Diisopropylethylamine → tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5 dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

HRID 58463Notes

Reaction equation

HRID 58463 reaction equation
Cl.[F:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]2[C:33]([C:36](O)=[O:37])=[N:34][NH:35][C:29]=2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]([CH:10]2[CH2:11][CH2:12][N:13]([C:36]([C:33]3[C:30]4[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][C:29]=4[NH:35][N:34]=3)=[O:37])[CH2:14][CH2:15]2)[CH:6]=[C:7]([F:9])[CH:8]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 219528526-Boc-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3-carboxylic acidHCID 1184833844-(3,5-Difluoro-2-(trifluoromethyl)phenyl)piperidine Hydrochloride

Product 1

HCID 118483423tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5 dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylateYield 23.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a suspension of 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (28, 500 mg, 1.66 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1Hpyrazolo[3,4-c]pyridine-3-carboxylic acid (443 mg, 1.66 mmol), and diisopropylethylamine (36 μL, 2.04 mmol) in DMF (5 mL) was added HBTU (1.10 g, 2.49 mmol). The resulting mixture was stirred at ambient temperature for 18 h. the reaction was diluted in H2O (50 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, 0-100% EtOAc in hexanes) to afford tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5 dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (59) as a white solid (200 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 7.017-6.876 (m, 1H), 6.876-6.741 (m, 1H), 5.306 (s, 1H), 4.632 (s, 2H), 3.776-3.581 (m, 2H), 2.762-2.631 (m, 2H), 1.986-1.653 (m, 4H), 1.500 (s, 9H), 1.399-1.189 (m, 4H).

Workup

  1. extractionextracted with EtOAc (3×75 mL)
  2. dry with materialThe combined organic extracts were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue was chromatographed over silica gel (40 g Redisep column, 0-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-67067fb94e5d4eb2abb6ae016eef1e15
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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