Preparation method of aripiprazole lauroxil

Abstract

The invention provides a preparation method of aripiprazole lauroxil. The method comprises steps as follows: S1, a compound (II) and halogenated silane react in amide solvents in the presence of an acid-binding agent, and a compound (III) is obtained, wherein R1, R2 and R3 are alkyls; S2, in alcohol solvents, the compound (III) and paraformaldehyde react in the presence of the acid-binding agent,a treated intermediate product reacts with n-dodecanoyl chloride in a furan or amide solvent in the presence of the acid-binding agent, and a compound (IV) is produced; S3, the compound (IV) is subjected to silyl ether removal in a furfural solvent by use of tetrabutylammonium fluoride, and a compound (V) is obtained; S4, the compound (V), 1-bromo-4-chlorobutane and 1-(2,3-dichlorophenyl) piperazine react in a mixed solvent of one or more of an acetone solvent, an amide solvent and a nitrile solvent in the presence of the acid-binding agent and sodium iodide, and aripiprazole lauroxil is prepared. The method adopts a simple process, can notably increase the yield and the purity of products, can be reproducible and facilitates industrial production.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a reproducible preparation method of aripiprazole laurate with simple process, significantly improved product yield and purity. Background technique [0002] The chemical name of aripiprazole dodecanoate is 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-2-oxo-3, 4-Dihydroquinoline-1(2H)-methyldodecanoate (CAS: 1259305-29-7), developed by Alkermes, Ireland, was approved by the U.S. Food and Drug Administration on October 5, 2015 ( FDA) approved listing, trade name is Aristada. The drug is a sustained-release injection suspension, a long-acting drug for the treatment of atypical schizophrenia that is injected once a month or once every 6 weeks, and is used for the treatment of schizophrenia in adults. The structure of aripiprazole dodecanoate is the following formula I: [0003] [0004] No. WO2010151689A1 patent document discloses the preparation method and ...

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Problems solved by technology

[0006] However, this method has the following disadvantages: (1) column chromatography is required for post-processing and purification, which is cumbersome to operate and inconvenient for industrial production; (2): the yield is low, and the two-step total yield is only 13.65%

[0009] This method is an extension of the patent document WO2010151689A1, and reacts with dodecanoyl chloride instead of dodecanoic anhydride. Although the yield is not disclosed, it is theoretically close to the yield of the patent document WO2010151689A1, and the preparation method still exists Post-treatment purification requires column chromatography, which is cumbersome to operate and inconvenient for industrial production

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