A kind of synthetic method of D-mannose

Abstract

The invention belongs to the field of pharmaceutical synthesis technology, and particularly relates to a new D-mannose synthesis method. The invention uses D-mannitol as a raw material, firstly protects two primary hydroxyl groups at the end by TBDMSCl, then protects the remaining four secondary hydroxyl groups by benzyl or acyl groups, then removes two primary hydroxyl silyl ether protecting groups, removes all hydroxyl protecting groups after oxidation, and finally reduces the aldehyde group to obtain D-mannose. The method has a mild reaction, greatly improves the synthesis yield, is easy to operate, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and more specifically relates to a method for synthesizing D-mannose. Background Art

[0002] 18 F-FDG, or fluorodeoxyglucose, is a fluorinated derivative of 2-deoxyglucose. 18 As a glucose analog, F-FDG can participate in glucose metabolism in the body and is taken up by cells with high glucose utilization rates, such as the brain, kidneys, and cancer cells. In these cells, the phosphorylation process will prevent glucose from being released from the cells in its original intact form. Before radioactive decay, 18 F-FDG phosphorylation 18 F-FDG-6-phosphate cannot undergo subsequent glycolysis due to the lack of oxygen at position 2 and cannot continue to be metabolized in the cell. 18 The distribution of F-FDG can well reflect the distribution of glucose uptake and phosphorylation in cells in the body. 18 F-FDG is the most commonly used imaging agent for PET / CT, the most important imaging test, and can be used to evaluate glucose metabolism in the heart, lungs, and brain. In tumor imaging, it can be used for cancer diagnosis, staging, and treatment monitoring. Most types of malignant tumor cells are metabolically active, and their glucose metabolism levels are much higher than those of normal tissues, which makes 18 F-FDG is widely distributed in tumor cells. 18 F-FDG-PET / CT can understand tumor metabolism information and obtain accurate anatomical positioning, which is of great significance for the formulation of disease treatment plans, surgery, and radiotherapy and chemotherapy plans.

[0003] 18The key precursor required for the synthesis of F-FDG is trifluoromannose, which is prepared from D-mannose. At present, the sources of D-mannose mainly include plant extraction, chemical synthesis and biotransformation: (1) Plant extraction is extracted from raw materials such as wood and palm fruit. Its production process requires high temperature and high concentration of acid / alkali solvents, which is easy to cause environmental pollution. In addition, this method requires a large number of plants, and the production and preparation are greatly affected by region and season. (2) The chemical synthesis method of D-mannose is often achieved by using molybdate to catalyze the phase isomerization reaction of D-glucose. However, this method must strictly control the processing concentration and temperature of the acid. Since inorganic catalysts have poor specificity for substrates, they are often accompanied by the production of many by-products, which are difficult to separate. Therefore, there are still many process challenges to overcome. In addition, D-mannitol can be used as a raw material to obtain it through chromic acid catalytic oxidation. However, since D-mannitol contains two primary hydroxyl groups, it is difficult to purify and separate it during the process, and the yield of the obtained product is not high. (3) Biotransformation is a process that uses microbial fermentation or certain isomerases to achieve the conversion of monosaccharides or polysaccharides to D-mannose. However, the catalytic efficiency of the isomerases used in current reports is not high, and a large number of by-products may appear in the product.

[0004] Patent CN201910202196.5 proposes a method for synthesizing D-mannose. D-mannitol is protected by silyl ether, protected by hydroxyl group, removed by one silyl ether, oxidized, and deprotected to obtain D-mannose. However, in the process of removing the silyl ether protecting group, about 50% of the main product of removing one silyl ether protecting group and 5% of the by-product of removing two silyl ether protecting groups and 45% of the unreacted raw materials will be produced, which makes the purification operation of this step difficult; and the yield of the final product D-mannose is low (30-35%), and the production cost is high. Therefore, it is urgent to further optimize the process, increase the yield of D-mannose, simplify the operation difficulty, and reduce the production cost.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The purpose of the present invention is to address the above-mentioned prior art problems and to provide a method suitable for industrial synthesis of D-mannose.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] A method for synthesizing D-mannose, the synthetic route of the method is as follows:

[0009]

[0010] Among them, R is Bn, Ac, Bz.

[0011] The method comprises the following steps:

[0012] In the first step, D-mannitol reacts with TBDMSCl to obtain compound Ⅰ.

[0013] Furthermore, in the first step reaction, D-mannitol reacts with TBDMSCl under the catalytic action of imidazole to obtain compound I; the reaction temperature is -10 to 30°C, preferably -10 to 0°C; the reaction solvent is DMF or a DMF-toluene mixed solution, preferably DMF; the molar ratio of D-mannitol:TBDMSCl:imidazole is 1:1 to 3:1 to 3, preferably the molar ratio of D-mannitol:TBDMSCl:imidazole is 1:2 to 2.5:2 to 2.5.

[0014] In the second step, all hydroxyl groups in compound I are protected to obtain compound II.

[0015] Furthermore, in the second step reaction, the hydroxyl protecting agent is selected from any one of BnBr, acetic anhydride and BzCl, preferably the hydroxyl protecting agent is BnBr; and the reaction temperature is -10 to 30°C.

[0016] In the third step, the two silyl ether protecting groups in compound II are removed to obtain compound III.

[0017] Furthermore, in the third step, tetrabutylammonium fluoride is used to remove the two silyl ether protecting groups in compound II; the reaction solvent is THF; and the reaction temperature is 0 to 30°C.

[0018] In the fourth step, the primary hydroxyl groups on both sides are oxidized to aldehyde groups to obtain dialdehyde compound IV.

[0019] Furthermore, in the fourth step reaction, the oxidant is selected from any one of DMSO-oxalyl chloride system, PCC or PDC, preferably the oxidant is dimethyl sulfoxide DMSO-oxalyl chloride system; the reaction solvent is dichloromethane.

[0020] In the fifth step, all hydroxyl protecting groups are removed, and the obtained intermediate undergoes an aldol condensation reaction to obtain compound V.

[0021] Furthermore, in the fifth step reaction, when the hydroxyl protecting group is Bn, Pd / C is used for hydrogenation deprotection; when the hydroxyl protecting group is Bz, sodium methoxide / methanol solution is used for deprotection; when the hydroxyl protecting group is Ac, K2CO3 is used for deprotection; the reaction temperature is 0-30°C.

[0022] In the sixth step, the aldehyde group is reduced to obtain the product D-mannose.

[0023] Furthermore, in the sixth step reaction, the reducing agent is selected from any one of LiAlH4, NaBH4, KBH4 or a borane reduction system, preferably NaBH4; the reaction solvent is methanol or THF; and the reaction temperature is 0 to 60°C.

[0024] Beneficial effects of the present invention:

[0025] The present invention discloses a new method for synthesizing D-mannose. Compared with the technical solution of the prior art CN201910202196.5 in which a silyl ether protecting group is removed in the third step reaction (total yield 30-35%), the present invention directly removes two silyl ether protecting groups in the third step reaction, and the yield of this step reaches about 85%, which greatly improves the total yield of the entire synthetic route (50-60%). At the same time, this step reaction does not need to be purified and can be directly put into the next step reaction, which greatly simplifies the operation process and reduces the difficulty of synthesis. The D-mannose synthesis method provided by the present invention has mild reaction conditions and is suitable for industrial production. DETAILED DESCRIPTION

[0026] The features and performance of the present invention are further described in detail below in conjunction with the examples. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially. The features and performance of the present invention are further described in detail below in conjunction with the examples.

[0027] Example 1

[0028] 1) Synthesis of Compound I

[0029]

[0030] D-mannitol (1 eq) was dissolved in anhydrous DMF (20 mL / g), protected by nitrogen, and cooled to -5 °C. After adding imidazole (2.2 eq), tert-butyldimethylsilyl chloride (2.2 eq) was added to the system, stirred for 30 min, and after the reaction was completed, DMF was evaporated under reduced pressure to obtain a crude product. It was dissolved in ethyl acetate, stirred for 5 min, and a white solid was precipitated. The filtrate was washed three times with ethyl acetate, and the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a refined compound I with a yield of 83%.

[0031] 2) Synthesis of Compound II-a

[0032]

[0033] Under nitrogen protection, compound I (1 eq) was dissolved in anhydrous THF, 60% NaH (6 eq) was added in three batches, BnBr (6 eq) THF solution and tetrabutylammonium bromide (0.05 eq) were added dropwise to the system, and stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction, THF was removed by rotary evaporation, ethyl acetate and water were added, and the organic phase was dried, filtered, and concentrated to obtain compound II-a with a yield of 94%. The crude product was directly used for the next step without purification.

[0034] 3) Synthesis of compound III-a

[0035]

[0036] Compound II (1 eq) was dissolved in 10 mL of anhydrous tetrahydrofuran, followed by the addition of 10 mL of a tetrahydrofuran solution of TBAF (6 eq), and the resulting mixture was stirred under argon for 24 h. The reaction was monitored by TLC. After the reaction was completed, NH4Cl (aqueous solution) was added to the mixture, and the mixture was extracted with ethyl acetate several times. The combined organic layer was dried over MgSO4. The combined organic layer was evaporated to obtain compound III-a with a yield of 84%.

[0037] 4) Synthesis of Compound IV-a

[0038]

[0039] Oxalyl chloride (1.5 eq) was added dropwise to dichloromethane, stirred and cooled to -78°C, DMSO (3 eq) in dichloromethane solution was added dropwise to the system, stirred for 30 min, compound III-a (1 eq) in dichloromethane solution was added dropwise to the system, after the addition was complete, the temperature was controlled at -78°C, and the reaction was monitored by TLC to complete. Triethylamine (6 eq) was added dropwise to the system, stirred, the system was slowly heated to 0°C, water was added, the liquid was separated, the organic phase was dried and concentrated, and compound IV-a was obtained with a yield of 96%. The crude product was directly put into the next step without purification.

[0040] 5) Synthesis of Compound V

[0041]

[0042] Compound IV-a was dissolved in methanol, 10% palladium on carbon was added, hydrogen was passed through, and the reaction was allowed to proceed overnight. TLC monitored the reaction to be complete. The reaction solution was filtered to remove palladium on carbon, and the filtrate was then dried to obtain compound V with a yield of 93%. The crude product was directly used in the next step without purification.

[0043] 6) Synthesis of D-mannose

[0044]

[0045] Compound Va (1 eq) was added to methanol, sodium borohydride (1 eq) was slowly added under ice-water bath conditions, then the temperature was raised to 45°C, stirred and refluxed for 3 hours, and the reaction was monitored by TLC to be complete. The methanol solvent was evaporated under reduced pressure, and then ethyl acetate and saturated sodium chloride (v:v=6:5) were added for extraction, dried over anhydrous magnesium sulfate, and the organic solvent was evaporated under reduced pressure. After column chromatography separation, the product D-mannose was obtained with a yield of 95%.

[0046] Example 2

[0047] 1) The synthesis process of compound I is the same as that of Example 1.

[0048] 2) Synthesis of Compound II-b

[0049]

[0050] Compound I (1 eq) was dissolved in pyridine, cooled to 0°C, BzCl (6 eq) was added dropwise with stirring, stirred at room temperature overnight, the reaction solution was poured into an appropriate amount of ice water, extracted with toluene, separated, the organic phase was dried, filtered, and concentrated to obtain compound II-b with a yield of 83%. The crude product was directly used for the next step reaction without purification.

[0051] 3) The synthesis process of compounds III-b to IV-b is the same as that of Example 1.

[0052] 4) Synthesis of Compound V

[0053]

[0054] Compound IV-b (1 eq) was dissolved in sodium methoxide / methanol solution and stirred at room temperature until the reaction was complete. Solid precipitated and filtered to obtain compound V with a yield of 95%. The crude product was directly used in the next step without purification.

[0055] 5) The synthesis process of D-mannose is the same as that in Example 1.

[0056] Example 3

[0057] 1) The synthesis process of compound I is the same as that of Example 1.

[0058] 2) Synthesis of Compound II-c

[0059]

[0060] Compound I (1 eq) was dissolved in pyridine, cooled to 0°C, acetic anhydride (6 eq) was added dropwise with stirring, stirred at room temperature overnight, the reaction solution was poured into an appropriate amount of ice water, extracted with toluene, separated, the organic phase was dried, filtered, and concentrated to obtain compound II-c with a yield of 98%. The crude product was directly used for the next step reaction without purification.

[0061] 3) The synthesis process of compounds III-c to IV-c is the same as that of Example 1.

[0062] 4) Synthesis of Compound V

[0063]

[0064] Compound IV-c (1 eq) was dissolved in a methanol / water (2:1) mixed solution, potassium carbonate (6 eq) was added to the system, and the mixture was stirred until the reaction was complete. The reaction solution was concentrated under reduced pressure, and all ethanol and part of the water were evaporated. Solids were precipitated, and the solids were filtered to obtain compound V with a yield of 93%. The crude product was directly used for the next step reaction without purification.

[0065] 5) The synthesis process of D-mannose is the same as that in Example 1.

[0066] The above describes in detail the preferred specific embodiments of the present invention. It should be understood that ordinary technicians in this field can make active modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in this technical field through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the existing technology should be within the scope of protection determined by the claims.

Claims

1. A method for synthesizing D-mannose, characterized in that: The synthetic route is as follows: Wherein, R is Bn, Ac, Bz; In the first step, D-mannitol reacts with tert-butyldimethylsilyl chloride to obtain compound I; The second step is to protect all hydroxyl groups in compound I to obtain compound II; The third step is to remove the silyl ether protecting groups on both sides of compound II to obtain compound III; The fourth step is to oxidize the primary hydroxyl groups on both sides to aldehyde groups to obtain compound IV; Step 5, removing all hydroxyl protecting groups to obtain compound V; The sixth step is aldehyde reduction reaction to obtain D-mannose.

2. The method for synthesizing D-mannose according to claim 1, characterized in that: In the first step, D-mannitol reacts with tert-butyldimethylsilyl chloride under the catalysis of imidazole.

3. The method for synthesizing D-mannose according to claim 1, characterized in that: In the second step reaction, the hydroxyl protecting agent is selected from any one of benzyl bromide, acetic anhydride and benzoyl chloride.

4. The method for synthesizing D-mannose according to claim 1, characterized in that: In the third step, tetrabutylammonium fluoride is used to remove the two silyl ether protecting groups in compound II.

5. The method for synthesizing D-mannose according to claim 1, characterized in that: In the fourth step reaction, the oxidant is selected from any one of dimethyl sulfoxide-oxalyl chloride system, pyridinium chlorochromate or pyridinium dichromate.

6. The method for synthesizing D-mannose according to claim 1, characterized in that: In the sixth step reaction, the reducing agent is selected from any one of LiAlH4, NaBH4, KBH4 or a borane reduction system.

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