Hydrochloric Acid → HCID 69002504, compound

HRID 1909762Notes

Reaction equation

HRID 1909762 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([C:32]#[N:33])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:32]#[N:33])[CH2:30][CH2:31]3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 673N,N-DimethylglycineHCID 10796Cesium carbonateHCID 27952731-(4-Bromophenyl)CyclopropanecarbonitrileHCID 68999591(R)-2-(4-Hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 69002504HCID 69002504, compoundYield 75%

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 press resistant vial which contained a solution of (R)-2-(4-Hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 2 (293 mg, 1 mmol) and the product from step 1 (340 mg, 1.5 mmol) in anhydrous dioxane (8 mL) were added cesium carbonate (450 mg, 2.5 mmol) and N,N-dimethylglycine.HCl (40 mg, 0.0.24 mmol) at rt. The reaction mixture was flushed with argon and copper (I) iodide (20 mg, 0.1 mmol) was added. The vial was sealed and the reaction mixture was stirred at 98° C. for 72 h. After cooled to rt, the mixture was poured onto 100 mL ice-water solution and this solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. The solvent was removed under vacuo to obtain the crude product which was purified by silica gel flash chromatography to yield the title product, (260 mg, 75%); LCMS; 93%, ESI+ Calcd: 434.5, found m/z: 335.6 (M+1-boc); 1H NMR (400 MHz, CDCl3); δ 1.33-1.39 (m, 2H), 1.47 (s, 9H), 1.66-1.68 (m, 2H), 1.81-2.10 (m, 4H), 3.30-3.45 (m, 2H), 3.75-4.21 (m, 3H), 6.90 (d, J 9.2 Hz, 2H), 6.91-6.94 (m, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.24-7.27 (m, 2H)

Workup

  1. customat rt
  2. additionwas added
  3. customThe vial was sealed
  4. temperatureAfter cooled to rt
  5. extractionthis solution was extracted with EtOAc (3×30 mL)
  6. washThe combined organic layers were washed with water (2×30 mL), brine (30 mL)
  7. dry with materialdried over anhydrous Na2SO4
  8. customThe solvent was removed under vacuo
  9. customto obtain the crude product which
  10. customwas purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-7b3a1030eed94441ad34cc7d3949e516
Source dataset
uspto-grants-2013_12
Patent number
US08598359B2

Reaction notes

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