Cesium carbonate → HCID 69069989, compound

HRID 216249Notes

Reaction equation

HRID 216249 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]([C:40]([OH:42])=[O:41])[CH2:37][C:36]=3[CH:43]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[ClH:1].[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]([C:40]([OH:42])=[O:41])[CH2:37][C:36]=3[CH:43]=2)[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[N:5]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 57636134HCID 57636134, compound2×HCID 68930679HCID 68930679, compound

Product 1

HCID 69069989HCID 69069989, compoundYield 31.8%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2(4-trifluoromethoxyphenyl)-ethyl]amine [475 mg, 1.36 mmol, Intermediate (13)], 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-carboxylic acid (266 mg, 0.91 mmol), Cs2CO3 (1.19 g, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (146 mg, 0.13 mmol) in water (2 mL) and ethylene glycol dimethyl ether (8 mL) is degassed with bubbling nitrogen for 5 minutes and heated at 60° C. for 23 hours. The reaction mixture is cooled, diluted with water (200 mL) and brine (50 mL), and acidified with 1N hydrochloric acid to pH 5. The mixture is extracted three times with EtOAc (150 mL) and the extracts are concentrated in vacuo. The residue is subjected to flash column chromatography on silica (5 g) eluting with 0 to 20% MeOH in ethyl acetate. The product is dissolved in ether and treated with 1 M hydrogen chloride in ether to afford 5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2,3-dihydro-benzofuran-2-carboxylic acid hydrochloride (148 mg, Example 88) as a solid. MS: 476 (M+H); LCMS: RT=2.78 minutes, MS: 474 (M−H). IC50=3.1 nM

Workup

  1. customis degassed with bubbling nitrogen for 5 minutes
  2. temperatureThe reaction mixture is cooled
  3. additiondiluted with water (200 mL) and brine (50 mL)
  4. extractionThe mixture is extracted three times with EtOAc (150 mL)
  5. concentrationthe extracts are concentrated in vacuo
  6. washeluting with 0 to 20% MeOH in ethyl acetate
  7. dissolutionThe product is dissolved in ether
  8. additiontreated with 1 M hydrogen chloride in ether

Sources & evidence

ORD record
ord-7eb1252dba9e4fe4b4fae60855cc03d1
Source dataset
uspto-grants-2012_06
Patent number
US08193183B2

Reaction notes

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