Preparation method of pyronaphthyridine metabolite
High-purity phenazine metabolites were prepared by catalytic coupling and alkaline hydrolysis of compounds A and B, solving the problem of lack of preparation methods in the existing technology and meeting the needs of phenazine metabolic mechanism research.
Patent Information
- Application Number
- CN202510985603.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-17
- Publication Date
- 2025-11-07
AI Technical Summary
The lack of existing methods for preparing phenazine metabolites has hindered research into their metabolic mechanisms.
Compound A and compound B are coupled together under the action of a catalyst to generate compound C. Then, compound C is hydrolyzed under alkaline conditions to obtain phenazine metabolite D. The specific steps include using boron trifluoride ether, trifluoromethanesulfonic acid or trimethylsilyl trifluoromethanesulfonate as catalysts, triethylamine, sodium methoxide or sodium hydroxide as alkaline reagents, monitoring the reaction progress by thin-layer chromatography and purifying with silica gel column chromatography.
The preparation of high-purity phenazine metabolites with a purity of over 97.0% has been achieved, simplifying the post-processing steps, making it suitable for pharmacokinetic studies, and providing important test samples.
Smart Images
Figure CN120904261A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of compound synthesis, and particularly relates to a preparation method of pyronaridine metabolite. BACKGROUND
[0002] Pyronaridine, the chemical name of which is 2-methoxy-7-chloro-10-(3',5'-bistetrahydro-pyrrol-1-methyl-4'-hydroxyphenyl)-amino-benzo[b]-1,5 naphthyridine, is an antimalarial drug developed in China, and its effect is better than that of pyrimethamine. Pyronaridine can mainly kill schizonts, and has significant antimalarial effect. The peak time of oral administration and intramuscular injection is 1.4 hours and 0.75 hours respectively; the oral bioavailability is about 40%; t1 / 2 is 2-3 days; the drug has the highest concentration in the liver, and is excreted in urine in 1-2%; the drug is effective for patients who are resistant to chloroquine; the drug is suitable for treating various malaria including cerebral malaria and critical patients with dangerous malaria; the drug can be used in combination with sulfadoxine, pyrimethamine or primaquine to enhance the curative effect, delay the generation of drug resistance and prevent relapse; and the side effect is lighter than that of chloroquine.
[0003] The pyronaridine metabolite has important significance and effect for the metabolic mechanism research of pyronaridine. The pyronaridine metabolite is mentioned in the periodical Journal of Mass Spectrometry (2004), 39(9), 1036-1043, but no specific synthesis method is given. At present, no literature reports the preparation method of the pyronaridine metabolite, and the corresponding preparation method needs to be developed to fill the gap and provide test samples for the metabolic mechanism research of pyronaridine. SUMMARY
[0004] The present application provides a preparation method of pyronaridine metabolite with high purity, which has the advantages of reasonable design, simple post-treatment, easy-to-obtain raw materials and strong operability.
[0005] The technical scheme is as follows: a preparation method of pyronaridine metabolite provided by the present application, characterized in that: compound A (4-((7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino)-2,6-bis(pyrrolidin-1-ylmethyl)phenol) is used as raw material, and reacts with compound B (2,3,4-tri-O-acetyl-alpha-D-glucuronide methyl trichloroacetimidate) under the action of a catalyst to obtain compound C; compound C is hydrolyzed under alkaline conditions to obtain compound D, i.e. pyronaridine metabolite; wherein:
[0006] The molecular formula of compound A is
[0007] The molecular formula of compound B is
[0008] The molecular formula of compound C is
[0009] The molecular formula of compound D, i.e. pyronaridine metabolite, is:
[0010] The preparation method of pyronaridine metabolite of the present application is characterized by comprising the following steps:
[0011] (1) Compound A is used as raw material, dissolved in organic solvent, compound B and catalyst are added for reaction, the molar ratio of compound A to compound B is 1:1-1:2, the molar ratio of compound A to catalyst is 1:0.5-1:1, and compound C is obtained by reaction;
[0012] (2) Compound C is added into organic solvent, and organic base or inorganic base is added, the molar ratio of compound C to organic base or inorganic base is 1:3-1:5, and compound D, i.e. pyronaridine metabolite, is obtained by reaction.
[0013] In the step (1), the catalyst is boron trifluoride etherate, trifluoromethanesulfonic acid, p-toluenesulfonic acid or trimethylsilyl trifluoromethanesulfonate.
[0014] In the step (1), the organic solvent is dichloromethane, 1,2-dichloroethane, tetrahydrofuran or dioxane.
[0015] In the step (1), the reaction temperature is -20℃-10℃, and the reaction time is 10h-20h.
[0016] In the reaction process, thin layer chromatography is used to monitor the reaction progress, and the mobile phase is dichloromethane / methanol.
[0017] In the step (2), the organic base or inorganic base is triethylamine, sodium methoxide, sodium hydroxide or lithium hydroxide.
[0018] In the step (2), the organic solvent is methanol, ethanol, dioxane or tetrahydrofuran.
[0019] In the step (2), the reaction temperature is 0-30℃, and the reaction time is 10h-20h.
[0020] In the reaction process, thin layer chromatography is used to monitor the reaction progress, and the mobile phase is acetonitrile / water.
[0021] Invention principle: Compound A is used as raw material, and compound C can be obtained by coupling compound A with compound B under the action of a catalyst, and then compound C is hydrolyzed under the action of an organic base or an inorganic base to obtain compound D, that is, a pyronaridine metabolite. In the reaction process, the reaction is relatively clean, and high-purity pyronaridine metabolite can be easily purified.
[0022] Beneficial effects: Compared with the prior art, the present application has the following remarkable advantages: (1) The synthetic route of the preparation method of the present application is reasonable in design, the raw materials are easy to obtain, the post-treatment is simple, only needs concentration and column chromatography purification, and the operability is strong, and the production conditions are easy to achieve; (2) The purity of the target product prepared by the preparation method of the present application can reach 97.0% or more, which can be used for pharmacokinetic research, and provides test samples for the metabolic mechanism research of pyronaridine, and has important application value. BRIEF DESCRIPTION OF DRAWINGS
[0023] Figure 1 The synthetic route map of the present application is shown in the following figure:
[0024] Figure 2 The mass spectrum of the pyronaridine metabolite prepared in Example 1 is shown in the following figure:
[0025] Figure 3 The nuclear magnetic hydrogen spectrum of the pyronaridine metabolite prepared in Example 1 is shown in the following figure:
[0026] Figure 4 The HPLC spectrum of the pyronaridine metabolite prepared in Example 1 is shown in the following figure. DETAILED DESCRIPTION
[0027] The technical solutions of the present application will be further described below in combination with the drawings and specific embodiments.
[0028] The test materials used in the present application can be obtained through conventional channels.
[0029] Example 1:
[0030] The preparation method of the pyronaridine metabolite of the present embodiment specifically includes the following steps:
[0031] (1) 15.00 g of compound A pyronaridine is dissolved in dichloromethane (150 ml), 13.86 g of compound B (2,3,4-tri-O-acetyl-α-D-glucuronide methyl ester trichloroacetyl imidate) and 4.11 g of boron trifluoride ether are added, and the mixture is reacted at-20℃ for 15 hours. Thin layer chromatography shows that the reaction is complete. The reaction solution is concentrated to dryness, and 18.20 g of compound C is obtained by silica gel column purification, with a yield of 75.34%.
[0032] (2) Take 18.00 g of compound C dissolved in dry methanol, add 1.17 g of sodium methoxide, react at 0°C for 20 hours, thin layer chromatography shows that the reaction is complete, the reaction is over, the reaction liquid is concentrated to dryness, silica gel column purification to obtain 10.50 g of compound D, i.e. pyronaridine metabolite, yield 70.11%.
[0033] Example 2:
[0034] The preparation method of the pyronaridine metabolite of this example specifically includes the following steps:
[0035] (1) Take 12.00 g of compound A pyronaridine dissolved in dichloromethane (150 ml), add 13.86 g of compound B (2,3,4-tri-O-acetyl-α-D-glucuronide methyl trichloroacetimidate) and 2.78 g of trifluoromethanesulfonic acid, the mixture is reacted at -10°C for 10 hours, thin layer chromatography shows that the reaction is complete, the reaction liquid is concentrated to dryness, silica gel column purification to obtain 15.50 g of compound C, yield 80.20%.
[0036] (2) Take 15.00 g of compound C dissolved in methanol, add 2.88 g of sodium hydroxide aqueous solution, react at 0°C for 15 hours, thin layer chromatography shows that the reaction is complete, the reaction is over, the reaction liquid is concentrated to dryness, silica gel column purification to obtain 9.7 g of compound D, i.e. pyronaridine metabolite, yield 77.72%.
[0037] Example 3:
[0038] The preparation method of the pyronaridine metabolite of this example specifically includes the following steps:
[0039] (1) Take 10.00 g of compound A pyronaridine dissolved in dichloromethane (150 ml), add 13.86 g of compound B (2,3,4-tri-O-acetyl-α-D-glucuronide methyl trichloroacetimidate) and 1.66 g of p-toluenesulfonic acid, the mixture is reacted at 0°C for 20 hours, thin layer chromatography shows that the reaction is complete, the reaction liquid is concentrated to dryness, silica gel column purification to obtain 11.7 g of compound C, yield 72.65%.
[0040] (2) Take 11.00 g of compound C dissolved in methanol, add 12.82 ml of triethylamine, react at 0°C for 8 hours, thin layer chromatography shows that the reaction is complete, the reaction is over, the reaction liquid is concentrated to dryness, silica gel column purification to obtain 6.8 g of compound D, i.e. pyronaridine metabolite, yield 74.29%.
[0041] From examples 1-3, it can be seen that the preparation method of the pyronaridine metabolite of the present application can be prepared in two steps, and the yield of each step is more than 60%, and the purity of the obtained pyronaridine metabolite is as high as 97.3011%, which is suitable for pharmacokinetic study and provides test samples for the metabolic mechanism study of pyronaridine, and has important application value.
Claims
1. A method of preparing a metabolite of pyronaridine, characterized by: The compound A is used as raw material, and reacts with compound B under the action of catalyst to obtain compound C. Compound C is hydrolyzed under alkaline condition to obtain compound D, i.e. pyronaridine metabolite; wherein: The molecular formula of Compound A is The molecular formula of compound B is The molecular formula of compound C is The molecular formula of compound D, a metabolite of pyronaridine, is:
2. The method of claim 1, wherein: Specifically comprising the following steps: (1) Compound A is used as raw material, and is dissolved in organic solvent. Compound B and catalyst are added, and the molar ratio of compound A to compound B is 1:1-1:2, and the molar ratio of compound A to catalyst is 1:0.5-1:
1. Compound A reacts to obtain compound C; (2) Compound C is added into organic solvent, and organic base or inorganic base is added. The molar ratio of compound C to organic base or inorganic base is 1:3-1:
5. Compound C reacts to obtain compound D, i.e. pyronaridine metabolite.
3. The method of claim 2, wherein: The catalyst in step (1) is boron trifluoride etherate, triflic acid, p-toluenesulfonic acid or trimethylsilyl triflate.
4. The method of claim 2, wherein: The organic solvent in step (1) is dichloromethane, 1,2-dichloroethane, tetrahydrofuran or dioxane.
5. The method of claim 2, wherein: The reaction temperature in step (1) is-20-10°C, and the reaction time is 10-20h.
6. The method of claim 5, wherein: The reaction process is monitored by thin layer chromatography, and the mobile phase is dichloromethane / methanol.
7. The method of claim 2, wherein: The organic base or inorganic base in step (2) is triethylamine, sodium methoxide, sodium hydroxide or lithium hydroxide.
8. The method of claim 2, wherein: The organic solvent in step (2) is methanol, ethanol, dioxane or tetrahydrofuran.
9. The method of claim 2, wherein: The reaction temperature in step (2) is 0-30°C, and the reaction time is 10-20h.
10. The method of claim 9, wherein: The reaction process is monitored by thin layer chromatography, and the mobile phase is acetonitrile / water.