6-Chloro-N,N-dimethyl-3-pyridinecarboxamide

Scheme 32 : Synthesis of 6-Chloro-N, V-dimethylnicotinamide [198 ] Compound [197 ] (3.0 g, 19.0 mmol) was dissolved in THF ( 100 ml) in a clean oven-dried two necked RB flask (250ml) and degassed with nitrogen. To this clear solution, EDC.HCl (4.02 g, 20.9 mmol) was added, followed by NMM (2.3 ml, 20.9 mmol). The reaction mixture was stirred and heated at RT for 10 min, under nitrogen atmosphere. Me(1) 6-Chloro-N, N-dimethylnicotinamide To a solution of commercially available 6-chloronicotinic acid (1.58 g, 10.0 mmol) in THF(40 mL) were added triethylamine (2.09 mL, 15.0 mmol), 50percent dimethylamine (1.26 mL, 14.0 mmol), and 1-ethyl-3-[3-(N, N-dimethylamino)propyl]-carbodiimide hydrochloride (2.26 g, 11.0 mmol), and the mixture was stirred at room temperature for 15 hours. Chloroform was added to the reaction mixture. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 6-chloro-N, N-dimethylnicotinamide (1.33 g, 7.20 mmol).yield: 72percentA tetrahydrofuran solution (14.2 ml, 28.4 mmol) of 2M-N, N-dimethylamine was added to a methylene chloride solution (17 ml) of 6-chloronicotinyl chloride (1.00 g, 5.68 mmol), at 0°C, and stirring was carried out at room temperature overnight. The reaction solution was concentrated and the resulting residue was diluted with methylene chloride, followed by sequential washing with water and saline, and the resulting organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated and the resulting residue was purified by silica gel column chromatography to afford 6-chloro-N, N-dimethylnicotinamide (1.02 g, yield 97percent) as a pale red oil. Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 6- chloro-A/, A/-dimethylpyridine-3-carboxamide (2) (369mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 , 4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (200mg, 41 %). (0197) LCMS (ES): Found 244.1 [M+Hf.Step 1 : Intermediate 6- 6-(6-Fluoro-3-pyridyl)-N, N-dimethyl-pyridine-3-carboxamide . [0455] A mixture of General procedure: To a solution of 6- chloro-2-methoxypyridine-3-carboxylic acid (190 mg, 1.01 mmol) in N, N-dimethylformamide (2 mL) was added HATU (722 mg, 1.90 mmol), dimethylamine hydrochloride (165 mg, 2.03 mmol) and DIEA (614 mg, 4.75 mmol) at room temperature. The resulting mixture was stirred for 6 h at 35 C. When the reaction was done, the reaction mixture was diluted with H20 (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in EtOAc (0 % to 10 % gradient) to yield 6-chloro-2-methoxy-N, N-dimethylpyridine-3-carboxamide as an yellow oil (129 mg, 59 %). MS: m/z = 214.9 [M+H]+.The title compound was prepared from 5-(6-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile and 3, 3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 muiotaetaomicron, Eq: 1, WO2014/202493 Al) was combined with dimethylacetamide (2 ml). Potassium carbonate (109 mg, 790 muiotaetaomicron, Eq: 2.00) and Step 2. 6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-1-yl)-ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N, N-dimethylnicotinamide bis(trifluoroacetate) A mixture of 1-{1-[5-chloro-2-ethoxy-4-methyl-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine (15 mg, 0.032 mmol), Step 1 In a sealed vessel, compound [198 ] (2.0 g, 10.86 mmol) was heated with POCI3 ( 1 .98 ml, 21.73 mmol) at 120oC for 15 min. The mixture was cooled to RT. Compound [202] (0.335 g, 32.62 mmol) was added and mixture was stirred at RT for 12 hrs. The reaction Mixture was poured in ice. The precipitates formed were filtered, dried and crude was purified by column chromatography (silica 100-200 mesh, 5 % ethyl acetate/cyclohexane) to obtain compound [211 ] ( 1 .50 g, 53 %) as white solid. ESIMS: 261 (M++ 1 )

Molecular Weight:184.62
XLogP3:1.3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:184.0403406
Monoisotopic Mass:184.0403406
Topological Polar Surface Area:33.2
Heavy Atom Count:12
Complexity:172
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes