阅读说明：本技术 一种2,3,4-三羟基苯甲醛的合成方法 (Synthesis method of 2,3, 4-trihydroxybenzaldehyde ) 是由 魏峰 葛二鹏 于 2019-11-25 设计创作，主要内容包括：本发明提供一种2,3,4-三羟基苯甲醛的合成方法,所述2,3,4-三羟基苯甲醛的合成是以邻苯三酚为起始原料,经过保护酚羟基、甲酰化、脱保护三个步骤。本发明原料廉价易得,操作简单,产品收率和纯度高,三废量少,所述方法具有优异的经济和环保效益。(The invention provides a method for synthesizing 2,3, 4-trihydroxy benzaldehyde, which takes pyrogallol as an initial raw material and comprises three steps of phenolic hydroxyl protection, formylation and deprotection. The method has the advantages of cheap and easily-obtained raw materials, simple operation, high product yield and purity, and less three wastes, and has excellent economic and environmental benefits.)

1. The method for synthesizing 2,3, 4-trihydroxybenzaldehyde is characterized in that 3-chloro pyridine is used as a starting material, and the method is prepared by the following reaction:

the method comprises the following steps of preparing a compound A, protecting two adjacent phenolic hydroxyl groups in the compound A through a step 1 to obtain a compound B, then performing formylation through a step 2 to obtain a compound C, and finally removing a protecting group to obtain a target product D.

2. The route according to claim 1, wherein said step 1 comprises: and reacting the compound A, triethylamine and diphenyl carbonate in a solvent to obtain a compound B.

3. The method of claim 1, wherein the step 2 comprises: and dissolving aluminum trichloride in a solvent, and then sequentially dropwise adding dichloromethyl ethyl ether and the solution of the compound B to react to obtain a compound C.

4. The method of claim 1, wherein step 3 comprises: and heating and refluxing the compound C in water to obtain a compound D.

5. The method according to claim 2, wherein the reaction temperature in the step 1 is 50 to 60 ℃ and the reaction temperature in the step 2 is 0 to 5 ℃.

6. The method of claim 2, wherein the molar ratio of the compound A, the triethylamine and the diphenyl carbonate in the step 1 is 1 (0.01-0.05) to (1.0-1.3).

7. The method as claimed in claim 3, wherein the molar ratio of the compound B, the aluminum trichloride and the dichloromethyl ethyl ether in the step 2 is 1 (1-1.2) to 1-1.2.

The technical field is as follows:

the invention relates to the field of medicinal chemistry, in particular to a novel synthesis method of 2,3, 4-trihydroxybenzaldehyde.

Background art:

2,3, 4-trihydroxybenzaldehyde is an important intermediate of the antiparkinson drug benserazide, which is a peripheral dopa decarboxylase inhibitor, usually benserazide: the L-dopa is prepared into a compound preparation at a ratio of 1:4, and has a remarkable effect of treating the Parkinson's disease.

Regarding the synthesis of 2,3, 4-trihydroxybenzaldehyde, there are numerous methods, but all the documents or patents are synthesized by directly using pyrogallol (also known as epigallophenol) as a starting material by the following methods:

the first method is to produce 2,3, 4-trihydroxybenzaldehyde by Gattermann reaction of pyrogallol and hydrocyanic acid or cyanide, such as hydrocyanic acid (Chemische Berichte; vol.31; (1898); (p.1768)), zinc cyanide (CN200410052772.6), etc., and the method is low in cost, but the produced hydrogen cyanide is extremely toxic and has a large production operation risk, so that the method is almost abandoned at present.

Secondly, the method takes the pyrogallol as the raw material to react with DMF and phosphorus oxychloride with Vilsmeier-Haack to generate the 2,3, 4-trihydroxybenzaldehyde (refer to Tetrahedron: Asymmetry; 2000; 11; 3375-.

In the third method, pyrogallol is used as a raw material to react with chloroform in an aqueous solution of sodium hydroxide by Reimer-Tiemann reaction (refer to Journal of the American Chemical Society; vol.105; nb.7; 1983); p.2018-2021), and the yield is usually low, and is 50% or less, and the ortho-para ratio is equivalent. Difficult to separate.

According to the method IV, pyrogallol is used as a raw material to directly carry out Friedel-Crafts reaction (Justus Liebigs Annalen der Chemie; vol.763 (1972); and p.109-120) with triethyl orthoformate, compared with other methods, the method is pure in reaction process, but the method contains three phenolic hydroxyl groups, so that the method has very good solubility in water and organic solvent and dark color in the post-treatment process, and the sewage amount is too large and is about 40-50 times of the feeding amount of the pyrogallol. This is extremely disadvantageous for industrial production.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a preparation method of 2,3, 4-trihydroxy benzaldehyde with high yield and environmental protection, and the specific synthetic route is as follows:

the synthesis scheme preferably comprises the following steps: (the first-step multiple of raw materials is relative to Compound A, the second-step multiple of raw materials is relative to Compound B, and the third-step multiple of raw materials is relative to Compound C)

The first step is as follows: adding a compound A, 0.05 time of triethylamine, 1.1 time of diphenyl carbonate and 5 times of methyl tert-butyl ether (the times are all based on the molar ratio of pyrogallol) into a reaction bottle, heating and refluxing for 6-8 hours, then cooling to room temperature (20-30 ℃), washing an organic layer for 3 times by using 5% NaOH, washing for 1 time by using water, washing for 1 time by using saturated sodium chloride aqueous solution, concentrating to remove 70% of solvent, cooling to-5 ℃ under stirring for crystallization, and carrying out suction filtration and drying to obtain a compound B, wherein the yield is distributed in 95-97% in a parallel test. In the reaction, the methyl tert-butyl ether can be repeatedly used; the sodium hydroxide aqueous solution can be used after being supplemented with sodium hydroxide; the saturated sodium chloride aqueous solution can be reused after being supplemented with sodium chloride.

The second step is that: adding 3 times of methyl tert-butyl ether into a reaction bottle, cooling to 0-5 ℃, adding 1 time of aluminum trichloride in batches, controlling the temperature to be 0-5 ℃, dropwise adding 1 time of dichloromethyl ethyl ether, controlling the temperature to be 0-5 ℃, dropwise adding 1 time of methyl tert-butyl ether solution of a compound B, controlling the temperature to be 0-5 ℃, reacting for 2-3 hours, slowly adding 3 times of water (the times are molar ratios based on the compound B), controlling the temperature to be below 10 ℃, layering, washing an organic layer for 2 times by using 5% sodium hydroxide aqueous solution, washing for 1 time by using saturated sodium chloride aqueous solution, carrying out reduced pressure distillation at 40 ℃ to concentrate the organic layer to the residual volume of about 30%, cooling to room temperature under stirring, then freezing to-5 ℃, stirring for 2 hours, carrying out suction filtration, and drying. And obtaining the compound C, wherein the yield of the step is distributed in 89-93% in parallel tests. In the reaction, the methyl tert-butyl ether can be repeatedly used; after the reaction is finished and water is added for quenching reaction, the separated water layer is repeatedly used for 3-4 times after the PH value is adjusted to be neutral; the sodium hydroxide aqueous solution can be used after being supplemented with sodium hydroxide; the saturated sodium chloride aqueous solution can be reused after being supplemented with sodium chloride.

The third step: adding a compound C and 3 times of water (the times are all molar ratios based on the compound C) into a reaction bottle, heating and refluxing for 1-1.5 hours, cooling to 5-10 ℃ under stirring, carrying out suction filtration and drying to obtain a compound D, wherein the yield is distributed in a range of 93-95% in a parallel test.

The total yield of the three reactions is 82-86%.

Compared with the prior art, the invention has the advantages that:

1. compared with direct formylation, although reaction steps of protection and deprotection are added, the used raw materials are cheap and easy to obtain, the separation is simple and convenient, the operation is simple, the sewage quantity is greatly reduced, the yield is improved, and the method is convenient for industrial production;

2. compared with various methods of direct formylation, the method can directly lead the content of the obtained product (compound D) to reach more than 99 percent after the operation; the direct formylation has more side reactions, the content of the direct formylation can reach more than 98% only by purifying for many times, and the yield is lost by 10-20% every time of purification, so that the product yield is generally low after the post-treatment of the direct formylation method is purified for many times.

Drawings

FIG. 1 is the HPLC detection spectrum of compound B.

FIG. 2 is an HPLC detection spectrum of Compound C.

FIG. 3 is an HPLC detection spectrum of Compound D (target product).

FIG. 4 is a reaction scheme diagram and an abstract figure.

Detailed Description

In order to make the technical means, creation features, working procedures and using methods of the present invention easily understood and appreciated, the present invention is further described below.

Synthesis of Compound B:

adding 126 g (1mol) of the compound A, 5.05 g (0.05mol) of triethylamine, 235.4 g (1.1mol) of diphenyl carbonate and 630ml of methyl tert-butyl ether into a reaction bottle, heating and refluxing for reaction for 6-8 hours, cooling to room temperature (20-30 ℃), washing an organic layer for 3 times by using 200ml of 5% NaOH, washing the organic layer for 1 time by using 200ml of water and washing the organic layer for 1 time by using 200ml of saturated sodium chloride aqueous solution, concentrating to remove 70% of solvent, cooling to-5 ℃ under stirring for crystallization, and performing suction filtration and drying to obtain 146.4 g of the compound B, wherein the yield is 96.3%.

The HPLC detection result of compound B is shown in FIG. 1.

Synthesis of Compound C:

adding 450ml of methyl tert-butyl ether into a reaction bottle, cooling to 0-5 ℃, adding 133.5 g (1mol) of aluminum trichloride, controlling the temperature to be 0-5 ℃, dropwise adding 129 g (1mol) of dichloromethyl ethyl ether, controlling the temperature to be 0-5 ℃, dropwise adding 304ml of methyl tert-butyl ether solution containing 152 g of compound B, controlling the temperature to be 0-5 ℃, reacting for 2-3 hours, slowly adding 400ml of water, controlling the temperature to be below 10 ℃, layering, washing an organic layer for 2 times by using 200ml of 5% sodium hydroxide aqueous solution, washing for 1 time by using 200ml of saturated sodium chloride aqueous solution, distilling and concentrating the organic layer at 40-50 ℃ under reduced pressure to remove 70% of solvent, stirring, cooling to room temperature, then freezing to-5-0 ℃, stirring for 2-3 hours, filtering, and drying. 167.0 g of compound C are obtained, the yield is 92.8 percent

The results of the HPLC detection of Compound C are shown in FIG. 2.

Synthesis of Compound D:

adding 180 g (1mol) of compound C and 540ml of water into a reaction bottle, heating and refluxing for 1-1.5 hours, cooling to 5-10 ℃ under stirring, and performing suction filtration and drying to obtain 145.7 g of compound D with the yield of 94.6%.

The results of HPLC detection of Compound D are shown in FIG. 3.

Nuclear magnetic data:

(CDCl₃,300MHz):9.83(s,1H)；7.68(d,J＝9.0Hz,1H)；6.84(d,J＝9.0Hz,1H).

the foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.