Method for synthesizing and refining arbidol hydrochloride intermediate

Abstract

The invention provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which comprises the following steps: by taking 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester, diphenyl disulfide and a reducing agent as raw materials, reacting to obtain a crude product of the arbidol hydrochloride intermediate, and refining the crude product to obtain the arbidol hydrochloride intermediate. The reaction product is 6-bromine-5-hydroxyl-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester, and the reaction product is 6-bromine-5-hydroxyl-1-methyl-2 The arbidol hydrochloride intermediate is prepared from diphenyl disulfide, the raw materials are easy to obtain, and the safety is remarkably improved compared with the prior art; meanwhile, a refining process of the product is developed, the high-purity drug intermediate with the purity up to 99.87% and the total single impurity content less than 0.13% can be prepared, and the refining yield is up to 91% or above; the reaction conditions are mild, the synthesis safety is greatly improved, the product quality is remarkably improved, and industrial large-scale preparation is facilitated.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing and refining an arbidol hydrochloride intermediate. Background Art

[0002] Arbidol hydrochloride is a commonly used antiviral drug that can block viral replication by inhibiting the fusion of influenza virus lipid membrane with host cells. It is an interferon inducer and immune enhancer. Its main indication is influenza caused by influenza A and B viruses. It may also have antiviral activity against some other respiratory viral infections.

[0003] 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethyl-indole-3-carboxylic acid ethyl ester is an important intermediate for the synthesis of hydrochloric acid arbidol, and its preparation method is generally carried out with 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester as raw material. For example, CN117586173B discloses a preparation method of arbidol, wherein 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester is joined in a methanol solvent containing potassium hydroxide and thiophenol and reacted, and the pH is adjusted to 4-5 to obtain 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethyl-indole-3-carboxylic acid ethyl ester. CN111269168A discloses a method for preparing an arbidol intermediate, which discloses that 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester is condensed with sodium thiophenol to obtain 5-hydroxy-6-bromo-2-phenylthiomethyl-1-methylindole-3-carboxylic acid ethyl ester.

[0004] The preparation method in the existing technology currently uses thiophenol, which is a highly toxic drug and has a foul odor, making it difficult to scale up production. The use of sodium thiophenol will introduce new salt impurities, increasing the difficulty of post-processing. The purity of the preparation is difficult to meet the high-purity requirements of pharmaceutical intermediates, resulting in low yield and purity of the subsequent arbidol.

[0005] In summary, developing a method for synthesizing and refining an arbidol hydrochloride intermediate with mild temperature, simple separation and purification, safe reaction, high purity and low impurity has become an urgent problem to be solved. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention aims to provide a method for synthesizing and refining an arbidol hydrochloride intermediate. The method provided by the present invention uses diphenyl disulfide to prepare an arbidol hydrochloride intermediate. The raw materials are readily available and the safety is significantly improved compared to the prior art. The present invention also develops a product refining process, which can prepare a high-purity pharmaceutical intermediate with a purity of up to 99.87% and a total impurity content of less than 0.13%, with a refining yield of more than 80%. The reaction conditions of the invention are mild, which greatly reduces the safety of the synthesis, significantly improves the product quality, and is conducive to industrial scale-up preparation.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] The object of the present invention is to provide a method for synthesizing and refining an arbidol hydrochloride intermediate, which comprises taking 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester, diphenyl disulfide and a reducing agent as raw materials, reacting to obtain a crude arbidol hydrochloride intermediate product, and refining the crude product to obtain the arbidol hydrochloride intermediate, i.e., 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester.

[0009] Specifically, the reducing agent includes one of sodium borohydride, sodium hydroxide, potassium hydroxide, and sodium hydride.

[0010] Specifically, diphenyl disulfide and a reducing agent are added to a reaction bottle, and a first solvent is added after vacuuming. After a first reaction occurs, 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester is added, and a second reaction occurs to obtain a crude intermediate of arbidol hydrochloride;

[0011] Preferably, after the second reaction is completed, washing with water and washing with ice methanol are carried out in sequence, and drying is performed to obtain a crude intermediate of arbidol hydrochloride.

[0012] Preferably, in the first reaction, the molar ratio of the diphenyl disulfide to the reducing agent is 1:(1.8-4), and the molar ratio of the 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester to diphenyl disulfide is 1:(0.5-0.75);

[0013] More preferably, the molar ratio of the diphenyl disulfide to the reducing agent is 1:(1.8-2.5), and the molar ratio of 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester to diphenyl disulfide is 1:(0.5-0.6).

[0014] Preferably, the temperature of the first reaction is 40-60°C, and the time is 0.5-2h; more preferably, the temperature of the first reaction can be 40°C, 45°C, 50°C, 55°C or 60°C, etc., and the time can be 0.5h, 1h, 1.5h or 2h, etc., but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0015] Preferably, the temperature of the second reaction is 15-35°C, and the time is 1-6h; more preferably, the temperature of the second reaction can be 15°C, 20°C, 25°C, 30°C or 35°C, etc., and the time can be 1h, 2h, 3h, 4h, 5h or 6h, etc., but is not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0016] Preferably, the first solvent comprises one of tetrahydrofuran, methanol, ethanol, acetonitrile and acetone;

[0017] More preferably, after vacuuming and adding the first solvent, stirring is carried out at room temperature for 0.5-3 hours; further preferably, the stirring time at room temperature can be 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours, etc., but is not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0018] Specifically, the refining comprises the following steps: dissolving the crude product in DMF, then adding water dropwise until turbidity for crystallization; filtering, eluting the filter cake with a second solvent, and drying to obtain the arbidol hydrochloride intermediate, i.e., ethyl 6-bromo-5-hydroxy-1-methyl 2-phenylthiomethyl indole-3-carboxylate;

[0019] Preferably, the second solvent is one selected from acetonitrile, methanol, ethanol, acetone and tetrahydrofuran.

[0020] Preferably, the mass volume ratio of the crude product to DMF is 1:(3-8);

[0021] Preferably, the volume ratio of DMF, water and the second solvent is 1:(0.1-0.3):(0.25-1);

[0022] More preferably, the volume ratio of DMF, water and the second solvent is 1:(0.1-0.2):(0.4-0.6).

[0023] Preferably, the crystallization time is 4-6 hours; more preferably, the crystallization time can be 4 hours, 5 hours or 6 hours, etc., but is not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0024] Preferably, the drying temperature is 50-70°C, and the drying time is 2-6 hours; more preferably, the drying temperature can be 50°C, 55°C, 60°C, 65°C or 70°C, and the drying time can be 2 hours, 3 hours, 4 hours, 5 hours or 6 hours, but are not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0025] Compared with the prior art, the present invention provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which has the following beneficial effects:

[0026] (1) The present invention uses diphenyl disulfide to prepare the arbidol hydrochloride intermediate, the raw materials are easily available, and the safety is significantly improved compared with the existing technology;

[0027] (2) The present invention also develops a product purification process, which can prepare a high-purity pharmaceutical intermediate with a purity of up to 99.87% and a total impurity content of less than 0.13%, and a purification yield of up to 91% or more;

[0028] (3) The reaction conditions of the invention are mild, which greatly improves the safety of the synthesis, significantly enhances the product quality, and is conducive to industrial scale-up preparation. DETAILED DESCRIPTION

[0029] In order to further illustrate the technical means and effects adopted by the present invention, the technical solutions of the present invention are further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0030] Example 1

[0031] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, comprising the following steps: adding 20 g of diphenyl disulfide and 6.93 g of sodium borohydride to a reaction flask, evacuating the flask, adding 100 mL of tetrahydrofuran, stirring at room temperature for 30 minutes until completely dissolved, heating to 50° C. to cause a first reaction for 0.5 h, then adding 79.3 g of ethyl 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylate, causing a second reaction at room temperature for 5 hours, washing with water and ice methanol in sequence, and drying to obtain 61.6 g of a crude arbidol hydrochloride intermediate; the yield is 80.0% and the purity is 95.2%.

[0032] Refining: Add 50g of off-white crude arbidol hydrochloride and 200mL of DMF to a bottle and dissolve them. Then add 25mL of water dropwise until the bottle becomes turbid and crystallize for 5 hours. After filtration, the filter cake is rinsed three times with 100ml of acetonitrile and air-dried at 60°C for 4 hours to obtain 45.0g of an off-white powdery solid with a yield of 90.0%, namely ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Samples were taken for LC testing, and the content was 99.85%, with single impurities of 0.08% and 0.07%, respectively. The product was qualified.

[0033] Example 2

[0034] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 7.3 g of sodium hydroxide is used as the reducing agent, and 60.5 g of a crude arbidol hydrochloride intermediate is obtained by drying; the yield is 78.6% and the purity is 95.1%.

[0035] Example 3

[0036] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 10.3 g of potassium hydroxide is used as the reducing agent, and 60.9 g of a crude arbidol hydrochloride intermediate is obtained by drying; the yield is 79.1% and the purity is 95.0%.

[0037] Example 4

[0038] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 6.3 g of sodium borohydride is added and dried to obtain 60.6 g of a crude arbidol hydrochloride intermediate; the yield is 78.8% and the purity is 94.8%.

[0039] Example 5

[0040] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 8.7 g of sodium borohydride is added and dried to obtain 61.0 g of a crude arbidol hydrochloride intermediate; the yield is 79.2% and the purity is 94.2%.

[0041] Example 6

[0042] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 13.9 g of sodium borohydride is added and dried to obtain 58.3 g of a crude arbidol hydrochloride intermediate; the yield is 75.8% and the purity is 94%.

[0043] Example 7

[0044] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 53.1 g of ethyl 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylate is added and dried to obtain 40.7 g of a crude arbidol hydrochloride intermediate; the yield is 79% and the purity is 94%.

[0045] Example 8

[0046] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that 66.41 g of 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester is added and dried to obtain 51.2 g of a crude arbidol hydrochloride intermediate; the yield is 79.5% and the purity is 93.2%.

[0047] Example 9

[0048] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that the temperature of the first reaction is 60°C, the reaction time is 1h, and drying is performed to obtain 60.0g of a crude arbidol hydrochloride intermediate; the yield is 77.9% and the purity is 92.1%.

[0049] Example 10

[0050] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that the temperature of the first reaction is 40°C, the reaction time is 2h, and drying is performed to obtain 60.3g of a crude arbidol hydrochloride intermediate; the yield is 78.3% and the purity is 94%.

[0051] Example 11

[0052] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that the temperature of the second reaction is 35°C, the reaction time is 2h, and drying is performed to obtain 60.9g of a crude arbidol hydrochloride intermediate; the yield is 79.1% and the purity is 92.4%.

[0053] Example 12

[0054] This embodiment provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that the temperature of the second reaction is 15°C, the reaction time is 3h, and drying is performed to obtain 61.0g of a crude arbidol hydrochloride intermediate; the yield is 79.3% and the purity is 95.1%.

[0055] Example 13

[0056] This example provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is substantially the same as Example 1, except that 250 mL of DMF is added during the refining process to obtain 44.0 g of an off-white powdery solid with a yield of 88%, namely, ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.8%, single impurities of 0.1% and 0.1%, and the product was qualified.

[0057] Example 14

[0058] This example provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is substantially the same as Example 1, except that 150 mL of DMF is added during the refining process to obtain 44.5 g of an off-white powdery solid with a yield of 89.0%, namely, ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.82%, single impurities of 0.1% and 0.08%, and the product was qualified.

[0059] Example 15

[0060] This example provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is substantially the same as Example 1, except that 400 mL of DMF is added during the refining process to obtain 42.5 g of an off-white powdery solid with a yield of 85%, namely, ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.89%, single impurities of 0.06% and 0.05%, and the product was qualified.

[0061] Example 16

[0062] The present embodiment provides a kind of synthesis and purification method of arbidol hydrochloride intermediate, it is substantially the same as Example 1, except that, in refining process, 30mL water is added dropwise, until turbidity in bottle, crystallization 5h.After filtration, filter cake is rinsed three times with 100ml acetonitrile, finally obtains off-white powder solid 45.6g, yield 91.1%, i.e. 6- bromo-5- hydroxy-1- methyl 2- phenylthiomethyl indole-3-carboxylic acid ethyl ester.Sampling detection LC, content 99.87%, single assorted 0.07% and 0.06%, product qualified.

[0063] Example 17

[0064] The present embodiment provides a kind of synthesis and purification method of arbidol hydrochloride intermediate, it is substantially the same as Example 1, except that, in refining process, 20mL water is added dropwise, until turbidity in bottle, crystallization 5h.After filtration, filter cake is rinsed three times with 200ml acetonitrile, finally obtains off-white powder solid 44.8g, yield 89.5%, i.e. 6- bromo-5- hydroxy-1- methyl 2- phenylthiomethyl indole-3-carboxylic acid ethyl ester.Sampling detection LC, content 99.75%, single assorted 0.18% and 0.07%, product qualified.

[0065] Example 18

[0066] The present embodiment provides a kind of synthesis and purification method of arbidol hydrochloride intermediate, it is substantially the same as Example 1, except that, in refining process, 40mL water is added dropwise, until turbidity in bottle, crystallization 5h.After filtration, filter cake is rinsed three times with 80ml acetonitrile, finally obtains off-white powder solid 45.0g, yield 89.9%, i.e. 6- bromo-5- hydroxy-1- methyl 2- phenylthiomethyl indole-3-carboxylic acid ethyl ester.Sampling detection LC, content 99.7%, single assorted 0.19% and 0.11%, product qualified.

[0067] Example 19

[0068] The present embodiment provides a kind of synthesis and purification method of arbidol hydrochloride intermediate, it is substantially the same as Example 1, except that, in refining process, 60mL water is added dropwise, until turbidity in bottle, crystallization 5h.After filtration, filter cake is rinsed three times with 162ml acetonitrile, finally obtains off-white powder solid 44.6g, yield 89.2%, i.e. 6- bromo-5- hydroxy-1- methyl 2- phenylthiomethyl indole-3-carboxylic acid ethyl ester.Sampling detection LC, content 99.8%, single assorted 0.13% and 0.07%, product qualified.

[0069] Example 20

[0070] This example provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is substantially the same as Example 1, except that the mixture is dried under forced air at 50°C for 6 h to obtain 44.2 g of an off-white powdery solid with a yield of 88.4%, i.e., ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. LC analysis of the sample showed a content of 99.7%, with single impurities of 0.18% and 0.12%, respectively. The product was qualified.

[0071] Example 21

[0072] This example provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is substantially the same as Example 1, except that the mixture is dried under forced air at 70°C for 2 h to obtain 43.8 g of an off-white powdery solid with a yield of 87.7%, i.e., ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. LC analysis of the sample showed a content of 99.80%, with single impurities of 0.15% and 0.05%, respectively, indicating that the product was qualified.

[0073] Example 22

[0074] This example provides a method for synthesizing and refining an intermediate of Arbidol hydrochloride, which is substantially the same as Example 1, except that the crystallization time is 4 hours, and 44.6 g of an off-white powdery solid is obtained with a yield of 89.2%, namely, ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.88%, single impurities of 0.09% and 0.03%, and the product was qualified.

[0075] Example 23

[0076] This embodiment provides a method for synthesizing and refining an intermediate of Arbidol hydrochloride, which is substantially the same as Example 1, except that the crystallization time is 6 hours, and 45.0 g of an off-white powdery solid is obtained with a yield of 89.8%, namely, ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.80%, single impurities of 0.12% and 0.08%, and the product was qualified.

[0077] Example 24

[0078] This embodiment provides a method for synthesizing and refining an intermediate of Arbidol hydrochloride, which is substantially the same as Example 1, except that after filtration, the filter cake is rinsed three times with 100 ml of ethanol to obtain 82.7 g of an off-white powdery solid with a yield of 88.4%, i.e., ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.79%, single impurities of 0.15% and 0.06%, and the product was qualified.

[0079] Example 25

[0080] This embodiment provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is substantially the same as Example 1, except that after filtration, the filter cake is rinsed three times with 100 ml of acetone to obtain 44.5 g of an off-white powdery solid with a yield of 89%, i.e., ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate. Sampling and LC testing showed a content of 99.80%, single impurities of 0.1% and 0.1%, and the product was qualified.

[0081] Comparative Example 1

[0082] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the refining process, 200 mL of ethyl acetate was added, and the off-white crude arbidol hydrochloride product could not be completely dissolved. Then, 25 mL of petroleum ether was added dropwise for slurrying, and the refining effect was poor. The LC content of the sample was 97.00%, the single impurity was 2% and 1%, and the product was unqualified.

[0083] Comparative Example 2

[0084] This comparative example provides a method for synthesizing and refining an intermediate of arbidol hydrochloride, which is basically the same as Example 1, except that, during the refining process, 200 mL of dichloromethane was added, and the off-white crude arbidol hydrochloride product could not be dissolved, and then 25 mL of n-hexane was added dropwise, the refining effect was poor, the refining yield was 99%, and the LC test of the sample showed 96.00%, 3% and 1% of single impurities, and the product was unqualified.

[0085] Comparative Example 3

[0086] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the refining process, 200 mL of DMF was added to dissolve the off-white arbidol hydrochloride crude product, and then 10 mL of water was added dropwise. The refining effect was poor, the refining yield was 60%, and the LC content of the sample was 96.50%, the single impurity was 2.8% and 0.7%, and the product was unqualified.

[0087] Comparative Example 4

[0088] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the refining process, 200 mL of DMF was added to dissolve the off-white arbidol hydrochloride crude product, and then 100 mL of water was added dropwise. The refining effect was poor, the refining yield was 95%, and the LC content of the sample was 96.2%, the single impurity was 2.5% and 1.3%, and the product was unqualified.

[0089] Comparative Example 5

[0090] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the synthesis process, 32.0 g of diphenyl disulfide and 11.08 g of sodium borohydride are added, and finally dried to obtain 35.0 g of a crude arbidol hydrochloride intermediate; the yield is 45.5% and the purity is 92%.

[0091] Comparative Example 6

[0092] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the synthesis process, 35.98 g of diphenyl disulfide and 12.46 g of sodium borohydride are added, and finally dried to obtain 32.0 g of a crude arbidol hydrochloride intermediate; the yield is 41.6% and the purity is 91%.

[0093] Comparative Example 7

[0094] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the synthesis process, the temperature of the first reaction is 70°C, the reaction time is 3h, and drying is performed to obtain 30.0g of a crude arbidol hydrochloride intermediate; the yield is 39% and the purity is 90%.

[0095] Comparative Example 8

[0096] This comparative example provides a method for synthesizing and refining an arbidol hydrochloride intermediate, which is basically the same as Example 1, except that, during the synthesis process, the temperature of the second reaction is 50°C, the reaction time is 6h, and drying is performed to obtain 28.0g of a crude arbidol hydrochloride intermediate; the yield is 36.44% and the purity is 91%.

[0097] The applicant declares that the present invention illustrates a method for synthesizing and refining an arbidol hydrochloride intermediate of the present invention by means of the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of the raw materials of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

[0098] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0099] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for synthesizing and refining an arbidol hydrochloride intermediate, characterized in that: Using 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester, diphenyl disulfide and a reducing agent as raw materials, a crude intermediate of arbidol hydrochloride is obtained by reaction. The crude product is refined to obtain the intermediate of arbidol hydrochloride, namely 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester.

2. The synthesis and purification method according to claim 1, characterized in that: The reducing agent includes one of sodium borohydride, sodium hydroxide, potassium hydroxide and sodium hydride.

3. The synthesis and purification method according to claim 1, characterized in that: Add diphenyl disulfide and a reducing agent to the reaction flask, evacuate the flask, add the first solvent, and after the first reaction, add 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester, and cause a second reaction to obtain a crude intermediate of arbidol hydrochloride; Preferably, after the second reaction is completed, washing with water and washing with ice methanol are carried out in sequence, and drying is performed to obtain a crude intermediate of arbidol hydrochloride.

4. The synthesis and purification method according to claim 3, characterized in that: The molar ratio of the diphenyl disulfide to the reducing agent is 1:(1.8-4), and the molar ratio of the 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester to diphenyl disulfide is 1:(0.5-0.75); Preferably, the molar ratio of the diphenyl disulfide to the reducing agent is 1:(1.8-2.5), and the molar ratio of 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester to diphenyl disulfide is 1:(0.5-0.6).

5. The synthesis and purification method according to claim 3, characterized in that: The temperature of the first reaction is 40-60° C., and the time is 0.5-2 h.

6. The synthesis and purification method according to claim 3, characterized in that: The temperature of the second reaction is 15-35° C., and the time is 1-6 hours.

7. The synthesis and purification method according to claim 3, characterized in that: The first solvent comprises one of tetrahydrofuran, methanol, ethanol, acetonitrile, and acetone; Preferably, after adding the first solvent under vacuum, stirring is carried out at room temperature for 0.5-3 hours.

8. The synthesis and purification method according to claim 1, characterized in that: The purification comprises the following steps: dissolving the crude product in DMF, then adding water dropwise until turbidity for crystallization; filtering, eluting the filter cake with a second solvent, and drying to obtain the arbidol hydrochloride intermediate, i.e., ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate; Preferably, the second solvent is one selected from acetonitrile, methanol, ethanol, acetone and tetrahydrofuran.

9. The synthesis and purification method according to claim 8, characterized in that: The mass volume ratio of the crude product to DMF is 1:(3-8); the volume ratio of DMF, water and the second solvent is 1:(0.1-0.3):(0.25-1); Preferably, the volume ratio of DMF, water and the second solvent is 1:(0.1-0.2):(0.4-0.6).

10. The synthesis and purification method according to claim 8, characterized in that: The crystallization time is 4-6h; Preferably, the drying temperature is 50-70° C., and the drying time is 2-6 hours.