Synthesis method of deuterium-labeled ciclopirox glucuronic acid

Abstract

The invention discloses a synthetic method of deuterium-labeled ciclopirox glucuronic acid. The synthetic method comprises the following steps: (1) reacting a compound I with an acylating agent to obtain an acyl chloride intermediate for later use; suspending boron trifluoride diethyl etherate in an organic solvent, respectively dropwise adding 3, 3-methyl dimethacrylate and the acyl chloride intermediate, and carrying out Friedel-Crafts acylation reaction to obtain an intermediate product II; (2) reacting the intermediate product II with hydroxylamine hydrochloride to generate an intermediate product III; (3) reacting the intermediate product III with di-tert-butyl azodicarboxylate, triphenylphosphine and 2, 3, 4-tri-O-acetyl-A-D-glucuronic acid methyl ester to obtain an intermediate product IV; and (4) carrying out ester hydrolysis reaction on the intermediate product IV to obtain a final product V. The purity of the synthesized deuterium-labeled ciclopirox glucuronic acid can reach 96% or above, the deuterium abundance can reach 98.5% or above, a test sample is provided for research of ciclopirox, and the deuterium-labeled ciclopirox glucuronic acid has important research value in clinical pharmacokinetic research.

Description

Technical Field

[0001] The invention relates to a method for preparing a compound, in particular to a method for synthesizing deuterium-labeled ciclopirox glucuronic acid. Background Art

[0002] Ciclopirox is a new broad-spectrum topical antifungal drug. Its chemical name is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, also known as Ciclopirox and Ciclopirox. Its CAS number is 29342-05-0, EINECS number is 249-577-2, molecular formula is C12H17NO2, and molecular weight is 207.27 g / mol. The structural formula is:

[0003]

[0004] Ciclopirox is commonly used in its ethanolamine salt for the treatment of local fungal infections, mainly by changing the integrity of the fungal cell membrane, causing the outflow of intracellular substances, and blocking the uptake of protein precursors, leading to fungal cell death. It has strong antibacterial and bactericidal effects on dermatophytes, yeasts, molds, etc., and has strong permeability. It also has a certain inhibitory effect on various actinomycetes, Gram-positive and Gram-negative bacteria, mycoplasmas, chlamydia, Trichomonas, etc.

[0005] In recent years, ciclopirox has attracted increasing attention for its several new and promising pharmacological effects in the treatment of cancer and several other diseases. In the European Journal of Drug Metabolism and Pharmacokinetics, 2024, vol. 49, #5, p. 619–629, it is mentioned that the drug exhibits anticancer activity in a variety of different ways, including inhibition of cell proliferation, migration and invasion, induction of apoptosis, and inhibition of angiogenesis and lymphangiogenesis. At the same time, ciclopirox olamine can treat type I diabetes by inhibiting the hypnosis of eIF5A and relieving diabetic foot ulcers. In addition, ciclopirox olamine can block the replication of human immunodeficiency virus (HIV) at clinically relevant concentrations (10 μM).

[0006] However, other routes of administration are required for treating other diseases. Literature indicates that ciclopirox can undergo extensive glucuronidation in the human body, that is, it is converted into ciclopirox glucuronic acid. There are almost no literature reports on the synthesis of ciclopirox glucuronic acid, and it is still a technical gap in this field for the time being.

[0007] Deuterium is a non-radioactive isotope of hydrogen, with the symbol D. The isotopic abundance of deuterium in nature is about 0.016%. Deuterium-labeled compounds are stable isotope-labeled compounds, which are compounds in which hydrogen atoms or part of hydrogen atoms in the compound are replaced by deuterium atoms. Deuterium-labeled compounds play an irreplaceable role in biomedicine and drug metabolism and pharmacokinetics. For example, parameters of drug metabolism pathways, metabolic mechanisms, and kinetics can be obtained. Isotope labeling technology must be used in drug metabolism safety evaluation in new drug research.

[0008] Isotope dilution mass spectrometry (IDMS) uses a standard substance with a natural isotope composition as a reference diluent to calibrate the concentration of the concentrated isotope, and then uses the calibrated concentrated isotope as a diluent to measure unknown samples. The position, number, and abundance of the labeled atoms in the isotope-labeled compound have a relatively large impact on the expected sensitivity, and also on the accuracy and reliability of the test value. If the isotope abundance is not enough, the expected sensitivity will be poor, and the accuracy and reliability of the test value will be poor.

[0009] In order to conduct a comprehensive analysis and study on the clinical, pharmacological, pharmacokinetics and toxicology of ciclopirox, it is necessary to design and develop a synthesis method of deuterium-labeled ciclopirox glucuronic acid based on existing technologies, so as to provide a reference substance for the comprehensive analysis of the clinical, pharmacological, pharmacological, toxicological and new drug development of ciclopirox. Summary of the invention

[0010] Purpose of the invention: The present invention aims to provide a method for synthesizing high-abundance deuterium-labeled ciclopirox glucuronic acid.

[0011] Technical solution: The method for synthesizing deuterium-labeled ciclopirox glucuronic acid of the present invention comprises the following steps:

[0012] (1) Compound I is dissolved in tetrahydrofuran, an acylating agent and a catalyst are added, and an acylation reaction is performed to obtain an acyl chloride intermediate for use; boron trifluoride etherate is suspended in an organic solvent, and 3,3-dimethylacrylate and the acyl chloride intermediate are added dropwise, respectively, to undergo Friedel-Crafts acylation to obtain an intermediate II;

[0013] (2) taking the intermediate product II synthesized in step (1), dissolving it in methanol, adding hydroxylamine hydrochloride and a catalyst sodium acetate to react to generate an intermediate, and then adding an alkaline aqueous solution to generate an intermediate product III by a cyclization reaction;

[0014] (3) dissolving the intermediate product III obtained in step (2) in an organic solvent, adding di-tert-butyl azodicarboxylate, triphenylphosphine and 2,3,4-tri-O-acetyl-Α-D-glucuronic acid methyl ester, and reacting to obtain the intermediate product IV;

[0015] (4) The intermediate product IV obtained in step (3) is dissolved in methanol, lithium hydroxide is added, and an ester hydrolysis reaction is carried out to obtain the final product V. The synthetic route is as follows:

[0016]

[0017] Preferably, in step (1), the acylating agent is oxalyl chloride and the catalyst is N,N-dimethylformamide (DMF).

[0018] Preferably, in step (1), the acylation reaction is carried out at a temperature of 50 to 80° C. and for a time of 1 to 8 hours.

[0019] In step (1), after the acylation reaction is completed, the product is concentrated and dried to obtain an acyl chloride intermediate for later use.

[0020] Preferably, in step (1), the temperature of the Friedel-Crafts acylation reaction is 20 to 30° C. and the time is 8 to 24 hours.

[0021] Preferably, in step (1), the molar ratio of compound I to the acylating agent, boron trifluoride etherate and 3,3-methyl dimethacrylate is 1:1:1:1 to 1:1.1:2.6:1.

[0022] Preferably, in step (1), the organic solvent in which the boron trifluoride etherate is suspended is dichloromethane.

[0023] Preferably, step (1) further comprises purification after the reaction is completed. The purification method is as follows: pouring the reaction solution into ice water under an ice bath to remove most of tetrahydrofuran and dichloromethane, extracting with dichloromethane three times, combining the organic layers, drying with anhydrous sodium sulfate, filtering, and spin drying to obtain a crude product, and separating by column chromatography (the stationary phase is 200-300 mesh silica gel, and the mobile phase is petroleum ether and ethyl acetate in a volume ratio of 40:1) to obtain a yellow oil II.

[0024] Preferably, in step (2), the molar ratio of the intermediate product II to hydroxylamine hydrochloride, sodium acetate, and the base in the alkaline aqueous solution is 1:1:1:1 to 1:5:5:5, and further preferably, 1:1:1 to 1:3:3.2:3; the temperature of the reaction to generate the intermediate is 20 to 30°C, and the time is 6 to 30 hours; the temperature of the cyclization reaction is 20 to 30°C, and the time is 1.5 to 15 hours.

[0025] Preferably, after the reaction in step (2) is completed, purification is further included. The purification method is: adding water under ice bath, then spinning away most of the methanol, first extracting three times with methyl tert-butyl ether (washing away impurities), then adjusting the pH of the aqueous phase to 5-6 under ice bath, and continuing to extract three times with 50 mL of dichloromethane. After the organic layers are combined, they are dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which is further refined and purified.

[0026] The refining and purification method comprises the following steps: dissolving the crude product in ethyl acetate, adding ethanolamine to form a salt, and precipitating a solid ethanolamine salt product; filtering the solid and suspending it in water, adjusting the pH of the aqueous phase to 5-6 under an ice bath, extracting it three times with dichloromethane, combining the organic layers, drying them with anhydrous sodium sulfate, filtering them, and spinning them to obtain a pure product.

[0027] Preferably, in step (3), the molar ratio of the intermediate product III to di-tert-butyl azodicarboxylate, triphenylphosphine, and methyl 2,3,4-tri-O-acetyl-Α-D-glucuronide is 1:1:1:1 to 1:5:5:5, and more preferably, the molar ratio is 1:1:1:1 to 1:3:3:3. Di-tert-butyl azodicarboxylate is a catalyst, and triphenylphosphine is a ligand to form a complex with the hydroxyl group of the intermediate product III.

[0028] Preferably, in step (3), the organic solvent is tetrahydrofuran, the reaction temperature is 30 to 60° C., and the reaction is carried out for 12 to 24 hours.

[0029] Preferably, after the reaction in step (3) is completed, purification is further included. The purification method is: adding dichloromethane under an ice bath, then washing twice with a 0.5M HCl aqueous solution, then washing once with water, separating the organic layer, drying with anhydrous sodium sulfate, filtering, spin-drying, and then purifying by column chromatography (the stationary phase is 200-300 mesh silica gel, and the mobile phase is dichloromethane and methanol in a volume ratio of 40:1) to obtain a yellow solid IV.

[0030] Preferably, in step (4), the molar ratio of the intermediate product IV to lithium hydroxide is 1:1 to 1:10, and a further preferred molar ratio is 1:1 to 1:5; the reaction temperature is 0 to 35°C, and the reaction is carried out for 3 to 24 hours.

[0031] Preferably, step (4) further comprises purification after the reaction is completed, and the purification method is: the reaction solution is concentrated to dryness and then purified through a C18 column (the mobile phase is pure water) to obtain a light yellow solid compound V.

[0032] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The synthesis method is reasonably designed and highly operable, and the purity of the obtained deuterium-labeled ciclopirox glucuronic acid can reach more than 96%, and the deuterium abundance can reach more than 98.5%; (2) The reagents used in the synthesis method are simple and easy to obtain; (3) The deuterium-labeled ciclopirox glucuronic acid (Compound V) synthesized by the present invention provides a test sample for the study of ciclopirox, and has important research value in clinical pharmacokinetic research. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is the synthetic route of the present invention;

[0034] Figure 2 is the mass spectrum of compound II;

[0035] Figure 3 is the NMR spectrum of compound III;

[0036] Figure 4 is the mass spectrum of compound III;

[0037] Figure 5 is the NMR spectrum of compound Ⅳ;

[0038] Figure 6 is the mass spectrum of compound IV;

[0039] Figure 7 is the NMR spectrum of compound V;

[0040] Figure 8 is the mass spectrum of compound V;

[0041] Fig. 9 is the liquid phase spectrum of compound V;

[0042] Fig.10 This is the LC-MS spectrum of compound V. DETAILED DESCRIPTION

[0043] The technical solution of the present invention is further described below in conjunction with embodiments.

[0044] Example 1

[0045] The method for synthesizing deuterium-labeled ciclopirox glucuronic acid of the present invention comprises the following steps:

[0046] (1) Synthesis of Compound II

[0047] Dissolve 5.00g of compound I in 50mL of tetrahydrofuran, add 5.01g of oxalyl chloride and 0.1mL of catalytic amount of DMF under ice bath to obtain a yellow solution. Raise the temperature of the reaction solution to 80℃ for 1 hour, slowly return to 25℃ and continue to concentrate and dry to obtain the acyl chloride intermediate for use;

[0048] In an ice bath, 13.35 g of boron trifluoride ether was suspended in 50 mL of dichloromethane, and 4.10 g of 3,3-dimethylacrylate and the above-prepared acyl chloride intermediate were slowly added dropwise, and the temperature was controlled at 0-5 ° C during the addition process. After returning to 25 ° C, stirring was continued for 18 hours, and the reaction was completed. The reaction solution was poured into 180 mL of ice water under an ice bath, and most of the tetrahydrofuran and dichloromethane were spun off, and extracted three times with 80 mL of dichloromethane. After the organic layers were combined, they were dried with anhydrous sodium sulfate, filtered, and spun to dryness to obtain 9.7 g of crude product. Column chromatography (stationary phase is 200-300 mesh silica gel, mobile phase is petroleum ether and ethyl acetate volume ratio 40:1) was separated to obtain 6.18 g of yellow oil II, with a yield of 73.12%.

[0049] like Figure 2 The mass spectrum of compound II is [M+H] + :236.2.

[0050]

[0051] (2) Synthesis of Compound III

[0052] Take 6.18g of compound II and dissolve it in 27.8mL of methanol. Add 2.10g of hydroxylamine hydrochloride and 2.61g of sodium acetate under ice bath. After reacting at 25°C for 17 hours, slowly add sodium hydroxide aqueous solution (prepared with 2.10g of sodium hydroxide and 4.2mL of water) under ice bath. Continue to react at room temperature for 1.5 hours, and the reaction is completed. Add 100 mL of water under ice bath, spin away most of the methanol, first extract three times with 50 mL of methyl tert-butyl ether (to wash away impurities), then adjust the pH of the aqueous phase to 5-6 under ice bath, continue to extract three times with 50 mL of dichloromethane, combine the organic layers, dry them with anhydrous sodium sulfate, filter, and spin dry to obtain 7.5 g of crude product, continue to refine and purify, dissolve the crude product in ethyl acetate, add ethanolamine to form salt, and precipitate solid ethanolamine salt product; filter the solid and suspend it in water, adjust the pH of the aqueous phase to 5-6 under ice bath, extract three times with dichloromethane, combine the organic layers, dry them with anhydrous sodium sulfate, filter, and spin dry to obtain 4.25 g of pure light yellow solid III, with a yield of 74.13%. Figure 3 The H NMR data of compound III are: 1H NMR (400 MHz, DMSO-d6) δ 6.19 (s, 1H), 5.95 (s, 1H), 2.12 (s, 3H, CH3-H). Figure 4 The mass spectrum of compound III is [M+H] + :219.2.

[0053]

[0054] (3) Synthesis of Compound IV

[0055] Take 4.25g of compound III and dissolve it in 11.6mL of tetrahydrofuran. Add 4.93g of di-tert-butyl azodicarboxylate, 5.62g of triphenylphosphine and 6.51g of 2,3,4-tri-O-acetyl-Α-D-glucuronic acid methyl ester under ice bath. React at 30°C for 24 hours until the raw materials react. Add 300mL of dichloromethane under ice bath, then wash twice with 100mL of 0.5M HCl aqueous solution, then wash once with 100mL of aqueous solution. After separating the organic layer, dry it with anhydrous sodium sulfate, filter it, spin dry it, and purify it by column chromatography (the stationary phase is 200-300 mesh silica gel, and the mobile phase is dichloromethane and methanol volume ratio 40:1) to obtain 5.10g of yellow solid IV, with a yield of 49.01%. Figure 5 The H NMR data of compound IV are: 1H NMR (400MHz, CDCl3) δ6.24 (s, 1H), 5.77 (s, 1H), 5.48 (d, 1H), 5.41 (t, 1H), 5.23 (m, 2H), 3.97 (d, 1H), 3.70 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.04 (d, 6H). Figure 6 , the mass spectrum of compound IV is [M+H] + :535.2.

[0056]

[0057] (4) Synthesis of Compound V

[0058] 5.10 g of compound IV was dissolved in 51 mL of methanol, and 0.40 g of lithium hydroxide monohydrate was added under ice bath, and stirred at 35°C for 3 h until the raw materials reacted completely. The reaction solution was concentrated to dryness and purified by C18 column to obtain 2.57 g of light yellow solid compound V, with a yield of 67.28%. Figure 7 The H NMR data of compound V are: 1H NMR (400MHz, CDCl3) δ7.20 (br, 1H), 6.24 (s, 1H), 6.04 (s, 1H), 5.94 (br, 1H), 4.98 (br, 1H), 4.87 (d, 1H), 3.20 (m, 3H), 3.10 (m, 1H), 2.14 (s, 3H). Figure 8 The mass spectrum of compound V is [M-Li] - :393.2. Fig. 9 , the liquid phase purity of compound V is: 96.09%. Fig.10 The deuterium abundance of compound V was calculated to be 98.54% based on the LC-MS spectrum, with no d0.

[0059]

[0060] Example 2

[0061] The method for synthesizing deuterium-labeled ciclopirox glucuronic acid of the present invention comprises the following steps:

[0062] (1) Synthesis of Compound II

[0063] Dissolve 6.00 g of compound I in 90 mL of tetrahydrofuran, add 10.25 g of oxalyl chloride and 0.1 mL of DMF under ice bath, heat the reaction solution to 80°C for 8 hours, slowly return the temperature to 25°C, and continue concentrating and drying to obtain the acyl chloride intermediate for use.

[0064] In an ice bath, 13.46 g of boron trifluoride etherate was suspended in 90 mL of dichloromethane, and 5.41 g of 3,3-dimethylacrylate and the prepared acyl chloride intermediate were slowly added dropwise, and the dripping was completed in 20 minutes. The reaction temperature was controlled at 0-5 °C during the dripping process. After the dripping was completed, the temperature was restored to 25 °C and continued to stir for 8 hours, and the reaction was completed. The reaction solution was poured into 300 mL of ice water under an ice bath, and most of the tetrahydrofuran and dichloromethane were spun off, and extracted three times with 150 mL of dichloromethane. After the organic layers were combined, they were dried with anhydrous sodium sulfate, filtered, and spun dry to obtain 12.6 g of crude product. Column chromatography (the stationary phase was 200-300 mesh silica gel, and the mobile phase was petroleum ether and ethyl acetate in a volume ratio of 40:1) was used to separate 5.83 g of yellow oil II, with a yield of 57.48%.

[0065]

[0066] (2) Synthesis of Compound III

[0067] 5.83 g of compound II was dissolved in 35 mL of methanol, and 2.58 g of hydroxylamine hydrochloride and 3.25 g of sodium acetate were added under ice bath. After reacting at 25°C for 6 hours, potassium hydroxide aqueous solution (prepared from 3.60 g of potassium hydroxide and 10.8 mL of water) was slowly added under ice bath, and the reaction was continued at 25°C for 12 hours, and the reaction was terminated. 150 mL of water was added under ice bath to spin away most of the methanol. The mixture was first extracted three times with 60 mL of methyl tert-butyl ether (to wash away impurities). The pH of the aqueous phase was adjusted to 5-6 under ice bath. The mixture was further extracted with 80 mL of dichloromethane for three times. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 7.2 g of a crude product. The mixture was further refined and purified. The crude product was dissolved in ethyl acetate, and ethanolamine was added to form a salt to precipitate a solid ethanolamine salt product. The solid was filtered out and suspended in water. The pH of the aqueous phase was adjusted to 5-6 under ice bath. The mixture was extracted three times with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 3.40 g of a pure light yellow solid III with a yield of 62.87%.

[0068]

[0069] (3) Synthesis of Compound IV

[0070] 3.40g of compound III was dissolved in 52.1mL of tetrahydrofuran, and 7.17g of di-tert-butyl azodicarboxylate, 8.17g of triphenylphosphine and 10.41g of 2,3,4-tri-O-acetyl-Α-D-glucuronic acid methyl ester were added under ice bath, and the reaction was carried out at 50°C for 12 hours until the raw materials were completely reacted. 280mL of dichloromethane was added under ice bath, and then washed twice with 90mL of 0.5M HCl aqueous solution, and then washed once with 90mL of aqueous solution, and the organic layer was separated and dried with anhydrous sodium sulfate, filtered, and then purified by column chromatography (stationary phase was 200-300 mesh silica gel, and the mobile phase was dichloromethane and methanol in a volume ratio of 40:1) to obtain 5.21g of yellow solid IV, with a yield of 62.58%.

[0071]

[0072] (4) Synthesis of Compound V

[0073] 5.21g of compound IV was dissolved in 156mL of methanol, 1.23g of lithium hydroxide monohydrate was added under ice bath, and stirred at room temperature (about 25°C) for 8h until the raw materials reacted. The reaction solution was concentrated to dryness and purified by C18 column (mobile phase was pure water) to obtain 2.33g of light yellow solid compound V, yield: 59.71%, HPLC: 96.13%.

[0074]

[0075] Example 3

[0076] The method for synthesizing deuterium-labeled ciclopirox glucuronic acid of the present invention comprises the following steps:

[0077] (1) Synthesis of Compound II

[0078] 5.00 g of compound I was dissolved in 125 mL of tetrahydrofuran, and 13.67 g of oxalyl chloride and 0.1 mL of DMF were added under ice bath to obtain a yellow solution. The reaction solution was heated to 40°C for 5 hours, and then slowly returned to 25°C and continued to be concentrated and dried to obtain an acyl chloride intermediate for use.

[0079] In an ice bath, 16.82g of boron trifluoride etherate was suspended in 125mL of dichloromethane, and 8.20g of 3,3-dimethylacrylate and the prepared acyl chloride intermediate were slowly added dropwise, and the temperature was controlled to be 0-5°C during the addition process. After the addition was completed, the temperature was restored to 25°C and continued to stir for 24 hours, and the reaction was completed. The reaction solution was poured into 300mL of ice water under an ice bath, most of the tetrahydrofuran and dichloromethane were spun off, and extracted three times with 120mL of dichloromethane. After the organic layers were combined, they were dried with anhydrous sodium sulfate, filtered, and spun to dryness to obtain 9.5g of crude product. Column chromatography (stationary phase was 200-300 mesh silica gel, and the mobile phase was petroleum ether and ethyl acetate in a volume ratio of 40:1) was used to separate 5.51g of yellow oil II, with a yield of 65.19%.

[0080]

[0081] (2) Synthesis of Compound III

[0082] 5.51 g of compound II was dissolved in 55.1 mL of methanol, and 4.88 g of hydroxylamine hydrochloride and 6.15 g of sodium acetate were added under ice bath. After reacting at 25°C for 30 hours, sodium hydroxide aqueous solution (prepared from 2.81 g of sodium hydroxide and 14.0 mL of water) was slowly added under ice bath, and the reaction was continued at 25°C for 15 hours, and the reaction was terminated. 150 mL of water was added under ice bath to spin away most of the methanol. The mixture was first extracted three times with 60 mL of methyl tert-butyl ether (to wash away impurities). The pH of the aqueous phase was adjusted to 5-6 under ice bath. The mixture was further extracted with 70 mL of dichloromethane for three times. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 7.2 g of a crude product. The mixture was further refined and purified. The crude product was dissolved in ethyl acetate, and ethanolamine was added to form a salt to precipitate a solid ethanolamine salt product. The solid was filtered out and suspended in water. The pH of the aqueous phase was adjusted to 5-6 under ice bath. The mixture was extracted three times with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 3.11 g of a pure light yellow solid III with a yield of 60.85%.

[0083]

[0084] (3) Synthesis of Compound IV

[0085] 3.11g of compound III was dissolved in 50mL of tetrahydrofuran, and 9.84g of di-tert-butyl azodicarboxylate, 11.21g of triphenylphosphine and 14.28g of 2,3,4-tri-O-acetyl-Α-D-glucuronic acid methyl ester were added under ice bath, and the reaction was carried out at 60°C for 12 hours until the raw materials were completely reacted. 320mL of dichloromethane was added under ice bath, and then washed twice with 120mL of 0.5M HCl aqueous solution, and then washed once with 120mL of aqueous solution, and the organic layer was separated and dried with anhydrous sodium sulfate, filtered, and then purified by column chromatography (stationary phase was 200-300 mesh silica gel, and the mobile phase was dichloromethane and methanol in a volume ratio of 40:1) to obtain 4.86g of yellow solid IV, with a yield of 63.82%.

[0086]

[0087] (4) Synthesis of Compound V

[0088] 4.86g of compound IV was dissolved in 145.8mL of methanol, 1.91g of lithium hydroxide monohydrate was added under ice bath, and stirred at 0℃ for 24h until the raw materials reacted completely. The reaction solution was concentrated to dryness and purified by C18 column (mobile phase was pure water) to obtain 2.07g of light yellow solid compound V, yield: 56.87%, HPLC: 96.02%.

[0089]

Claims

1. A method for synthesizing deuterium-labeled ciclopirox glucuronic acid, characterized in that: The following steps are involved: (1) Compound I is dissolved in tetrahydrofuran, an acylating agent and a catalyst are added, and an acylation reaction is performed to obtain an acyl chloride intermediate for use; boron trifluoride etherate is suspended in an organic solvent, and 3,3-dimethylacrylate and the acyl chloride intermediate are added dropwise, respectively, to undergo Friedel-Crafts acylation to obtain an intermediate II; (2) taking the intermediate product II synthesized in step (1), dissolving it in methanol, adding hydroxylamine hydrochloride and a catalyst sodium acetate to react to generate an intermediate, and then adding an alkaline aqueous solution to generate an intermediate product III by a cyclization reaction; (3) dissolving the intermediate product III obtained in step (2) in an organic solvent, adding di-tert-butyl azodicarboxylate, triphenylphosphine and 2,3,4-tri-O-acetyl-Α-D-glucuronic acid methyl ester, and reacting to obtain the intermediate product IV; (4) The intermediate product IV obtained in step (3) is dissolved in methanol, lithium hydroxide is added, and an ester hydrolysis reaction is carried out to obtain the final product V. The synthetic route is as follows:

2. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (1), the temperature of the Friedel-Crafts acylation reaction is 20 to 30° C. and the time is 8 to 24 hours.

3. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (1), the acylating agent is oxalyl chloride and the catalyst is N,N-dimethylformamide.

4. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 3, characterized in that: In step (1), the temperature of the acylation reaction is 50 to 80° C. and the time is 1 to 8 hours.

5. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (1), the molar ratio of compound I to the acylating agent, boron trifluoride etherate and 3,3-dimethylacrylate is 1:1:1:1 to 1:1.1:2.6:

1.

6. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (1), the organic solvent in which the boron trifluoride etherate is suspended is dichloromethane.

7. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (2), the molar ratio of the intermediate product II to hydroxylamine hydrochloride, sodium acetate, and the base in the alkaline aqueous solution is 1:1:1:1 to 1:5:5:5; the temperature for the reaction to generate the intermediate is 20 to 30°C, and the time is 6 to 30 hours; the temperature for the cyclization reaction is 20 to 30°C, and the time is 1.5 to 15 hours.

8. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (3), the molar ratio of the intermediate product III to di-tert-butyl azodicarboxylate, triphenylphosphine, and 2,3,4-tri-O-acetyl-Α-D-glucuronic acid methyl ester is 1:1:1:1 to 1:5:5:

5.

9. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (3), the organic solvent is tetrahydrofuran, the reaction temperature is 30 to 60° C., and the reaction is carried out for 12 to 24 hours.

10. The method for synthesizing deuterium-labeled ciclopirox glucuronic acid according to claim 1, characterized in that: In step (4), the molar ratio of the intermediate product IV to lithium hydroxide is 1:1 to 1:5; the reaction temperature is 0 to 35° C., and the reaction is carried out for 3 to 24 hours.

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