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A solution of ethyl 7-hydroxy-5-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate(4.4 g, 20 mmol) in POCI3(30 mL) was stirred at 95 °C for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and basified with sat. aHC03 solution (20 mL) to pH~7. The resulting mixture was separated, and the aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2S04and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give ethyl 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3- carboxylate (1.0 g, 21percent) as a white solid. LC-MS m/z: 239.0 [M+H , Purity (254 nm): >82percent, tR = 1.55 min.
A solution of ethyl 7-hydroxy-5-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate(4.4 g, 20 mmol) in POCI3(30 mL) was stirred at 95 C for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and basified with sat. aHC03 solution (20 mL) to pH~7. The resulting mixture was separated, and the aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2S04and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give ethyl 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3- carboxylate (1.0 g, 21%) as a white solid. LC-MS m/z: 239.0 [M+H , Purity (254 nm): >82%, tR = 1.55 min.
With N,N-dimethyl-aniline; trichlorophosphate; for 1.0h;Inert atmosphere; Reflux;
To a solution of ethyl 7-hydroxy-5-methylpyrazolo[ 1,5-al pyrimidine-3 -carboxylate (500 mg, 2.26 mmol) [CAS 58347-55-01 in POd3 (2 mL) under N2 was added N,N-dimethylaniline (0.29 mL, 2.26 mmol) dropwise. The mixture was heat to reflux, stirred for 1 h, and was recooled to RT. The mixture was poured onto ice and was extracted with CHC13 (3 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0-100% EtOAc/ethanol (3:1) in hexanes) to afford the title compound as a white solid. LC/MS (m/z): 240.0 (M+H).
With trichlorophosphate; at 95.0℃; for 1.0h;
A solution of ethyl 7-hydroxy-5-methylpyrazolo [1,5 -ajpyrimidine-3 -carboxylate (4.4 g, 20 mmol) in POd3 (30 mL) was stirred at 95 C for 1 h and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and basified with sat. NaHCO3 solution (20 mL) to pH7. The resulting mixture was separated, and the aqueous phase was extracted withEtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1:1) to give ethyl 7-chloro-5-methylpyrazolo[1,5-a]pynmidine-3-carboxylate (1.0 g, 21 /o) as a white solid. LC-MS m/z: 239.0 [M+H] , Punty (254 nm): >82%, tR= 1.55 mm.
7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With bis(tri-n-butyltin)oxide; In toluene; at 120.0℃; for 48.0h;
To a solution of ethyl 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18 mmol) in toluene (10 mL) was added (Bu3Sn)20 (5.0 g, 8.36 mmol). The reaction mixture was stirred at 120 C for 2 days, and concentrated in vacuo. The residue was dissolved in EtOAc (10 mL), and basified with sat. aHC03solution (10 mL) to pH~8-9. The aqueous phase was separated and acidified with 6N HC1 (10 mL) to pH~5. The solution was extracted with EtOAc (10 mL x 3). The organic phases were dried over anhydrous Na2S04, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (230 mg, 26%) as a white solid. LC-MS m/z: 211.0 [M+H]+, Purity (214 nm): >97%, tR= 1.23min.
230 mg
With bis(tri-n-butyltin)oxide; In toluene; at 120.0℃; for 48.0h;
To a solution of ethyl 7-chloro-5 -methylpyrazolo[ 1,5 -aj pyrimidine-3 -carboxylate (1.0 g, 4.18 mmol) in toluene (10 mL) was added (Bu3Sn)20 (5.0 g, 8.36 mmol). The reactionmixture was stirred at 120 C for 2 days, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc (10 mL), and basified with sat. NaHCO3 solution (10 mL) to pH8-9. The aqueous phase was separated and acidified with 6N HC1 (10 mL) to pH5. The solution was extracted with EtOAc (10 mL x 3). The organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EA; 1:1) to give 7-chloro-5-methylpyrazolo[1,5- ajpyrimidine-3-carboxylic acid (230 mg, 26%) as a white solid. LC-MS m/z: 211.0 [M+Hf?, Purity (214 nm): >97%, tR= 1.23mm.
1-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropan-1-amine hydrochloride[ No CAS ]
[ 58347-48-1 ]
ethyl 7-((1-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)amino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100.0℃; for 3.0h;Inert atmosphere;
To a solution of ethyl 7-chloro-5-methylpyrazolo[1,5-ajpyrimidine-3-carboxylate (100mg, 0.417 mmol) in NMP (2 mL) at RT under N2 was added 1-(3-fluoro-4-(trifluoromethyl)phenyl) cyclopropanamine hydrochloride (117 mg, 0.459 mmol) followed by dropwise addition of DIEA (0.22 mL, 1.25 mmol). The mixture was heated to 100 C, stirred for 3 h, and was cooled to RT.The mixture was diluted with EtOAc (50 mL) and washed with sat. aq. NH4C1 (2 x 30 mL) and brine (30 mL). The organic layer was dried over Na2504, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound as a solid. LC/MS (m/z): 423.1 (M+H).
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