Diisobutylaluminum hydride → 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanol

HRID 1521523Notes

Reaction equation

HRID 1521523 reaction equation
[C:1]([C:4]1[C:5]([C:34]([F:37])([F:36])[F:35])=[N:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]3[C:16]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([C:27](OC)=[O:28])=[CH:19][C:17]=4[N:18]=[C:12]3[C@H:11]2[CH:31]([CH3:33])[CH3:32])=[N:8][CH:9]=1)(=[O:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl>[OH:28][CH2:27][C:20]1[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:16]2[N:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:6]=[C:5]([C:34]([F:37])([F:36])[F:35])[C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][N:8]=4)[CH:11]([CH:31]([CH3:32])[CH3:33])[C:12]3=[N:18][C:17]=2[CH:19]=1

Participants

5

Reactant 3

HCID 14487Diisobutylaluminum hydrideHCID 25517Ammonium ChlorideHCID 89815953(R)-methyl 2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate

Product 1

HCID 781644011-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanolYield 56.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a 50 mL three-necked flask containing (R)-methyl 2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (150 mg, 0.278 mmol) in DCM (3 mL) was added DIBAL-H (1.10 mL, 1.11 mmol, 1.0 M in toluene) dropwise at −78° C. under N2. The mixture was stirred at −78° C. for 3 h. Sat. NH4Cl solution (10 mL) was added at −78° C. and the mixture was filtered. The aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the racemic mixture (81.0 mg, 56.7% yield) as a white solid. The racemic mixture was purified by SFC separation to give isomer 1 (10.60 mg, 47.1% yield) as a white solid, isomer 2 (7.10 mg, 31.6% yield) as a white solid, isomer 3 (4.70 mg, 26.1% yield) as a white solid and isomer 4 (6.00 mg, 33.3% yield) as a white solid.

Workup

  1. filtrationthe mixture was filtered
  2. extractionThe aqueous layer was extracted with DCM (3×20 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by preparative TLC

Sources & evidence

ORD record
ord-945de0bb5163478d9425def6b8344298
Source dataset
uspto-grants-2015_07
Patent number
US09073931B2

Reaction notes

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