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Intermediates of 2-acetonyl-3-methoxy piperidine and preparation method of 2-acetonyl-3-methoxy piperidine

A methoxypiperidine and acetone-based technology, which is applied in the field of drug synthesis, can solve the problems of complex synthesis, low yield, and high cost of raw material reagents, and achieve the effect of reducing the cost of raw materials and reagents and increasing yield

Inactive Publication Date: 2013-11-13
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Aiming at the defects in the prior art that the synthesis of the peroxide piperidine ring is complicated, the cost of raw material reagents is too high or the yield is low, the purpose of the present invention is to provide an intermediate of 2-acetonyl-3-methoxypiperidine and its preparation Method, 2-acetonyl-3-methoxypiperidine is an important intermediate compound in the preparation process of peroxide, and the present invention uses cheap and easy-to-obtain compound methoxyacetone as the starting material to prepare 2-acetonyl-3- Methoxypiperidine, and the hydrogenation reduction adopts palladium-carbon catalyst instead of rhodium-carbon catalyst, which greatly reduces the reaction cost and improves the yield

Method used

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  • Intermediates of 2-acetonyl-3-methoxy piperidine and preparation method of 2-acetonyl-3-methoxy piperidine
  • Intermediates of 2-acetonyl-3-methoxy piperidine and preparation method of 2-acetonyl-3-methoxy piperidine
  • Intermediates of 2-acetonyl-3-methoxy piperidine and preparation method of 2-acetonyl-3-methoxy piperidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The preparation process of the present embodiment is shown in reaction formula one:

[0054] Reaction formula one:

[0055]

[0056] The above-mentioned compounds are respectively:

[0057] Compound 1: Methoxyacetone;

[0058] Compound 2: 4-methoxy-5-oxocapronitrile;

[0059] Compound 3: 4-methoxy-5,7-dioxoctanonitrile;

[0060] Compound 4: 4-methoxy-5,7-ethylene glycol octanonitrile;

[0061] Compound 5: 4-methoxy-5,7-ethylene glycol octylamine;

[0062] Compound 6: 3-methoxy-2-(2-oxopropylidene)piperidine;

[0063] Compound 7: 2-acetonyl-3-methoxypiperidine.

[0064] The above reaction formula includes the following reaction steps: using methoxyacetone as a starting material, Michael addition occurs with acrylonitrile to obtain compound 2, ketoester condensation occurs between compound 2 and ethyl acetate to obtain diketone compound 3, compound 3 and ethylene diketone Alcohol reaction to obtain compound 4 after ketone carbonyl protection, reducing the nitril...

Embodiment 2

[0091] The preparation process of the present embodiment is shown in reaction formula two:

[0092] Reaction two:

[0093]

[0094] Compound 8: 4-methoxy-5-ethylene glycol capronitrile;

[0095] Compound 9: 4-methoxy-5-ethylene glycol hexylamine;

[0096] Compound 10: 2-methyl-3-methoxy-3,4,5,6-tetrahydropyridine.

[0097] The above reaction formula includes the following reaction steps: the ketone carbonyl in compound 2 is protected by ethylene glycol to obtain compound 8, the nitrile group in compound 8 is reduced to an amine group to generate compound 9, compound 9 removes the protecting group, and cyclizes under alkaline conditions Compound 10 was obtained. Compound 10 was reacted with butyllithium and acetonitrile to obtain compound 6, and the target compound 2-acetonyl-3-methoxypiperidine (compound 7) was obtained after selective reduction of ethylenic bonds.

[0098] Concrete preparation process is as follows:

[0099] 1, the preparation of 4-methoxy-5-ethylene ...

Embodiment 3

[0117] The preparation process of the present embodiment is shown in the following reaction formula three:

[0118] Reaction three:

[0119]

[0120] Compound 11: 2-methyl-3-methoxypiperidine.

[0121] The above reaction formula includes the following reaction steps: compound 2 is hydrogenolyzed and cyclized under the catalysis of Raney nickel to obtain compound 11 (2-methyl-3-methoxypiperidine), compound 11 and N-chlorosuccinyl Compound 10 was obtained by reaction of amine, compound 6 was obtained by reaction of compound 10 with butyllithium and acetonitrile, and the target compound 2-acetonyl-3-methoxypiperidine could be obtained after reduction of compound 6.

[0122] Concrete preparation process is as follows:

[0123] 1. The preparation of 2-methyl-3-methoxypiperidine (compound 11) has the following three methods:

[0124] (1) Take 4-methoxy-5-oxohexanenitrile (10g, 0.07mol), 10% ammonia solution in methanol (200mL) and add it to the autoclave, add Raney nickel cata...

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Abstract

The invention discloses intermediates for synthesizing 2-acetonyl-3-methoxy piperidine, including 4-methoxy-5,7-diethyl acetal octylamine, 3-methoxy-2-(2-oxopropylidene) piperidine, 4-methoxy-5-diethyl acetal hexanenitrile, 4-methoxy-5-diethyl acetal hexylamine, 2-methyl-3-methoxy-3,4,5,6-tetrahydropyridine and 2-methyl-3-methoxy piperidine, and a preparation method of 2-acetonyl-3-methoxy piperidine. The preparation method of 2-acetonyl-3-methoxy piperidine comprises the following steps: reacting methoxyacetone with acrylonitrile to obtain 4-methoxy-5-oxohexanenitrile; performing condensation reaction of 4-methoxy-5-oxohexanenitrile with ethyl acetate to obtain 4-methoxy-5,7-dioxooctanenitrile; reacting 4-methoxy-5,7-dioxooctanenitrile with ethanediol to obtain 4-methoxy-5,7-diethyl acetal octanenitrile; reducing nitrile groups into amino groups; removing ethanediol protecting groups; cyclizing to generate 3-methoxy-2-(2-oxopropylidene) piperidine; and reducing the ethylenic bond of 3-methoxy-2-(2-oxopropylidene) piperidine to obtain 2-acetonyl-3-methoxy piperidine. According to the invention, cheap methoxy acetone is adopted as a raw material in three reaction routes, the intermediates of piperidine are avoided, and palladium-carbon is used in hydrogenation and reduction, so that the reagent cost is reduced, and a possibility is provided for industrialization.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to an intermediate in the preparation process of hemosanone, in particular to an intermediate of 2-acetonyl-3-methoxypiperidine and a preparation method thereof. Background technique [0002] Halofuginone is a derivative of febrifugine extracted from the traditional Chinese medicine Changshan. It is mainly used for the prevention and treatment of domesticated animals such as poultry and livestock against coccidiosis and anti-malarial. It has broad-spectrum high-efficiency and irreversible , No recurrence after drug withdrawal, no cross-resistance, less toxicity, better safety and so on. In recent years, studies have found that Changshanone can be used to prevent liver fibrosis, pulmonary fibrosis, scleroderma and other diseases characterized by excessive synthesis of type I collagen, and it also has obvious inhibitory effect on wound healing and paralysis scar formation; it...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/74C07D211/42
CPCY02P20/55
Inventor 江涛王诗玺刘世旭顾艳艳
Owner OCEAN UNIV OF CHINA