Methanol → 2-(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)propan-2-ol

HRID 1482987Notes

Reaction equation

HRID 1482987 reaction equation
C[O:2][C:3]([C:5]1[C:6]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:22][N:21]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:34]=1)=O.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[OH:2][CH2:3][C:5]1[C:6]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:22][N:21]=4)[CH:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:34]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 14487Diisobutylaluminum hydrideHCID 89816015(R)-methyl-2-(5-(2-hydroxypropan-2-yl)-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 781643372-(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)propan-2-olYield 68.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-10 °C

Procedure

To a solution of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (109 mg, 0.196 mmol) in DCM (4 mL) was added a solution of DIBAL-H in DCM (0.98 mL of a 1.0 M solution, 0.98 mmol) dropwise at −78° C. The reaction slowly warmed to −10° C. over approximately 1 h, at which point 1 mL of MeOH was added to quench the excess DIBAL-H. Sat. aq. Rochelle salt (potassium sodium tartrate (KNaC4H4O6)) solution (5 mL) and DCM (5 mL) were added and the mixture stirred vigorously for 15 min. The DCM layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The DCM layers were combined, dried using Na2SO4 and evaporated to give the crude product. Purification using ISCO FCC eluting with 70% EtOAc in Hexanes gave 71 mg of 2-(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)propan-2-ol as a racemic mixture (69%). LC-MS MS (ESI) m/z 528.25 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.72 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 6.01 (d, J=7.6 Hz, 1H), 5.27 (d, J=4.4 and 14.0 Hz, 1H), 5.00-4.86 (m, 2H), 4.26-4.08 (m, 2H), 3.74-3.67 (m, 1H), 3.15 (s, 3H), 3.15-3.10 (m, 1H), 2.47-2.40 (m, 1H), 1.96 (b, 1H), 1.59 (s, 6H), 1.23 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

Workup

  1. customThe reaction
  2. additionwas added
  3. customto quench the excess DIBAL-H
  4. additionSat. aq. Rochelle salt (potassium sodium tartrate (KNaC4H4O6)) solution (5 mL) and DCM (5 mL) were added
  5. customThe DCM layer was separated
  6. extractionthe aqueous layer was extracted with DCM (2×5 mL)
  7. customdried
  8. customevaporated
  9. customto give the crude product
  10. customPurification
  11. washeluting with 70% EtOAc in Hexanes

Sources & evidence

ORD record
ord-374b23191a1141619dee3449e876bce0
Source dataset
uspto-grants-2016_08
Patent number
US09416135B2

Reaction notes

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