WO2011108009A2

WO2011108009A2 - Process for the preparation of fampridine

Info

Publication number: WO2011108009A2
Application number: PCT/IN2011/000134
Authority: WO
Inventors: Siva Kumar Venkata Bobba; Alok Pramod Tripathi; Eswara Rao Kodali; Girish Bansilal Patel; Sanjay Dashrath Vaidya
Original assignee: Enaltec Labs Pvt. Ltd.
Priority date: 2010-03-05
Filing date: 2011-03-03
Publication date: 2011-09-09
Also published as: WO2011108009A3

Abstract

The present invention relates to a process for the preparation of substantially pure fampridine compound of structural formula (I), (II), (III) comprising nitrifying pyridine-N-oxide hydrochloride with suitable nitrating agent; reducing with suitable reducing agent and purifying by recrystallizing in water followed by treating with an alkyl acetate solvent.

Description

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 II with suitable nitrating agent to obtain 4- nitro pyridine-N-oxide compound of structural formula III; reducing 4-nitro pyridine-N-oxide compound of structural formula III 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.

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.

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.

Scheme II

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.

Scheme III

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.l, 319,947 describes a process for the preparation of fampridine by subjecting the Hofmann degradation reaction of 4-pyridinecarboxamide in the presence of catalyst.

Scheme IV

Chinese Patent No.l, 31 1, 185 describes a process for the preparation of fampridine by reducing 4-nitro pyridine-N-oxide compound of formula III.

Formula III Formula I

Scheme V

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.

Organic Synthesis, Coll. Vol. 4, p. 828 (1963); Vol. 33, p. 79 (1953) describes pyridine-N- oxide hydrochloride compound of formula II.

Formula II

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 80-85 °C to obtain pyridine N-oxide; nitrifying with HN0₃/H₂S0₄ at 85-95°C, and reducing with H₂ 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.

4-Nitropyridine N-oxide 2-Aminopyridine 3-Aminopyridine 4-Hydroxypyridine piperidin-4-amine

Formula IV Formula V Formula VI Formula Vll Formula VIII

The prior art approach for the preparation of fampridine is not commercially viable pyridine-N-oxide compound, which is present in liquid state, gives inconsistent results terms of yield of the nitro pyridine-N-oxide compound of structural formula III.

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. 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 III and then reducing 4-nitro pyridine-N-oxide compound of structural formula III 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 III; reducing 4-nitro pyridine-N-oxide compound of structural formula III 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 III comprising crystallization of 4-nitro pyridine-N- oxide compound of structural formula III 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.

Formula II Formula II I Formula I

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.

4-Nitropyridine N-oxide 2-Aminopyridine 3-Aminopyridine 4-Hydrox} pyridine piperidin-4-amine

Formula IV Formula V Formula VI Formula VII Formula VIII

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.

Formula IV Formula V Formula VI Formula VII Formula VIII 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 II with suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural formula III and

Formula II

(b) reducing 4-nitro pyridine-N-oxide compound of structural formula III with suitable reducing agent to obtain fampridine compound of structural formula I.

O

Formula III 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 II with suitable nitrating agent to obtain 4-nitro pyridine-N-oxide compound of structural formula III,

Formula (b) reducing 4-nitro pyridine-N-oxide compound of structural formula III with suitable reducing agent to obtain crude fampridine compound of structural formula I and

Formula III 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 II 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 II, used in the invention may be present in solid state.

Nitration of pyridine-N-oxide hydrochloride compound of structural formula II may be carried out by a mixture of sulfuric acid and fuming nitric acid.

Nitration of pyridine-N-oxide hydrochloride compound of structural formula II may be carried out in the absence of organic solvent.

Nitration of pyridine-N-oxide hydrochloride compound of structural formula II may be carried out at a temperature in the range of 60°C to 125°C for 30 minutes to 4 hours.

4-Nitro pyridine-N-oxide compound of structural formula III 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, concentrating the organic layer under reduced pressure and precipitation with ketonic solvent at a temperature in the range of 10°C to 20°C. 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 III 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 III may be carried out in an alcoholic solvent.

The examples of alcoholic solvent may include methanol, ethanol, propanol, isopropanol, n- butanol, 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% w/w (By HPLC) of following chemical impurities of structural formula IV, V, VI, VII and VIII.

Formula IV Formula V Formula VI Formula VII Formula VIII

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 1 8 hours. The term "substantially pure crystalline fampridine compound of structural formula I" described herein refers to fampridine compound having 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.

4-Nitropyridine N-oxide 2-Aminopyridine 3-Aminopyridine 4-Hydroxypy ridinc piperidin-4-amine

Formula IV Formula V Formula VI Formula VII Formula VIII

The crystalline form of substantially pure fampridine 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.

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] d-spacing [A] Rel. Int. [%]

20.0767 22145.42 1807.07 4.41919 56.70

20.1890 37692.98 5126.25 4.39487 96.51

21.4846 10948.06 2382.30 4.13268 28.03

24.3697 20099.61 1640.13 3.64956 51.47

24.4925 39054.16 4249.09 3.63154 100.00

29.2756 23522.95 2559.30 3.04818 60.23

29.3713 11814.17 642.69 3.03846 30.25

33.1210 15852.41 1724.74. 2.70254 40.59 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.

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]: 51.0404 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

K- Alpha [A]: 1.54060

Generator Settings: 40 mA, 45 kV

Goniometer Radius [mm]: 240

Dist. Focus-Diverg.Slit [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 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-N- OXIDE 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 (1000 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 fampridine.

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: 0.0015%wt/wt)

3- Aminopyridine: Not Detected (By HPLC, Limit of Detection: 0.0015%wt/wt)

4- Hydroxypyridine: Not Detected (By HPLC, Limit of Detection: 0.0015%wt/wt)

XRD pattern: As depicted in figure 1.

Claims

WE CLAIM:

1. A process for the preparation of fampridine compound of formula I comprising the steps of:

Formula II

(b) reducing 4-nitro pyridine-N-oxide compound of structural formula III with suitable reducing agent to obtain crude fampridine compound of structural formula I.

Formula I

2. A process for the preparation of substantially pure crystalline fampridine compound of structural formula I comprising the steps of:

Formula II Formula III

(b) reducing 4-nitro pyridine-N-oxide compound of structural formula III with suitable reducing agent to obtain crude fampridine compound of structural formula I and

Formula III Formula I

3. The process according to claim no. 1 or 2, wherein nitration of pyridine-N-oxide hydrochloride compound of structural formula II is carried out by a mixture of sulfuric acid and fuming nitric acid at a temperature in the range of 60°C to 125°C 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 III 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 35°C 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.

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. 6 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 is dried at a temperature in the range of 45°C to 70°C under reduced pressure for a period of 4 hours tb 18 hours.

9. 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 % w/w (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 VII Formula VIII

10. The 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.

1 1. The substantially pure crystalline fampridine compound of structural formula I is characterized by X-ray powder diffraction pattern as depicted in Figure 1.

12. The use of pyridine-N-oxide hydrochloride compound of structural formula II for the preparation of crystalline fampridine compound of structural formula I.

Formula II Formula I

13. A pharmaceutical composition comprising crystalline form A of substantially pure fampridine compound of structural formula I and pharmaceutically acceptable carrier.

14. 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.

15. A process for the preparation of substantially pure crystalline fampridine compound of structural formula I comprising crystallization of crude fampridine in water.