Preparation of (S)-pyrrolidine-3-methanol_Industrial additives

Background and overview^[1-2]

(S)-pyrrolidine-3-methanol is a pharmaceutical intermediate that can be prepared through a five-step reaction from dimethyl itaconate as the starting material. There are reports in the literature that it can be used to prepare vanin-1 inhibitors.

Preparation^[1]

Step 1,

To a solution of dimethyl itaconate (25g, 158mmol) in methanol (150ml) was added (R)-1-phenylethylamine (20ml, 158mmol) at room temperature. The resulting mixture was stirred for 18 hours and concentrated. The residue was dissolved in toluene (100 ml) and p-toluenesulfonic acid (3.0 g, 16 mmol) was added at room temperature. The mixture was refluxed for 16 hours and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 1/1 to 1/3) to obtain (3S)-5-oxo-1-(((1R)-phenylethyl) (3R)-5-oxo-1-((1R)-1-benzene) as a white solid (14.0 g, 56.5 mmol, 36%) and as a yellow oil Ethyl)pyrrolidine-3-carboxylic acid methyl ester (18.7 g, 75.5 mmol, 48%).

Step 2,

To a slurry of lithium aluminum hydride (4.55 g, 120 mmol) in cyclopentyl methyl ether (100 ml) under a nitrogen atmosphere, (3S)-5-oxo-1-(((3S)-5-oxo-1-(( 1R)-phenylethyl)pyrrolidine-3-carboxylate (14.0 g, 56.5 mmol). The resulting mixture was stirred for 15 minutes and gradually warmed to room temperature. After one hour, the reaction was quenched by adding saturated aqueous sodium sulfate solution at 0°C, and the resulting solid material was removed by filtration. The filtrate was concentrated to obtain ((3S)-1-((1R)-1-phenylethyl)pyrrolidin-3-yl)methanol (6.62g, 32mmol, 57%).

Step 3,

To ((3S)-1-((1R)-1-phenylethyl)pyrrolidin-3-yl)methanol (6.62 g, 32 mmol) and imidazole (4.77 g, 70 tert-butyldimethylsilyl chloride (5.28 g, 35 mmol) was added to N,N-dimethylformamide (90 ml) of anti-aging agent, and the resulting mixture was heated to room temperature. The reaction mixture was stirred overnight and poured into water. Extract with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 90/10 to 75/25) to obtain (3S)-3-(((tert-butyl(dimethyl)) Silyl)oxy)methyl)-1-((1R)-1-phenylethyl)pyrrolidine (8.81 g, 27.6 mmol, 86%) as a colorless oil.

Step 4,

To (3S)-3-(((tert-butyl(dimethyl)silyl)oxy)methyl)-1-((1R)-1-phenylethyl) at room temperature To a solution of pyrrolidine (8.81 g, 27.6 mmol) in 1,2-dichloroethane (75 ml) was added 1-chloroethyl chloroformate (8.1 ml, 75 mmol). The resulting mixture was refluxed for 5 hours and then cooled to room temperature. To the brown solution was added diisopropylethylamine (2.3 ml, 13 mmol). The mixture was refluxed for an additional 3 hours and concentrated. The residue was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol (75 ml) and refluxed for 1 hour. After concentration under reduced pressure, 1N aqueous hydrochloric acid solution was added. The aqueous solution was washed with ethyl acetate and basified with solid potassium carbonate. The basic solution was cooled to 0°C and a solution of di-tert-butyl dicarbonate (6.3 g, 29 mmol) in tetrahydrofuran (75 ml) was added. The resulting mixture was stirred for 3 hours. The organic material was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 3/1 to 1/2) to obtain (S) 3-(hydroxymethyl)pyrrolidine- tert-Butyl-1-carboxylate (2.96 g, 14.7 mmol, 53%) as colorless oil.

Step 5,

At room temperature, mix (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-Hanwha PVC paste resin butyl ester (2.96g, 14.7mmol) and 4N hydrogen chloride in acetic acid in a round-bottomed flask. A solution of ethyl ester (30 ml) was mixed. The mixture was stirred for 2 hours and concentrated in vacuo. The residue was diluted with ethanol (10 ml) and solid potassium carbonate was added. Add a small amount of water to the resulting slurry until bubbles form. After 2 hours, filtration was performed to remove solid matter, and the filtrate was concentrated to obtain (S)-pyrrolidine-3-methanol (1.49g, 14.7mmol, >99%) as an orange oil.

References

[1]From PCT Int. Appl., 2011019090, 17 Feb 2011

[2] From PCT Int. Appl., 2020102575, 22 May 2020