CN114790135B

CN114790135B - A kind of preparation method of benzoylformic acid

Info

Publication number: CN114790135B
Application number: CN202210374611.7A
Authority: CN
Inventors: 朱锦桃; 罗茂; 陈淼; 周雍富; 刘彬; 华金锡
Original assignee: Zhejiang Jinnuohe Pharmaceutical Co ltd; Zhejiang Sci Tech University ZSTU
Current assignee: Zhejiang Jinnuohe Pharmaceutical Co ltd; Zhejiang Sci Tech University ZSTU
Priority date: 2022-04-11
Filing date: 2022-04-11
Publication date: 2023-12-19
Anticipated expiration: 2042-04-11
Also published as: CN114790135A

Abstract

The invention provides a synthesis method of benzoylformic acid, which uses mandelic acid or its ester as raw material, in the presence of a protonated polar solvent, uses nitrate or an amine salt formed of nitric acid and an organic base as the oxidant, and the copper salt is It is obtained by reacting under a catalyst. This process has mild reaction conditions, simple operation, less three wastes and high yield.

Description

Preparation method of benzoyl formic acid

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of benzoyl formic acid.

Background

The benzoyl formic acid is also called acetophenone acid, the molecular structure of which contains carbonyl and carboxyl, and the structural formula is shown as follows:

active groups in the molecular structure of the benzoyl formic acid make the benzoyl formic acid exhibit special properties, and the benzoyl formic acid is an intermediate for synthesizing a plurality of medicines and pesticides, can be used as a medicine intermediate to synthesize the stomach long ning for treating gastric ulcer, the cyclic mandelate for treating cerebral vascular disease and thrombus, the spasmolytic for treating frequent urination, the anticholinergic, the central nervous system stimulant pimolin, the antidepressant mirtazapine and the like by taking the benzoyl formic acid as raw materials. As a raw material of an intermediate of pesticides, the benzoylformic acid is mainly used for synthesizing triazinones herbicides such as oxaziclomefone, prometryn and the like. In addition, benzoic acid is widely used for the constitution of functional materials, and is used as a sensitizer for fluorescent materials, a catalyst for organic oxidation reactions, and the like by complexing with a metal element.

Although benzoic acid is an important pharmaceutical intermediate, the existing preparation methods are not numerous. PCT patent application number WO2015035051A discloses that diethyl oxalate is used as a raw material, phenyl magnesium bromide is added at the temperature of minus 78 ℃ to obtain ethyl benzoate, and then the ethyl benzoate is hydrolyzed to obtain the benzoyl formic acid. The method needs to be subjected to Grignard reaction and is produced at low temperature, and the conditions are harsh, so that the method is not beneficial to large-scale production.

Patent publication No. CN103103156A discloses a method for obtaining benzoyl formic acid by hydrolysis of benzoyl nitrile as a raw material. Although the reaction condition is relatively warm and the yield is relatively high, the raw material benzoyl nitrile is high in commodity price, benzoyl halide and sodium cyanide are needed for preparation, and the comprehensive cost is high.

Patent publication No. CN101503414A discloses a method for preparing benzoic acid by using styrene as a raw material and potassium permanganate as an oxidant. The method is simple to operate, but a large amount of waste water and manganese mud solid waste can be generated by using a large amount of potassium permanganate as an oxidant, so that the difficulty of three-waste treatment is increased, and the production cost is increased.

Document (Journal Of Applicable Chemistry (Lumami, india), 2017,615), 864-854) reports the preparation of benzoic acid starting from mandelic acid and chromic acid as the oxidizing agent in DMSO solvent. Heavy metal pollution is serious in the dichromic acid and the post-reaction treatment used by the method, and the production of the dichromic acid is difficult to adapt to the current environmental protection requirement.

The synthesis process has the problems of high raw material price, prominent three wastes generated by post-treatment, complex operation, strict reaction condition requirements and the like.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides the preparation method of the benzoyl formic acid, which has less three wastes, simple and convenient operation and low cost, by taking the mandelic acid or the ester thereof which is cheap and easy to obtain as the raw material.

In order to achieve the aim of the invention, the invention adopts the following technical scheme:

the preparation method of the benzoyl formic acid is characterized in that mandelic acid or ester thereof is used as a raw material, amine salt formed by ammonium nitrate or nitric acid and organic base is used as an oxidant in the presence of a protonated polar solvent, copper salt is used as a catalyst, and the reaction formula is as follows:

r is H or alkyl.

Further, the mandelate is selected from methyl mandelate, ethyl mandelate or propyl mandelate, and the mandelate is analyzed by experimental intermediate process to show that under the reaction conditions, the mandelate is firstly hydrolyzed in the system to form mandelic acid, and is further oxidized to form benzoyl formic acid.

Further, the protonated polar solvent is selected from the group consisting of water in admixture with formic acid, acetic acid, propionic acid, butyric acid or isobutyric acid.

The inventors have found that the reaction is substantially non-reactive with water alone and that the reaction rate is relatively slow with acetic acid as solvent, the latter probably being due to the poor solubility of the amine salt of the oxidising agent in acetic acid. The reaction time can be shortened by adding a certain amount of water, and the solubility of amine salts in the system can be increased by adding water appropriately so as to promote the reaction. However, too much water addition also reduces the solubility of mandelic acid, and the reactant concentration becomes dilute, thereby slowing the reaction.

Further, the amine salt is selected from ammonium nitrate and nitric acid and organic amine forming amine nitrate salts, further, the amine nitrate salts are selected from triethylamine nitrate, guanidine nitrate, trimethylamine nitrate, tripropylamine nitrate or tributylamine nitrate.

Further, the copper salt is selected from copper acetate, copper propionate, copper chloride, copper sulfate, copper bromide or copper iodide cupric salt; or a monovalent copper salt selected from the group consisting of cuprous chloride, cuprous iodide, and cuprous bromide.

These monovalent copper salts act under the reaction conditions to form divalent copper salts.

Further, the mol ratio of the reaction material mandelic acid or the ester thereof, the oxidant and the copper salt catalyst is 1:2-30:0.02-0.05; preferably, the molar ratio of the reaction mass mandelic acid or the ester thereof to the oxidant is 1:4-8.

Further, the protonated polar solvent is acetic acid aqueous solution, the volume concentration of the acetic acid aqueous solution is 10-90%, preferably 70-85% under the condition that ammonium nitrate oxidant and copper acetate are used as catalysts, the reaction temperature is 60-200 ℃, preferably 100-120 ℃, and the mole ratio of mandelic acid or ester thereof, ammonium nitrate and copper acetate is 1:4-8:0.02-0.05, with aqueous acetic acid as solvent, preferably copper acetate as catalyst to avoid addition of new anions or new salts as much as possible.

The ammonium nitrate adopted by the invention has better selectivity and the yield can reach more than 90 percent. The ammonium nitrate may be added to the system in solid portions or may be added to the reactor by dissolving it in water droplets. The feeding mole ratio of the ammonium nitrate is mandelic acid or the ester thereof: ammonium nitrate = 1:2-30:1, preferably 1:4 to 1:8, an excess of ammonium nitrate being necessary, during the reaction some of which decomposes to give off NO, which is visible in the air as reddish brown NO ₂ This means that the ammonium nitrate fed in ionizes in the system to form nitric acid, which at high concentrations is partly decomposed into NO.

The reaction temperature can be 60-200 ℃, the temperature is low, the reaction is slow, and the rising temperature of the system also depends on the solvent and whether the pressure is closed or not. If acetic acid is used as the solvent, the temperature is preferably 100-120 ℃.

The raw material mandelic acid adopted by the invention can be conveniently obtained by phase transfer catalytic reaction of benzaldehyde and chloroform in alkali. (refer to Jiangsu chemical industry, 1991,3.22-23)

Drawings

FIG. 1 is a 1H NMR spectrum of benzoylformic acid.

Detailed Description

The invention will be further illustrated by the following examples

Example 1

Into a 250ml three-necked flask, mandelic acid (4.0 g,26.0 mmol) was added, followed by a reaction for 12 hours at a temperature of about 105℃under stirring, by an aqueous solution (100 ml) of 80% strength by volume acetic acid, copper acetate monohydrate (0.26 g,1.3 mmol) and ammonium nitrate (14.6 g,182.0 mmol). Cooling to room temperature, suction filtering, concentrating the mother liquor to remove most of the solution, adding 50ml of water into the residue, extracting four times (4 x20 ml) with ethyl acetate, combining ethyl acetate extract, adding anhydrous magnesium sulfate for drying, and concentrating to obtain the benzoic acid with the yield of 3.56g and 91.1%. Benzoic acid: 1H-NMR (DMSO, 400 MHz) δ:7.57-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.90-7.95 (m, 2H).

MS：[M+H]+：151.0409.

In example 1, copper acetate may be replaced with copper propionate, copper chloride, copper sulfate, copper bromide, or copper iodide; the molar ratio of mandelic acid to ammonium nitrate is in the range of 1:2-30, but the optimum value is a ratio of 1:7; ammonium nitrate may be replaced with triethylamine nitrate, guanidine nitrate, trimethylamine nitrate, tripropylamine nitrate or tributylamine nitrate.

Example 2

Into a 250ml three-necked flask, mandelic acid (4.0 g,26.0 mmol), an aqueous acetic acid solution (100 ml) having a volume concentration of 90%, cupric acetate monohydrate (0.104 g,0.52 mmol), guanidine nitrate (12.2 g,100 mmol) were charged, and the temperature was raised to reflux (about 105 ℃ C.) with stirring to react for 12 hours. Cooling to room temperature, suction filtering, concentrating the mother liquor to remove most of the solution, adding 50ml of water into the residue, extracting four times (4 x20 ml) with ethyl acetate, combining ethyl acetate extract, adding anhydrous magnesium sulfate for drying, and concentrating to obtain the benzoyl formic acid, 3.37g, and the yield is 86.5%.

In example 1 guanidine nitrate can also be replaced by triethylamine nitrate, trimethylamine nitrate, tripropylamine nitrate or tributylamine nitrate, and mandelic acid can be replaced by methyl, ethyl or propyl mandelate.

Example 3

Into a 250ml three-neck flask, (4.0 g,26.0 mmol) of mandelic acid and 0.78mmol (according to 0.03 proportion) of copper chloride as 10% formic acid aqueous solution (100 ml) are added, the temperature is raised to 105 ℃, a solution prepared by dissolving (14.6 g,182.0 mmol) of ammonium nitrate in 30ml of water is added dropwise, then stirring reflux reaction is carried out for 12 hours, cooling is carried out to room temperature, suction filtration is carried out, the mother solution is concentrated to remove most of the solution, 50ml of water is added into the residue, extraction is carried out four times (4 x20 ml) with ethyl acetate, ethyl acetate extract is combined, anhydrous magnesium sulfate is added for drying, and then concentration is carried out, thus obtaining the benzoic acid, 3.42g and the yield is 87.8%.

In example 3, copper chloride may be replaced with copper propionate, copper sulfate, copper bromide, or copper iodide, or copper chloride, copper iodide, or copper bromide; the aqueous formic acid solution may be replaced by an aqueous solution of propionic acid, butyric acid or isobutyric acid.

Example 4

Into a 250ml three-necked flask were charged (4.0 g,26.0 mmol) of mandelic acid, 85% aqueous acetic acid (100 ml), 0.78mmol of cuprous chloride, 27% aqueous ammonia (23.6 g,182.0 mmol) and 65% concentrated nitric acid (17.64 g,

182.0 mmol) and allowed to warm to reflux (about 105 ℃ C.) with stirring, and allowed to react for 12 hours. Cooling to room temperature, suction filtering, concentrating the mother liquor to remove most of the solution, adding 50ml of water into the residue, extracting four times (4 x20 ml) with ethyl acetate, combining ethyl acetate extract, adding anhydrous magnesium sulfate for drying, and concentrating to obtain the benzoic acid with the yield of 3.44g and 88.3%.

In example 4, cuprous chloride may be replaced with cupric chloride, cupric propionate, cupric sulfate, cupric bromide or cupric iodide, or cuprous iodide or cuprous bromide; the aqueous formic acid solution may be replaced by an aqueous solution of propionic acid, butyric acid or isobutyric acid.

Example 5 (control example)

Into a 250ml three-necked flask, mandelic acid (4.0 g,26.0 mmol), an 80% aqueous acetic acid solution (100 ml), ammonium nitrate (14.6 g,182.0 mmol) were charged, and the mixture was heated to reflux (about 105 ℃ C.) with stirring and reacted for 12 hours. Cooling to room temperature, suction filtering, concentrating the mother liquor to remove most of the solution, adding 50ml of water into the residue, extracting four times (4 x20 ml) with ethyl acetate, combining ethyl acetate extract, adding anhydrous magnesium sulfate for drying, concentrating, and performing silica gel column chromatography (CH 2Cl2: CH3 OH=2:1) to obtain the benzoic acid, wherein the yield is 12.8 percent, and 0.5 g.

The above description is only of the preferred embodiments of the present invention, and is not intended to limit the present invention. Modifications, equivalents, improvements, etc. which fall within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims

1. A preparation method of benzoylformic acid, characterized in that mandelic acid is used as a raw material, in the presence of a protonated polar solvent, an amine salt formed by ammonium nitrate or nitric acid and an organic base is used as an oxidant, and a copper salt is used as a catalyst. It is obtained by the reaction, and its reaction formula is: R is H

The protonated polar solvent is selected from a mixture of water and formic acid, acetic acid, propionic acid, butyric acid or isobutyric acid.

2. A method for preparing benzoylformic acid according to claim 1, characterized in that the amine salt is selected from the group consisting of ammonium nitrate and amine nitrate salts formed by nitric acid and organic amines.

3. A kind of preparation method of benzoylformic acid according to claim 2, characterized in that the amine nitrate salt is selected from the group consisting of triethylamine nitrate, guanidine nitrate, trimethylamine nitrate, tripropylamine nitrate or tributyl nitrate. Amine nitrates.

4. a kind of preparation method of benzoylformic acid according to claim 1, is characterized in that said copper salt is selected from copper acetate, copper propionate, copper chloride, copper sulfate, copper bromide or copper iodide. valent copper salt; or selected from cuprous chloride, cuprous iodide or cuprous bromide monovalent copper salt.

5. a kind of preparation method of benzoylformic acid according to claim 1, is characterized in that the mol ratio of described reaction material mandelic acid, oxidant and copper salt catalyst is 1:2-30:0.02-0.05.

6. The preparation method of benzoylformic acid according to claim 1, characterized in that the molar ratio of the reaction material mandelic acid and the oxidizing agent is 1:4-8.

7. A kind of preparation method of benzoylformic acid according to claim 1, characterized in that after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the residue is added with water, extracted with ethyl acetate, and concentrated to obtain the target product.

8. A kind of preparation method of benzoylformic acid according to claim 1, characterized in that mandelic acid is a raw material, in the presence of a 10-90% acetic acid aqueous solution with a volume concentration, ammonium nitrate is an oxidant, and copper acetate is a catalyst, The mixture was heated to reflux while stirring to react. After the reaction was completed, it was cooled to room temperature and filtered with suction. The mother liquor was concentrated to remove most of the solution. The residue was added to water and extracted with ethyl acetate. The ethyl acetate extracts were combined and dried by adding anhydrous magnesium sulfate. Afterwards, it is concentrated to obtain benzoylformic acid. The molar ratio of mandelic acid, ammonium nitrate and copper acetate is 1:4-8:0.02-0.05.