A preparation method of 1-O-alkyl genipin derivatives

Abstract

The present invention belongs to the technical field of synthesis of genipin derivatives, and specifically relates to a method for preparing a 1-O-alkyl genipin derivative. The present invention mixes genipin, a low-carbon alcohol, a catalyst and a polar organic solvent for alkoxylation reaction; the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride etherate and water; when the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid, the temperature of the alkoxylation reaction is ≥rt; when the catalyst is a mixture of boron trifluoride etherate and water, the temperature of the alkoxylation reaction is ≥0°C. The preparation method provided by the present invention can achieve 1-O-alkyl genipin derivatives with high R configuration selectivity under mild reaction temperature conditions by selecting fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride etherate and water as a catalyst for alkoxylation reaction, and the preparation method is simple, the reaction conditions are mild, and it is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of genipin derivatives, and particularly relates to a method for preparing a 1-O-alkyl genipin derivative. Background Art

[0002] The Chinese medicine Gardenia is bitter and cold, and enters the heart, lung, and triple burner meridians. It can clear away the triple burner fire evil, drain heart fire and eliminate restlessness, and treat fever with intense fire toxicity, triple burner heat with high fever, irritability, and delirium.

[0003] Gardenia glycoside is the main component of the traditional Chinese medicine Gardenia, and its content is the main evaluation standard for the quality of Gardenia. The 2020 edition of the Pharmacopoeia stipulates that Gardenia is calculated based on the dry product and contains Gardenia glycoside (C 17 H 24 O 10 ) shall not be less than 1.8%; for the same medicinal material, the content of geniposide (C 17 H 24 O 10 ) shall not be less than 1.5%. Gardenia glycoside (C 17 H 24 O 10 ) has a significant neuroprotective effect and has a good preventive and therapeutic effect on central nervous system diseases.

[0004] Gardenia glycoside is a glycoside compound with a sugar ring, and its molecular formula is C 17 H 24 O 10 , contains multiple hydroxyl groups, has high molecular polarity, low oral bioavailability, and low brain penetration rate of only 0.38%, making it difficult to play a positive role in central nervous system diseases; its structural stability is poor and it is easily hydrolyzed in the body into aglycone genipin (such as Figure 1 As shown in Figure 2, genipin may be the main material basis for gardenia glycoside to exert CIRI effect in vivo. Studies have reported that genipin also has significant neuroprotective effects and other effects against central nervous system diseases.

[0005] Genipin can effectively inhibit the neurotoxicity of hippocampal neurons (PC12h) caused by β-amyloid protein Aβ, and has a significant effect on promoting the growth of neuronal cells; Genipin also has a good inhibitory effect on the neurotoxicity guided by calcium ion carrier A23187. Genipin has low toxicity and strong neuroprotective effect, but its structural stability is insufficient, which limits the research and application of its activity.

[0006] Japanese scholars have designed a series of 1-O-alkoxy substituted genipin derivatives (such as Figure 2As shown in Figure 2, the 1-O-alkyl genipin derivatives showed good neuron growth promoting activity in PC12 cell experiments, and their stability was also greatly improved, especially 1-O-isopropyl genipin, which had the strongest activity. These results show that 1-O-alkyl genipin derivatives enhance the neuroprotective activity of genipin and improve the activity and stability of the compound.

[0007] Moreover, current research shows that 1R-O alkyl-substituted genipin derivatives have better neuroprotective activity, while 1S-substituted derivatives have weaker activity. However, in existing literature reports, there are few reports on the preparation methods of R and S configurations, and even high-performance liquid chromatography is used for small-scale separation and purification, which is not convenient for quantitative preparation. Therefore, strengthening the research on the synthesis methods of R-isomers and S-isomers of genipin derivatives, thereby providing a material basis for the pharmacological activity research of genipin derivatives and their 1R / 1S configuration compounds, has a positive effect on the prevention and treatment of neurological diseases.

[0008] In the Chinese patent CN113831316A previously applied by the applicant, genipin is used directly as a reaction raw material or by changing the substituent of the ortho-10-OH of genipin (i.e., 10-O-Piv-1-O-NHCCl3 genipin is used as a raw material), to obtain a 1-O-alkoxy substituted genipin derivative product in which the 1R-O-alkyl genipin derivative configuration is dominant. However, when 10-O-Piv-1-O-NHCCl3 genipin is used as a raw material, 10-O-Piv-1-O-NHCCl3 genipin needs to be prepared from genipin first, and the preparation steps are complicated, the yield is low, and the process conditions are relatively harsh.

[0009] When unsubstituted genipin is used directly as a reaction raw material, the reaction steps are simple and more in line with the needs of industrial production. However, when the reaction is carried out at room temperature or above, the selectivity of the R configuration advantage in the product is poor, and the S / R is only about 55 / 100. It is necessary to react at -30 to -10°C to achieve an S / R of about 10 / 100 in the product, and the yield is 10 to 25%. The reaction temperature is too low and cannot be used for industrial production. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing 1-O-alkyl genipin derivatives. The method provided by the present invention has high R configuration selectivity, and the preparation method is simple and the reaction conditions are mild, which lays a foundation for the industrialization of 1-O-alkyl genipin derivative products with a dominant R configuration.

[0011] In order to achieve the above object, the present invention provides the following technical solutions:

[0012] The present invention provides a method for preparing a 1-O-alkyl genipin derivative, comprising the following steps:

[0013] Genipin, a low-carbon alcohol, a catalyst and a polar organic solvent are mixed for alkoxylation reaction to obtain a 1-O-alkyl genipin derivative; the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride etherate and water; in the mixture of boron trifluoride etherate and water, the volume ratio of water to boron trifluoride etherate is ≤1:1;

[0014] When the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid, the temperature of the alkoxylation reaction is ≥ rt;

[0015] When the catalyst is a mixture of boron trifluoride etherate and water, the temperature of the alkoxylation reaction is ≥ 0°C.

[0016] Preferably, when the catalyst is fluoroboric acid, the molar ratio of genipin to fluoroboric acid is 1:(1-10);

[0017] When the catalyst is a mixture of fluoroboric acid and boric acid, the molar ratio of genipin, fluoroboric acid and boric acid is 1:(1-9):(1-9);

[0018] When the catalyst is a mixture of boron trifluoride ethyl ether and water, the ratio of the amount of the mixture of boron trifluoride ethyl ether and water to the amount of genipin is (1-1.5):1.

[0019] Preferably, in the mixture of boron trifluoride etherate and water, the volume ratio of water to boron trifluoride etherate is 1:(1-1000).

[0020] Preferably, when the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid, the temperature of the alkoxylation reaction is rt to 80°C;

[0021] When the catalyst is a mixture of boron trifluoride etherate and water, the temperature of the alkoxylation reaction is 0 to 80°C;

[0022] The alkoxylation reaction time is 6 to 10 hours.

[0023] Preferably, the low-carbon alcohol includes isopropanol, ethanol, n-propanol, n-butanol or ethylene glycol.

[0024] Preferably, the molar ratio of genipin to low-carbon alcohol is 1:(1.0-6.0).

[0025] Preferably, the polar organic solvent is one or more of dichloromethane, toluene and acetonitrile.

[0026] Preferably, the 1-O-alkyl genipin derivatives include 1R-O-alkyl genipin derivatives and 1S-O-alkyl genipin derivatives, and the molar ratio of the 1R-O-alkyl genipin derivatives to the 1S-O-alkyl genipin derivatives is 100:(2-19).

[0027] Preferably, the alkoxylation reaction obtains a crude 1-O-alkyl genipin derivative; and further comprises purifying the crude 1-O-alkyl genipin derivative by column chromatography to obtain a pure 1-O-alkyl genipin derivative; the eluent for the column chromatography purification is ethyl acetate and petroleum ether; the volume ratio of ethyl acetate to petroleum ether is 1:3.

[0028] The present invention provides a method for preparing a 1-O-alkyl genipin derivative, comprising the following steps: mixing genipin, a low-carbon alcohol, a catalyst and a polar organic solvent for alkoxylation reaction to obtain a 1-O-alkyl genipin derivative; the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride etherate and water; in the mixture of boron trifluoride etherate and water, the volume ratio of water to boron trifluoride etherate is ≤1:1; when the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid, the temperature of the alkoxylation reaction is ≥rt; when the catalyst is a mixture of boron trifluoride etherate and water, the temperature of the alkoxylation reaction is ≥0°C. The preparation method provided by the present invention can achieve the 1-O-alkyl genipin derivative with high R configuration selectivity under mild reaction temperature conditions by selecting a specific catalyst: fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride etherate and water to catalyze the alkoxylation reaction of genipin, and has higher neuroprotective activity, and the preparation method is simple, the reaction conditions are mild, and it is more suitable for industrial production. The results of the embodiments show that, in the preparation method provided by the present invention, when the catalyst is fluoroboric acid, the S / R (i.e., the molar ratio of the 1S-O-alkyl genipin derivative to the 1R-O-alkyl genipin derivative) in the product is (5-15):100; when the catalyst is a mixture of fluoroboric acid and boric acid, the S / R in the product is (3-19):100; when the catalyst is a mixture of boron trifluoride etherate and water, the S / R in the product is (2-9):100. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The main active ingredients of Gardenia are Gardenia jasminoides and its hydrolyzate genipin;

[0030] Figure 2 The present invention is a preparation process of a 1-O-alkoxy substituted genipin derivative disclosed in the prior art;

[0031] Figure 3 The schematic diagram of the prior art using 1-O-alkoxy substituted genipin derivatives;

[0032] Figure 4 This is a reaction flow chart of Example 1 of the present invention;

[0033] Figure 5 This is a reaction flow chart of Example 2 of the present invention;

[0034] Figure 6 This is a reaction flow chart of Example 3 of the present invention;

[0035] Figure 7 This is the NMR data spectrum of 1R-O-isopropylgenipin prepared in Examples 1 to 3 of the present invention. DETAILED DESCRIPTION

[0036] The present invention provides a method for preparing a 1-O-alkyl genipin derivative, comprising the following steps:

[0037] Genipin, a low-carbon alcohol, a catalyst and a polar organic solvent are mixed for alkoxylation reaction to obtain a 1-O-alkyl genipin derivative; the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride etherate and water; in the mixture of boron trifluoride etherate and water, the volume ratio of water to boron trifluoride etherate is ≤1:1;

[0038] When the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid, the temperature of the alkoxylation reaction is ≥ rt;

[0039] When the catalyst is a mixture of boron trifluoride etherate and water, the temperature of the alkoxylation reaction is ≥ 0°C.

[0040] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art.

[0041] In the present invention, rt means room temperature.

[0042] In the present invention, the low-carbon alcohol preferably includes isopropanol, ethanol, n-propanol, n-butanol or ethylene glycol, more preferably isopropanol (i-PrOH).

[0043] In the present invention, the molar ratio of genipin to lower carbon alcohol is preferably 1:(1.0-6.0), more preferably 1:(1.1-6.0).

[0044] In the present invention, when the catalyst is fluoroboric acid, the molar ratio of genipin to fluoroboric acid is preferably 1:(1-10), more preferably 1:(1.2-10), further preferably 1:(1.2-3), most preferably 1:(1.2-1.5), specifically preferably 1:1.2, 1:1.5, 1:3, 1:6, 1:8 or 1:10. The temperature of the alkoxylation reaction is preferably rt-80°C, more preferably 45-80°C, further preferably 60°C-80°C, specifically preferably rt, 45°C, 60°C- or 80°C. The time of the alkoxylation reaction is preferably 6-10h. In a specific embodiment of the present invention, the molar ratio of genipin to fluoroboric acid is 1:(1.5-3), and the temperature of the alkoxylation reaction is 60-80°C. In the obtained 1-O-alkyl genipin derivative product, the molar ratio of the 1R-O-alkyl genipin derivative to the 1S-O-alkyl genipin derivative is 100:(7-9); at the same time, the yield of the 1-O-alkyl genipin derivative is 31-43%, achieving a high yield of the 1-O-alkyl genipin derivative and a high selectivity of the 1R-O-alkyl genipin derivative.

[0045] In the present invention, when the catalyst is a mixture of fluoroboric acid and boric acid, the molar ratio of genipin, fluoroboric acid and boric acid is preferably 1:(1-9):(1-9), more preferably 1:(1.5-9):(1.5-9), further preferably 1:(1.5-6):1.5, specifically preferably 1:1.5:1.5, 1:3:1.5, 1:3:1.5 or 1:6:1.5. In the present invention, the temperature of the alkoxylation reaction is preferably rt-80°C, more preferably rt-60°C, more preferably rt-45°C. The time of the alkoxylation reaction is preferably 6-10h. In a specific embodiment of the present invention, the molar ratio of the genipin, fluoroboric acid and boric acid is 1:(1.5-6):1.5, and when the temperature of the alkoxylation reaction is rt-45°C, the molar ratio of the 1R-O-alkyl genipin derivative and the 1S-O-alkyl genipin derivative in the obtained 1-O-alkyl genipin derivative product is 100:(8-9); at the same time, the yield of the 1-O-alkyl genipin derivative is 37-73%, achieving a high yield of the 1-O-alkyl genipin derivative and a high selectivity of the 1R-O-alkyl genipin derivative.

[0046] The present invention uses fluoroboric acid or a mixture of fluoroboric acid and boric acid as a catalyst, overcoming the technical prejudice in the prior art that alkoxylation reactions use Lewis acids with strong electron-accepting ability (e.g., boron trifluoride, boron trichloride, aluminum trichloride, tin trichloride, trimethylsilyl trifluoromethanesulfonate) as catalysts. The prior art teaches those skilled in the art that the Lewis acids (e.g., boron trifluoride ethyl ether) used can achieve smooth alkoxylation reactions at low temperatures (e.g., -30 to -10°C). The present invention uses fluoroboric acid or a mixture of fluoroboric acid and boric acid as a catalyst, and uses two acids with weak electron-accepting ability as catalysts for the alkoxylation reaction of genipin, thereby enabling the preparation of 1-O-alkyl genipin derivatives at above room temperature.

[0047] The invention adopts fluoroboric acid or a mixture of fluoroboric acid and boric acid as a catalyst for the alkoxylation reaction. When the temperature of the alkoxylation reaction is greater than or equal to rt, not only the alkoxylation reaction is smoothly carried out, but also 1-O-alkyl genipin derivatives are prepared from genipin and low-carbon alcohols as raw materials. Meanwhile, the selectivity of 1R-O-alkyl genipin derivatives in the 1-O-alkyl genipin derivative products is high, and the product yield is high. Therefore, the invention has significant progress.

[0048] In the present invention, when the catalyst is a mixture of boron trifluoride etherate and water, the volume ratio of water to boron trifluoride etherate in the mixture of boron trifluoride etherate and water is preferably 1:(1-1000), and is particularly preferably 1:5, 1:10, 1:20, 1:50, 1:100 or 1:1000. The molar ratio of the mixture of boron trifluoride etherate and water to genipin is preferably (1-1.5):1, more preferably (1.1-1.5):1, and most preferably 1.5:1. The temperature of the alkoxylation reaction is preferably 0-80°C, more preferably rt-80°C, and particularly preferably rt, 45°C, 60°C or 80°C. The time of the alkoxylation reaction is preferably 6-10h. In a specific embodiment of the present invention, the molar ratio of the mixture of boron trifluoride etherate and water to genipin is 1.5:1, the volume ratio of water to boron trifluoride etherate is preferably 1:(5-100), and when the temperature of the alkoxylation reaction is rt-80°C, the molar ratio of the 1R-O-alkyl genipin derivative and the 1S-O-alkyl genipin derivative in the obtained 1-O-alkyl genipin derivative is 100:(3-9); at the same time, the yield of the 1-O-alkyl genipin derivative is 55-76%, achieving a high yield of the 1-O-alkyl genipin derivative and a high selectivity of the 1R-O-alkyl genipin derivative.

[0049] The present invention uses a mixture of boron trifluoride ethyl ether and water as a catalyst, overcoming the technical prejudice in the prior art that alkoxylation reactions need to be carried out under anhydrous conditions using a Lewis acid with strong electron-accepting ability (such as boron trifluoride ethyl ether) as a catalyst. The prior art teaches those skilled in the art that when using a Lewis acid with strong electron-accepting ability (such as boron trifluoride ethyl ether) to catalyze alkoxylation reactions, it is necessary to carry out the reaction under anhydrous conditions, such as Figure 3 As shown: In existing reactions, anhydrous and oxygen-free operation is often required, that is, the solvent, substrate, etc. need to be anhydrous before the reaction, and an inert gas such as nitrogen needs to be passed during the reaction to form a positive pressure in the entire reaction system to prevent air and water in the air from entering the reaction system. Because when oxygen and water enter the reaction system, due to their high activity, they are easy to react with oxonium ions (high activity, unstable), thereby destroying the entire reaction or reducing the yield. The present invention uses a mixture of boron trifluoride and water as a catalyst. The mixture of boron trifluoride and water forms a complex with genipin, preventing the formation of oxonium ions, avoiding attacks from different surfaces, and forming a similar S N 2 Reaction mechanism of substitution.

[0050] In the prior art, the alkoxylation reaction needs to be carried out under anhydrous conditions. When a Lewis acid with strong electron-accepting ability (such as boron trifluoride ethyl ether) is used as a catalyst, the alkoxylation reaction needs to be carried out smoothly at a low temperature (such as -30 to -10°C). The present invention uses a mixture of boron trifluoride ethyl ether and water as a catalyst for the alkoxylation reaction. In the presence of a small amount of water, the present invention uses genipin and a low-carbon alcohol as raw materials and prepares a 1-O-alkyl genipin derivative product under a reaction temperature of ≥0°C (preferably rt to 80°C). At the same time, the selectivity of the 1R-O-alkyl genipin derivative in the 1-O-alkyl genipin derivative product is high (R / S ratio is 100:(3 to 9)), and the product yield is high (55 to 76%). Therefore, the present invention has significant progress.

[0051] In the present invention, the polar organic solvent is preferably one or more of dichloromethane, toluene and acetonitrile, more preferably dichloromethane. The present invention has no special requirements on the amount of the polar organic solvent, as long as the alkoxylation reaction proceeds smoothly.

[0052] In the present invention, when the catalyst is a mixture of boron trifluoride etherate and water, the present invention preferably premixes the boron trifluoride etherate and water before the mixing. In the present invention, the water is preferably distilled water. In the present invention, the premixing is preferably carried out under ice-water bath conditions, the premixing is preferably carried out under stirring conditions, and the stirring time is preferably 0.5h. In the present invention, the mixture of boron trifluoride etherate and water is preferably sealed and stored.

[0053] The present invention has no special requirements for the mixing of the genipin, low-carbon alcohol, catalyst and polar organic solvent, and the above raw materials can be mixed evenly.

[0054] In the present invention, the alkoxylation reaction time is preferably 12 to 24 hours. The alkoxylation reaction is carried out in an air atmosphere or a protective atmosphere, and the protective atmosphere is preferably a nitrogen atmosphere or an inert gas atmosphere, and more preferably a nitrogen atmosphere.

[0055] In the present invention, after the alkoxylation reaction, the alkoxylation reaction liquid obtained after the alkoxylation reaction is preferably post-treated to obtain the crude 1-O-alkyl genipin derivative.

[0056] In the present invention, the post-treatment preferably includes the following steps in sequence: reaction quenching, extraction, washing, drying and concentration.

[0057] In the present invention, the reaction quenching is preferably performed by mixing the alkoxylation reaction solution with ice water.

[0058] In the present invention, the extraction agent is preferably dichloromethane. In the present invention, the number of extractions is preferably 1 to 3 times, more preferably 3 times. The volume ratio of the extraction agent to the ice water is preferably 1: 1. In the present invention, the target product 1-O-alkyl genipin derivative is extracted into the extraction agent phase by extraction.

[0059] The present invention combines the extractant phases of each extraction and then washes the extractant phase. In the present invention, the washing includes sequentially washing with a saturated NaCl aqueous solution until it becomes neutral. The present invention removes water-soluble impurities in the extractant phase by washing with a saturated NaCl aqueous solution and adjusts the pH value of the extractant phase to neutral.

[0060] The present invention preferably dries the washed organic phase. In the present invention, the drying agent is preferably anhydrous sodium sulfate.

[0061] In the present invention, the dried organic phase is preferably concentrated. In the present invention, the concentration is preferably performed under vacuum conditions. In the present invention, part of the solvent in the organic phase is preferably removed by concentration.

[0062] After obtaining the crude 1-O-alkyl genipin derivative, the present invention preferably further comprises purifying the crude 1-O-alkyl genipin derivative by column chromatography to obtain a pure 1-O-alkyl genipin derivative; the eluent for the column chromatography purification is ethyl acetate and petroleum ether; the volume ratio of ethyl acetate to petroleum ether is 1:3.

[0063] In the present invention, the column chromatography purification is preferably performed using a silica gel chromatography column.

[0064] In the present invention, the 1-O-alkyl genipin derivatives include 1R-O-alkyl genipin derivatives and 1S-O-alkyl genipin derivatives, and the molar ratio of the 1R-O-alkyl genipin derivatives to the 1S-O-alkyl genipin derivatives is 100:(2-19).

[0065] In the present invention, when the catalyst is fluoroboric acid, in the obtained 1-O-alkyl genipin derivative product: the molar ratio of the 1R-O-alkyl genipin derivative to the 1S-O-alkyl genipin derivative is preferably 100:(7-9); at the same time, the yield of the 1-O-alkyl genipin derivative is preferably 31-43%.

[0066] In the present invention, when the catalyst is a mixture of fluoroboric acid and boric acid, in the obtained 1-O-alkyl genipin derivative product: the molar ratio of the 1R-O-alkyl genipin derivative to the 1S-O-alkyl genipin derivative is preferably 100:(8-9); at the same time, the yield of the 1-O-alkyl genipin derivative is preferably 37-73%.

[0067] In the present invention, when the catalyst is a mixture of boron trifluoride etherate and water, the molar ratio of the 1R-O-alkyl genipin derivative and the 1S-O-alkyl genipin derivative in the obtained 1-O-alkyl genipin derivative is preferably 100:(3-9); at the same time, the yield of the 1-O-alkyl genipin derivative is preferably 55-76%.

[0068] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0069] Example 1

[0070] according to Figure 4 Reaction process: 0.4 g (1.76 mmol) of genipin (GP), i-PrOH (5.28 mmol), fluoroboric acid (1.0-10.0 eq×1.76 mmol) and 20 mL of dichloromethane were added to a 50 mL round-bottom flask in sequence. After reacting for 8 h, the reaction system was poured into 50 mL of ice water for quenching, and extracted with dichloromethane (3×50 mL). The combined organic phase was washed with 100 mL of saturated brine until neutral, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography [V (ethyl acetate): V (petroleum ether) = 1:3] to obtain a pale white crystal of 1-O-isopropyl genipin. In Example 1, the molar ratio of GP: HBF4 and the reaction temperature are shown in Table 1, and the yield and S / R (i.e., the molar ratio of 1S-O-alkyl genipin derivative and 1R-O-alkyl genipin derivative) of the obtained 1-O-isopropyl genipin product are shown in Table 1.

[0071] Table 1 Synthesis parameters and results of 1-O-isopropyl kinene using HBF4 as catalyst in Example 1

[0072]

[0073]

[0074] Note: b The isolated yield is the ratio of the total output of R and S configurations (in moles) to the raw material genipin (in moles). c1 H-NMR integral confirmed.

[0075] Example 2

[0076] according to Figure 5 Reaction process: 0.4 g (1.76 mmol) of genipin (GP), i-PrOH (5.28 mmol), fluoroboric acid (1.0-10.0 eq×1.76 mmol), boric acid (1.0-10.0 eq×1.76 mmol) and 20 mL of dichloromethane were added in sequence into a 50 mL round-bottom flask. After reacting for 10 h, the reaction system was poured into 50 mL of ice water for quenching, and extracted with dichloromethane (3×50 mL). The combined organic phase was washed with 100 mL of saturated brine until neutral, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography [V (ethyl acetate): V (petroleum ether) = 1:3] to obtain a pale white crystal as 1-O-isopropyl genipin. In Example 2, the molar ratio of GP:HBF4:H3BO3 and the reaction temperature are shown in Table 2, and the yield and S / R (i.e., the molar ratio of 1S-O-alkyl genipin derivatives and 1R-O-alkyl genipin derivatives) of the obtained 1-O-isopropyl genipin product are shown in Table 2.

[0077] Table 2 Synthesis parameters and results of 1-O-isopropyl genistein using a mixture of HBF4 and H3BO3 as a catalyst in Example 2

[0078]

[0079]

[0080] Note: b The isolated yield is the ratio of the total output of R and S configurations (in moles) to the raw material genipin (in moles). c1 H-NMR integral confirmed.

[0081] Example 3

[0082] according to Figure 6Reaction process: Add 10 mL of boron trifluoride etherate (BF3·Et2O) into a 25 mL round-bottom flask, slowly add a certain amount of distilled water (2 mL, 1 mL, 0.5 mL, 0.2 mL, 0.1 mL, 0.01 mL, respectively, based on the volume ratio), stir under ice bath for 0.5 h to obtain a mixture of boron trifluoride etherate and water, seal it, and set aside.

[0083] Genipin (GP) 0.4 g (1.76 mmol), i-PrOH (5.28 mmol), a mixture of boron trifluoride etherate and water were added to a 50 mL round-bottom flask in sequence, wherein boron trifluoride etherate (1.0-10.0 eq × 1.76 mmol, dichloromethane 20 mL, reacted for 10 h, poured the reaction system into 50 mL ice water to quench, extracted with dichloromethane (3 × 50 mL), and the combined organic phase was washed with saturated brine 100 mL until neutral, anhydrous Na2S After drying with O4, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography [V (ethyl acetate): V (petroleum ether) = 1:3] to obtain a pale white crystal as 1-O-isopropyl genipin. In Example 3, the volume ratio of H2O: BF3·Et2O, the molar ratio of GP: aqueous BF3·Et2O, and the reaction temperature are shown in Table 3, and the yield and S / R (i.e., the molar ratio of 1S-O-alkyl genipin derivative and 1R-O-alkyl genipin derivative) of the obtained 1-O-isopropyl genipin product are shown in Table 3.

[0084] Table 3 Synthesis parameters and results of 1-O-isopropyl genistein using a mixture of boron trifluoride etherate and water as a catalyst in Example 3

[0085]

[0086] Note: b The isolated yield is the ratio of the total output of R and S configurations (in moles) to the raw material genipin (in moles). c1 H-NMR integral confirmed.

[0087] Figure 7 Structural characterization data of 1R-O-isopropyl genipin prepared in Examples 1 to 3: 1R-O-isopropyl genipin: 1H NMR (CDCl3, 600MHz), δ:H NMR (CDCl3, 600MHz), δ: 1.19 (3H, d, J = 6.0Hz), 1.29 (3H, d, J = 6.0Hz,), 2.05-2.09 (1H, m), 2.38 (1H, t, J = 6.0Hz), 2.59 (1H, t, J = 7.8Hz), 2.87-2.91(1H,m),3.20(1H,q,J=8.4Hz),3.73(s,3H),4.08-4.13(1H,m),4.26(s,2H),4.61(1H,d,J=8.4Hz),5.82(1H,s),7.51(1H,s).

[0088] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A 1- O - A method for preparing an alkyl genipin derivative, characterized in that: The following steps are involved: Genipin, low-carbon alcohol, catalyst and polar organic solvent are mixed to carry out alkoxylation reaction to obtain 1- O - alkyl genipin derivatives; the catalyst is fluoroboric acid or a mixture of fluoroboric acid and boric acid or a mixture of boron trifluoride ether and water, and the polar organic solvent is one or more of dichloromethane, toluene and acetonitrile; When the catalyst is fluoroboric acid, the molar ratio of genipin to fluoroboric acid is 1:(1.5-3), and the temperature of the alkoxylation reaction is 60-80° C.; When the catalyst is a mixture of fluoroboric acid and boric acid, the molar ratio of genipin, fluoroboric acid and boric acid is 1:(1.5-6):1.5, and the temperature of the alkoxylation reaction is rt-45°C; When the catalyst is a mixture of boron trifluoride ethyl ether and water, the molar ratio of the mixture of boron trifluoride ethyl ether and water to genipin is 1.5:1, the volume ratio of water to boron trifluoride ethyl ether is 1:(5~100), and the temperature of the alkoxylation reaction is rt~80°C.

2. The preparation method according to claim 1, characterized in that: The alkoxylation reaction time is 6 to 10 hours.

3. The preparation method according to claim 1, characterized in that: The molar ratio of genipin to low-carbon alcohol is 1:(1.0-6.0).

4. The preparation method according to claim 1, characterized in that: The polar organic solvent is one or more of dichloromethane, toluene and acetonitrile.

5. The preparation method according to claim 1, characterized in that: 1- O -Alkyl genipin derivatives including 1R- O -Alkyl genipin derivatives and 1S- O -Alkyl genipin derivatives; When the catalyst is fluoroboric acid, the 1R- O -Alkyl genipin derivatives and 1S- O -The molar ratio of the alkyl genipin derivative is 100:(7-9); When the catalyst is a mixture of fluoroboric acid and boric acid, the 1R- O -Alkyl genipin derivatives and 1S- O -The molar ratio of the alkyl genipin derivative is 100:(8-9); When the catalyst is a mixture of boron trifluoride etherate and water, the 1R- O -Alkyl genipin derivatives and 1S- O -alkyl genipin derivatives in a molar ratio of 100:(3~9).

6. The preparation method according to claim 1, characterized in that: The alkoxylation reaction yields 1- O - alkyl genipin derivative crude product; also comprising the step of: O The crude product of -alkyl genipin derivative was purified by column chromatography to obtain 1- O -pure product of alkyl genipin derivative; the eluent for column chromatography purification is ethyl acetate and petroleum ether; the volume ratio of ethyl acetate and petroleum ether is 1:3.

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