1,1,3,3-Tetramethylguanidine → HCID 89669873, compound

HRID 1775244Notes

Reaction equation

HRID 1775244 reaction equation
Br[C:2]1[C:11]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]([F:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20]([C@@:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])#[CH:21].CN(C)C(=N)N(C)C>CN(C=O)C.CC(=O)OCC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:19][C:9]1[CH:10]=[C:11]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:2]([C:21]#[C:20][C@@:22]2([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1

Participants

9

Reactant 3

HCID 664601,1,3,3-TetramethylguanidineHCID 89656053HCID 89656053, compoundHCID 127263151HCID 127263151, compound

Product 1

HCID 89669873HCID 89669873, compoundYield 53%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate (27.52 g, 80 mmol), (PPh3)2PdCl2 (2.8 g, 4 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (19.44 g, 80 mmol), copper(I) iodide (764 mg, 4 mmol) and tetramethylguanidine (27.6 g, 240 mmol) in DMF (200 mL) was heated at 80° C. with nitrogen protection system for 16 hours. The cooled reaction mixture was diluted with EA (3×200 mL) and water (800 mL). The organic layer was separated, washed with water (2×200 mL), dried (Na2SO4), and concentrated. The remaining residue was chromatographed on silica gel, eluted with gradient 0-30% EtOAc in hexane to give the product (R)-benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (21 g, 53%) as white solid. 1H NMR (DMSO-d1) δ 11.01 (s, 1H), 7.64-7.77 (m, 1H), 7.36 (m, 5H), 7.19-7.31 (m, 1H), 5.04-5.12 (m, 2H), 3.85 (s, 3H), 3.44-3.47 (m, 2H), 2.0-2.29 (m, 2H), 1.90-1.97 (m, 2H), and 1.69 (s, 3H). MS (ESI) m/e [M+1]+ 507.0.

Workup

  1. customThe cooled reaction mixture
  2. customThe organic layer was separated
  3. washwashed with water (2×200 mL)
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. customThe remaining residue was chromatographed on silica gel
  7. washeluted with gradient 0-30% EtOAc in hexane

Sources & evidence

ORD record
ord-049162d6bad84a96a1a2b3caebd7a766
Source dataset
uspto-grants-2016_02
Patent number
US09260440B2

Reaction notes

Loading…