Method for separating and purifying 2, 4-dihydroxy valerophenone through single column chromatography and application of 2, 4-dihydroxy valerophenone

Abstract

The invention discloses a method for separating and purifying 2, 4-dihydroxy valerophenone through single column chromatography and application, and belongs to the field of chemical engineering. According to the method, high purity (gt; 95%) and high yield (90%-95%) of the product are realized by optimizing post-treatment and column chromatography conditions of a synthetic reaction, and the problem that the high purity can be obtained only by multiple times of column chromatography and recrystallization in the traditional technology is solved. According to the method, water is added for extraction to remove impurities, so that the use of precursor reagent hydrochloric acid is avoided, the operation is simplified, and the risk of environmental pollution is reduced; water is directly added to replace ethyl acetate for extraction, so that the extraction yield is increased, and the cost is reduced; dichloromethane in column chromatography is used as a mobile phase and a diluent, the separation effect is improved, sample hardening is avoided, dichloromethane can be recycled, and the cost and pollution are further reduced; the method is suitable for various requirements from small-batch laboratory purification to large-scale industrial production, and promotes wide application and development of 2, 4-dihydroxy valerophenone in the industries of medicines, cosmetics and the like.

Description

Technical Field

[0001] The invention belongs to the field of chemical engineering, and specifically relates to a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography and application thereof. Background Art

[0002] 2,4-Dihydroxyvalerophenone is an important pharmaceutical intermediate and the starting material for the synthesis of 2-hydroxy-4-methoxyvalerophenone. Studies have shown that 2-hydroxy-4-methoxyvalerophenone has pharmacological effects such as antihypertensive, anti-inflammatory, antioxidant, and myocardial protection. It is gradually being used in the pharmaceutical, cosmetics and other industries, and has broad application prospects. At present, the purification method of 2,4-dihydroxyvalerophenone mainly adopts the method of recrystallization after initial separation by column chromatography. These purification methods have always been faced with many challenges, which seriously restricts its industrial production and application. Traditional purification methods for 2,4-dihydroxyvalerophenone usually involve multiple complex processes, such as extraction, distillation, recrystallization, etc. These methods are not only cumbersome to operate, but also require a large amount of organic solvents, resulting in high production costs; more importantly, these solvents are often difficult to recycle and reuse. In the process of column chromatography and crystallization, a large amount of mixed solvents are usually required to dissolve and purify the target compound. These mixed solvents are often unable to be effectively recycled and reused, which not only causes a waste of resources, but also may pollute the environment; in addition, the yield of traditional purification methods is generally low, which means that only a limited amount of pure products can be obtained with a large amount of raw material input. This not only increases production costs, but also limits the increase in production capacity, making it difficult for the production of 2,4-dihydroxyvalerophenone to meet the growing market demand; finally, the existing purification method requires crystallization, which is difficult to operate and has a low yield of the final product. This is because the 2,4-dihydroxyvalerophenone molecule contains two phenolic hydroxyl groups, which are easily soluble in most organic solvents and easily form hydrogen bonds with oxygen-containing solvents. Crystallization is difficult, so the yield is low. In order to improve the yield, low-temperature crystallization is usually used, and the temperature needs to be cooled to -10°C to 20°C. The operation is difficult and has high requirements on equipment, which cannot meet the needs of industrial production. Therefore, there is an urgent need for a method for separating and purifying 2,4-dihydroxyvalerophenone with high efficiency and simple process, while being able to ensure the purity and yield of 2,4-dihydroxyvalerophenone. Summary of the invention

[0003] In view of the problems that the current purification method of the pharmaceutical intermediate 2,4-dihydroxyvalerophenone has many steps, the solvent cannot be recycled and reused, the yield is low, and it is not suitable for industrial production, it is urgent to develop an efficient and simple separation and purification method, which not only reduces the cost and is suitable for industrial production, but also obtains 2,4-dihydroxyvalerophenone with high purity and high yield. The present invention aims to provide a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography.

[0004] In order to achieve the above object, the present invention adopts the following technical solution: The present invention provides a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography, comprising: Resorcinol, n-valeric acid and anhydrous zinc chloride are reacted, extracted and distilled under reduced pressure to obtain a crude 2,4-dihydroxyvalerophenone product. The crude 2,4-dihydroxyvalerophenone product is separated by column chromatography, and the eluent is concentrated and dried to obtain a pure 2,4-dihydroxyvalerophenone product.

[0005] The molar ratio of resorcinol, n-valeric acid and anhydrous zinc chloride is 1:1-1.5:1-1.2, the reaction temperature is 135-145° C., and the reaction time is 6-8 hours.

[0006] The extraction solvent is water, the added amount is 1 / 3 to 1 times the total volume of resorcinol, n-valeric acid and anhydrous zinc chloride, the extraction temperature is 70 to 90° C., and the extraction is performed 2 to 4 times.

[0007] The reduced pressure distillation temperature is 120-150° C., and the vacuum degree is 10-20 Kpa.

[0008] In the column chromatography, the mass ratio of the crude 2,4-dihydroxyvalerophenone to silica gel is 1:2.5-4, the particle size of the silica gel is 100-400 meshes, and the mobile phase is dichloromethane.

[0009] The flow rate of the mobile phase is 50-150 mL / min.

[0010] The column chromatography adopts TLC monitoring process, uses GF254 silica gel plate as stationary phase, and uses a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as developing solvent.

[0011] The concentration is carried out by atmospheric distillation at a distillation temperature of 40°C to 50°C.

[0012] The drying method is air drying at 40-50°C.

[0013] The purity of the purified 2,4-dihydroxyvalerophenone is greater than 95%.

[0014] Application of the method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography in the preparation of 2-hydroxy-4-methoxyvalerophenone.

[0015] Compared with the prior art, the technical solution of the present invention has achieved the following beneficial technical effects: The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography provided by the present invention successfully realizes separation and purification of 2,4-dihydroxyvalerophenone by single column chromatography by changing the post-synthesis reaction treatment and column chromatography conditions, and the purity of 2,4-dihydroxyvalerophenone reaches more than 95%, and the yield is between 90% and 95%, thereby overcoming the difficulty in the prior art that multiple column chromatography separations and recrystallization are required to obtain a higher purity, and at the same time, the yield of the purification process is significantly improved, and the method has broad industrial application prospects.

[0016] Furthermore, the method of water extraction is used to remove zinc chloride and resorcinol, avoiding the use of hydrochloric acid, a precursor reagent. This improvement not only simplifies the operating steps, but also reduces the risk of environmental pollution, because the purchase, storage, use and disposal of hydrochloric acid require strict control; the method of constant temperature extraction is adopted, the reaction liquid is in liquid state at 60-80°C, and water is directly added for extraction, avoiding the use of the organic reagent ethyl acetate, which not only improves the extraction yield but also reduces the production cost. In addition, ethyl acetate is a flammable and explosive reagent, and its use and disposal may also have a negative impact on the environment.

[0017] Furthermore, the column chromatography uses dichloromethane as the mobile phase and diluent, replacing the mixed solvent of ethyl acetate and petroleum ether in the existing method, which not only improves the separation effect, but also avoids the phenomenon of sample sticking during the loading process, making the column chromatography process smoother. Dichloromethane can also be recycled as a solvent, further reducing production costs and environmental pollution.

[0018] The application and method provided by the present invention are not only applicable to small-batch purification operations on a laboratory scale, but also to large-scale purification requirements in industrial production. By further optimizing process parameters and expanding production scale, this method is expected to become one of the mainstream purification technologies in the production field of 2,4-dihydroxyvalerophenone and 2-hydroxy-4-methoxyvalerophenone; the implementation of the present invention will help improve the production efficiency and product quality of 2,4-dihydroxyvalerophenone and 2-hydroxy-4-methoxyvalerophenone, promote their wide application and development in the pharmaceutical, cosmetics and other industries, and high-purity products will meet the needs of more high-end fields, providing strong support for the innovation and development of related industries. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The TLC monitoring of the separation process of crude 2,4-dihydroxyvalerophenone in the present invention; wherein 1 is crude 2,4-dihydroxyvalerophenone, and 2 is pure 2,4-dihydroxyvalerophenone; Figure 2 The HPLC chromatogram of 2,4-dihydroxyvalerophenone is obtained by the method of the present invention. DETAILED DESCRIPTION

[0020] The following examples are used to further illustrate the present invention, but these examples are only for better understanding of the invention and are not used to limit the scope or implementation principle of the present invention. The implementation of the present invention is not limited to the following contents. Unless otherwise specified, the test methods used are conventional methods, and the raw materials used are commercially available products.

[0021] Example 1 This embodiment provides a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography, and the specific steps are as follows: 165.02 g of resorcinol, 136.11 g of anhydrous zinc chloride, and 130 mL of n-pentanoic acid were added to a 1000 mL three-necked flask in sequence, and the temperature was slowly raised to 135 °C while stirring. During the reaction, the mixture was passed through a water separator, the water layer was discarded, and the reaction was kept warm for 6 h. After the reaction was completed, the temperature was lowered to 80 °C, 300 mL of pure water was added, stirred for 1 min, and the mixture was transferred to a separatory funnel for standing and separation, and the water phase was discarded. The operation was repeated and extracted twice with water. The residual liquid was distilled at 130 °C under reduced pressure to remove n-pentanoic acid, and 164.25 g of a yellow-brown viscous liquid was obtained, which was the crude product of 2,4-dihydroxyvalerophenone.

[0022] Column loading: Take 500.13 g of 100-200 mesh silica gel and add 1000 mL of dichloromethane. Stir thoroughly and then load into the chromatography column. The ratio of the chromatography column diameter to height is 1:8.

[0023] Loading: dilute the crude product with 50 mL of dichloromethane and then load the sample. The ratio of sample layer to column height is 2:17.

[0024] Elution: Use dichloromethane for elution at a flow rate of 150 mL / min.

[0025] Collection: The chromatography process was monitored by TLC, with GF254 silica gel plate as the stationary phase, petroleum ether:ethyl acetate = 5:1 as the developing solvent, observation at 254 nm, and the chromatographic solution of the pure point of 2,4-dihydroxyvalerophenone was collected.

[0026] Concentration: Combine the collected liquids to a total of 3200 mL, concentrate at normal pressure and apply the solvent. Dry the residual solid after concentration at 40°C with air blast to obtain 116.42 g of white solid powder, which is pure 2,4-dihydroxyvalerophenone with a purity of 96.33% and a single column chromatography yield of 92.06%.

[0027] Example 2 This embodiment provides a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography, and the specific steps are as follows: 825.14g of resorcinol, 1224.06g of anhydrous zinc chloride, and 812ml of n-pentanoic acid were added to a 5000mL three-necked flask in sequence, and the temperature was slowly raised to 145°C under stirring. During the reaction, the water layer was discarded through a water separator, and the reaction was kept warm for 8 hours. After the reaction was completed, the temperature was lowered to 70°C, 1500 mL of pure water was added, stirred for 1min, transferred to a separatory funnel and allowed to stand for separation, and the aqueous phase was discarded. Repeat the operation and extract with water twice more. The residual liquid was distilled at 140°C under reduced pressure to remove n-pentanoic acid, and 843.43 g of yellow-brown viscous liquid was obtained, which was the crude product of 2,4-dihydroxyvalerophenone.

[0028] Column loading: Take 2200.25 g of 200-300 mesh silica gel and add 3000 mL of dichloromethane. Stir thoroughly and then load into the chromatography column. The ratio of the chromatography column diameter to height is 1:10.

[0029] Loading: dilute the crude product with 300 mL of dichloromethane and then load the sample. The ratio of sample layer to column height is 1:6.5.

[0030] Elution: Use dichloromethane for elution at a flow rate of 120 mL / min.

[0031] Collection: The chromatography process was monitored by TLC, with GF254 silica gel plate as the stationary phase, petroleum ether:ethyl acetate = 5:1, observation at 254 nm, and the chromatographic solution containing the pure point of 2,4-dihydroxyvalerophenone was collected.

[0032] Concentration: Combine the collected liquids to a total of 26400 mL, concentrate at normal pressure and apply the solvent. Dry the residual solid after concentration at 40°C with forced air to obtain 601.52 g of white solid powder, which is pure 2,4-dihydroxyvalerophenone with a purity of 95.12% and a single column chromatography yield of 91.30%.

[0033] Example 3 Based on Example 2, this example provides a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography. A screening experiment was conducted on the above-mentioned TLC monitoring method, and the mobile phase of the column chromatography process was screened based on this. The effects of different mobile phases on the yield and purity of 2,4-dihydroxyvalerophenone are shown in Table 1 and the attached Figure 1 .

[0034]

[0035] From Table 1 and Appendix Figure 1The data show that when a mixed solvent of petroleum ether and ethyl acetate is used as the mobile phase, as the ratio of ethyl acetate increases (from 5:1 to 10:1), the Rf value of the target product gradually decreases, and the yield shows a trend of increasing first and then decreasing, reaching the highest (74.52%) at a ratio of 10:1, but the purity is not optimal. In contrast, when dichloromethane is used as the mobile phase, not only the yield is as high as 92.46%, but the purity also reaches 95.83%, both of which are the highest values ​​in all test conditions; Table 1 is only part of the experimental data of the experiment of this application. The experimental process found that when a mixed solvent of petroleum ether and ethyl acetate is used as the mobile phase, the obtained product is a yellow oil, and the solvent cannot be completely removed by vacuum distillation, and a white solid must be obtained by low-temperature recrystallization; and in the column chromatography process, due to the poor solubility of the petroleum ether ethyl acetate mixture in the crude product, it is easy to cause the chromatographic column sample layer to harden, thereby causing the column chromatography process to fail.

[0036] In summary, dichloromethane as the mobile phase showed the best effect in the single column chromatography separation and purification of 2,4-dihydroxyvalerophenone, which not only improved the yield and purity, but also avoided the operational complexity and column chromatography problems caused by the use of mixed solvents. Therefore, we recommend using dichloromethane as the mobile phase for this process.

[0037] Example 4 This embodiment provides a method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography, and the specific steps are as follows: In a 20 L reactor, 1650.32 g of resorcinol, 2040.17 g of anhydrous zinc chloride, and 1800 ml of n-pentanoic acid were added in sequence, and the temperature was slowly raised to 145 °C under stirring. During the reaction, the water layer was discarded through a water separator, and the reaction was kept warm for 8 h. After the reaction was completed, the temperature was lowered to 80 °C, 2000 mL of pure water was added, stirred for 1 min, transferred to a separatory funnel and allowed to stand for separation, and the aqueous phase was discarded. The operation was repeated and extracted with water three times. The residual liquid was distilled under reduced pressure at 120 °C to remove n-pentanoic acid, and 1617.25 g of a yellow-brown viscous liquid was obtained, which was the crude product of 2,4-dihydroxyvalerophenone.

[0038] Column loading: Take 4500.02 g of 200-300 mesh silica gel and add 10000 mL of dichloromethane. Stir thoroughly and then load into the chromatography column. The ratio of the chromatography column diameter to height is 1:12.

[0039] Loading: dilute the crude product with 600 mL of dichloromethane and then load the sample. The ratio of sample layer to column height is 1:6.2.

[0040] Elution: Use dichloromethane for elution at a flow rate of 140 mL / min.

[0041] Collection: The chromatography process was monitored by TLC, with GF254 silica gel plate as the stationary phase and dichloromethane as the developing solvent. The chromatography liquid with the pure point of 2,4-dihydroxyvalerophenone was collected under observation at 254 nm, thereby further improving the purity of the product.

[0042] Concentration: Combine the collected liquids to a total of 52400 mL, concentrate at normal pressure and apply the solvent. Dry the residual solid after concentration at 40°C with forced air to obtain 1152.28 g of white solid powder, which is pure 2,4-dihydroxyvalerophenone with a purity of 96.75% and a single column chromatography yield of 93.46%.

[0043] See attached Figure 2 , HPLC chromatogram of 2,4-dihydroxyvalerophenone obtained by the method of the present invention. The curve in the figure shows typical analytical characteristics, with the horizontal axis marked as time (min) and the vertical axis representing signal intensity (mAU). At about 15.9 minutes, a significant chromatographic peak can be clearly observed, and no other impurity peaks appear in the chromatogram, which indicates that the 2,4-dihydroxyvalerophenone obtained by single column chromatography separation has a high purity.

[0044] After the single column chromatography separation and purification of the present invention, the purity of the obtained 2,4-dihydroxyvalerophenone pure product is as high as 96.75%, far exceeding the 95% purity requirement that is difficult to achieve in the prior art, and the single column chromatography yield is as high as 93.46%. While ensuring high purity, it also achieves a relatively high yield (more than 90%), which is unmatched by the prior art; the post-treatment method and column chromatography separation technology in the present invention are not only suitable for small-batch purification operations on a laboratory scale, but also have good industrial application potential. By further optimizing process parameters and expanding production scale, it is expected to become one of the mainstream purification technologies in the field of 2,4-dihydroxyvalerophenone production.

[0045] In summary, the method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography provided by the present invention obtains pure 2,4-dihydroxyvalerophenone with high purity and high yield, provides high-quality raw material guarantee for the preparation of 2-hydroxy-4-methoxyvalerophenone, and helps to improve the purity and yield of the final product. The column chromatography separation technology in the present invention simplifies the preparation process, reduces production costs and environmental pollution risks, provides strong support for the industrial production of 2-hydroxy-4-methoxyvalerophenone, and has broad industrial application prospects and significant competitive advantages.

[0046] The above embodiments are only preferred implementations of the present invention, and their descriptions are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that for those skilled in the art, local modifications and improvements can be made to the invention in different ways without departing from the principles and concepts of the invention. The protection scope of the present invention shall be based on the claims and shall not be limited by the above specific implementations. All implementations within its scope are subject to the constraints of the present invention and belong to the protection scope of the present invention.

Claims

1. A method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography, characterized in that: include: Resorcinol, n-valeric acid and anhydrous zinc chloride are reacted, extracted and distilled under reduced pressure to obtain a crude 2,4-dihydroxyvalerophenone product. The crude 2,4-dihydroxyvalerophenone product is separated by column chromatography, and the eluent is concentrated and dried to obtain a pure 2,4-dihydroxyvalerophenone product.

2. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: The molar ratio of resorcinol, n-valeric acid and anhydrous zinc chloride is 1:1-1.5:1-1.2, the reaction temperature is 135-145° C., and the reaction time is 6-8 hours.

3. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: The extraction solvent is water, the added amount is 1 / 3 to 1 times the total volume of resorcinol, n-valeric acid and anhydrous zinc chloride, the extraction temperature is 70 to 90° C., and the extraction is performed 2 to 4 times.

4. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: The reduced pressure distillation temperature is 120-150° C., and the vacuum degree is 10-20 Kpa.

5. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: In the column chromatography, the mass ratio of the crude 2,4-dihydroxyvalerophenone to silica gel is 1:2.5-4, the particle size of the silica gel is 100-400 meshes, and the mobile phase is dichloromethane.

6. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 5, characterized in that: The flow rate of the mobile phase is 50-150 mL / min.

7. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: The column chromatography adopts TLC monitoring process, uses GF254 silica gel plate as stationary phase, and uses a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as developing solvent.

8. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: The concentration is carried out by atmospheric distillation at a distillation temperature of 40°C to 50°C.

9. The method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to claim 1, characterized in that: The drying method is air drying at 40-50°C.

10. Use of the method for separating and purifying 2,4-dihydroxyvalerophenone by single column chromatography according to any one of claims 1 to 9 in the preparation of 2-hydroxy-4-methoxyvalerophenone.

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