(S)-tert-butyl 1-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamoyl)-3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate → (S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-methyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide

HRID 1510410Notes

Reaction equation

HRID 1510410 reaction equation
[CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15][C:14]=2[C:13]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=2[F:35])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=2[F:35])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]

Participants

4

Reactant 1

HCID 66997658(S)-tert-butyl 1-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamoyl)-3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Product 1

HCID 46863441(S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-methyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamideYield 49%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Procedure

A solution of (S)-tert-butyl 1-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamoyl)-3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.92 g, 1.76 mmol) in TFA/DCM (1:1) was stirred at room temperature for 30 min. The reaction mixture was diluted with toluene and evaporated under vacuum. The resulting residue was dissolved in THF, to which formaldehyde (37%, 0.65 mL) and sodium triacetoxyborohydride (424 mg) was added sequentially. After stifling at room temperature for 2 h, THF was evaporated under vacuum. The residue was extracted between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column with a gradient of from 10% to 40% ethanol in MeCN to give (S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-methyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide 37 as a solid (412 mg, 49% yield for two steps). 1H NMR (CDCl3) δ 7.86 (d, J=9.4 Hz, 1H), 7.47-7.54 (m, 1H), 6.98-7.04 (m, 1H), 5.85 (br, 1H), 4.11 (d, J=9.4 Hz, 1H), 3.39 (s, 2H), 3.16-3.20 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.73 (t, J=6.2 Hz, 2H), 2.47 (s, 3H), 1.05 (s, 9H). LCMS (+ESI) m/z=438 [M+H]+.

Workup

  1. customevaporated under vacuum
  2. dissolutionThe resulting residue was dissolved in THF, to which formaldehyde (37%, 0.65 mL) and sodium triacetoxyborohydride (424 mg)
  3. additionwas added sequentially
  4. customTHF was evaporated under vacuum
  5. extractionThe residue was extracted between EtOAc and saturated aqueous sodium bicarbonate
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. customevaporated to dryness
  8. customThe crude mixture was purified by column with a gradient of from 10% to 40% ethanol in MeCN

Sources & evidence

ORD record
ord-260ebbe1f7804dcf9affcd103b10567b
Source dataset
uspto-grants-2012_07
Patent number
US08211926B2

Reaction notes

Loading…