Formic Acid → (+)-3-(2,3-Difluorophenyl)-1-methylpyrrolidin-3-OL

HRID 1931828Notes

Reaction equation

HRID 1931828 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.O.[CH:16](O)=O>C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]1

Participants

5

Reactant 3

HCID 284Formic AcidHCID 962WaterHCID 639883833-(2,3-Difluorophenyl)pyrrolidin-3-ol

Product 1

HCID 25143816(+)-3-(2,3-Difluorophenyl)-1-methylpyrrolidin-3-OL

Reagents, catalysts & solvents 1

HCID 712FormaldehydeSolvent

Procedure

Preparation according to Example 11: Enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol) in formic acid (7.2 mL) and aqueous formaldehyde (40%, 6.5 mL). 65° C. for 5 h. Water was added (50 mL), and the mixture was washed with diethyl ether. The water phase was basified with NaOH (5 M), extracted with ethyl acetate, dried (MgSO4) and evaporated. The crude compound was again treated with the same amount of formic acid and aqueous formaldehyde as above for 5 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1 to 2:1). Yield: 0.7 g. [α]D=−21.5° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 134.3° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 20), 58 (27), 141 (16), 127 (11), 57 (bp).

Workup

  1. customPreparation
  2. washthe mixture was washed with diethyl ether
  3. extractionextracted with ethyl acetate
  4. dry with materialdried (MgSO4)
  5. customevaporated
  6. additionThe crude compound was again treated with the same amount of formic acid and aqueous formaldehyde as above for 5 h
  7. customPurification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1 to 2:1)
  8. customrecrystallized from ethanol/diethyl ether

Sources & evidence

ORD record
ord-82b1a238d6514ce0a61e0dba10b0639c
Source dataset
uspto-grants-2012_05
Patent number
US08188301B2

Reaction notes

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