CN114436924B - Synthesis method of hydroxy pinacolone retinoic acid ester - Google Patents

Abstract

The invention belongs to the technical field of fine organic synthesis, and specifically relates to a synthesis method of hydroxypinacolone retinoate. The method includes the following steps: (1) Add an organic solvent to retinoic acid, then add an amide catalyst, stir evenly and then take an ice bath; (2) Add phosphorus trichloride to (1) under nitrogen protection to obtain In the material, react; (3) Let it stand to separate the lower inorganic solution, add 1-hydroxy-3,3-dimethylbutane-2-one under ice bath conditions, then add the acid binding agent, keep the reaction warm, and reduce The inorganic salt is filtered by pressure and suction, and the liquid phase is concentrated under reduced pressure; (4) Add a recrystallization solvent, cool down and crystallize to obtain hydroxypinalone retinoate. The raw materials and reagents used in the present invention are all commonly used chemical reagents, which are low-cost and easy to obtain; the solvent used in the reaction is toluene, and the next step of the reaction can be carried out without separation and purification; the two-step reaction can be completed in the same kettle. Less equipment is used and equipment utilization is high.

Description

A kind of synthesis method of hydroxypinacolone retinoate

Technical field

The invention belongs to the technical field of fine organic synthesis, and specifically relates to a synthesis method of hydroxypinacolone retinoate.

Background technique

Vitamin A, also known as retinol, is a natural fat-soluble vitamin. Vitamin A in a broad sense also includes retinols such as retinaldehyde, retinoic acid, retinyl acetate, and retinyl palmitate. Derivatives, various structures can be converted into each other. Vitamin A plays an important role in the growth, development, vision, immunity and other processes of vertebrates. In recent years, scientists have discovered that vitamin A is very effective in preventing and treating skin problems such as skin aging. It has attracted much attention as an active ingredient in preventing and repairing skin aging. It is used in various external medicines for skin diseases and is often added to In cosmetics. Vitamin A is extremely unstable due to its long electron-rich conjugated polyene chain and is easily destroyed when exposed to acids, oxides, high temperatures, and ultraviolet rays. To avoid its inactivation, chemical methods are often used to transform it into ester derivatives of vitamin A. Research has found that vitamin A ester derivatives not only have various physiological functions of vitamin A, but also have higher stability and a wider range of applications. Common vitamin A ester derivatives include vitamin A acetate, vitamin A palmitate, etc. However, current ester derivatives have shortcomings such as high irritation and low conversion efficiency. Therefore, it is of great significance to develop products with low irritation to the skin and high conversion efficiency.

Hydroxypinacolone retinoate, which is a kind of vitamin A ester derivative, is a new generation of esterification product of retinoic acid. Unlike other retinoic acid derivatives, it can directly produce effects without conversion. The principle is similar to that of all-trans A acid. Compared with retinoic acid, hydroxypinacolone retinoate is much less irritating, safer to use around the eyes, and has better transdermal penetration.

Regarding the synthesis method of hydroxypinacolone retinoate, the following patent documents have disclosed:

CN112522331A discloses a biological enzyme-catalyzed synthesis method of hydroxypinacolone retinoate. The above method uses retinoic acid ester and 1-hydroxy-3,3-dimethylbutan-2-one as raw materials. Hydroxypinacolone retinoate is prepared by reacting in an aqueous buffer solution with a pH of 7.0 to 10.0 containing an acyltransferase. The above-mentioned methods have some shortcomings, such as: biological enzymes have poor environmental adaptability, harsh production environment requirements, high enzyme prices, and relatively high production costs, which limit the large-scale industrial production of the above products.

CN113149880A provides a method for preparing hydroxypinacolone retinoate, which method uses chlorinated pinacolone to prepare the corresponding pinacolone through a hydrolysis reaction under strongly alkaline conditions, and then combines the pinacolone with vitamin C. A acid is obtained through condensation reaction under the conditions of condensing agent and catalyst. In the above-mentioned process, the DCC dehydrating agent used in the condensation reaction generates DCU solid waste after the reaction. The inventor made a rough calculation and found that each ton of product produced produces approximately 900KG of solid waste, which is close to one ton. The three waste treatment costs high. DCU and DMAP are difficult to remove and will remain in the product. They need to be washed with an acidic aqueous solution, producing a large amount of wastewater, or removed through a chromatographic column. If the method is passed through a chromatographic column, it will lead to low production efficiency and high cost.

Therefore, it is necessary to improve the above method and invent a production method of hydroxypinacolone retinoate with simple process, low production cost and high overall product yield.

Contents of the invention

In order to solve the above technical problems, the present invention provides a production method of hydroxypinacolone retinoate with simple process, low production cost and high overall product yield.

The present invention is accomplished through the following technical scheme: using retinoic acid and 1-hydroxy-3,3-dimethylbutan-2-one as raw materials, acylation and esterification are performed to obtain a crude product, which is refined and crystallized to obtain Finished product, specifically, the above production method includes the following steps:

(1) Add an organic solvent to retinoic acid, then add an amide catalyst, stir evenly and then take an ice bath;

(2) Add phosphorus trichloride to the material obtained in (1) under nitrogen protection and react;

(3) After the reaction in (2) is complete, let it stand to separate out the lower inorganic solution. Add 1-hydroxy-3,3-dimethylbutan-2-one under ice bath conditions, then add the acid binding agent and keep it warm. Reaction; after the reaction is completed, the inorganic salt is filtered under reduced pressure, and the liquid phase is concentrated under reduced pressure to obtain a yellow oily crude product;

(4) Add a recrystallization solvent to the yellow oily crude product obtained in (3), cool down and crystallize to obtain hydroxypinalone retinoate.

The main chemical reaction equations are as follows:

Preferably, in (1), the amide catalyst is N,N-dimethylformamide; the molar ratio of the amide catalyst to retinoic acid is 0.1 to 0.5:1; the organic solvent is toluene, and the molar ratio of toluene to retinoic acid is The ratio is 15~20:1; after stirring evenly, use an ice bath to control the temperature of the system at 5~15℃;

In (2), use a constant pressure dropping funnel to add phosphorus trichloride dropwise into the ice bath system in (1) under nitrogen protection. After the dropwise addition is completed, raise the temperature of the system to 20~40°C. Incubate for 5 to 7 hours, and the molar ratio of retinoic acid to phosphorus trichloride is 1:0.6 to 1. The ratio range of retinoic acid and phosphorus trichloride is the focus of the present invention. By adjusting the ratio of retinoic acid and phosphorus trichloride, the prepared hydroxypinacolone retinoate has high purity and few impurities.

Preferably, in (3), whether the reaction is complete is determined by liquid chromatography detection. If the reaction is complete, 1-hydroxy-3,3-dimethylbutan-2-one is added dropwise under ice bath conditions. After the addition is completed, the temperature rises to 20-35°C, and the acid-binding agent is slowly dripped using a constant pressure dropping funnel. After the dripping is completed, the acid-binding agent is kept warm for 5-7 hours.

In (3), the molar ratio of retinoic acid to 1-hydroxy-3,3-dimethylbutan-2-one is controlled to 1:1.2-2, and the molar ratio of retinoic acid to acid-binding agent is controlled to 1:1.2-3; The acid-binding agent is at least one of triethylamine, pyridine, and sodium hydroxide;

In (4), the recrystallization solvent is at least one of methanol, absolute ethanol, and isopropyl alcohol; the volume ratio of the recrystallization solvent to the concentrated liquid is 2 to 4:1.

The present invention has the following significant advantages over the synthesis methods reported in existing patent documents:

(1) The raw materials and reagents used in the present invention are all commonly used chemical reagents, which are easy to obtain, low in price and low in production cost;

(2) The organic solvent used in step (1) during the extraction process is toluene.

During the reaction in (3), the toluene remaining in the upper mixed solution can still continue to act as a solvent. It can be used for the next reaction without separation and purification, which greatly simplifies the reaction operation procedure and avoids the need to use different solvents. Purification results in cumbersome extraction steps;

(3) The product of the present invention has stable profits, the total yield after the two-step reaction can reach up to 92%, and the purity can reach 99.8%;

(4) The two-step reactions in (1) and (3) of the present invention can be completed in the same kettle, using less equipment and high equipment utilization, minimizing material transfer and intermediate refining and purification, which is suitable for large-scale industrialization. Production provides excellent basic production conditions.

Description of the drawings

Figure 1 is a physical diagram of the product hydroxypinalone retinoate of the present invention;

Figure 2 is a NMR spectrum characterization diagram of the product of Example 2 of the present invention;

Figure 3 is a liquid chromatogram of the product in Example 2;

Figures 4 to 13 are liquid chromatograms of different batches of products prepared using the method of the present invention.

Detailed ways

In order to enable those skilled in the art to better understand the present invention, the present invention will be further described in conjunction with specific embodiments.

Example 1

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 1g of N,N-dimethylformamide (0.014mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Use a constant pressure dropping funnel to add 5.8g (0.042mol) of phosphorus trichloride dropwise into the flask under nitrogen protection. After the addition is completed, raise the system temperature to 25°C and keep it warm for 6 hours;

S3: After the reaction is completed by liquid chromatography, let it stand to separate the lower inorganic solution, and start adding 10.5g (0.09mol) of 1-hydroxy-3,3-dimethylbutan-2-one under ice bath conditions. , after the dropwise addition is completed, it rises to room temperature, slowly drips 7.3g (0.07mol) of triethylamine using a constant pressure dropping funnel, and completes the dripping and insulation reaction for 6 hours. After the reaction is completed, the inorganic salt is filtered under reduced pressure, and the liquid phase is concentrated under reduced pressure. , to obtain a yellow oily crude product;

S4: Add 50 ml of absolute ethanol to the yellow oily crude product obtained in S3 to cool down and crystallize to obtain 20.3g of yellow solid powder. After conversion, the total yield of the product hydroxypinalone retinoate is 73%, and its purity is 99.3% as measured by HPLC.

Example 2

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 2g of N,N-dimethylformamide (0.028mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Use a constant pressure dropping funnel to add 6.7g (0.049mol) of phosphorus trichloride dropwise into the flask under nitrogen protection. After the addition is completed, raise the system temperature to 30°C and keep it warm for 6 hours;

S3: After the reaction is completed by liquid chromatography, let it stand to separate the lower inorganic solution, and start adding 10.5g (0.09mol) of 1-hydroxy-3,3-dimethylbutan-2-one under ice bath conditions. , after the addition is completed, it rises to room temperature and uses a constant pressure dropping funnel to slowly drip 8.5g (0.084mol) of triethylamine. After the dripping is completed, the insulation reaction is completed for 6 hours. After the reaction is completed, the inorganic salt is filtered under reduced pressure and the liquid phase is concentrated under reduced pressure. Obtain yellow oily crude product;

S4: Add 50 ml of methanol to the yellow oily crude product obtained in S3 to cool down and crystallize to obtain 25.6 g of yellow solid powder. The purity is 99.8% as measured by HPLC.

After conversion, the total yield of the product hydroxypinalone retinoate is 92%.

The physical picture of the product is shown in Figure 1, and the nuclear magnetic spectrum characterization is shown in Figure 2. From the liquid chromatography Figure 3, it can be seen that the tested product is hydroxypinalone retinoate and its purity reaches 99.8%.

Table 1 HPLC test results

Example 3

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 2g of N,N-dimethylformamide (0.028mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Use a constant pressure dropping funnel to add 6.7g (0.049mol) of phosphorus trichloride dropwise into the flask under nitrogen protection. After the addition is completed, raise the system temperature to 30°C and keep it warm for 6 hours;

S3: After the reaction is completed by liquid chromatography, let it stand to separate the lower inorganic solution, and start adding 10.5g (0.09mol) of 1-hydroxy-3,3-dimethylbutan-2-one under ice bath conditions. , after the dropwise addition is completed, it rises to room temperature and uses a constant pressure dropping funnel to slowly drip 7.1g (0.07mol) of triethylamine. After the dripping is completed, the insulation reaction is completed for 6 hours. After the reaction is completed, the inorganic salt is filtered under reduced pressure and the liquid phase is concentrated under reduced pressure. Obtain yellow oily crude product;

S4: Add 60 ml of absolute ethanol to the yellow oily crude product obtained in S3 to cool down and crystallize to obtain 23.4g of yellow solid powder.

After conversion, the total yield of the product hydroxypinalone retinoate is 84%, and its purity is 98.8% as measured by HPLC.

Example 4

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 2g of N,N-dimethylformamide (0.028mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Use a constant pressure dropping funnel to add 6.7g (0.049mol) of phosphorus trichloride dropwise into the flask under nitrogen protection. After the addition is completed, raise the system temperature to 30°C and keep it warm for 6 hours;

S3: After the liquid chromatograph detects that the reaction is complete, let it stand to separate the lower inorganic solution, and start adding 9.8g (0.084mol) of 1-hydroxy-3,3-dimethylbutan-2-one under ice bath conditions. , after the addition is completed, rise to room temperature and use a constant pressure dropping funnel to slowly drip 14.6g (0.14mol) of triethylamine. After the dripping is completed, the insulating reaction is carried out for 6 hours. After the reaction is completed, the inorganic salt is filtered under reduced pressure and the liquid phase is concentrated under reduced pressure. Obtain yellow oily crude product;

S4: Add 60ml of absolute ethanol to cool down and crystallize to obtain 21.8g of yellow solid powder.

After conversion, the total yield of the product hydroxypinalone retinoate is 82%, and its purity is 99.4% as measured by HPLC.

Example 5

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 2g of N,N-dimethylformamide (0.028mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Add 7.7g (0.056mol) of phosphorus trichloride dropwise into the flask using a constant pressure dropping funnel under nitrogen protection. After the addition is completed, raise the system temperature to 25°C and keep it warm for 6 hours;

S3: After the liquid chromatograph detects that the reaction is complete, let it stand to separate the lower inorganic solution, and start adding 9.8g (0.084mol) of 1-hydroxy-3,3-dimethylbutan-2-one under ice bath conditions. , after the addition is completed, it rises to room temperature and uses a constant pressure dropping funnel to slowly drip 8.5g (0.084mol) of triethylamine. After the dripping is completed, the insulation reaction is completed for 6 hours. After the reaction is completed, the inorganic salt is filtered under reduced pressure and the liquid phase is concentrated under reduced pressure. Obtain yellow oily crude product;

S4: Add 50 ml of isopropyl alcohol to cool down and crystallize to obtain 21.2 g of yellow solid powder.

After conversion, the total yield of the product hydroxypinalone retinoate is 76%, and its purity is 98.8% as measured by HPLC.

The product yield and purity in Examples 1 to 5 are reflected in the following table in tabular form:

Table 2 Product yield and purity (%) in Examples 1 to 5 and Comparative Examples 1 to 2

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative example 1 Comparative example 2 Overall yield 73 92 84 82 76 36 21.53 purity 99.3 99.8 98.8 99.4 98.8 97.6 94.6

The total yield refers to the yield of the final product hydroxypinalone retinoate.

Comparative example 1

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 2g of N,N-dimethylformamide (0.028mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Add 9.2g (0.077mol) of thionyl chloride dropwise into the flask using a constant pressure dropping funnel under nitrogen protection. After the addition is completed, raise the system temperature to 25°C and keep it warm for 6 hours;

S3: After the liquid chromatograph detects that the reaction is complete, remove the thionyl chloride under reduced pressure, and start adding 9.8g (0.084mol) of 1-hydroxy-3,3-dimethylbutan-2-one dropwise under ice bath conditions. ), rise to room temperature after the dropwise addition is completed, use a constant pressure dropping funnel to slowly drop 14.6g (0.14mol) of triethylamine, complete the dripping and keep the reaction for 6 hours, after the reaction is completed, filter the inorganic salt under reduced pressure, and depressurize the liquid phase Concentrate to obtain yellow oily crude product;

S4: Add 50 ml of absolute ethanol to cool down and crystallize to obtain 10 g of yellow solid powder.

After conversion, the total yield of the product hydroxypinalone retinoate is 36%, and its purity is 97.6% as measured by HPLC.

Comparative example 2

The synthesis method of hydroxypinacolone retinoate includes the following steps:

S1: Add 20g of retinoic acid (0.07mol), 100g of toluene (1.09mol), and 2g of N,N-dimethylformamide (0.028mol) into a 250ml three-necked flask. Stir evenly and lower the system temperature to Around 10℃;

S2: Add 6.9g (0.05mol) of phosphorus trichloride dropwise into the flask using a constant pressure dropping funnel under nitrogen protection. After the addition is completed, raise the system temperature to 30°C and keep it warm for 6 hours;

S3: After the liquid chromatograph detects that the reaction is complete, let it stand to separate the lower inorganic solution, add 2.8g (0.07mol) of sodium hydroxide to the mixture, and start adding 1-hydroxy-3,3-dihydroxide dropwise under ice bath conditions. 9.8g (0.084mol) of methylbutan-2-one was dropped and kept at 30°C for 6 hours. After the reaction, the inorganic salt was filtered under reduced pressure and the liquid phase was concentrated under reduced pressure to obtain a yellow oily crude product;

S4: Add 50 ml of absolute ethanol to cool down and crystallize to obtain 6 g of yellow solid powder.

After conversion, the total yield of the product hydroxypinalone retinoate is 21.53%, and its purity is 94.6% as measured by HPLC.

Example 6

The inventor also tested different batches of products respectively. The liquid chromatograms are shown in Figures 4 to 13;

Table 3 Liquid chromatography test results of sample 1

Table 4 Liquid chromatography test results of sample 2

Table 5 Liquid chromatography test results of sample 3

Table 6 Liquid chromatography test results of sample 4

Table 7 Liquid chromatography test results of sample 5

Table 8 Liquid chromatography test results of sample 6

Table 9 Liquid chromatography test results of sample 7

Table 10 Liquid chromatography test results of sample 8

Table 11 Liquid chromatography test results of sample 9

Table 12 Liquid chromatography test results of sample 10

From the above table and the liquid chromatograms of each batch of samples, it can be seen that the yield and purity of the product hydroxypinacolone retinoate prepared by the method of the present invention is relatively high.

Claims (1)

1. A synthesis method of hydroxy pinacolone retinoic acid ester comprises the following steps:

(1) Sequentially adding 20g of retinoic acid with the mass of 0.07mol of substances, 100g of toluene with the mass of 1.09mol of substances and 2g of N, N-dimethylformamide with the mass of 0.028mol of substances into a 250ml three-neck flask, uniformly stirring, and then cooling the system to 10 ℃ by an ice bath;

(2) Adding phosphorus trichloride with the mass of 6.7g and the mass of 0.049mol into a flask dropwise under the protection of nitrogen by utilizing a constant-pressure dropping funnel, and after the dropping is finished, raising the temperature of the system to 30 ℃ and preserving heat for 6 hours;

(3) After the reaction is detected to be complete by a liquid chromatograph, standing to separate out an inorganic solution at the lower layer, starting to dropwise add 1-hydroxy-3, 3-dimethylbutane-2-one with the mass of 10.5g and the mass of 0.09mol under the ice bath condition, after the completion of the dropwise addition, slowly adding triethylamine with the mass of 8.5g and the mass of 0.084mol by using a constant pressure dropping funnel to room temperature, after the completion of the dropwise addition, carrying out heat preservation reaction for 6 hours, carrying out vacuum filtration on inorganic salt under reduced pressure, and concentrating the liquid phase under reduced pressure to obtain a yellow oily crude product;

(4) And (3) adding 50ml of methanol into the yellow oily crude product obtained in the step (3) for cooling and crystallizing to obtain yellow solid powder of the hydroxy-pinacolone retinoic acid ester.