Preparation process and application of idebenone

Abstract

The invention provides a preparation process and application of idebenone, and belongs to the technical field of organic chemistry. The purified 10-hydroxydecanoic acid is obtained through the kaolin composite catalyst, the idebenone is prepared on the basis of the purified 10-hydroxydecanoic acid, meanwhile, the preparation process is improved, the elution crystallization treatment is matched, the purity of the idebenone is effectively improved, the content of impurities in the idebenone is reduced, and the idebenone is applied to cosmetics.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and specifically relates to a preparation process of idebenone and application thereof. Background Art

[0002] Idebenone was originally developed and researched by Takeda Pharmaceutical Co., Ltd. of Japan. In the mid-1980s, Takeda Pharmaceutical first launched it on the market in Japan. It is a modern high-efficiency therapeutic drug that can activate the mitochondrial respiration in brain cells and has a good improvement effect on mental illness caused by slowed energy metabolism and fluctuations in brain function due to insufficient cerebral blood flow. It is also added to daily skin care products to remove free radicals in cells on the surface of the skin, effectively inhibit lipid peroxidation in cells, inhibit inflammation, DNA damage, etc., and reduce the aggregation of cytochromes.

[0003] A Chinese patent (publication number CN117064772A) provides a method for preparing supramolecular idebenone and its application, which discloses a method for preparing supramolecular idebenone with small particle size, good appearance transparency, high encapsulation rate, good stability and high skin retention using ionic liquid as polar phase and idebenone as core component; the preparation method disclosed in the invention uses green solvent, is environmentally friendly and pollution-free, has a simple process, and can be industrialized and mass-produced. At the same time, supramolecular idebenone has a certain antioxidant effect in free radical scavenging test, a certain anti-wrinkle and firming effect in in vitro fibroblast test, no skin irritation reaction in multiple skin irritation tests, can be applied to cosmetic essence lotion, has no allergic and irritating effect in patch test, and has a certain anti-wrinkle and firming effect in human efficacy test. However, the patent requires the addition of other components of ionic liquid to treat idebenone, while the idebenone produced by the prior art still has the problem of low purity, and the impurities contained will reduce its melting point, resulting in poor effect when used in the cosmetic field.

[0004] Therefore, there is an urgent need for a preparation process of idebenone. By improving the raw material preparation and the preparation process and coordinating the purification process, the purity of idebenone can be effectively improved and the content of impurities in idebenone can be reduced, thereby obtaining a higher melting point and enabling it to increase the moisture content of the skin stratum corneum when used in cosmetics. Summary of the invention

[0005] The purpose of the present invention is to provide a preparation process of idebenone and application thereof, wherein purified 10-hydroxydecanoic acid is obtained by using a kaolin composite catalyst, and idebenone is prepared based on the purified 10-hydroxydecanoic acid. Meanwhile, the preparation process is improved, and a dissolution crystallization treatment is performed to effectively improve the purity of idebenone, reduce the content of impurities in idebenone, and apply the idebenone in cosmetics.

[0006] In order to achieve the above object, the present invention provides the following technical solutions: The first aspect of the present invention provides a process for preparing idebenone, comprising the following steps: Step S1: in parts by weight, 20-25 parts of kaolin composite catalyst, 400-500 parts of sebacic acid, 8-10 parts of lithium hydroxide and 150-200 parts of deionized water are mixed evenly, and in a hydrogen atmosphere, the reaction pressure is controlled to be 2-3 MPa, the reaction temperature is 240-250° C., and the reaction is carried out for 2-4 hours. After the reaction is completed, the reaction is filtered, and the filter residue is washed and dried to obtain compound I purified 10-hydroxydecanoic acid; Step S2: In parts by weight, 20-25 parts of purified 10-hydroxydecanoic acid of compound I, 30-35 parts of acetic anhydride and 0.2-0.5 parts of p-toluenesulfonic acid are mixed uniformly, stirred at 45-50° C. for 3-4 hours, cooled to room temperature after the reaction, and then 100-110 parts of ice water are added and stirred for 1-2 hours, and then the reaction solution is extracted with 150-180 parts of dichloromethane at 0-2° C., and the organic phase obtained by extraction is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, and finally dried with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain compound II; Step S3: In parts by weight, under a nitrogen atmosphere, 24 to 26 parts of compound II are added dropwise to 37 to 40 parts of an acyl chloride reagent and mixed evenly, and then stirred for reaction at 55 to 60° C. for 6 to 8 hours. After the reaction is completed, the mixture is distilled and dried to obtain compound III; Step S4: In parts by weight, under a nitrogen atmosphere and 0-5° C., 26-28 parts of Lewis acid and 75-80 parts of dichloromethane are stirred for 1-2 hours, and then 24-26 parts of compound III, 25-30 parts of dichloromethane and 17-20 parts of 3,4,5-trimethoxytoluene are added, and the mixture is reacted at -8--10° C. for 3-4 hours, and then the temperature is raised to 10-12° C. and the reaction is continued for 12-14 hours. After the reaction is completed, compound IV is obtained; Step S5: In parts by weight, at 0-2° C., 42-44 parts of magnesium iodide and 100-110 parts of dichloromethane are mixed uniformly, and then 25-30 parts of compound IV are added, and the temperature is raised to 10-12° C. and the reaction is continued for 3-4 hours. After the reaction is completed, the mixture is extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound V; Step S6: In parts by weight, under a nitrogen atmosphere, 6-8 parts of methanol and 0.3-0.5 parts of sodium hydroxide are mixed uniformly, and then 3-5 parts of compound V and 12-14 parts of methanol are added, and the mixture is reacted at room temperature for 1-2 hours. After the reaction is completed, the mixture is extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound VI; Step S7: In parts by weight, 1-2 parts of perchloric acid and 18-19 parts of acetic acid are mixed uniformly, and then 0.2-0.4 parts of a catalyst are added, and the mixture is stirred for 1-2 hours under a hydrogen atmosphere, and then 2-4 parts of compound VI are added, and the mixture is stirred and reacted at 60-65° C. for 10-12 hours. After the reaction is completed, the catalyst is removed by filtration, and then washed with 5% sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure to obtain compound VII; Step S8: Preparation of Compound VIII: by weight, add 1-3 parts of Compound VII, 3-4 parts of cerium ammonium nitrate, and 6-8 parts of deionized water to 12-24 parts of acetonitrile, stir at 0-2°C for 3-4 hours, wash with water, extract with ethyl acetate, dry over anhydrous sodium sulfate overnight, and remove the solvent by distillation under reduced pressure to obtain Compound VIII; Step S9: In parts by weight, 0.8-0.9 parts of lithium hydroxide are added to 20-25 parts of methanol, stirred and dissolved, and then 5-8 parts of compound VIII are added, and the reaction is stirred at room temperature for 24-30 hours. After the reaction is completed, the solvent is removed by reduced pressure distillation, and then 10-20 parts of deionized water are added, and the pH is adjusted to 5.1-5.3 with 10% hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by reduced pressure distillation to obtain crude idebenone; Step S10: purifying the crude idebenone in step S9 to obtain purified idebenone.

[0007] The preparation process of the present invention uses oxalyl chloride instead of thionyl chloride to avoid the generation of sulfur-containing impurities or gases, while reducing the amount of aluminum chloride used, reducing the cost of post-treatment, and effectively improving the purity of idebenone; at the same time, the process can effectively avoid the introduction of impurities, and generally the higher the purity of a substance, the higher the melting point, so the idebenone obtained by the preparation process has a higher melting point.

[0008] As a preferred scheme, the preparation method of the kaolin composite catalyst described in step S1 includes: adding 10 to 20 parts of acidified kaolin, 6 to 8 parts of hexadecyltrimethylammonium bromide, 2 to 4 parts of palladium nitrate, 2 to 4 parts of ruthenium nitrate, and 1 to 3 parts of sodium hydroxide to 300 to 350 parts of deionized water, stirring at 60 to 65° C. for 2 to 3 hours, and then transferring to a microwave reactor for microwave treatment. After the microwave treatment is completed, cooling, filtering, washing, and drying are performed to obtain a kaolin composite catalyst.

[0009] As a preferred solution, in the microwave treatment, the microwave output power is 700-800 W, the reaction temperature is 100-110° C., and the reaction time is 1-2 h.

[0010] As a preferred scheme, the preparation method of the acidified kaolin comprises: by weight, calcining 100-120 parts of kaolin at 800-820°C for 2-3 hours, cooling to room temperature, adding 300-350 parts of 20% mass concentration sulfuric acid solution and soaking for 4-6 hours, and then filtering, washing and drying to obtain the acidified kaolin.

[0011] The kaolin composite catalyst treats the acidified kaolin with microwaves, and utilizes the thermal and non-thermal effects of microwaves to promote and accelerate the entry of palladium ions and ruthenium ions into the interlayers of kaolinite, destroy the hydrogen bonds between the interlayers of kaolinite, and then insert into the interlayers of kaolinite, thereby increasing the interlayer distance of kaolinite, thereby increasing the specific surface area, increasing the porosity, and increasing the catalytic reaction rate, thereby realizing the preparation of purified 10-hydroxydecanoic acid, which is beneficial to improving the purity of subsequent idebenone.

[0012] As a preferred solution, the acyl chloride reagent in step S3 is oxalyl chloride.

[0013] As a preferred solution, the Lewis acid in step S4 is boron trifluoride.

[0014] As a preferred solution, the catalyst in step S7 is a palladium / carbon catalyst.

[0015] As a preferred solution, the purification treatment in step S10 includes: adding 13 to 19 parts of crude idebenone to 100 to 105 parts of dichloromethane by weight, stirring until the solid is completely dissolved, filtering, and transferring the filtrate to a crystallizer; adding 19 to 24 parts of n-hexane to the filtrate for dissolution and crystallization to obtain a solid-liquid mixture and vacuum filtering, washing the filter cake with n-hexane 2 to 3 times, and then vacuum drying to obtain purified idebenone.

[0016] As a preferred solution, the temperature of the dissolution crystallization is 0-5°C.

[0017] Impurities are dissolved in the solvent to the maximum extent through the dissolution crystallization method, and the purified idebenone is crystallized from the solvent. Dissolution crystallization can well control the content of impurities and achieve the purpose of purification and separation, thereby effectively improving the purity of idebenone. At the same time, since the idebenone after dissolution crystallization has fewer impurities, and impurities may cause the degradation or failure of the ingredients in the cream, low-impurity idebenone can effectively increase the moisture content of the skin's stratum corneum.

[0018] The second aspect of the present invention provides a use of idebenone prepared by the process described in the first aspect in cosmetics.

[0019] Compared with the prior art, the advantages and beneficial effects of the present invention are: 1. The preparation process of the present invention uses oxalyl chloride instead of thionyl chloride to avoid the generation of sulfur-containing impurities or gases, while reducing the amount of aluminum chloride used, reducing the cost of post-treatment, and effectively improving the purity of idebenone; at the same time, the process can effectively avoid the introduction of impurities, and the higher the purity of a general substance, the higher the melting point, so the idebenone obtained by the preparation process has a higher melting point.

[0020] 2. The kaolin composite catalyst of the present invention can promote and accelerate the entry of palladium ions and ruthenium ions into the interlayer of kaolinite by subjecting the acidified kaolin to microwave treatment and utilizing the thermal effect and non-thermal effect of microwaves, thereby destroying the hydrogen bonds between the interlayers of kaolinite and inserting the palladium ions and ruthenium ions into the interlayers of kaolinite, thereby increasing the interlayer distance of kaolinite, thereby increasing the specific surface area, increasing the porosity, and increasing the catalytic reaction rate, thereby realizing the preparation of purified 10-hydroxydecanoic acid, which is beneficial to improving the purity of subsequent idebenone.

[0021] 3. The present invention dissolves impurities in the solvent to the maximum extent through the method of dissolution crystallization, and the purified idebenone is crystallized from the solvent. The dissolution crystallization can well control the content of impurities to achieve the purpose of purification and separation, thereby effectively improving the purity of idebenone; at the same time, since the idebenone after dissolution crystallization has fewer impurities, and impurities may cause the degradation or failure of the ingredients in the cream, the low-impurity idebenone can effectively increase the moisture content of the stratum corneum of the skin. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the HPLC spectrum of idebenone. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] The sources of some components in the embodiments and comparative examples are as follows: Commercially available 10-hydroxydecanoic acid, CAS No. 1679-53-4, purity ≥96%, was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Commercially available idebenone, CAS number 58186-27-9, purity ≥98%, was purchased from Shanghai Chuangsai Technology Co., Ltd.; Kaolin, item number C-08, was purchased from Hengchang Mineral Products Processing Plant, Lingshou County; Sulfuric acid, CAS No. 7664-93-9, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Hexadecyltrimethylammonium bromide, CAS No. 57-09-0, was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Palladium nitrate, CAS No. 10102-05-3, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Ruthenium nitrate, CAS No. 34513-98-9, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Sodium hydroxide, CAS No. 1310-73-2, was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Sebacic acid, CAS No. 111-20-6, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Lithium hydroxide, CAS No. 1310-65-2, was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Acetic anhydride, CAS No. 108-24-7, was purchased from Sinopharm Chemical Reagent Co., Ltd.; p-Toluenesulfonic acid, product number 2585, was purchased from Weifang Shunfuyuan Chemical Co., Ltd.; Dichloromethane, CAS No. 75-09-2, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Sodium bicarbonate, CAS No. 144-55-8, was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; Sodium chloride, CAS No. 7647-14-5, was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; Anhydrous sodium sulfate, CAS No. 7757-82-6, was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; Oxalyl chloride, CAS No. 79-37-8, was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; Boron trifluoride, CAS No. 7637-07-2, was purchased from Sinopharm Chemical Reagent Co., Ltd.; 3,4,5-Trimethoxytoluene, CAS No. 6443-69-2, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Magnesium iodide, CAS No. 7790-32-1, was purchased from Shanghai Chuangsai Technology Co., Ltd.; Methanol, CAS No. 67-56-1, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Cerium ammonium nitrate, CAS No. 16774-21-3, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Acetonitrile, CAS No. 75-05-8, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Ethyl acetate, CAS No. 141-78-6, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Hydrochloric acid, CAS No. 7647-01-0, was purchased from Sinopharm Chemical Reagent Co., Ltd.; n-Hexane, CAS No. 110-54-3, was purchased from Sinopharm Chemical Reagent Co., Ltd.; Polyethylene glycol, product number 20240201, was purchased from Jiangxi Yipsheng Pharmaceutical Co., Ltd.; Sucrose stearate, CAS No. 25168-73-4, purchased from Wuhan Fengzhulin Chemical Technology Co., Ltd.; Stearyl alcohol, CAS No. 112-92-5, purchased from Jinan Century Tongda Chemical Co., Ltd.; Glyceryl monostearate, CAS No. 31566-31-1, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Jojoba oil, CAS No. 61789-91-1, was purchased from Nantong Runfeng Petrochemical Co., Ltd.; Glycerol, CAS No. 56-81-5, was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; 1,2-Propanediol, CAS No. 57-55-6, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Triethanolamine, CAS No. 102-71-6, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Carbomer 2020, CAS No. 176429-87-1, was purchased from Zhongshan Dixin Chemical Co., Ltd.

[0025] Example 1 This embodiment provides a preparation process of idebenone, comprising the following steps: Preparation of kaolin composite catalyst: (1) By weight, 120 parts of kaolin were calcined at 820°C for 2 hours, cooled to room temperature, added with 350 parts of 20% sulfuric acid solution and immersed for 6 hours, then filtered, washed and dried to obtain acidified kaolin. (2) By weight, 20 parts of acidified kaolin, 8 parts of hexadecyltrimethylammonium bromide, 4 parts of palladium nitrate, 4 parts of ruthenium nitrate and 3 parts of sodium hydroxide were added to 350 parts of deionized water, stirred at 65°C for 2 hours, then transferred to a microwave reactor for microwave treatment (microwave output power of 800 W, reaction temperature of 110°C and reaction time of 1 hour), cooled, filtered, washed and dried after microwave treatment to obtain a kaolin composite catalyst.

[0026] Step S1: in parts by weight, 25 parts of kaolin composite catalyst, 500 parts of sebacic acid, 10 parts of lithium hydroxide and 200 parts of deionized water are mixed evenly, and the reaction pressure is controlled to be 3MPa and the reaction temperature is 250°C under a hydrogen atmosphere for 2h. After the reaction is completed, the mixture is filtered, and the filter residue is washed and dried to obtain compound I purified 10-hydroxydecanoic acid; Step S2: In parts by weight, 25 parts of purified 10-hydroxydecanoic acid of compound I, 35 parts of acetic anhydride and 0.5 parts of p-toluenesulfonic acid were mixed evenly, stirred at 50° C. for 3 hours, cooled to room temperature after the reaction, and then 110 parts of ice water were added and stirred for 2 hours, and then the reaction solution was extracted with 180 parts of dichloromethane at 2° C., and the organic phase obtained by extraction was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, and finally dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound II; Step S3: In parts by weight, under a nitrogen atmosphere, 26 parts of compound II were added dropwise to 40 parts of oxalyl chloride and mixed evenly, and then stirred at 60° C. for 6 h. After the reaction was completed, the mixture was distilled and dried to obtain compound III; Step S4: In parts by weight, under a nitrogen atmosphere and 5° C., 28 parts of boron trifluoride and 80 parts of dichloromethane were stirred for 1 h, and then 26 parts of compound III, 30 parts of dichloromethane and 20 parts of 3,4,5-trimethoxytoluene were added, and the mixture was reacted at -10° C. for 4 h, and then the temperature was raised to 12° C. and the reaction was continued for 12 h. After the reaction, compound IV was obtained; Step S5: In parts by weight, at 2° C., 44 parts of magnesium iodide and 110 parts of dichloromethane were mixed evenly, and then 30 parts of compound IV were added, and the temperature was raised to 12° C. and the reaction was continued for 3 hours. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound V; Step S6: In parts by weight, under a nitrogen atmosphere, 8 parts of methanol and 0.5 parts of sodium hydroxide were mixed evenly, and then 5 parts of compound V and 14 parts of methanol were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound VI; Step S7: In parts by weight, 2 parts of perchloric acid and 19 parts of acetic acid were mixed evenly, and then 0.4 parts of palladium / carbon catalyst were added, and the mixture was stirred for 2 hours under a hydrogen atmosphere, and then 4 parts of compound VI were added, and the mixture was stirred and reacted at 65° C. for 12 hours. After the reaction was completed, the catalyst was filtered out, and then washed with 5% sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain compound VII; Step S8: Preparation of Compound VIII: by weight, 3 parts of Compound VII, 4 parts of cerium ammonium nitrate, and 8 parts of deionized water were added to 24 parts of acetonitrile, stirred at 2°C for 4 hours, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate overnight, and distilled under reduced pressure to remove the solvent to obtain Compound VIII; Step S9: In parts by weight, 0.9 parts of lithium hydroxide are added to 25 parts of methanol and stirred to dissolve, and then 8 parts of compound VIII are added, and the reaction is stirred for 30 hours at room temperature. After the reaction is completed, the solvent is removed by distillation under reduced pressure, and then 20 parts of deionized water are added, and the pH is adjusted to 5.3 with 10% hydrochloric acid by mass concentration, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure to obtain crude idebenone; Step S10: Purify the crude idebenone in step S9, wherein the purification process is as follows: by weight, add 19 parts of crude idebenone to 105 parts of dichloromethane, stir until the solid is completely dissolved, filter, and transfer the filtrate to a crystallizer; dropwise add 24 parts of n-hexane to the filtrate for dissolution and crystallization (temperature is 5° C.), obtain a solid-liquid mixture and perform vacuum filtration, wash the filter cake 3 times with n-hexane, and then vacuum dry to obtain purified idebenone.

[0027] Example 2 This embodiment provides a preparation process of idebenone, comprising the following steps: Preparation of kaolin composite catalyst: (1) By weight, 100 parts of kaolin were calcined at 800°C for 3 hours, cooled to room temperature, added with 300 parts of 20% sulfuric acid solution and immersed for 4 hours, then filtered, washed and dried to obtain acidified kaolin. (2) By weight, 10 parts of acidified kaolin, 6 parts of hexadecyltrimethylammonium bromide, 2 parts of palladium nitrate, 2 parts of ruthenium nitrate and 1 part of sodium hydroxide were added to 300 parts of deionized water, stirred at 60°C for 2 hours, then transferred to a microwave reactor for microwave treatment (microwave output power of 700 W, reaction temperature of 100°C and reaction time of 2 hours), cooled, filtered, washed and dried after microwave treatment to obtain a kaolin composite catalyst.

[0028] Step S1: in parts by weight, 20 parts of kaolin composite catalyst, 400 parts of sebacic acid, 8 parts of lithium hydroxide and 150 parts of deionized water are mixed evenly, and the reaction pressure is controlled to be 2MPa and the reaction temperature is 240°C under a hydrogen atmosphere for 2h. After the reaction is completed, the reaction is filtered, and the filter residue is washed and dried to obtain compound I purified 10-hydroxydecanoic acid; Step S2: In parts by weight, 20 parts of purified 10-hydroxydecanoic acid of compound I, 30 parts of acetic anhydride and 0.2 parts of p-toluenesulfonic acid were mixed evenly, stirred at 45°C for 3 hours, cooled to room temperature after the reaction, and then 100 parts of ice water were added and stirred for 1 hour, and then the reaction solution was extracted with 150 parts of dichloromethane at 0°C, and the organic phase obtained by extraction was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, and finally dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound II; Step S3: In parts by weight, under a nitrogen atmosphere, 24 parts of compound II were added dropwise to 37 parts of oxalyl chloride and mixed evenly, and then stirred at 55° C. for 6 hours. After the reaction was completed, the mixture was distilled and dried to obtain compound III; Step S4: In parts by weight, under a nitrogen atmosphere and 0°C, 26 parts of boron trifluoride and 75 parts of dichloromethane were stirred for 1 hour, and then 24 parts of compound III, 25 parts of dichloromethane and 17 parts of 3,4,5-trimethoxytoluene were added, and the mixture was reacted at -8°C for 3 hours, and then the temperature was raised to 10°C and the reaction was continued for 14 hours. After the reaction, compound IV was obtained; Step S5: In parts by weight, at 0°C, 42 parts of magnesium iodide and 100 parts of dichloromethane were mixed evenly, and then 25 parts of compound IV were added, and the temperature was raised to 10°C and the reaction was continued for 3 hours. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound V; Step S6: In parts by weight, under a nitrogen atmosphere, 6 parts of methanol and 0.3 parts of sodium hydroxide were mixed evenly, and then 3 parts of compound V and 12 parts of methanol were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound VI; Step S7: In parts by weight, 1 part of perchloric acid and 18 parts of acetic acid were mixed evenly, and then 0.2 parts of palladium / carbon catalyst were added, and the mixture was stirred for 1 hour under a hydrogen atmosphere, and then 2 parts of compound VI were added, and the mixture was stirred and reacted at 60° C. for 10 hours. After the reaction was completed, the catalyst was filtered out, and then washed with 5% sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain compound VII; Step S8: Preparation of Compound VIII: by weight, add 1 part of Compound VII, 3 parts of cerium ammonium nitrate, and 6 parts of deionized water to 12 parts of acetonitrile, stir at 0°C for 3 hours, wash with water, extract with ethyl acetate, dry over anhydrous sodium sulfate overnight, and remove the solvent by distillation under reduced pressure to obtain Compound VIII; Step S9: In parts by weight, 0.8 parts of lithium hydroxide are added to 20 parts of methanol and stirred to dissolve, and then 5 parts of compound VIII are added, and the reaction is stirred for 24 hours at room temperature. After the reaction is completed, the solvent is removed by distillation under reduced pressure, and then 10 parts of deionized water are added, and the pH is adjusted to 5.1 with 10% hydrochloric acid by mass concentration, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure to obtain crude idebenone; Step S10: Purify the crude idebenone in step S9, wherein the purification process is as follows: add 13 parts of crude idebenone to 100 parts of dichloromethane by weight, stir until the solid is completely dissolved, filter, and transfer the filtrate to a crystallizer; dropwise add 19 parts of n-hexane to the filtrate for dissolution and crystallization (temperature is 0° C.), obtain a solid-liquid mixture and perform vacuum filtration, wash the filter cake twice with n-hexane, and then vacuum dry to obtain purified idebenone.

[0029] Example 3 This embodiment provides a preparation process of idebenone, comprising the following steps: Preparation of kaolin composite catalyst: (1) By weight, 110 parts of kaolin were calcined at 810°C for 3 hours, cooled to room temperature, added with 330 parts of 20% sulfuric acid solution and immersed for 5 hours, then filtered, washed and dried to obtain acidified kaolin. (2) By weight, 18 parts of acidified kaolin, 7 parts of hexadecyltrimethylammonium bromide, 3 parts of palladium nitrate, 3 parts of ruthenium nitrate and 2 parts of sodium hydroxide were added to 330 parts of deionized water, stirred at 64°C for 3 hours, then transferred to a microwave reactor for microwave treatment (microwave output power of 780 W, reaction temperature of 105°C and reaction time of 1 hour), cooled, filtered, washed and dried after microwave treatment to obtain a kaolin composite catalyst.

[0030] Step S1: in parts by weight, 24 parts of kaolin composite catalyst, 480 parts of sebacic acid, 9 parts of lithium hydroxide and 180 parts of deionized water are mixed evenly, and the reaction pressure is controlled to be 3 MPa and the reaction temperature is 248° C. under a hydrogen atmosphere, and the reaction is carried out for 3 hours. After the reaction is completed, the reaction is filtered, and the filter residue is washed and dried to obtain compound I purified 10-hydroxydecanoic acid; Step S2: In parts by weight, 24 parts of purified 10-hydroxydecanoic acid of compound I, 33 parts of acetic anhydride and 0.4 parts of p-toluenesulfonic acid were mixed evenly, stirred at 48°C for 4 hours, cooled to room temperature after the reaction, and then 105 parts of ice water were added and stirred for 2 hours, and then the reaction solution was extracted with 165 parts of dichloromethane at 1°C, and the organic phase obtained by extraction was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, and finally dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound II; Step S3: In parts by weight, under a nitrogen atmosphere, 25 parts of compound II were dropwise added to 38 parts of oxalyl chloride and mixed evenly, and then stirred for reaction at 58° C. for 7 h. After the reaction was completed, the mixture was distilled and dried to obtain compound III; Step S4: In parts by weight, under a nitrogen atmosphere and at 2°C, 27 parts of boron trifluoride and 78 parts of dichloromethane were stirred for 2 hours, and then 25 parts of compound III, 28 parts of dichloromethane and 19 parts of 3,4,5-trimethoxytoluene were added, and the mixture was reacted at -9°C for 4 hours, and then the temperature was raised to 11°C and the reaction was continued for 13 hours. After the reaction, compound IV was obtained; Step S5: In parts by weight, at 1°C, 43 parts of magnesium iodide and 108 parts of dichloromethane were mixed evenly, and then 28 parts of compound IV were added, and the temperature was raised to 11°C and the reaction was continued for 4 hours. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound V; Step S6: In parts by weight, under a nitrogen atmosphere, 7 parts of methanol and 0.4 parts of sodium hydroxide were mixed evenly, and then 4 parts of compound V and 13 parts of methanol were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound VI; Step S7: In parts by weight, 2 parts of perchloric acid and 19 parts of acetic acid were mixed evenly, and then 0.3 parts of palladium / carbon catalyst was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere, and then 3 parts of compound VI were added, and the mixture was stirred and reacted at 63° C. for 11 hours. After the reaction was completed, the catalyst was filtered out, and then washed with 5% sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain compound VII; Step S8: Preparation of Compound VIII: by weight, 2 parts of Compound VII, 4 parts of cerium ammonium nitrate, and 7 parts of deionized water were added to 20 parts of acetonitrile, stirred at 1°C for 4 hours, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate overnight, and distilled under reduced pressure to remove the solvent to obtain Compound VIII; Step S9: In parts by weight, 0.8 parts of lithium hydroxide are added to 22 parts of methanol and stirred to dissolve, and then 6 parts of compound VIII are added, and the reaction is stirred for 26 hours at room temperature. After the reaction is completed, the solvent is removed by distillation under reduced pressure, and then 12 parts of deionized water are added, and the pH is adjusted to 5.2 with 10% hydrochloric acid by mass concentration, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure to obtain crude idebenone; Step S10: Purify the crude idebenone in step S9, wherein the purification process is as follows: by weight, add 16 parts of crude idebenone to 102 parts of dichloromethane, stir until the solid is completely dissolved, filter, and transfer the filtrate to a crystallizer; dropwise add 22 parts of n-hexane to the filtrate for dissolution and crystallization (temperature is 2° C.), obtain a solid-liquid mixture and perform vacuum filtration, wash the filter cake 3 times with n-hexane, and then vacuum dry to obtain purified idebenone.

[0031] Comparative Example 1 This comparative example provides a preparation process of idebenone. The difference between this comparative example and Example 1 is that commercially available 10-hydroxydecanoic acid is used instead of purified 10-hydroxydecanoic acid, and the rest is the same as Example 1.

[0032] Comparative Example 2 This comparative example provides a preparation process of idebenone. The difference between this comparative example and Example 1 is that the purification treatment in step S10 is not performed, and the other steps are the same as Example 1.

[0033] Comparative Example 3 This comparative example provides a preparation process of idebenone. The difference between this comparative example and Example 1 is that commercially available 10-hydroxydecanoic acid is used instead of purified 10-hydroxydecanoic acid, and the purification treatment in step S10 is not performed. The other aspects are the same as those in Example 1.

[0034] Comparative Example 4 In this comparative example, commercially available idebenone was purified by the following steps: by weight, 16 parts of crude idebenone were added to 102 parts of dichloromethane, stirred until the solid was completely dissolved, filtered, and the filtrate was transferred to a crystallizer; 22 parts of n-hexane were added dropwise to the filtrate for dissolution and crystallization (temperature was 2° C.), a solid-liquid mixture was obtained, and vacuum filtered, the filter cake was washed 3 times with n-hexane, and then vacuum dried to obtain purified idebenone.

[0035] Comparative Example 5 This comparative example is commercially available idebenone.

[0036] Performance Testing The idebenone of the above examples and comparative examples was subjected to the following tests: (1) Purity test method High performance liquid chromatography was adopted, the chromatographic column used was Apollo-C18 (250×4.6 mm, 5 μm), the column temperature was 30° C., the mobile phase was methanol: water = 72:28, the flow rate was 1 ml / min, and the injection volume was 20 μL; sample solution was prepared, 2 mg of idebenone of the embodiment and the comparative example were weighed, and each was diluted to 10 mL with the mobile phase for purity test.

[0037] (2) Melting point test method The melting points of idebenone in the examples and comparative examples were measured using a differential scanning calorimeter (DSC25, TA Instruments, USA) in a temperature range of 30-80° C. and a heating rate of 5° C. / min.

[0038] (3) Skin stratum corneum moisture content test The test was carried out with reference to the requirements of "T / GDCA 009-2022 Human Evaluation Method for the Repair Efficacy of Cosmetics", and the idebenone-containing cream was prepared using the idebenone of the embodiment and the comparative example, and the moisture content of the skin stratum corneum was tested using the idebenone-containing cream.

[0039] Preparation of idebenone-containing cream: 5 parts of idebenone, 2 parts of polyethylene glycol (item number 20240201, purchased from Jiangxi Yipu), 1 part of sucrose stearate (CAS number 25168-73-4, purchased from Wuhan Fengzhulin), 1 part of stearyl alcohol (CAS number 112-92-5, purchased from Jinan Century Tongda), 4.5 parts of glyceryl monostearate (CAS number 31566-31-1, purchased from Shanghai Aladdin), 3 parts of jojoba oil (CAS number 61789-91-1, purchased from Nantong Runfeng) were heated to 80°C, stirred at a stirring speed of 120 rpm / min until completely dissolved, and then kept warm and stirred for 30 minutes to prepare an oil phase; 5 1. 2-propanediol (CAS No. 57-55-6, purchased from Shanghai Aladdin), 0.3 parts of triethanolamine (CAS No. 102-71-6, purchased from Shanghai Aladdin), 0.2 parts of carbomer 2020 (CAS No. 176429-87-1, purchased from Zhongshan Dixin Chemical) and 73 parts of deionized water were heated to 80°C, stirred at a stirring speed of 120 rpm / min until completely dissolved, and then kept warm and stirred for 30 minutes to obtain an aqueous phase; the oil phase and the aqueous phase were mixed, stirred at a stirring speed of 120 rpm / min for 10 minutes, and mixed well to obtain a cream containing idebenone.

[0040] Table 1 Performance test results purity(%) Melting point (℃) Water content of skin stratum corneum (%) Example 1 99.73 54.96 26.11 Example 2 99.76 54.97 26.12 Example 3 99.71 54.94 26.08 Comparative Example 1 99.12 53.67 25.71 Comparative Example 2 99.13 53.69 25.80 Comparative Example 3 98.61 52.59 25.19 Comparative Example 4 98.58 52.57 25.15 Comparative Example 5 98.09 52.14 25.02 From the above performance test results, it can be seen that Examples 1-3 have good effects, with a purity of 99.71-99.76%, a melting point of 54.94-54.97°C, and a moisture content of the stratum corneum of the skin of 26.08-26.12%; this is because the purified 10-hydroxydecanoic acid is obtained by using a kaolin composite catalyst, and idebenone is prepared based on this, and the preparation process is improved at the same time, and the dissolution crystallization treatment is combined to effectively improve the purity of idebenone and reduce the content of impurities in idebenone, thereby reducing the melting point, and it is applied to cosmetics to increase the moisture content of the stratum corneum of the skin.

[0041] However, since the comparative example did not adopt the necessary technical solution, it was significantly inferior to the embodiment in the corresponding performance test. Compared with Example 1, Comparative Example 1 used commercially available 10-hydroxydecanoic acid instead of purified 10-hydroxydecanoic acid, and the purity, melting point, and moisture content of the stratum corneum of the skin were reduced; compared with Example 1, Comparative Example 2 did not perform the purification treatment of step S10, and the purity, melting point, and moisture content of the stratum corneum of the skin were reduced; compared with Example 1, Comparative Example 3 used commercially available 10-hydroxydecanoic acid instead of purified 10-hydroxydecanoic acid, and did not perform the purification treatment of step S10, and the purity, melting point, and moisture content of the stratum corneum of the skin were reduced. Comparative Example 4 uses commercially available idebenone for purification to obtain purified idebenone, and uses it to prepare a cream. In the performance test, the purity is 98.58%, the melting point is 52.57°C, and the moisture content of the stratum corneum of the skin is 25.15%. The test results are not as good as those in Example 1. Comparative Example 5 uses commercially available idebenone and uses it to prepare a cream. In the performance test, the purity is 98.09%, the melting point is 52.14°C, and the moisture content of the stratum corneum of the skin is 25.02%. The test results are not as good as those in Example 1. The above experimental results further prove the importance of the technical solution defined in the present invention for its technical effect.

[0042] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A process for preparing idebenone, characterized in that: The following steps are involved: Step S1: in parts by weight, 20-25 parts of kaolin composite catalyst, 400-500 parts of sebacic acid, 8-10 parts of lithium hydroxide and 150-200 parts of deionized water are mixed evenly, and in a hydrogen atmosphere, the reaction pressure is controlled to be 2-3 MPa, the reaction temperature is 240-250° C., and the reaction is carried out for 2-4 hours. After the reaction is completed, the reaction is filtered, and the filter residue is washed and dried to obtain compound I purified 10-hydroxydecanoic acid; Step S2: In parts by weight, 20-25 parts of purified 10-hydroxydecanoic acid of compound I, 30-35 parts of acetic anhydride and 0.2-0.5 parts of p-toluenesulfonic acid are mixed uniformly, stirred at 45-50° C. for 3-4 hours, cooled to room temperature after the reaction, and then 100-110 parts of ice water are added and stirred for 1-2 hours, and then the reaction solution is extracted with 150-180 parts of dichloromethane at 0-2° C., and the organic phase obtained by extraction is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, and finally dried with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain compound II; Step S3: In parts by weight, under a nitrogen atmosphere, 24 to 26 parts of compound II are added dropwise to 37 to 40 parts of an acyl chloride reagent and mixed evenly, and then stirred for reaction at 55 to 60° C. for 6 to 8 hours. After the reaction is completed, the mixture is distilled and dried to obtain compound III; Step S4: In parts by weight, under a nitrogen atmosphere and 0-5° C., 26-28 parts of Lewis acid and 75-80 parts of dichloromethane are stirred for 1-2 hours, and then 24-26 parts of compound III, 25-30 parts of dichloromethane and 17-20 parts of 3,4,5-trimethoxytoluene are added, and the mixture is reacted at -8--10° C. for 3-4 hours, and then the temperature is raised to 10-12° C. and the reaction is continued for 12-14 hours. After the reaction is completed, compound IV is obtained; Step S5: In parts by weight, at 0-2° C., 42-44 parts of magnesium iodide and 100-110 parts of dichloromethane are mixed uniformly, and then 25-30 parts of compound IV are added, and the temperature is raised to 10-12° C. and the reaction is continued for 3-4 hours. After the reaction is completed, the mixture is extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound V; Step S6: In parts by weight, under a nitrogen atmosphere, 6-8 parts of methanol and 0.3-0.5 parts of sodium hydroxide are mixed uniformly, and then 3-5 parts of compound V and 12-14 parts of methanol are added, and the mixture is reacted at room temperature for 1-2 hours. After the reaction is completed, the mixture is extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound VI; Step S7: In parts by weight, 1-2 parts of perchloric acid and 18-19 parts of acetic acid are mixed uniformly, and then 0.2-0.4 parts of a catalyst are added, and the mixture is stirred for 1-2 hours under a hydrogen atmosphere, and then 2-4 parts of compound VI are added, and the mixture is stirred and reacted at 60-65° C. for 10-12 hours. After the reaction is completed, the catalyst is removed by filtration, and then washed with 5% sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure to obtain compound VII; Step S8: Preparation of Compound VIII: by weight, add 1-3 parts of Compound VII, 3-4 parts of cerium ammonium nitrate, and 6-8 parts of deionized water to 12-24 parts of acetonitrile, stir at 0-2°C for 3-4 hours, wash with water, extract with ethyl acetate, dry over anhydrous sodium sulfate overnight, and remove the solvent by distillation under reduced pressure to obtain Compound VIII; Step S9: In parts by weight, 0.8-0.9 parts of lithium hydroxide are added to 20-25 parts of methanol, stirred and dissolved, and then 5-8 parts of compound VIII are added, and the reaction is stirred at room temperature for 24-30 hours. After the reaction is completed, the solvent is removed by reduced pressure distillation, and then 10-20 parts of deionized water are added, and the pH is adjusted to 5.1-5.3 with 10% hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent is removed by reduced pressure distillation to obtain crude idebenone; Step S10: purifying the crude idebenone in step S9 to obtain purified idebenone.

2. The preparation process according to claim 1, characterized in that: The preparation method of the kaolin composite catalyst in step S1 comprises: adding 10 to 20 parts of acidified kaolin, 6 to 8 parts of hexadecyltrimethylammonium bromide, 2 to 4 parts of palladium nitrate, 2 to 4 parts of ruthenium nitrate, and 1 to 3 parts of sodium hydroxide to 300 to 350 parts of deionized water, stirring at 60 to 65° C. for 2 to 3 hours, then transferring to a microwave reactor for microwave treatment, and cooling, filtering, washing, and drying after the microwave treatment to obtain a kaolin composite catalyst.

3. The preparation process according to claim 2, characterized in that: In the microwave treatment, the microwave output power is 700-800W, the reaction temperature is 100-110°C, and the reaction time is 1-2h.

4. The preparation process according to claim 2, characterized in that: The preparation method of the acidified kaolin comprises: calcining 100-120 parts of kaolin by weight at 800-820° C. for 2-3 hours, cooling to room temperature, adding 300-350 parts of 20% sulfuric acid solution by weight, soaking for 4-6 hours, and then filtering, washing and drying to obtain the acidified kaolin.

5. The preparation process according to claim 1, characterized in that: The acyl chloride reagent in step S3 is oxalyl chloride.

6. The preparation process according to claim 1, characterized in that: The Lewis acid in step S4 is boron trifluoride.

7. The preparation process according to claim 1, characterized in that: The catalyst in step S7 is a palladium / carbon catalyst.

8. The preparation process according to claim 1, characterized in that: The purification treatment in step S10 includes: adding 13 to 19 parts of crude idebenone to 100 to 105 parts of dichloromethane by weight, stirring until the solid is completely dissolved, filtering, and transferring the filtrate to a crystallizer; adding 19 to 24 parts of n-hexane to the filtrate for dissolution and crystallization to obtain a solid-liquid mixture and vacuum filtering, washing the filter cake with n-hexane 2 to 3 times, and then vacuum drying to obtain purified idebenone.

9. The preparation process according to claim 8, characterized in that: The temperature of the dissolution crystallization is 0-5°C.

10. Use of idebenone prepared by the process according to any one of claims 1 to 9 in cosmetics.

Images