Crystalline forms of a jak inhibitor compound
A technology of crystallization and hydrate, which is applied in the field of crystalline forms of JAK inhibitor compounds, can solve the problem of forming highly unpredictable and unreported crystalline salt forms of compound 1
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[0113] The following synthetic and biological examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way. In the examples below, the following abbreviations have the following meanings unless otherwise indicated. Abbreviations not defined below have their generally accepted meanings.
[0114] CAN = acetonitrile
[0115] CPME = cyclopentyl methyl ether
[0116] DCM = dichloromethane
[0117] DIPEA= N,N-Diisopropylethylamine
[0118] DMAc = dimethylacetamide
[0119] DMF = N,N-Dimethylformamide
[0120] EtOAc = ethyl acetate
[0121] h = hour
[0122] IPAc = isopropyl acetate
[0123] KOAc = potassium acetate
[0124] MeOH = Methanol
[0125] MeTHF = 2-methyltetrahydrofuran
[0126] min= minute
[0127] MTBE = methyl tert-butyl ether
[0128] NMP = N-methyl-2-pyrrolidone
[0129] Pd(amphos) 2 Cl 2 = bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II)
[0130] Pd(dppf)Cl 2 ...
example 1
[0209] Example 1: 5-Ethyl-2-fluoro-4-(3-(5-(1-methylpiperidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol hydrate
[0210]
[0211] To a 125 mL flask was added NMP (19.23 mL) and 5-ethyl-2-fluoro-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]pyridin-2-yl)-lH-indazol-6-yl)phenol 2HCl (6 g, 13.32 mmol), followed by addition of NMP (19.23 mL). Acetic acid (2.52 mL) was added, followed by 1-methylpiperidin-4-one (3.28 mL, 26.6 mmol) in one portion, the reaction mixture was stirred at 25 °C for 30 min and cooled to 15 °C. Sodium triacetoxyborohydride (7.91 g, 37.3 mmol) was added and after 20 min the external jacket was set to 20°C. After 3.5 h, the total solution volume was 35 mL. The reactor was washed with methanol (5 mL). Add half of the solution (17.5 mL) and half of the methanol wash (2.5 mL) sequentially to a premixed solution of methanol (28 mL), ammonium hydroxide (17 mL, 270 mmol) and water (9 mL), keeping the temperature below 5 °C...
example 2
[0212] Example 2: 5-Ethyl-2-fluoro-4-(3-(5-(1-methylpiperidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol crystalline hydrate
[0213] To 5-ethyl-2-fluoro-4-(3-(5-(1-methylpiperidin-4-yl)-4,5,6,7-tetrahydro-1H prepared as in Example A - To a solution of imidazo[4,5-c]pyridin-2-yl)-lH-indazol-6-yl)phenol (10 g, 21.07 mmol) in DMSO (19.99 mL) was added ethanol (19.93 mL). Undissolved solids were removed by filtration, and half of the DMSO solution was added to a stirred solution of 20% water in methanol (30 mL). After 10 min a slurry formed which was stirred at RT for 4 h and filtered. The resulting yellow solid was dried under nitrogen at 50 °C for 3 h. The solid was slurried in 20% water in acetone (110 mL) at 45°C with stirring for 35 h, filtered, washed with 15% water in acetone, and dried overnight to give the title compound (4.40 g, 88% yield).
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