CN111039768B - Synthesis method of targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone - Google Patents
Synthesis method of targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Abstract
The invention provides a method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone, which comprises the following steps of 1) dissolving 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in glacial acetic acid, adding reduced iron powder, stirring at room temperature for 1 hour, and heating for reflux reaction for 5 hours; 2) cooling, filtering the reaction mixture, evaporating the solvent in the filtrate under reduced pressure, recovering the recovered glacial acetic acid for reuse, dissolving the crude product with ethanol, adjusting the pH value to 9 with 5% sodium hydroxide aqueous solution, introducing air flow until the mixture turns into dark blue, and monitoring the reaction by TLC; 3) the reaction mixture was acidified to pH 4 with 10% HCl, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give an oily crude product, the ethyl acetate was recovered, and the crude product was purified by flash column on silica gel to give a pale yellow oily product. The invention synthesizes 2, 3-dimethyl-p-benzoquinone which is an intermediate of a mitochondrial antioxidant SKQ-1; the solvent can be reused, so that the production cost is saved; provides a raw material basis for the industrialized synthesis of the mitochondrial antioxidant SKQ 1.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone.
Background
In recent years, development of novel in vivo antioxidant drugs has been receiving attention from researchers because of their clinically excellent effects. Mitotech SA biotechnology enterprises in Luxembo develop an innovative mitochondrion-targeted antioxidant SKQ1 which passes clinical phase II tests, have significant effect on treating moderate to severe dry eye of patients, and can safely and effectively treat symptoms and signs of dry eye.
SKQ1 is useful for treating some diseases of human cell mitochondria and delaying human cell aging.
SkQ1 also selectively protects the cardiolipin of the membrane from oxidation and by doing so can prevent mitochondrial dysfunction and a process of cell death called apoptosis.
Russian researchers have newly found that an antioxidant SKQ1 can effectively kill a plurality of gram-positive and gram-negative bacteria, and a novel antibiotic is expected to be developed on the basis of the substance.
The SKQ1 antioxidant has certain antibacterial effect and no obvious toxicity to mammalian cells, so that the antioxidant has the potential to be developed into novel antibiotics for resisting drug-resistant bacteria which discharge common antibiotics by virtue of strong 'proton motility'.
The Lipidure PMB which is a medical bionic material and is developed by NOF has a structure and components similar to those of human cells, and has excellent moisturizing effect and biocompatibility. Therefore, the novel medical bionic material is widely applied to medical equipment and artificial organs, and can effectively prevent rejection of human tissues. The commercial product Lipidure PMB is added with the antibacterial agent phenoxyethanol, and the SKQ1 has excellent antibacterial effect and antioxidant effect, so that the Lipidure PMB is the best choice for replacing phenoxyethanol as an antibacterial agent.
At present, no company in China can carry out large-scale industrialization on the SKQ1 product, the synthesis scale of the SKQ1 product generally only reaches the gram level, and the SKQ1 product is only suitable for research and cannot provide long-term stable commodity supply. The synthesis route of SKQ1 reported in the literature has the problems of more byproducts, difficult purification, low yield and the like.
The synthesis process of the intermediate 2, 3-dimethyl-p-benzoquinone required in the existing synthesis route of SKQ1 has the problems of complex synthesis process, low yield and complex operation; concentrated sulfuric acid high-risk chemicals are used in the reaction; heavy metal wastewater is generated in the production process; the feeding proportion is difficult to control, and the byproducts are increased. Especially in the step of synthesizing the intermediate into quinones, the sublimation of quinones may cause a large loss in the post-treatment if the method is not proper.
Disclosure of Invention
In view of the above, the invention aims to provide a synthesis method of a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone, so as to overcome the defects in the prior art, avoid the use of hazardous chemical product concentrated sulfuric acid, and have mild reaction conditions; the solvent can be reused, so that the production cost is saved; no heavy metal wastewater is generated, and the method is green and environment-friendly. Provides a raw material basis for a new production process of the antioxidant SKQ 1.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a method for synthesizing a targeting antioxidant SKQ1 intermediate 2,3 dimethyl-p-benzoquinone comprises the following steps,
1) dissolving 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in glacial acetic acid, adding reduced iron powder, stirring at room temperature for 1 hour, and heating to perform reflux reaction for 5 hours;
2) cooling, filtering the reaction mixture, evaporating the solvent in the filtrate under reduced pressure, recovering the recovered glacial acetic acid for reuse, dissolving the crude product with ethanol, adjusting the pH value to alkalescence with 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring by TLC to complete the reaction;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give a crude product as an oil, the ethyl acetate was recovered, and the crude product was purified by flash column on silica gel to give a product as a pale yellow oil.
Preferably, in the step 1), the molar ratio of the 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone to the reduced iron powder is 1: 10.
preferably, in step 2), the reaction solution is adjusted to pH 9 with 5% sodium hydroxide solution in water.
Preferably, in the step 3), when the silica gel column is used for purification, the mobile phase is a mixed solvent of ethyl acetate and petroleum ether, and the ratio of ethyl acetate/petroleum ether = 1/20.
The reaction formula in the synthesis process is shown as follows,
compared with the prior art, the synthesis method of the mitochondria targeted antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone has the following advantages:
1. the invention has simple synthesis process and no complicated operation steps.
2. The invention has the advantages of few kinds of reaction raw materials, easily obtained raw materials and low price. The solvent can be repeatedly used, and the purpose of green synthesis is realized.
3. The synthesis process disclosed by the invention is free of hazardous chemicals, free of heavy metal wastewater and environment-friendly.
4. The method has simple and convenient post-treatment, can obtain high-quality products, can be operated in an amplification way, and realizes industrialization.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention.
In the drawings:
fig. 1 is a nuclear magnetic data diagram of synthetic targeted antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone according to the first embodiment of the present invention.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
Example one
A method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone comprises the following steps:
step 1) dissolving 29.2 g of 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in 230 ml of glacial acetic acid, adding 56 g of reduced iron powder, stirring at room temperature for 1 hour, and then heating for reflux reaction for 5 hours;
step 2) cooling the reaction liquid, filtering the reaction mixture, then evaporating the solvent in the filtrate under reduced pressure, recovering and reusing the recovered glacial acetic acid, dissolving the oily crude product by using ethanol, adjusting the pH value to 9 by using a 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring the reaction by TLC;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give an oily crude product, the ethyl acetate was recovered to give a crude product as a pale yellow oil, which was purified with a flash column on silica gel with a mobile phase of a mixed solvent of ethyl acetate and petroleum ether at a ratio of ethyl acetate/petroleum ether =1/20, and the solvent was concentrated to give 13.1 g of a pure product as a pale yellow oil with a yield of 96.3%.
The product was subjected to nuclear magnetic analysis, 1H NMR (400 MHz, CDCl3): delta 1.98(s,6H, -CH3), 6.71(s,2H, C = CH2)
From the nuclear magnetic spectrum, as can be seen in fig. 1, the characteristic peaks of the product hydrogen spectrum are obvious: the chemical shift position of 6.71 is a characteristic peak of a hydrogen bond on a quinone ring; the chemical shift at 1.98 is the characteristic peak of two methyl groups on the quinone ring. And the product purity is high in integral ratio, and should be over 98 percent.
According to nuclear magnetic analysis, the target product was obtained in high purity by the above procedure.
Example 2
A method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone comprises the following steps:
step 1) dissolving 29.2 g of 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in 230 ml of glacial acetic acid, adding 50 g of reduced iron powder, stirring at room temperature for 1 hour, and then heating for reflux reaction for 5 hours;
step 2) cooling the reaction liquid, filtering the reaction mixture, then evaporating the solvent in the filtrate under reduced pressure, recovering and reusing the recovered glacial acetic acid, dissolving the oily crude product by using ethanol, adjusting the pH value to 9 by using a 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring the reaction by TLC;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give an oily crude product, the ethyl acetate was recovered to give a crude product as a pale yellow oil, which was purified with a flash column on silica gel with a mobile phase of a mixed solvent of ethyl acetate and petroleum ether at a ratio of ethyl acetate/petroleum ether =1/20, and the solvent was concentrated to give a pure product as a pale yellow oil, 12.8 g, with a yield of 94.1%.
Example 3
A method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone comprises the following steps:
step 1) dissolving 29.2 g of 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in 230 ml of glacial acetic acid, adding 56 g of reduced iron powder, stirring at room temperature for 1 hour, and then heating for reflux reaction for 5 hours;
step 2) cooling the reaction liquid, filtering the reaction mixture, then decompressing and steaming off the solvent in the filtrate, recovering and reusing the recovered glacial acetic acid, dissolving the oily crude product by using ethanol, adjusting the pH value to 8 by using 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring the reaction by TLC;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give an oily crude product, the ethyl acetate was recovered to give a crude product as a pale yellow oil, which was purified with a flash column on silica gel with a mobile phase of a mixed solvent of ethyl acetate and petroleum ether at a ratio of ethyl acetate/petroleum ether =1/20, and the solvent was concentrated to give a pure product as a pale yellow oil, 12.5 g, with a yield of 91.9%.
Example 4
A method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone comprises the following steps:
step 1) dissolving 29.2 g of 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in 230 ml of glacial acetic acid, adding 60 g of reduced iron powder, stirring at room temperature for 1 hour, and then heating to carry out reflux reaction for 5 hours;
step 2) cooling the reaction liquid, filtering the reaction mixture, then evaporating the solvent in the filtrate under reduced pressure, recovering and reusing the recovered glacial acetic acid, dissolving the oily crude product by using ethanol, adjusting the pH value to 9 by using a 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring the reaction by TLC;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give an oily crude product, the ethyl acetate was recovered to give a crude product as a pale yellow oil, which was purified with a flash column on silica gel with a mobile phase of a mixed solvent of ethyl acetate and petroleum ether at a ratio of ethyl acetate/petroleum ether =1/20, and the solvent was concentrated to give 13.0 g of a pure product as a pale yellow oil with a yield of 95.6%.
Example 5
A method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone comprises the following steps:
step 1) dissolving 29.2 g of 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in 230 ml of glacial acetic acid, adding 56 g of reduced iron powder, stirring at room temperature for 1 hour, and then heating for reflux reaction for 5 hours;
step 2) cooling the reaction liquid, filtering the reaction mixture, then decompressing and steaming off the solvent in the filtrate, recovering and reusing the recovered glacial acetic acid, dissolving the oily crude product by using ethanol, adjusting the pH value to 10 by using 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring the reaction by TLC;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give an oily crude product, the ethyl acetate was recovered to give a crude product as a pale yellow oil, which was purified with a flash column on silica gel with a mobile phase of a mixed solvent of ethyl acetate and petroleum ether at a ratio of ethyl acetate/petroleum ether =1/20, and the solvent was concentrated to give 12.1 g of a pure product as a pale yellow oil in 88.9% yield.
The characterization results of the products obtained in examples 2 to 5 are the same as those in example 1.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the invention, so that any modifications, equivalents, improvements and the like, which are within the spirit and principle of the present invention, should be included in the scope of the present invention.
Claims (4)
1. A method for synthesizing a targeting antioxidant SKQ1 intermediate 2, 3-dimethyl-p-benzoquinone is characterized by comprising the following steps: comprises the following steps of (a) carrying out,
1) dissolving 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone in glacial acetic acid, adding reduced iron powder, stirring at room temperature for 1 hour, and heating to perform reflux reaction for 5 hours;
2) cooling, filtering the reaction mixture, evaporating the solvent in the filtrate under reduced pressure, recovering the recovered glacial acetic acid for reuse, dissolving the crude product with ethanol, adjusting the pH value to alkalescence with 5% sodium hydroxide aqueous solution, introducing air flow until the mixture becomes dark blue, and monitoring by TLC to complete the reaction;
3) the reaction mixture was acidified with 10% HCl to PH =4, most of the ethanol was evaporated under reduced pressure, then extracted three times with ethyl acetate, the organic phases were combined, the solvent was spin-dried to give a crude product as an oil, the ethyl acetate was recovered, and the crude product was purified by flash column on silica gel to give a product as a pale yellow oil.
2. The synthesis method of the intermediate 2, 3-dimethyl-p-benzoquinone of the targeted antioxidant SKQ1 as claimed in claim 1, wherein the synthesis method comprises the following steps: in the step 1), the molar ratio of the 2, 3-dibromo-5, 6-dimethyl-p-benzoquinone to the reduced iron powder is 1: 10.
3. the synthesis method of the intermediate 2, 3-dimethyl-p-benzoquinone of the targeted antioxidant SKQ1 as claimed in claim 1, wherein the synthesis method comprises the following steps: in the step 2), the pH value of the reaction solution is adjusted to 9 by using a 5% sodium hydroxide aqueous solution.
4. The synthesis method of the intermediate 2, 3-dimethyl-p-benzoquinone of the targeted antioxidant SKQ1 as claimed in claim 1, wherein the synthesis method comprises the following steps: in the step 3), when the mixture is subjected to silica gel flash column purification, the mobile phase is a mixed solvent of ethyl acetate and petroleum ether, and the ratio of ethyl acetate/petroleum ether = 1/20.
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