One-pot production process of chiral sulfonyl cyclopropylamine derivative

Abstract

The invention provides a one-pot production process of a chiral sulfonyl cyclopropylamine derivative, which comprises the following specific steps: S1, adding 1eq of L-phenyl propanol and 250mL of DCMinto a reaction flask, controlling the temperature at 35-40 DEG C, dropwisely adding 1.2 eq of dimethylaminosulfonyl chloride, keeping the internal temperature and conducting stirring for 4 hours, conducting cooling, and conducting staying overnight; S2, adding 1.1 eq of triethylamine into the reaction liquid in the step S1, dropwise adding 1.05 eq of methanesulfonyl chloride while the temperature is controlled to be 25-35 DEG C, cooling the reaction liquid to 25-28 DEG C after natural stirring, conducting filtering, washing a filter cake with 125 mL of dichloromethane, and combining filtrate; and S3, adding 2.4 eq of KOH aqueous solution into the filtrate obtained in the S2, conducting stirring at 20-25 DEG C for 1 hour, conducting standing for liquid separation, and conducting extracting, concentrating and crystallizing to obtain the chiral sulfonyl cyclopropylamine derivative. According to the method, amino is subjected to sulfonyl protection through a one-pot process, then methylsulfonyl chloride is used for protecting and activating hydroxyl, then deprotection and cyclization are conducted under the weak base condition, the product is obtained, the total yield reaches up to 85%, due to three-step continuous feeding, the yield of three wastes is reduced, and the production risk of strong base, highly toxic reagents and the like is avoided.

Description

technical field [0001] The invention relates to the field of pharmaceutical production, in particular to a one-pot production process of chiral sulfonylcyclopropylamine derivatives. Background technique [0002] Chiral sulfonylcyclopropylamine derivatives are important drug intermediates that can be used to treat neurodegenerative disorders such as Huntington's disease (WO2010115000). The synthesis of this intermediate, literature method is to prepare chiral cyclopropylamine by ring closure earlier, then prepares with sulfonyl chloride reaction, chiral cyclopropylamine is prepared in this method and uses hypertoxic triphenylphosphine (Synlett, (6), 833-836; 2006), or highly corrosive concentrated sulfuric acid, the production risk is high. In addition, chiral cyclopropylamine is expensive, and the production cost of direct purchase is high. Another literature method is to use chiral amphetamine to react with two equivalents of sulfonyl chloride, to protect the amino and hyd...

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Problems solved by technology

The synthesis of this intermediate, literature method is to prepare chiral cyclopropylamine by ring closure earlier, then prepares with sulfonyl chloride reaction, chiral cyclopropylamine is prepared in this method and uses hypertoxic triphenylphosphine (Synlett, (6), 833-836; 2006), or highly corrosive concentrated sulfuric acid, the production risk is high, and chiral cyclopropylamine is expensive, and the production cost of direct purchase is high

Another literature method is to use chiral amphetamine to react with two equivalents of sulfonyl chloride, to protect the amino and hydroxyl groups with sulfonyl groups, and then to deprotect and ring-close the hydroxyl groups under strong base conditions to obtain the product. The process has a large amount of waste and a total yield Low, the ring-closing reaction uses highly active sodium hydrogen, the yield is low, and the production risk is high (WO2010115000; WO2014057498); another kind of process to this method is to use chiral amphetamine to react with one equivalent of sulfonyl chloride, and amino Carry out sulfonyl protection, then use benzenesulfonyl chloride to activate the hydroxyl group, and then use weak base conditions to deprotect and ring-close to obtain the product (WO2014057498; Indian Pat.Appl., 2012CH04173). The overall yield of this process is not high, especially for ring-closing The yield in one step is not improved, and the amount of three wastes is also very large

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