A method for synthesizing azanemine bulk drug
By using nucleophilic substitution and amide condensation reactions with 2,6-dichloropyridazine as the starting material, combined with sodium hydroxide and sodium tetrafluoroborate catalysis, the synthesis process of azinmidate was optimized, solving the problem of the shortage of azinmidate raw material and achieving the production of azinmidate raw material with high yield and high purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ANHUI HERYI CHEM
- Filing Date
- 2025-05-20
- Publication Date
- 2026-05-19
AI Technical Summary
The existing synthesis process for azithromycin API is characterized by high process difficulty, numerous impurities, and low yield, leading to a shortage of domestic supply.
Azimidate was synthesized from 2,6-dichloropyridazine as the starting material via nucleophilic substitution and amide condensation reaction. Sodium hydroxide and sodium tetrafluoroborate were used as catalysts, and the reaction conditions were controlled to optimize the synthetic route.
This approach achieves readily available raw materials, mild reaction conditions, simple operation, high product yield and purity, reduces the generation of genotoxic impurities, and improves the safety and supply capacity of azintamide API.
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Figure CN120535467B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for synthesizing azithromycin raw material. Background Technology
[0002] Most patients with digestive tract diseases present with clinical manifestations such as diarrhea, abdominal discomfort, and decreased appetite. Therefore, the treatment of indigestion has always been a key area of research in both clinical and pharmaceutical fields. Clinically, compound azithromycin enteric-coated tablets are considered a relatively effective drug for treating digestive tract diseases. After administration, azithromycin increases bile secretion and pancreatic enzyme activity, directly enhancing the patient's digestive function.
[0003] Although azimide has significant efficacy and advantages in treating indigestion and other diseases, the production of its key intermediate, 3-chloro-6-mercaptopyridazine, is highly complex, and the potential genetic impurities chloroacetyl chloride and chloroacetic acid can negatively impact the active pharmaceutical ingredient (API). This has resulted in a lack of significant production breakthroughs in the domestic generic synthesis of azimide. Currently, the supply of azimide API is primarily imported from countries like India, leading to a persistent shortage in China. Therefore, optimizing the process and industrializing azimide API is of great value and urgency in addressing the domestic API shortage and optimizing the domestic market.
[0004] Patent CN114516840A discloses a method for preparing azinmid, which uses 3-chloro-6-mercaptopyridazine and N,N-diethylchloroacetamide through a condensation reaction. However, during its synthesis, many uncertain genotoxic impurities are generated, posing a great safety hazard to the quality of the product, and the overall yield is only about 57%.
[0005] Summary of the Invention
[0006] The technical problem to be solved by the present invention is to provide a method for synthesizing azinmid raw material, which uses 2,6-dichloropyridazine as the starting material and can synthesize azinmid raw material through two-step reaction. It has the advantages of readily available raw materials, mild reaction conditions, simple operation, and high product yield and purity, and is suitable for the industrial production of azinmid raw material.
[0007] The technical problem to be solved by this invention is achieved by the following technical solution:
[0008] This invention provides a method for synthesizing azithromycin raw material, comprising the following synthetic steps:
[0009] S1, 2,6-dichloropyridazine undergoes a nucleophilic substitution reaction with mercaptoacetic acid to give 2-((6-chloropyridazine-3-yl)thio)acetic acid;
[0010] S2, 2-((6-chloropyridazine-3-yl)thio)acetic acid reacts with diethylamine in an amide condensation reaction to give azinmidate.
[0011] The synthesis route is as follows:
[0012]
[0013] Furthermore, the nucleophilic substitution reaction is carried out under alkaline conditions, and the base includes, but is not limited to, at least one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.
[0014] Further, the molar ratio of 2,6-dichloropyridazine to mercaptoacetic acid and base is 1:(0.8-1):(1.5-3). By controlling the equivalent amount of mercaptoacetic acid, only one chlorine substituent in the 2,6-dichloropyridazine structure participates in the reaction, yielding 2-((6-chloropyridazine-3-yl)thio)acetic acid.
[0015] Furthermore, the solvent for the nucleophilic substitution reaction includes, but is not limited to, at least one of methanol, ethanol, and tert-butanol. Based on the solubility of 2,6-dichloropyridazine and bases, alcohols are preferred as solvents.
[0016] Furthermore, the amide condensation reaction comprises a two-step reaction: the reaction of 2-((6-chloropyridazine-3-yl)thio)acetic acid with a chlorinating agent to generate an acyl chloride intermediate, and the reaction of the acyl chloride intermediate with diethylamine to generate azimide.
[0017] Furthermore, the chlorination reagent includes, but is not limited to, at least one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and thionyl chloride.
[0018] Furthermore, the molar ratio of 2-((6-chloropyridazine-3-yl)thio)acetic acid, the chlorination reagent, and diethylamine is 1:(1-3):(1-3).
[0019] Furthermore, the amide condensation reaction is carried out under the action of a condensing agent, which includes, but is not limited to, at least one of carbodiimide condensing agents, onium salt condensing agents, and organophosphorus condensing agents. 1-Hydroxybenzotriazole (HOBt) is usually used in combination with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) to suppress side reactions and improve the yield and purity of the product.
[0020] Furthermore, the molar ratio of 2-((6-chloropyridazine-3-yl)thio)acetic acid to diethylamine and condensing agent is 1:(1-2):(1-2).
[0021] Furthermore, the solvent for the amide condensation reaction includes, but is not limited to, at least one of acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.
[0022] The beneficial effects of this invention are: This invention provides a method for preparing azinmid raw material from 2,6-dichloropyridazine via nucleophilic substitution and amide condensation reaction. This method not only has the advantages of readily available raw materials, mild reaction conditions, simple post-processing, and high product yield, but also reduces the generation of genotoxic impurities and improves the safety of azinmid raw material. Attached Figure Description
[0023] Figure 1 The image shows the 1H NMR spectrum of the product, azimite. Detailed Implementation
[0024] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.
[0025] Example 1
[0026] Synthesis of 2-((6-chloropyridazine-3-yl)thio)acetic acid:
[0027] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and sodium hydroxide (5.3 kg, 132.4 mol) was slowly added. Then, thioglycolic acid (6.1 kg, 66.2 mol) was slowly added dropwise, keeping the reaction temperature below 20 °C during the addition. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 hours. The reaction was stopped, and the solvent was removed by vacuum distillation. The pH was adjusted to acidic with 1 mol / L hydrochloric acid solution, and a solid precipitated. The solid was filtered, the residue was washed with water, and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 68.3% and a purity of 98.5%.
[0028] Synthesis of azinmit:
[0029] 100 L of acetonitrile and 10 kg (48.9 mol) of 2-((6-chloropyridazine-3-yl)thio)acetic acid were added to the reactor. Stirring and freezing with brine were started to lower the temperature of the reaction system to -5 °C. Then, 7.0 kg (58.7 mol) of thionyl chloride was added, and the mixture was heated to reflux for 1 h. Subsequently, 6.4 kg (58.7 mol) of diethylamine hydrochloride was added, and the temperature was lowered to -10 °C. A mixed solution of triethylamine (11.9 kg (117.4 mol)) and 60 L of dichloromethane was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 20 min. The reaction was stopped, and the reaction solution was washed successively with 1 mol / L hydrochloric acid solution (50 L, 100 L, 100 L), semi-saturated sodium bicarbonate solution (100 L), and salt water solution (100 L). The solution was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove most of the solvent. 100 L of n-hexane was added to the residue and the mixture was slurried, filtered, and dried to obtain azinmet with a yield of 94.2% and a purity of 99.1%. 1 H NMR(400MHz, CDCl3) δ7.40(d,J=9.0Hz,1H),7.31(d,J=8.8Hz,1H),4.34(s,2H ), 3.47 (dq, J = 22.8, 7.1Hz, 4H), 1.29 (t, J = 7.2Hz, 3H), 1.16 (t, J = 7.1Hz, 3H).
[0030] Example 2
[0031] Synthesis of 2-((6-chloropyridazine-3-yl)thio)acetic acid:
[0032] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and potassium tert-butoxide (22.3 kg, 198.6 mol) was slowly added, followed by the slow dropwise addition of mercaptoacetic acid (6.1 kg, 66.2 mol). The reaction temperature was controlled below 20 °C during the dropwise addition. After the dropwise addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 h. The reaction was stopped, the solvent was removed by vacuum distillation, and the pH was adjusted to acidic with 1 mol / L hydrochloric acid solution. A solid precipitated, which was filtered. The residue was washed with water and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 75.6% and a purity of 98.2%.
[0033] Synthesis of azinmit:
[0034] To 250 mL of acetonitrile, 2-((6-chloropyridazin-3-yl)thio)acetic acid (22.9 g, 112 mmol), diethylamine hydrochloride (12.3 g, 112 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.6 g, 123 mmol), 1-hydroxybenzotriazole (15.1 g, 112 mmol), and triethylamine (22.7 g, 224 mmol) were added, and the mixture was stirred at room temperature for 12 h. The reaction was stopped, and the reaction solution was concentrated to remove acetonitrile. 250 mL of water was added, and the mixture was extracted multiple times with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain azinmet in 83.9% yield and 97.2% purity.
[0035] Example 3
[0036] Synthesis of 2-((6-chloropyridazine-3-yl)thio)acetic acid:
[0037] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and sodium tert-butoxide (9.5 kg, 99.3 mol) was slowly added. Then, mercaptoacetic acid (4.9 kg, 53.0 mol) was slowly added dropwise, keeping the reaction temperature below 20 °C during the addition. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 h. The reaction was stopped, the solvent was removed by vacuum distillation, and the pH was adjusted to acidic with 1 mol / L hydrochloric acid solution. A solid precipitated, which was filtered. The residue was washed with water and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 55.4% and a purity of 98.2%.
[0038] Synthesis of azinmit:
[0039] To 250 mL of acetonitrile, 2-((6-chloropyridazin-3-yl)thio)acetic acid (22.9 g, 112 mmol), diethylamine hydrochloride (18.4 g, 168 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32.2 g, 168 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (63.9 g, 168 mmol), and triethylamine (34.0 g, 336 mmol) were added, and the mixture was stirred at room temperature for 12 h. The reaction was stopped, and the reaction solution was concentrated to remove acetonitrile. 250 mL of water was added, and the mixture was extracted multiple times with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain azinmet in 85.7% yield and 98.1% purity.
[0040] As can be seen from Examples 1-3, although a base was added as a catalyst in the reaction system for preparing 2-((6-chloropyridazine-3-yl)thio)acetic acid from 2,6-dichloropyridazine and mercaptoacetic acid, the yield of the intermediate 2-((6-chloropyridazine-3-yl)thio)acetic acid was not high, which would lead to a low overall yield of the azinmidation synthesis route provided by this invention. To solve this problem, the inventors tried various combinations of catalysts and bases or alternatives to bases, and finally screened out sodium tetrafluoroborate. The combination of sodium tetrafluoroborate and sodium hydroxide can achieve a yield of 2-((6-chloropyridazine-3-yl)thio)acetic acid of over 90% and a purity of not less than 98%.
[0041] This invention provides a method for synthesizing azithromycin raw material, comprising the following synthetic steps:
[0042] S1, 2,6-dichloropyridazine undergoes a nucleophilic substitution reaction with mercaptoacetic acid to give 2-((6-chloropyridazine-3-yl)thio)acetic acid;
[0043] S2, 2-((6-chloropyridazine-3-yl)thio)acetic acid reacts with diethylamine in an amide condensation reaction to give azinmidate.
[0044] The synthesis route is as follows:
[0045]
[0046] Furthermore, the nucleophilic substitution reaction is catalyzed by sodium hydroxide and sodium tetrafluoroborate.
[0047] Further, the molar ratio of 2,6-dichloropyridazine, mercaptoacetic acid, sodium hydroxide, and sodium tetrafluoroborate is 1:(0.8-1):(1-2):(0.2-0.5). By controlling the equivalent amount of mercaptoacetic acid, only one chlorine substituent in the 2,6-dichloropyridazine structure participates in the reaction, yielding 2-((6-chloropyridazine-3-yl)thio)acetic acid.
[0048] Furthermore, the solvent for the nucleophilic substitution reaction includes, but is not limited to, at least one of methanol, ethanol, and tert-butanol. Based on the solubility of 2,6-dichloropyridazine and bases, alcohols are preferred as solvents.
[0049] Furthermore, the amide condensation reaction comprises a two-step reaction: the reaction of 2-((6-chloropyridazine-3-yl)thio)acetic acid with a chlorinating agent to generate an acyl chloride intermediate, and the reaction of the acyl chloride intermediate with diethylamine to generate azimide.
[0050] Furthermore, the chlorination reagent includes, but is not limited to, at least one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and thionyl chloride.
[0051] Furthermore, the molar ratio of 2-((6-chloropyridazine-3-yl)thio)acetic acid, the chlorination reagent, and diethylamine is 1:(1-3):(1-3).
[0052] Furthermore, the amide condensation reaction is carried out under the action of a condensing agent, which includes, but is not limited to, at least one of carbodiimide condensing agents, onium salt condensing agents, and organophosphorus condensing agents. 1-Hydroxybenzotriazole (HOBt) is usually used in combination with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) to suppress side reactions and improve the yield and purity of the product.
[0053] Furthermore, the molar ratio of 2-((6-chloropyridazine-3-yl)thio)acetic acid to diethylamine and condensing agent is 1:(1-2):(1-2).
[0054] Furthermore, the solvent for the amide condensation reaction includes, but is not limited to, at least one of acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.
[0055] Example 4
[0056] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and sodium hydroxide (5.3 kg, 132.4 mol) and sodium tetrafluoroborate (1.45 kg, 13.24 mol) were slowly added. Then, thioglycolic acid (6.1 kg, 66.2 mol) was slowly added dropwise, keeping the reaction temperature below 20 °C during the addition. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 hours. The reaction was stopped, the solvent was removed by vacuum distillation, and the pH was adjusted to acidic with 1 mol / L hydrochloric acid solution. A solid precipitated, which was filtered. The residue was washed with water and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 92.9% and a purity of 98.3%.
[0057] Example 5
[0058] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and sodium hydroxide (2.65 kg, 66.2 mol) and sodium tetrafluoroborate (3.63 kg, 33.1 mol) were slowly added. Then, thioglycolic acid (6.1 kg, 66.2 mol) was slowly added dropwise, keeping the reaction temperature below 20 °C during the addition. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 hours. The reaction was stopped, the solvent was removed by vacuum distillation, and the pH was adjusted to acidic with 1 mol / L hydrochloric acid solution. A solid precipitated, which was filtered. The residue was washed with water and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 90.4% and a purity of 98.7%.
[0059] Example 6
[0060] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and sodium hydroxide (3.97 kg, 99.3 mol) and sodium tetrafluoroborate (2.55 kg, 23.2 mol) were slowly added. Then, thioglycolic acid (6.1 kg, 66.2 mol) was slowly added dropwise, keeping the reaction temperature below 20 °C during the addition. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 hours. The reaction was stopped, and the solvent was removed by vacuum distillation. The pH was adjusted to acidic with 1 mol / L hydrochloric acid solution, and a solid precipitated. The solid was filtered, the residue was washed with water, and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 91.6% and a purity of 98.3%.
[0061] Comparative Example 1
[0062] 300 L of anhydrous methanol and 10 kg (66.2 mol) of 2,6-dichloropyridazine were added to a reaction vessel. Stirring was started, and sodium tetrafluoroborate (14.5 kg, 132.4 mol) was slowly added. Then, thioglycolic acid (6.1 kg, 66.2 mol) was slowly added dropwise, keeping the reaction temperature below 20 °C during the addition. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 hours. The reaction was stopped, and the solvent was removed by vacuum distillation. The pH was adjusted to acidic with 1 mol / L hydrochloric acid solution, and a solid precipitated. The solid was filtered, the residue was washed with water, and dried to obtain 2-((6-chloropyridazine-3-yl)thio)acetic acid, with a yield of 43.7% and a purity of 65.2%.
[0063] As can be seen from Examples 1, 4-6 and Comparative Example 1, only by using sodium hydroxide in combination with sodium tetrafluoroborate can 2-((6-chloropyridazine-3-yl)thio)acetic acid be synthesized in high yield and high purity from the reaction of 2,6-dichloropyridazine with mercaptoacetic acid.
[0064] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.
Claims
1. A method for synthesizing azithromycin raw material, characterized in that, The synthesis steps include the following: S1, 3,6-dichloropyridazine undergoes a nucleophilic substitution reaction with mercaptoacetic acid to give 2-((6-chloropyridazine-3-yl)thio)acetic acid; S2, 2-((6-chloropyridazine-3-yl)thio)acetic acid reacts with diethylamine in an amide condensation reaction to give azimide; the amide condensation reaction includes two steps: the reaction of 2-((6-chloropyridazine-3-yl)thio)acetic acid with a chlorinating agent to generate an acyl chloride intermediate, and the reaction of the acyl chloride intermediate with diethylamine to generate azimide; The synthesis route is as follows: ； The nucleophilic substitution reaction was carried out using sodium hydroxide and sodium tetrafluoroborate as catalysts.
2. The method for synthesizing azithromycin raw material according to claim 1, characterized in that: The solvent for the nucleophilic substitution reaction is selected from at least one of methanol, ethanol, and tert-butanol.
3. The method for synthesizing azithromycin raw material according to claim 1, characterized in that: The chlorination reagent is selected from at least one of thionyl chloride, phosphorus trichloride, and phosphorus pentachloride.
4. The method for synthesizing azithromycin raw material according to claim 3, characterized in that: The molar ratio of 2-((6-chloropyridazine-3-yl)thio)acetic acid, the chlorinated reagent, and diethylamine is 1 : (1~3) : (1~3).
5. The method for synthesizing azithromycin raw material according to claim 1, characterized in that: The amide condensation reaction is carried out under the action of a condensing agent, which is selected from at least one of carbodiimide condensing agents, onium salt condensing agents, and organophosphorus condensing agents.
6. The method for synthesizing azithromycin raw material according to claim 5, characterized in that: The molar ratio of 2-((6-chloropyridazine-3-yl)thio)acetic acid to diethylamine and condensing agent is 1 : (1~2) : (1~2).
7. The method for synthesizing azithromycin raw material according to claim 1, characterized in that: The solvent for the amide condensation reaction is selected from at least one of acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.