FIELD OF THE INVENTION
The present invention relates to an efficient and industrially advantageous process
for preparation of benzazepine-2-one derivative of formula I. Benzazepine-2-one
derivative namely7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one, of
formula I, is a key intermediate in the preparation of ivabra5 dine.
Formula I
BACKGROUND OF THE INVENTION
Ivabradine, chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxy
benzocyclobut-1-yl) methyl-N-(methyl)amino)propyl)-1,3,4,5-tetrahydro-2H-3-
benzazepine-2-one is useful in many cardiovascular diseases such as angina
10 pectoris, myocardial infarction and associated rhythm disturbances and it is
represented by following structure.
Ivabradine and its pharmaceutically acceptable salts were first disclosed in US
patent 5,296,482. The patent also discloses a process for the preparation of
ivabradine and its pharmaceutically acceptable salts by the process as shown in
15 below scheme 1
Scheme 1
3
As shown above, compound 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-2H-
3-benzazepin-2-one of formula I, is an important intermediate in the preparation
of ivabradine. It is disclosed that 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-
2H-3-benzazepin-2-one of formula I is obtained using the method describes 5 ibes in
the literature Journal of Medicinal Chemistry1990, Volume 33(5), 1496-1504, and
the process isas depicted in below scheme 2:
Scheme 2
10 As shown above,(3,4-dimethoxyphenyl)acetic acid is reacted with thionyl
chloride to give (3,4-dimethoxyphenyl)acetic acid chloride. The resulting acid
chloride is reacted with N-(2,2-dimethoxyethyl)amine to give N-(2,2-
dimethoxyethyl)-2-(3,4-dimethoxy- phenyl)acetamide, followed by cyclisation of
the resulting phenylacetamide in the presence of concentrated hydrochloric acid
15 and glacial acetic acid to give 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one.
Several other patents such as US 4,584,293; US 4,604,389; and US 4,737,495
also disclose similar process for the preparation of 7,8-dimethoxy-1,3-dihydro-
2H-3-benzazepine-2-one, wherein (3,4-dimethoxyphenyl)acetic acid chloride
20 intermediate has been prepared as intermediate using thionyl chloride/oxalyl
chloride, during preparation of 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-
2H-3-benzazepin-2-one. All these processes give overall low yields, [40-57%]
with respect to (3,4-dimethoxyphenyl)acetic acid.
4
US patent 7,928,223 and CA patent 1215045 disclose two approaches to
prepare7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one . One is similar as
above, i.e. through theacid chloride intermediate. The second approach reported
for the preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one,
involves condensation of (3,4-dimethoxyphenyl)acetic acid with N-(5 (2,2-
dimethoxyethyl)amine in the presence of condensing agent to give N-(2,2-
dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide and followed by cyclisation
of the resulting phenylacetamide in the presence of acidic cyclizing agents in
acetic acid, as shown in below scheme 3
10
Scheme 3
The condensing agent can be selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI), 1-(3-dimethylaminopropyl)-3-ethyl15
carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT), 1-(3-
dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI)/1-hydroxy-7-
azabenzotriazole (HOAT), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride (EDCI)/N-hydroxysuccinimide (NHS), dicyclohexylcarbodiimide
(DCC), dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBT),
20 dicyclohexylcarbodiimide (DCC)/1-hydroxy-7-azabenzotriazole (HOAT),
dicyclohexylcarbodiimide (DCC)/N-hydroxysuccinimide (NHS), O-(7-azabenzo
triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU),
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU),
25 benzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate
(BOP), O-(benzotriazol-1-yl)-oxytripyrrolidinophosphoniumhexafluoro
phosphate (PyBOP), carbonyldiimidazole (CDI), n-propane phosphonic anhydride
(T3P).
5
US patent 7,928,223 shows advantage of not isolating N-(2,2-dimethoxyethyl)-2-
(3,4-dimethoxyphenyl)acetamide, intermediate.
It has been observed that the above processes suffer from several drawbacks, such
as a need for a separate activating step in acid chloride intermediate
process.Further, the use of thionyl chloride, which is a hazardous chemical and 5 nd is
difficult to handle, is not an attractive option for industrial use. During the
synthesis of acid chloride using thionyl chloride, an equivalent amount of
hydrogen chloride gas formed, which is very dangerous for the environment and
to absorb and neutralize this hazardous gas, cost of production of product
10 increases, economic point of view. Further its removal till trace amount, from
the reaction mass is very difficult and if it remains in the reaction, it hampers the
condensation reaction in next stage to prepare phenylacetamide, intermediate. The
acid chloride, formed in the reaction is found to be unstable and decomposes in
the presence of water and results in yield loss. Alternatively, each of condensing
15 agents has their own disadvantages being unstable, toxic, expensive or
commercially unavailable, and requires the removal of bye product.
Further it is also very cumbersome to carry out amidation reaction using
condensing agents like carbodiimide and carbonyldiimidazole on bigger scale,
since carbodiimides and carbonyldiimidazolesare unstable compounds and
20 hydrolyze very easily. Another drawback of using carbodiimide and
carbonyldiimidazole is that byproduct generated after their use is difficult to
remove completely and these compounds are allergic in nature.
We have not found any reference, for the synthesis of 7,8-dimethoxy-1,3-
dihydro-2H-3-benzazepine-2-one, wherein (3,4-dimethoxyphenyl)acetic acid is
25 reacted with N-(2,2-dimethoxyethyl)amine to give N-(2,2-dimethoxyethyl)-2-
(3,4-dimethoxy-phenyl) acetamide, without preparing acid halide [chloride] or
without using condensing agent.
In view of the above, there is an urgent need to develop an efficient, cost
effective, industrially viable process for the synthesis of 7,8-dimethoxy-1,3-
30 dihydro-2H-3-benzazepine-2-one, wherein use of acid chloride or condensing
6
agents can be avoided.Therefore, the present invention fulfills the need in the art
and provides a cost effective, environment friendly and industrially viable process
for the preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one
without using acid chloride intermediate and condensing agent.
5
OBJECT OF THE INVENTION
The main object of the present invention is to provide an efficient, environment
friendly and industrially advantageous process for the preparation of 7,8-
dimethoxy-1,3-dihydro-2H-3-benzazepine-2-oneofcompound of formula I.
Formula I
10 An another object of the present invention is to provide an efficient and
industrially advantageous process for the preparation of 7,8-dimethoxy-1,3-
dihydro-2H-3-benzazepine-2-oneof compound of formula I,
Formula I
and its application in the preparation of ivabradine or its pharmaceutically
acceptable salt thereof.
15
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient, environment friendly
and industrially advantageous process for preparation of 7,8-dimethoxy-1,3-
dihydro-2H-3-benzazepine-2-oneof compound of formula I,
Formula I
20 comprises:
7
i) reacting (3,4-dimethoxyphenyl)acetic acid of compound of formula II,
Formula II
with N-(2,2-dimethoxyethyl)amine at a suitable temperature in a suitable solvent,
in the absence of coupling/condensing agent to give N-(2,2-dimethoxyethyl)-2-
(3,4-dimethoxyphenyl) acetamide of compound of formula III,
Formula III
ii) cyclizing the resulting N-(2,2-dimethoxyethyl)-2-(3,4-dimethox5 y
phenyl)acetamide of compound of formula III in the presence of a suitable acid,
iii) isolating 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of formula I.
In another embodiment, the present invention provides an industrially
advantageous and efficient process for preparation of ivabradine having structure,
10 or its pharmaceutically acceptable salt thereof comprises:
i) reacting (3,4-dimethoxyphenyl)acetic acid of compound of formula II,
Formula II
with N-(2,2-dimethoxyethyl)amine at a suitable temperature in a suitable solvent,
in the absence of coupling/condensing agent to give N-(2,2-dimethoxyethyl)-2-
(3,4-dimethoxyphenyl)acetamide of compound of formula III,
8
Formula III
ii) cyclizing the resulting N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxy
phenyl)acetamide of formula III in the presence of a suitable acid,
iii) isolating 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound of
formula I,
Formula I
iv) converting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of co5 mpound
of formula I into ivabradine or its pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous, environment
10 friendly and efficient process for preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepine-2-oneof compound of formula I by reacting (3,4-
dimethoxyphenyl)acetic acid of formula II with N-(2,2-dimethoxyethyl)amine at
a suitable temperature in a suitable solvent, in the absence of
coupling/condensing agent to give a reaction mixture.
15 The suitable solvent used in the reaction mixture can be any suitable organic
solvent, which can form azeotrope with water. The suitable organic solvent can
be selected from toluene, cyclohexane; methyl ethyl ketone, methyl isobutyl
ketone, di-isobutyl ketone and a like or mixture thereof.
The suitable temperature used in the reaction can be in the range of 10°C to the
20 reflux temperature of the solvent and it takes about 5 hours to 30 hours for
completion of reaction.
9
The water generated in-situ during condensation reaction can be removed by
using any suitable means to give N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxy
phenyl) acetamide of compound of formula III. The resulting N-(2,2-
dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide of compound of formula III
can be isolated or can be used as such for next reaction without its isolation5 .
It has been observed that it is advantageous to remove the water, generated in-situ
during condensation reaction to avoid the backward reaction. The removal of
water can be accomplished by azeotropical distillation or using activated
molecular sieves.
10 Generally, after completion of reaction, solvent may be distilled out from reaction
mass to isolate N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl) acetamide.
Alternatively, reaction mass may be cooled to a temperature of below 35°C,and
proceeded for further cyclization step. The resulting reaction mass can be treated
with a suitable acid to carried out cyclization reaction of N-(2,2-dimethoxyethyl)-
15 2-(3,4-dimethoxyphenyl)acetamide of compound of formula III. The compound
of formula III, prepared by direct condensation of (3,4-dimethoxyphenyl)acetic
acid of compound of formula II with N-(2,2-dimethoxyethyl)amine is of high
synthetic applicability, since it avoids use of toxic reagents.
It is not crucial for next cyclization reaction, whether to isolate compound of
20 formula III or used as such from reaction mass.
The suitable acid used for cyclization reaction can be selected from concentrated
hydrochloric acid in aqueous solution, concentrated hydrochloric acid in solution
in acetic acid, hydrobromic acid, hydrobromic acid solution in acetic acid,
sulphuric acid, methanesulphonic acid or a mixture thereof.
25 The suitable temperature to carry out cyclization reaction is preferably 10 to
40°C. Generally, after completion of cyclization reaction, the reaction mixture is
diluted with a suitable medium. Preferably water is added to the reaction mixture
and reaction mass is further stirred for 2 to 10 hours for complete crystallization
of desired product. The resulting solid can optionally be purified by using a
30 suitable solvent. The suitable solvent includes but not limited to alcohols selected
10
from ethanol, methanol; ester and ether solvent such as ethylactetate, diethyl ether
and a like or mixture thereof. The compound of formula I, can be isolated from
reaction mass by using a suitable means known in the art like filtration,
centrifugation or the like. The resulting solid product can be washed with
suitable solvent including demineralized water and then can be dried at 5 t a
temperature range of 40°C to 80°C to give 7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepine-2-oneof compound of formula I. The completion of reaction can be
monitored by any one of chromatographic techniques such as thin layer
chromatography (TLC), high pressure liquid chromatography (HPLC), Ultra10
pressure liquid chromatography (UPLC) and the like
The 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound of
formula I, prepared according to present invention is highly useful in the synthesis
of ivabradine or its pharmaceutically acceptable salt thereof, as it is an important
intermediate.
15 Accordingly, the present invention provides a convenient, industrially
advantageous and efficient process for preparation of ivabradine or its
pharmaceutically acceptable salt thereof by using 7,8-dimethoxy-1,3-dihydro-
2H-3-benzazepine-2-one of compound of formula I prepared by reacting (3,4-
dimethoxy phenyl)acetic acid of compound of formula II with N-(2,2-
20 dimethoxyethyl)amine at a suitable temperature in a suitable solvent, in the
absence of coupling/condensing agent, to prepare N-(2,2-dimethoxyethyl)-2-(3,4-
dimethoxyphenyl)acetamide of compound of formula III, followed by cyclization
of N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide of compound of
formula III in acidic medium to prepare 7,8-dimethoxy-1,3-dihydro-2H-3-
25 benzazepine-2-one of compound of formula I, and converting 7,8-dimethoxy-1,3-
dihydro-2H-3-benzazepine-2-oneofcompound of formula I to ivabradine or its
pharmaceutically acceptable salt thereof by the methods known in the art or as
described.
Generally 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound of
30 formula I can be alkylated with 1-bromo-3-chloro-propane in presence of a
11
suitable base in an organic solvent to obtain 7,8-dimethoxy-3-[3-chloropropyl]-
1,3-dihydro-2H-3-benzazepin-2-one of compound of formula IV.
Formula IV
The compound of formula IV can be then condensed with methylamine derivative
of formula V or salt thereof,
Formula V
to prepare benzazepine intermediate of formula VI5 ;
Formula VI
which is then reduced to prepare ivabradine and converting into ivabradine
pharmaceutically acceptable salt thereof.
Particularly 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound of
formula I can be alkylated with 1-bromo-3-chloro-propane in presence of a
10 suitable base in an organic solvent to benzazepin-2-one compound of formula IV.
The suitable base includes potassium tertiary butoxide, alkali metal hydroxide
such as sodium hydroxide, potassium hydroxide or the like. The organic solvent
can be selected from acetone, dimethylsulfoxide, dimethylformamide, etc. or
mixtures thereof. Benzazepin-2-one compound of formula IV can optionally be
15 purified to achieve purity of greater than 99%w/w. Any suitable purification
method can be employed for purification; preferably benzazepin-2-one compound
of formula IV can be crystallized by using suitable solvent or a mixture of
solvents or slurry washed in a suitable solvent. The suitable solvent can be
12
selected from water, acetates, ketones and mixture thereof. Preferably water,
acetone and a mixture of acetone and ethyl acetate have been used.
Thereafter benzazepin-2-one compound of formula IV can be then condensed
with methylamine derivative of formula V or salt thereof, to prepare benzazepine
intermediate of formula VI5 .
The methylamine derivative of formula V or salt thereof can be prepared by
methods known in literature. Specifically camphorsulphonic acid salt of
methylamine derivative of formula V is used and treated with base to prepare
methylamine derivative of formula V. The methylamine derivative of formula V
10 can be isolated or used in situfor further reaction. The condensation reaction can
be carried out in demineralized water and in the presence of a base at 45-60°C
preferably at 50-55°C and it takes 10-20 hours for completion of reaction. The
progress of reaction can be monitored by high performance liquid
chromatography (HPLC). The suitable base used in the condensation step can be
15 selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal
hydroxides and preferably potassium carbonate is used. Benzazepine intermediate
of formula VI, prepared by process as given, can be hydrogenated and converted
into highly pure ivabradine or its pharmaceutically acceptable salt thereof.
Typically, the condensed product Benzazepine intermediate of formula VI is
20 converted to ivabradine or its pharmaceutically acceptable salt selected from
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid,
trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric
acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid,
methanesulphonic acid, benzenesulphonic acid and camphoric acid, and hydrates
25 thereof. Preferably hydrochloride or oxalate salt is prepared. The compound of
formula VI is catalytically hydrogenated using palladium on carbon catalyst in
suitable solvent such as alcohols like under hydrogen pressure of 3-10 kg/cm2.
The hydrogenation reaction is conducted at ambient temperature and it takes 4-12
hours for completion of reaction, which is monitored by high performance liquid
13
chromatography (HPLC). The catalyst is filtered out and the product is isolated
from reaction mass by removal of solvent by distillation from the filtrate.
Thereafter crude ivabradine is treated with suitable acid i.e. hydrochloric acid or
oxalic acid to prepare the desired salts. The acid salt is then purified using a
suitable solvent such as acetates, alcohols, nitriles, and the like and preferabl5 y
ethyl acetate, acetonitrile are used. Purification steps can be repeated, if required,
to achieve the desired purity level. Ivabrdaine salts can also be converted to one
another like ivabradine hydrochloride can be converted to ivabradine oxalate and
ivabradine oxalate can be converted to ivabradine hydrochloride. Preferably
10 hydrochloride or oxalate salt is prepared. In an alternate embodiment, compound
of formula IV can be reduced before condensation with compound of formula V
and results directly to prepare ivabradine.
Ivabradine prepared by using the compound of formula I, prepared by using
process of present invention, can be converted in to pharmaceutically acceptable
15 salt selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric
acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid,
succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid,
ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and
camphoric acid, and hydrates thereof. Ivabrdaineand its saltshave been prepared
20 in comparable purity and better yield by using 7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepine-2-one, prepared by using the process of present invention.
Major advantages realized in the present invention are that yield of 7,8-
dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one has been increased many folds,
asthionyl chloride has not been used. Further time cycle for preparation method
25 has alsobeen reduced. Since time cycle is reduced, so in same time period more of
the 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one, with improved yield
will be generated, so production cost will down and hence process is cost
effective.
14
EXAMPLES:
Example 1: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
To a suspension of (3,4-dimethoxyphenyl)acetic acid (50g) in toluene (175 ml) N-
(2,2-dimethoxyethyl)amine (32.5g) was added at 15-35ºC. The resulting reacti5 on
mixture was heated to reflux, and maintained at same temperature for 26 hours,
with removal of water azeotropically. After completion of reaction, the reaction
mixture was cooled to a temperature of 20°C to 30ºC. Concentrated hydrochloric
acid (150ml) was added to the reaction mixture and stirred. The layers were
10 separated and toluene layer was further extracted with concentrated hydrochloric
acid (100ml). The acidic layers were combined and concentrated sulphuric acid
(25ml) was added to it. The resulting reaction mixture was stirred at a temperature
of 25°C to 30ºC for 17 hours. After completion of reaction, demineralized water
(250ml) was added at a temperature of 20°C to 30ºC and reaction mixture was
15 further stirred for 4 hours for complete crystallization. Thereafter methanol
(25ml) was added, and reaction mixture was further stirred for 45 minutes. The
resulting solid was filtered and washed with demineralized water and dried at a
50-60ºC to obtain 44g of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one,
having purity 97.18% measured by HPLC.
20 Example 2: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
To a suspension of (3,4-dimethoxyphenyl)acetic acid (25g) in toluene (87.5ml) N-
(2,2-dimethoxyethyl)amine (16.2g) was added at 15-35 ºC. The resulting reaction
mixture was heated to reflux, maintained at reflux temperature for further 30
25 hours, and water was removed azeotropically. After completion of the reaction,
reaction mixture was cooled to a temperature of 25°C to 30ºC. Concentrated
hydrochloric acid (100ml) was added to the reaction mixture and stirred. The
layers were separated and toluene layer was further extracted with concentrated
hydrochloric acid (25ml). The acidic layers were combined and concentrated
30 sulphuric acid (12.5ml) was added to it. The resulting reaction mixture was stirred
15
at a temperature of 25°C to 30ºC for 15 hours. After completion of reaction,
demineralized water (125ml) was added at a temperature of 20°C to 30ºC and
reaction mixture was further stirred for 4 hours for complete crystallization.
Thereafter, methanol (12.5ml) was added and reaction mixture was further stirred
for 45 minutes. The resulting solid was filtered and washed with demineralize5 d
water and dried at 50-60ºC to afford 22.2 g of 7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepine-2-one, having purity 97.9% measured by HPLC.
Example 3: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
10 To a suspension of (3,4-dimethoxyphenyl)acetic acid (100g) in toluene (350ml)
N-(2,2-dimethoxyethyl)amine (65g) was added at 15-35ºC. The resulting reaction
mixture was heated to reflux, maintained reaction mixture at reflux temperature
for 30 hours, and water was removed azeotropically. After completion of the
reaction, the reaction mixture was cooled to a temperature of 20°C to 30ºC.
15 Concentrated hydrochloric acid (400ml) was added to the reaction mixture and
stirred. The layers were separated and toluene layer was further extracted with
concentrated hydrochloric acid (100ml). The acidic layers were combined and
concentrated sulphuric acid (50ml) was added to it. The resulting reaction mixture
was stirred at a temperature of 25°C to 30ºC for 15 hours. After completion of
20 reaction demineralized water (500ml) was added at a temperature of 20°C to 30ºC
and reaction mixture was further stirred for 4 hours for complete crystallization.
Thereafter, methanol (50ml) was added and reaction mixture was further stirred
for 45 minutes, The resulting solid was filtered and washed with demineralized
water and dried at 50-60ºC to afford 91g of 7,8-dimethoxy-1,3-dihydro-2H-3-
25 benzazepine-2-one, having purity 98.4% measured by HPLC.
Example 4: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
To a suspension of (3,4-dimethoxyphenyl)acetic acid (10g) in methyl isobutyl
ketone (40ml) N-(2,2-dimethoxyethyl)amine (6.5g) was added at 15-35ºC. The
30 resulting reaction mixture was heated to reflux, maintained at reflux temperature
16
for 27 hours, and water was removed azeotropically. After completion of reaction,
the reaction mixture was cooled to a temperature of 20°C to 30ºC. Concentrated
hydrochloric acid (50ml) was added to the reaction mixture and stirred. The
layers were separated and the acidic layers were combined and concentrated
sulphuric acid (5 ml) was added to it. The resulting reaction mixture was stirred 5 d at
a temperature of 25°C to 30ºC for 16 hours. After completion of reaction,
demineralized water (50ml) was added at a temperature of 20°C to 30ºC and
reaction mixture was further stirred for 4 hours for complete crystallization.
Thereafter methanol (5ml) was added, and reaction mixture was further stirred for
10 45 minutes. The resulting solid was filtered and washed with demineralized water
and dried at 50-60ºC to obtain the title compound.
Example 5: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
To a suspension of (3,4-dimethoxyphenyl)acetic acid (50g) in toluene (175ml) N-
15 (2,2-dimethoxyethyl)amine (22.5g) was added at 15-35ºC. The resulting reaction
mixture was reflux, maintained reaction mixture at reflux temperature for 29
hours, and water was removed azeotropically. After completion of reaction, the
reaction mixture was cooled to a temperature of 20°C to 30ºC. Concentrated
hydrochloric acid (200ml) was added to the reaction mixture and stirred. The
20 layers were separated and toluene layer was further extracted with concentrated
hydrochloric acid (50ml). The acidic layers were combined and divided into two
equal parts.
One part of acidic layer was stirred at a temperature of 25-30ºC for 15-17 hours
and demineralized water (125ml) was added and reaction mixture was further
25 stirred for 4 hours for complete crystallization. Thereafter methanol (12.5ml) was
added and reaction mixture was further stirred for 45 minutes. The resulting solid
was filtered and washed with demineralized water and dried at a 50-60ºC to
obtain 22g of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one.
To the second part of acidic layer, concentrated sulphuric acid (12.5ml) was
30 added slowly at a temperature of 20-30ºC and the resulting reaction mixture was
17
stirred for 15-17 hours. After completion of reaction, demineralized water
(125ml) was added at a temperature of 20°C to 30ºC and reaction mixture was
further stirred for 4 hours for complete crystallization. Thereafter methanol
(12.5ml) was added, and reaction mixture was further stirred for 45 minutes. The
resulting solid was filtered and washed with demineralized water and dried at 5 t a
50-60ºC to obtain 24.8g of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one
having purity 99.03% measured by HPLC.
Example 6: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
10 To a suspension of (3,4-dimethoxyphenyl)acetic acid (50g) in toluene (150ml) N-
(2,2-dimethoxyethyl)amine (32.5g) was added at 15-35ºC. The resulting reaction
mixture was heated to reflux, maintained at reflux temperature for 30 hours, and
water was removed azeotropically. After completion of reaction, the reaction
mixture was cooled to a temperature of 25°C to 30ºC. Concentrated hydrochloric
15 acid (250ml) was added to the reaction mixture. The resulting reaction mixture
was stirred at a temperature of 25°C to 30ºC for 22 hours. After completion of
reaction, demineralized water (150ml) was added at a temperature of 20°C to
30ºC and reaction mixture was further stirred for 3 hours for complete
crystallization. The resulting solid was filtered and washed with demineralized
20 water and dried at a 50-60ºC to obtain 7,8-dimethoxy-1,3-dihydro-2H-3-
benzazepine-2-one, having purity 98.07% measured by HPLC.
Example 7: Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
one
a)Preparation of N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide
25 To a suspension of (3,4-dimethoxyphenyl)acetic acid (50g) in toluene (175 ml) N-
(2,2-dimethoxyethyl)amine (32.5 g) was added at 15-35 ºC. The resulting reaction
mixture was heated to reflux, maintained reaction mixture at reflux temperature
for 30 hours, and water was removed azeotropically. Thereafter, toluene was
distilled to obtain N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl) acetamide.
30
18
b)Preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one
To the resulting N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide,
concentrated hydrochloric acid (250 ml) and concentrated sulphuric acid (25 ml)
were added. The resulting reaction mixture was heated at a temperature of 25°C to
30ºC for 4 hours. After completion of reaction, demineralized water (250 ml5 )
was added at a temperature of 20°C to 30ºC and reaction mixture was further
stirred for 4 hours for complete crystallization. Thereafter methanol (25 ml) was
added, and reaction mixture was further stirred for 45 minutes. The resulting solid
was filtered and washed with demineralized water and dried at a 50-60ºC to
10 obtain 43.6g of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one, having
purity 98.4% measured by HPLC.
Example 8: Preparation of 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-
2H-3-benzazepin-2-one
7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one (90 g) prepared as above,
15 was taken in dimethylformamide (270 ml) and potassium hydroxide (45 g) was
added. The resulting reaction mixture was stirred at a temperature of 0°C to 5ºC
for 15 minutes. Thereafter, 1-bromo-3-chloro-propane (67.5 ml) was added, and
maintained the reaction mixture at same temperature for 3 hours. After
completion of reaction (monitored by HPLC), demineralized water (270 ml) was
20 slowly added at a temperature of 0°C to 5ºC, and reaction mixture was further
stirred at a temperature of 25°C to 30ºC for 1 hour. The resultant product was
filtered, washed with demineralized water and dried at 50-60ºC to obtain 102 g
of title compound, having purity 98.5% measured by HPLC.
Example 9: Purification of 7,8-Dimethoxy-3-(3-chloropropyl)-1,3-dihydro-
25 2H-3-benzazepin-2-one
7,8-Dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepin-2-one, prepared
as above was taken in acetone (306 ml) and stirred at a temperature of 45°C to
55ºC for 30 minutes till complete dissolution. The resultant reaction mass was
filtered through hyflo and washed with acetone (102 ml). Combined acetone
30 solution was distilled out till acetone (120-125) remained. Thereafter
19
demineralized water (612 ml) was added to the resulting acetone solution at
temperature 40-45°C and maintained the reaction mixture at ambient temperature
for 1 hour. The resulting solid was filtered, washed with demineralized water and
dried at 50-60ºC to obtain 98 g of pure title compound , having purity 99.81%
measured by HPLC5 .
Example 10: Preparation of (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxy
benzocyclobut-1-yl)methyl]-N-(methylaminopropyl)-1,3-dihydro-2H-3-
benzazepine-2-one
To a mixture of (S)-[(4,5-dimethoxy benzocyclobut-1-yl)-methyl]-N-(methyl
10 amine camphorsulphonic acid (35 g) and water [ 47 ml], potassium carbonate
(44.3 g) was added at temperature below 30°C and stirred for 15-20 minutes. To
this, 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepin-2-one (23.8
g) was added and stirred for further 30 minutes. Thereafter the reaction mixture
was to 55-60°C and maintained the temperature for 24-30 hours. After completion
15 of reaction (monitored by HPLC), ethyl acetate (175 ml) was added at same
temperature, and stirred for 15 minutes. Thereafterwater (70 ml) was added and
cooled the reaction mixture to 30-35°C. The layers were separated and the
resulting aqueous layer was further extracted with ethyl acetate. The combined
ethyl acetate layer was washedtwice with sodium hydroxide solution (4 g sodium
20 hydroxide + 105 ml water). The ethyl acetate was distilled completely under
vacuum at 55-66°C to obtain 36g of the title compound as oil.
Example 11: Preparation of Ivabradinehydrochloride
Benzazepine compound (35 g) obtained as above, was taken in methanol [210ml]
and was hydrogenated in the presence of Pd/C [10% 7.0 g] under a hydrogen
pressure of 7-8 kg/cm2 25 at temperature of 25-30°C for about 8-10 hours. After
completion of hydrogenation, catalyst was filtered off and washed with methanol.
Methanol was distilled out completely under vacuum at 25-30°C. The resulting
reaction mass was taken in dilute hydrochloric acid solution [175 ml) and
methylene chloride [230ml]. The layers were separated and the resulting aqueous
30 layer was extracted twice with methylene chloride [2x140ml]. The combined
20
methylene chloride was filtered, and distilled completely under vacuum. To the
residue, acetonitrile (70ml) was added and distilled to remove traces of methylene
chloride. To the resulting reaction mass, acetonitrile (700ml) was added and
heated to reflux till clear solution. Thereafter 50% of acetonitrile was distilled out
and the reaction mixture was cooledto 25-30°C and stirred at same temperatur5 e
for further 2 hours. The resultant product was filtered, washed with acetonitrile
and suck dried. The same purification was repeated again in acetonitrile. Further
the resulting wet material was taken in ethyl acetate (420ml) and heated to reflux
till clear solution. Distilled out one sixth of ethyl acetate, cooled the reaction
10 mixture was to 30-35°C and stirred at same temperature for further 1 hour. The
product thus obtained was filtered, washed with ethyl acetate and dried at 70-
80°C to obtain the title compound (28.48 g), having purity 99.90% w/w by HPLC.
Example 12: Preparation of Ivabradine oxalate
Ivabradine (23 g) was taken in acetonitrile (230 ml) and the temperature was
15 raised to 65-70°C. To this, oxalic acid solution (7 g in 75 ml acetonitrile) was
added and filtered the reaction mixture and stirred for 15 minutes. The
temperature of reaction mixture was raised to 80-85°C and stirred for 2 hours.
Cooled the resulting solution to ambient temperature slowly and stirred for further
4 hours. The resulting solid was filtered and washed with acetonitrile (10 ml). The
20 wet cake was recrystallized in acetonitrile (230 ml) and resulting product was
dried under vacuum at 60-65°C to obtain 24.0 g of title compound.
Example 13: Preparation of Ivabradine oxalate
Ivabradine hydrochloride (25 g) was taken in demineralized water (75 ml) and
sodium hydroxide solution (6.25 g in 13 ml water) was added at temperature 25-
25 30°C, to adjust the pH above 11.5. Thereafter, ethyl acetate (125 ml) was added,
and stirred for further 30 minutes. The layers were separated and the resulting
aqueous layer was further extracted with ethyl acetate. The combined ethyl
acetate layer was washed with sodium hydroxide solution (1.5 g in 75 ml water),
21
then with ethyl acetate and then treated with sodium sulphate (2.5 g). The ethyl
acetate was distilled completely under vacuum at 55-60°C. To the residue,
acetonitrile was added (25 ml) to remove the traces of ethyl acetate from the
solution. Acetonitrile (225 ml) was added and raised the temperature to 65-70°C,
to this, oxalic acid solution (7 g in 75 ml acetonitrile) was added and filtered 5 d the
reaction mixture and stirred for 15 minutes. The temperature of reaction mixture
was raised to 80-85°C and stirred for 2 hours. Cooled the resulting solution to
ambient temperature slowly and stirred for further 4 hours. The resulting solid
was filtered and washed with acetonitrile (13 ml). The wet cake was recrystallized
10 in acetonitrile (250 ml) and resulting product was dried under vacuum at 60-65°C
to obtain 24.1 g of title compound.
It will be apparent to those skilled in the art that various modifications and
15 variations can be made in the present invention and specific examples are
provided herein without departing from the spirit and scope of the invention.
Thus, it is intended that the present invention covers the modifications and
variations of this invention that come within the scope of any claims and their
equivalents

WE CLAIM:
1. A process for preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-
oneof compound of formula I,
Formula I
comprises:
i) reacting (3,4-dimethoxyphenyl)acetic acid of compound of formula II5 ,
Formula II
with N-(2,2-dimethoxyethyl)amine at a suitable temperature in a suitable
solvent, in the absence of coupling/condensing agent to give N-(2,2-
dimethoxyethyl)-2-(3,4-dimethoxyphenyl) acetamide of compound of formula
III,
Formula III
10 ii) cyclizing the resulting N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)
acetamide of compound of formula III in the presence of a suitable acid,
iii) isolating 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of formula I.
2. The process as claimed in claim 1, wherein in step i) the suitable temperature
is from 10°C to the reflux temperature of the solvent used.
15 3. The process as claimed in claim 1, wherein in step i) the suitable solvent is an
organic solvent that forms azeotrope with water.
23
4. The process as claimed in claim 1, wherein in step i) the suitable solvent is
toluene, cyclohexane; methyl ethyl ketone, methyl isobutyl ketone, di-isobutyl
ketone and a like or mixture thereof.
5. The process as claimed in claim 1, wherein in step ii) the suitable acid is
selected from concentrated hydrochloric acid in aqueous solution, concentra5 ted
hydrochloric acid in solution in acetic acid, hydrobromic acid, hydrobromic
acid solution in acetic acid, sulphuric acid, methanesulphonic acid or a
mixture thereof.
6.The process as claimed in claim 1, wherein in step ii) the reaction is
10 performed at 10°C to 40°C.
7.A process for preparation of ivabradine of following formula,
or its pharmaceutically acceptable salt thereof comprises:
i) reacting (3,4-dimethoxyphenyl)acetic acid of compound of formula II,
Formula II
with N-(2,2-dimethoxyethyl)amine at a suitable temperature in a suitable
15 solvent, in the absence of coupling/condensing agent to give N-(2,2-
dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide of compound of formula
III,
Formula III
24
ii) cyclizing resulting N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)
acetamide of formula III in the presence of a suitable acid,
iii) isolating 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound
of formula I,
Formula I
iv) converting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one 5 of
compound of formula I into ivabradine or its pharmaceutically acceptable salt
thereof.
8. The process as claimed in claim 7, wherein in step iv) the converting of 7,8-
dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound of formula I
10 into ivabradine or its pharmaceutically acceptable salt thereof comprises the
step of
i) alkylating 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one of compound
of formula I with 1-bromo-3-chloro-propane in presence of a suitable base in
an organic solvent to obtain 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-
15 2H-3-benzazepin-2-one of compound of formula IV,
Formula IV
ii) condensing of the resulting compound of formula IV with methylamine
derivative of formula V or salt thereof,
Formula V
to prepare benzazepine intermediate of formula VI;
25
Formula VI
iii) reducing the benzazepine intermediate of formula VI by catalytic
hydrogenation to prepare ivabradine and
iv) convertingivabradine into ivabradine pharmaceutically acceptable salt
thereof by reacting with a suitable acid.
9. The process as claimed in claim 8, wherein in step i) the suitable base 5 is
selected from potassium tertiary butoxide, alkali metal hydroxide such as
sodium hydroxide, potassium hydroxide; the organic solvent is selected from
acetone, dimethylsulfoxide, dimethylformamide or mixtures thereof.
10. The process as claimed in claim 8, wherein in step ii) condensation is carried
10 out in demineralized water and in the presence of a base at 45-60°C; in step
iii) reduction is carried out using palladium on carbon catalyst in suitable
solvent under hydrogen pressure of 3-10 kg/cm2; in step iv) ivabradine is
converted to suitable acid by reacting with a suitable acid in a suitable
solvent.