02 alkaloids tropane_ ecgoninr_ isoquinoline derivatives

7/31/2019 02 Alkaloids Tropane_ Ecgoninr_ Isoquinoline Derivatives

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Lecture 2

Alkaloids of tropane,derivatives,

ecgonine, isoquinoline. Social

importance of the research to theanalgesics such as morphine.

As. Kozachok S.S.


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ropanebicyclic condensed system,

which contains the piperidine andpirrolidine cycles.

NH NH

N CH3

1 2

3

456

7

Pyrrolidine Piperidine Tropane


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ropane is a base of the alkaloids row and

their structural analogs. According to the

chemical structure these compounds aredivided into two groups: derivatives of

tropane alcohol (1) and derivatives of

tropane-2- carboxylicecgonine (2):

N CH3 OH N CH3

COOH

OH

1 2


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Tropanes alkaloids are in the plants of

Solanaceae family (belladonna, datura,

hioscyamus niger).


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The maine representatives of topanes alkaloids are racemicatropine, its left rotation isomer hyoscyamine and the analogue of

hyoscyamine - scopolamine.

Atropine was first isolated from belladonna in 1833. In the plantsit is contained in very small quantities with hyoscyamine and

scopolamine together.

Obtaining the atropine and hyoscyamine from plant materials in

the form of bases (after treatment with ammonia), organic solvents

(dichloromethane, benzene). Atropine is formed from hyoscyamine by

racemization at 114-116 C, at a higher temperature is formed

apoatropin having no pharmacological activity ofatropine. After

hyoscyamine separation from solution, scopolamine is released.


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Synthetically extracted from amber aldehyde,

methylamine, acetone and d, l-tropic acid.


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Atropine sulphate (Atropini sulfas) (SPhU)

bis(1R,R,5S)-3-[(RS)-(3-hydroxy-2-phenylpropanoate)oxy]-8-methyl-8-azabicyclo[3.2.1] octane sulfatemonohydrate

Bis[(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (2RS)-3-hydroxy-2-phenylpropanoate] sulphate monohydrate.

Tropine ester d,l-tropic acid sulfate monohydrate

N CH3 O C CH

CH2OH

C6H5

O

* H2SO4 * H2O

2


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Scopolamine hydrobromide

(Scopolamini hydrobromidum)

Scopolamine ester (-)-tropic acid hydrobromide, trihydrateIUPAC

()-(S)-3-hydroxy-2-phenylpropionicacid(1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester

N CH3 O C CH

CH2OH

C6H5

O

O * HBr * 3 H2O


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Physical properties

Atropine sulphate

White or almost white,

crystalline powder or

colourless crystals. Very

soluble in water, freely

soluble in ethanol (96 per

cent).Melting at 190 and

decomposing.

Scopolaminehydrobromide


crystalline powder orcolourless crystals.

Freely soluble in water

soluble in ethanol, veryslightly soluble in

chloroform.

t t


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ent cat onAtropine sulphate

1. According to the physical-chemical constants: infrared

spectroscopy and optical rotation(-0,5-+0,05).

2. Melting point of atropine picrate.

3. Vitali's-Morena reaction ( ontropic acid).

4. It gives the reactions of sulphates.5. It gives the reaction of alkaloids

Non pharmacopoeia reaction:

) Melting point of atropine base(115-117 ) after settled down

by ammonia solutiobn;b) formation of benzaldehyde (small

of bitter almond) at the heatingatropine with sulfuricconcentrated acid and crystallinepotassium dichromate:

Scopolamine hydrobromide

1. It gives the reactions ofbromides (three reaction

according to SPhU).2. Vitali's-Morena reaction ( on

tropic acid).

3. Melting point (192-196 ) andoptical rotation : -22 till -26

(5 %-water solution).4. It gives the reaction of alkaloids


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Formation ofbenzaldehyde


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Vitali's-Morena reaction

To about 1 mg add 0.2 ml offuming nitric acid R and evaporate to

dryness in a waterbath, formation a polynitrocompound of a

yellow colour. Dissolve the residue in 2 ml ofacetone R and add

0.1 ml of a 30 g/l solution ofpotassium hydroxide R in methanol

R. A violet colour develops.


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Purity testAtropine sulphate

1. Apoatropine(


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Quantitative determination

Atropine sulphate

1) Acid-base titration in

nonaqueous medium, a

direct titration with

potentiometric fixing of the

equivalent point. (=.).2) Alkalimetry in ethanol-

chloroform medium

(=./2).

3) Photocolorimetry by thereaction with picric acid.

Scopolamine

hydrobromide1) Acidimetry in

nonaqueous medium, a

direct titration at the

present of mercury (II)

acetate, the indicator -

crystal violet (=.).

2) Argentometry by the

Faience method in theacetate medium, the

indicator - bromophenol

blue (=.).


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N CH3 O C CH

CH2OH

C6H5

O

CH3COOH

N+ CH3 O C CH

CH2OH

C6H5

O

H N+ CH3 O C CH

CH2OH

C6H5

O

HClO4

- HSO4-

* H2SO4

2

+ HClO4

+

N CH3 O C CH

CH2OH

C6H5

O

OCH3COOH

N+ CH3 O C CH

CH2OH

C6H5

O

HO

* HBr + Hg(CH3COO)2 + 2 HClO4

+ HgBr2 + 2 CH3COOH2

2

ClO4-


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Storager, applcationAtropine sulphate

Protected from light.

Anticholinergic (spasmolytic,under the influence of atropine is astrong dilation of the pupils -midriatic effect ) medicine. Used tostudy the eye fundus, at thespasms of smooth muscles,antidote to acetylcholine.

Intravenous injection , inner muscularinjectio, eye drops. Producing -powder, ampoule 0,1% - 1,0.Poisoning substance. H.d..-0,001 g,H.d.d.- 0,003 g.

Preparations:

Atropine Eye DropsAtropine Eye Ointment

Atropine Injection

Atropine Tablets

Morphine and Atropine Injection

Scopolaminehydrobromide

Protected from light.Anticholinergic . Midriatic effect isnot continue. Exhibits a calmingeffect on the CNS. Treatment ofparkinsonism .

hypodermic injection, eye drop.Producing - powder, ampoule 0,05%- 1,0. Poisoning substance. H.d.-0,0005 g, h.d.d.- 0,0015 g.

Scopolamine butylbromide(Spazmobryu, Buscopan,Buskotsin-M)

S th ti l s f t i


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Synthetic analogues of atropineAtropine and scopolamine - valuable medicinal compounds, but

they often give side effects. In the search for new biologically

active compounds of the tropanes rows there were synthesized

esters of tropine with almond and diphenylacetate acids -

homatropine and tropacynHomatropine hydrobromide

(Homatropinihydrobromidum)

Tropine ester of almond acidhydrobromide

(N,N-dimethyl-8-azoniabicyclo[3.2.1]oct-

3-yl) 2-hydroxy-2-phenylacetatebromide

Tropacyn, Diphenyltropanehydrochloride (Tropacinum)

Tropine ester of diphenylacetate acidshydrochloride

N CH3 O C CH

OH

C6H5

O

* HBr

N CH3 O C CH

C6H5

C6H5

O

* HCl


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Tropaphenine(Tropaphenum). Expressed-adrenaline receptors

agonist, weakanticholinergic.

Producing:lyophilized powder

for injection.

Troventoline(Troventolum).Bronchodilatory drug.Aerosol.

Atrovent((Ipratropiumbromide). Bronchodilatory drug.

Aerosol.


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Obtaiing of synthetic

analogs of atropine

According to the interaction between

tropine and according acid or its

chlorhydride:

N CH3 OH

C CH

Cl

O

R2

R1

N CH3 O C

O

CH R2

R1


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Physical properties

Homatropinehydrobromide

White or almost white,crystalline powder. Freelysoluble in water, slightly

soluble in alcohol, veryslightly soluble in

chloroform, practically

insoluble in ether.

Tropacyn

White or almost creamy

white crystallinepowder. Freely soluble

in water, alcohol and

chloroform, practically

insoluble in ether andbenzole.

ent cat on


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ent cat onHomatropine hydrobromide

1. It gives the reactions of bromides(three reaction according to SPhU).

2. It gives the reaction of alkaloids

3. With iodine solution settled downthe brown sediment of substanceperiodide.

4. With solution whitesediment, its dissolved in theexcess of the reagent.

5. Homatropine base at the heatingwith mercury (II) chloride alcoholgives yellow colour which transfersinto red-orange (unlike from themost of alkaloids, except atropineand hyoscyamine).

6. Hydroxamic reaction .

7. Doesnt give Vitali's-Morenareaction.

Tropacyn

1. Give Vitali's-Morena reaction(on diphenylacetate acid).

2. Melting point.

3. It gives the reaction ofalkaloids

4. It gives the reactions ofchlorides (two reactionaccording to SPhU).

5. Hydroxamic reaction.

Vi li' M i


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Vitali's-Morena reaction on tropacyn:


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Homatropine

hydrobromide

1) Acidimetry in nonaqueous

medium, a direct titration at

the present of mercury (II)acetate, the indicator -crystal

violet (=.).

2) Alkalimetry in water-alcohol

medium at the present inchloroform (=.).

Tropacyn

1) Acidimetry in nonaqueous


the present of mercury (II)

acetate, the indicator -crystal violet (=.).

2) Tropacyn in tablets is

determined argentometric

by Folgard method(=.).

St li ti


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Storage, application

Homatropine

hydrobromideProtected from light.

Anticholinergic (midriatic)

medicine. Using eye drops 0,25-

0,5-1% solutions. Doesnt use atthe treatment of glaucoma.

Producing - powder, ampoules

0,1% - 1,0. Poisoning

substance. H.d.-0,001g, H.d.d.-

0,003 g.

Tropacyn


Anticholinergic. Midriatic effectis not continue,

actively influence on the central

holynoreactive system.

Treatment of Parkinson'sdisease, spasms of smooth

muscles of the abdominal

cavity, stomach ulcers.

Intravenous. Producing - powder,tablets 1, 3, 5, 10, 15 mg.

Poisoning substance. H.d.-0,03

H.d.d.- 0,1 g.


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Tropanes alkaloids ecgonine

types

Cocaine hydrochloride (Cocainihydrochloridum)

Hydrochloride of methyl ester benzoylecgonine

Cocaine is methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[ 3.2.1]octane-2-carboxylatehydrochloride

N CH3 O C C6H5

O

COOCH3

* HCl

(E th l C )


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(Erythroxylon Coca) May be obtained from the

leaves ofErythroxylumcocaLam. and other

species ofErythroxylumorby synthesis.

Physical properties


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Physical properties

Colourless crystals or a white,crystalline powder. Slightly volatile.

Very soluble in water; freely soluble in ethanol(96%), soluble in chloroform and glycerinein,practically insoluble in ether.

Identification1. It gives the reactions of chlorides.

2. Melting point (not lell 195 ); optical rotation

- from -71 till -73 (2,5 %-water solution);specific absorption rate .

3. Hydroxamic reaction (on the ester group).



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5. With potassium permanganate solution forming the violet

crystalline sediment- cocaine permanganate (differencefrom novocain):

6. If, in an aqueous solution of cocaine to add drop by drops a5% solution of chromic acid H2CrO4, then from each dropnot stable turbidity appears. With further addition of HCl

conc. formed an amorphous orange-yellow precipitate.


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7. At the heating of cocaine hydrochloride with sulfuric

concentrated acid appearance the acidic hydrolysis its

products are methyl alcohol, benzoic acid. These products

interact with each other to form methyl benzoate, which

has a characteristic odor:

At long staing from the reaction mixture crystals of benzoic

acid settle down

Purity test


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Purity test

l Unacceptable impurity cinnamoylcocaine and other reducingsubstanceswith n4 solution it doesnt colourlessed during 30minutes.

Impurity oftruxilline and other coca alkaloids are determinedby the addition of ammonia solution: if the impurities are notpresent the cocaine base settles down, if they are presentany sediment formation.

Quantitative determination Acidimetry in nonaqueous medium, a direct titration at the

present of mercury (II) acetate, the indicator -crystal violet(=.).

Alkalimetry in ethanol-chloroform medium(=.).

Iodometry, back titration after precipitation of polyiodidecocaine C17H21NO4HJJ2(=../2).

Storage



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Action and use


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Action and use

Local anaesthetic.

Used as a surface anesthetic for anesthesia of the cornea (1-3%

solution) and the mucous membranes of the nose, throat,

urinary tract (2-5% solution). Has a marked effect on the

CNS, can cause euphoria, excitement, and then CNS

depression (addictive - cocainism). Because the drug istoxic and quite deficient, synthesized series of its

substitutes (benzocaine, procaine, trimekain, lidocaine),

with account relationship between structure and action

local anaesthetic drugs.Producingpowder, ampoules 2%-1,0. Poisoning substance.

H.d.- 0,03 g, h.d.d.- 0,03 g.

Alk l id i i li d i ti


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Alkaloidisoqinoline derivatives

From the many alkaloids, isoquinoline derivatives in medicine is

mainly used as two groups of drugs: derivatives of 1-benzylisoquinoline and morphinan (phenantrenisoquinoline).

The source of the 1-benzylisoquinoline and morphinan of the alkaloids


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The source of the 1-benzylisoquinoline and morphinan of the alkaloids

derivatives are opium - the milky juice of the immature fruits

soporific poppy (Papaver somniferum). The composition of opium

(20-25%) is more than 20 alkaloids (morphine, narcotine,

papaverine, codeine, thebaine, etc.). Alkaloids found in opium in theform of salts of meconate ( -oxy- -pyrone- -dicarboxylic), lactic

and sulfuric acids. Narcotine and papaverine as a very weak basis

are in a free state.

The separation scheme of main opium alkaloids by the method of


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The separation scheme of main opium alkaloids by the method of

Kanevska-Klyachkina

Opium

4-th tymes extraction by water at 50-55 0C

The remainders from the extractioncontains ballast substances, a little papaverine,

and 2/3 half of all narcotine. Alkaloids are

extracted by the dichloroethane

Sediment

contains morphine, narcotine, meconateammonium which are not soluble in alcohol

Dichloroethane extract

Contains papaverine which is like a very weak

base doesnt form with acetatic acid at the

present of sodium acetate, salt. Remove thesolvent from the extract

Papaverine

is purified according to the formation of a

hard soluble salt

Water extract

(concentrated in vacuum at

60-70 0C add ammine and ethanol

Filtrate

acidified by an acetic acid at thepresent of sodium acetate and

extracted by dichloroethane

Water solution

contains codeine, thebaine and

other alkaloids which are formed

with acetic acid water solubility

acetates at the present of sodium

acetate

The precipitate obtained by the mixing of an aqueous extract of opium


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The precipitate obtained by the mixing of an aqueous extract of opium

with an alcoholic solution of ammonia, processed according to the

scheme:

The precipitate is heated with the diluted alcohol at 70 0C and filtrated

The filtrate

contains meconate ammonium

The precipitate

is extracted by an acetic acid.

Narcotine as a very weak base

doesnt form the salt. And it is insediment.Narcotine

sediment

is purified by a

crystalisation from

an alcohol or

acetone

Filtrate

contains morphine

acetate to add

ammine and to

filtrateMorphine

is purified by a

crystalisation from a

diluted hydrochloric

asid solution

meconate acid

Alk l id f 1 b li i li d i i


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Alkaloids of 1-benzylisoquinoline derivativesPapaverine hydrochloride

(Papaverini hydrochloridum)

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxyisoquinolinehydrochloride

Drotaverinehydrochloride

(Drotaverini hydrochloridum)

N-Shpa (Nospanum)

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro- isoquinoline

hydrochloride

N

H3CO

H3CO

CH2H3CO

H3CO

* HCl

1

2

3

45

6

7

8

11

21

31

41

51

61

NH

C2H5O

C2H5O

CHC2H5O

C2H5O

* HCl

1

2

3

45

6

7

8

11

21

31

41

51

61

Physical properties


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Physical properties

Papaverine hydrochloride (SPhU)

White or almost white crystalline powder or white

or almost white crystals. Sparingly soluble in water,slightly soluble in alcohol. It can fuse with KOH (forming

dimethoxyisoquinoline and dimethoxytoluol) and oxidized

by MnO4 (oxidation products are pyridine- threecarbonic

acid and 3,4-dimethoxybenzoate (veratic) acid).

It has reducing property according to the two

aromatic fragments bounding by methylene group, as well

as a four methoxide groups.Drotaverinehydrochloride

Yellow crystalline powder. Soluble in water and ethanol, not

soluble in an ether.

Identification of Papaverine hydrochloride


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Identification of Papaverine hydrochloride

1. Determination of specific absorption by UV spectroscopy.

2. Melting point of a papaverine base after it is settled down byammonia. To 10 ml of solution S (see Tests) add 5 ml ofammonia R dropwise and allow to stand for 10 min. Theprecipitate, washed and dried, melts (at 146 C to 149 C.

3. Karolinovs test : after the heating of the substance with aceticanhydride and sulphuric acid solution is pained in an yellow

colour with a green fluorescence.4. It gives reaction of chlorides.

5. Nonpharmacopoeia reactions:

) with a concentrated sulphuric acid the substance at the heating is

coloured in violet;

b) at mixing ethanols solutions of papaverine and iodine a dark-red crystals of the hydroiodide diiodopapaverineC29H19O4NJ2HJ settle down;


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c) It gives the reaction of alkaloids ;


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c) It gives the reaction of alkaloids ;

d) With nitric acid forming an yellow colour thattransfers into orange at the heating;

e) With bromine water papaverine forms an yellow

sediment brompapaverine hydrobromide

N

H3CO

H3CO

CH2

H3CO OCH3

HNO3

N

H3CO

H3CO

CH2

H3CO OCH3

NO2

O2N

N

H3CO

H3CO

CH2

H3CO OCH3

NO2

HNO3

t0C

f) With Marki reagent at the first step forming a red colour


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f) With Marki reagent at the first step forming a red colour

than yellow and bright-orange. Formed

methylendipapaverine with bromine water and ammine

gives a violet sediment, which is dissolved in analcohol and gives violet-red colour.

CH2

N

+ N+CH2

CH2

H H

H3CO

H3CO OCH3

OCH3

OCH3H3COOCH3OCH3

SO42-

Drotaverine hydrochloride


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DrotaverinehydrochlorideDrotaverines molecule is considered as the

condensation product of 6,7-dimethoxy-1,2,3,4-tetrahydro- isoquinoline and 3,4-Dimethoxybenzaldehide. The drug has acharacteristic absorption spectrum in the UV region

Drotaverine has more basic properties thanpapaverine, therefore, for the extraction of the basicsfrom the medicine solution you need to add alkalinesolution.

As well as papaverine, drotaverine has areducing properties. When added to a sample of thedrug a conc. H2SO4 and added followed by drop a

diluted HNO3 appearance a dark brown colour.

Quantitative determination of papaverine


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Quantitative determination of papaverine

hydrochloride Alkalimetry in a mixture medium of an alcohol and

0,01 chloric acid with potentiometric fixing of theequivalent point. (=.).

Acidimetry in nonaqueous medium, a direct titration at thepresent of mercury (II) acetate, the indicator - crystal

violet (=.).

Alkalimetry in a water-alcohol medium without

chloroform, cause papaverine is a very weak base(=.).

Argentometric by Folgard method.

Spectrophotometry (in dosage forms) (=.).

Quantitative determination of a drotaverine hydrochloride

by the same methods as a papaverine hydrochloride.

Storage application


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Storage, application Papaverine

hydrochloride

Protected from light

Phosphodiesterase inhibitor;

smooth muscle relaxant.

Using per oral 40-80 mg 3-4 timesa day, parenteral 1-2 ml of 2%

solution.

Producing - powder, tablets 40

mg, ampoules 2% - 2,0,

suppositories 0,2 g.

Strong action stuff.

Included in the tablets of Papazol,

andypal, Nicoverine.

Drotaverine

hydrochloride


smooth muscle relaxant.

Using per oral 40-80 mg 2-3 times

a day, inject i/m 2-4 ml of 2%

solution.

Producing - tablets 40 mg,

ampoules 2% - 2,0. Strong

action stuff.

Included in the tablets of Nishpan

(with nicotinic acid), Bishpan

(with isopropamide)

Alkaloid of morphinan derivatives


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Alkaloid of morphinan derivativesThe main alkaloid of opium is morphine, it is the derivatives of

morphinan:

Morphinan Morphine: 3,6-dioxy-N-methyl-

4,5-epoxymorphinen-7;

In the molecule of morphine are 5 asymmetric carbon atoms. High


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p y g

reactivity of oxygroups, yields to obtain a large number of its

semisynthetic derivatives:

Morphine hydrochloride (Morphini


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Morphine hydrochloride (Morphini

hydrochloridum)

Three hydrate hydrochloride 3,6 -dioxy-4,5 -epoxy-17methylmorphinen-7

7,8-Didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-diol

hydrochloride trihydrate.

HO

HO

N CH3

O* HCl * 3 H

2O

Physical and chemical properties of


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Physical and chemical properties of

MorphineWhite needle-shaped crystals or white crystalline

powder, slightly yellow during storage. Slowly soluble inwater, difficult soluble in alcohol, very slightly soluble inchloroform and ether.

Acid-base properties are explained by the presence of a

tertiary nitrogen atom (the center core) and phenolichydroxyl (center of acidity). The basic properties ofmorphine are less expresed than in ammonia, and acidic issomewhat stronger than in phenol .

Pronounced reducing properties are dued to the affiliation ofmorphine to a partially hydrogenated phenanthrene system,as well as the presence of phenolic hydroxyl and thesecondary alcohol group.

Identification of Morphine


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Identification of Morphine

hydrochloride

1. Optical rotation from -97 till -99 (2 % water solution).

Appearance of the 5 asymmetric carbon atoms (5, 6, 9, 13,

14) gives an optical activity for a substance.

2. It gives reaction of chlorides.

3. When to added an ammonia to a solution of a substancereleasing a white crystalline precipitate which is dissolved in

a solution of sodium hydroxide (according to the formation

ofsodiums salt due to the presence of phenolic hydroxyl).

4. It gives the reaction of alkaloids5. With Phrede reagent morphine gives a violet color, passing

into blue, at a staying - in green.

6. With Marki reagent appearance a purple coloration, rapidly

transforms into a blue-violet (unlike from codeine).


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7. Oxidation of morphine by Mandelina reagent (a solution


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p y g (

of ammonium vanadate in the conc. H2SO4) leads to the

formation of the purple product.

8. With Erdman reagent forming a red product.

9. Pellagry reaction. At the action of a concentrated H2SO4 or a


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concentrated HCl forming apomorphine, which from the addition

of a concentrated HNO3 becomes intense red color. If

apomorphine is dissolved in water, which is neutralized by

Na2CO3 and to add 1-3 drops of iodine solution, then appearance agreen color. If the green solution shake with ether, the ethereal

layer is painted in red and water remains green.

17H19O3N C17H17O2N + H2O

morphine apomorphine10. With a concentrated HNO3 formig an intramolecular chelate of

orange-red color.

11. The oxidizing by a potassium hexacyanoferrate (III)


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g y p y ( )in acidic medium with forming oxydimorphine. At the

further addition of iron (III) chloride to the prepared

solution it is formed "Prussian blue" (dark blue color):


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12. With a solution of iron (III) chloride appearance a blue coloration

(reaction to the phenolic hydroxyl), which quickly disappears

according to the oxidation of morphine by the reagent.

13. Halogenation (reaction to a phenolic hydroxyl).

14. With diazoniums salts it is formed an azo dye (due to the

presence of phenolic hydroxyl).

15. The Oxidation of the secondary alcoholic hydroxyl to a ketone with

a subsequent formation of an oximes, hydrazones, semicarbazone

16. Esterification goves either a phenolic or the secondary alcoholic

hydroxyl group.

17. Morphine, just like other phenols, easily is oxidized. Since theinteraction with HJO it releases a free iodine Alkaline solutions


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interaction with HJO3 it releases a free iodine. Alkaline solutionsof morphine are very easy oxidized and form oxydimorphine(dihydromorphine, psevdomorphine, oxyimorphine):

Quantitative determination of Morphine hydrochloride

Acidimetry in nonaqueous medium, a direct titration at thepresent of mercury (II) acetate, the indicator -crystal violet(=.).

Argentometric by Folgard method ( = ..).

Alkalimetry in ethanol-chloroform medium(=.).

Storager, application of morphine


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g , pp p


Opioid receptor agonist; analgesic.

Strong analgesic action. It has an antishock action at traumas,in bigger doses has a hypnotic effect. It is used in thepreparation and after surgery, at traumas, cancers.

Take per oral 10-20 mg in powder form, or in hypodermic

injection - 1% -1.0.Morphinomania is a passion to morphine using. Morphilong-

is a 0, 5% solution of morphine hydrochloride in 30%aqueous solution of polivinylpyrrolidone. Omnopon is a

mixture of hydrochlorides of opium alkaloids (up to 50%morphine, etc.).

Naltrexone hydrochloridel, nalorfin and Naloxone (SPhU) arethe antidotes to morphine, opiate receptor antagonists.

Codeine medicines


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Codeine medicines

Codeine (Codeinum)(SPhU)

4,5-epoxy-3-methoxy-17-methyl-7,8-Didehydro-morphinan-6-l;

7,8-Didehydro-4,5a-epoxy-3-methoxy-17-methylmorphinan-6a-ol.

Codeine phosphate (Codeiniphosphas)

Phosphate 3-methoxy-6-oxy-4,5-epoxyepoxy-17-methylmorphinan-7;

7,8-Didehydro-4,5a-epoxy-3-methoxy-17-methylmorphinan-6a-ol phosphatehemihydrate.

H3CO

HO

N CH3O

* H2O

H3CO

HO

N CH3

O * H3PO4 * 1,5 H2O

Ph i l ti


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Physical properties

Codeine



colourless crystals.Solubility

Soluble in boiling water,

freely soluble in ethanol(96 per cent). It has the

strongest basic properties

among all alkaloids (

codeine water solution 9,0).

Codeine phosphate



small, colourlesscrystals.

Solubility

Freely soluble in water,slightly soluble or very

slightly soluble in ethanol

(96 per cent).

Identification of Codeine medicines


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Identification ofCodeine medicines

1-3. Melting point, compare The IR spectra of the

pharmacopoeia sample and determine the maximal

absorption peaks by UV spectroscopy.


5.At the heated with concentrated sulfuric acid and a solution of

iron (III) chloride appearance a blue color (due to theformation of apomorphine containing phenolic hydroxide).

According to the apomorphine formation codeine gives

positive Pellagry reaction (look morphine).

6. Non pharmacopoeia reaction:

) With Marki reagent appearance blue-violet color

b) with a concentrated nitric acid appearance an orange color,


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b) with a concentrated nitric acid appearance an orange color,

which transfers to yellow.

c) With Phrede reagentviolet color;

d) With Erdman reagentred.

) The esterification of thesecondary alcoholic hydroxy.Identification ofCodeine phosphate:

) By the reaction of the detection of phosphate ion with a solutionof Silver nitrate on the formation of yellow precipitate.

PO43- + 3Ag+ Ag3 PO4

b) on phosphate ion with molybdenvanadium reagent

appearance yellow color;PO4

3- + HVO3 + 11H2MoO4 + 4NH4+

(NH4)4[PO4(MoO3)11VO3] + 11H2O + H+

c) Melting point of codeine base, precipitated by sodium

hydroxide (154-157 ).



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Quantitative determinationCodeine medicines

Codeine

Acidimetry in nonaqueous


the present of mercury (II)

acetate, the indicator -crystal violet (=.).

Codeine as a strong base is

determined by alkalimetry in

water-alcohol medium, theindicatormethyl red ( =..).

Codeine phosphate

Acidimetry in nonaqueous

medium( = ..).

Alkalimetry in chloroform-

alcohol medium, idicator -

phenolphthalein( =

../2).


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Storager, applcation of Codeine


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Storager, applcation of CodeineProtected from light.

Opioid receptor agonist; analgesic.Antitussive, mild analgesic effect. It is included in the

tablets of Kodterpine (terpinehydrate, sodiumbicarbonate), Tablets from cough, Pentalgin, sedalgin

Solpadein, Behterrov tincture (sodium bromide,tincture adonis).

Release formpowder, tablets. H.d.-0, 05 g;

H.d.d.-0, 2 g.Codeine phosphate as a less toxic (80% codeine base)

can be taken in higher doses for children. Produsing -

powder. H.d - 0, 1 g; H.d.d.-0, 3 g.

Ethylmorphine hydrochloride


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y p y

(Aethylmorphini hydrochloridum)

Dionine (Dioninum)

(5R, 6S) 4,5-epoxy-3-ethoxy-N-methylmorphine-

7-n-6-ol hydrochloride

Properties

Crystalline powder of

white or nearly white.Soluble in water and96% alcohol,practically insoluble in

ether.

C2H5O

HO

N CH3

O * HCl * 2 H2O

en ca on o Ethylmorphine


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hydrochloride

IR spectra.

Melting point of ethyl morphine base, precipitated

by sodium hydroxide.

At the heating a substance with a concentrated

H2SO4 and a solution of FeCl3 appearance a blue

color (formation of apomorphine), goes into the

red after the addition of a concentrated nitric acid

(Pellagry reaction).

It gives the reaction of chlorides.

Non pharmacopoeia reaction:


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) Iodoformic test. At the heating of a mixtuer of substance,

crystalline iodine and sodium hydroxide till boiling point,

appearance characteristic odor of iodoform:

b) 3 With a concentrated nitric acid appearance an orangecolor.

c) UV spectroscopy .



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Quantitative determination1) Acidimetry in nonaqueous medium, a direct titration

at the present of mercury (II) acetate, the indicator -

crystal violet (=.).

Alkalimetry in water-alcohol medium with addition of

chloroform ( = ..).

Storager

Protection from light

Application

Analgesic (narcotic), and antitussive medicine. For

the treatment of the eye as anti-inflammatory agent

(1-2% drops or ointment). Powder, tab. at 0.01 and

0.015 g, the H.d. - 0,03 g; H.d.d. - 0,1 g.

Synthetic analogue of morphine on the

h l i l ti O f th fi t i thi i


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pharmacological action. One of the first in this series

have been synthesized promedol, and more recently

- tramadol.

Other narcotic analgesics

P (F ) T bl l i l


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Pentasocyn (Fortran) - Tables, amp, a strong analgesic, lessrespiratory depression, rarely observed phenomenon ofaddiction and withdrawal.

Buprenorphine h/chl (SPhU) - Tables. to 0.2 mg.Butorphanol hydrotartratis (Beforal, moradol)containesin a car kits.Promedol - table, amp, syringe-tube, a strong analgesic forlabor analgesia.Fentanyl - amp, for sedation.Tramadol (Tramal) - Capps, amp, suppositories.Ketorolac (Ketanov, Ketorol, Ketolonga-Darnitsa, etc.) -

analgesic effect equated to morphine is not addictive,Table, amp.Ketoprofen (ketonal, F-gel, gel Fastum) - Tables,tabl.retard, capsules, suppositories, amp, gel, cream)

a o s o apomorp nei


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derivateves

(Apomorphinihydrochloridum)

5,6 dioxyapomorphine

N CH3

1

2

3

4

5

6

7

8

9 10

* HCl * 3/4 H2O

N CH3

HO

HO

Glaucine hydrochloride (Glaucini


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hydrochloridum) GlauventAlkaloid from the herba of Glaucii Flavi

4,5,7,8-tetramethoxyapomorphine

hydrochloride

N CH3

H3CO

OCH3

H3CO

H3CO

* HCl

Identification of apomorphine hydrochloride

1

It i th ti f hl id


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1. It gives the reaction of chlorides.

2. With HNO3 conc.blood-red color.

3. Alkali solution extract from the substance solution a freeapomorphine as a white precipitate which is dissolved in

excess of alkali (due to the formation of sodium salt due

to the presence of phenolic hydroxyl).

4. Oxidation reaction (Pellagry ): with iodine solution in the

presence of NaHCO3 and ether - the ether layer is painted

in red-violet color, and water becomes green.

5. Optical rotation from -46 till -52 (in HCl solution).6. With Marki reagentviolet color which transfers in

green.

7. Vitali's-Morena reaction.



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Quantitative determination1) Acidimetry in nonaqueous medium, a direct titration at the

present of mercury (II) acetate, the indicator - crystal violet

(=.).

Storager

Protected from light

ApplcationApomorphine hydrochloride emetic, expectorant. At

poisoning it is used of 0,2-0,5 ml solution of 1%

hypodermic injection. Expectorant action - 5.1 mg orally.

Glaucine hydrochloride antitussive medicine, unlike as

codeine does not suppress breathing, non-addictive, shows

a moderate hypotensive effect. Table. By 0,05 g.


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Thanks forattention

02 alkaloids tropane_ ecgoninr_ isoquinoline derivatives

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