FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF AZELNIDIPINE"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivli (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved and industrially advantageous process for preparation of Azelnidipine of formula (I).
BACKGROUND OF THE INVENTION:
Azelnidipine is chemically known as 3-[l-(diphenylmethyl)azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylate and is marketed under trade name Calblock®. Azelnidipine is a dihydropyridine calcium channel antagonist useful for treatment of hypertension.
US 4,772,596 (US '596) discloses preparation of Azelnidipine with following steps:
i) preparation of l-benzhydrylazetidin-3-yl-2-cyanoacetate in presence of DCC and
tetrahydrofuran, followed by purification using column chromatography;
ii) preparation of l-benzhydrylazetidin-3-yl-2-iminoester intermediate wherein the said intermediate is not isolated;
iii) preparation of Azelnidipine by treating l-benzhydrylazetidin-3-yl 2-amidinoacetate and (E)-isopropyl 2-(3-nitrobenzylidene)-3-oxobutanoate in presence of isopropanol and sodium methoxide, followed by purification using column chromatography.
However, the'596 patent suffers from various disadvantages, such as:
a) as described in i) above, the reaction is performed at higher temperature and the use of column chromatography is not commercially viable;
b) as described in ii) above, isolation of intermediate was not carried out which affects the purity of final Azelnidipine compound;
c) as described in iii) above, purification using column chromatography makes the process commercially unviable and time consuming.

Other references wherein process for preparation of Azelnidipine are disclosed in CN 100352818, CN 103509003, CN 103183663 and WO 2014139410.
The major draw-backs of the present prior arts are as follows:
1. Lower yield and lower purity of Azelnidipine
2. Use of column chromatographic technique for purifications at various stages making the process commercially unviable and time consuming.
The inventors of the present invention have found an improved process which avoids above mentioned disadvantages.
Overall, the processes for preparation of Azelnidipine and its intermediates described in various prior arts are not suitable for large scale production due to drawbacks discussed above. Therefore, there is a need for a simple, efficient and commercially viable process for preparation of Azelnidipine and/or intermediates thereof with higher purity levels.
The present invention provides such an improved process for the preparation of Azelnidipine and/or intermediates thereof, avoiding the above drawbacks.
SUMMARY OF INVENTION:
The present invention provides a process for preparation of Azelnidipine of formula (I),
comprising:
a) reacting a compound of formula A with a compound of formula B in presence of a suitable solvent to obtain a compound of formula C;

b) converting the compound of formula C to a compound of formula D;
c) converting the compound of formula D to a compound of formula II or salts thereof;
d) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III; and

e) reacting the compound of formula II obtained in step (c) with the compound of formula III obtained in step (d) to obtain Azelnidipine.
The present invention also provides a process for the preparation of compound of formula D, comprising converting the compound of formula C to a compound of formula D in the presence of a halogenated hydrocarbon.
The present invention further provides a process for the purification of Azelnidipine comprising recrystallizing crude Azelnidipine from a suitable solvent.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification the term "suitable solvent" includes, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as n-hexane, n-heptane and the like; acetonitrile; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water; or mixtures thereof.

As used throughout the specification the term "suitable base" includes organic and inorganic bases. An organic base used includes, but is not limited, to amine bases (primary, secondary or tertiary amines) such as methylamine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine and the like, heterocyclic compounds such as pyridine, piperidine and the like. Inorganic base used, includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, caesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
The present invention provides a process for preparation of Azelnidipine of formula (I),
comprising:
a) reacting a compound of formula A with a compound of formula B in presence of a suitable solvent to obtain a compound of formula C;
b) converting the compound of formula C to a compound of formula D;

c) converting the compound of formula D to a compound of formula II or salts thereof;
d) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III; and
e) reacting the compound of formula II obtained in step (c) with the compound of formula III obtained in step (d) to obtain Azelnidipine.

In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of a suitable solvent to obtain a compound of formula C.
The suitable solvent used is as described supra.
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of a halogenated hydrocarbon to obtain a compound of formula C.
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of dichloromethane to obtain a compound of formula C.
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B at a temperature of 0°C to 20°C, preferably 0°C to 10°C, more preferably 0°C to 5°C to obtain a compound of formula C.
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of a halogenated hydrocarbon at a temperature of 0°C to 5°C to obtain a compound of formula C.
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of dichloromethane at a temperature of 0°C to 5°C to obtain a
compound of formula C

In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of a coupling agent well known in the art. In one embodiment, the coupling agent selected is N,N'-dicyclohexylcarbodiimide (DCC).
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of a halogenated hydrocarbon and DCC at a temperature of 0°C to 5°C to obtain a compound of formula C.
In one embodiment, step (a) comprises reacting a compound of formula A with a compound of formula B in the presence of dichloromethane and DCC at a temperature of 0°C to 5°C to obtain a compound of formula C.
The inventors of present invention have surprisingly found that replacing tetrahydrofuran which is normally employed in the art with dichloromethane for preparation of the compound of formula C involving reaction between the compound of formula A and compound of formula B, eliminates the hazards associated with tetrahydrofuran. Also, the reaction may be performed at lower temperature than known in the art.
In one embodiment, the compound of formula (C) prepared in step (a) may optionally be isolated or purified by techniques known in the art. The compound of formula (C) may be purified by crystallization from a suitable solvent. The suitable solvent used is as described supra.
In one embodiment, step (a) comprises recrystallization of compound of formula (C) from a mixture of an acetate and a hydrocarbon solvent, preferably from a mixture of ethyl acetate and n-hexane.
In one embodiment, step (a) comprises recrystallization of compound of formula (C) from a mixture of an acetate and a hydrocarbon solvent at a temperature of about 40°C to 60°C.
In one embodiment, step (a) comprises recrystallization of compound of formula (C) from a mixture of ethyl acetate and n-hexane at a temperature of about 40°C to 60°C, preferably about 45°Cto50°C.
The process of recrystallization as described above leads to better purity of compound of formula (C). Also the process exemplified in the prior art US '596 leads to product in oil form whereas in the present invention product is obtained in solid form which is easy to handle and purify.

In one embodiment, the present invention provides a process for the preparation of compound of formula (C) by reacting the compound of formula A with the compound of formula B in presence of halogenated hydrocarbon, preferably dichloromethane.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon to obtain a compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula A with a compound of formula B in presence of dichloromethane to obtain a compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula A with a compound of formula B in presence of dichloromethane, at a temperature of about 0°C to 20°C to obtain a compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula A with a compound of formula B in presence of dichloromethane and coupling agent at a temperature of about 0°C to 20°C to obtain a compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to 20°C to obtain a compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to 5°C to obtain a compound of formula (C).
In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D.

In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D in presence of a suitable solvent. The suitable solvent used is as described supra.
In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D in the presence of mixture of a halogenated hydrocarbon and an alcohol.
In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D in the presence of mixture of dichloromethane and ethanol.
In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D at a temperature of -10°C to 10°C, more preferably -5°C to 0°C.
In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D in the presence of mixture of dichloromethane and ethanol at a temperature of -5°CtoO°C,
In one embodiment, step (b) comprises converting a compound of formula C to a compound of formula D in the presence of mixture of dichloromethane, ethanol and hydrochloride gas at a temperature of -5°C to 0°C.
In one embodiment, the compound of formula (D) prepared in step (b) may optionally be isolated and purified by techniques known in the art. The compound of formula (D) may be purified by recrystallization with a suitable solvent. The suitable solvent used is as described supra.
In one embodiment, step (b) comprises recrystallization of compound of formula (D) from acetonitrile. The recrystallization process may involve heating the isolated solid with acetonitrile, obtained after work up, to a temperature of about 35°C to 65°C, preferably to about 40°C to 60°C, more preferably 50°C to 60°C, followed by cooling to a temperature of about 0°C to 20°C, preferably to about 0°C to 10°C, more preferably to about 0°C to 5°C.

In one embodiment, step (b) comprises recrystallization of compound of formula (D) from acetonitrile to obtain the compound of formula (D) with HPLC purity of not less than about 99.0%, preferably not less than about 99.5%, more preferably not less than about 99.7%.
In one embodiment, the present invention provides a process for purification of compound of formula (D) comprising recrystallization from acetonitrile comprising heating the solid, obtained after work up, with acetonitrile to a temperature of about 35°C to 65°C, preferably to about 40°C to 60°C, more preferably 50°C to about 60°C, followed by cooling to a temperature of about 0°C to 20°C, preferably to about 0°C to 10°C, more preferably to about 0°C to 5°C.
The process of recrystallization as described herein leads to better purity of compound of formula (D). In the prior art US '596 the compound of formula (D) was prepared in-situ. Isolation of the compound of formula (D) as per present invention helps in purification of the compound leading to improved purity of azelnidipine.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising converting a compound of formula C to a compound of formula D in presence of mixture of a halogenated hydrocarbon and an alcohol, at a temperature of about -10°C to 10°C.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising converting a compound of formula C to a compound of formula D in presence of mixture of a halogenated hydrocarbon and an alcohol, at a temperature of about -10°C to 10°C.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol, at a temperature of about -5°C to 0°C.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, comprising recrystallization of compound of formula (D) from acetonitrile to obtain the compound of formula (D) with HPLC purity of not less than about 99.0%, preferably not less than about 99.5%.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,

(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D;
(c) optionally, isolating and purifying the compound of formula D
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane;
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol.
(c) optionally, isolating and purifying the compound of formula D
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane;
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol.
(c) isolating and purifying the compound of formula D
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a'compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to 10°C to obtain a compound of formula (C);
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol, at a temperature of about -5°C to 0°C.

(c) optionally, isolating and purifying the compound of formula D
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to 10°C to obtain a compound of formula (C);
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol, at a temperature of about -5°C to 0°C.
(c) isolating and purifying the compound of formula D.
In one embodiment, step (c) comprises converting a compound of formula D to a compound of formula II or salts thereof.
In one embodiment, step (c) comprises converting a compound of formula D to an acetate salt of compound of formula II.
In one embodiment, step (c) comprises converting a compound of formula D to a compound of formula II in presence of an ammonium acetate.
In one embodiment, step (c) comprises converting a compound of formula D to a compound of formula II in presence of a suitable solvent. The suitable solvent used is as described supra. In one embodiment, step (c) comprises converting a compound of formula D to a compound of formula II in presence of acetonitrile.
In one embodiment, step (c) comprises converting a compound of formula D to a compound of formula II in presence of acetonitrile and ammonium acetate.

In one embodiment, step (c) comprises heating the reaction mixture comprising compound of formula D, acetonitrile and ammonium acetate to temperature of 40°C to 60 °C, preferably to temperature of 45°C to 55 °C, followed by cooling to obtain the solid product (compound of formula II).
In one embodiment, the compound of formula D obtained in step (c) may optionally be isolated and purified by techniques known in the art.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising converting a compound of formula D to a compound of formula II or salts thereof in presence of acetonitrile and ammonium acetate.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), converting a compound of formula D to an acetate salt of compound of formula II in presence of acetonitrile and ammonium acetate.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D;
(c) converting a compound of formula D to a compound of formula II or salts thereof.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D in presence of mixture of a halogenated hydrocarbon and an alcohol;
(c) optionally, isolating and purifying the compound of formula D
(d) converting a compound of formula D to a compound of formula II or salts thereof.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;

(b) converting a compound of formula C to a compound of formula D in presence of mixture of a halogenated hydrocarbon and an alcohol;
(c) isolating and purifying the compound of formula D
(d) converting a compound of formula D to a compound of formula II or salts thereof;
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane;
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol;
(d) isolating and purifying the compound of formula D
(c) converting a compound of formula D to an acetate salt of compound of formula II.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to °C to obtain a compound of formula (C);
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol, at a temperature of about 0°C to 10°C;
(c) isolating and purifying the compound of formula D; and
(d) converting a compound of formula D to a compound of formula II in presence of acetonitrile and ammonium acetate.
In one embodiment, step (d) comprises reacting a compound of formula E with a compound of formula F to prepare a compound of formula III.

In one embodiment, step (d) comprises reacting a compound of formula E with a compound of formula F in the presence of a suitable solvent to prepare a compound of formula III. The suitable solvent used is as described supra.
In one embodiment, step (d) comprises reacting a compound of formula E with a compound of formula F in the presence of isopropanol to prepare a compound of formula III.
In one embodiment, step (d) comprises reacting a compound of formula E with a compound of formula F in the presence of isopropanol and a suitable base to prepare a compound of formula III. The suitable base used is as described supra.
In one embodiment, step (d) comprises reacting a compound of formula E with a compound of formula F in the presence of isopropanol and piperidine to prepare a compound of formula III.
In one embodiment, the compound of formula (III) prepared in step (d) may optionally be isolated and purified by techniques known in the art. The compound of formula (III) may be purified by recrystallization from a suitable solvent. The suitable solvent used is as described supra, preferably the solvent used is an alcohol.
In one embodiment, step (d) comprises recrystallization of compound of formula (III) from isopropanol.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula E with a compound of formula F to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula E with a compound of formula F in the presence of isopropanol to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting a compound of formula E with a compound of formula F in the presence of isopropanol and piperidine to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;

(b) converting a compound of formula C to a compound of formula D;
(c) converting a compound of formula D to a compound of formula II or salts thereof;
(d) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D;
(c) optionally, isolating and purifying the compound of formula D
(d) converting a compound of formula D to a compound of formula II or salts thereof;
(e) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D in presence of mixture of a halogenated hydrocarbon and an alcohol;
(c) optionally, isolating and purifying the compound of formula D; and
(d) converting a compound of formula D to a compound of formula II or salts thereof;
(e) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane;
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol;
(c) isolating and purifying the compound of formula D
(d) converting a compound of formula D to an acetate salt of compound of formula II;

(e) reacting a compound of formula E with a compound of formula F in the presence of isopropanol to prepare a compound of formula III.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to 10°C to obtain a compound of formula (C);
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol, at a temperature of about 0°C to 10°C;
(c) isolating compound of formula D and purifying it by treatment with acetonitrile;
(d) converting a compound of formula D to a compound of formula II in presence of acetonitrile and ammonium acetate;
(e) reacting a compound of formula E with a compound of formula F in the presence of isopropanol and piperidine to prepare a compound of formula III.
In one embodiment, step (e) comprises reacting the compound of formula II with the compound of formula III to obtain Azelnidipine of formula I.
In one embodiment, step (e) comprises reacting the compound of formula II with the compound of formula III in the presence of a suitable base and a suitable solvent to prepare a compound of formula I.
The suitable base and the suitable solvent used is as described supra, preferably the base used may be an organic amine base and the solvent used may be an acetate solvent. In one embodiment, step (e) comprises reacting the compound of formula II with the compound of formula III in the presence of triethylamine to prepare a compound of formula I.

In one embodiment, step (e) comprises reacting the compound of formula II with the compound of formula III in the presence of triethylamine and ethyl acetate to prepare a compound of formula I.
After completion of the reaction in step (e), suitable work up may be performed, as known to a skilled artisan, to isolate the compound of formula (I) before purification. In one embodiment, water was added to the reaction mixture after completion of the reaction and organic solvent layer, preferably ethyl acetate, was separated and washed with water and dried. The product may optionally be isolated by distillation of the solvent to get residue which may be further purified.
In one embodiment, the compound of formula (I) prepared in step (e) may optionally be isolated and purified by techniques known in the art. The compound of formula (I) may be purified by recrystallization with a suitable solvent. The suitable solvent used is as described supra, preferably the solvent used may be an aliphatic hydrocarbon.
In one embodiment, step (e) comprises recrystallization of compound of formula (I) from n-heptane.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting the compound of formula II with the compound of formula III in the presence of an amine base and a an aliphatic hydrocarbon solvent to prepare a compound of formula I.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting the compound of formula II with the compound of formula III in the presence of triethylamine as base to prepare a compound of formula I.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising reacting the compound of formula II with the compound of formula III in the presence of triethylamine as base and ethyl acetate as solvent to prepare a compound of formula I.
The inventors of present invention have surprisingly found that replacing isopropyl alcohol which is normally employed by US '596 with ethyl acetate, and replacing sodium methoxide with triethylamine as base improves the yield of Azelnidipine.

In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D;
(c) converting a compound of formula D to a compound of formula II or salts thereof;
(d) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III;
(e) reacting the compound of formula II with the compound of formula III to obtain Azelnidipine.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D;
(c) optionally, isolating and purifying the compound of formula D
(d) converting a compound of formula D to a compound of formula II or salts thereof;
(e) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III;
(f) reacting the compound of formula II with the compound of formula III to obtain Azelnidipine.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D in presence of a mixture of a halogenated hydrocarbon and an alcohol;
(c) isolating and purifying the compound of formula D;
(d) converting a compound of formula D to a compound of formula II or salts thereof;
(e) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III; and

(f) reacting the compound of formula II with the compound of formula III to obtain Azelnidipine.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of halogenated hydrocarbon;
(b) converting a compound of formula C to a compound of formula D in presence of a mixture of a halogenated hydrocarbon and an alcohol;
(c) isolating and purifying the compound of formula D;
(d) converting a compound of formula D to a compound of formula II or salts thereof;
(e) reacting a compound of formula E with a compound of formula F in presence of an alcohol and an organic base to prepare a compound of formula III; and
(f) reacting the compound of formula II with the compound of formula III in presence of an amine base and an acetate solvent to obtain Azelnidipine.
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising,
(a) reacting a compound of formula A with a compound of formula B in presence of dichloromethane and N,N'-dicyclohexylcarbodiimide at a temperature of about 0°C to 10°C to obtain a compound of formula (C);
(b) converting a compound of formula C to a compound of formula D in presence of mixture of dichloromethane and ethanol, at a temperature of about 0°C to 10°C;
(c) optionally isolating and purifying the compound of formula D
(d) converting a compound of formula D to a compound of formula II in presence of acetonitrile and ammonium acetate;
(e) reacting a compound of formula E with a compound of formula F in the presence of isopropanol and piperidine to prepare a compound of formula III;
(f) reacting the compound of formula II with the compound of formula III in the presence of triethylamine and ethyl acetate to prepare a compound of formula I.
In yet another embodiment, the present invention provides process for preparation of compound of formula D, comprising converting a compound of formula C to a compound of formula D in the presence of a halogenated hydrocarbon and an alcohol.

In one embodiment, the process comprises converting a compound of formula C to a compound of formula D in the presence of mixture of dichloromethane and ethanol.
In one embodiment, the process comprises converting a compound of formula C to a compound of formula D in the presence of mixture of dichloromethane and ethanol at a temperature of 0°C to 10°C, preferably at a temperature of about 0°C to 5 °C
In one embodiment, the present invention provides a process for the preparation of Azelnidipine, a compound of formula (I), comprising converting the compound of formula C to a compound of formula D in the presence of mixture of dichloromethane and ethanol.
In one embodiment, the present invention also provides a process for purification of Azelnidipine comprising recrystallizing crude Azelnidipine from a suitable solvent. The suitable solvent used is as described supra.
"Crude Azelnidipine" in the context of the present invention means Azelnidipine having a HPLC purity of not less than about 99%, preferably a HPLC purity of not less than about 99.5 %, more preferably HPLC purity of not less than about 99.7 %.
. In one embodiment, crude Azelnidipine is obtained after work up of the reaction between compound of formula II and III.
In one embodiment, the present invention provides a process for purification of Azelnidipine comprising recrystallizing crude Azelnidipine from an alcohol.
In one embodiment, the present invention provides a process for purification of Azelnidipine comprising recrystallizing crude Azelnidipine from methanol.
In one embodiment, the present invention provides a process for purification of Azelnidipine comprising recrystallizing crude Azelnidipine from an aliphatic hydrocarbon.

In one embodiment, the present invention provides a process for purification of Azelnidipine comprising recrystallizing crude Azelnidipine from n-heptane.
In one embodiment, the present invention provides a process for purification of Azelnidipine comprising recrystallizing crude Azelnidipine from cyclohexane.
In one embodiment, purification of crude Azelnidipine comprises recrystallizing crude Azelnidipine from a suitable solvent, the process comprising refluxing crude Azelnidipine with the solvent for about 1 to 3 hours. The solution so obtained may be cooled, to a temperature of about 20°C to 40°C, preferably to a temperature of about 25°C to 30°C. The product obtained may be filtered and dried.
In one embodiment, purification of crude Azelnidipine comprises recrystallizing crude Azelnidipine from methanol, the process comprising refluxing crude Azelnidipine with methanol for about 1 to 3 hours. The solution so obtained may be cooled, to a temperature of about 20°C to 40°C, preferably to a temperature of about 25°C to 30°'C. The product obtained may be filtered and dried.
In one embodiment, purification of crude Azelnidipine comprises recrystallizing crude Azelnidipine from n-heptane, the process comprising refluxing crude Azelnidipine with n-heptane for about 1 to 3 hours. The solution so obtained may be cooled, to a temperature of about 20°C to 40°C, preferably to a temperature of about 25°C to 30°C. The product obtained may be filtered and dried.
In one embodiment, purification of crude Azelnidipine comprises recrystallizing crude Azelnidipine from cyclohexane, the process comprising refluxing crude Azelnidipine with cyclohexane for about 1 to 3 hours. The solution so obtained may be cooled, to a temperature of about 20°C to 40°C, preferably to a temperature of about 25°C to 30°C. The product obtained may be filtered and dried.
In one embodiment, the present invention provides a process for preparation of (3 crystalline form of Azelnidipine the process comprising recrystallizing the Azelnidipine from a suitable solvent. The suitable solvent used is as described supra.
In one embodiment, the present invention provides a process for the preparation of (3-form of Azelnidipine, comprising recrystallizing Azelnidipine from methanol.

In one embodiment, the present invention provides a process for the preparation of P-form of Azelnidipine, comprising recrystallizing Azelnidipine from n-heptane.
In one embodiment, the present invention provides a process for the preparation of P-form of Azelnidipine, comprising recrystallizing Azelnidipine from cyclohexane.
In one embodiment, the polymorphic crystalline P-form of Azelnidipine is further characterized by an X-ray powder diffraction pattern with peaks expressed in degrees 20 ± 0.2 at about 6.3, 12.7, 13.8, 14.3, 14.5,15.5, 15.6, 17.6,18.6,19.1, 20'.1, 20.3, 21.5, 22.7, 23.3, 23.9, 24.6, 24.8, 25.5, 26.5, 27.8, 28.4, .28.7, 29.4 and 32.6.
In one embodiment, the polymorphic crystalline P-form of Azelnidipine is further characterized by an X-ray powder diffraction pattern with peaks expressed in degrees 20 ± 0.2 at about 2.1, 6.3, 9.5, 9.9, 11.8, 12.7, 13.8, 14.3, 14.5, 15.5, 15.6, 17.6, 18.6, 19.1, 20.1, 20.3, 21.0, 21.5, ; 22.7,23.3,23.6,23.9,24.6,24.8,25.4,25.9,26.4,27.4,27.8,28.4,28.7,29.3, 30.1,30.5,31.0, 32.5, 33.4, 34.4, 35.03, 35.9, 36.0, 36.6, 37.2, 37.6, 38.7, 38.7 and 40.8.
X-ray powder diffraction profile for Azelnidipine was obtained using an X-ray Diffractometer (Philips X' Pert Pro, PANalytical). The measurement were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°); target, Cu; filter, Ni; detector, X'Celerator [1]; Scanning Mode; PSD Length [°2 Theta] =3.35; generator 45KV ; tube current 40mAmp. The sample were scanned in the full 20 range of 2-50° with a "time-per-step" 1000 seconds.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.

Example-1: Preparation of l-benzhydrylazetidin-3-yl-2-cyanoacetate (compound C)
l-benzhydrylazetidin-3-ol (Compound A-lOO.Og, 1.0 mol. eq.) was added to dichloromethane (350 mL) in RBF at about 25-30°C and the reaction mass was cooled to about 0°C to 5°C. Cyanoacetic acid (Compound B-106.7 g, 1.2 mol. eq.) was added at about 0°C to 5°C. DCC solution (258.2 g DCC dissolved in 200 mL Dichloromethane) was slowly added to the reaction mass and the reaction mass was maintained at about 0°C to 5°C for about 1.0 hr. The reaction mass was filtered and the filtrate was washed with bicarbonate solution. The reaction mass was concentrated under vacuum to obtain a residue which was recrystallized from a mixture of ethyl acetate (190 mL nd n-Hexane at about 45°C to 50°C and filtered at about 5°C to 10°C to get l-benzhydrylazetidin-3-yl-2-cyanoacetate (yield=83.4% and purity=98.8%).
Example-2: Preparation of l-benzhydrylazetidin-3-yl-2-iminoester (compound D)
Ethanol (15.8 g) was added to a mixture of l-benzhydrylazetidin-3-yl-2-cyanoacetate (100.Og, 1.0 mol. eq.) and dichloromethane (1000 mL) in RBF at about 25-30°C and was cooled to about 0°C to -5°C. The reaction vessel was then purged with HC1 gas at about 0°C to -5°C for about 4.0 hr till acidic pH while maintaining for overnight at about 0°C. HC1 gas was removed by purging with nitrogen gas followed by purging of ammonia gas at about -5°C to -10°C for about 3.0 hr. 300 mL of liq. ammonia (300 mL) was charged into reaction mixture and the layers were separated. Aqueous layer was extracted with MDC, followed by drying the MDC layer. The MDC layer was concentrated to get oily residue which was isolated with acetonitrile (heated to about 50°C to 55°C and solid collected at about 0°C to 5°C) to get solid 1-benzhydrylazetidin-3-yl-2-iminoester (yield=82.5% and purity=99,7%).
Example-3: Preparation of l-benzhydrylazetidin-3-yl-2-amidinoacetate (compound II)
l-benzhydrylazetidin-3-yl-2-iminoester (100.Og, 1.0 mol. eq.) and 22.9 g ammonium acetate were added to acetonitrile (500 mL) in RBF at about 25-30°C and the resulting mixture was heated at about 50°C to 55°C to clear the reaction mass. The reaction mass was solidified at about 25°C to 30°C and separated to get solid l-benzhydrylazetidin-3-yl-2-amidinoacetate (compound II) (yield=93.0% and purity=99.3%).
ExampIe-4: Preparation of (E)-isopropyl 2-(3-nitrobenzylidene)-3-oxobutanoate (compound III)
Isopropyl alcohol (300 mL) was charged at about 25°C to 30°C in RBF and subsequently cooled at about 0°C to 5°C. To RBF was added piperidine (0.1 mol. eq.), acetic acid (0.1 mol.

eq.), isopropyl 3-oxobutanoate (compound -E) (lOO.Og, 1.0 mol. eq.) and nitrobenzaldehyde (compound F) at about 0°C to 5°C. The temperature of reaction mass was raised to about 25°C to 30°C and maintained for about 20.0 hrs at same temperature. The reaction mass was filtered at about 0°C to 5°C and further purified by 150 mL Isopropyl alcohol to get pure compound (E)-isopropyl 2-(3-nitrobenzylidene)-3-oxobutanoate (compound III) (yield=74.5% and purity=99.3%).
Example-5: Preparation of Azelnidipine Crude
The product of example 3 (compound II: l-benzhydrylazetidin-3-yl-2-amidinoacetate) (100.0 g, 1.0 mol. eq.) and example 4 (compound III: (E)-isopropyl 2-(3-nitrobenzylidene)-3-oxobutanoate) (72.3 g, 1.0 mol. eq.) were added in solvent ethyl acetate (800 mL) and base triethyl amine (26.4 g, 1.0 mol. eq.) in RBF. The resulting mixture was refluxed for about 4.0 hrs. The reaction mass was cooled to about 20°C to 25°C, followed by filtration and then washing the ethyl acetate layer with water. The aqueous layer was extracted with ethyl acetate and subsequently combined both aqueous layers. The aqueous layer was washed with brine solution. The organic layer was dried over sodium sulphate and the reaction mass was concentrated to give residue which was further crystallised with methanol (500 mL) to give Azelnidipine crude (Yield=86.2% and purity=99.7%; melting point- 189.5- 190.7 °C).
Example -6: Preparation of pure Azelnidipine
a) Using Cyclohexane: A mixture of Azelnidipine crude (100.0 g) and cyclohexane (1000 mL) was added in RBF at about 25°C to 30°C. The reaction mass was refluxed for about 2.0 hr. Subsequently, the reaction mass was cooled to about 25°C to 30°C and filtered the solid, to get Azelnidipine (yield=98.0% and purity=99.8%)
b) Using Methanol: A mixture of Azelnidipine crude (100.0 g) and methanol (600 mL) was added in RBF at about 25°C to 30°C. The reaction mass was refluxed for about 2.0 hr. Subsequently, the reaction mass was cooled to about 25°C to 30°C and filtered the solid, to get Azelnidipine (yield=88.0% and purity=99.9%).
Example -7: Preparation of crystalline p-form of Azelnidipine
A mixture of Azelnidipine crude (100. Og) and n-Heptane (1000 mL) was added in RBF at about 25°C to 30°C. The reaction mass was refluxed for about 1.0 hr. Subsequently, the reaction mass was cooled to about 25°C to 30°C and filtered the solid to get P-form of Azelnidipine (yield=97.0% and purity=99.8%).

We claim:
1. A process for preparation of Azelnidipine of formula-I comprising:
a) reacting a compound of formula-A with a compound of formula-B in presence of an
organic solvent to obtain a compound of formula-C;
b) converting the compound of formula-C to a compound of formula-D;
c) converting the compound of formula D to a compound of formula II or salts thereof.
d) reacting a compound of formula E with a compound of formula F to prepare a compound of formula III; and

e) reacting the compound of formula II obtained in step (c) with the compound of formula III obtained in step (d) to obtain Azelnidipine.
2. A process for preparation of azelnidipine according to claim 1, wherein the organic solvent used in step a) is a halogenated hydrocarbon.
3. A process for preparation of azelnidipine according to claim 1, wherein the organic solvent used in step b) is a halogenated hydrocarbon.
4. A process for preparation of compound of formula-D, comprising converting a compound of formula-C to a compound of formula-D in the presence of a halogenated hydrocarbon.

ft
5. A process for preparation of azelnidipine according to claims 2, 3 and 4 wherein the halogenated hydrocarbon is selected from group consisting of chloromethane, dichloromethane, chloroethane, and chloroform.
6. A process for preparation of a crystalline P-form of Azelnidipine comprising recrystallizing azelnidipine from a solvent selected from the group consisting of n-heptane, methanol or cyclohexane.