Processes for preparing (1 -(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidine-4-one)
A technology of piperidone and hydroxypiperidine, applied in the field of preparation of (1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-one), can solve uncontrollable bleeding , do not want and other issues
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[0039] The preparation of compounds may involve the protection and deprotection of a variety of chemical groups. The need for protecting and deprotecting groups and selection of appropriate protecting groups are readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th Edition, Wiley & Sons, 2007, which is hereby incorporated by reference in its entirety. Modifications of protecting groups and methods of formation and cleavage described herein can be tailored as desired for a variety of substituents.
[0040] The reactions of the methods described herein can be carried out in suitable solvents readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperatures at which the reactions are carried out, eg, may be at temperatures ra...
Embodiment 1
[0146] Example 1. Synthesis of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3- Fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (9)
[0147] Option I
[0148]
[0149]3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1 -yl) azetidine-1-carboxylic acid tert-butyl ester (3). To a 1 L flask equipped with a nitrogen inlet, a thermocouple and a mechanical stirrer was added sequentially isopropanol (IPA, 200 mL) at ambient temperature, 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8g, 64.4mmol, 0.125 equivalents), 4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)-1H-pyrazole (1,101 g, 520.51 mmol, 1.01 equiv) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate Ester (2, 100 g, 514.85 mmol), resulting in the reaction mixture as a suspension. The resulting reaction mixture was heated to reflux over 30 minutes to obtain a homogeneous solution and the mixture was maintained at reflux for an ...
Embodiment 2
[0154] Example 2: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro Alternative Synthesis of -2-(Trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile
[0155] Scheme II
[0156]
[0157] 2-(Azetidine-3-ylidene)acetonitrile hydrochloride (2a). To a 0.5 L flask equipped with nitrogen inlet, thermocouple and mechanical stirrer was added 3-(cyanomethylene base) tert-butyl azetidine-1-carboxylate (2, 30 g, 154.46 mmol) and dichloromethane (300 mL). The solution was then treated with 5M hydrogen chloride (HCl) in isopropanol (294.2 mL, 1.54 mol, 10 equiv) at ambient temperature and the resulting reaction mixture was stirred at ambient temperature for 18 hours. After the reaction was complete as monitored by HPLC, tert-butyl methyl ether (TBME, 150 mL) was added to the suspension, and the mixture was stirred at ambient temperature for 2 hours. The solid was collected by filtration, washed with n-heptane (2 x 100 mL), and dried on the ...
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