Diisopropylethylamine → (R)-ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

HRID 1482991Notes

Reaction equation

HRID 1482991 reaction equation
[CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([CH2:21][OH:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(O)C>[OH:22][CH2:21][C:14]1[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:16][C:10]2[N:6]3[CH2:7][CH2:8][N:9]([C:24]4[N:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][N:25]=4)[C@H:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[N:12][C:11]=2[CH:13]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2780355Ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylateHCID 89816105(R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol

Product 1

HCID 71736478(R)-ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylateYield 83.7%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of (R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (30 mg, 0.093 mmol) in CH2Cl2 (0.5 mL) and iPrOH (0.5 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (36 mg, 0.14 mmol) and DIEA (36 mg, 0.28 mmol). The mixture was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure. Water (5 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (42.0 mg, 83.7% yield) as a white solid. Analytical chiral HPLC: tR=9.927 min in 15 min chromatography, 96.74% ee (Method: OD-H_5_5_40_2.35 ML). LC-MS MS (ESI) m/z 542.1 [M+H]+. 1H NMR (CD3OD 300 MHz): δ 8.96 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 6.12-6.00 (m, 1H), 5.45-5.29 (m, 1H), 5.01 (s, 2H), 4.51-4.47 (m, 1H), 4.33-4.18 (m, 3H), 3.91 (t, J=10.8 Hz, 1H), 3.18 (s, 3H), 2.63-2.47 (m, 1H), 1.35-1.26 (m, 6H), 1.05 (d, J=6.6 Hz, 3H).

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. additionWater (5 mL) was added to the mixture
  3. extractionthe aqueous layer was extracted with EtOAc (3×10 mL)
  4. washThe combined organic layers were washed with water and brine
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified by preparative TLC

Sources & evidence

ORD record
ord-97d62a463ec54be8b486a7335a643a6c
Source dataset
uspto-grants-2016_08
Patent number
US09416135B2

Reaction notes

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