A drug molecule for treating cholestatic pruritus (±)-HEP-50768-D3, its synthesis method, and its application.

Abstract

This application relates to the field of pharmaceutical chemical synthesis technology, specifically to an anti-cholestatic pruritus drug molecule (±)-HEP-50768-D3, its synthesis method, and its applications. This invention starts from simple raw materials such as 1,3-dibromo-2-fluorobenzene to construct a complex trideuterated furan ring. Through steps including acylation, metal-catalyzed coupling, hydrogenation debenzylation, carbonyl α-position deuteration, sodium borodeuteration reduction, Mitsunobu (phototensotropic) reaction, cyanation, and 3+2 cycloaddition, the (±)-HEP-50768-D3 molecule is synthesized efficiently in a relatively short linear sequence. The raw materials for the synthesis reaction in this invention are readily available; the starting materials and reagents are all conventional chemical products. The operation is simple and safe, post-processing is convenient, and waste generation is minimal, significantly reducing production costs. The isotopic raw material utilization rate is high, and the site-directed substitution reaction of deuterium atoms is precise. The entire process route is stable and reliable, making it highly suitable for industrial-scale production.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical chemical synthesis technology, specifically to an anti-cholestatic pruritus drug molecule (±)-HEP-50768-D3 and its synthesis method and application. Background Technology

[0002] Mas-associated G protein-coupled receptor X4 (MRGPRX4) has been reported to have multiple biological functions and may be associated with a variety of conditions, disorders, or diseases. For example, patients with liver conditions, disorders, or diseases such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or progressive familial intrahepatic cholestasis (PFIC) often suffer from intractable pruritus, which severely impacts their quality of life and may lead to burnout, fatigue, depression, and even suicidal thoughts.

[0003] The invention patent application No. WO2024 / 083210A1 filed by Hypetech (Beijing) Biomedical Technology Co., Ltd. discloses a novel therapeutic agent, HEP-50768, which can be used to prevent or treat pruritus in PBC and pruritus in chronic kidney disease. Replacing some hydrogen atoms (H) in the HEP-50768 drug molecule with its stable isotope deuterium atoms (D) creates a new deuterated drug. This substitution has the potential to alter the pharmacokinetic properties of the drug, such as prolonging half-life, reducing toxic side effects, and decreasing toxicity caused by metabolites. (±)-HEP-50768-D3 is a deuterated derivative in which three deuterium atoms are introduced at specific positions on the furan ring of the HEP-50768 molecule. (±)-HEP-50768-D3 can be effectively used as a quantitative internal standard for the clinical detection of HEP-50768.

[0004] In clinical medicine, the main methods for detecting HEP-50768 residues include high performance liquid chromatography, gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, radioimmunoassay, and enzyme-linked immunosorbent assay. However, these methods have technical problems such as cumbersome pretreatment and significant matrix effects, which have a significant impact on the test results.

[0005] Isotope dilution mass spectrometry (IDMS) uses stable isotope-labeled compounds as internal standards, effectively combining the separation capabilities of chromatography with the qualitative capabilities of mass spectrometry. Accurate quantification is achieved by comparing the ratio of ions with corresponding mass numbers to the ratio of standards. Simultaneously, it effectively eliminates matrix effects and recovery differences caused by sample pretreatment, thus improving detection accuracy. Therefore, this method is a highly accurate and precise analytical approach.

[0006] Deuterium has almost identical chemical properties to hydrogen, so (±)-HEP-50768-D3 and the prototype drug HEP-50768 are highly similar in chromatographic behavior, extraction efficiency, and ionization efficiency. Due to their different atomic weights (D is heavier than H), (±)-HEP-50768-D3 will be approximately 3 mass units heavier than ordinary HEP-50768 in a mass spectrometer, and mass spectrometry can easily distinguish between the two. In detection and analysis, (±)-HEP-50768-D3 can serve as an essential and irreplaceable internal standard.

[0007] Currently, the conventional methods for synthesizing deuterated alicyclic compounds mainly include the following pathways:

[0008] A. Direct deuteration of unsaturated bonds by deuterium (D2) under noble metal catalysis, but this method has poor position selectivity and is difficult to precisely introduce multiple deuterium atoms.

[0009] B. Synthesis using deuterated starting materials such as D2O and CD3OD. Summary of the Invention

[0010] A synthetic method for an antichostatic pruritus drug molecule (±)-HEP-50768-D3, the synthetic route is shown in the figure below:

[0011]

[0012] The specific steps of the synthesis method of (±)-HEP-50768-D3 are as follows:

[0013] Step (1): 1,3-Dibromo-2-fluorobenzene is reacted with an organolithium reagent and N-methoxy-N-methylacetamide to generate 1-(3-bromo-2-fluorophenyl)ethyl-1-one (2.15 g), namely compound 3.

[0014] Step (2): The palladium catalyst, alkali metal compound, compound 3 and 1-(benzyloxy)-2-bromo-4-(trifluoromethyl)benzene are reacted in a solvent at elevated temperature to obtain 2-[2-(benzyloxy)-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)ethyl-1-one, i.e., compound 5.

[0015] Step (3): Palladium on carbon is added to compound 5 and reacted under a hydrogen atmosphere to obtain 1-(3-bromo-2-fluorophenyl)-2-[2-hydroxy-5-(trifluoromethyl)phenyl]ethyl-1-one, i.e., compound 6.

[0016] Step (4): DBU was added to the deuterated solvent of compound 6, and the reaction yielded 1-(3-bromo-2-fluorophenyl)-2-(2-(deuterated hydroxyl)-5-(trifluoromethyl)phenyl)-2,2-dideuterated-1-ethyl ketone, i.e., compound 7.

[0017] Step (5): Add a deuterating agent to compound 7 to give 2-[2-deuteroxy-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)(1,2,2-trideuterium)ethanol-1-ol, i.e., compound 8.

[0018] Step (6): Compound 8 is reacted with triphenylphosphine in a solvent to give 2-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran, i.e., compound 9.

[0019] Step (7): Add cuprous cyanide to compound 9 and heat the reaction to obtain 2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]benzene-1-carboxynitrile, i.e., compound 10.

[0020] Step (8): Compound 10, the azide reagent and dibutyltin oxide are mixed and refluxed in a solvent to obtain 5-{2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]phenyl}-1H-1,2,3,4-tetraazacyclopentane, which is the final product.

[0021] Furthermore, the specific steps of the (±)-HEP-50768-D3 synthesis method are as follows:

[0022] Step (1): Cool the tetrahydrofuran solution of 1,3-dibromo-2-fluorobenzene to -10℃ to -78℃. Maintaining the temperature at -78℃, add an organolithium reagent solution dropwise to the system. Then, add N-methoxy-N-methylacetamide at -78℃. After reacting at -78℃ for a period of time, raise the temperature to room temperature and stir overnight. Quench the reaction and extract with an organic solvent; combine the organic phases and concentrate and purify to obtain compound 3,1-(3-bromo-2-fluorophenyl)ethyl-1-one.

[0023] The volume of tetrahydrofuran, by mass and volume, is preferably 1-10 vol of 1,3-dibromo-2-fluorobenzene, more preferably 2-8 vol, and most preferably 5 vol. The molar equivalent of the organolithium reagent solution, by molar ratio, is preferably 1-4 eq of 1,3-dibromo-2-fluorobenzene, more preferably 2-3 eq, and most preferably 2 eq. The reaction temperature is preferably -10℃ to -78℃, and most preferably -78℃.

[0024] Step (2): Dissolve the palladium catalyst, alkali metal compound, compound 3 and compound 4 in 1,4-dioxane and react with the solution at a high temperature. After cooling, dilute, wash, dry and purify the solution in sequence to obtain compound 5: 2-[2-(benzyloxy)-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)ethyl-1-one.

[0025] The volume of 1,4-dioxane, by mass and volume, is preferably 1-30 vol of compound 3, more preferably 5-25 vol, and most preferably 20-25 vol. Here, the catalytic amount refers to the minimum amount of catalyst required in the chemical reaction, which can significantly increase the reaction rate without being consumed. By molar ratio, the catalytic amount of catalyst is preferably 0.05-0.25 eq, more preferably 0.1-0.2 eq, and most preferably 0.2 eq. The amount of alkali metal compound is preferably 1.5-3 eq. The reaction temperature is preferably 90-150℃, and most preferably 100℃. The reaction time is preferably 2-12 hours, more preferably 3-8 hours, and most preferably 4 hours.

[0026] Step (3): Palladium on carbon catalyst was added to the methanol solution of compound 5, and the reaction was carried out at room temperature under a hydrogen atmosphere. Thin-layer chromatography showed that the starting material was completely consumed. The reaction solution was filtered, concentrated, and purified to obtain compound 6: 1-(3-bromo-2-fluorophenyl)-2-[2-hydroxy-5-(trifluoromethyl)phenyl]ethyl-1-one.

[0027] The catalytic amount of palladium on carbon catalyst is preferably 1 wt%-20 wt% of compound 5, more preferably 5 wt%-10 wt%, and most preferably 5 wt% by mass percentage. The volume of methanol is preferably 5-20 vol of compound 5 by mass volume, more preferably 5-15 vol, and most preferably 10 vol.

[0028] Step (4): Under nitrogen protection, DBU was added to the deuterated solvent of compound 6 and reacted at room temperature. The reaction solution was washed and extracted in sequence, the organic phases were combined, dried, filtered, concentrated and purified to obtain compound 7: 1-(3-bromo-2-fluorophenyl)-2-(2-(deuterated hydroxyl)-5-(trifluoromethyl)phenyl)-2,2-dideuterated-1-ethyl ketone.

[0029] The volume of the deuterated solvent, by mass and volume, is preferably 0.5-20 vol of compound 6, more preferably 2-10 vol, and most preferably 5 vol. The amount of DBU, by molar ratio, is preferably 1-5 eq, more preferably 1.5-3 eq, and most preferably 2 eq. The reaction time is preferably 3-20 hours, more preferably 4-8 hours, and most preferably 5 hours.

[0030] Step (5): Under nitrogen protection, a deuterated reagent was added to the tetrahydrofuran solution of compound 7 and reacted at room temperature. The reaction solution was washed and extracted sequentially, the organic phases were combined, dried, filtered, concentrated and purified to obtain compound 8, namely 2-[2-deuteroxy-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)(1,2,2-trideuterium)ethanol-1-ol.

[0031] The volume of tetrahydrofuran is preferably 5-30 vol of compound 7, more preferably 15-25 vol, and most preferably 20 vol, by mass-volume. The amount of deuterated reagent is preferably 1-15 eq, more preferably 1.5-5 eq, and most preferably 2 eq, by molar ratio.

[0032] Step (6): Under argon protection, compound 8 and triphenylphosphine were dissolved in tetrahydrofuran and reacted at room temperature. Azodiisopropyl ester was added under argon atmosphere to continue the reaction. The reaction solution was washed and extracted sequentially, the organic phases were combined, dried, filtered, concentrated and purified to obtain compound 9, namely 2-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran.

[0033] The volume of tetrahydrofuran is preferably 1-50 vol of compound 8, more preferably 5-40 vol, and most preferably 30 vol, by mass-volume. The amount of triphenylphosphine is preferably 1.2 eq, and the amount of azodiisopropyl ester is preferably 1.2 eq.

[0034] Step (7): Add cuprous cyanide to the N-methylpyrrolidone solution of compound 9. The system is heated to react. The reaction solution is washed and extracted sequentially, the organic phases are combined, dried, filtered, concentrated and purified to obtain compound 10, namely 2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]benzene-1-carboxynitrile.

[0035] The volume of N-methylpyrrolidone, by mass and volume, is preferably 1-30 vol of compound 9, more preferably 5-15 vol, and most preferably 10 vol. The amount of cuprous cyanide, by molar ratio, is preferably 1.5-3 eq, and most preferably 2 eq. The reaction time is preferably 1-5 hours, and most preferably 2 hours.

[0036] Step (8): Compound 10, the azide reagent, and dibutyltin oxide were mixed and dissolved in toluene. The mixture was refluxed overnight under nitrogen protection. The reaction solution was washed and extracted sequentially, the organic phases were combined, dried, filtered, concentrated, and purified to obtain the final product (±)-HEP-50768-D3, namely 5-{2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]phenyl}-1H-1,2,3,4-tetraazacyclopentane.

[0037] The volume of toluene, by mass and volume, is preferably 1-30 vol of compound 10, more preferably 10-25 vol, and most preferably 25 vol. The amount of the azide reagent, by molar ratio, is preferably 1-3 eq, and most preferably 2 eq; the amount of dibutyltin oxide is preferably 0.1 eq. The reaction time is preferably 6-18 hours, and most preferably 12 hours.

[0038] The present invention has at least the following beneficial effects:

[0039] 1. This invention constructs a complex trideuterated furan ring from simple raw materials such as 1,3-dibromo-2-fluorobenzene. Through acylation, metal-catalyzed coupling, hydrogenation debenzylation, carbonyl α-position deuteration, sodium borodeuteration reduction, Mitsunobu reaction, cyanation, and 3+2 cycloaddition, the (±)-HEP-50768-D3 molecule is synthesized efficiently in a relatively short linear sequence. The raw materials for the synthesis reaction in this invention are readily available; the starting materials and reagents are all conventional chemical products. The operation is simple and safe, post-processing is convenient, and waste generation is minimal, significantly reducing production costs. The isotopic raw material utilization rate is high, and the site-directed substitution reaction of deuterium atoms is precise. The entire process route is stable and reliable, making it highly suitable for industrial-scale production.

[0040] 2. The compound (±)-HEP-50768-D3 of the present invention can be used as an internal standard reagent and can be effectively applied to the quantitative detection of HEP-50768.

[0041] 3. In this invention, (±)-HEP-50768-D3 can be used for internal standard detection, with an abundance of >95% and a chemical purity of 97% or higher. Attached Figure Description

[0042] Figure 1 The image shows the HPLC chromatogram of (±)-HEP-50768-D3 in Example 1.

[0043] Figure 2 For example, (±)-HEP-50768-D3 in Example 1 1 H NMR spectrum.

[0044] Figure 3 This is the mass spectrometry analysis chromatogram of (±)-HEP-50768-D3 in Example 1.

[0045] Figure 4 Compound 9 in Example 1 1 H NMR spectrum.

[0046] Figure 5 For compound 10 in Example 1 1 H NMR spectrum. Detailed Implementation

[0047] The present invention can be better understood through the following examples.

[0048] Example 1: A method for synthesizing an anti-cholestatic pruritus drug molecule (±)-HEP-50768-D3, the steps of which are as follows:

[0049]

[0050] Step (1): Preparation of 1-(3-bromo-2-fluorophenyl)ethyl-1-one

[0051] 1,3-Dibromo-2-fluorobenzene (5.0 g, 20.24 mmol) was dissolved in tetrahydrofuran (30 mL), and the mixture was cooled to -78 °C under argon protection. While maintaining the temperature at -78 °C, a solution of n-butyllithium (2.5 mol / L n-hexane solution, 16.2 mL, 40.49 mmol) was added dropwise to the system, and the mixture was stirred for 1 hour. Then, 2N-methoxy-N-methylacetamide (4.17 g, 40.49 mmol) dissolved in 30 mL of tetrahydrofuran was added at -78 °C. After stirring at -78 °C for 30 minutes, the mixture was brought to room temperature and stirred overnight. The reaction was quenched with an aqueous solution of ammonium chloride (30 mL), and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3,1-(3-bromo-2-fluorophenyl)ethyl-1-one (2.15 g), which was a yellow oil. It can be used directly in the next reaction.

[0052]

[0053] Step (2): Preparation of 2-[2-(benzyloxy)-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)ethyl-1-one

[0054] X-Phos palladium G3 catalyst (242 mg, 0.29 mmol), cesium carbonate (932 mg, 2.86 mmol), compound 3 (300 mg, 1.43 mmol), and compound 4 (567 mg, 1.71 mmol) were dissolved in 1,4-dioxane (8 mL). The system was heated to 100 °C and reacted for 4 hours, then cooled to room temperature. The mixture was diluted with 10 mL of ethyl acetate, and the organic phase was washed successively with water (10 mL) and saturated brine (10 mL), and dried over anhydrous magnesium sulfate. After removing the solvent by concentration under reduced pressure, the crude product was purified by silica gel column chromatography to give compound 5: 2-[2-(benzyloxy)-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)ethyl-1-one (435 mg), a brown oil. This was used directly in the next reaction.

[0055]

[0056] Step (3): Preparation of 1-(3-bromo-2-fluorophenyl)-2-[2-hydroxy-5-(trifluoromethyl)phenyl]ethyl-1-one

[0057] To a methanol (4 mL) solution of compound 5 (400 mg), 20 mg (5 wt%) of palladium catalyst on carbon was added. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 1 hour. Thin-layer chromatography (TLC) showed that the starting material was completely consumed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC to obtain the target product compound 6: 1-(3-bromo-2-fluorophenyl)-2-[2-hydroxy-5-(trifluoromethyl)phenyl]ethyl-1-one (259 mg), which was a colorless solid.

[0058]

[0059] Step (4): Preparation of 1-(3-bromo-2-fluorophenyl)-2-(2-(deuterated hydroxy)-5-(trifluoromethyl)phenyl)-2,2-dideuterated-1-ethyl ketone

[0060] Under nitrogen protection, DBU (200 mg, 1.32 mmol) was added to a solution of compound 6 (250 mg, 0.66 mmol) in deuterated methanol (2.5 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was washed with heavy water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 7: 1-(3-bromo-2-fluorophenyl)-2-(2-(deuterated hydroxy)-5-(trifluoromethyl)phenyl)-2,2-dideuterated-1-ethylone (230 mg), which was a yellow oil.

[0061] 1H NMR spectrum (400MHz, deuterated methanol) δ: 7.53-7.45 (multiple peaks) 1 H), 7.39 (triple peak, J=7.2Hz), 1 H), 7.27 (double peak, J=8.4Hz), 2 H), 7.20-7.09 (multiple peak, 1 H), 6.83 (double peak, J=8.4Hz), 1 H).

[0062]

[0063] Step (5): Preparation of 2-[2-deuteroxy-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)(1,2,2-trideuterium)ethanol-1-ol

[0064] Under nitrogen protection, sodium borodeuteride (76 mg, 1.8 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 7 (230 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction solution was washed with heavy water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8, namely 2-[2-deuteroxy-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)(1,2,2-trideuterium)ethanol-1-ol (200 mg), which was a colorless oil.

[0065] 1H NMR spectrum (400MHz, deuterated methanol) δ: 7.53-7.45 (multiple peaks) 1 H), 7.39 (triple peak, J=7.2Hz), 1 H), 7.27 (double peak, J=8.4Hz), 2 H), 7.20-7.09 (multiple peak, 1 H), 6.83 (double peak, J=8.4Hz), 1 H).

[0066]

[0067] Step (6): Preparation of 2-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran

[0068] Under argon protection, compound 8 (63.0 mg, 0.17 mmol) and triphenylphosphine (53.0 mg, 0.20 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred at room temperature for 10 minutes. Azodiisopropyl ester (DIAD, 40.0 mg, 0.20 mmol) was added under argon atmosphere, and the reaction was continued for 3 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was extracted twice with ethyl acetate (3 mL each time) by adding heavy water (2 mL). The ethyl acetate phase was washed successively with heavy water (3 mL) and saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 9, 2-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran (45.2 mg), as a yellow oil.

[0069] Liquid chromatography-mass spectrometry (electrospray ionization): mass-to-charge ratio (m / z = 362.27, [MH]) - ). 1H NMR spectrum (400MHz, deuterated methanol) δ: 8.19-8.11 (multiple peaks) 1 H), 7.75 (triple doublet, J=7.5, 1.8Hz), 1H), 7.60-7.42 (multiple peak, 3 H), 7.04 (double peak, J=8.4Hz), 1 H), 6.24 (double doublet, J=9.9, 7.6Hz), 1 H).

[0070]

[0071] Step (7): Preparation of 2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]benzene-1-carboxynitrile

[0072] To a solution of compound 9 (44 mg, 0.14 mmol) in N-methylpyrrolidone (NMP, 5 mL), cuprous cyanide (33.2 mg, 0.28 mmol) was added. The system was heated to 160 °C and stirred for 2 hours. The reaction solution was washed with heavy water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 10, namely 2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]benzene-1-carboxynitrile (30 mg), which is a yellow oil.

[0073] Liquid chromatography-mass spectrometry (electrospray ionization): mass-to-charge ratio (m / z = 309.08 [MH]) - ). 1H NMR spectrum (400MHz, deuterated methanol) δ: 8.19-8.11 (multiple peaks) 1 H), 7.75 (triple doublet, J=7.5, 1.8Hz), 1 H), 7.60-7.42 (multiple peak, 3 H), 7.04 (double peak, J=8.4Hz), 1 H).

[0074]

[0075] Step (8): Preparation of 5-{2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]phenyl}-1H-1,2,3,4-tetraazacyclopentane

[0076] Compound 10 (20 mg, 0.06 mmol), trimethylsilane azido (15 mg, 0.13 mmol), and dibutyltin oxide (1.6 mg, 0.006 mmol) were mixed and dissolved in toluene (0.5 mL). The mixture was refluxed overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was washed with heavy water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give the final product (±)-HEP-50768-D3, namely 5-{2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]phenyl}-1H-1,2,3,4-tetraazacyclopentane (12 mg), which is a white solid.

[0077] Liquid chromatography-mass spectrometry (electrospray ionization): mass-to-charge ratio (m / z = 354.1 [M+H]) + ). 1H NMR spectrum (400MHz, deuterated methanol) δ: 8.10 (quadruple doublet, J = 7.8, 6.8, 1.8Hz), 1 H), 7.75-7.67 (multiple peak, 1 H), 7.56-7.52 (multiple peak, 1 H), 7.49 (triple doublet, J=8.4, 2.1, 0.9Hz), 1 H), 7.43 (triple peak, J=7.8Hz), 1 H), 7.00 (double peak, J=8.4Hz), 1 H).

Claims

1. A method for synthesizing an antichostatic pruritus drug molecule (±)-HEP-50768-D3, characterized in that, Includes the following steps: Step (1): 1,3-Dibromo-2-fluorobenzene is reacted with an organolithium reagent and N-methoxy-N-methylacetamide to generate 1-(3-bromo-2-fluorophenyl)ethyl-1-one (2.15 g), i.e., compound 3; Step (2): The palladium catalyst, alkali metal compound, compound 3 and 1-(benzyloxy)-2-bromo-4-(trifluoromethyl)benzene are reacted in a solvent at elevated temperature to obtain 2-[2-(benzyloxy)-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)ethyl-1-one, i.e., compound 5; Step (3): Palladium on carbon was added to compound 5 and reacted under a hydrogen atmosphere to obtain 1-(3-bromo-2-fluorophenyl)-2-[2-hydroxy-5-(trifluoromethyl)phenyl]ethyl-1-one, i.e., compound 6; Step (4): DBU was added to the deuterated solvent of compound 6, and the reaction yielded 1-(3-bromo-2-fluorophenyl)-2-(2-(deuterated hydroxyl)-5-(trifluoromethyl)phenyl)-2,2-dideuterated-1-ethyl ketone, i.e., compound 7; Step (5): Add a deuterating agent to compound 7 to give 2-[2-deuteroxy-5-(trifluoromethyl)phenyl]-1-(3-bromo-2-fluorophenyl)(1,2,2-trideuterium)ethanol-1-ol, i.e., compound 8; Step (6): Compound 8 is reacted with triphenylphosphine in a solvent to give 2-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran, i.e., compound 9; Step (7): Add cuprous cyanide to compound 9 and heat the reaction to obtain 2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]benzene-1-carboxynitrile, i.e., compound 10; Step (8): Compound 10, the azide reagent and dibutyltin oxide are mixed and refluxed in a solvent to obtain 5-{2-fluoro-3-[5-(trifluoromethyl)-2,3-dihydro(2,3,3-trideuterium)-1-benzofuran-2-yl]phenyl}-1H-1,2,3,4-tetraazacyclopentane, which is the final product.

2. The synthesis method according to claim 1, characterized in that, The organolithium reagent in step (1) is n-butyllithium.

3. The synthesis method according to claim 1, characterized in that, The solvent in step (2) is 1,4-dioxane.

4. The synthesis method according to claim 1, characterized in that, In step (2), the palladium catalyst is an X-Phos palladium G3 catalyst, and / or The alkali metal compound in step (2) is cesium carbonate.

5. The synthesis method according to claim 1, characterized in that, In step (4), the deuterated solvent is deuterated methanol.

6. The synthesis method according to claim 1, characterized in that, The deuterated reagent in step (5) is sodium borodeuteride.

7. The synthesis method according to claim 1, characterized in that, The azidating agent in step (8) is trimethylsilane azido.

8. A drug molecule for treating cholestatic pruritus (±)-HEP-50768-D3, characterized in that, Prepared by the synthesis method according to any one of claims 1-7.

9. The application of an antichostatic pruritus drug molecule (±)-HEP-50768-D3, characterized in that, It is used for the treatment and prevention of pruritus associated with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or progressive familial intrahepatic cholestasis (PFIC); it is also used for the treatment and prevention of pruritus in chronic kidney disease.

10. The application of an antichostatic pruritus drug molecule (±)-HEP-50768-D3, characterized in that, When used in clinical testing, it serves as a quantitative internal standard for HEP-50768.

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