DESC:RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Provisional Patent Application No. 201741015681 filed on May 03, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention describes an improved process for the preparation of substantially pure Acrivastine, having purity greater than 99.5% as determined by HPLC.

BACKGROUND OF THE INVENTION
Acrivastine (I) is a second-generation H1-receptor antagonist antihistamine. It was approved by US as non-sedative antihistamine drug which help in blocking histamine H1 receptors and used for the treatment of allergies and hay fever. It is a synthetic alkylamine chemically known as (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid.

Several synthetic routes were reported in the literature for the preparation of Acrivastine (I). US Patent No. 4501893 describes various synthetic routes for the preparation of Acrivastine (I). according to which 4-tolunitrile reacts with 2,6-dibromopyridine to produce 2-bromo-6-(4-toluoyl) pyridine, which reacts with ethylene glycol in the presence of p-toluene sulfonic acid and benzene to afford 2-(6-bromo-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan. The bromo-compound on formylation in the presence of butyl lithium produces 2-(6-formyl-2-pyridyl)-2-(4-tolyl)-1,3-dioxolan which on condensation with triethyl phosphonoacetate, followed by acid hydrolysis of dioxolane group results the formation of ethyl (E)-3-[6-(4-toluoyl)-2-pyridyl] acrylate. Further acrylate compound undergoes Wittig reaction with triphenyI-2-pyrrolidinoethyI-phosphonium bromide to give ethyl [E]-3-[6-{3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl}-2-pyridyl]-acrylate, which on basic hydrolysis followed by acidification forms [E]-3-[6-{3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl}-2-pyridyl]-acrylic acid or Acrivastine (I).

An alternate synthetic approach for the preparation of Acrivastine (I) as reported in US4501893 discloses synthesis of Acrivastine by condensation of 1-pyrrolidino-3-(4-tolyl)-propan-1-one with 2-bromo-6-(1,3-dioxolan2-yl) pyridine in the presence of butyl lithium followed by acid hydrolysis to get 2-(1-hydroxy-3-pyrrolidino-1-(4-tolyl)-propyl) pyridine-6-aldehyde. Further, aldehyde undergoes Knoevenagel condensation with malonic acid followed by decarboxylation to afford (E)-3-[6-{1-(4-tolyl)-1-hydroxy-3-pyrrolidino-propyl}-2-pyridyl]-acrylic acid, which on further esterification with methanol and sulphuric acid formed methyl (E)-3-[6-{1-(4-tolyl)-1-hydroxy-3-pyrrolidino-propyl}-2-pyridyl]-acrylate. The acrylate formed above on re-isolation and saponification yielded [E]-3-[6-{3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl}-2-pyridyl]-acryIic acid (Acrivastine) (I).

The Indian Patent No. 614/MUM/2012 relates to the process of preparation of Acrivastine by base hydrolysis of the ester group of ethyl-E-3-[6-{1-(4-tolyl)-1-hydroxy-3-pyrrolidino-propyl}-2-pyridyl]-acrylate, dehydrating, neutralizing, removing excess solvent by distillation, recrystallizing, purifying and drying by lyophilizing to obtain pure E- isomer of Acrivastine.

The present invention aims at providing a novel process for the preparation of Acrivastine which is safe, economical, and feasible at commercial scale. The present invention also provides a method of purification of Acrivastine, as most of the prior art processes do not disclose the detailed process of purification and the percentage of purity of the final compound. Also, the use of palladium-non-borate catalytic coupling is advantageous as reactions can easily be carried out under mild conditions and thus is industrially feasible.

SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an improved process for the preparation of [E]-3-[6-{3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl}-2-pyridyl]-acrylic acid (Acrivastine) (I).

The one of the objects of the invention is to provide substantially pure Acrivastine (I), with purity greater than 99.5% as determined by HPLC.

Another object of the invention is to provide process for preparing Acrivastine (I), having total impurity level less than 0.5% as determined by HPLC.

Yet, another object of the present invention is to provide a novel process with high stereo selection for the preparation of substantially pure Acrivastine (I).

In one aspect of the invention, there is provided a method of preparing a substantially pure Acrivastine, whose isomeric purity (E, E isomer) is greater than or equal to 99.5% as determined by HPLC.

In another aspect of the invention, there is provided a process for the preparation of Acrivastine (I), the said process comprising the steps of,

a) coupling of 2,6-dibromo pyridine (VI)

with-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (V)

in presence of alkyl lithium reagent in an aprotic solvent and a base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-ol (IV);

b) dehydration of intermediate (IV) using strong acid to form stereoselective intermediate (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl)pyridine (III);

followed by purification from a mixture of protic and aprotic solvents to obtain stereoselectivity greater than 99%;
c) coupling of intermediate (III) with ethyl acrylate in the presence of a suitable ligand and suitable palladium catalyst in triethylamine medium to obtain (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II);

d) hydrolysis of intermediate (II) in presence of suitable base to obtain (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I); and
e) purification of Acrivastine (I) from an aprotic solvent or protic solvent or a mixture thereof.

In some embodiment of the invention, the alkyl lithium reagent employed in step a) of the above described process for the preparation of Acrivastine (I) is selected from the group comprising of methyl lithium, n-butyl lithium, t-butyl lithium, phenyl lithium or the like.

In some embodiment of the invention, the suitable acid employed in step b) of the above described process for the preparation of Acrivastine (I) is selected from a group comprising of concentrated sulphuric acid, nitric acid, hydrochloric acid, orthophosphoric acid, p-toluenesulfonic acid or the like.

In another embodiment of the invention, the suitable base employed in step a) of the above described process for the preparation of Acrivastine (I) is aqueous ammonia.

In some embodiment of the invention, the suitable ligand employed in step c) of the above described process for the preparation of Acrivastine (I) is selected from a group comprising of tri(O-tolyl)phosphine, triphenylphosphine or the like and the palladium catalyst employed is selected from a group comprising of palladium chloride, palladium acetate , palladium (II) trifluoroacetate or the like.

In some embodiment of the invention, the suitable base employed in step a) or step d) of the above described process for the preparation of Acrivastine (I) is selected from a group comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate and sodium bicarbonate or the like.

In another aspect of the invention, there is provided a process for the purification of Acrivastine (I), said process comprising the steps of:

a) providing a solution of Acrivastine (I) in a suitable aprotic solvent;
b) filtering the reaction mixture through 0.2 mm micron filter,
c) distilling the filtrate below 45°C;
d) adding a suitable protic solvent to the residue;
e) heating the reaction mass to 70-90°C; and
f) isolating pure Acrivastine (I) at 20-25°C.

In some embodiment of the invention, the aprotic solvent used in the present invention is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like.

In some other embodiment of the invention, the protic solvent used in the present invention is selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or the like.

In yet another aspect of the invention, there is provided a process for the preparation of crystalline form of Acrivastine (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about 12.0, 14.46, 16.65, 16.84, 17.17, 17.48, 18.01, 18.36, 18.94, 19.28, 19.52, 20.44, 21.45, 22.17, 22.38, 22.93 ± 0.2 degrees, said process comprising the steps of:

a) coupling of 2,6-dibromo pyridine (VI)

with-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (V)

in presence of alkyl lithium reagent in an aprotic solvent and a base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-ol (IV);

b) dehydration of intermediate (IV) using strong acid to form stereoselective intermediate (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III),

followed by purification from a mixture of protic and aprotic solvents to obtain stereoselectivity greater than 99%;
c) coupling of intermediate (III) with ethyl acrylate in the presence of a suitable ligand and suitable palladium catalyst in triethylamine medium to obtain (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II);

d) hydrolysis of intermediate (II) in presence of suitable base to obtain (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I);
e) providing a solution of Acrivastine (I) in a suitable aprotic solvent;
f) filtering the reaction mixture through 0.2 mm micron filter;
g) distilling the filtrate below 45°C;
h) adding a suitable protic solvent to the residue;
i) heating the reaction mass to 70-90°C; and
j) isolating crystalline form of Acrivastine (I) at 20-25°C.
Thus, the present invention provides a process for the preparation of Acrivastine having greater purity, greater stereoselectivity and higher yield.

BRIEF DESCRIPTION OF DRAWINGS
Figure-1 is characteristic X-ray powder diffraction pattern (XRD) of Acrivastine (I)
Figure-2 is characteristic Thermogravimetric analysis (TGA) thermogram of Acrivastine (I)
Figure-3 is characteristic FT-IR of Acrivastine (I)

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to provide an improved process for the preparation of preparation of [E]-3-[6-{3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl}-2-pyridyl]-acrylic acid (Acrivastine) (I).

The inventors of the present invention have surprisingly found an improved process for the preparation of substantially pure Acrivastine (I), having purity greater than 99.5% as determined by HPLC. The present invention provides a novel process with high stereo selection for the preparation of substantially pure Acrivastine (I).

Another object of the invention is to provide process for preparing Acrivastine (I), having total impurity level less than 0.5% as determined by HPLC.
In one aspect of the invention, there is provideda method of preparing a substantially pure Acrivastine, whose isomeric purity (E, E isomer) is greater than or equal to 99.5% as determined by HPLC.

The Acrivastine (I) according to invention is prepared as per reaction pathway disclosed in Scheme 1.

Scheme-1

In one aspect of the invention, there is provided a process for the preparation of Acrivastine (I), the said process comprising the steps of,

a) coupling of 2,6-dibromo pyridine (VI)

with-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (V)

in presence of alkyl lithium reagent in an aprotic solvent and a base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-ol (IV);

b) dehydration of intermediate (IV) using strong acid to form stereoselective intermediate (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl)pyridine (III),

followed by purification from a mixture of protic and aprotic solvents to obtain stereoselectivity greater than 99%;
c) coupling of intermediate (III) with ethyl acrylate in the presence of a suitable ligand and suitable palladium catalyst in triethylamine medium to obtain (E)- ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II);

d) hydrolysis of intermediate (II) in presence of suitable base to obtain (E)-3-(6- ((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I); and
e) purification of Acrivastine (I) from an aprotic solvent or protic solvent or a mixture thereof.

The first step proceeds with the coupling reaction of 2,6-dibromo pyridine (VI) with 3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (V) in the presence of suitable alkyl lithium reagent and a suitable aprotic solvent at optimum temperature followed by adjusting pH using suitable base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-ol (IV). In some embodiment of the invention, alkyl lithium reagent employed in the reaction is selected from the group comprising methyl lithium, n-butyl lithium, t-butyl lithium, phenyl lithium or the like; preferably n-butyllithium. In some other embodiment of the invention, the suitable solvent is selected from the group comprising of toluene, tetrahydrofuran or the like. In some embodiment of the invention, the coupling reaction is carried at optimum pH range of 9.5 to 11.5, preferably between 10.0 to 11.0; wherein the said pH is obtained by using a suitable base. In some embodiment, the suitable base employed for pH adjustment is selected from aqueous ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate and sodium bicarbonate; preferably aqueous ammonia.

The second step comprises of dehydration of 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-ol (IV) in the presence of strong acid followed by heating to a temperature of 125-130°C. The obtained reaction mass is quenched with ice water and the pH is adjusted with strong base to obtain stereoselective (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III). In some embodiment of the invention, strong acid employed in the dehydration step is selected from the group comprising of concentrated sulphuric acid, orthophosphoric acid, p-toluenesulfonic acid; more preferably concentrated sulphuric acid. Use of sulphuric acid is advantageous over prior art processes as it results in the formation of 95% E-isomer of (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III) at the temperature range of 125-130 °C. Further, the obtained (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III), is further purified from a mixture of protic and aprotic solvent. The crude (III) is dissolved and recovered from a slurry prepared from a mixture of suitable protic and aprotic solvent selected from the group of dichloromethane, acetone, toluene, ethyl acetate, acetonitrile, water, methanol, ethanol, preferably water and acetone mixture (3:1) which is useful in removing any inorganic impurities and any traces of excess Z-isomer to get more than 95% stereoselective (E, E) isomer of (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III).

The third step involves (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-(p-tolyl) prop-1-en-1-yl) pyridine (III) undergoing Heck reaction in the presence of ethyl acrylate, a suitable ligand and a suitable palladium catalyst in triethylamine medium at an optimum temperature under closed condition to obtain (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl)acrylate (II). In some embodiment of the invention, the suitable ligand employed is selected from tri(O-tolyl) phosphine, triphenylphosphine or the like and the suitable palladium catalyst employed in the reaction is selected from a group comprising of palladium chloride, palladium acetate or the like in triethylamine medium at an optimum temperature of 110-130°C preferably 115-120°C in closed condition which generates internal pressure and helps in the completion of the reaction. Use of palladium catalyst at a higher temperature converts any remaining amount Z-isomer to E-isomer thus increasing the stereoselectivity of the compound. Further workup using suitable protic solvents selected from water, methanol, ethanol, isopropyl alcohol or the like results in formation of (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II) with purity greater than 99.5%.

The fourth step involves hydrolysis of (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl)acrylate (II) in presence of suitable base, followed by pH adjustment to an optimum range using a suitable acid to provide (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I). In some embodiment of the invention, the base employed in the hydrolysis is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate and sodium bicarbonate or the like. In some embodiment of the invention, the pH is adjusted to the optimum range between 5.5-6.5 using suitable acid selected from the group comprising of acetic acid, formic acid, hydrofluoric acid or the like, to precipitate (E)-3-(6-((E)-3- (pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I).

Purification of crude Acrivastine (I) crude so obtained was carried out using suitable protic solvents selected from demineralized water, methanol, ethanol, isopropyl alcohol or the like, wherein methanol and isopropyl alcohol are being most suitable to remove 0.02 RRT impurity or any other unknown impurities below 0.01%. There is no process in the prior art to remove the unknown impurity at 0.02 RRT.

The final step involves purification of compound of crude (E)-3-(6-((E)-3- (pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I) from aprotic solvents followed by protic solvent. Aprotic solvent selected from dichloromethane, acetone, toluene, ethyl acetate or the like and a protic solvent which could be selected from methanol, ethanol, isopropyl alcohol or the like, wherein dichloromethane and isopropyl alcohol are being the most suitable solvents for purification. Prior art methods are using preparative chromatography and tedious purification methods followed by lyophilization to obtain more than 99% purity by HPLC. Whereas the present invention provides simple recrystallization techniques, which can be feasible on commercial scale to obtain the Acrivastine with more than 99.5% purity and isomer purity greater than 99% by chiral HPLC.

In some embodiment of the invention, there is provided a substantially pure Acrivastine (I), with purity greater than 99.5% as determined by HPLC.

In some other embodiment of the invention, there is provided a process for preparing Acrivastine (I), having total impurity level less than 0.5% as determined by HPLC.

In some other embodiment of the invention, there is provided a a novel process with high stereo selection for the preparation of substantially pure Acrivastine (I).

In some embodiment of the invention, there is provided a method of preparing a substantially pure Acrivastine, whose isomeric purity (E, E isomer) is greater than or equal to 99.5% as determined by HPLC.

In another aspect of the invention, there is provided a process for the purification of Acrivastine (I), said process comprising the steps of:

a) providing a solution of Acrivastine (I) in a suitable aprotic solvent;
b) filtering the reaction mixture through 0.2 mm micron filter,
c) distilling the filtrate below 45°C;
d) adding a suitable protic solvent to the residue;
e) heating the reaction mass to 70-90°C; and
f) isolating pure Acrivastine (I) at 20-25°C.

In some embodiment of the invention, the aprotic solvent used in the present invention is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like.

In some other embodiment of the invention, the protic solvent used in the present invention is selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or the like.

In yet another aspect of the invention, there is provided a process for the preparation of crystalline form of Acrivastine (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about 12.0, 14.46, 16.65, 16.84, 17.17, 17.48, 18.01, 18.36, 18.94, 19.28, 19.52, 20.44, 21.45, 22.17, 22.38, 22.93 ± 0.2 degrees, said process comprising the steps of:

a) coupling of 2,6-dibromo pyridine (VI)

with-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (V)

in presence of alkyl lithium reagent in an aprotic solvent and a base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-ol (IV);

b) dehydration of intermediate (IV) using strong acid to form stereoselective intermediate (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III);

followed by purification from a mixture of protic and aprotic solvents to obtain stereoselectivity greater than 99%;
c) coupling of intermediate (III) with ethyl acrylate in the presence of a suitable ligand and suitable palladium catalyst in triethylamine medium to obtain (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II);

d) hydrolysis of intermediate (II) in presence of suitable base to obtain (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I);
e) providing a solution of Acrivastine (I) in a suitable aprotic solvent;
f) filtering the reaction mixture through 0.2 mm micron filter;
g) distilling the filtrate below 45°C;
h) adding a suitable protic solvent to the residue;
i) heating the reaction mass to 70-90°C; and
j) isolating crystalline form of Acrivastine (I) at 20-25°C.

In some embodiment of the invention, there is provided a crystalline form of Acrivastine (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about 12.0, 14.46, 16.65, 16.84, 17.17, 17.48, 18.01, 18.36, 18.94, 19.28, 19.52, 20.44, 21.45, 22.17, 22.38, 22.93 ± 0.2 degrees.
The crystalline Acrivastine (I) so obtained in the above process is having purity greater than 99.5% and isomer purity is greater than 99% by chiral HPLC.

The crystalline Acrivastine (I), so obtained in the above process is having total impurities less 0.5% w/w, preferably less than 0.2 % (w/w), each single known impurity (Impurity A or Impurity B or Impurity C) is less than 0.15% (w/w) and any unknown impurity is less than 0.10% (w/w), which forms another embodiment of the invention.

In another aspect, Acrivastine (I) obtained in the above process is characterized by XRD as illustrated in Figure 1 & Table-1, the TGA as shown in Figure 2 and FT-IR as illustrated in Figure 3.

The crystalline form of Acrivastine (I) may produce an X-ray diffraction pattern comprising of 2(?) ± 0.2 degrees values as illustrated in Figure1 and tabulated in Table-1.

Table-1: X-ray diffraction patten of crystalline form of Acrivastine (I)
2(?) deg d spacing (A) Relative Intensity %
8.08 10.90 6
8.52 10.36 11
8.78 10.06 17
9.32 9.47 6
9.61 9.19 9
9.92 8.90 3
11.8 7.48 3
12.0 7.31 26
13.54 6.53 4
13.83 6.39 16
14.46 6.11 52
14.83 5.96 7
15.02 5.89 4
15.32 5.77 4
15.76 5.61 14
16.36 5.41 11
16.65 5.31 24
16.84 5.26 27
17.17 5.15 78
17.48 5.06 38
17.79 4.98 16
18.01 4.92 37
18.36 4.82 33
18.94 4.67 52
19.28 4.59 100
19.52 4.54 66
20.44 4.34 26
21.45 4.13 78
22.17 4.0 25
22.38 3.96 47
22.93 3.87 83
23.85 3.72 3
24.76 3.59 9
25.10 3.54 16
25.38 3.50 15
27.00 3.29 11
27.38 3.25 5
27.82 3.20 7
28.52 3.12 8
28.72 3.10 9
29.10 3.06 12
30.35 2.94 11
30.61 2.91 7
31.07 2.87 13
31.45 2.84 5
31.86 2.80 5
32.09 2.78 5
35.40 2.53 6

In one embodiment of the invention, the Acrivastine (I) so synthesized is characterised by the Thermogravimetric analysis (TGA) thermogram as illustrated in Figure 2.

In another aspect, Acrivastine (I) is further characterised by FT-IR spectrum ranging from 3432, 3050, 3026, 2957, 2917, 2874, 1912, 1677, 1639, 1572, 1512, 1484, 1443, 1346, 1313, 1212, 1183, 1156, 1111, 1011, 977, 935, 881, 852, 822, 809, 732, 680 ±2 cm-1 as shown in Figure 3.

The following examples further illustrate the present invention, but should not be construed in any way as to limit its scope.
EXAMPLES
Example 1:
Preparation of 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-ol (IV):
2,6-dibromo pyridine (100 g) was added slowly to a mixture of toluene and 1.6 M n-butyllithium solution(320 ml) in hexane in a clean and dry round bottom flask at -70°C and maintained for 45-60 mins. In another round bottom flask 3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (96.3 g) was dissolved in a mixture of DM water and toluene, pH was adjusted to 8-9 using 20% aqueous sodium carbonate solution. Aqueous and organic layers were separated and the organic layer was added to the above reaction mass at -70°C. On completion of reaction, the reaction mass was quenched with aqueous hydrochloric acid. The aqueous layer was separated and cooled to 0-5°C. Aqueous ammonia (20-25%) was added to adjust the pH to 10-11 and maintained for 60-90 min at 0-5°C. The precipitated solid was dissolved in methanol, filtered and washed with methanol. The solid so obtained was vacuum dried below 55°C to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-ol (IV).
Yield %: 35-40
Purity% (as determined by HPLC): 99.0

Example 2:
Preparation of (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-(p-tolyl) prop-1-en-1-yl)pyridine (III):
100 g (0.266 mol) of 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-ol (IV) was dissolved in a mixture of DM Water and concentrated sulphuric acid at 25-30°C and the temperature was raised slowly to 125-130°C and maintained for 6hrs. On completion of reaction, the reaction mixture was quenched in ice water and pH was adjusted to 10-11 with 20-25% of aqueous ammonia solution. The precipitated solid was filtered and washed with DM water with stirring for 20-30 min at 25-30°C. A mixture of water and acetone in the ratio (3:1) was added to the solid and stirred for 30 minutes at 25-30°C, filtered and dried under vacuum to obtain 2-bromo-6-(3-(pyrrolidin-1-yl)-1-(p-tolyl) prop-1-en-1-yl) pyridine (III).
Yield %: 42-45
Purity % (as determined by HPLC): 99.5

Example 3:
Preparation of (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II):
100 g (0.279 mol) of 2-bromo-6-(3-(pyrrolidin-1-yl)-1-(p-tolyl) prop-1-en-1-yl) pyridine (III) was added to a mixture of triethylamine (1000 ml), palladium acetate 0.62 g (0.0027 mol) and triphenyl phosphine 1.46 g (0.0055 mol) at 25-30°C. Further 42.3 g (0.422 mol) of ethyl acrylate was added and heated for 10 hrs at 115-120°C under nitrogen gas. The internal pressure generated due to the heating accelerates the reaction to completion. After completion of reaction, triethylamine was distilled off from the reaction mass below 60°C and cooled to 25-30°C. To the reaction mass, dichloromethane and activated carbon were added with stirring and filtered through Hyflo bed. The filtrate so obtained was vacuum distilled, isopropyl alcohol (250 ml) and DM water (150 ml) were added to the crude at 60oC then gradually cooled to 5-10°C under stirring. The solid so obtained was filtered, washed with a chilled isopropyl alcohol and DM Water. Finally, the solid was dried under vacuum to obtain (E)-ethyl-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl)-pyridin-2-yl) acrylate (II).
Yield%: 52-57
Purity % (as determined by HPLC): 97.97

Example 4:
Preparation of (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl)acrylic acid (I):
100 g (0.266 mol) of (E)-ethyl-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II) was dissolved in methanol and treated with aqueous sodium hydroxide at 25-30°C. After completion of reaction, the reaction mass was treated with activated charcoal to remove any colored impurities and filtered through Hyflo. The filtrate was vacuum distilled and dissolved in DM water at 25-30°C stirred and pH adjusted between 6.0-6.5 with acetic acid. The reaction mixture was stirred for 1-2 hrs, filtered, washed with DM water and vacuum dried. The solid so obtained was dissolved in methanol and heated for 1-2 hrs at 60-65°C, again the reaction mixture was further cooled at 20-25°C, stirred for 1-2 hrs. The solid so obtained was dissolved in isopropyl alcohol and heated for 3-4 hrs at 80-85°C, cooled to 20-25 °C and vacuum filtered. The solid was dried under vacuum to obtain compound of (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I).
Yield%: 60-73
Purity % (as determined by HPLC): 99.5

Example 5:
Purification of (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl)-acrylic acid Acrivastine (I):
100 g (0.286 mol) of crude (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl)pyridin-2-yl)acrylic acid (I) was dissolved in dichloromethane at 25-30°C. The reaction mixture was then filtered through 0.2 mm micron filter and distilled under vacuum at 45°C. To the crude so obtained isopropyl alcohol was added at 40-45 °C and heated to 80-85 °C with stirring for 3-4 hrs and then gradually cooled to 20-25°C. The precipitated solid was filtered and suck dried under vacuum to get pure (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl)-pyridin-2-yl)-acrylicacid (Acrivastine) (I).
Yield %: 85-90
Purity % (as determined by HPLC): 99.87
,CLAIMS:
1. A process for the preparation of Acrivastine (I), the said process comprising the steps of:

a) coupling of 2,6-dibromo pyridine (VI)

with-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-one hydrochloride (V)

in presence of alkyl lithium reagent in an aprotic solvent and a base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-ol (IV);

b) dehydration of intermediate (IV) using strong acid to form stereoselective intermediate (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl)pyridine (III);

followed by purification from a mixture of protic and aprotic solvents to obtain stereoselectivity greater than 99%;
c) coupling of intermediate (III) with ethyl acrylate in the presence of a suitable ligand and suitable palladium catalyst in triethylamine medium to obtain (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II);

d) hydrolysis of intermediate (II) in presence of suitable base to obtain (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I); and
e) purification of Acrivastine (I) from an aprotic solvent or protic solvent or a mixture thereof.

2. The process as claimed in claim 1, wherein the alkyl lithium reagent employed in step a) is selected from the group comprising of methyl lithium, n-butyl lithium, t-butyl lithium, phenyl lithium or the like.

3. The process as claimed in claim 1, wherein the suitable acid employed in step b) is selected from a group comprising of concentrated sulphuric acid, nitric acid, hydrochloric acid, orthophosphoric acid, p-toluenesulfonic acid or the like.

4. The process as claimed in claim 1, wherein the suitable base employed in step a) is aqueous ammonia.

5. The process as claimed in claim 1, wherein the suitable ligand employed in step c) is selected from a group comprising of tri(O-tolyl)phosphine, triphenylphosphine or the like and the palladium catalyst employed is selected from a group comprising of palladium chloride, palladium acetate , palladium(II) trifluoroacetate or the like.

6. The process as claimed in claim 1, wherein the suitable base employed in step a) and step d) is selected from a group comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate and sodium bicarbonate or the like.

7. A process for the purification of Acrivastine (I), said process comprising the steps of:

a) providing a solution of Acrivastine (I) in a suitable aprotic solvent;
b) filtering the reaction mixture through 0.2 mm micron filter,
c) distilling the filtrate below 45°C;
d) adding a suitable protic solvent to the residue;
e) heating the reaction mass to 70-90°C; and
f) isolating pure Acrivastine (I) at 20-25°C.

8. The process as claimed in claim 1 or claim 7, wherein the aprotic solvent is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like.

9. The process as claimed in claim 1 or claim 7, wherein the protic solvent is selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or the like.

10. A process for the preparation of crystalline form of Acrivastine (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about 12.0, 14.46, 16.65, 16.84, 17.17, 17.48, 18.01, 18.36, 18.94, 19.28, 19.52, 20.44, 21.45, 22.17, 22.38, 22.93 ± 0.2 degrees, said process comprising the steps of:

a) coupling of 2,6-dibromo pyridine (VI)

with-(pyrrolidin-1-yl)-1-(p-tolyl) propan-1-one hydrochloride (V)

in presence of alkyl lithium reagent in an aprotic solvent and a base to obtain 1-(6-bromopyridin-2-yl)-3-(pyrrolidin-1-yl)-1-(p-tolyl)propan-1-ol (IV);

b) dehydration of intermediate (IV) using strong acid to form stereoselective intermediate (E)-2-bromo-6-(3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridine (III),

followed by purification from a mixture of protic and aprotic solvents to obtain stereoselectivity greater than 99%;
c) coupling of intermediate (III) with ethyl acrylate in the presence of a suitable ligand and suitable palladium catalyst in triethylamine medium to obtain (E)-ethyl 3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylate (II);

d) hydrolysis of intermediate (II) in presence of suitable base to obtain (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-p-tolylprop-1-enyl) pyridin-2-yl) acrylic acid (I);
e) providing a solution of Acrivastine (I) in a suitable aprotic solvent;
f) filtering the reaction mixture through 0.2 mm micron filter;
g) distilling the filtrate below 45°C;
h) adding a suitable protic solvent to the residue;
i) heating the reaction mass to 70-90°C; and
j) isolating crystalline form of Acrivastine (I) at 20-25°C.