FIELD OF THE INVENTION
The present invention relates to an improved process for preparing Nimodipine (1). It further discloses the process for preparing Nimodipine (1) with purity more than 99.0% by High performance liquid chromatography (HPLC).
BACKGROUND OF THE INVENTION
Nimodipine is a member of dihydropyridine class of drugs belonging to the calcium channel antagonist, chemically isopropyl-2-methoxyethyl-l,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxylate. It is marketed asNimotop by Bayer AG indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with subarachnoid haemorrhage (SAH) from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).
Synthesis of Nimodipine was reported in few patents and non-patent literature, the contents of which are hereby incorporated as reference in their entirety.
US4510310 patent discloses process for the preparation of Nimodipine (1) by reacting compound (a) in presence of Sodium in glycol monomethyl ether. US '310 did not disclose purity of intermediates or purity of Nimodipine (1).

2736/MUM/2015 application discloses the process for the preparation of Nimodipine (1). (E)-2-methoxyethyl 2-(3-nitrobenzylidene)-3-oxobutanoate (3) was reacted with (Z)-isopropyl 3-aminobut-2-enoate (2) in presence of citric acid, morpholine to form Nisoldipine. But the yield reported was very less.

US6015906 patent discloses the process for the preparation of Nimodipine (1). 3-nitrobenzaldehyde (5) was reacted with 2-methoxyethyl 3-oxobutanoate (4) in presence of p-anisic acid, dimethyl amine in isopropanol to obtain intermediate (3), which was reacted with (Z)-isopropyl 3-aminobut-2-enoate (2) in presence of p-anisic acid and dimethyl amine to form Nimodipine (l).US '906 did not disclose the purity of Nimodipine.
The prior arts discussed herein, have drawbacks of less yield of the final product. Moreover, they don't disclose the purity and yield of intermediates. Hence, the present inventors, hereby report an improved process for the synthesis of Nimodipine (1) with better yield and purity.
OBJECTIVE OF THE INVENTION
In one objective of the present invention is to provide an improved process for the preparation of Nimodipine (1).
Another objective of the invention is to provide process for the purification of Nimodipine (1) to obtain purity greater than 99.0% by High performance liquid chromatography (HPLC).
SUMMARY OF THE INVENTION
Accordingly, in one aspect, the present invention provides an improved process for preparation of Nimodipine (1), comprising:
a) coupling of 3-Nitrobenzaldehyde (5) with 2-methoxyethyl 3-oxobutanoate (4) in presence of suitable base to obtain an intermediate 2-methoxy-ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate (3); and
b) reacting intermediate (3) with isopropyl 3-aminobut-2-enoate (2) in presence of acid to obtain Nimodipine (1).
In another aspect, the present invention provides process for the purification of Nimodipine (1), comprising:
i. providing Nimodipine (1) in a suitable solvent;
ii. heating the reaction mixture and filtering;
iii. adding another suitable solvent to the reaction mixture;

iv. cooling the reaction mixture to suitable temperature; v. adding seeding material to the reaction mixture; and vi. isolating pure Nimodipine (1).
In yet, another aspect, the present invention provides Nimodipine (1) having purity greater than 99.0% by HPLC.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1 is characteristic X-ray powder diffraction pattern (XRD) of crystalline
form I of Nimodipine (1).
Figure-2 is characteristic X-ray powder diffraction pattern (XRD) of crystalline
form II of Nimodipine (1).
Figure-3 is characteristic X-ray powder diffraction pattern (XRD) of crystalline
form III of Nimodipine (1).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of Nimodipine (1) having purity greater than 99.0 %.
In another embodiment, the present invention provides an improved process for the preparation of Nimodipine (1) as illustrated in scheme 2, comprising of the following steps:

a) coupling of 3-Nitrobenzaldehyde (5) with 2-methoxyethyl 3-oxobutanoate (4) in presence of suitable base and acid to obtain 2-methoxy-ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate (3); and
b) reacting intermediate (3) with isopropyl 3-aminobut-2-enoate (2) in presence of acid to obtain crude Nimodipine (1).
In some embodiment step a) involves coupling of 3-Nitrobenzaldehyde (5) with 2-methoxy ethyl 3-oxobutanoate (4) to obtain 2-methoxy-ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate (3) in presence of suitable organic base and acid. Organic base can be selected from the group comprising of pyridine, piperidine, dibutyl amine , diethyl amine, triethylamine, methylamine, isopropyl amine, di-isopropyl ethyl amine, morpholine, N-methyl morpholine, ammonia or the like; preferably dibutyl amine was used in the present invention.
In another embodiment, step b) involves reduction of 2-methoxy-ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate (3) with isopropyl 3-amino-but-2-enoate (2) in acid to yield Nimodipine (1).
The suitable solvents used in step a) and step b) may be selected rom organic or in-organic solvents, preferably organic solvents may be used. Organic solvents may further be selected from protic or aprotic solvents. Protic solvents may be selected from a group comprising of water, methanol, ethanol, isopropyl alcohol or the like, preferably isopropyl alcohol and water were used in the present invention. Aprotic solvents may be selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane (DCM), dimethyl sulfoxide (DMSO), ethyl acetate, N,N-dimethylformamide (DMF), methyl tertiary butyl ether (MTBE), hexane, cyclohexane, toluene, n-methyl pyrrolidone, dimethyl acetamide, tetrahydrofuran or the like; preferably dichloromethane and hexane were used in the present invention.
The suitable acid used in step a).and step b) may be selected from organic or inorganic acid. Organic acid used in step a) may be selected from the group comprising of acetic acid, formic acid, p-toluene sulfonic acid, methane sulfonic

acid, oxalic acid or the like; preferably acetic acid was used in the present invention. The inorganic acid used in step b) may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or the like, preferably hydrochloric acid was used in the present invention
In another embodiment, the present invention provides process for the purification of Nimodipine (1) comprising:
i. providing Nimodipine (1) in a suitable solvent;
ii. heating the reaction mixture and filtering;
iii. adding suitable solvent to the filtrate;
iv. cooling the reaction mixture;
v. adding seeding material to the reaction mixture; and
vi. isolating pure Nimodipine (1).
In some embodiment, step c) involves purification of Nimodipine (1). Nimodipine (1) may be dissolved in a suitable solvent and the reaction mass heated to 40-70 °C, preferably 55-60 °C and filtered. Another suitable solvent was added to the filtrate and cooled to 30-50°C. Seeding material was added to the filtrate and cooled to 20-40 °C, preferably to 25-30 °C and more preferably to 5-10 °C. The pure Nimodipine (1) formed was isolated from a mixture of suitable solvents.
In some embodiment, solvents used for the purification of crude Nimodipine (1) may be selected from a group comprising of protic or aprotic solvents, preferably protic solvents may be selected from a group comprising of water, methanol, ethanol, isopropyl alcohol or the like, preferably water, isopropyl alcohol were used in the present invention.
Nimodipine (1) obtained by the above process was having purity greater than 99.0% by HPLC.
In another embodiment, the present invention provides Nimodipine (1) having optical rotation between -0.10° to + 0.10°.

In another embodiment, the present invention provides Nimodipine (1) having heavy metal content less than between 10 ppm.
In another embodiment, the present invention provides a purification process to produce of Nimodipine (1) having impurity levels less than 0.1 % (w/w), preferably less than 0.05% (w/w).
In another embodiment, the present invention provides pure Nimodipine (1) having each individual impurity A, B and C less than 0.1% % (w/w), preferably less than 0.05% (w/w) as shown below:

In another embodiment, the present invention provides pure crystalline form I of Nimodipine (1), which produce an X-ray diffraction (XRD) pattern comprising of 2(0) theta values ± 0.2 degrees as illustrated in figure 1 and as tabulated in Table 1 below:

In another embodiment, the present invention provides crystalline form II of Nimodipine (1), which produce an X-ray diffraction (XRD) pattern comprising of 2(0) theta values ± 0.2 degrees as illustrated in figure 2 and as tabulated in Table 2 below:

In another embodiment, the present invention provides crystalline form III of Nimodipine (1), which produce an X-ray diffraction (XRD) pattern comprising of 2(0) theta values ± 0.2 degrees as illustrated in figure 3 and as tabulated in Table 3 below:

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-methoxy ethyl-2-(3-nitrobenzylidene)-3-
oxobutanoate (3)
lOOg of 3-Nitrobenzaldehyde (5) and 106g of 2-methoxyethyl-3-oxobutanoate (4)
were suspended in 1000 mL of n-Hexane. The reaction mass was heated to 50-55
°C and 10 mL of dibutyl amine and 10 mL of acetic acid were added at 65-70 °C.
On completion of the reaction, cool the reaction mass to 50-55 °C and separated the
layers. The aqueous layer was collected, and 400 mL of isopropyl alcohol was
added. The reaction mass was cooled to 5-10 °C and the solid formed was filtered.
Further, the solid was washed with mixture of isopropyl alcohol and
dichloromethane, dried under vacuum to yield 2-methoxy ethyl-2-(3-
nitrobenzylidene)-3-oxobutanoate (3). Yield: 70%; Purity: 98.0% (HPLC).
EXAMPLE-2: Preparation of Nimodipine (1)
100 g of 2-methoxy ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate (3), 60 g of isopropyl-3-amino-but-2-enoate (2) was dissolved in 300 mL of isopropyl alcohol at 25-30 °C . The reaction mass was then heated to 80-85 °C. On completion of reaction 8mL of hydrochloric acid was added to the reaction mass and then cooled to 50-55 °C. 150 mL of water and seeding material was added to the reaction mass at 45-50 °C and then cooled to 5-10 °C. The solid so formed was washed with mixture of water and isopropyl alcohol and dried under vacuum at below 50 °C to yield Nimodipine (1). Yield: 90 %; Purity:99.0% (HPLC).
EXAMPLE-3: Purification of Nimodipine (1)
100 g of Nimodipine (1) was suspended in 500 mL of isopropyl alcohol under nitrogen atmosphere and heated to 55-60 °C. The reaction mixture was filtered through micron filter. 300 mL of water and 250 mL of isopropyl alcohol were added to the filtrate at 55-60 °C. The reaction mixture was cooled to 45-50 °C and seeding material was added. The reaction mixture was further cooled to 5-10 °C and the

solid so obtained was washed with mixture of water and isopropyl alcohol, dried under vacuum to yield pure Nimodipine (1). Yield: 92%; Purity: 99.9 % (HPLC).
EXAMPLE-4: Purification of Nimodipine (1)
100 g of Nimodipine was suspended in 700 mL of isopropyl alcohol under nitrogen atmosphere and heated to 55-60 °C. The reaction mixture was fdtered through micron filter. To the filtrate 300 mL of water was added at 55-60 °C and seeding material was added. The reaction mixture was cooled to 5-10 °C. The solid formed was washed with a mixture of isopropyl alcohol and water and dried under vacuum to yield pure Nimodipine (1). Yield: 93%; Purity: 99.95 % (HPLC).

We Claim:
1. A process for the preparation of Nimodipine (1), comprising:
a) coupling of 3-Nitrobenzaldehyde (5) with 2-methoxyethyl 3-oxobutanoate (4) in presence of suitable base to obtain 2-methoxy-ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate (3); and
b) reacting intermediate (3) with isopropyl 3-aminobut-2-enoate (2) in presence of acid to obtain Nimodipine (1).

2. The process according to claim 1, wherein the suitable base used is selected from a group comprising of pyridine, piperidine, dibutyl amine, diethyl amine, triethylamine, methylamine, isopropyl amine, di-isopropyl ethyl amine, morpholine, N-methyl morpholine or ammonia.
3. The process according to claim 1, wherein the suitable acid is selected from a group comprising of acetic acid, formic acid, p-toluene sulfonic acid, methane sulfonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, or phosphoric acid.
4. A process for the purification of Nimodipine (1) comprising:

a) providing Nimodipine (1) in a suitable solvent;
b) heating the reaction mixture and filtering;
c) adding suitable solvent or mixture of solvents to the filtrate;
d) cooling the reaction mass;
e) adding seeding material to the reaction mixture; and
f) isolating pure Nimodipine (1).
5. The process according to claim 1 and claim 4, wherein the suitable solvent
used is selected from a group comprising of acetone, acetonitrile, 1,4-
dioxane, diethyl ether, dichloromethane (DCM), dimethyl sulfoxide
(DMSO), ethyl acetate, N,N-dimethylformamide (DMF), methyl tertiary
butyl ether (MTBE), hexane, cyclohexane, toluene, n-methyl pyrrolidone,
dimethyl acetamide, tetrahydrofuran, water, methanol, ethanol, isopropyl
alcohol or mixtures thereof.
6. The process according to claim 4, wherein pure Nimodipine (1) obtained is
having purity greater than 99.0% by HPLC.

7. The process according to claim 1, wherein Nimodipine (1) obtained is comprising:
no greater than 0.1% of impurity A(w/w) no greater than 0.1% (w/w) of impurity B no greater than 0.1% (w/w)of impurity C; and no greater than 0.5% of total impurities