Hydrazine → 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

HRID 339988Notes

Reaction equation

HRID 339988 reaction equation
[CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([Cl:16])[CH:4]=[N:3]1.Cl[C:18]1[N:23]=[CH:22][C:21]2[C:24](=[O:48])[N:25]([C@@H:27]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:28][N:29]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:26][C:20]=2[CH:19]=1.C(N(CC)C(C)C)(C)C.NN>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCCC1.CO>[NH2:29][CH2:28][C@@H:27]([N:25]1[CH2:26][C:20]2[CH:19]=[C:18]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]=3[Cl:16])[N:23]=[CH:22][C:21]=2[C:24]1=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1

Participants

10

Reactant 4

HCID 9321HydrazineHCID 81531DiisopropylethylamineHCID 755256674-chloro-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 866814752-[(2S)-2-(6-chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione

Product 1

HCID 715550332-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

Reagents, catalysts & solvents 5

HCID 178418851HCID 178418851, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 1-methyl-4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.4 mg, 0.0800 mmol), bis(tri-t-butylphosphine)palladium (3.4 mg, 0.0067 mmol), 2-[(2S)-2-(6-chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (30.0 mg, 0.0667 mmol) and N,N-diisopropylethylamine (34.8 μL, 0.200 mmol) in 1,4-dioxane (1 mL) and water (50 μL) was microwaved at 110° C. for 15 minutes. Filtered through a pad of celite and concentrated, the residue was purified by combi-flash chromatography eluted with EtOAc/hexane (50-100%). To the purified intermediate was added methanol (0.4 mL), tetrahydrofuran (0.4 mL) and hydrazine (0.2 mL, 6 mmol). The solution was stirred at room temperature overnight. Purification by prep.—HPLC (pH=10) gave the desired product as white solid. LC-MS found: 400.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.95 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.23 (m, 1H), 6.98 (m, 2H), 6.95 (dt, J1=9.30 Hz, J2=1.80 Hz, 1H), 4.59 (s, 2H), 4.41 (m, 1H), 3.93 (s, 3H), 3.02 (dd, J1=14.40 Hz, J2=5.10 Hz, 1H), 2.89 (m, 1H), 2.81 (d, J=6.60 Hz, 2H).

Workup

  1. customwas microwaved at 110° C. for 15 minutes
  2. filtrationFiltered through a pad of celite
  3. concentrationconcentrated
  4. customthe residue was purified by combi-flash chromatography
  5. washeluted with EtOAc/hexane (50-100%)
  6. customPurification by prep.—HPLC (pH=10)

Sources & evidence

ORD record
ord-33fd3b2e95d9430c82882fc5321ff83f
Source dataset
uspto-grants-2014_11
Patent number
US08895571B2

Reaction notes

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