Ethylamine → L-Leucine, N-acetyl-, compd. with (alphaS)-3-ethoxy-4-methoxy-alpha-((methylsulfonyl)methyl)benzenemethanamine (1:1)

HRID 1178452Notes

Reaction equation

HRID 1178452 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].CCN.[C:22]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:24])[CH3:23]>CO>[C:22]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])(=[O:24])[CH3:23].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]

Participants

5

Reactant 3

HCID 6341EthylamineHCID 70912N-Acetyl-L-leucineHCID 112887921-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine

Product 1

HCID 66648136L-Leucine, N-acetyl-, compd. with (alphaS)-3-ethoxy-4-methoxy-alpha-((methylsulfonyl)methyl)benzenemethanamine (1:1)Yield 90%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

Resolution of 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine. A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1-methylsulphonyl)-eth-2-ylamine (137.0 g 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30° C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 @pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm×4.6 mm, 0.5 mL/min., @240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).

Workup

  1. customA 3 L 3-necked round bottom flask was equipped with a mechanical stirrer
  2. temperatureThe stirred slurry was heated
  3. temperatureto reflux for 1 hour
  4. filtrationThe slurry was filtered
  5. washwashed with methanol (250 L)
  6. customThe solid was air-dried
  7. customdried in vacuo at ambient temperature to a constant weight
  8. customgiving 109.5 g (98% yield) of the crude product (85.8% ee)
  9. temperatureto reflux for 1 hour
  10. temperaturecooled to room temperature
  11. stirringstirred for an additional 3 hours at ambient temperature
  12. filtrationThe slurry was filtered
  13. washthe filter cake was washed with methanol (200 mL)
  14. customThe solid was air-dried
  15. customdried in vacuo at 30° C. to a constant weight

Sources & evidence

ORD record
ord-2c87cce1148a442181553b791d4a2f6f
Source dataset
uspto-grants-2007_10
Patent number
US07276529B2

Reaction notes

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