Trifluoroacetic acid → N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1-methyl-N2-[2-(methyloxy)ethyl]glycinamide

HRID 2354423Notes

Reaction equation

HRID 2354423 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]([CH2:30][CH2:31][O:32][CH3:33])[CH2:26][C:27]([OH:29])=O)[CH:21]=[CH:22][C:23]=1[Cl:24].[Li].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOCC.C(OCC)(=O)C.O.CC#N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:16])[C:27](=[O:29])[CH2:26][N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH2:30][CH2:31][O:32][CH3:33])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1

Participants

12

Reactant 7

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 516892Sodium BicarbonateHCID 3028194LithiumHCID 57418671HCID 57418671, compoundHCID 57425537[1-(4-Bromophenyl)-2-(1-pyrrolidinyl)ethyl]methylamine

Product 1

HCID 59809653N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1-methyl-N2-[2-(methyloxy)ethyl]glycinamideYield 67%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 18373917Acetonitrile--water (1/1)SolventHCID 21584169Diethylether ethylacetateSolvent

Procedure

1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (6.0 g of 50% purity, 10.5 mmol) was dissolved in 30 mL of anhydrous DMF and treated with N-(3,4-dichlorophenyl)-N-[2-(methyloxy)ethyl]glycine, lithium salt (3.0 g, 10.5 mmol), triethyl amine (2.9 mL, 21.0 mmol), and (1H-1,2,3-benzotriazol-1-yloxy) [tris(dimethylamino)]phosphonium hexafluorophosphate (BOP Reagent, 5.6 g, 12.6 mmol). The reaction mixture was stirred for 2 hours at room temperature, after which time HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that the reaction was complete. The reaction mixture was treated with 50 mL of 50% saturated aqueous sodium bicarbonate solution and stirred for 30 minutes. The mixture was poured into 100 mL of water and 300 mL of a 1:1 ether/ethyl acetate mixture. The layers were separated and the organic phase was washed with 50% saturated aqueous sodium bicarbonate solution (2×300 mL), 1M HCl (1×300 mL), 50% saturated aqueous sodium bicarbonate solution (1×300 mL), saturated NaCl (1×200 mL), dried over magnesium sulphate, filtered, and concentrated to an orange foam. The compound was adsorbed onto approximately 30 g of silica gel and purified by column chromatography (300 g silica gel 40 um, 20 minute isocratic flush with ethyl acetate followed by gradient elution from 0% MeOH/100% CH2Cl2 to 30% MeOH/70% CH2Cl2 over 90 minutes) to give N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1-methyl-N2-[2-(methyloxy)ethyl]glycinamide (3.85 g, 7.1 mmol, 67%) as a yellow glass. MS (ES) m/e 542, 544 [M+H]+.

Workup

  1. stirringstirred for 30 minutes
  2. customThe layers were separated
  3. washthe organic phase was washed with 50% saturated aqueous sodium bicarbonate solution (2×300 mL), 1M HCl (1×300 mL), 50% saturated aqueous sodium bicarbonate solution (1×300 mL), saturated NaCl (1×200 mL)
  4. dry with materialdried over magnesium sulphate
  5. filtrationfiltered
  6. concentrationconcentrated to an orange foam
  7. custompurified by column chromatography (300 g silica gel 40 um, 20 minute isocratic flush with ethyl acetate followed by gradient elution from 0% MeOH/100% CH2Cl2 to 30% MeOH/70% CH2Cl2 over 90 minutes)

Sources & evidence

ORD record
ord-fa37008403ef4037b1ca549b24e33a3d
Source dataset
uspto-grants-2010_07
Patent number
US07749998B2

Reaction notes

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