Preparation method of 2, 6-dihydroxyacetophenone

Abstract

The invention provides a preparation method of 2, 6-dihydroxyacetophenone, and belongs to the technical field of organic matter synthesis. According to the method, 2, 6-difluoroacetophenone is used as a raw material to be hydrolyzed in a strong alkaline environment, fluorine atoms are replaced with hydroxyl through nucleophilic substitution, the process is simple, and the yield is high; rearrangement is not needed, generation of a by-product 2, 4-dihydroxyacetophenone is avoided, and the product is easy to separate and high in purity; high-temperature, high-pressure and expensive catalysts are not needed, the operation is convenient, and the cost is low. The result of the embodiment shows that according to the preparation method provided by the invention, the yield is 82-87.7%, and the product purity is higher than 98%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing 2,6-dihydroxyacetophenone. Background Art

[0002] Cromoly sodium is an antiallergic drug that can be used to treat allergic asthma, allergic rhinitis or ulcerative colitis, etc. It can stabilize mast cell membranes, inhibit mast cell lysis and degranulation, and prevent the release of allergic mediators in the reaction of antigen and antibody. At present, the method for preparing sodium cromolybdate reported in the literature is relatively simple. The fundamental reason is that the synthetic route from 2,6-dihydroxyacetophenone to sodium cromolybdate is relatively simple. Therefore, 2,6-dihydroxyacetophenone becomes the key intermediate for preparing sodium cromolybdate.

[0003] There are relatively many synthetic routes for 2,6-dihydroxyacetophenone, which can be divided into two types according to the different raw materials: the first type uses resorcinol as the raw material, and the second type uses 5-hydroxy-2-phenethyl-4H-chromen-4-one as the raw material.

[0004] The first type of synthetic route is divided into three different synthetic routes: (1) Resorcinol is used as the raw material, and RaneyNi hydrogenation reduction is performed to obtain 1,3-cyclohexanediol, which is then acetylated to obtain 2-acetyl-1,3-cyclohexanediol, and then directly aromatized under a dehydrogenation catalyst such as Pd / C to obtain 2,6-dihydroxyacetophenone; this synthetic route is carried out by RaneyNi hydrogenation reduction and palladium carbon dehydrogenation, which is complicated and dangerous to operate, and the price of palladium carbon catalyst is expensive, so the industrial cost is high. (2) Resorcinol is used as the raw material, and acylation and rearrangement are performed to directly synthesize 2,6-dihydroxyacetophenone in one pot; this synthetic route is operated, but most of the acylated product generates a by-product 2,4-dihydroxyacetophenone during rearrangement, and the chemical properties of 2,4-dihydroxyacetophenone and 2,6-dihydroxyacetophenone are similar, and separation and purification are relatively complicated, so this synthetic route is not popular in actual production. (3) Resorcinol is used as the raw material. It reacts with ethyl acetoacetate under the action of concentrated sulfuric acid to produce 7-hydroxy-4-methylcoumarin, which is then acetylated to acyl ester by acetic anhydride. It then undergoes a rearrangement reaction under the action of anhydrous aluminum chloride and hydrolyzes and decarboxylates under alkaline conditions to obtain 2,6-dihydroxyacetophenone. This synthetic route uses a large amount of concentrated sulfuric acid, resulting in the production of a large amount of acidic wastewater. The rearrangement reaction is a solid-solid two-phase reaction. The reaction effect is strongly related to the uniformity of material mixing, resulting in high operating requirements for industrial production. In addition, a large amount of 2,4-dihydroxyacetophenone will be produced as a by-product during the rearrangement. Therefore, this synthetic route has not been popular in actual production.

[0005] The second synthetic route is to use 5-hydroxy-2-phenethyl-4H-chromene-4-one as the raw material, and synthesize 2,6-dihydroxyacetophenone through the cleavage of the carbon-oxygen single bond, ring opening, rearrangement and hydrolysis. The raw materials for this route are difficult to obtain and are expensive, and the overall reaction yield is low, only 12.3%. Therefore, this route remains in the pilot stage. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing 2,6-dihydroxyacetophenone. The preparation method provided by the present invention has simple process, high yield and high product purity.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The invention provides a method for preparing 2,6-dihydroxyacetophenone, comprising: mixing 2,6-difluoroacetophenone, a base and an aqueous solvent and then performing a hydrolysis reaction to obtain 2,6-dihydroxyacetophenone; the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

[0009] Preferably, the temperature of the hydrolysis reaction is 110-180°C.

[0010] Preferably, the hydrolysis reaction time is 6 to 12 hours.

[0011] Preferably, the molar ratio of the 2,6-difluoroacetophenone to the base is 1:(2-5).

[0012] Preferably, the mass ratio of the 2,6-difluoroacetophenone to the aqueous solvent is 1:(2-4).

[0013] Preferably, the aqueous solvent is a mixture of water and a high boiling point organic solvent.

[0014] Preferably, the mass ratio of water to the high boiling point organic solvent is 1:(0.6-2).

[0015] Preferably, the high boiling point organic solvent is one or more of dimethyl sulfoxide, sulfolane, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether.

[0016] Preferably, cooling is further performed after the hydrolysis reaction, and the cooling is ice water cooling.

[0017] Preferably, the cooling further includes post-treatment, and the post-treatment includes: adjusting the pH of the reaction system to 3-5, and then performing suction filtration, washing and drying in sequence.

[0018] The present invention provides a method for preparing 2,6-dihydroxyacetophenone, comprising: mixing 2,6-difluoroacetophenone, a base and an aqueous solvent and then performing a hydrolysis reaction to obtain 2,6-dihydroxyacetophenone; the base is an alkali metal hydroxide or an alkaline earth metal hydroxide. The present invention uses 2,6-difluoroacetophenone as a raw material and performs hydrolysis in a strong alkaline environment, and replaces the fluorine atom with a hydroxyl group through nucleophilic substitution, the process is simple, and the yield is high; no rearrangement is required, and the generation of a by-product 2,4-dihydroxyacetophenone is avoided, and the product is easy to separate and has high purity; no high temperature and high pressure and expensive catalysts are required, and the operation is convenient and the cost is low. The results of the embodiment show that the preparation method provided by the present invention has a yield of 82 to 87.7% and a product purity of more than 98%. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The synthetic route of 2,6-difluoroacetophenone used in the embodiments of the present invention;

[0020] Figure 2 The synthetic route for preparing 2,6-dihydroxyacetophenone in Example 1 of the present invention;

[0021] Figure 3 The NMR spectrum of 2,6-difluoroacetophenone used in the embodiments of the present invention;

[0022] Figure 4 This is the NMR spectrum of the intermediate product of Example 1 of the present invention;

[0023] Figure 5 This is the NMR spectrum of the final product of Example 1 of the present invention;

[0024] Figure 6 This is a liquid chromatogram of 2,6-dihydroxyacetophenone prepared in Example 1 of the present invention;

[0025] Figure 7 This is a liquid chromatogram of 2,6-dihydroxyacetophenone prepared in Example 2 of the present invention;

[0026] Figure 8 This is a liquid chromatogram of 2,6-dihydroxyacetophenone prepared in Example 3 of the present invention;

[0027] Fig. 9 This is a liquid chromatogram of 2,6-dihydroxyacetophenone prepared in Example 4 of the present invention;

[0028] Fig.10 This is a liquid chromatogram of 2,6-dihydroxyacetophenone prepared in Example 5 of the present invention. DETAILED DESCRIPTION

[0029] All raw materials of the present invention have no particular limitation on their sources and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0030] There is no particular limitation on the purity of all raw materials in the present invention. The present invention preferably uses analytically pure raw materials or raw materials with a purity commonly used in the field of organic synthesis.

[0031] The invention provides a method for preparing 2,6-dihydroxyacetophenone, comprising: mixing 2,6-difluoroacetophenone, a base and an aqueous solvent and then performing a hydrolysis reaction to obtain 2,6-dihydroxyacetophenone; the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

[0032] The invention mixes 2,6-difluoroacetophenone, a base and a water-containing solvent and then performs a hydrolysis reaction to obtain 2,6-dihydroxyacetophenone.

[0033] The present invention has no particular limitation on the source of the 2,6-difluoroacetophenone, and the 2,6-difluoroacetophenone can be prepared by a commercially available method or a method known to those skilled in the art. Figure 1 The specific route is: using 2,6-difluorobenzoic acid as the starting material to prepare the acyl chloride compound 1a, then replacing the chlorine atom with diethyl malonate to obtain compound 1b, and then replacing diethyl malonate with methyl to obtain compound 2, i.e. 2,6-difluoroacetophenone.

[0034] In the present invention, the base is an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide. The base has strong alkalinity and can hydrolyze the fluorine in 2,6-difluoroacetophenone into hydroxyl groups.

[0035] In the present invention, the molar ratio of the 2,6-difluoroacetophenone to the base is preferably 1:(2-5), more preferably 1:(3-4); as an embodiment of the present invention, the molar ratio of the 2,6-difluoroacetophenone to the base may be 1:2, 1:3, 1:4 or 1:5. The molar ratio of 2,6-difluoroacetophenone to the base within the above range is conducive to the hydrolysis reaction.

[0036] In the present invention, the aqueous solvent is preferably a mixture of water and a high boiling point organic solvent. The mass ratio of water to the high boiling point organic solvent is preferably 1: (0.6-2), more preferably 1: 1. The high boiling point organic solvent is preferably one or more of dimethyl sulfoxide, cyclopentane sulfone, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether. The use of the above solvents can increase the temperature of the hydrolysis reaction, which is conducive to the hydrolysis reaction.

[0037] In the present invention, the mass ratio of 2,6-difluoroacetophenone to the aqueous solvent is preferably 1:(2-4), more preferably 1:3. When the mass ratio of 2,6-difluoroacetophenone to the aqueous solvent is within the above range, 2,6-difluoroacetophenone can be fully dissolved, which is beneficial to the hydrolysis reaction.

[0038] The present invention has no particular limitation on the specific mixing method, and a conventional mixing method in the art can be used. As an embodiment of the present invention, the base and the solvent can be mixed and stirred, and then 2,6-difluoroacetophenone can be added dropwise while stirring for 30 minutes; the present invention has no particular requirement on the stirring speed, as long as the materials can be stirred evenly.

[0039] In the present invention, the temperature of the hydrolysis reaction is preferably 110-180° C., more preferably 120-150° C.; as an embodiment of the present invention, the temperature of the hydrolysis reaction may be 110° C., 120° C., 130° C., 140° C., 150° C., 160° C., 170° C. or 180° C. The temperature of the hydrolysis reaction is within the above range, which is conducive to the hydrolysis reaction while taking into account the reaction efficiency and energy consumption.

[0040] In the present invention, the hydrolysis reaction time is preferably 6 to 12 hours, more preferably 8 to 10 hours; as an embodiment of the present invention, the hydrolysis reaction time can be 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours. The hydrolysis reaction time within the above range is conducive to further improving the product yield.

[0041] In the present invention, the hydrolysis reaction is preferably followed by cooling, and the cooling is preferably cooling with cold water. The present invention has no particular limitation on the specific cooling method, and the conventional operation method in the art can be used. As an embodiment of the present invention, the reaction solution can be directly added to cold water.

[0042] In the present invention, the cooling preferably includes post-treatment, and the post-treatment preferably includes: adjusting the pH of the reaction system to 3-5, and then performing suction filtration, washing and drying in sequence. The present invention has no special requirements for the specific operation of the post-treatment, and the conventional operation method in the art can be adopted. As an embodiment of the present invention, concentrated hydrochloric acid can be used to adjust the pH of the reaction system. The solubility of 2,6-dihydroxyacetophenone in cold water is very low. Adjusting the pH of the reaction system to 3-5 can further reduce the solubility of 2,6-difluoroacetophenone according to the common ion effect, which is beneficial to improve the product yield.

[0043] The invention uses 2,6-difluoroacetophenone as a raw material and performs hydrolysis in a strongly alkaline environment, and replaces fluorine atoms with hydroxyl groups through nucleophilic substitution, and has a simple process and a high yield; no rearrangement is required, and the generation of a byproduct 2,4-dihydroxyacetophenone is avoided, and the product is easy to separate and has a high purity; high temperature and high pressure and expensive catalysts are not required, and the operation is convenient and the cost is low.

[0044] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0045] The specific steps for preparing 2,6-difluoroacetophenone in the embodiment of the present invention are as follows:

[0046] In a 1000mL reaction container equipped with a thermometer and a stirrer, 50g of 2,6-difluorobenzoic acid and 100g of EA were added in sequence and heated to 55°C; then 52.6g of thionyl chloride was added dropwise thereto, the mixture was kept warm for 1h, and 58g of compound 1a was obtained by concentrating under reduced pressure; 21g of anhydrous magnesium chloride was added to another 1000mL reaction container equipped with a thermometer and a stirrer, and a mixture of 60g of triethylamine and 55.7g of diethyl malonate was added dropwise at 30°C, the temperature was controlled at 30°C, the mixture was kept warm for 1h, 58g of compound 1a was added dropwise, the temperature was controlled at 30°C, the addition was completed, and the mixture was kept warm for 3h; during sampling, After the reaction was complete, 205 g of 6% dilute hydrochloric acid was added dropwise to the reaction system, stirred at 30°C for 1 h, and the layers were separated. The organic layer was concentrated and dried under reduced pressure in a water bath at 55°C to obtain 103 g of compound 1b. In another 1000 mL reaction container equipped with a thermometer and a stirrer, 100 g of glacial acetic acid, 100 g of water, 100 g of concentrated hydrochloric acid and 103 g of compound 1b were added in sequence. After reflux reaction at 100°C for 2 h, all the raw materials sampled in the central control were converted, and the reaction was completed. The temperature was lowered and the layers were separated. After the lower layer of oil was washed with water and alkali, 46 g of compound 2,6-difluoroacetophenone was obtained with a purity of 98.9% and a yield of 93.3%.

[0047] Example 1

[0048] A method for preparing 2,6-dihydroxyacetophenone, the preparation path is as follows Figure 2 As shown, 2,6-difluoroacetophenone is used as the starting material, and 2,6-dihydroxyacetophenone is obtained through the intermediate product 2'-fluoro-6'-hydroxyacetophenone; the specific preparation method is as follows:

[0049] In a 1000mL reaction container equipped with a thermometer, a constant pressure dropping funnel and a stirrer, 90g of potassium hydroxide, 150g of water and 150g of dimethyl sulfoxide were added in sequence, the temperature was raised to 120°C, 100g of 2,6-difluoroacetophenone was added dropwise to the reaction system, the addition was completed within 30 minutes, the reaction was kept warm for 5h, sampling was performed for mid-control, and the intermediate 2'-fluoro-6'-hydroxyacetophenone was converted to the intermediate 2'-fluoro-6'-hydroxyacetophenone, and the reaction was kept warm for 6h until the reaction was completed; the reaction solution was poured into 500g of ice water, the pH was adjusted to 3 with concentrated hydrochloric acid, a light yellow solid was precipitated, the solid was filtered, rinsed with water, and dried to obtain 83.9g of 2,6-dihydroxyacetophenone with a yield of 85%.

[0050] Example 2

[0051] A preparation method of 2,6-dihydroxyacetophenone, the specific preparation method is as follows:

[0052] In a 1000mL reaction container equipped with a thermometer, a constant pressure dropping funnel and a stirrer, 90g of potassium hydroxide, 150g of water and 150g of dimethyl sulfoxide were added in sequence, the temperature was raised to 150°C, 100g of 2,6-difluoroacetophenone was added dropwise to the reaction system, the addition was completed within 30 minutes, the reaction was kept warm for 4h, sampling was performed for mid-control, and the intermediate 2'-fluoro-6'-hydroxyacetophenone was converted to the intermediate 2'-fluoro-6'-hydroxyacetophenone, and the reaction was kept warm for 4h until the reaction was completed; the reaction solution was poured into 500g of ice water, the pH was adjusted to 4 with concentrated hydrochloric acid, a light yellow solid was precipitated, the solid was filtered, rinsed with water, and dried to obtain 86.5g of 2,6-dihydroxyacetophenone with a yield of 87.7%.

[0053] Example 3

[0054] A preparation method of 2,6-dihydroxyacetophenone, the specific preparation method is as follows:

[0055] In a 1000mL reaction container equipped with a thermometer, a constant pressure dropping funnel and a stirrer, 90g of potassium hydroxide, 150g of water and 150g of ethylene glycol monomethyl ether were added in sequence, the temperature was raised to 120°C, 100g of 2,6-difluoroacetophenone was added dropwise to the reaction system, the addition was completed within 30 minutes, the reaction was kept warm for 5h, sampling was performed for mid-control, and the intermediate 2'-fluoro-6'-hydroxyacetophenone was converted to the intermediate 2'-fluoro-6'-hydroxyacetophenone, and the reaction was kept warm for 5h until the reaction was completed; the reaction solution was poured into 500g of ice water, the pH was adjusted to 5 with concentrated hydrochloric acid, a light yellow solid was precipitated, suction filtered, rinsed with water, and dried to obtain 82.5g of 2,6-dihydroxyacetophenone with a yield of 83.6%.

[0056] Example 4

[0057] A preparation method of 2,6-dihydroxyacetophenone, the specific preparation method is as follows:

[0058] In a 1000mL reaction container equipped with a thermometer, a constant pressure dropping funnel and a stirrer, 64g of sodium hydroxide, 150g of water and 150g of ethylene glycol monomethyl ether were added in sequence, the temperature was raised to 120°C, 100g of 2,6-difluoroacetophenone was added dropwise to the reaction system, the addition was completed within 30 minutes, the reaction was kept warm for 5h, sampling was performed for mid-control, and the intermediate 2'-fluoro-6'-hydroxyacetophenone was converted to the intermediate 2'-fluoro-6'-hydroxyacetophenone, and the reaction was kept warm for 6h until the reaction was completed; the reaction solution was poured into 500g of ice water, the pH was adjusted to 5 with concentrated hydrochloric acid, a light yellow solid was precipitated, suction filtered, rinsed with water, and dried to obtain 81.5g of 2,6-dihydroxyacetophenone with a yield of 82.6%.

[0059] Example 5

[0060] A preparation method of 2,6-dihydroxyacetophenone, the specific preparation method is as follows:

[0061] In a 1000mL reaction container equipped with a thermometer, a constant pressure dropping funnel and a stirrer, 64g of sodium hydroxide, 150g of water and 150g of ethylene glycol monomethyl ether were added in sequence, the temperature was raised to 110°C, 100g of 2,6-difluoroacetophenone was added dropwise to the reaction system, the addition was completed within 30 minutes, the reaction was kept warm for 5h, sampling was performed for mid-control, and the intermediate 2'-fluoro-6'-hydroxyacetophenone was converted to the intermediate 2'-fluoro-6'-hydroxyacetophenone, and the reaction was kept warm for 6h until the reaction was completed; the reaction solution was poured into 500g of ice water, the pH was adjusted to 5 with concentrated hydrochloric acid, a light yellow solid was precipitated, suction filtered, rinsed with water, and dried to obtain 81g of 2,6-dihydroxyacetophenone with a yield of 82%.

[0062] Test Example 1

[0063] The initial raw material 2,6-difluoroacetophenone, the intermediate product and the final product in Example 1 were subjected to nuclear magnetic resonance detection to obtain a nuclear magnetic spectrum, such as Figure 3 , Figure 4 , Figure 5 shown.

[0064] from Figure 3 It can be seen that 1HNMR (500MHz, Chloroform-d) δ7.37 (ddd, J=14.7, 8.3, 6.5Hz, 1H), 6.92 (t, J=8.1Hz, 2H), 2.57 (d, J=1.6Hz, 3H), indicating that 2,6-difluoroacetophenone was successfully prepared.

[0065] from Figure 4It can be seen that 1H NMR (500MHz, Chloroform-d) δ12.71 (s, 1H), 7.36 (d, J = 6.4 Hz, 1H), 6.75 (dt, J = 8.5, 0.9 Hz, 1H), 6.58 (ddd, J = 11.6, 8.2, 1.1 Hz, 1H), 2.67 (d, J = 7.3 Hz, 3H); indicating that the intermediate product is 2'-fluoro-6'-hydroxyacetophenone.

[0066] from Figure 5 It can be seen that 1H NMR (500MHz, DMSO-d6) δ11.77 (s, 2H), 7.23 (t, J=8.2Hz, 1H), 6.36 (d, J=8.2Hz, 2H), 2.62 (s, 3H); indicating that 2,6-dihydroxyacetophenone was successfully prepared.

[0067] Test Example 2

[0068] The purity of the product was tested by liquid chromatography. Figures 6 to 10 The liquid chromatography parameters are as follows:

[0069] Mobile phase: A:B = 0.1% phosphoric acid water: acetonitrile;

[0070] Chromatographic column: ODS-C18, 4.6*250mm, 5μm;

[0071] Wavelength: 210 / 254nm;

[0072] Flow rate: 1.0 mL / min;

[0073] Injection volume: 5 μL, sample preparation: 1 mg / mL acetonitrile solution;

[0074] The time program is as shown in Table 1:

[0075] Table 1 Liquid chromatography time program

[0076] TIME / min 0 3 20 25 30 AmL / min 75 75 20 20 75 BmL / min 25 30 80 80 25

[0077] The purity of the products obtained in Examples 1 to 5 is shown in Table 2.

[0078] Table 2 Purity test results of the products obtained in each embodiment

[0079] Product purity (%) Example 1 98.433 Example 2 98.803 Example 3 98.230 Example 4 98.421 Example 5 98.070

[0080] It can be seen from the detection results of the embodiments and test examples that the preparation method provided by the present invention has a high yield and a high product purity, which meets the needs of industrial production.

[0081] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 2,6-dihydroxyacetophenone, comprising: 2,6-difluoroacetophenone, a base and a water-containing solvent are mixed and then subjected to a hydrolysis reaction to obtain 2,6-dihydroxyacetophenone; the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

2. The preparation method according to claim 1, characterized in that: The temperature of the hydrolysis reaction is 110-180°C.

3. The preparation method according to claim 1 or 2, characterized in that: The hydrolysis reaction time is 6 to 12 hours.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the 2,6-difluoroacetophenone to the base is 1:(2-5).

5. The preparation method according to claim 1, characterized in that: The mass ratio of the 2,6-difluoroacetophenone to the aqueous solvent is 1:(2-4).

6. The preparation method according to claim 1 or 5, characterized in that: The aqueous solvent is a mixture of water and a high boiling point organic solvent.

7. The preparation method according to claim 6, characterized in that: The mass ratio of the water to the high boiling point organic solvent is 1:(0.6-2).

8. The preparation method according to claim 7, characterized in that: The high boiling point organic solvent is one or more of dimethyl sulfoxide, sulfolane, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether.

9. The preparation method according to claim 1, characterized in that: The hydrolysis reaction is followed by cooling, wherein the cooling is performed by ice water cooling.

10. The preparation method according to claim 9, characterized in that: The method further includes post-processing after cooling, and the post-processing includes: adjusting the pH of the reaction system to 3-5, and then performing suction filtration, washing and drying in sequence.

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