Preparation method of R, S diastereoisomers of efinaconazole and intermediates of R, S diastereoisomers
The R and S diastereomers of iefluconazole and their intermediates were prepared by oxidation, reduction, nucleophilic substitution and nucleophilic addition reactions. This solved the problem of controlling the content of diastereomers in the prior art, realized the economical preparation of high-purity products, and ensured the safety and quality stability of the drug.
Patent Information
- Application Number
- CN202511632019.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-07
- Publication Date
- 2026-02-06
AI Technical Summary
The lack of effective preparation methods in the current technology to control the content of diastereomers of icoconazole leads to uncontrollable drug safety, efficacy and quality, affecting the clarity of drug components, efficacy and patient safety.
Ifluconazole R,S diastereomers and their intermediates were prepared using common reagents such as triethylamine and sodium iodide, through reaction steps including oxidation, reduction, nucleophilic substitution, and nucleophilic addition. Purity was improved by optimizing reaction conditions and post-processing steps.
This study provides an economical and efficient method for preparing iefluconazole R,S diastereomers and their intermediates. The reaction conditions are mild, the reagents are inexpensive and readily available, and the products have high optical purity, meeting the needs of drug research.
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Figure CN121471157A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of R, S diastereoisomer of efinaconazole and an intermediate thereof. BACKGROUND
[0002] Efinaconazole, chemical name (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylene piperidin-1-yl)-1-(1H-1, 2, 4-triazole-1-yl)-2-butanol, is a broad-spectrum and high-efficiency antifungal drug, which is mainly used for treating skin and nail infections caused by fungi. Its structure is shown as follows.
[0003]
[0004] There are many reported synthesis methods of efinaconazole in the prior art, and the route with industrial production value is to prepare the key intermediate compound 1, the intermediate compound 1-1 and efinaconazole by using R-methyl lactate as a starting material.
[0005]
[0006] Efinaconazole has two chiral centers, so the key intermediate compound 1, the intermediate compound 1-1 and efinaconazole all have one enantiomer and two diastereoisomers.
[0007] The enantiomer compound 1 of compound 1, the enantiomer compound 1-1 of compound 1-1 and the efinaconazole enantiomer compound 1-2 are shown as follows; the preparation of the related enantiomer can be carried out by taking S-methyl lactate as a starting material and referring to the preparation method of efinaconazole.
[0008]
[0009] However, there is no reported preparation method of the diastereoisomer compound 3 and compound 4 of compound 1, the diastereoisomer compound 4-1 and compound 4-1 of compound 1-1 and the efinaconazole diastereoisomer compound 4-2 and compound 4-2 at present. Their structures are shown as follows, respectively.
[0010]
[0011] The control of the content of diastereoisomers in chiral drugs can ensure the safety, effectiveness and controllability of the quality of the drugs, which is a crucial issue in drug research and production. Specifically: first, the drug molecules need to specifically bind with the biological macromolecules in the body to produce drug efficacy, and the presence of chiral centers makes the drug molecules and their diastereoisomers significantly different in three-dimensional structure, thereby leading to differences in activity and pharmacological effects; second, diastereoisomers may be metabolized into toxic substances in the body, or directly act on non-target organs to produce toxicity, and the content of diastereoisomers needs to be controlled to maximize the safety of patients; third, the absorption, distribution, metabolism and excretion of diastereoisomers in the body may be completely different from those of the drug, and these differences will make the concentration-time curve of the drug in the body complex and unpredictable, making it extremely difficult to determine the effective dose and dosing regimen; fourth, diastereoisomers have different chemical properties and may have different melting points, solubility, crystallization habit and chemical stability, and controlling the content of diastereoisomers can ensure that the drug production process is stable, the preparation quality is uniform, and the stability is maintained within the effective period; fifth, the ICH guideline series Q3 impurity guideline has clear and strict regulations on impurity control (generally <0.1%).
[0012] Therefore, strictly controlling the content of diastereoisomers in chiral drugs is the key to ensuring that the drug ingredients are clear, the efficacy is accurate, the safety is controllable, and the quality is stable. If effective control is lacking, it may lead to reduced efficacy, increased toxicity or unpredictable behavior in the body, ultimately endangering clinical efficacy and patient safety. The first prerequisite for achieving this control goal is to be able to prepare high-purity diastereoisomer standards in advance.
[0013] Therefore, the development of a preparation method for the diastereoisomers of efinaconazole and intermediates thereof is a technical problem that needs to be solved in the art. SUMMARY
[0014] The purpose of the present application is to provide a preparation method for the diastereoisomers of efinaconazole R,S and intermediates thereof.
[0015] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:
[0016] The present application claims a preparation method for the diastereoisomers of efinaconazole, comprising the following steps: using compound 1 as a starting material, obtaining compound 1-L through an oxidation reaction; obtaining compound 4 through a reduction reaction of compound 1-L; obtaining compound 4-1 through a nucleophilic substitution reaction of compound 4; obtaining compound 4-2 through a nucleophilic addition reaction of compound 4-1; the reaction route is as follows:
[0017]
[0018] In one aspect, the present application claims the preparation method of the above-mentioned R,S diastereoisomer of Eflucimide, comprising the following steps:
[0019] Step one: Compound 4 undergoes nucleophilic substitution reaction in a reaction solvent in the presence of an acid-binding agent and an activating agent. After the reaction is completed, post-treatment is performed, which includes quenching the reaction, extracting and separating, collecting the organic phase, and concentrating to obtain Compound 4-1.
[0020] Step two: Compound 4-1 undergoes nucleophilic addition reaction with 4-methylene piperidine hydrochloride in a reaction solvent in the presence of a catalyst. After the reaction is completed, post-treatment is performed, which includes quenching the reaction, extracting and separating, collecting the organic phase, concentrating, and recrystallizing the obtained oil to obtain Compound 4-2.
[0021]
[0022] In one preferred embodiment, the reaction solvent in step one includes one or more of dichloromethane, chloroform, and toluene.
[0023] In one preferred embodiment, the reaction solvent in step one is dichloromethane, which is beneficial for the reaction and post-treatment.
[0024] In one preferred embodiment, the acid-binding agent in step one includes one or more of triethylamine, N,N-diisopropyl ethylamine, and pyridine.
[0025] In one preferred embodiment, the acid-binding agent in step one is triethylamine, which is beneficial for the reaction and post-treatment.
[0026] In one preferred embodiment, the molar ratio of the acid-binding agent to Compound 4 in step one is 1:2 to 1:3, which is beneficial for the reaction and cost control.
[0027] In one preferred embodiment, the activating agent in step one includes one or more of methylsulfonyl chloride and p-methylbenzenesulfonyl chloride.
[0028] In one preferred embodiment, the activating agent in step one is methylsulfonyl chloride, which is beneficial for the reaction and post-treatment.
[0029] In one preferred embodiment, the molar ratio of the activating agent to Compound 4 in step one is 1:1 to 1:2, which is beneficial for the reaction and cost control.
[0030] In one preferred embodiment, the reaction time in step one is 1 to 3 hours.
[0031] In one preferred embodiment, the reaction temperature in step one is -10 to 30°C, which is beneficial for the reaction to proceed and for cost control.
[0032] In one preferred embodiment, the reaction solvent in step two includes one or more of acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran.
[0033] In one preferred embodiment, the reaction solvent in step two is acetonitrile, which is beneficial for the reaction and post-processing.
[0034] In one preferred embodiment, the catalyst in step two includes one or more of sodium iodide, potassium iodide, cuprous iodide, and cesium iodide.
[0035] In one preferred embodiment, the catalyst in step two is sodium iodide, which is beneficial for the reaction and post-processing.
[0036] In one preferred embodiment, the acid-binding agent in step two includes one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
[0037] In one preferred embodiment, the acid-binding agent in step two is lithium hydroxide, which is beneficial for the reaction and post-treatment.
[0038] In one preferred embodiment, the molar ratio of catalyst to compound 4-1 in step two is 2:1 to 3.5:1, which is beneficial for the reaction to proceed and for cost control.
[0039] In one preferred embodiment, the molar ratio of 4-methylenepiperidine hydrochloride to compound 4-1 in step two is 2:1 to 3:1, which is beneficial for the reaction to proceed and for cost control.
[0040] In one preferred embodiment, the reaction time in step two is 18–24 hours.
[0041] In one preferred embodiment, the reaction temperature in step two is 75–85°C, which is beneficial for the reaction to proceed and for cost control.
[0042] In a second aspect, the method for preparing the effluconazole R,S diastereomer intermediate 4 claimed in this invention includes the following steps: compound 1-L undergoes a reduction reaction in a reaction solvent in the presence of a reducing agent to obtain compound 4.
[0043]
[0044] In one preferred embodiment, the reaction solvent includes one or more of ethanol, isopropanol, tert-butanol, tetrahydrofuran, dichloromethane, chloroform, and toluene.
[0045] In one preferred embodiment, the reaction solvent is ethanol or isopropanol, which is beneficial for the reaction and post-processing.
[0046] In one preferred embodiment, the reaction temperature is -10 to 30°C, which is conducive to the reaction.
[0047] In one preferred embodiment, the reduction reaction time is 1-3 hours.
[0048] In one preferred embodiment, the reducing agent includes one or more of sodium borohydride, lithium aluminum hydride, lithium borohydride, potassium borohydride, DIBAL-H, and BH3 / THF complex.
[0049] In one preferred embodiment, the reducing agent is sodium borohydride or potassium borohydride, which is beneficial for the reaction and post-processing.
[0050] In one preferred embodiment, the molar ratio of the reducing agent to compound 1-L is 0.5 to 3.0, which is beneficial for the reaction to proceed.
[0051] In one preferred embodiment, the post-treatment of the reduction reaction is as follows: after the reaction is complete, the reaction is quenched, filtered and concentrated to obtain crude compound 4, the crude compound 4 is separated and purified using a reverse column chromatography system, the purified eluent is substantially concentrated, extracted, and the organic phase is collected and concentrated to dryness.
[0052] In one preferred embodiment, the eluent of the reverse column chromatography is acetonitrile:purified water = 50:50 to 100:0.
[0053] In one preferred embodiment, the eluent is acetonitrile:water = 80:20, which isocratic elution and facilitates sample separation.
[0054] In a third aspect, the method for preparing the 1-L intermediate of the diastereomer of icoconazole R,S includes the following steps: compound 1 is oxidized in a reaction solvent in the presence of an oxidant to obtain compound 1-L;
[0055]
[0056] In one preferred embodiment, the oxidation reaction is at least one of the following: PCC oxidation, PDC oxidation, Jones oxidation, Dess-Martin periodoyl alkane oxidation, IBX oxidation, Swern oxidation, Mukaiyama oxidation, Ley-Griffith oxidation, active manganese oxide oxidation, TEMPO oxidation, and Asano oxidation.
[0057] In one preferred embodiment, the oxidation reaction is an IBX oxidation reaction.
[0058] In one preferred embodiment, the oxidation reaction is an IBX oxidation reaction, and the reaction solvent includes one or more of N,N-dimethylformamide, dimethyl sulfoxide, chloroform, toluene, and acetonitrile.
[0059] In one preferred embodiment, the oxidation reaction is an IBX oxidation reaction, and the reaction solvent is N,N-dimethylformamide, which is beneficial for the reaction and post-processing.
[0060] In one preferred embodiment, the oxidation reaction is an IBX oxidation reaction, and the reaction temperature is 0–40°C, which is conducive to the reaction.
[0061] In one preferred embodiment, the oxidation reaction is an IBX oxidation reaction, and the oxidant includes 2-iodobenzoic acid, which is beneficial for the reaction and post-treatment.
[0062] In one preferred embodiment, the oxidation reaction is an IBX oxidation reaction, and the molar ratio of the oxidant to compound 1 is 1.0 to 3.0, which is beneficial to the reaction.
[0063] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction.
[0064] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction, and the reaction solvent includes one or more of dichloromethane / purified water, ethyl acetate / purified water, diethyl ether / purified water, and acetonitrile / purified water.
[0065] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction, and the reaction solvent is dichloromethane / purified water, which is beneficial for the reaction and post-processing.
[0066] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction, and the reaction temperature is -10 to 40°C, which is conducive to the reaction.
[0067] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction, and the oxidant includes sodium hypochlorite, which is beneficial for the reaction and post-treatment.
[0068] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction, and the molar ratio of the oxidant to compound 1 is 1.0 to 5.0, which is conducive to the reaction.
[0069] In one preferred embodiment, when the oxidation reaction is a TEMPO oxidation reaction, a catalyst is also used, the catalyst comprising 2,2,6,6-tetramethylpiperidine oxide and potassium bromide, which facilitates the reaction and post-treatment.
[0070] In one preferred embodiment, the oxidation reaction is a TEMPO oxidation reaction, and the molar ratio of the catalyst to compound 1 is 0.2 to 2.0, which is beneficial to the reaction.
[0071] In one preferred embodiment, the oxidation reaction time is 10-20 h.
[0072] In one preferred embodiment, the post-treatment of the oxidation reaction is as follows: after the reaction is complete, the reaction is quenched, extracted with ethyl acetate, and concentrated to dryness to obtain compound 1-L.
[0073] In one preferred embodiment, the post-treatment of the oxidation reaction is as follows: after the reaction is complete, the liquid phase is quenched and separated, the organic phase is washed with sodium sulfite solution, and concentrated to dryness to obtain compound 1-L.
[0074] In one preferred embodiment, the method for preparing the R,S diastereomer of ivermectin more specifically includes the following steps:
[0075] Step 1: Compound 1 is prepared by IBX oxidation or TEMPO oxidation in a reaction solvent at a reaction temperature of -10 to 40°C in the presence of an oxidant or oxidant / catalyst to obtain compound 1-L.
[0076] Step 2: Compound 1-L undergoes a reduction reaction in the reaction solvent at a reaction temperature of -10 to 30°C in the presence of a reducing agent. After the reaction is complete, post-processing is performed, which includes: quenching the reaction, filtering and concentrating to obtain crude compound 4, and separating compound 3 from crude compound 4 using a reverse column chromatography system.
[0077] Step 3: Compound 4 undergoes a nucleophilic substitution reaction in the reaction solvent at a reaction temperature of -10 to 30°C in the presence of an acid-binding agent and an activator. After the reaction is complete, post-treatment is performed, which includes: quenching the reaction, extraction and separation, and collection and concentration of the organic phase to obtain compound 4-1.
[0078] Step 4: Compound 4-1 undergoes a nucleophilic addition reaction with 4-methylenepiperidine hydrochloride in a reaction solvent at a reaction temperature of 65-85°C in the presence of a catalyst. After the reaction is complete, post-treatment is performed, which includes: quenching the reaction, extraction and separation, collection and concentration of the organic phase, and recrystallization of the resulting oil to obtain compound 4-2.
[0079]
[0080] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0081] 1. This invention fills a gap in the prior art and provides a method for preparing the R,S diastereomers of icoconazole and their intermediates, thus providing assistance for drug research;
[0082] 2. The reaction conditions of this invention are mild, and the reagents are inexpensive and readily available;
[0083] 3. The present invention has low economic and time costs, and the product obtained has high optical purity without the need for splitting and preparation. Attached Figure Description
[0084] Figure 1 The chromatogram for isomer detection of compound 4 prepared in Example 5;
[0085] Figure 2 The nuclear magnetic resonance (NMR) spectrum of compound 4 prepared in Example 5 is shown below.
[0086] Figure 3 The [M+H]+ spectrum of compound 4 prepared in Example 5 is shown.
[0087] Figure 4 The chromatogram for isomer detection of compound 4-1 prepared in Example 8 is shown below.
[0088] Figure 5 The nuclear magnetic resonance (NMR) spectrum of compound 4-1 prepared in Example 8 is shown below.
[0089] Figure 6 The [M+H]+ spectrum of compound 4-1 prepared in Example 8 is shown.
[0090] Figure 7 The chromatogram for isomer detection of compound 4-2 prepared in Example 9;
[0091] Figure 8 The nuclear magnetic resonance (NMR) spectrum of compound 4-2 prepared in Example 9 is shown below.
[0092] Figure 9The [M+H]+ spectrum of compound 4-2 prepared in Example 9 is shown. Detailed Implementation
[0093] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.
[0094] Compound 1 was prepared by starting with methyl R-lactic acid, which underwent an aminotransfer reaction with morpholine to give (R)-2-hydroxy-1-morpholinopropane-1-one; the hydroxyl group was then protected with 2,4-dihydropyran to give (2R)-1-morpholino-2-((tetrahydro-2H-pyran-2-yl)oxy)propane-1-one; and then reacted with 1-bromo-2,4-difluorobenzene in a Grignard reaction to give (2R)-1-(2,4-difluorophenyl)-2-[(tetrahydro-2H-pyran-2-yl)oxy)propane-1-one. [-2H-pyran-2-yl)oxy]-1-propanone; followed by cyclization of the carbonyl group via the Corey-Chaykovsky reaction, and then a one-pot ring-opening reaction with 1,2,4-triazolium to give (2R,3R)-2-(2,4-difluorophenyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol; finally, deprotection with methanesulfonic acid to give compound 1. The synthetic route is as follows:
[0095]
[0096] The room temperature described in this invention is 25-35℃.
[0097] Example 1: Synthesis of Compound 1-L
[0098] In a 500 ml three-necked flask, add 30.0 g (0.082 mol, 1.0 eq.) of compound 1 and 150.0 g of N,N-dimethylformamide. Cool to about 15 °C. Add 46.0 g (0.164 mol, 2.00 eq.) of 2-iodobenzoic acid in portions. After the addition is complete, stir at room temperature for 12 h. Cool the reaction solution to about 10 °C and add sodium hydroxide solution dropwise to adjust the pH to about 12. After the addition is complete, extract with ethyl acetate. Wash the obtained organic phase three times with purified water and concentrate to dryness to obtain 20.9 g of deep yellow oil (compound 1-L), which will be used for the next step.
[0099] Example 2 Synthesis of Compound 1-L
[0100] In a 1L three-necked flask, add 30.0g (0.082mol, 1.0eq.) of compound 1, 150.0g of dichloromethane, 150.0g of purified water, 19.5g (0.164mol, 2.0eq.) of potassium bromide, and 12.8g (0.082mol, 1.0eq.) of 2,2,6,6-tetramethylpiperidine oxide. Cool to 0℃ and add 125.0g (0.164mol, 2.0eq.) of 10% sodium hypochlorite solution dropwise. After the addition is complete, maintain the reaction temperature for 2 hours. Separate the liquid and wash the organic phase three times with sodium sulfite solution. Concentrate to dryness to obtain 21.2g of a deep yellow oily substance (compound 1-L), which will be used for the next step.
[0101] Example 3 Preparation of Compound 4
[0102] In a 250 ml three-necked flask, 18.5 g (0.069 mol, 1.0 eq.) of compound 1-L and 185.0 g of anhydrous ethanol were added. The mixture was stirred and cooled to approximately 0 °C, maintaining the temperature below 5 °C. 5.2 g (0.138 mol, 2.0 eq.) of sodium borohydride was added in portions. After the addition was complete, the temperature was raised to 15 °C and maintained for 2 h. The mixture was then cooled to approximately 0 °C, and methanesulfonic acid was added dropwise to adjust the pH to approximately 1. The mixture was then heated to reflux and stirred for 1 h. The mixture was filtered, and the filtrate was collected and concentrated to dryness. The filtrate was purified using a column chromatography system. The purified eluent was concentrated to near-complete concentration with acetonitrile, and sodium hydroxide solution was added to adjust the pH to approximately 12. The mixture was extracted with n-butanol, and the organic phase was collected and concentrated to dryness to obtain 3.8 g of compound 4.
[0103] Example 4: Preparation of Compound 4
[0104] In a 250 ml three-necked flask, 12.3 g (0.046 mol, 1.0 eq.) of compound 1-L and 125.0 g of anhydrous ethanol were added. The mixture was stirred and cooled to approximately 0 °C, maintaining the temperature below 5 °C. 2.0 g (0.092 mol, 2.0 eq.) of lithium borohydride was added in portions. After the addition was complete, the temperature was raised to 15 °C and maintained for 2 h. The mixture was then cooled to approximately 0 °C, and methanesulfonic acid was added dropwise to adjust the pH to approximately 1. The mixture was then heated to reflux and stirred for 1 h. The mixture was filtered, and the filtrate was collected and concentrated to dryness. The solution was purified using a column chromatography system. The purified eluent was concentrated to near-complete concentration with acetonitrile, and sodium hydroxide solution was added to adjust the pH to approximately 12. The solution was extracted with n-butanol, and the organic phase was collected and concentrated to dryness to obtain 2.4 g of compound 4.
[0105] Example 5 Preparation of Compound 4
[0106] In a 250 ml three-necked flask, 11.6 g (0.043 mol, 1.0 eq.) of compound 1-L and 115.1 g of isopropanol were added. The mixture was stirred and cooled to approximately 0 °C, maintaining the temperature below 5 °C. 3.3 g (0.087 mol, 2.0 eq.) of sodium borohydride was added in portions. After the addition was complete, the temperature was raised to 15 °C and maintained for 2 h. The mixture was then cooled to approximately 0 °C, and methanesulfonic acid was added dropwise to adjust the pH to approximately 1. The mixture was then heated to reflux and stirred for 1 h. The mixture was filtered, and the filtrate was collected and concentrated to dryness. The filtrate was purified using a column chromatography system. The purified eluent was concentrated to near-complete concentration with acetonitrile, and sodium hydroxide solution was added to adjust the pH to approximately 12. The mixture was extracted with n-butanol, and the organic phase was collected and concentrated to dryness to obtain 2.2 g of compound 4 with an ee value greater than 99%.
[0107] Example 6 Preparation of Compound 4
[0108] In a 250 ml three-necked flask, 15.0 g (0.056 mol, 1.0 eq.) of compound 1-L and 150.0 g of anhydrous ethanol were added. The mixture was stirred and cooled to approximately 0 °C, maintaining the temperature below 5 °C. 1.1 g (0.028 mol, 0.5 eq.) of sodium borohydride was added in portions. After the addition was complete, the temperature was raised to 20 °C and maintained for 2 h. The temperature was then lowered to approximately 0 °C, and methanesulfonic acid was added dropwise to adjust the pH to approximately 1. The mixture was then heated to reflux and stirred for 1 h. The mixture was filtered, and the filtrate was collected and concentrated to dryness. Purification was performed using a column chromatography system. The purified eluent was concentrated to near-complete concentration with acetonitrile, and sodium hydroxide solution was added to adjust the pH to approximately 12. Extraction was performed using n-butanol, and the organic phase was collected and concentrated to dryness to obtain 3.1 g of compound 4 with an ee value greater than 99%.
[0109] Example 7 Preparation of Compound 4
[0110] In a 250 ml three-necked flask, 13.2 g (0.049 mol, 1.0 eq.) of compound 1-L and 132.1 g of anhydrous ethanol were added. The mixture was stirred and cooled to approximately 0 °C, maintaining the temperature below 5 °C. 3.2 g (0.15 mol, 3.0 eq.) of lithium borohydride was added in portions. After the addition was complete, the temperature was raised to 30 °C and maintained for 2 h. The mixture was then cooled to approximately 0 °C, and methanesulfonic acid was added dropwise to adjust the pH to approximately 1. The mixture was then heated to reflux and stirred for 1 h. The mixture was filtered, and the filtrate was collected and concentrated to dryness. Purification was performed using a column chromatography system. The purified eluent was concentrated to near-complete concentration with acetonitrile, and sodium hydroxide solution was added to adjust the pH to approximately 12. Extraction was performed using n-butanol, and the organic phase was collected and concentrated to dryness to obtain 3.1 g of compound 4 with an ee value greater than 99%.
[0111] Example 8 Preparation of compound 4-1
[0112] In a 250 ml three-necked flask, 5.3 g (19.68 mmol, 1.0 eq.) of compound 4, 53.0 g of dichloromethane, and 3.6 g (35.43 mmol, 1.8 eq.) of triethylamine were added. The mixture was cooled to 5 °C, and 4.1 g (35.43 mmol, 1.8 eq.) of methanesulfonyl chloride was added dropwise. The mixture was kept at this temperature for 3 h, and then 14.0 g (78.74 mmol, 4.0 eq.) of 30% sodium methoxide solution was added dropwise. After the addition was complete, the mixture was kept at this temperature for 1 h, and then quenched with 5% ammonium chloride solution. The mixture was separated, and the organic phase was collected and concentrated to dryness to obtain 3.5 g of compound 4-1 with an ee value greater than 98%.
[0113] Example 9 Preparation of Compound 4-2
[0114] In a 100 ml three-necked flask, 12.5 g of acetonitrile, 2.2 g of sodium iodide (15.0 mmol, 1.5 eq.), 0.7 g of lithium hydroxide (25.0 mmol, 2.5 eq.), and 3.0 g of 4-methylenepiperidine hydrochloride (25.0 mmol, 2.5 eq.) were stirred for 0.5 h. Then, 2.5 g (10.0 mmol, 1.0 eq.) of compound 4-1 was added. After the addition was complete, the mixture was heated to reflux and reacted for 15 h. Purified water was added, and the organic phase was collected and concentrated to dryness to obtain an oily substance. The obtained oily substance was recrystallized from isopropanol / purified water to obtain 2.0 g of compound 4-2 with an ee value greater than 98%.
[0115] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all possible implementations here. All obvious variations or modifications derived from the technical solutions of this invention are still within the scope of protection of this invention.
Claims
1. A method for preparing an intermediate of ivermectin R,S diastereomers, characterized in that, Includes the following steps: Compound 1 was oxidized in a reaction solvent in the presence of an oxidizing agent to obtain compound 1-L; 2. The preparation method according to claim 1, characterized in that, The oxidation reaction is either an IBX oxidation reaction or a TEMPO oxidation reaction.
3. The preparation method according to claim 2, characterized in that, When the oxidation reaction is an IBX oxidation reaction, the reaction temperature is 0–40°C, and the reaction solvent includes one or more of N,N-dimethylformamide, dimethyl sulfoxide, chloroform, toluene, and acetonitrile. When the oxidation reaction is a TEMPO oxidation reaction, the reaction temperature is -10–40°C, and the reaction solvent includes one or more of dichloromethane / purified water, ethyl acetate / purified water, diethyl ether / purified water, and acetonitrile / purified water.
4. The preparation method according to claim 2, characterized in that, When the oxidation reaction is an IBX oxidation reaction, the oxidant includes 2-iodobenzoic acid; when the oxidation reaction is a TEMPO oxidation reaction, the oxidant includes sodium hypochlorite.
5. The preparation method according to claim 2, characterized in that, When the oxidation reaction is a TEMPO oxidation reaction, a catalyst is also used, which includes 2,2,6,6-tetramethylpiperidine oxide and potassium bromide.
6. A method for preparing an intermediate of ivermectin R,S diastereomers, characterized in that, Includes the following steps: Compound 1-L was reduced in a reaction solvent in the presence of a reducing agent to obtain compound 4; 7. The preparation method according to claim 6, characterized in that, The reaction temperature is -10 to 30°C.
8. The preparation method according to claim 6, characterized in that, The reducing agent includes one or more of sodium borohydride, lithium aluminum hydride, lithium borohydride, potassium borohydride, DIBAL-H, and BH3 / THF complex. The molar ratio of the reducing agent to compound 1-L is 0.5 to 3.
0.
9. The preparation method according to claim 6, characterized in that, The reaction solvent includes one or more of ethanol, isopropanol, tert-butanol, tetrahydrofuran, dichloromethane, chloroform, and toluene.
10. The preparation method according to claim 6, characterized in that, After the reduction reaction is complete, post-processing is performed, which includes: quenching the reaction, filtering and concentrating to obtain crude compound 4, separating and purifying the crude product using a reverse column chromatography system, concentrating the purified eluent, extracting after complete concentration, collecting the organic phase and concentrating it to dryness.
11. A method for preparing the R,S diastereomer of ivermectin, characterized in that, Includes the following steps: Step 1: Compound 4 undergoes an intramolecular dehydration cyclization reaction in the reaction solvent in the presence of an acid-binding agent and an activator. After the reaction is complete, post-treatment is performed, which includes: quenching the reaction, extraction and separation, and collection and concentration of the organic phase to obtain compound 4-1. Step 2: Compound 4-1 undergoes a nucleophilic addition reaction with 4-methylenepiperidine hydrochloride in a reaction solvent in the presence of a catalyst. After the reaction is complete, post-treatment is performed, which includes: quenching the reaction, extraction and separation, collection and concentration of the organic phase, and recrystallization of the resulting oil to obtain compound 4-2. In step one, the reaction solvent includes one or more of dichloromethane, chloroform, and toluene; the acid-binding agent includes one or more of triethylamine, N,N-diisopropylethylamine, and pyridine; and the activator includes one or more of methanesulfonyl chloride and p-toluenesulfonyl chloride. In step two, the reaction solvent includes one or more of acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran; the acid-binding agent includes one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide; and the catalyst includes one or more of sodium iodide, potassium iodide, cuprous iodide, and cesium iodide.
12. A method for preparing the R,S diastereomer of ivermectin, characterized in that, Includes the following steps: Step 1: Compound 1 is prepared by IBX oxidation or TEMPO oxidation in a reaction solvent at a reaction temperature of -10 to 40°C in the presence of an oxidant or oxidant / catalyst to obtain compound 1-L. Step 2: Compound 1-L undergoes a reduction reaction in the reaction solvent at a reaction temperature of -10 to 30°C in the presence of a reducing agent. After the reaction is complete, post-processing is performed, which includes: quenching the reaction, filtering and concentrating to obtain crude compound 4, and separating compound 3 from crude compound 4 using a reverse column chromatography system. Step 3: Compound 4 undergoes an intramolecular dehydration cyclization reaction in a reaction solvent at a reaction temperature of -10 to 30°C in the presence of an acid-binding agent and an activator. After the reaction is complete, post-treatment is performed, which includes: quenching the reaction, extraction and separation, and collection and concentration of the organic phase to obtain compound 4-1. Step 4: Compound 4-1 undergoes a nucleophilic addition reaction with 4-methylenepiperidine hydrochloride in a reaction solvent at a reaction temperature of 65-85°C in the presence of a catalyst. After the reaction is complete, post-treatment is performed, which includes: quenching the reaction, extraction and separation, collection and concentration of the organic phase, and recrystallization of the resulting oil to obtain compound 4-2.