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

HRID 58446Notes

Reaction equation

HRID 58446 reaction equation
Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[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[NH:29][N:30]=[C:31]([C:32](O)=[O:33])[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[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:32]([C:31]2[C:25]3[CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27][C:26]=3[NH:29][N:30]=2)=[O:33])[CH2:12][CH2:11]1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 509864325-[(tert-butoxy)carbonyl]-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-3-carboxylic acidHCID 1184834264-(2-Chloro-3-fluorophenyl)piperidine Hydrochloride

Product 1

HCID 118483431tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1Hpyrazolo[4,3-c]pyridine-5(4H)-carboxylateYield 83.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14, 90 mg, 0.36 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (96 mg, 0.36 mmol), and diisopropylethylamine (0.19 mL, 1.08 mmol) in DMF (7.8 mL) was added EDCI (83 mg, 0.43 mmol) and HOBt (58 mg, 0.43 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (30 mL), and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1Hpyrazolo[4,3-c]pyridine-5(4H)-carboxylate (41) as a white foam (139 mg, 82%): 1H NMR (500 MHz, DMSO-d6) δ 13.11-12.91 (m, 1H), 7.39-7.32 (m, 1H), 7.30-7.22 (m, 2H), 5.28-5.13 (m, 1H), 4.75-4.60 (m, 1H), 4.49-4.36 (m, 2H), 3.65-3.53 (m, 2H), 3.33-3.25 (m, 1H, overlaps with H2O), 3.24-3.08 (m, 1H), 2.91-276 (m, 1H), 2.67 (t, J=5.5 Hz, 2H), 1.91-1.75 (m, 2H), 1.67-1.50 (m, 2H), 1.41 (s, 9H); ESI MS m/z 463 [M+H]+.

Workup

  1. filtrationthe resulting precipitate was collected by filtration
  2. customThe obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2)

Sources & evidence

ORD record
ord-8b77ad3d74c5426b998f73f50869623d
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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