Cesium carbonate → tert-Butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 592379Notes

Reaction equation

HRID 592379 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:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=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]>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[CH:32][CH:31]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 21940085tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylateHCID 867122951-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

Product 1

HCID 86712296tert-Butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

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) (100 mg, 297 μmol), Cs2CO3 (291 mg, 892 μmol) and tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (164 mg, 595 μmol) in 1,4-dioxane (2.0 mL) was sonicated for 10 min. To this Xantphos (6.88 mg, 11.9 μmol) and Pd(OAc)2 (1.33 mg, 5.95 μmol) were added and the resulting mixture heated under microwave irradiation for 20 min at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A15 as a yellow oil (121 mg, 71%); 1H NMR (400 MHz, CDCl3) δ 8.25-8.22 (s, 1H), 7.54-7.46 (m, 3H), 7.43-7.38 (dt, J=7.4, 1.0 Hz, 1H), 7.34-7.29 (m, 2H), 7.29-7.22 (m, 1H), 7.19-7.12 (m, 2H), 5.93-5.80 (s, 1H), 5.41-5.26 (s, 1H), 4.39-4.18 (s, 2H), 3.31-3.06 (m, 4H), 2.90-2.69 (t, J=11.8 Hz, 2H), 2.69-2.54 (tt, J=12.0, 3.4 Hz, 1H), 1.88-1.68 (t, J=15.8 Hz, 4H), 1.68-1.53 (qd, J=13.0, 4.4 Hz, 2H), 1.53-1.46 (s, 9H), 1.19-1.07 (s, 2H). LCMS-A: rt 6.326 min; m/z 577 [M+H]+.

Workup

  1. customwas sonicated for 10 min
  2. custompurified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-439a8a3bf8e546049ff6f7d4bb95fd34
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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