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

HRID 912454Notes

Reaction equation

HRID 912454 reaction equation
Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10].C(N(CC)CC)C.O=C1CCC(=O)N1[C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:43]([O-])=[O:44])=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[CH:32]=2)[N:27]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:26]=1>CN(C)C=O.C(OCC)(=O)C>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[C:43]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10])=[O:44])[N:27]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:26]=[CH:25]2

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 67416125(S)-3-Amino-1-methylpiperidin-2-one hydrochlorideHCID 866310512,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate

Product 1

HCID 24864924(S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopiperidin-3-yl)-1H-indazole-6-carboxamideYield 60.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-3-Amino-1-methylpiperidin-2-one hydrochloride (56 mg, 0.34 mmol) was dissolved in triethylamine (95 μL, 0.68 mmol) and N,N-dimethylformamide (1.5 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; 152 mg, 0.34 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 a silica gel column, eluting with 70% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ie) (94 mg, 60%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 8.61 (br, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.90 (m, 1H), 4.48 (ddd, 1H), 4.22 (d, 2H), 3.36 (m, 2H), 2.97 (s, 3H), 2.73 (m, 1H), 2.36 (m, 1H), 1.99 (m, 2H), 1.66 (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 a silica gel column
  6. washeluting with 70% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-51d18ae1fea94fd98e677039a5b71353
Source dataset
uspto-grants-2011_09
Patent number
US08026233B2

Reaction notes

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