Triethylamine → (3S)-2,3-Dihydro-3-(2-propyn-1-ylamino)-1H-inden-5-yl N-ethyl-N-methylcarbamate

HRID 1454056Notes

Reaction equation

HRID 1454056 reaction equation
O[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:25]([NH2:28])[C:26]#[CH:27]>ClCCl>[CH2:25]([NH:28][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1)[C:26]#[CH:27]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 239041PropargylamineHCID 68829372HCID 68829372, compound

Product 1

HCID 6918437(3S)-2,3-Dihydro-3-(2-propyn-1-ylamino)-1H-inden-5-yl N-ethyl-N-methylcarbamateYield 70.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Methanesulfonyl anhydride (1.544 g, 8.9 mmol) as a solution in dichloromethane (7.5 mL+2.5 mL) was added to a stirred solution of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (1.04 g, 4.4 mmol) and triethylamine (2.5 mL, 17.7 mmol) in dichloromethane (10 mL) at −35° C. (external) over 10 minutes. The reaction was maintained at this temperature for 45 minutes before propargylamine (3.0 mL, 44.3 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (100 mL) and ice-water (100 mL). The organic material 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, 50 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 40 mL) before being extracted with ethyl acetate (50 mL). This final organic extract was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (842 mg, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, d, J8, Ar), 7.09 (1H, s, Ar), 6.94 (1H, brd, J, 8, Ar), 4.39 (1H, dd, J6 and 6, NHCH), 3.55 (1H, Dd, J 17 and 2, NCHH), 3.49 (1H, Dd, J 17 and 2, NCHH), 3.46 (rotamer A, 1H, q, J 8, MeCHHN), 3.40 (rotamer B, 1H, q, J 7, MeCHHN), 3.06 (rotamer A, 1.5H, s, MeN), 3.03-2.95 [2.5H, m, NCHCH2CHH and rotamer B, Me, incl. at 2.98 (rotamer B, 1.5H, s, MeN)], 2.83-2.75 (1H, m, NCHCH2CHH), 2.48-2.39 (1H, m, NCHCHH), 2.25 (1H, t, J2, ≡H), 1.92-1.83 (1H, m, NCHCHH), 1.23 (rotamer A, 1.5H, t, J7, MeN) and 1.18 (rotamer B, 1.5H, t, J7, MeN). Analysis of this material by chiral LC indicated it to be 62% e.e.

Workup

  1. additionwas added
  2. custombefore being partitioned between ethyl acetate (100 mL) and ice-water (100 mL)
  3. concentrationThe organic material was concentrated under reduced pressure
  4. customto afford a brown oil which
  5. customwas partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 50 mL)
  6. additionThe aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 40 mL)
  7. extractionbefore being extracted with ethyl acetate (50 mL)
  8. extractionThis final organic extract
  9. dry with materialwas dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-74fd89e431064b4b9e500179b259a8b1
Source dataset
uspto-grants-2009_01
Patent number
US07476757B2

Reaction notes

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