Method for producing hydrochloride of dopamine D4 receptor agonist A-412997

Abstract

The invention discloses a method for producing hydrochloride of a dopamine D4 receptor agonist A-412997. The method comprises the following steps of: obtaining lithium pyridine by using a cheap reagent of butyl lithium as an exchange reagent; reacting with N-Boc-4-piperidone to obtain a compound of 1-N-Boc-4-(2-pyridyl)-4-hydroxypiperidine; removing water molecules, adding Boc, hydrogenating, removing the Boc and performing other steps to obtain a compound of 4-(2-pyridyl)piperidine dihydrochloride; and performing substitution on the 4-(2-pyridyl)piperidine dihydrochloride and a compound of chloracetyl m-toluidine to obtain the target product, namely the hydrochloride of the dopamine D4 receptor agonist A-412997. The process flow is simple, the method is suitable for industrial production, the reagent has low price, the yield is high, the total yield is 44.5 percent, and the method is an effective method for producing the hydrochloride of A-412997.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a production method of dopamine D4 receptor agonist A-412997 hydrochloride. Background technique [0002] A dopamine agonist is a drug that is functionally similar to dopamine but has a different chemical structure. It can activate dopamine receptors like dopamine, thereby playing the same role as dopamine. A-412997 is a dopamine D4 receptor agonist developed by Abbott. The difference of the preparation method of existing dopamine receptor agonist mainly concentrates on the method of making intermediate 4-(2-pyridyl) piperidine dihydrochloride to be different, and many bibliographical reports (such as document Journal of Medicinal Chemistry, 2006 , Vol.49, No.25) subject 1-N-BOC-4-piperidone to Suzuki coupling or other coupling methods to obtain compound 1-N-Boc-4-(2-pyridyl)-1, 2,3,6-tetrahydropyridine, compound 1-N-Boc-4-(2-pyridyl)-1,2,3,6-tetrahydropyridine is ...

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Problems solved by technology

The difference of the preparation method of existing dopamine receptor agonist mainly concentrates on the method of making intermediate 4-(2-pyridyl) piperidine dihydrochloride to be different, and many bibliographical reports (such as document Journal of Medicinal Chemistry, 2006 , Vol.49, No.25) subject 1-N-BOC-4-piperidone to Suzuki coupling or other coupling methods to obtain compound 1-N-Boc-4-(2-pyridyl)-1, 2,3,6-tetrahydropyridine, compound 1-N-Boc-4-(2-pyridyl)-1,2,3,6-tetrahydropyridine is hydrogenated to obtain compound 4-(2-pyridyl ) piperidine dihydrochloride, but the coupling reagent used in this method is more expensive, and it is not conducive to large-scale production

Again, as reported in the literature Collect.Czech.Chem.Commun.(Vol.56)(1991), the piperidone is protected by benzyl, and the compound 1-N-BOC-4-piperidone is reacted to generate the compound 1-N-Boc -4-(2-pyridyl)-4-hydroxypiperidine, and then react further with compound 1-N-Boc-4-(2-pyridyl)-4-hydroxypiperidine to generate intermediate 4-(2-pyridine base) piperidine dihydrochloride, but the 1-N-Boc-4-(2-pyridyl)-4-hydroxypiperidine obtained in this method is difficult to purify and the yield is lower

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