Preparation method of siberian linker

Abstract

The invention belongs to the technical field of organic synthesis, and particularly provides a preparation method of a siberian linker, which comprises the following steps: S1, carrying out primary demethylation reaction on 2, 4-dimethoxyphenyl-2-fluorophenyl ketone to generate 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone; s2, enabling the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to be subjected to a ring closing reaction, so as to generate 3-methoxy xanthone, and enabling the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to be subjected to a ring closing reaction, so as to generate 3-methoxy xanthone; and S3, carrying out a secondary demethylation reaction on the 3-methoxyl xanthone, so as to obtain the siberian linker. The preparation method disclosed by the embodiment of the invention is simple and convenient to operate, mild in reaction condition, high in yield and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and more particularly relates to a preparation method of a siberian linker. BACKGROUND

[0002] Solid-phase synthesis technology is one of the ideal choices for the preparation of polypeptide drugs and small nucleic acid drugs due to its simple operation, easy automation, and the ability to improve synthesis efficiency and yield by adding raw materials step by step and effectively removing by-products.

[0003] As a "chemical bridge" in solid-phase synthesis, linkers play an important role in the synthesis of polypeptides and small nucleic acid drugs. Among them, the siberian linker is an acid-sensitive linker widely used in solid-phase polypeptide synthesis, which can be removed under mild acidic conditions to release the target peptide segment. At the same time, the linker also has the advantages of simple operation, low cost, and environmental friendliness.

[0004] At present, the methods for synthesizing siberian linkers mainly include the following: One is to react 2-methoxybenzoyl chloride and m-dimethyl ether in anhydrous ethyl ether to obtain intermediate 1, then perform a ring-closing reaction under microwave assistance to obtain intermediate 2, and finally reflux and demethylate under the action of aluminum chloride to obtain the siberian linker (Bioorg. Med. Chem. 2014, 22, 1049-1062). The specific synthesis route is shown in formula (1) as follows.

[0005] (1)

[0006] However, the overall yield of this synthesis route is low, with a total yield of 31% in three steps. Moreover, the anhydrous ethyl ether used is an extremely flammable reagent with high safety risk, and the ring-closing step uses microwave assistance, which is difficult to realize industrial production.

[0007] In addition to the above method, there is also a report that o-fluorobenzoic acid and m-dimethyl ether are used as raw materials to react to obtain 2,4-dimethoxyphenyl-2-fluorophenyl ketone, and then the ring-closing and demethylation reactions are simultaneously performed by heating to about 100℃ in a strong acidic environment to obtain the siberian linker (CN114539201A). The specific synthesis route is shown in formula (2) as follows.

[0008] (2) However, although this synthesis route has a short step, the reaction conditions are relatively severe, requiring long-time high-temperature reaction in a strong acidic system, which has high requirements for the corrosion resistance of equipment. At the same time, the solvent consumption is large in the reaction and purification process, and the cost is high. SUMMARY

[0009] Therefore, the present application aims to provide a preparation method of Siberian linker, which is simple in operation, high in safety coefficient, mild in reaction condition, and high in yield, and is suitable for large-scale production.

[0010] To solve the above technical problems, the present application adopts the following technical solutions: The preparation method of Siberian linker according to the present application comprises: Step S1, performing a first demethylation reaction on 2,4-dimethoxyphenyl-2-fluorophenyl ketone to generate 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone; Step S2, performing a ring closure reaction on the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to generate 3-methoxyxanthone; Step S3, performing a second demethylation reaction on the 3-methoxyxanthone to obtain Siberian linker.

[0011] According to some embodiments of the present application, the first demethylation reaction is performed in a first solvent under the action of a first demethylation reagent, the first demethylation reagent is selected from any one or more of boron tribromide, aluminum trichloride, and pyridine hydrochloride, and the first solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, and trichloroethylene.

[0012] Further, the molar ratio of the 2,4-dimethoxyphenyl-2-fluorophenyl ketone to the first demethylation reagent is 1: (1.0-1.5), the reaction temperature is 0-50°C, and the reaction time is 2-8 h.

[0013] Further, after the first demethylation reaction is completed, an acid is added for quenching, washing, drying, and vacuum concentration to obtain the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone.

[0014] According to some embodiments of the present application, the ring closure reaction is performed in a second solvent in the presence of an inorganic base, the inorganic base is sodium hydroxide, potassium hydroxide, or a mixture thereof, and the second solvent is selected from any one or more of methanol, ethanol, and isopropanol.

[0015] Further, the inorganic base is sodium hydroxide, the molar ratio of the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to the sodium hydroxide is 1: (1.0-2.0), the reaction temperature of the ring closure reaction is 20-80°C, and the reaction time is 2-8 h.

[0016] Further, in the step S2, after the ring closure reaction is completed, suction filtration, beating, and drying are performed to obtain the 3-methoxyxanthone.

[0017] According to some embodiments of the present application, the secondary demethylation reaction is carried out in a third solvent under the action of a second demethylation reagent, the second demethylation reagent is selected from any one or more of boron tribromide, aluminum trichloride, and pyridine hydrochloride, and the third solvent is selected from any one or more of toluene, dimethylbenzene, and acetonitrile.

[0018] Further, the molar ratio of the 3-methoxyxanthone to the second demethylation reagent is 1: (1.0-3.0), the reaction temperature is 20-80°C, and the reaction time is 2-10 h.

[0019] Further, after the secondary demethylation reaction is completed, an acid is added for quenching, filtration is performed, and beating and purification are performed to obtain the Siberian linker.

[0020] The above technical solution of the present application has at least one of the following beneficial effects: According to the preparation method of the Siberian linker in the embodiments of the present application, 2,4-dimethoxyphenyl-2-fluorophenyl ketone is used as a starting material, one methyl unit is removed from the 2-methoxy group, a ring closure reaction is then performed, and then one methyl unit is removed from the remaining methoxy group after the ring closure reaction, the ring closure reaction and the demethylation reaction are performed in steps, and secondary demethylation is performed, which can effectively reduce the reaction temperature and energy consumption and the requirements on equipment; In addition, each reaction is mild and easy to operate, and has few side reactions, so that the overall high yield is achieved. In addition, the raw and auxiliary materials used are green and safe, and are suitable for industrial production. DETAILED DESCRIPTION

[0021] To make the purpose, technical solutions, and advantages of the embodiments of the present application clearer, the technical solutions of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the described embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present application.

[0022] First, the preparation method of the Siberian linker according to the embodiments of the present application will be described in detail below.

[0023] The preparation method of the Siberian linker according to the embodiments of the present application comprises: Step S1, one demethylation reaction is performed on 2,4-dimethoxyphenyl-2-fluorophenyl ketone to generate 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone; Step S2, a ring closure reaction is performed on the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to generate 3-methoxyxanthone; Step S3, subjecting the 3-methoxy xanthone to a second demethylation reaction to obtain the Siberian linker.

[0024] Specifically, the synthetic route is shown in the following formula (3): (3) That is, according to the preparation method of the embodiment of the present application, taking 2,4-dimethoxyphenyl-2-fluorophenyl ketone as the starting material, one methyl unit is first removed from the 2-methoxy group, and then a ring closure reaction is performed, and after the ring closure reaction, one methyl unit is removed from the remaining methoxy group. In other words, the entire route is divided into two steps of demethylation, and due to the different positions of the two methoxy groups, factors such as electronic effects will affect the reactivity, and through repeated research and a large number of experiments, the inventors take advantage of this structural characteristic to remove the methyl in two steps, which not only effectively reduces the occurrence of side reactions and the difficulty of purification, but also effectively reduces the reaction temperature and energy consumption, making the reaction conditions more mild.

[0025] Next, each step will be described.

[0026] (1) First demethylation reaction (i.e., step S1) According to the preparation method of the present application, as shown in the above formula (3), taking 2,4-dimethoxyphenyl-2-fluorophenyl ketone as the starting material, first perform a first demethylation reaction, i.e., remove one methyl unit from the 2-methoxy group. The methoxy group at position 2 will form a stable transition state due to the effect of the adjacent carbonyl group after coordination with the first demethylation reagent to form a complex, so that the methyl is more easily attacked by the nucleophile and is first removed.

[0027] According to some embodiments of the present application, the first demethylation reaction is performed in a first solvent under the action of a first demethylation reagent.

[0028] As the first demethylation reagent, for example, any one or more of boron tribromide, aluminum trichloride, and pyridine hydrochloride can be selected, and aluminum trichloride is preferred. Aluminum trichloride has moderate activity, but is much cheaper than boron tribromide, has much lower molecular weight than boron tribromide, and has less actual dosage, while pyridine hydrochloride has slightly lower activity and usually needs to be heated to promote the reaction.

[0029] In addition, as the first solvent, for example, any one or more of dichloromethane, 1,2-dichloroethane, and trichloroethylene can be selected, and dichloromethane is preferred. Dichloromethane is inexpensive and has a low boiling point, making it easy to handle.

[0030] Further, the molar ratio of 2,4-dimethoxyphenyl-2-fluorophenylmethanone to the first demethylation reagent is 1: (1.0-1.5), preferably, the molar ratio of 2,4-dimethoxyphenyl-2-fluorophenylmethanone to the first demethylation reagent is 1:1.1. The first demethylation reagent is slightly excessive, which ensures complete reaction of the raw material and avoids removal of another methyl group.

[0031] The reaction temperature can be 0-50°C, and the reaction time is 2-8h. Preferably, the reaction temperature is 20-25°C, and the reaction time is 6h. The reaction activity of the first demethylation reaction is high, and it is not necessary to increase the reaction rate by heating, which is more simple and easy to operate, has low requirements for equipment, and low energy consumption.

[0032] Further, after the first demethylation reaction is completed, the reaction is quenched with acid, washed, dried, and concentrated under reduced pressure to obtain the 2-hydroxy-4-methoxyphenyl-2-fluorophenylmethanone.

[0033] (B) ring-closing reaction (i.e., step S2) After obtaining the intermediate 2-hydroxy-4-methoxyphenyl-2-fluorophenylmethanone, a ring-closing reaction is performed to generate 3-methoxyxanthone.

[0034] As shown in the above formula (3), the ring-closing reaction is actually that the hydroxyl group on the benzene ring forms a phenolate with an inorganic base, and then removes the fluorine on the other benzene ring in MF units, so that the benzene rings at both ends are closed.

[0035] In fact, the first demethylation reaction and the ring-closing reaction can be performed in a “one-pot” manner, that is, the intermediate product 2-hydroxy-4-methoxyphenyl-2-fluorophenylmethanone does not need to be purified, but only needs to be quenched, washed, dried, and concentrated under reduced pressure after the first demethylation reaction, and then directly used for the ring-closing reaction. The intermediate treatment in the reaction is simple, the waste is less, and it is beneficial to improve the yield.

[0036] According to some embodiments of the present application, the ring-closing reaction is performed in the presence of an inorganic base in a second solvent. As described above, the present reaction is actually the removal of one MF unit, that is, the activation of the hydroxyl group and the maintenance of the alkaline environment by using an inorganic base can promote the reaction to proceed.

[0037] As the inorganic base, sodium hydroxide, potassium hydroxide, or a mixture thereof can be selected, and sodium hydroxide is preferred. Sodium hydroxide has moderate alkalinity and low cost.

[0038] As the second solvent, any one or more of methanol, ethanol, and isopropanol can be selected. Ethanol is preferred.

[0039] Further, the molar ratio of 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to sodium hydroxide is 1: (1.0-2.0), preferably, the molar ratio of 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to sodium hydroxide is 1: 1.1, and a slight excess of sodium hydroxide can ensure that the raw material can be completely salified, thereby improving the yield.

[0040] The reaction temperature of the ring closure reaction is 20-80°C, and the reaction time is 2-8 h. Preferably, the reaction temperature is 60°C, and the reaction time is 2 h. Appropriately increasing the reaction temperature can accelerate the reaction.

[0041] Further, after the ring closure reaction in step S2 is completed, the product is filtered, beaten, and dried to obtain the 3-methoxyxanthone. That is, the by-products in the previous two steps can be removed by simple purification to obtain the 3-methoxyxanthone with high purity for subsequent reactions, which can not only ensure the purity of the product but also help to obtain a higher yield.

[0042] (III) Secondary demethylation reaction (i.e., step S3) That is, after obtaining the intermediate 3-methoxyxanthone, a secondary demethylation reaction is performed to remove a methyl unit from the residual methoxy group, thereby obtaining the target Siberian linker.

[0043] According to some embodiments of the present application, the secondary demethylation reaction is performed in a third solvent under the action of a second demethylation reagent.

[0044] The second demethylation reagent is selected from any one or more of boron tribromide, aluminum trichloride, and pyridine hydrochloride. It should be noted that the second demethylation reagent can be the same as or different from the first demethylation reagent.

[0045] The third solvent can be selected from any one or more of toluene, xylene, and acetonitrile. Preferably, toluene is used because toluene is easy to separate into layers and is convenient for post-treatment.

[0046] Further, the molar ratio of 3-methoxyxanthone to second demethylation reagent is 1: (1.0-3.0); preferably, the molar ratio of 3-methoxyxanthone to demethylation reagent is 1: 2.0. The activity of the removed methyl group is lower, and a larger proportion of the demethylation reagent is beneficial to the complete secondary demethylation reaction.

[0047] The reaction temperature is 20-80°C, and the reaction time is 2-10 h. Appropriately heating can promote the reaction, and preferably, the reaction temperature is 65°C, and the reaction time is 4 h.

[0048] Further, after the secondary demethylation reaction is completed, the reaction solution is quenched with acid, filtered, and washed to obtain the Siberian linker.

[0049] As described above, the present application can provide a simple and effective method for preparing Siberian linker. In addition, the method of the present application is simple in operation, mild in reaction conditions, less in side reactions, high in purity, and suitable for industrial production.

[0050] The preparation method of Siberian linker of the present application will be further described in detail through specific examples.

[0051] Example 1 (I) Preparation of 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone In a 500 mL three-necked round-bottom flask, 300 mL of dichloromethane and 40 g of 2,4-dimethoxyphenyl-2-fluorophenyl ketone were added, and then the temperature was lowered to 0-5°C, 22.54 g of aluminum chloride was added in batches, and after the addition was completed, the temperature was maintained at 20-25°C and the reaction was stirred for 6 h.

[0052] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, stirred for 1.5 h, and separated into organic and aqueous phases. The organic phase was washed with 130 mL of water twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone.

[0053] (II) Preparation of 3-methoxyxanthone In a 500 mL three-necked round-bottom flask, the above-mentioned 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone crude product was added to 160 mL of ethanol, the temperature of the system was controlled at about 40°C, 6.76 g of sodium hydroxide was added, and after the addition was completed, the temperature was raised to 60°C and the reaction was carried out for 2 h.

[0054] After the reaction was completed, the temperature was lowered to 5-10°C, stirred for 1 h, filtered, the filter cake was washed with ethanol, and the obtained solid was washed with water at 40°C, and dried to obtain 3-methoxyxanthone 31.82 g with a yield of 91.5%.

[0055] (III) Preparation of Siberian linker In a 500 mL three-necked round-bottom flask, 300 mL of toluene and 40 g of 3-methoxyxanthone were added, the temperature was raised to 45°C, 47.15 g of aluminum chloride was added in batches, and after the addition was completed, the temperature was raised to 65°C and the reaction was carried out for 4 h.

[0056] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, the temperature was controlled at 35°C and stirred for 2 h, filtered, the filter cake was washed with water, and the obtained solid was washed with 150 mL of ethanol at 70°C, and dried to obtain Siberian linker 28.51 g with a yield of 76.0%.

[0057] The NMR data of the product are shown below: 1 H NMR (400 MHz, DMSO- d 6) δ 10.98 (s, 1H), 8.17 (dd, J = 7.9, 1.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.87 – 7.76 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 6.97 – 6.83 (m, 2H). Data shows that its structure matches that of the target product, Siber linker.

[0058] Example 2 (I) Preparation of 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone In a 500 mL three-necked round-bottom flask, add 300 mL of dichloromethane and 40 g of 2,4-dimethoxyphenyl-2-fluorophenyl ketone, then cool to 0-5 °C and add 26.64 g of aluminum trichloride in portions. After the addition is complete, maintain the temperature at 20-25 °C and stir the reaction for 6 h.

[0059] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, stirred for 1.5 h, separated, the organic phase was washed twice with 130 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2-hydroxy-4-methoxyphenyl-2-fluorophenyl methyl ketone.

[0060] (II) Preparation of 3-methoxy-zanthonone In a 500 mL three-necked round-bottom flask, the above crude 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone was added to 160 mL of ethanol. The system temperature was controlled at around 40 °C, and 9.22 g of sodium hydroxide was added. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 2 h.

[0061] After the reaction was completed, the temperature was lowered to 5-10℃, stirred for 1 h, filtered, the filter cake was washed with ethanol, the obtained solid was slurried with water heated to 40℃, dried, and 30.46 g of 3-methoxy-tonone was obtained, with a yield of 87.6%.

[0062] (III) Preparation of Siberian Linking Agent In a 500 mL three-necked round-bottom flask, add 300 mL of toluene and 40 g of 3-methoxyzantonone, heat to 45 °C, add 37.72 g of aluminum trichloride in portions, and then heat to 65 °C and react for 4 h.

[0063] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, and the temperature was controlled at 35℃ and stirred for 2 h. The mixture was then filtered, the filter cake was washed with water, and the resulting solid was slurried with 150 mL of ethanol at 70℃ and dried to obtain 26.94 g of Siber linkage agent, with a yield of 71.8%.

[0064] The NMR data of the product are shown below: 1 H NMR (400 MHz, DMSO- d 6) δ 10.98 (s, 1H), 8.17 (dd, J = 7.9, 1.2 Hz,1H), 8.06 (d, J = 8.7 Hz, 1H), 7.87 – 7.76 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 6.97 – 6.83 (m, 2H). Data shows that its structure matches that of the target product, Siber linker.

[0065] Example 3 (I) Preparation of 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone In a 500 mL three-necked round-bottom flask, add 300 mL of dichloromethane and 40 g of 2,4-dimethoxyphenyl-2-fluorophenyl ketone, then cool to 0-5 °C and add 22.54 g of aluminum trichloride in portions. After the addition is complete, heat to 40-45 °C and stir the reaction for 6 h.

[0066] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, stirred for 1.5 h, separated, the organic phase was washed twice with 130 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2-hydroxy-4-methoxyphenyl-2-fluorophenyl methyl ketone.

[0067] (II) Preparation of 3-methoxy-zanthonone In a 500 mL three-necked round-bottom flask, the crude 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone was added to 160 mL of ethanol. The system temperature was controlled at around 40 °C, and 6.76 g of sodium hydroxide was added. After the addition was complete, the reaction was kept at this temperature for 2 h.

[0068] After the reaction was completed, the temperature was lowered to 5-10℃, stirred for 1 h, filtered, the filter cake was washed with ethanol, the obtained solid was slurried with water heated to 40℃, dried, and 28.93 g of 3-methoxy-tonone was obtained, with a yield of 83.2%.

[0069] (III) Preparation of Siberian Linking Agent In a 500 mL three-necked round-bottom flask, add 300 mL of toluene and 40 g of 3-methoxyzantonone, heat to 45 °C, and add 47.15 g of aluminum trichloride in portions. After the addition is complete, keep the mixture at this temperature for 4 h.

[0070] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, and the temperature was controlled at 35℃ and stirred for 2 h. The mixture was then filtered, the filter cake was washed with water, and the resulting solid was slurried with 150 mL of ethanol at 70℃ and dried to obtain 26.34 g of Siber linkage agent, with a yield of 70.2%.

[0071] The NMR data of the product are shown below: 1 H NMR (400 MHz, DMSO- d 6) δ 10.98 (s, 1H), 8.17 (dd, J = 7.9, 1.2 Hz,1H), 8.06 (d, J = 8.7 Hz, 1H), 7.87 – 7.76 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 6.97 – 6.83 (m, 2H). Data shows that its structure matches that of the target product, Siber linker.

[0072] Example 4 (I) Preparation of 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone In a 500 mL three-necked round-bottom flask, add 300 mL of dichloromethane and 40 g of 2,4-dimethoxyphenyl-2-fluorophenyl ketone, then cool to 0-5 °C and add 19.54 g of pyridine hydrochloride in portions. After the addition is complete, maintain the temperature at 20-25 °C and stir the reaction for 6 h.

[0073] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, stirred for 1.5 h, separated, the organic phase was washed twice with 130 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2-hydroxy-4-methoxyphenyl-2-fluorophenyl methyl ketone.

[0074] (II) Preparation of 3-methoxy-zanthonone In a 500 mL three-necked round-bottom flask, the crude 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone was added to 160 mL of isopropanol. The temperature of the system was controlled at around 40 °C, and 6.76 g of sodium hydroxide was added. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 2 h.

[0075] After the reaction was completed, the temperature was lowered to 5-10℃, stirred for 1 h, filtered, the filter cake was washed with ethanol, the obtained solid was slurried with water heated to 40℃, dried, and 27.09 g of 3-methoxy-tonone was obtained, with a yield of 77.9%.

[0076] (III) Preparation of Siberian Linking Agent In a 500 mL three-necked round-bottom flask, add 300 mL of toluene and 40 g of 3-methoxyzantonone, heat to 45 °C, add 88.59 g of boron tribromide, and then heat to 65 °C and maintain the temperature for 4 h.

[0077] After the reaction was completed, the reaction solution was transferred to dilute hydrochloric acid for quenching, and the temperature was controlled at 35℃ and stirred for 2 h. The mixture was then filtered, the filter cake was washed with water, and the resulting solid was slurried with 150 mL of ethanol at 70℃ and dried to obtain 27.76 g of Siber linkage agent, with a yield of 74.0%.

[0078] The NMR data of the product are shown below: 1 H NMR (400 MHz, DMSO- d 6) δ 10.98 (s, 1H), 8.17 (dd, J = 7.9, 1.2 Hz,1H), 8.06 (d, J = 8.7 Hz, 1H), 7.87 – 7.76 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 6.97 – 6.83 (m, 2H). Data shows that its structure matches that of the target product, Siber linker. The above description represents a preferred embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles described herein, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method of preparing a Siberlinker, characterized by, The method comprises the following steps: S1, performing a first demethylation reaction on 2,4-dimethoxyphenyl-2-fluorophenyl ketone to obtain 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone; S2, performing a ring closure reaction on the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to obtain 3-methoxyxanthone; S3, performing a second demethylation reaction on the 3-methoxyxanthone to obtain the Siberian linker.

2. The production method according to claim 1, characterized by, The first demethylation reagent is selected from any one or more of boron tribromide, aluminum trichloride, and pyridine hydrochloride, and the first solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, and trichloroethylene.

3. The production method according to claim 2, characterized by, The molar ratio of the 2,4-dimethoxyphenyl-2-fluorophenyl ketone to the first demethylation reagent is 1: (1.0-1.5), the reaction temperature is 0-50°C, and the reaction time is 2-8 h.

4. The production method according to claim 2, characterized by, After the first demethylation reaction is completed, an acid is added for quenching, washing, drying, and concentration under reduced pressure to obtain the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone.

5. The preparation method according to claim 1, characterized in that, The ring closure reaction is performed in the presence of an inorganic base in a second solvent, the inorganic base is sodium hydroxide, potassium hydroxide, or a mixture thereof, and the second solvent is selected from any one or more of methanol, ethanol, and isopropanol.

6. The production method according to claim 5, characterized by, The inorganic base is sodium hydroxide, the molar ratio of the 2-hydroxy-4-methoxyphenyl-2-fluorophenyl ketone to the sodium hydroxide is 1: (1.0-2.0), the reaction temperature of the ring closure reaction is 20-80°C, and the reaction time is 2-8 h.

7. The preparation method according to claim 5, characterized in that, In the step S2, after the ring closure reaction is completed, suction filtration, beating, and drying are performed to obtain the 3-methoxyxanthone.

8. The method of claim 1, wherein, The second demethylation reagent is selected from any one or more of boron tribromide, aluminum trichloride, and pyridine hydrochloride, and the third solvent is selected from any one or more of toluene, xylene, and acetonitrile.

9. The production method according to claim 8, characterized by, The molar ratio of the 3-methoxyxanthone to the second demethylation reagent is 1: (1.0-3.0), the reaction temperature is 20-80°C, and the reaction time is 2-10 h.

10. The preparation method according to claim 8, characterized in that, After the second demethylation reaction is completed, an acid is added for quenching, suction filtration, and beating purification to obtain the Siberian linker.

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