Method for preparing mitoquinone by oxidation

Abstract

The invention discloses a method for preparing mitoquinone by oxidation, comprising the following steps: S1, dissolving a salt of an intermediate A in an organic solvent, adding a metal ion oxidant, and stirring to react to obtain a crude product of the mitoquinone salt; S2, purifying the crude product to obtain the mitoquinone salt; wherein the structural formula of the intermediate A is shown in the following formula: The invention uses cheap and readily available metal ions as oxidants to oxidize the mesylate or bromide salt of the intermediate A at room temperature to obtain mitoquinone; the method provided by the invention effectively reduces oxidation costs, avoids the use of dangerous and toxic reagents, and effectively reduces the generation of three industrial wastes; and the process is simple, the operation is convenient, the raw materials are cheap and readily available, the yield is high, and the method is conducive to large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing mitoquinone by oxidation. Background Art

[0002] Mitochondria are the main target organs for the production and attack of reactive oxygen species in the body. The loss of mitochondrial structure and function induced by ROS imbalance is associated with a variety of age-related diseases. ROS imbalance in mitochondria leads to mitochondrial lipid and protein oxidation, mitochondrial RNA / DNA damage, Ca 2+ It relies on activation of the permeability transition pore protein and the release of cytochrome c, inducing the formation of apoptotic bodies and further promoting cell apoptosis, ultimately leading to irreversible organic damage to the organism (or organelle). Mitoquinone is a TPP-based, mitochondrial-targeted antioxidant that blocks H2O2-induced intracellular ROS reactions and prevents oxidative damage. Currently, mitoquinone has been widely used in anti-aging, anti-tumor, and neurodegenerative diseases.

[0003] Mitoquinone is composed of a triphenylphosphonium cation and a quinone group with antioxidant properties covalently bonded via a fatty chain, and usually exists in the form of a mitoquinone salt. Its structural formula is shown below:

[0004]

[0005] The existing synthesis method of mitoquinone generally first synthesizes idebenone or directly uses idebenone as a raw material, then constructs OMs or obtains the corresponding bromide through the Appel reaction, further reduces the quinone to phenol, and then reacts with triphenylphosphine to obtain the corresponding salt, and finally obtains mitoquinone mesylate or mitoquinone bromide through oxidation. The current oxidation process uses air or oxygen for oxidation, but the oxidation time is too long, and oxygen is flammable and explosive, which is dangerous. If other oxidants are used, such as potassium permanganate, potassium dichromate, periodic acid, etc., they are highly toxic, corrosive, and have a great impact on the environment. Therefore, it is necessary to propose a new oxidation method to solve some of the problems existing in the above process. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing mitoquinone by oxidation in view of the deficiencies in the above-mentioned prior art.

[0007] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for preparing mitoquinone by oxidation, comprising the following steps:

[0008] S1. The salt of intermediate A is dissolved in an organic solvent, a metal ion oxidant is added, and the mixture is stirred to react to obtain a crude product of mitoquinone salt;

[0009] S2, purifying the crude product to obtain mitoquinone salt;

[0010] The structural formula of intermediate A is shown below:

[0011]

[0012] Preferably, the metal ion oxidant is one or more of ferric chloride, ferric sulfate, copper chloride, and copper bromide.

[0013] Preferably, the salt of intermediate A is a methanesulfonate salt of intermediate A or a bromide salt of intermediate A;

[0014] The mesylate of intermediate A is prepared by using idebenone as a raw material, constructing OMs, reducing, and then forming a salt with triphenylphosphine. The bromide of intermediate A is prepared by using idebenone as a raw material, constructing OMs, brominating, reducing, and then forming a salt with triphenylphosphine.

[0015] Preferably, the molar ratio of the salt of intermediate A to the metal ion oxidant is 1:0.01 to 0.20.

[0016] Preferably, the organic solvent is one or more of ethanol, methanol, and dichloromethane;

[0017] The volume of the organic solvent is 5 to 20 times the weight of the salt of the intermediate A, wherein the unit of volume is mL and the unit of weight is g.

[0018] Preferably, the reaction time in step S1 can be 0.5-12 h, and the reaction temperature is room temperature.

[0019] Preferably, the purification process in step S2 is a combination of one or more of recrystallization, chemical precipitation, and column chromatography.

[0020] Preferably, step S2 is specifically:

[0021] S2-1, adding the crude product of mitoquinone salt to the recrystallization solvent, stirring at 30-120°C for 1-4 hours, and then cooling to 25°C;

[0022] S2-2. Pour off the supernatant, add the product to the recrystallization solvent, stir at 30-120°C for 1-4 hours, then cool to 25°C, and then concentrate under reduced pressure at 40°C to obtain mitroquinone salt.

[0023] Preferably, the recrystallization solvent is one or more of ethyl acetate, toluene, n-hexane, and diethyl ether, and the volume of the recrystallization solvent is 1 to 10 times the weight of the crude mitoquinone, wherein the unit of volume is mL and the unit of weight is g.

[0024] Preferably, step S2 is specifically as follows: adding the crude product of mitoquinone salt to diethylaminetetraacetic acid, stirring at room temperature for 1-4 hours, filtering with suction, rinsing the filter cake with ethanol, and concentrating the filtrate under reduced pressure at 40° C. to obtain mitoquinone salt.

[0025] Preferably, step S2 is specifically as follows: purifying the crude product of mitroquinone salt by column chromatography with 200-300 mesh silica gel, eluting with a mixture of dichloromethane and methanol in a volume ratio of 50:1, and concentrating the obtained eluate under reduced pressure at 40° C. to obtain mitroquinone salt.

[0026] The beneficial effects of the present invention are:

[0027] The present invention provides a method for preparing mitoquinone by oxidation. In the present invention, cheap and readily available metal ions are used as oxidants to oxidize the mesylate or bromide salt of an intermediate A at room temperature to obtain mitoquinone. The method provided by the present invention effectively reduces oxidation costs, avoids the use of dangerous and toxic reagents, and effectively reduces the generation of three industrial wastes. In addition, the process is simple, the operation is convenient, the raw materials are cheap and readily available, the yield is high, and it is conducive to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the synthetic route of intermediate A methanesulfonate;

[0029] Figure 2 is the H NMR spectrum of intermediate A methanesulfonate;

[0030] Figure 3 This is the synthetic route for the bromide salt of intermediate A;

[0031] Figure 4 is the H NMR spectrum of the bromide salt of intermediate A;

[0032] Figure 5 HPLC spectrum of the mitroquinone salt product obtained in Example 3;

[0033] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the mitroquinone salt product prepared in Example 3. DETAILED DESCRIPTION

[0034] The present invention is further described in detail below with reference to the embodiments so that those skilled in the art can implement the invention with reference to the description.

[0035] It should be understood that terms such as “having”, “including” and “comprising” used herein do not preclude the existence or addition of one or more other elements or combinations thereof.

[0036] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Materials and reagents used in the following examples are commercially available unless otherwise specified. In the following examples, where specific conditions are not specified, the experiments were conducted under conventional conditions or those recommended by the manufacturer. Reagents and instruments used, where the manufacturer is not specified, are commercially available conventional products.

[0037] The present invention provides a method for preparing mitoquinone by oxidation, comprising the following steps:

[0038] S1. The salt of intermediate A is dissolved in an organic solvent, a metal ion oxidant is added, and the mixture is stirred to react to obtain a crude product of mitoquinone salt;

[0039] S2, purifying the crude product to obtain mitoquinone salt;

[0040] The structural formula of intermediate A is shown below:

[0041]

[0042] The reaction route is as follows:

[0043]

[0044] In a preferred embodiment, the metal ion oxidant is one or more of ferric chloride, ferric sulfate, copper chloride, and copper bromide.

[0045] In a preferred embodiment, the salt of intermediate A is a methanesulfonate salt of intermediate A or a bromide salt of intermediate A;

[0046] Among them, the mesylate of intermediate A is prepared by using idebenone as the raw material, constructing OMs, reducing, and then forming a salt with triphenylphosphine. The bromide of intermediate A is prepared by using idebenone as the raw material, constructing OMs, brominating, reducing, and then forming a salt with triphenylphosphine.

[0047] In a preferred embodiment, the molar ratio of the salt of intermediate A to the metal ion oxidant is 1:0.01 to 0.20. For example, it can be 1:0.01, 1:0.05, 1:0.10, 1:0.20, or any value therebetween, and is most preferably 1:0.05.

[0048] In a preferred embodiment, the organic solvent is one or more of ethanol, methanol, and dichloromethane; most preferably, ethanol.

[0049] The volume of the organic solvent is 5 to 20 times the weight of the salt of intermediate A, where the unit of volume is mL and the unit of weight is g. For example, it can be 5, 10, 15, 20 times or any value in between, and is most preferably 15 times.

[0050] In a preferred embodiment, the reaction time in step S1 can be 0.5-12 h, and the reaction temperature can be room temperature, for example, 0.5, 2, 5, 8 h, or any value therebetween, and most preferably 5 h.

[0051] In a preferred embodiment, the purification process in step S2 is a combination of one or more of recrystallization, chemical precipitation, and column chromatography, and recrystallization is most preferred.

[0052] In a preferred embodiment, step S2 is specifically as follows:

[0053] S2-1, adding the crude product of mitoquinone salt to the recrystallization solvent, stirring at 30-120°C for 1-4 hours, and then cooling to 25°C;

[0054] S2-2. Pour off the supernatant, add the product to the recrystallization solvent, stir at 30-120°C for 1-4 hours, then cool to 25°C, and then concentrate under reduced pressure at 40°C to obtain mitroquinone salt.

[0055] In a preferred embodiment, the recrystallization solvent is one or more of ethyl acetate, toluene, n-hexane, and diethyl ether, and most preferably is ethyl acetate.

[0056] In a preferred embodiment, the volume of the recrystallization solvent is 1 to 10 times the weight of the crude mitoquinone, where volume is expressed in mL and weight is expressed in g. For example, the volume may be 1, 3, 7, or 10 times, or any value in between, with 3 times being most preferred. The recrystallization temperature is 30 to 120°C, for example, 30°C, 50°C, 80°C, or 100°C, with 70°C being most preferred.

[0057] In a preferred embodiment, step S2 specifically comprises: adding the crude product of mitoquinone salt to diethylaminetetraacetic acid, stirring at room temperature for 1-4 hours, filtering with suction, rinsing the filter cake with ethanol, and concentrating the filtrate under reduced pressure at 40° C. to obtain mitoquinone salt.

[0058] In a preferred embodiment, step S2 specifically comprises: purifying the crude product of mitogen-activated quinone salt by column chromatography with 200-300 mesh silica gel, eluting with a mixture of dichloromethane and methanol in a volume ratio of 50:1, and concentrating the resulting eluate under reduced pressure at 40° C. to obtain mitogen-activated quinone salt.

[0059] The above is the overall concept of the present invention. Detailed embodiments and comparative examples are provided below to further illustrate the present invention.

[0060] In the following examples, the preparation methods of the methanesulfonate salt and the bromide salt of intermediate A are as follows.

[0061] 1. Methanesulfonate of intermediate A

[0062] The mesylate of intermediate A (abbreviated as intermediate A mesylate) is prepared from idebenone by constructing OMs, reducing it, and then salifying it with triphenylphosphine. The synthetic route is as follows: Figure 1 As shown, the specific synthesis method is:

[0063] To a 5L three-necked flask, add idebenone (200g, 0.59mol), dichloromethane (3L, 15V), and triethylamine (173ml, 1.24mol). Cool to below 5°C in an ice-water bath, then slowly add methyl yellow acid chloride (91ml, 1.18mol) dropwise. Warm to room temperature and stir for 1 hour. Add 500ml of 1N hydrochloric acid to the reaction mixture and stir for 20 minutes. Separate the liquid, extract the organic phase once with 500ml of water, separate the liquid again, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. This yields 240g of a reddish-brown oil, with a yield of 99.53%.

[0064] To a 10L three-necked flask, add the reddish-brown oil obtained above (240g, 0.59mol) and methanol (3.6L). Under argon, cool the mixture to approximately 5°C in an ice-water bath. Slowly add sodium borohydride (66.96g, 1.77mol) in portions. Warm the mixture to room temperature and stir for 1 hour. After the reaction is complete, quench with 500ml of 1N hydrochloric acid and stir for 30 minutes. Then, add 3L of chloroform to extract the product. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. 240g of a light yellow oil is obtained, yielding 99.45%.

[0065] The pale yellow oil obtained above was transferred to a 5L single-necked flask, and 1,4-dioxane (2.4L) and triphenylphosphine (231g, 0.88mol) were added. The mixture was heated to reflux and stirred under argon for 72 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 2 / 3 of the solvent. 2.4L of diethyl ether was added to the remaining reaction solution and stirred at room temperature for 30 minutes. The supernatant was removed, and the viscous precipitate below was concentrated under reduced pressure to obtain 375g of the mesylate salt of Intermediate A in an 89.49% yield.

[0066] The NMR data of intermediate A mesylate are as follows:

[0067] 1 H NMR (400MHz, CDCl3): δ7.9-7.6(15H,m,-P + PH3),3.87(6H,s,2×-OCH3),3.6-3.5(2H,m,-CH2-P + PH3),2.73(3H,s,-S -O3-CH3), 2.58-2.54(2H,t,J=8,ubiquinone-CH2-), 2.13(3H,s,-CH3), 1.6-1.2(16H,m,(CH2)8-).

[0068] Its H NMR spectrum is Figure 2 shown.

[0069] 2. Bromine salt of intermediate A

[0070] The bromide salt of intermediate A (referred to as intermediate A bromide salt) is prepared from idebenone by constructing OMs, brominating, reducing, and then salifying with triphenylphosphine; the synthetic route is as follows: Figure 3 As shown, the specific synthesis method is:

[0071] To a 5L three-necked flask, add idebenone (200g, 0.59mol), dichloromethane (3L, 15V), and triethylamine (173ml, 1.24mol). Cool to below 5°C in an ice-water bath, then slowly add methyl yellow acid chloride (91ml, 1.18mol) dropwise. Warm to room temperature and stir for 1 hour. Add 500ml of 1N hydrochloric acid to the reaction mixture and stir for 20 minutes. Separate the liquid, extract the organic phase once with 500ml of water, separate the liquid again, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. This yields 240g of a reddish-brown oil, with a yield of 99.53%.

[0072] To a 5L single-necked flask, add the reddish-brown oil (240g, 0.59mol), acetone (3L), and lithium bromide (102.5g, 1.18mol). Heat to 60°C and stir for 6h. After the reaction is complete, filter and concentrate the filtrate under reduced pressure to obtain 230g of a reddish-brown oil, with a yield of 97.13%.

[0073] To a 10L three-necked flask, add the reddish-brown oil obtained above (230g, 0.57mol) and methanol (3.45L). Under argon, cool the mixture to approximately 5°C in an ice-water bath. Slowly add sodium borohydride (64.17g, 1.70mol) in portions. Warm the mixture to room temperature and stir for 1h. After the reaction is complete, quench with 480ml of 1N hydrochloric acid and stir for 30min. Then, add 2.9L of chloroform to extract the product. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. 228g of a light yellow oil is obtained, yielding 98.63%.

[0074] The pale yellow oil obtained above was transferred to a 5L single-necked flask. 1,4-dioxane (2.3L) and triphenylphosphine (217g, 0.83mol) were added. The mixture was heated to reflux and stirred under argon for 72 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 2 / 3 of the solvent. 2.3L of diethyl ether was added to the remaining reaction solution and stirred at room temperature for 30 minutes. The supernatant layer was removed, and the viscous precipitate below was concentrated under reduced pressure to obtain 338g of the bromide salt of Intermediate A in an 89.83% yield.

[0075] The NMR data of intermediate A bromide salt are as follows:

[0076] 1 H NMR (400MHz, CDCl3): δ7.9-7.6(15H,m,-P + PH3),3.97,3.87(6H,s,2×-OCH3),3.8-3.78(2H,m,-CH2-P + PH3), 2.57, 2.41 (2H,t,J=8, ubiquinone-CH2-), 2.12, 1.99 (3H,s,-CH3), 1.6-1.2(16H,m,(CH2)8-).

[0077] Its H NMR spectrum is Figure 4 shown.

[0078] Example 1

[0079] S1. Synthesis of crude mitroquinone salt

[0080] To a 5L single-necked flask, add the methanesulfonate salt of Intermediate A (260g, 0.38mol) and ethanol (3.9L, 15V). Stir at room temperature until Intermediate A is completely dissolved. Then, add anhydrous ferric chloride (3.08g, 0.019mol) and stir at room temperature for 5 hours. HPLC monitoring is performed until the residual amount of Intermediate A is <0.1%. Concentrate the reaction mixture under reduced pressure at 40-45°C to obtain 263g of a brown oil, the crude product of mitroquinone salt.

[0081] S2. Purification of crude mitoquinone salt

[0082] Transfer 253 g of the oil to a 2 L three-necked flask, add 750 ml of ethyl acetate, heat to 75°C, maintain stirring for 2 hours, then cool naturally to room temperature (25°C). Discard the supernatant and repeat this process once. Finally, concentrate the precipitate under reduced pressure at 40°C to obtain 247 g of mitoquinone salt as a brown waxy solid (95.28% yield).

[0083] Example 2

[0084] S1. Synthesis of crude mitroquinone salt

[0085] To a 5 L single-necked flask, add the bromide salt of intermediate A (250 g, 0.38 mol), then add ethanol (3.9 L, 15 V), and stir at room temperature until intermediate A is completely dissolved. Then add anhydrous ferric chloride (6.16 g, 0.038 mol), and stir at room temperature for 3 h; monitor by HPLC until the residual intermediate A is <0.1%, to obtain the crude product of mitroquinone salt.

[0086] S2. Purification of crude mitoquinone salt

[0087] Diethylaminetetraacetic acid (11.11 g, 0.038 mol) was added to the product obtained in step S1, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filter cake was rinsed once with 200 ml of ethanol. The filtrate was concentrated under reduced pressure at 40°C to obtain 240 g of brown waxy solid mitoquinone salt in a yield of 96.33%.

[0088] Example 3

[0089] S1. Synthesis of crude mitroquinone salt

[0090] To a 5L three-necked flask, add the bromide salt of Intermediate A (200g, 0.30mol) and ethanol (3.6L, 18V). Stir at room temperature until Intermediate A is completely dissolved. Then, add anhydrous copper chloride (4.04g, 0.03mol) and stir at room temperature while ventilating for 5 hours. Monitor by HPLC until the residual amount of Intermediate A is <0.1%. Concentrate the reaction mixture under reduced pressure at 40-45°C to obtain 203g of a brown oil, the crude product of mitroquinone salt.

[0091] S2. Purification of crude mitoquinone salt

[0092] The brown oil was purified by column chromatography using 200-300 mesh silica gel and eluted with dichloromethane / methanol = 50:1. The eluate was concentrated under reduced pressure at 40° C. to obtain 182 g of brown waxy solid mitoquinone salt in a yield of 91.31%.

[0093] The HPLC data of the mitroquinone salt product obtained in Example 3 are as follows: retention time = 11.60 min, product purity > 99.8, absorption wavelength = 273 nm. Figure 5 shown.

[0094] The nuclear magnetic resonance data of the mitroquinone salt product obtained in Example 3 are as follows:

[0095] 1 H NMR (400MHz, CDCl3): δ7.9-7.6(15H,m,-P + PH3),3.98(6H,s,2×-OCH3),3.86-3.8(2H,m,-CH2-P +PH3), 2.41(2H,t,J=8,ubiquinone-CH2-), 1.99(3H,s,-CH3), 1.6-1.2(16H,m,(CH2)8-).

[0096] Its H NMR spectrum is Figure 6 shown.

[0097] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the description and implementation methods. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing mitoquinone by oxidation, characterized in that: The following steps are involved: S1. The salt of intermediate A is dissolved in an organic solvent, a metal ion oxidant is added, and the mixture is stirred to react to obtain a crude product of mitoquinone salt; S2, purifying the crude product to obtain mitoquinone salt; The structural formula of intermediate A is shown below: The metal ion oxidant is one or more of ferric chloride, ferric sulfate, copper chloride and copper bromide.

2. The method for preparing mitoquinone by oxidation according to claim 1, wherein The salt of intermediate A is the methanesulfonate of intermediate A or the bromide of intermediate A; The mesylate of intermediate A is prepared by using idebenone as a raw material, constructing OMs, reducing, and then forming a salt with triphenylphosphine. The bromide of intermediate A is prepared by using idebenone as a raw material, constructing OMs, brominating, reducing, and then forming a salt with triphenylphosphine.

3. The method for preparing mitoquinone by oxidation according to claim 2, wherein: The molar ratio of the salt of intermediate A to the metal ion oxidant is 1:0.01-0.

20.

4. The method for preparing mitoquinone by oxidation according to claim 1, wherein The organic solvent is one or more of ethanol, methanol, and dichloromethane; The volume of the organic solvent is 5 to 20 times the weight of the salt of the intermediate A, wherein the unit of volume is mL and the unit of weight is g.

5. The method for preparing mitoquinone by oxidation according to claim 1, characterized in that: The reaction time in step S1 can be 0.5-12 hours, and the reaction temperature is room temperature.

6. The method for preparing mitoquinone by oxidation according to claim 1, characterized in that: The purification process in step S2 is a combination of one or more of recrystallization, chemical precipitation, and column chromatography.

7. The method for preparing mitoquinone by oxidation according to claim 6, characterized in that: Step S2 is specifically as follows: S2-1, adding the crude product of mitoquinone salt to the recrystallization solvent, stirring at 30-120°C for 1-4 hours, and then cooling to 25°C; S2-2. Pour off the supernatant, add the product to the recrystallization solvent, stir at 30-120°C for 1-4 hours, then cool to 25°C, and then concentrate under reduced pressure at 40°C to obtain mitroquinone salt.

8. The method for preparing mitoquinone by oxidation according to claim 7, characterized in that: The recrystallization solvent is one or more of ethyl acetate, toluene, n-hexane and ether, and the volume of the recrystallization solvent is 1 to 10 times the weight of the crude product of mitoquinone, wherein the unit of volume is mL and the unit of weight is g.

9. The method for preparing mitoquinone by oxidation according to claim 6, characterized in that: Step S2 is specifically as follows: adding the crude product of mitoquinone salt to diethylaminetetraacetic acid, stirring at room temperature for 1-4 hours, filtering with suction, rinsing the filter cake with ethanol, and concentrating the filtrate under reduced pressure at 40° C. to obtain mitoquinone salt.

10. The method for preparing mitoquinone by oxidation according to claim 6, characterized in that: Step S2 is specifically as follows: the crude product of mitroquinone salt is purified by column chromatography with 200-300 mesh silica gel, eluted with a mixture of dichloromethane and methanol in a volume ratio of 50:1, and the obtained eluate is concentrated under reduced pressure at 40° C. to obtain mitroquinone salt.

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