Methane → (R)-Methyl 5-((5-((4-methylpiperazin-1-yl)methyl)-2-nitrophenyl)amino)-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxylate

HRID 883572Notes

Reaction equation

HRID 883572 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C>O1CCOCC1.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.CCCCCCC>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1

Participants

8

Reactant 4

HCID 297MethaneHCID 10796Cesium carbonateHCID 25111423(R)-Methyl 5-amino-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxylateHCID 441854911-(3-Bromo-4-nitrobenzyl)-4-methylpiperazine

Product 1

HCID 44185548(R)-Methyl 5-((5-((4-methylpiperazin-1-yl)methyl)-2-nitrophenyl)amino)-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxylateYield 70%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 8900HeptaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine (0.675 g, 2.15 mmol), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.794 g, 2.30 mmol), Cs2CO3 (3.50 g, 10.7 mmol), XANTPHOS (0.053 g, 0.088 mmol) and tris(benzylideneacetone)dipalladium(0) (0.039 g, 0.043 mmol) in dioxane (5.4 mL) was heated to 55° C. for 1.5 h, analysed by HPLC, then cooled to room temperature. Heptane (2.4 mL), charcoal (0.27 g) and celite (0.27 g) were added. The suspension was stirred for 30 min at room temperature, and then filtered over celite, rinsing with toluene (13.5 mL×3). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (DCM:MeOH:NEt3 9:1:0.1) to give the title compound (0.867 g, 70%) as a red amorphous solid.

Workup

  1. temperatureby HPLC, then cooled to room temperature
  2. filtrationfiltered over celite
  3. washrinsing with toluene (13.5 mL×3)
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. custompurified by flash column chromatography (DCM:MeOH:NEt3 9:1:0.1)

Sources & evidence

ORD record
ord-203c886be18c4adca8ac5a160f9338af
Source dataset
uspto-grants-2012_08
Patent number
US08236954B2

Reaction notes

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