* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Add methylsulfonic acid (0.131 ml, 0.393 mmol) into the isopropanol solution of N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (204 mg, 0.393 mmol) and stir the solution at room temperature for 3 h to obtain a white precipitate, filter the slurry and wash it with ethyl ether to obtain N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazo-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide methanesulfonate, which is a white crystals (221 mg, 87percent yield). 1HNMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H) 7.92-8.05 (m, 1H), 7.56-7.72 (m, 1H), 6.91-7.50 (m, 7H), 5.83-5.98 (m, 1H), 2.18-2.32 (m, 3H), 1.36 (s, 9H). j0114] The X-ray powder diffraction pattern of the obtained crystals as shown in FIG. 10 is consistent with that mentioned in the patent documents W02009/137391 or CN200980126781 .6.10115] The DSC thermogram is shown in FIG. 11: the melting range of the Known Crystal Form I is 247° C.250°C.10116] The TGA thermogram is shown in FIG. 12: the decomposition temperature is 261° C.
85.1%
at 20 - 60℃;
Method 5: Compound B (alternative mesylate salt embodiment) - A/-{3-[5-(2-amino-4- pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonateA/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 ml_). A pre-filtered solution of mesic acid (1 .1 eq., 5.02 mmol, 0.48 g) in H2O (0.75 eq., 1 .78 ml_) was added at 20°C. The temperature of the resulting mixture was raised to 50- 60°C while maintaining a low agitation speed. Once the mixture temperature reached to 50-60°C, a seed slurry of A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1 .0 percentw/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60°C for 2 hr. The mixture was then cooled to 0-5°C at 0.25°C/min and held at 0-5°C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filteredacetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50°C under vacuum, yielding 2.39 g (85.1 percent yield) of product.
85.1%
at 20 - 60℃;
N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 , 1-dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre-filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20°C. The temperature of the resulting mixture was raised to 50-60°C while maintaining a low agitation speed. Once the mixture temperature reached to 50- 60°C, a seed slurry of A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1-dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1.0 percentw/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60°C for 2 hr. The mixture was then cooled to 0-5°C at 0.25°C/min and held at 0-5°C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50°C under vacuum, yielding 2.39 g (85.1 percent yield) of product.
85.1%
at 50 - 60℃; for 2 h;
Method 5: Compound B (alternative mesylate salt embodiment) - N-{3-[5-(2- amino-4-pyrimidinyl)-2-(l, 1 -dimethyl ethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonate N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre-filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20°C. The temperature of the resulting mixture was raised to 50-60°C while maintaining a low agitation speed. Once the mixture temperature reached to 50- 60°C, a seed slurry of N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol- 4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1.0 percentw/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60°C for 2 hr. The mixture was then cooled to 0-5°C at 0.25°C/min and held at 0-5°C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50°C under vacuum, yielding 2.39 g (85.1percent yield) of product.
85.1%
at 20 - 60℃; for 2 h;
Method 5: Dabrafenib (alternative mesylate salt embodiment) - N-{3-[5-(2-amino-4- pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonate: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre- filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20 °C. The temperature of the resulting mixture was raised to 50-60 °C while maintaining a low agitation speed. Once the mixture temperature reached to 50-60 °C, a seed slurry of N-{3- [5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonate (1.0 percentw/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60 °C for 2 hr. The mixture was then cooled to 0-5°C at 0.25°C/min and held at 0-5 °C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50 °C under vacuum, yielding 2.39 g (85.1percent yield) of product.
Add methylsulfonic acid (0.131 ml, 0.393 mmol) into the isopropanol solution of <strong>[1195765-45-7]N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide</strong> (204 mg, 0.393 mmol) and stir the solution at room temperature for 3 h to obtain a white precipitate, filter the slurry and wash it with ethyl ether to obtain N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazo-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide methanesulfonate, which is a white crystals (221 mg, 87% yield). 1HNMR (400 MHz, DMSO-d6) delta ppm 10.85 (s, 1H) 7.92-8.05 (m, 1H), 7.56-7.72 (m, 1H), 6.91-7.50 (m, 7H), 5.83-5.98 (m, 1H), 2.18-2.32 (m, 3H), 1.36 (s, 9H). j0114] The X-ray powder diffraction pattern of the obtained crystals as shown in FIG. 10 is consistent with that mentioned in the patent documents W02009/137391 or CN200980126781 .6.10115] The DSC thermogram is shown in FIG. 11: the melting range of the Known Crystal Form I is 247 C.250C.10116] The TGA thermogram is shown in FIG. 12: the decomposition temperature is 261 C.
85.1%
In water; acetonitrile; at 20 - 60℃;Product distribution / selectivity;
Method 5: Compound B (alternative mesylate salt embodiment) - A/-{3-[5-(2-amino-4- pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonateA/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}- 2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 ml_). A pre-filtered solution of mesic acid (1 .1 eq., 5.02 mmol, 0.48 g) in H2O (0.75 eq., 1 .78 ml_) was added at 20C. The temperature of the resulting mixture was raised to 50- 60C while maintaining a low agitation speed. Once the mixture temperature reached to 50-60C, a seed slurry of A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1 .0 %w/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60C for 2 hr. The mixture was then cooled to 0-5C at 0.25C/min and held at 0-5C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filteredacetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50C under vacuum, yielding 2.39 g (85.1 % yield) of product.
85.1%
In water; acetonitrile; at 20 - 60℃;
N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 , 1-dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre-filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20C. The temperature of the resulting mixture was raised to 50-60C while maintaining a low agitation speed. Once the mixture temperature reached to 50- 60C, a seed slurry of A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1-dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1.0 %w/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60C for 2 hr. The mixture was then cooled to 0-5C at 0.25C/min and held at 0-5C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50C under vacuum, yielding 2.39 g (85.1 % yield) of product.
85.1%
In water; acetonitrile; at 50 - 60℃; for 2.0h;
Method 5: Compound B (alternative mesylate salt embodiment) - N-{3-[5-(2- amino-4-pyrimidinyl)-2-(l, 1 -dimethyl ethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonate N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre-filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20C. The temperature of the resulting mixture was raised to 50-60C while maintaining a low agitation speed. Once the mixture temperature reached to 50- 60C, a seed slurry of N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol- 4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1.0 %w/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60C for 2 hr. The mixture was then cooled to 0-5C at 0.25C/min and held at 0-5C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50C under vacuum, yielding 2.39 g (85.1% yield) of product.
85.1%
In water; acetonitrile; at 20 - 60℃; for 2.0h;
Method 5: <strong>[1195765-45-7]Dabrafenib</strong> (alternative mesylate salt embodiment) - N-{3-[5-(2-amino-4- pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonate: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre- filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20 C. The temperature of the resulting mixture was raised to 50-60 C while maintaining a low agitation speed. Once the mixture temperature reached to 50-60 C, a seed slurry of N-{3- [5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide methanesulfonate (1.0 %w/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60 C for 2 hr. The mixture was then cooled to 0-5C at 0.25C/min and held at 0-5 C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50 C under vacuum, yielding 2.39 g (85.1% yield) of product.
83%
In isopropyl alcohol; at 20℃; for 3.0h;
To a solution of N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4- yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (204 mg, 0.393 mmol) in isopropanol (2 mL), methanesulfonic acid (0.131 mL, 0.393 mmol) was added and the solution was allowed to stir at room temperature for 3 hours. A white precipitate formed and the slurry was filtered and rinsed with diethyl ether to give the title product as a white crystalline solid (210 mg, 83% yield). ?H NIVIR (400 MHz, DMSO-d6) oe ppm 10.85 (s, 1 H) 7.92 - 8.05 (m, 1 H) 7.56 - 7.72 (m, 1 H) 6.91 -7.50 (m, 7H) 5.83-5.98 (m, 1 H)2.18 -2.32 (m, 3 H) 1.36(s, 9H). MS (ESI): 520.0[M+H].
N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.1%
In water; acetonitrile; at 50 - 60℃;
N- {3-[5-(2-amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide (as may be prepared according to example 58a) (2.37g, 4.56 mmol) was combined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). A pre-filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H20 (0.75 eq., 1.78 mL) was added at 20C. The temperature of the resulting mixture was raised to 50-60C while maintaining a low agitation speed. Once the mixture temperature reached to 50- 60C, a seed slurry of N-{3-[5-(2-amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol- 4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate (1.0 %w/w slurried in 0.2 vol of pre-filtered acetonitrile) was added, and the mixture was aged while agitating at a speed fast enough to keep solids from settling at 50-60C for 2 hr. The mixture was then cooled to 0-5C at 0.25C/min and held at 0-5C for at 6 hr. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50C under vacuum, yielding 2.39 g (85.1% yield) of product.
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