C

H3CO

N

C6H5

N

C CH3

CH3

O O

+ 4FeCl3+ 4H2O 4FeCl2 + 4HCl +

+ 4FeCl2 + 4HCl

4. Reaction with solution of iron (ІІІ) chlorideAt action on water-alcoholic solution of substance several drops of solution iron(ІІІ) chloride FeCl3 there is a red-brown colour, which is passed after addition chloride acid HCl to the yellow colour.

5. Reaction with generalalkaliodal reagents (on tertiary atom of Nitrogen)With generalalkaliodal reagents the preparation forms precipitates of complex salts.

NN

O

CH3

CH3

C6H5

CH

H3C

H3C ++ HClO4

O O

CH3COOHN

NO

CH3

CH3

C6H5

CH

H3C

H3C

H

._

ClO4

AssayAcidimetry, non-aqueous titration

Shot of substance dissolve in dioxane and titrate with standard solution of perchloric acid HClO4 in the presence of ice СН3СООН (indicator - crystal violet).

StorageThe list of strong substances. In densely corked container, in

the place protected from light.Action and use

Anaesthetic, antipyretic, resolvent. Is a part of the combined preparations.

Derivatives of pyrazolidine-3,5-dionePhenylbutazone

General Notices

Phenylbutazonum ButadionButadionumPyrazolidin

NN

O

H2CO

H2CH2CH3C

1

2

34

5

C19H20N2O2  308.4   DEFINITION

4-Butyl-1,2-diphenylpyrazolidine-3,5-dione. Content

99.0 per cent to 101.0 per cent (dried substance).

SynthesisCondensation of diethyl ester of butylmalonic acid with hydrazono-benzene:

NN

O

C4H9

ONaC4H9

HC

C

C

O

OC2H5

OC2H5

O

N C6H5

H

N

C6H5

H

+

C2H5ONa

2C2H5OH_C6H5

C6H5

H+

NN

O

C4H9

O

C6H5

C6H5

CHARACTERS Appearance

White or almost white, crystalline powder. Solubility

Practically insoluble in water, sparingly soluble in alcohol. It dissolves in alkaline solutions.

IDENTIFICATION First identification A, C. Second identification A, B, D. A. Melting point (2.2.14): 104 °C to 107 °C. B. Thin-layer chromatography (2.2.27). C. Infrared absorption spectrophotometry.

D. Reaction of oxidation by sodium nitrite in the acetic mediumChemism. Reaction is based on splitting (decomposition) of butadiene molecule and oxidation of hydrazono-benzene С6Н5–NH–NH–C6H5 to painted azobenzene: С6Н5–N=N–C6H5 (A brownish-red to violet-red precipitate is formed):

N N

N N

H H

[O]

NN

O

C4H9

O

C6H5

C6H5

H

C CC4H9

H

C

O OH

O

OH

CO2_

C4H9 CH2 COOH

+

N N

[H+]

H

+HSO3

_

TESTSThe inadmisible impurities are not presents in the test substance

ASSAY Alkalimetry, direct titration in the presence of acetone

(acid properties of phenylbutazone)(indicator - bromothymol blue solution. Titrate until a blue colour is obtained).

Em = М. м.

NN

O

C4H9

O

C6H5

C6H5

H

NN

O

C4H9

OH

C6H5

C6H5

NaOH

NN

O

C4H9

ONa

C6H5

C6H5

H2O_

STORAGE

Protected from light.

Action and use

Anti-inflammatory; analgesic.

Ph Eur

TribuzonumTribuzonum**

The chemical name: The chemical name: 4 (4,4-4 (4,4-dimethyl-3-oxopenthyl)-dimethyl-3-oxopenthyl)-1,2-diphenyl-1,2-diphenyl-pyrazolidindione-3,5 pyrazolidindione-3,5

Kebuzone*Kebuzone* KetophezonKetophezon

The chemical name: The chemical name: 1,2- diphenyl -4 (3 '-1,2- diphenyl -4 (3 '-oxobutyl)- oxobutyl)- pyrazolidindione-3,5 pyrazolidindione-3,5

C

CH3

CH3

CH3

C CH2

O

CH2

NN

O

C6H5

C6H5

O

H

4

5

3

21

CH3 C CH2

O

CH2

NN

O

C6H5

C6H5

O

H

4

5

3

21

Tribuzonum show anti-inflammatory, analgetic and febrifugal (antipyretic) action.

The release form: tablets for 0,25

Kebuzone also show anti-inflammatory and analgetic action.

The release forms: drage (0,25 g), ampoules (5 ml of 20 % of intravenously solution for injection).

Thanks for attention!