A preparation method of vortioxetine metabolite
By reacting with a hydroxylamine compound in an organic solvent and combining extraction and column chromatography purification, the problems of low yield and high impurities in the preparation of vortioxetine metabolites were solved, and high-purity preparation and industrial production were achieved.
Patent Information
- Application Number
- CN202410834055.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-06-26
- Publication Date
- 2025-10-03
- Estimated Expiration
- 2044-06-26
AI Technical Summary
Existing methods for preparing vortioxetine metabolites have the problems of low yield, high impurities and difficulty in large-scale production.
Vortioxetine metabolites are prepared by reacting a hydroxylamine compound with vortioxetine in an organic solvent, followed by pH adjustment, extraction, drying and column chromatography purification.
The preparation of vortioxetine metabolites with high purity (above 99%) and easy industrial production was achieved, providing a basis for the qualitative and quantitative analysis of vortioxetine.
Smart Images
Figure CN118852058B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing a compound, in particular to a method for preparing a vortioxetine metabolite. Background Art
[0002] Vortioxetine, chemical name 1-[2-(2,4-methylphenylthio)phenyl]piperazine, molecular weight is: 298.45, structural formula is as follows:
[0003]
[0004] Vortioxetine (Compound I) is a new drug for the treatment of depression, jointly developed by Lundbeck of Denmark and Takeda Pharmaceuticals of Japan. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on September 30, 2013, under the trade name Brintellix, for the treatment of major depressive disorder (MDD). In October 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended that vortioxetine be granted a European Marketing Authorization for the treatment of major depression. Vortioxetine was officially launched in Europe in January 2014.
[0005] The molecular weight of the vortioxetine metabolite (Compound II) is 314.45, the molecular formula is C18H22N2OS, the chemical name is: 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-ol, and the structural formula is as follows:
[0006]
[0007] Pharmacokinetics, a new technology developed over the past 40 to 50 years, plays an increasingly important role in drug research and development. The increasing application of technologies to drug metabolism has shortened drug development cycles, reduced drug development costs, and provided a new avenue for new drug discovery.
[0008] Drug Metabolism & Disposition (2012), 40(7), 1357-1365 reported a one-step oxidation of vortioxetine (Compound I) using a recombinant enzyme. The synthesis route is as follows:
[0009]
[0010] The recombinant enzyme required by this method does not specify its specific CAS, which is not conducive to production; and this method easily produces other impurities, which is not conducive to separation and large-scale production.
[0011] The four-step total synthesis reported in Drug Metabolism and Disposition (2011), 39(12), 2264-2274 is as follows:
[0012]
[0013] This method has a low yield, and the sugar used in the fourth step cannot be purchased and needs to be synthesized by oneself, which results in a low yield of the overall route and is not conducive to large-scale production.
[0014] Compound III and other impurities can be easily obtained by oxidizing vortioxetine (Compound I) with m-chloroperbenzoic acid. The structural formula of Compound III is shown below:
[0015]
[0016] Therefore, it is necessary to find a method that is simple, easy to operate and has a high yield to obtain vortioxetine metabolites. Summary of the Invention
[0017] Purpose of the invention: The present invention aims to provide a method for preparing vortioxetine metabolites, which is simple and easy to operate.
[0018] Technical solution: The method for preparing a vortioxetine metabolite of the present invention comprises the following steps: dissolving Compound I vortioxetine in an organic solvent, adding a hydroxylamine compound, and reacting at 20-25°C to obtain Compound II. The synthetic route is as follows:
[0019]
[0020] Preferably, the hydroxylamine compound is any one of hydroxylamine hydrochloride, hydroxylamine aqueous solution, N-hydroxysuccinimide, hydroxyurea, benzamide oxime or tert-butyl N-hydroxycarbamate.
[0021] Preferably, the organic solvent is any one of dioxane, tetrahydrofuran, DMF or DMSO. Further preferably, the organic solvent is dioxane.
[0022] Preferably, the molar ratio of the compound I to the hydroxylamine compound is 1:3 to 10. Further preferably, the molar ratio of the compound I to the hydroxylamine compound is 1:3 to 4.
[0023] Preferably, the reaction time is 1 to 10 hours.
[0024] After the reaction is completed, purification is further performed, and the purification comprises the following steps: adjusting the pH of the reaction system to 8-9, extracting with ethyl acetate, drying, removing the solvent, and then purifying by column chromatography to obtain the target product II.
[0025] The stationary phase of the column chromatography is silica gel, and the mobile phases are dichloromethane and methanol.
[0026] Preferably, the desiccant is anhydrous sodium sulfate.
[0027] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The preparation method is highly operable, the process design is reasonable, and industrial production can be realized. In addition, the reagents used in the synthesis method are simple and easy to obtain, and there are fewer by-products. The purity of the prepared vortioxetine metabolites is as high as more than 99%; (2) The vortioxetine metabolites prepared by this method provide reference materials for the qualitative and quantitative analysis of vortioxetine, provide an important basis for the scientific evaluation of the quality, safety and efficacy of vortioxetine, and have important application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Figure 1 This is the synthetic route of the present invention;
[0029] Figure 2 is the mass spectrum of compound II;
[0030] Figure 3 is the NMR spectrum of compound II;
[0031] Figure 4 is the HPLC spectrum of compound II;
[0032] Figure 5 This is the NMR spectrum of compound III. DETAILED DESCRIPTION
[0033] The technical solution of the present invention will be further described below in conjunction with embodiments.
[0034] Example 1
[0035] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0036] 10.0 g of vortioxetine and 9.3 g of hydroxylamine hydrochloride were dissolved in 10 volumes of dioxane and stirred at 25°C for 4 hours. A spot plate (mobile phase: dichloromethane: methanol in a volume ratio of 100:3) showed no residual starting material. The reaction solution was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and spin-dried to obtain 15.5 g of a crude product. 8 g of product II was separated on a silica gel column (mobile phase: dichloromethane: methanol in a volume ratio of 100:3) to obtain 8 g of product II in a yield of 76%.
[0037] The mass spectrum of product II is shown in Figure 2 .
[0038] Figure 3This is the nuclear magnetic spectrum of product II, 1H-NMR (CDCl3) δ (ppm): 7.37 (1H, d), 7.15 (1H, d), 7.05 (3H, m), 6.87 (1H, m), 6.53 (2H, m), 3.35 (4H, m), 2.98 (4H, m), 3.34 (6H, d).
[0039] Figure 4 This is the HPLC spectrum of compound II. It can be seen from the figure that its purity is 99.8036%.
[0040] Example 2
[0041] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0042] 15.0 g of vortioxetine and 16.0 g of hydroxylamine hydrochloride were dissolved in 10 volumes of dioxane and stirred at 25°C for 10 hours. The plate showed no residual starting material. The reaction solution was adjusted to pH 8-9 with alkali and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and spin-dried to obtain 20.6 g of crude product. 10.0 g of product II was separated on a silica gel column (mobile phase: dichloromethane and methanol in a volume ratio of 100:3) to obtain 63% yield.
[0043] Example 3
[0044] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0045] 20.0 g of vortioxetine and 25.0 g of hydroxylamine hydrochloride were dissolved in 10 volumes of dioxane and stirred at 25°C for 6 hours. The plate showed no residual starting material. The reaction solution was adjusted to pH 8-9 with alkali and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and spin-dried to obtain 25.8 g of crude product. 11.0 g of product II was separated on a silica gel column (mobile phase: dichloromethane and methanol in a volume ratio of 100:3) to obtain 52% yield.
[0046] Example 4
[0047] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0048] 5.0 g of vortioxetine and 5.0 g of hydroxylamine aqueous solution (50% by mass) were dissolved in 10 volumes of dioxane and stirred at 25°C for 12 hours. The plate showed no residual starting material. The reaction solution was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and spin-dried to obtain 8.5 g of crude product. 1.0 g of product II was separated on a silica gel column (mobile phase: dichloromethane and methanol in a volume ratio of 100:3) to obtain 18.98% yield.
[0049] Example 5
[0050] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0051] 6.0 g of vortioxetine and 2.3 g of N-hydroxysuccinimide were dissolved in 10 volumes of dioxane and stirred at 25°C for 3 hours. A spectrophotometer indicated no residual starting material. The reaction solution was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and spin-dried to obtain 8.1 g of a crude product. The crude product was separated on a silica gel column (mobile phase: dichloromethane and methanol in a volume ratio of 100:3) to obtain 1.0 g of product II in a yield of 15.82%.
[0052] Example 6
[0053] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0054] 9.0 g of vortioxetine and 2.3 g of hydroxyurea were dissolved in 10 volumes of dioxane and stirred at 25°C for 6 hours. The plate showed no residual starting material. The reaction solution was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product (10.5 g) was obtained by spin drying. The crude product was separated on a silica gel column (mobile phase: dichloromethane and methanol in a volume ratio of 100:3) to obtain 3.0 g of product II in a yield of 31.64%.
[0055] Example 7
[0056] The method for preparing the vortioxetine metabolite of the present invention comprises the following steps:
[0057] 3.0 g of vortioxetine and 1.4 g of benzamide oxime were dissolved in 10 volumes of dioxane and stirred at 25°C for 10 hours. The plate showed no residual starting material. The reaction solution was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The product was dried by spin drying to obtain 4.0 g of crude product, which was separated by silica gel column (mobile phase: dichloromethane and methanol in a volume ratio of 100:3) to obtain 0.8 g of product II with a yield of 25.31%.
[0058] Comparative Example 1
[0059] 1 g of vortioxetine was dissolved in 10 volumes of dichloromethane, 1.16 g of m-chloroperbenzoic acid was added under ice bath, and the mixture was stirred at 25°C for about 2 hours. The plate showed that no starting material remained. The reaction solution was quenched with saturated sodium thiosulfate solution, and then the pH was adjusted to 7-8 with saturated NaHCO3 solution. The mixture was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column with the eluent being dichloromethane:methanol = 200:1 to 100:1. The pure fraction was concentrated to obtain 0.25 g. NMR showed that it was compound III. The NMR spectrum is shown in FIG. Figure 5 It can be seen that the target compound II cannot be obtained by using an oxidizing agent.
Claims
1. A method for preparing a vortioxetine metabolite, characterized in that: The method comprises the following steps: dissolving compound I vortioxetine in an organic solvent, adding a hydroxylamine compound, and reacting at 20-25° C. to obtain compound II. The synthetic route is as follows: ； The hydroxylamine compound is any one of hydroxylamine hydrochloride, hydroxylamine aqueous solution, N-hydroxysuccinimide, hydroxyurea, benzamide oxime or tert-butyl N-hydroxycarbamate.
2. The method for preparing a vortioxetine metabolite according to claim 1, wherein: The organic solvent is any one of dioxane, tetrahydrofuran, DMF or DMSO.
3. The method for preparing a vortioxetine metabolite according to claim 2, wherein: The organic solvent is dioxane.
4. The method for preparing a vortioxetine metabolite according to claim 1, wherein: The molar ratio of the compound I to the hydroxylamine compound is 1:3-10.
5. The method for preparing vortioxetine metabolites according to claim 4, characterized in that: The molar ratio of the compound I to the hydroxylamine compound is 1:3-4.
6. The method for preparing vortioxetine metabolites according to claim 1, characterized in that: The reaction time is 1 to 10 hours.
7. The method for preparing vortioxetine metabolites according to claim 1, characterized in that: After the reaction is completed, purification is further performed, and the purification comprises: adjusting the pH of the reaction system to 8-9, then extracting with ethyl acetate, drying, removing the solvent, and then purifying by column chromatography to obtain the target product II.
8. The method for preparing vortioxetine metabolites according to claim 7, characterized in that: The stationary phase of the column chromatography is silica gel, and the mobile phases are dichloromethane and methanol.
9. The method for preparing vortioxetine metabolites according to claim 7, characterized in that: The drying agent used in the drying is anhydrous sodium sulfate.