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

HRID 920615Notes

Reaction equation

HRID 920615 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([C:33](OC)=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([C:33](=[O:34])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1

Participants

5

Reactant 3

HCID 79732-BromopyridineHCID 583333606-O-tert-butyl 4a-O-methyl 1-(4-fluorophenyl)-4,5,7,8-tetrahydropyrazolo(3,4-g)isoquinoline-4a,6-dicarboxylateHCID 178418339Butyllithium

Product 1

HCID 86709979(R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateYield 100.3%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent3×

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-3ca940d507b5447e91c7be8bbdba280c
Source dataset
uspto-grants-2016_03
Patent number
US09273047B2

Reaction notes

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