Lithium hydroxide, monohydrate → (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid

HRID 1521527Notes

Reaction equation

HRID 1521527 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([S:37]([CH3:40])(=[O:39])=[O:38])=[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]CC)=[O:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:36]=1)(=O)C.O[Li].O>CO.O>[OH:4][CH2:5][C:6]1[C:7]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[C:24]([C:31]([OH:33])=[O:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:36]=1.[OH:4][CH2:5][C:6]1[C:7]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[C:24]([C:31]([OH:33])=[O:32])=[CH:23][N:22]=4)[C@@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:36]=1

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 117935637(R)-ethyl 2-(8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

Product 2

HCID 71736481(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acidYield 40%HCID 71736482(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acidYield 7%

Reagents, catalysts & solvents 1

HCID 22242641Methanol--water (1/1)Solvent

Procedure

(R)-ethyl 2-(8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (0.1 g, 0.17 mmol) in MeOH/H2O (5 mL/1 mL) was added LiOH H2O (86 mg, 2 mmol). The mixture was stirred at rt for 16 h. The excess methanol was removed by vacuum at 40° C. Water (5 ml) was added and the mixture was neutralized by 1N HCl at 0° C. slowly to pH=6. The aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give crude product. The crude product was purified by SFC to afford (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (34.50 mg, 40% yield, isomer 1) as a white solid and (S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (6.40 mg, 7% yield, isomer 2) as white solid.

Workup

  1. customThe excess methanol was removed by vacuum at 40° C
  2. additionWater (5 ml) was added
  3. customwas neutralized by 1N HCl at 0° C. slowly to pH=6
  4. extractionThe aqueous layer was extracted with CH2Cl2 (4×10 mL)
  5. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customto give crude product
  9. customThe crude product was purified by SFC

Sources & evidence

ORD record
ord-fa69bea27b0e45d7ae77d8b5c74aa2e9
Source dataset
uspto-grants-2015_07
Patent number
US09073931B2

Reaction notes

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