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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 7: 4-Fluoropyrazolori ,5-alpyridine-3-carboxylic acidTo a solution of ethyl 4-fluoropyrazolo[1 ,5-a]pyridine-3-carboxylate (79mg, 0.379mmol) in THF (2ml_) stirred at ambient temperature was added 2M sodium hydroxide (1.897ml_, 3.79mmol) in one charge. The reaction mixture was stirred at 50C for 20 hours and then partitioned between DCM (5ml_) and water (5ml_). 2M HCI (5ml_) was added and the aqueous layer was extracted with ethyl acetate (5ml_). The organic extract was dried using a hydrophobic frit and evaporated in vacuo to give the title compound as a yellow solid (34 mg).LCMS (System A): tRET = 0.51 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%.
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