Structure Elucidation of Reserpine (M. Pharm)

M. Pharm. (Pharmaceutical Chemistry)

1. STRUCTURE ELUCIDATION
OF RESERPINE
PRESENTED BY:
MOHD SHAFEEQUE
M. PHARM. 1
ST
SEM.
(PHARM. CHEMISTRY)
JAMIA HAMDARD

2. CONTENTS:
➢INTRODUCTION
➢PROPERTIES
➢ISOLATION
➢IDENTIFICATION TESTS
➢USES
➢STRUCTURE ELUCIDATION
➢SYNTHESIS
➢REFERENCES

3. RESERPINE
(Indole Alkaloid)
Synonyms: Crystosprine, Eskaserp, Reserpoid, Rivasin, Sandril,
Sedaraupinetc.
Biological source:Major source of Reserpine is dried roots of the
Rauvolfiaserpentina(Apocynaceae).
Chemical Structure:
(3b,16b,17a,18b,20a)-11,17-Dimethoxy-18-[(3,4,5-trimethoxy benzoyl)oxy]
yohimban-16-carboxylic acid methyl ester.C
33
H
40
N
2
O
9 NH
N
H
3
CO
OCH
3
OCO
OCH
3
OCH
3
OCH
3
H
3
COOC
H
H
H

4. PROPERTIES:
➢Colour–White or pale buff to slightly yellow coloured. Darkens
slowly on exposure to light when powder, more rapidly when
solution.
➢State–Small crylstalsor crystalline powder.
➢Odour–Odourless
➢Reserpine is a weakly basic in nature, pKa-6.6
➢It decomposes at 264 –265 °C
➢It is found to freely soluble in chloroform (~1g/6ml), glacial acetic
acid, methylene chloride; soluble in benzene, ethyl acetate; slightly
soluble in acetone, methanol, ethanol (1g/1800ml), ether,inaqueous
solutions of citric acids; and very sparingly soluble in water.

5. ISOLATION:
Roots are powdered & moisten with 10% NaHCO3& extracted with Benzene, until the
extract gives a weak positive reaction with HgI2
Concentrate it , add Ether & Dil. HCl. The combined acidic solution is washed with Ether
filtered and extracted with CHCl3
The extract is washed subsequently with 10% Sod. Carbonate Solution followed by
water so as to get rid of any free acid present
The resulting extract is finally evaporated to dryness under vacuum
The residue is dissolved in anhydrous Methanol and seeded with pure crystal of
Reserpine
Pure crystal of Reserpine obtained

6. IDENTIFICATION TEST:
A.Most Solutions of reserpine upon standing acquire a distanctyellow
colourationand a marked and pronounced fluorescence, especially after the
addition of an acid or upon exposure to light.
B.Reserpine Hydrochloride Hydrate (C
33H
43Cl N
2O
10): It is obtained as crystals
which decomposes at 224 °C.
USES:
A.It is a hypotensive drug which exhibits strong hypotensive and sedative
activity.
B.It is employed to alleviate mild anxiety conditions. (Tranquillizing Effect)

7. STRUCTURE ELUCIDATION OF RESERPINE:
1.Molecular Formula:
The mol. Formula of reserpine is C
33H
40N
2O
9.
2.Presence of 5 Methoxy Group:
On heating with HI it gives 5 moles of Methyl Iodide (ZieselMethod)
indicating the presence of 5 methoxy groups.
3.Nature of Nitrogen Atom:
Reserpine forms monoacetyldtv. Indicating the presence of an –NH-
(secondary nitrogen) group. It is further confirmed by IR spectra which
reveals the presence of an indole nucleus. Reserpine readily gives a
methiodide, so the second nitrogen atom must be tertiary.
4.Hydrolysis:
Reserpine upon alkaline hydrolysis gives-METHANOL, 3,4,5-
TRIMETHOXYBENZOIC ACID and another ACID A (ReserpicAcid).

8. •Since reserpine has no –COOH or –OH group, the introduction of two
carboxyl acidic grp and two hydroxyl groups in the hydrolysis products
suggest that reserpine is a diester.
•This is further confirmed by the reduction of reserpine with LiAlH4to
reserpicalcohol and 3,4,5-trimethoxybenzyl alcohol.C
33
H
40
N
2
O
9
2H
2
O CH
3
OH C
22
H
28
N
2
O
5+
COOH
H
3
CO
OCH
3
OCH
3
+ +
NaOH
Reserpine
ReserpicAcid
3,4,5-Trimethoxybenzoic
acid

9. 5.Structure of ReserpicAcid:
i.Bytheusualtestreserepicacidisfoundtopossesstwomethoxy,onecarboxylic,
onesecondaryalcoholic,onesecondaryandonetertiaryaminogroups.
ii.PresenceofIndoleNucleus:
Onpermanganateoxidation-
iii.Reserpicacidonfusionwithpotashgives5-hydroxyisophthalicacid.Nowsince
oneoftheacidicgroupsofisophthalicacidmustbetheacidicgroupofreserpic
acidaremetatoeachother.Thesameisconfirmedbythefactthatreserpicacid
yieldsag-lactoneonheatingwithAc2O.C
22
H
28
N
2
O
5
H
3
CO N
COOH
COOH
O
H
KMnO
4
4-Methoxy-N-oxalyl anthranilic acidC
22
H
28
N
2
O
5
COOH
OHHOOC
KOH
Fusion OHHOOC
CO
O

10. iv.On Selenium Dehydrogenation:
Methyl reserpateaffords a compound of the composition C
19H
16N
2 (Yobyrine) as
one of the principal product.
The compound yobyrinecondenses with aldehydes suggesting the presence of
pyridine ring with a -CH2-substituent adjacent to nitrogen. It gives 3-ethylindole
and isoquinolineon zinc dust distillation , pthallicacid on permanganate
oxidation, and ortho-toluic acid on chromic acid oxidation. C
19
H
16
N
2
CH
3
COOH
COOH
COOH
N
C
2
H
5
H
N
+
KMnO
4Chromic
Acid
Zn dust
o-toluic acid
Phthalic acid
Yobyrine
3-Ethylindole
IsoquinolineN
N
H
H
➢All these reaction suggest the following
structure to yobyrine.
➢The above proposed structure for yobyrine
is confirmed by its synthesis.

11. ➢The formation of yobyrinefrom reserpicacid indicates that the latter
has the following type of carbon skeleton.8
13
9
12
10
11
7
2
N
1
6
5
3
N
4
14 15
19
18
20
17
16
21
H N
N
H
CH
3
CH
3
OH
✓From point (II)-Methoxy group is present at C-11 (meta
position to the –NH-grp of indole.
✓Presence of carboxyl group at C-16 indicated by the
dehydrogenation of reserpicacid with selenium to 11-
hydroxy-16-methylyobyrine (during dehydrogenation –
COOH grp is converted into -CH3).
✓From point (III) –We can conclude –OH grp present at C-
18 position because –COOH & -OH grp present at meta
to each other.
✓The second methoxy group has been assigned position
C-17 on biogenetic reason.
11-hydroxy-16-methylyobyrine

12. ❑Thus the complete structure of reserpicacid may be
written as:NH
N
H
3
CO
OCH
3
OCO
OCH
3
OCH
3
OCH
3
H
3
COOC
6.On the basis of the above structure of reserpicacid , reserpine (a diester
of reserpicacid ) has been assigned the following structure.NH
N
H
3
CO
OCH
3
HOOC
OH

13. 7.The structure of reserpine has been proved by its synthesis.
Synthesis of Reserpine:O
O
CH
2
HOOC
O
O COOH O COOH
OH
O COOH
OH
O
O COOH
O
O
O
O
O
O
OH
Diel's Alder
Reaction+
NaBH
4
C
6
H
5
CO
3
H
Ac
2
O
-
AcONaAluminium
isopropoxide
-H
2
O

14. O
O
O
O
O
O
OCH
3
O
O
O
OCH
3
OH
Br
O
O
O
OCH
3
O
Br
OCH
3
O
OH
COOH
OCH
3
O
OAc
OH
OH
COOCH
3
OHC
H
3
COOC
OCH
3
OAc
COOCH
3
H
3
COOC
OCH
3
OAc
COOCH
3
H
3
COOC
N
NH
H
3
CO
NH
2
NH
H
3CO
CH
3
ONa
CH
3
OH
NBS
-
H
2
SO
4
CH
3
COOHCrO
3
Zn
CH
3
COOH
(
1
) CH
2
N
2
(
2
) Ac
2
O
-
Pyridine
(
3
) OSO
4
-
H
2
O
(
1
) HIO
4
(
2
) CH
2
N
2
(
6
-
Methoxytryptamine) NaHB
4

15. NH
N
H
3
CO
OC OC
OCH
3
H
3COOC
OCH
3
OAc
COOCH
3
H
3COOC
NH
NH
H
3
CO
NH
N
H
3
CO
OCH
3
OA c
H
3
COOC
NH
N
OAc
OCH
3
H
3COOC
H
3CO
O
NH
N
H
3
CO
OCH
3
OCO
OCH
3
OCH
3
OCH
3
H
3
COOC
-CH
3
OH
(
1
) POCl
3
(
2
) NaHB
4
(
1
) Resolve
(
2
) NaOH
(
3
) HCl
(
4
) DCC
OCH
3
OCH
3
OCH
3
C lOC
(
1
) Isomerism
(
2
) CH
3
OH
(
3
) Reserpine
(Isoreserpicacid lactone)

16. REFERENCES:
•O. P. Agarwal; Chemistry Of Natural products, Vol-1, Goel Publishing
House, Delhi, Page no.-290 –295.
•Ashutosh Kar; Pharmacognosy and Pharmacobiotechnology, New Age
International Pvt Ltd, New Delhi, Page no.-512,513.

17. THANK YOU