Preparation method of prasugrel metabolite
Through the inorganic base ring opening, organic base and tert-butylsulfinyl chloride conversion, and acid-catalyzed ring-closing reaction of Compound A, high-purity pragrarene metabolites were successfully prepared, which solved the synthesis problems in the prior art and provided the use of Test samples for pharmacokinetics and metabolic mechanism studies.
Patent Information
- Application Number
- CN202411370397.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-29
- Publication Date
- 2025-01-07
AI Technical Summary
The existing technology failed to effectively synthesize the prasugrel metabolite M18, which made it difficult to isolate metabolites in the study of its metabolic pathways, lack of synthesis methods, and affects the study of pharmacokinetics and metabolic mechanisms.
Compound A is used as the raw material, and the sulfhydryl group is converted into sulfhydryl group by inorganic base ring opening reaction, organic base and tert-butylsulfinyl chloride, followed by acid-catalyzed ring-off reaction to prepare a high-purity pragrarene metabolite. The specific steps include reacting compound A with an inorganic base to form compound B, reacting compound B with an organic base and tert-butylsulfinyl chloride to form compound C, and finally compound C obtains pragrarene metabolite through acid catalytic reaction.
The preparation of high-purity (98.0% or more) pragrarene metabolites was achieved, the synthesis route and post-treatment were simplified, and it was suitable for pharmacokinetic research, providing test samples for the metabolic mechanism of pragrarene, which had important applications. value.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing prasugrel metabolites. Background Art
[0002] Prasugrel (Ametoctradin) is a new generation of potent thiophene pyridine antiplatelet drugs. It is mainly used clinically to treat cardiovascular and cerebrovascular diseases, as well as patients with acute coronary syndrome who need percutaneous coronary intervention. It has a faster platelet inhibition rate, a stronger effect, a high efficacy, a stable blood concentration, and a long-lasting effect.
[0003] The metabolic pathway of prasugrel was studied in the document Xenobiotica (2007), 37 (8), 884-901, wherein M18 (i.e., the prasugrel metabolite prepared by the present invention) was found in dog feces. By synthesizing and studying the metabolites of prasugrel, the relevant biological metabolism, pharmacokinetics, etc. of prasugrel can be studied, and test samples can be provided for the metabolic mechanism research of prasugrel. The metabolites detected in the metabolic pathway are generally detected by LC-MS and HPLC, and multiple metabolites often coexist, so it is very difficult for the metabolites to be separated from the metabolic pathway. In addition, no method for synthesizing the metabolite has been found in the literature, so inventing a method for preparing a prasugrel metabolite (M18) plays a very important role in the metabolic mechanism research of prasugrel. Summary of the invention
[0004] Purpose of the invention: The purpose of the present invention is to provide a preparation method capable of obtaining high-purity prasugrel metabolite M18.
[0005] Technical solution: The preparation method of prasugrel metabolites of the present invention comprises the following steps: using compound A as a raw material, subjecting compound A to a ring-opening reaction using an inorganic base to obtain compound B, converting the thiol group in compound B into a thiocarbonyl group to obtain compound C, and subjecting compound C to a ring-closing reaction using an acid catalysis to obtain prasugrel metabolites;
[0006]
[0007] Wherein, the above preparation method specifically comprises the following steps:
[0008] (1) Compound A: 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7-1-tetrahydrothieno[3,2-c]pyridin-2(4H)-one is used as a raw material, dissolved in an organic solvent or a mixed solvent formed by an organic solvent and water, the molar ratio of compound A to inorganic base is 1:1 to 1:4, and an inorganic base is added to react to obtain compound B;
[0009] (2) adding compound B to an organic solvent, adding an organic base, tert-butylsulfenyl chloride and 3A molecular sieves, wherein the molar ratio of compound B to the organic base is 1:1 to 1:3, and the molar ratio of compound B to tert-butylsulfenyl chloride is 1:1 to 1:5, and reacting to obtain compound C;
[0010] (3) Compound C is added to an organic solvent, and after acid catalysis, the molar ratio of compound C to acid is 1:1 to 1:3, and the reaction obtains compound D, i.e., prasugrel metabolite.
[0011] Wherein, in step (1), the inorganic base is sodium hydroxide, potassium hydroxide or lithium hydroxide.
[0012] Wherein, in step (1), the organic solvent is tetrahydrofuran, methanol, DMF or dioxane.
[0013] Wherein, in step (1), the reaction temperature is 0 to 20° C. and the reaction time is 10 to 20 hours.
[0014] Wherein, in step (2), the organic base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine.
[0015] Wherein, in step (2), the organic solvent is toluene, benzene, dioxane or xylene.
[0016] Wherein, in step (2), the reaction temperature is 90-110° C. and the reaction time is 10-20 hours; the reaction progress is monitored by thin layer chromatography, and the mobile phase is n-hexane / ethyl acetate.
[0017] Wherein, in step (3), the acid is hydrochloric acid, acetic acid, sulfuric acid or p-toluenesulfonic acid.
[0018] Wherein, in step (3), the reaction temperature is 60-80°C and the reaction time is 15-20 hours; the reaction progress is monitored by thin layer chromatography, and the mobile phase is n-hexane / ethyl acetate.
[0019] Principle of the invention: The preparation method of prasugrel metabolites of the present invention uses compound A as a raw material, and compound B can be obtained by hydrolyzing and ring-opening the carbonylthiolactone of compound A with an inorganic base, and then the thiol group of compound B is converted into a thiocarbonyl group under the action of tert-butylsulfenyl chloride triethylamine to obtain compound C, and compound C is subjected to a carboxyl-to-thiocarbonyl nucleophilic addition reaction under acid catalysis to obtain prasugrel metabolites. In this reaction process, the reaction is relatively clean and it is easier to purify to obtain high-purity prasugrel metabolites.
[0020] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The synthetic route design of the preparation method of the present invention is reasonable, the raw materials are easily available, the post-treatment is simple, and only extraction and chromatographic column purification are required. It has strong operability, the production conditions are easy to achieve, and it is convenient for industrial large-scale production; (2) The purity of the target product obtained by the preparation method of the present invention can reach more than 98.0%, which can be used for pharmacokinetic research and provide test samples for the metabolic mechanism research of prasugrel, which has important application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 The synthetic route of the preparation method of the prasugrel metabolite of the present invention;
[0022] Figure 2 is the mass spectrum of compound D prepared in Example 1;
[0023] Figure 3 is the H NMR spectrum of compound D prepared in Example 1;
[0024] Figure 4 The HPLC spectrum of compound D prepared in Example 1. DETAILED DESCRIPTION
[0025] The technical scheme of the present invention is further described below in conjunction with the examples. The test materials used in the examples can all be purchased through conventional channels.
[0026] Example 1
[0027] The method for preparing prasugrel metabolites of the present invention specifically comprises the following steps:
[0028] (1) 14.00 g of the compound 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7-1-tetrahydrothieno[3,2-c]pyridin-2(4H)-one was dissolved in tetrahydrofuran (2:1, 120 ml), and 3.25 g of anhydrous lithium hydroxide was added. The mixed solution was reacted at 10° C. for 15 hours. Thin layer chromatography showed that the reaction was complete. The reaction solution was acidified and concentrated to remove tetrahydrofuran. The mixture was purified by silica gel column to obtain 12.20 g of compound B in a yield of 77.12%.
[0029]
[0030] (2) 12.00 g of compound B was dissolved in dry toluene, and 7.14 ml of triethylamine, 9.66 g of tert-butylsulfenyl chloride and 120 mg of 3A molecular sieve were added. The mixture was reacted at 90° C. for 1.5 hours. TLC showed that the reaction was complete. The reaction was terminated, and water was added for extraction. The mixture was purified by silica gel column to obtain 8.50 g of compound C with a yield of 71.25%.
[0031]
[0032] (3) 8.00 g of compound C was dissolved in tetrahydrofuran, 4 ml of 6N hydrochloric acid was added, and the mixture was stirred at 60°C for 18 hours. TLC showed that the reaction was complete. The mixture was concentrated to dryness and purified by silica gel column to obtain 5.10 g of compound D, i.e., prasugrel metabolite, with a yield of 63.75%.
[0033]
[0034] like Figure 2 The mass spectrum of compound D is shown in Figure 2, MS: 348.1 [M+H] + ;like Figure 3 As shown, it is the NMR hydrogen spectrum of compound D; Figure 4 As shown, the HPLC spectrum of compound D, the product purity is 98.4392%.
[0035] Example 2
[0036] The method for preparing prasugrel metabolites of the present invention comprises the following steps:
[0037] (1) 10.00 g of the compound 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7-1-tetrahydrothieno[3,2-c]pyridin-2(4H)-one was dissolved in tetrahydrofuran and water (2:1, 100 ml), and 3.98 g of potassium hydroxide was added. The mixed solution was reacted at 20° C. for 12 hours. Thin layer chromatography showed that the reaction was complete. The reaction solution was acidified and concentrated to remove tetrahydrofuran. The solution was purified by silica gel column to obtain 7.20 g of compound B with a yield of 68.31%.
[0038]
[0039] (2) 7.00 g of compound B was dissolved in dry toluene, and 3.50 ml of N,N-diisopropylethylamine, 3.38 g of tert-butylsulfenyl chloride and 70 mg of 3A molecular sieve were added. The mixture was reacted at 100° C. for 2.5 hours. TLC showed that the reaction was complete. The reaction was terminated, and water was added for extraction. The mixture was purified by silica gel column to obtain 4.50 g of compound C with a yield of 64.65%.
[0040]
[0041] (3) 2.00 g of compound C was dissolved in tetrahydrofuran, 2 ml of 6N sulfuric acid was added, and the mixture was stirred at 70°C for 14 hours. TLC showed that the reaction was complete. The mixture was concentrated to dryness and purified by silica gel column to obtain 5.10 g of compound D, i.e., prasugrel metabolite, with a yield of 63.75%.
[0042]
[0043] Example 3
[0044] The method for preparing prasugrel metabolites of the present invention comprises the following steps:
[0045] (1) 12.00 g of the compound 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7-1-tetrahydrothieno[3,2-c]pyridin-2(4H)-one was dissolved in tetrahydrofuran and water (2:1, 120 ml), and 2.62 g of sodium hydroxide was added. The mixed solution was reacted at 0° C. for 18 hours. Thin layer chromatography showed that the reaction was complete. The reaction solution was acidified and concentrated to remove tetrahydrofuran, and purified by silica gel column to obtain 9.20 g of compound B with a yield of 72.73%.
[0046]
[0047] (2) 9.00 g of compound B was dissolved in dry toluene, and 2.08 ml of pyridine, 4.35 g of tert-butylsulfenyl chloride and 90 mg of 3A molecular sieve were added. The mixture was reacted at 110° C. for 1.0 hour. TLC showed that the reaction was complete. The reaction was terminated, and water was added for extraction. The mixture was purified by silica gel column to obtain 5.70 g of compound C with a yield of 67.06%.
[0048]
[0049] (3) 5.00 g of compound C was dissolved in tetrahydrofuran, 2 g of p-toluenesulfonic acid was added, and the mixture was stirred at 80°C for 20 hours. TLC showed that the reaction was complete. The mixture was concentrated to dryness and purified by silica gel column to obtain 5.10 g of compound D, i.e., prasugrel metabolite, with a yield of 63.75%.
[0050]
[0051] It can be seen from Examples 1 to 3 that the preparation method of prasugrel metabolites of the present invention can be prepared through three steps, and the yield of each step is more than 60%. The purity of the obtained prasugrel metabolites is as high as 98.4392%, which is suitable for pharmacokinetic research and provides test samples for the metabolic mechanism research of prasugrel.
Claims
1. A method for preparing a prasugrel metabolite, characterized in that: The preparation method comprises the following steps: using compound A as a raw material, performing a ring-opening reaction on compound A using an inorganic base to obtain compound B, converting the thiol group in compound B into a thiocarbonyl group to obtain compound C, and performing a ring-closing reaction on compound C using acid catalysis to obtain prasugrel metabolite; 2. The preparation method according to claim 1, characterized in that: The preparation method specifically comprises the following steps: (1) Compound A is used as a raw material, dissolved in an organic solvent or a mixed solvent formed by an organic solvent and water, and an inorganic base is added for reaction, wherein the molar ratio of compound A to the inorganic base is 1:1 to 1:4, and the reaction obtains compound B; (2) adding compound B to an organic solvent, adding an organic base, tert-butylsulfenyl chloride and 3A molecular sieves, wherein the molar ratio of compound B to the organic base is 1:1 to 1:3, and the molar ratio of compound B to tert-butylsulfenyl chloride is 1:1 to 1:5, and reacting to obtain compound C; (3) Compound C is added to an organic solvent, and after acid catalysis, the molar ratio of compound C to acid is 1:1 to 1:3, and the reaction obtains compound D, i.e., prasugrel metabolite.
3. The preparation method according to claim 2, characterized in that: In step (1), the inorganic base is sodium hydroxide, potassium hydroxide or lithium hydroxide.
4. The preparation method according to claim 2, characterized in that: In step (1), the organic solvent is tetrahydrofuran, methanol, DMF or dioxane.
5. The preparation method according to claim 2, characterized in that: In step (1), the reaction temperature is 0 to 20° C. and the reaction time is 10 to 20 hours.
6. The preparation method according to claim 2, characterized in that: In step (2), the organic base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine.
7. The preparation method according to claim 2, characterized in that: In step (2), the organic solvent is toluene, benzene, dioxane or xylene.
8. The preparation method according to claim 2, characterized in that: In step (2), the reaction temperature is 90 to 110° C. and the reaction time is 10 to 20 hours.
9. The preparation method according to claim 2, characterized in that: In step (3), the acid is hydrochloric acid, acetic acid, sulfuric acid or p-toluenesulfonic acid.
10. The preparation method according to claim 2, characterized in that: In step (3), the reaction temperature is 60 to 80° C. and the reaction time is 15 to 20 hours.