FIELD OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially
advantageous process for the preparation of narwedine, and use thereof in the preparation
of galanthamine or salt thereof.
BACKGROUND OF THE INVENTION
(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-l 1 -methyl-6H-benzofuro-[3a,3,2ef]
[2]benzazepin-6-one, commonly known as narwedine of Formula I is a tertiary
amaryllidaceae alkaloid which is useful as intermediate in synthesis of (-)-galanthamine
of Formula II. Galanthamine is a 6-hydroxy derivative of narwedine, ((-)-[4aS-
(4aa,6p\8aR)]-4a,5,9,10,11,12-hexahydro-3-methoxy-l 1 -methyl-6H-benzofuro-
[3a,3,2,efj[2]benzazepine-6-ol) of Formula II, and is indicated for treatment of
Alzheimer's disease, dementia, mania, fatigue syndrome, schizophrenia and inhibiting
acetyl cholinesterase activity.
H,CO. P H3CO 0*7 /,
„OH
Formula I
Narwedine was first isolated from bulbs of 19 species of trumpet narcissus, 12 species of
cup narcissus, and 8 species of filled narcissus by the extraction process followed by
chromatographic purification of fractions to get crystalline narwedine as reported by
Boite/tf/ChemischeBerichte, 90, 2197-2202, (1957).
Barton et al, Journal of the Chemical Society, Abstracts, 806-817 (1962) describes
several synthetic processes for the preparation of narwedine from galanthamine and other
related alkaloids. Narwedine is isolated from reaction mass by different column
2
chromatography techniques. One such technique uses 95% ethanol, wherein racemic
narwedine is obtained.
In addition there are several processes available in literature for synthesis of racemic or
(+) or (-)-narwedine like EP363415, US5428159, US6369238, US6043359, US6407229,
US6018043, US6093815, US6346618 and US6392038, Journal of Organic Chemistry,
58(15), 3877-3885 (1993), Tetrahedron Letters, 38(45), 7931-7932 (1997), Organic
Process Research & Development, 3(6), 425-431 (1999).
Narwedine prepared as per existing processes posed challenges firstly with respect to
purity of intermediates of narwedine and secondly the high batch cycle-time and purity of
narwedine. These two factors contribute majorly in increasing the cost of process at large
scale and high energy consumption making the processes uneconomical and environment
unfriendly.
Thus, keeping in view the requirement of an efficient synthetic process for the
preparation of narwedine and thereby to galanthamine, the present invention provides an
improved process for the preparation of narwedine and use thereof for the preparation of
galanthamine or its slats, which not only is economical in terms of high purity and yield
of narwedine but also reduces batch-cycle times consuming much lesser energy and thus
providing a viable solution for the need.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to provide an efficient synthetic process
for the preparation of narwedine, which has better control of impurity formation and is
capable of providing narwedine in high yield and purity in simple, economically viable
and environment friendly way.
Another object of the present invention is to provide a process for the preparation of
galanthamine involving use of narwedine obtained by following the improved process,
thereby providing galanthamine in an efficient, economical and environment friendly
process.
3
In accordance with principal object, the present invention provides an improved process
for the preparation of narwedine of Formula I,
H,CO. P
Formula I
comprising the steps of:
(a) hydrolyzing compound of Formula III using suitable acid and isolating compound
of Formula IV by acid-base treatment at pH 5-6.5;
M e O ^ ^ X H O HO^/^XHO XX XX
M e C r ^ ^ B r MeCT^^Br
Formula HI Formula IV
(b) reductive amination of compound of Formula IV with tyramine of Formula V in
presence of reducing agent to afford compound of Formula VI;
OH
NH2 4 H O y ^N
HO' ^ MeO^^Br"
Formula V Formula VI
(c) formylating compound of Formula VI using formylating agent to afford
compound of Formula VII;
4
.OH
r ir
HO..A ^nCHO
MeO ^ ^ Br
Formula VII
(d) oxidative coupling of compound of Formula VII using oxidizing agent to afford
compound of Formula VIII;
MeO
Formula VIII
(e) ketalizing compound of Formula VIII only in presence of propylene glycol to
afford compound of Formula IX;
-N
Br CHO
Formula IX
(f) reducing compound of Formula IX using reducing agent to afford narwedine of
Formula I.
According to another object, the present invention provides a process for preparing
galanthamine and salts thereof, involving use of narwedine of Formula I
5
o
CH3
Formula I
as an intermediate, wherein narwedine is prepared by the process of present invention.
DESCRIPTION OF THE INEVNTION
While this specification concludes with claims particularly pointing out and distinctly
claiming that, which is regarded as the invention, it is anticipated that the invention can
be more readily understood through reading the following detailed description of the
invention and study of the included examples.
In an effort to develop a simple, efficient, environment friendly and high yielding process
for the preparation of narwedine, an intermediate of galanthamine, the inventors of
present invention found that the process as disclosed in US6407229 for the regioselective
demethylation of compound of Formula IV yields compound of Formula IV having an
impurity at RRT = 0.22 in more than 1.0% amount on large scale, which then needed reprocessing
of intermediate of Formula IV to make it compatible for required
specifications to be used for next step. The reprocessing and purification is not only time
consuming, laborious and demand utilities, but also leads to lowering yields and consume
solvents in large volumes, which generates large volumes of effluent making the process
uneconomical and environment unfriendly. The inventors of present invention
successfully identified the bottle-neck of the prior art process, wherein after the
demethylation reaction is complete, the reaction mixture is subjected to basification and
the desired product of compound of Formula IV is isolated by addition of concentrated
hydrochloric acid. The addition of hydrochloric acid was not done under monitoring of
pH of the reaction mixture, it was successfully observed and concluded that while
addition of hydrochloric acid, the impurity at RRT = 0.22 is largely formed when the pH
6
of reaction mixture drops below 3-3.5, which largely contributes to formation of impurity
and thereby compels the purification of resulting intermediate. As a remedy, a process
was very successfully devised by present inventors, wherein the addition of hydrochloric
acid during isolation of compound of Formula IV is kept under control i.e. between 5-6.5,
as a result the precipitated compound of Formula IV was of required specifications to be
used as such for next step to prepare narwedine.
Furthermore, in the application of process for the preparation of narwedine and then to
galanthamineas disclosed in US6407229 on large scale, it was observed by present
inventors that the ketalization reaction of compound of Formula VIII to Formula IX
involving use of propylene glycol and toluene as solvent in the presence of sulphamic
acid took about 5-7 days for reaction completion and also compound of Formula IX was
not obtained in yields compatible for large scale production. These aspects of process
contributed to large energy consumptions in terms of maintaining temperature conditions
for such long time which not only is inconvenient and expensive but also leads to
formation of impurities, thereby requiring purification of resulting intermediate, which
subsequently affects the yield. The extensive studies by inventors of present invention
successfully led them to obtain the optimum reaction conditions, wherein they found that
carrying out ketalization of compound of Formula VHIonly in propylene glycol i.e. using
it as a reagent as well as solvent gave completion of reaction to compound of Formula IX
in 7-11 hours as against the 5-7 days as was achieved by prior art process. These
optimized conditions not only provided achievement in terms of highly reduced reaction
time but also gave added advantage of improved yield, which made the process highly
suitable for commercial production.
Understanding, the limitations of prior art and for the need of an advantageous process
for the preparation of galanthamine, the present invention is directed to an improved
process of preparing narwedine by careful selection of reaction conditions involving use
of control on pH during work-up stepto isolate compound of Formula IV and
subsequently use of single solvent for reaction of compound of Formula VIII to IX. Thus,
the resulting reaction conditions of present invention not only saved multiple purification
steps to make the final product qualify for required standards but by reducing reaction
time, it saved the overall time-cycle of a batch, a lot of energy making the process dual
advantageous in terms of energy saving and being environment friendly on commercial
scale.
According to one embodiment, the present invention provides an improved process for
the preparation of narwedine of Formula I in simple, efficient and environment friendly
way
H3CO,
Formula I
comprising the steps of:
(a) hydrolyzing compound of Formula III using suitable acid and isolating compound
of Formula IV by acid-base treatment at pH 5-6.5;
M e O . / ^ X H O HO^^XHO XX XX
MeCT^^^Br MeCT^^Br
Formula III Formula IV
(b) reductive amination of compound of Formula IV with tyramine of Formula V in
presence of reducing agent to afford compound of Formula VI;
8
fr0H
NH2 HO_^^N/-^A^
HO' ^ MeO-^^Br"
Formula V Formula VI
(c) formylating compound of Formula VI using formylating agent Lo afford
compound of Formula VII;
rr0H
M ^A^AD CHO
MeO ^ ^ Br
Formula VII
(d) oxidative coupling of compound of Formula VII using oxidizing agent to afford
compound of Formula VIII;
-N
Br fcHO
Formula VIII
(e) ketalizing compound of Formula VIII only in presence of propylene glycol to
afford compound of Formula IX;
-N
Br tHO
Formula IX
9
(f) reducing compound of Formula IX using reducing agent to afford narwedine of
Formula I.
According to present invention, the compound of formula III is hydrolyzed in step (a)
using an acid wherein the acid used is selected from the group comprising of inorganic
acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and the like;
organic acid such as acetic acid, formic acid, and the like. The solvent used for hydrolysis
is selected from the group comprising of alcohols such as ethanol, butanol and the like;
esters such as ethyl acetate, propyl acetate and the like; water and mixtures thereof. The
hydrolysis reaction is carried out at a temperature of about 70-90 °C in about 4-6 hours.
The reaction is monitored and on completion of reaction, acid-base treatment of reaction
mixture is used for isolation of resulting compound of Formula IV, wherein the reaction
mixture is first basified using a base selected from the alkali or alkaline earth metal
hydroxide, carbonate and bicarbonate. The desired compound when extracted in aqueous
layer as a salt is then subjected to acidification wherein the acidification of solution is
done up to pH 5-6.5 so as to obtain the compound of Formula IV is the very pure form
with highly controlled impurity of RRT = 0.22. The acid used for acidifying the aqueous
layer is selected from the group comprising of hydrochloric acid, hydrobromic acid,
acetic acid and the like. The isolated compound of Formula IV is of very high purity and
does not require any further purification to match the specifications to be used in next
step.
According to the present invention, the compound of Formula IV is reductively aminated
in step (b) using tyramine of Formula V in presence of reducing agent and solvent to
afford compound of Formula VI. The solvent used is selected from the group comprising
of alcohols such as methanol, ethanol, butanol and the like; esters such as ethyl acetate,
propyl acetate and the like; water and mixtures thereof. The reducing agent used is
selected from the group comprising of sodium borohydride, lithium aluminium hydride,
sodium hydride and the like. The reaction is optionally catalyzed using a base selected
from the group comprising of sodium hydroxide, potassium hydroxide and the like. The
reductive amination is carried out at reflux temperature for about 2-6 hours to afford
compound of Formula VI.
10
According to present invention, the compound of Formula VI is formylated in step (c)
using a formylating agent in solvent to obtain compound of Formula VII. The
formylating agent used is selected from the group comprising of formic
acid/ethyl formate, Vilsmeier-Haack reagent and the like. The solvent used for
formylation is selected from the group comprising of amides such as dimethylformamide
and the like. The reaction is carried out at 65-80 °C for about 9-11 hours to afford
compound of Formula VII.
According to present invention, the compound of Formula VII is subjected to oxidative
coupling using an oxidizing agent in presence of solvent in step (d) to obtain compound
of Formula VIII. The oxidizing agent used is selected from the group comprising of
potassium ferrocyanide, potassium permanganate, sodium hypochlorite, hydrogen
peroxide and the like. The solvent used is selected from the group comprising of esters
such as ethyl acetate, propyl acetate and the like; aromatic hydrocarbons such as, toluene,
xylene and the like; water and mixtures thereof. The reaction is optionally catalyzed
using a base selected from the group comprising of alkali and alkaline earth metal
hydroxide, carbonate and bicarbonate, wherein the alkali and alkaline earth metal is
selected from the group comprising of sodium potassium, calcium and the like. The
oxidative coupling is carried out at about 55-70 °C for about 2-4 hours On completion of
reaction monitored by HPLC, the compound of Formula VIII is isolated by work-up
techniques known in the art.
According to the present invention, the compound of Formula VIII is subjected to
ketalization reaction in step (e) to compound of Formula IX, wherein propylene glycol is
used as both the reagent and solvent in presence of catalyst selected from the group
comprising of sulfamic acid and the like. The reaction is carried out at about 105-120 °C
for about 7-11 hours. The use of propylene glycol as reagent and solvent provides an
edge to present invention by completing the reaction in just 7-11 hours as against about 7
days as per prior art process used for large scale production. The compound of Formula
IX so obtained is optionally isolated for next reaction and is mostly used in-situ for next
step, as the controlled reaction time provides compound of Formula IX in the required
specifications, which needs no or very fewer purification treatment.
11
According to present invention, the compound of Formula IX is subjected to reduction
using reducing agent in step (f) to obtain narwedine.' The reducing agent used to affect
reduction of compound of Formula IX is selected from the group comprising of sodium
hydride, lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride
(vitride) and the like. The reaction is carried out using solvent selected from the group
comprising of aromatic hydrocarbon such as toluene, xylene and the like; water and
mixtures thereof. The reduction reaction is carried out at temperature of about 90-110 °C
for about 2-5 hours. The reaction is monitored by HPLC and on completion of reaction
the narwedine is isolated by usual work-up techniques known in the prior art.
According to another embodiment, the narwedine obtained by following the process of
present invention is used for the preparation of galanthamine and salts thereof by
processes well known in the art.
The starting materials and regents for the process of present invention are either
commercially available, known in the literature or may be prepared following literature
methods. The intermediates or final product involved in the present process may be
purified by crystallization, distillation or combination of techniques well-known in the
art.
EXAMPLES:
Example 1: Preparation of 2-bromo-5-hydroxy-4-methoxybenzaldehyde:
To sulphuric acid (1104 gm), charged 2-bromo-4,5-dimethoxybenzaldehyde (100 gm) at
about 45 °C, and raised the temperature of resulting reaction mixture to about 85 °C. The
reaction mixture was stirred at about 85 °C for about 6 hours. The progress of reaction
. was monitored by HPLC. On completion of reaction, the reaction mixture was gradually
cooled to 25 °C and poured in water (2000 ml) at about 10 °C, the reaction mixture was
then stirred and the solid so obtained was filtered and dried. The solid was then added to
a sodium hydroxide (24.5 gm) solution in water (1000 ml) at about 25 °C. The
temperature of reaction mixture was raised to about 85 °C and maintained for 1 hour
while stirring. The temperature was lowered to about 45 °C and layers were separated.
12
The aqueous layer was cooled to about 30 °C and then concentrated hydrochloric acid
was added slowly while monitoring the pH of reaction mixture and adjusted to pH 6.0-
6.5. The reaction mixture was then maintained at about 30°C for about 2 hours, the solid
material was filtered, washed with water and dried to.afford the title compound with
Assay (HPLC w/w) ~ 98%.
Example 2: Preparation of 4-bromo-5-(((4-hydroxyphenethyl)amino)methyl)-2-
methoxyphenol
To a solution of tyramine (54.4 gm) in methanol (425 ml) was added 2-bromo-5-
hydroxy-4-methoxybenzaldehyde (100 gm). The reaction mixture was allowed to reflux
for about 4 hours and then cooled to 5-10 °C. In the cooled reaction mixture, slowly
added sodium borohydride solution (12.66 gm in 0.125% sodium hydroxide solution),
and stirred the reaction mixture for about 1 hour at 20-25°C. The progress of reaction was
monitored by HPLC. On completion of reaction, the reaction mixture was poured into ice
water (1600 ml) while stirring. The solid obtained was filtered and washed with water to
afford title compound.
Example 3: Preparation of N-(2-bromo-5-hydroxy-4-methoxybenzyl)-N-(4-
hydroxyphenethyl)formamide
To a solution of 4-bromo-5-(((4-hydroxyphenethyl)amino)methyl)-2-methoxyphenol
(100 gm) in dimethylformamide (400 ml), ethyl formate (114.1 ml) and formic acid (20
ml) were added at 20-25°C. The temperature of reaction mixture was raised to 70-75 °C
and maintained for about 10 hours. After completion of reaction, the reaction mixture
was cooled to about 30-35 °C, poured into water (2000 ml) and stirred. The solid material
was filtered and washed with water (400 ml) and dried to afford title compound.
Example 4: Preparation of l-bromo-3-methoxy-6-oxo-4a,5,9,10-tetrahydro-6Hbenzo[
2,3]benzofuro[4,3-cd]azepine-l l(12H)-carbaldehyde
To a solution of potassium carbonate (200 gm) in toluene (13000 ml), added a solution of
potassium ferricyanide (400 gm) in water (2000 ml). The temperature of the reaction
mixture was raised to 60-65 °C and added l-bfomo-3-methoxy-6-oxo-4a,5,9,10-
13
tetrahydro-6H-benzo[2,3]benzofuro[4,3-cd]azep'ihe-l l(12H)-carbaldehyde (100 gm). The
resulting reaction mixture was then stirred for about 3 hours. After completion of
reaction, the reaction mixture was filtered and layers were separated and aqueous layer
was extracted with toluene. The solvent from organic layer was distilled to afford title
compound.
Example 5: Preparation of l-bromo-3-methoxy-4'-methyl-4a,5,9,10-
tetrahydrospiro[benzo[2,3]benzofuro[4,3-cd]azepine-6,2'-[l,3]dioxolane]-ll(12H)-
carbaldehyde
To a solution of l-bromo-3-methoxy-6-oxo-4a,5,9,10-tetrahydro-6Hbenzo[
2,3]benzofuro[4,3-cd]azepine-ll(12H)-carbaldehyde (70 gm) in propylene glycol
(840 ml), added sulfamic acid (6 gm) at 25-30°C. The temperature of reaction mixture
was raised to about 110-120 °C and maintained for about 3 hours while stirring. A
fraction of solvent from reaction mixture was slowly distilled in about 9 hours keeping
temperature of 110-120 °C. The reaction was monitored by HPLC, on completion of
reaction, the reaction mixture was cooled to about 45°C and toluene (420 ml) was added
and stirred. The layers were separated and solvent was distilled out from organic layer to
obtain title compound as oily liquid used as such in next step.
Example 6: Preparation of narwedine
To a solution of l-bromo-3-methoxy-4'-methyl-4a,5,9,10-tetrahydrospiro[benzo[2,3]
benzofuro [4,3-cd]azepine-6,2'-[l,3]dioxolane]-ll(12H)-carbaldehyde (obtained as oily
liquid from Example 5) in toluene (400 ml), slowly added 70% vitride solution in toluene
(123 ml) at 5-10°C under inert atmosphere. The temperature of reaction mixture was
raised to about 105°C, maintained for 3-4 hours and then lowered the temperature to
about 80°C and monitored the progress of reaction by HPLC. After the completion of
reaction, the reaction mixture was further cooled to about 10°C and an aqueous solution
of sodium hydroxide was added (47 gm sodium hydroxide in 240 ml water). The reaction
mixture was stirred and layers were separated. The solvent from organic layer was
distilled out to obtain oily residue, which was treated with isopropyl alcohol-hydrochloric
acid at about 15°C. The temperature of reaction mixture was raised to about 60°C and
14
maintained for about 1 hour while stirring. The reaction mixture was then cooled slowly
to obtain solid precipitates, which was filtered washed with isopropyl alcohol and dried to
obtain narwedine.
HPLC purity: 98.4%
Yield: 60%
15
<

CLAIMS:
1. A process for the preparation of narwedine of Formula I,
Formula I
comprising the steps of:
(g) hydrolyzing compound of Formula III using suitable acid and isolating compound
of Formula IV by acid-base treatment at pH 5-6.5;
M e O ^ ^ X H O HO^/^XHO
M e C T ^ ^ B r MeCT^^Br
Formula III Formula IV
(h) reductive amination of compound of Formula IV with tyramine of Formula V in
presence of reducing agent to afford compound of Formula VI;
f^Y0H
H C T ^ MeCT^Br"
Formula V Formula VI
(i) formylating compound of Formula VI using formylating agent to afford
compound of Formula VII;
16
,, ^ A ^ 0 CHO MeO ^^ Br
Formula VII
(j) oxidative coupling of compound of Formula VII using oxidizing agent to afford
compound of Formula VIII;
Formula VIII
(k) ketalizing compound of Formula VIII only in presence of propylene glycol to
afford compound of Formula IX;
Formula IX
(1) reducing compound of Formula IX using reducing agent to afford narwedine of
Formula I.
2. The process as claimed in claim 1, wherein the acid used in step (a) is selected
from the group comprising of inorganic acid selected from hydrochloric acid,
hydrobromic acid, sulphuric acid, nitric acid; organic acid selected from acetic
acid and formic acid.
1.1^0; D E L H I ZB:-- 8 r l - •zener JLTT
17
: 2;§;
3. The process as claimed in claim 1, wherein the reducing agent used in step (b) is
selected from the group comprising of sodium borohydride, lithium aluminium
hydride and sodium hydride.
4. The process as claimed in claim 1, wherein the formylating agent used in step (c)
is selected from the group comprising of formic acid/ethylformate and Vilsmeier-
Haack reagent.
5. The process as claimed in claim 1, wherein the oxidizing agent used in step (d) is
selected from the group comprising of potassium ferrocyanide, potassium
permanganate, sodium hypochlorite and hydrogen peroxide.
6. The process as claimed in claim 1, wherein the reducing agent used in step (f) is
selected from the group comprising of sodium hydride, lithium aluminium
hydride and sodium bis(2-methoxyethoxy)aluminium hydride (vitride).
7. A process for the preparation of galanthamine or salts thereof comprising
narwedine of Formula I
Formula I
as an intermediate, wherein narwedine is prepared by a process comprising the
steps of:
(a) hydrolyzing compound of Formula III using suitable acid and isolating compound
of Formula IV by acid-base treatment at pH 5-6.5;
M e O ^ ^ / C H O HO^/^XHO
M e C T ^ ^ B r MeCT^^Br
Formula III Formula IV
j 18
I . F ©" Q;ELM I. 2:0 - S 1 . - - 2 B 1 6 - 17 £.:
(b) reductive amination of compound of Formula IV with tyramine of Formula V in
presence of reducing agent to afford compound of Formula VI;
rr0H
H C T ^ MeO-^^Br1 11
Formula V Formula VI
(c) formylating compound of Formula VI using formylating agent to afford
compound of Formula VII;
OH
r fir
MecA^BrCH°
Formula VII
(d) oxidative coupling of compound of Formula VII using oxidizing agent to afford
compound of Formula VIII;
MeO II
-N
Br tHO
Formula VIII
(e) ketalizing compound of Formula VIII only in presence of propylene glycol to
afford compound of Formula IX;
/
19
-N
Br CHO
Formula IX
(f) reducing compound of Formula IX using reducing agent to afford narwedine of
Formula I.