Methyl 4-aminobenzoate → Methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoate

HRID 350460Notes

Reaction equation

HRID 350460 reaction equation
C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([F:19])[CH2:16][CH:15]1[CH2:20]O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.ClCCCl.CC(O)=O.O.C(N(CC)CC)C.CS(C)=O>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([F:19])[CH2:16][CH:15]1[CH2:20][NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1)=[O:13])([CH3:8])([CH3:9])[CH3:10]

Participants

11

Reactant 4

HCID 12082Methyl 4-aminobenzoateHCID 65578Oxalyl chlorideHCID 5049666Sodium triacetoxyborohydrideHCID 56973583Tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Product 1

HCID 23511875Methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoateYield 77%

Reagents, catalysts & solvents 6

HCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of oxalyl chloride (0.28 ml, 2.3 mmol) in CH2Cl2 (20.0 ml) was added DMSO (0.39 ml) at −78° C. After 5 minutes, to the mixture was added 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinylmethanol (500 mg, 2.28 mmol) in CH2Cl2 (5.0 ml). The mixture was stirred for 30 minutes at −78° C., and triethylamine (1.6 ml) was added. The mixture was stirred for 30 minutes at −78° C., and stirred for 30 minutes at room temperature. Water was added to the mixture, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, methyl 4-aminobenzoate(302 mg, 2.0 mmol), and AcOH (0.13 ml) in DCE (10 ml) was added NaBH(OAc)3 (656 mg, 3.09 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. Sat. NaHCO3 was added to the residue, and extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:3, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoate (541 mg, 77%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.55–1.59 (m, 1H), 2.16–2.27 (m, 1H), 2.89–3.03 (m, 2H), 3.19–3.28 (m, 2H), 3.69–3.73 (m, 1H), 3.84 (s, 3H), 5.15 and 5.29 (each s, total 1H), 6.55–6.58 (m, 2H), 7.84–7.86 (m, 2H).

Workup

  1. stirringThe mixture was stirred for 30 minutes at −78° C.
  2. stirringstirred for 30 minutes at room temperature
  3. extractionextracted with CH2Cl2
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe crude product was used to the subsequent reaction without further purification
  7. stirringThe reaction mixture was stirred at room temperature for 18 hr
  8. concentrationThe mixture was concentrated in vacuo
  9. additionSat. NaHCO3 was added to the residue
  10. extractionextracted with CH2Cl2
  11. washThe extract was washed with brine
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated in vacuo
  14. customThe residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:3

Sources & evidence

ORD record
ord-f94de10be7b44ad0896ba87df3b7c455
Source dataset
uspto-grants-2007_02
Patent number
US07179819B2

Reaction notes

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