Triethylamine → (S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamide

HRID 912458Notes

Reaction equation

HRID 912458 reaction equation
Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[C:4]1=[O:11].C(N(CC)CC)C.O=C1CCC(=O)N1[C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:44]([O-])=[O:45])=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH:33]=2)[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=1>CN(C)C=O.C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[C:44]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[C:4]1=[O:11])=[O:45])[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=[CH:26]2

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 67416985(S)-3-amino-1-(2-hydroxyethyl)pyrrolidin-2-one hydrochlorideHCID 866310512,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate

Product 1

HCID 24865099(S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamideYield 74%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-3-Amino-1-(2-hydroxyethyl)pyrrolidin-2-one hydrochloride (101 mg, 0.558 mmol) was dissolved in triethylamine (0.141 mL, 1.01 mmol) and N,N-dimethylformamide (2.5 mL). To this solution was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 225 mg, 0.507 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel, loaded and eluted with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamide (Ig) (177 mg, 74%). Mass spec: 473 (M+1). 1H NMR (CDCl3) δ 8.37 (br, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.16 (m, 1H), 7.01 (m, 2H), 6.92 (m, 1H), 4.53 (m, 1H), 3.83 (m, 3H), 3.56 (m, 3H), 3.44 (m, 1H), 3.15 (t, 1H), 2.74 (m, 1H), 2.36 (m, 1H), 2.08 (m, 1H), 0.92 (d, 6H).

Workup

  1. washwashed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine
  2. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude product was purified by flash chromatography on silica gel
  6. washeluted with 100% acetone

Sources & evidence

ORD record
ord-47de10ad07344683b1d2ef01253e63b5
Source dataset
uspto-grants-2011_09
Patent number
US08026233B2

Reaction notes

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