WO2021259051A1

WO2021259051A1 - Method for improving synthesis process of hypidone free base

Info

Publication number: WO2021259051A1
Application number: PCT/CN2021/098608
Authority: WO
Inventors: 汪有贵; 蔡长清; 郭攀; 朱元勋; 颜峰峰
Original assignee: 浙江华海药业股份有限公司
Priority date: 2020-06-23
Filing date: 2021-06-07
Publication date: 2021-12-30
Also published as: CN111747926A; CN111747926B

Abstract

Provided is a preparation method for improving the conversion of an improved hypidone free base, the method comprising reacting 2-hydroxypyridine and an epoxy represented by formula (I) under the action of a phase transfer catalyst and an inorganic base in an organic solvent, so as to obtain a hypidone free base as represented by formula (II). The preparation provided by the present invention greatly improves the reaction efficiency, reduces the reaction time, improves the reaction yield, and is very suitable for industrialized production.

Description

Method for improving synthesis process of piperpirox free base

Technical field

The invention specifically relates to the field of medicine, and relates to a method for improving the synthesis process of piperpirox free base.

technical background

Hydrochloride hydrochloride, English name (Hydione Hydrochloride), chemical name is 1-[(1-benzyl-4-hydroxypiperidin-4-yl)-methyl]-pyridine-2(1H)-one hydrochloride Salt. The structural formula of piperpyrone hydrochloride is as follows:

The compound is a dual-target antidepressant independently developed by the Institute of Toxicology and Drugs of the Chinese Academy of Military Medical Sciences. It can be used to prevent or treat central nervous system diseases related to 5-HT system dysfunction, including depression, mania, and cognition. Cognitive deficits, schizophrenia, pain, etc.

Patent CN102241667A discloses piperpirox compound and its preparation method:

Method 1: Using ethylene glycol monomethyl ether and water as the reaction solvent, using 2-aminopyridine and the epoxy compound represented by formula I as raw materials, reacting for 3 days, adding ethanol and fumaric acid to dissolve After lowering the temperature, adding diethyl ether and evaporating the organic phase to dry the solvent, adding sodium hydroxide and sodium acetate to basify, extracting with dichloromethane, and column chromatography to obtain the free base of piperpyrone represented by formula II.

The process uses ethylene glycol monomethyl ether as the reaction solvent, which has a long production reaction time in the workshop, complex column chromatography procedures, difficult to control, and the yield is too low, which is not suitable for large-scale production in the workshop.

Method 2: Use DMF as the reaction solvent, 2-hydroxypyridine and epoxy as raw materials, carry out the addition reaction under the action of alkali for 1 day, wash with potassium carbonate aqueous solution, evaporate the solvent, and then add petroleum ether-ethyl acetate The ester crystallized and filtered to obtain the free base of piperpyrone.

The process has a long reaction time and low process yield. In view of the defects in the process, the synthesis process is improved.

Summary of the invention

The purpose of the present invention is to provide an improved method for the synthesis of piperpirox free base.

Specifically, the present invention provides a preparation method for improving the free base conversion rate of piperpirox, which comprises subjecting 2-hydroxypyridine and the epoxy compound represented by formula I to a phase transfer catalyst and an inorganic base under the action of an organic The reaction is carried out in a solvent to obtain the free base of piperpirox as shown in formula II, and the reaction formula is shown as follows:

In the above preparation method of piperpirox free base, the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, One or more of benzyl trimethyl ammonium bromide, benzyl triethyl ammonium chloride, and benzyl triethyl ammonium bromide.

In the above preparation method of piperpirox free base, the molar ratio of the epoxy, 2-hydroxypyridine and the inorganic base is 1:0.7~1.3:0.05~0.5, preferably 1:1.0~1.1:0.10~ 0.15.

In the above preparation method of piperpirox free base, the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate inorganic base aqueous solution or solid, preferably an inorganic base aqueous solution, more preferably potassium carbonate aqueous solution.

In the above preparation method of piperpirox free base, the organic solvent is selected from toluene or xylene, preferably toluene.

In the above preparation method of piperpirox free base, the molar ratio of the epoxy compound to the phase transfer catalyst is 1:0.02-0.4, preferably 1:0.05-0.1.

In the above preparation method of piperpirox free base, the volume ratio of the epoxy compound to the organic solvent is 1:3-12 g/mL, preferably 1:5-7 g/mL.

In the above preparation method of piperpirox free base, the reaction temperature is 50° C. to 90° C., the reaction time is 6 to 24 hours, and more preferably, the reaction temperature is 55° C. to 65° C., and the reaction time is 8 to 10 hours.

The innovations of the method for preparing piperpirox free base provided by the present invention include:

(1) The addition of a phase transfer catalyst greatly improves the reaction efficiency, reduces the reaction time, and improves the reaction yield, which is very suitable for industrial production.

(2) The purity of the free base of piperpyrone obtained in the present invention is high, and the purity of the obtained piperpyrone hydrochloride can reach 99.8% after further salt formation.

(3) The prior art uses DMF as the reaction solvent, which brings about the discharge of a large amount of nitrogen-containing wastewater; the present invention preferably uses toluene or xylene as the solvent, which is easy to post-process and recycle, and is more environmentally friendly.

detailed description

The following specific preparation examples are intended to illustrate the present invention in detail, and the examples are only used for more detailed description, and do not limit the present invention in any form.

Example 1

At room temperature, weigh 20.3g epoxy, 9.97g 2-hydroxypyridine, 1.70g tetrabutylammonium hydrogen sulfate, 102mL toluene and mix, then add 1.38g potassium carbonate in the aqueous solution, warm up to 55～65℃ to keep the reaction 8-10h, add 60mL of water and stir, let stand to separate the layers, concentrate the toluene phase to dryness, then add 61mL of ethanol to raise the temperature to dissolve and slowly cool to 0℃～10℃, filter and dry to obtain the white piperpyrone free Alkali, the yield is 83.5%, and the purity is 97.1%.

Example 2

At room temperature, weigh 20.3g epoxy, 9.97g 2-hydroxypyridine, 1.70g tetrabutylammonium hydrogen sulfate, 102mL toluene and mix, then add 1.38g potassium carbonate solid, heat up to 55～65℃, keep the temperature for 8～10h , Add 60mL water and stir, let stand for layering, the toluene phase is concentrated to dryness, then 61mL ethanol is added to raise the temperature and the temperature is slowly cooled to 0℃～10℃, filtered and dried to obtain the white piperpyrone free base. The rate is 77.5% and the purity is 96.8%.

Example 3

At room temperature, weigh 20.3g epoxy, 9.97g 2-hydroxypyridine, 0.64g tetrabutylammonium bromide, 61mL xylene and mix, then add 1.38g potassium carbonate in the aqueous solution, warm up to 55～65℃ After reacting for 8-10 hours, add 60 mL of water and stir, let stand to separate the layers, concentrate the toluene phase to dryness, then add 21 mL of ethanol to raise the temperature to dissolve, slowly cool to 0℃～10℃, and filter to obtain the white piperpyrone free base. The yield was 84.2%, and the purity was 96.5%.

Example 4

At room temperature, weigh 1.0kg epoxy, 491.2g 2-hydroxypyridine, 83.5g tetrabutylammonium bisulfate, 5.0L toluene and mix, then add 68.0g potassium carbonate in the aqueous solution, warm up to 55～65℃ React for 8-10h, add 2.5L of water and stir, let stand to separate the layers, concentrate the toluene phase to dryness, add 3.0L of ethanol to raise the temperature to dissolve, slowly cool to 0℃～10℃, filter and dry to obtain white hydroxypiper Pyridone free base, the yield is 84.3%, and the purity is 96.9%.

Example 5

At room temperature, weigh 60.0kg epoxy, 29.47kg 2-hydroxypyridine, 5.01kg tetrabutylammonium bisulfate, 300L toluene and mix, then add 4.08kg potassium carbonate in the aqueous solution, heat up to 55～65℃ for reaction 8～10h, add 200L of water and stir, let stand to separate the layers, concentrate the toluene phase to dryness, then add 180L of ethanol to raise the temperature to dissolve and slowly cool down to 0℃～10℃, filter and dry to obtain the white piperpyrone free Alkali, the yield is 84.3%, and the purity is 97.0%.

Claims

A preparation method of piperpirox free base, which is characterized in that the epoxy compound shown in formula I and 2-hydroxypyridine are reacted in an organic solvent under the action of a phase transfer catalyst and an inorganic base to obtain the formula II The free base of piperpirox shown, the reaction formula is as follows:
The preparation method according to claim 1, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, and benzyltrimethyl chloride. One or more of ammonium, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, and benzyltriethylammonium bromide.
The preparation method according to claim 1, wherein the organic solvent is selected from toluene or xylene, preferably toluene.
The preparation method according to claim 1, wherein the inorganic base is selected from an inorganic base aqueous solution or an inorganic base solid, preferably an inorganic base aqueous solution.
The preparation method according to claim 1, wherein the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate, preferably potassium carbonate.
The preparation method according to claim 1, wherein the molar ratio of the epoxy, 2-hydroxypyridine and the inorganic base is 1:0.7-1.3:0.05-0.5, preferably 1:1.0-1.1:0.10 ~0.15.
The preparation method according to claim 1, wherein the molar ratio of the epoxy compound to the phase transfer catalyst is 1:0.02-0.4, preferably 1:0.05-0.1.
The preparation method according to claim 1, wherein the volume ratio of the epoxy substance to the organic solvent is 1:3-12 g/mL, preferably 1:5-7 g/mL.
The preparation method according to claim 1, wherein the reaction temperature is 50°C to 90°C, and the reaction time is 6 to 24 hours.
The preparation method according to claim 9, wherein the reaction temperature is 55°C to 65°C, and the reaction time is 8-10 hours.