Preparation method of impurities II and III of oxaggolil sodium
A method using pivalic acid or Oxone as an oxidant with controlled reaction conditions and solvents simplifies the preparation of elagolix sodium impurities II and III, achieving high yields and purities, addressing the inefficiencies of previous methods.
Patent Information
- Application Number
- CN202411589181.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-08
- Publication Date
- 2024-12-27
AI Technical Summary
Existing methods for preparing oxidized impurities of elagolix sodium, such as those described in Chinese invention patent application CN111499581A, suffer from low conversion rates and complex, costly separation processes, making them unsuitable for large-scale production.
A method using pivalic acid or Oxone as an oxidant, with specific reaction conditions and solvents, followed by pH adjustment, solvent separation, and crystallization, to prepare elagolix sodium impurities II and III, avoiding the use of hydrogen peroxide and meta-chloroperbenzoic acid, and simplifying the post-processing.
The method achieves high yields and purities of over 96.5% for impurity II and over 90% for impurity III, with simplified and cost-effective processes, suitable for quality research and process control of elagolix sodium.
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Figure CN119192089A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for preparing an impurity of elagolid sodium, and specifically relates to a method for preparing oxidized impurities II and III of elagolid sodium. Background Art
[0002] Elagolix Sodium (trade name Orilissa), whose chemical name is (R)-4-[[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)-benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]amino]butyrate sodium, was jointly developed by AbbVie and Neurocrine Biosciences Inc. It was approved by the US FDA on July 24, 2018 for the treatment of endometriosis (EMs) and the relief of its related pain symptoms. It is the first oral non-peptide gonadotropin-releasing hormone (GnRH) antagonist approved in 10 years. It competitively binds to the pituitary GnRH receptors in the hypothalamus-pituitary-gonadal axis, reversibly blocking the transmission of GnRH signals in the hypothalamus-pituitary-gonadal axis, thereby inhibiting the release of progesterone and follicle-stimulating hormone, ultimately reducing the secretion of estrogen and progesterone in the ovaries and relieving pain symptoms.
[0003] The impurities of elegans sodium are of great significance for the in-depth study of elegans sodium.
[0004] Chinese invention patent application CN111499581A reports that three oxidized impurities of elagolid sodium (structures are shown in formulas Ⅰ, Ⅱ, and Ⅲ, respectively) are prepared using elagolid sodium as a raw material and oxidized with hydrogen peroxide. However, the conversion rate of this preparation method is low, and the reaction products are relatively complex, requiring separation by a preparative liquid phase method, which is costly and not suitable for large-scale preparation.
[0005] Summary of the invention
[0006] The purpose of the present invention is to provide a method for preparing an impurity of elagolid sodium having structures shown in formula II and III, and to provide an impurity reference substance for the quality study of elagolid sodium.
[0007] The technical solution of the present invention is as follows:
[0008] A method for preparing an oxidized impurity of elagolid sodium shown in formula II, the synthetic route is as follows:
[0009]
[0010] The method comprises: using pivalic acid or Oxone as an oxidant, and allowing compound EL-1 and the oxidant to undergo an oxidation reaction in a reaction solvent; after the reaction is completed, adding an oxidation terminator to terminate the reaction, adjusting the pH value of the reaction solution to 8-10 with an alkali solution, separating the liquids, collecting the organic layer, drying the organic layer over anhydrous sodium sulfate, concentrating to dryness, adding a benign solvent to dissolve, then adding a poor solvent, stirring and crystallizing at a temperature of 0±5°C, filtering, and obtaining the impurity product of elagolid sodium shown in formula II.
[0011] The molar ratio of the compound EL-I to the oxidant is 1:1.0 to 1:3.0, preferably 1:1.2 to 1:1.5.
[0012] The oxidation reaction temperature is 0 to 100° C., preferably 10 to 40° C., more preferably 20 to 35° C.; the oxidation reaction time is 1 minute to 24 hours, preferably 0.5 to 12 hours, more preferably 1 hour to 2 hours.
[0013] The amount of reaction solvent used will affect the yield of the product. The mass volume ratio of the compound EL-I to the reaction solvent is 1:1 to 1:10 g / ml, preferably 1:4 to 1:6 g / ml.
[0014] The reaction solvent is one or more of water, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, dichloromethane and the like, preferably a mixed solvent of water and at least one organic solvent selected from methanol and acetone in a volume ratio of 1:3 to 3:1, more preferably a mixed solvent of water and at least one organic solvent selected from methanol and acetone in a volume ratio of 1:2 to 2:1.
[0015] Specifically, the reaction solvent is a mixed solvent of water and methanol in a volume ratio of 1:1.5, a mixed solvent of water and acetone in a volume ratio of 2:1, and a mixed solvent of water and methanol and acetone in a volume ratio of 1:1:1.
[0016] The oxidation terminator is a sodium thiosulfate solution or a sodium bisulfite solution, preferably a sodium bisulfite solution. The concentration of the sodium thiosulfate solution is 10% to 40% (mass volume ratio), and the concentration of the sodium bisulfite solution is 10% to 40% (mass volume ratio), preferably 20% to 30%.
[0017] The alkaline solution is a sodium carbonate solution, a sodium bicarbonate solution or a sodium hydroxide solution, preferably a saturated sodium carbonate solution, a saturated sodium bicarbonate solution or a sodium hydroxide solution with a mass fraction of 10% to 40%.
[0018] As a preferred technical scheme for the preparation method of the oxidized impurity of elagolix sodium represented by formula II of the present invention, when the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, and the organic layer is collected; the non-water-soluble solvent is selected from at least one of ethyl acetate, isopropyl acetate, dichloromethane, etc.
[0019] As a preferred technical scheme for the preparation method of the oxidized impurity of elagolix sodium shown in Formula II of the present invention, when the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8 to 10 with an alkaline solution, an extraction solvent is added according to a volume ratio of the extraction solvent to the water-soluble solvent of 1:1 to 1:3.5, the liquids are separated, and the organic layer is collected; the water-soluble solvent is selected from at least one of tetrahydrofuran, acetone, acetonitrile, ethanol, methanol, etc., and the extraction solvent is ethyl acetate, dichloromethane or isopropyl acetate.
[0020] The mass volume ratio of the compound EL-I to the benign solvent is 1:1 to 1:8 g / ml, preferably 1:1.5 to 1:4 g / ml, and more preferably 1:1.5 to 1:2 g / ml; the volume ratio of the benign solvent to the poor solvent is 1:1 to 1:20, preferably 1:5 to 1:10, and more preferably 1:8 to 1:8.125.
[0021] The good solvent can be selected from but not limited to one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, preferably methanol, ethanol or acetone; the poor solvent can be selected from but not limited to one or more of methyl tert-butyl ether, isopropyl ether, n-hexane, n-heptane, preferably methyl tert-butyl ether.
[0022] As a preferred technical solution of the present invention, a good solvent is added to dissolve, activated carbon is added to decolorize, filtered, and a poor solvent is added to the filtrate.
[0023] The mass ratio of the compound EL-1 to the activated carbon is 20:1 to 20:2. The decolorization time of the activated carbon is 5 to 15 minutes.
[0024] Specifically, when the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidative terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, concentrated to dryness, a benign solvent is added to dissolve at a temperature of 20-40°C, activated carbon is added for decolorization, filtered, and then a poor solvent is added, cooled to 0±5°C, stirred for crystallization, and filtered to obtain the sodium aragolide impurity product shown in formula II.
[0025] When the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, an extraction solvent is added, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, and then concentrated to dryness; a good solvent is added to dissolve at a temperature of 20-40°C, and activated carbon is added for decolorization, and the mixture is filtered, a poor solvent is added to the filtrate, and the mixture is cooled to 0±5°C, stirred for crystallization, filtered, and dried to obtain the impurity product of sodium aragolide shown in formula II.
[0026] A method for preparing an oxidized impurity of elagolid sodium represented by formula III, the synthetic route is as follows:
[0027]
[0028] include:
[0029] Step (1), using pivalic acid or Oxone as an oxidant, compound EL-1 and the oxidant undergo an oxidation reaction in a reaction solvent; after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, concentrated to dryness, a benign solvent is added to dissolve, and then a poor solvent is added, and crystallization is carried out at a temperature of 0±5°C with stirring, and filtration is performed to obtain the sodium eleragolix impurity shown in formula II;
[0030] Step (2), using pivalic acid or Oxone as an oxidant, the sodium oxalate impurity shown in formula II and the oxidant undergo an oxidation reaction in a reaction solvent; after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, concentrated to dryness, a benign solvent is added to dissolve, a poor solvent is added, crystallization is performed, and filtering is performed to obtain the sodium oxalate impurity product shown in formula III.
[0031] In step (2), the molar ratio of the sodium elagolid impurity represented by formula II to the oxidant is 1:1.0 to 1:4.0, preferably 1:1.5 to 1:2.0.
[0032] The oxidation reaction temperature is 0 to 100° C., preferably 10 to 40° C., more preferably 20 to 35° C.; the oxidation reaction time is 1 minute to 24 hours, preferably 0.5 to 12 hours, more preferably 1 hour to 4 hours.
[0033] The mass volume ratio of the alagorix sodium impurity shown in Formula II to the reaction solvent is 1:1 to 1:15 g / ml, preferably 1:8 to 1:15 g / ml.
[0034] The reaction solvent is one or more of water, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, dichloromethane and the like, preferably a mixed solvent of water and at least one organic solvent selected from dichloromethane, acetonitrile and acetone in a volume ratio of 1:1 to 1:4.
[0035] Specifically, the reaction solvent is a mixed solvent of water and dichloromethane in a volume ratio of 1:1, a mixed solvent of water and acetonitrile in a volume ratio of 1:1, and a mixed solvent of water, acetone and dichloromethane in a volume ratio of 1:1:1.
[0036] The oxidation terminator is a sodium thiosulfate solution or a sodium bisulfite solution, preferably a sodium bisulfite solution. The concentration of the sodium thiosulfate solution is 10% to 40% (mass volume ratio), and the concentration of the sodium bisulfite solution is 10% to 40% (mass volume ratio), preferably 10% to 30%.
[0037] The alkaline solution is a sodium carbonate solution, a sodium bicarbonate solution or a sodium hydroxide solution, preferably a saturated sodium carbonate solution, a saturated sodium bicarbonate solution or a sodium hydroxide solution with a mass fraction of 10% to 40%.
[0038] As a preferred technical scheme for the preparation method of the oxidized impurity of elagolix sodium represented by formula III of the present invention, when the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, and the organic layer is collected; the non-water-soluble solvent is selected from at least one of ethyl acetate, isopropyl acetate, dichloromethane, etc.
[0039] As a preferred technical solution for the preparation method of the oxidized impurity of olagolid sodium represented by formula III of the present invention, when the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8 to 10 with an alkaline solution, an extraction solvent is added according to a volume ratio of the extraction solvent to the water-soluble solvent of 1:0.5 to 1:2, the liquids are separated, and the organic layer is collected; the water-soluble solvent is selected from at least one of tetrahydrofuran, acetone, acetonitrile, ethanol, methanol, etc., and the extraction solvent is ethyl acetate, dichloromethane or isopropyl acetate.
[0040] The mass volume ratio of the alagorix sodium impurity shown in Formula II to the benign solvent is 1:1 to 1:8 g / ml, preferably 1:2 to 1:4 g / ml; the volume ratio of the benign solvent to the poor solvent is 1:1 to 1:20, preferably 1:5 to 1:10, and more preferably 1:7.5 to 1:8.
[0041] The good solvent can be selected from but not limited to one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and isopropyl acetate, preferably at least one of methanol and ethyl acetate; the poor solvent can be selected from but not limited to one or more of methyl tert-butyl ether, isopropyl ether, n-hexane, and n-heptane.
[0042] As a preferred technical solution of the present invention, a good solvent is added to dissolve, activated carbon is added to decolorize, filtered, and a poor solvent is added to the filtrate.
[0043] The mass ratio of the sodium elagolid impurity represented by formula II to the activated carbon is 20:1 to 20:2.5. The decolorization time of the activated carbon is 5 to 15 minutes.
[0044] Specifically, when the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, and then concentrated to dryness. A benign solvent is added to dissolve the organic layer at a temperature of 20-40°C, activated carbon is added to decolorize the organic layer, the organic layer is filtered, a poor solvent is added, the organic layer is cooled to 0±5°C, the organic layer is stirred for crystallization, and the impurity product of sodium aragolide shown in formula III is obtained.
[0045] When the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, and an extraction solvent is added according to a volume ratio of the extraction solvent to the water-soluble solvent of 1:0.5-1:2. The liquids are separated, and the organic layer is collected. The organic layer is dried over anhydrous sodium sulfate and concentrated to dryness. A good solvent is added to dissolve it at a temperature of 20-40°C, and activated carbon is added for decolorization. The mixture is filtered, a poor solvent is added, and the mixture is cooled to 0±5°C. The mixture is stirred for crystallization and filtered to obtain the impurity product of sodium aragolide shown in Formula III.
[0046] Another object of the present invention is to provide the use of the impurities of elagolid sodium represented by formula II and III in the inspection of related substances of elagolid sodium and quality research; for example, it can be used as an impurity reference substance for quality research of elagolid sodium.
[0047] Compound EL-I, chemical name is (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amine.
[0048] The impurity of elagolix sodium shown in formula II has the chemical name: (R)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-3-(2-(hydroxyamino)-2-phenylethyl)-6-methylpyrimidine-2-,4(1H,3H)-dione;
[0049] The impurity of elagolix sodium shown in formula III has a chemical name: (E)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)-3-(2-(hydroxyimino)-2-phenylethyl)-6-methylpyrimidine-2-,4(1H,3H)-dione.
[0050] Compared with the prior art, the present invention has the following beneficial effects:
[0051] The present invention avoids the use of oxidants such as hydrogen peroxide and meta-chloroperbenzoic acid, which results in a more complex reaction product and requires a complex and costly post-processing method such as column chromatography and preparation of a liquid phase.
[0052] The present invention can be used to prepare the oxidation impurities II and III of elagolix sodium in a directional manner, and the reaction route is short, the reaction conditions are mild, the operation is simple, and the safety is high and the cost is low during the entire reaction process. The method of the present invention has high yield, good stability, and simple post-processing. The yield of the oxidation impurity II of elagolix sodium reaches more than 96.5%, and the purity reaches more than 99%; the yield of the oxidation impurity III of elagolix sodium reaches more than 90%, and the purity reaches more than 99%.
[0053] The invention has important significance for the quality research and process control of elagolid sodium. BRIEF DESCRIPTION OF THE DRAWINGS
[0054] Figure 1 is the H NMR spectrum of compound II ( 1 1H NMR).
[0055] Figure 2 This is the mass spectrum of compound II.
[0056] Figure 3 is the H NMR spectrum of compound III ( 1 1H NMR).
[0057] Figure 4 This is the mass spectrum of compound III. DETAILED DESCRIPTION
[0058] The technical scheme of the present invention is further illustrated by the following examples, which are only used to more specifically illustrate the preferred embodiments of the present invention and are not used to limit the technical scheme of the present invention. Any method and material similar or equivalent to the contents contained herein can be used in the present invention. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art.
[0059] The experimental methods in the following examples without specifying specific conditions were generally prepared according to conventional conditions.
[0060] Example 1
[0061] Preparation of Compound II
[0062] To a three-necked flask, add (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amine (Compound EL-I, 50.0 g, 91.66 mmol), Oxone (67.62 g, 110.0 mmol), water (100 ml) and methanol (150 ml), stir to dissolve, and stir to react at 25±2°C for 1.5 h. After the reaction, add 20% sodium bisulfite solution (40 ml) and stir for 10 min. in to terminate the reaction, adjust the pH value of the reaction solution to 9 with a saturated sodium bicarbonate solution, then add 150 ml of ethyl acetate, extract and separate the liquids, collect the organic layer, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness; at room temperature, add 75 ml of methanol to dissolve, add 2.5 g of activated carbon, decolorize at room temperature for 10 min, filter, add 600 ml of methyl tert-butyl ether to the filtrate at room temperature, cool the system to 0±5°C, stir and crystallize for 2 h, a large amount of solid precipitates, filter, and dry to obtain compound II product (light yellow solid, 49.71 g, yield 96.58%, HPLC purity 99.4%). 1 H NMR (400MHz, DMSO-d6) δ: 7.53(m,3H,Ar-H), 7.21(m,7H,Ar-H), 6.71(m,1H,Ar-H), 5.93(s,1H,-NH), 5.27(s,2H,Ar-CH2), 4.20(m,1H,-CH), 4.01(m,2H,-CH2), 3.85(s,3H,-CH3), 2.09(s,3H,-CH3); TOF MS ES(+)(m / z):562.2[M+H] + .
[0063] Preparation of compound III
[0064] Compound II (20.0 g, 35.62 mmol), Oxone (26.28 g, 42.75 mmol), water (100 ml) and dichloromethane (100 ml) were added to a three-necked flask, stirred to dissolve, and stirred to react at a temperature of 30±2°C for 3 h. After the reaction was completed, 10% sodium bisulfite solution (30 ml) was added and stirred for 10 min to terminate the reaction. The pH value of the reaction solution was adjusted to 9 with a saturated sodium carbonate solution, and then the liquids were separated and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness, 80 ml of methanol and 2.5 g of activated carbon were added thereto, and the mixture was decolorized at room temperature for 10 min. The mixture was filtered, and 640 ml of methyl tert-butyl ether was added to the filtrate at room temperature. The system was cooled to 0±5°C and stirred for crystallization for 3 h. A large amount of solid was precipitated. After filtering and drying, a light yellow compound III product (solid, 19.35 g, yield 97.09%, HPLC purity 99.3%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ: 11.38(s,1H,OH), 7.53(m,2H,Ar-H), 7.34(m,2H,Ar-H), 7.23(m,2H,Ar-H), 7.13(m, TOF MS ES(-)(m / z): 558.4[MH] - .
[0065] Example 2
[0066] Preparation of Compound II
[0067] Add (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amine (Compound EL-I, 40.0 g, 73.33 mmol), pivalic acid (9.64 g, 94.39 mmol), water (120 ml) and acetone (60 ml) to a three-necked flask, stir to dissolve, and stir to react at a temperature of 30±2°C for 2 h; after the reaction, add 20% sodium bisulfite solution (30 ml) and stir for 10 min To terminate the reaction, adjust the pH value of the reaction solution to 8.5 with a saturated sodium bicarbonate solution, then add 200 ml of ethyl acetate, extract and separate the liquids, collect the organic layer, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness; add 80 ml of ethanol to dissolve at room temperature, add 2.0 g of activated carbon, decolorize at room temperature for 5 min, filter, add 650 ml of methyl tert-butyl ether to the filtrate at room temperature, cool the system to 0±5°C, stir and crystallize for 2 h, a large amount of solid precipitates, filter, and dry to obtain compound II product (light yellow solid, 39.88 g, yield 96.87%, HPLC purity 99.5%).
[0068] Preparation of compound III
[0069] Compound II (20.0 g, 35.62 mmol), pivalic acid (4.68 g, 45.82 mmol), water (80 ml) and acetonitrile (80 ml) were added to a three-necked flask, stirred to dissolve, and stirred to react at a temperature of 30±2°C for 4 h; after the reaction, 20% sodium bisulfite solution (10 ml) was added and stirred for 10 min to terminate the reaction, and the pH value of the reaction solution was adjusted to 8 with a saturated sodium bicarbonate solution, and 160 ml of ethyl acetate was added to extract and separate the liquids, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness, 80 ml of ethyl acetate and 2.0 g of activated carbon were added thereto, and the mixture was decolorized at room temperature for 10 min, filtered, and 600 ml of n-hexane was added to the filtrate at room temperature. The system was cooled to 0±5°C and stirred for crystallization for 3 h. A large amount of solid was precipitated, filtered, and dried to obtain a light yellow compound III product (solid, 19.17 g, yield 96.17%, HPLC purity 99.3%).
[0070] Example 3
[0071] Preparation of Compound II
[0072] Add (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amine (Compound EL-I, 50.0 g, 91.66 mmol), Oxone (77.89 g, 126.70 mmol), water (100 ml), acetone (100 ml) and methanol (100 ml) to a three-necked flask, stir to dissolve, and stir to react at 25±2°C for 1 h; after the reaction, add 30% sodium bisulfite solution (25 ml ) was stirred for 10 min to terminate the reaction, the pH value of the reaction solution was adjusted to 8 with a saturated sodium bicarbonate solution, and 200 ml of ethyl acetate was added to extract and separate the liquids, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness; 80 ml of acetone was added to dissolve at room temperature, 2.5 g of activated carbon was added, and the mixture was decolorized at room temperature for 10 min, filtered, and 640 ml of methyl tert-butyl ether was added to the filtrate at room temperature. The system was cooled to 0±5°C and stirred for crystallization for 2 h. A large amount of solid was precipitated. After filtering and drying, compound II product (light yellow solid, 49.96 g, yield 97.07%, HPLC purity 99.4%) was obtained.
[0073] Preparation of compound III
[0074] Compound II (20.0 g, 35.62 mmol), Oxone (30.63 g, 49.83 mmol), water (100 ml), acetone (100 ml) and dichloromethane (100 ml) were added to a three-necked flask, and the mixture was stirred to dissolve. The mixture was stirred at 25 ± 2 °C for 1 h. After the reaction, 20% sodium bisulfite solution (20 ml) was added and stirred for 10 min to terminate the reaction. The pH value of the reaction solution was adjusted to 8.5 with saturated sodium bicarbonate solution, and dichloromethane was added. 100 ml of chloromethane was used for extraction and separation. The organic layer was collected and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness, and 80 ml of methanol and 2.5 g of activated carbon were added thereto. The mixture was decolorized at room temperature for 10 min and filtered. 600 ml of isopropyl ether was added to the filtrate at room temperature. The system was cooled to 0±5°C and stirred for crystallization for 2 h. A large amount of solid was precipitated. After filtering and drying, a light yellow compound III product (solid, 19.03 g, yield 95.48%, HPLC purity 99.1%) was obtained.
Claims
1. A method for preparing an oxidized impurity of elagolid sodium represented by formula II, characterized in that: The synthetic route is as follows: The method comprises: using pivalic acid or Oxone as an oxidant, and subjecting compound EL-1 and the oxidant to an oxidation reaction in a reaction solvent; after the reaction is completed, adding an oxidation terminator to terminate the reaction, adjusting the pH value of the reaction solution to 8-10 with an alkali solution, separating the liquids, collecting the organic layer, drying the organic layer over anhydrous sodium sulfate, concentrating to dryness, adding a benign solvent to dissolve, then adding a poor solvent, crystallizing, filtering, and obtaining the impurity product of elagolid sodium shown in formula II; Wherein, the molar ratio of the compound EL-I to the oxidant is 1:1.0 to 1:3.0; The oxidation reaction temperature is 0 to 100° C.; the oxidation reaction time is 1 minute to 24 hours.
2. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The molar ratio of the compound EL-I to the oxidant is 1:1.2 to 1:1.
5.
3. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The oxidation reaction temperature is 10-40°C, preferably 20-35°C; the oxidation reaction time is 0.5-12 hours, preferably 1 hour to 2 hours.
4. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The mass volume ratio of the compound EL-I to the reaction solvent is 1:1 to 1:10 g / ml, preferably 1:4 to 1:6 g / ml; the reaction solvent is one or more of water, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, and dichloromethane solvents, preferably a mixed solvent of water and at least one organic solvent selected from methanol and acetone with a volume ratio of 1:3 to 3:
1.
5. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The oxidation terminator is sodium thiosulfate solution or sodium bisulfite solution; the alkaline solution is sodium carbonate solution, sodium bicarbonate solution or hydroxide solution.
6. The method for preparing oxidized impurities of elagolid sodium according to claim 1 or 4, characterized in that: When the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, and the organic layer is collected; the non-water-soluble solvent is selected from at least one of ethyl acetate, isopropyl acetate, and dichloromethane; When the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, an extraction solvent is added according to a volume ratio of the extraction solvent to the water-soluble solvent of 1:1-1:3.5, the liquids are separated, and the organic layer is collected; the water-soluble solvent is selected from at least one of tetrahydrofuran, acetone, acetonitrile, ethanol, and methanol, and the extraction solvent is ethyl acetate, dichloromethane or isopropyl acetate.
7. The method for preparing oxidized impurities of elagolid sodium according to claim 1, characterized in that: The mass volume ratio of the compound EL-I to the benign solvent is 1:1 to 1:8 g / ml, preferably 1:1.5 to 1:4 g / ml, and more preferably 1:1.5 to 1:2 g / ml; the volume ratio of the benign solvent to the poor solvent is 1:1 to 1:20, preferably 1:5 to 1:10; the benign solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and isopropyl acetate, preferably methanol, ethanol or acetone; the poor solvent is selected from one or more of methyl tert-butyl ether, isopropyl ether, n-hexane, and n-heptane, preferably methyl tert-butyl ether.
8. A method for preparing the oxidized impurity of elagolid sodium represented by formula III, characterized in that: The synthetic route is as follows: include: Step (1), preparing the sodium oxadiazine impurity represented by formula II according to the method of claim 1; Step (2), using pivalic acid or Oxone as an oxidant, the sodium elagolix impurity shown in formula II and the oxidant undergo an oxidation reaction in a reaction solvent; after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquids are separated, the organic layer is collected, the organic layer is dried over anhydrous sodium sulfate, concentrated to dryness, a benign solvent is added to dissolve, a poor solvent is added, crystallization is performed, and filtering is performed to obtain the sodium elagolix impurity product shown in formula III; wherein the molar ratio of the sodium elagolix impurity shown in formula II to the oxidant is 1:1.0-1:4.0; the oxidation reaction temperature is 0-100°C, and the oxidation reaction time is 1 minute to 24 hours.
9. The method for preparing oxidized impurities of elagolid sodium according to claim 8, characterized in that: In step (2), the molar ratio of the sodium elagolid impurity represented by formula II to the oxidant is 1:1.5 to 1:2.0; The oxidation reaction temperature is 10-40°C, preferably 20-35°C; the oxidation reaction time is 0.5-12 hours, preferably 1 hour to 4 hours; The mass volume ratio of the sodium oxalagrilide impurity represented by Formula II to the reaction solvent is 1:1 to 1:15 g / ml, preferably 1:8 to 1:15 g / ml; The reaction solvent is one or more of water, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, dichloromethane and the like, preferably a mixed solvent of water and at least one organic solvent selected from dichloromethane, acetonitrile and acetone in a volume ratio of 1:1 to 1:4; The oxidation terminator is sodium thiosulfate solution or sodium bisulfite solution; The alkaline solution is sodium carbonate solution, sodium bicarbonate solution or hydroxide solution; The mass volume ratio of the alagorix sodium impurity shown in formula II to the benign solvent is 1:1 to 1:8 g / ml, preferably 1:2 to 1:4 g / ml; the volume ratio of the benign solvent to the poor solvent is 1:1 to 1:20, preferably 1:5 to 1:10, and more preferably 1:7.5 to 1:8; The good solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, and isopropyl acetate, preferably at least one of methanol and ethyl acetate; the poor solvent is selected from one or more of methyl tert-butyl ether, isopropyl ether, n-hexane, and n-heptane.
10. The method for preparing oxidized impurities of elagolid sodium according to claim 8, characterized in that: In step (2), when the reaction solvent is a mixed solvent of water and a non-water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, the liquid is separated, and the organic layer is collected; the non-water-soluble solvent is selected from at least one of ethyl acetate, isopropyl acetate, and dichloromethane; When the reaction solvent is a mixed solvent of water and a water-soluble solvent, after the reaction is completed, an oxidation terminator is added to terminate the reaction, the pH value of the reaction solution is adjusted to 8-10 with an alkaline solution, and an extraction solvent is added according to a volume ratio of the extraction solvent to the water-soluble solvent of 1:0.5-1:2, the liquids are separated, and the organic layer is collected; the water-soluble solvent is selected from at least one of tetrahydrofuran, acetone, acetonitrile, ethanol, and methanol; the extraction solvent is ethyl acetate, dichloromethane or isopropyl acetate.