Tetrahydrofuran → 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol

HRID 1501390Notes

Reaction equation

HRID 1501390 reaction equation
[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].C1COCC1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.O>[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:1])[CH2:3][CH2:4][OH:5]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 21225700DiisobutylaluminumhydrideHCID 57477580ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate

Product 1

HCID 574775823-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-olYield 96%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-10 °C

Procedure

To a solution of ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at −78° C. was added diisobutylaluminum hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction mixture was stirred for 3 hours during which time the reaction slowly warmed to −10° C. To the mixture at −10° C. was carefully added K/Na tartrate tetrahydrate in water. The mixture was stirred for 2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (185 mg, 96%), which was used without further purification. A portion of the alcohol so obtained (15 mg, 0.000037 mol) was stirred in TFA (1 mL) for 2 hours. The TFA was removed in vacuo and the residue was stirred with 2 mL MeOH containing 0.5 mL NH4OH for 16 hours. Volatiles were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol as the trifluoroacetate salt (8.0 mg, 57%). 1H NMR (300 MHz, d6-DMSO): δ 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H), 7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS (ES): 271 (M+1).

Workup

  1. customthe reaction
  2. customat −10° C.
  3. stirringThe mixture was stirred for 2 hours
  4. extractionwas extracted with three portions of ethyl acetate
  5. washThe combined organic extracts were washed with two portions of water and one portion of brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-509e11c8445c4d698498ba5b6e639ba1
Source dataset
uspto-grants-2015_12
Patent number
US09206187B2

Reaction notes

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