Water → 4-Hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

Temperature

-40 °C

To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430 mL) at −78° C. was added a solution of diethyl 2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) prepared by the procedure described in Example 168 (step B) in THF (10 mL). The resulting mixture was slowly warmed to −40° C. over 1 hour and stirred for 1.5 hours at −40° C. To the −40° C. reaction mixture was added water (500 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the THF. The resulting aqueous mixture was quenched with 6 N aqueous HCl at 0° C., and acidified to pH 1 to 2. The resulting mixture was stirred for 16 hours at room temperature. The precipitates were filtered off and triturated with CH2Cl2 to afford 7.21 g (47%) of the desired product. The filtrate was extracted with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 3.56 g (23%) of additional desired product. The aqueous layer was extracted again with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 1.32 g (9%) of additional desired product. A total of 12.09 g (79%) of the desired product was obtained.

1. customprepared by the procedure
2. customTo the −40° C. reaction mixture
3. temperatureThe reaction mixture was warmed to room temperature
4. stirringstirred for 3 hours
5. concentrationThe reaction mixture was concentrated under reduced pressure
6. customto remove the THF
7. customThe resulting aqueous mixture was quenched with 6 N aqueous HCl at 0° C.
8. stirringThe resulting mixture was stirred for 16 hours at room temperature
9. filtrationThe precipitates were filtered off
10. customtriturated with CH2Cl2

ORD record

ord-0bbb8004aac04875b7973e5ce61afa2c

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08101611B2