Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/78—Separation; Purification; Stabilisation; Use of additives
  • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

Definitions

• This invention relates to the one-pot synthesis of m-hydroxyacetophenone.
• 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 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 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.
• 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;
• Direct introduction method the hydroxyethyl ketone is directly introduced into the hydroxyl group.
• 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;
• 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 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.
• 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:
• 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 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.
• 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.
• 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.
• 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
• % 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;
• 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:

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• Crystallography & Structural Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2014
  • 2014-12-12 CN CN201410756502.7A patent/CN104402695B/zh active Active
• 2015
  • 2015-04-24 DE DE112015005543.6T patent/DE112015005543B4/de active Active
  • 2015-04-24 WO PCT/CN2015/000289 patent/WO2016090707A1/zh active Application Filing

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