2-Bromopyridine → (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

Alternative Procedure: 2-Bromopyridine (110.0 g, 690 mmole) as a solution in diethyl ether (200 mL) was added to a cooled (−65° C.) solution of 2.5 M n-BuLi (275 mL, 690 mmol) in diethyl ether (200 mL). The mixture was stirred for 1 h at −70° C. to −65° C. To this solution was then added a suspension of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (100.0 g, 230 mmol) in diethyl ether (1.0 L), keeping the temperature below −65° C. The resulting solution was stirred for 2 hours at −70° C. to −65° C. The reaction mixture was quenched with glacial acetic acid (50 mL) and diluted with water (200 mL). The organic layer was washed with 20% aqueous sodium chloride solution (250 mL), dried over magnesium sulphate and concentrated to give a yellow foam. The crude product was purified over silica gel (350 g, 240-400 mesh) by elution with heptane/ethyl acetate (8:1 to 2:1) to give (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (109.5 g) as a yellow foam.

1. additionTo this solution was then added
2. customthe temperature below −65° C
3. stirringThe resulting solution was stirred for 2 hours at −70° C. to −65° C
4. customThe reaction mixture was quenched with glacial acetic acid (50 mL)
5. additiondiluted with water (200 mL)
6. washThe organic layer was washed with 20% aqueous sodium chloride solution (250 mL)
7. dry with materialdried over magnesium sulphate
8. concentrationconcentrated
9. customto give a yellow foam
10. customThe crude product was purified over silica gel (350 g, 240-400 mesh) by elution with heptane/ethyl acetate (8:1 to 2:1)

ORD-Eintrag

ord-5eafe174ddda4f54a6276cebbde7160c

Quelldatensatz

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08859774B2