Field of the Invention
The present invention relates to an improved process for the preparation of labetalol
hydrochloride. The present invention also relates to a process for the purification of
labetalol hydrochloride.
Background of the Invention
The substance labetalol is known from US4012444 by Allen & Hanburys limited. It has
two asymmetric centers and therefore exists as a molecular complex of two
diastereoisomeric pairs. Dilevalol, the R,R' stereoisomer, makes up 25% of racemic
labetalol. Labetalol hydrochloride, also known by brand name "Trandate" is an
adrenergic receptor blocking agents that have both selective alpha 1 -adrenergic and nonselective
beta-adrenergic.receptor blocking actions.
Labetalol hydrochloride when used in combination with hydrochlorothiazide is known as
"Normozide" is a mixed alphafbeta adrenergic antagonist, which is used to treat high
blood pressure. Labetalol hydrochloride is a racemic compound and chemically known as
5-[l-hydroxy-2-(l-methyl-3-phenylpropyl)-aminoethy1] salicylamide hydrochloride,
which is represented by Formula 1.
Formula 1
US4012444 describes labetalol hydrochloride as a white solid and is prepared by
recrystallisation of crude labetalol hydrochloride using ethanol and ethyl acetate.
British patent GB2152931 describes a process for the preparation of labetalol
hydrochloride of Formula I. The process comprises the reaction of 2-hydroxy-5-(Ihydroxy-
2-aminoethy1)-benzamide. hydrochloride and I-phenyl-but-I-ene-3-one-to give 2=-. . --. -.
hydroxy-5-(I-hydroxy-2-[(I -phenyl-but- 1 -ene-3-y1idene)iminol-ethyl)benzamide.The
obtained compound is further treated with palladium on charcoal catalyst using a solvent
to form labetalol. It is further converted to its hydrochloride salt using ethanolic hydrogen
chloride.
British patent GB2149399 describes a process for the preparation of labetalol
hydrochloride of Formula 1 in which 1-phenyl-3-aminobutane and 4-hydroxy-3-
carbamoylphenacylbromide is condensed in presence of ethanol and concentrated
hydrogen chloride is then added, the product is crystallized. Further, reduced to obtained
labetalol free base using a reducing agent such as sodium borohydride. Labetalol free
base is then converted to labetalol hydrochloride of Formula 1 using acetone and
concentrated hydrogen chloride.
The process can be illustrated by the below Scheme -1
Formula 2 Formula 3 Formula 4A
CONH,
OH
pNH@/Ha OH - HO CONH2
Formula 1 Formula 1A
Scheme -1
None of the methods reported in prior art involving the process of purification of
labetalol hydrochloride by using solvent / anti-solvent method.
The advantage of the anti-solvent crystallization is that the process can be carried out at
temperatures near the ambient temperature. Also, the process would demand less energy
than a solvent evaporation process. Thus, there is a need to develop a simple, cost
effective, high yielding and easy to implement on industrial scale process for the
preparation of labetalol hydrochloride.
Obiect of the invention
One object of the present invention is to provide an improved, efficient, safe and
convenient process for preparation of labetalol hydrochloride.
Another object of the present invention is to provide a process for the purification of
labetalol hydrochloride by using solvent / anti-solvent method.
Summaw of the invention
In accordance with principal embodiment, the present invention provides an improved
process for the preparation of labetalol hydrochloride of Formula 1 comprising the steps
of
(a) reacting 5-bromoacetyl salicylamide of Formula 2
Formula 2
with 2-amino-4-phenylbutane of Formula 3 in presence of a suitable solvent, with
or without water
Formula 3
to provide compound of Formula 4
Formula 4
optionally, purifying compound of Formula 4 by acid-base treatment or by
crystallization or as it's salts;
(b) treating with a reducing agent in presence of a solvent or solvent mixture, suitable
base to provide labetalol;
(c) optionally converting labetalol to its hydrochloride salt;
(d) dissolving in a suitable solvent;
(e) optionally treating with activated carbon and filtering the reaction mixture;
(f) adding suitable anti-solvent and;
(g) isolating labetalol or hydrochloride thereof.
In accordance with another embodiment, the present invention provides a process for the
purification of labetalol hydrochloride of Formula 1, which comprises the steps of:
(a) contacting labetalol hydrochloride with a suitable solvent;
(b) optionally treating with activated carbon and filtering the reaction mixture;
. - (c) adding suitable anti=sol.v.ent and;- - - -- - - - - - - - - - - - - -- -
(d) isolating compound of Formula 1.
In accordance with yet another embodiment, the present invention provides an improved
process for the preparation of labetalol hydrochloride of Formula 1 which comprises the
steps of
(a) reacting 5-bromoacetyl salicylamide of Formula 2 ;
1 Formula 2
I with 2-amino-4-phenylbutane of Formula 3 in presence of methanol
Formula 3
to provide compound of Formula 4
Formula 4
optionally, purifying compound of Formula 4 by acid-base treatment or by
crystallization or as it's salts;
r (b) treating with a sodium borohydride in water and suitable base to provide labetalol;
(c) converting labetalol to its hydrochloride salt; - -
(d) dissolving in methanol;
(e) optionally treating with activated carbon and filtering the reaction mixture;
(f) adding ethyl acetate and;
(g) isolating labetalol hydrochloride compound of Formula 1.
Detail description of the drawings:
, Fig. 1 . XRD of labetalol hydrochloride obtained according to example 3.
Fig.2. XRD of labetalol hydrochloride obtained according to example 4.
Detail description of the invention
Accordingly the present invention provides an improved and industrially advantageous
process for the preparation of labetalol hydrochloride.
Accordingly, the present invention also provides a process for the preparation of labetalol
hydrochloride of Formula 1 comprising the steps of reacting 2-amino-4-phenylbutane
with 5-bromoacetyl salicylamide in the presence of suitable solvent, with or without
water. Generally reaction may be carried out at a temperature of 0 to 40 OC for few
minutes to few hours or till completion of reaction. Preferably reaction is conducted at a
temperature of 0 to 5 OC and it takes 5 to 10 hours for completion of the reaction.
Solvent includes but not limited to alcohol selected from the group comprising of
methanol,' ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like, preferably
solvent used is methanol. The reaction completion is monitored by techniques such as
thin layer chromatography (TLC), high performance liquid chromatography (HPLC),
ultra performance liquid chromatography (UPLC) and like thereof.
._After completion.of reaction,-the conc. hydrochloric acid may be added.to.adjust.the pH -
to about 1-2. Generally addition may be carried out at a temperature of 0-10 OC in few
minutes to hour. Thereafter reaction mixture is stirred at a temperature of 0-10 OC for
few minutes to few hours till complete precipitation. Preferably reaction mixture is stirred
for 8-10 hours at 0-5 OC. The precipitated solid hydrochloride salt of compound of
Formula 4 can be isolated by suitable techniques such as filtration, centrifugation and the
like thereof. Excess 2-amino-4-phenylbutane can be recovered from mother liquor by
distillation of solvent followed by basification in water and extraction in a solvent
followed by distillation.
Thereafter, the salt of compound of Formula 4 may be treated with a suitable base in the
presence of solvent. The solvent is selected from alcohol, ether, water or mixture thereof.
The solution is further cooled and suitable reducing agent is added. The reaction mixture
is stirred at a temperature of 20-40 "C for few minutes to few hours till completion of the
reaction. The base used may be selected from organic or inorganic base, wherein
inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates
selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium
hydroxide, sodium carbonate, potassium carbonate, calcium carbonateor the like,
preferably base used is sodium hydroxide. The reducing agent may be selected from
sodium borohydride, lithium borohydride, vitride, selectride and the like thereof,
preferable reducing agent used is sodium borohydride.
After completion of the reaction, reaction mixture is cooled to 0-1 0 OC, solvent is added,
adjusted the pH to around 1-2 using conc. hydrochloric acid. The solvent used in this step
may be selected from ester solvent seleceted from the group comprising of methyl
acetate, ethyl acetate, n-propyl acetate, isopropyl acetate and the like, preferably ester
solvent used is ethyl acetate. The resulting labetalol hydrochloride can be isolated by
suitable techniques such as filtration, centrifugation and the like thereof known in the art.
The compound may be further washed with water, solvent or mixture thereof.
. Labetalol hydrochloride may-- further be- purified by . solvent-antisolvent method
comprising the steps of contacting labetalol hydrochloride with a suitable solvent
followed by optionally treating with finely powdered activated carbon or silica gel. The
carbon or silica gel treatment can be performed at a temperature of 25°C to reflux
temperature of solvent for 30 to 60 minutes. Preferably carbon or silica gel treatment may
be done at 40 to 65 "C, more preferably carbon treatment is done at 50 to 60 "C. The
carbon or silica gel can be removed by the suitable technique such as centrifugation,
direct filtration or filtration through hyflo. Suitable solvent may be selected from alcohol
selected from as the group comprising of methanol, ethanol, n-propanol, isopropanolol,
n-butanol, isobutanol and the like. Thereafter suitable anti solvent may be added slowly
at a temperature range of 0 to 25 "C, preferably 0 to 5 "C to precipitate the desired
compound. Suitable anti solvent may be selected from ester selected from the group
comprising of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl
acetate and the like, preferably ester solvent used is ethyl acetate. The resulting
compound labetalol hydrochloride can be isolated by suitable techniques such as
filtration, centrifugation and the like thereof known in the art. Labetalol hydrochloride
may also be purified by using acid base treatment.
Major advantages realized in the present invention are that process can be easily and
conveniently scaled-up for industrial large scale production. The process is simple
economic high through output operationally efficient environment friendly.
Although the following examples illustrate the present invention in more detail but the
examples are not intended in any way to limit the scope of the present invention. It will
thus be readily apparent to the one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the
scope and spirit of the invention. Thus it should be understood that although the present
invention has been specifically disclosed by preferred embodiments and optional features
modifications and variation of the concepts herein disclosed may be resorted to by those
skilled in the art and that such modifications and variations are considered to be falling
within .the scope of the invention. . . -
Example 1
Preparation of 2-hydr~-5-[2-[[-1-methyl-3-phenyl-propyl]amino]acetyl]
benzamide hydrochloride
To a solution of 2-amino-4-phenylbutane (150gm) in methanol (350ml) was added 5-
bromoacetyl salicylamide (50gm) at 0-5OC and stirred for 7 hour. After completion of the
reaction, the pH -1.0-1.5 of the reaction mixture was adjusted by using conc.
hydrochloric acid and stirred for another 8-10 hours at 0-5 OC. Filtered, washed with
methanol and dried to obtain the title compound.
Example 2
Preparation of 2-hydroxy-5-[2-[[-l-methyl-3-phenyl-propyl]amino]ace~1]
benzamide hydrochloride
To a solution of 2-amino-4-phenylbutane (I 50gm) in methanol (300ml) and water (50ml)
was added 5-bromoacetyl salicylamide (50gm) at 0-5OC and stirred for 7 hour. After
completion of the reaction, the pH -1.0-1.5 of the reaction mixture was adjusted by using
conc. hydrochloric acid and stirred for another 8-10 hours at 0-5 OC. Filtered, washed
with methanol and dried to obtain the title compound.
Example 3
Preparation of labetalol hydrochloride
To the solution of sodium hydroxide (1 1 gm) in water at 0-5OC, 1 lot of sodium
borohydride (1.25gm) was added. To the reaction mixture, 50 gm of 2-hydroxy-5-[2-[[-1-
methyl-3-phenyl-propyl]amino]acetyl] benzamide hydrochloride was added at 0-5OC.
Thereafter, sodium borohydride (3.75gm) was added. The temperature of the reaction
mixture was raised to 25-35OC, stirred for 18-20 hours. After completion of reaction,
cooled the reaction mixture to 0-5OC and ethyl acetate (50 ml) was added. Adjusted pH
to 6-7 by using conc. hydrochloric acid. Again added ethyl acetate (150 ml) and adjusted
the pH to -1-1.5-by using conc..hydrochloric acid. The reaction mixture was stirred for 2-
3 hours at 0-5 "C. Filtered, washed with ethyl acetate and collected the wet material. The
collected wet material was again stirred in water (300 ml) at 25-30 "C for 1 hour and then
stirred at 0-5 "C for 2-3 hours. The solid mass was filtered and washed with chilled water
(1 00 ml) and dried to obtain the title compound.
Example 4
Purification of labetalol hydrochloride
The mixture of labetalol hydrochloride (50gm) in methanol (200ml) at 25-30°C was
heated to 55-60°C to get the clear solution. To it, activated carbon (2.0gm) was added.
The reaction mixture was stirred for 30 minutes at 50-55OCY filtered through hyflo and
cooled to 0-5OC. Ethyl acetate (600 ml) was added slowly at 0-5OC. The reaction mixture
was stirred for 2-3 hours at 0-5 OC. Filtered, washed with ethyl acetate and dried to obtain
the title compound.
We Claim: . .- . -
1. An improved process for the preparation of labetalol hydrochloride of Formula 1
comprising the steps of:
(a) reacting 5-bromoacetyl salicylamide of Formula 2
Formula 2
with 2-amino-4-phenylbutane of Formula 3 in presence of a suitable solvent, with
or without water
C H ~
Formula 3
to provide compound of Formula 4
Formula 4
optionally, purifying compound of Formula 4 by acid-base treatment or by
crystallization or as it's salts;
(b) treating with a reducing agent in presence of solvent and suitable base, to provide
labetalol;
- _-(c.) -optionally converting-labetalol to its hydrochloride salt; -. -
. . .
(d) dissolving in a suitable solvent;
(e) optionally treating with activated carbon and filtering the reaction mixture;
(0 adding suitable anti-solvent and
(g) isolating labetalol or hydrochloride thereof.
2. The process according to claim 1, wherein in step a) suitable solvent is selected
from alcohol selected from the group comprising of methanol, ethanol, npropanol,
isopropanol, n-butanol, isobutanol and mixture thereof.
3. The process according to claim 1, wherein in step b) reducing agent is selected
from the group comprising of sodium borohydride, lithium borohydride, vitride,
selectride, and base is selected from organic or inorganic base, wherein inorganic
base is alkali or alkaline earth metal hydroxides or carbonates selected from the
group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide,
sodium carbonate, potassium carbonate, calcium carbonate.
4. The process according to claim 1, wherein in step d) suitable solvent is selected
from alcohol selected from the group comprising of methanol, ethanol, npropanol,
isopropanol, n-butanol, isobutanol and mixture thereof.
5. The process according to claim 1, wherein in step f) suitable anti-solvent is
selected from ester solvent selected from the group comprising of methyl acetate,
ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate.
6. A process for the purification of labetalol hydrochloride of Formula 1 comprising
the steps of:
(a) contacting labetalol hydrochloride with a suitable solvent;
(b) optionally treating with activated carbon and filtering the reaction mixture;
(c)-.adding suitable anti-solxent.and;- - . - - . - A -
(d) isolating compound of Formula 1.
7. The process according to claim 6, wherein in step a) suitable solvent is selected
from alcohol selected from the group comprising of methanol, ethanol, npropanol,
isopropanol, n-butanol, and mixture thereof.
8. The process according to claim 6, wherein in step d) suitable anti-solvent is
selected from ester solvent selected from the group comprising of methyl acetate,
ethyl acetate, n-propyl acetate, isopropyl acetate and butyl acetate.
9. An improved process for the preparation of labetalol hydrochloride of Formula 1
which comprises the steps of: .
(a) reacting 5-bromoacetyl salicylamide of Formula 2;
Formula 2
with 2-amino-4-phenylbutane of Formula 3 in presence of methanol
Formula 3
to provide compound of Formula 4
Formula 4
optionally, purifying compound of Formula 4 by acid-base treatment or by
crystallization or as it's salts;
(b) treating with a sodium borohydride in presence of water and suitable base to
provide labetalol;
(c) converting labetalol to its hydrochloride salt;
(d) dissolving in methanol;
(e) optionally treating with activated carbon and filtering the reaction mixture;
( f ) adding ethyl acetate and;
(g) isolating labetalol hydrochloride compound of Formula 1.
10. Labetalol hydrochloride having PXRD pattern, as depicted in figure 2.