Triethylamine → (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-carboxamide

HRID 1482995Notes

Reaction equation

HRID 1482995 reaction equation
[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([C:28]([OH:30])=O)=[CH:20][N:19]=4)[C@H:14]([CH:15]([CH3:17])[CH3:16])[C:9]3=[N:8][C:7]=2[CH:31]=1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:62](CC)CC.[NH4+].[Cl-]>CN(C=O)C.O>[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([C:28]([NH2:37])=[O:30])=[CH:20][N:19]=4)[C@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:31]=1.[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([C:28]([NH2:62])=[O:30])=[CH:20][N:19]=4)[C@@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:31]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)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 acid

Product 2

HCID 71736631(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-carboxamideYield 56.7%HCID 71736632(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-carboxamideYield 10.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (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 (100 mg, 0.19 mmol, partially racemized) in DMF (2 mL) was added HATU (97 mg, 0.25 mmol) and Et3N (52 mg, 0.51 mmol). The mixture was stirred at rt for 1 h. NH4Cl (19 mg, 0.34 mmol) was added in one portion. The mixture was stirred at rt for 16 h. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (4×10 mL). The combined organic layers were washed with water (3×10 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC and SFC separation 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-carboxamide (55.2 mg, 56.7% 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-carboxamide (10.5 mg, 10.8% yield, isomer 2) as white solid.

Workup

  1. stirringThe mixture was stirred at rt for 16 h
  2. extractionthe aqueous layer was extracted with EtOAc (4×10 mL)
  3. washThe combined organic layers were washed with water (3×10 mL) and brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by preparative TLC and SFC separation

Sources & evidence

ORD record
ord-c4576e83d9624c7994838cd7cab2781b
Source dataset
uspto-grants-2016_08
Patent number
US09416135B2

Reaction notes

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