Transcript Presence N-Methyl groups

Morphine and atropine
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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
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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:-
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
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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
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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
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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
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Constitution
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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
[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
nz
yl
ati
o
C17H17ON(OCOCH3)2
n
C17H17ON(OCOC6H5)2
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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 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
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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
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H3CO
codeimethiodide
AC2O
ACO
+
ACONa
Me2NCH2CH2OH
3-methoxy-4-acetoxy phenanthrene
H3CO
AC2O
codeinenemethiodide
ACONa
ACO
+
Me2NCH2CH2OH
CAO
3-methoxy-4,6-diacetoxy phenanthrene
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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
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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
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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:-
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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
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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:HO
O
NCH3
HO
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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
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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
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(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
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Of morphine
HO
7
Oxidation of 6-OH gives ketone –decreases
the activity
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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
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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: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
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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
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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
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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
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
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CH2OH O
C
CH2
C
C
OH
O
C
OH
H
+
I
OH
atropic acid
II
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
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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
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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
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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: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.
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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
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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
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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
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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:
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
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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
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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
H
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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
•www.wikipedia.com
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