6-BROMO-PYRAZOLO[1,5-A]PYRIMIDINE

Will V be non-material (15 · lg, lOOmmol)And the formula II is not material (8.3g, lOOmmol)Placed in a 250 ml round bottom flask, Add 120 ml of ethanol, Cooled to 0 ° C, add 12ml concentrated hydrochloric acid, return to room temperature, stirring 2h, The reaction precipitated a pale yellow solid. After direct filtration, the cake was washed with saturated NaHC03 solution and then washed with water.After drying, 17 g of the intermediate represented by formula VI was obtained. The yield of the intermediate represented by formula VI was calculated to be 86percent.The 3-aminopyrazole (2.0g, 23.9 mmol) and 20 mL of ethanol were added 100 mL three-neck flask, and stirred to dissolve, then 2-bromo-malonaldehyde (2.4 g, 16.0 mmol) was added in the flask. The system presents a reddish brown after the mixture was heated under reflux for 2 h. The reaction was cooled to room temperature and the organic solvent is evaporated to dryness. The residue was purified by column chromatography: gel (eluent petroleum ether / ethyl acetate). Pale yellow crystalline solid, yield: 30percent. At room temperature, 3-amino-1H-pyrazole (120 mmol, 10 g)A solution in 50 ml of anhydrous acetic acid was added dropwise to bromomalonaldehyde (120 mmol, 18.9 g)In a suspension of 50 mL of anhydrous acetic acid, The resulting brown solution was stirred at room temperature for 3 hours.Evaporating acetic acid under reduced pressure, Adding chloroform to the residue;The organic phase is saturated with NaHCO3 solution, Washed with brine and dried over sodium sulfate.After the column, the product was obtained (14g, 58percent).Synthesis of 4-[6-(4-Piperazin-l-ylphenyl)pyrazolo[l , 5-a]pyrimidin-3-yllquinoline hydrochloride salt (13 HCH; A mixture of 2-bromomalondialdehyde (1.5 g, 10 mmol) and lH-pyrazol-3- ylamine (4b, 0.83 g, 10 mmol) in a mixture of EtOH (15 mL) and acetic acid (5 mL) was heated at 80 °C for 1.5 h. The reaction mixture was concentrated and the resulting residue purified by column chromatography using hexane/EtOAc (5:1 ) to give 15a (1.15 g, 58percent yield) as light yellow crystals.Preparation 16-Bromo-pyrazolo[1 , 5-a]pyrimidine[00117] A solution of 3-amino-1 H-pyrazole (120 mmol, 10g) in 50ml of anhydrous acetic acid is added dropwise to a suspension of bromomalonaldehyde (120 mmol, 18.9 g) in 50 mL anhydrous acetic acid at room temperature. The resulting brown solution is stirred at room temperature for 3 hours, acetic acid is evaporated at reduced pressure and chloroform is added to the residue. The organic phase is washed with saturated solution of NaHCODissolve bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and 3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 ML) and reflux the resulting mixture under nitrogen for 2 h. Concentrate under reduced pressure. Dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad diatomaceous earth and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 50percent ethyl acetate/50percent hexane to obtain 365 mgs (11percent) of the subtitled compound as a light yellow solid. High Resolution Mass Spectrum: 197.9674 (M+1).A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3, 4-b]pyridine x80 (yield: 2.1 percent; LC-MS (MHTo a solution of l-(3-azetidinyl)-4-methyl-piperizine (3.00 g, 19.3 mmol) and 6- bromopyrazolo[l, 5-a]pyrimidine (4.59 g, 23.2 mmol) in dioxane (30.0 mL) was added XPhos (1.84 g, 3.86 mmol) and CS2CO3 (12.6 g, 38.7 mmol) at 25C. The mixture was degassed and purged with N2 (3x) after which Pd2(dba)3 (1.77 g, 1.93 mmol) was added and the mixture was degassed and repurged with N2. The mixture was stirred at 100C for 36 hrs until there was no more starting material detected by LC/MS. The reaction mixture was then diluted with MeOH (30.0 mL) and filtered after which the filter cake was washed with MeOH (50.0 mL). The combined the organic layers were concentrated under reduced pressure to give a residue which was redissolved with water (30.0 mL) and EtOAc (30.0 mL). The aqueous phase was extracted with EtOAc (30.0 mL) and the combined organic layers were washed with water (30.0 mL x 2). All aqueous layers were combined and extracted with CH2Cl2/MeOH (5/1, 50.0 mL x 3). The combined organic phases was washed with brine (30.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Dichloromethane/Methanol, gradient of 100/1 to 1/1) to afford compound 306 (1.50 g, 5.51 mmol, 28.5% yield) as a yellow solid.6-bromo-pyrazolo[1, 5-alpha]pyrimidine 30g and 2.5g palladium chloride, 21g of triethylamine was added to the jar, Add 100ml DMF, 400ml MeOH, Pressurized 8 atm plus CO reaction, After the reaction is completed, the methanol is added to the water and filtered.The filter cake was washed with a small amount of EA to give product (21 g, 74%).The intermediate of formula VI (30 mmOl, 5.9 g)And the substance of formula VII (30 mmol, 4.6 g)Was placed in a 250 ml round bottom flask equipped with a reflux condenser, potassium carbonate (90 mmol, 12.4 g) and Pd (PPh3) 4 (3 mmol, 3.3 g) were added, dioxane (90 ml) and water (30 ml ), Stirred under nitrogen for three times, heated under nitrogen to 110 C, stirred for 4 h, After completion of the reaction, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. The mixture was extracted with 100 ml of water and 100 ml of dichloromethane. The organic phase was separated and the aqueous phase was extracted with dichloromethane 50 ml chi 3 for 3 times. Dried over sodium sulfate, the solvent was removed by suction filtration, and the residue was purified by column chromatography with ethyl acetate / petroleum ether to give 5.5 g of a pale yellow product.The pale yellow product is an intermediate of formula III-1, The yield of the intermediate of formula III-1 was calculated to be 82%.

Molecular Weight:198.02
XLogP3:1
Hydrogen Bond Acceptor Count:2
Exact Mass:196.95886
Monoisotopic Mass:196.95886
Topological Polar Surface Area:30.2
Heavy Atom Count:10
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes