Application of (1R,2R)-1,2-cyclohexanedimethanol_Industrial additives

Overview^[1]

lurasidone is a new type of atypical antipsychotic drug, which is a benzodiazepine derivative. Chiral (1R, 2R)-1,2-cyclohexanedimethanol is an important intermediate in the preparation of this drug and has great market demand. At present, (1R,2R)-1,2-cyclohexanedimethanol is mainly obtained by reducing chiral cyclohexanedicarboxylic acid and its derivatives using lithium aluminum tetrahydride or sodium borohydride. This method will generate a large amount of solid waste. Lithium metaphosphate or sodium metaborate requires complex post-processing and consumes a large amount of water, which is very unfriendly to the environment. Therefore, industry researchers urgently need to develop low-cost and environmentally friendly catalysts to accelerate the industrial production of this reaction.

Preparation^[2]

(1R,2R)-1,2-cyclohexanedimethanol is prepared as follows:

1) Use trans-1,2-cyclohexanedicarboxylic acid (SM-1) as raw material to prepare 1R,2R-cyclohexanedicarboxylic acid (SM-2) through separation; trans-1,2- Cyclohexanedioic acid and R-(+)-α-phenylethylamine react at 5°C to form a salt, which is filtered and dried at room temperature; then reconstituted in hot ethanol/toluene (1:1) mixed solvent. Crystallize once, finally add hydrochloric acid to free it, and extract with diethyl ether to obtain (R, R)-1,2-cyclohexanedicarboxylic acid.

2) Methyl esterification to prepare 1R, 2R-cyclohexanedicarboxylic acid dimethyl ester; add 1R, 2R-cyclohexanedicarboxylic acid to ml of methanol, add concentrated sulfuric acid dropwise at room temperature and then heat to reflux, react for 5 hours .

3) 1R,2R-cyclohexanedimethanol is prepared by reduction; add 1R,2R-cyclohexanedioic acid dimethyl ester, THF, and NaBH4 into the reaction flask, heat to 45°C, slowly add methanol dropwise, and finish dripping After refluxing for 2.5h, 1R,2R-cyclohexanedimethanol was obtained through post-treatment.

Apply^[2]

(1R,2R)-1,2-cyclohexanedimethanol can be used to prepare lurasidone:

1) Methanesulfonic acid esterification reaction prepares 1R,2R-cyclohexanedimethanesulfonate; add dichloromethane and triethylamine to 1R,2R-cyclohexanedimethanol, and add methane dropwise Sulfonyl chloride. After the dropwise addition, the temperature was raised to 30°C and allowed to react for 1 hour. After post-treatment, wash, dry and concentrate to obtain a crude product, which is recrystallized from ethyl acetate and n-hexane to obtain 1R, 2R-cyclohexanedimethyl dimethane sulfonate.

2) Condensation reaction to obtain crude lurasidone; use 3-piperazinyl-1,2-benzisothiazole (SM-4) and 1R,2R-cyclohexanedimethyldimethanesulfonate ( SM-5) Stir in DMF, while adding potassium carbonate and tetra-n-butylammonium bisulfate to reflux. The generated quaternary ammonium salt was added to DMF, exonorbornimide (SM-5), potassium carbonate and a trace amount of water for reflux reaction for 6 hours, washed with water, extracted with DMF, and concentrated to obtain lurasidone.

3) Recrystallization of the crude product; dissolve the crude product of lurasidone in DMF and recrystallize it in 10 times the amount of DMF.

4) Salt formation to obtain lurasidone hydrochloride; lurasidone is prepared in acetone and 3.6% dilute hydrochloric acid to obtain lurasidone hydrochloride. After calculation, the yield was about 84.2%, and the purity monitored by HPLC was 99.83%.

Main reference materials

[1] CN201810709488.3 Synthesis catalyst of chiral cyclohexanedimethanol compounds, its preparation method and application

[2]CN201510997534.0 Preparation method of lurasidone hydrochloride