FORM 2
THE PATENT ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF DALFAMPRIDINE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

FIELD OF THE INVENTION:
The present invention relates to an improve process for the preparation of Dalfampridine compound represented by structural formula I comprising reacting 4-cyano pyridine compound represented by structural formula II with an oxidizing agent in the absence of base.

BACKGROUND OF THE INVENTION:
Fampridine is an old compound; chemically it is 4-amino pyridine and is represented by compound of formula I.

Fampridine-SR has been approved in USA by name "Dalfampridine". It is indicated for an oral treatment to improve walking in patients with multiple sclerosis (MS). The proprietor name of "Dalfampridine" is AMPYRA.
U.S. Patent No. 1,879,324 describes a process for the preparation of fampridine by reacting pyridine with thionyl chloride and decomposing the intermediate product formed with an

alkaline reacting agent of the group consisting of alkali and alkaline earth metal hydroxides and ammonia in the cold and heating the reaction mixture with a dilute strong mineral acid.

U.S. Patent No. 3.812,137 describes a process for the preparation of fampridine by reacting isonicotinic acid, ammonia and a compound of a polyvalent metal selected from copper and palladium in a higher valence state, in presence of water at reaction temperature in the range from 100°C to 350°C under pressure in the range from atmospheric pressure to about 2000 p.s.i.g.

U.S. Patent No. 4,140,853 discloses a process for the preparation of fampridine, which involves heating 4-pyridylpyridinium chloride hydrochloride in formamide under agitation at 150°C, followed by the distillation of pyridine and reacting with sodium hydroxide solution in water.

Yang, Yuan-Yuan; Zhou, Guo-Quan; Chen, Xin-Zhi. College of Material Science and Chemical Engineering, Zhejiang University, Huangzhou, Peop. Rep. China. Yingyong Huaxue (2004), 21(5), 530-531 discloses a process for the preparation of fampridine, wherein 4-cyanopyridine is

first catalytically hydrolyzed to give isonicotinamide in the presence of Mg-Fe oxides which is converted into 4-aminopyridine by Hofmann reaction using iodobenzene as catalyst.
Chinese Patent No. 1, 319,947 describes a process for the preparation of fampridine by subjecting the Hofmann degradation reaction of 4-pyridinecarboxamide in the presence of catalyst.

Chinese Patent No.l, 311, 185 describes a process for the preparation of fampridine by reducing 4-nitro pyridine-N-oxide compound of formula III.

Chinese Patent Application nos. 1,807,415 and 1,311,185 disclose the isolation of fampridine by crystallization in benzene solvent. The benzene solvent is carcinogenic and therefore the crystallization of fampridine in benzene solvent at commercial scale is not advisable.
Wang, Zhixiang; Zhang, Zhibing. School of Pharmacy, China Pharmaceutical University, Nanjing, Peop. Rep. China. Zhongguo Yiyao Gongye Zazhi (2001), 32(2), 83-84 discloses a process for the preparation of fampridine, which involves oxidizing pyridine with H2O2 in the

presence of acetic acid at 80-85° to obtain pyridine N-oxide; nitrifying with HNO3/H2SO4 at 85-95°, and reducing with H2 in ethanol in the presence of Raney Ni.
U.S. Publication no. 2011319628 discloses a process for the preparation of Dalfampridine, comprising reacting 4-pyridinecarbonitrile with an oxidizing agent in the presence of a base and in absence of a catalyst.
The prior art processes involves multistep reactions, which negatively affects yields and makes the process more cumbersome and therefore there is a need in the art to develop an improved process for the preparation of Dalfampridine compound of structural formula I, which obviate the problems reported in the prior-art.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process for the preparation of Dalfampridine compound represented by structural formula I comprising reacting 4-cyano pyridine compound represented by structural formula II with an oxidizing agent in the absence of base.

Another aspect of the present invention is to provide a process for preparing amino pyridine compounds represented by structural formula V comprising reacting cyano pyridine compounds represented by structural formula IV with an oxidizing agent in the absence of base.


Wherein Ri is Cyano group and R2 is amino group.
BRIEF DESCRIPTION OF THE INVENTION:
4-Cyano pyridine compound represented by structural formula II is commercially available at very low prices.
The examples of oxidizing agent may include but not limited to calcium hypochlorite, sodium hypochlorite, potassium hypochlorite or the combination thereof.
The oxidizing agent may be used in the range of 0.5 moles to 10 moles of 4-cyano pyridine compound represented by structural formula II.
The reaction of 4-cyano pyridine compound represented by structural formula II with an oxidizing agent may be carried out in polar solvent.
The examples of polar solvent may include water, alcohol and mixtures thereof.
The reaction of 4-cyano pyridine compound represented by structural formula II with an oxidizing agent may be carried out at a temperature in the range of 10°C to 100°C.
The reaction of 4-cyano pyridine compound represented by structural formula II with an oxidizing agent may be carried out for a period of 30 minutes to 5 hours.
The resulting reaction mixture may be cooled to an ambient temperature (25°C to 30°C) and Dalfampridine compound represented by structural formula I may be extracted with an alcoholic solvent.
The alcoholic solvent may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or mixture (s) thereof.
Dalfampridine compound represented by structural formula I may be isolated by process steps selected from concentration of Dalfampridine solution in alcoholic solvent under reduced pressure, recrystallization, filtration, washing, drying and the combination thereof.

The concentration of Dalfampridine solution in alcoholic solvent may be carried out under reduced pressure at a temperature in the range of 35°C to 60°C to get crude Dalfampridine.
The recrystallization of crude Dalfampridine may be carried out in an alkyl acetate solvent or ketone solvent.
The alkyl acetate solvent may be selected from the group comprising of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The alkyl acetate solvent may be used in the range of 2 volumes / weight to 10 volumes / weight of crude Dalfampridine.
The ketone solvent may be selected from the group comprising of acetone, diethyl ketone, methyl isobutyl ketone, diisopropyl ketone, ethyl propyl ketone or mixture(s) thereof.
The ketone solvent may be used in the range of 2 volumes / weight to 20 volumes / weight of crude Dalfampridine.
The recrystallization of crude Dalfampridine may be carried out at a temperature in the range of-10°C to 35°C.
The substantially pure Dalfampridine compound represented by structural formula I may be isolated by the steps of filtration, centrifugation, washing, drying or combination thereof.
The substantially pure Dalfampridine compound represented by structural formula I may be washed with water.
The substantially pure Dalfampridine compound represented by structural formula I may be dried under reduced pressure.
The substantially pure Dalfampridine compound represented by structural formula I may be dried at a temperature in the range of 40°C to 70°C for a period of 1 hour to 18 hours.
The isolated substantially pure Dalfampridine compound represented by structural formula I may be crystalline in nature.

The term "Crude Dalfampridine" compound refers herein describe Dalfampridine compound having 99% purity or less than 99% purity as determined by HPLC technique.
The term "substantially pure Dalfampridine" compound refers herein describe Dalfampridine compound having more than 99% purity as determined by HPLC technique.
The term "Crude 3-amino pyridine" compound refers herein describe 3-amino pyridine compound having 99% purity or less than 99% purity as determined by HPLC technique.
The term "substantially pure 3-amino pyridine" compound refers herein describe 3-amino pyridine" compound having more than 99% purity as determined by HPLC technique.
The term "Crude 2-amino pyridine" compound refers herein describe 2-amino pyridine compound having 99% purity or less than 99% purity as determined by HPLC technique.
The term "substantially pure 2-amino pyridine" compound refers herein describe 2-amino pyridine" compound having more than 99% purity as determined by HPLC technique.
The examples of compound represented by structural formula IV may include following compounds:

The examples of compound represented by structural formula V may include following compounds:


The compounds represented by structural formula VI and VII may be converted into compounds of structural formula VIII and IX respectively be using similar methods described above for converting compound represented by structural formula II into Dalfampridine compound represented by structural formula I.
EXAMPLE
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
EXAMPLE 1: PREPARATION OF SUBSTANTIALLY PURE DALFAMPRIDINE
The 4-cyano pyridine (50gm) was dissolved in water (800ml) and Calcium hypochlorite (70gm) was added. The resulting reaction mixture was stirred 3 hours at 60-70° and then it was extracted with isopropanol (300ml) at 30°C by salting. The resulting organic layer was concentrated under reduced pressure at 50°C to get crude Dalfampridine (43gm). The crude Dalfampridine (43gm) was recrystallized in ethyl acetate (170ml) at 10°C to get title compound.
Yield:41.4gm
Purity: 99.9% (By HPLC method)
EXAMPLE 2: PREPARATION OF SUBSTANTIALLY PURE 3-AMINO PYRIDINE

The 3-cyano pyridine (20gm) was dissolved in water (300ml) and Calcium hypochlorite (34gm) was added. The resulting reaction mixture was stirred 3 hours at 60-70° and then it was extracted with isopropanol (120ml) at 30°C by salting. The resulting organic layer was concentrated under reduced pressure at 45°C to get crude 3-amino pyridine (17gm). The crude 3-amino pyridine (17gm) was recrystallized in ethyl acetate (68ml) at 10°C to get title compound.
Yield: 16.2gm
Purity: 99.8% (By HPLC method)
EXAMPLE 3: PREPARATION OF SUBSTANTIALLY PURE 2-AMINO PYRIDINE
The 2-cyano pyridine (20gm) was dissolved in water (320ml) and Calcium hypochlorite (30gm) was added. The resulting reaction mixture was stirred 2.5 hours at 65°C and then it was extracted with isopropanol (lOOml) at 25°C by salting. The resulting organic layer was concentrated under reduced pressure at 50°C to get crude 2-amino pyridine (17.3gm). The crude 2-amino pyridine (17.3gm) was recrystallized in acetone (60ml) at 10°C to get title compound.
Yield: 16.4gm
Purity: 99.8% (By HPLC method)

WE CLAIM:
1. A process for the preparation of Dalfampridine compound represented by structural formula I comprising reacting 4-cyano pyridine compound represented by structural formula II with an oxidizing agent in the absence of base.

2. A process for preparing amino pyridine compounds represented by structural formula V comprising reacting cyano pyridine compounds represented by structural formula IV with an oxidizing agent in the absence of base.

Wherein R1 is Cyano group and R2 is amino group.
3. The process according to claim nos. 1 and 2, wherein oxidizing agent is selected from the group comprising of hypohalite is selected from calcium hypochlorite, sodium hypochlorite,

potassium hypochlorite, sodium hypobromite, potassium hypobromite, sodium hypoiodite, potassium hypoiodite, magnesium hypochlorite, lithium hypochlorite and mixtures thereof.
4. The process according to claim no 1. wherein oxidizing agent is used in the range of 0.5 moles
to 10 moles of 4-cyano pyridine compound represented by structural formula II.
5. The process according to claim no. 1, wherein reaction of 4-cyano pyridine compound represented by structural formula II with an oxidizing agent is carried out in the presence of polar solvent such as water, alcohol and mixtures thereof.
6. The process according to claim no. 2, wherein reaction of cyano pyridine compounds represented by structural formula IV with an oxidizing agent is carried out in the presence of polar solvent such as water, alcohol and mixtures thereof.
7. The process according to claim no. 2, wherein examples of compound represented by structural formula IV are as follows:

8. The process according to claim no. 2, wherein examples of compound represented by structural formula V are as follows:


9. The process according to claim no. 1 wherein reaction of 4-cyano pyridine compound represented by structural formula II with an oxidizing agent is carried out at a temperature in the range of 10°C to 100°C for a period of 30 minutes to 5 hours.