WO2016090707A1

WO2016090707A1 - Synthesis of m-hydroxyacetophenone by one-pot method

Info

Publication number: WO2016090707A1
Application number: PCT/CN2015/000289
Authority: WO
Inventors: 王红平
Original assignee: 北京天弘天达医药科技有限公司
Priority date: 2014-12-12
Filing date: 2015-04-24
Publication date: 2016-06-16
Also published as: DE112015005543T5; CN104402695B; DE112015005543B4; CN104402695A

Abstract

The present invention relates to synthesis of m-hydroxyacetophenone by means of a one-pot method, which comprises the following steps: S1, water is added to a reaction kettle, reduced iron powders are added under stirring, then a concentrated hydrochloric acid is added, same is heated, and m-nitroacetophenone is added in batches; S2, after the completion of the reaction, filtering is carried out immediately, a concentrated sulfuric acid is slowly added into the filtrate to form a solution system after the filtrate is cooled to room temperature, and after the completion of the addition, cooling and adding a sodium nitrite solution, after the completion of the addition, cooling the solution system, then adding urea, and continuously stirring, and then the solution system is heated until reflux, then cooled and crystallized, and centrifuged to obtain a crude m-hydroxyacetophenone product, the crude product is directly placed into water for recrystallization and decarburization without drying, and after cooling, centrifuging and drying are performed to obtain a pure m-hydroxyacetophenone product, and the mother liquor of the recrystallization is recycled. The beneficial effect of the present invention lies in that: in the present invention, a synthesis of m-hydroxyacetophenone by means of a one-pot method is provided, which is simple in technical process, is easy to operate, high in product yield, high in purity, low in pollution, and does not require the separation of the reaction product of each step.

Description

One-pot synthesis of m-hydroxyacetophenone

Technical field

This invention relates to the one-pot synthesis of m-hydroxyacetophenone.

Background technique

M-hydroxyacetophenone is an important organic chemical product, an intermediate for the drug phenylephrine, and an important intermediate for the treatment of mild to moderate Alzheimer's type dementia drug rivastigmine tartrate. Phenylephrine is clinically used for infection toxicity and anaphylactic shock, supraventricular tachycardia, prevention of hypotension and dilated sputum during general anesthesia and spinal anesthesia, and also for surgical surgery to prolong anesthesia. The swelling and anti-inflammatory embolism of nasal mucosa congestion, the drug is widely used in clinical practice, is an essential drug in surgery, and m-hydroxyacetophenone is an important intermediate, and its dosage is considerable; The aging of society, more and more elderly people need rivastigmine tartrate as a drug for the treatment of Alzheimer's type dementia, while m-hydroxyacetophenone is important for the Alzheimer's type dementia drug rivastigmine tartrate Intermediates are also used in large amounts.

The current production process of m-hydroxyacetophenone is a three-step chemical reaction of m-nitroacetophenone by reduction, diazotization, hydrolysis and one-step purification to obtain pure m-hydroxyacetophenone. The reduction, diazotization and hydrolysis reactions of the current process have a large amount of waste acid, and the post-process treatment is complicated, which makes the process complicated, the wastewater discharge is difficult, the pollution is serious, and the cost is high. The invention technology is realized first. The step reduction, the second step of diazotization and the third step of the hydrolysis reaction do not require a one-pot synthesis of each step of the reaction product to obtain m-hydroxyacetophenone, and the recirculation of the refined mother liquor is achieved, thereby reducing the reaction step, The process flow is greatly simplified, the cost is reduced, the reaction yield is improved, and the pollution is greatly reduced and the energy consumption is small in actual production, which not only obtains good economic benefits, but also has good environmental benefits, so that the entire process is completely The scope of green chemistry.

There are two methods for synthesizing the synthesis of m-hydroxyacetophenone in the literature:

1. A derivative of benzene or benzene is used as a starting material, first introducing a protecting agent group on the m-hydroxy group, and then removing the m-hydroxy protecting group to obtain m-hydroxyacetophenone, such as Park et al. in Synlett Magazine The published literature is the introduction of methylation. The literature published by Zhou linna et al. on Tetrahedron Letters introduces benzyl protection. The literature published by Narender et al. in Synthetic Communications introduces acetyl protection, in which the introduction of hydroxyl groups is compared. Difficult, and need to be protected and deprotected after introduction, so that the entire process steps are long, the yield is low, and it is not suitable for industrial production;

Second, the introduction of hydroxyl method

1. Direct introduction method: the hydroxyethyl ketone is directly introduced into the hydroxyl group. For example, the acetophenone used by Palmisano et al. and Gesson et al. is used as a starting material to synthesize m-hydroxyacetophenone. This method has few reaction steps but exists. The yield is low, the product is not easy to separate, and the reaction conditions are quite harsh, making the process unsuitable for industrial production;

2. Indirect introduction of hydroxyl method: The indirect method is to convert other groups in the meta position of acetophenone into hydroxyl groups. This method has relatively mild reaction conditions and is easy to realize industrial production, as published by Sun Li et al. in Journal of Chemical Research. The literature is to convert halogens to hydroxyl groups, and as published by Jung et al. in Organic Letters, the conversion of borate esters to hydroxyl groups, both of which require the use of expensive metal catalysts, resulting in greatly increased production costs; The literature published by King et al. in the Journal of American Chemical Society is converted from a nitro group to a hydroxyl group. The method has the advantages of easy availability of raw materials, relatively simple operation, high yield, easy separation of products, high product purity and the like. The preferred process; China's chemists have carried out a large number of process optimization work with the support of relevant literature, such as Jinxi Refining and Chemicals General Factory Yuan Xingyu, Zhejiang University Chen Zhixin, and patent CN201110115115.1 are all using m-nitrophenyl Ketone as a starting material, the first step is to obtain m-aminoacetophenone under iron powder reduction, and the second step is ammonia. The acetophenone is diazotized and then subjected to the third hydrolysis reaction to obtain crude m-hydroxyacetophenone. Finally, the crude m-hydroxyacetophenone is recrystallized in water to obtain pure m-hydroxyacetophenone. Although the process can be industrialized. However, the method still has problems such as complicated treatment after treatment, low yield, and large amount of wastewater.

The current production process of m-hydroxyacetophenone is a three-step chemical reaction of m-nitroacetophenone by reduction, diazotization, hydrolysis and one-step purification to obtain pure m-hydroxyacetophenone. The reduction and diazotization of the current process. There is a large amount of waste acid in the reaction and hydrolysis reaction, and after each step of the chemical reaction, the reaction liquid is subjected to complicated post-treatment to obtain a product, and then the next reaction is carried out, so that the process is complicated, the wastewater discharge is difficult, and the pollution is serious. , low yield, high cost and other issues.

Summary of the invention

In view of the above problems in the prior art, the main object of the present invention is to solve the defects of the prior art, and the present invention provides a simple process flow, high product yield, high purity, low pollution, and no need for each step reaction product. Separate one-pot synthesis of m-hydroxyacetophenone.

The invention provides a one-pot synthesis of m-hydroxyacetophenone, comprising the following steps:

S1: Add 300-660 kg of water in a 500-1000 L reactor, add 50-95 kg of reduced iron powder under stirring, add 5-10 kg of concentrated hydrochloric acid, and raise the temperature to 80 ° C, between 80-100 ° C. Adding 50-100 kg of m-nitroacetophenone in batches, and monitoring by TLC during the reaction;

S2: After the reaction is completed, it is filtered while hot, and the filtrate is cooled to room temperature, and then 75 to 150 kg of 98% concentrated sulfuric acid is slowly added thereto. Forming a solution system, controlling the temperature below 50 ° C, after the completion of the feeding, cooling to below 0 ° C, the adjusted sodium nitrite solution control temperature is added to the above solution system below 5 ° C, after the completion of the feeding, the solution system After cooling for 1 hour, 0.2-0.5 kg of urea was added, and stirring was continued for 30 minutes. After that, the solution system was heated to reflux for 2 hours, and then cooled to below 15 ° C for 2 hours, and then centrifuged to obtain crude m-hydroxyacetophenone. Moisture content, without direct drying, the crude product is put into 15 times of water for decarburization purification, and after centrifugation, 23.7-53.7 kg of white to white-like solid powder m-hydroxyacetophenone with a purity of 99% or more is obtained, and the refined mother liquor can be recycled;

S3: recycling of the refined mother liquor, placing 100 kg of crude m-hydroxyacetophenone in the mother liquor refined in the step S2, heating and dissolving, decolorizing the activated carbon, finally cooling and crystallization, centrifuging and drying to obtain 85.2 kg of purity 99. More than % white to off-white solid powder m-hydroxyacetophenone.

Optionally, the sodium nitrite solution in the step S2 is composed of 21 to 42 kg of sodium nitrite and 85 to 168 kg of water.

The invention has the following advantages and beneficial effects: the invention provides a one-pot synthesis of m-hydroxyacetophenone, and the invention has realized the first step of iron powder reduction, the second step of diazotization and the third step of hydrolysis reaction. The method of synthesizing, that is, after the completion of the first step of iron powder reduction, it is not necessary to separately treat the reaction, but the solution of m-aminoacetophenone is directly used for the next diazotization reaction, and the diazotization reaction is not required. After the post-treatment, the hydrolysis reaction is directly carried out, and then the temperature is lowered to obtain a crude m-hydroxyacetophenone. The crude m-hydroxyacetophenone is recrystallized directly in water without drying to obtain a pure product of m-hydroxyacetophenone, which reduces the reaction step. The process flow is greatly simplified, the cost is reduced, the reaction yield is improved, and the pollution is greatly reduced and the energy consumption is small in actual production, which not only obtains good economic benefits, but also has good environmental benefits, so that the entire process is completely The scope of green chemistry; at the same time, the present invention solves the problem of large amount of sewage, difficulty in discharge, and complicated post-treatment in the current process technology of m-hydroxyacetophenone. The problem of low reaction yield and high production cost, the amount of sewage generated by the production process according to the present invention is less than half of the current process, and the one-pot synthesis method solves the complexity of the current process operation, so that the post-treatment becomes It is simple and convenient, and the reaction yield is also increased by 5% compared with the current process, thereby reducing the production cost and directly generating great economic benefits.

detailed description

The invention will now be further described with reference to specific embodiments.

The one-pot synthesis of m-hydroxyacetophenone in the embodiment of the present invention comprises the following steps:

S1: Add 300-660 kg of water in a 500-1000 L reactor, add 50-95 kg of reduced iron powder under vigorous stirring, add 5-10 kg of concentrated hydrochloric acid, and raise the temperature to 80 ° C, between 80-100 ° C. Add 50-100 kg of m-nitroacetophenone in batches, and use TLC monitoring during the reaction;

S2: After the reaction is completed, it is filtered while hot. After the filtrate is cooled to room temperature, 75-150 kg of 98% concentrated sulfuric acid is slowly added to form a solution system, and the control temperature is below 50 ° C. After the addition is completed, the temperature is lowered to below 0 ° C. Configured sodium nitrite The solution control temperature is added to the above solution system at a temperature below 5 ° C. The sodium nitrite solution is composed of 21 to 42 kg of sodium nitrite and 85 to 168 kg of water. After the addition is completed, the solution system is cooled for 1 hour, after which the solution system is cooled for 1 hour. Add 0.2-0.5 kg of urea, continue stirring for 30 minutes, then warm the solution system to reflux for 2 hours, then cool down to below 15 °C for 2 hours, then centrifuge to obtain crude m-hydroxyacetophenone, measure the water content, do not dry The crude product is directly put into 15 times of water for decarburization purification, and after centrifugation, 23.7-53.7 kg of white to off-white solid powder m-hydroxyacetophenone with a purity of 99% or more is obtained, and the refined mother liquor can be recycled;

S3: Recycling of the refined mother liquor, placing 100 kg of crude m-hydroxyacetophenone in 1500 kg of the refined mother liquor of step S2, heating and dissolving, decolorizing the activated carbon, finally cooling, crystallization, centrifugation and drying to obtain 85.2 kg of purity 99% The above white to off-white solid powder is m-hydroxyacetophenone.

Example 1

Add 660 kg of water to a 1000 L reactor, add 95 kg of reduced iron powder under vigorous stirring, add 10 kg of concentrated hydrochloric acid, raise the temperature to 80 ° C, and add m-nitroacetophenone 100 in batches between 80-100 ° C. Kilograms, when the feeding is intense, the heat is released quickly, and the heat is sprayed quickly. It needs to be fed in batches slowly. At the same time, TLC monitoring is used in the reaction process. After the reaction is completed, it is filtered while hot, and the filtrate is cooled to room temperature and then 150 kg 98. % concentrated sulfuric acid is slowly added to it and forms a solution system. The control temperature is below 50 ° C. After the addition is completed, the temperature is lowered to below 0 ° C. The controlled temperature of the prepared sodium nitrite solution is added to the above solution system below 5 ° C. The sodium nitrite solution consists of 42 kg of sodium nitrite and 168 kg of water. After the addition is completed, the solution system is cooled for 1 hour, then 0.5 kg of urea is added, and stirring is continued for 30 minutes, after which the solution system is heated to reflux 2 After an hour, then cool down to below 15 °C for 2 hours, then centrifuge to obtain crude m-hydroxyacetophenone, measure the water content, and directly put the crude product into 15 times of water without drying. Purified, centrifuged and dried to obtain 51.1 kg of 99% purity or more white to off-white solid powder between hydroxyacetophenone, purification mother liquor can be recycled applied.

Example 2

Add 300 kg of water to a 500 L reactor, add 45 kg of reduced iron powder under vigorous stirring, add 5 kg of concentrated hydrochloric acid, raise the temperature to 80 ° C, and add m-nitroacetophenone 50 in batches between 80-100 ° C. Kilograms, when the feeding is intense, the heat is released quickly, and the heat is quickly sprayed. It is easy to spray the material. It needs to be fed in batches slowly. At the same time, TLC monitoring is used in the reaction process. After the reaction is completed, it is filtered while hot, and the filtrate is cooled to room temperature and 80 kg 98. % concentrated sulfuric acid is slowly added to form a solution system, the control temperature is below 50 ° C, after the completion of the addition, the temperature is lowered to below 0 ° C, and the controlled sodium nitrite solution control temperature is added to the above solution system below 5 ° C, The sodium nitrite solution consisted of 21 kg of sodium nitrite and 85 kg of water. After the addition was completed, the solution system was cooled for 1 hour, then 0.2 kg of urea was added, stirring was continued for 30 minutes, and then the solution was warmed to reflux for 2 hours. After that, the temperature is lowered to below 15 ° C for 2 hours, and then centrifuged to obtain crude m-hydroxyacetophenone, and the water content is measured. The crude product is directly poured into 15 times of water for decarburization without drying. After centrifugation and drying, 25.9 kg of white to off-white solid powder m-hydroxyacetophenone with a purity of 99% or more is obtained, and the refined mother liquor can be recycled;

Recycling of the refined mother liquor: 100 kg of crude m-hydroxyacetophenone is placed in 1500 kg of the above-mentioned refined mother liquor, heated and dissolved, decolorized by activated carbon, finally cooled and crystallized, centrifuged and dried to obtain 85.2 kg of white with a purity of 99% or more. To a white solid powder m-hydroxyacetophenone.

The one-pot synthesis of m-hydroxyacetophenone provided by the present embodiment: the chemical formula of m-nitroacetophenone by iron powder reduction reaction, sodium nitrite diazotization reaction and acid hydrolysis reaction to form m-hydroxyacetophenone is:

It should be noted that the above-mentioned embodiments are only used to explain the technical solutions of the present invention, and are not limited thereto; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand The technical solutions described in the foregoing embodiments may be modified, or some or all of the technical features may be equivalently replaced; and the modifications or substitutions do not deviate from the technical solutions of the embodiments of the present invention. The scope.

Claims

One-pot synthesis of m-hydroxyacetophenone, which is characterized by the following steps:

S1: Add 300-660 kg of water in a 500-1000 L reactor, add 50-95 kg of reduced iron powder under stirring, add 5-10 kg of concentrated hydrochloric acid, and raise the temperature to 80 ° C, between 80-100 ° C. Adding 50-100 kg of m-nitroacetophenone in batches, and monitoring by TLC during the reaction;

S2: After the reaction is completed, it is filtered while hot. After the filtrate is cooled to room temperature, 75-150 kg of 98% concentrated sulfuric acid is slowly added to form a solution system, and the control temperature is below 50 ° C. After the addition is completed, the temperature is lowered to below 0 ° C. The prepared sodium nitrite solution is controlled to be added to the above solution system at a temperature below 5 ° C. After the addition is completed, the solution system is cooled for 1 hour, and then 0.2 to 0.5 kg of urea is added, and stirring is continued for 30 minutes, after which the solution system is heated to After refluxing for 1 hour, then cooling to below 15 ° C for 2 hours, then centrifuging to obtain crude m-hydroxyacetophenone, measuring the water content, directly into the 15 times of water without re-drying for recrystallization decarburization, cooling and centrifuging After drying, 23.7-53.7 kg of pure white to white solid powder m-hydroxyacetophenone pure product is obtained, and the recrystallization mother liquor can be recycled;

S3: recycling of the recrystallization mother liquor, placing the crude m-hydroxyacetophenone in the mother liquor after recrystallization in the step S2, heating and dissolving, decolorizing the activated carbon, finally cooling the crystal, centrifuging and drying to obtain a purity of 99% or more. White to white solid powder of pure hydroxyacetophenone.
The one-pot synthesis of m-hydroxyacetophenone according to claim 1, wherein the sodium nitrite solution in the step S2 consists of 21 to 42 kg of sodium nitrite and 85 to 168 kg of water.