Synthesis method of iremifungin intermediate
Through a simplified four-step reaction route, the use of titanate and other reagents to synthesize irefenin intermediates, the problems of high cost and cumbersome steps in the existing technology are solved, and cost-effective synthesis and separation and purification are achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510562451.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-30
- Publication Date
- 2025-07-04
AI Technical Summary
In the prior art, the synthesis method of irefenin intermediate has problems such as high cost, complicated steps or the use of precious metal catalysts, making it difficult to achieve cost-effective and efficient industrial production.
The four-step reaction route was adopted, using condensation reagents such as titanate, sulfide reagent, deprotection reagent and Ts protection reagent, and through the conversion of compounds 1 and 2, an optically pure (R)-2-(tert-butyl)-2-methyl-1-tosylaziridine intermediate was generated, avoiding the use of high-priced raw materials and precious metal catalysts, and gentle reaction conditions and simple separation and purification methods were used.
It realizes simple and efficient synthesis of irefenin intermediates, reduces synthesis costs, simplifies the separation and purification process, and is easy to achieve industrial production, providing an economical and reliable technical solution for stable supply.
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Figure CN120247761A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing an aerefungin intermediate. Background Art
[0002] A variety of factors have led to a continuous increase in the incidence of invasive fungal infections in clinical practice. For example, excessive use of chemotherapy or radiotherapy in the treatment of various diseases has damaged or defective the body's immune function, thereby increasing the risk of fungal infection. Invasive fungal infection refers to the invasion of fungi into the body, attacking various tissues, organs and blood systems, causing severe inflammatory reactions and tissue damage in patients. At present, the development of new drugs against invasive fungal infections is far from meeting the needs of clinical treatment. For more than two decades, the safe and effective varieties used in clinical practice have mainly been three types of drugs, namely triazoles, polyenes and echinocandin. However, due to factors such as drug resistance and adverse reactions, the development of new antifungal drugs is imminent.
[0003] As a new generation of triterpenoid antifungal drug with a new mechanism of action, Arifungin targets β-1,3-glucan synthase and directly kills fungal cells by destroying the intact cell wall of the fungus.
[0004] As a key intermediate of arifungin, the reliable, efficient and economical synthesis of (R)-2-(tert-butyl)-2-methyl-1-tosylaziridine is of great significance for stable clinical supply.
[0005] Figure 1 The synthetic route shown is to react 2,2,3-trimethylbut-1-ene with chloramine T and phenyltrimethylammonium tribromide in acetonitrile to obtain a product, but this method can only obtain a racemate, and cannot obtain an optically pure (R)-2-(tert-butyl)-2-methyl-1-tosylaziridine intermediate.
[0006] There are two main methods for synthesizing optically pure (R)-2-(tert-butyl)-2-methyl-1-tosylaziridine. Figure 2 As shown, it mainly includes the following three steps: pinacolone and (R)-toluenesulfenamide are dehydrated and condensed under the catalysis of tetraethyl titanate, followed by reaction with sulfur ylide to form N-heterocyclopropane intermediate, which is then oxidized to obtain the target product. Although this route has simple steps and good conversion rates in each step, the cost of commercial (R)-toluenesulfenamide raw materials is relatively high and is not suitable for industrial production.
[0007] Another synthetic method of optically pure (R)-2-(tert-butyl)-2-methyl-1-tosylaziridine is as follows Figure 3 As shown. Although the starting materials of this route are cheap and easily available, the synthetic steps are long and a precious metal catalyst is required, resulting in a high synthesis cost. Summary of the Invention
[0008] In view of the deficiencies of the prior art, the present invention provides a synthetic method of an efinaconazole intermediate. The object of the present invention is to provide a reliable, efficient and economical synthetic method of the efinaconazole intermediate (R)-2-(tert-butyl)-2-methyl-1-tosylaziridine.
[0009] The present invention provides a synthetic method of an efinaconazole intermediate, adopting the following synthetic route:
[0010]
[0011] Including the following steps:
[0012] Step 1: Compound 1 and Compound 2 are converted into Compound 3 under the action of a condensation reagent;
[0013] Step 2: Compound 3 is converted into Compound 4 under the action of a sulfur ylide reagent;
[0014] Step 3: Compound 4 is converted into Compound 5 under the action of a deprotection reagent;
[0015] Step 4: Compound 5 is converted into Compound 6 under the action of a Ts protection reagent, namely the efinaconazole intermediate.
[0016] Advantages of the Present Invention
[0017] The synthetic route of this method is concise. The synthesis of the efinaconazole intermediate can be completed only through four-step reactions, which is more economical and efficient compared with some existing methods that require multiple-step reactions or use precious metal catalysts; the starting materials used are all commercial materials, with relatively low costs, avoiding the use of high-cost raw materials such as (R)-p-toluenesulfinamide, and reducing the synthesis cost from the source; harsh reaction conditions are not required during the synthesis process, the reaction temperature is mild, solvents can be used, separation and purification are simple, and large-scale production is easy to achieve, providing an economical and reliable technical solution support for the stable clinical supply of efinaconazole.
[0018] In addition, the reaction yield and product purity can be further improved by optimizing the dosage of the condensation reagent, the type of sulfur ylide reagent, and the deprotection / protection conditions. Brief Description of the Drawings
[0019] Figure 1The present invention is a route map for synthesizing racemic intermediates in the prior art.
[0020] Figure 2 The invention provides a route map for synthesizing optically pure erefungin intermediates in the prior art.
[0021] Figure 3 The invention provides another route for synthesizing optically pure erefungin intermediates in the prior art.
[0022] Figure 4 The present invention provides a route for synthesizing an optically pure etefungin intermediate.
[0023] Figure 5 This is the 1H NMR spectrum (400 MHz, DMSO) of compound 3 (condensation reaction product) in Example 1.
[0024] Figure 6 This is the 1H NMR spectrum (400 MHz, DMSO) of compound 4 (sulfur ylide reaction product) in Example 1.
[0025] Figure 7 1H NMR spectrum (400 MHz, DMSO) of compound 5 (deprotection reaction product) in Example 1.
[0026] Figure 8 1H NMR spectrum (400 MHz, DMSO) of the target product compound 6 (arifungin intermediate) in Example 1. DETAILED DESCRIPTION
[0027] The present invention provides a method for synthesizing an intermediate of Arifungin, using the following synthetic route:
[0028]
[0029] The following steps are involved:
[0030] Step 1: Compound 1 and compound 2 are converted into compound 3 under the action of a condensation reagent;
[0031] Step 2: Compound 3 is converted into compound 4 under the action of a sulfur ylide reagent;
[0032] Step 3: Compound 4 is converted into compound 5 under the action of a deprotecting agent;
[0033] Step 4: Compound 5 is converted into compound 6, i.e. the said erefungin intermediate, under the action of a Ts protecting agent.
[0034] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 1, the condensation reagent is a titanate, such as tetraethyl titanate, tetraisopropyl titanate, etc.
[0035] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 1, the amount of the condensation reagent used is 1.0-1.5 equivalents of the molar amount of compound 2.
[0036] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 1, the condensation reaction temperature is 60-80° C., and the solvent is ethylene dichloride.
[0037] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 1, the reaction is quenched with water after sufficient condensation reaction, and after quenching, diatomaceous earth filtration and PE / EA=3:1 to 5:1 column chromatography are used to separate and purify to obtain compound 3.
[0038] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 1, the condensation reagent is tetraethyl titanate; the molar ratio of compound 1 pinacolone: compound 2 tert-butylsulfenamide: titanate is 1.2:1:1.2.
[0039] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 2, the sulfur ylide reagent is selected from: trimethyl sulfoxide chloride, trimethyl sulfoxide iodide, and trimethyl coronium iodide.
[0040] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 2, the deprotonation effect of an organic lithium reagent is used to promote the formation of a sulfur ylide intermediate.
[0041] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 2, the organic lithium reagent is selected to be n-butyl lithium, and the amount used is 2.5-3.5 equivalents of the molar amount of compound 3.
[0042] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 2, the solvent for the reaction is tetrahydrofuran.
[0043] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 2, the reaction is carried out in stages at 0°C to room temperature. After sufficient reaction, compound 4 is obtained by quenching, extraction and column chromatography purification. The purification adopts PE / EA=7:1 to 10:1 column chromatography.
[0044] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 3, the deprotection reagent is an alcohol solution of an acid.
[0045] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 3, the acid used as the deprotection reagent is selected from: hydrochloric acid, hydrobromic acid, and hydroiodic acid; the alcohol used as the deprotection reagent is selected from: methanol, ethanol, and propanol.
[0046] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 3, after sufficient deprotection reaction under acidic conditions, compound 4 is obtained by quenching, neutralization, extraction and column chromatography.
[0047] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 4, the Ts protecting reagent is TsCl.
[0048] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 4, compound 5 is converted into compound 6 under the action of a Ts protecting agent and under alkaline conditions; the raw material providing the alkalinity is selected from: triethylamine and diisopropylethylamine.
[0049] As a further optimization scheme for the synthesis of the intermediate of Arifungin, in step 4, the amount of the Ts protecting agent used is 1.8-2.2 equivalents of the molar amount of compound 5.
[0050] As a further optimization scheme for the synthesis method of the intermediate of Arifungin, in step 4, the alkaline catalyst is a combination of triethylamine and DMAP, the amount of triethylamine used is 3.0 equivalents, and the amount of DMAP used is 0.2 equivalents.
[0051] The present invention is further illustrated by specific examples below. The examples are exemplary and are intended to illustrate the problem and explain the present invention, but are not intended to be limiting.
[0052] Example 1
[0053] like Figure 4 As shown, the following steps are included.
[0054] Step 1: Add compound 1 (24g, 240mmol, 1.2eq) and compound 2 (24.24g, 200mmol, 1.0eq) to a 1L reaction bottle, and add 500ml DCE to dissolve. Slowly add tetraethyl titanate (54.75g, 240mmol, 1.2eq) under nitrogen protection, and heat to 70°C for reaction after addition. After the reaction is no longer converted, add water to quench the reaction, and a large amount of colloidal solids appear. Filter with diatomaceous earth, separate the filtrate, extract the aqueous phase with DCM, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and column chromatography, PE / EA=4:1 column chromatography to obtain yellow oily liquid compound 3, 34.57g, yield 85%. 1 H NMR (400MHz, DMSO) δ2.28(s,3H),1.15(s,9H),1.13(s,9H). 1 H NMR spectrum Figure 5 shown.
[0055] Step 2: In a 1 L reaction flask, add trimethylsulfoxonium chloride (31.31 g, 243.8 mmol, 3.0 eq), and dissolve it in 200 mL of THF. Cool to 0 °C, and slowly add n-butyllithium (97.4 mL, 243.43 mmol, 3.0 eq). After the addition is complete, react at 0 °C for half an hour. Subsequently, slowly add a THF solution of compound 3 (16.5 g in 40 mL THF, 81.14 mmol, 1.0). After the addition is complete, react at 0 °C for 3 hours, and then raise the temperature to room temperature and react overnight. After the reaction is complete, quench with saturated ammonium chloride solution, extract with EA, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and perform column chromatography with PE / EA = 8:1 to obtain the product (compound 4). The product is a colorless oily liquid, 14.5 g, with a yield of 82%. 1 H NMR (400 MHz, DMSO) δ 2.07 (s, 1H), 2.03 (s, 1H), 1.28 (s, 3H), 1.16 (s, 9H), 0.90 (s, 9H). 1 The H NMR spectrum is as Figure 6 shown.
[0056] Step 3: In a 25 mL reaction flask, add compound 4 (435 mg, 2.0 mmol, 1.0 eq), and cool to 0 °C. Add HCl ethanol solution (2.5 mL, 4 M, 10.0 mmol, 5.0 eq), and slowly raise the temperature to room temperature after the addition. TLC shows that the reaction is complete. Quench with saturated sodium bicarbonate solution, adjust the pH to 8, distill off ethanol under reduced pressure, extract with DCM, dry, concentrate, and perform column chromatography. Column chromatography on an EA column gives a white solid (compound 5), 170 mg, with a yield of 75%. 1 H NMR (400 MHz, DMSO) δ 7.47 (s, 1H), 3.50 (d, J = 9.1 Hz, 1H), 3.01 (d, J = 9.1 Hz, 1H), 1.31 (s, 3H), 0.91 (s, 9H). 1 The H NMR spectrum is as Figure 7 shown.
[0057] Step 4: In a 25 mL reaction flask, add compound 5 (113 mg, 1.0 mmol, 1.0 eq) under nitrogen protection, and dissolve it in 2 mL of DCM. Add triethylamine (303 mg, 3.0 mmol, 3.0 eq), DMAP (24 mg, 0.2 mmol, 0.2 eq), and stir evenly at room temperature. Add p-toluenesulfonyl chloride (381 mg, 2.0 mmol, 2.0 eq), react at room temperature, and monitor the reaction by TLC. After the reaction is complete, filter, concentrate the filtrate, and perform column chromatography. Column chromatography with PE / EA = 30:1 gives the target product, a colorless oily liquid that turns into a white solid after standing for a long time (compound 6, the target product), 240 mg, with a yield of 90%.1 1H NMR (400 MHz, DMSO) δ 7.79 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 2.50 (s, 1H), 2.47 (s, 1H), 2.42 (s, 3H), 1.62 (s, 3H), 0.88 (s, 9H). 1 The 1H NMR spectrum is as Figure 8 shown below.
[0058] The above embodiments are exemplary, aiming to illustrate the technical concept and features of the present invention, so that those skilled in this field can understand the content of the present invention and implement it accordingly. However, the protection scope of the present invention cannot be limited thereby. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.
Claims
1. A method for synthesizing an efinaconazole intermediate, characterized in that, The following synthetic route is adopted: It includes the following steps: Step 1: Compound 1 and Compound 2 are converted into Compound 3 under the action of a condensation reagent; Step 2: Compound 3 is converted into Compound 4 under the action of a sulfur ylide reagent; Step 3: Compound 4 is converted into Compound 5 under the action of a deprotection reagent; Step 4: Compound 5 is converted into Compound 6, namely the anidulafungin intermediate, under the action of a Ts protection reagent.
2. The synthesis method of the efinaconazole intermediate according to claim 1, characterized in that, In Step 1, the condensation reagent is a titanate.
3. The synthesis method of the efinaconazole intermediate according to claim 2, wherein, In Step 1, the dosage of the condensation reagent is 1.0 - 1.5 equivalents of the molar amount of Compound 2.
4. The synthesis method of the efinaconazole intermediate according to claim 1, wherein, In Step 2, the sulfur ylide reagent is selected from: trimethylsulfoxonium chloride, trimethylsulfoxonium iodide, trimethylsulfonium iodide.
5. The synthesis method of the efinaconazole intermediate according to claim 4, characterized in that, In Step 2, the deprotonation of an organolithium reagent is used to promote the formation of the sulfur ylide intermediate; the dosage of the organolithium reagent is 2.5 - 3.5 equivalents of the molar amount of Compound 3.
6. The synthesis method of the efinaconazole intermediate according to claim 1, wherein, In Step 3, the deprotection reagent is an alcoholic solution of an acid.
7. The synthesis method of the efinaconazole intermediate according to claim 6, wherein, In Step 3, the acid used in the deprotection reagent is selected from: hydrochloric acid, hydrobromic acid, hydroiodic acid; the alcohol used in the deprotection reagent is selected from: methanol, ethanol, propanol.
8. The synthesis method of the efinaconazole intermediate according to claim 1, wherein, In Step 4, the Ts protection reagent is TsCl.
9. The synthesis method of the efinaconazole intermediate according to claim 8, characterized in that, In Step 4, Compound 5 is converted into Compound 6 under the action of the Ts protection reagent and under basic conditions; the raw materials providing the alkalinity are selected from: triethylamine, diisopropylethylamine.
10. The synthesis method of the efinaconazole intermediate according to claim 9, characterized in that, In Step 4, the dosage of the Ts protection reagent is 1.8 - 2.2 equivalents of the molar amount of Compound 5.