Azide → HCID 86757877, compound

Participants

Reaction Conditions

Reaction Steps

A 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, addition funnel, nitrogen inlet, and steam pot, was charged with a solution of methyl (5S)-5-(3-fluorophenyl)-3-oxohept-6-enoate 8 (8823 g of solution, 1300 g of ketoester in 1,2-dichloroethane). Additional 1,2-dichloroethane (7 L) was charged to the flask, followed by 4-acetamidobenzenesulfonyl azide (1.25 kg). The solution was heated from about 18° C. to 21° C. with steam. (Note: the dissolution of azide was endothermic.) Triethylamine (2.17 L) was added over 40 min with water bath cooling to maintain a temperature of 19-23° C. The reaction was stirred at 18-23° C. for approximately 9 h. The reaction was mildly exothermic. The reagent product, 4-acetamidobenzenesulfonyl amide, began to precipitate from the reaction during the addition of triethylamine and eventually formed a thick slurry. The reaction was followed by HPLC and was judged complete when the amount of starting material was <0.5%. When completed, the reaction mixture was filtered, and the cake was washed four times with 1,2-dichloroethane (3×2 L displacement washes, 1×1 L slurry wash). The filtrate and washes were combined and extracted with cold (5-10 C) 2N HCl (7.4 L). The extraction was exothermic and was done in a 50 L extractor with cooling to maintain a temperature of 20-22° C. The pH of the aqueous phase was 1.0. The organic layer was extracted twice with water (2×7 L). The organic extract was charged to a 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, nitrogen inlet, and stopper. The solution was dried for 4 h with sodium sulfate (1 kg). The organic solution was passed through a 5 μ inline filter. The final weight of organic solution was 25.6 kg. Final yield of 9 was >95%.

Provenance & Evidence