Synthesis method of anomalachite
Through the alkylation and debenzylation reaction of fentanine, aberine was successfully synthesized, which solved the difficulty of synthesizing aberine in the existing technology and achieved an efficient, simple synthesis process and high-purity products.
Patent Information
- Application Number
- CN202310857369.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-13
- Publication Date
- 2025-01-14
AI Technical Summary
The prior art is difficult to effectively synthesize abnormal pyrosine, resulting in the failure to fully utilize its potential in drug applications.
By using erythromine as raw material and a two-step reaction of alkylation and debenzylation, anomaline was successfully synthesized. The process is simple, easy to purify, and the product obtained has high purity.
The efficient synthesis of abnormal alkaloids has been achieved, with simple process, high purification yield and high product purity, meeting the needs of pharmaceutical applications.
Smart Images
Figure BDA0004336409370000011 
Figure BDA0004336409370000012
Abstract
Description
Technical Field
[0001] The invention relates to the field of drug synthesis, and in particular to a method for synthesizing abnormal alkaloids. Technical Background
[0002] Legend has it that the plant Changshan can treat malaria. The ancient Chinese prescription "Ben Jing" also records: "Changshan has the effects of inducing vomiting, killing insects, anti-malarial, and antipyretic". According to research, there are two main antimalarial active ingredients in Changshan: febrifugine and isofebrifugine. Isofebrifugine is the cis isomer of febrifugine, but because the cis structure is unstable, the keto carbonyl and the hydroxyl on the piperidine ring are prone to isomerization to form a hemiketal structure. The chemical structures of febrifugine and isofebrifugine are as follows:
[0003]
[0004] Both febrifugine and quinazolin are natural alkaloids with important physiological activity and good pharmacological effects. They belong to the quinazolinone class of compounds and are currently mainly used for the prevention and treatment of coccidiosis and malaria. Efficacy tests have shown that the antimalarial activity of febrifugine is 100 times that of quinine, and the antimalarial activity of quinazolin is equivalent to that of quinine, and neither of them shows drug resistance. Summary of the invention
[0005] The purpose of the present invention is to provide a method for synthesizing abnormal alkali.
[0006] The purpose of the present invention is achieved through the following technical measures:
[0007] The invention uses febrifugine as raw material and synthesizes abnormal febrifugine through two steps of alkylation and debenzylation. The synthesis process is simple, easy to purify, and the obtained product has high purity.
[0008] The present invention provides a method for synthesizing abnormal behenyl alkali, and the specific reaction equation is as follows:
[0009]
[0010] The present invention provides a method for synthesizing abnormal behenyl alkali, and the specific reaction steps are as follows:
[0011] Step 1: febrifugine, potassium carbonate and benzyl bromide are kept warm in solvent A for a certain period of time. After the reaction is completed, the reaction solution is concentrated to dryness, and the concentrate is recrystallized in solvent B with activated carbon to obtain benzyl febrifugine (intermediate).
[0012] Wherein, the mass ratio of febrifugine, potassium carbonate, benzyl bromide and solvent A is 1:(0.8-1.5):(0.5-0.8):(10-15), preferably 1:1.2:0.6:12;
[0013] Further, the solvent A is methanol, ethanol, isopropanol, tert-butanol, 1,2-dichloroethane, carbon tetrachloride, acetonitrile, acetone, tetrahydrofuran, toluene, etc., preferably acetonitrile;
[0014] Further, the reaction temperature is 55 to 110° C., and the reaction time is 8 to 16 hours;
[0015] Furthermore, the solvent B is methanol, ethanol, isopropanol, etc., preferably ethanol.
[0016] Step 2: benzyl febrifugine and ammonium cerium nitrate (CAN) are kept warm in solvent C for a certain period of time. After the reaction is completed, the reaction solution is poured into water, stirred evenly, and extracted twice with methyl tert-butyl ether. After the organic layers are combined, anhydrous sodium carbonate is added to remove residual water, filtered, and the filtrate is concentrated to dryness. The concentrate is recrystallized in solvent D with activated carbon to obtain abnormal febrifugine.
[0017] Wherein, the mass ratio of benzyl febrifugine, CAN and solvent C is 1:(3-6):(10-20), preferably 1:5:15;
[0018] Further, the solvent C is acetonitrile, propionitrile, tetrahydrofuran, methyltetrahydrofuran, etc., preferably acetonitrile;
[0019] Furthermore, the reaction temperature is 20 to 50° C., and the reaction time is 10 to 15 hours;
[0020] Furthermore, the solvent D is ethanol, isopropanol, tert-butanol, etc., preferably isopropanol.
[0021] The synthesis method of abnormal behenyl alkali of the present invention has the following advantages:
[0022] The process is simple, the purification yield is high, and the product purity is high. DETAILED DESCRIPTION
[0023] The following examples can enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way.
[0024] Example 1
[0025] Synthesis of benzyl febrifugine:
[0026] Add 50 g of febrifugine, 600 g of acetonitrile, 60 g of potassium carbonate and 30 g of benzyl bromide to the reaction bottle, control the temperature at 75-80 ° C, stir and react for 12-13 hours, filter, distill the filtrate under reduced pressure to dry acetonitrile, add 400 g of ethanol and 2 g of activated carbon, heat and reflux for one hour, filter while hot, cool the filtrate to 0-10 ° C for crystallization, and dry at 60-70 ° C to obtain 61 g of benzyl febrifugine with a yield of 94.0%.
[0027] Synthesis of abnormal alkali:
[0028] 50 g of benzyl febrifugine and 750 g of acetonitrile were added to the reaction flask, 250 g of ammonium cerium nitrate was added in batches under stirring at a temperature of 25-35 ° C, and the reaction was continued for 12-13 hours after the addition. The reaction solution was fully mixed with 1000 g of water, extracted with 200 ml of methyl tert-butyl ether, repeated twice, the organic layers were combined, 30 g of anhydrous sodium sulfate was added and dried for three hours, filtered, concentrated under reduced pressure, 500 g of isopropanol and 2 g of activated carbon were added, heated to reflux for one hour, filtered while hot, the filtrate was cooled to 0-5 ° C for crystallization, and dried at 55-65 ° C to obtain 31.2 g of abnormal febrifugine with a yield of 81.1%.
[0029] Example 2
[0030] Synthesis of benzyl febrifugine:
[0031] Add 50 g of febrifugine, 600 g of tert-butanol, 60 g of potassium carbonate and 30 g of benzyl bromide to the reaction bottle, control the temperature at 80-83 ° C, stir and react for 10-11 hours, filter, distill the filtrate under reduced pressure to dry acetonitrile, add 400 g of ethanol and 2 g of activated carbon, heat and reflux for one hour, filter while hot, cool the filtrate to 0-10 ° C for crystallization, and dry at 60-70 ° C to obtain 56 g of benzyl febrifugine, with a yield of 86.3%.
[0032] Synthesis of abnormal alkali:
[0033] 50 g of benzyl febrifugine and 600 g of tetrahydrofuran were added to the reaction flask, 250 g of ammonium cerium nitrate was added in batches under stirring at a temperature of 25-40 ° C, and the reaction was continued for 15-16 hours after the addition. The reaction solution was fully mixed with 1000 g of water, extracted with 200 ml of methyl tert-butyl ether, repeated twice, the organic layers were combined, 30 g of anhydrous sodium sulfate was added and dried for three hours, filtered, concentrated under reduced pressure, 500 g of isopropanol and 2 g of activated carbon were added, heated to reflux for one hour, filtered while hot, the filtrate was cooled to 0-10 ° C for crystallization, and dried at 55-65 ° C to obtain 26.5 g of abnormal febrifugine with a yield of 68.8%.
[0034] The present invention has been described in detail above using general descriptions and specific embodiments. However, some modifications or improvements may be made on the basis of the present invention, which are within the scope of protection required by the present invention without departing from the spirit of the present invention.
Claims
1. A method for synthesizing abnormal alkali, characterized in that: The steps include: Step (a): mixing febrifugine with solvent A, potassium carbonate and benzyl bromide, and keeping the mixture warm for a certain period of time; after the reaction is completed, filtering with suction, concentrating the filtrate to dryness, adding activated carbon to the concentrate, heating it in solvent B until it is completely dissolved, cooling it for crystallization, filtering it, and drying the filter cake to obtain benzyl febrifugine. Step (b): benzyl febrifugine is mixed with solvent C, ammonium cerium nitrate is added in batches, and the mixture is kept warm for a certain period of time; after the reaction is completed, water is added and mixed thoroughly, and then extracted with methyl tert-butyl ether, the extract is concentrated to dryness, the concentrate is added with activated carbon, heated in solvent D until it is completely dissolved, cooled for crystallization, filtered, filtered cake, and dried to obtain abnormal febrifugine.
2. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that: In the step (a), the mass ratio of febrifugine, solvent A, potassium carbonate and benzyl bromide is 1:(10-15):(0.8-1.5):(0.5-0.8).
3. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that: In the step (a), the solvent A is methanol, ethanol, isopropanol, tert-butanol, 1,2-dichloroethane, carbon tetrachloride, acetonitrile, acetone, tetrahydrofuran, toluene, etc.
4. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that The reaction temperature and reaction time in step (a) are 55-110° C. and 8-16 hours respectively.
5. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that In the step (a), the solvent B is methanol, ethanol, isopropanol, etc.
6. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that In the step (b), the mass ratio of benzyl febrifugine, solvent C and ammonium cerium nitrate is 1:(10-20):(3-6).
7. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that In the step (b), the solvent C refers to acetonitrile, propionitrile, tetrahydrofuran, methyltetrahydrofuran, etc.
8. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that The reaction temperature and reaction time in step (b) are 20-50° C. and 10-15 hours respectively.
9. The method for synthesizing abnormal behenyl alkali according to claim 1, characterized in that In the step (b), the solvent D is ethanol, isopropanol, tert-butanol, etc.