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

A technology of A-412997 and receptor agonist, which is applied in the field of medicine and chemical industry, can solve the problems of expensive coupling reagents, unfavorable scale-up production, difficult purification, etc., and achieve the effect of low reagent price, favorable scale-up production, and high yield

Inactive Publication Date: 2011-11-16
ITIC MEDCHEM CO LTD
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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 ...

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

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Embodiment Construction

[0022] The preferred embodiments of the present invention will be described in detail below in conjunction with the chemical reaction equations of each step of the present invention.

[0023] Such as figure 1 As shown, first add 2-bromopyridine (950g, 6.01mol) and dissolve it in 6.6LTHF. Keep warm for 2 hours, drop the compound 1-N-BOC-4-piperidone (945g dissolved in 2L of THF) into the reaction flask, after the drop, naturally warm up to room temperature, monitor the reaction by TLC, after the reaction is complete, add 3L Water, liquid separation, the aqueous phase was extracted 3 times with 4L ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate for 2 hours, concentrated, petroleum ether: ethyl acetate (5:1) crystallized to obtain 1.4 kg yellow solid compound 1-N-Boc-4-(2-pyridyl)-4-hydroxypiperidine, purity>90%, yield 93.5%. .

[0024] Then 2.4kg of thionyl chloride was added to the reaction flask, and the comp...

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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 ...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 丁靓
Owner ITIC MEDCHEM CO LTD
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