LECTURE LECTURE № № 1144

Theme: Theme: Derivatives of barbituric acid: Derivatives of barbituric acid: properties, analysis, storage, action and properties, analysis, storage, action and use. Primidone as structural analog of use. Primidone as structural analog of

barbituratesbarbiturates

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

The planThe plan

1.1. Medical preparations from group of Medical preparations from group of derivatives derivatives of barbituric acidof barbituric acid:: barbitalbarbital, , barbital sodiumbarbital sodium, , phenobarbitalphenobarbital, , phenobarbital sodiumphenobarbital sodium, , benzonalbenzonal, , hexenalhexenal, , thiopental sodiumthiopental sodium..

2.2. PrimidonePrimidone as structural analog of barbituratesas structural analog of barbiturates..

Derivatives of pyrimidineDerivatives of pyrimidine In structure of many natural and synthetic drugs is In structure of many natural and synthetic drugs is

pyrimidine pyrimidine – – hexatomic heterocycle with two atoms of hexatomic heterocycle with two atoms of

Nitrogene,Nitrogene, which are in the position 1,3: which are in the position 1,3:

HN

HN1

2

3 4

5

6

N

N

N

N

1

2

3

1

2

3

Completely hydrogenated cycle of pyrimidine names

hexahydropyrimidine:  

In medical practice the synthetic preparations, which contains In medical practice the synthetic preparations, which contains hexahydropyrimidinehexahydropyrimidine cyclecycle with three hydroxy-groupswith three hydroxy-groups --СС==ОО in the position 2,4,6 – in the position 2,4,6 – derivatives of barbituric acidderivatives of barbituric acid are are

widely appliedwidely applied::

  

Barbituric acidBarbituric acid – – is is hexahydropyrimidinehexahydropyrimidine-2,4,6--2,4,6-trionetrione..

Barbituric acidBarbituric acid is cyclic ureideis cyclic ureide – – product of product of condensation condensation of carbamideof carbamide (urea) (urea) and dibasic malonic acidand dibasic malonic acid (propane (propane diacid)diacid)::

HN

HN

O

O

O1

3

2

4

5

6

O C

NH2

NH2

C

C

C

HO

HO

O

O

R1

R2 HN

HN

O

O

O

R1

R2

+-2H2O

1

3

2

4

5

6

Derivatives of barbituric acidarbituric acid areare products of products of condensation of condensation of

carbamidecarbamide (urea) (urea) and derivatives of malonic acidand derivatives of malonic acid:

O C

NH2

NH2

C

C

C

HO

HO

O

O

H

H HN

HN

O

O

O

H

H

+-2H2O

1

3

2

4

5

6

BarbituratesBarbiturates are cyclic imides used as hypnotics andare cyclic imides used as hypnotics and (in the case of phenobarbital) (in the case of phenobarbital) as anticonvulsants.as anticonvulsants. They are They are derivatives of barbituric acid (which is not derivatives of barbituric acid (which is not pharmacologically active) and differ only in their pharmacologically active) and differ only in their substituents on the 5-position of the ring. substituents on the 5-position of the ring.

The hypnagogue action of barbiturates was revealed The hypnagogue action of barbiturates was revealed in the earlyin the early ХХ ХХ-th-th century bycentury by FisherFisher and Meringand Mering. . In the In the 1904 1904 Fisher was synthesized barbitalFisher was synthesized barbital, , after that were after that were synthesized many barbiturates and was fixed relationship synthesized many barbiturates and was fixed relationship between structure and actionbetween structure and action..

1. 1. The hypnagogue action is characteristic for derivatives of The hypnagogue action is characteristic for derivatives of barbituric acidbarbituric acid, , which have in the positionwhich have in the position 5,5 5,5 alkylalkyl, , aryl or aryl or other radicalsother radicals..

2. 2. The impact surface and valid time of barbiturates are The impact surface and valid time of barbiturates are increased at increase of lenght of hydrocarbonic chain in the increased at increase of lenght of hydrocarbonic chain in the alkyl substitute in the position alkyl substitute in the position 5,5 5,5 until 5-6 atoms of Carbon.until 5-6 atoms of Carbon. Then lenght of hydrocarbonic chain in the barbiturates is Then lenght of hydrocarbonic chain in the barbiturates is more? Such drugs have stimulant actionmore? Such drugs have stimulant action..

3. 3. The pharmacological effect at hydrocarbonic chain The pharmacological effect at hydrocarbonic chain branchingbranching, , presence of unsaturated bondspresence of unsaturated bonds, , alkoholic alkoholic hydroxylhydroxyl –ОН, –ОН, atom of halogen atom of halogen ((especiallyespecially Br) Br) is intensifiedis intensified..

4. 4. Then action of barbiturates is more intensified the Then action of barbiturates is more intensified the hypnagogue effect is shothypnagogue effect is shot..

5. 5. With one phenyl radicalWith one phenyl radical (C(C66HH55)) on the 5-position of the ringon the 5-position of the ring to intensifyto intensify actionaction, , not change duration of actionnot change duration of action, , but then but then second phenyl radicalsecond phenyl radical on the 5-position is presents the on the 5-position is presents the hypnagogue action is decreasedhypnagogue action is decreased..

6. 6. Then alkyl radical is on the 1- or 3-position (nearly imide Then alkyl radical is on the 1- or 3-position (nearly imide group)group) valid time of drugs is abbreviatedvalid time of drugs is abbreviated..

7. 7. The change of hydrogen on the 1-position on the rest of The change of hydrogen on the 1-position on the rest of aromatic acidaromatic acid ( (for example, benzoic acidfor example, benzoic acid) ) add to drug add to drug antiepileptic actionantiepileptic action ( (benzonalbenzonal).).

8. 8. ThenThen atoms of hydrogen of imide groups (1- and 3-positions atoms of hydrogen of imide groups (1- and 3-positions of the ring) are substituted such drug can make of the ring) are substituted such drug can make convulsionsconvulsions..

9. 9. Derivatives of thiobarbituric acid (atom of sulphur on the 2-Derivatives of thiobarbituric acid (atom of sulphur on the 2-position of the ringposition of the ring ) ) have more intensive and short-time have more intensive and short-time action unlike oxygen analogue of barbituratesaction unlike oxygen analogue of barbiturates..  

Chemical properties of barbituric acid and barbituratesBarbiturates contain nitrogen atoms, but the lone pair on the Barbiturates contain nitrogen atoms, but the lone pair on the

nitrogen is not available for reaction with protons, so nitrogen is not available for reaction with protons, so barbiturates barbiturates are not basic.are not basic.

Barbituric acid and derivatives have the acid nature. Thus barbituric acid in 5–6 times is stronger then acetic acid. 5-Monosubstituted of barbituric acid (for example, 5-ethylbarbituric acid) – enough strong acids, and 5,5-disubstituted of barbituric acid (for example, 5,5-diethylbarbituric acid) – very weak acid.

Acid properties of these compounds are caused keto-enol tautomerism of barbituric acid – at the expense of Hydrogene atoms of

methylene groups –СН2–. HN

HN

O

O

O

H

H HN

HN

OH

O

O

H

кето-форма енольная форма

HN

HN

O

O

O

H

H

HN

HN

O

OH

O

H

кето-формаенольная форма

Besides, at the expense of Hydrogene atoms of imide groups-NH - it is possible imido-imidolnic tautomerism:

HN

HN

O

O

O

R1

R2 HN

N

O

OH

O

R1

R2 N

HN

O

O

OH

R1

R2 HN

N

HO

O

O

R1

R2

For barbiturates, which Hydrogene atoms of methylene groups are substituted on radicals, is possible only imido-imidolnic tautomerism (lactam-lactim

tautomerism).

HN

HN

O

O

O

HN

N

O

OH

O

N

HN

O

O

OH

HN

N

HO

O

O

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:

HN

N

O

O

O

R1

R2 N

N

O

ONa

ONa

R1

R2

H+ NaOH

-H2O

HN

N

O

O

O

R1

R2

Na+ NaOH_

pH ~10

_

pH~13

Barbituric acid and its salts do not have medical properties and

consequently are not drugs.

General formula of barbituratesGeneral formula of barbiturates (imide form):(imide form):   

N

N

O

O

O

R1

R2

H

R1

2

34

5

6

N

N

NaO

O

O

R1

R2

R

(NaS)1

2

34

5

6

General formula of Na-salts (imidol-form):

Synthesis of barbituratesSynthesis of barbiturates Derivatives of barbituric acid are synthezed by Derivatives of barbituric acid are synthezed by condensation of urea condensation of urea

and corresponding esters of malonic acid.and corresponding esters of malonic acid. Therefore synthesis Therefore synthesis consists of consists of two stagestwo stages..

1. Synthesis corresponding esters of malonic acid:1. Synthesis corresponding esters of malonic acid:

R1

C

C

R2 C

O

O

OC2H5

OC2H5

2. Condensation of ester and urea in the presence of Na-alcoholate in the solution of absolute alcohol.

N

HN

NaO

O

O

C2H5

C2H5

H

C

C

H C

O

O

OC2H5

OC2H5

2C2H5Br

C2H5ONa

C2H5

C

C

C2H5 C

O

O

OC2H5

OC2H5

C OH2N

H2N

C2H5ONa-C2H5OH

HN

HN

O

O

O

C2H5

C2H5

HCl

-2HBr

For example, synthesis of barbital:

Chemical structure and properties of derivatives of barbituric acid

N

HN

O

O

O

C2H5

C2H5

H1

2

4

5

6

3Barbital

General Notices (Ph Eur monograph 0170) Barbitalum

C8H12N2O3  184.2  57-44-3 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.

HN

HN

O

O

O

C2H5

C6H51

2

4

5

6

3PhenobarbitalGeneral 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.

N

HN

O

O

O

C2H5

C6H5

CO

C6H5

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.

N

HN

NaO

O

O

C2H5

C2H5

Barbital sodium Barbitalum-Natricum

sodium 5,5-diethyl-barbiturate

CHARACTERS A white, crystalline powder without smell, bitter taste. Water solution has alkaline reaction;

freely soluble in water, slightly soluble in alcohol, practically insoluble in ether.

N

N

NaO

O

O

CH3

H3C1

2

4

5

6

3Hexenal HexenalumHexobarbitalum

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.

H2C

H2C CH

CH3

CH3N

HN

NaO

O

O

C2H5

C5H111

2

4

5

6

3

Barbamyl Barbamylum

sodium 5-ethyl-5-isoamyl-1Н,3Н,5Н-pyrimidine-2,4,6-trion

CHARACTERS A white fine-crystalline powder without smell, hygroscopic;

freely soluble in water, practically insoluble in ether.

HC

H2C

H2C CH3

CH3

2 3 4 5

1

N

HN

NaS

O

O

C2H5

C5H11

Thiopental sodium(Thiopental Sodium and Sodium Carbonate,

Ph Eur monograph 0212) Thiopentalum-Natriсum(mix with anhydrous Na2CO3)

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.

IdentificationIdentification 1. Formation of the painted complexes 1. Formation of the painted complexes (various colours for (various colours for

different barbiturates)different barbiturates) with salts of heavy metals (Co (NO3) with salts of heavy metals (Co (NO3) 2 in the presence of CaCl2, CuSO4 in the presence of 2 in the presence of CaCl2, CuSO4 in the presence of КНСОКНСО3 and 3 and КК22СОСО3, CuSO4 3, CuSO4 in neutral medium (that not are in neutral medium (that not are formed precipitates formed precipitates MeMe((OHOH))nn))..

This is group reaction.This is group reaction.

N

N

O

O

O

R1

R2

Cu

NH

N

HN

N C2H5

C6H5

O

O

OO

C2H5

C6H5

O

O

Cu

2. Fusion with alkalis2. Fusion with alkalis

Molecules of barbiturates are break up to ammonia Molecules of barbiturates are break up to ammonia NHNH33 andand

sodium carbonatesodium carbonate NaNa22COCO33..  

Then product of reaction dilute in water and add dilute hydrochloric Then product of reaction dilute in water and add dilute hydrochloric acidacid HClHCl, , gasgas COCO2 2 is allocated and is present characteristic smell of is allocated and is present characteristic smell of

conforming conforming disubstituted aciddisubstituted acid ( (for examplefor example, , diethylacetic acid – diethylacetic acid – smell of rancid buttersmell of rancid butter, 2-, 2-phenylpentanoic acidphenylpentanoic acid – – smell of acaciasmell of acacia))  

3. Reactions of condensation with 3. Reactions of condensation with aldehydes and the concentrated sulphatic aldehydes and the concentrated sulphatic acid acid

At heating with At heating with formaldehydeformaldehyde НСНОНСНО and and concentrated sulphatic acidconcentrated sulphatic acid H2SO4 H2SO4 (the Mark (the Mark reactant) reactant) the products painted in various the products painted in various colour are formed: colour are formed: phenobarbital phenobarbital and and benzonalbenzonal – – pink colouringpink colouring (for phenylacetic (for phenylacetic acid); acid); hexenalhexenal – – dark reddark red colouring with colouring with green green fluorescencefluorescence..

From steam-dimethylaminobenzaldehyde From steam-dimethylaminobenzaldehyde and concentrated H2SO4:and concentrated H2SO4:

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. .

HN

HN

NaO

O

O

R1

R2 HN

HN

O

O

O

R1

R2

+ HCl + NaCl

HC C

OCH3

O

O

HC C

OCH3

O

ONa_ + Na+

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.

HN

HN

O

O

O

C2H5

HN

HN

O

O

O

C2H5

NO2

NaNO3

-H2OH2SO4(conc)

H

2. Reaction for benzoate-ion after alkaline 2. Reaction for benzoate-ion after alkaline hydrolysis of preparation hydrolysis of preparation (benzonal)(benzonal)

SPU. To 1 ml of test solution add 0,5 ml SPU. To 1 ml of test solution add 0,5 ml solution of solution of iron(iron(ІІІІІІ) chloride R1) chloride R1; ; the the pale yellow precipitatepale yellow precipitate, soluble in , soluble in etherether R R is formed: is formed:

3. Reaction for double bound3. Reaction for double bound (hexenal)(hexenal) – – decolouration decolouration solution of potassium permanganate solution of potassium permanganate KMnO4 or KMnO4 or bromic waterbromic water

Br2.Br2.

N

N

NaO

O

O

CH3

H3C

N

N

NaO

O

O

CH3

Br

Br

H3C

+ Br2

Fe Fe(OH)3 7H2OCO

OC

O

ONa6 + 2FeCl3 + 10 H2O

3

+ 3C6H5COOH + 6NaCl

. .

4. Reactions for revealing of Sulphur4. Reactions for revealing of Sulphur (thiopental sodium)(thiopental sodium) a) At heating of test substance in the presence of a) At heating of test substance in the presence of

sodium hydroxide sodium hydroxide NaOH and NaOH and lead acetatelead acetate (CH3COO) 2Pb a (CH3COO) 2Pb a

black precipitateblack precipitate is formed ( is formed (lead sulphidelead sulphide PbS). PbS).

black precipitateblack precipitate

b) Atb) At mineralization of preparation mineralization of preparation with mix for sintering with mix for sintering (mix (mix Na2CO3 and NaNO3) Sulphur passes in anions SO42 - which Na2CO3 and NaNO3) Sulphur passes in anions SO42 - which reveals by means of solution BaCl2:reveals by means of solution BaCl2:

SOSO442–2– + + BaBa2+2+ → → BaSOBaSO44↓↓

white precipitatewhite precipitate

HN

N

NaS

O

O

C2H5

CH

CH3

H2C

H2C CH3

6NaOHHC

C2H5

COONa

HC

CH3

H2C

H2C CH3 + Na2S + NH3 + 2Na2CO3

Na2S + Pb(CH3COO)2 PbS + 2CH3COONa

 

5. Reaction with silver nitrate AgNO3 in the 5. Reaction with silver nitrate AgNO3 in the medium of soda Na2CO3medium of soda Na2CO3

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

N

N

O

OH

OH

R1

R2 N

N

O

ONa

OH

R1

R2

Na2CO3 AgNO3

-NaNO3

N

N

O

OAg

OH

R1

R2

N

N

O

OAg

OH

R1

R2

Na2CO3

N

N

O

OAg

ONa

R1

R2

AgNO3

N

N

O

OAg

OAg

R1

R2

TestsTests

Specific impurities – products of Specific impurities – products of semisynthesissemisynthesis

1. Barbital – ethylbarbituric acid1. Barbital – ethylbarbituric acid

2. Phenobarbital – phenylbarbituric 2. Phenobarbital – phenylbarbituric acidacid

3. Barbamyl, thyopental sodium, 3. Barbamyl, thyopental sodium, hexenal – methanolhexenal – methanol

Assay of barbituratesAssay of barbiturates For quantitative definition of barbituratesFor quantitative definition of barbiturates

various methods are used:various methods are used: 1. Titrimetric:1. Titrimetric: a) acid- base titration in water, a) acid- base titration in water,

aqueous-alcoholic and non-aqueous aqueous-alcoholic and non-aqueous mediums;mediums;

b) argentometry;b) argentometry; c) bromatometry;c) bromatometry; d) iodo-chlorometry (for d) iodo-chlorometry (for

barbiturates with nonsaturated bonds, for barbiturates with nonsaturated bonds, for example, hexenal).example, hexenal).

2. Gravimetry.2. Gravimetry. 3. Photocolorimetry.3. Photocolorimetry.

1. Alkalimetry, non-aqueous titrationThis 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 C6H6 to blue colour.

This method is based on ability of barbiturates to tautomeric transformations and formation imidolic or the acid-form, which have acid character:

N

HN

O

O

O

R1

R2

R

H C

O

NCH3

CH3

N

N

O

O

O

R1

R2

R

H C

O

NCH3

CH3H

+ +

_

+

а) Titrant – solution of sodium methylate CH3ONa: Em = М. m.

H C

O

NCH3

CH3H

N

N

O

O

O

R1

R2

R

CH3OHH C

O

NCH3

CH3

N

N

NaO

O

O

R1

R2

R

_

+ CH3ONa + CH3O_

+ CH3O_+

+

b) Titrant – solution of sodium hydroxide NaOH: Em = М. m.

H C

O

NCH3

CH3H

+ NaOH

N

N

O

O

O

R1

R2

R

H C

O

NCH3

CH3

N

N

NaO

O

O

R1

R2

R

+

_+ Na+

+ H2O + Na+

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.

EEm = М. m = М. mm..

N

HN

O

O

O

R1

R2

R

N

N

HO

O

O

R1

R2

R

C2H5OH

N

N

NaO

O

O

R1

R2

R

+ NaOH + H2O

3. Alkalimetry in the aqueous-alcoholic 3. Alkalimetry in the aqueous-alcoholic mediummedium

This methodThis method can be used can be used for for quantitative definition quantitative definition of of all barbitrate, which have all barbitrate, which have acidacid character. character.

Titrant - Titrant - solution sodium hydroxide solution sodium hydroxide NaOH.NaOH. Indicator –Indicator – thymolphthaleine thymolphthaleine. . Shot of preparation dissolve in Shot of preparation dissolve in neutralised on neutralised on

thymolphthaleine alcoholthymolphthaleine alcohol СС22НН55ОНОН ( (for solubility improvement of for solubility improvement of barbiturates and preventions of hydrolysis formed sodium saltbarbiturates and preventions of hydrolysis formed sodium salt).).

EEm = М. m = М. mm..

N

HN

O

O

O

R1

R2

R

N

N

HO

O

O

R1

R2

R

C2H5OH

N

N

NaO

O

O

R1

R2

R

+ NaOH + H2O

4. Acidimetry in the water medium4. Acidimetry in the water mediumThis method can be used for quantitative definition This method can be used for quantitative definition of sodium salts of of sodium salts of

barbituratesbarbiturates, which have , which have basic basic charactercharacter ( (barbital-sodiumbarbital-sodium, , barbamylbarbamyl, , hexenalhexenal).).

Titrant - Titrant - hydrochloric acid hydrochloric acid HCl.HCl.Indicator –Indicator – methyl orange or methyl red. methyl orange or methyl red.

Na-salts of barbiturates Na-salts of barbiturates are hydrolyzedare hydrolyzed in water solutions in water solutions with formationwith formation alkaline medium alkaline medium ((рНрН 77 77) and therefore their can titrate ) and therefore their can titrate with acids, for example, with with acids, for example, with hydrochloric acid hydrochloric acid HCl in the presence of HCl in the presence of methyl orangemethyl orange or or methyl redmethyl red as indicator (to as indicator (to pinkpink colour). colour).

Em = М. м.

N

N

NaO

O

O

R1

R2

R

N

HN

O

O

O

R1

R2

R

+ HCl + NaCl

The free alkaly (NaOH), which is formed at hydrolysis of sodium salts of barbiturates, titrate with acid too:

N

N

NaO

O

O

R1

R2

R

N

N

HO

O

O

R1

R2

R

+ HOH + NaOH

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).

KNaOHmoisturem

TKpVХ

shot

HCl

%

)%.100(

100100

5. Argentometry1. 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).

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.

Na2CO3 AgNO3

N

N

O

OAg

OH

R1

R2N

N

O

ONa

OH

R1

R2N

N

O

OH

OH

R1

R2

-NaNO3

Na2CO3 AgNO3

N

N

O

OAg

OH

R1

R2 N

N

O

OAg

ONa

R1

R2 N

N

O

OAg

OAg

R1

R2

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

N

N

NaO

O

O

CH3

H3C

N

N

NaO

O

O

CH3

Br

Br

H3C

+ Br2

Br2 + 2KI = I2 + 2KBr I2 + 2Na2S2O3 = 2NaI + Na2S4O6

Carry out the control test. Еm(hexenal) = М. m./2

7. Iodo-chlorometry, back titrationThis 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):

N

N

NaO

O

O

CH3

H3C

N

N

NaO

O

O

CH3

Cl

I

H3C

+ ICl

ICl + KI = I2 + KClI2 + Na2S2O3 = 2NaI + Na2S4O6

Carry out the control test.

Еm(hexenal) = М. m./2

8. GravimetryGravimetric method usually is used for quantitative definitions of

Na-salts of 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 70C to constant mass

and weigh.

HN

HN

NaO

O

O

R1

R2 HN

HN

O

O

O

R1

R2

+ HCl + NaCl

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).

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.

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.

O

O

HN

HN

C2H5

C6H61

2

3

5

4

6

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

Primidone is synthezed from phenylethylmalonic ester:

C

C2H5

C2H5

CO OC2H5

CO OC2H5

KOHC

C2H5

C2H5

COOH

COOH

PCl5C

C2H5

C2H5

COCl

COCl

2NH4OH

O

O

HN

HN

C2H5

C6H6

-HCl-C2H5OK

C

C2H5

C2H5

CONH2

CONH2

HCO

NH2

1

2

3

5

4

6

-2HCl

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.

IDENTIFICATIONA. (BrPh). Measure of ratio of the absorbance.B. (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 CO2 is allocated too:

Na2CO3 + H2SO4 = Na2SO4 + H2O + CO2

The formaldehyde can be identified by reaction C.

HNO

O

C2H5+NaOH

HNC6H6

2NH3 HC

O

H

CHCOONaC2H5

C2H51

2

3

5

4

6

t0C+ Na2CO3 + +

CHCOONaC2H5

C2H5

+H2SO4 CHCOOHC2H5

C2H5

+NaHSO4

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. OH

OH

SO3Na

SO3Na

CHO

H

H2SO4CH2

OH

OH

SO3H

SO3H

OH

OH

HO3S

HO3S

CH

OH

OH

SO3H

SO3H

OH

O

HO3S

HO3S

2 +[O]

H2O 

TESTS

IMPURITIES Specified impurities A, 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

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, CuSO4 and concentrated H2SO4. Nitrogen is passed to ammonium hydrosulphate NH4HSO4, which react with 30 % solution of NaOH and ammonia gas NH3 is formed :

NH4HSO4 + 2NaOH NH3 + Na2SO4 + 2H2OObtaned ammonia distil off to flask with HCl:

NH3 + HCl NH4ClAmmonia chloride titrate with 0,1 М solution of NaOH:

NH4Cl + NaOH NH4OH + NaClEm = М. m./2

Storage List of strong preparations.

In the dense corked container. Action and use

Anticonvulsant.

Preparations Primidone Oral Suspension Primidone Tablets Ph Eur

Thanks for attention!