CN109776625B

CN109776625B - Synthesis method of D-mannose

Info

Publication number: CN109776625B
Application number: CN201910202196.5A
Authority: CN
Inventors: 罗志刚; 王正; 戴娟; 徐建锋
Original assignee: Nanjing Pet Tracer Co ltd
Current assignee: Nanjing Pet Tracer Co ltd
Priority date: 2019-03-18
Filing date: 2019-03-18
Publication date: 2022-08-23
Anticipated expiration: 2039-03-18
Also published as: CN109776625A

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 the advantages of mild reaction, high synthesis yield and simple and convenient operation, and is suitable for industrial large-scale production.

Description

Synthesis method of D-mannose

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a brand-new D-mannose synthesis method.

Background

¹⁸ F-FDG is the most common tracer in PET diagnosis and accounts for more than 90% of clinical application. It has almost the same molecular structure as glucose, can participate in glucose metabolism in vivo, and can be administered by intravenous injection ¹⁸ F-FDG can enter the interior of the cell through active transport of glucose transporters; the vast majority of malignant cells are characterized by unlimited proliferation, which requires a large amount of energy, and metabolic aspects are reflected in that glucose metabolism is always at a high level, far above normal tissue, which results in ¹⁸ F-FDG is distributed in large numbers in tumor cells. ¹⁸ F is converted into ¹⁸ O, positron (. beta.) ⁺ ) Neutrino and partial energy; beta is a ⁺ Annihilation radiation is rapidly generated and converted into 2 gamma photons with opposite directions and energy of 511KeV each, and then the gamma photons are detected by a coincidence circuit to find out the corresponding spatial position, thereby finding out the position of the cancer cell. Further, the PET functional image is formed by computer processing. The patient carries out high-resolution CT scanning again under the condition of not moving the body position to obtain a more detailed anatomical image of the tumor, and the accurate resolution of the anatomical image can reach 2 mm; the obtained PET image is fused with the CT image, so that the PET-CT image can be obtained, a clinician can obtain accurate anatomical positioning while knowing the tumor metabolic information, and the PET-CT image has great significance for making treatment schemes of diseases, operations and chemoradiotherapy schemes.

¹⁸ F-FDG is glucoseThe analog of (a), by a series of chemical reactions, ¹⁸ the F group replaces one OH group of the glucose molecule to form ¹⁸ F-FDG. The key precursor required for synthesizing the mannose triflate is mannose triflate, Yangxije, Zhou Sai Chun, chemical engineering journal, 2004,18(7),34-35, the specific synthetic route is as follows:

at present, the sources of D-mannose mainly comprise: 1) the extraction method comprises the following steps: d-mannose can be extracted from various raw materials such as wood, palm fruit and the like, but the purification steps are complicated, solvent residue is easily caused, and the generation of byproducts is caused; 2) chemical synthesis method: d-mannose can be prepared by hydrolyzing D-mannose-rich glycans (Eleocharis camentus, yeast mannan, etc.); d-glucose can be directly obtained under the action of a catalyst, but the temperature and the acid concentration are strictly controlled in the process, and the reaction conditions are severe; can also be prepared by chromic acid (in the form of micellar aqueous phase: SDS, TX-100, CPC) catalytic oxidation, which requires the use of a promoter (PA, phen and bpy) and micellar catalysis, but because D-mannitol contains two primary hydroxyl groups, a dialdehyde group is generated as a byproduct; in addition, D-mannose can be hydrolyzed from starch by a microwave-assisted one-step process, but the by-product D-glucose is relatively large, in a ratio to D-mannose of about 2: 1; 3) the biological method comprises the following steps: most of the D-mannose produced by the enzyme method is in laboratory level, the production scale is small, and the yield is low.

Disclosure of Invention

The present invention has been made in view of the above problems, and an object of the present invention is to provide a novel method for synthesizing D-mannose.

The purpose of the invention can be realized by the following technical scheme:

a synthetic method of D-mannose comprises the following synthetic route:

wherein R is Bn, Ac or Bz.

The method comprises the following steps:

in the first 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 catalytic action of imidazole to prepare a compound I; the reaction temperature is-10 to 30 ℃, and the preferable reaction temperature is-10 to 0 ℃; the reaction solvent is DMF or a DMF-toluene mixed solution, and the preferred reaction solvent is DMF; the D-mannitol: TBDMSCl: the molar ratio of imidazole is 1: 1-3: 1-3, preferably D-mannitol: TBDMSCl: the molar ratio of imidazole is 1: 2-2.5: 2 to 2.5.

In the second step of reaction, 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, preferably the hydroxyl protecting reagent is BnBr; the reaction temperature is-10-30 ℃.

In the third step of reaction, one silyl ether protecting group in the compound II is removed to obtain a compound III.

Further, in the third reaction step, 1% by mass of I was used ₂ Removing one silyl ether protecting group in the compound II by using methanol solution. In one technical scheme, tetrahydrofuran is added to make the system homogeneous, and the reaction is promoted; the reaction temperature is 0-30 ℃.

In the fourth step of reaction, hydroxyl in the compound III is oxidized into aldehyde group to obtain a compound IV.

Further, in the fourth step of 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 was dichloromethane.

In the fifth step of reaction, the silyl ether protecting group in the compound IV is removed to obtain a compound V.

Further, in the fifth step of reaction, TBAF is used for removing the silyl ether protecting group in the compound IV; the reaction solvent is THF; the reaction temperature is 0-30 ℃.

In the sixth step of reaction, all hydroxyl protecting groups are removed, and the obtained intermediate undergoes an aldol condensation reaction to finally obtain the D-mannose.

Further, in the sixth reaction step, when the hydroxyl protecting group is Bn, Pd/C is used for hydrogenation to remove the protecting group; when the hydroxyl protecting group is Bz, deprotecting the group by using sodium methoxide/methanol solution; when the hydroxyl protecting group is Ac, K is used ₂ CO ₃ Removing a protecting group; the reaction temperature is 0-30 ℃.

The invention has the advantages of

The invention discloses a brand new D-mannose synthesis method, which takes D-mannitol as an initial raw material, the total yield of the D-mannose obtained by the method is about 30-35 percent, compared with the prior art, the method is obviously improved, the reaction condition is mild, the operation is simple and convenient, the cost of the used raw materials is low, and the method is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, without limiting the scope of the invention:

example 1

1) Synthesis of Compound I

D-mannitol (1.0eq.) was dissolved in anhydrous DMF (20mL/g) under nitrogen and cooled to-5 ℃. After imidazole (2.2eq.) was added thereto, tert-butyldimethylsilyl chloride (2.2eq.) was added to the system, and the mixture was stirred for 30min, after the reaction was completed, DMF was distilled off under reduced pressure to obtain a crude product. Dissolving with ethyl acetate, stirring for 5min, separating out white solid, vacuum filtering, washing filtrate with ethyl acetate for three times, washing organic phase with sodium chloride solution, drying with anhydrous sodium sulfate, vacuum filtering, and concentrating to obtain refined compound I with yield of 80%.

2) Synthesis of Compound II-a

Under the protection of nitrogen, dissolving a compound I (1eq.) in anhydrous THF, adding 60% NaH (6eq.) in three batches, dropwise adding a THF solution of BnBr (6eq.) and tetrabutylammonium bromide (0.05eq.) into the system, stirring at room temperature for 2 hours, adding water after the reaction is finished, quenching the reaction, removing THF by rotary evaporation, adding ethyl acetate and water, separating liquid, drying an organic phase, performing suction filtration and concentration to obtain a compound II-a with the yield of 93%. The crude product is directly put into the next reaction without purification.

3) Synthesis of Compound III-a

At room temperature, the compound II-a (1eq.) was dissolved in anhydrous THF, a 1% by mass solution of iodomethanol (10mL/g) was added dropwise to the system, and after completion of the addition, the reaction was allowed to proceed overnight, and the completion of the reaction was monitored by TLC. Adding Na dropwise into the system ₂ S ₂ O ₃ Evaporating the organic solvent under reduced pressure to obtain oily substance, adding ethyl acetate and water solution, standing, separating, drying the organic phase, and concentrating to obtain crude product. The crude product was purified by silica gel column to obtain the refined compound III-a with a yield of 56%.

4) Synthesis of Compound IV-a

Adding oxalyl chloride (1.5eq.) dropwise into dichloromethane, stirring and cooling to-78 ℃, adding a dichloromethane solution of DMSO (3eq.) dropwise into the system, stirring for 30min after adding dropwise, adding a dichloromethane solution of a compound III-a (1eq.) dropwise into the system, controlling the temperature to-78 ℃ after adding dropwise, and monitoring the reaction completion by TLC. And (3) dropwise adding triethylamine (6eq.) into the system, stirring, slowly raising the system to 0 ℃, adding water, separating, drying and concentrating an organic phase to obtain a compound IV-a with the yield of 96%.

5) Synthesis of Compound V

At room temperature, the compound IV-a (1eq.) is dissolved in anhydrous THF, TBAF (1.5eq.) is added into the system, the reaction is carried out for 2h, and the completion of the reaction is monitored by TLC. And adding ethyl acetate into the system, separating, and distilling under reduced pressure to remove the organic solvent to obtain the compound V with the yield of 91%. The product is directly put into the next reaction without purification.

6) D-mannose synthesis

Dissolving the compound V-a (1eq.) in methanol, adding 10% palladium carbon, reacting overnight by using hydrogen, monitoring by HPLC (high performance liquid chromatography), precipitating a large amount of solid after the reaction is finished, performing suction filtration, adding a proper amount of water into a filter cake to dissolve, stirring for 30min, performing suction filtration to remove the palladium carbon, reducing the pressure of a filtrate, and steaming to remove water to obtain the D-mannose with the yield of 93%.

Example 2

1) The synthesis of compounds I-b was performed as in example 1.

2) Synthesis of Compound II-b

Dissolving a compound I (1eq.) in pyridine, cooling to 0 ℃, dropwise adding acetic anhydride (6eq.) while stirring, stirring at room temperature overnight, pouring the reaction solution into a proper amount of ice water, extracting with toluene, separating liquid, drying an organic phase, performing suction filtration and concentration to obtain a compound II-b with the yield of 98%. The crude product is directly put into the next reaction without purification.

3) The synthesis of compounds III-b to V-b was performed as in example 1.

4) D-mannose synthesis

Dissolving the compound V-b (1eq.) in a methanol/water (2: 1) mixed solution at room temperature, adding potassium carbonate (6eq.) into the system, stirring until the reaction is finished, concentrating the reaction solution under reduced pressure, evaporating all ethanol and part of water, precipitating a solid, and filtering by suction to obtain the D-mannose with the yield of 80%.

Example 3

1) The synthesis of compounds I-c was performed as in example 1.

2) Synthesis of Compound II-c

Dissolving the compound I (1eq.) in pyridine, cooling to 0 ℃, dropwise adding BzCl (6eq.) while stirring, stirring at room temperature overnight, pouring the reaction solution into a proper amount of ice water, extracting with toluene, separating liquid, drying the organic phase, performing suction filtration and concentration to obtain a compound II-c with the yield of 81%. The crude product is directly put into the next reaction without purification.

3) The procedure for the synthesis of compounds III-c to V-c was as in example 1.

4) D-mannose synthesis

Dissolving the compound V-c (1eq.) in sodium methoxide/methanol solution, stirring at room temperature until the reaction is completed, separating out solids, and performing suction filtration to obtain the D-mannose with the yield of 88%.

Claims

1. A synthetic method of D-mannose is characterized in that the synthetic route is as follows:

wherein R is Bn, Ac, Bz;

the method comprises the following steps:

firstly, reacting D-mannitol with tert-butyldimethylsilyl chloride (TBDMSCl) to obtain a compound I;

secondly, protecting all hydroxyl groups in the compound I to obtain a compound II;

thirdly, removing a silyl ether protecting group in the compound II to obtain a compound III;

fourthly, oxidizing primary hydroxyl in the compound III into aldehyde group to obtain a compound IV;

fifthly, removing the silyl ether protecting group in the compound IV to obtain a compound V;

sixthly, removing all hydroxyl protecting groups to obtain D-mannose;

in the sixth step of reaction, when the hydroxyl protecting group is Bn, Pd/C is used for hydrogenation to remove the protecting group; when the hydroxyl protecting group is Bz, using sodium methoxide/methanol solution to deprotect the group; when the hydroxyl protecting group is Ac, K is used ₂ CO ₃ Removing a protecting group; the reaction temperature is 0-30 ℃.

2. The method for synthesizing D-mannose according to claim 1, wherein in the first reaction step, D-mannitol is reacted with TBDMSCl under imidazole catalysis.

3. The method for synthesizing D-mannose according to claim 1, wherein the hydroxyl protecting reagent is any one selected from benzyl bromide (BnBr), acetic anhydride and benzoyl chloride (BzCl) in the second reaction step.

4. The method of claim 1, wherein 1% by mass of I is used in the third reaction step ₂ Methanol solution removes only one silyl ether protecting group from compound II.

5. The method for synthesizing D-mannose according to claim 1, wherein the oxidizing agent is any one selected from a dimethyl sulfoxide (DMSO) -oxalyl chloride system, pyridinium chlorochromate (PCC), and Pyridinium Dichromate (PDC) in the fourth reaction step.

6. The process for the synthesis of D-mannose according to claim 1, wherein in the fifth reaction step, the silyl ether protecting group in the compound IV is removed using tetrabutylammonium fluoride (TBAF).