阅读说明：本技术 一种5,6-二甲基呫吨酮-4-乙酸的合成方法 (Synthetic method of 5, 6-dimethylxanthenone-4-acetic acid ) 是由 张一曼 吕海军 杨尚金 于 2020-06-19 设计创作，主要内容包括：本发明涉及一种5,6-二甲基呫吨酮-4-乙酸的合成方法,首先用2,3-二甲基苯酚与2,3-二氯苯甲醛反应生成4-氯-5,6-二甲基呫吨酮,然后与丙二酸二乙酯反应得到5,6-二甲基呫吨酮-4-乙酸乙酯,最后碱性水解得到5,6-二甲基呫吨酮-4-乙酸,该方法所需原料价格适中,收率高,所得产物纯度大于98%。(The invention relates to a method for synthesizing 5, 6-dimethylxanthenone-4-acetic acid, which comprises the steps of firstly reacting 2, 3-dimethylphenol with 2, 3-dichlorobenzaldehyde to generate 4-chloro-5, 6-dimethylxanthenone, then reacting with diethyl malonate to obtain 5, 6-dimethylxanthenone-4-ethyl acetate, and finally performing alkaline hydrolysis to obtain the 5, 6-dimethylxanthenone-4-acetic acid, wherein the price of raw materials required by the method is moderate, the yield is high, and the purity of the obtained product is more than 98%.)

1. A method for synthesizing 5, 6-dimethylxanthenone-4-acetic acid, comprising the steps of:

1) reacting 2, 3-dimethylphenol with 2, 3-dichlorobenzaldehyde to generate 4-chloro-5, 6-dimethylxanthone;

2) carrying out conversion reaction on the 4-chloro-5, 6-dimethylxanthone to obtain 5, 6-dimethylxanthone-4-ethyl acetate;

3) hydrolyzing the 5, 6-dimethylxanthenone-4-acetic acid ethyl ester in the presence of alkali, and then acidifying to generate a crude product of the 5, 6-dimethylxanthenone-4-acetic acid.

2. The method of claim 1, wherein: the molar ratio of the 2, 3-dimethylphenol to the 2, 3-dichlorobenzaldehyde in the step 1) is as follows: (1-2): 1, the reaction solvent in the step 1) is toluene.

3. The method of claim 1, wherein: the reaction temperature in the step 1) is 0-150 ℃.

4. The method of claim 1, wherein: and in the step 1), triphenylphosphine, anhydrous copper chloride and potassium phosphate are added, wherein the molar ratio of the anhydrous copper chloride to the 2, 3-dimethylphenol is (0.01-5): the molar ratio of 1, triphenylphosphine to 2, 3-dimethylphenol is (0.01-1): 1, the molar ratio of potassium phosphate to 2, 3-dimethylphenol is (1-5): 1.

5. the method of claim 4, wherein: the anhydrous copper chloride in the step 1) can also be elemental copper, and the molar ratio of the elemental copper to the 2, 3-dimethylphenol is (0.01-1): 1.

6. the method of claim 1, wherein: the reagent used in the conversion reaction in the step 2) is diethyl malonate, and the molar ratio of the diethyl malonate to the 4-chloro-5, 6-dimethylxanthone is (1-10): 1.

7. the method of claim 1, wherein: in the step 2), bis (dibenzylideneacetone) palladium (0), tri-tert-butylphosphine tetrafluoroborate, potassium phosphate, 18-crown ether-6, and the molar ratio of bis (dibenzylideneacetone) palladium (0) to 4-chloro-5, 6-dimethylxanthone is (0.001-1): the molar ratio of the 1, tri-tert-butylphosphine tetrafluoroborate to the 4-chloro-5, 6-dimethylxanthone is (0.01-1): 1, the molar ratio of potassium phosphate to 4-chloro-5, 6-dimethylxanthone is (1-5): the molar ratio of 1, 18-crown-6 to 4-chloro-5, 6-dimethylxanthone is (0.05-10): 1.

8. the method of claim 1, wherein: the reaction temperature in the step 2) is 50-200 ℃.

9. The method of claim 1, wherein: the reaction temperature in the step 3) is 10-100 ℃, and the alkali is sodium hydroxide or potassium hydroxide.

10. The method of claim 1, wherein: the method also comprises the steps of recrystallizing the crude 5, 6-dimethylxanthenone-4-acetic acid in an organic solvent or/and neutralizing the crude 5, 6-dimethylxanthenone-4-acetic acid with acid and alkali to obtain pure 5, 6-dimethylxanthenone-4-acetic acid;

the recrystallization process comprises the following steps: adding ethyl acetate or dichloromethane or tert-butyl methyl ether or diethyl ether into the crude product of 5, 6-dimethylxanthone-4-acetic acid for dissolving, then adding petroleum ether, cooling overnight to obtain solid, and filtering to obtain 5, 6-dimethylxanthone-4-acetic acid;

the acid-base neutralization process comprises the following steps: suspending the crude 5, 6-dimethylxanthenone-4-acetic acid product in methanol and water, adding ammonia water to remove insoluble substances, acidifying, filtering water, and washing to obtain pure 5, 6-dimethylxanthenone-4-acetic acid.

Technical Field

The invention relates to the technical field of medicine preparation, in particular to a synthesis method of 5, 6-dimethylxanthenone-4-acetic acid.

Background

5, 6-Dimethylxanthone-4-acetic acid (DMXAA) is an antitumor compound developed by the research center for tumors of the university of Oakland, New Zealand (Rehman, F.; Rustin, G.Exp.Opin.Inv.drugs 2008,17, 1547-1551), classified as a vascular proliferation inhibitor due to its ability to induce endothelial cell apoptosis, which is also an effective cytokine inducer in addition to rapidly causing tumor vascular apoptosis, and is a key compound for research on anticancer drugs [ Journal of Biological Chemistry, (287), (47), 3979-3978 ] although not showing efficacy in phase III clinical trials, and is synthesized as an important intermediate for other anticancer compounds (CN 105906602A).

There are several alternatives to the synthesis of 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) [ European journal of Medicinal Chemistry 37(2002)825-828], and introduction of nitro group starting from 3, 4-dimethylbenzoic acid is one of the easily scalable methods:

and 3, 4-dimethylbenzoic acid is taken as a raw material, dibromination is carried out, and then the dibromination is condensed with o-hydroxyphenylacetic acid, cyclization and catalytic hydrogenation are carried out to prepare (Tetrahedron Letters 2009, 3945-:

this method was also used for the synthesis of DMXAA Pyranoxanthone hybrid compounds (CN 107445970A). The problems faced by the method need dangerous catalytic hydrogenation reaction and diazotization reaction, and have long route and complicated operation.

Disclosure of Invention

The invention provides a synthesis method of 5, 6-dimethylxanthenone-4-acetic acid (DMXAA), which starts with a commercially available chemical raw material and obtains a product through three-step chemical reaction, wherein the raw material is easy to obtain, and the reaction yield is high.

The technical scheme of the invention is as follows:

the method specifically comprises the following steps:

1) reacting 2, 3-dimethylphenol with 2, 3-dichlorobenzaldehyde to generate 4-chloro-5, 6-dimethylxanthone;

2) carrying out conversion reaction on the 4-chloro-5, 6-dimethylxanthone to obtain 5, 6-dimethylxanthone-4-ethyl acetate;

3) hydrolyzing 5, 6-dimethylxanthenone-4-ethyl acetate in the presence of alkali, and then acidifying to generate a crude product of 5, 6-dimethylxanthenone-4-acetic acid;

4) recrystallizing the 5, 6-dimethylxanthenone-4-acetic acid crude product in an organic solvent or/and neutralizing with acid and alkali to obtain pure 5, 6-dimethylxanthenone-4-acetic acid.

Preferably, the reaction molar ratio of the 2, 3-dimethylphenol and the 2, 3-dichlorobenzaldehyde in the step 1) is (1-2): 1; the reaction solvent in the step 1) is toluene.

Further preferably, the reaction molar ratio of the 2, 3-dimethylphenol to the 2, 3-dichlorobenzaldehyde is 1: 1.

preferably, the reaction temperature in the step 1) is 0-150 ℃.

Preferably, triphenylphosphine, anhydrous copper chloride and potassium phosphate are also added in the step 1).

Further preferably, the molar ratio of the anhydrous copper chloride to the 2, 3-dimethylphenol is (0.01-5): the molar ratio of 1, triphenylphosphine to 2, 3-dimethylphenol is (0.01-1): 1, the molar ratio of potassium phosphate to 2, 3-dimethylphenol is (1-5): 1.

still more preferably, the molar ratio of anhydrous cupric chloride addition to reactants is 0.05: 1, the molar ratio of triphenylphosphine to reactants was 0.07: 1

Further preferably, the anhydrous copper chloride in the step 1) can also be elemental copper, and the molar ratio of the elemental copper to the 2, 3-dimethylphenol is (0.01-1): 1, the molar ratio of potassium phosphate to reactant is 2.2: 1.

preferably, the reagent used in the conversion reaction of the step 2) is diethyl malonate, and the diethyl malonate is 4-chloro-5, 6-dimethylxanthone with a molar ratio of (1-10): 1.

more preferably, in the step 2), the reaction molar ratio of diethyl malonate to 4-chloro-5, 6-dimethylxanthone is (1-5): 1.

preferably, sodium hydride is also added in the conversion reaction in the step 2).

More preferably, the molar ratio of the sodium hydride to the 4-chloro-5, 6-dimethylxanthone is (2 to 10): 1.

preferably, bis (dibenzylideneacetone) palladium (0), tri-tert-butylphosphine tetrafluoroborate, potassium phosphate, 18-crown-6 may also be added in the conversion reaction of step 2).

Further preferably, the molar ratio of bis (dibenzylideneacetone) palladium (0) to 4-chloro-5, 6-dimethylxanthone is (0.01 to 1): the molar ratio of the 1, tri-tert-butylphosphine tetrafluoroborate to the 4-chloro-5, 6-dimethylxanthone is (0.01-1): 1, the molar ratio of potassium phosphate to 4-chloro-5, 6-dimethylxanthone is (1-5): the molar ratio of 1, 18-crown-6 to 4-chloro-5, 6-dimethylxanthone is (1-10): 1.

still more preferably, the molar ratio of potassium phosphate to 4-chloro-5, 6-dimethylxanthone is 3.5: 1.

preferably, the reaction temperature in the step 2) is 50-200 ℃.

Further preferably, the reaction temperature of the step 2) is 160 ℃.

Preferably, the reaction temperature in the step 3) is 10-100 ℃.

The alkali is sodium hydroxide or potassium hydroxide.

Further preferably, the reaction temperature of the step 3) is 40 ℃.

Further preferably, the method further comprises recrystallizing the crude 5, 6-dimethylxanthone-4-acetic acid in an organic solvent or/and neutralizing with an acid or an alkali to obtain pure 5, 6-dimethylxanthone-4-acetic acid;

the recrystallization process comprises the following steps: adding ethyl acetate or dichloromethane or tert-butyl methyl ether or diethyl ether into the crude product of 5, 6-dimethylxanthone-4-acetic acid for dissolving, then adding petroleum ether, cooling overnight to obtain solid, and filtering to obtain 5, 6-dimethylxanthone-4-acetic acid;

the acid-base neutralization process comprises the following steps: suspending the crude 5, 6-dimethylxanthenone-4-acetic acid product in methanol and water, adding ammonia water to remove insoluble substances, acidifying, filtering water, and washing to obtain pure 5, 6-dimethylxanthenone-4-acetic acid.

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

1. the method comprises the steps of taking 2, 3-dimethylphenol and 2, 3-dichlorobenzaldehyde as raw materials, condensing under the catalysis of copper chloride to obtain 4-chloro-5, 6-dimethylxanthone, reacting with diethyl malonate to introduce ethyl acetate group to obtain 5, 6-dimethylxanthone-4-ethyl acetate, hydrolyzing in the presence of sodium hydroxide to obtain 5, 6-dimethylxanthone-4-acetic acid, treating a crude product with ammonia water, acidifying the crude product with acetic acid, filtering, washing with water and washing with methanol to obtain a product with the content of more than 98%, wherein the total yield is more than 49%.

2. The preparation method only has three steps of reactions, the yield is improved, and the product purity is higher than 98%.

3. The reagent used in the reaction is easy to obtain, and the reaction condition is mild.

Description of the drawings:

FIG. 1 liquid chromatogram of 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) obtained in example 3

Detailed Description

The invention is further illustrated by the following examples, but the scope of the invention as claimed is not limited to the scope of the examples.