5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinamine

To a stirred 500 ml four-necked flask equipped with a thermometer and a condenser, 100 g of 1, 2-dichloroethane, 12.5 g (0.1 mol) of 2-amino-5-aminomethylpyridine (IV), 30.0 grams of potassium carbonate, A solution of 25.0 g (0.15 mol) of N, N-diethylethanamine and 20 g of 1, 2-dichloroethane was added dropwise between 30 and 35 ° C over a period of about 2 hours.After 30 ~ 35 °C for 6 hours. Cooled to 20 ~ 25 °C, layered, The aqueous layer was extracted twice with 1, 2-dichloroethane, 20 g each time, The organic phases were combined, 1, 2-dichloroethane was distilled off, To the residue was added 75 g of methyl tert-butyl ether, 0.5 g of activated charcoal, 80 ~ 82 ° C under stirring for 1 hour, filtered while hot, The filtrate is cooled to 0-5 ° C to crystallize, filtered, dried, 18.2 g of 5- (4-ethylpiperazin-1-yl) methyl-2-aminopyridine was obtained as a white solid in a yield of 82.7percent and a liquid phase purity of 99.3percent.NaHB(OAc)A solution of 1 - ((6-bromopyridin-3-yl) methyl) -4-ethylpiperazine (2.84 g, 10 mmol) prepared in the first step was added to the reaction flask, 2-dicyclohexylphosphinylbiphenyl (0.7 g, 2 mmol), Pd2 (dba) 3 (915 mg, 1 mmol) and anhydrous toluene (30 mL).The mixture was purged three times with nitrogen, LiHMDS (1 M in THF, 20 mL, 20 mmol) was added.The mixture was stirred at 80 ° C for 12 hours under a nitrogen atmosphere.Cool to room temperature, add water (50 mL), ethyl acetate (50 mL x 2).The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, Suction filter. The residue was purified by column chromatography (DCM / MeOH / Et3N = 10: 1: 0.5percent)The resulting residue was purified to give the title compound (1.34 g, brown solid) in 61percent yield.A solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (5.00g 17.70 mmol) prepared in the first step was added to the reaction flask, 2-dicyclohexylphosphinylbiphenyl (1.20 g, 3.54 mmol), PdThe above compound (6.98 g, 24.6 mmol, 1.0 eq.), cuprous oxide (97 mg, 1.23 mmol, 0.05 eq.) and methanol (10 ml) was dissolved in aqueous ammonia (30 ml), the reaction temperature was raised to 70 °C for 16 hours. Cooled and filtered, extracted with dichloromethane, concentrated under reduced pressure and purified by silica gel column chromatography give 5-((4-ethyl-piperidine-1-yl)methyl)pyridine-2-amine (2.0g, yield: 36.4percent).A solution of 1- (6-bromo-pyridin-3-ylmethyl) -4-ethyl-piperazine (960 mg, 3.38 mmol) in anhydrous tetrahydrofuran (8 mL)Was added 2- (dicyclohexylphosphino) biphenyl (120 mg, 0.338 mmol)Tris (dibenzylideneacetone) dipalladium (154 mg, 0.169 mmol).Lithium hexamethyldisilazide (4.06 mL, 1 M, 4.06 mmol) was slowly added under nitrogen.The reaction flask was heated to 65 ° C, After 20 minutes the reaction flask was cooled to room temperature, 50 mL of ethyl acetate was added, 30mL water, Mixed after the liquid, The aqueous layer was again added with 30 mL of ethyl acetate, Liquid separation, Combined organic layer, Dried over anhydrous sodium sulfate and evaporated to dryness as a pale brown solid.The product of formula V-1 (670 mg) was purified by column chromatography, As a pale yellow solid.A reaction flask was charged with 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.84 g, 10 mmol) preparedin Step 1, 2-(dicyclohexylphosphino)biphenyl (700mg, 2mmol), Pd2(dba)3 (915 mg, 1 mmol) and toluene (30 mL), LHMDS(1 N) (20 ml, 20 mmol) was added under the protection of nitrogen gas. The mixture was heated to 80°C and allowedto react overnight, then cooled to room temperature, filtered, concentrated and separated by column chromatography(DCM/MeOH = 100:1-10:1) to give 1.52 g of the titled product (brown solid). MS (ESI): mass calcd. for C13H21N3 220.2, m/z found 221.2 [M+H]+.2-Chloro-5-chloromethylpyridine (162 g, 1.0 mol), tap water 300 mL, and N-ethylpiperazine (171 g, 1.5 mol) were added to a 1 L reaction flask.Raise to 60-70 ° C, stir for 2 h, cool to room temperature, Potassium carbonate (138 g, 1.0 mol) was added and stirred for 10 minutes, the aqueous phase was separated, and dried to give 225 g of product, yield 94percent.Compound 8a (216 mg, 0.7 mmol), compound 12 (154 mg, 0.7 mmol), sodium carbonate (74 mg, 0.7 mmol), 4 5-bisdiphenylphosphino-9 9-dimethyloxanthene (Xantphos) , 121 mg, 0.21 mmol) dissolved in 1, 4-dioxane (20 mL), added with palladium acetate (16 mg, 0.07 mmol) under nitrogen atmosphere, reacted at 90 C for 10 hours, and the reaction solution was cooled to room temperature. into 50 mL of water, extracted three times with dichloromethane (30mL x3), the organic phases were combined, dried over anhydrous sodium sulfate filtered, and spin dry solid was recrystallized from ethyl acetate to give a yellow solid T-1 (150 mg, 44%) .Compound 9 (24.23 g, 110 mmol) and toluene (160 mL) were added to a three-neck flask. Stir well and cool to -5 to 0 C. Add hexamethylsilylamine lithium tetrahydrofuran solution (1.0 M, 120 mL, 120 mmol), After stirring at low temperature for 30 to 45 minutes, compound 5 (32.27 g, 100 mmol) was added dropwise. After the addition is completed, the temperature is raised to room temperature at 25 to 30 C for 10 to 16 hours. At the end of the reaction, saturated ammonium chloride (323 mL) was added. Extracted 3 times with ethyl acetate (160 mL). The organic phase was washed twice with saturated brine (160 mL). Dry over anhydrous sodium sulfate, After concentration, it was recrystallized from methylene chloride ethyl acetate mixture to afford compound 10 (43.57 g, 86%).Compound 10 (50.66 g, 100 mmol) was added to a three-necked flask. Add absolute ethanol (251 mL), After stirring and stirring, methanesulfonic acid (14.42 g, 150 mmol) was added. After the addition is completed, the temperature is raised to 50 to 55 C for 4 to 5 hours. The reaction was slowly cooled to 0 to 5 C for 1 hour. filter, The solid was washed with ethanol (50 mL). dry, The product Abemaciclib methanesulfonate 11 (56.65 g, 94%) was obtained.

Molecular Weight:220.31
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:220.16879665
Monoisotopic Mass:220.16879665
Topological Polar Surface Area:45.4
Heavy Atom Count:16
Complexity:201
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes