Acetic Acid → rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester

HRID 527484Notes

Reaction equation

HRID 527484 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.CC(C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+].CCN([CH:55]([CH3:57])[CH3:56])C(C)C.Cl[C:59]([O:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)=[O:60]>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[F:68][C:65]1[CH:66]=[CH:67][C:62]([O:61][C:59](=[O:60])[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)[CH:55]([CH3:56])[CH3:57])=[CH:63][CH:64]=1

Participants

12

Reactant 7

HCID 176Acetic AcidHCID 180AcetoneHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 27332564-Fluorophenyl chloroformateHCID 5049666Sodium triacetoxyborohydrideHCID 669406161-Benzyl-4-(4-chlorophenyl)pyrrolidin-3-amine

Product 1

HCID 58312665rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl esterYield 61.5%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 3.1 g (10.8 mmol) rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-amine, 785 mg (13.5 mmol) acetone, 974 mg (16.2 mmol) acetic acid and 3.44 g (16.2 mmol) sodium triacteoxyborohydride in 50 mL THF was stirred for 4 h at room temperature. Water and Na2CO3 aq. was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered off and evaporated to dryness. The residue was dissolved in 50 mL DCM and 1.75 g (13.5 mmol) DIPEA and 13.2 mg (0.1 mmol) DMAP was added. The mixture was cooled to 0-5° C. and 2.08 g (11.9 mmol) 4-fluorophenyl chloroformate in 20 mL DCM was added. The mixture was stirred at room temperature over night and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from TBME and heptane. The product containing fractions were evaporated to yield 3.1 g (61%) of the title compound as light yellow viscous oil. MS m/e: 467.2 [M+H]+

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried with Na2SO4
  4. filtrationfiltered off
  5. customevaporated to dryness
  6. dissolutionThe residue was dissolved in 50 mL DCM
  7. temperatureThe mixture was cooled to 0-5° C.
  8. stirringThe mixture was stirred at room temperature over night
  9. customevaporated to dryness
  10. customThe residue was purified by flash column chromatography on silica eluting with a gradient
  11. customformed from TBME and heptane
  12. additionThe product containing fractions
  13. customwere evaporated

Sources & evidence

ORD record
ord-16c16ec8359d48c290027924601ca2ae
Source dataset
uspto-grants-2016_05
Patent number
US09346786B2

Reaction notes

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