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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
192
Pharmaceutical Chemistry of Natural Products
CH COOH
2
N
H
CH CH⫽
2
CH COOH
2
N
H
CH
25
Meroquinene, IV Cincholoipon
Zn
HI
(If structure III is correct, then propyl group must have been introduced at position 4.)
Thus, the oxidative and degraded products are described as follows.
CH COOH
2
CH CH⫽
2
N
H
CH COOH
2
COOH
N
H
COOH
COO
H
N
H
Meroquinene Cincholoiponic acid Loiponic acid
[O]
11. Point of linkage between quininic acid and meroquinene in quinine: Oxidation
products of quinine, quininic acid and meroquinene have free carboxylic groups but
quinine has no carboxylic group, indicating that the two moieties are linked with each
other by means of the carboxylic carbon atoms.
Further, quinine is a ditertiary base, while meroquinene has a secondary nitrogen atom
which shows that during oxidation, the second half moiety of quinine is oxidized in such a
way that its 3° N atom is converted into 2° N with the introduction of one –COOH group.
A possible precursor of meroquinene may have the following structure:
HC
2
HC
2
H
C
CH
2
CH
2
N
CH
CH
2
1
2
3
4
5
7
8
6
C
H
CH
2
CrO
3
3-Vinylquinuclidine
HC
2
COOH
H
C
CH
2
CH
2
HN
CH
CH
2
CH COOH
2
CH CH⫽
2
N
H
Meroquinine
CH
CH
2
The possibility of the existence of the above type of structure (quinuclidine structure)
is confi rmed by the synthesis of 3-ethyl quinuclidine.
Therefore, it is concluded that the quinoline moiety is joined at position C-4 to the
quinuclidine moiety at position C-8.
12. Position of the 2° alcoholic group:
Rabe oxidized quinine to quininone by gentle oxidation using CrO
3
. Quininone on
treatment with amyl nitrite and hydrogen chloride gives quininic acid and an oxime,
which is a characteristic reaction of the –CO–CH group. The oxime on hydrolysis affords
hydroxylamine and meroquinene, which indicates that the quinoline and quinuclidine
units are linked through –CHOH group.
Alkaloids
193
CO CH
HONO
COOH ⫹ HC
NO
Isomerises
Acid
C
NOH
O
xime
Hence, the structure of quinine may be represented as shown below which explains
all its reactions.
CH CH⫽
2
N
CH
HCO
3
N
HO
13. Synthesis: The above structure of quinine is proved by its synthesis.
CH CH⫽
2
N
COPh
EtO C
2
CO Et
2
MeO
⫹
Ethyl quininate
N
EtONa
(Claisen condensation)
CH CH⫽
2
HN
EtO C
2
OC
()⫾ -Quinotoxine
MeO
MeO
HCl
CH CH⫽
2
N
COPh
OC
N
Resolution
()⫾ -Isomer
(i) NaOBr
(ii) NaOH
MeO
OC
CH CH⫽
2
N
N
()⫾ -Quininone
Al/EtOH/EtONa
EtO C
2
N
194
Pharmaceutical Chemistry of Natural Products
CH CH⫽
2
N
CH
HO
MeO
N
()⫾ -Quinine
Resolution
()⫺ -Quinine
Isoquinoline Alkaloids
Papaverine
1
2
3
4
5
6
7
8
N
CH
2
1’
2’
3’
4’
5’
6’
OCH
3
OCH
3
HCO
3
HCO
3
1-(3’,4’-Dimethoxybenzyl)-6,7-dimethoxyisoquinoline
Papaverine is an alkaloid obtained from opium, a dark brown resinous material obtained from
the poppy (P. somniferum) capsule. Opium has two types of alkaloids, namely (i) phenanthrene
derivatives and (ii) benzylisoquinoline derivatives. Papaverine belongs to benzylisoquinoline
derivative.
Papaverine as HCl, along with morphine HCl and codeine HCl, is available as papaveretum BP,
which is used for premedication and as analgesics during and after surgery.
Structural elucidation
The structure of papaverine is established as follows:
1. Molecular formula: The molecular formula of papaverine is found to be C
20
H
21
NO
4
.
2. Presence of two 3° N: Papaverine forms quaternary ammonium salt with a molecule of
methyl iodide which indicates the presence of tertiary nitrogen.
3. Presence of four methoxy groups: By Zeisel’s method, the four oxygen atoms are found
to be present as –OCH
3
.
4. Presence of –CH
2
group: A 2° alcohol (papaverinol) is obtained by the oxidation of
papaverine with cold KMnO
4
, which on further oxidation with hot dilute KMnO
4
yields
papaveraldine (C
20
H
19
NO
5
). This reaction indicates the presence of –CH
2
group.
Alkaloids
195
C H NO (CH )
19 19 4 2
Papaverine
O
C H NO (CHOH)
19 19 4
O
C H NO (CO)
19 19 4
PapaveraldinePapaverinol
5. Fusion with KOH: Upon fusion with KOH, papaverine mainly yields two compounds,
namely compound A, with the molecular formula of C
11
H
11
NO
2
and compound B with the
molecular formula of C
9
H
12
O
2
along with some veratric acid. The structures of compounds
A and B are needed to be established to know the structure of papaverine.
(a) Compound A: (Molecular formula: C
11
H
11
NO
2
)
Presence of 3° N: Results from the usual standard tests reveal that it possesses one 3°
N.
Presence of two methoxy groups: By Zeisel’s method, the two oxygen atoms were found
to be present as two methoxy groups.
Presence of isoquinoline nucleus: Isoquinoline which was obtained by demethylation
and zinc dust distillation of A indicates that it is a dimethoxy quinoline.
CHNO
11 11 2
CHNO
97 2
( 2CH I)⫺
3
Zn dust
N
Isoquinoline
Position of two methoxy groups: The position of two methoxy groups is accounted on
the basis of the oxidation product (m-hemipinic acid) obtained from compound A. The
formation of m-hemipinic acid indicates compound A is 6,7-dimethoxy isoquinoline.
HCO
3
HCO
3
N
HCO
3
HCO
3
COOH
COOH
CHNO
11 11 2
(A)
m-Hemipinic acid
Further, the structure of A is confi rmed by the synthesis from veratric aldehyde
and aminoacetal.
MeO
MeO
CHO
CHO
25
OC H
25
CH
CH
2
NH
2
MeO
MeO
OC H
25
N
⫺CHOH
25
MeO
MeO
N
(A)
+
(b) Structure of compound B: (Molecular formula C
9
H
12
O
2
)
Presence of two methoxy groups: The two oxygen atoms were found to be present as
–OCH
3
by Zeisel’s method.
Oxidation: 3,4-Dimethoxy benzoic acid (veratric acid) was obtained on oxidation of
the compound B .
196
Pharmaceutical Chemistry of Natural Products
Protocatechuic acid was obtained from B on demethylation followed by oxidation.
Hence, compound B must be 3,4-dimethoxytoluene (homoveratrole).
COOH COOHCH
3
Protocatechuic acid
OH
OH
OCH
3
OCH
3
OCH
3
OCH
3
[O]
(i) HI
(ii) [O]
3,4-Dimethoxytoluene Veratric acid
(B)
The above reaction also explains the formation of veratric acid during KOH fusion
of papaverine.
(c) Point of linkage between compounds A and B
6,7-Dimethoxy isoquinoline-1-carboxylic acid and 2,3,4-pyridine tricarboxylic acid
(cinchomeronic acid) are obtained on oxidation of papaverine.
HCO
3
HCO
3
COOH
N
HOOC
HOOC
COOH
N
From these oxidation products and the formation of veratric acid during fusion or
oxidation, it is confi rmed that the A and B are linked through the carbon atom of –CH
2
group.
From these observations, the structure of papaverine may be drawn as follows,
which explains all the aforementioned chemical reactions.
Oxidation of papaverine by cold dilute potassium permanganate
HCO
3
HCO
3
N
CH
2
OCH
3
OCH
3
Papaverine
Cold dil.KMnO
4
HCO
3
HCO
3
N
CHOH
Hot dil. KMnO
4
OCH
3
OCH
3
HCO
3
HCO
3
Papaverinol Papaveraldine
OCH
3
OCH
3
CO
N
Alkaloids
197
Prolonged hot dil. KMnO
4
CO
OCH
3
OCH
3
Papaverinic acid
HOOC
N
HOOC
Oxidation of papaverine
HCO
3
HCO
HCO
3
HCO
3
HCO
3
HCO
3
CH
2
OCH
3
OCH
3
[O]
[O]
HCO
3
HCO
3
N
COOH
⫹
6,7-Dimethoxyisoquinoline-1-carboxylic acid
Papaverine
OCH
3
OCH
3
COOH
COOH
COOH
COOH
HOOC
HOOC
COOH
N
N
Veratric acid
m-Hemipinic acid Cinchomeronic acid (pyridine-2,3,4-
tricarboxylic acid)
N
⫹
198
Pharmaceutical Chemistry of Natural Products
Fusion of papaverine with potash
HCO
3
HCO
3
CH
2
Potash
OCH
3
OCH
3
HCO
3
HCO
3
N
OCH
3
OCH
3
CH
3
[O]
COOH
OCH
3
OCH
3
Papaverine
6,7-Dimethoxyisoquinoline (A) 3,4-Dimethoxytoluene (B)
Veratric acid
⫹
N
Synthesis: Finally, the above structure of papaverine is confi rmed by the synthesis.
Step 1. Synthesis of homoveratrylamine and homoveratryl chloride from veratrole
HCO
3
HCO
3
Veratrole
HCHO–HCl
HCO
3
HCO
3
CH Cl
2
KCN
HCO
3
HCO
3
CH
2
CN
3,4-Dimethoxybenzyl cyanide
Homoveratrylamine Homoveratryl chloride
HCO
3
HCO
3
CH
2
NH
2
H –Ni
2
(i) Hydrolysis
(ii) PCl
5
HCO
3
HCO
3
CH
2
COCl
Alkaloids
199
Step 2. Condensation of homoveratrylamine and homoveratryl chloride
HCO
3
HCO
3
CH
3
NH
2
Homoveratrylamine
COCl
CH
2
OCH
3
OCH
3
⫹
Heat
HCO
3
HCO
3
NH
OC
CH
2
OCH
3
OCH
3
(i) Enolization
(ii) H O
( reaction)
⫺
2
Bischler–Napieralski
PO
25
HCO
3
HCO
3
N
CH
2
OCH
3
OCH
3
Papaverine
Palladized asbestos
HCO
3
HCO
3
N
CH
2
OCH
3
OCH
3
Dihydropapaverine
at 200°C
( 2H)⫺
Emetine
HCO
3
HCO
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
N
CH
25
CH
2
HCO
3
HCO
3
NH
1’
2’
3’
4’5’
6’
7’
8’
200
Pharmaceutical Chemistry of Natural Products
Emetine is the principal alkaloid obtained from the roots of Cephaelis ipecacuanha. Ipecacuanha also
contains cephaeline, psychotrine, o-methylpsychotrine and emetamine. These alkaloids are called
ipecacuanha alkaloids.
Properties and uses: It is a white powder, sparingly soluble in water and completely soluble in
organic solvents. It is used as an emetic, expectorant and in the treatment of amoebic dysentery.
Structural elucidation
The structure of emetine is established as follows:
1. Molecular formula: The molecular formula of emetine is found to be C
29
H
40
N
2
O
4
.
2. Presence of one 2° N and one 3° N: Results from the usual standard tests reveal that
emetine possesses one 2° N atom and one 3° N. But no N-methyl group is present.
3. Presence of four methoxy groups: By Zeisel’s test it is found to possess four –OCH
3
groups
4. Presence of isoquinoline unit: Oxidation of emetine with KMnO
4
in acetone affords
m-hemipinic acid (I), and small amounts of 6,7-dimethoxyisoquinoline-1-carboxylic acid (II).
HCO
3
HCO
3
COOH
COOH
HCO
3
HCO
3
COOH
N
HCO
3
HCO
3
O
O
O
NH
m-Hemipinic acid, I 6,7-Dimethoxyisoquinoline
-1-carboxylic acid, II
4,5-Dimethoxyphthalonimide, III
Oxidation of emetine with chromic acid yields 4,5-dimethoxyphthalonimide (III). These
reactions indicate the presence of at least one 6,7-dimethoxyisoquinoline unit in emetine.
Absorption spectra of emetine are similar to that of 1,2,3,4-tetrahydroisoquinoline
derivatives. Hence, it must be a derivative of tetrahydroisoquinoline.
5. Presence of two dimethoxy benzene units: The UV absorption spectrum of emetine
closely resembles that of tetrahydropapaverine, indicating that the emetine molecule must
contain two o-dimethoxybenzene units.
6. Presence of two 6,7-dimethoxy isoquinoline: Upon gentle oxidation with alkaline
KMnO
4
, emetine fi rst yields corydaldine (IV). After its removal, the residue is further
oxidized to yield m-hemipinic acid (I).
HCO
3
HCO
3
NH
HCO
3
HCO
3
COOH
COOH
Corydaldine, IV m-Hemipinic acid , I
O
Alkaloids
201
The combined yield of these two products amounted to 0.96 mole per mole of emetine,
indicating the presence of two 6,7-dimethoxyisoquinoline units in emetine as the alkaloids
(e.g. papaverine) having only one 6,7-dimethoxyisoquinoline unit give only about half the
yield of these products.
The presence of two 6,7-dimethoxyisoquinoline is further confi rmed by the following
two observations:
(a) Cephaeline (another ipecacuanha alkaloid) when ethylated gives ethyl ether of
cephaline, which on oxidation yields a mixture of corydaldine and ethoxymethoxy
tetrahydroisoquinolin-1-one, which although could not be separated affords
m-hemipinic acid (I) and 4-ethoxy-5-methoxyphthalic acid upon oxidation.
HCO
3
CHO
25
COOH
COOH
HCO
3
COOH
COOH
HCO
3
m-Hemipinic acid, I 4-Ethoxy-5-methoxyphthalic acid, V
(b) 75% of m-hemipinic acid is yielded during oxidation of emetine, while alkaloids such
as papaverine having only one 6,7-dimethoxyisoquinoline unit yield only 25–30% of
m-hemipinic acid.
7. Point of linkage: The position of oxo or carboxyl group in compounds II, III and IV
represents the point of attachment of the two tetrahydroisoquinoline units to the remaining
molecule. Further, one of the N atoms in emetine is 3° and hence one of the two N atoms
is also linked to the remaining part of the molecule. Therefore, the partial structure of
emetine may be represented as below.
HCO
3
HCO
3
CH
2
N
CH
2
[CH]
47
CH
2
HN
OCH
3
OCH
3
Emetine
8. Nature of C
4
H
7
fragment: The nature of C
4
H
7
fragment is ascertained by Hofmann
exhaustive methylation of emetine.