Preparation method of piribedil

Abstract

The invention relates to a preparation method of piribedil. The method is characterized in that piperidine is used as a starting raw material, and piperonyl chlorine is prepared through a Blanc reaction; in addition, 2-cloro pyridine is used as a starting raw material to carry out single alkylation on piperazine to obtain 1-(2-pyrimidyl)piperazine; and the prepared piperonyl chlorine and the 1-(2-pyrimidyl)piperazine are subjected to an N-alkylation reaction to obtain the piribedil. The invention has the advantages that the raw material piperidine has low price and is easy to obtain; the reaction condition is moderate, and reactions of all steps can be quickly carried out at lower temperature without high temperature, high pressure or special catalysts; the yield of products is higher; a purification method is simple; the purity is better (the purity content of HPLC is not lower than 99.8 percent), and the like, thus the method is a route which has simple operation, higher yield, lower cost and stable quality and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, in particular to a preparation method of piribedil. Background technique [0002] Pirabedil is suitable for Parkinson's patients and is a dopaminergic agonist that stimulates the post-synaptic D in the nigrostriatum of the brain. 2 Receptors and mesocortical, mesolimbic pathway D 2 and D 3 receptors, providing potent dopamine effects. Its structure is as follows: [0003] [0004] At present, the preparation of piribedil reported in the literature mainly contains the following methods: [0005] Route 1 [0006] [0007] route 2 [0008] [0009] Route 3 [0010] [0011] Route 4 [0012] [0013] Route 5 [0014] [0015] References: Route 1: CN1884280 (2006); Route 2: 1) J.Am.Chem.Soc.131(5), 1766-1774, 2009; 2) Tetrahetron letts.48(47), 8263-8265, 2007 ; Route 3: Tetrahedron Letts.47(15), 2549-2552, 2006; Route 4: 1) PL167397(1995); 2) Arch.Pharm.(weinheim...

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Problems solved by technology

2) With DMF as solvent, the method is the same as 1) (J.Med.Chem.11,1151-1155,1968; Acta.Polon.Pharm., 41(5),525-528,1984), these two methods need The use of solvents with high toxicity or high boiling point will bring inconvenience to industrial production

This method yield is higher (87%), and weak point is: ruthenium reagent and piperonyl alcohol price are higher, and ruthenium reagent consumption is bigger

Wherein the synthesis of 1-(2-pyrimidinyl) piperazine all adopts the method of document: J.Org.Chem.18,1484-1488,1953. report, is about to 2-chloropyrimidine (1 times amount) and anhydrous piperazine (2.66 times the amount) obtained by refluxing in 95% ethanol for 1.5h, with a low yield (60%)

[0022] Especially the synthetic scheme of route 5, there are following technical problems in actual production: 1) the preparation of 1-(2-pyrimidinyl) piperazine has many by-products, and the yield is low, and in the production process, there are a large amount of 2) do not provide a kind of synthetic scheme of effective piperonyl chloride; 3) reaction solvent xylene toxicity is bigger, and boiling point is higher, brings inconvenience to industrial production; 4) yield is lower, The total yield is only 32.4% (in terms of 2-chloropyrimidine)

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