CN103408486A

CN103408486A - Preparation method of 4-pyridinemethanol

Info

Publication number: CN103408486A
Application number: CN2013104060810A
Authority: CN
Inventors: 张哲�; 阮乐; 严刚; 倪福松
Original assignee: Guilin University of Technology
Current assignee: Guilin University of Technology
Priority date: 2013-09-09
Filing date: 2013-09-09
Publication date: 2013-11-27

Abstract

The invention discloses a preparation method of 4-pyridinemethanol. The preparation method comprises the following steps of enabling sodium borohydride and lithium chloride to form a reductive mixture in tetrahydrofuran; dropwise adding methyl isonicotinate into the reductive mixture; carrying out heating reflux for 6-8h, and then, ending the reaction; adding an acid solution to quench; and then, treating the product by using a conventional method to obtain the 4-pyridinemethanol. The preparation method is simple in process flow, cheap in raw material cost, easy to obtain raw materials, easy to operate and control the reaction, relatively high in product yield and quality as comparison with those of other known methods and relatively high in actual application value for synthesizing donepezil hydrochloride.

Description

A kind of preparation method of 4-piconol

Technical field

The present invention relates to a kind of preparation method of E 2020 important intermediate, particularly a kind of method for preparing the 4-piconol.

Background technology

4-piconol (chemical compounds I) has another name called 4-4-hydroxymethylpiperidine, pyridine-4-methyl alcohol, that a kind of very important chemical intermediate is the key intermediate for preparing the acetylcholinesterase depressant E 2020, be the requisite part of synthetic hydrochloric acid E2020, its structural formula is as follows:

。

The method that prepare at present the 4-piconol is to take the 4-picoline to be raw material, and the employing catalytic oxidation obtains; Or take Isonicotinic acid (γ-picolinic acid) and be starting raw material, through steps such as over-churning, hydrazinolysis, oxidations, obtain.(referring to J.A.C.S., 1954,76,1286-1291; Chem Rev, 1958,58: 439-460).

Summary of the invention

The objective of the invention is for a kind of method of relatively simple, the maneuverable 4-of preparation piconol is provided.

Concrete steps are:

1) under protection of inert gas, catalyzer, reductive agent are added in non-protonic solvent, under-20 ℃ ~ 60 ℃, drip the mixture of compound ii and non-protonic solvent, heating reflux reaction obtained reaction solution in 6 ~ 8 hours; The mol ratio of each reactant is catalyzer: reductive agent: compound ii=1 ~ 5:1 ~ 4:1, the non-protonic solvent total mass is 10 ~ 20 times of compound ii quality.

2) in step (1) gained reaction solution, slowly drip acid solution cancellation reaction, control temperature at-5 ℃ ~ 5 ℃, add rear stirring 2-6 hour, add the 30-80mL water filtration to remove insolubles, the filtrate stratification, tetrahydrofuran (THF) aqueous layer extracted three times, merge organic layer, anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent, obtain the 4-piconol.

Described rare gas element is nitrogen or argon gas.

Described relevant non-protonic solvent is one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran and toluene.

The structural formula of described compound ii is as follows:

Figure 2013104060810100002DEST_PATH_IMAGE002

。

Wherein R is a kind of in ester, acid amides and carboxylic acid halides.

Compound ii is Isonicotinic acid methyl esters, Isonicotinic acid ethyl ester, N, N-dimethyl-Isonicotinamide, N, a kind of in N-diethyl-Isonicotinamide, 4-pyridine formyl chloride and 4-pyridine formyl bromine.

Described catalyzer is one or both in lithium chloride and zinc chloride.

Described reductive agent is one or both in sodium borohydride and POTASSIUM BOROHYDRIDE.

Described acid solution is that mass percent concentration is a kind of in 10% ~ 30% hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and the quality of acid solution is 1 ~ 5 times of compound ii quality.

Described tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, Isonicotinic acid methyl esters, Isonicotinic acid ethyl ester, N, N-dimethyl-Isonicotinamide, N, N-diethyl-Isonicotinamide, 4-pyridine formyl chloride and 4-pyridine formyl bromine are analytical pure.

Beneficial effect:

1) with synthetic method in the past, compare, adopt the Isonicotinic acid derivative to do initial raw material, raw material is easy to get and low price.

2) reductive agent, catalyzer are and are easy to get very much, the low-cost compound that routinizes.

3) with synthetic method in the past, compare, the inventive method reaction conditions gentleness, easy and simple to handle, be easy to control, there is no high poison, high-risk operation.

Embodiment

Embodiment 1:

1) under nitrogen protection; in the 250mL there-necked flask, add 8.8g lithium chloride, 7.9g sodium borohydride and 60mL tetrahydrofuran (THF); the mixture that slowly adds Isonicotinic acid methyl esters (10g, 0.073mol) and 40mL tetrahydrofuran (THF) under agitation condition; the temperature of reaction dripped is controlled at-5 ℃ ~ 5 ℃; after dripping fully; reflux 6 hours, to reacting completely, cool to room temperature.

2) to slowly dripping the 30mL mass percent concentration in step (1) gained reaction solution, be 30% hydrochloric acid cancellation reaction, control temperature at-5 ℃ ~ 5 ℃, add rear stirring 4 hours, add the 50mL water filtration to remove insolubles, the filtrate stratification, tetrahydrofuran (THF) aqueous layer extracted three times, merge organic layer, anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent, finally light yellow crystallization 4-piconol, m.p.55 ~ 57 ℃.

Following chemical equation means the synthesis technique of the present embodiment 1:

Figure 2013104060810100002DEST_PATH_IMAGE003

。

Embodiment 2:

1) under argon shield; in the 250mL there-necked flask, add 8.8g lithium chloride, 8.2g POTASSIUM BOROHYDRIDE and 60mL tetrahydrofuran (THF); the mixture that slowly adds Isonicotinic acid methyl esters (10g, 0.073mol) and 40mL tetrahydrofuran (THF) under agitation condition; the temperature of reaction dripped is controlled at-5 ℃ ~ 5 ℃; after dripping fully; reflux 6 hours, to reacting completely, cool to room temperature.

2) subsequent operations, with embodiment 1, obtains light yellow crystallization 4-piconol.

Following chemical equation means the synthesis technique of the present embodiment 2:

Figure 2013104060810100002DEST_PATH_IMAGE004

。

Chemical reagent and raw material described in embodiment 1,2 are without the outer analytical pure that is of explanation.

Claims

1. the preparation method of a 4-piconol is characterized in that concrete steps are:

1) under protection of inert gas, catalyzer, reductive agent are added in non-protonic solvent, under-20 ℃ ~ 60 ℃, drip the mixture of compound ii and non-protonic solvent, heating reflux reaction obtained reaction solution in 6 ~ 8 hours; The mol ratio of each reactant is catalyzer: reductive agent: compound ii=1 ~ 5:1 ~ 4:1, and the non-protonic solvent total mass is 10 ~ 20 times of compound ii quality;

2) in step (1) gained reaction solution, slowly drip acid solution cancellation reaction, control temperature at-5 ℃ ~ 5 ℃, add rear stirring 2-6 hour, add the 30-80mL water filtration to remove insolubles, the filtrate stratification, tetrahydrofuran (THF) aqueous layer extracted three times, merge organic layer, anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent, obtain the 4-piconol;

Described rare gas element is nitrogen or argon gas;

Described relevant non-protonic solvent is one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran and toluene;

The structural formula of described compound ii is as follows:

Wherein R is a kind of in ester, acid amides and carboxylic acid halides;

Compound ii is Isonicotinic acid methyl esters, Isonicotinic acid ethyl ester, N, N-dimethyl-Isonicotinamide, N, a kind of in N-diethyl-Isonicotinamide, 4-pyridine formyl chloride and 4-pyridine formyl bromine;

Described catalyzer is one or both in lithium chloride and zinc chloride;

Described reductive agent is one or both in sodium borohydride and POTASSIUM BOROHYDRIDE;

Described acid solution is that mass percent concentration is a kind of in 10% ~ 30% hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and the quality of acid solution is 1 ~ 5 times of compound ii quality;