Deuterated carbohydrate compound as well as synthesis method and application thereof

Abstract

The invention provides a deuterated carbohydrate compound and a synthesis method and application thereof, the synthesis method comprises the following steps: using carbohydrates as raw materials, carrying out group protection primary alcohol selective deprotection on the carbohydrates, reacting the primary alcohol with an oxidant to generate corresponding carboxylic acid, reducing the carboxylic acid into deuterated alcohol by a reductive deuterated reagent, and finally removing a protecting group to obtain a deuterated product. The synthesis method disclosed by the invention is high in reaction conversion rate, and the synthesis cost of the type of compound can be reduced; the whole synthesis process has the advantages of high reactant yield, low cost, simple and feasible separation process, easily available raw materials and mild process conditions, and is suitable for large-scale synthesis. The method disclosed by the invention can be used for preparing the deuterated carbohydrate compound efficiently and quickly at low cost, and has a relatively high industrial popularization value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and relates to a deuterated saccharide compound and a synthesis method and application thereof. BACKGROUND

[0002] Glucose metabolism is one of the most basic life activities, and has been the focus of cancer research because malignant tumor cells exhibit completely different metabolic characteristics compared with normal tissue cells, namely metabolic reprogramming. Among them, the reprogramming of glucose metabolism (referred to as sugar metabolism) increases the uptake of glucose by malignant tumor cells, improves the glycolysis effect, also known as the Warburg effect, thereby providing more and faster energy supply for tumor cells, promoting tumor cell proliferation. The Warburg effect provides an important clue for early diagnosis of cancer. The increased levels of lactic acid and pyruvic acid downstream of glycolysis can not only be used as a biomarker for early cancer, but also can be spatially positioned and quantitatively analyzed through DMI technology, providing multi-dimensional metabolic information for early diagnosis, efficacy evaluation and prognosis monitoring of tumors, significantly improving the clinical application value of precise diagnosis and treatment of cancer. In the diagnosis and treatment of solid tumors, the visualization of the Warburg effect can reveal the significant correlation between the HER2-positive subtype of breast cancer and the activity of glycolysis, and the predictive value of early lactic acid accumulation in pancreatic cancer for chemotherapy resistance.

[0003] Compared to 18F-FDG: Deuterated glucose metabolism imaging has revolutionary advantages over traditional 18F-FDG PET imaging: it is labeled with stable isotopes, can fully participate in glycolysis and TCA cycle, and provides multi-dimensional metabolic information by dynamically monitoring metabolites such as lactic acid and glutamic acid, while 18F-FDG only reflects glucose uptake and the metabolic pathway is easily blocked. [6,6'-2H2]-D-glucose non-invasively quantifies glucose uptake and visualizes its metabolic pathway, which is extremely important for understanding the pathogenesis of diseases (such as tumors, neurological diseases, and metabolic-related diseases) and monitoring their progression. Positron emission tomography (PET) using the radioactive analogue 2-[18F]fluorodeoxyglucose (FDG) has been widely used for disease diagnosis by detecting abnormal glucose uptake. However, 18FDG-PET cannot reflect subsequent glucose metabolism, so it cannot provide information about its metabolic pathway. This technology has the special advantages of zero radiation and repeatable detection, especially for children and pregnant women, while quantifying metabolic flow changes; it shows more precise clinical value in tumor metabolic typing and treatment monitoring. The half-life of 18F-FDG is short (110 minutes), and it cannot be stored, but only prepared using a nearby cyclotron and then transported. Compared to 18F-FDG, [6,6'-2H2]-D-glucose has no half-life and can be purchased and stored directly. Deuterated glucose imaging only requires upgrading of conventional MRI equipment, and the cost of a single detection is reduced, providing a new paradigm for precision medicine with safer, more economical, and more information-rich metabolic evaluation.

[0004] Compared to [13C] pyruvate: The main advantages of 2H (deuterium) glucose MRS in clinical practice are its non-invasiveness, safety, and long-term metabolic monitoring capability. Compared to [13C] pyruvate, which requires intravenous injection and hyperpolarization processing, deuterated glucose can not only be administered intravenously but also be taken orally, greatly improving patient compliance, especially for children, long-term follow-up, or repetitive studies. Since 2H is a stable isotope and naturally exists, there is no need for hyperpolarization or paramagnetic agents, avoiding the complex preparation process and potential toxicity risks required for [13C] pyruvate, making it more suitable for repeated detection and long-term metabolic studies. In addition, 2H glucose can directly reflect glucose uptake and overall glycolytic flux, while [13C] pyruvate only shows downstream pyruvate metabolism (such as lactic acid conversion), so it is more comprehensive in studying whole-body glucose homeostasis (such as liver and brain tissue metabolism). However, the sensitivity of 2H is lower, and it is currently mainly used for research, while [13C] pyruvate is more suitable for rapid dynamic imaging of cancer and myocardial ischemia due to the high signal enhancement of hyperpolarization technology. Both complement each other, with 2H glucose focusing on basic metabolic evaluation and [13C] pyruvate excelling in acute pathological metabolism capture.

[0005] Overall, [6,6'-2H2]-D-glucose diagnosis has the following significant advantages:

[0006] 1. No risk of ionizing radiation: Compared with radioactive examination methods such as PET-CT, DMI completely avoids ionizing radiation exposure, and is particularly suitable for cases that require long-term follow-up monitoring;

[0007] 2. High-specificity probe: Deuterium-labeled probes have stable chemical properties, clear metabolic pathways in vivo, and are not affected by endogenous water and fat signals;

[0008] 3. Simultaneous detection of multiple metabolites: Multiple metabolites (such as lactic acid and pyruvic acid) can be quantified simultaneously, providing more comprehensive metabolic pathway information;

[0009] 4. Dynamic monitoring capability: Achieving whole-process metabolic kinetics monitoring from probe uptake to end product generation;

[0010] 5. Excellent convenience: Deuterium, as a naturally occurring stable isotope, can be purchased and stored directly, and can also be taken orally, greatly improving patient compliance.

[0011] Compared with traditional techniques, the breakthrough of metabolic imaging technology provides a new means for non-invasive detection of tumors. Among them, deuterium metabolic imaging (DMI) introduces exogenous deuterium (2H)-labeled molecular probes (such as 2H-glucose) into the body, and uses magnetic resonance spectroscopy imaging (MRSI) technology to non-invasively, dynamically, and quantitatively track the metabolic process of molecular probes in vivo. This technology realizes the dynamic visualization monitoring of the sugar metabolism pathway by spectroscopic quantification and imaging of downstream metabolites (such as lactic acid and glutamine). The emergence of this technology marks that metabolic imaging is becoming an important breakthrough in the field of tumor diagnosis.

[0012] [6,6'-2H2]-D-glucose is a new type of non-radiation metabolic tracer, which has important application value in the fields of tumor metabolism research (such as glioma, pancreatic cancer, liver cancer, breast cancer, etc.), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, stroke, brain injury, etc.), and metabolic-related disease diagnosis and treatment. This product uses deuterium stable isotope labeling technology, breaking through the radiation limitation of traditional tracers, and is particularly suitable for the long-term dynamic monitoring needs of sensitive groups such as children and pregnant women, while meeting the urgent needs of precision and safe metabolic imaging in clinical practice.

[0013] The existing [6,6'-2H2]-D-glucose synthesis method has the following problems: no clear synthesis method, low selectivity, traditional catalytic deuterium exchange method is easy to cause multi-site deuteration, and affects the accuracy of subsequent metabolic detection, low yield, chemical reduction method has many side reactions, and product purification is difficult, and high cost: some methods need expensive catalysts or deuterium reagents, which is not conducive to industrial production. SUMMARY

[0014] In view of the deficiencies of the prior art, the purpose of the present application is to provide a synthesis method of deuterated sugar compounds.

[0015] To achieve this purpose, the present application adopts the following technical solutions:

[0016] On the one hand, the present application provides a synthesis method of deuterated sugar compounds, wherein the deuterated sugar compounds have the following structure shown in formula I:

[0017] ;

[0018] Wherein, n is selected from an integer from 0 to 5 (for example, 0, 1, 2, 3, 4 or 5), m is selected from an integer from 0 to 5 (for example, 0, 1, 2, 3, 4 or 5), and when n and m are each 0, the group does not exist;

[0019] The R groups are each independently selected from any one of OH, hydrogen, C3-C7 (for example, C3, C4, C5, C6 or C7) branched or branched alkyl, acyl, halogen, ester group or C5-C7 (C5, C6 or C7) aryl.

[0020] The R groups are each independently selected from n same or different substituents;

[0021] Ring A is an optional C3-7 cycloalkyl, C6-10 aryl ring, fused heterobicyclic group, aryl heterocyclic group or 5-7 membered monocyclic heterocyclic group; the heteroatoms in the fused heterobicyclic group or monocyclic heterocyclic group are at least one of nitrogen, oxygen or sulfur atom;

[0022] X is independently selected from oxygen, nitrogen, sulfur or carbon atom;

[0023] The synthesis method comprises the following steps:

[0024] (1) the alcohol of formula (a) is reacted with R2X2 compound to obtain the compound of formula (b);

[0025] (2) the compound of formula (b) is subjected to deprotection reaction, and then subjected to ester hydrolysis reaction to obtain the compound of formula (c);

[0026] (3) the compound of formula (c) is reacted with an oxidizing agent to obtain the compound of formula (d);

[0027] (4) reacting the compound of formula (d) with a deuterium reagent to obtain a compound of formula (e);

[0028] (5) deprotecting the compound of formula (e) under the action of a deprotecting reagent to obtain a deuterated saccharide compound of formula (I), and the reaction flow is as shown below:

[0029]

[0030] X2 is selected from halogen, for example, can be F or Br.

[0031] Preferably, the deuterated saccharide compound is selected from any one of the following structures:

[0032] .

[0033] Preferably, the molar ratio of the alcohol of formula (a) to the R2X2 compound in step (1) is 1: (1-12), for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:8, 1:10, 1:11 or 1:12.

[0034] Preferably, R2 in the R2X2 compound in step (1) is selected from an alkyl group or a silane group.

[0035] Preferably, R2 is selected from benzyl, methyl or a silane group; more preferably benzyl.

[0036] Preferably, the reaction in step (1) is carried out in the presence of a basic substance.

[0037] Preferably, the basic substance is selected from any one or a combination of at least two of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate.

[0038] Preferably, the molar ratio of the basic substance to the R2X2 compound is 1: (1-12), for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:8, 1:10, 1:11 or 1:12.

[0039] Preferably, the temperature of the reaction in step (1) is -75 ~ -80°C, for example -75°C, -60°C, -40°C, -20°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C or 80°C, preferably 0°C ~ 30°C.

[0040] Preferably, the deprotection reaction in step (2) is carried out in the presence of a Lewis acid.

[0041] Preferably, the Lewis acid is selected from zinc chloride.

[0042] Preferably, the deprotection reaction in step (2) is carried out in a solvent selected from a mixture of acetic acid and acetic anhydride, preferably, the volume ratio of acetic acid and acetic anhydride is 1:(3-6), for example, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6.

[0043] Preferably, the deprotection reaction in step (2) is carried out at a temperature of 0-70℃, for example, 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃ or 70℃, and the reaction time is 1-24 hours, for example, 1 hour, 2 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0044] Preferably, the ester hydrolysis reaction in step (2) is carried out in the presence of a basic substance.

[0045] Preferably, the basic substance is any one or a combination of at least two of sodium methoxide, sodium ethoxide or potassium tert-butoxide.

[0046] Preferably, the ester hydrolysis reaction in step (2) is carried out in a solvent selected from any one or a combination of at least two of methanol, ethanol or tert-butanol.

[0047] Preferably, the ester hydrolysis reaction in step (2) is carried out at room temperature, and the reaction time is 1-24 hours, for example, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0048] Preferably, the oxidant in step (3) is at least two of 2,2,6,6-tetramethylpiperidine oxide (TEMPO), diacetoxyiodobenzene or iodonium ylide.

[0049] Preferably, the molar ratio of the compound of formula (c) to the oxidant in step (3) is 1:(1-1.1), for example, 1:1, 1:1.03, 1:1.05, 1:1.08 or 1:1.1.

[0050] Preferably, the reaction in step (3) is carried out in a solvent selected from a mixture of dichloromethane, chloroform, acetone, acetonitrile and water, and the molar ratio of acetonitrile to water in the mixture of acetonitrile and water is (1-5):1; for example, 1:1, 2:1, 3:1, 4:1 or 5:1.

[0051] Preferably, the temperature of the reaction of step (3) is 0-30 °C, for example 0 °C, 5 °C, 8 °C, 10 °C, 15 °C, 18 °C, 20 °C, 25 °C or 30 °C, and the time of the reaction is 1-48 hours, for example 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 28 hours, 32 hours, 36 hours, 40 hours, 42 hours or 48 hours.

[0052] Preferably, the deuterated reagent of step (4) is selected from at least one of lithium aluminum deuteride or sodium borodeuteride.

[0053] Preferably, the molar ratio of the compound of formula (d) to the deuterated reagent of step (4) is 1:(0.5-1.1), for example 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or 1:1.1.

[0054] Preferably, the deprotection reagent used in the deprotection reaction of step (5) is at least one of hydrogen (palladium on carbon), Lewis acid, sulfide or fluoride.

[0055] Preferably, the temperature of the deprotection reaction of step (5) is 0-30 °C, for example 0 °C, 5 °C, 10 °C, 15 °C, 18 °C, 20 °C, 25 °C, 28 °C or 30 °C, and the time of the reaction is 1-24 hours, for example 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0056] Preferably, the deprotection reagent used in the deprotection reaction of step (5) is at least one of hydrogen (palladium on carbon), Lewis acid, sulfide or fluoride.

[0057] Preferably, the molar ratio of the compound of formula (e) to the deprotection reagent of step (5) is 1:(0.5-1.1), for example 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or 1:1.1.

[0058] Preferably, the deprotection reaction of step (5) is carried out in a solvent, which includes an alcohol solvent, preferably methanol.

[0059] Preferably, the temperature of the deprotection reaction of step (5) is 0-30 °C, for example 0 °C, 5 °C, 10 °C, 15 °C, 18 °C, 20 °C, 25 °C, 28 °C or 30 °C, and the time of the reaction is 1-24 hours, for example 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0060] The synthesis method of this invention is simpler, has shorter process steps, and higher reaction yield; it avoids the use of precious metal catalysts and organometallic compounds, the reaction raw materials are cheap and readily available, and the process is safer; in particular, the deuteration sites of the obtained product are precise, the deuteration rate is high, and the purity is better. This method can be used for the deuteration reaction of various sugar primary alcohols.

[0061] The reaction of this invention can be directly fed into subsequent processes after simple post-processing, resulting in high reaction conversion rates and reduced synthesis costs for this type of compound. The entire synthesis process offers advantages such as high reactant yield, low cost, simple and easy separation process, readily available raw materials, and mild process conditions, making it suitable for large-scale synthesis of deuterated sugars and their derivatives. The intermediates synthesized using this method can be used for the preparation of deuterated sugars and their derivatives in a low-cost, efficient, and rapid manner, demonstrating high industrial application value.

[0062] On the other hand, the present invention provides deuterated sugar compounds prepared by the synthetic method described above.

[0063] The preparation method of this invention produces products with precise deuteration sites, high deuteration rate, and better purity.

[0064] On the other hand, the present invention provides stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels, or prodrugs of the deuterated sugar compounds as described above.

[0065] In this invention, derivatives can also be prepared by introducing aliphatic, halogenated, heterocyclic, or aromatic substituents onto the rings of the compound molecule shown in Formula I.

[0066] On the other hand, the present invention provides a pharmaceutical composition comprising, as described above, a deuterated sugar compound or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels or prodrugs and pharmaceutically acceptable excipients.

[0067] Preferably, the excipients include any one or a combination of at least two of the following: carrier, excipient, diluent, binder, wetting agent, disintegrant, emulsifier, cosolvent, solubilizer, osmotic pressure regulator, surfactant, colorant, pH adjuster, antioxidant, antibacterial agent, or buffer.

[0068] On the other hand, the present invention provides the use of the deuterated sugar compounds or their stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels or prodrugs, or pharmaceutical compositions thereof as described above in the preparation of deuterated tracers.

[0069] On the other hand, the present invention provides the use of the deuterated sugar compounds or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels or prodrugs, or pharmaceutical compositions thereof as described above in the preparation of nuclear magnetic resonance diagnostic reagents for deuterated imaging.

[0070] The diseases to be diagnosed include tumor metabolism research (such as glioma, pancreatic cancer, liver cancer, breast cancer, etc.), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, stroke, brain injury, etc.) and metabolic-related diseases.

[0071] On the other hand, the present invention provides the use of the deuterated sugar compounds or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels or prodrugs, or pharmaceutical compositions thereof as described above in the preparation of deuterated drugs.

[0072] Terminology Explanation

[0073] The term "alkyl" as used refers to a saturated hydrocarbon group or an unsaturated chain alkyl group. "Chain alkyl" refers to a straight-chain or branched alkyl group. For example, C1-C6 chain alkyl refers to a saturated or unsaturated, straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples of saturated straight-chain alkyl groups include, but are not limited to, ethyl and n-propyl. Examples of saturated branched alkyl groups include, but are not limited to, isopropyl and tert-butyl. Examples of unsaturated straight-chain alkyl groups include, but are not limited to, vinyl and propenyl. Examples of unsaturated branched alkyl groups include, but are not limited to, 2-methylpropenyl. "Cycloalkyl" refers to an alkyl group with a cyclic structure. For example, C3-C6 cycloalkyl refers to a saturated or unsaturated alkyl group with a cyclic structure having 3 to 6 carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and ethyl-substituted cyclohexyl. Examples of unsaturated cycloalkyl groups include, but are not limited to, cyclopentene.

[0074] The term "halogen" refers to F, Cl, Br, I, etc., with F, Cl, and Br being preferred, and F and Cl being particularly preferred.

[0075] The term "alkoxy" refers to a group in which an alkyl group is directly bonded to an oxygen group, such as methoxy and ethoxy.

[0076] The term "substituted" refers to the replacement of a hydrogen group in a specific structure with a specified substituent. In the general formula, the short line drawn from outside the ring to inside the ring indicates that the substituent is not fixed in its substitution position on the ring and can be substituted at any position allowed by the chemical bonds.

[0077] This invention includes the free form of compounds of formula (I), as well as their pharmaceutically acceptable salts and stereoisomers. Pharmaceutically acceptable salts of this invention can be synthesized from compounds of this invention containing either a basic or acidic moiety using conventional chemical methods. Typically, salts of basic compounds are prepared by ion-exchange chromatography or by reacting a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0078] Therefore, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting an alkaline compound of the present invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, etc.

[0079] If the compounds of this invention are acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary, and tertiary amines, wherein substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

[0080] Compared with the prior art, the present invention has the following beneficial effects:

[0081] The synthesis method of this invention exhibits high reaction conversion rate, reducing the synthesis cost of this type of compound. The entire synthesis process boasts advantages such as high reactant yield, low cost, simple and easy separation process, readily available raw materials, and mild process conditions, making it suitable for large-scale synthesis. Using the method of this invention, deuterated sugar compounds can be prepared in a low-cost, efficient, and rapid manner, with product yields >80% and purity >98%. Compared with the traditional deuterium-water catalytic deuteration exchange method, the raw materials of this invention are inexpensive and readily available, avoid multi-site deuteration side reactions, and have the advantages of high reaction selectivity and low cost, thus possessing high industrial application value. Attached Figure Description

[0082] Figure 1 The intermediate 5 described in Embodiment 1 of the present invention 1 H NMR spectrum;

[0083] Figure 2 The [6,6'-2H2]-D-glucose described in Example 1 of this invention 1 H NMR spectrum;

[0084] Figure 3 The intermediate compound 7 described in Example 2 of this invention 1 H NMR spectrum. Detailed Implementation

[0085] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0086] In the following preparation examples, the inventors have described in detail the preparation process of the compounds of the present invention using some of the compounds of the present invention as examples.

[0087] Example 1:

[0088]

[0089] Step 1: Synthesis of Intermediate 1

[0090]

[0091] In a three-necked flask equipped with a gas adapter and a dropping funnel, glucose (4.13 g, 22.9 mmol) and DMF (solvent) were added, maintaining a nitrogen atmosphere. The suspension was stirred at room temperature. Sodium hydride (2.6 g, 108.3 mmol) was added in portions, and the mixture was stirred at room temperature for 30 minutes. Then, benzyl bromide (8.8 mL, 74.1 mmol) was added dropwise while cooling in an ice bath. After the addition was complete, the mixture was stirred in an ice bath for another 10 minutes, and then reacted at room temperature for 2.5 hours.

[0092] Add the second portion of sodium hydride (2.5 g, 104.2 mmol), stir at room temperature for 30 minutes, and then add benzyl bromide (8.8 mL, 74.1 mmol) dropwise while cooling in an ice bath. Continue stirring at room temperature for 2.5 hours, and finally add the third portion of sodium hydride (2.0 g, 83.3 mmol), stir for 30 minutes, and then add benzyl bromide (6.4 mL, 53.9 mmol) dropwise. The resulting brownish-yellow suspension is stirred overnight at room temperature.

[0093] The reaction was quenched by adding 7 mL of methanol, and most of the DMF was removed by rotary evaporation under reduced pressure. The residue was diluted with 150 mL of dichloromethane and 100 mL of deionized water. After separation, the organic phase was washed three times with deionized water (150 mL each time). The combined aqueous phases were back-extracted with 50 mL of dichloromethane, and the combined organic phases were washed twice with saturated brine (100 mL each time) and dried over anhydrous sodium sulfate. After filtration, the bright yellow solution was concentrated to obtain a yellow oil, which was recrystallized from approximately 230 mL of methanol. The final product was a white needle-like crystal (benzyl-2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside) 9.21 g (14.6 mmol), yield 64%.

[0094] Step 2: Synthesis of Intermediate 2

[0095]

[0096] In a three-necked flask equipped with a gas connector, zinc chloride (ZnCl2, 10.7 g, 78.2 mmol) was added, and the mixture was heated under vacuum to remove residual moisture. After cooling to 0°C under a nitrogen (N2) atmosphere, an acetic acid:acetic anhydride mixture (62 mL, v / v 1:5) was added, and the mixture was cooled in an ice bath with stirring. Subsequently, benzyl-2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside, dissolved in an equal proportion of acetic acid:acetic anhydride mixture (62 mL), was slowly added to the system. The reaction mixture was slowly raised to room temperature over 90 minutes and stirred for 1 hour. The clear yellow reaction mixture was poured into approximately 300 mL of an ice-water mixture. A white solid precipitated, and after drying, 6.2 g of the product (benzyl-6-O-acetyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside) was obtained. The crude product was not used directly in subsequent reactions.

[0097] 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.22 (m, 20H), δ 5.02 – 4.94 (m, 3H), 4.91 – 4.67 (m, 4H), 4.61 – 4.53 (m, 2H), 4.41 – 4.38 (m, 1H), 4.29 – 4.25 (m, 1H), 3.72 – 3.67 (m, 1H), 3.61-3.51 (m, 3H), 2.08 (s, 3H).

[0098] Step 3: Synthesis of Intermediate 3

[0099]

[0100] In a 250 mL round-bottom flask, sodium methoxide (0.7 g) was dissolved in anhydrous methanol (70 mL), and crude benzyl 6-O-acetyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside was added. The mixture was stirred at room temperature for 5 hours. Thin-layer chromatography (TLC, developing solvent ratio 2:1 hexane:ethyl acetate) showed complete conversion of the starting material. The clear yellow reaction solution was poured into approximately 280 mL of ice water. A milky white suspension was formed, which was allowed to stand overnight. After cooling in an ice bath, the white solid product was collected by filtration and washed with ice water. The product (benzyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside) was 4.5 g, with an overall yield of 57% for both steps.

[0101] Step 4: Synthesis of Intermediate 4

[0102]

[0103] Diacetoxyiodobenzene (6.44 g, 20 mmol) was added to a mixture of dichloromethane (60 mL) and water (30 mL) containing benzyl-2,3,4-tri-O-benzyl-α-D-glucopyranoside (5.4 g, 10 mmol) and TEMPO (234 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was then quenched by adding an aqueous solution of sodium thiosulfate (Na₂S₂O₃) (50 mL). The organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate (Na₂SO₄), concentrated under reduced pressure, and purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 80 / 20) to give the target carboxylic acid compound. The product (benzyl-2,3,4-tri-O-benzyl-α-D-glucopyranoside) was 5.76 g, 90% yield, as a white solid.

[0104] Step 5: Synthesis of Intermediate 5

[0105]

[0106] Crude benzyl 6-O-acetyl-2,3,4-tris-O-benzyl-β-D-glucopyranoside was added to a 250 mL round-bottom flask and dissolved in 50 mL of tetrahydrofuran solution. The mixture was stirred at room temperature for 2 hours. Thin-layer chromatography (TLC, developing solvent ratio 2:1 n-hexane:ethyl acetate) showed complete conversion of the starting material. The reaction was then quenched by adding 1 mL of aqueous solution. The solid insoluble matter was removed by diatomaceous earth filtration, and the mixture was washed with methanol. The organic phase filtrate was collected. After concentration under reduced pressure, the filtrate was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 80 / 20) to obtain the target product as a white solid (6,6- 2 H2-benzyl-2,3,4-tris-O-benzyl-α-D-glucopyranoside) 0.49 g, yield 90%.

[0107] 1H NMR spectrum as follows Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.56 – 7.20 (m, 20H), 5.05 (d, J = 10.9 Hz, 1H), 4.97 – 4.81 (m, 3H), 4.78 – 4.66 (m, 3H), 4.59 (dd, J =12.1, 4.6 Hz, 2H), 4.11 (t, J = 9.3 Hz, 1H), 3.74 (d, J = 10.0 Hz, 1H), 3.63– 3.42 (m, 2H).

[0108] Step 6: [6,6'- 2 Synthesis of H2-D-glucose

[0109]

[0110] In a 250 mL round-bottom flask, add 6,6- 2 H2-benzyl-2,3,4-tris-O-benzyl-α-D-glucopyranoside (0.27 g) was dissolved in anhydrous methanol (10 mL), then 0.5 mL of acetic acid was added, followed by 10% Pd / C, and the mixture was stirred at room temperature for 18 hours. Thin-layer chromatography (TLC, developing solvent ratio 2:1 n-hexane:ethyl acetate) showed complete conversion of the starting material. The solid insoluble matter was removed by diatomaceous earth filtration, and the mixture was washed with methanol, and the organic phase filtrate was collected. After concentration under reduced pressure, the target product was obtained as a transparent viscous solid. The product ([6,6'- 2 0.89 g of [H2]-D-glucose, yield 97%.

[0111] 1H NMR spectrum as follows Figure 2 As shown,1 H NMR (400 MHz, D2O) δ 5.26 (d, J = 3.7 Hz, 1H), 3.85 (d, J = 10.1 Hz, 1H), 3.74 (t, J = 9.5 Hz, 1H), 3.56 (dd, J = 9.8, 3.8Hz, 1H), 3.46 – 3.38 (m, 1H).

[0112] Example 2:

[0113]

[0114] 1. Synthesis of intermediate 6

[0115] The compound (2,3,4-tris-O-benzyl-α-D-glucopyranoside methyl ester, 1 mmol, 464 mg) was dissolved in 30 mL of a mixture of dichloromethane and water (V 二氯甲烷 :V 水 = 2:1), added CBI (2.6 mmol, 548 mg), TEMPO (2.6 mmol, 548 mg), reacted at room temperature for 16 hours. After the reaction was complete as detected by TLC, 10 mL of 10% Na2S2O3 aqueous solution was added to quench the reaction. Extracted twice with 20 mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain intermediate 6. Crude product was obtained by column chromatography (dichloromethane:methanol = 200:1), yielding compound C as a white solid 480 mg, with a yield of 76%. It was identified as the target compound by mass spectrometry: MS-ESI (m / z) = 316.4 [M+H] + .

[0116] 2. Synthesis of Intermediate 7

[0117] Compound 3 was dissolved in 2 mL of tetrahydrofuran, and 2 g of deuterated lithium aluminum hydride was added at 0 °C. The reaction solution was then brought to room temperature and reacted at room temperature for 30 hours. After the reaction was confirmed to be complete by TLC, the reaction was quenched with water at 0 °C. The insoluble matter was removed by diatomaceous earth filtration, and the product was washed with ethyl acetate and the solvent was evaporated to obtain the crude intermediate 7.

[0118] 1H NMR spectrum as follows Figure 3 As shown, 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.22 (m, 15H), 5.02 (d, J = 10.9 Hz, 1H), 4.94 – 4.80 (m, 3H), 4.68 (dd, J = 11.6, 9.3 Hz, 2H), 4.59 (d, J = 3.5 Hz, 1H), 4.03 (t, J = 9.3 Hz, 1H), 3.67 (d, J = 10.0 Hz, 1H), 3.54 (ddd, J = 9.6, 7.6, 6.3 Hz, 2H), 3.39 (s, 3H).

[0119] 3. Synthesis of Intermediate 8

[0120] The crude product compound D was dissolved in 5 mL of ethanol, and 100 mg of 5% palladium on carbon was added. The mixture was reacted at room temperature for 24 hours. The palladium on carbon was filtered off and the solvent was evaporated to dryness. 2 mL of sodium hydroxide aqueous solution (1M) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered off, and the solvent was evaporated to dryness to obtain the crude product compound E, and thus the crude product intermediate 8.

[0121] 4. Synthesis of [6,6'-2H2]-D-glucose

[0122] Dissolve intermediate 8 in 5 mL of concentrated hydrochloric acid, react overnight at room temperature, evaporate the solvent to dryness, [6,6'- 2 [H2]-D-glucose is a white solid. Weight: 254 mg, two-step yield: 53%.

[0123] 1H NMR spectrum as follows Figure 2 As shown, 1 H NMR (400 MHz, D2O) δ 5.12 (d, J = 3.7 Hz, 1H), 3.71 (d, J = 10.1 Hz, 1H), 3.61 (t, J = 9.6 Hz, 1H), 3.42 (dd, J = 9.8, 3.8Hz, 1H), 3.35 – 3.29 (m, 1H).

[0124] The applicant declares that the present invention illustrates the deuterated sugar compounds, their synthesis methods, and applications through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing a deuterated sugar compound, characterized in that, The deuterated sugar compound has the structure shown in Formula I: ； Where n is selected from integers from 0 to 5, m is selected from integers from 0 to 5, and when n and m are both 0, the corresponding group does not exist; Each R group is independently selected from any one of OH, hydrogen, C3-C7 branched or branched alkyl, acyl, halogen, ester or C5-C7 aryl; each R group is independently selected from n identical or different substituents; Ring A is optionally a C3-7 cycloalkyl group, a C6-10 aromatic ring, a fused heterobicyclic group, an aromatic heterocyclic group, or a 5-7 membered monocyclic heterocyclic group; the heteroatom in the fused heterobicyclic group or monocyclic heterocyclic group is at least one of nitrogen, oxygen, or sulfur atoms; X is independently selected from oxygen, nitrogen, sulfur, or carbon atoms; The synthesis method includes the following steps: (1) The alcohol with the structure shown in formula (a) reacts with the R2X2 compound to obtain the compound shown in formula (b); (2) The compound shown in formula (b) was subjected to a deprotection reaction, followed by an ester hydrolysis reaction, to obtain the compound shown in formula (c); (3) The compound shown in formula (c) is reacted with an oxidizing agent to obtain the compound shown in formula (d); (4) The compound shown in formula (d) is reacted with a deuterated reagent to obtain the compound shown in formula (e); (5) The compound shown in formula (e) is subjected to a deprotection reaction in the presence of a deprotecting agent to obtain the deuterated sugar compound shown in formula (I). The reaction process is shown below: ； X2 is selected from halogens.

2. The preparation method according to claim 1, characterized in that, The deuterated sugar compound is selected from any one of the following structures: 。 3. The preparation method according to claim 1 or 2, characterized in that, In step (1), the molar ratio of the alcohol with the structure shown in formula (a) to the R2X2 compound is 1:(1-12); Preferably, in the R2X2 compound of step (1), R2 is selected from alkane groups or silane groups; Preferably, R2 is selected from benzyl, methyl, or silyl; more preferably, it is benzyl. Preferably, the reaction in step (1) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one or a combination of at least two of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate; Preferably, the molar ratio of the alkaline substance to the R2X2 compound is 1:(1-12); Preferably, the temperature of the reaction in step (1) is -75~80℃, more preferably 0℃~30℃; Preferably, the deprotection reaction in step (2) is carried out in the presence of a Lewis acid; Preferably, the Lewis acid is selected from zinc chloride; Preferably, the deprotection reaction in step (2) is carried out in a solvent selected from a mixed solvent of acetic acid and acetic anhydride, and preferably, the volume ratio of acetic acid and acetic anhydride is 1:(3-6). Preferably, the temperature of the deprotection reaction in step (2) is 0~70℃, and the reaction time is 1-24 hours; Preferably, the ester hydrolysis reaction in step (2) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is any one or a combination of at least two of sodium methoxide, sodium ethoxide, or potassium tert-butoxide; Preferably, the ester hydrolysis reaction in step (2) is carried out in a solvent, wherein the solvent is selected from any one or a combination of at least two of methanol, ethanol or tert-butanol; Preferably, the ester hydrolysis reaction in step (2) is carried out at room temperature for 1 to 24 hours.

4. The preparation method according to any one of claims 1-3, characterized in that, The oxidant in step (3) is at least two of 2,2,6,6-tetramethylpiperidine oxide, diethyl iodophenyl ester, or diacetoxyiodophenyl. Preferably, the molar ratio of the compound shown in formula (c) in step (3) to the oxidant is 1:(1-1.1). Preferably, the reaction in step (3) is carried out in a solvent, which is selected from dichloromethane, chloroform, acetone, a mixture of acetonitrile and water, and the molar ratio of acetonitrile to water in the mixture of acetonitrile and water is (1-5):1; Preferably, the temperature of the reaction in step (3) is 0-30°C, and the reaction time is 1-48 hours; Preferably, the deuterated reagent in step (4) is selected from at least one of lithium aluminum tetradeuterium or sodium borodeuteride; Preferably, the molar ratio of the compound shown in formula (d) in step (4) to the deuterated reagent is 1:(0.5-1.1). Preferably, the reaction in step (4) is carried out in a solvent, which is selected from ether solvents, preferably tetrahydrofuran; Preferably, the temperature of the reaction in step (4) is 0-30°C, and the reaction time is 1-24 hours; Preferably, the deprotecting agent used in the deprotection reaction in step (5) is at least one of hydrogen-palladium on carbon, Lewis acid, sulfide or fluoride; Preferably, the molar ratio of the compound shown in formula (e) in step (5) to the deprotecting agent is 1:(0.5-1.1). Preferably, the deprotection reaction in step (5) is carried out in a solvent, which includes an alcohol solvent, preferably methanol; Preferably, the temperature of the deprotection reaction in step (5) is 0-30°C, and the reaction time is 1-24 hours.

5. The deuterated sugar compound prepared by the synthetic method according to any one of claims 1-4.

6. Stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels, or prodrugs of the deuterated sugar compound according to claim 5.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the deuterated sugar compound of claim 5 or the stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, isotope label, or prodrug and pharmaceutically acceptable excipient of claim 6.

8. The use of the deuterated sugar compound of claim 5 or the stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, isotope label or prodrug of claim 6, or the pharmaceutical composition of claim 7 in the preparation of a deuterated tracer.

9. The use of the deuterated sugar compound according to claim 5 or the stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, isotope label or prodrug according to claim 6, or the pharmaceutical composition according to claim 7 in the preparation of nuclear magnetic resonance diagnostic reagents for deuterated imaging.

10. The use of the deuterated sugar compound of claim 5 or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, isotope labels or prodrugs, or the pharmaceutical composition of claim 7 in the preparation of a deuterated drug.

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