Preparation method of 6-benzofuran phenol

Abstract

The invention provides a preparation method of 6-benzofuran phenol, which comprises the following steps: step S1, 6-hydroxy-2H-benzofuran-3-ketone and a methylation reagent are subjected to a reaction to generate 6-hydroxymethyl-2H-benzofuran-3-ketone, and the methylation reagent is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate and the like; step S2, enabling the 6-hydroxymethyl-2H-benzofuran-3-ketone to react with a reducing agent, so as to generate 6-hydroxymethyl-2H-benzofuran-3-alcohol; s3, the 6-hydroxymethyl-2H-benzofuran-3-alcohol is subjected to a demethylation reaction and an elimination reaction, and the 6-benzofuran phenol is generated. According to the preparation method of the 6-benzofuran phenol, the phenolic hydroxyl group is protected by methyl, demethylation and alcohol elimination are completed by a one-pot method, and an intermediate product has few impurities and is simple to purify.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and more specifically, relates to a method for preparing 6-benzofuranol. Background Art

[0002] As a commonly used drug intermediate, 6-benzofuranol has important applications in the synthesis of integrin αvβ3 receptor antagonists. Integrin αvβ3 is one of the most studied and discussed extracellular matrix adhesion receptors. Due to its high expression in tumor angiogenesis, αvβ3 has become an important target for tumor diagnosis and anti-tumor drug research. The natural ligands of αvβ3 all contain an arginine-glycine-aspartic acid (RGD) sequence, which is involved in activities such as tumor cell proliferation and metastasis. This property of RGD can be used to construct molecular imaging probes for tumor diagnosis in vitro and drugs for targeted therapy. Based on the key role of integrin αvβ3 in tumor diagnosis and treatment, the structure and function of αvβ3 and its role in cancer diagnosis and treatment have received widespread attention.

[0003] At present, the preparation method of 6-benzofuranol reported in the literature is mainly: 6-hydroxy-2H-benzofuran-3-one is protected with tert-butyldimethylsilyl chloride reagent, then reduced with sodium borohydride and deprotected and eliminated under acidic conditions. However, this method has many impurities and is difficult to purify, and a chromatography column is required to obtain a pure product. Summary of the invention

[0004] In view of this, the object of the present invention is to provide a method for preparing 6-benzofuranol with good intermediate purity, high yield, high reaction and operation safety, and suitable for industrial production.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] The preparation method of 6-benzofuranol according to an embodiment of the present invention comprises the following steps:

[0007] Step S1, reacting 6-hydroxy-2H-benzofuran-3-one with a methylating agent to generate 6-hydroxymethyl-2H-benzofuran-3-one, wherein the methylating agent is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, etc.;

[0008] Step S2, reacting the 6-hydroxymethyl-2H-benzofuran-3-one with a reducing agent to generate 6-hydroxymethyl-2H-benzofuran-3-ol;

[0009] Step S3, demethylating and eliminating the 6-hydroxymethyl-2H-benzofuran-3-ol to generate 6-benzofuranol.

[0010] Furthermore, the methylating agent is dimethyl carbonate, and the step S1 comprises:

[0011] The 6-hydroxy-2H-benzofuran-3-one is reacted with dimethyl carbonate in the presence of an inorganic base and under the action of a catalyst to generate the 6-hydroxymethyl-2H-benzofuran-3-one.

[0012] Furthermore, the inorganic base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, etc., and the catalyst is 18-crown ether-6.

[0013] Furthermore, the molar ratio of the 6-hydroxy-2H-benzofuran-3-one to dimethyl carbonate, potassium carbonate and 18-crown ether-6 is 1:(2-4):(1-2):(0.01-0.1).

[0014] Furthermore, the reducing agent is one or more of sodium borohydride, lithium aluminum tetrahydride, and red aluminum.

[0015] Furthermore, the reducing agent is red aluminum, and the step S2 comprises:

[0016] The 6-hydroxymethyl-2H-benzofuran-3-one is added to toluene, and red aluminum is added dropwise to the reaction system to react to generate the 6-hydroxymethyl-2H-benzofuran-3-ol.

[0017] Furthermore, in step S2, the molar ratio of 6-hydroxymethyl-2H-benzofuran-3-one to red aluminum is 1:(1-1.1), the reaction temperature is 5-10° C., and the reaction time is 2-4 hours.

[0018] Furthermore, the step S3 comprises:

[0019] 6-Hydroxymethyl-2H-benzofuran-3-ol is added to dichloromethane, and aluminum chloride is added thereto in portions to cause demethylation and elimination reactions to generate the 6-benzofuranol.

[0020] Furthermore, the step S3 further includes:

[0021] After the reaction was completed, the reaction solution was poured into 6 mol / L hydrochloric acid in batches to quench the aluminum salt, and stirred at 30° C. for 1 hour. Thereafter, the organic phase was separated and post-treated to obtain the 6-benzofuranol.

[0022] Furthermore, the post-processing includes:

[0023] The organic phase was washed once with 1 mol / L dilute hydrochloric acid, once with water, and once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product;

[0024] The crude product was recrystallized from ethyl acetate:n-heptane at a volume ratio of 1:2 to obtain purified 6-benzofuranol.

[0025] The above technical solution of the present invention has at least one of the following beneficial effects:

[0026] According to the preparation method of 6-benzofuranol in an embodiment of the present invention, the phenolic hydroxyl group is protected by a methyl group, and the demethylation and alcohol elimination are completed in one pot;

[0027] Furthermore, using the methylating agent of the present application for protection instead of tert-butyldimethylsilyl chloride is beneficial to further improve the purity of the intermediate and make the final purification simpler and easier to operate;

[0028] Furthermore, aluminum chloride is used to complete the demethylation and alcohol elimination in one pot, which is simpler to operate. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0030] The following first describes in detail the preparation method of 6-benzofuranol according to an embodiment of the present invention.

[0031] The preparation method of 6-benzofuranol according to an embodiment of the present invention comprises the following steps:

[0032] Step S1, reacting 6-hydroxy-2H-benzofuran-3-one with a methylating agent to generate 6-hydroxymethyl-2H-benzofuran-3-one, wherein the methylating agent is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, etc.;

[0033] Step S2, reacting the 6-hydroxymethyl-2H-benzofuran-3-one with a reducing agent to generate 6-hydroxymethyl-2H-benzofuran-3-ol;

[0034] Step S3, demethylating and eliminating the 6-hydroxymethyl-2H-benzofuran-3-ol to generate 6-benzofuranol.

[0035] According to the preparation method of 6-benzofuranol in an embodiment of the present invention, the phenolic hydroxyl group is protected by a methyl group, and the demethylation and alcohol elimination are completed in one pot; in addition, the methylation reagent of the present application is used for protection instead of tert-butyldimethylchlorosilane, which is beneficial to further improve the purity of the intermediate and make the final purification simpler and easier to operate.

[0036] The following describes steps S1, S2 and S3 in detail.

[0037] (i) Step S1, reacting 6-hydroxy-2H-benzofuran-3-one with a methylating agent to generate 6-hydroxymethyl-2H-benzofuran-3-one, wherein the methylating agent is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, etc.

[0038] That is to say, in the preparation method of the present application, the methylating agent is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, etc., and the use of these methylating agents for methyl protection can improve the purity of the intermediate and make the final purification simpler and easier to operate compared to the prior art using tert-butyldimethylsilyl chloride reagent.

[0039] In some embodiments of the present invention, the methylating agent is dimethyl carbonate. Compared with dimethyl sulfate and methyl iodide, dimethyl carbonate has lower toxicity and is therefore preferred.

[0040] In some embodiments of the present invention, step S1 comprises:

[0041] The 6-hydroxy-2H-benzofuran-3-one is reacted with dimethyl carbonate in the presence of an inorganic base and under the action of a catalyst to generate the 6-hydroxymethyl-2H-benzofuran-3-one.

[0042] That is to say, in the presence of an inorganic base, by using a catalyst so as to promote the smooth reaction. As the inorganic base, one or more of sodium carbonate, potassium carbonate, cesium carbonate etc. can be selected, wherein potassium carbonate is preferably used. In addition, as a catalyst, 18-crown ether-6 can be selected.

[0043] One of the most important characteristics of crown ethers is that they can form stable complexes with various metal salts, ammonium salts, organic cationic compounds, etc. By utilizing this property, alkali metals and organic alkali metal compounds can be dissolved in organic solvents, and the cations can be chelated inside the ring. At the same time, due to the outward-facing organic gene, complexes can be formed, and they can also be dissolved in non-polar organic solvents. At this time, the unsolvated anions exist in the solvent in the form of naked anions, so they are extremely active, thereby promoting the methylation reaction.

[0044] In this case, the reaction formula is as shown in the following formula (1):

[0045]

[0046] In some embodiments of the present invention, the molar ratio of 6-hydroxy-2H-benzofuran-3-one to dimethyl carbonate, potassium carbonate, and 18-crown ether-6 is 1:(2-4):(1-2):(0.01-0.1), preferably 1:3:1.5:0.05.

[0047] The reaction temperature is 80-120°C, preferably 100°C; the reaction time is 2-6 hours, preferably 4 hours.

[0048] (ii) Step S2, reacting the 6-hydroxymethyl-2H-benzofuran-3-one with a reducing agent to generate 6-hydroxymethyl-2H-benzofuran-3-ol.

[0049] That is, after obtaining the intermediate 6-hydroxymethyl-2H-benzofuran-3-one, the ketone is reduced to alcohol by a reducing agent to obtain 6-hydroxymethyl-2H-benzofuran-3-ol.

[0050] Among them, as the reducing agent, one or more of sodium borohydride, lithium aluminum tetrahydride, and red aluminum can be selected. Red aluminum is preferred because it is less dangerous, moderately active, easy to operate, and does not produce a large amount of hydrogen gas compared to sodium borohydride, which brings certain safety hazards.

[0051] Specifically, the reaction formula of 6-hydroxymethyl-2H-benzofuran-3-one and red aluminum is shown in the following formula (2):

[0052]

[0053] In some embodiments of the present invention, step S2 includes:

[0054] The 6-hydroxymethyl-2H-benzofuran-3-one is added to toluene, and red aluminum is added dropwise to the reaction system to react to generate the 6-hydroxymethyl-2H-benzofuran-3-ol.

[0055] Furthermore, in step S2, the molar ratio of the 6-hydroxymethyl-2H-benzofuran-3-one to red aluminum is 1:(1-1.1), preferably 1:1.1. A slightly excess amount of red aluminum helps to promote the reaction and improve the yield, and the red aluminum that does not participate in the reaction is easier to remove than 6-hydroxymethyl-2H-benzofuran-3-one.

[0056] The reaction temperature of the reduction reaction can be controlled at 5-10°C and the reaction time is 2-4 hours. This condition has strong operability and high reaction efficiency.

[0057] (iii) Step S3, causing the 6-hydroxymethyl-2H-benzofuran-3-ol to undergo demethylation and elimination reactions to generate 6-benzofuranol.

[0058] That is, a demethylating agent is used to convert 6-hydroxymethyl-2H-benzofuran-3-ol into 6-benzofuranol while simultaneously acting as an eliminating agent for demethylation.

[0059] In some embodiments of the present invention, step S3 includes:

[0060] 6-Hydroxymethyl-2H-benzofuran-3-ol is added to dichloromethane, and aluminum chloride is added thereto in portions to cause demethylation and elimination reactions to generate the 6-benzofuranol.

[0061] That is, demethylation and alcohol elimination were accomplished in one pot using aluminum chloride.

[0062] Specifically, the reaction formula of 6-hydroxymethyl-2H-benzofuran-3-ol and aluminum chloride is shown in the following formula (3):

[0063]

[0064] Furthermore, the step S3 further includes:

[0065] After the reaction was completed, the reaction solution was poured into 6 mol / L hydrochloric acid in batches to quench the aluminum salt, and stirred at 30° C. for 1 hour. Thereafter, the organic phase was separated and post-treated to obtain the 6-benzofuranol.

[0066] That is, after the reaction is completed, post-treatment is performed to purify the product 6-benzofuranol.

[0067] In some embodiments of the present invention, the post-processing includes:

[0068] The organic phase was washed once with 1 mol / L dilute hydrochloric acid, once with water, and once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product;

[0069] The crude product was recrystallized from ethyl acetate:n-heptane at a volume ratio of 1:2 to obtain purified 6-benzofuranol.

[0070] It can be seen from this that the preparation method of the present invention does not require column purification for the obtained product, and only requires recrystallization for purification, which makes the purification simpler and easier to operate.

[0071] In order to enable technical researchers in the field to better understand the technical solution of the present invention, the present invention is further described in detail below in conjunction with embodiments.

[0072] Embodiment 1:

[0073] Step S1, add 6-hydroxy-2H-benzofuran-3-one (35g, 0.233mol, 1.0eq) and potassium carbonate powder (48.33g, 0.35mol, 1.5eq) to dimethyl carbonate (63g, 0.699mol, 3.0eq), and add catalyst 18-crown ether-6 (3.08g, 0.012mol, 0.05eq), and heat to 100°C for 4h. The reaction solution is filtered, the filter cake is washed with a small amount of dichloromethane (15g), and the filtrate is concentrated under reduced pressure to obtain 34.83g of 6-hydroxymethyl-2H-benzofuran-3-one, with a yield of 91.0%.

[0074] Step S2, add 6-hydroxymethyl-2H-benzofuran-3-one (34.83g, 0.212mol, 1.0eq) to toluene (70mL, 2P), cool to 5°C in an ice-water bath, add red aluminum (67.4g, 0.233mol, 1.1eq), control the temperature at 5-10°C, and keep warm for 3h. Add the reaction solution dropwise to 70mL, 3mol / L ammonium chloride aqueous solution to quench and layer, wash the organic phase with water and saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 30.71g of 6-hydroxymethyl-2H-benzofuran-3-ol, with a yield of 87.1%.

[0075] Step S3, add 6-hydroxymethyl-2H-benzofuran-3-ol (30.71g, 0.185mol, 1.0eq) to dichloromethane (150mL, 5P), add aluminum chloride (61.6g, 0.462mol, 2.5eq) in batches, control the temperature at 30-35°C, and keep warm for 4h. Pour the reaction solution into 108mL, 6mol / L hydrochloric acid in batches to quench the aluminum salt, and keep stirring at 30°C for 1h, separate the liquid, wash the organic phase with 60mL, 1mol / L dilute hydrochloric acid once, wash it with water once, wash it with saturated salt water once, then dry it with anhydrous sodium sulfate, filter it, and concentrate it to obtain 23g of crude product. The crude product is recrystallized with ethyl acetate: n-heptane 1:2 (total 46mL) to obtain 20.45g of 6-benzofuranol, with a yield of 82.5%.

[0076] The reactants were subjected to nuclear magnetic resonance experiments to confirm the product structure, and the data are as follows:

[0077] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz): δ7.56 (s, 1H), 7.45-7.47 (d, 1H), 7.00 (s, 1H), 6.80-6.85 (d, 1H), 6.72 (s, 1H), 5.09 (br, 1H), the detection results are consistent with the structure.

[0078] Embodiment 2:

[0079] Step S1, add 6-hydroxy-2H-benzofuran-3-one (120g, 0.799mol, 1.0eq) and potassium carbonate powder (165.71g, 1.199mol, 1.5eq) to dimethyl carbonate (216g, 2.398mol, 3.0eq), add catalyst 18-crown ether-6 (10.56g, 0.04mol, 0.05eq), heat to 100°C and react for 4h. The reaction solution is filtered, the filter cake is washed with a small amount of dichloromethane (60g), and the filtrate is concentrated under reduced pressure to obtain 120.06g of 6-hydroxymethyl-2H-benzofuran-3-one, with a yield of 91.5%.

[0080] Step S2, add 6-hydroxymethyl-2H-benzofuran-3-one (120.06g, 0.731mol, 1.0eq) to toluene (240mL, 2P), cool to 5°C in an ice-water bath, add red aluminum (232.34g, 0.805mol, 1.1eq), control the temperature at 5-10°C, and keep warm for 3h. Add the reaction solution dropwise to 250mL, 3mol / L ammonium chloride aqueous solution to quench and layer, wash the organic phase with water and saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 105.25g of 6-hydroxymethyl-2H-benzofuran-3-ol, with a yield of 86.6%.

[0081] Step S3, add 6-hydroxymethyl-2H-benzofuran-3-ol (105.25g, 0.633mol, 1.0eq) to dichloromethane (530mL, 5P), add aluminum chloride (211.13g, 1.583mol, 2.5eq) in batches, control the temperature at 30-35°C, and keep warm for 4h. Pour the reaction solution into 370mL, 6mol / L hydrochloric acid in batches to quench the aluminum salt, and keep stirring at 30°C for 1h, separate the liquid, wash the organic phase with 200mL, 1mol / L dilute hydrochloric acid, wash it with water, wash it with saturated salt water, and then dry it with anhydrous sodium sulfate, filter it, and concentrate it to obtain 78.5g of crude product. The crude product is recrystallized with ethyl acetate: n-heptane 1:2 (total 157mL) to obtain 71.36g of 6-benzofuranol, with a yield of 84%.

[0082] The reactants were subjected to nuclear magnetic resonance experiments to confirm the product structure, and the data are as follows:

[0083] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz): δ7.55 (s, 1H), 7.44-7.47 (d, 1H), 7.01 (s, 1H), 6.81-6.85 (d, 1H), 6.72 (s, 1H), 5.01 (br, 1H), the detection results are consistent with the structure.

[0084] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 6-benzofuranol, characterized in that: The steps include: Step S1, reacting 6-hydroxy-2H-benzofuran-3-one with a methylating agent to generate 6-hydroxymethyl-2H-benzofuran-3-one, wherein the methylating agent is one or more of dimethyl sulfate, methyl iodide, dimethyl carbonate, etc.; Step S2, reacting the 6-hydroxymethyl-2H-benzofuran-3-one with a reducing agent to generate 6-hydroxymethyl-2H-benzofuran-3-ol; Step S3, demethylating and eliminating the 6-hydroxymethyl-2H-benzofuran-3-ol to generate 6-benzofuranol.

2. The preparation method according to claim 1, characterized in that: The methylating agent is dimethyl carbonate, and the step S1 comprises: The 6-hydroxy-2H-benzofuran-3-one is reacted with dimethyl carbonate in the presence of an inorganic base and under the action of a catalyst to generate the 6-hydroxymethyl-2H-benzofuran-3-one.

3. The preparation method according to claim 2, characterized in that: The inorganic base is one or more of sodium carbonate, potassium carbonate, cesium carbonate and the like, and the catalyst is 18-crown ether-6.

4. The preparation method according to claim 3, characterized in that: The molar ratio of 6-hydroxy-2H-benzofuran-3-one to dimethyl carbonate, potassium carbonate and 18-crown ether-6 is 1:(2-4):(1-2):(0.01-0.1).

5. The preparation method according to claim 1, characterized in that: The reducing agent is one or more of sodium borohydride, lithium aluminum tetrahydride, and red aluminum.

6. The preparation method according to claim 5, characterized in that: The reducing agent is red aluminum, and the step S2 comprises: The 6-hydroxymethyl-2H-benzofuran-3-one is added to toluene, and red aluminum is added dropwise to the reaction system to react to generate the 6-hydroxymethyl-2H-benzofuran-3-ol.

7. The preparation method according to claim 6, characterized in that: In the step S2, the molar ratio of 6-hydroxymethyl-2H-benzofuran-3-one to red aluminum is 1:(1-1.1), the reaction temperature is 5-10° C., and the reaction time is 2-4 hours.

8. The preparation method according to claim 1, characterized in that: The step S3 comprises: 6-Hydroxymethyl-2H-benzofuran-3-ol is added to dichloromethane, and aluminum chloride is added thereto in portions to cause demethylation and elimination reactions to generate the 6-benzofuranol.

9. The preparation method according to claim 8, characterized in that: The step S3 further comprises: After the reaction was completed, the reaction solution was poured into 6 mol / L hydrochloric acid in batches to quench the aluminum salt, and stirred at 30° C. for 1 hour. Thereafter, the organic phase was separated and post-treated to obtain the 6-benzofuranol.

10. The preparation method according to claim 9, characterized in that: The post-processing includes: The organic phase was washed once with 1 mol / L dilute hydrochloric acid, once with water, and once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product; The crude product was recrystallized from ethyl acetate:n-heptane at a volume ratio of 1:2 to obtain purified 6-benzofuranol.

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