A preparation method of 1-deuterated-2-deoxy-D-glucose

Abstract

The present invention belongs to the technical field of chemical synthesis, and in particular to a method for preparing 1-deuterated 2-deoxy-D-glucose. The preparation method provided by the present invention: the glucose, trialkylphosphine compound, Lewis acid catalyst and aprotic solvent of the structure shown in formula I are subjected to glycosylation reaction, the compound of the structure shown in the obtained formula II, the strong base and the heavy water undergo elimination reaction, the compound of the structure shown in the obtained formula III, the alcohol base and the alcohol solvent undergo deprotection reaction, the compound of the structure shown in the obtained formula IV, the protonic acid and the water undergo hydration reaction, and 1-deuterated 2-deoxy-D-glucose is obtained. The present invention does not need to convert the protecting group, greatly shortens the synthesis route, and improves the product yield of 1-deuterated 2-deoxy-D-glucose. At the same time, the use of zinc powder and alkyl lithium is avoided, and the preparation process is more environmentally friendly and safe, and is easy to industrialize and produce.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a method for preparing 1-deuterated-2-deoxy-D-glucose. Background Art

[0002] Accurate diagnosis plays a vital role in the treatment of any disease. The detection of key biomarkers such as cell morphology, physiological and metabolic status is widely used in the disease diagnosis process. Compared with normal cells, cells in various pathological states have an abnormally increased demand for glucose. In nuclear medicine, this abnormal consumption of glucose is an important means of tumor diagnosis.

[0003] The most advanced medical imaging technology at present is positron emission tomography (PET), which relies on the specific enrichment of positron-emitting drugs in target organs, can achieve high-resolution imaging of cell metabolism and function, and conduct non-invasive, three-dimensional, and dynamic research on the physiological and biochemical processes of the human body at the molecular level. PET is the only new imaging technology that can display the metabolism of biological molecules, receptors, and neurotransmitter activities in living bodies. It is now widely used in the diagnosis and differential diagnosis of various diseases, disease assessment, efficacy evaluation, organ function research, and new drug development. At present, the most important positron-emitting drugs used in PET detection are 2- 18 F-fluorodeoxyglucose (2- 18 F-FDG) has played a huge role in the diagnosis of tumors. 18 F is a positron-emitting radionuclide. Although the amount of the nuclide used is very small and its half-life is short, it does not stay in the body of the subject for a long time after physical decay and biological metabolism. However, cancer patients often need multiple tests, and there is still a risk of secondary damage. In addition, due to the 2- 18 F-FDG can accumulate in some non-tumor cells with high metabolic activity caused by inflammation or infection. Therefore, another prominent disadvantage is that it has no specificity and is limited in diagnosing the pathological properties of tumors.

[0004] Most MRIs used clinically are based on protons ( 1 H) Detection of magnetic signals. In most cases, it is possible to detect abnormal signal areas corresponding to tumors. However, in clinical practice, MRI is not always able to distinguish benign tumors or tumors that do not require emergency treatment from malignant tumors. This needs to be enhanced by using contrast agents. 1Specificity of HMRI. Currently, a variety of gadolinium contrast agents are widely used in MRI diagnosis. However, in recent years, it has been found that short-term and multiple use of gadolinium contrast agents can lead to gadolinium deposition in related tissues (mainly brain, bone, and kidney, etc.), and evidence of gadolinium in blood and urine. However, gadolinium deposition is still under study, and there is a lack of quantitative standards for disease definition, but affected patients usually report symptoms such as kidney problems, skin changes, neurological diseases (headache, dizziness, and sensory impairment, etc.), and muscle pain. Therefore, the development of diagnostic reagents that do not contain gadolinium, such as 1-deuterated-2-deoxy-D-glucose, is of great clinical significance and has a good market prospect.

[0005] At present, the method for preparing 1-deuterated-2-deoxy-D-glucose mainly uses fully acetylated glucose as raw material, undergoes bromination and zinc powder reduction to generate triacetyl glucal, and then after the protective group conversion, carries out hydrogen-deuterium exchange in the presence of alkyl lithium to obtain hydroxyl-fully protected 1-deuterated glucal, and then undergoes deprotection and hydration reaction to obtain 1-deuterated-2-deoxy-D-glucose.

[0006] The above-mentioned method for preparing 1-deuterated-2-deoxy-D-glucose requires conversion of the protecting group, has many synthesis steps and a long route, resulting in low product yield and difficulty in industrial production. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing 1-deuterated-2-deoxy-D-glucose. The preparation method provided by the present invention uses fully hydroxyl-protected glucose as a raw material, but does not require conversion of protecting groups, greatly shortens the synthesis route, and improves the yield of 1-deuterated-2-deoxy-D-glucose products.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] The present invention provides a method for preparing 1-deuterated-2-deoxy-D-glucose, comprising the following steps:

[0010] Mixing glucose with full hydroxyl protection of the structure shown in Formula I, a trialkylphosphine compound, a Lewis acid catalyst and an aprotic solvent to undergo a glycosylation reaction to obtain a compound of the structure shown in Formula II;

[0011]

[0012] In formula I, R is acetyl and / or benzoyl; in formula II, R' is a hydrocarbon group;

[0013] The compound of the structure represented by formula II, a strong base and heavy water are mixed to undergo an elimination reaction to obtain a compound of the structure represented by formula III;

[0014]

[0015] The compound of the structure represented by formula III, an alcohol base and an alcohol solvent are mixed to undergo a deprotection reaction to obtain a compound of the structure represented by formula IV;

[0016]

[0017] The compound with the structure shown in formula IV, protonic acid and water are mixed to cause a hydration reaction to obtain 1-deuterated-2-deoxy-D-glucose.

[0018] Preferably, the trialkylphosphine compound is triphenylphosphine;

[0019] The Lewis acid catalyst includes trimethylsilyl trifluoromethanesulfonate and / or boron trifluoride;

[0020] The aprotic solvent includes one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran and toluene.

[0021] Preferably, the molar ratio of the fully hydroxyl-protected glucose of the structure shown in Formula I, the Lewis acid catalyst and the trialkylphosphine compound is 1:1 to 1.5:1 to 1.5.

[0022] Preferably, the glycosylation reaction is carried out at a temperature of 0 to 40° C. and for a time of 2 to 24 hours.

[0023] Preferably, the strong base includes one or more of sodium tert-butoxide, potassium tert-butoxide, sodium deuterium oxide and potassium deuterium oxide; the molar concentration of the strong base solution formed by the strong base and heavy water is 0.5 to 3 mol / L.

[0024] Preferably, the temperature of the elimination reaction is 10-80° C. and the time is 0.5-6 h.

[0025] Preferably, the alcohol base comprises sodium alcoholate and / or potassium alcoholate;

[0026] The molar ratio of the compound of the structure represented by formula III to the alcohol base is 1:0.01-4.

[0027] Preferably, the temperature of the deprotection reaction is 0 to 40° C. and the time is 0.5 to 12 h.

[0028] Preferably, the protonic acid is an inorganic protonic acid; the mass percentage of the protonic acid solution formed by the protonic acid and water is 0.5-15%.

[0029] Preferably, the hydration reaction is carried out at a temperature of -10 to 40°C and for a time of 12 to 36 hours.

[0030] The present invention provides a method for preparing 1-deuterated-2-deoxy-D-glucose, comprising the following steps: mixing glucose with full hydroxyl protection of the structure shown in formula I, a trialkylphosphine compound, a Lewis acid catalyst and a non-protonic solvent, and performing a glycosylation reaction to obtain a compound with the structure shown in formula II; mixing the compound shown in formula II, a strong base and heavy water, and performing an elimination reaction to obtain a compound with the structure shown in formula III; mixing the compound with the structure shown in formula III, an alcohol base and an alcohol solvent, and performing a deprotection reaction to obtain a compound with the structure shown in formula IV; mixing the compound with the structure shown in formula IV, a protonic acid and water, and performing a hydration reaction to obtain 1-deuterated-2-deoxy-D-glucose. The preparation method provided by the present invention uses glucose with full hydroxyl protection as a raw material, and sequentially performs a glycosylation reaction, an elimination reaction, a deprotection reaction and a hydration reaction, and can prepare 1-deuterated-2-deoxy-D-glucose without performing a conversion of a protecting group, thereby greatly shortening the synthesis route and improving the yield of 1-deuterated-2-deoxy-D-glucose products. At the same time, the present invention abandons the steps of reducing with zinc powder and exchanging hydrogen-deuterium with alkyl lithium when preparing 1-deuterated-2-deoxy-D-glucose using fully hydroxyl-protected glucose as a raw material in the prior art, thereby avoiding the use of zinc powder and alkyl lithium, making the preparation process more environmentally friendly and safe, and easy to industrialize. DETAILED DESCRIPTION

[0031] The present invention provides a method for preparing 1-deuterated-2-deoxy-D-glucose, comprising the following steps:

[0032] Mixing glucose with full hydroxyl protection of the structure shown in Formula I, a trialkylphosphine compound, a Lewis acid catalyst and an aprotic solvent to undergo a glycosylation reaction to obtain a compound of the structure shown in Formula II;

[0033]

[0034] In formula I, R is acetyl and / or benzoyl; in formula II, R' is a hydrocarbon group;

[0035] The compound represented by formula II, a strong base and heavy water are mixed to undergo an elimination reaction to obtain a compound represented by formula III;

[0036]

[0037] The compound of formula III, an alcohol base and an alcohol solvent are mixed to undergo a deprotection reaction to obtain a compound of formula IV;

[0038]

[0039] The compound with the structure shown in formula IV, protonic acid and water are mixed to cause a hydration reaction to obtain 1-deuterated-2-deoxy-D-glucose.

[0040] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art.

[0041] The present invention mixes glucose with full hydroxyl protection of the structure shown in formula I, a trialkylphosphine compound, a Lewis acid catalyst and an aprotic solvent (hereinafter referred to as the first mixture) to undergo a glycosylation reaction to obtain a compound of the structure shown in formula II;

[0042]

[0043] In formula I, R is acetyl and / or benzoyl; in formula II, R' is a hydrocarbon group.

[0044] In the present invention, the fully hydroxyl-protected glucose of the structure shown in Formula I is preferably fully acetylated glucose or fully benzoylated glucose.

[0045] In the present invention, the trihydrocarbylphosphine compound is preferably triphenylphosphine.

[0046] In the present invention, the Lewis acid catalyst preferably includes trimethylsilyl trifluoromethanesulfonate (TMSOTf) and / or boron trifluoride, more preferably TMSOTf or boron trifluoride, and further preferably TMSOTf.

[0047] In the present invention, the aprotic solvent preferably includes one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran and toluene, and more preferably dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran or toluene.

[0048] In the present invention, the molar ratio of the fully hydroxyl-protected glucose of the structure shown in Formula I, the Lewis acid catalyst and the trialkylphosphine compound is preferably 1:1-1.5:1-1.5, specifically preferably 1:1.0-1.2:1.0-1.2 or 1:1.2-1.5:1.2-1.5.

[0049] The present invention has no special requirement on the amount of the aprotic solvent, as long as the glycosylation reaction is ensured to proceed smoothly.

[0050] In the present invention, the first mixing preferably comprises the following steps: dissolving the fully hydroxyl-protected glucose and trialkylphosphine compound of the structure shown in Formula I in the aprotic solvent to obtain a mixed solution; cooling the mixed solution to 0°C and then adding the Lewis acid catalyst dropwise.

[0051] In the present invention, the temperature of the glycosylation reaction is preferably 0-40°C, more preferably 25-40°C, and the time is preferably 2-24h, specifically preferably 2h, 6h, 10h, 24h. In the present invention, the glycosylation reaction is preferably carried out under stirring conditions, and the present invention has no special requirements for the specific implementation process of the stirring. The present invention preferably determines whether the glycosylation reaction is completed by detecting the raw materials.

[0052] In the present invention, the glycosylation reaction obtains a glycosylation reaction liquid containing a compound having a structure shown in Formula II. The present invention does not require post-treatment and purification of the glycosylation reaction liquid containing a compound having a structure shown in Formula II, and directly uses the glycosylation reaction liquid containing a compound having a structure shown in Formula II as a reaction raw material to carry out the elimination reaction.

[0053] In the present invention, the fully hydroxyl-protected glucose of the structure shown in Formula I is preferably bound to the trialkylphosphine through the glycosylation reaction.

[0054] After obtaining the compound having the structure shown in Formula II (i.e., the glycosylation reaction solution having the compound having the structure shown in Formula II), the present invention mixes the compound shown in Formula II, a strong base and heavy water (hereinafter referred to as the second mixing) to undergo an elimination reaction to obtain a compound having the structure shown in Formula III;

[0055]

[0056] In the present invention, the strong base preferably includes one or more of sodium tert-butoxide, potassium tert-butoxide, sodium deuterium oxide and potassium deuterium oxide, more preferably sodium deuterium oxide and / or potassium deuterium oxide, and further preferably sodium deuterium oxide.

[0057] In the present invention, the second mixing preferably comprises the following steps: dissolving the strong base in heavy water to form a strong base solution; the molar concentration of the strong base solution formed by the strong base and heavy water is preferably 0.5 to 3 mol / L, specifically preferably 0.5 mol / L, 1 mol / L, 2 mol / L, 3 mol / L. The glycosylation reaction solution containing the compound of formula II is mixed with the strong base solution.

[0058] The present invention has no special requirements on the mass ratio between the glycosylation reaction solution containing the compound of the structure shown in Formula II and the strong base solution. The strong base solution is in excess to ensure that the elimination reaction proceeds smoothly.

[0059] In the present invention, the temperature of the elimination reaction is preferably 10-80°C, specifically preferably 10°C, 25°C, 40°C, 60°C or 80°C; the time is preferably 0.5-6h, specifically preferably 0.5h, 1h, 2h, 4h or 6h. In the present invention, the elimination reaction is preferably carried out under stirring, and the present invention has no special requirements for the specific implementation process of the stirring.

[0060] In the present invention, after the elimination reaction, an elimination reaction liquid is obtained. The present invention preferably performs post-treatment on the elimination reaction liquid to obtain a compound of the structure shown in formula III. In the present invention, the post-treatment preferably includes the following steps: mixing the elimination reaction liquid with heavy water to obtain a mixed reaction liquid; mixing the mixed reaction liquid with an organic extractant for extraction, collecting the extracted organic phase; washing, drying, desolventizing and column chromatography separation of the extracted organic phase in sequence to obtain the compound of the structure shown in formula III. In the present invention, the organic extractant is preferably ethyl acetate; the washing solvent is preferably saturated saline, the drying agent is preferably anhydrous sodium sulfate, the specific implementation of the desolventizing is preferably reduced pressure distillation, the column chromatography is preferably silica gel column chromatography, the elution solvent of the silica gel column chromatography is preferably a mixed solvent of petroleum ether and ethyl acetate, and the elution is preferably gradient elution; during the gradient elution, the volume percentage of the ethyl acetate in the mixed solvent of petroleum ether and ethyl acetate is preferably 0-50%.

[0061] In the present invention, the compound with the structure shown in formula III is a light yellow oil.

[0062] After obtaining the compound of formula III, the present invention mixes the compound of formula III, an alcohol base and an alcohol solvent (hereinafter referred to as the third mixture) to undergo a deprotection reaction to obtain a compound of formula IV;

[0063]

[0064] In the present invention, the alcohol base preferably includes sodium alcoholate and / or potassium alcoholate, and more preferably is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide.

[0065] In the present invention, the alcohol solvent preferably includes one or more of methanol, ethanol and tert-butanol.

[0066] In a specific embodiment of the present invention, the alcohol solvent is preferably of the same type as the alcohol in the alcohol base.

[0067] In the present invention, the molar ratio of the compound of formula III to the alcohol base is preferably 1:0.01-4, specifically preferably 1:0.01, 1:0.05, 1:0.2, 1:1, 1:3 or 1:4.

[0068] In the present invention, the temperature of the deprotection reaction is preferably 0-40°C, more preferably 25-40°C, specifically preferably 0°C, 25°C or 40°C; the time is preferably 0.5-12h, specifically preferably 0.5h, 2h, 4h, 6h or 12h. In the present invention, the deprotection reaction is preferably carried out under stirring conditions. The present invention has no special requirements for the specific implementation process of the stirring. The present invention preferably identifies whether the deprotection reaction is completed by detecting whether the raw materials of the deprotection reaction are completely reacted.

[0069] In the present invention, after the deprotection reaction, a deprotection reaction liquid is obtained. In the present invention, the deprotection reaction liquid is preferably post-treated to obtain the compound of the structure shown in Formula IV. In the present invention, the post-treatment preferably includes the following steps: removing the solvent from the deprotection reaction liquid to obtain the compound of the structure shown in Formula IV. In the present invention, the specific embodiment of removing the solvent is preferably reduced pressure distillation.

[0070] In the present invention, the compound of formula IV is a light yellow oil. The present invention only needs to remove the solvent from the deprotection reaction solution to obtain the compound of formula IV, and there is no need to further purify the product after the solvent removal, and the steps are simple.

[0071] After obtaining the compound of formula IV, the present invention mixes the compound of formula IV, protonic acid and water (hereinafter referred to as the fourth mixture) to undergo a hydration reaction to obtain 1-deuterated-2-deoxy-D-glucose.

[0072] In the present invention, 1-deuterated-2-deoxy-D-glucose has the structure shown in Formula V:

[0073]

[0074] In the present invention, the protonic acid is preferably an inorganic protonic acid, and the inorganic protonic acid is preferably sulfuric acid or hydrochloric acid.

[0075] In the present invention, the fourth mixing preferably comprises the following steps: dissolving the protonic acid in water to obtain a protonic acid solution; mixing the protonic acid solution with the compound of structure IV. In the present invention, the mass percentage of the protonic acid solution formed by the protonic acid and water is preferably 0.5-15%, specifically preferably 0.5%, 1%, 3%, 5%, 10% or 15%.

[0076] The present invention has no special requirements on the mass ratio between the protonic acid solution and the compound with the structure shown in IV. The protonic acid solution is in excess to ensure that the hydration reaction proceeds smoothly.

[0077] In the present invention, the temperature of the hydration reaction is preferably -10 to 40°C, specifically preferably -10°C, 0°C, 25°C or 40°C, and the time is preferably 12 to 36 hours, specifically preferably 12 hours, 24 hours or 36 hours. In the present invention, the hydration reaction is preferably carried out under stirring, and the present invention has no special requirements for the specific implementation process of the stirring.

[0078] In the present invention, the hydration reaction obtains a hydration reaction liquid. In the present invention, the hydration reaction liquid is preferably post-treated to obtain pure 1-deuterated-2-deoxy-D-glucose. In the present invention, the post-treatment preferably includes the following steps: adjusting the pH value of the hydration reaction liquid to 7 with an inorganic alkaline solution to obtain a neutralization reaction liquid; mixing the neutralization reaction liquid with activated carbon for decolorization, and obtaining a decolorized reaction liquid after a first solid-liquid separation; concentrating the decolorized reaction liquid to obtain a concentrated reaction liquid; freezing and crystallizing the concentrated reaction liquid, and obtaining an initial purified reaction liquid after a second solid-liquid separation; removing the solvent from the initial purified reaction liquid to obtain a crude 1-deuterated-2-deoxy-D-glucose product; dissolving the crude 1-deuterated-2-deoxy-D-glucose product in ethanol for recrystallization, and obtaining a wet 1-deuterated-2-deoxy-D-glucose product after a third solid-liquid separation; and drying the wet 1-deuterated-2-deoxy-D-glucose product to obtain a pure 1-deuterated-2-deoxy-D-glucose product. In the present invention, the inorganic alkali solution is preferably a saturated sodium hydroxide solution; the first solid-liquid separation is preferably filtration; the concentration is preferably reduced pressure distillation; the second solid-liquid separation is preferably filtration, the present invention preferably precipitates the proton acid alkali metal salt through the freezing crystallization, the present invention preferably removes the proton acid alkali metal salt through the second solid-liquid separation; the desolventizing is preferably reduced pressure distillation; the drying is preferably vacuum drying, and the temperature of the vacuum drying is preferably 60°C.

[0079] The preparation method of 1-deuterated-2-deoxy-D-glucose provided by the present invention has the following advantages: no need to convert the protecting group, greatly shortening the synthesis route and improving the yield; abandoning the use of zinc powder and alkyl lithium, being more environmentally friendly and safe; mild reaction conditions and easy industrial production.

[0080] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0081] Example 1

[0082] (1) 200 g of peracetylated glucose (512 mmol) and 161 g of triphenylphosphine (615 mmol) were dissolved in 800 mL of dichloromethane, cooled to 0° C., 125 g of TMSOTf (564 mmol) was added dropwise under stirring, and the temperature was raised to 25° C. after the addition, and the mixture was stirred for 10 h. After the reaction of the peracetylated glucose raw material was completed, a reaction solution containing 2,3,4,6-tetra-O-acetyl-D-glucosyltriphenylphosphonium trifluoromethanesulfonate was obtained, which was directly used in the next step without further purification;

[0083] (2) The reaction solution containing 2,3,4,6-tetra-O-acetyl-D-glucosyltriphenylphosphonium trifluoromethanesulfonate obtained in step (1) was added to a 1 mol / L deuterated sodium deuteride heavy water solution, and the mixture was stirred at 25° C. for 4 h. 800 mL of heavy water was then added, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate solvent was removed by distillation under reduced pressure. After separation and purification by silica gel column chromatography, 131 g of 3,4,6-tri-O-acetyl-1-deuteroglucal was obtained as a light yellow oil. The combined yield of the two steps (1) to (2) was 94.0%. 1 HNMR (400MHz, CDCl3) δ5.34(dd,J=5.4,3.2Hz,1H),5.22(dd,J=7.4,6.0Hz,1H),4.84(d,J=3.2Hz,1H),4.40(dd,J=1 2.0,5.8Hz,1H),4.25(dd,J=10.8,5.4Hz,1H),4.19(dd,J=12.0,3.2Hz,1H),2.09(s,3H),2.07(s,3H),2.04(s,3H);

[0084] (3) 131 g of 3,4,6-tri-O-acetyl-1-deuteroglucal (481 mmol) was dissolved in 390 mL of methanol, 1.31 g of sodium methoxide (24.1 mmol) was added, the temperature was controlled at 25° C. and stirred for 2 h, and the 3,4,6-tri-O-acetyl-1-deuteroglucal raw material was detected. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain 1-deuteroglucal as a light yellow oil, which was directly used in the next step without further purification;

[0085] (4) The obtained 1-deuterated glucal was dissolved in 390 mL of dilute sulfuric acid (5%), cooled to 0° C. and stirred for reaction for 24 h. After the reaction of 1-deuterated glucal was detected, the reaction was completed. Saturated sodium hydroxide solution was slowly added to neutralize the reaction solution to a pH value of 7. 13 g of activated carbon was added and stirred for decolorization. After filtration, the reaction was concentrated under reduced pressure to one-third of the volume, frozen for crystallization, sodium sulfate was filtered out, and the reaction was concentrated under reduced pressure again to obtain a crude product of 1-deuterated-2-deoxy-D-glucose. The crude product was recrystallized from ethanol and dried in vacuo at 60° C. to obtain 56.3 g of 1-deuterated-2-deoxy-D-glucose as a white powdery solid. The combined yield of the two steps (3) to (4) was 71.3%. 1 HNMR(400MHz,D2O)δ3.66–3.97(m,7H),3.22–3.40(m,3H),2.25(dd,J=12.0,5.2Hz,1 H), 2.11 (dd, J=13.2, 5.2Hz, 1H), 1.68 (dd, J=13.2, 12.0Hz, 1H), 1.49 (t, 12.0Hz, 1H).

[0086] Example 2

[0087] (1) 200 g of perbenzoyl glucose (285 mmol) and 89.9 g of triphenylphosphine (343 mmol) were dissolved in 800 mL of dichloromethane, cooled to 0° C., and 69.8 g of TMSOTf (314 mmol) was added dropwise under stirring. After the addition was completed, the temperature was raised to 25° C. and stirred for reaction for 24 h. After the reaction of the raw materials was detected, a reaction solution containing 2,3,4,6-tetra-O-benzoyl-D-glucosyltriphenylphosphonium trifluoromethanesulfonate was obtained, which was directly used in the next step without further purification;

[0088] (2) The obtained reaction solution containing 2,3,4,6-tetra-O-benzoyl-D-glucosyltriphenylphosphonium trifluoromethanesulfonate was added to a 1 mol / L sodium deuteride heavy water solution, and the mixture was stirred for reaction at 25° C. for 6 h. 800 mL of heavy water was then added, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate solvent was removed by distillation under reduced pressure. After separation and purification by silica gel column chromatography, 119 g of 3,4,6-tri-O-benzoyl-1-deuteroglucal was obtained as a light yellow oil. The combined yield of the two steps (1) to (2) was 90.7%. 1 HNMR(400MHz, CDCl3)δ8.00–8.08(m,6H),7.51–7.58(m,3H),7.38–7.45(m,6H), 5.82(t,J=5.6Hz,1H),5.73(t,J=4.0Hz,1H),5.13(d,J=3.6Hz,1H),4.71(s,3H);

[0089] (3) 119 g of 3,4,6-tri-O-benzoyl-1-duteoglucal (259 mmol) was dissolved in 360 mL of methanol, 42.0 g of sodium methoxide (777 mmol) was added, and the mixture was stirred at 25° C. for 6 h. After the reaction of the raw materials was completed, the solvent was evaporated under reduced pressure to obtain a crude 1-duteoglucal product as a light yellow oil, which was directly used in the next step without further purification;

[0090] (4) The obtained 1-deuterated glucal was dissolved in 360 mL of dilute hydrochloric acid (3%), and the mixture was stirred at 25° C. for 12 h. After the reaction was detected, a saturated sodium hydroxide solution was slowly added to neutralize the reaction solution to a pH value of 7. 12 g of activated carbon was added and stirred for decolorization. After filtration, the mixture was concentrated under reduced pressure to one-third of the volume, frozen for crystallization, and sodium sulfate was filtered out. The mixture was concentrated under reduced pressure again to obtain a crude product of 1-deuterated-2-deoxy-D-glucose. The crude product was recrystallized from ethanol and dried under vacuum at 60° C. to obtain 29.1 g of 1-deuterated-2-deoxy-D-glucose as a white powdery solid. The combined yield of the two steps (3) to (4) was 68.0%. 1 HNMR(400MHz,D2O)δ3.66–3.97(m,7H),3.22–3.40(m,3H),2.25(dd,J=12.0,5.2Hz,1 H), 2.11 (dd, J=13.2, 5.2Hz, 1H), 1.68 (dd, J=13.2, 12.0Hz, 1H), 1.49 (t, 12.0Hz, 1H).

[0091] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 1-deuterated-2-deoxy-D-glucose, characterized in that: The following steps are involved: The fully hydroxy-protected glucose of the structure shown in formula I, triphenylphosphine, trimethylsilyl trifluoromethanesulfonate and dichloromethane are mixed to undergo a glycosylation reaction to obtain a compound of the structure shown in formula II; the molar ratio of the fully hydroxy-protected glucose of the structure shown in formula I, the trimethylsilyl trifluoromethanesulfonate and the triphenylphosphine is 1:1-1.5:1-1.5; the temperature of the glycosylation reaction is 0-40° C., and the time is 2-24 hours; In formula I, R is acetyl or benzoyl; in formula II, R' is a hydrocarbon group; The compound of the structure shown in formula II, sodium deuterium oxide and heavy water are mixed, the molar concentration of the strong base solution formed by the strong base and heavy water is 0.5-3 mol / L, and an elimination reaction occurs. The temperature of the elimination reaction is 10-80°C and the time is 0.5-6h. The compound of the structure shown in formula II, sodium deuterium oxide and heavy water are mixed, which includes the following steps: dissolving the sodium deuterium oxide in heavy water to form a strong base solution; mixing the glycosylation reaction solution containing the compound of the structure shown in formula II and the strong base solution; the strong base solution is excessive; After the elimination reaction, an elimination reaction liquid is obtained, and the elimination reaction liquid is post-treated to obtain a compound with a structure shown in Formula III; the post-treatment comprises the following steps: mixing the elimination reaction liquid with heavy water to obtain a mixed reaction liquid; mixing the mixed reaction liquid with an organic extractant for extraction, and collecting the extracted organic phase; washing, drying, desolventizing and column chromatography separation are performed on the extracted organic phase in sequence, wherein the organic extractant is ethyl acetate, the column chromatography is silica gel column chromatography, the elution solvent of the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the elution is gradient elution; during the gradient elution, the volume percentage of the ethyl acetate in the mixed solvent of petroleum ether and ethyl acetate is 0-50%; The compound of the structure represented by the formula III, sodium methoxide and an alcohol solvent are mixed to undergo a deprotection reaction to obtain a compound of the structure represented by the formula IV; the molar ratio of the compound of the structure represented by the formula III to sodium methoxide is 1:0.01-4; the temperature of the deprotection reaction is 0-40° C.; and the time is 0.5-12 hours; The compound with the structure shown in formula IV, an inorganic protonic acid and water are mixed to undergo a hydration reaction to obtain 1-deuterated-2-deoxy-D-glucose; the mass percentage of the protonic acid solution formed by the inorganic protonic acid and water is 0.5 to 15%; the temperature of the hydration reaction is -10 to 40°C, and the time is 12 to 36 hours.

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