Cesium carbonate → 1-(2-(2-(5-Chloro-2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

HRID 592382Notes

Reaction equation

HRID 592382 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:30]2[CH:35]=[N:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=2)=[N:3][CH:4]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27377445-Amino-2-(trifluoromethyl)pyridineHCID 867122951-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

Product 1

HCID 732965711-(2-(2-(5-Chloro-2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamideYield 30.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (A14) (150 mg, 446 μmol), Cs2CO3 (436 mg, 1.34 mmol) and 5-amino-2-trifluoromethylpyridine (145 mg, 892 μmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (10.3 mg, 17.8 μmol) and Pd(OAc)2 (2.00 mg, 8.92 μmol) were added and the resulting mixture was heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-40% MeOH in EtOAc). The purified solid was dissolved in acetone (0.2 mL) and petroleum benzene 40-60° C. (30 mL) added. The precipitate was collected by vacuum filtration and the filter cake dried under high vacuum to yield the title compound 9 as a tan solid (62 mg, 30%); 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=2.6 Hz, 1H), 8.43-8.34 (m, 2H), 7.69 (d, J=8.7 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.36 (dd, J=7.8, 3.1 Hz, 2H), 7.30 (d, J=4.9 Hz, 1H), 5.39 (d, J=8.9 Hz, 2H), 3.35-3.17 (m, 4H), 1.78 (s, 2H), 1.16 (s, 2H). LCMS-A: rt 4.816 min; m/z 462 [M+H]+.

Workup

  1. customwas sonicated for 10 minutes
  2. custompurified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.
  3. dissolutionThe purified solid was dissolved in acetone (0.2 mL)
  4. additionpetroleum benzene 40-60° C. (30 mL) added
  5. filtrationThe precipitate was collected by vacuum filtration
  6. customthe filter cake dried under high vacuum

Sources & evidence

ORD record
ord-510ef9b142194b93b813550c2d299f65
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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