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