CN111943937A - Synthesis method of triphenyl candesartan - Google Patents

Abstract

The application relates to the field of candesartan preparation, and particularly discloses a synthesis method of triphenyl candesartan. The synthesis method of triphenyl candesartan comprises the following steps: s1: preparing tributyltin azide, and carrying out azide reaction on tributyltin chloride and sodium azide to obtain tributyltin azide; s2: preparing a candesartan intermediate C7, and carrying out tetrazolylation reaction on 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester and tributyl tin azide to obtain a candesartan intermediate C7; s3: preparing a candesartan intermediate C8, firstly carrying out hydrolysis reaction on the candesartan intermediate C7 in an alkaline agent, then reacting with hydrochloric acid, and acidifying to obtain a candesartan intermediate C8; s4: preparing a triphenyl candesartan intermediate, and reacting the candesartan intermediate C8 with a triphenyl compound to obtain the triphenyl candesartan intermediate. The preparation method of the invention has the advantages of shortening the process flow and improving the yield.

Description

Synthesis method of triphenyl candesartan

Technical Field

The invention relates to the technical field of candesartan, in particular to a synthesis method of triphenyl candesartan.

Background

Candesartan is a good active ingredient of antihypertensive drugs. Candesartan cilexetil, as a prodrug form, is absorbed enterally in the body, undergoes complete hydrolysis to the Candesartan (Candesartan) active metabolite, binds with high selectivity to angiotensin II subtype I receptor (AT1), producing an antihypertensive effect.

Triphenylcandesartan, chemical name: the structural formula of the 2-ethoxy-3- [ [4- [2- (1-trityl-1H-tetrazole-5-yl) phenyl ] methyl ] -3H-benzimidazole-4-carboxylic acid is shown as the formula (I), and the compound is a key intermediate for synthesizing candesartan cilexetil.

The existing common synthesis process of triphenyl candesartan, such as the synthesis route in candesartan cilexetil literature (Kubo K, Kohara Y, etc., J.Med.Chem, 1993,36: 2182-.

During the synthesis of the triphenylcandesartan, the intermediate of the structural formula (II) usually takes 2-nitro-1, 2-phthalic acid as a starting material and undergoes esterification reaction; performing azide reaction, Boc protection, condensation, Boc protection removal and nitro reduction; the intermediate of the structural formula (II) is obtained after the product generated by the reaction of the reduction product and tetraethoxymethane is tetrazolized.

The above prior art solutions have the following drawbacks: the synthesis process of the triphenyl candesartan involves more reactions, the required synthesis process flow is longer, and the loss of raw materials or intermediates inevitably exists in each step of the process flow, so that the yield of the triphenyl candesartan is low.

Disclosure of Invention

In order to improve the yield of the triphenyl candesartan, the application provides a synthesis method of the triphenyl candesartan.

The synthesis method of triphenyl candesartan provided by the application adopts the following technical scheme:

the synthesis method of triphenyl candesartan comprises the following steps:

s1: preparing tributyltin azide, and carrying out azide reaction on tributyltin chloride and sodium azide to obtain tributyltin azide;

s2: preparing a candesartan intermediate C7, and carrying out tetrazolylation reaction on 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester and tributyl tin azide to obtain a candesartan intermediate C7;

s3: preparing a candesartan intermediate C8, firstly carrying out hydrolysis reaction on the candesartan intermediate C7 in an alkaline agent, then reacting with hydrochloric acid, and acidifying to obtain a candesartan intermediate C8;

s4: preparing a triphenyl candesartan intermediate, and reacting the candesartan intermediate C8 with a triphenyl compound to obtain the triphenyl candesartan intermediate.

By adopting the technical scheme, the triphenyl candesartan intermediate can be obtained through four-step reaction, and the process steps of production are reduced through optimization of the process steps, so that the loss of raw materials or the intermediate in the production process is reduced, and the yield and the production efficiency of the triphenyl candesartan are improved.

Preferably, the step S1 specifically includes the following steps:

step a: adding sodium azide into water, stirring and dissolving to obtain a mixed solution a;

step b: controlling the reaction temperature to be 10-25 ℃, adding tributyltin chloride into the mixed solution a, and stirring for reaction for 3-4 hours to obtain a mixed solution b;

step c: and (3) adding toluene into the mixed solution b, stirring and extracting, standing for layering, and washing an organic layer with saturated sodium chloride water to obtain a tributyl tin azide toluene solution.

Preferably, the step S2 specifically includes the following steps:

adding 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester into a tributyl tin azide toluene solution, stirring and dissolving, controlling the reaction temperature to be 110-120 ℃, and carrying out heat preservation reaction for 90-110 hours. The intermediate C7 of candesartan is obtained.

Preferably, the specific process parameters in step S2 are as follows: adding 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester into tributyl tin azide toluene solution, stirring and dissolving, controlling the reaction temperature to be 115 ℃, and keeping the temperature for reaction for 100 hours. The intermediate C7 of candesartan is obtained.

By adopting the technical scheme, if the reaction temperature is controlled to be lower than 110 ℃ in the step S2, the heat provided at the temperature is not enough to activate the reaction, so that the reaction cannot be continuously carried out; if the reaction temperature is controlled to be higher than 110 ℃, the reaction temperature is too high, and the energy consumption is too large. Therefore, the reaction temperature in step S2 is controlled to be 110-120 ℃, so that the equilibrium point of low energy consumption and high reaction efficiency can be reached. At 115 ℃, the reaction efficiency in the step S2 was improved most, and the reaction time was controlled at 100h, so that the reaction degree in the step S2 was also maintained to be optimal.

Preferably, the step S3 specifically includes the following steps:

step a: adding 15% sodium hydroxide solution in batches into the toluene solution of the candesartan intermediate C7, controlling the temperature to be 110 ℃, decompressing and recovering toluene, combining alkaline water phases and retaining;

step b: controlling the temperature of the alkali water phase obtained in the step a to be 30-50 ℃, and carrying out heat preservation reaction for 5-7 h;

step c: after the reaction is finished, reducing the temperature of an alkaline water phase to room temperature, then adding dichloromethane, stirring and extracting, and retaining a water phase;

step d: c, adjusting the pH of the water phase reserved in the step c to 3-4 by using hydrochloric acid with the mass concentration of 30% at the temperature of 20-30 ℃, repeatedly measuring the pH until the pH is stable and unchanged, and performing filter pressing to obtain a filter cake;

step e: and washing the filter cake with water, and drying the filter cake at 40-60 ℃ under reduced pressure to obtain the candesartan cilexetil intermediate C8.

Preferably, the specific steps of step S4 are as follows:

step a: stirring, mixing and dissolving the candesartan intermediate C8, dichloromethane and triethylamine;

step b: adding triphenylchloromethane, and controlling the temperature to be 35-50 ℃ to perform heat preservation reaction for 6-8 hours, and finishing the reaction;

step c: adding a sodium bicarbonate solution with the mass concentration of 10% for washing for several times, standing for layering, and taking an organic layer;

step d: controlling the organic layer to be below 30 ℃, adjusting the pH to 3-4 by using hydrochloric acid with the mass concentration of 30%, repeating until the pH is unchanged, and filtering to obtain a wet product;

step e: and d, refining and drying the wet product obtained in the step d to obtain the triphenyl candesartan intermediate.

Preferably, the step e is as follows: uniformly mixing the wet product and acetone according to a proportion, controlling the reaction temperature to be 50-60 ℃, keeping the temperature and stirring for 2-3 hours, cooling to 0-10 ℃, stirring for crystallization, filtering to obtain a refined product, and drying the refined product at 40-60 ℃ under reduced pressure to obtain the triphenyl candesartan.

Preferably, the specific steps of step S4 are as follows:

step a: stirring, mixing and dissolving the candesartan intermediate C8, dichloromethane and triethylamine;

step b: b, adding triphenylchloromethane into the mixed solution obtained in the step a, and controlling the temperature to be 45 ℃ to perform heat preservation reaction for 8 hours to finish the reaction;

step c: adding a sodium bicarbonate solution with the mass concentration of 10% for washing for several times, standing for layering, and taking an organic layer;

step d: controlling the organic layer below 30 ℃, adjusting the pH to 3 by using hydrochloric acid with the mass concentration of 30%, repeating until the pH is unchanged, and filtering to obtain a wet product;

step e: and d, refining and drying the wet product obtained in the step d to obtain the triphenyl candesartan intermediate.

By adopting the technical scheme, the triethylamine hydrochloride component is washed away and removed by adopting the sodium bicarbonate solution with the mass concentration of 10% in a fractional manner, carbon dioxide gas can be released from the sodium bicarbonate in the process of neutralizing hydrogen ions, and the released carbon dioxide gas has a mechanical stirring effect on the reacted mixed solution, so that the sodium bicarbonate solution which does not participate in the reaction and the reacted mixed solution are driven to be uniformly mixed more quickly, and the washing efficiency and the washing effect are improved.

In summary, the present application has the following beneficial effects:

1. because the method adopts the process flow with fewer flows, the loss of raw materials or intermediates is reduced after the process is shortened, and the effect of improving the product yield is obtained;

2. according to the method, the product after reaction is washed by the sodium bicarbonate solution for multiple times in the step S4, triethylamine hydrochloride in the solution after reaction can be quickly neutralized and removed in a layered manner, and therefore the production efficiency of the triphenylcandesartan is improved.

Detailed Description

The present application will be described in further detail with reference to examples.

Candesartan intermediate C7, 2-ethoxy-3- [ [4- [2- (1H-tetrazol-5-yl) phenyl ] methyl ] -3H-benzimidazole-4-carboxylic acid ethyl ester;

candesartan intermediate C8, 2-ethoxy-3- [ [4- [2- (1H-tetrazol-5-yl) phenyl ] methyl ] -3H-benzimidazole-4-carboxylic acid;

the intermediate of triphenyl candesartan, namely 2-ethoxy-3- [ [4- [2- (1-trityl-1H-tetrazole-5-yl) phenyl ] methyl ] -3H-benzimidazole-4-carboxylic acid.

Example 1

The synthesis method of triphenyl candesartan comprises the following process steps:

s1: the preparation method of the tributyl tin azide specifically comprises the following steps:

step a: adding 200kg of sodium azide into 600kg of water, and stirring and dissolving to obtain a mixed solution a;

step b: controlling the reaction temperature to be 20 ℃, adding 670kg of tributyltin chloride into the mixed solution a obtained in the step a, and stirring for reaction for 3.5 hours to obtain mixed solution b;

step c: 1200kg of toluene was added to the mixed solution b, followed by extraction with stirring, standing for layering, and the organic layer was washed with 600kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

S2: the preparation method of the candesartan intermediate C7 specifically comprises the following steps:

310kg of 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester is added into the tributyltin azide toluene solution prepared in the step S1, stirred and dissolved, the reaction temperature is controlled at 120 ℃, and the reaction is carried out for 90 hours under the condition of heat preservation. The intermediate C7 of candesartan is obtained.

S3: the preparation method of the candesartan intermediate C8 specifically comprises the following steps:

step a: adding 1175kg of sodium hydroxide solution with the mass concentration of 15% into the toluene solution of the candesartan intermediate C7 in 5 batches, controlling the temperature to be 110 ℃ to recover toluene under reduced pressure, and combining and retaining alkaline water;

step b: b, transferring the alkaline water phase obtained in the step a into a hydrolysis kettle, and controlling the temperature to perform heat preservation reaction for 5 hours at 50 ℃;

step c: b, cooling the alkaline water phase after the reaction in the step b to room temperature, adding 900kg of dichloromethane, stirring and extracting, and keeping the water phase; the dichloromethane phase is transferred into a recovery kettle for normal pressure recovery and reuse.

Step d: c, transferring the water phase reserved in the step c into an acid adjusting kettle controlled at 25 ℃, adjusting the pH to 4 by using hydrochloric acid with the mass concentration of 30%, repeatedly measuring the pH until the pH is stable and unchanged, and performing pressure filtration to obtain a filter cake;

step e: the filter cake is washed with water and dried at 60 ℃ under reduced pressure to obtain the intermediate C8 of candesartan cilexetil.

S4: the preparation method of the triphenyl candesartan intermediate specifically comprises the following steps:

step a: stirring, mixing and dissolving 300kg of candesartan intermediate C8, 1500kg of dichloromethane and 84kg of triethylamine;

step b: b, adding 210kg of triphenylchloromethane into the mixed solution obtained in the step a, and controlling the temperature to be 50 ℃ to perform heat preservation reaction for 6 hours to finish the reaction;

step c: adding 10% sodium bicarbonate solution with mass fraction concentration of 1200kg in the mixed solution after the reaction in the step b for 5 times, washing for several times, standing for layering after washing, and taking an organic layer;

step d: transferring the organic layer into an acid adjusting kettle controlled at 25 ℃, adjusting the pH to 4 by using hydrochloric acid with the mass concentration of 30%, repeating the process until the pH is unchanged, and performing centrifugal filtration to obtain a wet product and a mother solution; the wet product is reserved, and the mother liquor is neutralized by liquid caustic soda and then the dichloromethane is recovered under normal pressure;

step e: adding 1000kg of acetone into the wet product, stirring and mixing uniformly, controlling the reaction temperature to be 60 ℃, keeping the temperature and stirring for 2 hours, cooling the wet product to 10 ℃ through 1 hour, stirring for crystallization, filtering to obtain a refined product, and drying the refined product at 60 ℃ under reduced pressure to obtain the triphenylcandesartan.

Example 2:

the synthesis method of triphenyl candesartan comprises the following process steps:

s1: the preparation method of the tributyl tin azide specifically comprises the following steps:

step a: adding 200kg of sodium azide into 600kg of water, and stirring and dissolving to obtain a mixed solution a;

step b: controlling the reaction temperature to be 10 ℃, adding 670kg of tributyltin chloride into the mixed solution a obtained in the step a, and stirring for reaction for 4 hours to obtain a mixed solution b;

step c: 1200kg of toluene was added to the mixed solution b, followed by extraction with stirring, standing for layering, and the organic layer was washed with 600kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

S2: the preparation method of the candesartan intermediate C7 specifically comprises the following steps:

310kg of 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester is added into the tributyltin azide toluene solution prepared in the step S1, stirred and dissolved, the reaction temperature is controlled at 110 ℃, and the reaction is carried out for 110 hours under the condition of heat preservation. The intermediate C7 of candesartan is obtained.

S3: the preparation method of the candesartan intermediate C8 specifically comprises the following steps:

step a: adding 1175kg of sodium hydroxide solution with the mass concentration of 15% into the toluene solution of the candesartan intermediate C7 in 5 batches, controlling the temperature to be 110 ℃ to recover toluene under reduced pressure, and combining and retaining alkaline water;

step b: b, transferring the alkaline water phase obtained in the step a into a hydrolysis kettle, and controlling the temperature to perform heat preservation reaction for 7 hours at 30 ℃;

step c: b, cooling the alkaline water phase after the reaction in the step b to room temperature, adding 900kg of dichloromethane, stirring and extracting, and keeping the water phase; the dichloromethane phase is transferred into a recovery kettle for normal pressure recovery and reuse.

Step d: c, transferring the water phase reserved in the step c into an acid adjusting kettle controlled at 20 ℃, adjusting the pH to 3 by using hydrochloric acid with the mass concentration of 30%, repeatedly measuring the pH until the pH is stable and unchanged, and performing pressure filtration to obtain a filter cake;

step e: the filter cake is washed with water and dried at 40 ℃ under reduced pressure to obtain candesartan cilexetil intermediate C8.

S4: the preparation method of the triphenyl candesartan intermediate specifically comprises the following steps:

step a: stirring, mixing and dissolving 300kg of candesartan intermediate C8, 1500kg of dichloromethane and 84kg of triethylamine;

step b: b, adding 210kg of triphenylchloromethane into the mixed solution obtained in the step a, and controlling the temperature to be kept at 35 ℃ for reaction for 8 hours to finish the reaction;

step c: adding 10% sodium bicarbonate solution with mass fraction concentration of 1200kg in the mixed solution after the reaction in the step b for 5 times, washing for several times, standing for layering after washing, and taking an organic layer;

step d: transferring the organic layer into an acid adjusting kettle controlled at 20 ℃, adjusting the pH to 4 by using hydrochloric acid with the mass concentration of 30%, repeating the process until the pH is unchanged, and performing centrifugal filtration to obtain a wet product and a mother solution; the wet product is reserved, and the mother liquor is neutralized by liquid caustic soda and then the dichloromethane is recovered under normal pressure;

step e: adding 1000kg of acetone into the wet product, stirring and mixing uniformly, controlling the reaction temperature to be 50 ℃, keeping the temperature and stirring for 2 hours, cooling the wet product to 0 ℃ through 1 hour, stirring for crystallization, filtering to obtain a refined product, and drying the refined product at 40 ℃ under reduced pressure to obtain the triphenylcandesartan.

Example 3

The synthesis method of triphenyl candesartan comprises the following process steps:

s1: the preparation method of the tributyl tin azide specifically comprises the following steps:

step a: adding 200kg of sodium azide into 600kg of water, and stirring and dissolving to obtain a mixed solution a;

step b: controlling the reaction temperature to be 25 ℃, adding 670kg of tributyltin chloride into the mixed solution a obtained in the step a, and stirring for reaction for 3 hours to obtain a mixed solution b;

step c: 1200kg of toluene was added to the mixed solution b, followed by extraction with stirring, standing for layering, and the organic layer was washed with 600kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

S2: the preparation method of the candesartan intermediate C7 specifically comprises the following steps:

310kg of 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester is added into the tributyltin azide toluene solution prepared in the step S1, stirred and dissolved, the reaction temperature is controlled at 115 ℃, and the reaction is carried out for 100 hours under the condition of heat preservation. The intermediate C7 of candesartan is obtained.

S3: the preparation method of the candesartan intermediate C8 specifically comprises the following steps:

step a: adding 1175kg of sodium hydroxide solution with the mass concentration of 15% into the toluene solution of the candesartan intermediate C7 in 5 batches, controlling the temperature to be 110 ℃ to recover toluene under reduced pressure, and combining and retaining alkaline water;

step b: b, transferring the alkaline water phase obtained in the step a into a hydrolysis kettle, and controlling the temperature to perform heat preservation reaction for 6 hours at 40 ℃;

step c: b, cooling the alkaline water phase after the reaction in the step b to room temperature, adding 900kg of dichloromethane, stirring and extracting, and keeping the water phase; the dichloromethane phase is transferred into a recovery kettle for normal pressure recovery and reuse.

Step d: c, transferring the water phase reserved in the step c into an acid adjusting kettle controlled at 30 ℃, adjusting the pH to 3 by using hydrochloric acid with the mass concentration of 30%, repeatedly measuring the pH until the pH is stable and unchanged, and performing filter pressing to obtain a filter cake;

step e: the filter cake is washed with water and dried at 50 ℃ under reduced pressure to obtain candesartan cilexetil intermediate C8.

S4: the preparation method of the triphenyl candesartan intermediate specifically comprises the following steps:

step a: stirring, mixing and dissolving 300kg of candesartan intermediate C8, 1500kg of dichloromethane and 84kg of triethylamine;

step b: b, adding 210kg of triphenylchloromethane into the mixed solution obtained in the step a, and controlling the temperature to be kept at 40 ℃ for reaction for 7 hours to finish the reaction;

step c: adding 10% sodium bicarbonate solution with mass fraction concentration of 1200kg in the mixed solution after the reaction in the step b for 5 times, washing for several times, standing for layering after washing, and taking an organic layer;

step d: transferring the organic layer into an acid adjusting kettle controlled at 30 ℃, adjusting the pH to 4 by using hydrochloric acid with the mass concentration of 30%, repeating the process until the pH is unchanged, and performing centrifugal filtration to obtain a wet product and a mother solution; the wet product is reserved, and the mother liquor is neutralized by liquid caustic soda and then the dichloromethane is recovered under normal pressure;

step e: adding 1000kg of acetone into the wet product, stirring and mixing uniformly, controlling the reaction temperature to be 55 ℃, keeping the temperature and stirring for 2.5 hours, cooling the wet product to 5 ℃ through 1 hour, stirring for crystallization, filtering to obtain a refined product, and drying the refined product at 50 ℃ under reduced pressure to obtain the triphenylcandesartan.

Example 4

The synthesis method of triphenyl candesartan comprises the following process steps:

s1: the preparation method of the tributyl tin azide specifically comprises the following steps:

step a: adding 200kg of sodium azide into 600kg of water, and stirring and dissolving to obtain a mixed solution a;

step b: controlling the reaction temperature to be 25 ℃, adding 670kg of tributyltin chloride into the mixed solution a obtained in the step a, and stirring for reaction for 3 hours to obtain a mixed solution b;

step c: 1200kg of toluene was added to the mixed solution b, followed by extraction with stirring, standing for layering, and the organic layer was washed with 600kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

S2: the preparation method of the candesartan intermediate C7 specifically comprises the following steps:

310kg of 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester is added into the tributyltin azide toluene solution prepared in the step S1, stirred and dissolved, the reaction temperature is controlled at 115 ℃, and the reaction is carried out for 100 hours under the condition of heat preservation. The intermediate C7 of candesartan is obtained.

S3: the preparation method of the candesartan intermediate C8 specifically comprises the following steps:

step a: adding 1175kg of sodium hydroxide solution with the mass concentration of 15% into the toluene solution of the candesartan intermediate C7 in 5 batches, controlling the temperature to be 110 ℃ to recover toluene under reduced pressure, and combining and retaining alkaline water;

step b: b, transferring the alkaline water phase obtained in the step a into a hydrolysis kettle, and controlling the temperature to perform heat preservation reaction for 6 hours at 40 ℃;

step c: b, cooling the alkaline water phase after the reaction in the step b to room temperature, adding 900kg of dichloromethane, stirring and extracting, and keeping the water phase; the dichloromethane phase is transferred into a recovery kettle for normal pressure recovery and reuse.

Step d: c, transferring the water phase reserved in the step c into an acid adjusting kettle controlled at 30 ℃, adjusting the pH to 3 by using hydrochloric acid with the mass concentration of 30%, repeatedly measuring the pH until the pH is stable and unchanged, and performing filter pressing to obtain a filter cake;

step e: the filter cake is washed with water and dried at 50 ℃ under reduced pressure to obtain candesartan cilexetil intermediate C8.

S4: the preparation method of the triphenyl candesartan intermediate specifically comprises the following steps:

step a: stirring, mixing and dissolving 300kg of candesartan intermediate C8, 1500kg of dichloromethane and 84kg of triethylamine;

step b: b, adding 210kg of triphenylchloromethane into the mixed solution obtained in the step a, and controlling the temperature to be 45 ℃ to perform heat preservation reaction for 8 hours to finish the reaction;

step c: adding 10% sodium bicarbonate solution with mass fraction concentration of 1200kg in the mixed solution after the reaction in the step b for 5 times, washing for several times, standing for layering after washing, and taking an organic layer;

step d: transferring the organic layer into an acid adjusting kettle controlled at 30 ℃, adjusting the pH to 3 by using hydrochloric acid with the mass concentration of 30%, repeating the process until the pH is unchanged, and performing centrifugal filtration to obtain a wet product and a mother solution; the wet product is reserved, and the mother liquor is neutralized by liquid caustic soda and then the dichloromethane is recovered under normal pressure;

step e: adding 1000kg of acetone into the wet product, stirring and mixing uniformly, controlling the reaction temperature to be 55 ℃, keeping the temperature and stirring for 2.5 hours, cooling the wet product to 5 ℃ through 1 hour, stirring for crystallization, filtering to obtain a refined product, and drying the refined product at 50 ℃ under reduced pressure to obtain the triphenylcandesartan.

Comparative example

Comparative example 1:

the synthesis method of triphenyl candesartan is as follows:

dissolving 3-amino-2- (((2-cyanobiphenyl-4-yl) methyl) amino) methyl benzoate in acetonitrile to prepare a 10% (m/v) acetonitrile solution for later use, and uniformly mixing 200mL of tetraethyl orthocarbonate and 20mL of glacial acetic acid for later use. Setting the temperature of a reaction area of a G1 reactor of corning to 220 ℃, setting the temperature reduction area to 15 ℃, carrying out backpressure on the whole microchannel reaction system to 1.2MPa by using acetonitrile, simultaneously starting two material conveying pumps, wherein the flow rate of a conveying pump for conveying 3-amino-2- (((2-cyanobiphenyl-4-yl) methyl) amino) methyl benzoate acetonitrile solution is 20mL/min, the flow rate of a conveying pump for tetraethoxymethane and glacial acetic acid is 1.4mL/min, detecting complete reaction by TLC (ethyl acetate: n-hexane is 8: 1), collecting a reaction liquid into a 5L four-mouth flask, collecting the reaction liquid for 100min, adding 1800mL of ice water into the obtained reaction liquid under stirring, cooling to 10 ℃, dropwise adding a 4% potassium hydroxide aqueous solution, controlling the pH to be between 6.0 and 6.5, stirring for 1h below 10 ℃, and filtering, washing with water, and pumping dry. And drying the obtained intermediate I wet product at 50 ℃ for 16h in vacuum, wherein the vacuum degree is not lower than 0.09 MPa.

Preparing a sodium azide solution: adding 320mL of water purified water into a clean four-mouth reaction bottle at room temperature, slowly adding 128.0g of sodium azide under stirring, cooling to 0 ℃ after dissolving, dropwise adding 534mL of tributyltin chloride into the reaction bottle, wherein the dropwise adding process is not more than 5 ℃, dropwise adding the tributyltin chloride for 1-2 hours, preserving heat for 30 minutes after dropwise adding, slowly heating to 25 ℃, adding 2400mL of dichloromethane, stirring for 20 minutes, standing for layering, extracting an aqueous layer with 600mL of dichloromethane once, combining organic layers, drying for 1 hour by 160g of anhydrous magnesium sulfate, and filtering to obtain a sodium azide solution for later use.

Under the protection of nitrogen at room temperature, a dry and clean 10L reaction flask was charged with intermediate I320.0g and 1800mL of xylene, and a solution of sodium azide in methylene chloride was added dropwise with stirring. After the dripping is finished, slowly raising the temperature to 142-144 ℃ under stirring, distilling at normal pressure to recover dichloromethane until the content of the dichloromethane is lower than 0.5% through gas chromatography analysis. And after distillation, adding 800mL of xylene into the reaction solution, controlling the temperature to be 142-144 ℃, carrying out reflux reaction for 18h, detecting by TLC (ethyl acetate: ethanol is 10: 1) that the reaction is complete, cooling to below 90 ℃ after the reaction is complete, keeping the vacuum degree to be not lower than-0.09 MPa, and concentrating the xylene until the xylene is dry. Adding 960mL of ethanol into the concentrated residue, uniformly stirring, dropwise adding 211.2g of nitrosyl sulfuric acid at 20-25 ℃, completing dripping within 45-60 min, preserving heat for 1h, detecting by TLC (ethyl acetate: ethanol is 10: 1), adding 640mL of ethyl acetate and 1280mL of n-hexane after complete reaction, and stirring for 90 min. After the reaction is finished, cooling to 5-10 ℃, adjusting the pH to 3.0-3.5 by using a 4% potassium hydroxide aqueous solution, stirring for 1h at 5-10 ℃, filtering, and performing vacuum drying for 16h at 50 ℃, wherein the vacuum degree is not lower than 0.09 MPa. The obtained white-like solid is the intermediate II.

Synthesis of candesartan (intermediate III)

1174mL of purified water is added into a clean 5L reaction bottle at room temperature, 105.8g of sodium hydroxide is slowly added under stirring and stirred to be dissolved clearly, the temperature in the reaction bottle is controlled to be 10-15 ℃, the intermediate II252.0g is added within 20min, the temperature is kept at 10-15 ℃ after the addition, the temperature is raised to 70 ℃ for dissolving clearly within 2h, the temperature is kept for 1h, and TLC (ethyl acetate: methanol is 1: 3) detection reaction is carried out. After completion of the reaction, 1500mL of ice water and 25.0g of activated carbon were added, and the mixture was stirred at 50 ℃ for 30min, filtered while hot, the filter cake was washed with 250mL of 50 ℃ hot water, the filtrates were combined, extracted once with 150mL of chloroform, the organic layer was discarded, and the aqueous layer was left. Adding methanol into the water layer, stirring and cooling to 2 ℃, and adjusting the pH to 3.0-3.5 by using 3N hydrochloric acid. Cooling to 10 ℃, and keeping the temperature for crystallization for 2 hours. And (5) after heat preservation, filtering, and washing with water until the effluent liquid is neutral. The obtained wet product is dried in vacuum at 55 ℃ for 16h, and the vacuum degree is not lower than-0.09 MPa. Obtaining the white powdery intermediate IV.

Synthesis of triphenylcandesartan (intermediate IV)

Adding 240mL of dichloromethane into a dry and clean 2000mL four-mouth reaction bottle under the protection of nitrogen at room temperature, adding 80g of intermediate III, 0.3g of tetrabutylammonium fluoride and 64mL of triethylamine under stirring, stirring to dissolve, heating to reflux, then beginning to dropwise add a mixed solution of 58.64g of triphenylchloromethane and 112mL of dichloromethane, completing dropwise addition for about 3 hours, continuing reflux reaction for 1 hour after the dropwise addition is completed, and carrying out liquid phase control detection reaction until the percentage of the intermediate III is less than 0.5%. Cooling to 20-25 ℃, adding 300mL of dichloromethane, adding 400mL of water, stirring for 45min, controlling the temperature below 25 ℃, dropwise adding 1N hydrochloric acid to adjust the pH value to 3.0-3.5, and stirring for 15 min; then, 400mL of methylene chloride was added thereto, and the mixture was stirred for 45 min. Standing for layering, discarding the water layer, adding 450mL of water into the organic layer, stirring, dropwise adding 1N hydrochloric acid to adjust the pH value to 3.0, stirring for 10min, standing for layering, discarding the water layer, washing the organic layer twice (500mL multiplied by 2), adding 16g of activated carbon into the organic layer for decoloring for 15min, filtering, concentrating the filtrate at a temperature below 45 ℃ under reduced pressure until the filtrate is dry, adding 500mL of N-heptane into the residue, stirring, heating up for refluxing for 2h, slowly cooling to 10 ℃, and performing heat preservation and crystallization for 12h to fully crystallize. And (5) after heat preservation, filtering, leaching with a small amount of n-heptane, and draining. And drying the wet intermediate IV in vacuum at 40 ℃ for 8-10 h to obtain white powder.

Comparative example 2 differs from example 1 in that: the sodium bicarbonate solution wash in step S4 is replaced with a sodium hydroxide solution wash.

Detection method

A batch of triphenylcandesartan products are produced by adopting the methods in examples 1-4 and comparative example 1 respectively, the purities of the examples 1-4 and the comparative example 1 are detected by an HPLC method, and finally the yields of the examples 1-4 and the comparative example 1 are obtained by calculating the quality and the purity of the obtained products. The results are shown in Table 1.

Examples	Purity (%)	Yield (%)
			Example 1	97	76
Example 2	97	77
			Example 3	98	78
Example 4	98	78
			Comparative example 1	86	65
Comparative example 2	88	63

And (4) conclusion: combining example 1 and comparative example 1 with table 1, it can be seen that the product synthesized by the synthesis method of the present application has higher purity, and the corresponding yield is improved due to the shortened process. By combining example 1 and comparative example 2 and table 1, it can be seen that in the process of synthesizing triphenylcandesartan according to the present application, the sodium bicarbonate solution has better effect on removing impurities than the use of alkali liquids such as sodium hydroxide, etc., and has certain influence on yield and purity.

Combining examples 1,2, 3, 4 and table 1 it can be seen that the parameter settings of reaction temperature and reaction time in examples 3 and 4 have a certain effect on the improvement of purity and yield of triphenylcandesartan.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.

Claims (8)

1. The synthesis method of triphenyl candesartan is characterized by comprising the following steps:

s1: preparing tributyltin azide, and carrying out azide reaction on tributyltin chloride and sodium azide to obtain tributyltin azide;

s2: preparing a candesartan intermediate C7, and carrying out tetrazolylation reaction on 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester and tributyl tin azide to obtain a candesartan intermediate C7;

s3: preparing a candesartan intermediate C8, firstly carrying out hydrolysis reaction on the candesartan intermediate C7 in an alkaline agent, then reacting with hydrochloric acid, and acidifying to obtain a candesartan intermediate C8;

s4: preparing a triphenyl candesartan intermediate, and reacting the candesartan intermediate C8 with a triphenyl compound to obtain the triphenyl candesartan intermediate.

2. The method of synthesizing triphenylcandesartan according to claim 1, wherein: the step S1 specifically includes the following steps:

step a: adding sodium azide into water, stirring and dissolving to obtain a mixed solution a;

step b: controlling the reaction temperature to be 10-25 ℃, adding tributyltin chloride into the mixed solution a, and stirring for reaction for 3-4 hours to obtain a mixed solution b;

step c: and (3) adding toluene into the mixed solution b, stirring and extracting, standing for layering, and washing an organic layer with saturated sodium chloride water to obtain a tributyl tin azide toluene solution.

3. The method of synthesizing triphenylcandesartan according to claim 1, wherein: the step S2 specifically includes the following steps:

adding 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester into a tributyl tin azide toluene solution, stirring and dissolving, controlling the reaction temperature to be 110-120 ℃, and carrying out heat preservation reaction for 90-110 hours. The intermediate C7 of candesartan is obtained.

4. The method of synthesizing triphenylcandesartan according to claim 1, wherein: the step S3 specifically includes the following steps:

step a: adding 15% sodium hydroxide solution in batches into the toluene solution of the candesartan intermediate C7, controlling the temperature to be 110 ℃, decompressing and recovering toluene, combining alkaline water phases and retaining;

step b: controlling the temperature of the alkali water phase obtained in the step a to be 30-50 ℃, and carrying out heat preservation reaction for 5-7 h;

step c: after the reaction is finished, reducing the temperature of an alkaline water phase to room temperature, then adding dichloromethane, stirring and extracting, and retaining a water phase;

step d: c, regulating the pH of the water phase reserved in the step c to 3-4 by using hydrochloric acid with the mass concentration of 30% at the temperature below 30 ℃, repeatedly measuring the pH until the pH is stable and unchanged, and performing filter pressing to obtain a filter cake;

step e: and washing the filter cake with water, and drying the filter cake at 40-60 ℃ under reduced pressure to obtain the candesartan cilexetil intermediate C8.

5. The method of synthesizing triphenylcandesartan according to claim 1, wherein: the specific steps of step S4 are as follows:

step a: stirring, mixing and dissolving the candesartan intermediate C8, dichloromethane and triethylamine;

step b: adding triphenylchloromethane, and controlling the temperature to be 35-50 ℃ to perform heat preservation reaction for 6-8 hours, and finishing the reaction;

step c: adding a sodium bicarbonate solution with the mass concentration of 10% for washing for several times, standing for layering, and taking an organic layer;

step d: controlling the temperature of the organic layer at 20-30 ℃, adjusting the pH to 3-4 by using hydrochloric acid with the mass concentration of 30%, repeating the adjustment until the pH is unchanged, and filtering to obtain a wet product;

step e: and d, refining and drying the wet product obtained in the step d to obtain the triphenyl candesartan intermediate.

6. The method of synthesizing triphenylcandesartan according to claim 5, wherein: the step e is as follows: uniformly mixing the wet product and acetone according to a proportion, controlling the reaction temperature to be 50-60 ℃, keeping the temperature and stirring for 2-3 hours, cooling to 0-10 ℃, stirring for crystallization, filtering to obtain a refined product, and drying the refined product at 40-60 ℃ under reduced pressure to obtain the triphenyl candesartan.

7. The method of synthesizing triphenylcandesartan according to claim 1, wherein: the specific process parameters of the step S2 are as follows: adding 2-ethoxy-1- [ [ (2' -cyanobiphenyl-4-substituted) methyl ] benzimidazole ] -7-carboxylic acid ethyl ester into tributyl tin azide toluene solution, stirring and dissolving, controlling the reaction temperature to be 115 ℃, and keeping the temperature for reaction for 100 hours. The intermediate C7 of candesartan is obtained.

8. The method of synthesizing triphenylcandesartan according to claim 1, wherein: the specific steps of step S4 are as follows:

step a: stirring, mixing and dissolving the candesartan intermediate C8, dichloromethane and triethylamine;

step b: b, adding triphenylchloromethane into the mixed solution obtained in the step a, and controlling the temperature to be 45 ℃ to perform heat preservation reaction for 8 hours to finish the reaction;

step c: adding a sodium bicarbonate solution with the mass concentration of 10% for washing for several times, standing for layering, and taking an organic layer;

step d: controlling the temperature of the organic layer at 30 ℃, adjusting the pH to 3 by using hydrochloric acid with the mass concentration of 30%, repeating until the pH is unchanged, and filtering to obtain a wet product;

step e: and d, refining and drying the wet product obtained in the step d to obtain the triphenyl candesartan intermediate.