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Morphine and atropine 1 Morphine 2 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 3 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 4 Isolation:- Raw material + cold2-3 vol of methylene chloride extraction removes papavarine and narcotine and gum methylene chloride extract is evoparated residue + dil.HCl extraction treated with charcoal filter filterate neutralised with ammonia ppted out 5 narcotine and papavarine extracted with hot alcohol dissolve papavarine ppted as acid oxalate recrystallization, purification crude narcotine present in residue + hot alcohol purification residue from the CH2Cl2 + H2O + milled with 10 vol of lime water extraction below 20o c lime water containing morphine, codine ,thebaine Extracted several times with benzene to remove codeine And thebaine 6 neutralised to PH-8.0 pptation of crude morphine filterate and evoparated in vaccum and extracted with amyl alcohol crude mophine filtered through charcoal fiterate nuteralised with ammonia and some amount of alcohol morphine ppted out dissolved in dil.HCl to a saturated solution cool crystals of mophine chloride recrystallisation morphine 7 Properties and uses:1. Morphine is colorless prismatic substance 2. M.Pt :254oc 3. Bitter in taste 4. Levo rotatory 5. Insoluble in water, little soluble in benzol, ether , chloroform sufficiently soluble in alcohol and alkali solution 7. Used as analgesic and sedative 8. Depressant action on various parts of the nervous system but habit forming. 9. 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 8 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 9 Molecular formula:C17H19O3N Nature of nitrogen:nitrogen is tertiary in nature [C17H19O3] N CH3I Morphine [C17H19O3] N CH3 quaternary salt Nature of oxygen atom:i) Presence of 2 hydroxyl groups Acetylation C17H17ON[OH]2 morphine Be nzy l C17H17ON(OCOCH3)2 at i on C17H17ON(OCOC6H5)2 10 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. 11 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:CH3I heat Ag2O N N CH3 H3C OH CH3 N H3C CH3 12 Structure of methyl morphol:by pschorr synthesis;-codeimethine Heating with alkali -codeimethine Morphol Methyl morphenol HBr morphenol 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-methoxy4,6-diacetoxy phenanthrene along with dimethyl amino ethanol respectively. which reveals the presence of CH2CH2NCH3 group 13 H3CO codeimethiodide AC2O ACO + ACONa Me2NCH2CH2OH 3-methoxy-4-acetoxy phenanthrene H3CO AC2O codeinenemethiodide ACONa ACO + Me2NCH2CH2OH CAO 3-methoxy-4,6-diacetoxy phenanthrene 14 H3CO Methyl morphol further confirmed by:- + H3CO HOOC CHO 2-phenylacetic acid NO2 3,4-dimethoxy-2-nitrobenzaldehyde H3CO H3CO i)[H] ii)NaNO2-H2SO4 iii)Cu powder CH NO2 CCOOH 3,4-dimethoxy-2-nitro pheny cinnamic acid H3CO H3CO HEAT HO HO COOH 15 METHYL MORPHOL Presence N-Methyl groups:. By herzig-mayer method one >N-CH3 group is present Presence of third oxygen atom and ether linkage:HO HO HO KOH O HO HO 3,4,5,6 tetrahydroxyl phenanthrene mophenol 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 16 Structure of morphine:-by the above information we can know that the presence of following groups HO O + NMe-CH2-CH2 + One double bond HO 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:- 17 O OH 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. O (O) C17H19O3N O several reactions + morphine 9,10 phenanthroquinone H3C N CH2 H2C 9-ethyl methyl amino phenanthrene 18 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:HO O NCH3 HO 19 Further confirmed by synthesis:-GATES synthesis HO HO HO C6H5COCl NaNO2 Pyridine CH3COOH ON OH OCOC6H5 OCOC6H5 H2\Pd-C O SO2-CH3OH REDUCTION O HO FeCl3 (O) OCOC6H5 H2N OCOC6H5 20 HO (CH3)2SO4\K2CO3 H3CO Protection of OH groups HO H3CO OCOC6H5 i)KOH ii)HCl OCOC6H5 H3CO O i)NaNO2-CH3COOH H3CO ii)H2-Pd-C iii) FeCl3 H3CO H3CO O OH 21 (C2H5)3N-H2O Micheals condensation CH2CNCOOC2H5 H3CO H3CO K3Fe(CN)6/OH O H3CO Mild oxidation O H3CO H2N H2N CH CH O O COOC2H5 COOC2H5 i)KOH-CH3OH-H2O ii)HCl H3CO H3CO O CH2=CH-CH=CH2 O H3CO CN H3CO OH NC C H2 13 STEPS C2H5N\HCl O 220O HO O NCH3 22 HO MORPHINE SAR of morphine :2 A-aromatic ring B-cyclo hexane C-cyclo hexane D-pyridine E-tetra hydrofuran HO 1 3 A 11 4 12 B 10 D 9 O E At 3,6 position,-OH groups:Conversion of 3-OH to 3-methoxy gives codeine-decreases activity upto 15% of 13 5 morphine C Conversion of 6-OH to 6-methoxy gives heterocodeine- increases 6fold activity 6 Of morphine HO 7 Oxidation of 6-OH gives ketone –decreases the activity 14 NCH3 8 Note:-absence of 7,8 double bond in morphine --- decreases the activity 37%\ Absence of double bond and presence of ketone ----increases the activity 23 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 24 Atropine 25 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 26 Isolation: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 H-OH C17H23NO3 Atropine Ba(OH)2 C9H10O3 tropic acid + C8H15NO tropine 27 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 1. Tropic acid with bromine gives no decolorisation of bromine indicate saturated compound (absence of double bond). C9H10O3 tropic acid + NaOH [C9H9O3] Na monosodium salt of tropic acid 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 28 COOH C9H10O3 tropic acid -H2O heat C9H8O2 KMnO4 BENZOIC ACID 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 :C3H5O3 C3H3O2 HEAT -H2O tropic acid Atropic acid 29 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 O C C H H C OH CH2 O C C OH ATROPIC ACID CINNAMIC ACID Further structure of atropic acid is confirmed by oxidising tropic acid in KMnO4 Tropic acid KMnO4 O O C C OH Phenyl glyoxal Phenyl glyoxal is the same oxidation product of atopic acid 30 CH2OH O C CH2 O C C OH H + I OH atropic acid II C OH H CH3 O C C OH OH As the tropic acid consists of primary alcohol functional group the probable structure of tropic acid will be CH2OH O C I C OH H 31 Further structure of the tropic acid is established by its synthesis (Mekenje and Wood ) OH CH3 + C NaCN C O CH3 CN H2O\H CH2 -H2O C COOH C COOH CH3 Atropic acid antimorkonikovs rule OH peroxide HCl CH2OH CH2Cl aq.NaOH C C COOH H H COOH tropic acid 32 The tropic acid formed is recemic mixture. Determination of structure of tropine:1. mol.formula:-C8H15NO 2. Tropine reacts with bromine no decolorisation is seen hence it is a saturated comp. 3. Tropine when reacts with methyl iodide it consumes 1 mole to give a quaternary ammonium salt C8H15ON + CH3I [C8H15ON] CH3IH It indicates that nitrogen atom in tropine is tertiary in nature Detection of presence of N-Methyl group:- herzig meyer method 1500 C8H15ON + HI CH3I + C7H12ON AgNO3 AgI 33 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:O C8H14N(OH) + Cl C -HCl tropine benzoyl chloride C8H14N(OCOC6H5) mono benzoyl derivative 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. 34 tropine CrO3 Tropinone (O) Tropinic acid (a dicarboxylic acid) (O) O O N CH3 N-methyl succinamide 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:- C C N C CH3 C 35 Tropic acid on hoffmann exhaustive methylation yields a unsaturated dicarboxylic acid which on reduction gives pimelic acid C8H13NO4 tropinic acid H.E.M C7H8O4 Reduction unsaturated acid CH2CH2COOH H2C CH2CH2COOH 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 36 HC tropine H2SO4 tropidine HEM C H CH2 reduction CH HC H C CH H2C H2 C CH2 CH2 H2C H2 C CH2 Cycloheptane There is another important reaction which reveals structure of tropine HI C8H15NO tropine <1500 CH3Cl + C8H14NI tropine iodide C7H14N [H] distill.HCl C8H15N dihydro tropidine Zn-dust distill. nordihydro tropidine C7H9N 2-ethyl pyridine 37 Formation of 2-ethyl pyridine reveals the presence of a reduced pyridine ring in the tropine molecule By the above discussion conclusions are: 1. Tropine possess a 7 membered carbon ring. 2. It contains a reduced pyridine ring in the structure 3. It possess reduced pyrrole (pyrollidine) ring in the structure 4. 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 H2C H C CH2COOH H2C H C NCH3 H2C C H COOH Tropinic acid NCH3 C H2C H2C CH2 C H Tropinone CH2 H C CH2 NCH3 CHOH O H2C C H CH2 Tropine 38 Tropine may also written as:- 1 2 7 NCH3 6 3 OH 4 5 Tropine Atropine structure:Tropine 1 + Tropic acid CH2OH O 2 7 NCH3 6 3 4 5 Tropine OH + C I C OH H 39 1 2 O CH2OH 7 NCH3 6 OC 3 4 5 C H ATROPINE Atropine structure confirmed by Synthesis:- Fischer esterification:- NCH3 + OH HO O CH2OH C C H Tropic acid Tropine -H2O HCl O NCH3 ATROPINE OC CH2OH C 40 H 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 41 References:•Chemistry of natural products – o.p agarwal •Chemistry of natural products by chetwal •www.wikipedia.com 42 43