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

HRID 920624Notes

Reaction equation

HRID 920624 reaction equation
[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3[CH:27]=[C:28]4[C@:33]([C:35](OC)=[O:36])([CH2:34][C:25]=3[CH:24]=[N:23]2)[CH2:32][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:29]4)=[CH:18][CH:17]=1.O>CCOCC>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3[CH:27]=[C:28]4[C@:33]([C:35]([C:5]5[S:4][C:3]([Si:2]([CH3:9])([CH3:8])[CH3:1])=[N:7][CH:6]=5)=[O:36])([CH2:34][C:25]=3[CH:24]=[N:23]2)[CH2:32][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:29]4)=[CH:18][CH:17]=1

Participants

6

Reactant 4

HCID 962WaterHCID 5884532-TrimethylsilylthiazoleHCID 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 86709986(R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateYield 27.2%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent3×

Conditions

Temperature
-78 °C

Procedure

2-(Trimethylsilyl)thiazole (285 μl, 1.784 mmol) in dry ether (2 mL) was added to butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dry ether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. A solution 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 (250 mg, 0.585 mmol) in dry ether (6 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (88 mg) as a yellow solid. LCMS (Method F, ES-API): RT 2.38 min, m+H=481.2.

Workup

  1. stirringthe reaction mixture was stirred for 0.5 hour at −78° C
  2. stirringthe reaction mixture was stirred at room temperature for 10 minutes
  3. extractionThe aqueous layer was extracted with ethyl acetate (3×15 mL)
  4. washThe combined organic extracts were washed with brine (20 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give an orange solid
  9. customThe crude product was purified by chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane)

Sources & evidence

ORD record
ord-e4aa67d5773444989012434043288d66
Source dataset
uspto-grants-2016_03
Patent number
US09273047B2

Reaction notes

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