2-AMINOPYRIMIDINE-5-BORONIC ACID, PINACOL ESTER

Light Beige Solid

3.5 g (20.1 mmol) of 5-bromopyrimidin-2-amine and 5.6 g (22.1 mmol) of bis (pinacolato) diboron and 5.9 g (60.3 mmol) of potassium acetate were dissolved in 35 ml of 1, 4- , And then 1.41 g (2.01 mmol) of bis (triphenylphosphine) palladium (II) dichloride was added thereto, followed by stirring at 110 ° C for 4 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate, and sonicated for 5 minutes. The resulting mixture was washed with celite-filled filter with ethyl acetate, filtered under reduced pressure, and the resulting filtrate was washed sequentially with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The obtained residue was dissolved in 100 ml of a mixed solvent of dichloromethane: hexane (1: 3 (volume ratio)) and stirred at room temperature for 1 hour. Washed and filtered under reduced pressure. The resulting solid was dried under reduced pressure to give 4 g (yield: 90percent) of the title compound.In the 500 ml round bottom flask in three adding 2 - amino -5 - bromo pyrimidine (10.44g, 60mmol), joint boric acidfrequency that alcohol ester (19.05g, 75mmol), acetonitrile 300 ml, potassium acetate (17.67g, 180mmol), Pd (dppf) Cl2.CH2Cl2 (2.45g, 3mmol). The mixture of the reaction bottle 85 °C stirring for 6.5 hours. TLC and HPLC to determine the completion of reaction. After the reaction, steaming and to remove the solvent, to obtain crude product, crude methylene chloride: hexane=1:3 beating, then ethyl acetate recrystallization to obtain the pure product 2 - amino pyrimidine -5 - boric acid frequency which ester borate, after drying, calculating yield 80percent, purity 99.45percent (HPLC).0236] To a dry 500-mL flask was added 2-amino-5-bromopyrimidine (10 g, 57.5 mmol), potassium acetate (16.9 g, 172 mmol), 4, 4, 5, 5-tetrarnethyl-2-(4, 4, 5, 5- tetramethyl-l, 3, 2-dioxaborolan-2yl)-l, 3, 2-dioxaborolane (16.1 g, 63.0 mmol) and dioxane (30O mL). Argon was bubbled through the solution for 15 minutes, at which time dichloro[l, r-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (Pd(dppf)ClMethod 1 [0079] S idine-2-ylamine[0080] To a dry 500-mL flask was added 2-amino-5-bromopyrimidine (10 g, 57.5 mmol), potassium acetate (16.9 g, 172 mmol), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2yl)-l , 3, 2-dioxaborolane (16.1 g, 63.0 mmol) and dioxane (300 mL). Argon was bubbled through the solution for 15 minutes, at which time dichloro[l, l'- bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (Pd(dppf)Cl2 CH2CI2) (2.34 g, 2.87 mmol) was added. The reaction mixture was refluxed in a 115 °C oil bath for 4 hours under argon. After cooling to room temperature, EtOAc (500 mL) was added and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organic extracts were washed with HTo a mixture of 5-bromopyrimidin-2-amine (500 mg, 2.9 mmol, 1 .0 eq), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi(1, 3, 2-dioxaborolane) (1.47 g, 5.8 mmol, 2.0 eq) in dioxane (20 mL) were added KOAc (865 mg, 8.7 mmol, 0.1 eq) and Pd(dppf)CITo a mixture of 5-bromopyrimidin-2-amine (500 mg, 2.87 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi(l, 3, 2-dioxaborolane) (802 mg, 3.16 mmol), and potassium acetate (844 mg, 8.61 mmol) in dioxane (20 mL) was added [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (117 mg, 0.14 mmol). The reaction mixture was flushed thoroughly with argon and heated in a sealed tube at 110 °C for overnight. After cooled to rt, the reaction mixture was diluted with EtOAc (60 mL) and filtered through a Celite plug. The filtrate was washed sequentially with water and brine. The organic layer was separated, dried over MgSC , filtered through a short silica gel plug. The filtrate was concentrated under reduced pressure. The residue was sonicated with DCM/hexane (1 :3, 6 mL), the precipitate was collected through filtration, and dried to afford 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyrimidin-2-amine (441 mg, 69percent) as a white solid. LC-MS (ESI) m/z 222 (M + H)Bromo-pyrimidin-2-amine (3.48 g, 20 mmol) was dissolved in 100 mL dioxane, 4, 4, 4 ', 4', 5, 5, 5 ', 5'-octamethyl-2, 2'-bis (1, 3, 2-dioxaborolane) (7.62 g, 30 mmol ), [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (500 mg, 2 mmol) and potassium acetate (3.91 g, 40 mmol)Argon replacement three times, And reacted at 85 ° C for 12 hours.filter, The filtrate was concentrated under reduced pressure, The resulting residue was beaten with petroleum ether, The crude title product, 5- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane) pyrimidin-2-amine Ib (5.4 g, white solid) was obtained.A mixture of 212.3 g (1.22 mole) 5-bromo-pyrimidin-2-ylamin, 211.8 g (1.16 mole) benzophenone and 11.1 g (58.2 mmole) p-toluenesulfonic acid in 1000 g toluene is heated to boiling for 24 h under reflux, whereby the generated water is removed. Eventually obtained solid substance is filtered, the filtrate is distillatively freed from toluene. Crystallization of the residue is initiated by slow addition of methanol in the cold. The crystals are sucked off, washed with toluene and dried under vacuum. The thereby prepared solid is the protected amine benzhydryliden-(5-bromo-pyrimidin-2-yl)-amine.Yield: 286.5 g (0.847 mole, 73percent).25.0 g (73.9 mmole) benzhydryliden-(5-bromo-pyrimidin-2-yl)-amine are dissolved in 185 g dry THF and cooled to -78° C. At this temperature 22.1 g (81.3 mmole) of 2.5 M n-butyllithium solution in hexane is slowly added. The mixture is continually stirred for 60 min and then cooled to -85° C. 9.25 g (88.7 mmole) of trimethylborate are slowly added. The mixture is again stirred for 60 min, then left to warm up to -10° C. and then poured into a prepared solution of 12.0 g of 96percent sulphuric acid in 166 g water covered with a layer of 65 g toluene. The mixture is intensively stirred for one hour. After completion of phase separation the aqueous phase is covered with a layer of 249 g of fresh toluene and 10.5 9 (88.7 mmole) pinacol are added. By adding 68.9 g of 10percent sodium hydroxide solution a pH-value of about 8.5 is set. The mixture is stirred intensely for 12 h, then again phase separation takes place. From the organic phase the bulk of the solvent is removed at 100-150 mbar. The residue is cooled to -5° C. The thereby obtained solid substance is sucked off, washed and dried under vacuum. Thus, colorless crystals of (2-aminopyrimidin-5-yl)-boronic acid pinacol ester are obtained.Yield: 12.1 g (54.7 mmole, 74percent).Yield over all steps: 54percent.In a 100 mL autoclave, 12.1 g (50 mmol) of 2-chloropyrimidine-5-boronic acid pinacol ester obtained in the second step was added to 22.5 g of 28percent aqueous ammonia (180 mmol). 100°C sealed reaction for 6 hours. After the solution was dried, 150 mL of ethyl acetate was added to dissolve it. After evaporation of the solvent again, recrystallization from methanol gave 8.6 g of 2-aminopyrimidine-5-boronic acid pinacol ester as a white crystalline solid, yield 78percent.

2-Aminopyrimidine-5-boronic Acid Pinacol Ester is used in the preparation of phosphoinositide-3-kinases (PI3K) inhibitors.

Molecular Weight:221.07
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:221.1335569
Monoisotopic Mass:221.1335569
Topological Polar Surface Area:70.3
Heavy Atom Count:16
Complexity:249
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes