Methanol → {2-Fluoro-4-[4-((S)-2-methyl-pyrrolidin-1-yl)-cyclohex-1-enyl]-phenyl}-carbamic acid benzyl ester

HRID 1027435Notes

Reaction equation

HRID 1027435 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH:21](OS(C)(=O)=O)[CH2:20][CH:19]=2)=[CH:14][C:13]=1[F:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH:21]([N:32]3[CH2:33][CH2:34][CH2:35][C@@H:31]3[CH3:30])[CH2:20][CH:19]=2)=[CH:14][C:13]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 6999702(2S)-2-methylpyrrolidineHCID 86678095Methanesulfonic acid 4-(4-benzyloxycarbonylamino-3-fluoro-phenyl)-cyclohex-3-enyl ester

Product 1

HCID 54591450{2-Fluoro-4-[4-((S)-2-methyl-pyrrolidin-1-yl)-cyclohex-1-enyl]-phenyl}-carbamic acid benzyl ester

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

Methanesulfonic acid 4-(4-benzyloxycarbonylamino-3-fluoro-phenyl)-cyclohex-3-enyl ester (200 mg, 0.47 mmol, 1 equiv.) was dissolved in 5 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (159 mg, 1.88 mmol, 4 equiv.) and K2CO3 (285 mg, 2.07 mmol, 4.4 equiv.). The suspension was de-aerated by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. externally with stirring under nitrogen for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction is complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (10 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product. The crude product was purified on a silica gel column, eluted with DCM, followed by 5% MeOH in DCM and 5% of 7N NH3-MeOH in DCM. The combined fractions containing the product were concentrated to yield the title compound.

Workup

  1. customThis solution was transferred into a flask
  2. temperatureheated on an oil bath
  3. customset at 80° C.
  4. customAcetonitrile was removed in vacuo
  5. customThe two layers were separated
  6. extractionthe aqueous layer was extracted with DCM (2×10 mL)
  7. washThe combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL)
  8. dry with materialdried (K2CO3)
  9. filtrationThe solution was filtered
  10. concentrationThe filtrate was concentrated in vacuo
  11. customto obtain a crude product
  12. customThe crude product was purified on a silica gel column
  13. washeluted with DCM
  14. additionThe combined fractions containing the product
  15. concentrationwere concentrated

Sources & evidence

ORD record
ord-f1f73c07f3aa43ae8222324d66e966e5
Source dataset
uspto-grants-2014_05
Patent number
US08735385B2

Reaction notes

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