3-METHYL-4-PHENYLISOXAZOLO[3,4-D]PYRIDAZIN-7(6H)-ONE synthesis

Yield:17334-68-8 84.9%

Reaction Conditions:

with hydrazine in methanol;water at 0 - 40; for 5.25 h;Product distribution / selectivity;

Steps:

1; 3

EXAMPLE 12Og (0,123 mol) of 1-phenylbutane-1 ,3-dιone and 4OmL methanol are introduced under nitrogen atmosphere, into a four-necked flask fitted with mechanical stirrer and addition funnel and the suspension is cooled down to 10-15⁰C 24 4g of a 30% solution of sodium methoxide in methanol are added dropwise over 30mιn at 10-15⁰C The addition funnel is washed with 2mL of methanolThe reaction mixture is stirred at 10-15⁰C for about 30mιn and then cooled to 0-5⁰C A solution of 20 5g (0, 135 mol) of ethyl-2-chloro-2-(hydroxyιmιno)acetate in 4OmL MeOH is added dropwise over 1 h to the reaction mixture at 0-5⁰C, the addition funnel is washed with 2mL methanolThe reaction mixture is then warmed to 20-25°C and stirred for 2h Without any isolation or purification step, 7 4g (0,148 mol) NH₂NH₂ H₂O are then added dropwise over 15mιn at 40°C the addition funnel is washed with 2mL of methanol and the reaction mixture is stirred at 4O⁰C for 4h then cooled to 20-25°CFinally 6OmL of water are added and the reaction mixture is stirred for 1 h at 20-25⁰C then 30mιn at 0-5⁰CThe resulting mixture is filtered, the resulting solid is washed with 2x40mL cold MeOH/H₂O 1 1 and vacuum dried at 40°C overnight Yielding 22,5 g (0,099 mol) of 3- methyl-4-phenylιsoxazolo[3,4-d]pyrιdazιn-7(6H)-one (yield = 80,5%); COMPARATIVE EXAMPLE 3 The 262,86 g of impure oil from Comparative example 2 were dissolved in 550 ml of methanol, warmed to 20-25⁰C and stirred for 2h 78,12 g (1 ,56 mol) of NH₂NH₂ H₂O are then added dropwise over 15mιn at 4O⁰C, the addition funnel is washed with 2OmL of methanol and the reaction mixture is stirred at 4O⁰C for 4h then cooled to 20-25⁰CFinally 48OmL of water are added and the reaction mixture is stirred for 1h at 20-25⁰C then 30mι? at 0-5⁰CThe resulting mixture is filtered, the resulting solid is washed with 2x40mL cold MeOH/H₂O 1 1 and vacuum dried at 40°C overnight Yielding 168,2 g (0,740 mol) of 3- methyl-4-phenylιsoxazolo[3,4-d]pyrιdazιn-7(6H)-one (yield = 84,9%) HPLC-MS(+/-)= 228 MS-FIA= 228After cooling with an ice bath, a precipitate was formed and collected by filtration and washed with some pre-cooled alcoholic solventsThe combined yield of comparative examples 2 and 3 representing the yield of manufacturing 3-methyl-4-phenylιsoxazolo[3,4-d]py?dazιn-7(6H)-one in a two step reacting with isolation of the intermediate ethyl 4-benzoyl-5-methylιsoxazole-3-carboxylate is 74,0% (87,1 % X 84,9%)

References:

WO2008/107064,2008,A1 Location in patent:Page/Page column 6; 7