CN113372338A - Preparation method of losartan impurity - Google Patents
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- CN113372338A CN113372338A CN202110749073.0A CN202110749073A CN113372338A CN 113372338 A CN113372338 A CN 113372338A CN 202110749073 A CN202110749073 A CN 202110749073A CN 113372338 A CN113372338 A CN 113372338A
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Abstract
The invention relates to a preparation method of losartan potassium impurities. The invention discovers a new losartan alkylation impurity in the production process, wherein the impurity has obvious influence on the quality of a finished product and is a key impurity in the preparation process. No report is made on the synthesis of this impurity. The invention provides a method for synthesizing the losartan impurity, which has the advantages of short reaction steps, easily obtained raw materials, high yield and good regioselectivity.
Description
Technical Field
The invention relates to the field of drug synthesis, and in particular relates to a preparation method of losartan impurities.
Background
Losartan potassium (Losartan), chemically known as 2-butyl-4-chloro-5- (hydroxymethyl) -1- { [2' - (1H-tetrazol-5-) biphenyl ] } imidazole, was the first non-peptide angiotensin II receptor antagonist on the market. The drug is jointly developed by Merck Company and Dupont Merck Pharmaceutical Company, is firstly marketed in Switzerland in 1994, is approved to be produced by the Minshadong Pharmaceutical Co., Ltd in 2000, is approved to be produced by the national food and drug administration in 2004, is approved by the United states Food and Drug Administration (FDA), and is a first-line drug for treating hypertension clinically in recent years, and has great progress in domestic clinical application. The losartan potassium can be used for treating patients with mild, moderate and severe hypertension, and has the blood pressure reducing effect similar to that of the existing first-line blood pressure reducing medicament calcium antagonism, angiotensin converting enzyme inhibitor medicament and the like, but has the advantages of less side effect, long action duration, good tolerance and the like. The World Health Organization (WHO) has therefore listed it in 1999 as one of 6 major classes of drugs for the treatment of hypertension.
The inventor finds in the current research and development work that alkylation impurities inevitably occur in losartan potassium synthesized by the existing synthesis route, and the chemical structural formula of the impurities is as follows:
since impurities may have potential toxicity to human bodies, the research on impurities is an important component of pharmaceutical research, the impurities can affect the purity of losartan potassium raw material medicaments, the generation of the impurities should be controlled in the synthesis process, however, no document reports about a preparation method of the impurities at present, and the impurities are important impurity standards for the quality research of losartan potassium.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of losartan potassium impurities, which has the advantages of mild reaction conditions, simple process method, high purity of the obtained product, suitability for industrial popularization and capability of providing research standards for quality research of losartan potassium.
The technical scheme adopted for solving the technical problems is as follows: a preparation method of alkylated impurities of losartan potassium comprises the following steps:
A. taking losartan potassium as a raw material, and reacting under the conditions of an alkylating reagent, alkali and an organic solvent;
B. after the reaction is finished, adding acid into the system for treatment, cooling, stirring, crystallizing, and filtering to obtain a crude product;
C. recrystallizing the crude product, crystallizing at room temperature, and drying to obtain pure alkylated losartan impurities;
the reaction formula is shown as follows,
the alkylating reagent is R-X, the R group is selected from one of alkyl with 1-4C atoms, and the X group is selected from halogen groups or-OTs.
Further, the alkylating agent is used in an amount of 1 to 10 equivalents.
Further, in the step A, the alkali is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine, the solvent is selected from acetone, chloroform and dichloromethane, the dosage of the alkali is 0.5-10 equivalents, and the concentration of losartan potassium in the solution is 0.3-0.6M.
Further, the reaction temperature in the step A is 20-40 ℃, preferably 25 ℃, and the reaction time is 6-15 hours.
Further, the acid in the step B is selected from hydrochloric acid, sulfuric acid, acetic acid and citric acid, the pH value of the system is adjusted to be 1-6 by using acid, the pH value is preferably 4-5, and the temperature for cooling and crystallizing is 0-10 ℃.
In step C, the solvent used for recrystallization is acetone, and the volume of acetone is 1.5 times of the mass of the raw material.
Compared with the prior art, the invention has the advantages that: the invention reports a preparation method of losartan impurity, the impurity is an inevitable impurity generated in the existing losartan potassium synthesis route, the impurity has obvious influence on the quality of a finished product, but the content of the impurity of the losartan potassium finished product is low, the separation and purification are difficult, the generation path of the impurity is researched, the impurity is directionally synthesized, and the preparation method has important significance on the quality control of losartan potassium raw material medicines; the invention designs a simple and feasible preparation method of the losartan impurity, and the method has the advantages of short reaction steps, easily obtained raw materials and high yield. Compared with the prior art, regioisomer by-products cannot be obtained in the reaction, and the selectivity is obviously improved.
Drawings
FIG. 1 is an HPLC chromatogram shown in example 1 of the present invention
FIG. 2 is an HPLC chromatogram shown in example 2 of the present invention
Detailed Description
Example 1
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, 12.9g of methyl iodide (0.0911 mol, 1.05 eq.) in 20ml of acetone was added to the reaction mixture, and the mixture was allowed to return to room temperature and reacted at room temperature for 6 h. Monitoring by TLC that losartan potassium is reacted completely, concentrating reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, uniformly stirring, adjusting pH = 4-5 by 13g of glacial acetic acid in the reaction liquid, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for dissolution, naturally cooling to room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 30.7g of N-methyl losartan, wherein the purity is 99.9% and the yield is 87.2%.1H NMR（400MHz，DMSO-d6）δ7.734~7.775（m,1H, ArH）,7.597~7.669(m,3H, ArH),7.029~7.082（m,4H, ArH），5.249（s,2H,-CH2-），5.218~5.231（m,1H, -OH），4.323~4.335（d,2H,-CH2-），3.44（s,3H,-CH3），2.426~2.509（m,2H,-CH2-），1.403~1.478（m,2H,-CH2-），1.194~1.286（m,2H,-CH2-），0.788~0.825（m,3H,-CH3），ESI-MS（m/z）:436.9[M+H]+
Example 2
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, then 19.5g isopropyl p-toluenesulfonate (0.0911 mol, 1.05 eq.) in 20ml acetone was added to the reaction mixture, and after the addition was completed, the mixture was returned to room temperature and reacted at room temperature for 8 h. Monitoring the completion of the losartan potassium reaction by TLC, concentrating the reaction solution under reduced pressure to dryness, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction solution to adjust the pH = 4-5, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for clearing, naturally cooling, stirring for crystallization for 4h at room temperature,filtering, washing a filter cake with water, continuously performing suction filtration till the filter cake is dry, and drying the filter cake to obtain 31.5g of N-isopropyl losartan, wherein the yield is 83.0 percent and the purity is 99.8 percent.
1H NMR（400MHz，DMSO-d6）δ7.779~7.798（m,1H, ArH）,7.638~7.60(m,1H, ArH),7.565~7.528（m,1H, ArH），7.479~7.46（m,1H, ArH），7.09~7.07（m,2H, ArH），7.01~6.99（m,2H, ArH），5.507（s,2H,-CH2-），5.251（m,1H, -OH），5.027~4.961（m,1H,-CH-），4.321~4.308（d,2H,-CH2-），2.507~2.468（m,2H,-CH2-），1.538~1.462（m,2H,-CH2-），1.389~1.372（d,6H,-CH3），1.289~1.216（m,2H,-CH2-），0.837~0.801（m,3H,-CH3）ESI-MS（m/z）:464.2 [M+H]+
Example 3
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.5211 mol, 0.7 eq.) and stirred well, and then 14.2g of iodoethane (0.0911 mol, 1.05 eq.) in 20ml of acetone was added to the reaction solution, and the reaction was allowed to return to room temperature for 8h at room temperature. Monitoring by TLC that losartan potassium is reacted completely, concentrating reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction liquid to adjust the pH = 4-5, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for dissolving, naturally cooling to room temperature, stirring and crystallizing for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 32.02g of N-ethyl losartan, wherein the yield is 81.8% and the purity is 99.96%.
Example 4
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, either 17.2g of n-butyl iodide (0.0911 mol, 1.05 eq.) in 20ml of acetone is added to the reaction mixture, the temperature is returned to room temperature after addition and the reaction is allowed to proceed for 7h at room temperature. Monitoring the completion of the losartan potassium reaction by TLC, concentrating the reaction solution under reduced pressure to dryness, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction solution to adjust the pH to be = 4-5, and reducing the pHStirring and crystallizing for 2 hours at the temperature of only 0-5 ℃, filtering, mixing a wet product with 60ml of acetone, heating until the mixture is dissolved and clear, then naturally cooling, stirring and crystallizing for 4 hours at the room temperature, filtering, washing a filter cake with water, continuously performing suction filtration until the filter cake is dry, and drying the filter cake to obtain 34.2g of N-butyl losartan, wherein the yield is 82.3%, and the purity is 99.9%.
Example 5
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of tetrahydrofuran are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, and then 20ml of acetone solution containing 12.9g of methyl iodide (0.0911 mol, 1.05 eq.) was added to the reaction solution, and the reaction was allowed to return to room temperature for 8h at room temperature. Monitoring the completion of losartan potassium reaction by TLC (thin layer chromatography), concentrating the reaction solution under reduced pressure to dryness, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction solution to adjust the pH = 4-5, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for dissolution, naturally cooling to room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to dryness, drying the filter cake to obtain 31.4g of N-methyl losartan, wherein the yield is 89.8%, and the purity is 99.4%
Comparative example 1
40g of losartan potassium (0.0868 mol, 1 equivalent) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and K containing 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) was reacted with a solution of 12.9g methyl iodide (0.0911 mol, 1.05 eq.) in 20ml acetone cooled to 10 ℃ for 8 h. Monitoring by TLC that losartan potassium is reacted completely, concentrating reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction liquid to adjust the pH = 4-5, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for dissolution, naturally cooling only at room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 21.4 g of N-methyl losartan, wherein the yield is 51.3% and the purity is 69.8%.
Comparative example 2
40g of losartan potassium (0.0868 mol, 1 equivalent) and 200mL of acetone are added into a 500mL four-mouth bottle, and the mixture is stirred and cooledTo 10 ℃ C, 7.2g of K are added2CO3(0.0511 mol, 0.7 eq.) was reacted with a solution of 15.5g 2-iodopropane (0.0911 mol, 1.05 eq.) in 20ml acetone at room temperature for 8 h. Monitoring by TLC that losartan potassium is reacted completely, concentrating reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction liquid to adjust the pH = 4-5, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of dichloromethane, heating to reflux for dissolution, naturally cooling only at room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 26.39g of N-isopropyl losartan, wherein the yield is 65.4% and the purity is 95.2%.
Comparative example 3
40g of losartan potassium (0.0868 mol, 1 equivalent) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and K containing 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) was reacted with isopropyl p-toluenesulfonate (16.4 g, 0.0694mol, 0.8 eq.) in 20ml of acetone at room temperature for 8 h. And after TLC monitoring reaction is finished, concentrating the reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, uniformly stirring, adding glacial acetic acid into the reaction liquid to adjust the pH to be = 4-5, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux and dissolving, naturally cooling, stirring and crystallizing for 4h only at room temperature, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 24.7N isopropyl losartan, wherein the yield is 61.3%, and the purity is 95.1%.
Comparative example 4
40g of losartan potassium (0.0868 mol, 1 equivalent) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and K containing 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) was reacted with a solution of isopropyl p-toluenesulfonate (19.5 g, 0.0694mol, 1.05 eq.) in 20ml of acetone, heated to 50 ℃ for 8 h. After TLC monitoring reaction, concentrating the reaction solution under reduced pressure to dryness, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction solution to adjust the pH = 4-5, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for dissolving, naturally cooling, and only stirring and separating at room temperatureCrystallizing for 4h, filtering, washing a filter cake with water, continuously performing suction filtration till the filter cake is dry, and drying the filter cake to obtain 23.9g of N-isopropyllosartan, wherein the yield is 59.2 percent and the purity is 90.9 percent.
Comparative example 5
40g of losartan potassium (0.0868 mol, 1 equivalent) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and K containing 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) was reacted with a solution of 15.5g 2-iodopropane (0.0694 mol, 1.05 eq.) in 20ml acetone heated to 50 ℃ for 8 h. And after TLC monitoring reaction is finished, concentrating the reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, uniformly stirring, adding glacial acetic acid into the reaction liquid to adjust the pH to be = 4-5, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux and dissolving, naturally cooling, stirring and crystallizing for 4h only at room temperature, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 25.2g of N-isopropyllosartan, wherein the yield is 62.5% and the purity is 88.6%.
Comparative example 6
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, 8.3g dimethyl carbonate (0.0911 mol, 1.05 eq.) in 20ml acetone was added to the reaction mixture, and the mixture was allowed to return to room temperature and allowed to react at room temperature for 8 h. TLC (thin layer chromatography) monitoring reaction stopping, concentrating the reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction liquid to adjust the pH = 4-5, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux and dissolving, naturally cooling to room temperature, stirring and crystallizing for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 6.1g of N-methylated losartan, wherein the purity is 99.1%, and the molar yield is 16.1%.
Comparative example 7
40g of losartan potassium (0.0868 mol, 1 equivalent) and 400ml of acetone are added into a 1000ml four-mouth bottle, stirred and cooled to 10 ℃, and K containing 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) with 16.9g (0) of methyl p-toluenesulfonate-containing solution0911mol, 1.05 eq) in 20ml of acetone, and brought back to room temperature for 8 h. Monitoring the losartan potassium reaction completion by TLC, concentrating the reaction solution under reduced pressure to dryness, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction solution to adjust the pH = 4-5, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for clearing, naturally cooling only at room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to dryness, drying the filter cake to obtain 19.4 g of N-methyl losartan, wherein the yield is 51.1%, the purity is 97.2%
Comparative example 8
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, 8.3g of methyl p-toluenesulfonate 16.9g (0.0911 mol, 1.05 eq.) of 20ml of acetone solution was added to the reaction mixture, and the mixture was allowed to return to room temperature and reacted at room temperature for 8 hours. And (3) monitoring reaction stop by TLC, concentrating the reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction liquid to adjust the pH to be = 4-5, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, mixing a wet product with 60ml of acetone, adding a large amount of N-hexane for crystallizing for 1h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 31.6g of N-methylated losartan, wherein the yield is 83.3% and the purity is 73.3%.
Comparative example 9
40g of losartan potassium (0.0868 mol, 1 equivalent) and 200ml of methanol are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and K containing 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and a solution of methyl p-toluenesulfonate 16.9g (0.0911 mol, 1.05 eq.) in 20ml of methanol, brought to room temperature for 8 h. Monitoring the completion of losartan potassium reaction by TLC (thin layer chromatography), concentrating the reaction solution under reduced pressure to dryness, adding 100ml of dichloromethane and 100ml of water, stirring uniformly, adding glacial acetic acid into the reaction solution to adjust the pH = 4-5, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 60ml of acetone, heating to reflux for dissolution, naturally cooling only at room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to dryness, and drying the filter cake to obtain 24.6 g of N-methyl complexThe yield of the sartan is 64.8 percent, and the purity is 85.9 percent.
Comparative example 10
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, 12.9g of methyl iodide (0.0911 mol, 1.05 eq.) in 20ml of acetone was added to the reaction mixture, and the mixture was allowed to return to room temperature and reacted at room temperature for 6 h. Monitoring by TLC that losartan potassium is reacted completely, concentrating reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, uniformly stirring, adjusting pH = 4-5 by 13g of glacial acetic acid in the reaction liquid, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 35ml of acetone, heating to reflux for dissolution, naturally cooling to room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 32.9g of N-methyl losartan, wherein the purity is 72.1% and the yield is 86.7%.
Comparative example 11
40g of losartan potassium (0.0868 mol, 1 eq) and 200ml of acetone are added into a 500ml four-mouth bottle, stirred and cooled to 10 ℃, and 7.2g of K is added2CO3(0.0511 mol, 0.7 eq.) and stirred well, 12.9g of methyl iodide (0.0911 mol, 1.05 eq.) in 20ml of acetone was added to the reaction mixture, and the mixture was allowed to return to room temperature and reacted at room temperature for 6 h. Monitoring by TLC that losartan potassium is reacted completely, concentrating reaction liquid under reduced pressure to be dry, adding 100ml of dichloromethane and 100ml of water, uniformly stirring, adjusting pH = 4-5 by 13g of glacial acetic acid in the reaction liquid, cooling to 0-5 ℃, stirring for crystallization for 2h, filtering, mixing a wet product with 90ml of acetone, heating to reflux for dissolution, naturally cooling to room temperature, stirring for crystallization for 4h, filtering, washing a filter cake with water, continuously performing suction filtration to be dry, and drying the filter cake to obtain 12.2g of N-methyl losartan, wherein the purity is 99.9% and the yield is 32.1%.
Claims (5)
1. A preparation method of alkylated impurities of losartan potassium is characterized by comprising the following steps of:
A. taking losartan potassium as a raw material, and reacting under the conditions of an alkylating reagent, alkali and an organic solvent;
B. after the reaction is finished, adding acid into the system for treatment, cooling, stirring, crystallizing, and filtering to obtain a crude product;
C. recrystallizing the crude product, crystallizing at room temperature, and drying to obtain pure alkylated losartan impurities;
the reaction formula is shown as follows
2. The preparation method according to claim 1, wherein the base is one or more selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine and diisopropylethylamine, and the solvent is one or more selected from acetone, chloroform and dichloromethane.
3. The preparation method according to claim 1, wherein the reaction temperature in the step A is 20-40 ℃ and the reaction time is 6-15 hours.
4. The preparation method according to claim 1, wherein the acid in step B is selected from hydrochloric acid, sulfuric acid, acetic acid and citric acid, the pH of the system is adjusted to 1-6 by using acid, and the temperature for cooling and crystallizing is 0-10 ℃.
5. The method according to claim 1, wherein the solvent used for recrystallization in step C is acetone.
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