4-Methylmorpholine → HCID 69290243, compound

HRID 2211838Notes

Reaction equation

HRID 2211838 reaction equation
CN1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([OH:28])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.[CH2:40]([CH:47]1[NH:53][CH2:52][CH2:51][CH2:50][N:49]([CH3:54])[C:48]1=[O:55])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)C.CC1C=C(Cl)C=CC=1OCCCC(O)=O>C1COCC1.CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([N:53]1[CH2:52][CH2:51][CH2:50][N:49]([CH3:54])[C:48](=[O:55])[C@H:47]1[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:28])=[O:22])([CH3:17])([CH3:18])[CH3:19]

Participants

8

Reactant 5

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 7146288(R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acidHCID 21962109HCID 21962109, compoundHCID 131725911HCID 131725911, compound

Product 1

HCID 69290243HCID 69290243, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

N-Methylmorpholine (0.048 mL) and isobutyl chloroformate (0.026 mL) were added to a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (67 mg) in THF (1 mL) at −20° C. and the resultant mixture was stirred for 1 h. 3-Benzylhexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride obtained in Step B above (48 mg) and N-methylmorpholine (0.024 mL) in DMF (1 mL) were added. The mixture was stirred for 30 min at −20° C. and for 36 h at ambient temperature, and then evaporated. The residue was treated with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic extract evaporated. The product obtained was purified by preparative TLC (silica gel, methanol/concentrated ammonium hydroxide/dichloromethane 4.4:0.1:95.5) to obtain the coupled product as a mixture of diastereomers. The isomers were resolved by HPLC (ChiralPAK AD, 14% ethanol/bexane) and the faster eluting (R,S)-isomer and slower eluting (R,R)-isomer were collected.

Workup

  1. customevaporated
  2. additionThe residue was treated with saturated aqueous ammonium chloride solution
  3. extractionextracted with ethyl acetate
  4. extractionthe organic extract
  5. customevaporated
  6. customThe product obtained
  7. customwas purified by preparative TLC (silica gel, methanol/concentrated ammonium hydroxide/dichloromethane 4.4:0.1:95.5)
  8. customto obtain the coupled product
  9. additionas a mixture of diastereomers
  10. washthe faster eluting (R,S)-isomer
  11. washslower eluting (R,R)-isomer
  12. customwere collected

Sources & evidence

ORD record
ord-d9d0606bd09a4918b6729143ee4d8e67
Source dataset
uspto-grants-2006_09
Patent number
US07101871B2

Reaction notes

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