Lithium Hydroxide → (S)-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)ethanone

HRID 1482985Notes

Reaction equation

HRID 1482985 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:34]=1)(=O)C.[Li+].[OH-]>C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:34]=1.[OH:4][CH2:5][C:6]1[C:7]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=4)[C@@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:34]=1

Participants

6

Reactant 2

HCID 3939Lithium HydroxideHCID 89815881(R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate

Product 2

HCID 89815950(S)-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)ethanoneHCID 89816060(R)-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)ethanone

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate (100 mg, 0.181 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH (38 mg, 0.905 mmol). The mixture was stirred at rt for 10 min. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by basic preparative HPLC to afford the crude product (53.1 mg, 55.9% yield). The crude product was separated by SFC to afford (R)-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)ethanone (32.90 mg, isomer 1) as a white solid and (S)-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)ethanone (16.90 mg, isomer 2) as a white solid. Isomer 1: (R)-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)ethanone. Analytical chiral HPLC: tR=7.280 min in 15 min chromatography (Method: AS-H_5_5_40_2.35 ML). LC-MS m/z 512.1 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 9.00 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 6.11-6.07 (m, 1H), 5.49-5.32 (m, 1H), 5.10 (s, 2H), 4.54 (dd, J=3.6 Hz and 12.4 Hz, 1H), 4.24 (dt, J=4.8 and 12.0 Hz, 1H), 3.98-3.90 (m, 1H), 3.25 (s, 3H), 2.61-2.57 (m, 1H), 2.56 (s, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H). Isomer 2: (S)-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)ethanone Analytical chiral HPLC: tR=8.485 min in 15 min chromatography (Method: AS-H_5_5_40_2.35 ML). LC-MS m/z 512.1 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 9.00 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 6.12-6.08 (m, 1H), 5.48-5.31 (m, 1H), 5.11 (s, 2H), 4.56 (dd, J=3.6 Hz and 12.4 Hz, 1H), 4.24 (dt, J=4.8 and 12.0 Hz, 1H), 3.98-3.91 (m, 1H), 3.26 (s, 3H), 2.61-2.58 (m, 1H), 2.56 (s, 3H), 1.29 (d, J=6.0 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H).

Workup

  1. extractionThe mixture was extracted with EtOAc (3×10 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customThe residue was purified by basic preparative HPLC
  7. customto afford the crude product (53.1 mg, 55.9% yield)
  8. customThe crude product was separated by SFC

Sources & evidence

ORD record
ord-16479708774e45eba223dcf39d47ceae
Source dataset
uspto-grants-2016_08
Patent number
US09416135B2

Reaction notes

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