A method for preparing dimethyl curcumin

Abstract

The invention provides a method for preparing dimethyl curcumin, comprising steps: 1) acetylacetone and boron oxide react in isopropyl acetate to obtain acetylacetone boron complex; 2) acetylacetone boron complex, veracrucal and tributyl borate react in dimethylacetamide or N-methylpyrrolidone in the presence of an organic base catalyst, after the reaction is terminated, the reaction is quenched with aqueous hydrochloric acid solution, then water is added for crystallization, and dimethyl curcumin is obtained; wherein the molar ratio of hydrochloric acid to organic weak base is (1-2): 1; the amount of water added is 1-3 times of the volume of the reaction solution. The method of the present invention is simple to operate, short in reaction time, convenient for post-processing, high in product yield and purity, environmentally friendly, and suitable for industrialized large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing dimethyl curcumin. Background Art

[0002] Cancer is an important disease threatening human health in today's society. Currently, many drugs for treating cancer have been developed. In the prior art, many natural and synthetic curcumin analogs show anticancer activity against many cancer cell types, but most of these curcumin analogs exert their anticancer activity through cytotoxic effects.

[0003] Dimethylcurcumin (ASC-J9) is a curcuminoid derivative that can effectively inhibit the growth of prostate tumor cells. ASC-J9 selectively promotes AR degradation by destroying the interaction between AR and selective AR coordinators such as AR-associated protein 55 (ARA55) and AR-associated protein 70 (ARA70). In addition, ASC-J9 has a good inhibitory effect on the proliferation of colorectal cancer, estrogen-dependent breast cancer cells, and liver cancer cells, and has good clinical application prospects.

[0004] At present, there have been reports on the synthesis process of ASC-J9, including conventional chemical methods and microwave-assisted methods. Generally, the microwave-assisted method has a short reaction time, few by-products, is environmentally friendly, and produces less waste liquid. However, the industrialization of the microwave-assisted method is not yet mature and is not suitable for industrial production. Compared with the microwave-assisted method, the conventional chemical method has more prospects for industrial production. The conventional chemical synthesis process of ASC-J9 is shown in Route I and Route II.

[0005] Route I (QIU X, et al. Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors. Bioorganic & Medicinal Chemistry, 2008, 16 (17): 8035-41. DOI: 10.1016 / j.bmc.2008.07.054): Acetylacetone and boron oxide are used as starting materials, ethyl acetate is used as solvent, and the boron complex is prepared by reacting at 70°C for 3 hours, removing the solvent ethyl acetate and washing with n-hexane. The obtained white solid, veracrucal aldehyde and tributyl borate are dissolved in ethyl acetate, stirred at 70°C for 30 minutes, and then the catalyst n-butylamine is added dropwise within 1 hour, and stirred at the same temperature for 24 hours. Finally, the pH is adjusted to 5 with 1N HCl, stirred at 60°C for 30 minutes, and the layers are separated. The organic phase is collected, concentrated, and then recrystallized from ethyl acetate to obtain the product. This route has a long reaction time and a complicated post-treatment, which will increase the production cost and is not conducive to industrial production.

[0006]

[0007] Route II (SOMSAKEESIT LO, et.al. Influence of side-chain changes on histone deacetylase inhibitory and cytotoxicity activities of curcuminoid derivatives. Bioorganic & Medicinal Chemistry Letters, 2020, 30 (11). 127171, DOI: 10.1016 / j.bmcl.2020.127171) uses curcumin as raw material and tetrahydrofuran as solvent, adds potassium carbonate and stirs for 10 minutes, then adds potassium iodide, and refluxes and stirs for 3-5 hours to prepare dimethyl curcumin. Route II is simple to operate, but the yield is not high, and a variety of by-products will be produced. Purification is relatively difficult and is not suitable for industrial production.

[0008]

[0009] With the deepening of research on dimethyl curcumin (ASC-J9), a method for preparing dimethyl curcumin with high yield, low cost, simple operation and suitable for industrial production is urgently needed. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing dimethyl curcumin, which has the advantages of simple operation, short reaction time, convenient post-treatment, high yield and is suitable for industrial production.

[0011] In order to achieve the purpose, the present invention provides a method for preparing dimethyl curcumin, comprising the steps of:

[0012] 1) Acetylacetone reacts with boron oxide in a solvent to obtain an acetylacetone boron complex;

[0013] 2) reacting acetylacetone boron complex, veracraldehyde and tributyl borate in a solvent in the presence of an organic base catalyst to obtain dimethyl curcumin;

[0014] The reaction formula is as follows:

[0015]

[0016] Wherein, the solvent of step 1) is isopropyl acetate or ethyl acetate; the solvent of step 2) is one of N,N-dimethylacetamide (DMA) or N-methylpyrrolidone (NMP).

[0017] In some embodiments, in step 1), the molar ratio of acetylacetone to boron oxide is 1:0.7 to 1.0, preferably 1:0.7.

[0018] In some embodiments, in step 2), the organic base catalyst is selected from organic weak base reagents, such as n-butylamine, triethylamine, benzylamine, etc., preferably n-butylamine. The molar ratio of acetylacetone to the organic weak base is 1:0.1-0.3; preferably 1:0.2.

[0019] In some embodiments, the reaction temperature of step 1) is 70-80°C.

[0020] In some embodiments, the reaction temperature of step 2) is 70-100°C, preferably 75-90°C, more preferably 80-90°C.

[0021] In some embodiments, in step 2), after the reaction is completed, the reaction is quenched with aqueous hydrochloric acid solution, and then water is added for crystallization to obtain dimethyl curcumin; wherein the molar ratio of hydrochloric acid to the organic weak base is (1-2):1, preferably 1.5:1; and the amount of water added is 1-3 times the volume of the reaction solution, preferably 2 times.

[0022] In some embodiments, seed crystals are preferably added during the crystallization process in step 2).

[0023] In some embodiments, step 2) optionally includes a recrystallization step. The recrystallization solvent can be selected from a mixed solvent of N,N-dimethylacetamide (DMA) / water, a mixed solvent of N,N-dimethylformamide (DMF) / water, a mixed solvent of N,N-dimethylformamide / dichloromethane, and one of ethyl acetate, preferably a mixed solvent of DMA / water.

[0024] In some embodiments, the volume ratio of DMA to water is 1:1-2, such as 1:1.2, 1:1.5, 1:1.7. The weight volume ratio of the crude product to the recrystallization solvent can be 1 g: (2-5) mL.

[0025] In a specific embodiment, the present invention provides a method for preparing dimethyl curcumin, comprising the following steps:

[0026]

[0027] The method comprises one or more of the following features:

[0028] Step 1) Acetylacetone reacts with boron oxide in isopropyl acetate to obtain an acetylacetone boron complex;

[0029] Step 2) reacting the acetylacetone boron complex, veracrucal aldehyde and tributyl borate in the presence of a base catalyst in N,N-dimethylacetamide or N-methylpyrrolidone to obtain dimethylcurcumin;

[0030] In step 1), the reaction temperature is 70-80°C,

[0031] In step 1), the molar ratio of acetylacetone to boron oxide is 1:0.7 to 1.0, preferably 1:0.7;

[0032] In step 2), the reaction temperature is 75 to 90°C, preferably 80 to 90°C;

[0033] In step 2), the base catalyst is n-butylamine; the molar ratio of acetylacetone to n-butylamine is 1:0.2;

[0034] In step 2), after the reaction is completed, the reaction is quenched with an aqueous hydrochloric acid solution, and then water is added for crystallization to obtain dimethyl curcumin; wherein the molar ratio of hydrochloric acid to n-butylamine is (1-2):1, preferably 1.5:1; and the amount of water added is about 2-3 times the volume of the reaction solution, preferably 2 times.

[0035] In step 2), seed crystals are optionally added during the crystallization process;

[0036] In step 2), a recrystallization step of dimethylcurcumin may be optionally included, wherein the recrystallization solvent is a mixed solvent of N,N-dimethylacetamide and water;

[0037] In step 2), preferably, the volume ratio of N,N-dimethylacetamide to water in the recrystallization solvent is 1:1.5.

[0038] The method of the present invention has the following beneficial effects:

[0039] 1) In step 1, isopropyl acetate is used as solvent, and the reaction conversion rate is high;

[0040] 2) In step 2, DMA or NMP is used as a solvent, which increases the solubility of the substrate and shortens the reaction time. At the same time, the post-treatment operation is simple, and no extraction, stratification, concentration and other steps are required. By screening and adjusting the amount of hydrochloric acid aqueous solution for reaction quenching and the amount of water used in the crystallization process, under optimal conditions, no recrystallization step is required, and a very high yield and product purity can be achieved, which is suitable for industrial production;

[0041] 3) Using a mixed solvent of N,N-dimethylacetamide and water as a recrystallization solvent can achieve a higher recrystallization yield, does not require additional solvents, and reduces the generation of impurities; and produces less waste liquid, is easy to handle, and is more environmentally friendly. DETAILED DESCRIPTION

[0042] The present invention is described in detail below by way of examples. It should be understood that the methods in the examples are for illustrative purposes only and do not constitute any limitation to the present invention. In the examples, the methods used are conventional methods unless otherwise specified and can be carried out under conventional conditions or under conditions recommended by the manufacturer. At the same time, in the examples, the materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Unless otherwise specified, in the present invention, the term "equivalent" refers to the amount of reagent corresponding to 1 equivalent of the raw material acetylacetone; the water volume multiple is based on the solvent volume of the reaction. The yield in the examples refers to the total yield of the two reaction steps.

[0043] Example 1 Preparation of dimethyl curcumin

[0044] Add acetylacetone (100.0 g, 1 mol) and isopropyl acetate (1000 mL) to the reaction flask, stir evenly at 70°C, add boron oxide (48.7 g, 0.7 mol) under stirring, and react at 70°C for 3 h. Stir the reaction solution and cool it to 25°C, filter to remove the solvent, wash the filter cake with petroleum ether, and drain to obtain 147.7 g of acetylacetone boron complex.

[0045] Veratraldehyde (332g, 2mol), tributyl borate (460g, 2mol), DMA (500mL) were added to the reaction bottle as solvent, stirred at 80°C for 30min, and after the system was dissolved, 147.7g of the acetylacetone boron complex obtained above was added under stirring, stirred for 10min, and then n-butylamine (14.6g, 0.2mol) was slowly added within 30min, and stirred at the same temperature for 3h. TLC monitoring reaction was completed. Preheated HCl (0.3mol) aqueous solution 108mL was added to the reaction solution, stirred at 60°C for 30min, water (1000mL, 2V) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3h, filtered, and yellow solid dimethyl curcumin 377.0g was obtained, with a yield of 95.1% and a purity of 98.6%.

[0046] 1 H NMR (400MHz, DMSO-d6) δ7.59(d,J=15.8Hz,2H),7.36(d,J=2.0Hz,2H),7.27(dd,J=8.4,2.0Hz,2H),7.0 2(d,J=8.4Hz,2H),6.84(d,J=15.9Hz,2H),6.12(s,1H),3.83(d,J=8.6Hz,12H).m / z(ESI+):397.1[M+H] + .

[0047] Example 2 Preparation of dimethyl curcumin

[0048] Step 1. Preparation of acetylacetonate boron complex

[0049] Add acetylacetone (10.0 g, 0.1 mol) and isopropyl acetate (100 mL) to the reaction flask, stir evenly at 70°C, add boron oxide (4.9 g, 0.07 mol) under stirring, and react at 70°C for 3 h. Stir the reaction solution and cool it to 25°C, filter to remove the solvent, wash the filter cake with petroleum ether, and dry to obtain 13.7 g of white solid acetylacetone boron complex.

[0050] Step 2. Preparation of dimethylcurcumin

[0051] Add veratraldehyde (33.2g, 0.2mol), tributyl borate (46.0g, 0.2mol), DMA (50mL) as solvent to the reaction bottle in sequence, stir at 80℃ for 30min, and after the system is dissolved, add 13.7g of acetylacetone boron complex obtained in step 1 under stirring, stir for 10min, then slowly add n-butylamine (1.46g, 0.02mol) within 30min, and stir at the same temperature for 3h. TLC monitors the completion of the reaction. Add 10mL of preheated HCl (0.02mol) aqueous solution to the reaction solution, stir at 60℃ for 30min, add water (100mL), add seed crystals, cool to room temperature, then crystallize in an ice-water bath for 3h, filter, and obtain 34.7g of orange powdery solid crude product, with a yield of 87.6% and a purity of 96.8%.

[0052] The obtained crude product was recrystallized with 80 mL of DMA / H2O=1:1.5 (v / v) system to obtain 32.5 g of yellow solid with a yield of 82.1% and a purity of 98.9%.

[0053] Example 3 Preparation of dimethyl curcumin

[0054] Step 1. Preparation of acetylacetonate boron complex

[0055] Add acetylacetone (10.0 g, 0.1 mol) and isopropyl acetate (100 mL) to the reaction flask, stir evenly at 70°C, add boron oxide (6.3 g, 0.09 mol) under stirring, and react at 70°C for 3 h. Stir the reaction solution to room temperature, filter to remove the solvent, wash the filter cake with petroleum ether, and dry to obtain 14.8 g of white solid acetylacetone boron complex.

[0056] Step 2. Preparation of dimethylcurcumin

[0057] Add veratraldehyde (33.2g, 0.2mol), tributyl borate (46.0g, 0.2mol), DMA (50mL) as solvent to the reaction bottle in sequence, stir at 80℃ until the system is dissolved, add 14.8g of acetylacetone boron complex obtained in step 1 under stirring, stir for 10min, then slowly add n-butylamine (1.46g, 0.02mol) within 30min, stir at the same temperature for 3h. TLC monitors the completion of the reaction. Add 12mL of preheated HCl (0.03mol) aqueous solution to the reaction solution, stir at 60℃ for 30min, add water (100mL), add seed crystals, cool to room temperature, then crystallize in an ice-water bath for 3h, filter, and obtain 37.1g of yellow powdery solid crude product, with a yield of 93.7% and a purity of 98.5%.

[0058] The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 (v / v) to obtain 36.1 g of a yellow solid product with a yield of 91.2% and a purity of 99.0%.

[0059] Example 4 Preparation of dimethyl curcumin

[0060] Step 1. Preparation of acetylacetonate boron complex

[0061] Add acetylacetone (100.0 g, 1.0 mol) and isopropyl acetate (1000 mL) to the reaction flask, stir evenly at 70°C, add boron oxide (48.7 g, 0.7 mol) under stirring, and react at 70°C for 3 h. Stir the reaction solution to room temperature, filter to remove the solvent, wash the filter cake with petroleum ether, and drain to obtain 130.0 g of acetylacetone boron complex.

[0062] Step 2. Preparation of dimethylcurcumin

[0063] Add veratraldehyde (33.2g, 0.2mol), tributyl borate (46.0g, 0.2mol), DMA (50mL) as solvent to the reaction bottle in sequence, stir at 80℃ for 30min, and after the system is dissolved, add 13.0g of acetylacetone boron complex obtained in step 1 under stirring, stir for 10min, then slowly add n-butylamine (1.46g, 0.02mol) within 30min, and stir at the same temperature for 3h. TLC monitors the completion of the reaction. Add 20mL of preheated HCl (0.04mol) aqueous solution to the reaction solution, stir at 60℃ for 30min, add water (100mL), add seed crystals, cool to room temperature, then crystallize in an ice-water bath for 3h, filter, and obtain 33.4g of orange powdery solid crude product, with a yield of 84.3% and a purity of 94.4%.

[0064] The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 (v / v) to obtain 32.7 g of a yellow solid with a yield of 82.6% and a purity of 99.0%.

[0065] Example 5 Preparation of dimethyl curcumin

[0066] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, stirred at 80 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 3 h. TLC monitored the completion of the reaction. 15 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (50 mL) was added, cooled to room temperature, crystallized in an ice-water bath for 5 h, and filtered to obtain 31.7 g of orange powdery solid crude product, with a yield of 80.0% and a purity of 96.8%.

[0067] The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 (v / v) to obtain 30.1 g of a yellow solid with a yield of 76.0% and a purity of 99.1%.

[0068] Example 6 Preparation of dimethyl curcumin

[0069] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, stirred at 80 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 3 h. TLC monitored the completion of the reaction. 15 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (150 mL) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, and 36.9 g of orange powdery solid crude product was obtained, with a yield of 93.2% and a purity of 92.9%.

[0070] The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 (v / v) to obtain 33.6 g of a yellow solid with a yield of 84.8% and a purity of 98.5%.

[0071] Example 7 Preparation of dimethyl curcumin

[0072] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, stirred at 90 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 3 h. TLC monitored the completion of the reaction. 12 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (100 mL) was added, cooled to room temperature, crystallized in an ice-water bath for 5 h, and filtered to obtain 36.1 g of orange powdery solid crude product, with a yield of 91.0% and a purity of 93.3%.

[0073] The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 (v / v) to obtain 33.0 g of a yellow solid with a yield of 83.3% and a purity of 98.7%.

[0074] Example 8 Preparation of dimethyl curcumin

[0075] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and NMP (50 mL) were added to the reaction bottle as solvents, stirred at 75 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 5 h. TLC monitoring showed that the reaction was nearly completed. 12 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (100 mL) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, and 33.6 g of dark reddish brown block solid crude product was obtained, with a yield of 84.8% and a purity of 94.6%.

[0076] The obtained crude product was recrystallized with 80 mL of a DMF / H2O=1:1.5 (v / v) mixed solvent to obtain 30.6 g of a yellow solid with a total yield of 77.3% and a purity of 98.5%.

[0077] Example 9 Preparation of dimethyl curcumin

[0078] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, stirred at 80 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 3 h. TLC monitoring of the reaction was complete. 15 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (25 mL) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, only a small amount of solid product was precipitated, and a large amount of product remained in the filtrate. The filtrate was extracted with ethyl acetate and dried to obtain 31.1 g of a dark brown oily crude product. The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 (v / v) to obtain 29.4 g of a yellow solid with a yield of 74.2% and a purity of 98.1%.

[0079] Example 10 Preparation of dimethyl curcumin

[0080] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, stirred at 80 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 3 h. TLC monitored the completion of the reaction. 15 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (300 mL) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, and 32.0 g of orange powdery solid crude product was obtained, with a yield of 80.8% and a purity of 86.2%.

[0081] The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 to obtain 26.7 g of a yellow solid with a yield of 67.4% and a purity of 97.7%.

[0082] Example 11 Preparation of dimethyl curcumin

[0083] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, stirred at 80 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, and stirred at the same temperature for 3 h. TLC monitored the completion of the reaction. 8 mL of preheated HCl (0.01 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (100 mL) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, and 12.9 g of a dark red solid crude product was obtained, with a yield of 32.7% and a purity of 94.3%.

[0084] Example 12 Preparation of dimethyl curcumin

[0085] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), and DMA (50 mL) were added to the reaction bottle as solvents, and stirred at 70 ° C. After the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, stirred at the same temperature for 3 h, and the reaction was not completed by TLC monitoring. Stirring was continued for 5 h, and the reaction was close to the end point by TLC monitoring. 15 mL of HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (150 mL) was added, and seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, and 34.8 g of orange solid crude product was obtained, with a yield of 87.9% and a purity of 94.1%.

[0086] The obtained crude product was recrystallized in 80 mL of a mixed solvent of DMA / H2O=1:1.5 to obtain 30.0 g of a yellow solid with a yield of 76.8% and a purity of 98.2%.

[0087] Example 13 Preparation of dimethyl curcumin

[0088] Veratraldehyde (33.2 g, 0.2 mol), tributyl borate (46.0 g, 0.2 mol), DMA (50 mL) were added to the reaction bottle as solvent, stirred at 100 ° C for 30 min, and after the system was dissolved, 13.0 g of the acetylacetone boron complex obtained in step 1 of Example 4 was added under stirring, stirred for 10 min, and then n-butylamine (1.46 g, 0.02 mol) was slowly added within 30 min, stirred at the same temperature for 3 h, and the reaction was completed by TLC monitoring. 12 mL of preheated HCl (0.03 mol) aqueous solution was added to the reaction solution, stirred at 60 ° C for 30 min, water (100 mL) was added, seed crystals were added, cooled to room temperature, and then crystallized in an ice-water bath for 3 h, filtered, and 35.8 g of dark reddish brown block solid crude product was obtained, with a yield of 90.4% and a purity of 73.3%. The obtained crude product was recrystallized with 80 mL of a mixed solvent of DMA / H2O=1:1.5 to obtain 24.7 g of a yellow solid with a yield of 62.4% and a purity of 98.1%.

[0089] Comparative Example 1 Preparation of dimethyl curcumin

[0090] Dimethyl curcumin was prepared by referring to the method for preparing curcumin in document 3 (Study on Synthesis Technology of Natural Product Curcumin, Chinese Journal of Traditional Chinese Medicine, 2011, 29(09):2101-3).

[0091] Acetylacetone (10.0 g, 0.1 mol), ethyl acetate (210 mL), and boric oxide (6.9 g, 1.0 mol) were added to a three-necked flask and stirred at 75°C for 30 min. The reaction solution was cooled to room temperature and the solvent was removed by filtration to obtain 14.4 g of a white solid.

[0092] Add veratraldehyde (33.2g, 0.2mol), tributyl borate (46.0g, 0.2mol) and dry DMF (50mL) to a three-necked flask, stir at 80℃ for 10min, add the solid obtained in step 1, and after the system is dissolved, add n-butylamine (4.3g, 0.06mol) dropwise within 1h. After the dropwise addition, stir at the same temperature for 3h. TLC monitors the reaction completion. Add 10%wt acetic acid aqueous solution (201.2g) preheated to 60℃ to the reaction solution to quench the reaction, stir at this temperature for 1h, cool and crystallize, filter, and obtain 22.9g of crude product, with a yield of 57.8% and a purity of about 83.4%. The crude product is recrystallized with 180mL of a mixed solvent of dichloromethane / methanol = 1:1 to obtain 19.6g of product, with a yield of 49.9% and a purity of 98.4%.

[0093] Comparative Example 2 Preparation of dimethyl curcumin

[0094] Take a 50mL three-necked flask, add acetylacetone (95mg, 0.95mmol), veratraldehyde (120mg, 0.72mmol), DMF (10mL), boron oxide (70mg, 1.05mmol) in sequence, and stir at 80℃ for 6h under nitrogen protection. Add 0.5N HCl (8mL) to quench the reaction, and let stand to precipitate the product. No product precipitated, and no product spot was observed by TLC monitoring. The results showed that under this condition, when DMF was used as the reaction solvent, the reaction could not proceed.

[0095] Comparative Example 3 Preparation of dimethyl curcumin

[0096] Dimethyl curcumin was prepared according to route I of the background art (QIU X, et al. Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors. Bioorganic & Medicinal Chemistry, 2008, 16 (17): 8035-41. DOI: 10.1016 / j.bmc.2008.07.054).

[0097] Boron oxide (1.74 g, 24.97 mmol), ethyl acetate (50 mL), and acetylacetone (5.00 g, 49.94 mmol) were added to the reactor in sequence, and stirred at 70° C. for 3 h. The mixture was filtered and the filter cake was washed with petroleum ether to obtain 6.1 g of boron complex.

[0098] The prepared boron complex, veratraldehyde (16.60g, 99.88mmol), tributyl borate (23.00g, 99.88mmol), and 100mL of ethyl acetate were added to the reactor as solvent, and stirred at 70°C to dissolve. After diluting n-butylamine (4.99mmol) with 2mL of ethyl acetate, add it to the system within 15min. After the addition, stir at the same temperature for 24h. Quench the reaction with 1N HCl aqueous solution, adjust the pH to 5, and stir at 60°C for 30min. Extract with ethyl acetate (100mL×3), spin dry, and recrystallize the crude oil with ethyl acetate to obtain 14.4g of light yellow solid, with a yield of 72.9% and a purity of 98.9%. This method has a long reaction time, and extraction, concentration and other steps are required after the reaction, which increases the difficulty of post-processing.

[0099] The method of the present invention can obtain a higher product yield by optimizing the solvent, temperature and post-treatment steps of the reaction, especially optimizing and screening the reaction conditions of step 2). The solvent is preferably DMA or NMP. The reaction temperature is preferably 75-90°C, more preferably 80-90°C; the reaction temperature is low and the reaction time is long; if the reaction temperature is too high, it may lead to an increase in side reactions, a low product yield and a reduced purity. In the post-treatment, an HCl aqueous solution is added to quench the reaction, and the amount of HCl is preferably 1-2 times the molar amount of the base catalyst, preferably 1.5 times the molar amount; based on acetylacetone, the volume weight ratio of the volume of the HCl aqueous solution to the volume of acetylacetone is about (0.8-1.5) mL: 1g; the volume of the subsequent water addition can be 1-3 times the volume of the reaction system (or the volume of the solvent), preferably 2 times; when the volume of water added is small, the purity of the crude product is high, but the yield is low; when the volume of water added is too much, the purity of the precipitated product is reduced, and the overall yield is also low. Under the preferred reaction conditions, the obtained product has a higher yield and can have a higher purity without the need for a recrystallization step. When the crude product is recrystallized as needed, the recrystallization solvent is preferably a mixed solvent of DMA and water, which does not produce additional impurities and has a high yield.

[0100] The method for preparing dimethyl curcumin provided by the invention has the advantages of simple operation, short reaction time, convenient post-treatment, high product purity, less waste liquid generation, environmental friendliness and being more suitable for large-scale industrial production.

[0101] The technical scheme of the present invention is described in detail through the above embodiments. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing dimethyl curcumin, comprising the steps of: ； in, In step 1, acetylacetone reacts with boron oxide in isopropyl acetate to obtain acetylacetone boron complex; In step 2, acetylacetone boron complex, veracrucal aldehyde and tributyl borate react in dimethylacetamide in the presence of a base catalyst to obtain dimethylcurcumin; In step 1, the reaction temperature is 70-80°C; In step 1, the molar ratio of acetylacetone to boron oxide is 1:0.7; In step 2, the reaction temperature is 80°C; In step 2, the base catalyst is n-butylamine; the molar ratio of acetylacetone to n-butylamine is 1:0.2; In step 2, after the reaction is completed, the reaction is quenched with an aqueous hydrochloric acid solution, and then water is added to crystallize to obtain dimethyl curcumin; wherein the molar ratio of hydrochloric acid to n-butylamine is 1.5:1; the amount of water added is twice the volume of the reaction solution; and seed crystals are added during the crystallization process.

2. the method for claim 1, wherein in step 2, comprises the recrystallization step of dimethylcurcumin, and the recrystallization solvent is a mixed solvent of N,N-dimethylacetamide and water.

3. The method of claim 2, wherein in step 2, the volume ratio of N,N-dimethylacetamide to water in the recrystallization solvent is 1:1.5.

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