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AMORPHOUS 4-[4-[[4-CHLORO-3-(TRIFLUOROMETHYL) PHENYL]CARBAMOYLAMINO]PHENOXY]-N-METHYL-PYRIDINE-2-CARBOXAMIDE

IP.com Disclosure Number: IPCOM000177782D
Publication Date: 2008-Dec-31
Document File: 5 page(s) / 192K

Publishing Venue

The IP.com Prior Art Database

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    AMORPHOUS 4-[4-[[4-CHLORO-3-(TRIFLUOROMETHYL) PHENYL]CARBAMOYLAMINO]PHENOXY]-N-METHYL-PYRIDINE-2- CARBOXAMIDE

4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide (referred as SFB) base of the following formula:

NH

Cl

CF3

N

H

O

O

N

O NH

is an intermediate for SFB salts, such as SFB tosylate of the following formula:

NH

SO3H

.

Cl

CF3

N

H

O

O

N

O NH

SFB tosylate is marketed under the trade name Nexavar ® by Bayer for treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received "Fast Track" designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer).

An amorphous form was found and is described below.

Amorphous SFB base

The amorphous SFB base can be characterized by data selected from a group consisting of: A PXRD having broad hump and no distinct diffraction signals and by a solid-state 13C NMR spectrum having characteristic signals at about: a broad signal at 166.0 ppm and a broad signal at 121.6, and additional signals at 152.8, 149.1, 139.2, 135.9, 132.7, 114.2, and 110.6 ppm ± 0.2 ppm.

The amorphous SFB base can be further characterized by data selected from a group consisting of: a PXRD pattern depicted in Figure 1; a solid-state 13C-NMR spectrum depicted in Figure 2; a DSC thermogram having an exothermic peak at a temperature

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of about 115°C to about 130°C, and an endothermic peak at a temperature of about 210°C and a DSC thermogram depicted in Figure 3.

Amorphous SFB base, when prepared according to the process described in examples 1 and 2, can be further characterized by SFB base form 1 content of not more than about 15% by weight, preferably not more than about 10%, more preferably not more than 5%.

Generally, the detection of peaks of Form 1 in form A of SFB can be done by any method known to the skilled artisan. Such a detection can be done, for example by monitoring he absence or presence and intensity of a peak or a number of peaks from the following list of peaks at about 24.7 ± 0.2 degrees two theta at a scan rate slow enough, according to the common knowledge of the skilled in the

Fig.1 PXRD pattern of amorphous SFB base

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Figure 2: Solid state 13C-NMR spectrum of amorphous SFB base.

Sorafenib base, AJ 051207/A2, amorf, 13C RAMP/CP MAS, 11kHz.

198.04

166.09

152.79

149.12

139.17

135.94

132.65

121.64

14.18

10.55

78.59

69.45

61.65

47.99

30.66

26.27

8e+007

6e+007

4e+007

2e+007

0e+000

200

180

160

140

120

100

80

60

40

20

ppm

Sorafenib base, AJ 051207/A2, amorf, 13C RAMP/CP MAS, 11kHz.

198.04

166.09

152.79

149.12

139.17

135.94

132.65

121.64

14.18

10.55

8e+007

6e+007

4e+007

2e+007

0e+000

200

190

180

170

160

150

140

130

120

110

ppm

Figure 3: A DSC thermogram of amorphous SFB base.

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