A Simple Method for Synthesizing Coenzyme Q10

Abstract

The present invention discloses a method for simply synthesizing coenzyme Q 10 . This method uses coenzyme Q0 and decaprenol as raw materials, and under the catalysis of Hantzsch ester and Lewis acid, a coupling reaction occurs at room temperature to obtain coenzyme Q 10 in one-step reaction. The operation of the present invention is simple, the product is easy to purify, the yield is high, the reaction conditions are mild, the production process is safe and controllable, and it has the value of industrial production.

Description

Technical Field

[0001] The present invention relates to the field of organic drug synthesis, and particularly relates to a simple preparation method of coenzyme Q 10 . Background Art

[0002] Coenzyme Q10 is used as a drug for the prevention and treatment of cardiovascular diseases, and has certain curative effects on viral hepatitis, acute cancer, scurvy, duodenal ulcer, emphysema, etc. Due to its functions of improving human immunity and enhancing antioxidant capacity, it is also widely used in health products and cosmetics. Since coenzyme Q10 has no toxic and side effects and is very safe to use, it has a very large international and domestic market.

[0003] The production methods of coenzyme Q10 mainly include chemical synthesis method, microbial fermentation method and extraction method from animal and plant tissues. Among them, the microbial fermentation method has the advantages of high process stability, easy large-scale production, simple operation, high biological activity of products and easy absorption, and is currently the research focus of coenzyme Q10 production. However, the crude extract of coenzyme Q10 mainly contains coenzyme Q homologues with different numbers of isoprenyl units on the side chain, which are very similar in properties to coenzyme Q10. It is difficult to separate them by techniques such as silica gel column chromatography and recrystallization, with large solvent consumption, long time consumption and low efficiency.

[0004] The chemical synthesis method of coenzyme Q can be further divided into semi-synthesis and total synthesis methods. The synthesis of coenzyme Q mainly uses the semi-synthesis method, and the synthesis work is basically carried out around the synthesis of the quinone nucleus, the construction and modification of the side chain, and the research on the connection method between the two. In 1959, Ruegg R et al. proposed to extend the chain with solanesol to increase an isoprenyl unit to transform into decaprenyl (primary) alcohol, and then carry out a Friedel-Crafts reaction with 2,3-dimethoxy-5-methyl-1,4-hydroquinone under the catalysis of Lewis acid to introduce this side chain, and then oxidize to obtain CoQ10. This route represents a most classic semi-synthesis strategy of CoQ10, and then West DD, Nuruta, Terao Shinji, Yoshizawa Toyokichi, etc. all further improved this route, but the improved routes of coenzyme Q10 reported all have the characteristics of cumbersome reaction steps, expensive and large amount of catalysts, poor reaction stereoselectivity and low yield. (Li Quan, Gu Kun, Cheng Xiaohong. Research progress on the synthesis method of coenzyme Q10[J]. Chinese Journal of Synthetic Chemistry, 2007, 73(03):266-269.).

[0005] Therefore, there is currently no simple and efficient one-step preparation method for synthesizing coenzyme Q10 on the market. Summary of the Invention

[0006] 1. Problems to be Solved by the Invention:

[0007] The object of the present invention is to fill the defects of the prior art and provide a preparation method for the one-step synthesis of coenzyme Q10.

[0008] 2. Solution to the problem:

[0009] The technical solution adopted by the present invention is as follows: As shown in Formula 1, using coenzyme Q0 and decaprenol as raw materials, under nitrogen protection, after reacting at room temperature for about 2 hours, Hantzsch ester and Lewis acid are added for catalysis. After the reaction is complete, the crude product is extracted and subjected to silica gel column chromatography to obtain a single product, coenzyme Q10. The reaction formula is as follows:

[0010] Formula 1.

[0011] The crude product is extracted three times with dichloromethane and saturated brine solution. Then, the organic phase is dried with anhydrous sodium sulfate and filtered. Finally, pure coenzyme Q10 is obtained through silica gel column chromatography;

[0012] The organic solvent for the reaction is any one of dichloromethane, methanol, ethanol, DMF, DMSO, THF, acetone, 1,4-dioxane, and acetonitrile. The preferred organic solvent is dichloromethane;

[0013] The Hantzsch ester is diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, one of the 1,4-dihydropyridine derivatives;

[0014] The Lewis acid can be any one of boron trifluoride diethyl etherate, aluminum trichloride, ferric trichloride, boron trichloride, indium chloride, copper trifluoromethanesulfonate, titanium tetrachloride, scandium trifluoromethanesulfonate, etc.

[0015] The reaction conditions are carried out under nitrogen protection;

[0016] The molar ratio of the reaction raw materials coenzyme Q0 and Hantzsch ester is 1:0.1, and the molar ratio of coenzyme Q0 to decaprenol is 1:1;

[0017] The reaction temperature is room temperature;

[0018] The yield of coenzyme Q10 prepared by the present invention can reach 95%.

[0019] 3. Effects of the invention

[0020] Compared with the prior art, the present invention can rapidly synthesize coenzyme Q10 in one step, with simple steps, low cost, small loss rate, a yield that can reach 95%, strong competitiveness, and no toxic or harmful waste gas or residue generated during the whole reaction process, making it suitable for industrial-scale production. Description of the drawings

[0021] Figure 1 This is the HPLC chromatogram of coenzyme Q10 prepared in Example 1 of the present invention. Detailed implementation manners

[0022] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. However, it should be understood that these embodiments are only used for more detailed and specific description, and should not be construed as limiting the present invention in any form.

[0023] Example 1

[0024] Formula 2.

[0025] Weigh coenzyme Q0 (9.1 g, 0.05 mol) and dipicolinate (0.005 mol) into a 500 mL round-bottom flask, then add 80 mL of ethyl acetate and 1,4-dioxane (1:1) as the solvent, stir at room temperature. After the solution color gradually changes from orange-red to light red, add decaprenol (0.05 mol). Under nitrogen protection, add about 30 mL of boron trifluoride diethyl ether solution to the flask, gradually heat up to 50 °C, and the reaction solution slowly changes from colorless to brown-red. Continue the reaction and monitor the reaction process with TLC. After the reaction is complete, add about 50 mL of saturated ammonium chloride solution to quench the reaction. Pour the reaction solution into a separatory funnel, extract and wash it three times with 1,2-dichloroethane and saturated NaCl aqueous solution. Finally, dry the organic phase with anhydrous sodium sulfate and filter. Concentrate the filtrate to recover 1,2-dichloroethane, and cool and crystallize to obtain the crude product. Recrystallize with toluene to obtain orange-yellow crystal powder of coenzyme Q10. Melting point: 50 - 51 °C. 1 HNMR(400 MHz, CDCl3): δ1.56 - 1.60(m,27H), δ1.68(s, 3H), δ1.74(s, 3H), δ2.02(s, 3H), δ1.96 - 2.10(m, 29H), δ3.19(d,2H), δ3.98(s, 3H), δ4.00(s, 3H), δ5.08 - 5.13(d, 9H).

[0026] Formula 3.

[0027] Example 2: Weigh coenzyme Q0 (1.82 g, 0.01 mol) and dipicolinate (0.001 mol) separately into a 100 mL round-bottom flask, and then add 30 mL of dichloromethane as a solvent. The color of the solution changes from colorless to orange-red. After the reaction proceeds for about 1 h, add decaprenol (0.01 mol). After the addition, add scandium trifluoromethanesulfonate (0.001 mol) to the flask, and the reaction solution changes from red-orange to light yellow. Monitor the reaction by TLC. After the reaction is complete, stop the reaction. Pour the reaction solution into a separatory funnel, extract it three times with 50 mL of dichloromethane, then combine the organic layers and wash with saturated NaCl aqueous solution. Dry the organic phase with anhydrous Na2SO4, finally filter, rotary evaporate, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain orange-red coenzyme Q10. The yield is 95%, an orange-red solid, and the melting point is 49 - 50 °C. 1 HNMR(400 MHz, CDCl3): δ1.56 - 1.60(m, 27H), δ1.68(s, 3H), δ1.74(s, 3H), δ2.02(s, 3H), δ1.96 - 2.10(m, 29H), δ3.19(d, 2H), δ3.98(s, 3H), δ4.00(s, 3H), δ5.08 - 5.13(d, 9H).

Claims

1. A new method for synthesizing coenzyme Q10, characterized in that: Using coenzyme Q0 and decaprenol as raw materials, 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester as the Hantzsch ester, and a Lewis acid as the catalyst, coenzyme Q10 is synthesized in one step at room temperature. The reaction formula is as follows: 。 2. The method according to claim 1, wherein: The Lewis acid is boron trifluoride diethyl ether, aluminum trichloride, iron trichloride, indium chloride, copper trifluoromethanesulfonate, titanium tetrachloride or scandium trifluoromethanesulfonate.

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