Sodium Hydroxide → HCID 42635307, compound

HRID 409434Notes

Reaction equation

HRID 409434 reaction equation
Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([O:7]C(=O)C2C=CC=CC=2)[CH2:3]1.[CH:16]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]2[N:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH2:24][C@H:23]1[CH2:50][CH3:51])=[O:21])([CH3:18])[CH3:17].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.CO>[CH:16]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]2[N:33]=[CH:32][C:31]([N:2]3[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]3)=[CH:30][N:29]=2)[CH2:24][C@H:23]1[CH2:50][CH3:51])=[O:21])([CH3:18])[CH3:17]

Participants

10

Reactant 5

HCID 14798Sodium HydroxideHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 11521463HCID 11521463, compoundHCID 23676156Sodium t-butoxideHCID 42633161HCID 42633161, compound

Product 1

HCID 42635307HCID 42635307, compoundYield 71%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

The resulting benzoic acid (S)-pyrrolidin-3-yl ester hydrochloride (0.45 mmol), (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.196 mmol; 114 mg), tris(dibenzylideneacetone)dipalladium(0) (0.0098 mmol; 9.0 mg), 2-(di-tert-butylphosphino)biphenyl (0.0196 mmol; 5.8 mg) and sodium tert-butoxide (0.784 mmol; 75.3 mg) are dissolved in toluene (1 mL). The mixture is stirred for 2.5 hours at 100° C. To the mixture are added aqueous 1 M NaOH (5 mL), MeOH (10 mL) and THF (3 mL) at room temperature. After stirring for 5 hours, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (82 mg, 71%); ESI-MS m/z: 590 [M+1]+, Retention time 2.15 min (condition A).

Workup

  1. stirringAfter stirring for 5 hours
  2. customthe reaction mixture is quenched with saturated aqueous ammonium chloride solution
  3. extractionThe product is extracted three times with EtOAc
  4. washThe combined organic layer is washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc)

Sources & evidence

ORD record
ord-326757f61230470fa58dd9c13720c6d3
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Reaction notes

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