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Morphine and atropine
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Morphine
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Introduction:- It is important among the opium alkaloid.
The amout being nearly 3-23% The other two closely related alkaloids are codeine and thebaine Due to the presence of phenanthrene nucleus these are also known as phenanthere alkaloids
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Source:- opium or gum opium poppy or poppy capsules
It is obtainted from dried latex of unripe capsules of papavarine species(by Vertical incisions 0.1 to 0.5 mm depth) Papavarine sominiferum P . bractatum P . oriantale P . rhoeaes Commercial varieties :- Turkis opium Indian opium Chainese opium Russian opium
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Isolation:-
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Extracted several times with benzene to remove codeine
And thebaine
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Properties and uses:- Morphine is colorless prismatic substance
2. M.Pt :254oc 3. Bitter in taste 4. Levo rotatory Insoluble in water, little soluble in benzol, ether , chloroform sufficiently soluble in alcohol and alkali solution Used as analgesic and sedative Depressant action on various parts of the nervous system but habit forming. Diacetyl derivative of mophine- heroin (more habit forming than morphine) 10. Codeine sulfate less effective anagesic and antitussive causes addiction 11.Thebaine little medicinal values and produces convulsions
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Constitution Molecular formula Nature of nitrogen Nature of oxygen
Presence of ethylenic bond Presence of benzene neucleus Presence of cyclic tertiary base system Presence of phenanthrene moiety 1)structure of methyl morphol 2)presence of N-Methyl group 3)position of 3 oxygen atoms 4)structure of morphenol 5)structure of mophine 6)point of linkage of –CH2-CH2-N-CH3 chain 7)position of double bond Synthesis
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Molecular formula:- C17H19O3N Nature of nitrogen:- nitrogen is tertiary in nature Nature of oxygen atom:- i) Presence of 2 hydroxyl groups
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ii) Nature of hydroxyl groups:-
With FeCl3 gives characteristic color treating with aq.NaOH gives soluble mono sodium salt of morphine reconverted into morphine with CO2 Note:- one of the two hydroxyl groups is phenolic in nature iii) With halogen acid gives monohalogen derivative that is one –OH group is replaced by halogen acid this reaction is characteristic of alcohol. Hence second –OH group is alcoholic in nature (secondary alcohol) iv) From the unreactivity of third oxygen and by degradation studies it is revealed that third oxygen is in ether linkage Presence of ethylenic bond:- when codeine is reduced catalytically in the presence of Pd it takes one molecule of hydrogen. Presence of benzene nucleus:- a) bromination :-gives mono bromo derivatives it reveals that morphine contain benzene ring.
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Presence of cyclic tertiary base system:-
Presence of phenanthrene ring:- with zinc dust :- gives phenanthrene moiety –contain phenanthrene moiety Presence of cyclic tertiary base system:- this is confirmed by the fat that codeine when subjected to exhaustive methylation, yield codeine , the formula of which contains one more CH2 than codeine itself and the nitrogen atom remains intact i.e., it is not lost. If codeine possess a cyclic t-amino system, then the product obtained would posses lesser number of carbon atoms and there also occurs loss of nitrogen If codeine contains a tertiary cyclic base system, the result are than readily explained by the following reactions:-
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Structure of methyl morphol:- by pschorr synthesis;-
Heating with alkali -codeimethine -codeimethine Morphol Methyl morphenol morphenol HBr Na\C2H5OH Na\C2H5OH HBr Methyl morphol Presence of CH2CH2NCH3 group:- codiemethiodide and codinenemethiodide on heating separately with a mixture of AC2O-ACONa gives 3-methoxy 4-acetoxy phenanthere and 3-methoxy- 4,6-diacetoxy phenanthrene along with dimethyl amino ethanol respectively. which reveals the presence of CH2CH2NCH3 group
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Methyl morphol further confirmed by:-
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Presence N-Methyl groups:-
. By herzig-mayer method one >N-CH3 group is present Presence of third oxygen atom and ether linkage:- The above reaction explains the placing two oxygen atoms in the form of –OH present at c-3 and C-6. And the second oxygen is ether linkage between C-4 and C-5 of phenanthrene nucleus
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Structure of morphine:-by the above information we can know that the presence of
following groups Position of double bond:-codeine on treating with PCl5 gives chlorocodide further Hydrolysis with acetic acid gives mixture of codeine, isocodeine, psuedocodeine, and allopsuedocodeine. In which psuedocodeine on oxidation gives pseudocodinone ( -C=O group at C-8 Position). By above results the double bond is present as:-
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Formation of 9-amino phenanthrene indicates the N-CH3 group of morphine is
attached to C-9. Further position of N-CH3group at 9th position is supported by Steric view.
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After several chemical reactions the tertiary nitrogen attached through ethylene
Bridge and attached to C-13.And hence the mophine structure can be given as:-
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Further confirmed by synthesis:-GATES synthesis
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SAR of morphine :- A-aromatic ring B-cyclo hexane C-cyclo hexane
D-pyridine E-tetra hydrofuran At 3,6 position,-OH groups:- Conversion of 3-OH to 3-methoxy gives codeine-decreases activity upto 15% of morphine Conversion of 6-OH to 6-methoxy gives heterocodeine- increases 6fold activity Of morphine Oxidation of 6-OH gives ketone –decreases the activity Note:-absence of 7,8 double bond in morphine --- decreases the activity 37%\ Absence of double bond and presence of ketone ----increases the activity
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Removal of 6-OH (desoxymorphine) increases 10 fold in the dihydro series
Acetylation of morphine:- heroin—2-3 times more potent than morphine If the ether linkage is opened up, to offered secondary alcohol on the aromatic ring at the 4th position—decreases activity drasticaliy Uses :- Analgesic Hypnotic and sedative Potent analgesic due to its central narcotic effect CTZ stimulation in the medulla Codeine is used as antitussive Heroin is used as more narcotic and analgesic (habit forming drug) Apomorphine has emetic action Dihydromorphine –potent narcotic drug Synthetic morphine compounds lilke opiods which are non habit forming but possess the medicinal activity of mophine
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Atropine
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Introduction:- Prominent tropane alkaloid is atropine
Source:-deadly night shade atropa belladona , a thorn plant datura stromanium, in plants available as L-hyoscyamine hyoscyamine on heating gives + hyoscyamin recemic mixture of hyoscyamin is known as atropine Physical properties:- Color:- colorless State :-crystals Odour:-odourless Taste :-bitter Solubility:-sparingly soluble in water and soluble in organic solvents Melting point:-118oc
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Isolation:- Constitution:-
Atropine is extracted either from belladona roots or from the juice of datura plant In practice the juice which also contains hyoscyamine is heated with K2CO3 solution When hyoscyamine is recimised to atropine then this atropine is extracted with chloroform. The chloroform is recovered by evoparation and the residue is then extracted with dil. H2SO4 This solution made alkaline with K2CO3 when atropine is ppted out. The ppted atropine is extracted with ether and purified by converting into an oxalate or sulphate Constitution:- Molecular formula:- C17H23NO3 Atropine structure is established by hydrolytic degradation process
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Determination of structure of tropic acid :-
Atropine on hydrolysis gave tropine so it is an ester of tropic acid hence atropine Is considered as tropine tropate Determination of structure of tropic acid :- Mol.Formula:-C9H10O3 Tropic acid with bromine gives no decolorisation of bromine indicate saturated compound (absence of double bond). 2. Formation of monosodium salt of tropic acid indicates that tropic acid consists of a single carboxylic acid. Absence of phenolic OH group is observed by FeCl3 From 1 and 2 it can be predicted that tropic acid is saturated mono carboxylic acid
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By the above oxidation process it is observed that atropic acid and in turn tropic
acid consists of benzene molecule with a substituent Hence the structure can be written as :-
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On acetylation mono acetyl derivative is obtained it indicates that presence of hydroxyl
group. The 2 possible structures that can be drawn for the molecular formula of atropic acid are Further structure of atropic acid is confirmed by oxidising tropic acid in KMnO4 Phenyl glyoxal is the same oxidation product of atopic acid
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As the tropic acid consists of primary alcohol functional group the probable structure
of tropic acid will be
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Further structure of the tropic acid is established by its synthesis
(Mekenje and Wood )
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The tropic acid formed is recemic mixture.
Determination of structure of tropine:- mol.formula:-C8H15NO Tropine reacts with bromine no decolorisation is seen hence it is a saturated comp. Tropine when reacts with methyl iodide it consumes 1 mole to give a quaternary ammonium salt It indicates that nitrogen atom in tropine is tertiary in nature Detection of presence of N-Methyl group:- herzig meyer method
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The amount of AgI formed is equal to 1 methy group indicating that the nitrogen
in tropine is substituted with methyl group Nature of oxygen atom:- Indicates presence of OH group Detection of basic nucleus:- Tropine on oxidation gives ketone it indicates presence of secondary alcohol tropinone on oxidation gives tropinic acid which on further oxidation gives N-methyl succinamide it reveals that presence of N-methyl pyrollidine ring in tropinone and hence in tropine.
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The presence of N-methyl pyrollidine ring accounts for 5 carbon atoms as against the
8 carbon atoms present in tropine. As the latter compound is a dibasic acid it means that The remaining 3 carbon atoms must be present as COOH and CH2COOH groups. The two groups attached to various and positions in that pyrollidine ring . The positions have been ascertained as follows:-
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Tropic acid on hoffmann exhaustive methylation yields a unsaturated dicarboxylic
acid which on reduction gives pimelic acid As pimelic acid has 7 carbon atoms joined in series it means that tropinic acid also contain 7 carbon atoms in similar fashion but the difference that its 8th carbon atom is present in N-CH3 this is only possible if the two groups COOH and CH2COOH are attached to and positions this reaction reveals that the tropinone similar to Tropinic acid has also 7 membered carbon ring this confirmed by the dehydration of Tropine yields tropidine which on H.E.M yields cycloheptatriene or tropilidene the reduction of latter compound yields cycloheptane
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There is another important reaction which reveals structure of tropine
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Formation of 2-ethyl pyridine reveals the presence of a reduced pyridine ring in the
tropine molecule By the above discussion conclusions are: Tropine possess a 7 membered carbon ring. It contains a reduced pyridine ring in the structure It possess reduced pyrrole (pyrollidine) ring in the structure It possess N-Methyl group As tropine contains only one nitrogen atom it means that this should also remain common to pyrollidine and piperidine( reduced pyridine ) rings and it should be as N- CH3 group
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Atropine structure:- Tropine may also written as:-
Tropine Tropic acid +
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Fischer esterification:-
Atropine structure confirmed by Synthesis:- Fischer esterification:- ATROPINE
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USES:- Anticholinergic agent. Smooth muscle relaxant – antispasmodic.
Pupil dialation. A single drop of solution containing one part of atropine in 40,000 parts of water is sufficient to dialate the pupil of the eye Atropine has also been used to relive the night sweats which are a distressing feature of tuberculosis and to deminish the activity of salivary and gastric glands
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References:- Chemistry of natural products – o.p agarwal
Chemistry of natural products by chetwal
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thanq
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