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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
182
Pharmaceutical Chemistry of Natural Products
From these facts the partial structure of morphine can be drawn as follows:
HO
O
HO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
-CH -CH -NCH one double bond
(formed as ethylene)
23
⫹
2
Now the position of double bond and the chain –CH
2
–CH
2
–N–CH
3
has to be accounted
to explain all reactions of morphine.
(b) Point of attachment of –CH
2
–CH
2
–N–CH
3
chain:
Codeine Hydroxycodeine Ketocodeimethine Methoxy diacetoxy phenanthrene
CrO
3
HEM Ac O
2
[O]
Methoxy acetoxy phenanthraquinone
The loss of acetyl group during last oxidation indicates that one of the acetoxyl groups
in methoxy diacetoxy phenanthrene must be present in either ninth or tenth position.
Because the acetoxy group is introduced via the ketonic group during aromatization
with acetic anhydride, the ketonic group in keto codeimethine and hence the new –OH
group in hydroxy codeine must be at ninth or tenth position.
As the 2° alcohol group of hydroxy codeine is converted to the ketonic group during
HEM, the double bond must be introduced between C
9
and C
10
during fi ssion of the
nitrogen ring and thus the nitrogen must be attached to C
9
or C
10
. The exact position of
C
9
is confi rmed after the synthesis of morphine.
Thus, the part of the structure of hydroxy codeine may be drawn as follows to
explain the above reactions:
Codeine
CrO
3
HCO
3
O
HO
OH
NCH⭈
3
CH
2
CH
2
Hydroxycodeine
HEM
Hydroxycodeimethine
HCO
3
O
HO
OH
N(CH )
32
CH
2
CH
2
Alkaloids
183
HCO
3
AcO
OAc
Ac O
2
Methoxy diacetoxy phenanthrene Ketocodeimethine
⫺CH CO
3
[O]
HCO
3
AcO
O
O
Methoxy mono acetoxy phenanthraquinone
CH
2
CH
2
N(CH )
32
HO
HCO
3
O
O
As we have noted, the side chain having nitrogen atom is always eliminated with the
aromatization of the nucleus. Gulland and Robinson in 1923 stated that the formation
of the phenanthrene derivatives can take place for structural reactions, unless ethamine
chain is displaced.
Now the ‘N’ end of side chain has been shown to attach with C
9
and the carbon
end must be located at an angular position so that its elimination from that position
becomes essential for aromatization. Between the two positions C
13
and C
14
, C
13
is
selected, because such structure explains the rearrangement of thebaine to thebenine.
Hence, the partial structure of morphine is drawn as mentioned below.
HO
O
HO
NCH⭈
3
184
Pharmaceutical Chemistry of Natural Products
10. Position of double bond:
Formation of same ketone I indicates codeine and isocodeine differ only on the position
of –OH group at C
6
, while the formation of same ketone II from pseudocodeine and
allopseudocodeine differs in the position of –OH at C
8
. These reactions are possible only if
the double bond is between C
7
and C
8.
Codeine
PCl
5
Alpha-chloro codide
Acetic acid
Codeine, Isocodeine
(I) Ketone
Pseudocodeine,
Allopseudocodeine
(Positional isomers)
(O)
(O)
⫹
(II) Ketone
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Morphine Codeine
NCH
3
OH
O
HO
HO
O
HCO
3
NCH
3
H
H
The foregoing reaction of morphine may be explained as follows:
Morphine
HO
HO
O
N(CH )
33
H
(CH)SO
32 4
HCO
3
O
HO
Codeine ␣-Codeimethine
HCO
3
O
HO
N(CH )
32
(Shifting of double bond)
⌬
(i) MeI
(ii) OH
⫺
NCH
3
N(CH )
32
HCO
3
HO
O
−Codeimethine
N (CH)OH
⫹⫺
33
−Codeimethine
Heat
(HO)⫺
2
(i) MeI
(ii) OH
⫺
N (CH)OH
⫹
33
⫺
HCO
3
HO
O
HCO
3
O
H
Heat with
(CH CO) O
32
Alkaloids
185
HCO
3
(CH ) N + CH CH
33 2 2
⫽⫹⌷
HBr
Methyl morphenol Morphenol Morphol
HO
O
Na–C H OH
25
HO
HO
Synthesis: Finally the proposed structure of morphine is confi rmed by the synthesis.
3,4-Dimethoxy-
phenylacetic acid
CH
2
COOH
OCH
3
OCH
3
HCO
3
NH
2
m–Methoxyphenyl-
ethylamine
Condensation
HCO
3
O
C
NH
CH
2
OCH
3
OCH
3
Bischler–Napieralski synthesis
POCl -140°C
3
OCH
3
OCH
3
CH
2
C
N
HCO
3
Na–Hg/Alcohol
OCH
3
OCH
3
CH
2
NH
HCO
3
i) CH I
3
ii) NaOH
OCH
3
OCH
3
CH
2
CH
3
N
HCO
3
Birch reduction
Na (CH COH⫹
3
)
3
CH
3
N
HCO
3
CH
2
OCH
3
OH
10% HCl Reflux
+
186
Pharmaceutical Chemistry of Natural Products
HCO
3
HO
O
N
CH
3
Ring closure
HCO
3
O
O
NCH
3
i) Resolved by
( )-tartaric acid
and ( )-form taken
⫹
⫺
ii) Br –CH COOH
23
N
CH
3
Br
O
O
HCO
3
7-Bromo codeinone
LiAlH /THF
Reflux
4
CH
3
N
Codeine
O
HCO
3
OH
C H N/HCl
55
Morphine
O
OH
HO
CH
3
N
( )-Dihydro thebainone⫾
Demethylation
Quinoline Alkaloids
Quinine
HCO
3
N
1
2
3
4
5
6
7
8
9
C
H
HO
N
CH CH⫽
2
1
2
3
4
5
6
7
8
(6-Methoxyquinolin-4-yl)-(5-vinylquinuclidin-2-yl)methanol
Quinine is a cinchona alkaloid obtained from cinchona bark ( Cinchona offi cinalis). Among the 17
alkaloids obtained from the bark, quinine is the most important one. It is the levo isomer and for
many years it was the most effective antimalarial agent. Quinine and its analogue cinchonine were
discovered by Pelletier in 1820.
Alkaloids
187
Mode of action: Three different mechanisms of actions are suggested.
DNA interaction: Mechanism of action for quinine was that drug intercalated into the DNA of
the parasite. It is based upon the fact that the concentration required for inhibition of nucleic acid
synthesis is signifi cantly higher than that necessary for inhibition of the plasmodium parasite.
Ferriprotoporphyrin IX: The plasmodium parasite utilizes host haemoglobin as a source of amino
acid. On digestion of haemoglobin, haeme is released as ferriprotoporphyrins IX and it produces
haemolysis of erythrocytes parasites. So the ferriprotoporphyrin released is converted to nontoxic
product to hemozoites by polymerase. The step involved in the conversion of ferriprotoporphyrin
to hemozoites is inhibited by chloroquine.
Weak base hypothesis: Quinine is a weak base and because of this pK
a
they are thought to
accumulate in an acidic location (parasite lysosome pH: 4.8–5.2). As the extracellular fl uid of the
parasite is at pH 7.4, the weak base will move towards a more acidic pH of lysosome. Once the
acid–base reaction occurs, pH in the lysosome is elevated which in turn reduces the parasite’s
ability to digest haemoglobin and thereby, reducing the availability of amino acids.
Properties and uses: Quinine hydrochloride is a fi ne, silky needle, often in clusters, colourless,
soluble in water and alcohol. Quinine acts as a blood schizonticide and has gametocytocidal activity
against Plasmodium vivax and P. malariae. Therefore, it is used in the treatment of malaria. It has a
special place in the management of severe P. falciparum malaria in areas with known resistance to
chloroquine.
It is metabolized in the liver to 2-hydroxy derivative followed by additional hydroxylation on
the quinoline ring with 2,3-dihydroxy derivative as the major metabolite. This metabolite has low
activity and is rapidly excreted in urine.
Structural elucidation
The structure of quinine is established as follows:
1. Molecular formula: The molecular formula of quinine is found to be C
20
H
24
N
2
O
2
.
2. Presence of two 3° N atoms: It forms two different series of 4° N salts when treated with
2 moles of CH
3
I. This indicates that it has two different types of 3° N atoms.
3. Presence of 2° alcohol group: Results from the usual standard tests revealed that quinine
possesses one alcoholic –OH group (i.e. by benzoylation, acetylation, chlorination with
halogen acids) which is found to be 2° alcohol (by oxidation test).
4. Presence of a methoxy group: By Zeisel’s test, the second oxygen atom is found to be
–OCH
3
group.
5. Presence of an olefi nic double bond: It is found to possess one double bond (C=C) by
the catalytic reduction and bromination test.
6. Presence of a vinyl group: Furthermore, quinine on mild oxidation with KMnO
4
yields
a monocarboxylic acid along with formic acid, which suggests the presence of a vinyl
group.
7. Presence of quinoline ring: Quinine on fusion with KOH yields 6-methoxyquinoline
and lepidine (γ-methyl-quinoline) along with other products. These products indicate the
presence of a quinoline nucleus in quinine.
188
Pharmaceutical Chemistry of Natural Products
6-Methoxyquinoline Lepidine
HCO
3
N
N
CH
3
8. Presence of meroquinene: Quinine yields quininic acid and meroquinene upon oxidation
with chromic acid.
CHNO
20 24 2 2
Quinine
CrO
3
CHNO
11 9 3
+
CH NO
915 2
Quininic acid Meroquinene
Therefore, in order to establish the structure of quinine, the structure of quininic acid
and meroquinene must be known.
9. Structure of quininic acid (C
11
H
9
NO
3
):
(a) On heating with soda lime, quininic acid gives 6-methoxyquinoline which reveals that
quininic acid is a 6-methoxyquinoline derivative.
Quininic acid is converted to 6-hydroxyquinoline when heated with HCl, which
confi rms that –OCH
3
group is at the sixth position.
6-Hydroxyquinoline
N
HO
(i)–OCH OH
(ii) CO
3
2
–
–
HCl
C H NO
11 9 3
Quininic acid
6-Methoxyquinoline
Soda lime
(CO)
2
–
N
HCO
3
(b) Pyridine-2,3,4-tricarboxylic acid is obtained on oxidation of quininic acid with chromic
acid, which reveals that the benzene ring of the quininic acid having the methoxy
group is oxidized. Further, the –COOH group at C-4 indicates that in quininic acid also
the –COOH group is present at the C-4 position. Thus, quininic acid may be written as
follows:
HCO
3
N
CrO
3
COOH
Quininic acid
HOOC
HOOC
COOH
Pyridine-2,3,4-tricarboxylic acid
N
Alkaloids
189
(c) The synthesis of quininic acid proved the above proposed structure.
HCO
3
NH
2
CH COCH COOC H
3225
(Acetoacetic ester)
(i) Enolization
(ii) Cyclization
HCO
3
CH
2
OC
CH
3
CO
N
H
HSO
24
CH
3
N
OH
HCO
3
POCl
3
PCl
5
CH
3
Cl
HCO
3
N
Al–CH COOH
3
( HCl)⫺
HCO
3
N
CH
3
C H CHO
65
ZnCl
2
HCO
3
HC CHC H
65
KMnO
4
⫺C H COOH
65
COOH
N
HCO
3
N
10. Structure of meroquinene C
9
H
15
NO
2
:
(a) Presence of two 2° N, –COOH group and olefi nic double bond: Results from the usual
standard chemical tests reveal that meroquinene has a 2° N atom, a –COOH group and
an olefi nic double bond.
(b) On oxidation with cold acidic permanganate, meroquinene gives formic acid and a
dicarboxylic cincholoiponic acid which on further oxidation gives another dicarboxylic
acid called loiponic acid.
CH NO
915 2
O
HCOOH + C H NO
813 4
O
CH NO
711 4
Meroquinene Cincholoiponic
acid
Loiponic
acid
Presence of vinyl group in meroquinene moiety is indicated by the formation of
formic acid. Molecular formulae of the cincholoiponic and loiponic acids reveal that
cincholoiponic is the higher homologue (having one –CH
2
more) between the two.
190
Pharmaceutical Chemistry of Natural Products
(c) Loiponic acid is somewhat less stable and isomerizes to more stable hexahydrocin-
chomeronic acid with the molecular formula of C
7
H
11
NO
4
(piperidine-3,4-dicarboxylic
acid) on treatment with KOH at about 200°C; hence, loiponic acid should also be pip-
eridine-3-4-dicarboxylic acid.
COOH
COOH
N
H
Loiponic acid
(d) As cincholoiponic acid has one more –CH
2
than the loiponic acid, it must be either I or
II.
CH COOH
2
COOH
N
H
COOH
CH COOH
2
N
H
III
Cincholoiponic acid is found to be compound I, because upon heating with
concentrated H
2
SO
4
it yields γ-picoline.
CH COOH
2
COOH
N
H
Conc. H SO
24
( 3H , 2CO )⫺
22
⫺
␥-Picoline
N
CH
3
Synthesis of cincholoiponic acid further proves the structure of I for cincholoiponic
acid.
CH(OC H )
252
CH
2
CH Cl
2
2 NH
3
⫹
(CHO)HC
25 2
CH
2
HC
2
N
H
CH(OC H )
252
CH
2
CH
2
Iminodipropionacetal-Chloropropionacetal
OHC
CH
2
HC
2
N
H
CHO
CH
2
CH
2
HCl
Alkaloids
191
CH(COOC H )
252
CN
N
H
(i) Ba(OH)
(ii) HCl
2
CH COOH
2
COOH
( )-Cincholoiponic acid⫾
N
H
CH (COOCH)/CHONa
225225
(Michael condensation)
CN
N
H
(i) NH OH
2
(ii) SOCl
2
CHO
N
H
(e) Cincholoiponic acid, along with HCOOH, was obtained upon oxidation of meroquinene
(a monocarboxylic acid); hence, the meroquinene must have a grouping of the type
–CH=CH
2
. Therefore, meroquinene may be either III or IV.
CH CH CH
22
⫽
COOH
N
H
CH COOH
2
CH CH⫽
2
N
H
III IV
The following observations indicate that the structure of IV is correct:
Meroquinene on heating with hydrochloric acid at about 240°C gives 3-ethyl-4-
methylpyridine.
CH COOH
2
CH CH⫽
2
N
H
HCl
240°C
Meroquinene, IV
CH
3
CH
25
N
(If structure III is correct, then 4-propyl pyridine must have been obtained.)
Meroquinene on reduction with zinc and hydriodic acid gives cincholoipon,
C
9
H
17
NO
2
, which is having –COOH and –C
2
H
5
groups.