Tetrahydrofuran → cyclopropyl[4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)phenyl]methanone

HRID 494879Notes

Reaction equation

HRID 494879 reaction equation
C[C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21](C#N)=[CH:20][CH:19]=3)=[CH:14][C:12]=2[CH:13]=1.[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH:31]1([Mg]Br)CC1>[Cu]I>[CH:29]1([C:30]([C:21]2[CH:24]=[CH:25][C:18]([C:15]3[CH:16]=[CH:17][C:11]4[O:10][C:9]([CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C@H:2]5[CH3:31])=[CH:13][C:12]=4[CH:14]=3)=[CH:19][CH:20]=2)=[O:26])[CH2:27][CH2:28]1

Participants

5

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 9818903Benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-HCID 178418630HCID 178418630, compound

Product 1

HCID 10109898cyclopropyl[4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)phenyl]methanoneYield 44%

Reagents, catalysts & solvents 1

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Solvent

Conditions

Temperature
60 °C

Procedure

The product from Example 1D (330 mg, 1.0 mmol) was dissolved into tetrahydrofuran (1 mL), treated with ˜0.7 M cyclopropylmagnesium bromide in tetrahydrofuran (2 mL, ˜1.4 mmol) and copper(I) iodide (a few milligrams), and heated at 45° C. for one day and at 60° C. for two days. The reaction was brought to room temperature, quenched with 0.4 M aqueous hydrochloric acid (5 mL), and extracted with EtOAc. The organic phase was washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (40 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL/min.] to provide the title compound as a powder (44% yield). MS (ESI APCI) m/z 374 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.06-1.21 (m, 7H), 1.38-1.53 (m, 1H), 1.73-1.86 (m, 2H), 1.94-2.08 (m, 1H), 2.23-2.34 (m, 1H), 2.40-2.59 (m, 2H), 2.83-3.15 (m, 3H), 3.19-3.34 (m, 2H), 6.62 (s, 1H), 7.51 (d, 1H), 7.56 (dd, 1H), 7.76-7.85 (m, 3H), 8.12 (d, 2H).

Workup

  1. customwas brought to room temperature
  2. customquenched with 0.4 M aqueous hydrochloric acid (5 mL)
  3. extractionextracted with EtOAc
  4. washThe organic phase was washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. custompurified by HPLC [Waters Nova-Pak HR C18 column (40 mm×100 mm, 6 μm particle size)
  8. customover 12 min
  9. custom(15 min run time)

Sources & evidence

ORD record
ord-7cc7844bf2cc44ae9e682bf048a70e23
Source dataset
uspto-grants-2009_05
Patent number
US07538138B2

Reaction notes

Loading…