Triphenylphosphine → tert-Butyl 4-(5-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

HRID 592372Notes

Reaction equation

HRID 592372 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]1([C:62]([O:64][CH3:65])=[O:63])[CH2:61][CH2:60]1)#[CH:52]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:65][O:64][C:62]([C:59]1([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[C:51]#[C:52][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[N:3]=2)[CH2:61][CH2:60]1)=[O:63]

Participants

7

Reactant 3

HCID 11776TriphenylphosphineHCID 86712270Methyl 1-(2-ethynylphenyl)cyclopropanecarboxylateHCID 86712273tert-Butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

Product 1

HCID 86712291tert-Butyl 4-(5-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A stirred suspension of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (K5) (152 mg, 0.332 mmol), PdCl2(PPh3)2 (12 mg, 0.017 mmol), PPh3 (9 mg, 0.03 mmol), CuI (6 mg, 0.03 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (80 mg, 0.40 mmol) in DMF (4.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed in vacuo and the residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C. then 10-45% EtOAc in petroleum benzine 40-60° C.) to give the title compound A10 as yellow oil (141 mg, 68%); 1H NMR (400 MHz, d6-DMSO) δ 10.53 (s, 1H), 8.84 (s, 1H), 8.77 (d, J=2.5 Hz, 1H), 8.12 (d, J=6.5 Hz, 1H), 7.61 (dd, J=7.6, 1.0 Hz, 1H), 7.54-7.38 (m, 3H), 7.28 (d, J=8.5 Hz, 1H), 4.05 (br, 2H), 3.51 (s, 3H), 2.94-2.72 (m, 3H), 1.81 (d, J=10.5 Hz, 2H), 1.63 (q, J=4.1 Hz, 2H), 1.61-1.49 (m, 2H), 1.41 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 5.913 min; m/z 622 [M+H]+.

Workup

  1. customwas degassed with nitrogen for 10 minutes
  2. additionEt3N (1.0 mL) was added
  3. customThe volatiles were removed in vacuo
  4. custompurified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.

Sources & evidence

ORD record
ord-e033798b1cdf45a5a0b1687923e5d704
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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