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1-amino-3-fluoropyridinium 2,4,6-trimethylbenzenesulfonate[ No CAS ]
[ 623-47-2 ]
[ 1352625-28-5 ]
[ 1352625-27-4 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h;Inert atmosphere;
Intermediate 4: Ethyl 6-fluoropyrazoloH ,5-alpyridine-3-carboxylate and Intermediate 5: Ethyl4-fluoropyrazoloH ,5-alpyridine-3-carboxylate Trifluoroacetic acid (10m L, 130mmol) was added to 1 , 1-dimethylethyl [(2,4,6- trimethylphenyl)sulfonyl]oxy}carbamate (4.138g, 13.12mmol) under nitrogen and the mixture stirred at ambient temperature for 2 hours and then poured onto ice water (100ml_). The mixture was stirred until the ice had melted when the resulting precipitate was collected by filtration and washed with water. This solid was dissolved in 1 ,2-dimethoxyethane (DME) (20ml_) and was dried over molecular sieves for 90 min and then filtered though a Celite cartridge washing through with more DME (2 x 10ml_). To the filtrate was added 3- fluoropyridine (1.338g, 13.78mmol) and the mixture stirred at ambient temperature for 65 hours and then evaporated in vacuo. The residue was triturated with diethyl ether (20m L) and the resulting solid collected by filtration, rinsed with diethyl ether, and dried to give 1- amino-3-fluoropyridinium 2, 4, 6-trimethylbenzenesulfonate as off-white solid (1.249g) which was used directly. This material (1.244g, 3.98mmol) was stirred with ethyl propiolate (0.509ml_, 4.98mmol) in DMSO (6ml_) under nitrogen at ambient temperature. A solution of potassium hydroxide (0.145g, 2.59mmol) and potassium carbonate (0.413g, 2.99mmol) in DMSO (6m L) was added in one charge and the mixture was stirred at ambient temperature for 4 hours and then washed with water (2 x 25ml_). The combined aqueous layers were re- extracted with ethyl acetate (2 x 25ml_) and the combined organic extracts were washed with brine (25ml_) and dried over sodium sulphate, filtered and evaporated to leave brown oil (809mg). This crude material was dissolved in dichloromethane and purified on a silica gel cartridge (50g) using a 0-25% ethyl acetate-cyclohexane gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the 6-fluoro isomer Intermediate 4 as an orange solid (125 mg) and 4-fluoro isomer Intermediate 5 as a brown oil (79 mg).Intermediate 4: LCMS (System B): tRET = 2.28 min; MH+ 209Intermediate 5: LCMS (System A): tRET = 2.14 min; MH+ 209
Intermediate 3: (2-(r4-(1 , 1-Dimethylethyl)-3-fluorophenyll oxy) ethvDamine hydrochlorideTo a stirred suspension of zirconium tetrachloride (3.12g, 13.38mmol) in anhydrous DCM (40ml_) at 0C was added anhydrous methyl-tert-butyl ether (1.6ml_, 13.43mmol) and the mixture stirred at 0C under a nitrogen atmosphere for 30 min. A solution of 3-fluorophenol (1.2ml_, 13.38mmol) in anhydrous DCM (10ml_) was then added drop wise over 5 min and the mixture was heated at 60C for 16 hours. Quenching with saturated aqueous sodium bicarbonate (50ml_) resulted in significant gas evolution and water (20ml_) and dichloromethane (20ml_) were then added. The organic phase was separated, dried using a hydrophobic frit and concentrated in vacuo to give a pink oil which rapidly darkened to purple/brown. This material was subjected to two sequential purifications on silica gel (100g cartridge) using a 0-25% ethyl acetate-cyclohexane gradient over 60 min to give crude 4-(1 , 1-dimethylethyl)-3-fluorophenol (198mg, purity ca 80%) as and an off-white solid. This material (190mg) was dissolved in anhydrous THF (7m L) and 1 , 1-dimethylethyl (2- hydroxyethyl)carbamate (273mg, 1.694mmol), di-isopropylazodicarboxylate (0.44ml_, 2.263mmol) and triphenylphosphine (593mg, 2.259mmol) were added and the mixture stirred at ambient temperature under an atmosphere of nitrogen for 20 hours.The reaction was concentrated in vacuo and the residue was dissolved in DCM (10m L) and washed successively with 2M aqueous sodium hydroxide (10ml_), water (10ml_) and dried (hydrophobic frit) and concentrated in vacuo to give yellow oil. This material was dissolved in DCM and purified on a silica cartridge (20g) using a 0-25% ethyl acetate-cyclohexane gradient over 40 min to give impure 1 , 1-dimethylethyl (2-[4-(1 , 1-dimethylethyl)-3- fluorophenyl]oxy}ethyl)carbamate as a colourless oil (95mg). This material (90mg, 0.289mmol) was dissolved in anhydrous 1 ,4-dioxane (2ml_) at ambient temperature and 4M HCI in 1 ,4 dioxane (1 ml_, 4.0mmol) was added in one charge and the mixture stirred at ambient temperature for 16 hours. Diethyl ether (10ml_) was added and the mixture stirred vigorously. The resultant precipitate was collected by filtration and dried in vacuo to give the title compound as a white solid (30 mg).LCMS (System A): tRET = 0.78 min; MH+ 212
Intermediate 6: 6-Fluoropyrazolori ,5-alpyridine-3-carboxylic acid To a solution of ethyl 6-fluoropyrazolo[1 ,5-a]pyridine-3-carboxylate (125mg, 0.6mmol) in THF (2ml_) stirred at 50C was added 2M sodium hydroxide (3ml_, 6mmol) and the mixture stirred at 50C for 22 hours. The reaction mixture was partitioned between DCM (5m L) and water (5ml_). 2M Hydrochloric acid (5ml_) and DCM (5ml_) was added, which resulted in the formation of a precipitate and unclear separation of the organic and aqueous layers. More DCM (100ml_) and water (100ml_) was added and the mixture was filtered to give the title compound as a white solid (8 mg).LCMS (System A): tRET = 0.59 min; MH+ 181Evaporation of the organic layer afforded a further quantity of the title compound (25mg). LCMS (System A): tRET = 0.58 min; MH+ 181
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;
4.1) 158 g Step 3.4) The obtained Compound 6 and 138 g of potassium carbonate were successively added to a solution of 50 g of ethyl propiolate in DMF, and stirred at room temperature for 3 days, and the mixture was partitioned between ethyl acetate and water;4.2) phase, after extraction the organic extracts were dried over anhydrous MgSO extracted with ethyl acetate step 4.1) in water4berecrystallized (ethyl acetate, toluene or petroleum ether), dried and evaporated, the remaining residue, separating, Washing and drying gave twoproducts, ethyl 6-fluoropyrazole [1,5-a]pyridine-3-carboxylic acid as a white solid, yield 36 g, 34%, ethyl 4-fluoropyrazole [1,5-a] pyridine-3-carboxylate was a white solid, yield 70 g, 61%.