CN116410244A - Synthesis method of D-mannose - Google Patents

Synthesis method of D-mannose Download PDF

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CN116410244A
CN116410244A CN202111636333.XA CN202111636333A CN116410244A CN 116410244 A CN116410244 A CN 116410244A CN 202111636333 A CN202111636333 A CN 202111636333A CN 116410244 A CN116410244 A CN 116410244A
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compound
mannose
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synthesis
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徐建锋
戴娟
王正
罗志刚
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Nanjing Pet Tracer Co ltd
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Nanjing Pet Tracer Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a brand-new D-mannose synthesis method. The method has mild reaction, greatly improved synthesis yield, simple and convenient operation and suitability for industrialized mass production.

Description

Synthesis method of D-mannose
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing D-mannose.
Background
18 F-FDG, fluorodeoxyglucose, is a fluoroderivative of 2-deoxyglucose. 18 F-FDG, a glucose analog, is involved in glucose metabolism in vivo and is taken up by glucose high-availability cells such as brain, kidney and cancer cells. Within such cells, the phosphorylation process will prevent glucose from being released from the cells in its original intact form. Before the radioactive decay time of the sample, 18 formed by F-FDG phosphorylation 18 F-FDG-6-phosphate cannot be subjected to subsequent glycolysis due to the deficiency of oxygen at the 2-position, and cannot be metabolized continuously in cells. Thus, the first and second substrates are bonded together, 18 the distribution of F-FDG reflects well the distribution of glucose uptake and phosphorylation by cells in vivo. 18 F-FDG is the most important imaging examination for PET/CT most commonly usedCan be used for assessing glucose metabolism of heart, lung and brain, and can be used for diagnosis, staging and treatment monitoring of cancers in tumor imaging. Most types of malignant cells are actively metabolized, and glucose metabolism levels are far higher than in normal tissues, which results in 18 F-FDG is abundantly distributed in tumor cells. Clinically can pass through 18 F-FDG-PET/CT knows the tumor metabolism information, obtains accurate anatomical localization, and has great significance for the treatment scheme of diseases, the formulation of surgery and radiotherapy and chemotherapy schemes.
18 The key precursor required for F-FDG synthesis is mannose triflate, which is prepared by D-mannose. At present, the sources of D-mannose mainly include plant extraction, chemical synthesis and bioconversion: (1) The plant extraction method is used for extracting raw materials such as wood, palm fruits and the like, the production process of the plant extraction method needs high temperature and high concentration of solvents such as acid/alkali and the like, environmental pollution is easy to cause, and the method needs a large number of plants, and the production and preparation are greatly influenced by regions and seasons; (2) The chemical synthesis method for preparing D-mannose is usually realized by catalyzing D-glucose with molybdate to carry out a differential phase isomerization reaction, but the method has to strictly control the processing concentration and the temperature of acid, and has a lot of process challenges to be overcome because of the poor specificity of inorganic catalysts to substrates and the difficulty of separation along with the generation of a plurality of byproducts; in addition, D-mannitol can be used as a raw material to be prepared by chromic acid catalytic oxidation, but because the D-mannitol contains two primary hydroxyl groups, the purification and separation challenges are large in the process, and the yield of the obtained product is not high; (3) Bioconversion is a process that utilizes microbial fermentation or certain isomerase enzymes to effect the conversion of monosaccharides or polysaccharides to D-mannose, but the isomerase enzymes used in current reports are not efficient in catalysis and a large amount of by-products may occur in the product.
In patent CN201910202196.5, a synthetic method of D-mannose is proposed, where D-mannitol is subjected to silyl ether protection, hydroxyl protection, removal of a silyl ether, oxidation, and deprotection to obtain D-mannose, but in the process of removing a silyl ether protecting group, about 50% of a main product from which a silyl ether protecting group is removed, 5% of a byproduct from which two silyl ether protecting groups are removed, and 45% of unreacted raw materials are produced, which results in great difficulty in purification operation in the step; and the yield of the final product D-mannose is lower (30-35%), and the production cost is higher. Therefore, further optimization of the process is urgently needed, the yield of D-mannose is improved, the operation difficulty is simplified, and the production cost is reduced.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims at solving the problems in the prior art and aims at providing a method suitable for industrially synthesizing D-mannose.
The aim of the invention can be achieved by the following technical scheme:
a synthetic method of D-mannose comprises the following synthetic route:
Figure BDA0003442192840000021
wherein R is Bn, ac, bz.
The method comprises the following steps:
in the first reaction step, D-mannitol reacts with TBDMSCl to obtain a compound I.
Further, in the first step of reaction, D-mannitol reacts with TBDMSCl under the catalysis of imidazole to prepare a compound I; the reaction temperature is-10 to 30 ℃, preferably-10 to 0 ℃; the reaction solvent is DMF or DMF-toluene mixed solution, preferably DMF; the D-mannitol: TBDMSCl: the molar ratio of imidazole is 1:1 to 3:1 to 3, preferably D-mannitol: TBDMSCl: the molar ratio of imidazole is 1:2 to 2.5:2 to 2.5.
In the second reaction step, all hydroxyl groups in the compound I are protected to obtain a compound II.
Further, in the second step of reaction, the hydroxyl protecting reagent is selected from any one of BnBr, acetic anhydride and BzCl, and preferably the hydroxyl protecting reagent is BnBr; the reaction temperature is-10-30 ℃.
In the third step of reaction, two silyl ether protecting groups in the compound II are removed to obtain a compound III.
Further, in the third reaction step, tetrabutylammonium fluoride is used to remove two silyl ether protecting groups in the compound II; the reaction solvent is THF; the reaction temperature is 0-30 ℃.
In the fourth step of reaction, the primary hydroxyl groups on two sides are oxidized into aldehyde groups to obtain the dialdehyde compound IV.
Further, in the fourth reaction step, 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 was methylene chloride.
And in the fifth step of reaction, removing all hydroxyl protecting groups, and carrying out aldol condensation reaction on the obtained intermediate to obtain the compound V.
Further, in the fifth step of reaction, when the hydroxyl protecting group is Bn, pd/C hydrogenation is used for removing the protecting group; when the hydroxyl protecting group is Bz, deprotecting the hydroxyl protecting group by using sodium methoxide/methanol solution; when the hydroxyl protecting group is Ac, K is used 2 CO 3 Removing protecting groups; the reaction temperature is 0-30 ℃.
In the sixth step, aldehyde group is reduced to obtain the product D-mannose.
Further, in the sixth reaction, the reducing agent is selected from LiAlH 4 、NaBH 4 、KBH 4 Or any one of the borane reduction systems, preferably the reducing agent is NaBH 4 The method comprises the steps of carrying out a first treatment on the surface of the The reaction solvent is methanol or THF; the reaction temperature is 0-60 ℃.
The invention has the beneficial effects that:
the invention discloses a brand new method for synthesizing D-mannose. Compared with the technical scheme of removing one silyl ether protecting group in the third reaction step of CN201910202196.5 in the prior art (total yield is 30-35%), the invention directly removes two silyl ether protecting groups in the third reaction step, the yield of the step reaches about 85%, and the total yield of the whole synthesis route is greatly improved (50-60%). Meanwhile, the reaction does not need purification, can be directly put into the next reaction, greatly simplifies the operation flow and reduces the synthesis difficulty. The method for synthesizing the D-mannose has mild reaction conditions and is suitable for industrial production.
Detailed Description
The features and capabilities of the present invention are described in further detail below in connection with the examples. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
1) Synthesis of Compound I
Figure BDA0003442192840000031
D-mannitol (1 eq) was dissolved in anhydrous DMF (20 mL/g), nitrogen blanketed, and cooled to-5 ℃. After imidazole (2.2 eq) was added thereto, t-butyldimethylchlorosilane (2.2 eq) was added to the system, stirred for 30min, and after completion of the reaction, DMF was distilled off under reduced pressure to obtain a crude product. Dissolving with ethyl acetate, stirring for 5min, precipitating white solid, suction filtering, washing filtrate with ethyl acetate for three times, washing organic phase with sodium chloride solution, drying with anhydrous sodium sulfate, suction filtering, concentrating to obtain refined compound I with yield of 83%.
2) Synthesis of Compound II-a
Figure BDA0003442192840000032
Under the protection of nitrogen, the compound I (1 eq) is dissolved in anhydrous THF, 60 percent of NaH (6 eq) is added in three batches, THF solution of BnBr (6 eq) and tetrabutylammonium bromide (0.05 eq) are added dropwise into the system, the mixture is stirred for 2 hours at room temperature, water is added for quenching reaction after the reaction is finished, THF is removed by rotary evaporation, ethyl acetate and water are added, liquid separation is carried out, and an organic phase is dried, filtered by suction and concentrated to obtain the compound II-a, and the yield is 94 percent. The crude product is directly put into the next reaction without purification.
3) Synthesis of Compound III-a
Figure BDA0003442192840000041
Compound II (1 eq) was dissolved in 10mL of anhydrous tetrahydrofuran, followed by addition of 10mL of tetrahydrofuran solution of TBAF (6 eq), the resulting mixture was stirred under argon for 24h, the reaction was monitored by TLC, and NH was added to the mixture after the reaction was completed 4 Cl (aqueous solution), the mixture was extracted multiple times with ethyl acetate. Over MgSO 4 The combined organic layers were dried on. The combined organic layers were evaporated to give compound III-a in 84% yield.
4) Synthesis of Compound IV-a
Figure BDA0003442192840000042
Oxalyl chloride (1.5 eq) is added dropwise into dichloromethane, stirring and cooling are carried out to-78 ℃, a dichloromethane solution of DMSO (3 eq) is added dropwise into the system, stirring is carried out for 30min after the dropwise addition is finished, a dichloromethane solution of a compound III-a (1 eq) is added dropwise into the system, after the dropwise addition is finished, the temperature is controlled to-78 ℃, and TLC monitoring reaction is complete. Triethylamine (6 eq) is added dropwise into the system, stirring is carried out, the system is slowly heated to 0 ℃, water is added, liquid separation is carried out, and the organic phase is dried and concentrated, thus obtaining the compound IV-a with 96 percent of yield. The crude product is directly put into the next reaction without purification.
5) Synthesis of Compound V
Figure BDA0003442192840000043
The compound IV-a was dissolved in methanol, 10% palladium on charcoal was added, the reaction was allowed to proceed overnight, and TLC monitored for completion. The reaction solution was filtered to remove palladium on charcoal, and then the filtrate was dried by spin to give compound V in 93% yield. The crude product is directly put into the next reaction without purification.
6) Synthesis of D-mannose
Figure BDA0003442192840000044
Compound V-a (1 eq) was added to methanol, sodium borohydride (1 eq) was slowly added under ice water bath, then warmed to 45 ℃, stirred for 3h under reflux, and tlc monitored the reaction was complete. The methanol solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate and saturated sodium chloride (v: v=6:5), drying over anhydrous magnesium sulfate, and distillation of the organic solvent under reduced pressure, column chromatography, gave the product D-mannose in 95% yield.
Example 2
1) The procedure for the synthesis of compound I was as in example 1.
2) Synthesis of Compound II-b
Figure BDA0003442192840000051
Compound I (1 eq) was dissolved in pyridine, cooled to 0 ℃, bzCl (6 eq) was added dropwise with stirring, stirred overnight at room temperature, the reaction solution was poured into a suitable amount of ice water, extracted with toluene, separated, and the organic phase was dried, filtered and concentrated to give compound II-b in 83% yield. The crude product is directly put into the next reaction without purification.
3) The synthesis of the compounds III-b to IV-b was carried out as in example 1.
4) Synthesis of Compound V
Figure BDA0003442192840000052
And (3) dissolving the compound IV-b (1 eq) in sodium methoxide/methanol solution, stirring at room temperature until the reaction is completed, separating out solid, and filtering to obtain the compound V with the yield of 95%. The crude product is directly put into the next reaction without purification.
5) The synthesis of D-mannose was the same as in example 1.
Example 3
1) The procedure for the synthesis of compound I was as in example 1.
2) Synthesis of Compound II-c
Figure BDA0003442192840000053
Compound I (1 eq) was dissolved in pyridine, cooled to 0 ℃, acetic anhydride (6 eq) was added dropwise with stirring, stirred overnight at room temperature, the reaction solution was poured into a suitable amount of ice water, extracted with toluene, the solution was separated, and the organic phase was dried, filtered with suction, concentrated to give compound II-c in 98% yield. The crude product is directly put into the next reaction without purification.
3) The synthesis of the compounds III-c to IV-c is the same as in example 1.
4) Synthesis of Compound V
Figure BDA0003442192840000054
Dissolving the compound IV-c (1 eq) in a methanol/water (2:1) mixed solution, adding potassium carbonate (6 eq) into the system, stirring until the reaction is completed, concentrating the reaction solution under reduced pressure, evaporating all ethanol and part of water, separating out solids, and carrying out suction filtration to obtain the compound V with the yield of 93%. The crude product is directly put into the next reaction without purification.
5) The synthesis of D-mannose was the same as in example 1.
The foregoing describes in detail preferred embodiments of the present invention. It should be understood that active modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without the need for creative efforts. Therefore, the technical solutions obtained by those skilled in the art through logic analysis, reasoning or limited experiments based on the prior art according to the present invention should be within the protection scope defined by the claims.

Claims (7)

1. The synthesis method of the D-mannose is characterized by comprising the following steps of:
Figure FDA0003442192830000011
wherein R is Bn, ac, bz.
2. The method for synthesizing D-mannose according to claim 1, comprising the steps of:
firstly, reacting D-mannitol with tert-butyldimethyl chlorosilane (TBDMSCl) to obtain a compound I;
secondly, protecting all hydroxyl groups in the compound I to obtain a compound II;
step three, removing the silyl ether protecting groups on two sides of the compound II to obtain a compound III;
fourthly, oxidizing the primary hydroxyl groups at two sides into aldehyde groups to obtain a compound IV;
fifthly, removing all hydroxyl protecting groups to obtain a compound V;
and sixthly, carrying out reduction reaction on aldehyde groups to obtain D-mannose.
3. The method for synthesizing D-mannose according to claim 2, wherein in the first step, D-mannitol is reacted with TBDMSCl under imidazole catalysis.
4. The method for synthesizing D-mannose according to claim 2, wherein in the second step, the hydroxyl protecting agent is selected from any one of benzyl bromide (BnBr), acetic anhydride, and benzoyl chloride (BzCl).
5. The method for synthesizing D-mannose according to claim 2, wherein in the third reaction step, tetrabutylammonium fluoride (TBAF) is used to remove two silyl ether protecting groups in compound ii.
6. The method for synthesizing D-mannose according to claim 2, wherein in the fourth step, the oxidizing agent is selected from any one of Dimethylsulfoxide (DMSO) -oxalyl chloride system, pyridinium chlorochromate (PCC) or Pyridinium Dichromate (PDC).
7. The combination of D-mannose according to claim 2The method is characterized in that in the sixth reaction, the reducing agent is selected from LiAlH 4 、NaBH 4 、KBH 4 Or any of the borane reduction systems.
CN202111636333.XA 2021-12-29 2021-12-29 Synthesis method of D-mannose Pending CN116410244A (en)

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