4-Methylmorpholine → HCID 69290248, compound

HRID 2211831Notes

Reaction equation

HRID 2211831 reaction equation
CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:17][C:18]([OH:20])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[CH3:40][C@H:41]1[NH:47][CH2:46][CH2:45][CH2:44][NH:43][C:42]1=[O:48]>ClCCl.CN(C=O)C>[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:17][C:18]([N:47]1[CH2:46][CH2:45][CH2:44][NH:43][C:42](=[O:48])[C@H:41]1[CH3:40])=[O:20])=[O:14])([CH3:9])([CH3:10])[CH3:11]

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 7146288(R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acidHCID 68810550HCID 68810550, compound

Product 1

HCID 69290248HCID 69290248, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of N-methylmorpholine (0.38 μL) and (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (1.0 g) in 20 mL of dichloromethane at −20° C. was added isobutyl chloroformate (0.39 mL). The resultant mixture was stirred for 1 h. (3R)-hexahydro-3-methyl-2H-1,4-diazepin-2-one hydrochloride (500 mg) and N-methylmorpholine (0.40 mL) in dichloromethane (5 mL) and DMF (8 mL) were added. The mixture was stirred for 28 h, initially at −20° C. and then with slow warming to ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted sequentially with dichloromethane and ethyl acetate. The combined organic layer was washed sequentially with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (silica gel, 3 to 7% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane) to afford the coupled product. This was further purified by dissolving the product in a mixture of ethanol (7.5 mL) and hexane (16 mL) at 50° C. The solution was allowed to cool to ambient temperature overnight, and then placed in the refrigerator for 3 h. The solid was collected and washed with cold 5% ethanol/hexane to give the title compound.

Workup

  1. additionwere added
  2. temperaturewith slow warming to ambient temperature
  3. customThe reaction was quenched by the addition of saturated ammonium chloride solution
  4. extractionextracted sequentially with dichloromethane and ethyl acetate
  5. washThe combined organic layer was washed sequentially with water and brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was purified by chromatography (silica gel, 3 to 7% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane)
  9. customto afford the coupled product
  10. customThis was further purified
  11. dissolutionby dissolving the product
  12. additionin a mixture of ethanol (7.5 mL) and hexane (16 mL) at 50° C
  13. temperatureto cool to ambient temperature overnight
  14. waitplaced in the refrigerator for 3 h
  15. customThe solid was collected
  16. washwashed with cold 5% ethanol/hexane

Sources & evidence

ORD record
ord-eaf4635b503b4c64a2e993b9a3051996
Source dataset
uspto-grants-2006_09
Patent number
US07101871B2

Reaction notes

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