Method for preparing polychlorinated spirolactone from phenol

Abstract

The invention provides a polychlorinated spirolactonization reaction method of a phenolic compound. The polychlorinated spirolactonization reaction method is used for preparing a spirolactone compound. According to the method, 2-(3 '-hydroxyphenyl) benzoic acid and derivatives thereof are used as raw materials, trichloroisocyanuric acid is used as an oxidizing agent and a chlorine source, and the dearomatization polychlorinated spirolactonization reaction of phenolic compounds is realized through one-step operation. The key of the reaction lies in participation of halide, rapid construction of a plurality of C-Cl bonds is promoted, and spirolactone rings are formed through oxygen atom migration. The method is mild in reaction condition, simple and convenient to operate, wide in substrate application range, high in yield and selectivity, safe in preparation, low in cost, suitable for industrial production and capable of meeting the requirements of the market for wide range and large quantity.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis methodology in organic chemistry, and particularly relates to a method for synthesizing spiro lactones by de-aromatizing and poly-chlorinating phenols at the meta-position. Background Art

[0002] Spironolactone is a potassium-sparing diuretic that is often used in combination with other diuretics to counteract the potassium-excreting effect of the latter and enhance the diuretic effect. The spironolactone skeleton is widely present in natural products and bioactive compounds. In addition, the spironolactone skeleton also plays a key role in the development of new multifunctional chiral auxiliaries. It is a structurally complex three-dimensional molecule, and the synthesis method mainly constructs spiro lactone compounds by de-aromatizing phenolic compounds. Many research groups have reported intramolecular spiro lactonization reactions of hypervalent iodine, mainly at the 2-position and 4-position, to obtain conjugated dienones. However, the reaction to form a spiro lactone ring at the meta-position of phenol, that is, a pentahalogenated monoene structure, has only been reported by the applicant's research group in 2023, but the poly-chlorination synthesis therein also uses high-cost hypervalent iodine synthesis (J. Org. Chem. 2023, 88, 1075 - 1084). The transportation cost and danger of hypervalent iodine are too high and are not suitable for large-scale synthesis.

[0003] As a method for preparing poly-chlorinated spiro lactones from phenols, this method can supplement the current methods for synthesizing poly-chlorinated spiro lactones and provide conditions for synthesizing a wide variety of poly-chlorinated spiro lactones. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing poly-chlorinated spiro lactones from phenols in view of the scarcity and deficiencies of existing methods for synthesizing poly-chlorinated spiro lactones. This method uses 2-(3'-hydroxyphenyl)benzoic acid as a raw material and trichloroisocyanuric acid (TCCA) as a chlorine source, and the synthesis method has a certain generality. The reaction conditions of this method are mild, the requirements for production equipment are low, the process is simple, the preparation reaction is safe, the yield is relatively high, and the purification is simple.

[0005] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0006] The present invention uses 2-(3'-hydroxyphenyl)benzoic acid and its derivatives as raw materials, and uses TCCA (trichloroisocyanuric acid) as an oxidant and halogen source to achieve the de-aromatization and spiro lactonization reactions of phenolic compounds through one-step operation. The key to the reaction lies in the participation of chlorides, which promotes the rapid construction of multiple C-Cl bonds and forms a spiro lactone ring through oxygen atom migration. The reaction conditions are mild, the operation is simple, the substrate scope is wide, and it has a high yield and selectivity, and is suitable for industrial production.

[0007]

[0008] Among them:

[0009] R 1 is a halogen, an alkyl group or a methoxy group;

[0010] The oxidation condition is solid trichloroisocyanuric acid (TCCA);

[0011] The solvent is one of ethyl acetate (EA), dichloromethane (DCM), and tetrahydrofuran (THF);

[0012] The implementation operation of the described technical solution is as follows: 0.1 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.35 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is refluxed under condensation at 40 °C for 2 hours. The reaction progress is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times in the forward direction and three times in the reverse direction with dichloromethane (5 mL × 6). The organic phase is collected and concentrated under vacuum after drying with anhydrous MgSO 4 The residue is separated and purified by column chromatography to obtain the target polychlorospirolactone product. Detailed implementation manners

[0013] The monitoring method in any implementation manner of the present invention is: thin layer chromatography;

[0014] The structure confirmation technical means are all common technical means known to those skilled in the art: nuclear magnetic resonance technology, high-resolution mass spectrometry;

[0015] The present invention will be further described below in conjunction with embodiments, but the present invention is not limited thereby.

[0016] Example 1

[0017]

[0018] A method for preparing polychlorospirolactone from a phenol, the specific steps are as follows:

[0019] The solvent is dichloromethane (DCM). 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of DCM solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted at room temperature for 2 hours. The reaction progress is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3)The solution was quenched and extracted three times with dichloromethane (5 mL×6) in the forward direction and three times in the reverse direction. The organic phase was collected and dried over anhydrous MgSO 4 After drying, it was concentrated under vacuum. The residue was separated, and the yield of 2a was 41%.

[0020] Example 2

[0021] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0022] The solvent was tetrahydrofuran (THF). 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of THF solvent were successively added to a 50 mL round-bottom flask, and then the mixed solution was reacted at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution and extracted three times with dichloromethane (5 mL×6) in the forward direction and three times in the reverse direction. The organic phase was collected and dried over anhydrous MgSO 4 After drying, it was concentrated under vacuum. The residue was separated, and the yield of 2a was 58%.

[0023] Example 3

[0024] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0025] The solvent was ethyl acetate (EA). 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent were successively added to a 50 mL round-bottom flask, and then the mixed solution was reacted at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution and extracted three times with dichloromethane (5 mL×6) in the forward direction and three times in the reverse direction. The organic phase was collected and dried over anhydrous MgSO 4 After drying, it was concentrated under vacuum. The residue was separated, and the yield of 2a was 63%.

[0026] Example 4

[0027] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0028] The temperature is 0 °C. 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted in an ice bath for 2 hours. The reaction is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times in the forward direction and three times in the reverse direction with dichloromethane (5 mL×6). The organic phase is collected and concentrated in vacuo after drying with anhydrous MgSO 4 . The residue is separated, and the yield of 2a is 76%.

[0029] Example 5

[0030] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0031] The temperature is 30 °C. 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted under reflux in an oil bath at 30 °C for 2 hours. The reaction is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times in the forward direction and three times in the reverse direction with dichloromethane (5 mL×6). The organic phase is collected and concentrated in vacuo after drying with anhydrous MgSO 4 . The residue is separated, and the yield of 2a is 65%.

[0032] Example 6

[0033] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0034] The temperature is 40 °C. 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted under reflux in an oil bath at 40 °C for 2 hours. The reaction is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times in the forward direction and three times in the reverse direction with dichloromethane (5 mL×6). The organic phase is collected and concentrated in vacuo after drying with anhydrous MgSO 4 . The residue, the separation yield of 2a is 78%.

[0035] Example 7

[0036] A method for preparing polychlorinated spironolactone from phenol, the specific steps are as follows:

[0037] The temperature is 50 °C. 0.2 mmol of 2-(3'-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.6 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted under reflux in an oil bath at 50 °C for 2 hours. The reaction is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times in the forward direction and three times in the reverse direction with dichloromethane (5 mL × 6). The organic phase is collected and dried over anhydrous MgSO 4 After drying, it is concentrated under vacuum. For the residue, the separation yield of 2a is 71%.

[0038] Example 8

[0039] A method for preparing polychlorinated spironolactone from phenol, the specific steps are as follows:

[0040] 0.2 mmol of 2-(3'-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.5 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted under reflux in an oil bath at 40 °C for 2 hours. The reaction is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times in the forward direction and three times in the reverse direction with dichloromethane (5 mL × 6). The organic phase is collected and dried over anhydrous MgSO 4 After drying, it is concentrated under vacuum. For the separated residue, the yield of 2a is 69%.

[0041] Example 9

[0042] A method for preparing polychlorinated spironolactone from phenol, the specific steps are as follows:

[0043] 0.2 mmol of 2-(3'-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.7 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent are successively added to a 50 mL round-bottom flask, and then the mixed solution is reacted under reflux in an oil bath at 40 °C for 2 hours. The reaction is monitored by TLC. After the reaction is completed, it is quenched with saturated sodium thiosulfate (Na 2 S 2 O 3)The solution was quenched and extracted three times with dichloromethane (5 mL×6) in the forward direction and three times in the reverse direction. The organic phase was collected and dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was separated, and the yield of 2a was 95%.

[0044] Example 10

[0045] A method for preparing polychlorinated spironolactone from phenol, the specific steps are as follows:

[0046] 0.2 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.8 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent were successively added to a 50 mL round-bottom flask, and then the mixed solution was reacted under reflux with condensation in an oil bath at 40 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution and extracted three times with dichloromethane (5 mL×6) in the forward direction and three times in the reverse direction. The organic phase was collected and dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was separated, and the yield of 2a was 69%.

[0047] Example 11

[0048] A method for preparing polychlorinated spironolactone from phenol, the specific steps are as follows:

[0049] 0.1 mmol of 2-(3′-hydroxyphenyl)-4-methylbenzoic acid raw material, 0.35 mmol of TCCA (trichloroisocyanuric acid) oxidant, and 2.0 mL of EA solvent were successively added to a 50 mL round-bottom flask, and then the mixed solution was refluxed with condensation at 40 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution and extracted three times with dichloromethane (5 mL×6) in the forward direction and three times in the reverse direction. The organic phase was collected and dried over anhydrous MgSO 4 and concentrated in vacuo. The residue was separated and purified by column chromatography. The eluent (EA:PE = 1:50) was passed through a silica gel column to obtain the target 2a, and the separation yield was 41%, a white solid.

[0050] Example 12

[0051]

[0052] A method for preparing polychlorinated spironolactone from phenol, the specific steps are as follows:

[0053] To a 50 mL round-bottom flask, 0.3 mmol of 2-(3′-hydroxyphenyl)benzoic acid was added successively as the raw material, 1.05 mmol of TCCA (trichloroisocyanuric acid) as the oxidant, and 2.0 mL of EA solvent. Then the mixed solution was refluxed under condensation at 40 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S 2 0 3 ) solution, and extracted three times with dichloromethane (5 mL×6) by normal extraction and three times by back extraction. The organic phase was collected and dried over anhydrous MgSO 4 . After drying, it was concentrated under vacuum. The residue was separated and purified by column chromatography. The eluent (EA:PE = 1:50) was passed through a silica gel column to obtain the white solid target product 3a with a separation yield of 63%.

[0054] Example 13

[0055]

[0056] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0057] To a 50 mL round-bottom flask, 0.3 mmol of 4-fluoro-2-(3′-hydroxyphenyl)benzoic acid was added successively as the raw material, 1.05 mmol of TCCA (trichloroisocyanuric acid) as the oxidant, and 2.0 mL of EA solvent. Then the mixed solution was refluxed under condensation at 40 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S 2 O 3 ) solution, and extracted three times with dichloromethane (5 mL×6) by normal extraction and three times by back extraction. The organic phase was collected and dried over anhydrous MgSO 4 . After drying, it was concentrated under vacuum. The residue was separated and purified by column chromatography. The eluent (EA:PE = 1:50) was passed through a silica gel column to obtain the white solid target product 4a with a separation yield of 75%.

[0058] Example 14

[0059]

[0060] A method for preparing polychlorinated spiro lactone from phenol, the specific steps are as follows:

[0061] To a 50 mL round-bottom flask, 0.3 mmol of 2-(3′-hydroxyphenyl)-4-methoxybenzoic acid was added successively as the raw material, 1.05 mmol of TCCA (trichloroisocyanuric acid) as the oxidant, and 2.0 mL of EA solvent. Then the mixed solution was refluxed under condensation at 40 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated sodium thiosulfate (Na 2 S2 O 3 ) The solution was quenched and extracted three times with dichloromethane (5 mL×6) by normal extraction and three times by back extraction. The organic phase was collected and dried over anhydrous MgSO 4 After drying, it was concentrated under vacuum. The residue was separated and purified by column chromatography. The eluent (EA:PE = 1:50) was passed through a silica gel column to obtain the white solid target product 5a with a separation yield of 65%.

Claims

1. A method for preparing polychlorinated spironolactones from phenol, characterized in that The specific steps are as follows: 2-(3′-hydroxyphenyl)benzoic acid raw material, trichloroisocyanuric acid oxidant, and reaction solvent were added to a round-bottom flask in sequence, and the mixed solution was reacted at 0°C to 50°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, saturated sodium thiosulfate solution was used to quench the reaction, and dichloromethane was used for extraction. The organic phase was collected and dried over anhydrous MgSO4 and then concentrated in vacuo. The residue was separated by silica gel column chromatography to obtain the product, wherein: The 2-(3′-hydroxyphenyl)benzoic acid is one of unsubstituted 2-(3′-hydroxyphenyl)benzoic acid, 2-(3′-hydroxyphenyl)-4-methylbenzoic acid, 2-(3′-hydroxyphenyl)-4-fluorobenzoic acid, and 2-(3′-hydroxyphenyl)-4-methoxybenzoic acid; The solvent is one of ethyl acetate, dichloromethane and tetrahydrofuran.

2. A method for preparing polychlorinated spironolactones from phenol according to claim 1, characterized in that: In step (1), the raw material is 2-(3′-hydroxyphenyl)-4-methylbenzoic acid, the oxidant is trichloroisocyanuric acid, the solvent is ethyl acetate, and the reaction is continued at 40° C. for 2 hours; After quenching the reaction, extraction, concentration and separation by silica gel column chromatography, a white solid 2a was obtained.

3. A method for preparing polychlorinated spironolactones from phenol according to claim 1, characterized in that: In step (1), the raw material is unsubstituted 2-(3′-hydroxyphenyl)-4-methylbenzoic acid, the oxidant is trichloroisocyanuric acid, the solvent is ethyl acetate, and the reaction is continued at 40° C. for 2 hours; After quenching the reaction, extraction, concentration and separation by silica gel column chromatography, a white solid 3a was obtained.

4. A method for preparing polychlorinated spironolactones from phenol according to claim 1, characterized in that: In step (1), the raw material is unsubstituted 2-(3′-hydroxyphenyl)-4-fluorobenzoic acid, the oxidant is trichloroisocyanuric acid, the solvent is ethyl acetate, and the reaction is continued at 40° C. for 2 hours; After quenching the reaction, extraction, concentration and separation by silica gel column chromatography, a white solid 4a was obtained.

5. A method for preparing polychlorinated spironolactones from phenol according to claim 1, characterized in that: In step (1), the raw material is unsubstituted 2-(3′-hydroxyphenyl)-4-methoxybenzoic acid, the oxidant is trichloroisocyanuric acid, the solvent is ethyl acetate, and the reaction is continued at 40° C. for 2 hours; After quenching the reaction, extraction, concentration and separation by silica gel column chromatography, a white solid 5a was obtained.

Images