Triethylamine → Rasagiline

HRID 1454057Notes

Reaction equation

HRID 1454057 reaction equation
[C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([NH2:21])[C:19]#[CH:20].C(OCC)(=O)C>ClCCl>[CH2:18]([NH:21][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:19]#[CH:20]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 239041PropargylamineHCID 6971242(S)-(+)-1-Indanol

Product 1

HCID 3052776RasagilineYield 68%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Methanesulfonyl anhydride (3.0 g, 17.2 mmol) as a solution in dichloromethane (8 mL+4 mL) was added to a stirred solution of (S)-1-indanol (1.02 g, 7.6 mmol) and triethylamine (4.4 mL, 31.5 mmol) in dichloromethane (20 mL) at −26° C. (internal, −35° C. external) over 10 minutes. During the addition the internal temperature rose to −20° C. The reaction was maintained at −29° C. (internal, −35° C., external) for 45 minutes before propargylamine (5 mL, 78 mmol) was added over 2 minutes. The reaction was allowed to warm slowly to room temperature overnight before being portioned between ethyl acetate (50 mL) and ice-water (75 mL, pH of solution 9.7). The organic layer was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 40 mL, pH of solution <1). The aqueous layer was basified to pH>12.5 by addition of aqueous sodium hydroxide solution (2M, 30 mL) before being extracted with ethyl acetate (50 mL+30 mL). The combined final organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as a brown liquid (0.81 g, 68%). Analysis of this material by chiral GC indicated it to be 46% e.e.

Workup

  1. additionDuring the addition the internal temperature
  2. customrose to −20° C
  3. additionwas added over 2 minutes
  4. concentrationThe organic layer was concentrated under reduced pressure
  5. customto afford a brown oil which
  6. customwas partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 40 mL
  7. additionThe aqueous layer was basified to pH>12.5 by addition of aqueous sodium hydroxide solution (2M, 30 mL)
  8. extractionbefore being extracted with ethyl acetate (50 mL+30 mL)
  9. dry with materialwere dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-fbf38848d4b445bab399f065201bc50b
Source dataset
uspto-grants-2009_01
Patent number
US07476757B2

Reaction notes

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