Diisopropylethylamine → 2-[(1R)-2-amino-1-phenylethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one

HRID 340000Notes

Reaction equation

HRID 340000 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.Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:21]2.C(N(CC)C(C)C)(C)C>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>[NH2:30][CH2:29][C@H:28]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[C:18]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]=3[Cl:16])[CH:19]=2)[C:23]1=[O:27])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 755256674-chloro-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86681489tert-butyl [(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate

Product 1

HCID 866814882-[(1R)-2-amino-1-phenylethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-oneYield 25.1%

Reagents, catalysts & solvents 3

HCID 178418851HCID 178418851, compoundCatalystHCID 962WaterSolventHCID 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 (69.5 mg, 0.334 mmol), bis(tri-t-butylphosphine)palladium (14 mg, 0.028 mmol), tert-butyl [(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate (120.0 mg, 0.2782 mmol) and N,N-diisopropylethylamine (145 μL, 0.835 mmol) in 1,4-dioxane (1000 μL) and water (50 μL) was microwaved at 110° C. for 15 minutes. After filtering and concentration, the residue was purified by prep.—HPLC (pH=10). To the purified intermediate was added methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL). The solution was stirred at room temperature for 1 h. After concentration, the residue was neutralized with TEA (0.5 mL) then concentrated. Purification by prep.—HPLC (pH=10) afforded 25.6 mg (25% yield) of the desired product as white solid. LC-MS found: 367.1 (M+H)+.

Workup

  1. customwas microwaved at 110° C. for 15 minutes
  2. filtrationAfter filtering
  3. concentrationconcentration
  4. customthe residue was purified by prep.—HPLC (pH=10)
  5. additionTo the purified intermediate was added methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL)
  6. concentrationAfter concentration
  7. concentrationthen concentrated
  8. customPurification by prep.—HPLC (pH=10)

Sources & evidence

ORD record
ord-93d5876a6bee48a59dd215f6591b36fe
Source dataset
uspto-grants-2014_11
Patent number
US08895571B2

Reaction notes

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