Acetone → (3RS,4SR)-1-[(Benzyloxy)carbonyl]-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid
Reaction equation
[OH-].[Na+].[C:3]([O:7][C:8](=[O:19])[CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH:14]([CH3:15])[CH2:13][NH:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].CC(C)=O.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][CH:14]([CH3:15])[C:10]([CH2:9][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:19])([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- 0.5 °C
Procedure
A 2 N aqueous sodium hydroxide solution (20.2 ml) was added to a mixture of (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Reference Example 1a (9.84 g, 40.5 mmol), acetone (39 ml) and water (49 ml) with stirring under ice-cooling (0 to 1° C.), and the reaction mixture was dissolved by stirring for 45 minutes. Benzyl chloroformate (6.35 ml, 44.5 mmol) and a 2 N aqueous sodium hydroxide solution (22.3 ml) were simultaneously added dropwise to the reaction mixture at an internal temperature of 3.5° C. or lower with stirring under ice-cooling (0 to 1° C.) over 20 minutes. The reaction liquid was stirred in an ice bath and gradually returned to mom temperature. This was stirred at mom temperature overnight. A 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction liquid with stirring under ice-cooling (internal temperature: about 15° C.), and the mixture was adjusted to pH 12. This reaction liquid was returned to room temperature and washed three times by adding ethyl ether. The aqueous layer was adjusted to pH 2 to 3 by sequentially adding a 2 N aqueous hydrochloric acid solution (20.2 ml) and a 1N aqueous hydrochloric acid solution (13 ml) with stirring under ice-cooling (internal temperature: 5° C. or lower). The aqueous layer was returned to mom temperature and extracted with ethyl acetate three times. The organic layer was washed with brine, and then dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water four times and then with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (14.53 g, yield: 95.1%).
Workup
- dissolutionthe reaction mixture was dissolved
- stirringby stirring for 45 minutes
- stirringlower with stirring under ice-
- temperaturecooling (0 to 1° C.) over 20 minutes
- customThe reaction liquid
- stirringwas stirred in an ice bath
- stirringThis was stirred at mom temperature overnight
- stirringwith stirring under ice-
- temperaturecooling (internal temperature: about 15° C.)
- customThis reaction liquid
- customwas returned to room temperature
- washwashed three times
- additionby adding ethyl ether
- additionby sequentially adding a 2 N aqueous hydrochloric acid solution (20.2 ml)
- stirringa 1N aqueous hydrochloric acid solution (13 ml) with stirring under ice-
- temperaturecooling (internal temperature: 5° C. or lower)
- extractionextracted with ethyl acetate three times
- washThe organic layer was washed with brine
- dry with materialdried over sodium sulfate
- filtrationfiltered
- concentrationconcentrated
- dissolutionThe residue was dissolved in ethyl acetate
- washwashed with water four times
- dry with materialwith brine, dried over sodium sulfate
- filtrationfiltered
- concentrationconcentrated
Sources & evidence
- ORD record
- ord-d675e5f9faf04a07b5b0ea371f15d748
- Source dataset
- uspto-grants-2013_07
- Patent number
- US08476301B2
Reaction notes
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