Cesium carbonate → 2-(3-{6-[(2,3-Dihydro-benzofuran-2-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid

HRID 2110782Notes

Reaction equation

HRID 2110782 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH2:16][CH:12]1[CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 442489972-(3-Boronophenyl)-2-methylpropanoic acidHCID 86615711(6-Chloro-2-methoxy-pyrimidin-4-yl)-(2,3-dihydro-benzofuran-2-ylmethyl)-amine

Product 1

HCID 576359972-(3-{6-[(2,3-Dihydro-benzofuran-2-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acidYield 58.1%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,3-dihydro-benzofuran-2-ylmethyl)-amine (167 mg, 0.57 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (155 mg, 0.75 mmol), and Cs2CO3 (0.46 g, 1.43 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine) palladium (0) (33 mg, 0.03 mmol) at room temperature. The mixture is heated at 85° C. for 3 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (10 mL). The aqueous layer is separated, acidified to pH 2.5 with 1M HCl solution, and extracted with EtOAc (2×10 mL). The extracts are dried (MgSO4), filtered through a short pad of SiO2 to afford 2-(3-{6-[(2,3-dihydro-benzofuran-2-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (139 mg, Example 90). LCMS: RT=2.05 minutes; MS: 420 (M+H); 1H NMR (300 MHz, DMSO-d6) □12.4 (1H, s), 8.05-7.8 (2H, m), 7.5-7.1 (5H, m), 6.8-6.75 (2H, m), 5 (1H, s), 4 (3H, brs), 3.65 (2H, brs), 3.4-2.95 (2H, m), 1.48 (6H, s).

Workup

  1. customis degassed
  2. customby bubbling with Ar gas for 5 minutes
  3. extractionextracted with EtOAc (10 mL)
  4. customThe aqueous layer is separated
  5. extractionextracted with EtOAc (2×10 mL)
  6. dry with materialThe extracts are dried (MgSO4)
  7. filtrationfiltered through a short pad of SiO2

Sources & evidence

ORD record
ord-5d36eeb1752c415785976090838f4db3
Source dataset
uspto-grants-2009_04
Patent number
US07517889B2

Reaction notes

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