Trifluoroacetic acid → (R)-(2-(2-amino-3-(3-methylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone

HRID 1028970Notes

Reaction equation

HRID 1028970 reaction equation
Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].COC1C=CC(C[NH:23][C:24]2[C:33]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@H:35]3[CH3:40])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29](B4OC(C)(C)C(C)(C)O4)[CH:30]=3)[N:25]=2)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:23][C:24]1[C:33]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][C@H:35]2[CH3:40])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:10])[CH:30]=2)[N:25]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 62657Potassium Phosphate, TribasicHCID 21081571Dicyclohexyl(2',4',6'-tripropyl-[1,1'-biphenyl]-2-yl)phosphineHCID 665791491-(2-Bromo-3-methylbenzoyl)pyrrolidineHCID 71253179(R)-N-(4-methoxybenzyl)-3-(3-methylmorpholino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine

Product 1

HCID 53328994(R)-(2-(2-amino-3-(3-methylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
140 °C

Procedure

A mixture of (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.115 g, 0.429 mmol), (R)—N-(4-methoxybenzyl)-3-(3-methylmorpholino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.07 g, 0.143 mmol), potassium phosphate, anhydrous (0.121 g, 0.572 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.014 g, 0.029 mmol), and Pd2(dba)3 (0.013 g, 0.014 mmol) was purged with N2 followed by the addition of degassed dioxane (1 mL) and degassed water (0.5 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using 0-5% MeOH/DCM to afford a yellow oil. To the product was added TFA (10 mL, 130 mmol) and the solution was heated at 60° C. for 18 h until the starting material was consumed. The mixture was concentrated and chromatographed on silica gel using 0-5% 2 M NH3 in MeOH/DCM to afford a yellow solid as (R)-(2-(2-amino-3-(3-methylmorpholino)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 431 (M+1).

Workup

  1. customwas purged with N2
  2. additionfollowed by the addition of degassed dioxane (1 mL)
  3. customdegassed water (0.5 mL)
  4. filtrationwas filtered
  5. concentrationconcentrated
  6. customchromatographed on silica gel using 0-5% MeOH/DCM
  7. customto afford a yellow oil
  8. temperaturethe solution was heated at 60° C. for 18 h until the starting material
  9. customwas consumed
  10. concentrationThe mixture was concentrated
  11. customchromatographed on silica gel using 0-5% 2 M NH3 in MeOH/DCM

Sources & evidence

ORD record
ord-9fab89c868fb4869a0dda607c1ba3c5e
Source dataset
uspto-grants-2014_05
Patent number
US08735384B2

Reaction notes

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