Tris(hydroxymethyl)aminomethane → 5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide

HRID 912468Notes

Reaction equation

HRID 912468 reaction equation
[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C:33]1C(=O)NC=CC=1.C(N(C(C)C)C(C)C)C.C(O)C(N)(CO)CO>ClCCl>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C:17]1[C:18](=[O:22])[NH:19][CH:20]=[CH:33][CH:21]=1)=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2

Participants

6

Reactant 4

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 81531DiisopropylethylamineHCID 3223533-Amino-2-pyridinolHCID 17751071(S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide

Product 1

HCID 577365565-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamideYield 32.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 100 mg, 0.226 mmol) in dichloromethane (1.1 mL) was added 3-aminopyridin-2(1H)-one (26.1 mg, 0.237 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.039 mL, 0.226 mmol). After 48 h, the reaction was treated with tris-amine resin (silica supported amine 3, 100 mg, loading=1.76 mmol/g). After 45 minutes, the reaction was filtered though a silica gel plug, washing well with ethyl acetate. The filtrate was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organics were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of 50% to 100% ethyl acetate/hexanes to yield 5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide (32 mg, 32%). Mass spec: 439 (M+1). 1H NMR (CDCl3) δ 10.8 (s, 1H), 8.68 (dd, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.28-6.88 (m, 6H), 6.36 (dd, 1H), 4.25 (d, 2H), 2.38 (m, 1H), 0.95 (d, 6H).

Workup

  1. waitAfter 45 minutes
  2. filtrationthe reaction was filtered though a silica gel plug
  3. washwashing well with ethyl acetate
  4. washThe filtrate was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride
  5. dry with materialThe organics were dried with sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by silica gel column chromatography
  9. washeluting with a gradient of 50% to 100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-be37087b58454912ac7459f3887994ad
Source dataset
uspto-grants-2011_09
Patent number
US08026233B2

Reaction notes

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