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

HRID 1483004Notes

Reaction equation

HRID 1483004 reaction equation
[CH:1]1([C:4]2[C:9]([C:10](OC)=[O:11])=[CH:8][N:7]=[C:6]([N:14]3[CH2:19][CH2:18][N:17]4[C:20]5[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([C:31](OC)=[O:32])=[CH:23][C:21]=5[N:22]=[C:16]4[C@H:15]3[CH:35]([CH3:37])[CH3:36])[N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([N:14]3[CH2:19][CH2:18][N:17]4[C:20]5[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([CH2:31][OH:32])=[CH:23][C:21]=5[N:22]=[C:16]4[C@H:15]3[CH:35]([CH3:37])[CH3:36])[N:5]=2)[CH2:2][CH2:3]1.[CH:1]1([C:4]2[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([N:14]3[CH2:19][CH2:18][N:17]4[C:20]5[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([CH2:31][OH:32])=[CH:23][C:21]=5[N:22]=[C:16]4[C@@H:15]3[CH:35]([CH3:37])[CH3:36])[N:5]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 3

HCID 14487Diisobutylaluminum hydrideHCID 25517Ammonium ChlorideHCID 89816093(R)-methyl 2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate

Product 2

HCID 71736793(R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanolYield 24.5%HCID 71736794(S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanolYield 15.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of (R)-methyl 2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (50 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added DIBAL H (1M in toluene, 1 mL, 1 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h and then rt for 1 h. Sat. NH4Cl solution (5 mL) was added slowly at 0° C. and the mixture was filtered. The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC and then SFC separation to afford (R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol (11.50 mg, 24.5% yield, isomer 1) as a colorless oil and (S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol (7.10 mg, 15.1% yield, isomer 2) as a colorless oil.

Workup

  1. waitrt for 1 h
  2. filtrationthe mixture was filtered
  3. extractionThe aqueous layer was extracted with EtOAc (3×5 mL)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified by preparative TLC
  9. customSFC separation

Sources & evidence

ORD record
ord-3a44dd885125483abd3f8118be8ba3b7
Source dataset
uspto-grants-2016_08
Patent number
US09416135B2

Reaction notes

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