Hydrochloric Acid → (R)-2-[4-(4-Thiophen-3-yl-phenoxy)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1909757Notes

Reaction equation

HRID 1909757 reaction equation
[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[CH:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][CH:8]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 673N,N-DimethylglycineHCID 10796Cesium carbonateHCID 41303424-(Thiophen-3-yl)phenolHCID 44819166(R)-2-(4-Iodo-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 69000335(R)-2-[4-(4-Thiophen-3-yl-phenoxy)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 70.9%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
98 °C

Procedure

To a 25 mL pressure resistant vial which contained a solution of the product from step 1 (44 mg, 0.25 mmol) and the product from step 2 (130 mg, 0.33 mmol) in anhydrous dioxane (4 mL) were added cesium carbonate (300 mg, 1.5 mmol) and N,N-dimethylglycine.HCl (25 mg, 0.66 mmol) at rt. The reaction mixture was flushed with argon and copper (I) iodide (14 mg, 0.06 mmol) was added. The vial was sealed and the reaction mixture was stirred at 98° C. for 72 h. After cooling to rt, the mixture was poured onto 50 mL ice-water solution and this solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (80 mg, 70%); LCMS; 100%, APCI+ Calcd: 451.6, found m/z: 451.6 (M); 1H NMR (400 MHz, CDCl3); δ 1.48 (s, 9H), 1.81-2.09 (m, 4H), 3.27-3.48 (m, 2H), 3.70-3.97 (m, 1H), 4.02-4.21 (m, 2H), 6.88-7.05. (m, 6H), 7.32-7.38 (m, 3H), 7.52 (d, J=8.8 Hz, 2H):

Workup

  1. customat rt
  2. additionwas added
  3. customThe vial was sealed
  4. temperatureAfter cooling to rt
  5. extractionthis solution was extracted with EtOAc (3×20 mL)
  6. washThe combined organic layers were washed with water (2×20 mL), brine (20 mL)
  7. dry with materialdried over anhydrous Na2SO4
  8. customThe solvent was removed in vacuo
  9. customto obtain the crude product which
  10. customwas purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-685370ab5406432e8fa28094fa31dc89
Source dataset
uspto-grants-2013_12
Patent number
US08598359B2

Reaction notes

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