Process for preparing optic pure 2-fluoro-alphar-methyl-[1,1'-diphenyl]-4-acetic acid
A diphenyl and methyl technology, applied to optically pure 2-fluoro-α-methyl-[1, can solve the problems of only 90-95% optical purity, not allowing optically pure compounds, and severe reaction conditions, etc. Achieve the effect of high yield, low cost and high optical purity of the product
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Embodiment 1
[0024] Example 1: Preparation of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid
[0025] Take 100 g (409 mmol) of the racemate of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid and (-)-1-deoxy-1-n-octylamino-D- Put 60 g (204.5 mmol) of glucitol into a reaction flask, add 1500 ml of isopropanol, and heat to reflux in an oil bath for 15 minutes. After the reaction was finished, stand at room temperature for more than 10 hours to crystallize, filter to obtain 95g (177mmol) of white solid ([α] D 20 =-17.8° (c=1, MeOH)), yield 86.4%.
[0026] The above white solid was recrystallized twice, the salt / isopropanol ratio was 1g / 13.5ml, and 80g (149mmol) of white solid was obtained ([α] D 20 =-19.0° (c=1, MeOH)), yield 72.7%.
[0027] Take 80 g (149 mmol) of the solid obtained in the third crystallization, put it into a round bottom flask, add 900 ml of 2N sulfuric acid aqueous solution and 600 ml of ethyl acetate, stir to dissolve the solid, perform liquid-liquid exchange...
Embodiment 2
[0029] Example 2: Racemization
[0030] The filtrate obtained by combining the reaction and recrystallization of Example 1 was concentrated under reduced pressure to obtain 80 g of a light yellow solid, which was put into a reaction flask, 400 ml of 4N sodium hydroxide solution was added, and the mixture was heated to reflux in an oil bath for 6 hours. After the reaction, cool to room temperature, add 140ml concentrated hydrochloric acid and 300ml ethyl acetate, stir to dissolve the solid, perform liquid-liquid exchange, extract the aqueous solution with ethyl acetate, combine the ethyl acetate extracts, wash with water, and dry over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure to obtain 59.7 g of the racemate ([α] D 20 =0° (c=1, MeOH)), yield 93.8%.
Embodiment 3
[0031] Example 3: Preparation of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid
[0032] Take 100 g (409 mmol) of the racemate of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid and (-)-1-deoxy-1-n-octylamino-D- Put 60 g (204.5 mmol) of glucitol into a reaction flask, add 1400 ml of absolute ethanol, and heat to reflux in an oil bath for 15 minutes. After the reaction was finished, stand at room temperature for more than 10 hours to crystallize, filter to obtain 59.2 g (110 mmol) of white solid ([α] D 20 =-18.3° (c=1, MeOH)), yield 53.6%.
[0033] Put 59.2g (110mmol) of the obtained white solid into a round-bottomed flask, add 670ml of 2N sulfuric acid aqueous solution, stir for 2 hours, filter, wash the solid with a small amount of water, and dry to obtain (S)-(+)-2-fluoro-α-methyl -[1,1'-diphenyl]-4-acetic acid 25.2g (103mmol) ([α] D 20 =+42.6° (c=1, EtOH)), ee value 0.95, yield 50.4% (based on (S)-enantiomer), chemical purity greater than 98%.
[0034] Add co...
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