A method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation

Abstract

The invention discloses a method for synthesizing 1,4-dipalmitoyl hydroxyproline by step-by-step acylation, and belongs to the technical field of organic heterocyclic synthesis. The method uses hydroxyproline as a raw material, firstly reacts with palmitoyl chloride under the action of a strong alkaline solution to generate an intermediate N-palmitoyl hydroxyproline, and then reacts with palmitoyl chloride in an acidic organic solution to generate 1,4-dipalmitoyl hydroxyproline by O-acylation. The preparation method adopts a step-by-step synthesis strategy, greatly improves the acylation rate of the reaction, and the separation and purification of the product is simple, the yield is high, and the product purity is high; in addition, the reaction conditions are mild, the operation is simple, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 1,4-dipalmitoyl hydroxyproline, in particular to a method for synthesizing 1,4-dipalmitoyl hydroxyproline by stepwise acylation, and belongs to the technical field of organic heterocyclic synthesis. Background Art

[0002] As we age, fine lines and wrinkles will gradually appear on the skin, affecting the appearance and function of the skin. In order to delay skin aging, more and more people are beginning to pay attention to anti-aging and anti-wrinkle skin care products. With the deepening of anti-aging mechanism research, many active substances with anti-aging properties have been discovered and developed, and have been applied to anti-aging and anti-wrinkle skin care products, such as retinol, peptides, bosine, collagen, hyaluronic acid, squalane, vitamin C, and hyaluronic acid, etc. Studies have shown that 1,4-dipalmitoylhydroxyproline is a very effective skin anti-aging agent. Compared with vitamin C, it has a stronger effect of stimulating collagen fiber contraction and inhibiting elastase activity. It can more effectively remove oxygen free radicals and play an anti-aging and anti-wrinkle role. In addition, 1,4-dipalmitoylhydroxyproline is also a common amino acid surfactant. Because of its better wetting properties, it is often used in moisturizers, shampoos, shower gels and other products to increase the consistency and texture of the product.

[0003] In the prior art, the synthesis of 1,4-dipalmitoylhydroxyproline is usually prepared by the Schotten-Baumann condensation method in an alkaline aqueous solution or an organic solvent / alkaline water mixed solution through the condensation reaction of fatty acid chloride and amino acid. For example, the document ("Synthesis Process of 1,4-Dipalmitoylhydroxyproline", Jiang Huiliang et al., Chemical Industry Progress, Vol. 27, No. 8, 2008, 1254-1257) specifically discloses that palmitic acid is first prepared into palmitoyl chloride by phosphorus trichloride method, and then condensed with L-trans hydroxyproline to generate l,4-dipalmitoylhydroxyproline; the condensation reaction conditions are: the molar ratio of hydroxyproline to palmitoyl chloride is 1:2.5, the volume ratio of acetone is 50%, the pH is 9-10, the reaction temperature is 15°C, and the reaction time is 4h. However, the yield of this method is low, such as the maximum yield is less than 70%, and the product purity is not high, and the purity of the purified product is only 90%. At present, the domestic demand for l,4-dipalmitoylhydroxyproline mainly relies on imports. Sample analysis of imported products found that its purity was very low (less than 60%), containing a large amount of intermediates N-monopalmitoylhydroxyproline and palmitic acid, and the color was poor (slightly yellowish). It is possible that similar synthesis processes are also used abroad. The preparation of l,4-dipalmitoylhydroxyproline by direct condensation of hydroxyproline and palmitoyl chloride in one step is prone to low reaction yield and poor product purity. The reason is that under alkaline conditions, hydroxyproline first undergoes N-acylation reaction to generate intermediate N-palmitoylhydroxyproline, which is easy to precipitate from the reaction system and is difficult to fully undergo O-acylation reaction. Excessive addition of palmitoyl chloride and increased reaction temperature are required, and the reaction is still incomplete, resulting in a lot of residual intermediates and palmitic acid, and it is not easy to separate and purify. Therefore, it is very necessary to develop a new process to synthesize high-purity l,4-dipalmitoylhydroxyproline, which can replace imports and launch competitive international products. Summary of the invention

[0004] In view of the technical problems of low acylation rate and poor product purity in the existing 1,4-dipalmitoylhydroxyproline synthesis method, the purpose of the present invention is to provide a method for synthesizing 1,4-dipalmitoylhydroxyproline by step-by-step acylation. The method adopts a step-by-step synthesis strategy, and sequentially conducts N-acylation reaction and O-acylation reaction of hydroxyproline and palmitoyl chloride under different conditions, thereby greatly improving the acylation efficiency, having high yield of target product, simple separation and purification of target product, and high purity, thereby meeting the requirements of industrial production.

[0005] In order to achieve the above technical purpose, the present invention provides a method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation, which comprises the following steps:

[0006] 1) dissolving hydroxyproline and an organic co-solvent in an alkaline aqueous solution to form a hydroxyproline salt solution, and simultaneously adding palmitoyl chloride and a strong alkaline solution to the hydroxyproline salt solution to carry out an N-acylation reaction. After the N-acylation reaction is completed, the reaction solution is acidified, allowed to stand for stratification, and the upper organic phase is poured into an acidic aqueous solution to precipitate a crude N-palmitoyl hydroxyproline product;

[0007] 2) The crude N-palmitoyl hydroxyproline product is dissolved in an acidic organic solution, and then palmitoyl chloride is added to carry out an O-acylation reaction. After the O-acylation reaction is completed, the reaction solution is poured into an acidic aqueous solution to precipitate the crude 1,4-dipalmitoyl hydroxyproline product.

[0008] In the existing one-step condensation process for synthesizing l,4-dipalmitoylhydroxyproline, on the one hand, palmitoyl chloride is easily hydrolyzed in an alkaline solution to generate palmitic acid, and on the other hand, the acylation reaction activities of the amino group and the hydroxyl group of hydroxyproline are different, and the N-acylation reaction is mainly carried out first and then the O-acylation reaction, while the monoacylation reaction intermediate has poor solubility and is easily precipitated from the reaction system, resulting in difficulty in its further acylation, thereby resulting in the presence of a large amount of N-monopalmitoylhydroxyproline intermediate and palmitic acid in the final product. The key point of the invention is to adopt a step-by-step condensation method, firstly carry out an N-acylation reaction in an organic-water mixed solvent under alkaline conditions with high selectivity, so that hydroxyproline can be efficiently converted into N-monopalmitoyl hydroxyproline, and N-monopalmitoyl hydroxyproline can be easily separated, especially N-monopalmitoyl hydroxyproline can be directly used for subsequent O-acylation reaction without purification; the O-acylation reaction adopts an acidic organic solution, which can improve the solubility of N-monopalmitoyl hydroxyproline, and acid catalysis is adopted to avoid the use of a strong alkaline solution, thereby reducing the hydrolysis side reaction of palmitoyl chloride, thereby improving the yield of the target product 1,4-dipalmitoyl hydroxyproline, and the by-product content in the crude 1,4-dipalmitoyl hydroxyproline is low, and the purity can be increased to more than 95% by simple recrystallization.

[0009] As a preferred solution, the organic co-solvent is at least one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and 1,4-dioxane. The preferred organic co-solvent is a hydrophilic polar organic solvent, because palmitoyl chloride is insoluble in water, and the introduction of a hydrophilic organic solvent can play a solubilizing role and improve the acylation reaction efficiency of palmitoyl chloride and hydroxyproline.

[0010] As a preferred solution, the amount of the organic co-solvent is 0.4 to 0.6 times the volume of the alkaline aqueous solution. If the amount of the organic co-solvent is too high, it will increase the difficulty of separating the N-palmitoyl hydroxyproline intermediate product. If the amount of the organic co-solvent is too low, it will affect the efficiency of the N-acylation reaction.

[0011] As a preferred solution, the strong alkali solution is a sodium hydroxide and / or potassium hydroxide solution with a mass percentage concentration in the range of 5 to 50%. The strong alkali solution mainly neutralizes the hydrochloric acid produced by the condensation reaction and stabilizes the pH of the reaction. As a more preferred solution, the dropwise acceleration rate of the strong alkali solution is to control the system pH to 10.5 to 11.5 during the N-acylation reaction. If the pH of the reaction is too high, the hydrolysis reaction of palmitoyl chloride is increased.

[0012] As a preferred solution, the alkaline aqueous solution is at least one of potassium hydroxide solution, sodium hydroxide solution, potassium carbonate solution, sodium carbonate solution, potassium bicarbonate solution, and sodium bicarbonate solution. The alkaline aqueous solution mainly converts the carboxyl group of hydroxyproline into salt to increase its solubility in water.

[0013] As a preferred embodiment, the molar ratio of hydroxyproline to palmitoyl chloride is 1:0.8-1.5.

[0014] As a preferred solution, the reaction conditions of the N-acylation reaction are: reaction temperature of 0-20° C., and reaction time of 30 min-2 h.

[0015] As a preferred solution, the temperature of the acidification treatment is 30-60° C. The purpose of the acidification reaction is to convert the N-palmitoyl hydroxyproline salt into acid, reduce its solubility, and make the solution system easier to separate.

[0016] As a preferred embodiment, the acidic organic solution contains at least one acid catalyst selected from phosphoric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. The acidic organic solution contains at least one organic solvent selected from acetonitrile, trifluoroacetic acid, dichloromethane, toluene, and tetrahydrofuran. It should be noted that trifluoroacetic acid is used as both an acid catalyst and a solvent.

[0017] As a preferred solution, the molar ratio of N-palmitoyl hydroxyproline to palmitoyl chloride is 1:1 to 1:2. An appropriate excess of palmitoyl chloride is beneficial to improving the O-acylation reaction efficiency of N-palmitoyl hydroxyproline, and the solubility of palmitoyl chloride or its hydrolysis product is quite different from that of 1,4-dipalmitoyl hydroxyproline, so it is easy to remove by subsequent recrystallization.

[0018] As a preferred solution, the conditions of the O-acylation reaction are: reaction temperature is 30-80° C., and reaction time is 2-12 h.

[0019] As a preferred solution, the crude 1,4-dipalmitoyl hydroxyproline product is recrystallized to obtain 1,4-dipalmitoyl hydroxyproline crystals with a purity higher than 95%; the recrystallization uses ethanol, methanol, acetone, acetonitrile, ethanol-water mixture, methanol-water mixture, acetone-water mixture or acetonitrile-water mixture as a recrystallization solvent. The crude 1,4-dipalmitoyl hydroxyproline product has a low content of intermediate byproducts and is easy to be recrystallized and purified.

[0020] Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects:

[0021] 1) The step-by-step synthesis strategy is adopted, and the intermediate product does not need to be highly purified, which greatly improves the efficiency of the acylation reaction. The separation and purification of the product is simple and the yield is high. The product is high in purity and pure white in color;

[0022] 2) The O-acylation reaction occurs under organic solvent / acid catalysis conditions, avoiding the large-scale hydrolysis of palmitoyl chloride in alkaline aqueous solution at higher temperatures. DETAILED DESCRIPTION

[0023] The following specific examples are intended to further illustrate the present invention rather than to limit the scope of protection of the claims.

[0024] Example 1

[0025] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-p-hydroxyproline, 5.60g sodium hydroxide and 200mL water, and stir to dissolve at room temperature. Then add 100mL acetone, cool the reaction solution to 15°C while stirring, slowly drip 49.48g palmitoyl chloride (0.9 equivalents), and at the same time drip about 60g 15% sodium hydroxide aqueous solution to maintain pH at 10.5-11.5, the dripping process is about 1.5h. After the dripping is completed, stir at room temperature for another 1h. Slowly add 30mL concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, let stand to separate, and separate the upper organic phase. The organic phase was slowly poured into 500 mL of acidic water (dilute hydrochloric acid) while stirring, and a white solid was precipitated. After filtration, washing and drying, 61.85 g of white intermediate N-palmitoyl hydroxyproline was obtained, with a yield of 93% and a HPLC purity of 97%. NMR data: 1H NMR (400 MHz, CDCl3)δ 6.69 (br s, 2H), 4.60-4.53 (m, 2H), 3.69 (dd, J = 8.0, 4.0 Hz, 1H), 3.52(d, J = 8.0 Hz, 1H), 2.33-2.24 (m, 3H), 1.61-1.56 (m, 2H), 1.35-1.20 (m, 24H), 0.87 (t, J = 6.0 Hz, 6H) ppm.

[0026] Example 2

[0027] In a 1000 mL four-necked round-bottom flask equipped with a stirrer, add 26.23 g of L-p-hydroxyproline, 5.60 g of sodium hydroxide and 200 mL of water, and stir to dissolve at room temperature. Then add 100 mL of acetone, cool the reaction solution to 15°C while stirring, slowly drop 54.98 g of palmitoyl chloride (1.0 equivalent), and at the same time drop about 65 g of 15% sodium hydroxide aqueous solution to maintain the pH at 10.5-11.5, the dropping process is about 1.5 hours. After the dropwise addition is completed, stir at room temperature for another 1 hour. Slowly add 30 mL of concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, let stand to separate the layers, and separate the upper organic phase. The organic phase was slowly poured into 500 mL of acidic water (dilute hydrochloric acid) while stirring, and a white solid was precipitated. After filtration, water washing and drying, 66.51 g of white intermediate N-palmitoyl hydroxyproline was obtained with a yield of 90% and an HPLC purity of 95%.

[0028] Example 3

[0029] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-p-hydroxyproline, 5.60g sodium hydroxide and 200mL water, and stir to dissolve at room temperature. Then add 100mL acetone, cool the reaction solution to 15°C while stirring, slowly drip 60.48g palmitoyl chloride (1.1 equivalents), and at the same time drip about 70g 15% sodium hydroxide aqueous solution to maintain pH at 10.5-11.5, the dripping process is about 1.5h. After the dripping is completed, stir at room temperature for another 1h. Slowly add 30mL concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, let stand to separate, and separate the upper organic phase. The organic phase was slowly poured into 500 mL of acidic water (dilute hydrochloric acid) while stirring, and a white solid was precipitated. After filtration, water washing and drying, 67.25 g of white intermediate N-palmitoyl hydroxyproline was obtained with a yield of 91% and an HPLC purity of 93%.

[0030] Example 4

[0031] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-p-hydroxyproline, 5.60g sodium hydroxide and 200mL water, and stir to dissolve at room temperature. Then add 100mL acetone, cool the reaction solution to 10°C while stirring, slowly drip 49.48g palmitoyl chloride (0.9 equivalents), and at the same time drip about 60g 15% sodium hydroxide aqueous solution to maintain pH at 10.5-11.5, the dripping process is about 1.5h. After the dripping is completed, stir at room temperature for another 2h. Slowly add 30mL concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, let stand to separate, and separate the upper organic phase. The organic phase was slowly poured into 500 mL of acidic water (dilute hydrochloric acid) while stirring, and a white solid was precipitated. After filtration, water washing and drying, 59.86 g of white intermediate N-palmitoyl hydroxyproline was obtained with a yield of 90% and a HPLC purity of 97%.

[0032] Example 5

[0033] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-p-hydroxyproline, 5.60g sodium hydroxide and 200mL water, and stir to dissolve at room temperature. Then add 100mL acetonitrile, cool the reaction solution to 15°C while stirring, slowly drop 49.48g palmitoyl chloride (0.9 equivalents), and at the same time drop about 60g 15% sodium hydroxide aqueous solution to maintain pH at 10.5-11.5, the dropping process is about 1.5h. After the dropwise addition is completed, stir at room temperature for another 2h. Slowly add 30mL concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, let stand to separate, and separate the upper organic phase. The organic phase was slowly poured into 500 mL of acidic water (dilute hydrochloric acid) while stirring, and a white solid was precipitated. After filtration, water washing and drying, 56.50 g of white intermediate N-palmitoyl hydroxyproline was obtained with a yield of 85% and a HPLC purity of 96%.

[0034] Example 6

[0035] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-hydroxyproline, 5.60g sodium hydroxide and 200mL water, and stir to dissolve at room temperature. Then add 100mL acetone, cool the reaction solution to 15°C while stirring, slowly drip 49.48g palmitoyl chloride (0.9 equivalents), and at the same time drip about 30g 30% sodium hydroxide aqueous solution to maintain pH at 10.5~11.5, the dripping process is about 1.5h. After the dropwise addition is completed, stir at room temperature for another 2h. Slowly add 30mL concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, stand and separate the upper organic phase. Slowly pour the organic phase into 500mL of acidic water, stirring while pouring, and a white solid precipitates. After suction filtration, washing with water, and drying, 60.21g of white intermediate N-palmitoylhydroxyproline is obtained, with a yield of 91% and an HPLC purity of 96%.

[0036] Example 7

[0037] In a 50mL round-bottom flask, add 7.39g N-palmitoylhydroxyproline (prepared in Example 1) and 15mL trifluoroacetic acid, heat to 50°C, stir to dissolve, and slowly drop 6.60g palmitoyl chloride (1.2 equivalents). The addition was completed in 10 minutes, and the reaction was stirred at 50°C for 4 hours. Cool to room temperature, slowly pour the reaction solution into 200mL water, stirring while pouring, and a white solid precipitated. After suction filtration, washing with water, and drying, 11.52g of white solid product 1,4-palmitoylhydroxyproline was obtained, with a yield of 95%. Recrystallization was performed using ethanol / water to obtain 10.92g of a white product with an HPLC purity greater than 95%. NMR data: 1 H NMR (400 MHz, CDCl3) δ 5.42 (br s, 1H), 5.31 (s, 1H), 4.65 (t, J = 8.0 Hz, 1H), 3.80 (dd, J= 12.0, 4.0 Hz, 1H), 3.63 (d, J = 12.0 Hz, 1H), 2.60-2.48 (m, 1H), 2.41-2.17(m, 5H), 1.74-1.50 (m, 4H), 1.35-1.20 (m, 48H), 0.87 (t, J = 6.0 Hz, 6H) ppm.

[0038] Example 8

[0039] In a 50mL round-bottom flask, add 7.39g N-palmitoylhydroxyproline (prepared in Example 1) and 15mL trifluoroacetic acid, heat until dissolved, and slowly drop 6.60g palmitoyl chloride (1.2 equivalents). The addition was completed in 10 minutes, and the reaction was stirred at 70°C for 2 hours. After cooling to room temperature, the reaction solution was slowly poured into 200mL of water, stirring while pouring, and a white solid was precipitated. After suction filtration, washing with water, and drying, 11.32g of a white solid product 1,4-palmitoylhydroxyproline was obtained, with a yield of 93%. Recrystallization was performed using ethanol / water to obtain 10.21g of a white product with an HPLC purity of more than 95%.

[0040] Example 9

[0041] In a 50mL round-bottom flask, add 7.39g N-palmitoylhydroxyproline (prepared in Example 2) and 15mL trifluoroacetic acid, heat until dissolved, and slowly drop 8.25g palmitoyl chloride (1.5 equivalents). The addition was completed in 10 minutes, and the reaction was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction solution was slowly poured into 200mL of water, stirring while pouring, and a white solid was precipitated. After suction filtration, washing with water, and drying, 11.64g of white solid product 1,4-palmitoylhydroxyproline was obtained, with a yield of 96%. Recrystallization was performed using ethanol / water to obtain 10.21g of a white product with an HPLC purity of more than 95%.

[0042] Example 10

[0043] In a 50mL round-bottom flask, add 7.39g N-palmitoyl hydroxyproline (prepared in Example 2), 0.1g phosphoric acid and 20mL acetonitrile, heat to 50°C, stir to dissolve, and slowly drop 8.25g palmitoyl chloride (1.5 equivalents). The addition was completed in 10 minutes, and the reaction was stirred at 50°C for 12 hours. Cool to room temperature, slowly pour the reaction solution into 200mL water, stirring while pouring, and a white solid precipitated. After suction filtration, washing with water, and drying, 7.42g of white solid product 1,4-palmitoyl hydroxyproline was obtained, with a yield of 61%. Recrystallization was performed using ethanol / water to obtain 6.10g of a white product with an HPLC purity of more than 95%.

[0044] Embodiment 11

[0045] In a 50mL round-bottom flask, add 7.39g N-palmitoylhydroxyproline (prepared in Example 5), 0.1g phosphoric acid and 20mL dichloromethane, stir to dissolve, and slowly drop 8.25g palmitoyl chloride (1.5 equivalents). The addition was completed in 10 minutes, and the reaction was stirred at 40°C for 12 hours. After cooling to room temperature, the reaction solution was slowly poured into 200mL of water, stirring while pouring, and a white solid was precipitated. After suction filtration, washing with water, and drying, 7.14g of white solid product 1,4-palmitoylhydroxyproline was obtained, with a yield of 59%. Recrystallization was performed using ethanol / water to obtain 5.44g of a white product with an HPLC purity of more than 95%.

[0046] Example 12

[0047] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-p-hydroxyproline, 5.60g sodium hydroxide and 200mL water, and stir to dissolve at room temperature. Then add 100mL acetone, cool the reaction solution to 15°C while stirring, slowly drip 54.98g palmitoyl chloride (1.0 equivalent), and at the same time drip about 60g 15% sodium hydroxide aqueous solution to maintain the pH at 10.5~11.5, the dripping process is about 1.5h. After the dropwise addition is completed, stir at room temperature for another 1h. Slowly add 30mL concentrated hydrochloric acid to acidify, heat the reaction solution to 50°C, transfer to a separatory funnel, stand and separate the upper organic phase. Slowly pour the organic phase into 500mL of acidic water (dilute hydrochloric acid), stirring while pouring, and a white solid is precipitated. After suction filtration, washing with water, and drying, a white intermediate N-palmitoyl hydroxyproline is obtained. Place it in a 500mL round-bottom flask, add 120mL trifluoroacetic acid, heat to 50°C, stir to dissolve, slowly drop 54.98g palmitoyl chloride, dropwise within 1h, and stir to react at 50°C for 4h. Most of the trifluoroacetic acid is recovered under reduced pressure, cooled to room temperature, and the reaction solution is slowly poured into 500mL water while stirring to precipitate a white solid. After filtration, washing, and drying, a white solid crude product is obtained, which is then simply recrystallized using ethanol / water to obtain 98.47g white 1,4-palmitoylhydroxyproline, with a yield of 81% and an HPLC purity of more than 95%.

[0048] Comparative Example

[0049] In a 1000mL four-necked round-bottom flask equipped with a stirrer, add 26.23g L-hydroxyproline, 5.60g sodium hydroxide and 200mL water, stir to dissolve, then add 200mL acetone, stir evenly, and cool the reaction solution to 15°C. Use a constant pressure dropping funnel to slowly drop 137.45g palmitoyl chloride (2.5 equivalents) and 15% sodium hydroxide aqueous solution, respectively, maintaining the pH at 9.0-10.0, and the dropping process is about 1.5h. After the dropwise addition is completed, stir at room temperature for another 1h. Slowly add concentrated hydrochloric acid to acidify, add water to dilute, precipitate a white solid, and obtain 72.45g of a white solid product after filtration, washing with water, and drying. TLC and NMR analysis show that most of the product is the intermediate N-palmitoylhydroxyproline and palmitic acid, while the content of 1,4-palmitoylhydroxyproline is less than 10%.

Claims

1. A method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation, characterized in that: The following steps are involved: 1) Dissolve hydroxyproline and an organic cosolvent in an alkaline aqueous solution to form a hydroxyproline salt solution, and simultaneously add palmitoyl chloride and a strong alkaline solution to the hydroxyproline salt solution. N -acylation reaction, after the N-acylation reaction is completed, the reaction solution is acidified, allowed to stand for stratification, and the upper organic phase is poured into an acidic aqueous solution to precipitate N - palmitoyl hydroxyproline crude product; 2) N -The crude palmitoyl hydroxyproline product was dissolved in an acidic organic solution, and then palmitoyl chloride was added to O -Acylation reaction, wait O After the acylation reaction is completed, the reaction solution is poured into an acidic aqueous solution to precipitate a crude 1,4-dipalmitoylhydroxyproline product; the acidic organic solution contains a trifluoroacetic acid catalyst.

2. The method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1, characterized in that: The organic co-solvent is at least one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and 1,4-dioxane.

3. A method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1 or 2, characterized in that: The amount of the organic co-solvent used is 0.4 to 0.6 times the volume of the alkaline aqueous solution.

4. The method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1, characterized in that: The strong alkali solution is a sodium hydroxide and / or potassium hydroxide solution with a mass percentage concentration in the range of 5-50%.

5. A method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1 or 4, characterized in that: The dropping rate of the strong base solution is to control the system pH to be 10.5-11.5 during the N-acylation reaction.

6. A method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1, 2 or 4, characterized in that: The reaction conditions of the N-acylation reaction are: reaction temperature of 0-20° C., and reaction time of 30 min-2 h.

7. The method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1, characterized in that: The temperature of the acidification treatment is 30-60°C.

8. The method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1, characterized in that: Said O -Acylation reaction conditions are: reaction temperature is 30~80℃, reaction time is 2~12 h.

9. The method for synthesizing 1,4-dipalmitoylhydroxyproline by stepwise acylation according to claim 1, characterized in that: The crude 1,4-dipalmitoyl hydroxyproline product is recrystallized to obtain 1,4-dipalmitoyl hydroxyproline crystals with a purity higher than 95%; the recrystallization uses ethanol, methanol, acetone, acetonitrile, ethanol-water mixed solution, methanol-water mixed solution, acetone-water mixed solution or acetonitrile-water mixed solution as a recrystallization solvent.