FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE

Specification
(See section 10 and rule 13)
A PROCESS FOR MANUFACTURING BETA BLOCKING AGENTS
EMCURE PHARMACEUTICALS LIMITED
an Indian Company
of Emcure House, T-184, M.I.D.C., Bhosari, Pune 411 026,
Maharashtra, India,
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES
THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:-


FIELD OF THE INVENTION
This invention relates to a method for manufacturing beta-blocking agents.
This invention particularly relates to a process for manufacturing atenolol,
particularly S-atenolol.
Still particularly, this invention relates to a process for producing atenolol and
still particularly, optically active nd intermediate thereof via a novel route.
BACKGROUND OF THE INVENTION
Beta-blockers are a class of compounds, which are used to treat high blood
pressure, congestive heart failure, abnormal heart rhythms, chest pain and
are sometimes administered for preventing subsequent heart attacks.
Beta-blockers "block" the effect of adrenaline on human body's beta-
receptors by slowing down the nerve impulses due to which the heart needs
less blood and oxygen and hence the heart has to work less.
Atenolol known chemically as 4-[2-hydroxy-3- [(1-methyl ethyl) amino]
propoxy] benzene acetamide, is a beta blocker (US 3 663 607), which block
beta-receptors in the heart, lungs and other organs of body. Blocking these
receptors prevents the action of two chemicals called nor-adrenaline and
adrenaline. Blocking the beta-receptors in the heart causes the heart to beat
more slowly and with less force. The pressure at which the blood is pumped
out of the heart is reduced. This is just one of the ways in which beta-
blockers help to reduce blood pressure.
2


Atenolol
Atenolol (empirical formula): C14H22N2O3
4[2-hydroxy [1-methylethyl) amino] propoxy] benzeneacetamide
Or
(RS)- 4-(2-hydroxy-3-isopropylaminopropoxy) phenylacetamide
Relative Molecular Mass = 266.3
CAS: 2912268-7
Most beta blockers such as Acebutolol, Atenolol, Betaxolol, Esmolol,
Labetolol, Metoprolol, Nadolol, Oxprenolol, Pindolol, Propanolol, Sotalol, and
Timolol are non specific, i.e. they have both beta1 and beta2 effects. These
inhibitors interfere with the action of stimulating hormones on beta-
adrenergic receptors in the nervous system. Beta-blockers can be subdivided
into two distinct groups, known as beta1 and beta2 blockers. Beta! blockers
mainly affect the heart; beta2 blockers mainly affect receptors in bronchial
tissue.
Atenolol and Acebutolol, Atenolol, Betaxolol, Esmoiol, and Metoprolol are
selective beta1 blockers.
Atenolol is therefore useful as a beta-adrenergic blocker for the treatment of
angina pectoris, arrhythmia and hypertension.
Atenolol works by competing for receptor sites on the cardiac muscle. This
attenuates the strength of the heart's contractions and reduces its oxygen
3

requirements and the volume of blood it has to pump. Atenolol treats
hypertension (high blood pressure) because of its ability to increase the
diameter of the blood vessels thus allowing blood to flow under less pressure.
Atenolol is also used to treat myocardial infarction (heart attack) and
arrhythmias (rhythm disorders), angina (chest pain), and disorders arising
from decreased circulation and vascular constriction, including migraine.
Atenolol is used to help combat cardiac arrhythmias primarily due to beta
blockade activity, and is a class II anti-arrhythmic agent. It is also used to
help control the ventricular response rate in chronic arterial fibrilation, supra-
ventricular tachycardia and in symptomatic premature ventricular complexes.
Atenolol is also effective in controlling sympathetic over activity associated
with hyperthyroidism including tremor, anxiety, and muscle weakness.
Atenolol has also been used in the pre-operative management of
hyperthyroidism. Atenolol is used in acute stress reactions, generalised
anxiety disorder, and panic disorder. It is considered most effective in
patients with somatic anxiety, and especially helps in the reduction of tremor
and/or palpitations.
It is known that atenolol has l-aryloxy-3-aminopropan-2-ol nucleus wherein
the hydroxy-bonded carbon is an asymmetric carbon and hence includes R-
and S optical isomers, and the S-isomer thereof is particularly useful as beta-
adrenergic blocker in view of superior pharmacological activities. It is
reported that only S-isomer of atenolol has hypotensive activity and activity
on brachycardia (cf. A. A. Pearson, T. E. Gaffney, T. Walle, P. J. Privitera; J.
Pharmacol. Exp. Ther., 250 (3), 759, 1989).
One method of preparation of atenolol and analogues is to react a phenol
compound with epihalohydrin (e.g. epichlorohydrin) to obtain glycidyl ether
and then allow the glycidyl ether to react with isopropyl amine (cf. U.S. Pat.
Nos. 3,663,607, 3,836,671 and 3,934,032)
4

Phenol compound is reacted with an excess of epichlorohydrin in the
presence of a catalyst such as piperidine or its salt at 95 to 100°C for several
hours to give the glycidyl ether intermediate, which on further reaction with
an alkylamine, such as isopropylamine gives l-phenoxy-3-amino-2-propanol
derivatives.
In this process even if an optically active epichlorohydrin is used,
racemization occurs in the reaction with the phenol compound and hence the
optical purity of the intermediate glycidyl ether is less than 70%, thereby
resulting in the final product having optical purity less than 70 %.
US Patent No. 5,223,646 (Takehira; Yoshikazu et al) discloses that when
the phenol compound is reacted with an optically active epihalohydrin (e.g.
epichlorohydrin) in the presence of an alkali metal hydroxide at a lower
temperature, the optically active intermediate glycidyl ether can be obtained
in high yield without occurrence of undesirable racemization, and thereby the
desired optically active atenolol thus obtained by reacting the optically active
intermediate glycidyl ether with isopropyl amine is of high optica! purity and
also in high yield.
US 4,182,911 discloses the methods of preparation of optically active
atenolol i.e. (S) atenolol according to the following scheme.
5


However, this process has certain disadvantages. Multiple steps are required
to produce atenolol from D-mannitol. The starting compound has a secondary
as well as a primary hydroxy group and during conversion of the primary
hydroxy group the carbamoylmethyl group functional group in the starting
compound has a tendency to react with the reactant and is converted into
cyanomethyl group thereby decreasing the purity and yield of atenolol to less
than 50%.
US 5,290,958 disclose methods for preparation of atenolol according to the
scheme disclosed herein below. Atenolol can be prepared making use of
quaternary ammonium salts of high alkyl groups or tertiary ammonium salts
of lower alkyl groups, which are used as phase transfer catalyst (PTC), in the
reaction of p-hydroxyphenyl acetamide and epichlorohydrin to yield epoxide
and halohydrin intermediates.
6


U.S. Patent. No. 5,034,535 (Keding et al) describes reaction of 4-(2-
methoxyethyl) phenol with (S)-5-hydroxymethyl-3-isopropyloxazolidin-2-one
sulfonic acid ester to prepare an intermediate in the preparation of S-
metoprolol. This process also recommends the use of isopropylamine as the
starting material.
7


This method utilizes hazardous chemicals like benzene sulphonyl chloride,
which is hazardous for industrial use.
The use of isopropylamine is required in excess to prevent racemization.
Another beta-blocker, which shows a similar spectrum of activity, is
Metoprolol, which is known chemically as l-[4(2-methoxyethyl) phenoxy]-3-
[(1-methylethyl) amino]-2-propanol and marketed as Lopressor.
US 3,998,790 disclose a method, starting from p-hydroxyphenyl acetamide
and epichlorohydrin. The intermediate thus formed is reacted with isopropyi
amine to give Metoprolol.
8


Isopropyl amine has the following drawbacks:
Isopropyl amine is a colorless, flammable liquid with a pungent, ammonia-
like odor. An air odor threshold concentration of 1.2 parts per million (ppm)
parts of air has been reported for isopropyl amine. What makes it a
dangerous liquid to handle is its low boiling point (at 760 mm Hg): 32.4
degrees C (90.32 degrees F)
In addition it is highly incompatible and contact between liquid
isopropylamine and strong acids will cause explosive spattering. Contact with
strong oxidizers, like perchloryl fluoride, or 1-chloro-l, 3-epoxypropane may
cause fires and explosions.
Further, isopropylamine has hazardous decomposition products, which
include toxic gases, and vapors (such as oxides of nitrogen and carbon
monoxide), which may be released in a fire involving isopropylamine.
Exposure to isopropyl amine can occur through inhalation, ingestion, eye or
skin contact, and absorption through the skin. Humans exposed to 10 to 20
9

ppm airborne concentrations of isopropyl amine experience irritation of the
nose and throat after brief periods of exposure. Workers exposed to an
unspecified airborne concentration for 8 hours complained of seeing halos
around lights; this effect, which was transient, was probably caused by mild
corneal edema. Contact of the eye with the liquid can cause severe eye burns
and permanent visual impairment. Contact of the liquid with the skin causes
irritation and may lead to skin burns. Repeated contact with the skin may
result in dermatitis [Hathaway et al. 1991]. Acute exposure to
isopropylamine vapors may cause irritation of the eyes, nose, throat, and
lungs. Severe exposure may cause coughing, chest pain, and pulmonary
edema. Contact with the liquid and with vapors of isopropylamine can cause
corrosion of the skin and eyes. Eye exposure may cause corneal edema
accompanied by visual haloes. If the exposure is severe, burns and
permanent visual impairment may result. Ingestion of liquid isopropylamine
is corrosive to the esophagus [Genium 1986; Sax and Lewis 1989].
Hence Isopropylamine is a very unsuitable reactant to work with.
It would be evident from the foregoing that prior art methods contain several
drawbacks like,
a) multiple steps are required for preparation of beta-blockers,
b) formation of impurities during the synthesis of the beta-blocker,
reduces the purity of the beta-blocker. Any purification step for
removing the impurities will result in loss in yield, which makes the
overall process less cost-effective.
In order to overcome the above difficulties encountered in the prior art, the
present inventors propose the use of cyanuric acid for the production of a
beta blocking agent, particularly atenolol and particularly, (S)-atenolol.
10


It is also made commercially by the pyrolysis of urea, biuret, or urea
cyanurate or mixtures thereof. The pyrolysis can be carried out either in a
dry state, that is, in the absence of a solvent, such as described in U.S. Pat.
No. 2,943,088, or in the presence of various inert organic solvents,
dipropylene, glycol, alkyl sulfones, diphenyl, oxyzolidinones, sulfolane, N-
cyclohexyl pyrrolidone and / or glycol ethers.
OBJECT OF THE INVENTION
An object of the invention is to provide a cost-effective general method for
preparation of beta-blockers of high purity, substantially free from impurities.
Another object of the invention is to provide a cost-effective method for the
preparation of atenolol, preferably (S)-atenolol.
Yet another object of the invention is to provide a method for preparation of
(S)-atenolol of high purity.
SUMMARY OF THE INVENTION
One aspect of the invention relates to a cost-effective method for the
preparation of beta-blockers of formula (I) having high purity.
11


Another aspect of the invention relates to a cost-effective method for the
preparation of beta blockers of formula (I) comprising reaction of cyanuric
acid of formula (II) with epichlorohydrin of formula (III) in the presence of
benzyltrimethyl ammonium halide and a base to provide a compound of
formula (IV), which on reaction with a phenol derivative of formula (V) gives
a oxazolidin-2-one intermediate of formula (VI), further hydrolysis with an
aqueous base in a water-miscible organic solvent gives the respective beta
blocker in high yields and with the desired purity.
DETAILED DESCRIPTION OF THE INVENTION
12
1. According to this invention there is provided a process for the
preparation of a beta-blocker of formula (I)


wherein the substituent R1 is selected from a group of
hydrogen, -CH2CONH2, -(CH2)2-CO-CH3, -(CH2)2OCH3,-
(CH2)2-O-CH2-cyclopropyl/ -NH-CO-(CH2)2-CH3, and -
COCH3;
the substituent R2 is typically -CH(CH3)2,
the substituent R3 is selected from a group consisting of
hydrogen, allyloxy, acetyl, methylene, and methyl,
the substituent R4 is selected from a group consisting of
hydrogen, methyl, and methylene,
the substituent R5 is selected from a group consisting of
methyl and hydrogen
and its pharmaceutically acceptable salt, said process comprising
the steps of,
a. reacting cyanuric acid of formula (II)

With epichlorohydrin of formula (III)

In the presence of a phase transfer catalyst at reflux
temperature in water, to give a compound of formula (IV),

13

b. reacting compound of formula (IV) obtained in step (a) with a
phenol derivative of formula (V)

in an organic solvent and in the presence of a base, to give
a compound of formula (VI)

c. reacting compound of formula (VI) obtained in step (b) with an
alkyl halide R2X of formula (VII); wherein X is selected from a
group of halides consisting of -CI, -Br, -I, and -F; in an organic
solvent and in the presence of a base, to give a compound of
formula (VIII)

d. treating compound of formula (VIII) obtained in step c with a
base in an organic solvent to give a compound of formula (I),
and

14

optionally treating compound (I) with a suitable acid to give
the pharmaceutically acceptable salt.
The present invention relates to a method as disclosed in Scheme-I for a
general method for the preparation of beta-blocker of formula (I) employing
a relatively cheap and easily available compound like cyanuric acid of formula
(II).
The process of this invention envisages the use of relatively inexpensive
purified cyanuric acid (II). It is proposed in accordance with a preferred
embodiment of this invention that purified cyanuric acid (II) is reacted
sequentially with a epihalohydrin such as epichlorohydrin, an appropriate
phenol and an alkyl halide such as isopropyl halide, such as isopropyl
chloride.

The isopropyl and epoxide group attaches to each of the nitrogen atom after
ring splitting, resulting in three molecules of the oxazolidin-2-one
intermediate for each molecule of cyanuric acid, which on further hydrolysis,
using aqueous alcohol with an alkali such as sodium or potassium hydroxide
selectively results in a beta blocker like atenolol particularly (S)-atenolol.
The tri-substituted alkylation of cyanuric acid according to the present
invention, as shown in Scheme-1, is obtained by use of excess
epihalohydrin, such as epichlorohydrin with or without a phase transfer agent
such as tetra alkyl ammonium halide.
15


Scheme -1: Method according to present invention for the preparation of
beta blockers employing cyanuric acid.
16

The reaction with cyanuric acid provides the adduct i.e. alkylated cyanuric
acid such as adduct (III), wherein one or more of the nitrogen are
respectively alkylated. In accordance with a preferred embodiment of this
invention optically pure epihalohydrin is selected as the reactant, which
directly results in the optically active adduct. However, if racemic
epihalohydrin is selected further separation may be necessary.
The alkylated cyanuric acid is then treated with a suitable anion of hydroxy
aromatic compound such as sodium or potassium salt of a hydroxy aromatic
compound, such as substituted or unsubstituted phenols or naphthalene or
naphthols for development of the oxazolidin-2-one derivative. Aromatic
hydroxy compounds (i.e. Ar - OH) have aromatic groups, containing one or
more heteroatom selected from oxygen, sulfur or nitrogen. The aromatic
group may be substituted or unsubstituted, fused bicyclic. Reaction with
selective aromatic hydroxy anions will lead to the formation of the beta-
blocking agent of choice. Thus, the oxazolidin-2-ones can be obtained..
Further alkylation by nucleophilic aliphatic substitution using an alkyl halide
(using R1-X; wherein R1 is straight chain or branched C1-6 alkyl), such as
isopropyl chloride [or n-butyl, n-pentyl, n-hexyl, cyclohexyl and the like].
Advantageously, a 'weak' Lewis acid catalyst such as HF may be used to
achieve mono substitution. Selective hydrolysis then results in the formation
of the beta blocker molecules, such as metoprolol, propranolol, carteolol,
penbutolol, carvedilol, bisoprolol, nadolol, oxprenolol, pindolol, timolol,
atenolol, acebutolol, betaxolol, esmolol and the like
In a specific embodiment,
Step-I; Preparation of 1, 3, 5-tris(oxiran-2-Y\methvl)-1. 3. 5-triazine-
2. 4. 6-trione of formula (IV)
Cyanuric acid of formula (II) is added to an aqueous solution of a phase
transfer catalyst like tetraalkyl ammonium halide.
17

The phase transfer catalyst is selected from the group comprising of
tetramethyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl
ammonium bromide, benzyltrimethyl ammonium bromide, benzyltrimethyi
ammonium chloride, benzyltriethyl ammonium bromide etc.
The preferred phase transfer catalyst is benzyltrimethyl ammonium
chloride or benzyltriethyl ammonium chloride.
The amount in moles of benzyltrimethyl ammonium chloride added is
between 0.075 and 0.125 moles per mole of cyanuric acid of formula
(II).
The preferred amount of benzyltrimethyl ammonium chloride added is
between 0.090 and 0.105 moles per mole of cyanuric acid of formula
(II).
The amount of water employed as reaction medium for carrying out
the reaction is between 0.75 volumes and 1.25 volumes per gram of
cyanuric acid of formula (II).
The preferred amount of water added as reaction medium is between
0.90 volumes and 1.10 volumes per gram of cyanuric acid of formula
(II).
Epichlorohydrin of formula (III), which is racemic (III) or its (R) isomer
of formula (III-A), or its (S) isomer of formula (III-B) is added to the
reaction mixture at ambient temperature.

18

The amount of epichlorohydrin added to the mixture is between 8.0
moles and 12.0 moles of epichlorohydrin per mole of cyanuric acid of
formula (I).
The preferred amount of epichlorohydrin in molar equivalent added is
between 9.0 moles and 11.0 moles of per mole of cyanuric acid of
formula (II).
Epichlorohydrin either of formula (III) or (III-A) or (III-B) is added to
the reaction mixture and refluxed between 85°C and 100°C.
The preferred temperature for carrying out the reaction is at 95 ± 2°C.
The reaction mixture is refluxed till completion of the reaction, which is
usually one hour.
The reaction mixture is partially concentrated under reduced pressure
for removal of excess epichlorohydrin (III) or (III-A) or (III-B).
The reaction mixture is cooled between 5°C and 20°C. The preferred
temperature is 15°C.
The reaction mixture is neutralized with an inorganic base, which is
selected from the group comprising of bicarbonates, carbonates or
hydroxides of alkali, or alkaline earth metal.
The preferred inorganic base employed is the hydroxide of the alkali
metal.
The alkali metal is selected from the group comprising of lithium,
sodium and potassium.
10

The preferred inorganic base is sodium hydroxide.
The amount of sodium hydroxide added to the reaction mixture is
between 2.75 moles and 3.5 moles per mole of cyanuric acid of
formula (II).
The preferred amount of sodium hydroxide added is between 3.10 and
3.30 moles per gram of cyanuric acid of formula (II).
The reaction mixture was stirred at ambient temperature for 20-40
minutes.
An organic solvent selected from the group comprising of chlorinated
hydrocarbons, esters, aliphatic hydrocarbons,
The preferred solvent is a chlorinated hydrocarbon.
The chlorinated hydrocarbon is selected from the group comprising of
chloroform, dichloromethane, and dichloroethane.
The preferred chlorinated hydrocarbon is dichloromethane.
The amount of dichloromethane added to the reaction mixture is
between 3.0 volumes and 7.0 volumes per gram of cyanuric acid of
formula (II).
The preferred amount of dichloromethane added is between 4.0 and
6.0 volumes per gram of cyanuric acid of formula (II).
The biphasic mixture is stirred for 90-150 minutes at ambient
temperature.
20

The reaction mixture was filtered and the mixture concentrated under
reduced pressure.
The reaction mixture was cooled between 5°C and 10°C and diluted
with a water-miscible organic solvent selected from the group
comprising of alcohol or ketone. The preferred organic solvent is an
alcohol.
The alcohol is selected from the group comprising of methanol,
ethanol, isopropanol, n-butanol, secondary butanol, tertiary butanol
etc.
The preferred alcohol is methanol.
The volume of methanol added is between 1.50 volumes and 3.0
volumes per gram of cyanuric acid of formula (II).
Methanol is added to the concentrated residue and stirred at 5-10°C
for 3-4 hours for complete precipitation of 1, 3, 5-tris(oxiran-2-
ylmethyl)-1, 3, 5-triazine-2, 4, 6-trione of formula (IV), which is then
filtered and dried to get compound (IV) of desired purity.
Steo-II: Preparation of compound (VI)
1, 3, 5-tris(oxiran-2-yImethyl)-1, 3, 5-triazine-2, 4, 6-trione of formula
(IV) is dissolved in an organic solvent selected from the group
comprising of ketones, esters, ethers etc.
The preferred organic solvent is a ketone.
21

The ketone is selected from the group comprising of acetone, methyl
ethyl ketone, and methyl isobutyl ketone. The preferred ketone is
methyl isobutyl ketone.
The amount of methyl isobutyl ketone employed is between 3.0
volumes and 7.0 volumes per gram of compound (IV).
The preferred amount of the solvent is between 4.0 and 6.0 volumes
per gram of the compound (IV).
A suitable phenol derivative of formula (V) is added to the reaction
mixture.
The amount of the phenol derivative of formula (V) added to the
reaction mixture is between 2.75 moles and 3.75 moles per gram of
compound (IV).
The preferred amount of compound (V) is between 3.00 and 3.50
moles per gram of compound (IV).
An inorganic base selected from the group comprising of bicarbonates,
carbonates or hydroxides of alkali, or alkaline earth metal is added to
the reaction mixture.
The preferred inorganic base employed is the hydroxide of the alkali
metal.
The alkali metal is selected from the group comprising of lithium,
sodium and potassium.
The preferred inorganic base is potassium hydroxide.
22

The reaction mixture is heated at 115-120°C for 60-120 minutes for
completion of reaction; which is monitored by TLC.
The reaction mixture is cooled between 5°C and 10°C, and stirred at
the same temperature for 120 minutes.
The solid separating out was filtered and added to an organic solvent.
The organic solvent was selected from the group comprising of a
chlorinated hydrocarbon, aliphatic hydrocarbon, and ester.
The preferred solvent is a chlorinated solvent.
The chlorinated solvent is selected from the group comprising of
chloroform, dichloromethane, and dichloroethane.
The preferred chlorinated hydrocarbon is dichloromethane.
The amount of dichloromethane added to the reaction mixture is
between 300.0 volumes and 500.0 volumes per gram of compound of
formula (IV).
The preferred volume of dichloromethane is between 350 volumes and
400 volumes per gram of compound of formula (IV).
An aqueous solution of an inorganic base was added to the reaction.
The inorganic base was selected from the group comprising of
bicarbonates, carbonates or hydroxides of alkali, or alkaline earth
metal is added to the reaction mixture.
23

The preferred inorganic base employed is the hydroxide of the alkali
metal.
The alkali metal is selected from the group comprising of lithium,
sodium and potassium.
The preferred inorganic base is sodium hydroxide.
The concentration of the aqueous inorganic base is between 5% and
15% aqueous solution of sodium hydroxide
The preferred concentration of the aqueous inorganic base is 10%.
The resulting mixture was stirred for 15-45 minutes and the aqueous
layer containing the sodium salt of the phenol of formula (V) was
separated.
The product of formula (VI) present in the organic layer after optional
further treatment with an aqueous solution of an inorganic base was
concentrated under reduced pressure.
The resulting residue containing the product of formula (VI) was
diluted with an alcohol.
The alcohol was selected from the group comprising of methanol,
ethanol, and isopropanol.
The preferred alcohol is methanol.
The volume of methanol is between 1.0 and 2.0 volumes per gram of
compound (VII).
24

The preferred volume of methanol is between 1.5 volumes per gram of
compound (VII).
The mixture is stirred for complete precipitation of the compound (VI),
which is then filtered and dried to give compound (VI) of desired
purity.
Step-III: Preparation of compound (VIII).
The compound of formula (VI) was dissolved in dimethyl sulphoxide to
which a base was added.
The base selected from the group comprising of bicarbonates,
carbonates, hydroxides or hydrides of alkali, or alkaline earth metal
was added to the reaction mixture.
The preferred inorganic base employed is the hydride of the alkali
metal.
The alkali metal is selected from the group comprising of lithium,
sodium and potassium.
The preferred base is sodium hydride.
The amount in moles of sodium hydride added is between 3.5 moles
and 4.5 moles per mole of compound (VI).
The preferred amount of sodium hydride is between 3.8 moles and 4.2
moles per mole of compound (VI).
Sodium hydride is added at a temperature of 0-5°C.
25

An alkyl bromide, preferably isopropyl bromide was added to the
reaction mixture and gradually stirred at 50°C for 60-90 minutes. The
completion of the reaction was monitored by TLC.
The reaction mixture was quenched with acetic acid followed by
addition of cold water.
The compound of formula (VIII) thus separating out was filtered and
dried to give compound (VIII) of desired purity.
Step-IV: Preparation of compound of formula (I)
The compound of formula (VIII) was dissolved in a water-miscible
organic solvent selected from the group comprising of alcohols,
ketones, ethers etc.
The preferred water-miscible solvent is an alcohol.
The alcohol is selected from the group comprising of methanol,
ethanol, isopropanol, n-butanol etc.
The preferred alcohol is methanol or ethanol.
The volume of the methanol added is between 30 volumes and 40
volumes per gram of compound (VIII).
The preferred volume of the methanol is between 34 and 36 volumes
per gram of compound (VIII).
An aqueous solution of an inorganic base was added to the reaction.
26

The inorganic base was selected from the group comprising of
bicarbonates, carbonates or hydroxides of alkali, or alkaline earth
metal is added to the reaction mixture.
The preferred inorganic base employed is the hydroxide of an alkali
metal.
The alkali metal is selected from the group comprising of lithium,
sodium and potassium.
The preferred inorganic base is potassium hydroxide.
The concentration of the aqueous inorganic base is between 5% and
15% aqueous solution of sodium hydroxide
The preferred concentration of the aqueous inorganic base is 10%.
The resulting mixture was refluxed for duration between 7.0 and 9.0
hours at a temperature selected between 90°C and 105°C.
After completion of the reaction, the reaction mixture was
concentrated to remove the alcohol. The pH of the resulting mixture
containing compound (I) was adjusted to 7.0 by addition of acetic acid.
The mixture was extracted with an organic solvent selected from the
group comprising of chlorinated hydrocarbon, ester, aliphatic
hydrocarbon etc.
The preferred solvent is a chlorinated hydrocarbon.
The chlorinated hydrocarbon is selected from the group comprising of
chloroform, dichloromethane, and dichloroethane.
27

The preferred solvent is dichloromethane.
The reaction mixture is extracted with dichloromethane and the
organic layer after separation from the aqueous layer is concentrated
to give the compound of formula (I) with purity of above 99%.
The compound (I) is then suitably converted to its pharmaceutically
acceptable salts by treatment with a suitable inorganic or organic acid.
As will be readily appreciated, numerous variations and combinations
of the features set forth above can be utilized without departing from
the present invention as set forth in the above description of the
invention . Such variations are not regarded as a departure from the
spirit and scope of the invention, and all such modifications are
intended to be included within the scope of the above description.
This invention is illustrated by the following examples but should not
be construed to be limited thereto.
Example-1
Preparation of 1, 3, 5-tris(oxiran-2-ylmethyl)-1, 3, 5-triazine-2, 4, 6-trione
(IVc) Metoprolol intermediate)
Cyanuric acid (II) (1.0 kg; 7.75 moles) was added to an aqueous solution of
benzyl trimethyl ammonium chloride (0.175 kg; 0.77 moles) dissolved in
water (1.0 litres). Epichlorohydrin (III) (6.0 litres; 77.5 moles) was added
gradually to the reaction mixture and heated at 95-100°C with stirring for 60
minutes. After completion of reaction, excess of epichlorohydrin was distilled
off under vacuum. The reaction mixture was cooled to 15°C and solid sodium
hydroxide (1 kg; 25 moles) was added. The reaction mixture was stirred for
30 minutes and cooled. Dichloromethane (5.0 litres) was added with stirring.
28

The reaction mixture was further stirred for 120 min and filtered. The
mixture was cooled and methanol (1.75 litres) was added & stirred at 5-10°C
for 3 to 4 hrs. The product was filtered and dried.
Yield: 1.7-1.8 Kg
%Yield: 74-78%
Example-2
Preparation of compound (Vic); Metoprolol intermediate)
1, 3, 5-tris(oxiran-2-ylmethyl)-1, 3, 5-triazine-2,4,6-trione (IV-c; 3.4 moles)
was dissolved in methyl isobutylketone (5.25 litres) in a round bottom flask.
Potassium hydroxide (0.05 kg; 0.89 moles) followed by 4-(2-
methoxyethylphenol) (V-c; 1.66 kg; 10.90 moles) were added to the reaction
mixture and heated at 115-120°C for 1.5 hrs. The reaction mixture was
cooled to 5-10°C and stirred. The product was filtered and dissolved in
dichloromethane (375.0 litres). Aqueous 10% sodium hydroxide solution
(125 litres) was added and stirred for 30 mins- The dichloromethane layer
was separated and after treatment with charcoal was refluxed for 2 hours.
The reaction mixture was cooled, filtered and distilled to remove
dichloromethane. Methanol (1.50 litres) was added for complete precipitation
of compound (VI-c), which was then filtered and dried.
Yield: 1.0 kg; Quantitative yield.
Example-3
Preparation of compound of formula (VIIIc); Metoprolol intermediate)
Compound (VI-c; 1000 gms; 4.0 moles) was dissolved in dimethyl
sulphoxide (100.0 ml). Sodium hydride (4.48 kg; 186.66 moles) was
added at 0-5°C. Isopropyl bromide (1.73 kg; 14.0 moles) was then
added at 0-5°C. The reaction mixture was heated to 50°C and stirred.
After completion of reaction, the reaction mixture was quenched with
acetic acid and diluted with cold water. The solid separating out was
filtered and dried.
Yield: 0.8 kg
29

% Yield: 69%
Example-4
Preparation of compound (I-c); Metoprolol free base
Compound VIII-c (1.0 kg; 0.024 moles) was suspended in ethanol (35.0
litres) with stirring. Potassium hydroxide solution (3.42 Kg; 61.0 moles)
dissolved in water (35.0 litres) was added to the reaction mixture and heated
to 90-95°C. The reaction mixture was refluxed for 8 hours for completion of
reaction. Ethanol was removed by distillation under reduced pressure. Acetic
acid was added to the residue till the pH was 7.0. The reaction mixture was
extracted with dichloromethane and the organic layer after separation was
concentrated till dryness
Yield: 0.7 Kg
% Yield: 77%.
Example-5
Preparation of Metoprolol succinate (I-A)
Metoprolol free base (I; 1.0 kg; 0.029) was charged in acetone (2 litres) with
stirring. The reaction mixture was further stirred for 20-30 minutes. A
solution of succinic acid (0.267 Kg dissolved in 10.0 litres acetone) was
added and the reaction mixture was stirred for twenty hours at 20-30°C and
further stirred at 0-10°C for 2.0 hrs. The reaction mixture was filtered and
washed with acetone (16.0 ml) at 0-10°C. The reaction mixture was dried at
50-55°C.
Yield: 0.625 kg
% Yield:
Purity: 99.33%.

We Claim:
1. A process for the preparation of a beta-blocker of formula (I)

wherein the substituent R1 is selected from a group of
hydrogen, -CH2CONH2, -(CH2)2-CO-CH3, -(CH2)2OCH3,.-
(CH2)2-O-CH2-cyclopropyl, -NH-CO-(CH2)2-CH3, and -
COCH3;
the substituent R2 is typically -CH(CH3)2,
the substituent R3 is selected from a group consisting of
hydrogen, allyloxy, acetyl, methylene, and methyl,
the substituent R4 is selected from a group consisting of
hydrogen, methyl, and methylene,
the substituent R5 is selected from a group consisting of
methyl and hydrogen
and its pharmaceutically acceptable salt, said process comprising
the steps of,

with epichlorohydrin of formula (III)

a. reacting cyanuric acid of formula (II)
in the presence of a phase transfer catalyst at reflux
temperature in water, to give a compound of formula (IV),
31

b. reacting compound of formula (IV) obtained in step (a) with a
phenol derivative of formula (V)

in an organic solvent and in the presence of a base, to give
a compound of formula (VI)

c. reacting compound of formula (VI) obtained in step (b) with an
alkyl halide R2X of formula (VII); wherein X is selected from a
group of halides consisting of -CI, -Br, -I, and -F; in an organic
solvent and in the presence of a base, to give a compound of
formula (VIII)
32


d. treating compound of formula (VIU) obtained in step c with a
base in an organic solvent to give a compound of formula (I),
and

optfonaffy treating compound (r) with a suitable acid to give
the pharmaceutically acceptable salt.
2. A process as claimed in claim 1, wherein the said phase transfer
catalyst is selected from a group consisting of tetramethyl ammonium
bromide, tetraethyl ammonium bromide, tetrabutyl ammonium
bromide, benzyltrimethyl ammonium bromide, benzyltrimethyl
ammonium chloride, and benzyltriethyl arnmonium bromide.
3. A process as claimed in claim 1, wherein the said phase transfer
catalyst benzyltrialkyl ammonium halide is benzyltrimethyl ammonium
chloride or benzyltriethyl ammonium brornide.
4. A process as claimed in claim 1, wherein the said phase transfer
catalyst is benzyltrimethyl ammonium chloride added between 0.075
and 0.125 and preferably between 0.090 and 0.105 moles per mole of
cyanuric acid of formula (II).
5. A process as claimed in claim 1, wherein the amount of water
employed as reaction medium for carrying out the reaction in step a is
33

between 0.75 volumes and 1.25 volumes per gram of cyanuric acid of
formula (II), preferably between 0.90 volumes and 1.10 volumes per
gram of cyanuric acid of formula (II).
6. A process as claimed in claim 1, wherein the amount of
epichlorohydrin in molar equivalent added to the reaction mixture in
step a is between 8.0 moles and 12.0 moles and preferably between
9.0 moles and 11.0 moles of epichlorohydrin per mole of cyanuric acid
of formula (I).
7. A process as claimed in claim 1, wherein the reaction mixture in step
(a) is neutralized with an inorganic base selected from a group
consisting of bicarbonates, carbonates or hydroxides of alkali, and
alkaline earth metal.
8. A process as claimed in claim 7, wherein the inorganic base employed
is a hydroxide of an alkali metal.
9. A process as claimed in claim 8, wherein the alkali metal is selected
from a group consisting of lithium, sodium and potassium.
10. A process as claimed in claim 7, wherein the inorganic base is sodium
hydroxide.
11. A process as claimed in claim 7, wherein the amount of inorganic base
added to the reaction mixture in step a is between 2.75 moles and 3.5
and preferably between 3.10 and 3.30 moles per mole of cyanuric acid
of formula (II).
12. A process as claimed in claim 1, wherein the reaction between
compound of formula (IV) and compound of formula (V) in step b is
carried out in an organic solvent.
34

13.A process as claimed in claim 1, wherein the organic solvent in step b
is selected from a group consisting of ketones, esters, and ethers.
14.A process as claimed in claim 12, wherein the organic solvent is a
ketone.
15.A process as claimed in claim 14, wherein the ketone is selected
from a group consisting of acetone, methyl ethyl ketone, and
methyl isobutyl ketone.
16.A process as claimed in claim 14, wherein the ketone is methyl
isobutyl ketone.
17.A process as claimed in any one of claims 12 to 16 , wherein
the amount of organic solvent employed is between 3.0 volumes
and 7.0 volumes and preferably between 4.0 and 6.0 volumes
per gram of compound (IV).
18.A process as claimed in claim 1, wherein the reaction in step b is
carried out at a temperature betweenl00-140°C and preferably
between 115°C and 120°C.
19. A process as claimed in claim 1, wherein the phenol derivative of
formula (V) of which the substituent R1 of compound (V) is hydrogen,
-CH2CONH2, -(CH2)2-CO-CH3, --(CH2)2OCH3,.-(CH2)2-O-OV
cyclopropyl, -NH-CO-(CH2)2-CH3/ -OCOCH3 is added to the reaction
mixture in step b.
20. A process as claimed in claim 1, wherein the phenol derivative of
formula (V) of which the substituent R3 of compound (V) is hydrogen,
35

allyloxy, acetyl, methylene, or methyl is added to the reaction mixture
in step b.
21. A process as claimed in claim 1, wherein the phenol derivative of
formula (V) of which the substituent R4 of compound (V) is hydrogen,
methyl, or methylene is added to the reaction mixture in step b.
22, A process as claimed in claim 1, wherein the phenol derivative of
formula (V) of which the substituent R5 of compound (V) is methyl or
hydrogen is added to the reaction mixture in step b.
23.A process as claimed in any one of claims 19 to 22, wherein the
amount of the phenol derivative of formula (V) added to the reaction
mixture in step b is between 2.75 moles and 3.75 moles and
preferably between 3.00 and 3.50 moles per gram of compound (IV).
24.A process as claimed in claim 1, wherein an inorganic base selected
from the group consisting of bicarbonates, carbonates or hydroxides of
alkali, or alkaline earth metal is added to the reaction mixture in step
b.
25.A process as claimed in claim 24, wherein the inorganic base employed
is the hydroxide of an alkali metal.
26.A process as claimed in claim 25, wherein the alkali metal is selected
from the group consisting of lithium, sodium and potassium.
27.A process as claimed in claim 24, wherein the inorganic base is
potassium hydroxide.
28.A process as claimed in claim 1, wherein the reaction mixture in step b
is heated between 115-120°C for 60-120 minutes.
36

29.A process as claimed in claim 1, wherein the reaction between
compound of formula (VI) and compound of formula (VII) in step c is
carried out in dimethyl sulphoxide.
30.A process as claimed in claim 1, wherein the alkyl halide compound
used in step c of formula (VII) is isopropyl bromide or isopropyl iodide.
31. A process as claimed in claim 1, wherein the reaction between
compound of formula (VI) and compound of formula (VII) in step c is
carried out in the presence of an inorganic base.
32. A process as claimed in claim 31, wherein the inorganic base is
selected from the group consisting of bicarbonates, carbonates,
hydroxides or hydrides of alkali, or alkaline earth metal.
33. A process as claimed in claim 31, wherein the inorganic base
employed is the hydride of an alkali metal.
34. A process as claimed in claim 33, wherein the alkali metal is
selected from the group consisting of lithium, sodium and
potassium.
35. A process as claimed in claim 31, wherein the inorganic base is
sodium hydride.
36. A process as claimed in any one of claims 31 to 35 wherein the
amount in moles of the inorganic base is between 3.5 moles and
4.5 moles per mole and preferably between 3.8 moles and 4.2
moles of compound of formula (VI).
37. A process as claimed in claim 1, wherein in step c the alkyl
halide is isopropyl bromide or isopropyl iodide.
37

38.A process as claimed in claim 1, wherein the conversion of
compound of formula (VIII) to compound of formula (I) in step
d is carried out in an organic solvent.
39. A process as claimed in claim 38, wherein the organic solvent
is selected from a group consisting of alcohols, ketones or
ethers.
40. A process as claimed in claim 39, wherein the organic solvent is
an alcohol.
41. A process as claimed in claim 40, wherein the alcohol is
selected from the group selected from methanol, ethanol, n-
propanol, isopropanol, and n-butanol.
42. A process as claimed in claim 40, wherein the alcohol is
methanol or ethanol.
43r A process as claimed in claim any one of claims 38 to 42, ,
wherein the volume of the organic solvent added is between 30
volumes and 40 volumes per gram of compound (VIII).
44. A process as claimed in claim 1 , wherein in step d the
conversion of compound of formula (VIII) to compound of
formula (I) is carried out in the presence of an aqueous solution
of an inorganic base selected from the group consisting of
bicarbonates, carbonates or hydroxides of alkali, or alkaline
earth metal.
45. A process as claimed in claim 1, wherein the inorganic base
employed in step d is the hydroxide of an alkali metal.
38

46. A process as claimed in claim 45, wherein the alkali metal is
selected from the group consisting of lithium, sodium and
potassium.
47. A process as claimed in claim 45, wherein the inorganic base is
potassium hydroxide.
48. A process as claimed in any one of claims 44 to 47 , wherein the
concentration of the aqueous inorganic base is between 5% and
15% and preferably 10%.
49. A process as claimed in claim 1, wherein the resulting reaction
mixture in step d is refluxed for a duration between 7.0 and 9.0
hours at a temperature selected between 90 °C and 105 °C.
50. A process for preparing the beta-blockers substantially as herein
described and illustrated with reference to the examples.
Dated this 7th day of October 2005.

39

ABSTRACT
This invention relates to a method for manufacturing beta-blocking agents,
by employing cyanuric acid.