Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
162
Pharmaceutical Chemistry of Natural Products
The number of hydroxyl (OH) groups present in the compound is determined by the following
methods:
Acetylation method:
H
+
R—OH + (CH
3
CO)
2
O R—O—CO—CH
3
By determining the amount of acetic anhydride that reacted with alcohol to form an ester, the
number of hydroxyl groups is determined.
Zerewitinoff active hydrogen determination method: When alcohol is heated with CH
3
MgI, methane
is obtained. By measuring the methane so formed, the amount of alcohol can be determined.
R—OH
⫹
CH MgI
3
CH
4
⫹
Mg
I
OR
–OH = CH
4
= 22.4 L of alcohol at normal temperature and pressure.
Carbonyl group
The presence of aldehydes and ketones is detected by their reaction with hydroxylamine,
semicarbazide and phenylhydrazine to form the corresponding oxime, semicarbazone and
phenylhydrazone, respectively.
C O
NH OH. HCl
2
⫺HO
2
C
N OH
⫹
HCl
Oxime
By determining the HCl formed, the ketones are estimated quantitatively.
C O
Ph—NHNH
2
⫺HO
2
C
N NH—Ph
⫹
HCl
Phenylhydrazone
C O
ON
2
NHNH
2
NO
2
ON
2
NH
NO
2
N ⫽ C
Dinitrophenylhydrazone
C O
H N—NH—C—NH
2
2
⫺HO
2
C N NH C NH
2
Semicarbazone
O
O
The aldehydes and ketones are distinguished by their oxidation or reduction products.
The carbonyl groups of aldehydes, ketones and carboxyl are further confi rmed by their spectral
data such as IR, ultraviolet (UV) and NMR.
Alkaloids
163
Carboxyl group (–COOH)
The presence of carboxyl group is determined by the following:
Its solubility in weak bases such as NH
3
, NaHCO
3
and Na
2
CO
3
.
Esterifi cation with alcohols.
Specifi c IR and NMR signals.
Quantitatively by acid–alkali titration: Performed by titrating the carboxylic acid with NaOH using
phenolphthalein as an indicator. By knowing the volume of NaOH consumed the number of
–COOH groups are determined.
Ester group (RCOOR)
Esters and related groups like amides and lactones are detected by their reaction with water, dilute
acids or alkali to the hydroxyl and acidic compounds. By elucidating the acid and alcohol, the
nature of alkaloids is determined.
R COOR’— R COOH— R’OH
⫹
R—CONH
2
R COOH— NH
3
⫹
R—CH—CH —CH
22
O CO
NaOH
R—CH—CH —CH
22
OH COONa
Alkoxy group (–OR)
Determined by Zeisel’s method—alkoxy group such as methoxy on reacting with hydroiodic acid
followed by silver nitrate yields equal amount of silver iodide. From the amount of silver iodide
formed, the number of alkoxy groups is calculated.
OCH
3
126°C
⫹ HI –OH ⫹ CH I
3
AgNO
3
AgI
Boil
+ CH
3
NO
2
Estimation of C-methyl group (Kuhn Roth method): By estimating the acetic acid formed upon
oxidation, the C-methyl groups are quantifi ed.
C CH
3
KCrO/ HSO
227 2 4
CH COOH
3
Functional nature of nitrogen: Most alkaloids contain ‘N’ in their ring structure, which may exist
as 2° or 3°.
164
Pharmaceutical Chemistry of Natural Products
The 2°and 3° amines are distinguished as follows:
2° Amines (acetylated or benzoylated) undergo Libermann’s nitroso reaction.
2° Amines take up 2 moles of alkyl halide to form 4° ammonium salt.
3° Amines take up 1 mole of alkyl halide to form 4° ammonium salt.
N
(O)
3° N
30% H O
22
N O
Amine oxide
Alkaloid Methylamine, Dimethylamine, Trimethylamine
–(indicates the presence of 1 or 2 alkyl groups
attached to amine ‘N’)
–Ammonia (indicates the presence of primary amine)
Distillation
Further, the nature of ‘N’ is confi rmed by degradation methods such as Hoffmann Exhaustive
Methylation (HEM).
The N-alkyl groups are estimated by Herzig–Meyer method:
N CH
3
HI
N HCHI
3
150–300°C
Under pressure*
AgNO
3
EtOH
AgI
⫹
N CH
25
HI
N H CHI
52
150–300°C
Under pressure*
AgNO
3
EtOH
AgI
⫹
*Differs form –OR (alkoxy group) estimation
From the amount of silver iodide formed, the number of N-alkyl groups is calculated.
Degradation of Alkaloids
Degradation of alkaloids gives rise to some identifi able products of known structure and hence by
knowing structure of the degraded products and the changes occurred during the degradation it is
convenient to know the structure of the original molecule. Different degradation reactions carried
out in elucidating the structure of alkaloids are as follows:
1. HEM method
2. Emde method
3. Von Braun’s (VB) method for 3° cyclic amines
4. Reductive degradation
5. Oxidation
6. Zinc distillation
7. Alkali fusion
8. Dehydrogenation
1. HEM method: Originally this method was applied by Willstater in 1870 for naturally occurring
alkaloids. It was further developed by Hoffmann and hence it is known as HEM. Principle of this
method is that the quaternary ammonium hydroxides yield olefi n with the cleavage of carbon–
nitrogen linkage upon heating with the loss of water molecule (H from β-carbon atom with respect
to N and OH from the 4° ammonium hydroxide).
Alkaloids
165
Quaternization is done by complete methylation of the amine followed by hydrolysis with
moist Ag
2
O or KOH.
R—CH —CH —NCH
22 3
2 CH I
3
RCHCHN(CH)I
22 33
⫹
———
Moist Ag O
2
(AgOH)
R—CH —CH —N (CH ) OH
22 33
⫹⫺
–H O
N(CH )
2
33
–
⌬
RCH CH
Olefin
⫽
2
This method can be applied to the reduced ring system but fails with unsaturated analogues
and hence, the unsaturated rings are fi rst saturated and then HEM is performed.
N N
H
H –Ni
2
2CH I
3
AgOH
N
⫹
(CH )
32
⌬
⫺HO
2
N
(CH )
32
(i) CH I
(ii) AgOH
3
Isomerism
⌬
-H O
-N(CH )
2
33
N
⫹
(CH )
33
OH
⫺
OH
⫺
As β-hydrogen atom is needed to cleave C–N bond and eliminate water molecule, the HEM
fails on the ring system that does not have β-hydrogen atom. For example, in the degradation
of isoquinoline, the cleavage of N does not occur at the fi nal step as there is no β-hydrogen with
respect to ‘N’.
N
Na—EtOH
NH
(i) 2CH I
3
(ii) AgOH
N
⫹
(CH )
32
OH
⫺
⫺HO
2
⌬
N
(CH )
32
(i) 2CH I
3
(ii) AgOH
N
⫹
(CH )
33
OH
⫺
166
Pharmaceutical Chemistry of Natural Products
However, there are some cases in which HEM fails even if the β-hydrogen atom is present (the
following reaction explains this).
N
H
(i) 2CH I
3
(ii) AgOH
N
⫹
OH
⫺
(CH )
32
⌬
⫺CH OH
3
N
CH
3
(95%)
⫺
HO
2
N
(CH )
32
(5%)
2. Emde method: Emde modifi cation may be used in the above two cases, where HEM failed. In this
method, 4° ammonium halide is reduced with sodium amalgam in aqueous ethanol or Na–liquid
NH
3
or catalytically.
N
Na—EtOH
NH
(i) 2CH I
3
(ii) AgOH
N
⫹
(CH )
32
OH
⫺
N (CH )
32
(i) 2CH I
3
(ii) AgOH
⫺HO
2
(CH ) OH
32
⫺
N
⫹
(Beta hydrogen absent)
Na–liq. NH
(or)
Na–Hg
H O–EtOH
3
2
(Alpha methyl styrene)
CH
3
⌬
Alkaloids
167
Tetrahydroquinoline is degraded as follows:
NI
⫹⫺
(CH )
32
Na liq. NH
3
–
3-Phenyl-N,N-dimethyl
propylamine
N
HC
3
CH
3
N
HC
3
CH
3
O-Propyldimethyl aniline
Emde degradation on tetrahydroisoquinoline also proceeds as follows:
N
⫹
(CH )
32
I
⫺
N
⫹
(CH )
32
HPt
(or)
Na–Hg
2
–
(I) CH I
(ii)Na Hg
3
–
N
(CH )
32
CH
3
HEM
CH
3
3. VB method:
(a) For 3° cyclic amines: The 3° N atom in the ring upon reaction with CNBr followed by hydrolysis
yields brominated 2° amine.
N
R
BrCN
N
⫹
RCN
Br
⫺
N
CH Br
2
Hydrolysis
HBr
NH
R
CH Br
2
2° Amine
RCN
This method is applied on compounds which do not respond to HEM. Ring opening takes
place differently in VB and HEM method which is shown in the following degradation.
N
(CH )
32
N
(CH )
32
HEM
VB
CH Br
2
N
CH
3
CN
168
Pharmaceutical Chemistry of Natural Products
In general, CNBr cleaves the unsymmetrical amines to yield the bromides or shorter bromides.
However, in the VB method only dealkylation may occur without ring cleavage in some cases.
N—CH
3
COOCH
3
OCOC
6
H
5
CNBr
N—CN
COOCH
3
OCOC
6
H
5
(i) HCl
(ii) CO⫺
2
N—H
COOCH
3
OCOC
6
H
5
(b) For 2° cyclic amines:
N
H
N
COC H
65
C H COCl
65
PBr –
5
Br
2
N
Br—C—C H
65
Br
Distil under
reduced pressure
Br—(CH ) Br + C H CN
25 6 5
1,5-Dibromo pentane
4. Reductive degradation: Ring system is opened by treating with HI in many cases.
HI
N N
H
(or)
300°C
CH —(CH ) —CH + NH
3233 3
n-Pentane
5. Oxidation: Oxidation gives valuable information about the fundamental structure of alkaloids
and the position and nature of functional groups, side chains, etc.
For example, picolinic acid obtained upon oxidation of coniine indicates that the coniine is an
α-substituted pyridine.
(O)
N
COOH
Picolinic acid
Coniine
By varying the strength of oxidizing agents, a variety of products may be obtained. Different
types of oxidizing agents used are as follows:
1. For mild oxidation: H
2
O
2
, O
3
, I
2
.
2. For moderate oxidation: acid or alkali KMnO
4
, CrO
3
in CH
3
COOH.
3. For vigorous oxidation: K
2
Cr
2
O
7
–H
2
SO
4
, concentrated HNO
3
or MnO
2
–H
2
SO
4
.
6. Zinc distillation: Distillation of alkaloid over zinc dust degrades it into a stable aromatic
derivative.
Phenanthrene
Morphine
Zinc dust
distillation
Alkaloids
169
The reaction indicates that morphine is possessing phenanthrene nucleus.
7. Alkali fusion: Fusion of alkaloids with solid KOH gives simple fragments from which the nature
of alkaloid can be derived.
Substituted isoquinoline
Papaverine
Fusion with
KOH
The reaction indicates papaverine is containing isoquinoline nucleus.
Adrenaline
KOH
fusion
COOHHO
HO
Protocatechuic acid
The reaction indicates adrenaline is a monosubstituted catechol derivative.
8. Dehydrogenation: Distillation of alkaloid with catalysts such as S, Se and Pd yields simple and
recognizable products from which the gross skeleton of the alkaloid may be derived.
Thus with the help of degradation, nature of various fragments obtained, nature of nucleus
and type of linkages are established. The fragments obtained are arranged in the possible ways
with the possible linkages and the one that will explain all the properties is selected and confi rmed
by synthesis. Optical activity of an alkaloid helps greatly in establishing the structure of alkaloid.
Physical Methods in Conjunction with Chemical Methods
The developments in spectroscopic methods not only curtailed time consumption as compared to
degradation studies, but also helped in determining the molecular structure of complex alkaloids.
Morphine structure was established after the developments of the below-mentioned physical
methods. The complete structure of vindoline (including confi guration) has been established by
spectroscopic methods. Thelepogine, another alkaloid structure, has been established using X-ray
analysis technique without performing any of the chemical analysis.
The important physical methods used in structural elucidation of alkaloids are as follows:
1. IR spectroscopy
2. UV spectroscopy
3. NMR spectroscopy
4. Mass spectroscopy
5. X-ray analysis
6. Optical rotatory dispersion (ORD) and circular dichroism
7. Conformational analysis
IR spectroscopy: This method is used to identify the presence of functional groups such as –OH,
–NH
2
, –NH and –C=O. The groups such as –OCH
3
, –NCH
3
, –OH, –NH
2
and –NH can be detected by
IR spectroscopy but quantifi ed by NMR spectroscopy.
NMR spectroscopy: This method helps to detect protons of alkyl, alkenyl, N-methyl, O-methyl,
C-methyl, aryl and heteroaryl groups, etc. It also helps in quantitative estimation of these groups.
Aromatic and heteroaromatic protons are exactly quantifi ed by using NMR spectroscopy.
170
Pharmaceutical Chemistry of Natural Products
UV spectroscopy: UV spectrum of a compound is characteristic of chromophoric system and not the
whole compound. Hence, it helps to establish the likely structural type or class of the alkaloid
under investigation.
Mass spectroscopy: This method is used to confi rm the proposed molecular structure of the alkaloid by
determining the molecular weight of compounds and the fragments of the degradation products.
It also helps to confi rm the side chain or attached groups by analysing the fragmentation pattern.
X-ray analysis: This method is used to distinguish the various possible structures of alkaloids.
ORD and circular dichroism: This method is used to confi rm the structure of optically active
stereoisomers.
Conformational analysis: It is an experimental technique used to establish the stereochemistry as
well as physical properties and chemical reactivity of alkaloids.
Synthesis
The above-mentioned chemical and analytical work helps to propose a tentative structure (or
structures) of the alkaloid under investigation. Synthesis always gives additional evidence for the
assigned structure even though the physical methods (mentioned above) provide fi nal proof of
the proposed structure.
ALKALOIDS OF PHARMACEUTICAL IMPORTANCE
Source of medicinally important alkaloids with their pharmacological properties and uses are
depicted in Table 5.1.
Table 5.1 Source pharmacological properties and uses of alkaloids
S. no. Alkaloids Source (Family) Pharmacological properties/uses
1. Piperine Piper nigrum and other Piper spp
(Piperaceae)
Aromatic, stimulant, stomachic, carminative,
condiment stimulates taste buds and gastric
juice.
2. Nicotine Nicotiana tobaccum (Solanaceae) Stimulant effects on heart and nervous system.
3. Arecoline Areca catechu
(Palmae)
Parasympathomimetic, anthelmentic drug.
4. Lobeline Lobelia nicotianaefolia (Campanulaceae
or Lobeliaceae)
Used in asthma and as respiratory stimulant.
5. Pelletierine Punica granatum (Euphorbiaceae) Anthelmintic against tapeworm. Astringent in
the treatment in diarrhoea.
6. Quinine, quinidine,
cinchonine,
cinchonidine
Cinchona offi cinalis and other Cinchona
spp (Rubiaceae)
Antimalarial, bitter stomachics, antipyretic
Alkaloids
171
S. no. Alkaloids Source (Family) Pharmacological properties/uses
7. Quinidine C. offi cinalis and other Cinchona spp
(Rubiaceae)
Antiarrhythmic
8.
Morphine Papaver somniferum (Papaveraceae) Hypnotic, sedative and analgesic. It sedates
respiratory centre, emetic centre and the
cough refl ux.
9. Codeine P. somniferum (Papaveraceae) Used in the treatment of cough.
10. Thebaine, papaverine,
noscapine, narceine
P. somniferum (Papaveraceae) Hypnotic sedative and analgesic.
11. Berberine Various genera of Berberidaceae
(Ranunculaceae, Papaveraceae)
In the treatment of cutaneous Leishmaniasis.
12. Emetine, cephaline Cephaelis ipecacuanha, Cephalis
accuminata (Rubiaceae)
Expectorant in small doses and emetic in
higher doses. Antiprotozoal against Entamoeba
histolytica.
13. Tubocurarine Chondrodendeon tomentoscum
(Menispermaceae)
Neuromuscular blocking agent, skeletal
muscle relaxant.
14. Galanthamine Leucojum aestivum (Amaryllidaceae) Used in the treatment of Alzheimer’s disease
15. Ergometrine Claviceps purpurea (Clavicipitaceae) Oxytocic in obstetrics.
16. Ergotamine C. purpurea (Hypocreaceae) Specifi c analgesic in the treatment of migraine.
17. Lysergic acid amide Rivea corymbosa
(Convolvulaceae)
As a psychotomimetic.
18. Physostigmine Physostigma venenosum (Leguminosae) Parasympathomimetic (ophthalmic) activity.
19. Reserpine Rauwolfi a serpentine
(Apocynaceae)
As an antihypertensive and in the treatment of
neuropsychiatric disorder.
20. Serpentine R. serpentine
(Apocynaceae)
As an antihypertensive and in the treatment of
neuropsychiatric disorder.
21. Yohimbine Aspidosperma spp
(Apocynaceae)
In the treatment of erectile dysfunction.
22. Vincristine Catharanthus roseus
(Apocynaceae)
As an antineoplastic, for treating leukaemia in
children, as hypotensive and in the treatment
of diabetes.
23. Vinblastine C. roseus
(Apocynaceae)
In the treatment of Hodgkin’s disease.
24. Strychnine Strychnos nux-vomica
(Loganiaceae)
Stomachic, tonic, stimulant to CNS, CVS and
respiratory. Increases blood pressure and
hence used in the treatment of heart failure.
25. Brucine S. nux-vomica
(Loganiaceae)
Stomachic, tonic, stimulant to CNS, CVS and
respiratory. Increases blood pressure and
hence used in the treatment of heart failure.
26. Hygrines Erythroxylum coca
(Erythroxylaceae)
Local anaesthetic and stimulant.
27. Atropine, Hyoscine,
Hyoscyamine
Atropa belladonna, Datura stramonium
and Hyoscyamus spp
(Solanaceae)
Parasympatholytic agent, decreases saliva,
sweat, gastric juice.
28.
Cocaine Cocca spp (Erythroxylaceae) Local anaesthetic, CNS stimulant.
29. Pilocarpine Pilocarpus jaborandi (Rutaceae) Physiological antagonist of atropine, increases
sweating, used in the treatment of glaucoma.