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 EFONIDIPINE"
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 the preparation of 2-[phenyl(phenylmethyl)amino)ethyl 5-(5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3-carboxylate given by formula (I), commonly known as efonidipine.
The process provides efonidipine in higher yield and purity compared to the previously known processes.

BACKGROUND OF THE INVENTION
Efonidipine is a dihydropyridine calcium channel blocker believed to be acting on the L-type and T-type calcium channels. Therapeutically, it is used for the treatment of hypertension.
Efonidipine was disclosed first time in U.S. Patent No. 4,885,284, which also discloses its method of preparation by reacting 2-(N-benzyl-N-phenyl)ethyl-3-aminocrotonate of formula (II) with 2,2-dimethylpropylene a-(3-nitrobenzylidene)acetonylphosphonate of formula (III).


US Patent No. 5,177,237 discloses efonidipine intermediate namely, hydrazine derivative of formula (X) and its method of preparation. The process involves reaction of 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) with 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX) in presence of propargyl alcohol. It further discloses conversion of compound of formula (X) to 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (XI).

Sakoda R, et al. [Chem Pharm Bull 1992, 40(9), 2377] also discloses method of preparation of efonidipine intermediate namely, 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III) by reacting 5,5-dimethyl-2-(2-oxopropyl)-l,3,2-dioxaphosphorinan-2-one of formula (XI) with dimorpholino(3-nitrophenyl)methane of formula (XII) in presence of trifluoroacetic acid in toluene.


Bihan G, et al. [J Med Chem, 1999, 42(9), 1587-1603] discloses preparation of efonidipine intermediate namely, 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) using N-(2-hydroxyethyl)aniline of formula (a) and benzyl chloride of formula (b).

Guo, Yimeng, et al. [Zhongguo Yaowu Huaxue Zazhi, 18(1), 35-37, 2008] discloses preparation of efonidipine intermediate namely, 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) using ethyl acetoacetate and 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) in presence of p-toluenesulfonic acid catalyst.


Still there is need for a simple, efficient and commercially viable process for preparation of efonidipine and its intermediates with shorter reaction time and higher yield.
The present invention provides such an improved process for the preparation of efonidipine and its intermediates which is applicable to industrial scale and gives efonidipine and its intermediates with high purity and high yield.
SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of efonidipine, represented by formula (I) or pharmaceutically acceptable salts thereof;

by reacting 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II) with 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (III).

The present invention also provides an improved process for preparation of efonidipine intermediate namely, 2-(benzylphenylamino)-ethyl-3-aminocrotonate, represented by formula (II) comprising;


(a) reacting 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) with 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) to give 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI)

(b) converting 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) to 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II).
The other object of the present invention is to provide an improved process for preparation of another efonidipine intermediate, namely 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane, represented by formula (III) comprising;


(a) converting 2,2-dimethylpropane-l,3-diol of formula (VII) to 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) in presence of phosphorous trichloride;

(b) converting 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) to 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX);

(c) reacting 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX) with hydrazine hydrate to give 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (X);

(d) converting 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane of formula (X) to 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (XI);

(e) reacting 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) with 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) to give 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III).


Efonidipine free base obtained after reacting 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II) with 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III) is isolated and purified to give pure efonidipine.
Another object of the present invention is to provide an improved process for preparation of the pharmaceutically acceptable salt of efonidipine using efonidipine base.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for preparation of efonidipine, represented by formula (I) or pharmaceutically acceptable salts thereof;

by reacting 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II) with 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III).


The present invention also provides an improved process for preparation of efonidipine intermediate namely, 2-(benzylphenylamino)-ethyl-3-aminocrotonate, represented by formula (II) comprising;

(a) reacting 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) with 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) to give 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI);

(b) converting 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) to 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II).
In one of the embodiment, 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) is prepared by reacting N-(2-hydroxyethyl)aniline and 1 -(chloromethyl)benzene, in

presence of base. The base can be selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and mixtures thereof. More preferably the base is sodium bicarbonate. The solvent for this reaction is selected from the group consisting of water, N,N-dimethylformamide and N,N-dimethylacetamide. More preferably the solvent is water. The temperature for the above reaction is about 50°C to about 90°C. More preferably the reaction temperature is about 80°C to about 85°C.
In another embodiment, 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) is prepared by reacting 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) with 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) in suitable solvent selected from the group consisting of toluene, 1,4-dioxane and xylene. More preferably the suitable solvent is toluene.
The mole ratio of 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) to 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) can be from 0.95 to 1.3 mole equivalent.
The reaction between 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) to 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) can be carried out at temperature of about 95°C to about 140°C. More preferably the reaction temperature is about 112°C to about 117°C.
In one of the embodiment, 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) formed in above reaction can be further treated with ammonium carbonate, in presence of p-toluenesulphonic acid catalyst and suitable solvent, to give efonidipine intermediate of formula (II) namely, 2-(benzylphenylamino)-ethyl-3-aminocrotonate.
The mole ratio of 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) to ammonium carbonate can be from 1.5 to 3.5 mole equivalent.
The suitable solvent for the above reaction can be selected from the group consisting of methanol, isopropyl alcohol, ethanol and the like. More preferably the suitable solvent is methanol.

The present invention further provides an improved process for preparation of the efonidipine intermediate, namely 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane, represented by formula (III) comprising;

(a) converting 2,2-dimethylpropane-l,3-diol of formula (VII) to 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII);

(b) converting 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) to 2-allenyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (IX);

(c) reacting 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX) with hydrazine hydrate to give 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (X);

(d) converting 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane of formula (X) to 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (XI);

(e) reacting 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) with 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) to give 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III).

In one of the embodiment, 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) is prepared by reacting 2,2-dimethylpropane-l,3-diol of formula (VII) with phosphorous trichloride in presence of suitable solvent.
The suitable solvent for the above reaction can be selected from the group consisting of diethylether, isopropyl ether, methylene dichloride, chloroform and toluene. More preferably the suitable solvent is diethylether.
The mole ratio of 2,2-dimethylpropane-l,3-diol of formula (VII) to phosphorous trichloride can be from 1.0 to 1.5.
Phosphorous trichloride can be added to solution of 2,2-dimethylpropane-l,3-diol of formula (VII) in suitable solvent at the temperature of about 0°C to about 20°C. More preferably, it is added at the temperature of about 0°C to about 5°C. The reaction between 2,2-dimethylpropane-l,3-diol of formula (VII) and phosphorous trichloride

can be carried out at about 20°C to about 35°C. More preferably, the reaction temperature is about 25°C to about 30°C.
In another embodiment, 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula
(VIII) is converted to 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of
formula (IX), in presence of propargyl alcohol, suitable base and suitable solvent.
The suitable base can be selected from the group consisting of triethylamine, pyridine, lautidine, morpholine, N-methylmorpholine and mixtures thereof. More preferably the base is triethylamine.
In another embodiment, suitable solvent for the reaction can be selected from the group consisting of acetonitrile, acetone, tetrahydrofuran and 1,4-dioxane. More preferably the suitable solvent is acetonitrile.
The mole ratio of the base to 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane can be from 0.8 to 1.1 mole equivalent and the mole ratio of propargyl alcohol to 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) can be from 0.8 to 1.1 mole equivalent.
In one of the embodiment, 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX) is converted to 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (X), in presence of hydrazine hydrate and acetonitrile.
The mole ratio of 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula
(IX) to hydrazine hydrate can be from 1.2 to 1.9 mole equivalent. The temperature at
which hydrazine hydrate is added to 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane of formula (IX) is about 0°C to about 30°C. More preferably
hydrazine hydrate is added to 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane
of formula (IX) at the temperature of about 10°C to about 15°C.
2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of
formula (X) is converted to 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) in presence of an acid selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid and the like. More preferably the acid is hydrochloric acid.

In another embodiment, efonidipine intermediate namely, 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III) is prepared by reacting 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) with 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII), in presence of an acid catalyst and suitable solvent.
The acid catalyst can be selected from the group consisting of methane sulphonic acid, trifluoroacetic acid, p-toluenesulphonic acid and mixtures thereof. Preferably, the acid catalyst is trifluoroacetic acid. The suitable solvent for the above reaction can be selected from the group consisting of toluene, xylene and 1,4-dioxane. More preferably, the suitable solvent is toluene.
The mole ratio of 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) to trifluoroacetic acid can be from 1.5 to 2.0 mole equivalent; while the mole ratio of 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) to 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) can be from 0.8 to 1.1 mole equivalent.
The reaction between 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) and 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) can be carried out at about 10°C to about 30°C. More preferably, the reaction temperature is about 25°C to about 30°C.
In one of the embodiment, 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) used in above reaction is prepared by reacting 3-nitrobenzaldehyde and morpholine, in presence of boron trioxide. The solvent used for this reaction can be selected from the group consisting of toluene, isopropanol, xylene and 1,4-dioxane. Preferably, the solvent is toluene.
The mole ratio of 3-nitrobenzaldehyde to morpholine can be from 2.5 to 4.0 mole equivalent; while the above reaction be carried out at about 25°C to about 70°C. More preferably, the reaction temperature is about 50°C.
In another embodiment, 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula
(II) and 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-

dioxaphosphorinane of formula (III) obtained in above processes are reacted in suitable solvent to give efonidipine.
The suitable solvent for the above reaction can be selected from the group consisting of toluene, xylene, isopropanol, ethylacetate, methanol and ethanol. More preferably, the suitable solvent is toluene.
The mole ratio of 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II) to 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III) can be from 0.85 to 1.1 mole equivalent.
The reaction between 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II)
to 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane of formula (III) can be carried out at about 60°C to about 117°C. More preferably, the reaction temperature for the above reaction is about 112°C to about 117°C. The reaction is completed within 10 hrs.
Efonidipine formed after above reaction can be isolated and purified by techniques known in the art. In one of the embodiment, efonidipine having high purity can be obtained by recrystallization method using solvent selected from the group consisting of ethyl acetate, n-hexane, toluene, ethyl acetate, methanol, ethanol and mixtures thereof.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.
Example-1: Preparation of 2-(N-benzyl-N-phenylamino)ethanol
N-(2-hydroxyethyl)aniline (100 g, 1.0 mol) and 1 -(chloromethyl)benzene were added at 25°C to 30°C to solution of sodium bicarbonate (76.5 g, 1.25 mol) in water (153 ml). The reaction mass was heated at 80°C to 85°C for 7 to 8 hrs. After completion of reaction, reaction mass was cooled at 25°C to 30°C. To the obtained reaction mass, water (400 ml) and toluene (400 ml) were added. Organic layer was separated from the resulting mixture and washed sequentially with aqueous HC1 solution (25 ml cone. HC1 in 400 ml water), sodium bicarbonate solution (35.0 g sodium bicarbonate in 500 ml water) and water (600 ml) and concentrated under vacuum to get 2-(N-benzyl-N-phenyl amino)ethanol. (Yield: 90.0%).

Example-2: Preparation of 2-(benzylphenylamino)-ethyl acetoacetate
2,2,6-trimethyl-4H-l,3-dioxin-4-one (67.0 g, 1.07 mol) was added to the solution of 2-(N-benzyl-N-phenylamino)ethanol (100.0 g, 1.0 mol) in toluene (700 ml) and mixed at 25°C to 30°C. The reaction mass was heated at 112°C to 117°C for 5 to 6 hrs. After completion of reaction, the reaction mass was cooled to 45°C to 50°C and concentrated under vacuum to get 2-(benzylphenylamino)-ethyl acetoacetate. (Yield: 92.0%).
ExampIe-3: Preparation of 2-(benzylphenyIamino)-ethyl-3-aminocrotonate (Efonidipine Intermediate-II)
Ammonium carbonate (92.6 g, 3.0 mol) and p-toluenesulphonic acid (16.6 g, 0.3 mol) were added to a solution of 2-(benzylphenylamino)-ethyl acetoacetate (100.0 g, 1.0 mol) in methanol (700 ml) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 12 to 14 hrs. After completion of reaction, the reaction mixture was cooled to 0°C to 5°C and the solid was filtered off to get 2-(benzylphenylamino)-ethyl-3-aminocrotonate. (Yield: 75%).
Example-4: Preparation of 2-chloro-5,5-dimethyl-l,3j2-dioxaphosphinane
To a solution of 2,2-dimethylpropane-l,3-diol (100.0 g, 1.0 mol) in diethylether (300 ml) was added phosphorous trichloride (84.0 g, 1.0 mol) at 0°C to 5°C. The resulting mixture was maintained at 25°C to 30°C for 2 hrs. After completion of the reaction, reaction mixture was concentrated under vacuum to get 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinane. (Yield: 65%).
Example-5: Preparation of 2-allenyI-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane
To a mixture of propargyl alcohol (100.0 g, 1.0 mol), acetonitrile (700 ml) and triethyl amine (149.8 g, 0.83 mol) was added 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane (249.3 g, 0.83 mol) at 0°C to 5°C. The resulting mixture was stirred at 0°C to 5°C for 1 hr and at 25°C to 30°C for 4 hrs. The salt formed was then filtered off. The resulting mother liquor was refluxed for 2 hrs, concentrated under vacuum and extracted with MDC. MDC layer was concentrated under vacuum and to the resulted solid was added diethylether. The resulting suspension was stirred and filtered to get 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane as solid. (Yield: 60%).

Example-6: Preparation of 2-acetonyI-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane
To a mixture of 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane (100.0 g, 1.0 mol) and acetonitrile (5.7 vol), hydrazine hydrate (106.4 g, 4.0 mol) was added at 10°C to 15°C. The reaction mixture was stirred at 25°C to 30°C for 5 to 6 hrs. After completion of reaction, the resulting mixture was concentrated under vacuum. To the residue diisopropylether was added and resulting slurry was treated with dil. HC1 (709.5 g cone. HC1 in 1774 ml water) in acetonitrile, extracted with MDC and concentrated under vacuum get compound 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane. (Yield: 57.0%).
Example-7: Preparation of 4-(morpholino-(3-nitrophenyl)methyl)morpholine
A mixture of 3-nitrobenzaldehyde (100.0 g, 1.0 mol), toluene (600 ml), boron trioxide (109.0 g, 2.37 mol) and morpholine (197.6 g, 3.43 mol) was heated at 50°C for 2 to 3 hrs. After completion of reaction, the reaction mass was cooled to 25°C to 30°C and the unwanted solid was filtered off. Collected mother liquor was distilled out and 4-(morpholino-(3-nitrophenyl)methyl)morpholine was crystallized from the solution using isopropyl ether. (Yield: 80.0%).
ExampIe-8: Preparation of 2-[l-Acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3>2-dioxaphosphorinane (Efonidipine Intermediate-Ill)
A mixture of 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane (from example 6) (100.0 g, 1.0 mol), toluene (300 ml) trifluoroacetic acid (106.7 g, 1.93 mol) and 4-(morpholino-(3-nitrophenyl)methyl)morpholine (137.1 g, 0.92 mol) was stirred at 25°C to 30°C for 14 to 15 hrs. After completion of reaction, water (325 ml) was added and the precipitated solid was filtered off to get 2-[l-Acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane. (Yield: 60.0%).
Example-9: Preparation of Efonidipine Base (crude)
A mixture of 2-(benzylphenylamino)-ethyl-3-aminocrotonate (82.3 g, 0.9 mol), 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane (100.0 g, 1.0 mol) and toluene (800 ml) was heated at 112°C to 117°C for 10 hrs. After completion of reaction, the reaction mass was cooled to 25°C to 30°C and the precipitated solid was filtered off to get efonidipine base (crude). (Yield: 73.0%).

Example-10: Purification of efonidipine Base (crude)
a) Using ethyl acetate
A mixture of efonidipine base (crude) (100.0 g) and ethyl acetate (600 ml) was heated at 78°C to 80°C for 1 hr. The reaction mass was further cooled to 25°C to 30°C and the precipitated solid was filtered off to get pure efonidipine base. (Yield: 80.0%).
b) Using ethyl acetate/n-hexane (mixture)
A mixture of efonidipine base (crude) (100.0 g) and ethyl acetate (500 ml) was heated at 70°C and n-hexane (500 ml) was added. The reaction mass was further cooled to 25 °C to 30°C and the precipitated solid was filtered off to get pure efonidipine base. (Yield: 87.0%).
c) Using toluene
A mixture of efonidipine base (crude) (100.0 g) and toluene (800 ml) was heated at 90°C to 95°C for 1 hr. The reaction mass was further cooled to 25°C to 30°C and the precipitated solid was filtered off to get pure efonidipine base. (Yield: 85.0%).
d) Using ethyl acetate/methanol (mixture)
A mixture of efonidipine base (crude) (100.0 g) and ethyl acetate (300 ml) was heated at 80°C and methanol (200 ml) was added. The reaction mass was further cooled to 0°C to 5°C and the precipitated solid was filtered off to get pure efonidipine base. (Yield: 75.0%).
e) Using ethanol
A mixture of efonidipine base (crude) (100.0 g) and ethanol (400 ml) was heated at 78°C to 80°C for 30 min. The reaction mass was further cooled to 25°C to 30°C and the precipitated solid was filtered off to get pure efonidipine base. (Yield: 70.0%).
f) Using methanol
A mixture of efonidipine base (crude) (100.0 g) and methanol (300 ml) was heated at 65°C for 30 min. The reaction mass was further cooled to 25°C to

30°C and the precipitated solid was filtered off to get pure efonidipine base. (Yield: 67.0%).
Example-11: Preparation of efonidipine hydrochloride ethanolate
To a mixture of efonidipine base (100.0 g) and ethanol (1450 ml) heated at 55°C to 60°C, aqueous HC1 (436 g, 13 to 15% cone. HC1 in water) was added. The reaction mass was stirred at 55°C to 60°C for 30 min., cooled to 25°C to 30°C and the precipitated solid was filtered off to get efonidipine hydrochloride ethanolate. (Yield: 78.0%).

We claim:
1. A process for preparation of efonidipine of formula (I) or pharmaceutically acceptable salt thereof,

by reacting 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II) with 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III).

2. A process according to claim 1, wherein 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II) is prepared by;
(a) reacting 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) with 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) to give 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI);

(b) converting 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) to 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II).
3. A process according to claim 1, wherein 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III) is prepared by; (a) converting 2,2-dimethylpropane-l,3-diol of formula (VII) to 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) in presence of phosphorous trichloride;

(b) converting 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) to 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX);

(c) reacting 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX) with hydrazine hydrate to give 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (X);

(d) converting 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane of formula (X) to 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (XI);

(e) reacting 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) with 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) to give 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III).

4. A process according to claim 2, wherein the solvent used in step (a) is selected from the group consisting of toluene, 1,4-dioxane and xylene.
5. A process according to claim 3, wherein the solvent used in step (a) is selected from the group consisting of diethylether, isopropyl ether, methylene dichloride, chloroform and toluene.
6. A process for preparation of efonidipine intermediate, 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II), comprising;

reacting 2-(N-benzyl-N-phenylamino)ethanol of formula (IV) with 2,2,6-trimethyl-4H-l,3-dioxin-4-one of formula (V) to give 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI);
(b) converting 2-(benzylphenylamino)-ethyl acetoacetate of formula (VI) to 2-(benzylphenylamino)-ethyl-3-aminocrotonate of formula (II).

7. A process for preparation of efonidipine intermediate, 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dirnethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (III), comprising;

(a) converting 2,2-dimethylpropane-l,3-diol of formula (VII) to 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) in presence of phosphorous trichloride;


(b) converting 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphinane of formula (VIII) to 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX);

(c) reacting 2-allenyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (IX) with hydrazine hydrate to give 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (X);

(d) converting 2-(2-hydrazino-propen-l-yl)-5,5-dimethyl-2-oxo-l,3,2-
dioxaphosphorinane of formula (X) to 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane of formula (XI);

(e) reacting 2-acetonyl-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (XI) with 4-(morpholino-(3-nitrophenyl)methyl)morpholine of formula (XII) to give 2-[l-acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-2-oxo-l,3,2-dioxaphosphorinane of formula (III).