Water → HCID 86710002, compound

HRID 537281Notes

Reaction equation

HRID 537281 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47](OC)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[N:20]1)[CH3:18].O>O1CCCC1>[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47]([C:2]4[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=4)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:25])=[O:26])[CH:21]=[N:20]1)[CH3:18]

Participants

6

Reactant 4

HCID 962WaterHCID 27815432-Bromo-4-(trifluoromethyl)pyridineHCID 86710003HCID 86710003, compoundHCID 178418339Butyllithium

Product 1

HCID 86710002HCID 86710002, compoundYield 8.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

2-Bromo-4-(trifluoromethyl)pyridine (171 μl, 1.382 mmol) in dry tetrahydrofuran (1 mL) was added to butyllithium (2.5 M in Hexanes) (885 μl, 1.416 mmol) in dry tetrahydrofuran (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes, then a solution of (R)-methyl 6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (220 mg, 0.453 mmol) in dry tetrahydrofuran (2 mL) was added dropwise and the reaction mixture stirred for 1 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (2×15 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) and preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-70% acetonitrile in water) to afford (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (23 mg) as a white solid. LCMS (Method F, ES-API): RT 3.00 min, m+H=601.2; 1H NMR (400 MHz, CDCl3): δ 8.88-8.87 (1H, m), 8.15 (1H, m), 7.71-7.69 (2H, m), 7.67 (1H, d, J=0.6 Hz), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.44 (1H, dd, J=12.0, 2.0 Hz), 4.22-4.16 (3H, m), 3.80-3.76 (1H, m), 2.94 (1H, d, J=16.9 Hz), 2.88-2.79 (1H, m), 2.67 (1H, d, J=12.3 Hz), 2.52-2.40 (2H, m), 1.51 (3H, t, J=7.3 Hz).

Workup

  1. stirringthe reaction mixture stirred for 1 hour at −78° C
  2. stirringthe reaction mixture was stirred at room temperature for 10 minutes
  3. extractionThe aqueous phase was extracted with ethyl acetate (2×15 mL)
  4. washthe combined organic layers were washed with brine (20 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give an orange oil
  9. customThe crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) and preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-70% acetonitrile in water)

Sources & evidence

ORD record
ord-e155618bc02a4426ab85c87d6a73e0c9
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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