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

HRID 912460Notes

Reaction equation

HRID 912460 reaction equation
Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[C:4]1=[O:12].C(N(CC)CC)C.O=C1CCC(=O)N1[C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:45]([O-])=[O:46])=[C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[CH:34]=2)[N:29]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:28]=1>CN(C)C=O.C(OCC)(=O)C>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[C:45]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[C:4]1=[O:12])=[O:46])[N:29]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:28]=[CH:27]2

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 67416461HCID 67416461, compoundHCID 866310512,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate

Product 1

HCID 24865100(S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopiperidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamideYield 80%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-3-Amino-1-(2-hydroxyethyl)piperidin-2-one hydrochloride (52 mg, 0.27 mmol) was dissolved in triethylamine (0.075 mL, 0.54 mmol) and N,N-dimethylformamide (1 mL). To this was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 119 mg, 0.268 mmol), and the reaction mixture was allowed to stir at ambient temperature for 48 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 a silica gel column, eluting with 50% acetone/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopiperidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamide (1 h) (104 mg, 80%). Mass spec: 487 (M+1). 1H NMR (CDCl3) δ 8.57 (brd, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.14 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 4.47 (ddd, 1H), 4.22 (d, 2H), 3.82 (m, 2H), 3.68 (m, 1H), 3.47 (m, 3H), 2.90 (m, 1H), 2.62 (m, 1H), 2.36 (m, 1H), 2.00 (m, 2H), 1.74 (m, 1H), 0.93 (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 a silica gel column
  6. washeluting with 50% acetone/hexanes

Sources & evidence

ORD record
ord-32c9ada06453464b8dd0c0ccc5f7aff2
Source dataset
uspto-grants-2011_09
Patent number
US08026233B2

Reaction notes

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