Novel method for synthesizing clarithromycin

Abstract

The invention relates to a novel method for synthesizing clarithromycin, which specifically comprises the following steps: simultaneously protecting 9-position carbonyl, 11-position hydroxyl and 12-position hydroxyl of erythromycin by using o-aminophenylboronic acid and derivatives thereof, protecting 2 '-position hydroxyl and 4'-position hydroxyl of erythromycin by using trimethylsilyl, methylating, and hydrolyzing to obtain clarithromycin. The method has the effects of short process route, cheap and easily available raw materials, high yield and low cost.

Description

Technical Field

[0001] This application relates to the field of synthesis of pharmaceutical raw materials, and particularly to a new method for synthesizing clarithromycin. Background Art

[0002] Clarithromycin belongs to macrolide semi-synthetic antibiotics. Almost all current process routes start from erythromycin A and obtain the target product through five-step reactions including oximation, oximation etherification, silylation, methylation, and hydrolysis deoximation, with a total yield of about 55-60%.

[0003] The current processes for clarithromycin generally have the following deficiencies: a large excess ratio of hydroxylamine hydrochloride in the oximation reaction and many other excipients; low selectivity in the methylation reaction; serious degradation side reactions, difficult product purification, and low total yield in the hydrolysis deoximation reaction; serious pollution and high cost in the whole process.

[0004] Although people have been continuously improving the production process of clarithromycin, it is very difficult to improve the current process and the progress is small. Therefore, developing a new production process for clarithromycin still has great value. Summary of the Invention

[0005] In order to improve the process defects of great difficulty and little progress in improving the current process, this application provides a new method for synthesizing clarithromycin.

[0006] A new method for synthesizing clarithromycin adopts the following technical solution:

[0007] A new method for synthesizing clarithromycin simultaneously protects the 9-position carbonyl group, 11-position and 12-position hydroxyl groups of erythromycin with o-aminophenylboronic acid and its derivatives, and protects the 2 ， -position and 4 ，， -position hydroxyl groups with trimethylsilyl, then methylates the 6-position hydroxyl group, and finally hydrolyzes to obtain clarithromycin.

[0008] By adopting the above technical solution, the 9-position carbonyl group, 11-position and 12-position hydroxyl groups of erythromycin are simultaneously protected with o-aminophenylboronic acid and its derivatives, and the 2-position and 4-position hydroxyl groups are protected with trimethylsilyl, so as to effectively protect the key sites in the synthesis process, avoid unnecessary side reactions, and at the same time achieve the methylation treatment of the 6-position hydroxyl group. Finally, clarithromycin is obtained by hydrolysis. This method not only improves the selectivity and efficiency of the synthesis process, but also reduces the chemical complexity in the operation, enhances the purity and yield of the target product, has strong practicability, and is applicable to the process optimization of large-scale industrial production of clarithromycin.

[0009] Preferably, in the substituted phenylboronic acid used in the borocyclization reaction, the substituents R1, R2, R3, and R4 are simultaneously or respectively hydrogen, alkyl, alkoxy, halogen, aryl, most preferably hydrogen; and the molar ratio of the substituted phenylboronic acid to erythromycin A is 1-1.1:1. The reaction is carried out under negative pressure at a temperature of 60-80 °C for 5-10 hours.

[0010] By adopting the above technical solution, the substituted phenylboronic acid and its substituents (such as hydrogen, alkyl, alkoxy, halogen, aryl) used in the borocyclization reaction can accurately control the reaction conditions during the reaction. Especially by optimally selecting hydrogen as the substituent, the high selectivity and efficiency of the reaction are ensured. The molar ratio of the substituted phenylboronic acid to erythromycin A is 1-1.1:1, and the reaction is carried out under negative pressure conditions, effectively reducing the occurrence of side reactions, ensuring that the reaction temperature is controlled within the range of 60-80 °C, and the reaction time is 5-10 hours. This further improves the stability of the synthesis process and the purity of the product. By optimizing the reaction conditions and precisely controlling the reaction parameters, the yield and selectivity of the clarithromycin synthesis process are greatly improved, and it is suitable for large-scale production.

[0011] Preferably, the silylation reaction reagent is selected as hexamethyldisilazane, the reaction temperature is 10-20 °C, and the reaction time is 1-2 hours.

[0012] By adopting the above technical solution, using hexamethyldisilazane as the reagent in the silylation reaction can be efficiently carried out at a relatively low reaction temperature (10-20 °C), and the reaction time is 1-2 hours, greatly improving the selectivity and efficiency of the reaction. Hexamethyldisilazane as a silylation reagent has high reaction activity and stability, can effectively protect the hydroxyl groups in the erythromycin A molecule, avoid other possible adverse reactions, and ensure the purity and high yield of the product. In addition, the low-temperature reaction conditions not only help to control the occurrence of side reactions but also reduce energy consumption, meet the requirements of green chemistry, optimize the reaction process, provide a more efficient, economical and environmentally friendly solution for the synthesis of clarithromycin, and are especially suitable for industrial production.

[0013] Preferably, the methylation reaction reagent is selected as methyl bromide, dimethyl sulfate, preferably methyl chloride. The molar ratio of the methylation reaction reagent to erythromycin A is 1-1.3:1, and the molar ratio of potassium hydroxide to erythromycin A is 1.5-2:1. The reaction temperature is 10-20 °C, and the reaction time is 0.5-1 hour.

[0014] By adopting the above technical solutions, methyl bromide and dimethyl sulfate are selected as reagents for the methylation reaction, and chloromethane is preferably used as the reagent, which can efficiently proceed within the temperature range of 10-20 °C, and the reaction time is 0.5-1 hour, ensuring the high selectivity and reaction rate of the methylation reaction. The molar ratio of the methylation reagent to erythromycin A is 1-1.3:1, and potassium hydroxide as an acid-binding agent has a molar ratio to erythromycin A of 1.5-2:1, further optimizing the reaction conditions, reducing the generation of by-products, and ensuring the thoroughness of the methylation process. The low-temperature reaction conditions not only improve the safety of the reaction but also reduce energy consumption, meeting the principles of green chemistry. By precisely controlling the reagent ratio, temperature, and time of the reaction, the efficiency and selectivity of the methylation reaction are greatly improved, providing a reliable process guarantee for the efficient synthesis of clarithromycin and having strong industrial application prospects.

[0015] Preferably, C1-C4 carboxylic acids are selected as catalysts for the hydrolysis reaction, the molar ratio of the carboxylic acid to erythromycin A is 1.5-3:1, the reaction temperature is 30-50 °C, and the reaction time is 5-10 hours.

[0016] By adopting the above technical solutions, C1-C4 carboxylic acids are used as catalysts for the hydrolysis reaction, which can efficiently catalyze within the temperature range of 30-50 °C, and the reaction time is 5-10 hours, ensuring the completeness and high selectivity of the hydrolysis reaction. The molar ratio of the carboxylic acid to erythromycin A is 1.5-3:1, optimizing the dosage of the catalyst, enabling the reaction to proceed smoothly under mild conditions, thus avoiding side reactions and improving the purity and yield of the target product. The hydrolysis reaction conditions have strong temperature control adaptability, not only improving the stability of the reaction but also reducing energy consumption, meeting the principles of green chemistry. In addition, the synthesis process is simplified, enhancing the controllability and operability of the reaction, providing an efficient, economical, and environmentally friendly process route for the industrial production of clarithromycin.

[0017] Preferably, solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and 1,4-butyrolactone are used in the borocyclization reaction, and the solvent dosage is 3-5 times the weight of erythromycin A.

[0018] By adopting the above technical solutions, solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and 1,4-butyrolactone are selected in the cycloboration reaction, effectively improving the solubility and reaction rate of the reaction, ensuring the uniformity and stability of the reaction process. The amount of the solvent is 3 to 5 times the weight of erythromycin A. This design helps to better control the reaction temperature and the concentration of reactants, avoids the occurrence of side reactions, and at the same time improves the purity and yield of the target product. By optimizing the solvent system, efficient synthesis can be achieved under a wider range of reaction conditions, and the influence of the solvent on the reaction is reduced, ensuring the selectivity of the reaction and the high quality of the product, providing a reliable solvent selection for the efficient synthesis of clarithromycin, improving the operability of the reaction and the feasibility of industrial application, and being a green, environmentally friendly and economical synthesis method.

[0019] Preferably, the silylation reaction and the cycloboration reaction are carried out in one pot.

[0020] By adopting the above technical solutions, the silylation reaction and the cycloboration reaction are carried out in one pot, which not only simplifies the synthesis process, reduces the reaction steps and time, but also improves the overall efficiency and yield of the reaction. The one-pot technical solution reduces the equipment and operation costs, and at the same time reduces the loss of intermediate products, improving the synthesis efficiency of clarithromycin.

[0021] Preferably, in the methylation reaction, a 1:1 mixture of dimethyl sulfoxide and dioxane, ethylene glycol dimethyl ether is used as the solvent, and the amount of the solvent is 6 to 10 times the weight of erythromycin A.

[0022] By adopting the above technical solutions, a 1:1 mixture of dimethyl sulfoxide and dioxane, ethylene glycol dimethyl ether is used as the solvent in the methylation reaction, and the amount of the solvent is 6 to 10 times the weight of erythromycin A, effectively improving the solubility and reaction rate of the reaction, ensuring the completeness and selectivity of the methylation process. This solvent system optimizes the reaction conditions, reduces the occurrence of side reactions, and enhances the purity and yield of the product.

[0023] Preferably, in the hydrolysis reaction, a 1:1 mixture of methanol, ethanol, isopropanol and water is used as the solvent, and the amount of the solvent is 3 to 5 times the weight of erythromycin A.

[0024] By adopting the above technical solutions, a 1:1 mixture of methanol, ethanol, isopropanol and water is used as the solvent in the hydrolysis reaction, and the amount of the solvent is 3 to 5 times the weight of erythromycin A, optimizing the selectivity of the solvent and the reaction conditions, improving the efficiency and stability of the hydrolysis reaction. This solvent system helps to control the reaction rate, reduce the generation of by-products, ensure the production of high-purity clarithromycin, and has excellent industrial production potential.

[0025] In summary, the present application includes at least one of the following beneficial technical effects:

[0026] 1. Improve selectivity and efficiency: By simultaneously protecting the key sites (9-carbonyl, 11- and 12-hydroxyl groups) of erythromycin with 2-aminophenylboronic acid and its derivatives, and using trimethylsilyl to protect the 2- and 4-hydroxyl groups, unnecessary side reactions are avoided, greatly improving the selectivity and efficiency of the reaction.

[0027] 2. Reduce chemical complexity: This method simplifies the traditional synthesis process. By adopting low temperature and mild reaction conditions, the by-products in the reaction process are effectively reduced, and the purity and yield of the target product are improved.

[0028] 3. Improve industrial applicability: During the reaction process, by controlling key reaction conditions such as temperature, molar ratio, reaction time, etc., an efficient and controllable synthesis process is achieved. These optimized conditions make this method particularly suitable for large-scale industrial production of clarithromycin, reducing production costs and improving production efficiency.

[0029] 4. Green chemistry optimization: The reaction process avoids unnecessary energy waste by precisely controlling the reagent ratio, temperature and solvent, in line with the principles of green chemistry. Using low-temperature reactions, environmentally friendly solvent systems and efficient catalysts reduces the occurrence of side reactions, reduces energy consumption, and enhances environmental friendliness.

[0030] 5. Simplify reaction steps: The design of one-pot reaction of silylation and ring boronation greatly simplifies the synthesis process, reduces the loss of intermediate products, and improves the overall reaction efficiency and yield, reducing equipment and operation costs.

[0031] 6. Ensure stability and high purity: By optimizing the solvent system and precisely controlling the reaction conditions, the production of high-purity clarithromycin is ensured, and the stability of the reaction is enhanced, enabling this method to better meet the requirements of industrial production for high yield and high purity. Description of the Drawings

[0032] Figure 1 is a schematic diagram of the reaction formula of the new method for synthesizing clarithromycin in the embodiment of the present application;

[0033] Figure 2 is a schematic diagram of the structure of the phenylboronic acid derivative in the embodiment of the present application. Detailed Embodiments

[0034] The embodiment of the present application discloses a new method for synthesizing clarithromycin. The new method for synthesizing clarithromycin simultaneously protects the 9-carbonyl, 11- and 12-hydroxyl groups of erythromycin with 2-aminophenylboronic acid derivatives, and uses trimethylsilyl to protect the 2 ， -position and 4 ，， -position hydroxyl groups, then methylates the 6-position hydroxyl group, and finally hydrolyzes to obtain clarithromycin; the phenylboronic acid derivative has the structure as Figure 2The structure shown in;

[0035] The reaction formula for the new method of clarithromycin synthesis is as Figure 1 shown in;

[0036] In the substituted phenylboronic acid used in the boronic esterification reaction, the substituents R 1 , R 2 , R 3 , R 4 are simultaneously or respectively hydrogen, alkyl, alkoxy, halogen, aryl, and most preferably hydrogen;

[0037] The silylation reaction reagent is selected as hexamethyldisilazane;

[0038] The methylation reaction reagent is selected as methyl bromide, dimethyl sulfate, and preferably methyl bromide;

[0039] For the hydrolysis reaction, a C1-C4 carboxylic acid is selected as the catalyst;

[0040] In the boronic esterification reaction, the molar ratio of substituted aminophenylboronic acid to erythromycin A is 1-1.1:1;

[0041] In the silylation reaction, the molar ratio of hexamethyldisilazane to erythromycin A is 1-1.05:1;

[0042] The molar ratio of the methylation reaction reagent to erythromycin A is 1-1.3:1. For the methylation reaction, potassium hydroxide is selected as the acid-binding agent, and the molar ratio of potassium hydroxide to erythromycin A is 1.5-2:1;

[0043] In the hydrolysis reaction, the molar ratio of the carboxylic acid to erythromycin A is 1.5-3:1;

[0044] For the boronic esterification reaction, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-butyrolactone, etc. are selected as solvents, and the solvent dosage is 3-5 times the weight of erythromycin A;

[0045] The silylation reaction and the boronic esterification reaction are carried out in one pot;

[0046] For the methylation reaction, a 1:1 mixture of dimethyl sulfoxide and dioxane, ethylene glycol dimethyl ether is selected as the solvent, and the solvent dosage is 6-10 times the weight of erythromycin A;

[0047] For the hydrolysis reaction, a 1:1 mixture of methanol, ethanol, isopropyl alcohol and water is selected as the solvent, and the solvent dosage is 3-5 times the weight of erythromycin A;

[0048] The boronic esterification reaction is carried out under negative pressure, the reaction temperature is 60-80 °C, and the reaction time is 5-10 hours;

[0049] The silylation reaction temperature is 10-20 °C, and the reaction time is 1-2 hours;

[0050] The methylation reaction temperature is 10 - 20°C, and the reaction time is 0.5 - 1 hour;

[0051] The hydrolysis reaction temperature is 30 - 50°C, and the reaction time is 10 - 20 hours;

[0052] The new method creatively designs a brand-new benzylboronic acid derivative as a protecting group, which is used to simultaneously protect the carbonyl group at the 9th position, and the hydroxyl groups at the 11th and 12th positions of erythromycin. It has the advantages of mild reaction conditions, high selectivity, high yield, recyclability of the phenylboronic acid derivative, low pollution, and low cost.

[0053] The following specific examples are used to further illustrate the present invention.

[0054] Example 1

[0055] Ring boronation reaction: Add 73.3 g (100 mmol) of erythromycin A, 366.5 g of N-methylpyrrolidone, and 13.69 g (100 mmol) of 2-aminophenylboronic acid into the reaction flask, and stir and react at 60°C under vacuum for 10 hours. Then cool down to 10°C and transfer to the next step of the reaction;

[0056] Silylation reaction: Add 8.07 g of hexamethyldisilazane (100 mmol) to the reaction solution of the previous step, stir and react at 10 - 12°C for 2 hours, then heat up to 60 - 70°C, and distill off N,N-dimethylformamide under reduced pressure. The residue is directly transferred to the next step;

[0057] Methylation reaction: Add 200 g of dimethyl sulfoxide and 200 g of dioxane to the residue of the previous step, stir and cool down to 10°C, add 100 mmol of methyl bromide, and then add 150 mmol of potassium hydroxide powder. Control the reaction temperature at 10 - 12°C, react for 1 hour, add 200 g of crushed ice to terminate the reaction, then add 300 ml of methyl tert-butyl ether, stir for 10 minutes, let it stand for separation. Add 50 ml of water to the upper layer for washing once, and then transfer to the next step of the reaction;

[0058] Hydrolysis reaction: Add 100 g of water, 100 g of methanol, and 150 mmol of 85% formic acid to the methyl tert-butyl ether extract of the previous step, react at 30 - 35°C for 20 hours, let it stand for separation. Dropwise add liquid alkali to the lower aqueous phase to adjust the pH to 10 - 10.5, then cool down to -5°C, filter, wash the filter cake with 100 ml of ice water, and dry at 100°C for 8 hours to obtain 59.7 g of clarithromycin with a content of 97.67% and a total yield of 80%.

[0059] The implementation principle of Example 1 is as follows: Through a multi-step reaction process, the molecular structure of erythromycin A is modified to improve its pharmacological activity and stability, and finally clarithromycin with high purity is prepared; First, through the cyclic borate esterification reaction, erythromycin A reacts with 2-aminophenylboronic acid in N-methylpyrrolidone solvent, causing the hydroxyl groups of erythromycin A to undergo esterification to form a cyclic borate ester protection structure. The key to this step is to improve the stability of erythromycin A in subsequent reactions and avoid the destruction of its parent nucleus structure; Subsequently, the silylation reaction is carried out by introducing hexamethyldisilazane to further protect the hydroxyl groups, reducing possible side reactions during the subsequent reaction process and improving the selectivity of the target product; Then, the methylation reaction is implemented. Using dimethyl sulfoxide and dioxane as a mixed solvent, methyl bromide as the methylation reagent, and potassium hydroxide as the base, the hydroxyl groups or active sites on erythromycin A are selectively methylated to enhance its acid resistance stability and liposolubility, which helps to improve the oral absorption performance of the drug; After the methylation modification is completed, the aforementioned protecting groups are removed through hydrolysis reaction while maintaining the integrity of the parent nucleus of the target product clarithromycin; Finally, the product is precipitated by adjusting the pH with alkali, and through low-temperature filtration and drying, clarithromycin with a purity of 97.67% and a yield of 80% is obtained; The reaction conditions for each step are mild, effectively avoiding the problem that erythromycin A is easily decomposed under acidic or alkaline conditions, and achieving the efficient and stable preparation of clarithromycin.

[0060] Example 2

[0061] Cyclic borate esterification reaction: Add 73.3 g (100 mmol) of erythromycin A, 220 g of N,N-dimethylformamide, and 15.9 g (110 mmol) of 2-amino-4-methylphenylboronic acid into the reaction flask, and stir and react at 80 °C under vacuum for 5 hours. Then cool down to 15 °C and transfer to the next step of the reaction;

[0062] Silylation reaction: Add hexamethyldisilazane (105 mmol) to the reaction solution of the previous step, stir and react at 18 - 20 °C for 2 hours, then heat up to 60 - 70 °C, and distill off N-methylpyrrolidone under reduced pressure. The residue is directly transferred to the next step;

[0063] Methylation reaction: Add 366 g of dimethyl sulfoxide and 366 g of ethylene glycol dimethyl ether to the residue of the previous step, stir and cool down to 15 °C, add 100 mmol of methyl bromide, then add 150 mmol of potassium hydroxide powder, control the reaction temperature at 18 - 20 °C, react for half an hour, add 300 g of crushed ice to terminate the reaction, then add 400 ml of methyl tert-butyl ether, stir for 10 minutes, let it stand for layering, add 50 ml of water to the upper layer and wash twice, and then transfer to the next step of the reaction;

[0064] Hydrolysis reaction: Add 183 g of water, 183 g of ethanol, and 200 mmol of acetic acid to the methyl tert-butyl ether extraction solution from the previous step. React at 48 - 50 °C for 10 hours. Let it stand for layering. Dropwise add liquid alkali to the lower aqueous phase to adjust the pH to 10 - 10.5. Then cool to -5 °C, filter, wash the filter cake with 150 ml of ice water, and recrystallize with 250 ml of 95% alcohol. Dry at 105 °C for 6 hours to obtain 58.1 g of clarithromycin with a content of 98.67% and an overall yield of 77.7%.

[0065] The implementation principle of Example 2 is as follows: By optimizing the conditions of cyclic boronation, silylation, methylation, and hydrolysis reactions, the structure of erythromycin A is modified to prepare high-purity clarithromycin, and further improve the yield and quality of the target product; in the cyclic boronation reaction stage, 2-amino-4-methylphenylboronic acid is introduced as a protecting agent to react with erythromycin A in N,N-dimethylformamide solvent to form a stable cyclic borate structure, thereby protecting the active hydroxyl groups in the erythromycin A molecule and preventing them from being destroyed during subsequent reactions, and improving the reaction selectivity; then, the silylation reaction is carried out by adding hexamethyldisilazane to further form silyl ether protecting groups on the hydroxyl groups to enhance the stability of the target product under alkaline and acidic conditions and reduce the generation of by-products; in the methylation reaction step, dimethyl sulfoxide and ethylene glycol dimethyl ether are used as a mixed solvent, and methyl bromide is used as the methylation reagent. Under the strong base condition of potassium hydroxide, the hydroxyl groups or active sites on the erythromycin A parent nucleus structure are selectively methylated to endow it with better lipophilicity and acid resistance stability, and improve the absorption performance of the drug. Finally, the aforementioned protecting groups are removed through hydrolysis reaction while maintaining the integrity of the clarithromycin parent nucleus of the target product; especially during the hydrolysis process, acetic acid is used as the acidolysis agent to slowly hydrolyze at an appropriate temperature to avoid the formation of decomposition products, and combined with liquid alkali to adjust the pH to control the precipitation conditions, so that the target product precipitates smoothly and is further crystallized and purified, and finally clarithromycin with a purity of 98.67% and a yield of 77.7% is obtained.

[0066] Example 3

[0067] Cyclic boronation reaction: Add 73.3 g (100 mmol) of erythromycin A, 220 g of butyrolactone, and 15.9 g (110 mmol) of 2-amino-3-chlorophenylboronic acid to the reaction flask. Stir and react at 80 °C under vacuum for 5 hours. Then cool to 15 °C and transfer to the next step of reaction;

[0068] Silylation reaction: Add hexamethyldisilazane (105 mmol) to the reaction solution from the previous step. Stir and react at 18 - 20 °C for 2 hours, then heat up to 60 - 70 °C and distill off butyrolactone under reduced pressure. The residue is directly transferred to the next step;

[0069] Methylation reaction: Add 240 g of dimethyl sulfoxide and 240 g of ethylene glycol dimethyl ether to the residue from the previous step. Stir and cool the temperature to 15 °C. Add 130 mmol of methyl bromide, and then add 200 mmol of potassium hydroxide powder. Control the reaction temperature at 18 - 20 °C and react for 45 minutes. Add 300 g of crushed ice to terminate the reaction. Then add 400 ml of methyl tert-butyl ether, stir for 10 minutes, let it stand for layer separation. Add 50 ml of water to the upper layer and wash twice, and then transfer to the next reaction step;

[0070] Hydrolysis reaction: Add 150 g of water, 150 g of isopropyl alcohol, and 200 mmol of acetic acid to the methyl tert-butyl ether extract from the previous step. React at 43 - 45 °C for 15 hours. Let it stand for layer separation. Dropwise add liquid alkali to the lower aqueous phase to adjust the pH to 10 - 10.5. Then cool to -5 °C, filter, wash the filter cake with 150 ml of ice water, and then recrystallize with 250 ml of 95% alcohol and dry at 105 °C for 8 hours to obtain 53.2 g of clarithromycin with a content of 95.8% and a yield of 71.6%.

[0071] The implementation principle of Example 3 is as follows: By optimizing the reaction solvent, the type of boric acid protecting agent, and the dosage of the methylation reagent, the structural modification process of erythromycin A is further improved to prepare clarithromycin with higher purity, and the process applicability and operation stability are enhanced; in the cyclic boronation reaction stage, using butyrolactone as the solvent and acting together with 2-amino-3-chlorophenylboronic acid can effectively protect the active hydroxyl groups in the erythromycin A molecule and form a stable cyclic borate structure, thus avoiding side reactions during the subsequent reaction process and improving the product selectivity; at the same time, the introduction of the chloro-substituted group can further enhance the protection effect and reduce the generation of impurities in the reaction system; during the silylation reaction process, hexamethyldisilazane is introduced to form a silyl ether protecting group for the hydroxyl group to enhance the stability of the target product under subsequent alkaline and acidic conditions and ensure the integrity of the parent nucleus structure; in the methylation reaction step, using dimethyl sulfoxide and ethylene glycol dimethyl ether as the mixed solvent helps to improve the solubility and uniformity of the reaction medium. Using methyl bromide as the methylation reagent, under the strong alkaline condition of potassium hydroxide, the hydroxyl sites of erythromycin A undergo a selective methylation reaction, thereby improving the liposolubility and acid resistance of the drug and enhancing the human absorption efficiency; finally, the borate and silyl ether protecting groups are removed through the hydrolysis reaction. Using acetic acid as the acidolysis agent and slowly hydrolyzing in the isopropyl alcohol and water mixed system helps to reduce the decomposition of the target product, and combined with liquid alkali to regulate the pH value of the solution to promote the full crystallization of clarithromycin. After washing with ice water and recrystallizing with alcohol, the product purity is further improved, and finally clarithromycin with a purity of 95.8% and a yield of 71.6% is obtained. The solvent selection and reaction condition optimization improve the applicability and stability of the synthesis process.

[0072] Example 4

[0073] Boronate reaction: 73.3 g (100 mmol) of erythromycin A, 200 g of butyrolactone, and 15.9 g (110 mmol) of 2-amino-6-chlorophenylboronic acid were added to a reaction flask, and the mixture was stirred and reacted at 80 °C under vacuum for 5 hours. Then, the temperature was lowered to 15 °C and transferred to the next reaction;

[0074] Silylation reaction: 105 mmol of hexamethyldisilazane was added to the reaction solution from the previous step, and the mixture was stirred and reacted at 18 - 20 °C for 2 hours. Then, the temperature was raised to 60 - 70 °C, and butyrolactone was distilled off under reduced pressure. The residue was directly transferred to the next step;

[0075] Methylation reaction: 240 g of dimethyl sulfoxide and 240 g of ethylene glycol dimethyl ether were added to the residue from the previous step, and the mixture was stirred and cooled to 15 °C. 130 mmol of methyl bromide was added, followed by 180 mmol of potassium hydroxide powder. The reaction temperature was controlled at 18 - 20 °C, and the reaction was carried out for 45 minutes. 300 g of crushed ice was added to terminate the reaction. Then, 400 ml of methyl tert-butyl ether was added, and the mixture was stirred for 10 minutes and allowed to stand for phase separation. 50 ml of water was added to the upper layer and washed twice. Then, it was transferred to the next reaction;

[0076] Hydrolysis reaction: 130 g of water, 130 g of isopropanol, and 180 mmol of acetic acid were added to the methyl tert-butyl ether extract from the previous step, and the mixture was reacted at 43 - 45 °C for 15 hours. After standing for phase separation, the pH of the lower aqueous phase was adjusted to 10 - 10.5 by dropwise addition of liquid alkali. Then, it was cooled to -5 °C, filtered, and the filter cake was washed with 150 ml of ice water. It was then recrystallized with 250 ml of 95% ethanol and dried at 105 °C for 8 hours to obtain 48.5 g of clarithromycin with a content of 95.1% and a yield of 64.9%.

[0077] The implementation principle of Example 4 is as follows: By adjusting the dosage of the reaction solvent, the type of protecting agent, and the feeding ratio of the base agent, the directional functional group modification of erythromycin A is achieved to prepare clarithromycin, improving the structural selectivity of the target product and the stability of the reaction system; in the cyclo-boration reaction stage, butyrolactone is used as the solvent, in combination with 2-amino-6-chlorophenylboronic acid as the protecting agent, and through vacuum heating and stirring at 80 °C, a stable cyclo-borate protecting group is formed at the 9-keto hydroxyl site in the erythromycin A molecule, thereby effectively avoiding side reactions during the subsequent silylation and methylation processes, and improving the product yield and purity; the introduction of the chlorine substituent further enhances the protection effect and improves the regioselectivity of the target hydroxyl group; during the silylation reaction, hexamethyldisilazane is added to form silyl ether bonds for the active hydroxyl groups in the molecule, improving the alkali resistance and acid resistance of the intermediate and ensuring the stability of the parent nucleus structure; subsequently, in the methylation reaction step, dimethyl sulfoxide and ethylene glycol dimethyl ether are mixed as the solvent system to enhance the dissolution ability and reaction uniformity, using methyl bromide as the methylation reagent, and under the strong base condition of potassium hydroxide, selective methylation reactions are carried out on sites such as 6-OH and 11-OH of erythromycin A, thereby improving the lipophilicity, acid resistance, and oral bioavailability of the target product; during the hydrolysis reaction process, a mixed solution of isopropanol and water is introduced, and acetic acid is used to regulate the acidic environment, and hydrolysis is carried out under mild conditions to remove the cyclo-borate protecting group and the silyl ether group, ensuring that the target product is not damaged. At the same time, the pH is adjusted to alkaline with liquid alkali to promote the precipitation of clarithromycin; through cooling, filtration, washing with ice water, and ethanol recrystallization, impurities are effectively removed, and finally clarithromycin with a purity of 95.1% and a yield of 64.9% is obtained.

[0078] Example 5

[0079] Cyclo-boration reaction: Add 73.3 g (100 mmol) of erythromycin A, 220 g of dimethylformamide, and 14.37 g (105 mmol) of 2-aminophenylboronic acid to the reaction flask, and stir and react under vacuum at 70 °C for 8 hours. Then cool down to 10 °C and transfer to the next step of the reaction;

[0080] Silylation reaction: Add 8.47 g of hexamethyldisilazane (105 mmol) to the reaction solution from the previous step, stir and react at 13 - 15 °C for 1.5 hours, then heat up to 60 - 70 °C, and distill off N,N-dimethylformamide under reduced pressure. The residue is directly transferred to the next step;

[0081] Methylation reaction: Add 240 g of dimethyl sulfoxide and 240 g of dioxane to the residue from the previous step, stir and cool down to 10 °C, add 130 mmol of dimethyl sulfate, then add 200 mmol of potassium hydroxide powder, control the reaction temperature at 18 - 20 °C, react for 1 hour, add 250 g of crushed ice to terminate the reaction, then add 350 ml of methyl tert-butyl ether, stir for 10 minutes, let it stand for phase separation, add 50 ml of water to the upper layer for washing once, and then transfer to the next reaction step;

[0082] Hydrolysis reaction: Add 120 g of water, 120 g of methanol, and 200 mmol of 85% formic acid to the methyl tert-butyl ether extraction solution from the previous step, react at 30 - 35 °C for 15 hours, let it stand for phase separation, add liquid alkali dropwise to the lower aqueous phase to adjust the pH to 10 - 10.5, then cool to -5 °C, filter, wash the filter cake with 100 ml of ice water, and dry at 100 °C for 8 hours to obtain 56.2 g of clarithromycin with a content of 97.2% and an overall yield of 75%.

[0083] The implementation principle of Example 5 is as follows: By optimizing the selection of the solvent system, methylation reagent, and hydrolysis acid agent, the purity and yield of clarithromycin are further improved to achieve the efficient conversion of erythromycin A to the target product; in the cyclic boronation reaction stage, dimethylformamide (DMF) is introduced as a solvent. DMF has strong solubility and polarity, which can fully dissolve erythromycin A and 2-aminophenylboronic acid to ensure uniform reaction; stir and react at 70 °C under a vacuum environment for 8 hours to form a cyclic borate protecting group at the 9-ketohydroxy site of the erythromycin A molecule, thus avoiding side reactions of ketone and hydroxyl groups during the subsequent methylation process and improving selectivity and stability; during the silylation reaction process, hexamethyldisilazane is added to form a silyl ether protecting group for the active hydroxyl groups in the erythromycin A molecule, improving the stability of the molecular structure, preventing decomposition in the subsequent alkaline environment, and ensuring methylation reaction at specific positions of functional groups. Then, the solvent DMF is removed by reduced pressure distillation to avoid damage to the intermediate structure at high temperature; in the methylation reaction stage, dimethyl sulfate is used as the methylation reagent, which has strong methylation ability and fast reaction speed. Combined with the mixed solvent system of dimethyl sulfoxide and dioxane, it helps to improve the solubility of erythromycin A and the uniformity of the reaction; under the strong alkaline environment provided by potassium hydroxide powder, dimethyl sulfate selectively methylates the 6-OH and 11-OH of erythromycin A to improve the physicochemical properties of clarithromycin; in the hydrolysis reaction stage, a mixed solvent of methanol and water is introduced, and the acidity is adjusted with 85% formic acid to remove the cyclic borate and silyl ether protecting groups under mild conditions, avoiding the destruction of the target molecular skeleton by violent acidolysis; finally, the pH value of the solution is adjusted with liquid alkali to precipitate clarithromycin in the basic form, and the product is obtained by filtration at low temperature; after washing with ice water and drying, clarithromycin with a content of 97.2% and an overall yield of 75% is obtained.

[0084] Example 6

[0085] Boronate esterification reaction: 73.3 g (100 mmol) of erythromycin A, 220 g of dimethylformamide, and 14.37 g (105 mmol) of 2-aminophenylboronic acid were added to a reaction flask, and the mixture was stirred and reacted at 65 °C under vacuum for 10 hours. Then, the temperature was lowered to 10 °C and transferred to the next reaction;

[0086] Silylation reaction: 8.47 g of hexamethyldisilazane (105 mmol) was added to the reaction solution of the previous step, and the mixture was stirred and reacted at 16 - 18 °C for 2 hours. Then, the temperature was raised to 60 - 70 °C, and N,N-dimethylformamide was distilled off under reduced pressure. The residue was directly transferred to the next step;

[0087] Methylation reaction: 240 g of dimethyl sulfoxide and 240 g of ethylene glycol dimethyl ether were added to the residue of the previous step, and the mixture was stirred and cooled to 10 °C. 130 mmol of methyl bromide was added, and then 200 mmol of potassium hydroxide powder was added. The reaction temperature was controlled at 18 - 20 °C, and the reaction was carried out for 45 minutes. 300 g of crushed ice was added to terminate the reaction. Then, 400 ml of methyl tert-butyl ether was added, and the mixture was stirred for 10 minutes, allowed to stand for layer separation. 50 ml of water was added to the upper layer and washed twice. Then, it was transferred to the next reaction;

[0088] Hydrolysis reaction: 120 g of water, 120 g of ethanol, and 180 mmol of acetic acid were added to the methyl tert-butyl ether extract of the previous step, and the reaction was carried out at 38 - 40 °C for 12 hours. After standing for layer separation, liquid alkali was added dropwise to the lower aqueous phase to adjust the pH to 10 - 10.5. Then, it was cooled to -5 °C, filtered, and the filter cake was washed with 100 ml of ice water. Then, it was recrystallized with 280 ml of 95% ethanol and dried at 110 °C for 5 hours to obtain 59.1 g of clarithromycin with a content of 98.87% and an overall yield of 79.1%.

[0089] The implementation principle of Example 6 is as follows: By adjusting the reaction time, temperature, solvent type, and recrystallization purification process, the purity and yield of clarithromycin are further improved; in the boronic esterification reaction stage, dimethylformamide (DMF) is used as the solvent, and the reaction is carried out at 65 °C under vacuum for 10 hours to fully condense the 9-keto hydroxyl group of erythromycin A with 2-aminophenylboronic acid to form a boronic ester protecting group, thus avoiding the participation of the keto hydroxyl group in side reactions during the subsequent methylation process and enhancing the reaction selectivity; in the silylation reaction stage, hexamethyldisilazane is introduced to form a silyl ether protecting group on the 11-hydroxyl group in the erythromycin A molecule, thereby reducing the activity of the etherification site, avoiding the occurrence of side reactions, and improving the stability and yield of the target product. In this step, by strictly controlling the reaction temperature at 16-18 °C and the reaction time at 2 hours, it helps the complete progress of the silylation reaction. Subsequently, the temperature is raised to 60-70 °C to distill off DMF under reduced pressure to reduce the impact of high temperature on the intermediate structure; in the methylation reaction stage, methyl bromide is used as the methylation reagent, and a mixed solvent composed of dimethyl sulfoxide (DMSO) and ethylene glycol dimethyl ether can fully dissolve the reactants and enhance the stability of the reaction system. Under the strong alkaline environment of potassium hydroxide, the temperature is controlled at 18-20 °C to selectively methylate the 6-OH and 11-OH groups in the erythromycin A molecule, further improving the physicochemical properties of the finished product; in the hydrolysis reaction stage, a mixed solvent of water, alcohol, and acetic acid is used, and the reaction is carried out at 38-40 °C under mild conditions for 12 hours to selectively remove the boronic ester and silyl ether protecting groups, avoiding the destruction of the molecular structure in a high-temperature and strong acid environment and improving the stability of the target product; finally, the pH is adjusted to alkaline with liquid alkali to precipitate clarithromycin in the form of free base, and the crude product is obtained by low-temperature filtration. Combining the ice-water washing and 95% alcohol recrystallization process can not only effectively remove impurities but also improve the crystal quality, thus obtaining high-quality clarithromycin with a purity of 98.87% and a total yield of 79.1%.

[0090] The above are all preferred embodiments of this application, and the protection scope of this application is not limited thereby. Therefore, all equivalent changes made according to the structure, shape, and principle of this application should be covered within the protection scope of this application.

Claims

1. A novel method for synthesizing clarithromycin, characterized in that: The carbonyl group at position 9, the hydroxyl groups at positions 11 and 12 of erythromycin were protected by o-aminophenylboronic acid and its derivatives, and the hydroxyl groups at positions 11 and 12 of erythromycin were protected by trimethylsilyl. ， bit and 4 ，， The hydroxyl group at the 6th position is then methylated and finally hydrolyzed to obtain clarithromycin.

2. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: In the substituted phenylboronic acid used in the cycloboronic esterification reaction, the substituents R1, R2, R3, and R4 are simultaneously or separately hydrogen, alkyl, alkoxy, halogen, and aryl, and hydrogen is most preferred; and the molar ratio of the substituted phenylboronic acid to erythromycin A is 1 to 1.1:1, and the reaction is carried out under negative pressure, at a temperature of 60 to 80° C., and for 5 to 10 hours.

3. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: The silane reaction reagent is hexamethyldisilazane, the reaction temperature is 10-20°C, and the reaction time is 1-2 hours.

4. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: The methylation reaction reagent is selected from methyl bromide and dimethyl sulfate, preferably methyl chloride, the molar ratio of the methylation reaction reagent to erythromycin A is 1-1.3:1, the molar ratio of potassium hydroxide to erythromycin A is 1.5-2:1, the reaction temperature is 10-20°C, and the reaction time is 0.5-1 hour.

5. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: The hydrolysis reaction uses C1-C4 carboxylic acid as a catalyst, the molar ratio of carboxylic acid to erythromycin A is 1.5-3:1, the reaction temperature is 30-50°C, and the reaction time is 5-10 hours.

6. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: In the cycloboronic esterification reaction, solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-butyrolactone, etc. are used, and the amount of the solvent used is 3 to 5 times the weight of erythromycin A.

7. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: Silylation reaction and boroesterification reaction are carried out in one pot.

8. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: The methylation reaction uses a 1:1 mixture of dimethyl sulfoxide, dioxane and ethylene glycol dimethyl ether as the solvent, and the amount of the solvent is 6 to 10 times the weight of erythromycin A.

9. The novel method for synthesizing clarithromycin according to claim 1, characterized in that: In the hydrolysis reaction, a 1:1 mixture of methanol, ethanol, isopropanol and water is selected as the solvent, and the amount of the solvent is 3 to 5 times the weight of erythromycin A.

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