Isopropylamine → 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide

HRID 246070Notes

Reaction equation

HRID 246070 reaction equation
[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]1[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[CH:20][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:16]3=[N:17][CH:18]=1)=[N:5][N:6]2[CH3:12].C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.C(N)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)CCl>[CH:37]([NH:39][C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:4]3[C:3]4[C:7](=[CH:8][C:9]([F:11])=[CH:10][C:2]=4[F:1])[N:6]([CH3:12])[N:5]=3)[N:14]=2)[N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[CH:20]=1)=[O:24])([CH3:38])[CH3:36]

Participants

7

Reactant 4

HCID 6363Isopropylamine2×HCID 757711-Hydroxybenzotriazole2×HCID 81531DiisopropylethylamineHCID 712797012-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid

Product 1

HCID 712800752-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamideYield 37.5%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (75 mg, 0.16 mmol), HOBt (63 mg, 0.38 mmol) and EDC (72 mg, 0.38 mmol) in DMF was added isopropylamine (84 ul, 0.98 mmol). The reaction mixture was stirred at room temperature for 1.5 h then additional HOBt, EDC, and isopropylamine were added. The reaction mixture was stirred at room temperature overnight then diisopropylethylamine (170 ul, 0.98 mmol) was added. The reaction was stirred for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with 10% citric acid, sat NaHCO3, sat LiCl, and brine then dried over MgSO4 and concentrated. The residue was chromatographed over silica gel with 20% to 100% EtOAc/heptane to afford 30 mg (37%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a white solid.

Workup

  1. stirringThe reaction mixture was stirred at room temperature overnight
  2. stirringThe reaction was stirred for 1 h
  3. customthen quenched with water
  4. extractionextracted with EtOAc (2×)
  5. washThe combined organic layers were washed with 10% citric acid
  6. dry with materialthen dried over MgSO4
  7. concentrationconcentrated
  8. customThe residue was chromatographed over silica gel with 20% to 100% EtOAc/heptane

Sources & evidence

ORD record
ord-0367242e86824bcaa8833641cf8b100b
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…