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