Method for synthesizing bortezomib

Abstract

The invention belongs to the field of synthesizing medicaments, and discloses a method for synthesizing bortezomib. In the method, 3-methyl butyraldehyde and R-(+)-1-phenylethylamine are used as initiative materials, and the [(1R)-3-methyl-1-[[(2S)-1-oxygen-3-phenyl-2[(pyrazine formyl) amino] propyl]amino]butyl]-boric acid is obtained by condensation, selective boric acid ester addition, hydrogenation deprotection, chiral condensation with L-phenylalanine, condensation with 2-carboxyl-piperazine and boric acidification. The synthesis method has the advantages of readily available raw materials, higher yield of the whole reaction route, mild reaction conditions, easy operation, lower production cost and the suitability for industrialized production.

Description

technical field The invention belongs to the field of drug synthesis and relates to a synthesis method of bortezomib. Specifically pertaining to [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino]propyl]amino]butyl]-boronic acid (Bortezomib, Bortezomib) synthetic method. Background technique Bortezomib (trade name: Velcade) is the first new drug approved for the treatment of multiple myeloma in the past ten years, and it is also the first cancer drug that targets protein-degrading enzyme complexes. About its mechanism of action His research won the Nobel Prize in Chemistry in 2004. Velcade Bortezomib was first discovered in early clinical trials in patients with multiple myeloma relapse and ineffective to other therapies. Since phase II clinical trials can significantly improve the condition of patients, it has been approved by the U.S. Food and Drug Administration (FDA) quickly. It was approved and officially launched in May 2003. On April 26, 2004, Europ...

AI Technical Summary

Problems solved by technology

The current patent route uses 2-methylpropaneboronic acid as a raw material, and (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol is condensed as a chiral ligand to form a borate, and then in anhydrous Under the catalysis of zinc dichloride, the insertion reaction of chloromethylene is carried out, followed by nucleophilic substitution of amine group, detrimethylsilyl group, then coupling with amino acid, and finally coupling with piperazine acid, through six-step synthesis Bortezomib, because (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol is more expensive, there is no large-scale production in China; and the second step anhydrous zinc dichloride catalyzed chlorine The methyl insertion reaction needs to be carried out at minus 78 degrees, the conditions are harsh, and the reaction molar yield is low (only more than 50%); the third step of ditrimethylsilylamine is expensive, and the reaction also needs to be carried out at minus 78 degrees

Therefore, the raw materials of this route are expensive, the yield is low, and the synthesis conditions are harsh, which is not conducive to industrial operation.

Therefore, the cost of this route is relatively high, and it is not suitable for industrialized production.

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