1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate

HRID 58452Notes

Reaction equation

HRID 58452 reaction equation
Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[C:29]([C:32](O)=[O:33])=[N:30][NH:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][CH2:12][N:13]([C:32]([C:29]2[C:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:24][C:25]=3[NH:31][N:30]=2)=[O:33])[CH2:14][CH2:15]1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 219528526-Boc-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3-carboxylic acidHCID 1184835134-(2-Chloro-5-fluorophenyl)piperidine Hydrochloride

Product 1

HCID 118483375tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylateYield 44%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (104 mg, 0.39 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (65 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×20 mL). The combined organic extracts were washed with a saturated brine solution (9×20 mL), H2O (2×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (47) as a white solid (57 mg, 44%): 1H NMR (300 MHz, DMSO-d6) δ 13.16-12.78 (m, 1H), 7.48 (dd, J=9.0, 5.7 Hz, 1H), 7.28 (dd, J=10.5, 3.3 Hz, 1H), 7.17-7.05 (m, 1H), 4.90-4.59 (m, 2H), 4.53-4.40 (m, 2H), 3.62-3.48 (m, 2H), 3.28-3.07 (m, 2H), 2.92-2.73 (m, 1H), 2.64-2.50 (m, 2H, overlaps with solvent), 1.93-1.69 (m, 2H), 1.68-1.49 (m, 2H), 1.42 (S, 9H); ESI MS m/z 463 [M+H]+.

Workup

  1. extractionextracted with EtOAc (4×20 mL)
  2. washThe combined organic extracts were washed with a saturated brine solution (9×20 mL), H2O (2×20 mL)
  3. concentrationconcentrated to dryness under reduced pressure
  4. customThe obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-b937b397333a4e99ba581f128b5e375c
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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