FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFlCATION
(See section 10 and rule 13)
Title of the invention
"PROCESS FOR THE PREPARATION OF FAMPRIDINE
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17'~loor, Kesar Solitaire,
Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be
performed.
01 0
5 MAR 2030
PROCESS FOR THE PREPARATION OF FAMPRIDINE
FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of substantially pure fampridine
compound of structural formula I comprising the steps of nitrifying pyridine-N-oxide
hydrochloride compound of structural formula I1 with suitable nitrating agent to obtain 4-
nitro pyridine-N-oxide compound of structural formula 111; reducing 4-nitro pyridine-N-oxide
compound of structural formula 111 with suitable reducing agent to obtain crude fampridine
compound of structural formula I and purifying crude fampridine compound of structural
formula I by recrystallizing in water followed by treating with an alkyl acetate solvent.
BACKGROUND OF THE INVENTION:
Fampridine is an old compound; chemically it is 4-amino pyridine and is represented by
compound of formula I.
NH2 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.
3 MAR 2011
Scheme I
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.
NH3 1 Cuo
Scheme I1
US. 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.
Formamide *
NaOH
Scheme I11
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 isonicotinarnide in the
presence of Mg-Fe oxides which is converted into 4-aminopyridine by Hofmann reaction
using iodobenzene as catalyst.
3
3 MAR 2011
Chinese Patent No. 1, 3 19,947 describes a process for the preparation of fampridine by
subjecting the Hofmann degradation reaction of 4-pyridinecarboxamide in the presence of
catalyst.
i"'
Scheme IV
Chinese Patent No.1, 31 1, 185 describes a process for the preparation of fampridine by
reducing 4-nitro pyridine-N-oxide compound of formula 111.
Formula I11 Formula I
Scheme V
Chinese Patent Application nos. 1,807,4 15 and 1,3 1 1,185 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.
Organic Synthesis, Coll. Vol. 4, p. 828 (1963); Vol. 33, p. 79 (1953) describes pyridine-Noxide
hydrochloride compound of formula 11.
Formula 11
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
H202 in the presence of acetic acid at 80-85OC to obtain pyridine N-oxide; nitrifying with
HNO3IH2S04 at 85-95OC, and reducing with Hz in ethanol in the presence of Raney Ni.
The applicant of this patent has observed that prior-art processes for isolating fampridine
always yield impure fampridine compound, which is being contaminated by following
chemical impurities of structural formula IV, V, VI, VII and VIII.
Formula IV Formula V Formula VI Formula V11 Formula VllI
The prior art approach for the preparation of fampridine is not commercially viable as
pyridine-N-oxide compound, which is present in liquid state, gives inconsistent results in
terms of yield of the nitro pyridine-N-oxide compound of structural formula 111.
There is a need in the art to obviate the prior-art problems and for the development of
commercially viable process for the preparation of fampridine compound of structural
formula I.
5
3 MAR 2813
SUMMARY OF THE INVENTION:
It is an object of the present invention to solve the problems associated with the prior art and
provides an efficient process. The process provides obvious benefits with respect to
economics and convenience to operate on a commercial scale.
In one general aspect there is provided a process for the preparation of fampridine compound
of structural formula I comprising nitrifying pyridine-N-oxide hydrochloride with suitable
nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural formula I11 and
then reducing 4-nitro pyridine-N-oxide compound of structural formula I11 with suitable
reducing agent to obtain fampridine compound of structural formula I.
In another general aspect there is provided a process for the preparation of substantially pure
fampridine compound of structural formula I comprising nitrifying pyridine-N-oxide
hydrochloride with suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of
structural formula 111; reducing 4-nitro pyridine-N-oxide compound of structural formula I11
with suitable reducing agent to obtain fampridine compound of structural formula I and
purifying fampridine compound of structural formula I by recrystallizing in water followed
by treating with an alkyl acetate solvent.
In another general aspect there is provided a process for the purification of 4-nitro pyridine-
N-oxide compound of structural formula I11 comprising crystallization of 4-nitro pyridine-Noxide
compound of structural formula I11 in ketonic solvents.
In another general aspect there is provided a process for the preparation of fampridine
compound of structural formula I as depicted in schematic diagram VI.
l:unnula I I Formula I l l
Scheme VI
In another general aspect there is provided a process for the preparation of substantially pure
crystalline fampridine compound of structural formula I comprising the steps of:
a. crystallizing crude fampridine compound of structural formula I in water.
b. treating fampridine obtained form step a with alkyl acetate solvents and
c. isolating substantially pure fampridine compound of structural formula I
Another aspect of the present invention is to provide substantially pure fampridine compound
of structural formula I containing less than about 0.14 % w/w (By HPLC) of one or more of
following chemical impurities of structural formula IV, V, VI, VII and VIII.
Formula 1V Formula V Formula VI Formula VI1 Formula VllI
Another aspect of the present invention is to provide substantially pure crystalline form A of
fampridine compound of structural formula I containing less than about 0.14 % w/w (By
HPLC) of one or more of following chemical impurities of structural formula IV, V, VI, VII
and VIII.
Forniula IV Forniula V Forniula VI Formula V11 Formula Vlll
7
3 MAR 2011
DETAIL DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of fampridine compound of
structural formula I comprising the steps of:
(a) nitrifying pyridine-N-oxide hydrochloride compound of structural formula I1 with
suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural
formula 111 and
Formula 11 Formula 111
(b) reducing 4-nitro pyridine-N-oxide compound of structural formula 111 with suitable
reducing agent to obtain fampridine compound of structural formula I.
Reduction
Formula I11 Formula I
The present invention also provides a process for the preparation of substantially pure
crystalline fampridine compound of structural formula I comprising the steps of:
(a) nitrifying pyridine-N-oxide hydrochloride compound of structural formula I1 with
suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural
formula HJ,
Formula II Fortnula 111
(b) reducing 4-nitro pyridine-N-oxide compound of structural formula 111 with suitable
reducing agent to obtain crude fampridine compound of structural formula I and
Formula 111 Formula I
(c) purifying crude fampridine compound of structural formula I by recrystallizing in
water followed by treating with an alkyl acetate solvent.
Pyridine-N-oxide hydrochloride compound of structural formula I1 may be prepared by
methods known in the literature such as those described in Organic Synthesis, Coll. Vol. 4, p.
828 (1963); Vol. 33, p. 79 (1953), which is incorporated herein by reference only.
Pyridine-N-oxide hydrochloride compound of structural formula 11, used in the invention may
be present in solid state.
Nitration of pyridine-N-oxide hydrochloride compound of structural formula I1 may be
carried out by a mixture of sulfuric acid and fuming nitric acid.
Nitration of pyridine-N-oxide hydrochloride compound of structural formula I1 may be
carried out in the absence of organic solvent.
Nitration of pyridine-N-oxide hydrochloride compound of structural formula I1 may be
carried out at a temperature in the range of 60°C to 125OC for 30 minutes to 4 hours.
4-Nitro pyridine-N-oxide compound of structural formula 111 may be isolated by the steps
consisting of quenching the reaction mass by water at a temperature in the range of 25°C to
35"C, extraction at pH between 9 and 12 by halogenated aliphatic hydrocarbon solvent,
washing the organic layer with water, concentration the organic layer under reduced pressure
and precipitation with ketonic solvent at a temperature in the range of 10°C to 20°C.
9
3 MAR 201%
The pH between 9 and 12 of reaction mass may be adjusted with 20% sodium hydroxide
solution in water.
Examples of halogenated aliphatic hydrocarbon solvent may include methylene dichloride,
ethylene dichloride, chloroform or carbon tetrachloride.
Examples of ketonic solvent may include acetone, 3-pentanone, diisopropyl ketone, methyl
isobutyl ketone, methyl ethyl ketone.
Reduction of 4-nitro pyridine-N-oxide compound of structural formula I11 may be carried out
by hydrogenation in the presence of a catalyst of the group consisting of palladium, nickel,
platinum dioxide, platinum black or rhodium.
The catalytic hydrogenation reaction of 4-nitro pyridine-N-oxide compound of structural
formula I11 may be carried out in an alcoholic solvent.
The examples of alcoholic solvent may include methanol, ethanol, propanol, isopropanol, nbutanol,
2-butanol, pentanol or mixture(s) thereof.
The catalytic hydrogenation reaction may be performed at a temperature in the range of 25°C
to 35°C for 10 hours to 15 hours.
The hydrogen pressure used in the catalytic hydrogenation reaction may be in the range of 10
p.s.i.g (pound-force per square inch gauge) to 40 p.s.i.g.
Crude fampridine compound of structural formula I may be isolated by filtering reaction
mass on hyflow-bed to remove metal catalyst followed by concentrating filtrate under
reduced pressure to obtain residue and precipitation of residue with an alkyl acetate solvent.
Examples of alkyl acetate solvent may include methyl acetate, ethyl acetate, propyl acetate,
isopropyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof.
The crude fampridine compound of structural formula I may contain more than 0.14% wlw
(By HPLC) of following chemical impurities of structural formula IV, V. VI. VII and VIII.
10
3 MAR 2011
Formula IV Formula V Formula VI Formula VII Formula VlII
The crude fampridine compound of structural formula I may be treated with water at a
temperature in the range of 60°C to 90°C for a period of 30 minutes to 4 hours.
The solution of crude fampridine compound of structural formula I in water may be treated
with charcoal at a temperature in the range of 60°C to 100°C for a period of 30 minutes to 2
hours and then the resulting solution may be filtered on hyflow-bed. The hyflow-bed may be
washed with water.
The filtrate of fampridine solution may be stirred at a temperature in the range of 0°C to 15°C
for 30 minutes to 4 hours and then resulting solids may be filtered, washed with water and
dried at a temperature in the range of 45°C to 70°C under reduced pressure.
The fampridine obtained from the crystallization in water may be treated with an alkyl acetate
solvent at a temperature in the range of 0°C to 25°C for a period of 30 minutes to 5 hours.
The examples of alkyl acetate solvents may include methyl acetate, ethyl acetate, n-propyl
acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The substantially pure crystalline fampridine compound of structural formula I may be
isolated by the steps of filtration, centrifugation, washing, drying or combination thereof.
The substantially pure crystalline fampridine compound of structural formula I may be dried
at a temperature in the range of 45°C to 70°C under reduced pressure for a period of 4 hours
to 18 hours.
The term "substantially pure crystalline fampridine compound of structural formula I"
described herein refers to fampridine compound having less than about 0.14 % wlw (By
HPLC) of one or more of following chemical impurities of structural formula IV, V, VI, VII
and VIII.
Formula IV Formula V Formula VI Formula V11 Formula Vlll
The crystalline form of substantially pure farnpridine compound of structural formula I
obtained by following the present invention may be designated herein after as "Form A".
The crystalline form of substantially pure crystalline fampridine compound of structural
formula I may be characterized by data selected from a group comprising of powder X-ray
diffraction pattern having peaks at 20.0, 20.1, 21.4, 24.3, 24.4, 29.2, 29.3, 33.1 + 0.2 degrees
two-theta.
The crystalline form A of substantially pure fampridine compound of structural formula I
may be characterized by X-ray powder diffraction pattern as depicted in Figure 1.
Pos. ["2Th.]
3 MAR 2091
Height [cts] Area [cts*'2Th.] d-spacing [A] Rel. lnt. [%]
A pharmaceutical composition comprising crystalline form A of substantially pure
fampridine compound of structural formula I and pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE FIGURE:
Figure 1 depicts XRPD pattern of substantially pure crystalline form A of fampridine
compound of structural formula I
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions
were as follows:
Scan range ["2-theta]: 2-39.9854;
Scan mode: continuous; Step size ["2-theta]: 0.0170";
Scan step time[s]: 5 1.0404 seconds;
Sample spin: 15 rpm; Sample holder: glass;
PSD Length ["2Th]: 2.12
Irradiated Length [mm]: 10.00
Specimen Length [mm]: 10.00
Measurement Temperature ["C]: 25
Anode Material: Cu
Generator Settings: 40 mA, 45 kV
Goniometer Radius [mm]: 240
Dist. Focus-DivergSlit [mm]: 100.00
Prior to analysis, the samples were gently ground by means of mortar and pestle in order to
obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the
environment contamination by airborne particles coming from the powder. The ground
13
3 MAR 2011
sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and
the surface of the sample was smoothed by means of a cover glass.
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 FAMPRIDINE
STEP A: PREPARATION OF 4-NITRO PYRIDINE-N-OXIDE FROM PYRIDINE-NOXIDE
HYDROCHLORIDE
A solution of pyridine-N-oxide hydrochloride (100 gm) in sulfuric acid (100 ml) was added a
mixture of fuming nitric acid (100 ml) and sulfuric acid (100 ml) at 100°C. The resulting
reaction mixture was stirred for 3 hours at 120°C. After cooling, the reaction mass was
quenched with water (1 000 ml) and extracted with methylene chloride at pH 10. The organic
layer was washed with water (100 ml), concentrated under reduced pressure to get an oily
residue of 4-nitro pyridine-N-oxide compound, which was crystallized by acetone (200 ml) at
a temperature in the range of 10°C to 15°C.
Yield: 85 gm
Purity: 99.5% (By HPLC)
STEP B: PREPARATION OF FAMPRIDINE FROM 4-NITRO PYRIDINE-N-OXIDE
A solution of 4-nitro pyridine-N-oxide (100 gm) in methanol (1000 ml) was hydrogenated
over Raney Nickel catalyst (50 gm) at 30°C temperature under 1.0 Kg /cm2 pressure for 12
hours. The Raney Nickel catalyst was filtered over hyflow-bed, and filtrate was concentrated
under reduced pressure to get a residue, which was precipitated by ethyl acetate (50 ml) to get
crude Fampridine (45 gm).
STEP C: PURIFICATION OF CRUDE FAMPRIDINE
A solution of crude fampridine (100 gm) in water (300 ml) was added active carbon (10 gm)
at 80°C and resulting solution was stirred for 30 minutes. The active carbon was filtered,
filtrate was stirred one hour at 10°C and resulting solids were filtered and recrystallized in
ethyl acetate (200 ml) to get pure farnpridine.
Yield: 70 gm
Purity: 99.95% (By HPLC)
4-Nitropyridine N-oxide: .01% (By HPLC, Limit of Detection: 0.0015%wt/wt)
2-Aminopyridine: Not Detected (By HPLC, Limit of Detection: 0.001 5%wt/wt)
3-Aminopyridine: Not Detected (By HPLC, Limit of Detection: 0.001 S%wt/wt)
4-Hydroxypyridine: Not Detected (By HPLC, Limit of Detection: 0.0015%wt/wt)
XRD pattern: As depicted in figure 1.
Dated this (3'*) day of March, 201 1
(Signed) V . S I ~
Dr. B.V. Siva Kumar
Chief Scientific Officer
(Enaltec Labs Private Limited)
WE CLAIM:
1. A process for the preparation of Fampridine compound of formula I comprising the steps
of:
(a) nitrifying pyridine-N-oxide hydrochloride compound of structural formula I1 with
suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural
formula I11 and
Formula I1 Formula I11
(b) reducing 4-nitro pyridine-N-oxide compound of structural formula I11 with suitable
reducing agent to obtain crude fampridine compound of structural formula I.
Formula I11 Formula I
2. A process for the preparation of substantially pure crystalline fampridine compound of
structural formula I comprising the steps of:
(a) nitrifying pyridine-N-oxide hydrochloride compound of structural formula I1 with
suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural
formula 111,
Formula I1 Formula 111
(b) reducing 4-nitro pyridine-N-oxide compound of structural formula 111 with suitable
reducing agent to obtain crude fampridine compound of structural formula I and
Formula 111 Formula I
(c) purifying crude fampridine compound of structural formula I by recrystallizing in
water followed by treating with an alkyl acetate solvent.
3. The process according to claim no. 1 or 2, wherein nitration of pyridine-N-oxide
hydrochloride compound of structural formula I1 is carried out by a mixture of sulfuric acid
and fuming nitric acid at a temperature in the range of 60°C to 125OC for 30 minutes to 4
hours in the absence of organic solvent.
4. The process according to claim no. 1 or 2, wherein reduction of 4-nitro pyridine-N-oxide
compound of structural formula 111 is carried out by hydrogenation in the presence of a
catalyst of the group consisting of palladium, nickel, platinum dioxide, platinum black or
rhodium in an alcoholic solvent such as methanol, ethanol, propanol, isopropanol, n-butanol,
2-butanol, or pentanol at a temperature in the range of 25°C to 35OC for 10 hours to 15 hours
and hydrogen pressure in the range of 10 p.s.i.g (pound-force per square inch gauge) to 40
p.s.i.g.
17
, 3 MAR 204%
5. The process according to claim no. 1 or 2, wherein crude fampridine compound of
structural formula I is further purified by active carbon treatment in aqueous solution
followed by the crystallization in an alkyl acetate solvent such as methyl acetate, ethyl
acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof.
6. A process for the preparation of substantially pure crystalline fampridine compound of
structural formula I comprising the steps of:
a. crystallizing crude fampridine compound of structural formula I in water;
b. treating fampridine obtained from step a with an alkyl acetate solvent and
c. isolating substantially pure crystalline fampridine compound of structural formula I.
7. The process according to claim no. 10, wherein crude fampridine compound of structural
formula I is crystallized in water at a temperature in the range of 60°C to 90°C for a period of
30 minutes to 4 hours and fampridine obtained form step a is treated with an alkyl acetate
solvent selected from the group comprising of methyl acetate, ethyl acetate, n-propyl acetate,
isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof at a temperature in
the range of 0°C to 25°C for a period of 30 minutes to 5 hours.
8. The process according to claim no 2 or 6 wherein substantially pure crystalline fampridine
compound of structural formula I having less than about 0.14 % wlw (By HPLC) of one or
more of following chemical impurities of structural formula IV, V, VI, VII and VIII.
Formula IV Formula V Fonnula VI Fonnula V11 Forniula Vlll
9. The process according to claim no 2 or 6 wherein substantially pure crystalline fampridine
compound of structural formula I is characterized by data selected from a group comprising
of powder X-ray diffraction pattern having peaks at 20.0, 20.1, 21.4, 24.3, 24.4, 29.2, 29.3,
33.1 -+ 0.2 degrees two-theta.
3 MAR 2041
10. The use of pyridine-N-oxide hydrochloride compound of structural formula I1 for the
preparation of crystalline fampridine compound of structural formula I.
Formula I1 Formula I
11. A process for the preparation of substantially pure crystalline fampridine compound of
structural formula I comprising crystallization of crude fampridine in water, alkyl acetate
solvent or mixture of water and alkyl acetate solvent.
12. A process for the preparation of substantially pure crystalline fampridine compound of
structural formula I comprising crystallization of crude fampridine in water.