4-Methylmorpholine → 1,1,1-Trifluoro-3-[(N-acetylprolyl)alanylprolylamino]butan-2-ol

HRID 366935Notes

Reaction equation

HRID 366935 reaction equation
[NH:1]1[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].CN1CC[O:25][CH2:24][CH2:23]1.C(OC(Cl)=O)C(C)C.Cl.[OH:37][CH:38]([C:42]([F:45])([F:44])[F:43])[CH:39]([NH2:41])[CH3:40]>C(#N)C.C(Cl)(Cl)Cl>[F:43][C:42]([F:45])([F:44])[CH:38]([OH:37])[CH:39]([NH:41][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[C@@H:2]1[CH2:18][CH2:19][CH2:20][N:1]1[C:24](=[O:25])[CH3:23])[CH3:40]

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 9817252L-prolyl-L-alanyl-L-prolineHCID 145032453-Amino-1,1,1-trifluorobutan-2-ol hydrochloride

Product 1

HCID 145032661,1,1-Trifluoro-3-[(N-acetylprolyl)alanylprolylamino]butan-2-olYield 23%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
-15 °C

Procedure

Ac-L-prolyl-L-alanyl-L-proline (1.17 g, 3.61 mmol) was suspended in dry acetonitrile (55 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and internal thermometer. The suspension was cooled to -15° C. and N-methylmorpholine (0.40 ml, 3.61 mmol) was added followed by isobutylchloroformate (0.47 ml, 3.61 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Ten minutes after the addition was completed, a mixture of 3-hydroxy-4,4,4-trifluoro-2-butyl-amine hydrochloride (0.65 g, 3.61 mmol) and N-methylmorpholine (0.40 ml, 3.61 mmol) in chloroform (25 ml) was added at such a rate as to maintain the internal reaction temperature at -100 to -15° C. The reaction mixture was allowed to warm slowly to room temperature and then stirred at room temperature for 4 hours. The reaction mixture was evaporated on a rotary evaporator to an oily residue which was dissolved in water (65 ml) and treated with a mixed bed resin (J. T. Baker--ANGMI-615, 17 g). After 15 minutes the mixture was filtered and the filtrate evaporated on a rotary evaporator. Chromatography using methylene chloride--10% methanol as the eluent gave the above-named product, (0.37 g) in 23% yield.

Workup

  1. customfitted with an overhead stirrer
  2. temperatureto maintain the internal reaction temperature at -10° to -15° C
  3. additionTen minutes after the addition
  4. additionwas added at such a rate as
  5. temperatureto maintain the internal reaction temperature at -100 to -15° C
  6. temperatureto warm slowly to room temperature
  7. customThe reaction mixture was evaporated on a rotary evaporator to an oily residue which
  8. dissolutionwas dissolved in water (65 ml)
  9. additiontreated with a mixed bed resin (J. T. Baker--ANGMI-615, 17 g)
  10. filtrationAfter 15 minutes the mixture was filtered
  11. customthe filtrate evaporated on a rotary evaporator
  12. customgave the above-named product, (0.37 g) in 23% yield

Sources & evidence

ORD record
ord-7f9e32f2d025493b973507e4bf6ee24d
Source dataset
uspto-grants-2000_10
Patent number
US06130315

Reaction notes

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