Water → (S)-3-{(3-Chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester

HRID 409441

Reaction equation

HRID 409441 reaction equation
[CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([C:25]2[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[N:34]1.C(=O)([O-])O.[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[C:25]2[N:30]=[CH:29][C:28]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[CH:27][N:26]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 516892Sodium BicarbonateHCID 27600771-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 59614376(S)-3-{(5-bromo-pyrimidin-2-yl)-[3-chloro-5-(trifluoromethyl)benzyl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester

Product 1

HCID 42633159(S)-3-{(3-Chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-pyrrolidine-1-carboxylic acid isopropyl esterYield 67.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
95 °C

Procedure

To a mixture of (S)-3-{(5-bromo-pyrimidin-2-yl)-[3-chloro-5-(trifluoromethyl)benzyl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (0.19 mmol, 100 mg), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.23 mmol, 48 mg), tetrakis(triphenylphosphine)palladium(0) (0.02 mmol, 22 mg) and 2M aqueous sodium hydrogen carbonate (0.19 mL) in 1,2-dimethoxy-ethane (0.6 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: CH2Cl2/EtOAc). To the obtained mixture in CH2Cl2 (1 mL) is added saturated aqueous sodium carbonate (0.04 mL) and NaIO4 (82 mg). The mixture is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3-Chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (67 mg, 67%); ESI-MS m/z: 523 [M+1]+, Retention time 2.16 min (condition A).

Workup

  1. temperatureThe mixture is cooled to room temperature
  2. extractionThe mixture is extracted with CH2Cl2
  3. dry with materialThe combined organic layer is dried over Na2SO4
  4. filtrationfiltrated
  5. concentrationconcentrated under reduced pressure
  6. customThe obtained residue is purified by silica gel column chromatography (eluent: CH2Cl2/EtOAc)
  7. additionTo the obtained mixture in CH2Cl2 (1 mL) is added saturated aqueous sodium carbonate (0.04 mL) and NaIO4 (82 mg)
  8. stirringThe mixture is stirred at room temperature for 3 hours
  9. concentrationThe mixture is concentrated under reduced pressure
  10. customThe obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc)

Sources & evidence

ORD record
ord-1973ae08e1d2482d9ab2b841a67e78eb
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Linked notes

Loading…