FIELD OF THE INVENTION
The invention relates to an improved process for the preparation Nisoldipine (1). More particularly, the invention relates to an improved process for the preparation of Nisoldipine (1) in a substantially pure form with a purity level greater than 99.0 %. The invention also relates to highly pure crystalline form of Nisoldipine (1) and a process for the preparation thereof.
BACKGROUND OF THE INVENTION
Nisoldipine is a second-generation calcium channel blocker and 1, 4-dihydropyridine
derivative. It is commonly used an antihypertensive agent as a potent arterial
vasodilator in patients with cardiac failure and angina. Chemically it is known as 3-
isobutyl 5-methyl 2,6-dimethyl-4-(2-nitrophenyl)-l,4-dihydropyridine-3,5-
dicarboxylate. Nisoldipine was approved by the U.S. Food and Drug administration (FDA) on Feb 2, 1995. It was developed and marketed as SULAR by Covis Pharma Sari. SULAR (©(Nisoldipine) is an extended release tablet dosage form for the treatment of hypertension.
The synthesis of Nisoldipine (1) was reported in many patents and non-patent literature. The contents of which are hereby incorporated as reference in their entirety.
acid isobutyl ester ..«.».—r.™
Scheme-1
US 4,154,839 patent discloses different processes for the preparation of Nisoldipine (1). In one process 2'-nitrobenzylideneacetoacetic acid isobutyl ester was reacted with methyl 3-aminocrotonate to obtain Nisoldipine as shown in scheme-1. Optionally,

Nisoldipine (1) was prepared by reacting 2'-nitrobenzylideneacetoacetic acid isobutyl ester together with acetoacetic acid methyl ester and aqueous ammonia solution. Also, Nisoldipine (1) was prepared by treating methyl 3-aminocrotonate together with 2-nitrobenzaldehyde and acetoacetic acid isobutyl ester to form Nisoldipine (1) but the processes were silent about the purity of Nisoldipine (1).
US 4,600,778 patent discloses the synthesis of Nisoldipine, but the impurities formed results in low yield.
US 7,060,838 patent discloses the new process for the synthesis of Nisoldipine by reacting isobutyl 2-2(nitrobenzylidene)acetoacetate with 4-dimethylaminopyridine and methyl 3-aminocrotonate in cyclohexane with yield of 52.9 %.
WO2005023768 application discloses preparation of Nisoldipine by reacting 3-aminocrotonoic acid isobutyl ester with 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester in the presence toluene and refluxing with diisopropyl ether.
The processes used in prior art literature results in formation of undesired by products and purification of Nisoldipine becomes tedious as it involves repeated crystallization and chromatographic purification. It is also observed that normal crystallization techniques do not yield the required purity. Also, the prior arts do not disclose the purity of the intermediates clearly. Hence, the present inventors hereby report an improved process for the preparation of Nisoldipine (1) using mild and simple reaction conditions making the reaction simple, eco-friendly, inexpensive, readily available to give high yields. It further discloses simple purification process of Nisoldipine (1) and its intermediates to limit to obtain the product with desired quality.

SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an improved process for the preparation Nisoldipine (1)
In another object of the invention provides substantially pure Nisoldipine (1), with purity greater than 99.0 % by High-performance liquid chromatography (HPLC).
In another object, the present invention provides improved process for the Nisoldipine (1) as depicted in scheme-2, which comprises:
a) Reacting 2-nitrobenzaldehyde (5) with methyl acetoacetate, (4) in presence of a suitable base and solvent to form 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3)
b) reacting of 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3) with 3-aminocrotonoic acid isobutyl ester (2) in presence of a suitable acid and solvent to form Nisoldipine (1)
c) optionally, purifying Nisoldipine (1) in a suitable solvent.
Another object of the invention is to provide process for the purification Nisoldipine (1) to obtain substantially pure Nisoldipine (1), which comprises of the following steps: i. suspending Nisoldipine (1) in a suitable solvent
ii. heating the reaction mixture to 50-70 °C
iii. optionally, filtering the reaction mixture through micron filter
iv. adding a suitable protic solvent to the filtrate
v. optionally, cooling the reaction mixture to 0-15 °C
vi. isolating pure Nisoldipine (1)
In yet another objective of the invention, Nisoldipine (1) produced after purification is having purity more than 99.0 % by HPLC.

Yet, in another objective of the invention, the Nisoldipine (1) produced after purification is crystalline having 2 theta values at 8.89, 9.36, 9.83, 10.17, 11.31, 12.50, 13.58, 14.17, 14.99,17.83, 18.91, 19.08, 19.72, 20.52, 22.01, 22.75, 23.17, 24.00, 24.79, 25.33, 26.14, 27.22, 27.54, 28.54, 31.48, 31.95, 34.47, 36.54 and 41.76 ± 0.2 characterized by X-ray diffraction pattern as shown in figure -1 and sharp endothermic peak at 152.34 ° in the Differential Scanning Calorimetry thermogram as illustrated in figure 2.
Yet in another objective of the invention, crystalline form of Nisoldipine (1) obtained after purification is having purity greater than 99.0 %.
In another object, the present invention discloses the process for the preparation of 3-aminocrotonoic acid isobutyl ester (2) by reacting isobutyl 3-oxobutanote (6) with ammonia gas as depicted in scheme-3.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates the X-Ray powder diffraction pattern (XRPD) of Nisoldipine (1). Figure 2: illustrates the differential scanning calorimetry (DSC) of Nisoldipine (1).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the first aspect of the invention provides an improved process for the preparation Nisoldipine (1) which comprises:
a) reacting 2-nitrobenzaldehyde (5) with methyl acetoacetate, (4) in presence of a suitable base to form 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3)
b) reacting of 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3) with 3-aminocrotonoic acid isobutyl ester (2) in presence of a suitable acid to form Nisoldipine (1)
c) Optionally, purifying Nisoldipine (1) in a suitable solvent to obtain substantially pure Nisoldipine (1).

The term " substantially pure as used herein refers to Nisoldipine (1) with purity greater than 99.0%, preferably greater than 99.5% and more preferably greater than 99.9% by HPLC.
The preparation of Nisoldipine (1) according to the present invention is represented in scheme-2
Scheme-2
In one embodiment step a) involves reacting 2-nitrobenzaldehyde (5) with methyl acetoacetate (4) in presence of base. Suitable base that may be used in step (a) is dibutyl amine and the suitable acid used in step a) is acetic acid. The temperature at which step a) may be carried out between about 0 °C. and about 100 °C, preferably between 35 °C to about 55 °C. The suitable solvent used is selected from protic or aprotic solvents or mixture thereof.
In another embodiment, step b) proceeds with reacting 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3) with 3-aminocrotonoic acid isobutyl ester (2) in presence of a suitable acid to form Nisoldipine (1). The said reaction may be carried out at a

temperature of 0-100 °C, preferably 25-30 °C in some instances, 40-60 °C in some instances and 70-90 °C in other instances. The solvent was distilled off and the residue was finally isolated from a mixture of suitable solvent or mixtures thereof to form Nisoldipine (1).
The suitable acid used in step b) may be selected from organic or inorganic acid, preferably from a group of inorganic acid comprising of sulphuric acid, hydrochloric acid, phosphoric acid or the like, more preferably hydrochloric acid was used in the present invention.
Step c) involves the purification of Nisoldipine (1). Purification of Nisoldipine (1) may be carried out strictly in the presence of sodium lamp. Nisoldipine (1) may be dissolved in a suitable solvent and heated at 50-70 °C, preferably at 60-65 °C. The reaction mass after cooling may be isolated from a suitable solvents or mixtures thereof to obtain pure Nisoldipine (1). The said reaction mass may be cooled to 0-20°C, preferably 5-10°C.
The processes of the present invention may also include isolation of individual intermediate or processed for further steps without isolation of intermediates wherever applicable.
In some embodiment, the present invention provides process for the preparation of 3-aminocrotonoic acid isobutyl as illustrated in scheme-3. It may be carried out by dissolving isobutyl 3-oxobutanote (6) in a suitable solvent and reacting with ammonia. The reaction temperature may be about 0-50 °C, preferably between 0-30 °C.
Schemc-3
The suitable solvents used in scheme-2 and scheme-3 may be selected from a group comprising of protic or aprotic solvents. The suitable protic solvents may be selected

from a group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, water or the like. Preferably, isopropyl alcohol and water were used in the present invention. The suitable aprotic solvents used may be selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, n-hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably n-hexane, dichloromethane and acetonitrile were used in the present invention.
In another embodiment the mixture of protic and aprotic solvents used in step b) of scheme-2 was water and acetonitrile, preferably 10% water in acetonitrile was used in the present invention.
Another embodiment of the invention is to provide process for the purification of
Nisoldipine (1) using suitable solvents comprising of the following steps:
i. suspending Nisoldipine (1) in a suitable first solvent
ii. heating the reaction mixture to 50-70 °C
iii. optionally, filtering the reaction mixture through micron filter
iv. adding a suitable second solvent to the filtrate
v. optionally, cooling the reaction mixture to 0-15 °C
vi. isolating pure Nisoldipine (1)
Purification of Nisoldipine (1) in step i) to step iv) may be carried out in a suitable first and second solvents. The suitable solvents used in the purification may be selected from aprotic and protic solvents. The aprotic solvents may be selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, n-hexane, cyclohexane, toluene, tetrahydrofuran and the protic solvents may be selected from a group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, water or mixtures thereof. Preferably acetonitrile, water or mixtures thereof were used in the

present invention. The temperature at which step ii) and step v) may be carried out in between about 0°C and about 100 °C, preferably between about 0 °C and about 70 °C.
The pure Nisoldipine (1) produced in the above purification process is crystalline, with purity greater than 99.0 % by High-performance liquid chromatography (HPLC).
Yet, in another embodiment Nisoldipine (1) obtained after purification is having total impurities less than 0.5% (w/w), preferably impurity A, B, C, D and E are less than 0.5% (w/w), preferably less than 0.25% (w/w), most preferably less than 0.15% (w/w).

Nisoldipine (1) obtained in the present invention is having impurity A less than 0.2°/ (w/w), more preferably less than 0.15 % (w/w), still more preferably less than 0.1°/ (w/w) and impurity D is less than 0.1% (w/w).
In another embodiment, Nisoldipine (1) obtained in the present invention is having water content by Karl Fischer method less than 0.5% (w/w) and total heavy metal: level less than 20 ppm and has a specific rotation between -10°and +10°.
In another embodiment, the pure Nisoldipine (1) obtained after purification was having X-Ray powder diffraction (XRPD) pattern as shown in figure 1 and the 2 theta value; ± 0.2 were provided in table 1.
Tablel:
Two (0) deg. Relative Intensity (%)
8.89 X20
9.36 203
9.83 100
10.17 2/70
11.31 472
12.50 103
13.58 4^80
14.17 2^40
14.99 6^60
17.83 57l0
18.91 263
19.08 3L7
19.72 140
20.52 930
22.01 4790
22.75 542

23.17 I 3.00
24.00 340
24.79 340
25.33 14~1
26.14 16\9
27.22 6^60
27.54 17^9
28.54 3lK)
31.48 3/70
31.95 4^60
34.47 5XX)
36.54 420
41.76 2T0O
In another embodiment, the crystalline form of Nisoldipine (1) obtained after purification is having sharp endothermic peak at 152.34 ° in the Differential Scanning Calorimetry thermogram as illustrated in figure 2
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE-1: Preparation Of 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3)
lOOg of 2-nitrobenzaldehyde (5) was suspended in lOOOmL of n-hexane at 25-30 °C and 77g of methyl acetoacetate (4) was added to it. The reaction mass was heated at 50-55 °C. lOg of dibutyl amine and lOg of acetic acid were added. 23.05 g of methyl acetoacetate (4) was added to the reaction mass and stirred for 60-75 minutes at 55-60

°C. On completion of reaction, the reaction mass was cooled to 25-30 °C and the solid formed was filtered under nitrogen atmosphere. The solid was then dissolved in 250 mL of isopropyl alcohol, cooled to 10-15 °C and filtered to obtain the solid. The solid so obtained was washed with 75mL of cold isopropyl alcohol and dried. The obtained solid was added to lOOmL of dichloromethane at 25-30 °C and heated to 35-45 °C. Further 50 mL of isopropyl alcohol was added to the clear solution and the reaction mixture was stirred at 25-30 °C. The solid so obtained was washed with 80mL of isopropyl alcohol and dried below 40 °C to obtain 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3). Yield: 80%; Purity: 99.67%.
EXAMPLE-2: Preparation of Nisoldipine (1)
lOOg of intermediate (3) was dissolved in lOOOmL of isopropyl alcohol at 25-30 °C under nitrogen atmosphere and 85g of 3-aminocrotonoic acid isobutyl ester (2) was added. The reaction mass was heated at 80-85 °C for 2 to 2.5hrs, then cooled to 25-30 °C and further 12.6 g of 3-aminocrotonoic acid isobutyl ester (2) was then added to the reaction mass. On completion of reaction, the reaction mass was cooled to 45-50 °C and 8.0 mL of hydrochloric acid was added. The solvent was distilled off and the residue was treated with a mixture of 300mL of acetonitrile and 150mL of water at 50-55 °C for 10-15 min. The reaction mass was then cooled to 25-30 °C, filtered and the solid obtained was washed with 30% water and acetonitrile mixture and dried under vacuum below 50 °C. The solid so formed was added to 300 mL of acetonitrile and heated to 60-65 °C. Further, 30 mL of water was added to the reaction mass and the reaction mass cooled to 5-10 °C. The solid formed was filtered under nitrogen atmosphere and washed with 10% water in acetonitrile mixture and dried under vacuum below 45 °C to obtain Nisoldipine (1). Yield: 70%; Purity: 99.5%.

EXAMPLE-3: Purification of Nisoldipine (1)
lOOg of Nisoldipine (1) was dissolved in 350 mL of acetonitrile and heated to 60-65 °C. The reaction mass was then filtered through 0.2 mm micron filter and the filtrate was treated with water at 60-65°C. The reaction mass was cooled to 45-50 °C and further to cooled to 5-10 °C. The solid formed was filtered under vacuum below 10 °C. and washed with 50 mL of chilled water in acetonitrile under nitrogen atmosphere. The final solid was then dried under vacuum at below 45 °C to obtain pure Nisoldipine (1). Yield: 88%; Purity:99.8%.
EXAMPLE-4: Preparation of 3-aminocrotonoic acid isobutyl ester (2)
lOOg of isobutyl 3-oxobutanote (6) was dissolved in 400 mL of isopropyl alcohol and cooled to 0-5 °C. Ammonia gas (-200 g) was passed through reaction mass for 5-6hrs at 0-5 °C and reaction was maintained at 25-30 °C for 4-5hrs. On completion of reaction, the solvent was first distilled off under vacuum and the volatiles impurities were removed by distillation at 65-70 °C for 5-6hrs under vacuum and at 85-90 °C for 2-3hrs under vacuum to obtain 3-aminocrotonoic acid isobutyl ester (2). Yield: 90%; Purity: 99.95%.

We Claim:
1. A process for preparing of Nisoldipine (1) comprising the steps of:
(1)
a) reacting 2-nitrobenzaldehyde (5)
with methyl acetoacetate (4)
:
\ •>
in presence of a base to form 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3);
b) reacting of 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester (3) with
3-aminocrotonoic acid isobutyl ester (2)
MII r»

in presence of acid to form Nisoldipine (1); and c) optionally, purifying Nisoldipine (1) obtained in step b) in a suitable solvent.
2. The process of claim I, wherein the base used in step a) is selected from a group comprising of N -methylamine, N, N-dimethylamine, butylamine or Di-«-butylamine.
3. The process of claim 1, wherein the acid used in step b) is selected from the group comprising of sulphuric acid, hydrochloric acid, phosphoric acid or any combination thereof.
4. The process of claim 1, wherein the solvent is selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, dimethyl sulfoxide, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, n-hexane, cyclohexane, toulene, tetrahydrofuran, methanol, ethanol, n-propanol, n-butanol, isopropyl alcohol, isobutyl alcohol, water or from mixtures thereof
5. A process for the purification of Nisoldipine (1) comprising:
i. suspending Nisoldipine (1) in a suitable solvent;
ii. heating the reaction mixture to 60-70 °C; iii. optionally, filtering the reaction mixture through micron filter; iv. adding a suitable protic solvent to the filtrate;
v. cooling the reaction mixture to a suitable temperature and vi. isolating crystalline Nisoldipine (1).
6. The process of claim 5, wherein the solvent is selected is selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, dimethyl sulfoxide, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, n-hexane, cyclohexane, toluene, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, water or from mixtures thereof.
7. The crystalline form of Nisoldipine (1) as claimed in claim 5, characterized by X-ray powder diffraction (XRPD) pattern comprising one or more of the reflections at value 8.89, 9.36, 9.83, 10.17, 11.31, 12.50, 13.58, 14.17, 14.99,

17.83, 18.91, 19.08, 19.72, 20.52, 22.01, 22.75, 23.17, 24.00, 24.79, 25.33, 26.14,27.22, 27.54, 28.54, 31.48, 31.95, 34.97, 36.47, 36.54 and 41.76 ± 0.2 degrees 2 theta (20°) and X-ray diffraction pattern as shown in figure 1.
8. The crystalline form of Nisoldipine (1) as claimed in claim 5, characterized by a sharp endothermic peak at 152.34 ° in the Differential Scanning Calorimetry thermogram as illustrated in figure 2.
9. The process of claim 5, wherein Nisoldipine (1) is having purity greater than 99.5% and one or more off the following:
i) less than 0.15% of impurities A; ii) less than 0.2 % of impurity C; and ii) less than 0.1% of impurity D.