CN102976899A

CN102976899A - Method for preparing medetomidine intermediate 1-(2, 3-xylyl) ethanol

Info

Publication number: CN102976899A
Application number: CN2012105594492A
Authority: CN
Inventors: 张哲�; 阮乐; 贾明子; 严刚; 倪福松
Original assignee: Guilin University of Technology
Current assignee: Guilin University of Technology
Priority date: 2012-12-21
Filing date: 2012-12-21
Publication date: 2013-03-20

Abstract

The invention discloses a method for preparing a medetomidine intermediate 1-(2, 3-xylyl) ethanol. 2, 3-dimethyl bromobenzene and magnesium react with each other to generate a Grignard reagent, the Grignard reagent is slowly dropwise added into N, N-dimethyl acetamide, water is added to quench after the reaction is completed, sodium borohydride is added in batches for reduction, diluted acid is added for quenching reaction after the reaction is carried out for 6-8 hours, and the 1-(2, 3-xylyl) ethanol is obtained after the subsequent treatment according to a conventional method. The method is simple in technological process, raw materials are low in price and easily obtained, the reaction is easy to operate and control, both the product yield and quality are better than those of other known methods, and the method has an important practical application value on synthesizing medetomidine.

Description

The preparation method of medetomidine intermediate 1-(2,3-xylyl) ethanol

Technical field

The present invention relates to a kind of preparation method of medetomidine intermediate, particularly 1-(2, the 3-xylyl) preparation method of ethanol.

Background technology

1-(2,3-xylyl) ethanol is the key intermediate of preparation α-2 receptor stimulant hydrochloric acid medetomidine, is the requisite part of synthetic hydrochloric acid medetomidine, and its structural formula is as follows:

Present preparation 1-(2,3-xylyl) method of ethanol is to be raw material with 2,3-dimethyl chlorination benzene, form Grignard reagent with MAGNESIUM METAL after, low temperature drips acetaldehyde solution, adds water and diluted acid cancellation reaction again, gets through rectification under vacuum again.(referring to J.A.C.S., 1940,62,2639 ~ 2642; J.O.C., 1953,18,806 ~ 809).

Summary of the invention

The objective of the invention is for a kind of relatively simple, maneuverable preparation 1-(2,3-xylyl are provided) method of ethanol.

Concrete steps are:

1) under protection of inert gas, supplied for electronic metal simple-substance, catalyst iodine are added in the non-protonic solvent, drip the mixed solution of compd A and non-protonic solvent, reaction obtains organo-metallic halogenide; The temperature of reaction of the dropping of compd A is controlled at-20 ℃ ~ 60 ℃.

2) step (1) gained organo-metallic halogenide is added drop-wise in the mixed solution of compd B and non-protonic solvent, reflux to reaction finishes, add the shrend reaction of going out, remove in the backward solution of insolubles and add reductive agent in batches, the control temperature is at 0 ℃ ~ 20 ℃, reacted 6 ~ 8 hours, and added diluted acid cancellation reaction, remove by filter insolubles, the filtrate standing demix, non-protonic solvent aqueous layer extracted three times merges organic layer, anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent, last rectification under vacuum gets colourless oil liquid 1-(2, the 3-xylyl) ethanol.

The mol ratio of above-mentioned each reactant is:

Supplied for electronic metal simple-substance: catalyzer: compd A=1 ~ 1.5:0.01 ~ 0.05:1; Compd A: compd B: reductive agent=1:1 ~ 1.5:0.3 ~ 0.8.

Described rare gas element is nitrogen or argon gas.

Described supplied for electronic metal simple-substance is one or both or three kinds in magnesium, lithium and the zinc, preferable alloy magnesium.

Described relevant non-protonic solvent is the one or two or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran and the toluene, preferred tetrahydrofuran (THF), and the non-protonic solvent total mass is 10 ~ 20 times of compd A quality.

The structural formula of described compd A is as follows:

Wherein: R is fluorine, chlorine, bromine or iodine, preferred bromine.

Described compd B is methyl acetate, ethyl acetate, N,N-dimethylacetamide, N, a kind of in N-diethyl acetamide, Acetyl Chloride 98Min. and the acetyl bromide, preferred N,N-dimethylacetamide.

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

Described diluted acid is that mass percent concentration all is a kind of in 10% ~ 30% hydrochloric acid, sulfuric acid and the nitric acid, preferred hydrochloric acid, and the consumption of diluted acid is 1 ~ 5 times of compd A quality.

Beneficial effect of the present invention:

A) compare with synthetic method in the past, adopt 2,3-dimethyl bromobenzene to do initial raw material, raw material is easy to get and low price;

B) the compound III is and is easy to get very much, the low-cost compound that routinizes.

C) with in the past synthetic method relatively, the inventive method reaction conditions is gentle, and is easy and simple to handle, is easy to control, do not have high poison, high-risk operation.

Embodiment

Embodiment 1:

(1) under nitrogen protection; in the 250mL there-necked flask, add 3g magnesium, 0.56g iodine and 20mL analytical pure tetrahydrofuran (THF), under agitation condition, slowly add 19g (0.103 mol) 2, the mixture of 3-dimethyl bromobenzene and 180mL analytical pure tetrahydrofuran (THF); after causing successfully; slowly drip remaining mixture, after the dropping fully, reflux; to reacting completely; cool to room temperature gets organo-metallic halogenide, and the temperature of reaction of dropping is controlled at-20 ℃ ~ 60 ℃.

(2) step (1) gained organo-metallic halogenide is added drop-wise to 11.4gN, in the mixing solutions of N-N,N-DIMETHYLACETAMIDE and 50mL analytical pure tetrahydrofuran (THF), added the post-heating stirring and refluxing 4 hours; Adding 50mL shrend is gone out after being cooled to room temperature, filters out unreacted magnesium chips.

(3) in step (2) gained solution, add sodium borohydride in batches amount to 1.52g, reacted under the room temperature 6 ~ 8 hours, adding 30mL mass percent concentration was 20% hydrochloric acid cancellation reaction after reaction finished, and removed by filter insolubles, the filtrate standing demix, tetrahydrofuran (THF) aqueous layer extracted three times merges organic layer, anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent, last rectification under vacuum gets colourless oil liquid 1-(2, the 3-xylyl) ethanol.

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

。

Embodiment 2:

(1) under argon shield; in the 250mL there-necked flask, add 3g magnesium, 0.56g iodine and 20mL analytical pure tetrahydrofuran (THF), under agitation condition, slowly add 19g (0.103 mol) 2, the mixture of 3-dimethyl bromobenzene and 180mL analytical pure tetrahydrofuran (THF); after causing successfully; slowly drip remaining mixture, after the dropping fully, reflux; to reacting completely; cool to room temperature gets organo-metallic halogenide, and the temperature of reaction of dropping is controlled at-20 ℃ ~ 60 ℃.

(2) step (1) gained organo-metallic halogenide is added drop-wise in the mixing solutions of 11.6g ethyl acetate and 50mL analytical pure tetrahydrofuran (THF), added the post-heating stirring and refluxing 4 hours; Adding 50mL shrend is gone out after being cooled to room temperature, filters out unreacted magnesium chips.

(3) with embodiment 1.

Claims

1. 1-(2, the 3-xylyl) preparation method of ethanol is characterized in that concrete steps are:

1) under protection of inert gas, supplied for electronic metal simple-substance, catalyst iodine are added in the non-protonic solvent, drip the mixed solution of compd A and non-protonic solvent, reaction obtains organo-metallic halogenide; The temperature of reaction of the dropping of compd A is controlled at-20 ℃ ~ 60 ℃;

2) step (1) gained organo-metallic halogenide is added drop-wise in the mixed solution of compd B and non-protonic solvent, reflux to reaction finishes, add the shrend reaction of going out, remove in the backward solution of insolubles and add reductive agent in batches, the control temperature is at 0 ℃ ~ 20 ℃, reacted 6 ~ 8 hours, and added diluted acid cancellation reaction, remove by filter insolubles, the filtrate standing demix, non-protonic solvent aqueous layer extracted three times merges organic layer, anhydrous sodium sulfate drying, filter, the concentrating under reduced pressure solvent, last rectification under vacuum gets colourless oil liquid 1-(2, the 3-xylyl) ethanol;

The mol ratio of above-mentioned reactant is:

Supplied for electronic metal simple-substance: catalyzer: compd A=1 ~ 1.5:0.01 ~ 0.05:1; Compd A: compd B: reductive agent=1:1 ~ 1.5:0.3 ~ 0.8;

Described rare gas element is nitrogen or argon gas;

Described supplied for electronic metal simple-substance is one or both or three kinds in magnesium, lithium and the zinc;

Described relevant non-protonic solvent is the one or two or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran and the toluene, and the non-protonic solvent total mass is 10 ~ 20 times of compd A quality;

The structural formula of described compd A is:

Wherein: R is fluorine, chlorine, bromine or iodine;

Described compd B is methyl acetate, ethyl acetate, N,N-dimethylacetamide, N, a kind of in N-diethyl acetamide, Acetyl Chloride 98Min. and the acetyl bromide;

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

Described diluted acid is that mass percent concentration all is a kind of in 10% ~ 30% hydrochloric acid, sulfuric acid and the nitric acid, and the consumption of diluted acid is 1 ~ 5 times of compd A quality.