Preparation method of (S)-(+)-3-hydroxytetrahydrofuran_Industrial additives

Background and overview of the preparation method of (S)-(+)-3-hydroxytetrahydrofuran

(S)-(+)-3-Hydroxytetrahydrofuran is used as an intermediate for the first-line treatment of advanced non-small cell lung cancer and the raw material drug afatinib in patients with HER2-positive advanced breast cancer.

Preparation method of (S)-(+)-3-hydroxytetrahydrofuran

Preparation method report 1 of (S)-(+)-3-hydroxytetrahydrofuran,

A synthesis method of (S)-(+)-3-hydroxytetrahydrofuran, including the following steps:

(1) Add 250g (1.86mol) L-malic acid and 500ml methanol into a 1000ml four-neck reaction flask, start stirring, add 20g (0.1mol) concentrated sulfuric acid, complete the addition, turn on the condensed water, and keep the oil bath at 75°C , react under reflux for 2 hours, take a sample and send it to the gas phase to detect that the reaction is complete. After cooling to room temperature, add sodium carbonate to adjust the pH to 8, remove the methanol under reduced pressure, add 100ml of water, and extract the water phase with dichloromethane three times, 100ml each time. After three extractions, check whether the water phase has been extracted cleanly. If it is not extracted cleanly, use 100ml of methylene chloride to extract again, combine the organic phases, remove the solvent under reduced pressure, and evaporate 277gL-malic acid dimethyl ester. The yield is 92%;

(2) Add 100ml tetrahydrofuran into a 500ml four-neck reaction flask, add 4.663g (0.123mol) sodium borohydride with stirring, open the condensed water, pyridinium chlorochromate, and then add 10g (0.0617mol) L-apple Slowly drop the acid dimethyl ester into the reaction bottle. After the drop is completed, the oil bath is heated to reflux. 20 ml of methanol is added dropwise to the reaction solution under reflux. After the drop is completed, the dimethyl acid dicarbonate is returned to the flow of di-tert-butyl dicarbonate and stirred for 2 hours. Take a sample to check that the reaction is complete. Cool to room temperature to get a mixed solution, then add 500ml absolute ethanol into a 1000ml four-neck reaction bottle, start stirring, pour the mixed solution into absolute ethanol, slowly add 15g (0.15mol) phosphoric acid dropwise, stir at room temperature for 25min, and filter , the filter cake was rinsed three times with absolute ethanol, 20 ml each time, the organic phases were combined, and the solvent was removed under reduced pressure to obtain 5.8 g of crude chiral 1,2,4-butanetriol, with a yield of 90%;

(3) Add the obtained crude chiral 1,2,4-butanetriol into a vacuum distillation device, raise the temperature to 120°C to react with itself, and steam out (S)-(+)-3-hydroxyl under reduced pressure. A mixture of tetrahydrofuran and water was then dehydrated under reduced pressure at a temperature of 76°C to obtain 2.4g (S)-(+)-3-hydroxytetrahydrofuran, with a yield of 45% and an optical purity >99%ee (by hand determined by gas chromatography).

Preparation method report 2 of (S)-(+)-3-hydroxytetrahydrofuran,

Preparation of L-malic acid dimethyl ester 2: Dissolve 30g L-malic acid (0.224mol) in 90ml methanol, cool to -10°C, add 39ml sulfoxide dichloride (0.55mol) dropwise while stirring, for 1.5h Finished adding. Stir at room temperature for 4 hours, then heat to reflux for 1 hour to stop the reaction. Concentrate under reduced pressure, add 125 ml of 20% sodium carbonate solution, and adjust pH=7. Extract with ethyl acetate three times, 100ml each time. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 33.68g of colorless oily liquid with a yield of 93%.

Preparation of butanetriol 3: Dissolve 32.4g L-dimethyl malate (0.2mol) in 100ml methanol, add 8.48g potassium borohydride (0.16mol) and 17g lithium chloride (0.4mol), and heat to reflux. After that, add 4.24g potassium borohydride (0.08mol) every 20 minutes for a total of 5 times. After the addition is complete, continue refluxing for 3 hours. TLC detects that there is no raw material point, and the reaction is stopped. A large amount of solids were first removed by filtration, and the pH value of the filtrate was adjusted to 3 with sulfuric acid. The precipitated solids were removed by filtration again, and concentrated under reduced pressure. The obtained solid-liquid mixture was diluted with 20 ml of ethyl acetate and 20 ml of ethanol, stirred, and filtered. The filtrate was concentrated under reduced pressure to obtain 21g of yellow viscous liquid.

Preparation of (S)-(+)-3-hydroxytetrahydrofuran 4: Add 2g (0.01mol) of p-toluenesulfonic acid monohydrate to the crude product obtained in the previous step, heat to dissolve and continue to raise the temperature to 200°C. Fractional distillation under reduced pressure (87°C/22mmHg) collected 7.6g of yellow oily liquid, with a two-step yield of 43%.

References

[1][Chinese invention] CN201710564259.2 A synthesis method of (S)-3-hydroxytetrahydrofuran

[2][China invention, China invention authorization] CN200610036592.8 A method of synthesizing S-(3)-hydroxytetrahydrofuran