CN109721560A

CN109721560A - A kind of preparation method of irsogladine maleate

Info

Publication number: CN109721560A
Application number: CN201711030839.XA
Authority: CN
Inventors: 于鹏
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-10-28
Filing date: 2017-10-28
Publication date: 2019-05-07

Abstract

The invention belongs to organic synthesis fields, and in particular to a kind of preparation method of irsogladine maleate.The preparation method is using paracide as starting material, through acetylation, bromoform reaction, cyaniding, cyclization, at the obtained target compound of five step of salt reaction.The present invention uses a kind of novel preparation method of irsogladine maleate, can dramatically speed up reaction rate and improve yield, not only reduce cost, protect environment, and easy to operate, convenient post-treatment, is suitble to industrialized production.

Description

A kind of preparation method of irsogladine maleate

Technical field

The invention belongs to organic synthesis fields, and in particular to a kind of preparation method of irsogladine maleate.

Background technique

Irsogladine maleate [2,4- diamino -6- (2,5- dichlorophenyl) -1,3,5-triazines maleate] is A kind of successfully novel amino triazines anti-ulcer agent is developed by Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan.Initial Public Offering in 1989, this Product can enhance gastric mucosal blood flow, promote the regeneration of ulcer spot mucous membrane, protect regenerative cell from destroying and preventing ulcer portion The advantages that lesion occurs for position, has good effect, and dosage is small, and toxicity is low, and adverse reaction is few.

Currently, there are many irsogladine maleate synthetic route, but there is expensive raw material price mostly, route is complicated, receives The low defect of rate.

Summary of the invention

The purpose of the present invention is to provide a kind of preparation method of irsogladine maleate, this method high income, synthesis letters It is single, it is suitble to industrialized production.

To achieve the goals above, the present invention adopts the following technical scheme: a kind of preparation method of irsogladine maleate, The preparation method is using paracide as starting material, and through acetylation, bromoform reaction, cyaniding, cyclization reacts at five step of salt and be made Target compound.

A kind of preparation method of irsogladine maleate, the preparation method include the following steps:

Step 1: it takes paracide and aluminum trichloride (anhydrous) to be added in reaction flask, chloracetyl is added dropwise at room temperature, is heated to 150 DEG C, It is stirred to react 1 h, it is cooling, it is poured into 100 ml, in ice water, separates organic layer, water layer chloroform recovery, organic layer merges drying, Organic solvent is boiled off, raffinate vacuum distillation collects 152-154 DEG C/1.3 kPa fractions, obtains pale yellowish oil liquid；

Step 2: sodium hydroxide being dissolved in into 200 ml, in water, 0-5 DEG C is cooled to, bromine is added dropwise, then be added dropwise 2,5- dichloro Acetophenone, drop finish, and react at room temperature 2 h, divide and remove bromofom layer, and water layer hydrochloric acid tune pH value to 3 filters, and washing is shallowly dry Yellow solid, ethyl alcohol recrystallization obtain white crystals；

Step 3: taking 2,5- dichlorobenzoic acid, Methyl benzenesulfonyl and phosphorus pentachloride are added in reaction flask, heated after mixing evenly To 22 0 DEG C of 1 h of reaction, after cooling, hot water is added, filters, washing is dry that yellow solid, ethyl alcohol recrystallization obtain white Color crystallization；

Step 4:2,5- dichlorobenzonitrile, cyanoguanidines and potassium hydroxide are added in reaction flask, and hydroxypropyl methyl ether is added, is heated to reflux 3 h, it is cooling, it is poured into water, filters, washing is dry that faint yellow solid, ethyl alcohol recrystallization obtain white crystals；Step 5: will Irsogladine and maleic acid are dissolved in hydroxypropyl methyl ether, are heated to reflux 1 h, cooling, filter, washing, dry faint yellow solid, Ethyl alcohol recrystallization obtain white crystals to get.

The preparation method of kind of irsogladine maleate, paracide in the step 1, aluminum trichloride (anhydrous) and chloracetyl Molar ratio is 1:2:1.

Compared with prior art, effect of the invention is that: the present invention using a kind of irsogladine maleate prepare it is new Method not only reduces cost, protects environment, and easy to operate, convenient post-treatment, high income, and synthesis is simple, fits Close industrialized production.

Specific embodiment

Embodiment 1

Step 1: 14 .7 g of paracide (0 .1 mol) and 26.7 g of aluminum trichloride (anhydrous) (0 .2 mol) being taken to be added In reaction flask, 8 .6 g of chloracetyl (0.1 mol) is added dropwise at room temperature, is heated to 150 DEG C, is stirred to react 1 h, it is cooling, it is poured into 100 ml in ice water, separate organic layer, water layer chloroform recovery, and organic layer merges drying, boils off organic solvent, raffinate subtracts Pressure distillation, collects 152-154 DEG C/1.3 kPa fractions, obtains pale yellowish oil liquid 15.7g, yield: 83.1%；

Step 2: 40.0 g of sodium hydroxide (0.1 mol) being dissolved in 200 ml water, is cooled to 0-5 DEG C, bromine is added dropwise 32.0g (0.1 m o1), then 2 are added dropwise, 5- dichloroacetophenone 18.9g (0.1m o1), drop finishes, and reacts at room temperature 2 h, divides and goes Bromofom layer, water layer hydrochloric acid tune pH value to 3 filter, and washing is dry that light yellow solid, ethyl alcohol recrystallization obtain white crystals 14.9g, yield: 78 154-156 DEG C of .9 %, m p；Step 3: 2,5- dichlorobenzoic acid 19.1g (0.1m o1) is taken, 34.2 g of Methyl benzenesulfonyl (0 .2 mo1) and phosphorus pentachloride 20.9g (0.1mo1) is added in reaction flask, is stirred evenly After be heated to 22 0 DEG C of 1 h of reaction, after cooling, 100 ml of hot water is added, filters, washing, dry yellow solid, ethyl alcohol weight Crystallization, obtains white crystals 14.8g, yield: 128-130 DEG C of 86.5%, mp；

Step 4:2,5- dichlorobenzonitrile 17.2g (0.1m o1), 12 .6 g of cyanoguanidines (0 .15 m o1) and hydrogen-oxygen Change 5.6 g of potassium (0.1m o1) to be added in reaction flask, 100 ml of hydroxypropyl methyl ether is added, is heated to reflux 3 h, it is cooling, incline Enter in 300 ml water, filters, washing, dry that faint yellow solid, ethyl alcohol recrystallization obtain white crystals 11.4g, yield: 268-269 DEG C of 79.2%, mp.Step 5: Irsogladine 25.6g and maleic acid 11.6g being dissolved in hydroxypropyl methyl ether, heated back 1 h is flowed, it is cooling, it filters, washing, it is dry that faint yellow solid, ethyl alcohol recrystallization obtain white crystals to get maleic acid Aesop drawing Determine 31.5g, yield 85.4%.

Embodiment 2

Step 1: taking paracide 14 .9g and aluminum trichloride (anhydrous) 26.5g to be added in reaction flask, chloroethene is added dropwise at room temperature Acyl 8.5g is heated to 150 DEG C, is stirred to react 1 h, cooling, is poured into 100 ml, in ice water, separates organic layer, water layer chloroform It extracts, organic layer merges drying, boils off organic solvent, and 152-154 DEG C/1.3 kPa fractions are collected in raffinate vacuum distillation , obtain pale yellowish oil liquid 15.5g, yield: 82.1%；

Step 2: 40.2 g of sodium hydroxide is dissolved in 200 ml water, is cooled to 0-5 DEG C, bromine 32.0g is added dropwise, then 2,5- dichloroacetophenone 18.9g is added dropwise, drop finishes, and reacts at room temperature 2 h, and divide and removes bromofom layer, water layer hydrochloric acid tune pH value to 3, Filtering, washing are dry that light yellow solid, ethyl alcohol recrystallization obtain white crystals 14.2g, yield: 78 .9 %, m p 154 -156℃；Step 3: taking 2,5- dichlorobenzoic acid 19.6g, to Methyl benzenesulfonyl, 33.5g and phosphorus pentachloride 20.9g add Enter in reaction flask, be heated to 22 0 DEG C of 1 h of reaction after mixing evenly, after cooling, 100 ml of hot water is added, filters, washes, does It is dry that yellow solid, ethyl alcohol recrystallization obtain white crystals 14.8g, yield: 128-130 DEG C of 86.5%, mp；

Step 4:2,5- dichlorobenzonitrile 17.2g, cyanoguanidines 12.9g and potassium hydroxide 5.9g are added in reaction flask, and hydroxyl is added 100 ml of propyl methyl ether is heated to reflux 3 h, cooling, is poured into 300 ml water, filters, washing, dry pale yellow colored solid Body, ethyl alcohol recrystallization obtain white crystals 11.4g, yield: 268-269 DEG C of 79.2%, mp.Step 5: by Irsogladine 25.9g and maleic acid 11.8g are dissolved in hydroxypropyl methyl ether, are heated to reflux 1 h, cooling, filter, washing, dry faint yellow solid , ethyl alcohol recrystallization obtains white crystals to get irsogladine maleate 30.2g, yield 83.6%.

The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.

Claims

1. a kind of preparation method of irsogladine maleate, which is characterized in that the preparation method is that starting is former with paracide Material, through acetylation, bromoform reaction, cyaniding, cyclization, at the obtained target compound of five step of salt reaction.

2. a kind of preparation method of irsogladine maleate according to claim 1, which is characterized in that the preparation method packet Include following steps:

Step 1: it takes paracide and aluminum trichloride (anhydrous) to be added in reaction flask, chloracetyl is added dropwise at room temperature, is heated to 150 DEG C, It is stirred to react 1 h, it is cooling, it is poured into 100 m I, in ice water, separates organic layer, water layer chloroform recovery, organic layer merges dry It is dry, organic solvent is boiled off, raffinate vacuum distillation collects 152-154 DEG C/1.3 kPa fractions, obtains pale yellowish oil liquid Body；

3. a kind of preparation method of irsogladine maleate according to claim 1, which is characterized in that in the step 1 The molar ratio of paracide, aluminum trichloride (anhydrous) and chloracetyl is 1:2:1.