Phenethylamine → Pyrrolidine-1-carboxylic acid 4-phenethylcarbamoyloxy-cyclohexylmethyl ester

HRID 68483Notes

Reaction equation

HRID 68483 reaction equation
[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C1N=CN([C:15]([N:17]2[CH:21]=N[CH:19]=[CH:18]2)=[O:16])C=1.N1CCCC1.[CH3:27]I.[CH2:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[O:38]1CCC[CH2:39]1>O.C(#N)C>[CH2:29]([NH:37][C:39]([O:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][O:1][C:15]([N:17]2[CH2:18][CH2:19][CH2:27][CH2:21]2)=[O:16])[CH2:4][CH2:5]1)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1

Participants

9

Reactant 6

HCID 1001PhenethylamineHCID 6328Methyl iodideHCID 8028TetrahydrofuranHCID 31268PyrrolidineHCID 682631,1'-Carbonyldiimidazole2×HCID 12892866Rac-(1s,4s)-4-(hydroxymethyl)cyclohexanol

Product 1

HCID 56953266Pyrrolidine-1-carboxylic acid 4-phenethylcarbamoyloxy-cyclohexylmethyl esterYield 55%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

To a solution of 4-hydroxymethylcyclohexanol (2 mmol) in 10 mL of tetrahydrofuran (THF) was added CDI (2.2 mmol) and the resulting mixture was stirred for 2 hours at room temperature. Then, pyrrolidine (3 mmol) was added and stirred for 2 hours at 60° C. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:1) to provide a intermediate compound. The intermediate compound was dissolved in acetonitrile (10 mL), and CDI (2.2 mmol) was added. After 1 hour stirring at 80° C., methyl iodide (10 mmol) was added and stirred for additional 1 hour at 80° C. The resulting reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), and phenethylamine (3 mmol) was added and stirred for 4 hours at 80° C. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:3), thereby completing the preparation of a target compound (411 mg, 55% yield).

Workup

  1. stirringstirred for 2 hours at 60° C
  2. extractionfollowed by few times of extraction with methylene chloride
  3. dry with materialThe combined organic layer was dried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:1)
  7. customto provide a intermediate compound
  8. stirringAfter 1 hour stirring at 80° C.
  9. stirringstirred for additional 1 hour at 80° C
  10. customThe resulting reaction mixture
  11. concentrationwas concentrated under reduced pressure
  12. dissolutionThe residue was dissolved in acetonitrile (10 mL)
  13. stirringstirred for 4 hours at 80° C
  14. extractionfollowed by few times of extraction with methylene chloride
  15. dry with materialThe combined organic layer was dried over anhydrous magnesium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated under reduced pressure
  18. customThe residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:3)

Sources & evidence

ORD record
ord-0a11e633b30447f1beaaca692222b610
Source dataset
uspto-grants-2014_09
Patent number
US08822463B2

Reaction notes

Loading…