A kind of resolution method of 4-amino-12-bromo[2.2] to cyclopan

Abstract

A resolution method for 4-amino-12-bromo[2.2]paracyclophane is provided. L-proline protected by t-butyloxycarbonyl and racemic 4-amino-12-bromo[2.2]paracyclophane are reacted to generate a mixture of intermediates having configurations of (Rp, S) and (Sp, S). By utilizing a physical property difference (polar difference) of the intermediates having configurations of (Rp, S) and (Sp, S), the intermediates are separated by utilizing column chromatography, then recrystallization is performed for purification, and acidolysis is performed to obtain optically pure Sp-4-amino-12-bromo[2.2]paracyclophane and Rp-4-amino-12-bromo[2.2]paracyclophane. A resolution agent used in the method is cheap and nontoxic, resolution operation steps are simple, and high yields and good optical purities can be achieved, so that the method is suitable for large-scale preparation of the optically pure 4-amino-12-bromo[2.2]paracyclophane.

Description

technical field [0001] The invention relates to a method for resolving 4-amino-12-bromo[2.2] to cyclophenone, which belongs to the field of preparation of organic compounds. Background technique [0002] The chiral ligands have been widely used in the field of asymmetric catalysis, and [2.2] the chiral ligands of the cyclosporins are easier to construct a chiral environment due to their unique skeleton structure to achieve better The performance of stereo control makes this kind of ligands favored by scientific researchers, and plays a pivotal role in the field of asymmetric catalysis. Among them, 4-amino-12-bromo[2.2] is a typical representative of cyclofan, because the special skeleton structure of [2.2] makes 4-amino-12-bromo[2.2] has a chirality of cyclofan, its R p , S p The structures of the isomers are: [0003] [0004] So far, there have been many literatures reporting the application of 4-amino-12-bromo[2.2] chiral ligands to cyclophenone and their derivativ...

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Problems solved by technology

For example, Chinese patent document CN103664896 A discloses a new synthesis process method of anti-tumor molecular targeting drug crizotinib, which uses Boc-L-proline (N-tert-butoxycarbonyl-L- Proline) and the catalytic resolution method that catalyzer p-toluenesulfonic acid and condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are combined, 1-(2, 6-dichloro-3-fluorophenyl) ethanol racemate is resolved into S-type alcohol and R-type alcohol, and the split by-product mixture is hydrolyzed, and configuration conversion is carried out to obtain S-type alcohol 1-( 2,6-dichloro-3-fluorophenyl)ethanol, the total yield is 76%; but this invention adopts Boc-L-proline (N-tert-butoxycarbonyl-L-proline) and Catalyst p-toluenesulfonic acid and condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride combined catalytic resolution method, used more raw materials, higher cost, and yield rate is not high; as another example, Chinese patent literature CN102775314 A discloses a preparation method of trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine, which uses N-protection Proline, under the action of condensing agent and catalyst, the racemic chlorinated phenylethanol is resolved to obtain chiral chlorohydrins; then through a series of reactions to obtain the target compound; the resolution method used in this invention obtains The yield of chiral chlorohydrins is 40%, and the yield is lower, and the raw materials used are many, and the cost is higher

[0006] And, there is no report about the resolution of racemic 4-amino-12-bromo[2.2] in the prior art to cyclopan

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