A method for synthesizing 3,4-dihydroxyphenyl ethanol lactate

Abstract

The application discloses a synthesis method of 3,4-dihydroxyphenethyl alcohol lactate. The method uses 3,4-dihydroxyphenethyl alcohol as a starting material, and reacts with a lactic acid reagent under the action of an acid catalyst to generate 3,4-dihydroxyphenethyl alcohol lactate. The synthesis method of 3,4-dihydroxyphenethyl alcohol lactate disclosed by the application is easy to obtain raw materials, simple in process and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and discloses a method for preparing 3,4-dihydroxyphenylethanol lactate. Background Technology

[0002] 3,4-Dihydroxyphenylethanol lactate is a natural phenolic compound with a catechol structure, isolated from the medicinal insect *Ligustrum lucidum*. Studies have shown that this compound exhibits significant antioxidant activity through its unique catechol hydroxyl structure, while also possessing immunomodulatory and potential antitumor activities. In recent years, with the rising incidence of free radical-related diseases (such as cardiovascular disease and neurodegenerative diseases), 3,4-dihydroxyphenylethanol lactate, with its multi-target biological activities, has become a hot candidate molecule in the field of antioxidant development.

[0003] Currently, there are very few reports on 3,4-dihydroxyphenylethanol lactate. CN106905159B and CN108567798B report methods for extracting the target product from the body of the beak-tailed beetle. These methods are complex and have extremely low yields. Furthermore, insect resources are limited by seasonality and geographical location, making it difficult to guarantee the stability of raw material supply, which severely restricts its industrial application. Summary of the Invention

[0004] The present invention describes a method for preparing 3,4-dihydroxyphenylethanol lactate. The method described in this invention uses readily available raw materials, has a simple process, and is suitable for industrial production.

[0005] The present invention provides a method for preparing 3,4-dihydroxyphenylethanol lactate, which uses 3,4-dihydroxyphenylethanol as the starting material and reacts with a lactating agent under the action of an acid catalyst to generate 3,4-dihydroxyphenylethanol lactate. The reaction solution is then extracted, washed, dried, concentrated, and purified to obtain the final product.

[0006]

[0007] Wherein: R is selected from: methyl (Me), ethyl (Et), n-propyl (Pr), and isopropyl (i-Pr).

[0008] In some embodiments, the molar ratio of the lactating agent to 3,4-dihydroxyphenylethanol is (0.9–1.2):1.0; the preferred molar ratio is 1.0:1.0. When the ratio of lactic acid ester reagents increases, impurities increase, reducing the yield. When the ratio of lactic acid ester reagents decreases, the feed conversion rate decreases, and the yield also decreases.

[0009] In some embodiments, the reaction solvent is 1,4-dioxane, dimethyl sulfoxide, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane.

[0010] In some embodiments, the reaction temperature is 90–100°C, preferably 100°C. When the reaction temperature is too low, the reaction rate is slow and the yield is reduced. The reaction temperature is limited by the boiling point of the solvent and cannot be increased further.

[0011] In some embodiments, the acid catalyst is boron trifluoride. In some embodiments, the molar ratio of boron trifluoride to 3,4-dihydroxyphenylethanol is (0.04 to 0.06):1, preferably 0.05:1.0.

[0012] In some embodiments, the reaction time of the present invention is 2 to 4 hours, preferably 3 hours.

[0013] The reaction solution of this invention can be extracted, washed, dried, and concentrated according to conventional methods in the art. In one specific example, the washing, drying, and concentration are as follows: the reaction solution is cooled to room temperature, the solvent is removed by rotary evaporation, the concentrate is dissolved in an appropriate amount of water by stirring, the aqueous layer is extracted with ethyl acetate 2-4 times, the ethyl acetate layers are combined, the ethyl acetate layers are washed once with saturated sodium bicarbonate and twice with water, and the ethyl acetate layers are dried.

[0014] Filtration, concentration.

[0015] The separation and purification of the reaction in this invention can be achieved using column chromatography or molecular distillation, or a combination of column chromatography and molecular distillation. When the product quantity is small, the separation and purification can specifically involve purifying the crude product using 200-300 mesh silica gel column chromatography, with a 2:1 volume ratio of petroleum ether and ethyl acetate as the eluent, and the eluent concentrated to obtain the final product. When the reaction is on a kilogram scale, the crude product can be obtained by rapid column chromatography using 200-300 mesh alumina, and the crude product can be separated and purified using multi-stage molecular distillation.

[0016] This application reports for the first time a chemical synthesis method for 3,4-dihydroxyphenylethanol lactate. Using inexpensive and readily available 3,4-dihydroxyphenylethanol and lactate reagents as starting materials, 3,4-dihydroxyphenylethanol lactate is prepared by reaction under acid catalysis. The reaction process is simple and suitable for industrial production.

[0017] Compared with traditional extraction processes, this process has the following significant advantages:

[0018] (1) Improved synthesis efficiency: The lactic acid reagent used in the method of the present invention has a high reaction yield, with a total yield of over 80%, and the single batch output has reached the kilogram level, far exceeding the scale of natural extraction. Moreover, the process is stable after the kilogram-level scale-up production.

[0019] (2) Reduced raw material costs: Using bulk chemicals to replace scarce insect resources, completely eliminating biological dependence.

[0020] (3) Enhanced quality controllability: When the method described in this invention is used for kilogram-level production, the HPLC purity can reach 99% after purification by alumina rapid column chromatography combined with multi-stage molecular distillation technology, avoiding interference from complex impurities in natural products, meeting pharmaceutical-grade standards, and enhancing quality controllability.

[0021] In summary, this patent not only proposes a method for synthesizing 3,4-dihydroxyphenylethanol lactate, but also provides a stable and reliable source of high-purity raw materials for the antioxidant market through a low-cost and high-efficiency industrialization solution, which is of great strategic significance for promoting the prevention and treatment of free radical-related diseases. Attached Figure Description

[0022] Figure 1 : 1H NMR spectrum of 3,4-dihydroxyphenylethanol-L-lactic acid ester in Example 1.

[0023] Figure 2 : Mass spectrometry of 3,4-dihydroxyphenylethanol-L-lactic acid ester in Example 1. Detailed Implementation

[0024] The following description, in conjunction with several preferred embodiments, further illustrates the technical solution of the present invention in a non-limiting manner. Reagents or instruments used without a specified manufacturer are considered to be conventional products that can be purchased on the market.

[0025] Example 1: Small-scale test of 3,4-dihydroxyphenylethanol lactate

[0026] At room temperature, 20 g (0.13 mol) of 3,4-dihydroxyphenylethanol, 100 mL of 1,4-dioxane, and 0.9 g (0.006 mol) of a 48% boron trifluoride tetrahydrofuran solution were added to a four-necked flask, and the temperature was raised to 100 °C. 13.5 g (0.13 mol) of methyl lactate was slowly added dropwise. After the addition was complete, the reaction was continued for 3 hours.

[0027] After the reaction was complete, the reaction solution was cooled to room temperature, and the solvent was removed by rotary evaporation. The concentrate was dissolved in an appropriate amount of water by stirring. The aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed once with saturated sodium bicarbonate, and twice with water. The ethyl acetate layer was dried, filtered, concentrated, and purified by silica gel column chromatography (200-300 mesh) using petroleum ether / ethyl acetate = 2 / 1 eluent. The eluent was concentrated to give 24.8 g of the final product, yield: 84.5%, HPLC: 99.16%. H-NMR data are shown below. Figure 1 MS data can be found Figure 2 .

[0028] Example 2: Ethyl lactate as a lactating agent

[0029] The difference from Example 1 is that 15.3 g (0.13 mol) of ethyl lactate was added dropwise. Everything else was the same as in Example 1.

[0030] After the reaction was completed, the post-processing and purification procedures were as described in "Example 1", yielding 23.4g of final product, with a yield of 79.8% and an HPLC yield of 99.22%.

[0031] Example 3: Propyl lactate as a lactating agent

[0032] The difference from Example 1 is that 17.2 g (0.13 mol) of propyl lactate was added dropwise. Everything else was the same as in Example 1. Referring to the feed ratio, reaction process, post-treatment process, and purification process of Example 1, 19.2 g of final product was obtained, yield: 65.3%, HPLC: 99.36%.

[0033] Example 4: Isopropyl lactate as a lactating agent

[0034] The difference from Example 1 is that 17.2 g (0.13 mol) of isopropyl lactate was added dropwise. Everything else was the same as in Example 1. Referring to the feed ratio, reaction process, post-treatment process, and purification process in Example 1, 19.7 g of final product was obtained, yield: 67.2%, HPLC: 99.60%.

[0035] Example 5

[0036] Following the same feed ratio and reaction process as in Example 1, with a reaction temperature of 80°C and other parameters identical to Example 1, 18.3g of final product was obtained, yielding 62.3% and HPLC 98.85%.

[0037] Example 6: Dimethyl sulfoxide as a solvent

[0038] At room temperature, 20 g (0.13 mol) of 3,4-dihydroxyphenylethanol, 100 ml of 1,4-dioxane, 0.9 g (0.006 mol) of 48% boron trifluoride tetrahydrofuran solution, and 40 ml of DMSO were added to a four-necked flask. All other steps were the same as in Example 1. After the reaction was completed, the post-processing and purification were performed according to Example 1. 22.4 g of final product was obtained, yield: 76.2%, HPLC: 99.82%.

[0039] Example 7

[0040] Referring to "Example 1", the only difference is that the amount of methyl lactate added is 0.156 mol (1.2 eq), yielding 19.0 g of final product, with a yield of 64.9% and an HPLC result of 97.84%.

[0041] Example 8

[0042] Referring to "Example 1", the only difference is that the amount of methyl lactate added is 0.117 mol (0.9 eq), yielding 21.6 g of final product, with a yield of 73.5% and an HPLC result of 98.10%.

[0043] Example 9: Scale-up of the 3,4-dihydroxyphenylethanol lactate method of Example 1

[0044] At room temperature, 1.5 kg (9.73 mol) of 3,4-dihydroxyphenylethanol, 7.5 L of 1,4-dioxane, and 68 g (0.006 mol) of a 48% boron trifluoride tetrahydrofuran solution were added to a four-necked flask, and the temperature was raised to 100 °C. 1.01 kg (9.73 mol) of methyl lactate was slowly added dropwise. After the addition was complete, the reaction was continued for 3 hours.

[0045] After the reaction was complete, the reaction solution was cooled to room temperature, and the solvent was removed by rotary evaporation. The concentrate was dissolved in an appropriate amount of water by stirring. The aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed once with saturated sodium bicarbonate and twice with water. The ethyl acetate layer was dried, filtered, and concentrated. The concentrate was subjected to rapid column chromatography on acidic alumina (petroleum ether / ethyl acetate = 1 / 1) using a 200–300 mesh screen to obtain a pale yellow crude product with a purity of 94.66%. The crude product was subjected to two molecular distillations to obtain 1.61 kg of final product, yield: 73.2%, HPLC: 99.65%.

[0046] This embodiment was scaled up to the kilogram level, and the process was stable.

[0047] Comparative Example 1: React with other lactizing agents

[0048] 1. Lactic acid as a lactating agent

[0049] Referring to the feed ratio, reaction process, post-processing process and purification process in "Example 1", 17.1g of final product was obtained, with a yield of 58.4% and an HPLC result of 98.70%.

[0050] 2. Lactate reagents

[0051] 2.1 Lithium lactate as a lactating agent

[0052] At room temperature, 20 g (0.13 mol) of 3,4-dihydroxyphenylethanol, 100 ml of 1,4-dioxane, 12.5 g (0.13 mol) of lithium lactate, and 0.9 g (0.006 mol) of a 48% boron trifluoride tetrahydrofuran solution were added to a four-necked flask. The internal temperature was raised to 100 °C and the reaction was carried out for 3 h. After the reaction was completed, the post-processing and purification procedures were followed as in "Example 1", yielding 1.4 g of final product, yield: 4.9%, HPLC: 98.53%.

[0053] 2.2 Aluminum lactate as an emulsifying agent

[0054] At room temperature, 20 g (0.13 mol) of 3,4-dihydroxyphenylethanol, 100 ml of 1,4-dioxane, 13.0 g (0.44 mol) of aluminum lactate, and 0.9 g (0.005 mol) of a 48% boron trifluoride tetrahydrofuran solution were added to a four-necked flask. The internal temperature was raised to 100 °C and the reaction was carried out for 3 h. After the reaction was completed, the post-processing and purification procedures were followed as in "Example 1", yielding 4.3 g of final product, yield: 14.6%, HPLC: 98.27%.

[0055] 3. Other lactate ester reagents,

[0056] 3.1 Butyl lactate as a lactating agent

[0057] Referring to the feed ratio, reaction process, post-processing process and purification process in "Example 1", 12.9g of final product was obtained, with a yield of 43.9% and an HPLC result of 99.10%.

[0058] 4. Lactic acid derivatives

[0059] 4.1 Lactide as a lactating agent

[0060] At room temperature, 20 g (0.13 mol) of 3,4-dihydroxyphenylethanol, 100 ml of 1,4-dioxane, 9.3 g (0.065 mol) of lactide, and 0.9 g (0.006 mol) of a 48% boron trifluoride tetrahydrofuran solution were added to a four-necked flask. The internal temperature was raised to 100 °C and the reaction was carried out for 3 h. After the reaction was completed, the post-processing and purification procedures were followed as in "Example 1", yielding 11.1 g of final product, yield: 37.7%, HPLC: 98.97%.

[0061] 4.2 Acetyl ethyl lactate as a lactating agent

[0062] At room temperature, 20 g (0.13 mol) of 3,4-dihydroxyphenylethanol, 100 ml of 1,4-dioxane, 28.1 g (0.13 mol) of butyryl lactate, and 0.9 g (0.006 mol) of a 48% boron trifluoride tetrahydrofuran solution were added to a four-necked flask. The internal temperature was raised to 100 °C and the reaction was carried out for 3 h. After the reaction was completed, the post-processing and purification procedures were as described in "Example 1", yielding 1.6 g of final product, yield: 5.6%, HPLC: 98.91%.

[0063] In summary, Comparative Example 1 investigated the effects of different types of lactating reagents on the reaction yield and purity. The results showed that the use of lactate ester reagents in this application was significantly superior to other lactating reagents, with methyl lactate and ethyl lactate showing the most significant advantages.

[0064] Comparative Example 2: Comparison of Reaction Solvents

[0065] 1. Solvent-free reaction

[0066] Referring to the feed ratio (solvent-free), reaction process, post-treatment process and purification process of "Example 1", 14.0 g of final product was obtained, with a yield of 47.7% and an HPLC result of 97.45%.

[0067] 2. The effect of tetrahydrofuran as a solvent on the reaction

[0068] Following the feed ratio (tetrahydrofuran: 100 ml), reaction process (temperature: 65 °C), post-treatment process, and purification process of "Example 1", 14.1 g of final product was obtained, with a yield of 48.1% and an HPLC yield of 98.58%.

[0069] In summary, the absence of a solvent, or the use of other solvents such as tetrahydrofuran, leads to a significant decrease in yield, while the solvent of this application can significantly improve the yield.

[0070] Comparative Example 3: Comparison of Catalysts

[0071] 1. The effect of aluminum trichloride as a catalyst on the reaction

[0072] Referring to the feed ratio (1.8g 0.05eq aluminum trichloride), reaction process, and post-treatment process in "Example 1", 4.8g of final product was obtained, with a yield of 16.4% and an HPLC result of 98.84%.

[0073] 2. The effect of sulfuric acid as a catalyst on the reaction

[0074] Referring to the feed ratio (0.6g 0.05eq 98% sulfuric acid), reaction process, and post-treatment process in "Example 1", 9.3g of final product was obtained, with a yield of 31.6% and an HPLC result of 98.36%.

[0075] 3. The effect of phosphoric acid as a catalyst on the reaction

[0076] Referring to the feed ratio (0.7g 0.05eq 85% phosphoric acid), reaction process, and post-treatment process in "Example 1", 3.4g of final product was obtained, with a yield of 11.6% and an HPLC result of 97.45%.

[0077] In summary, the catalyst used in this application can significantly improve the yield, while other catalysts have a significant impact on the reaction yield and purity.

[0078] The scope of protection of this invention is not limited to the above embodiments. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in this invention and are protected by the appended claims.

Claims

1. A method for preparing 3,4-dihydroxyphenylethanol lactate, characterized in that, Starting with 3,4-dihydroxyphenylethanol, the product reacts with a lactating agent under the action of an acid catalyst to generate 3,4-dihydroxyphenylethanol lactate. The reaction solution is then extracted, washed, dried, concentrated, and purified to obtain the final product. Wherein: R is selected from: methyl (Me), ethyl (Et), n-propyl (Pr), and isopropyl (i-Pr).

2. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 1, characterized in that, The molar ratio of the lactating agent to 3,4-dihydroxyphenylethanol is (0.9–1.2):1.

0.

3. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 2, characterized in that, The molar ratio of the lactating agent to 3,4-dihydroxyphenylethanol is 1.0:1.

0.

4. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 1, characterized in that, The reaction solvent is 1,4-dioxane, dimethyl sulfoxide, or acetonitrile.

5. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 4, characterized in that, The reaction solvent is 1,4-dioxane.

6. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 1, characterized in that, The reaction temperature is 90–100°C, with 100°C being the preferred reaction temperature.

7. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 1, characterized in that, The acid catalyst is boron trifluoride.

8. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 7, characterized in that, The molar ratio of boron trifluoride to 3,4-dihydroxyphenylethanol is (0.04-0.06):1, with a preferred molar ratio of 0.05:1.

0.

9. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 1, characterized in that, The reaction time is 2 to 4 hours, preferably 3 hours.

10. The method for preparing 3,4-dihydroxyphenylethanol lactate according to claim 1, characterized in that, The separation and purification methods are column chromatography, molecular distillation, or a combination of both.

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