Sulfuric Acid → HCID 178504787, compound

Temperature

107.5 °C

To a one liter, bottom discharge jacketed glass reactor equipped with overhead agitation, reflux condenser and nitrogen blanket bubbler was added (2-fluoro-4-methanesulfonyl-phenyl)-hydrazine (50.0 g, 0.244 mol) with the aid of methanol (200 mL, 4 vol Eq.). The resulting reaction mixture was a light slurry and subsequently cooled to −5° C. In a separate vessel was made a suspension of ethoxymethylene malononitrile (EMM) (32.9 g, 0.270 mol) in methanol (205 mL, 4.1 Vol. Eq.). The resulting EMM/MeOH suspension was added dropwise to the reaction containing (2-fluoro-4-methanesulfonyl-phenyl)-hydrazine at a rate that maintains the reaction temperature at about −5C. The reaction mixture was then held at about −5° C. until all of the starting material ((2-fluoro-4-methanesulfonyl-phenyl)-hydrazine) was consumed, typically about 2-4 hrs. The resulting reaction mixture was heated to reflux for about 2-4 hours until complete conversion to intermediate 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile (shown in bracket above) is greater then 99%. The reaction mixture was then stripped to near dryness under full house vacuum (<20 torr) with a maximum jacket temperature of 65° C. to afford a soft orange solid. The solid was then dissolved in formic acid (250 mL, 5 Vol. Eq.) and sulfuric acid (24.0 g, 0.245 mol) yielding a dark red transparent solution. The solution was heated to reflux (105-110° C.) and held until reaction was complete (about 4-5 hrs). The addition of sulfuric acid showed nearly complete conversion of intermediate 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile to another intermediate 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylic acid amide as well as the title compound in one hour with no unknown intermediate (m/z 327 (m+H)+ present. The disappearance of 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylic acid amide and appearance of the title compound was then followed until the reaction was complete. After the reaction was complete, the reaction mixture was cooled to 65° C. and water (100 mL, 2 Vol Eq.) was slowly added to aid in product precipitation. Water was added slowly as it was slightly exothermic, also rapid addition will make reaction mixture very thick. Slower addition maintains reaction stirrability. Higher temperature additions may alleviate any stirring problems. The reaction was allowed to stir for 1-2 hrs at 20-25° C. and was filtered. Filtration was quite rapid. Cooling to 0-5° C. may aid in additional yield. The cake was washed with water (2×100 mL) followed by sodium bicarbonate (aqueous 5%, 1×150 mL) to neutralize residual acid. Cake was again washed with water (1×150 mL) and dried overnight, 65° C., full house vacuum (<20 torr) to afford 67.4 grams of dried light tan/white of the title compound @ about 100.0% HPLC purity. The overall molar yield was 89.2%.

1. temperatureThe solution was heated
2. customheld until reaction
3. custom(about 4-5 hrs)

ORD record

ord-4e2dcfac293544d280e902cc33128f69

Source dataset

uspto-grants-2008_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07425630B2