Acetic Acid → rac-4-fluorophenyl (3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl(ethyl)carbamate

HRID 527479Notes

Reaction equation

HRID 527479 reaction equation
[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+].CCN(C(C)C)C(C)C.Cl[C:58]([O:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)=[O:59]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[F:67][C:64]1[CH:65]=[CH:66][C:61]([O:60][C:58](=[O:59])[N:20]([C@H:10]2[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH2:21][CH3:22])=[CH:62][CH:63]=1

Participants

11

Reactant 7

HCID 176Acetic AcidHCID 177AcetaldehydeHCID 10340Sodium Carbonate2×HCID 81531DiisopropylethylamineHCID 27332564-Fluorophenyl chloroformateHCID 5049666Sodium triacetoxyborohydrideHCID 669406161-Benzyl-4-(4-chlorophenyl)pyrrolidin-3-amine

Product 1

HCID 58312658rac-4-fluorophenyl (3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl(ethyl)carbamate

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of 2.14 g (7.09 mmol) rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)-pyrrolidin-3-amine, 540 uL (9.5 mmol) acetaldehyde, 609 uL (10.6 mmol) acetic acid and 2.25 g (10.6 mmol) sodium triacetoxyborohydride was stirred at 20° C. over night. Water and Na2CO3 aq. was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with Na2SO4 and evaporated to dryness. The residue was taken up in 60 mL DCM. 1.15 g DIPEA (8.86 mmol) and 43.3 mg DMAP (354 μmol) was added. The brownish solution was cooled with an ice-bath. A solution of 1.48 g (8.51 mmol) 4-fluorophenyl chloroformate in 15 mL DCM was added drop-wise and the mixture was stirred at 0-5° C. for 1 h. Na2CO3 aq. was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from TBDME and heptane to yield after evaporation of the product containing fractions 1.62 g (50%) of the title compound as yellow oil. MS m/e: 453.3 [M+H]+.

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. dry with materialThe combined organic layers were dried with Na2SO4
  3. customevaporated to dryness
  4. temperatureThe brownish solution was cooled with an ice-bath
  5. stirringthe mixture was stirred at 0-5° C. for 1 h
  6. extractionthe mixture was extracted with DCM
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried with Na2SO4
  9. customevaporated to dryness
  10. customThe residue was purified by flash column chromatography on silica eluting with a gradient
  11. customformed from TBDME and heptane
  12. customto yield
  13. customafter evaporation of the product
  14. additioncontaining fractions 1.62 g (50%) of the title compound as yellow oil

Sources & evidence

ORD record
ord-d49aab882bde4c23b3869d5e43abaffe
Source dataset
uspto-grants-2016_05
Patent number
US09346786B2

Reaction notes

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