Iridium-based catalyst, preparation method thereof and application of iridium-based catalyst in preparation of deuterium-labeled voriconazole

Abstract

The invention discloses an iridium catalyst, a preparation method thereof and application of the iridium catalyst in preparation of deuterium-labeled voriconazole, and belongs to the technical field of catalysts. The structure of the iridium catalyst is innovatively improved, that is, large-steric-hindrance 1, 2, 4-tri (2, 6-diisopropylphenyl)-1, 2, 3-triazole carbene is used as a ligand, and meanwhile, traditional monodentate coordinated chloride ions of anions are changed into bidentate coordinated acetate, so that the obtained catalyst can catalyze voriconazole to carry out hydrogen-deuterium exchange reaction. When the catalyst disclosed by the invention catalyzes a hydrogen-deuterium exchange reaction, only heterocycle of the reaction is obviously different from the hydrogen-deuterium exchange reaction of an iridium catalyst reported in the prior art, which mainly occurs on a benzene ring, four deuterium atoms can be simultaneously introduced into the heterocycle of voriconazole, and meanwhile, the deuteration rate exceeds 98%, so that the requirement of quantitative analysis is met.

Description

Technical Field

[0001] The present invention belongs to the technical field of catalysts, and particularly relates to an iridium-based catalyst, a preparation method thereof, and an application thereof in the preparation of deuterium-labeled voriconazole. Background Art

[0002] Voriconazole tablets are a broad-spectrum triazole antifungal drug, and its indications are as follows: treating invasive aspergillosis; treating severe invasive infections caused by Candida resistant to fluconazole (including Candida krusei); treating severe infections caused by Scedosporium apiospermum and Fusarium spp.

[0003] Isotope dilution mass spectrometry based on deuterium-labeled compounds has been widely used in quantitative analysis. It is less affected by matrix effects and has the advantages of fast speed, high accuracy, high sensitivity, and good repeatability. Therefore, it plays an important role in the fields of analytical chemistry, biology, pharmacy, medicine, etc. In the fields related to biomedicine, it can be applied to the quantitative analysis of drugs and biomarkers. In addition, by deuterating drugs and combining them with mass spectrometry, data can be obtained and analyzed quickly, which makes this technology widely used in the research of the absorption, distribution, metabolism, and excretion (ADME) processes of drugs in the body. In these quantitative analysis processes, the deuterium-labeled drug molecules usually used need to contain 3 or more deuterium atoms and have a high deuteration rate.

[0004] In order to comprehensively analyze and study the clinical, pharmacological, pharmacokinetic, and toxicological properties of voriconazole, it is very necessary to design and develop a synthesis method of deuterium-labeled voriconazole on the basis of the existing technology, so as to provide a reference substance for the comprehensive analysis of the clinical, pharmacological, pharmacokinetic, and toxicological properties of voriconazole and the research and development of new drugs. US20090062310 A1 reports various deuterium-labeled voriconazoles obtained based on chemical synthesis methods. In this patent, deuterated aromatic hydrocarbons are used as deuterated substances, and through multiple chemical reactions, deuterium-labeled voriconazole is obtained. However, this synthesis strategy has many reaction steps, resulting in low yield and high cost.

[0005] In recent years, the hydrogen-deuterium exchange reaction has received increasing attention in the synthesis of deuterated compounds. The hydrogen-deuterium exchange method utilizes the exchange of active hydrogen in a compound with active deuterium in deuterated solvent molecules or other deuterium sources to synthesize deuterium-labeled compounds. Using the hydrogen-deuterium exchange method, the target drug molecule or precursor can be directly used as the starting material, and the deuterium-labeled target drug molecule can be rapidly constructed through a one-step reaction. Usually, only inexpensive deuterium sources are required during the reaction, and the deuterated sites are diverse. For example, Kerr et al. used N-heterocyclic carbene-cyclooctadiene-iridium(I) chloride as a catalyst to achieve the hydrogen-deuterium exchange reaction at the ortho position of various substrates (such as nitrobenzene, acetophenone, benzaldehyde, sulfonamide, etc.). The research group of Yan Xiaoyu used 1,2,3-triazole carbene-cyclooctadiene-iridium(I) chloride as a catalyst to achieve the hydrogen-deuterium exchange reaction at the ortho position of aniline and phenol. However, there are still relatively few reports on the direct hydrogen-deuterium exchange reaction of drug molecules using the currently developed catalysts. The main problems are as follows: 1. The functional group compatibility of the catalyst is not ideal, and the reaction is not good when there are multiple functional groups in complex drug molecules. 2. The currently reported reactions are usually for the ortho position of benzene ring functional groups, and usually 2 deuterium atoms can be introduced, which does not meet the requirement that the deuterium-labeled drug molecules for quantitative analysis need to contain 3 or more deuterium atoms. 3. In some cases, more than 3 deuterium atoms can be introduced, but the deuteration rate decreases significantly, unable to meet the requirements of quantitative analysis. 4. The reaction usually occurs on the benzene ring, and there is less research on the reaction of heterocycles. Summary of the Invention

[0006] In view of the above-mentioned prior art, the present invention provides an iridium-based catalyst, its preparation method and its application in the preparation of deuterium-labeled voriconazole to solve the technical problem that the existing catalysts cannot introduce multiple deuterium atoms into the azole heterocycle of voriconazole.

[0007] To achieve the above object, the technical solution adopted by the present invention is to provide an iridium-based catalyst, and the structural formula of the iridium-based catalyst is shown in Formula I. , wherein Dipp is 2,6-diisopropylphenyl; COD is 1,5-cyclooctadiene ligand.

[0008] The present invention also discloses a preparation method of the above-mentioned iridium-based catalyst, including the following steps: S1: Add 1,2,4-tris(2,6-diisopropylphenyl)-1,2,3-triazolium salt and potassium bis(trimethylsilyl)amide into a reaction vessel, cool to -75~-80 °C in an inert atmosphere, then add a first solvent to dissolve, and keep stirring for reaction for 45~90 min; then raise the temperature to room temperature, remove the solvent and purify to obtain a first intermediate. S2: Co - dissolve the first intermediate and [IrCl(COD)]2 in a second solvent, stir and react at room temperature for 10 - 16 h, collect the product and purify it to obtain the second intermediate; S3: Co - dissolve the second intermediate and an equimolar amount of silver acetate in a third solvent, stir overnight at room temperature, then collect the product and purify it to obtain the target product.

[0009] Based on the above - mentioned technical solutions, the present invention can be further improved as follows.

[0010] Further, the material ratio of 1,2,4 - tris(2,6 - diisopropylphenyl)-1,2,3 - triazolium salt, potassium bis(trimethylsilyl)amide to the first solvent is 1 mmol: 1.1 mmol: 30 mL.

[0011] Further, the inert atmosphere is a nitrogen atmosphere; the first solvent is tetrahydrofuran; the final cooling temperature in S1 is - 78 °C, and the stirring reaction time is 1 h.

[0012] Further, the method for removing the solvent and purifying in S1 is as follows: evacuate the reaction system until the solvent completely volatilizes; then extract the obtained solid with toluene, collect the organic phase; and then evacuate the organic phase until the liquid completely volatilizes to obtain the first intermediate.

[0013] Further, the molar ratio of the dosage of [IrCl(COD)]2 to 1,2,4 - tris(2,6 - diisopropylphenyl)-1,2,3 - triazolium salt for preparing the first intermediate is 1:2; the material ratio of [IrCl(COD)]2 to the second solvent is 0.5 mmol: 20 mL.

[0014] Further, the second solvent is tetrahydrofuran; the purification method in S2 is column chromatography, and the eluent used for column chromatography is dichloromethane.

[0015] Further, the third solvent is dichloromethane; the purification method in S3 is column chromatography, and the eluent used for column chromatography is dichloromethane.

[0016] The present invention also discloses the application of the above - mentioned iridium - based catalyst in the preparation of deuterium - labeled voriconazole.

[0017] Further, the structural formula of deuterium - labeled voriconazole is shown as Formula II, , which is prepared through the following steps: Add voriconazole and the iridium - based catalyst into a reaction vessel, then add 2 - methylfuran to dissolve, and then replace the atmosphere in the reaction vessel with an atmospheric deuterium gas atmosphere, stir and react at 80 °C for 48 h, and then separate by column chromatography using ethyl acetate and petroleum ether as eluents to obtain the product.

[0018] The beneficial effects of the present invention are as follows: 1. By innovatively improving the structure of the iridium-based catalyst, that is, using 1,2,4-tris(2,6-diisopropylphenyl)-1,2,3-triazolium carbene with a large steric hindrance as a ligand, and at the same time changing the anion from the conventionally monodentate-coordinated chloride ion to the bidentate-coordinated acetate ion, the obtained catalyst can catalyze the hydrogen-deuterium exchange reaction of voriconazole.

[0019] 2. Through the structural improvement of the catalyst, the present invention overcomes the dependence of iridium catalysts on functional groups in the prior art.

[0020] 3. When the catalyst in the present invention catalyzes the hydrogen-deuterium exchange reaction, the reaction only occurs on the heterocycle and does not occur on the benzene ring, which is significantly different from the hydrogen-deuterium exchange reaction of iridium catalysts reported in the prior art that mainly occurs on the benzene ring.

[0021] 4. Using the iridium-based catalyst in the present invention to catalyze the hydrogen-deuterium exchange reaction of voriconazole, 4 deuterium atoms can be simultaneously introduced onto the heterocycle of voriconazole, and the deuteration rate exceeds 98%, meeting the requirements of quantitative analysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the preparation flow chart of the iridium-based catalyst; Figure 2 is the reaction equation for preparing deuterium-labeled voriconazole. DETAILED DESCRIPTION OF THE INVENTION

[0023] The following detailed description of the specific embodiments of the present invention will be given in conjunction with the examples.

[0024] Example 1 An iridium-based catalyst, whose structural formula is shown in Formula I, , where Dipp is 2,6-diisopropylphenyl; and COD is a 1,5-cyclooctadiene ligand.

[0025] The preparation process of the iridium-based catalyst in this example is as Figure 1 shown; the specific preparation method includes the following steps: S1: Add 1 mmol of 1,2,4-tris(2,6-diisopropylphenyl)-1,2,3-triazolium salt and 1.1 mmol of potassium bis(trimethylsilyl)amide into a clean and dry Schlenk flask, and displace the air in the Schlenk flask with nitrogen; then cool it to -78 °C, add 30 mL of anhydrous tetrahydrofuran, keep the temperature and stir for 60 min; then slowly warm it up to room temperature, evacuate the obtained reaction system until the solvent in the reaction system completely evaporates to obtain a white solid, then extract the white solid with toluene and filter, collect the organic phase, and then evacuate the organic phase until the liquid completely evaporates to obtain the first intermediate; S2: Weigh 0.5 mmol of [IrCl(COD)]2 in a glove box and add it to the first intermediate, then add 20 mL of anhydrous tetrahydrofuran, and stir at room temperature for 12 h; after the reaction, the product is purified by flash column chromatography with dichloromethane as the eluent to obtain a yellow solid (372 mg, 83%), which is the second intermediate; S3: Add an equimolar amount of silver acetate to the second intermediate, then add 5 mL of dichloromethane, and stir at room temperature overnight; after the reaction, the product is purified by flash column chromatography with dichloromethane as the eluent to obtain a yellow solid, which is the iridium-based catalyst with a yield of 92%.

[0026] The characterization results of the obtained iridium-based catalyst are as follows: 11H NMR (400 MHz, CDCl3) δ 7.48 - 7.36 (m, 5H), 7.33 (d, J = 7.7 Hz, 2H), 7.18 (d, J = 7.3 Hz, 2H), 7.09 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 4.9 Hz, 2H), 4.82 – 4.74 (m, 1H), 4.71 – 4.64 (m, 1H), 4.28 – 4.19 (m, 1H), 3.32 – 3.19 (m, 1H), 2.47 – 2.39 (m, 2H), 2.36 – 2.27 (m, 1H), 2.23 – 2.13 (m, 2H), 2.04 – 1.93 (m, 6H), 1.82 (d, J = 6.6 Hz, 3H), 1.64 – 1.56 (m, 1H), 1.34 (s, 3H), 1.31 – 1.21 (m, 11H), 1.20 – 1.15 (m, 6H), 1.03 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.90 – 0.81 (m, 2H), 0.23 (d, J = 6.5 Hz, 3H), 0.06 (d, J = 4.1 Hz, 3H). 13 13C NMR (151 MHz, CDCl3) δ 177.6, 171.7, 151.1, 147.6, 146.9, 146.7, 145.4, 144.8, 144.6, 135.7, 132.2, 131.3, 130.4, 130.3, 126.0, 125.9, 125.8, 124.9, 124.1, 123.8, 123.6, 81.9, 79.9, 53.6, 34.0, 31.9, 31.3, 30.8, 29.9, 29.9, 29.8, 29.7, 29.5, 28.5, 28.4, 26.4, 25.5, 25.2, 24.8, 24.2, 23.8, 23.70, 23.6, 23.2, 22.1, 21.7. Example 2 Using the iridium-based catalyst in Example 1 to catalyze voriconazole for hydrogen-deuterium exchange reaction to prepare deuterium-labeled voriconazole, the reaction equation is as follows Figure 2As shown below. Specifically, it includes the following steps: Add a clean magnetic stir bar of appropriate size to a dry 25 mL reaction tube. Subsequently, weigh 0.1 mmol of voriconazole and 0.01 mmol of the iridium-based catalyst prepared in Example 1 and add them to the reaction tube. Then, add 1 mL of 2-methylfuran as the reaction solvent to the reaction tube, and replace the air in the reaction tube with an atmosphere of normal pressure deuterium gas. Subsequently, seal the reaction tube. Heat the reaction tube to 80 °C and react at this temperature for 48 hours. After the reaction is completed, separate the mixture by column chromatography using ethyl acetate and petroleum ether as eluents to obtain the target product (voriconazole-D4). The yield is 91%, and the deuteration rate is confirmed to be >98% by 1H NMR.

[0027] The characterization results of the obtained deuterium-labeled voriconazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.59 – 7.46 (m, 1H), 6.77 (m,2H), 6.43 (s, 1H), 4.66 (d, J = 13.9 Hz, 1H), 4.26 (d, J = 13.9 Hz, 1H), 4.07 (q, J = 6.8 Hz, 1H), 1.04 (d, J = 6.9 Hz, 3H). Although the specific embodiments of the present invention have been described in detail in conjunction with the examples, it should not be construed as a limitation on the protection scope of this patent. Within the scope described in the claims, various modifications and deformations that can be made by those skilled in the art without creative efforts still fall within the protection scope of this patent.

Claims

1. An iridium-based catalyst, characterized in that: The structural formula of the iridium-based catalyst is shown in Formula I, ， wherein Dipp is 2,6-diisopropylphenyl; COD is 1,5-cyclooctadiene ligand.

2. The preparation method of the iridium-based catalyst according to claim 1, characterized in that, It includes the following steps: S1: Add 1,2,4-tris(2,6-diisopropylphenyl)-1,2,3-triazolium salt and potassium bis(trimethylsilyl)amide into a reaction vessel, cool to -75~-80 °C in an inert atmosphere, then add a first solvent to dissolve, and keep stirring for reaction for 45~90 min; subsequently, raise the temperature to room temperature, then remove the solvent and purify to obtain a first intermediate; S2: Co-dissolve the first intermediate and [IrCl(COD)]2 in a second solvent, stir and react at room temperature for 10~16 h, collect the product and purify to obtain a second intermediate; S3: Co-dissolve the second intermediate and an equimolar amount of silver acetate in a third solvent, stir overnight at room temperature, then collect the product and purify to obtain the target product.

3. The preparation method according to claim 2, wherein: The material ratio of 1,2,4-tris(2,6-diisopropylphenyl)-1,2,3-triazolium salt, potassium bis(trimethylsilyl)amide to the first solvent is 1 mmol: 1.1 mmol: 30 mL.

4. The preparation method according to claim 3, characterized in that: The inert atmosphere is a nitrogen atmosphere; the first solvent is tetrahydrofuran; the final cooling temperature in S1 is -78 °C, and the stirring reaction time is 1 h.

5. The preparation method according to claim 2, characterized in that, The method for removing the solvent and purifying in S1 is: evacuate the reaction system until the solvent completely volatilizes; then extract the obtained solid with toluene, collect the organic phase; then evacuate the organic phase until the liquid completely volatilizes to obtain the first intermediate.

6. The preparation method according to claim 2, wherein: The molar ratio of the amount of [IrCl(COD)]2 used to 1,2,4-tris(2,6-diisopropylphenyl)-1,2,3-triazolium salt for preparing the first intermediate is 1:2; the material ratio of [IrCl(COD)]2 to the second solvent is 0.5 mmol: 20 mL.

7. The preparation method according to claim 6, characterized in that: The second solvent is tetrahydrofuran; the purification method in S2 is column chromatography, and the eluent used for column chromatography is dichloromethane.

8. The preparation method according to claim 2, wherein: The third solvent is dichloromethane; the purification method in S3 is column chromatography, and the eluent used for column chromatography is dichloromethane.

9. Use of the iridium-based catalyst according to claim 1 in the preparation of deuterium-labeled voriconazole.

10. The application according to claim 9, wherein The structural formula of the deuterium-labeled voriconazole is shown in Formula II, ， which is prepared through the following steps: Add voriconazole and the iridium-based catalyst into a reaction vessel, then add 2-methylfuran to dissolve, and then replace the atmosphere in the reaction vessel with an atmosphere of normal pressure deuterium gas, stir and react at 80 °C for 48 h, and then separate by column chromatography using ethyl acetate and petroleum ether as eluents to obtain the product.

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