A method for synthesizing furosemide-d5

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a novel and efficient furosemide-D5 synthesis method. The furosemide-D5 molecule is efficiently synthesized in a short linear step from simple raw materials such as trans-2,3-dibromo-2-butene-1,4-diol and the like through an oxidation cyclization, a low-temperature metallization-carboxylation, a Lewis acid catalysis bromination, a catalytic deuterium decomposition and a LiAlD4 reduction and the like. In the application, the synthesis reaction raw materials are easy to obtain, the operation is simple and safe, waste is less, the isotopic raw material utilization rate is high, and the precise site substitution reaction of deuterium atoms is realized.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a method for synthesizing furosemide-D5. Background Technology

[0002] Furosemide, also known as furosemide, is a widely used diuretic. It exerts its diuretic effect by inhibiting the reabsorption of Cl- and Na+ in the medullary and cortical portions of the ascending limb of the loop of Henle. Its diuretic effect is rapid and potent, and it is often used in severe cases where other diuretics are ineffective. However, due to significant water and electrolyte loss, it is not suitable for routine use. In cases of drug poisoning, it can be used to accelerate the excretion of toxins. Clinically, it is mainly used to treat cardiac edema, renal edema, ascites due to cirrhosis, peripheral edema caused by functional or vascular disorders, and can also promote the expulsion of upper urinary tract stones.

[0003] Replacing some of the hydrogen atoms (H) in the furosemide drug molecule with its stable isotope deuterium atoms (D) creates a new deuterated drug. This substitution can alter the pharmacokinetic properties of the drug, such as prolonging half-life, reducing toxic side effects, and minimizing the toxicity caused by metabolites. Furosemide-D5 is a deuterated derivative in which five deuterium atoms are introduced at specific positions on the furan ring and amino side chain of the furosemide molecule. It has advantages in pharmacokinetic aspects such as prolonging half-life and reducing metabolites, making it a hot area of ​​research in drug development.

[0004] In clinical medicine, the main methods for detecting furosemide 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 considerable 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 a standard. 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 furosemide-D5 and the original drug furosemide show highly similar chromatographic behavior, extraction efficiency, and ionization efficiency. Due to their different atomic weights (D is heavier than H), furosemide-D5 will be approximately 5 mass units heavier than regular furosemide in a mass spectrometer, making them easily distinguishable. In detection and analysis, furosemide-D5 serves as an essential and irreplaceable internal standard.

[0007] Currently, the conventional methods for synthesizing deuterated aromatic 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 is costly, and deuterium atoms are easily lost or exchanged in the multi-step reaction, resulting in a decrease in the deuteration rate.

[0010] Therefore, existing synthetic routes for the structurally complex furosemide-D5 often suffer from the following technical problems:

[0011] 1) The route is lengthy, starting from non-deuterated starting materials and involving many steps to introduce deuterium atoms in the later stages, resulting in a low overall yield.

[0012] 2) Low deuteration rate: When using deuteration reagents for simple exchange or reduction, the reaction is incomplete or reverse exchange occurs, making it difficult for the deuteration purity of the final product to meet pharmaceutical grade standards.

[0013] 3) It is costly and overly reliant on expensive deuterated reagents, making it uneconomical for industrial production.

[0014] 4) The operation is complex, involving ultra-low temperature reactions that are sensitive to air or water, such as metallization reactions below -78°C, or requiring the use of highly dangerous deuterium high-pressure equipment, which places extremely high demands on equipment and operation.

[0015] In the synthesis of furosemide-D5, conventional furan synthesis methods such as the Paal-Knorr reaction are not always suitable for this particular substituted furan skeleton that is prone to subsequent functional group transformations.

[0016] In addition, the traditional deuterium exchange method refers to the direct exchange of hydrogen atoms in a compound with a deuterium source such as D2O under the action of a catalyst. This method has inherent difficulties in the synthesis of furosemide-D5: poor selectivity, furosemide molecules contain hydrogen atoms in various chemical environments, such as hydrogen on aromatic rings, amino groups and carboxyl groups. If direct exchange is performed, it is difficult to accurately introduce deuterium atoms at only five specific positions, which easily produces a mixture with uncertain deuteration positions and quantities. At the same time, it is also difficult to meet the analytical standards and serve as an internal standard for analysis and detection, which requires fixed deuteration positions and high deuteration rates.

[0017] Chinese Invention Patent No. 202211743601.2 discloses a method for synthesizing furosemide impurity D with high yield and high purity, comprising the following steps: first, furosemide and furfurylamine are dissolved in a solvent; then an inorganic base and ligand are added, followed by a catalyst, and the mixture is purged with an inert gas; the reaction is heated for a period of time; then two recrystallizations are performed to obtain furosemide impurity D. This patent can obtain a large amount of furosemide impurity D reference standard, which can facilitate the impurity analysis and research of furosemide raw materials and their preparations. However, this patent is a non-deuterated synthesis of furosemide impurity D, focusing on impurity control rather than isotope labeling. Summary of the Invention

[0018] To address the above technical problems, this invention provides a novel and efficient method for synthesizing furosemide-D5, which uses readily available reaction materials, is simple and safe to operate, generates little waste, has high utilization of isotopic raw materials, and involves precise site-directed substitution of deuterium atoms.

[0019] The present invention provides a method for synthesizing furosemide-D5 to solve the above technical problems, the steps of which are as follows:

[0020] (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol in 7.5% sulfuric acid / n-hexane, heat to 70-120℃, and add potassium dichromate in 25% sulfuric acid solution dropwise; after the addition is complete, maintain the reaction at 70-120℃ until complete to obtain 3,4-dibromofuran; the ratio of 7.5% sulfuric acid to n-hexane is 1:1-5; the mass-volume ratio (g:mL) of potassium dichromate in 25% sulfuric acid solution is 1:5-10;

[0021] The ratio of trans-2,3-dibromo-2-butene-1,4-diol, sulfuric acid / n-hexane solution, and potassium dichromate / sulfuric acid solution by mass and volume is 1:5-20:3-10.

[0022] (2) Dissolve 3,4-dibromofuran in tetrahydrofuran, add a strong base at 0-78℃, maintain for 30-60 min, add dry ice, and react at 0-78℃ for 1-4 h. Quench with water to obtain 3,4-dibromofuran-2-carboxylic acid.

[0023] The ratio of 3,4-dibromofuran, tetrahydrofuran and dry ice, by mass and volume, is 1:5-30:0.1-5.

[0024] (3) Dissolve 3,4-dibromofuran-2-carboxylic acid in methanol, add concentrated sulfuric acid in a catalytic amount, and reflux for 24-48 h to obtain methyl 3,4-dibromofuran-2-carboxylic acid;

[0025] The ratio of the amount of 3,4-dibromofuran-2-carboxylic acid, methanol, and concentrated sulfuric acid used, by mass and volume, is 1:5-20:0.05-0.2.

[0026] Here, catalytic amount refers to the minimum amount of catalyst required in a chemical reaction that can significantly increase the reaction rate without being consumed.

[0027] (4) Dissolve methyl 3,4-dibromofuran-2-carboxylic acid in solvent I, add Lewis acid and bromine, or add Lewis acid and NBS (N-bromosuccinic acid imine) to halogenate to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid.

[0028] The methyl 3,4-dibromofuran-2-carboxylic acid ester, by mass and volume, is in a solvent ratio of 1:5-20.

[0029] The molar ratio of methyl 3,4-dibromofuran-2-carboxylic acid, Lewis acid, bromine, or NBS is 1:1-2:1-2.

[0030] (5) 3,4,5-tribromofuran-2-carboxylic acid methyl ester was dissolved in methanol-D1 and reduced under palladium catalyst and deuterium to obtain furanoic acid-D3 methyl ester;

[0031] The mass-volume ratio of methyl 3,4,5-tribromofuran-2-carboxylic acid, methanol-D1, and palladium catalyst is 1:5-20:0.1-0.5. The amount of deuterium gas used is 2 bar.

[0032] (6) Add furanoic acid-D3 methyl ester to a mixed solution of tetrahydrofuran, methanol and water and stir until homogeneous. Then add base I and hydrolyze at room temperature for 2-8 hours to obtain furanoic acid-D3.

[0033] The volume ratio of tetrahydrofuran, methanol and water in the mixed solvent is 4:2:1 by mass volume.

[0034] The ratio of furanoic acid-D3 methyl ester to mixed solvent is 1:5-20 by mass and volume.

[0035] The molar ratio of furanoic acid-D3 methyl ester to base I is 1:1.5-3.

[0036] (7) Dissolve furanoic acid-D3 in solvent II and condense it with NH4Cl or ammonia to obtain furfural-D3;

[0037] The ratio of furanoic acid-D3 to solvent II is 1:5-20 by mass and volume.

[0038] On a molar basis, furanoic acid-D3:NH4Cl or ammonia water = 1:5-20.

[0039] (8) Dissolve furfuramide-D3 in tetrahydrofuran, add LiAlD4 in batches, heat under reflux for 2-8 hours to obtain furfuramide-D5, cool to room temperature, add dilute hydrochloric acid and stir for 30 minutes to obtain furfuramide-D5 hydrochloride; LiAlD4 reduction is highly specific and can quantitatively introduce the last two deuterium atoms.

[0040] By mass and volume, furfural-D3:tetrahydrofuran = 1:5-20.

[0041] On a molar basis, furfural-D3:LiAlD4:dilute hydrochloric acid = 1:2-4:2-10.

[0042] (9) Furfurylamine-D5 hydrochloride and 2,4-dichloro-5-sulfonamide benzoic acid are dissolved in solvent III, and base II is added. The reaction is carried out at 20-100℃ for 2-8 hours. Once the reaction is complete, furosemide-D5 is obtained.

[0043] On a molar basis, furfurylamine-D5 hydrochloride : 2,4-dichloro-5-sulfonamide benzoic acid : base II = 1-3 : 1 : 1-5;

[0044] By mass and volume, 2,4-dichloro-5-sulfonamide benzoic acid: solvent III = 1:5-20.

[0045] The above structure of furanoic acid-D3 methyl ester is as follows: The structural formula of furanoic acid-D3 is: The structural formula of furfural-D3 is: The structural formula of furfurylamine-D5 is: .

[0046] This invention starts from simple raw materials such as trans-2,3-dibromo-2-butene-1,4-diol, and synthesizes furosemide-D5 molecules efficiently in a shorter linear process through steps such as oxidative cyclization, low-temperature metallization-carboxylation, Lewis acid-catalyzed bromination, catalytic deuteration, and LiAlD4 reduction. The deuterium atom is clearly targeted for substitution throughout the process, the raw materials are stable, and the technical problem of deuterium loss in multi-step reactions is effectively avoided.

[0047] In step (2), the strong base is NaH, LDA, or NaHMDS.

[0048] In step (4), solvent I is DCM, THF or DCE.

[0049] In step (7), solvent II is tetrahydrofuran or N,N-dimethylformamide.

[0050] In step (4), the Lewis acid is AlCl3 or AlBr3.

[0051] In step (5), the palladium catalyst is palladium on carbon or palladium hydroxide on carbon. The Pd / D2 catalyzes the deuteration reaction under mild conditions, and can introduce four deuterium atoms in a single step with high yield and high deuteration rate.

[0052] In step (6), alkali I is sodium hydroxide or lithium hydroxide.

[0053] In step (9), solvent III is ethylene glycol, acetonitrile, or N,N-dimethylformamide.

[0054] The alkali II is DIPEA, TEA, or K2CO3.

[0055] This invention starts with simple and inexpensive chain diols to construct complex deuterated furan rings, employing a unique route design. Furthermore, the raw material costs are low, with both starting materials and reagents being conventional chemical products, significantly reducing production costs. In addition, the reaction conditions are mild, each step is simple to operate, post-processing is convenient, and the entire process route is stable and reliable, making it highly suitable for industrial-scale production.

[0056] In this invention, furosemide-D5 can be used as an internal standard for detection, with an abundance of >98% and a chemical purity of 98.02% or higher. Attached Figure Description

[0057] Figure 1 This is a synthetic route diagram of furosemide-D5 in this invention.

[0058] Figure 2 This is the HPLC chromatogram of furosemide-D5 in Example 6 of the present invention.

[0059] Figure 3 This is the NMR spectrum of furosemide-D5 in Example 6 of the present invention.

[0060] Figure 4 This is the mass spectrometry analysis chromatogram of furosemide-D5 in Example 6 of the present invention.

[0061] Figure 5 The image shows the 1H NMR spectrum of compound 3,4-dibromofuran-2-carboxylic acid in Example 6 of this invention.

[0062] Figure 6 The image shows the 1H NMR spectrum of compound methyl 3,4-dibromofuran-2-carboxylic acid from Example 6 of this invention.

[0063] Figure 7 The image shows the 1H NMR spectrum of compound 3,4,5-tribromofuran-2-carboxylic acid methyl ester in Example 6 of this invention.

[0064] Figure 8 The image shows the HNMR spectrum of compound furfural-D3 in Example 6 of this invention.

[0065] Figure 9The image shows the HNMR spectrum of furfurylamine-D5 hydrochloride, a compound from Example 6 of this invention. Detailed Implementation

[0066] The present invention will be further described below with reference to specific embodiments:

[0067] Example 1

[0068] A method for synthesizing furosemide-D5, comprising the following steps:

[0069] (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol in 7.5% sulfuric acid / n-hexane, heat to 70°C, and add potassium dichromate in 25% sulfuric acid solution; after the addition is complete, maintain the reaction at 70°C until complete to obtain 3,4-dibromofuran; the ratio of 7.5% sulfuric acid to n-hexane is 1:1; the mass-volume ratio (g:mL) of potassium dichromate in 25% sulfuric acid solution is 1:5.

[0070] This invention utilizes the oxidative cyclization reaction of potassium dichromate in a two-phase system of sulfuric acid / n-hexane to efficiently construct a dibromofuran core skeleton, while introducing two bromine atoms as directing and protecting groups, converting a chain diol into 3,4-dibromofuran in one step under mild conditions and with high yield.

[0071] The ratio of trans-2,3-dibromo-2-butene-1,4-diol, sulfuric acid / n-hexane solution, and potassium dichromate / sulfuric acid solution by mass and volume is 1:5:3.

[0072] (2) Dissolve 3,4-dibromofuran in tetrahydrofuran, add a strong base (NaH, LDA or NaHMDS) at -78℃, keep for 30 min, add dry ice, and react at -78℃ for 1 h. Quench with water to obtain 3,4-dibromofuran-2-carboxylic acid. Under the action of a strong base, the selective carboxylation reaction in the low-temperature region directly introduces a carboxyl group at the 2 position of the furan ring, which is beneficial for subsequent transformation.

[0073] The ratio of 3,4-dibromofuran, tetrahydrofuran, and dry ice by mass and volume is 1:5:0.1.

[0074] (3) Dissolve 3,4-dibromofuran-2-carboxylic acid in methanol, add concentrated sulfuric acid in a catalytic amount, and reflux for 24 h to obtain methyl 3,4-dibromofuran-2-carboxylic acid;

[0075] The ratio of 3,4-dibromofuran-2-carboxylic acid, methanol, and concentrated sulfuric acid, by mass and volume, is 1:5:0.05.

[0076] (4) Dissolve methyl 3,4-dibromofuran-2-carboxylate in solvent I (DCM, THF or DCE), add Lewis acid (AlCl3 or AlBr3) and bromine or NBS to halogenate to obtain methyl 3,4,5-tribromofuran-2-carboxylate; under Lewis acid activation, introduce a third bromine atom at the 5-position of the carboxylate methyl ester to obtain a tribromo intermediate with high symmetry and easy subsequent deuteration, thus completing the construction of the fully brominated furan skeleton.

[0077] The methyl 3,4-dibromofuran-2-carboxylic acid ester, by mass and volume, has a solvent ratio of 1:5.

[0078] The molar ratio of methyl 3,4-dibromofuran-2-carboxylic acid, Lewis acid, bromine, or NBS is 1:1:1.

[0079] (5) 3,4,5-tribromofuran-2-carboxylic acid methyl ester is dissolved in methanol-D1 (deuterated methanol) and subjected to catalytic deuteration reaction under palladium catalyst (palladium on carbon, palladium hydroxide on carbon) and deuterium gas (D2) to reduce to furanoic acid-D3 methyl ester; this step replaces all three bromine atoms at the 3,4,5-position with deuterium atoms in one step to form furan-D3 ring, while methanol-D1 also deuterates the carboxylic acid methyl ester (CD3) to obtain furanoic acid-D3 methyl ester.

[0080] The mass-volume ratio of methyl 3,4,5-tribromofuran-2-carboxylic acid, methanol-D1, and palladium catalyst is 1:5:0.1. The amount of deuterium gas used is 2 bar.

[0081] Steps (4) and (5) utilize catalytic deuteration to introduce four deuterium atoms in a single, highly selective manner, namely on three rings and one ester group. The source of deuterium atoms is stable and not easily lost, resulting in a high deuteration rate. This reaction sequence avoids the loss or exchange of deuterium atoms introduced in the early stages in subsequent reactions, thus ensuring the deuteration rate.

[0082] (6) Dissolve furanoic acid-D3 methyl ester in tetrahydrofuran, methanol and water, add alkali (sodium hydroxide, lithium hydroxide), and hydrolyze at room temperature for 2 h to obtain furanoic acid-D3;

[0083] The volume ratio of tetrahydrofuran, methanol and water in the mixed solvent is 4:2:1 by mass volume.

[0084] The ratio of furanoic acid-D3 methyl ester to mixed solvent is 1:5 by mass and volume.

[0085] The molar ratio of furanoic acid-D3 methyl ester to base I is 1:1.5.

[0086] (7) Dissolve furanoic acid-D3 in solvent II and condense it with NH4Cl or ammonia to obtain furfurylamide-D3; hydrolyze the deuterated ester to an acid and convert it into an amide.

[0087] The ratio of furanoic acid-D3 to solvent II is 1:5 by mass and volume.

[0088] On a molar basis, furanoic acid-D3:NH4Cl or ammonia = 1:5.

[0089] (8) Dissolve furfuramide-D3 in tetrahydrofuran, add LiAlD4 in batches, heat under reflux for 2-8 hours to obtain furfuramide-D5, cool to room temperature, add dilute hydrochloric acid and stir for 30 minutes to obtain the deuterated amine intermediate furfuramide-D5 hydrochloride;

[0090] Using LiAlD4 as a reducing agent, the carbonyl group of the amide is reduced to a methylene group (CD2), and the last two deuterium atoms are precisely introduced, thus completing the introduction of all five deuterium atoms.

[0091] By mass and volume, furfural-D3:tetrahydrofuran = 1:5.

[0092] On a molar basis, furfural-D3:LiAlD4:dilute hydrochloric acid = 1:2-4:2.

[0093] (9) Furfurylamine-D5 hydrochloride and 2,4-dichloro-5-sulfonamide benzoic acid were dissolved in solvent III (ethylene glycol, acetonitrile or N,N-dimethylformamide), and base II (DIPEA, TEA or K2CO3) was added. The reaction was carried out at 20°C for 8 h. The condensation reaction was completed to obtain furosemide-D5.

[0094] On a molar basis, furfurylamine-D5 hydrochloride : 2,4-dichloro-5-sulfonamide benzoic acid : base II = 1 : 1 : 1;

[0095] By mass and volume, 2,4-dichloro-5-sulfonamide benzoic acid: solvent III = 1:5.

[0096] The specific synthetic route of furosemide-D5 in this invention is as follows: Figure 1 As shown.

[0097] Example 2

[0098] A method for synthesizing furosemide-D5, comprising the following steps:

[0099] (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol in 7.5% sulfuric acid / n-hexane, heat to 120°C, and add potassium dichromate in 25% sulfuric acid solution; after the addition is complete, maintain the reaction at 120°C until complete to obtain 3,4-dibromofuran; the ratio of 7.5% sulfuric acid to n-hexane is 1:5; the mass-volume ratio (g:mL) of potassium dichromate in 25% sulfuric acid solution is 1:10.

[0100] The ratio of trans-2,3-dibromo-2-butene-1,4-diol, sulfuric acid / n-hexane solution, and potassium dichromate / sulfuric acid solution by mass and volume is 1:20:10.

[0101] (2) Dissolve 3,4-dibromofuran in tetrahydrofuran, add a strong base (NaH, LDA or NaHMDS) at 0°C, keep for 60 min, add dry ice, and react at 0°C for 1 h. Quench with water to obtain 3,4-dibromofuran-2-carboxylic acid.

[0102] The ratio of 3,4-dibromofuran, tetrahydrofuran, and dry ice by mass and volume is 1:30:5.

[0103] (3) Dissolve 3,4-dibromofuran-2-carboxylic acid in methanol, add concentrated sulfuric acid in a catalytic amount, and reflux for 48 h to obtain methyl 3,4-dibromofuran-2-carboxylic acid;

[0104] The ratio of 3,4-dibromofuran-2-carboxylic acid, methanol, and concentrated sulfuric acid, by mass and volume, is 1:20:0.2.

[0105] (4) Dissolve methyl 3,4-dibromofuran-2-carboxylic acid in solvent I (DCM, THF or DCE), add Lewis acid (AlCl3 or AlBr3) and bromine or NBS to halogenate to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid.

[0106] The methyl 3,4-dibromofuran-2-carboxylic acid ester, by mass and volume, has a solvent ratio of 1:20.

[0107] The molar ratio of methyl 3,4-dibromofuran-2-carboxylic acid, Lewis acid, bromine, or NBS is 1:2:2.

[0108] (5) 3,4,5-tribromofuran-2-carboxylic acid methyl ester was dissolved in methanol-D1 (deuterated methanol) and subjected to catalytic deuteration reaction under palladium catalyst (palladium on carbon, palladium hydroxide on carbon) and deuterium gas (D2) to reduce it to furanoic acid-D3 methyl ester.

[0109] The mass-volume ratio of methyl 3,4,5-tribromofuran-2-carboxylic acid, methanol-D1, and palladium catalyst is 1:20:0.5. The amount of deuterium gas used is 2 bar.

[0110] (6) Dissolve furanoic acid-D3 methyl ester in tetrahydrofuran, methanol and water, add alkali (sodium hydroxide or lithium hydroxide), and hydrolyze at room temperature for 2-8 hours to obtain furanoic acid-D3;

[0111] The volume ratio of tetrahydrofuran, methanol and water in the mixed solvent is 4:2:1 by mass volume.

[0112] The ratio of furanoic acid-D3 methyl ester to mixed solvent is 1:20 by mass and volume.

[0113] The molar ratio of furanoic acid-D3 methyl ester to base I is 1:3.

[0114] (7) Dissolve furanoic acid-D3 in a solvent and condense it with NH4Cl or ammonia to obtain furfurylamide-D3; hydrolyze the deuterated ester to an acid and convert it into an amide.

[0115] The ratio of furanoic acid-D3 to solvent II is 1:20 by mass and volume.

[0116] On a molar basis, furanoic acid-D3:NH4Cl or ammonia water = 1:20.

[0117] (8) Dissolve furfuramide-D3 in tetrahydrofuran, add LiAlD4 in batches, heat under reflux for 2-8 hours to obtain furfuramide-D5, cool to room temperature, add dilute hydrochloric acid and stir for 30 minutes to obtain the deuterated amine intermediate furfuramide-D5 hydrochloride;

[0118] By mass and volume, furfural-D3:tetrahydrofuran = 1:20.

[0119] On a molar basis, furfural-D3:LiAlD4:dilute hydrochloric acid = 1:4:10.

[0120] (9) Furfurylamine-D5 hydrochloride and 2,4-dichloro-5-sulfonamide benzoic acid were dissolved in solvent III (ethylene glycol, acetonitrile or N,N-dimethylformamide), and alkali (DIPEA, TEA or K2CO3) was added. The reaction was carried out at 100℃ for 2 h. The condensation reaction was completed to obtain furosemide-D5.

[0121] On a molar basis, furfurylamine-D5 hydrochloride : 2,4-dichloro-5-sulfonamide benzoic acid : base II = 3 : 1 : 5;

[0122] The mass-volume ratio of 2,4-dichloro-5-sulfonamide benzoic acid to solvent III is 1:20.

[0123] Example 3

[0124] A method for synthesizing furosemide-D5, comprising the following steps:

[0125] (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol in 7.5% sulfuric acid / n-hexane, heat to 80°C, and add potassium dichromate in 25% sulfuric acid solution; after the addition is complete, maintain the reaction at 80°C until complete to obtain 3,4-dibromofuran; the ratio of 7.5% sulfuric acid to n-hexane is 1:3; the mass-volume ratio (g:mL) of potassium dichromate in 25% sulfuric acid solution is 1:8.

[0126] The ratio of trans-2,3-dibromo-2-butene-1,4-diol, sulfuric acid / n-hexane solution, and potassium dichromate / sulfuric acid solution by mass and volume is 1:10:7.

[0127] (2) Dissolve 3,4-dibromofuran in tetrahydrofuran, add strong base I (NaH, LDA or NaHMDS) at -50℃, keep for 45 min, add dry ice, and react at -50℃ for 3 h. Quench with water to obtain 3,4-dibromofuran-2-carboxylic acid.

[0128] The ratio of 3,4-dibromofuran, tetrahydrofuran, and dry ice by mass and volume is 1:20:3.

[0129] (3) Dissolve 3,4-dibromofuran-2-carboxylic acid in methanol, add concentrated sulfuric acid in a catalytic amount, and reflux for 35 h to obtain methyl 3,4-dibromofuran-2-carboxylic acid;

[0130] The ratio of 3,4-dibromofuran-2-carboxylic acid, methanol, and concentrated sulfuric acid by mass and volume is 1:12:0.1.

[0131] (4) Dissolve methyl 3,4-dibromofuran-2-carboxylic acid in solvent I (DCM, THF or DCE), add Lewis acid (AlCl3 or AlBr3) and bromine or NBS to halogenate to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid.

[0132] The methyl 3,4-dibromofuran-2-carboxylic acid ester, by mass and volume, has a solvent ratio of 1:12.

[0133] The molar ratio of methyl 3,4-dibromofuran-2-carboxylic acid, Lewis acid, bromine, or NBS is 1:1.5:1.5.

[0134] (5) 3,4,5-tribromofuran-2-carboxylic acid methyl ester was dissolved in methanol-D1 (deuterated methanol) and subjected to catalytic deuteration reaction under palladium catalyst (palladium on carbon, palladium hydroxide on carbon) and deuterium gas (D2) to reduce it to furanoic acid-D3 methyl ester.

[0135] The mass-volume ratio of methyl 3,4,5-tribromofuran-2-carboxylate, methanol-D1, and palladium catalyst is 1:12:0.3. The amount of deuterium gas used is 2 bar.

[0136] (6) Dissolve furanoic acid-D3 methyl ester in tetrahydrofuran, methanol and water, add alkali (sodium hydroxide, lithium hydroxide), and hydrolyze at room temperature for 5 h to obtain furanoic acid-D3;

[0137] The volume ratio of tetrahydrofuran, methanol and water in the mixed solvent is 4:2:1 by mass volume.

[0138] The ratio of furanoic acid-D3 methyl ester to mixed solvent is 1:12 by mass and volume.

[0139] The molar ratio of furanoic acid-D3 methyl ester to base I is 1:2.

[0140] (7) Dissolve furanoic acid-D3 in solvent II and condense it with NH4Cl or ammonia to obtain furfurylamide-D3; hydrolyze the deuterated ester to an acid and convert it into an amide.

[0141] The ratio of furanoic acid-D3 to solvent II is 1:12 by mass and volume.

[0142] On a molar basis, furanoic acid-D3:NH4Cl or ammonia water = 1:12.

[0143] (8) Dissolve furfuramide-D3 in tetrahydrofuran, add LiAlD4 in batches, heat under reflux for 6 h to obtain furfuramide-D5, cool to room temperature, add dilute hydrochloric acid and stir for 30 min to obtain deuterated amine intermediate furfuramide-D5 hydrochloride;

[0144] By mass and volume, furfural-D3:tetrahydrofuran = 1:12.

[0145] On a molar basis, furfural-D3:LiAlD4:dilute hydrochloric acid = 1:3:6.

[0146] (9) Furfurylamine-D5 hydrochloride and 2,4-dichloro-5-sulfonamide benzoic acid were dissolved in solvent III (ethylene glycol, acetonitrile or N,N-dimethylformamide), and base II (DIPEA, TEA or K2CO3) was added. The reaction was carried out at 60°C for 4 h, and the condensation reaction was completed to obtain furosemide-D5.

[0147] On a molar basis, furfurylamine-D5 hydrochloride: 2,4-dichloro-5-sulfonamide benzoic acid: base II = 2:1:3;

[0148] The mass-volume ratio of 2,4-dichloro-5-sulfonamide benzoic acid to solvent III is 1:12.

[0149] Example 4

[0150] A method for synthesizing furosemide-D5, comprising the following steps:

[0151] (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol (100 g, 406.67 mmol) in 7.5% sulfuric acid / n-hexane (1.5 L, V:V=3:10), heat to 70 °C, and add potassium dichromate (119.5 g, 406.67 mmol) in 25% sulfuric acid (500 mL). After the addition is complete, keep the reaction at 60 °C until complete, and directly separate the liquid and dry the organic phase with anhydrous sodium sulfate to obtain a hexane solution of 3,4-dibromofuran, which can be used directly in the next step of the reaction without purification.

[0152] (2) The hexane solution of 3,4-dibromofuran obtained in step one was diluted with tetrahydrofuran. An appropriate amount of LDA was added at -78°C, and the mixture was kept at -78°C for 40 min. Dry ice was added, and the reaction was continued at -78°C for 1 h. The mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed from the solvent under reduced pressure. The crude product was purified by silica column chromatography to obtain 3,4-dibromofuran-2-carboxylic acid (20 g, 74.07 mmol). The total yield of the two steps was 18.21%.

[0153] (3) Dissolve 5 g of 3,4-dibromofuran-2-carboxylic acid (18.52 mmol) in methanol (50 mL), add 1 mL of concentrated sulfuric acid, reflux for 24 h, remove methanol directly under reduced pressure, and purify by silica column chromatography to obtain methyl 3,4-dibromofuran-2-carboxylic acid (4.5 g, 15.85 mmol); the yield of this step is 85.58%.

[0154] (4) Methyl 3,4-dibromofuran-2-carboxylic acid (4 g, 14.09 mmol) was dissolved in ultradry DCE (70 mL), AlBr3 was added, followed by the dropwise addition of bromine (2.7 g, 16.91 mmol). The reaction was carried out overnight at room temperature, washed with sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid (2.1 g, 5.79 mmol); the yield of this step was 41.09%. The molar ratio of methyl 3,4-dibromofuran-2-carboxylic acid to AlBr3 was 1:1.

[0155] (5) Methyl 3,4,5-tribromofuran-2-carboxylic acid ester (5 g, 13.78 mmol) was dissolved in methanol-D1 (30 mL), palladium hydroxide on carbon (300 mg) was added, the mixture was purged with argon three times, and then purged with deuterium three times. The reaction was carried out overnight at room temperature, the catalyst was removed by filtration, and the mixture was dried under reduced pressure to obtain methyl furanoate-D3 (1 g, 7.75 mmol); the yield of this step was 56.24%.

[0156] (6) Methyl furanoate-D3 (1 g, 7.75 mmol) was dissolved in tetrahydrofuran / methanol / water (20 mL; V:V:V=4:2:1), sodium hydroxide (620 mg, 15.50 mmol) was added, and hydrolysis was carried out at room temperature for 8 h until the reaction was complete. The pH was adjusted to 2 with 2 mol / L hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product. Furanoate-D3 (800 mg, 6.95 mmol) was purified by silica column chromatography. The yield of this step was 89.68%.

[0157] (7) Furanic acid-D3 (2 g, 17.37 mmol) was dissolved in DMF (20 mL), and HATU (7.9 g, 20.85 mmol), DIPEA (6.7 g, 52.11 mmol) and NH4Cl (4.6 g, 86.85 mmol) were added sequentially. The mixture was reacted at room temperature for 5 h, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furfural-D3 (1 g, 9.38 mmol); the yield of this step was 54.00%.

[0158] (8) Furfural-D3 (1 g, 9.38 mmol) was dissolved in tetrahydrofuran (30 mL), and LiAlD4 (985 mg, 23.45 mmol) was added in portions. The mixture was heated under reflux for 4 h until the reaction was complete. After cooling to room temperature, dilute hydrochloric acid was added and stirred for 30 minutes. The mixture was extracted with ethyl acetate and the aqueous phase was lyophilized to obtain furfural-D5 hydrochloride (450 mg, 3.25 mmol). The yield of this step was 34.65%.

[0159] (9) Furfurylamine-D5 hydrochloride (1 g, 7.21 mmol) and 2,4-dichloro-5-sulfonamide benzoic acid (1.8 g, 7.21 mmol) were dissolved in DMF (30 mL), and K2CO3 (3 g, 21.63 mmol) was added. The reaction mixture was reacted overnight at room temperature, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furosemide-D5 (726 mg, 2.16 mmol). The yield of this step was 29.96%. The overall yield was 0.60%.

[0160] Example 5

[0161] A method for synthesizing furosemide-D5, comprising the following steps:

[0162] (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol (100 g, 406.67 mmol) in 7.5% sulfuric acid / n-hexane (1.5 L, V:V = 3:10), heat to 90 °C, and add potassium dichromate (119.5 g, 406.67 mmol) in 25% sulfuric acid (500 mL). After the addition is complete, maintain the reaction at 90 °C until complete, and directly separate the liquid phase. Dry the organic phase with anhydrous sodium sulfate to obtain a hexane solution of 3,4-dibromofuran, which can be used directly in the next reaction without purification.

[0163] (2) The hexane solution of 3,4-dibromofuran obtained in step one was diluted with tetrahydrofuran. An appropriate amount of LDA was added at -78°C, and the mixture was kept at this temperature for 30 min. Dry ice was added, and the reaction was continued at -78°C for 1 h. The mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed from the solvent under reduced pressure. The crude product was purified by silica column chromatography to obtain 3,4-dibromofuran-2-carboxylic acid (26 g, 96.30 mmol). The yield of both steps was 23.68%.

[0164] (3) Dissolve 5 g of 3,4-dibromofuran-2-carboxylic acid (18.52 mmol) in methanol (50 mL), add 1 mL of concentrated sulfuric acid, reflux for 16 h, remove methanol directly under reduced pressure, and purify by silica column chromatography to obtain methyl 3,4-dibromofuran-2-carboxylic acid (3.8 g, 13.38 mmol); the yield of this step is 72.25%.

[0165] (4) Methyl 3,4-dibromofuran-2-carboxylic acid (4 g, 14.09 mmol) was dissolved in ultradry DCM (70 mL), AlCl3 (3.7 g, 28.18 mmol) was added, followed by the dropwise addition of bromine (2.7 g, 16.91 mmol). The mixture was reacted overnight at room temperature, washed with sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid (3.5 g, 9.65 mmol); the yield of this step was 68.49%.

[0166] (5) Methyl 3,4,5-tribromofuran-2-carboxylic acid (5 g, 13.78 mmol) was dissolved in methanol-D1 (30 mL), palladium on carbon (300 mg) was added, the mixture was purged with argon three times, and then purged with deuterium three times. The reaction was carried out overnight at room temperature, the catalyst was removed by filtration, and the mixture was dried under reduced pressure to obtain methyl furanoate-D3 (1.2 g, 9.30 mmol); the yield of this step was 67.49%.

[0167] (6) Methyl furanoate-D3 (1 g, 7.75 mmol) was dissolved in tetrahydrofuran / methanol / water (20 mL; V:V:V=4:2:1), sodium hydroxide (620 mg, 15.50 mmol) was added, and hydrolysis was carried out at room temperature for 8 h until the reaction was complete. The pH was adjusted to 2 with 2 mol / L hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furanoate-D3 (800 mg, 6.95 mmol); the yield of this step was 89.68%.

[0168] (7) Furanic acid-D3 (2 g, 17.37 mmol) was dissolved in DMF (20 mL), and HATU (7.9 g, 20.85 mmol), DIPEA (6.7 g, 52.11 mmol) and NH4Cl (4.6 g, 86.85 mmol) were added sequentially. The mixture was reacted at room temperature for 5 h, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furfural-D3 (1 g, 9.38 mmol); the yield of this step was 54.00%.

[0169] (8) Furfural-D3 (1 g, 9.38 mmol) was dissolved in tetrahydrofuran (30 mL), and LiAlD4 (985 mg, 23.45 mmol) was added in portions. The mixture was heated under reflux for 4 h until the reaction was complete. After cooling to room temperature, dilute hydrochloric acid was added and stirred for 30 min. The mixture was extracted with ethyl acetate and the aqueous phase was freeze-dried to obtain furfural-D5 hydrochloride (450 mg, 3.25 mmol). The yield of this step was 34.65%.

[0170] (9) Furfurylamine-D5 hydrochloride (1 g, 7.21 mmol) and 2,4-dichloro-5-sulfonamide benzoic acid (1.8 g, 7.21 mmol) were dissolved in DMF (30 mL), and K2CO3 (3 g, 21.63 mmol) was added. The reaction mixture was reacted overnight at room temperature, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Furosemide-D5 (726 mg, 2.16 mmol) was purified by silica column chromatography. The yield of this step was 29.96%. Overall yield: 0.40%.

[0171] Example 6

[0172] A method for synthesizing furosemide-D5, comprising the following steps:

[0173] (1) Dissolve 100 g (406.67 mmol) of trans-2,3-dibromo-2-buten-1,4-diol in 7.5% sulfuric acid / n-hexane (1.5 L, V:V=3:10), heat to 90 °C, and add 500 mL of 25% sulfuric acid solution containing potassium dichromate (119.5 g, 406.67 mmol). After the addition is complete, maintain the reaction at 90 °C until complete, and directly separate the liquid phase. Dry the organic phase with anhydrous sodium sulfate to obtain a hexane solution of 3,4-dibromofuran, which can be used directly in the next reaction without purification.

[0174] (2) The hexane solution of 3,4-dibromofuran obtained in step one was diluted with tetrahydrofuran. An appropriate amount of NaHMDS was added at -40°C, and the mixture was kept at -40°C for 60 min. Dry ice was added, and the reaction was carried out at -40°C for 1 h. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed from the solvent under reduced pressure. The crude product was purified by silica column chromatography to obtain 3,4-dibromofuran-2-carboxylic acid (10 g, 37.04 mmol); the yield of the above two steps was 9.11%.

[0175] (3) Dissolve 5 g of 3,4-dibromofuran-2-carboxylic acid in 50 mL of methanol, add 1 mL of concentrated sulfuric acid, reflux for 48 h, remove methanol directly under reduced pressure, and purify by silica column chromatography to obtain methyl 3,4-dibromofuran-2-carboxylic acid (4.6 g, 16.20 mmol); the yield of this step is 87.47%.

[0176] (4) Methyl 3,4-dibromofuran-2-carboxylic acid (4 g, 14.09 mmol) was dissolved in ultradry DCE (70 mL), AlCl3 was added (3.7 g, 28.18 mmol), and bromine (2.7 g, 16.91 mmol) was added dropwise. The mixture was reacted overnight at room temperature, washed with sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid (4.1 g, 11.30 mmol); the yield of this step was 80.20%.

[0177] (5) Methyl 3,4,5-tribromofuran-2-carboxylic acid (5 g, 13.78 mmol) was dissolved in methanol-D1 (30 mL), palladium hydroxide on carbon (300 mg) was added, the mixture was purged with argon three times, and then purged with deuterium three times. The reaction was carried out overnight at room temperature, the catalyst was removed by filtration, and the mixture was dried under reduced pressure to obtain methyl furanoate-D3 (1 g, 7.75 mmol); the yield of this step was 56.24%.

[0178] (6) Methyl furanoate-D3 (1 g, 7.75 mmol) was dissolved in tetrahydrofuran / methanol / water (20 mL; V:V:V=4:2:1), and lithium hydroxide (372 mg, 15.50 mmol) was added. The mixture was hydrolyzed at room temperature for 4 h until the reaction was complete. The pH was adjusted to 2 with 2 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furanoate-D3 (815 mg, 7.09 mmol). The yield of this step was 91.48%.

[0179] (7) Furanic acid-D3 (2 g, 17.37 mmol) was dissolved in THF (20 mL), and ethyl chloroformate (7.9 g, 20.85 mmol) and TEA (6.7 g, 52.11 mmol) were added sequentially at 0 °C. The mixture was kept for 30 min, and ammonia (11.3 g, 173.70 mmol) was added. The mixture was reacted at room temperature for 3 h, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furfural-D3 (1.6 g, 13.90 mmol). The yield of this step was 80.02%.

[0180] (8) Furfural-D3 (1 g, 9.38 mmol) was dissolved in tetrahydrofuran (30 mL), and LiAlD4 (985 mg, 23.45 mmol) was added in portions. The mixture was heated under reflux for 4 h until the reaction was complete. After cooling to room temperature, dilute hydrochloric acid was added and stirred for 30 min. The mixture was extracted with ethyl acetate and the aqueous phase was freeze-dried to obtain furfural-D5 hydrochloride (450 mg, 3.25 mmol). The yield of this step was 34.65%.

[0181] Furfurylamine-D5 hydrochloride (1 g, 7.21 mmol) and 2,4-dichloro-5-sulfonamide benzoic acid (1.8 g, 7.21 mmol) were dissolved in ethylene glycol (30 mL), and TEA (2.2 g, 21.63 mmol) was added. The reaction mixture was reacted at 80 °C for 4 h, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography to obtain furosemide-D5 (1.6 g, 4.81 mmol). The yield of this step was 66.71%.

[0182] The furosemide-D5 obtained in Example 6 of this invention was analyzed by HPLC, NMR for confirmation, and LCMS for mass spectrometry. Figure 2 , Figure 3 and Figure 4As shown. HPLC analysis, NMR confirmation, and LCMS analysis were performed using conventional methods. The LC-MS instrument used was an Agilent 1100 Series+ 6120 Quadrupole LC / MS; the HPLC instrument was a DIONEX UltiMate 3000 Pump; and the NMR instrument was a Bruker QUANTUM-I. The detection temperature was ambient temperature (20-25℃).

[0183] from Figure 2 The results show that the purity of furosemide-D5 (main peak) is >98.6%, the total amount of impurities is <1.4%, and the sample purity is high. The furosemide-D5 peak is completely separated from the impurity peaks and there is no overlap, which can effectively distinguish furosemide-D5 from impurities.

[0184] from Figure 3 As can be seen from the data, the structure contains a deuterated group, and the hydrogen nucleus of the deuterated group in the structure was successfully replaced, which shows the effectiveness of the deuteration modification, and the abundance of furosemide-D5 is >98%.

[0185] Figure 4 The liquid chromatography-mass spectra of furosemide-D5 are shown below. Figures 5-9 The figure shows the HNMR spectra of the corresponding intermediate compounds in the reaction, which shows that the compounds obtained in the reaction of this invention are present.

[0186] The following is a comparative experiment on the synthesis of furanoic acid-D3 methyl ester (equivalent to step 5) using the traditional deuterium exchange method:

[0187] Methyl furanoate was dissolved in a D2O / CD3OD mixed solvent, and a Pd / C catalyst was added. The reaction was carried out at 80°C for 48 h under a D2 atmosphere (1 MPa). Conventional LC-MS analysis after the reaction showed that the product was a mixture with uncertain deuteration positions and amounts. Approximately 30% of the hydrogen moiety at the 2-position of the furan ring was deuterated, and approximately 50-60% of the hydrogen moiety at the 3 and 4-positions was deuterated, accompanied by significant byproducts (hydrogenation, ring-opening, etc.). High-purity D3 methyl furanoate could not be obtained.

[0188] The above embodiments / experimental examples are merely illustrative and not intended to limit the implementation methods. Those skilled in the art will recognize that various variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementation methods. However, obvious variations or modifications derived therefrom remain within the scope of this invention.

Claims

1. A method for synthesizing furosemide-D5, characterized in that: The preparation steps include the following: ； (1) Dissolve trans-2,3-dibromo-2-buten-1,4-diol in 7.5% sulfuric acid / n-hexane, heat to 70-120℃, and add potassium dichromate in 25% sulfuric acid solution to react and obtain 3,4-dibromofuran; the ratio of 7.5% sulfuric acid to n-hexane is 1:1-5; the mass-volume ratio of potassium dichromate in 25% sulfuric acid solution is 1:5-10; (2) Dissolve 3,4-dibromofuran in tetrahydrofuran, add a strong base at 0-78℃, maintain for 30-60 min, add dry ice and react for 1-4 h, quench with water to obtain 3,4-dibromofuran-2-carboxylic acid; the strong base is NaH, LDA or NaHMDS; (3) Dissolve 3,4-dibromofuran-2-carboxylic acid in methanol, add concentrated sulfuric acid, and reflux for 24-48 h to obtain methyl 3,4-dibromofuran-2-carboxylic acid; (4) Dissolve methyl 3,4-dibromofuran-2-carboxylic acid in solvent I, add Lewis acid and bromine or NBS for halogenation to obtain methyl 3,4,5-tribromofuran-2-carboxylic acid; (5) 3,4,5-tribromofuran-2-carboxylic acid methyl ester was dissolved in methanol-D1 and reduced under palladium catalyst and deuterium to obtain furanoic acid-D3 methyl ester; (6) Add furanoic acid-D3 methyl ester to a mixed solution of tetrahydrofuran, methanol and water and stir until homogeneous. Then add base I and hydrolyze at room temperature for 2-8 hours to obtain furanoic acid-D3. (7) Dissolve furanoic acid-D3 in solvent II and condense it with NH4Cl or ammonia to obtain furfural-D3; (8) Dissolve furfuramide-D3 in tetrahydrofuran, add LiAlD4, heat under reflux for 2-8 hours to obtain furfuramide-D5, cool to room temperature, add dilute hydrochloric acid and stir to obtain furfuramide-D5 hydrochloride; (9) Furfurylamine-D5 hydrochloride and 2,4-dichloro-5-sulfonamide benzoic acid are dissolved in solvent III, and base II is added. The mixture is reacted at 20-100℃ for 2-8 hours to obtain furosemide-D5.

2. The method for synthesizing furosemide-D5 according to claim 1, characterized in that: In step (4), solvent I is DCM, THF or DCE.

3. The method for synthesizing furosemide-D5 according to claim 1, characterized in that: In step (7), solvent II is tetrahydrofuran or N,N-dimethylformamide.

4. The method for synthesizing furosemide-D5 according to claim 1, characterized in that: In step (4), the Lewis acid is AlCl3 or AlBr3.

5. The method for synthesizing furosemide-D5 according to claim 1, characterized in that: In step (5), the palladium catalyst is palladium on carbon or palladium hydroxide on carbon.

6. The method for synthesizing furosemide-D5 according to claim 1, characterized in that: In step (6), alkali I is sodium hydroxide or lithium hydroxide.

7. The method for synthesizing furosemide-D5 according to claim 1, characterized in that: In step (9), solvent III is ethylene glycol, acetonitrile, or N,N-dimethylformamide.

8. A method for synthesizing furosemide-D5 according to any one of claims 1-7, characterized in that: The alkali II is DIPEA, TEA or K2CO3.

Images