Preparation method of (S)-(-)-2-bromo-1-α-methylbenzyl alcohol_Industrial additives

Background and overview^[1-2]

(S)-(-)-2-Bromo-1-α-methylbenzyl alcohol is a chiral secondary alcohol and an important intermediate for the synthesis of optically active drugs. It is generally selectively prepared from o-bromoacetophenone. Prepared by reduction.

Preparation^[1-2]

Report 1,

Asymmetric synthesis of (S)-(-)-2-bromo-1-α-methylbenzyl alcohol:

Add 0.5 mmol of 1-(2-bromophenyl)ethanol into the test tube, add 1.5 mmol of dipropylene glycol dimethyl ether, fill it with an oxygen balloon, and react at 120°C for 12 hours until the reaction is complete. Add sodium formate to the reaction system. 2.5 mmol, then add 0.0025 mmol catalyst B, add 4 mL of methanol: water (3:1), replace with nitrogen 3 times, react at 50°C for 12 hours, wash with water after the reaction, extract the aqueous phase with ethyl acetate 3 times, and combine the organic phases Concentrated to dryness, separated by column chromatography (petroleum ether: ethyl acetate = 10:1), Rohm and Haas obtained (S)-(-)-2-bromo-1-α-methylbenzyl alcohol (67.3 mg) , the yield is 91%, and the ee value is 88%. HPLC separation conditions: chiral column Daicel OD-H column, mobile phase: n-hexane/isopropyl alcohol = 97:3 (volume ratio), flow rate: 1.0ml/min, wavelength: 215nm, temperature, 25°C, t1= 20.63min, t2=23.05min; ¹H NMR (MHz, CDCl₃): δ=7.61-7.52 (m, 2H), 7.38-7.34 (m, 1H ),7.17-7.12(m,1H),5.24(q,J＝6.4Hz,1H),2.85(s,1H), 1.48(d,J＝6.4Hz,3H);¹³ C NMR (100MHz, CDCl₃): δ=144.7,132.6,128.8,127.9, 126.7,121.7,69.1,23.6.

Report 2,

Add phenylruthenium dichloride (〔RuCl₂beneze〕2) (0.05mmol, 25 mg) into a 100mL Schlenk bottle, and bridge the chiral bisphosphine ligand (Rax)-BuP( 0.105mmol, 64.3mg), N,N-dimethylformamide 6 mL, stir the reaction at 100°C under nitrogen protection. After cooling the solution to room temperature, add chiral diamine (R, R)-DPEN (0.105 mmol, 23 mg), continue to stir the reaction at this temperature, distill the solvent under reduced pressure, add dichloromethane to dissolve the solid, and concentrate the solution , add hexane to the concentrated solution to produce a brown precipitate, filter, and distill the filtrate solvent under reduced pressure to obtain an earthy yellow solid as a ruthenium catalyst precursor. ³¹p NMR (CDCl₃, 202MHz) δ=47.5ppm(s) of the ruthenium catalyst precursor.

Add ruthenium catalytic precursor (0.0025mmol, 2.5mg), potassium tert-butoxide 0.114mmol, and n-butanol 1mL into a 100mL Schlenk bottle. Stir and dissolve at room temperature. Add o-bromoacetophenone (2.5mmol, 2.5mmol, 0.34mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 5MPa, stirring and reaction at 20°C for 48 hours. The hydrogen in the kettle was evacuated, followed by flash column chromatography and concentration under reduced pressure. The reaction conversion rate measured by gas chromatography was 99wt%, and the product was 89%ee(S)-(-)-2-bromo-1-α-methylbenzyl alcohol.

References

[1] [Chinese invention] CN201910258055.5 A method for deracemization to synthesize chiral alcohols