CN113929627A - Synthetic method of bindarit - Google Patents
Synthetic method of bindarit Download PDFInfo
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- CN113929627A CN113929627A CN202111214510.5A CN202111214510A CN113929627A CN 113929627 A CN113929627 A CN 113929627A CN 202111214510 A CN202111214510 A CN 202111214510A CN 113929627 A CN113929627 A CN 113929627A
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Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of bindarit. The invention provides a synthesis method of bindarit, which comprises the following steps: indazole-3-carboxylic acid and methanol are subjected to esterification reaction to obtain indazole-3-carboxylic acid methyl ester; carrying out benzylation reaction on the indazole-3-carboxylic acid methyl ester and benzyl bromide to obtain 1-benzyl indazole-3-carboxylic acid methyl ester; carrying out reduction reaction on the 1-benzyl indazole-3-carboxylic acid methyl ester and a reducing agent to obtain 1-benzyl indazole-3-methanol; mixing the 1-benzyl indazole-3-methanol with acetone and chloroform, and carrying out condensation hydrolysis reaction to obtain the bindarit. The synthesis method of the bindarit has the advantages of cheap and easily obtained raw materials, few synthesis steps, relatively high yield and easy industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of bindarit.
Background
The 2- [ (1-benzyl-1H-indazole-3-yl) methoxy ] -2-methylpropanoic acid, also known as Bindali (BIN), is a monocyte chemotactic protein-1 (MCP-1) selective inhibitor, can effectively prevent the chronic inflammation and reduce the potential toxic and side effects of the inflammation in vivo, and is particularly suitable for treating diseases such as lupus nephritis, acute pancreatitis, rheumatoid arthritis and the like. In addition, the bindarit can also inhibit the secretion of interleukin-6, and plays a great role in treating diseases such as tumor, coronary artery stent restenosis and the like. Although the clinical studies of bindari are very intensive, there are few reports on the synthesis method thereof.
In the prior art, the synthesis of the bindarit mainly comprises the following steps: the preparation method is characterized in that 3-bromoindazole is used as a raw material and is prepared through a benzylation reaction, a Grignard reaction, a chlorination reaction, an ether formation reaction and a hydrolysis reaction in sequence, and the total yield is low and is only 13.2%.
Disclosure of Invention
In view of the above, the present invention provides a method for synthesizing bindarit. The synthesis method of the bindarit has the advantages of cheap and easily-obtained raw materials, few synthesis steps, high yield and easy industrial production.
In order to achieve the above object, the present invention provides a method for synthesizing bindarit, comprising the following steps:
indazole-3-carboxylic acid and methanol are subjected to esterification reaction to obtain indazole-3-carboxylic acid methyl ester;
carrying out benzylation reaction on the indazole-3-carboxylic acid methyl ester and benzyl bromide to obtain 1-benzyl indazole-3-carboxylic acid methyl ester;
carrying out reduction reaction on the 1-benzyl indazole-3-carboxylic acid methyl ester and a reducing agent to obtain 1-benzyl indazole-3-methanol;
mixing the 1-benzyl indazole-3-methanol, acetone and chloroform, and carrying out condensation hydrolysis reaction to obtain the bindarit.
Preferably, the molar ratio of indazole-3-carboxylic acid to methanol is 1: 75-90.
Preferably, the temperature of the esterification reaction is 60-70 ℃, and the reaction time is 3-4 h.
Preferably, the molar ratio of indazole-3-carboxylic acid methyl ester to benzyl bromide is 1: (1.3-2.2).
Preferably, the temperature of the benzylation reaction is 55-65 ℃, and the reaction time is 1.5-2.5 h.
Preferably, the reducing agent is a mixture comprising a metal reducing agent and methanol; the metal reducing agent comprises one or more of sodium borohydride, lithium aluminum hydride and red aluminum.
Preferably, the temperature of the reduction reaction is 50-60 ℃, and the reaction time is 0.5-1.5 h.
Preferably, the molar ratio of 1-benzylindazole-3-methanol to chloroform is 1: (4-6).
Preferably, the molar ratio of the 1-benzylindazole-3-methanol to acetone is 1: 60-90.
Preferably, the temperature of the condensation hydrolysis reaction is 55-65 ℃ and the time is 2.5-3.5 h.
The invention provides a synthesis method of bindarit, which comprises the following steps: indazole-3-carboxylic acid and methanol are subjected to esterification reaction to obtain indazole-3-carboxylic acid methyl ester; carrying out benzylation reaction on the indazole-3-carboxylic acid methyl ester and benzyl bromide to obtain 1-benzyl indazole-3-carboxylic acid methyl ester; carrying out reduction reaction on the 1-benzyl indazole-3-carboxylic acid methyl ester to obtain 1-benzyl indazole-3-methanol; mixing the 1-benzyl indazole-3-methanol with acetone and chloroform, and carrying out condensation hydrolysis reaction to obtain the bindarit. The synthesis method of the bindarit takes indazole-3-carboxylic acid, methanol, benzyl bromide, acetone and chloroform as raw materials, and the raw materials are cheap and easy to obtain; the bindarit can be obtained through esterification reaction, benzylation reaction, reduction reaction and condensation hydrolysis reaction, the synthesis steps are few, the yield is high, and the industrial production is easy to realize.
The data of the examples show that: the yield of the bindarit in the synthetic method of the bindarit can reach 38.4 percent.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of bindarit prepared in example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the benzylation reaction product prepared in example 1.
Detailed Description
The invention provides a synthesis method of bindarit, which comprises the following steps:
indazole-3-carboxylic acid and methanol are subjected to esterification reaction to obtain indazole-3-carboxylic acid methyl ester;
carrying out benzylation reaction on the indazole-3-carboxylic acid methyl ester and benzyl bromide to obtain 1-benzyl indazole-3-carboxylic acid methyl ester;
carrying out reduction reaction on the 1-benzyl indazole-3-carboxylic acid methyl ester and a reducing agent to obtain 1-benzyl indazole-3-methanol;
mixing the 1-benzyl indazole-3-methanol, acetone and chloroform, and carrying out condensation hydrolysis reaction to obtain the bindarit.
In the present invention, the starting materials used in the present invention are preferably commercially available products unless otherwise specified.
Indazole-3-carboxylic acid and methanol are subjected to esterification reaction to obtain indazole-3-carboxylic acid methyl ester.
In the present invention, the molar ratio of indazole-3-carboxylic acid to methanol is 1: 75-90, more preferably 1: 80-85. In the present invention, the esterification reaction is preferably carried out under the condition of a dehydrating agent, and the dehydrating agent preferably includes concentrated sulfuric acid. In the invention, the volume ratio of the dehydrating agent to the methanol is preferably (90-100): 1, more preferably 100: 1.
in the present invention, the esterification reaction is preferably performed by heating under reflux; the temperature of the esterification reaction is preferably 60-70 ℃, and more preferably 65 ℃; the time is preferably 3 to 4 hours, and more preferably 3.5 hours.
In the present invention, the esterification reaction is preferably carried out in a three-necked reaction flask.
In the invention, the reaction flow of the esterification reaction is shown as formula I:
after the esterification reaction, the method preferably further comprises the steps of sequentially cooling and concentrating the feed liquid obtained by the esterification reaction to obtain a solid; redissolving the solid in ethyl acetate, and then washing with a detergent to obtain an ethyl acetate phase; and drying the ethyl acetate phase by using a drying agent, performing rotary evaporation and concentration in sequence, and drying the obtained solid in vacuum to obtain the indazole-3-carboxylic acid methyl ester.
In the invention, the target cooling temperature of the feed liquid obtained by the esterification reaction is preferably 20-25 ℃, and the cooling time is preferably 1-2 h. The operation of the concentration is not particularly limited in the present invention, and the solvent can be removed to obtain a solid by an operation well known to those skilled in the art, specifically, rotary evaporation. In the present invention, the washing preferably comprises washing with distilled water, washing with a saturated sodium bicarbonate solution, and washing with a saturated sodium chloride solution in this order; the number of times of the distilled water washing, the saturated sodium bicarbonate solution washing and the saturated sodium chloride washing is preferably 2-3 times independently. In the present invention, the drying agent is preferably anhydrous sodium sulfate. In the invention, the temperature of the vacuum drying is preferably 50-60 ℃, and the time of the vacuum drying is preferably 6-8 h.
After indazole-3-carboxylic acid methyl ester is obtained, the present invention carries out benzylation reaction of indazole-3-carboxylic acid methyl ester with benzyl bromide to obtain 1-benzyl indazole-3-carboxylic acid methyl ester.
In the present invention, the molar ratio of indazole-3-carboxylic acid methyl ester to benzyl bromide is preferably 1: (1.3-2.2), more preferably 1: 1.35 to 2.2. The benzyl bromide is easy to volatilize, and the amount of the benzyl bromide is excessive relative to the indazole-3-carboxylic acid methyl ester, so that the indazole-3-carboxylic acid methyl ester can completely react, and the product yield is improved.
In the present invention, the raw material of the benzylation reaction preferably further comprises an acid-binding agent, and the acid-binding agent preferably comprises cesium fluoride, sodium hydride or potassium carbonate, and more preferably potassium carbonate.
In the invention, the mass ratio of the acid-binding agent to the indazole-3-carboxylic acid methyl ester is 1.5-4: 1.
In the present invention, the benzylation reaction is preferably carried out under the condition of a polar organic solvent; the polar organic solvent is preferably acetone, acetonitrile, tetrahydrofuran or N, N' -dimethylformamide, and is more preferably acetone. In the present invention, the indazole-3-carboxylic acid methyl ester and the polar organic solvent are preferably used in a ratio of 1 g: 16-22 mL.
In the invention, the preferable adding sequence of the materials for the benzylation reaction comprises the steps of mixing indazole-3-carboxylic acid methyl ester with an acid-binding agent and a polar organic solvent in sequence to obtain a benzylation mixed solution; benzyl bromide was added dropwise to the benzylated mixed solution. In the present invention, the dropping speed is 0.15 to 0.4g/min, and more preferably 0.15 to 0.35 g/min.
In the invention, the temperature of the benzylation reaction is preferably 55-65 ℃, and further preferably 60 ℃; the time of the benzylation reaction is preferably 1.5-2.5 h, and further preferably 2 h; in the present invention, the time for the benzylation reaction is timed from the completion of the benzyl bromide addition. In the present invention, the benzylation reaction is preferably carried out in a three-necked flask equipped with a condenser and a stirrer.
In the invention, the reaction flow of the benzylation reaction is shown as formula II:
after the benzylation reaction, the invention also comprises the steps of preferably and sequentially cooling, filtering and concentrating feed liquid obtained by the benzylation reaction, sequentially cooling and precipitating the obtained viscous liquid, cooling and precipitating obtained solid, washing, filtering and drying in vacuum to obtain the 1-benzyl indazole-3-carboxylic acid methyl ester.
In the invention, the target temperature for cooling the feed liquid is preferably 20-25 ℃; the cooling time is preferably 1-2 h, and more preferably 1 h. The concentration is not particularly limited in the present invention, and most of the solvent can be removed by a procedure well known to those skilled in the art to obtain a viscous liquid. In the invention, the cooling and precipitating temperature is preferably 2-8 ℃, and more preferably 3-5 ℃; the cooling precipitation time is preferably 1-2 h, and more preferably 1.5 h. In the invention, the detergent for cooling and precipitating the solid for washing is preferably n-hexane; the dosage ratio of the detergent to the solid is preferably (14-16) mL: 1g of a compound; the number of washing is preferably 2 to 3. The suction filtration and vacuum drying are not particularly limited in the present invention, and may be performed by procedures well known to those skilled in the art.
After obtaining the methyl 1-benzyl indazole-3-carboxylate, the invention carries out reduction reaction on the methyl 1-benzyl indazole-3-carboxylate and a reducing agent to obtain the 1-benzyl indazole-3-methanol.
In the present invention, the reducing agent is preferably a mixture comprising a metal reducing agent and methanol; the metal reducing agent comprises one or more of sodium borohydride, lithium aluminum hydride and red aluminum, and sodium borohydride is further preferable. In the invention, the mass ratio of the methyl 1-benzyl indazole-3-carboxylate to the methanol is 1:2 to 4, and more preferably 1:2 to 3. In the invention, the molar ratio of the methyl 1-benzyl indazole-3-carboxylate to the metal reducing agent is 1: 4-5.
In the present invention, the reduction reaction is preferably carried out in tetrahydrofuran.
In the invention, the step of the reduction reaction is preferably to mix tetrahydrofuran with 1-benzyl indazole-3-carboxylic acid methyl ester and sodium borohydride in sequence and heat the mixture to obtain a reduction mixed material liquid; and then, dropwise adding methanol into the reduction mixed liquid, continuously heating, and carrying out reduction reaction to obtain the 1-benzyl indazole-3-methanol. In the invention, the mixing mode is preferably magnetic stirring, and the rotating speed of the magnetic stirring is preferably 600-700 rpm. In the invention, the temperature of the reduction mixed material liquid is preferably 45-55 ℃, and more preferably 50 ℃. In the invention, the dripping speed is preferably 0.15-0.5 mL/min.
In the invention, the temperature of the reduction reaction is preferably 50-60 ℃, and more preferably 55 ℃; the time of the reduction reaction is preferably 0.5-1.5 h, and more preferably 1 h. In the present invention, the reduction reaction is preferably carried out in a three-necked round-bottomed flask.
In the invention, the reaction flow of the reduction reaction is shown as formula III:
after the reduction reaction, the invention preferably also comprises the steps of cooling and concentrating the feed liquid obtained by the reduction reaction to obtain viscous liquid; extracting the obtained viscous liquid, and drying and filtering the obtained organic phase to obtain filtrate; and carrying out rotary evaporation concentration and vacuum drying on the obtained filtrate to obtain the 1-benzyl indazole-3-methanol.
In the invention, the target cooling temperature of the feed liquid obtained by the reduction reaction is preferably 20-25 ℃, and the cooling time is preferably 60-80 min. The concentration is not particularly limited in the present invention, and a viscous liquid can be obtained by removing most of the solvent by a procedure well known to those skilled in the art.
In the invention, the extracting agent for extraction is preferably a mixed solvent of distilled water and dichloromethane; the volume ratio of distilled water to methylene chloride in the mixed solvent is preferably 1: (1-2), more preferably 1: 1. In the invention, the extraction step is preferably to mix the obtained viscous liquid with distilled water, then adjust the pH value to 2-3 by using dilute hydrochloric acid, then add dichloromethane for extraction, extract for 3 times, and combine organic phases. In the invention, the viscous liquid and the distilled water are preferably mixed by stirring, and the stirring time is preferably 25-35 min, and more preferably 30 min. In the invention, the pH is adjusted to be acidic by using dilute hydrochloric acid, so that the product is prevented from being salified in an alkaline environment, and the salified part is dissolved in water, so that the loss of the product is caused, and the yield is reduced.
In the present invention, the drying operation is preferably the same as the drying operation in the esterification reaction, and will not be described herein. In the present invention, the rotary evaporation concentration and vacuum drying of the filtrate are not particularly limited, and may be performed by a method known to those skilled in the art.
After the 1-benzyl indazole-3-methanol is obtained, the 1-benzyl indazole-3-methanol, acetone and chloroform are mixed and subjected to condensation hydrolysis reaction to obtain the bindarit.
In the invention, the molar ratio of the 1-benzyl indazole-3-methanol to the chloroform is 1: 4-6, and more preferably 1: 5. in the invention, the chloroform is preferably used in the form of a chloroform-acetone solution, and the concentration of the chloroform in the chloroform-acetone solution is preferably 5-6 mol/L.
In the invention, the molar ratio of the 1-benzyl indazole-3-methanol to the acetone is 1: 60-90, more preferably 1: 65-85.
In the present invention, the condensation hydrolysis reaction is preferably performed under a strong alkali condition, and the strong alkali is preferably sodium hydroxide.
In the present invention, the step of mixing is preferably: mixing the 1-benzyl indazole-3-methanol, sodium hydroxide and acetone to obtain a condensation hydrolysis mixed material liquid, and then dropwise adding chloroform into the condensation hydrolysis mixed material liquid to obtain a condensation hydrolysis reaction liquid. In the invention, the mixing temperature of the 1-benzyl indazole-3-methanol, the sodium hydroxide and the acetone is preferably 20-25 ℃, and the mixing mode is preferably stirring. In the invention, the dripping speed is preferably 0.05-0.2 mL/min.
In the invention, the temperature of the condensation hydrolysis reaction is preferably 55-65 ℃, further preferably 60 ℃, and the time is preferably 2.5-3.5 h, further preferably 3 h.
In the invention, the reaction flow of the condensation hydrolysis reaction is as follows:
after the condensation hydrolysis reaction, the invention preferably further comprises cooling and concentrating feed liquid obtained by the condensation hydrolysis reaction to obtain a sticky substance; mixing the obtained viscous substance, water and ethyl acetate, extracting, and mixing water phases; adjusting the pH value of the water phase to 2-3 by using dilute hydrochloric acid, and separating out a crude product of the bindarit; and recrystallizing the crude product of the bindarit to obtain the bindarit.
In the invention, the optimal target temperature for cooling the feed liquid obtained by the condensation hydrolysis reaction is 20-25 ℃ and the cooling time is 1-1.5 h; the concentration is not particularly limited in the present invention, and a viscous substance can be obtained by removing most of the solvent by a procedure well known to those skilled in the art.
In the present invention, the volume ratio of ethyl acetate to water is preferably 1:1 to 2, and more preferably 1: 1. In the present invention, the number of the extractions is preferably 3; the specific operation of 3 extractions preferably comprises the following steps: mixing the sticky matter, water and ethyl acetate, and performing first extraction to obtain a first water phase and a first ethyl acetate phase; mixing the first ethyl acetate phase with water, and performing second extraction to obtain a second water phase and a second ethyl diacetate phase; mixing the second ethyl acetate phase with water, and performing third extraction to obtain a third water phase and a third ethyl acetate phase; the first, second and third aqueous phases are combined as the aqueous phase.
In the present invention, the recrystallization is preferably a two-solvent recrystallization, and the two-solvent recrystallization preferably includes a first solvent and a second solvent; the first solvent is preferably acetic acid and the second solvent is preferably water. The volume ratio of the first solvent to the second solvent is preferably 1: (1-3). The recrystallization operation of the present invention is not particularly limited, and may be performed by a method known to those skilled in the art.
The following examples are provided to illustrate the methods for synthesizing bindarit of the present invention, but they should not be construed as limiting the scope of the present invention.
Example 1
(1) Synthesis of indazole-3-carboxylic acid methyl ester
Indazole-3-carboxylic acid (15g, 92.5mmol) and methanol (300mL) are added into a 500mL three-mouth reaction bottle, then 3mL concentrated sulfuric acid is added, the mixture is heated to 65 ℃ for esterification reaction, the reaction lasts for 3.5 hours, heating is stopped, the material liquid obtained by the esterification reaction is cooled for 1 hour at the temperature of 20 ℃, the cooled material liquid is subjected to rotary evaporation, the methanol is removed, the obtained solid is dissolved in 200mL ethyl acetate, then the solid is sequentially washed for 3 times by distilled water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, the ethyl acetate phase obtained by washing is dried by anhydrous sodium sulfate, moisture is removed, then rotary evaporation concentration is carried out, and vacuum drying is carried out (drying is carried out for 6-8 hours at the temperature of 50-60 ℃) to obtain 15.29g of indazole-3-methyl carboxylate, wherein the yield is 93.8%.
(2) Synthesis of methyl 1-benzylindazole-3-carboxylate
Adding indazole-3-carboxylic acid methyl ester (15.29g, 86.79mmol), potassium carbonate (35.98g, 260.37mmol) and 300mL of acetone in sequence into a three-neck flask provided with a condenser tube and a stirrer, uniformly mixing at the temperature of 25 ℃, and slowly dropping benzyl bromide (29.68g, 173.58mmol) into the reaction bottle (the dropping time is about 1.5h) to obtain a benzylation reaction solution; and heating the obtained benzylation reaction solution to 60 ℃ to carry out benzylation reaction for 2 hours, and stopping heating.
Sequentially cooling feed liquid obtained by the benzylation reaction (at the temperature of 20 ℃ for 80min), filtering and concentrating to obtain viscous liquid; and (3) cooling the obtained viscous liquid in a refrigerator to separate out a solid (the cooling temperature is 2-8 ℃, the cooling time is 1h), fully washing the obtained solid for 3 times by using 150mL of n-hexane, sequentially carrying out suction filtration on the washed liquid, and carrying out vacuum drying to obtain 14.87g of 1-benzyl indazole-3-methyl carboxylate, wherein the yield is 64.4%.
The invention also performs nuclear magnetic resonance on the benzylation reaction product prepared in the example 1 to obtain a nuclear magnetic resonance hydrogen spectrum, and the spectrum information is as follows:
1H NMR(300MHz,CDCl3)δ8.24(d,J＝8.0Hz,1H)，7.36–7.21(m,8H)，5.71(s,2H)，4.05(s,3H)。
(3) synthesis of 1-benzylindazole-3-methanol
Tetrahydrofuran (250mL), 1-benzyl indazole-3-carboxylic acid methyl ester (14.87g, 55.84mmol) and sodium borohydride (9.5g, 251.27mmol) were sequentially added to a 500mL three-necked round-bottomed flask, and magnetic stirring was performed at a rotation speed of 600rpm while heating to 50 ℃ to obtain a mixed solution; then, 50mL of methanol is dropwise added to the reduction mixed solution (the dropwise adding time is about 2 hours), and after the dropwise adding is finished, the solution is heated to 55 ℃ for reduction reaction, the reaction is carried out for 1 hour, and the heating is stopped.
Sequentially cooling the feed liquid obtained by the reduction reaction (the cooling temperature is 20-25 ℃, the cooling time is 60-80 min), and concentrating to obtain viscous liquid; adding 150mL of distilled water into the obtained viscous liquid, fully stirring for 30min, then adjusting the pH to 2-3 by using dilute hydrochloric acid, then adding 150mL of dichloromethane, extracting for 3 times, combining dichloromethane phases to serve as extract liquor, drying the obtained extract liquor by using anhydrous sodium sulfate, performing suction filtration, concentrating and vacuum drying to obtain 13.0g of 1-benzyl indazole-3-methanol, wherein the yield is 97.7%.
(4) Synthesis of bindarit
Adding 1-benzyl indazole-3-methanol (5.0g, 20.98mmol), sodium hydroxide (10.9g, 272.74mmol) and 100mL of acetone into a reaction bottle in sequence, stirring at room temperature, slowly dropping 20mL of chloroform-acetone solution (chloroform content 104.9mmol) into the condensation hydrolysis mixed liquid (dropping time is about 2h), heating the obtained condensation hydrolysis reaction liquid to 60 ℃ after dropping, reacting for 3h, and stopping heating.
Sequentially cooling the obtained condensation hydrolysis reaction liquid (the cooling temperature is 25 ℃, the time is 1h), concentrating to obtain a sticky substance, mixing the obtained sticky substance, water (150mL) and ethyl acetate (150mL), and performing first extraction to obtain a first water phase and a first ethyl acetate phase; continuously adding water (150mL) into the first ethyl acetate phase for second extraction to obtain a second water phase and a second ethyl diacetate phase; adding 150mL of water into the obtained second ethyl acetate successively for carrying out extraction for the third time to obtain a third water phase and a third ethyl acetate phase; the resulting aqueous phases were combined as extracts. Adjusting the pH of the obtained extract to 2-3 by using dilute hydrochloric acid, and separating out a crude product of the bindarit; the obtained crude product of the bindarit is recrystallized by double solvents by acetic acid and distilled water to obtain 4.4g of the bindarit with the yield of 65 percent.
The invention also performs nuclear magnetic resonance on the bindarit prepared in the embodiment 1 to obtain a nuclear magnetic resonance hydrogen spectrum, and the spectrum information is as follows:
1H NMR(300MHz,DMSO)δ12.75(s,1H)，7.93(d,J＝8.1Hz,1H)，7.67(d,J＝8.4Hz,1H)，7.40–7.12(m,7H)，5.61(s,2H)，4.75(s,2H)，1.44(s,6H)。HR-MS(ESI)：[M+H]+experimental 570.1202, theoretical 570.1212.
Example 2
(1) Synthesis of indazole-3-carboxylic acid methyl ester
Indazole-3-carboxylic acid (10g, 61.7mmol) and methanol (200mL) are added into a 500mL three-mouth reaction bottle, then 2mL concentrated sulfuric acid is added, the mixture is heated to 65 ℃ for esterification reaction, the reaction lasts for 3.5 hours, heating is stopped, the material liquid obtained by the esterification reaction is cooled for 1 hour at the temperature of 20 ℃, the cooled material liquid is subjected to rotary evaporation, the methanol is removed, the obtained solid is dissolved in 120mL ethyl acetate, then the solid is sequentially washed for 3 times by distilled water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, the ethyl acetate phase obtained by washing is dried by anhydrous sodium sulfate, moisture is removed, then rotary evaporation concentration is carried out, and vacuum drying is carried out (drying is carried out for 6-8 hours at the temperature of 50-60 ℃) to obtain 15.09g of indazole-3-methyl carboxylate, wherein the yield is 92.6%.
(2) Synthesis of methyl 1-benzylindazole-3-carboxylate
Adding indazole-3-carboxylic acid methyl ester (15.09g, 85.65mmol), potassium carbonate (23.99g, 173.58mmol) and 200mL of acetone in sequence into a three-neck flask provided with a condenser tube and a stirrer, uniformly mixing at the temperature of 25 ℃, and slowly dropping benzyl bromide (19.79g, 115.72mmol) into a reaction bottle (the dropping time is about 1.5h) to obtain a benzylation reaction solution; and heating the obtained benzylation reaction solution to 60 ℃ to carry out benzylation reaction for 2 hours, and stopping heating.
Sequentially cooling feed liquid obtained by the benzylation reaction (at the temperature of 20 ℃ for 80min), filtering and concentrating to obtain viscous liquid; and (3) cooling the obtained viscous liquid in a refrigerator to separate out a solid (the cooling temperature is 2-8 ℃, the cooling time is 1h), fully washing the obtained solid for 3 times by using 100mL of n-hexane, sequentially carrying out suction filtration on the washed liquid, and carrying out vacuum drying to obtain 9.83g of 1-benzyl indazole-3-methyl carboxylate, wherein the yield is 63.9%.
(3) Synthesis of 1-benzylindazole-3-methanol
Tetrahydrofuran (150mL), 1-benzyl indazole-3-carboxylic acid methyl ester (9.83g, 36.91mmol) and sodium borohydride (6.3g, 167.51mmol) were sequentially added to a 250mL three-necked round-bottomed flask, and magnetic stirring was performed at a rotation speed of 600rpm while heating to 50 ℃ to obtain a mixed solution; and then, dropwise adding 35mL of methanol into the reduction mixed solution (the dropwise adding time is about 2 hours), heating to 55 ℃ after the dropwise adding is finished to perform reduction reaction, reacting for 1 hour, and stopping heating.
Sequentially cooling the feed liquid obtained by the reduction reaction (the cooling temperature is 20-25 ℃, the cooling time is 60-80 min), and concentrating to obtain viscous liquid; adding 100mL of distilled water into the obtained viscous liquid, fully stirring for 30min, then adjusting the pH to 2-3 by using dilute hydrochloric acid, then adding 100mL of dichloromethane, extracting for 3 times, combining dichloromethane phases to serve as an extract, drying the obtained extract by using anhydrous sodium sulfate, performing suction filtration, concentrating, and drying in vacuum to obtain 8.59g of 1-benzyl indazole-3-methanol, wherein the yield is 96.8%.
(4) Synthesis of bindarit
Adding 1-benzyl indazole-3-methanol (6.0g, 25.18mmol), sodium hydroxide (13.08g, 327.29mmol) and 110mL of acetone into a reaction bottle in sequence, stirring at room temperature, slowly dropping 22mL of chloroform-acetone solution (with chloroform content of 138.49mmol) into the condensation hydrolysis mixed solution (dropping time is about 2h), heating the obtained condensation hydrolysis reaction solution to 60 ℃ after dropping, reacting for 3h, and stopping heating.
Sequentially cooling the obtained condensation hydrolysis reaction liquid (the cooling temperature is 25 ℃, and the time is 1h), concentrating to obtain a sticky substance, mixing the obtained sticky substance, water (200mL) and ethyl acetate (200mL), and performing first extraction to obtain a first water phase and a first ethyl acetate phase; continuously adding water (200mL) into the first ethyl acetate phase for second extraction to obtain a second water phase and a second ethyl diacetate phase; adding 200mL of water into the obtained second ethyl acetate successively for carrying out extraction for the third time to obtain a third water phase and a third ethyl acetate phase; the resulting aqueous phases were combined as extracts. Adjusting the pH of the obtained extract to 2-3 by using dilute hydrochloric acid, and separating out a crude product of the bindarit; the obtained crude product of the bindarit is recrystallized by a double solvent by acetic acid and distilled water to obtain 5.29g of the bindarit with the yield of 65.1 percent.
Example 3
(1) Synthesis of indazole-3-carboxylic acid methyl ester
Indazole-3-carboxylic acid (5g, 30.85mmol) and methanol (100mL) are added into a 250mL three-mouth reaction bottle, 1mL concentrated sulfuric acid is added and heated to 65 ℃ for esterification reaction, the reaction lasts for 3.5h, heating is stopped, the feed liquid obtained by the esterification reaction is cooled for 1h at the temperature of 20 ℃, the cooled feed liquid is subjected to rotary evaporation to remove the methanol, the obtained solid is dissolved in 60mL ethyl acetate and then washed by distilled water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution for 3 times respectively, the ethyl acetate phase obtained by washing is dried by anhydrous sodium sulfate to remove water, then rotary evaporation concentration is carried out, and vacuum drying (drying is carried out for 6-8 h at the temperature of 50-60 ℃) is carried out to obtain 7.36g of indazole-3-methyl carboxylate, wherein the yield is 90.3%.
(2) Synthesis of methyl 1-benzylindazole-3-carboxylate
Adding indazole-3-carboxylic acid methyl ester (7.36g, 41.78mmol), potassium carbonate (21.93g, 158.69mmol) and 150mL of acetone in sequence into a three-neck flask provided with a condenser tube and a stirrer, uniformly mixing at the temperature of 25 ℃, and slowly dropping benzyl bromide (13.57g, 79.34mmol) into a reaction bottle (the dropping time is about 1.5h) to obtain a benzylation reaction solution; and heating the obtained benzylation reaction solution to 60 ℃ to carry out benzylation reaction for 2 hours, and stopping heating.
Sequentially cooling feed liquid obtained by the benzylation reaction (at the temperature of 20 ℃ for 80min), filtering and concentrating to obtain viscous liquid; and (3) cooling the obtained viscous liquid in a refrigerator to separate out a solid (the cooling temperature is 2-8 ℃, the cooling time is 1h), fully washing the obtained solid for 3 times by using 50mL of n-hexane, sequentially carrying out suction filtration on the washed liquid, and carrying out vacuum drying to obtain 6.48g of 1-benzyl indazole-3-methyl carboxylate, wherein the yield is 58.3%.
(3) Synthesis of 1-benzylindazole-3-methanol
Tetrahydrofuran (70mL), 1-benzyl indazole-3-carboxylic acid methyl ester (6.48g, 24.33mmol) and sodium borohydride (4.14g, 109.48mmol) were sequentially added to a 250mL three-necked round-bottomed flask, and magnetic stirring was performed at a rotation speed of 600rpm while heating to 50 ℃ to obtain a mixed feed liquid; then, 22mL of methanol is dropwise added to the reduction mixed solution (the dropwise adding time is about 2 hours), and after the dropwise adding is finished, the solution is heated to 55 ℃ for reduction reaction, the reaction is carried out for 1 hour, and the heating is stopped.
Sequentially cooling the feed liquid obtained by the reduction reaction (the cooling temperature is 20-25 ℃, the cooling time is 60-80 min), and concentrating to obtain viscous liquid; adding 60mL of distilled water into the obtained viscous liquid, fully stirring for 30min, then adjusting the pH value to 2-3 by using dilute hydrochloric acid, then adding 60mL of dichloromethane, extracting for 3 times, combining dichloromethane phases to serve as an extract, drying the obtained extract by using anhydrous sodium sulfate, performing suction filtration, concentrating and vacuum drying to obtain 5.43g of 1-benzyl indazole-3-methanol, wherein the yield is 93.6%.
(4) Synthesis of bindarit
Adding 1-benzyl indazole-3-methanol (3.0g, 12.59mmol), sodium hydroxide (6.54g, 163.65mmol) and 60mL of acetone into a reaction bottle in sequence, stirring at room temperature, slowly dropping 10mL of chloroform-acetone solution (with chloroform content of 75.54mmol) into the condensation hydrolysis mixed solution (dropping time is about 2h), heating the obtained condensation hydrolysis reaction solution to 60 ℃ after dropping, reacting for 3h, and stopping heating.
Sequentially cooling the obtained condensation hydrolysis reaction liquid (the cooling temperature is 25 ℃, and the time is 1h), concentrating to obtain a sticky substance, mixing the obtained sticky substance, water (100mL) and ethyl acetate (100mL), and performing first extraction to obtain a first water phase and a first ethyl acetate phase; adding water (100mL) into the first ethyl acetate phase continuously for second extraction to obtain a second water phase and a second ethyl diacetate phase; adding 100mL of water into the obtained second ethyl acetate successively for carrying out extraction for the third time to obtain a third water phase and a third ethyl acetate phase; the resulting aqueous phases were combined as extracts. Adjusting the pH of the obtained extract to 2-3 by using dilute hydrochloric acid, and separating out a crude product of the bindarit; the obtained crude product of the bindarit is recrystallized by a double solvent by acetic acid and distilled water to obtain 2.56g of the bindarit with the yield of 62.8 percent.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The synthesis method of the bindarit is characterized by comprising the following steps of:
indazole-3-carboxylic acid and methanol are subjected to esterification reaction to obtain indazole-3-carboxylic acid methyl ester;
carrying out benzylation reaction on the indazole-3-carboxylic acid methyl ester and benzyl bromide to obtain 1-benzyl indazole-3-carboxylic acid methyl ester;
carrying out reduction reaction on the 1-benzyl indazole-3-carboxylic acid methyl ester and a reducing agent to obtain 1-benzyl indazole-3-methanol;
mixing the 1-benzyl indazole-3-methanol, acetone and chloroform, and carrying out condensation hydrolysis reaction to obtain the bindarit.
2. The method of synthesis of claim 1, wherein the molar ratio of indazole-3-carboxylic acid to methanol is 1: 75-90.
3. The synthesis method according to claim 1 or 2, wherein the esterification reaction is carried out at a temperature of 60-70 ℃ for 3-4 hours.
4. The method of synthesis according to claim 1, wherein the molar ratio of indazole-3-carboxylic acid methyl ester to benzyl bromide is 1: (1.3-2.2).
5. The synthesis method according to claim 1 or 4, wherein the temperature of the benzylation reaction is 55-65 ℃ and the reaction time is 1.5-2.5 h.
6. The synthesis method according to claim 1, wherein the reducing agent is a mixture comprising a metal reducing agent and methanol; the metal reducing agent comprises one or more of sodium borohydride, lithium aluminum hydride and red aluminum.
7. The synthesis method according to claim 1 or 6, wherein the temperature of the reduction reaction is 50-60 ℃ and the reaction time is 0.5-1.5 h.
8. The method of synthesis of claim 1, wherein the molar ratio of 1-benzylindazole-3-methanol to chloroform is 1: (4-6).
9. The method of synthesis of claim 1, wherein the molar ratio of 1-benzylindazole-3-methanol to acetone is 1: 60-90.
10. The synthesis method according to claim 1, 8 or 9, wherein the condensation hydrolysis reaction is carried out at a temperature of 55-65 ℃ for 2.5-3.5 h.
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