Trifluoroacetic acid → 2-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-methyl-N-[(1R)-1-[3'-(4-morpholinylcarbonyl)-4-biphenylyl]-2-(1-pyrrolidinyl)ethyl]acetamide

HRID 2354435Notes

Reaction equation

HRID 2354435 reaction equation
[NH2:1][C:2](=[O:32])[CH2:3][N:4]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:5][C:6]([N:8]([C@H:10]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:9])=[O:7].[N:33]1([C:39]([C:41]2[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=2)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.O.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2](=[O:32])[CH2:3][N:4]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:5][C:6]([N:8]([CH3:9])[C@H:10]([C:17]1[CH:22]=[CH:21][C:20]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])[CH:46]=2)=[CH:19][CH:18]=1)[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7]

Participants

9

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 36029163-(Morpholine-4-carbonyl)phenylboronic acidHCID 574255432-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N-methylacetamide

Product 1

HCID 574890342-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-methyl-N-[(1R)-1-[3'-(4-morpholinylcarbonyl)-4-biphenylyl]-2-(1-pyrrolidinyl)ethyl]acetamideYield 59.1%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
160 °C

Procedure

2-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N-methylacetamide (138 mg, 0.254 mmol) was dissolved in 1 mL of 1,4-Dioxane and combined with [3-(4-morpholinylcarbonyl)phenyl]boronic acid (89.8 mg, 0.382 mmol), Pd(dppf)2Cl2 (6.23 mg, 0.0076 mmol), and 400 uL of 2 M Na2CO3 in water in a glass reaction tube (0.5-2.0 mL Smith Process Vial) that was equipped with a magnetic stir bar. The tube was fitted with a rubber septum and hermetically sealed with a crimped metal foil seal. Using a Personal Chemistry Emrys Optimizer microwave unit, the reaction mixture was magnetically stirred and irradiated with microwave energy of dynamically adjusted power in order to maintain a temperature of 160° C. for 360 seconds. After allowing the mixture to cool to room temperature, it was diluted with 1.0 mL DMSO, acidified with trifluoroacetic acid and filtered through a 0.45 μm PTFE Acrodisk. The crude residue was purified by preparative HPLC (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 96 mg (0.15 mmol) of the title compound as an off-white amorphous solid. MS (ES) m/e 651 [M+H]+.

Workup

  1. customwas equipped with a magnetic stir bar
  2. customThe tube was fitted with a rubber septum
  3. customhermetically sealed with a crimped metal foil
  4. customseal
  5. customirradiated with microwave energy of dynamically adjusted power in order
  6. temperatureto cool to room temperature
  7. filtrationfiltered through a 0.45 μm PTFE Acrodisk
  8. customThe crude residue was purified by preparative HPLC (Phenomenex 75×30 mm column, 40 mL/min flow rate

Sources & evidence

ORD record
ord-7d3777e295434c53a10cb3343e00ec53
Source dataset
uspto-grants-2010_07
Patent number
US07749998B2

Reaction notes

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