CN112125939A

CN112125939A - Method for preparing high-purity 5-deoxy-D-ribose

Info

Publication number: CN112125939A
Application number: CN202010696067.9A
Authority: CN
Inventors: 王相承; 王刚; 王思宇; 李江存; 李建; 齐秀丽; 李丹
Original assignee: Insititute Of Nbc Defence
Current assignee: Insititute Of Nbc Defence
Priority date: 2020-07-16
Filing date: 2020-07-16
Publication date: 2020-12-25

Abstract

The invention discloses a preparation method of high-purity 5-deoxy-D-ribose, belonging to the technical field of chemical manufacturing separation. The technical scheme of the invention comprises the following steps: acylating 2, 3-O-isopropylidene-D-furan type methyl glucoside at 120 ℃ to obtain an intermediate A after the reaction is finished; recrystallizing 1 part of the intermediate A by using 5-20 parts of mixed solvent (mass number), wherein the mixed solvent consists of isopropanol and methanol in a mass ratio of 5: 1, and recrystallizing and purifying to obtain an intermediate B; and (3) carrying out ammonolysis reaction on the intermediate B at the reaction temperature, and carrying out post-treatment after the reaction is finished to obtain the 5-deoxy-D-ribose. Compared with the prior art, the invention has the advantages that: simple synthetic route, easily obtained raw materials, mild process conditions, low cost and convenient industrial production. The content of the 5-deoxy-D-ribose prepared by the method of the invention reaches more than 99 percent, and the purity is high.

Description

Method for preparing high-purity 5-deoxy-D-ribose

Technical Field

The invention relates to a preparation method of high-purity 5-deoxy-D-ribose, belonging to the technical field of chemical manufacturing separation.

Background

Among antitumor and antiviral drugs, a large number of nucleoside compounds are clinically used, and they are based on the principle of metabolic antagonism. The disease resistance effect is generated by interfering or inhibiting the nucleic acid replication of viruses and tumor cells. Generally, biologically active nucleosides require the presence of a 5-hydroxy group to function by phosphorylation in vivo. While removal of the 5-hydroxyl group results in a series of compounds that are of interest for biochemical and physiological studies. 5-deoxy-D-ribose is an important nucleoside drug precursor, and is widely applied to antiviral and antitumor drugs, such as 5-deoxy-5-fluorouridine, 5-deoxythymidine, 5-deoxyadenosine, Capecitabine (Capecitabine) and the like.

D-ribose has hydroxyl groups at 1-, 2-, 3-, and 5-positions, and the removal of oxygen at different positions results in different biological properties, of which 2-deoxy-D-ribose and 5-deoxy-D-ribose are particularly appreciated for their biological activity.

The synthesis technology of the 5-deoxy-D-ribose has great difficulty. 5-deoxynucleosides are generally obtained by removing the-5-hydroxyl group from the corresponding nucleoside. Because the route for synthesizing the nucleoside is long and the yield is low, the yield of the target product can be reduced more seriously by carrying out deoxidation after obtaining the nucleoside. The 5-deoxyribose is successfully developed, the 5-deoxyribose and the corresponding basic group are subjected to condensation reaction to obtain the 5-deoxynucleoside in one step, the process of the 5-deoxynucleoside compound is fundamentally changed, the yield of the target product is greatly improved, and the method has important significance.

The major problem in the synthesis of 5-deoxy-D-ribose is the difficulty of the isolation method, as described in "Kiss J D, Souza R, et al Helv Chim Acta, 1982, 65 (5): 1522-: 5534 and 5540 ", the method adopts D-ribose as raw material, halogenated (brominated or iodinated) after hydroxyl protection, and separated by a column after reduction and dehalogenation; "Wangcheng, Wanggang, Qucongol. chemical world, 2008, 4: 226- "improves the synthesis method of 5-deoxy-D-ribose, uses D-ribose as raw material, forms 2, 3-O-isopropylidene-D-furan type methyl glucoside by acetone/methanol protection, after iodomethane is iodinated, catalytic hydrogenation is carried out, and hydrolysis is carried out under the condition of acidic cation resin to obtain 5-deoxy-D-ribose, but the problem of column separation of the final product is still not solved. The column separation efficiency is low, a large amount of leacheate is needed, the energy consumption is high, time and labor are wasted, and the industrial application is difficult.

The content of the 5-deoxy-D-ribose sold in the market at present is 95 to 98 percent, the price is high, and the method is greatly limited by the productivity and the separation technology. In the synthesis process of the ribose compounds, the post-treatment is difficult, the syrup is easy to be formed, and the separation and purification method is always difficult.

Disclosure of Invention

The invention aims to overcome the problems in the prior art and provide a preparation method of high-purity 5-deoxy-D-ribose. The method takes 2, 3-O-isopropylidene-D-furan type methyl glycoside (namely 1-methyl-2, 3-O-isopropylidene-5-deoxy-D-furanoside) as a starting material to prepare high-purity 5-deoxy-D-ribose through two-step reaction. The production technology of the used raw materials is mature, cheap and easily available, the process conditions are simple and mild, and the industrial production is convenient to realize. The content of the 5-deoxy-D-ribose prepared by the method reaches more than 99 percent.

In order to achieve the technical purpose, the invention adopts the following technical scheme.

A method for preparing high-purity 5-deoxy-D-ribose, which is characterized by comprising the following steps:

a) acylating 2, 3-O-isopropylidene-D-furan type methyl glucoside at 120 ℃ to obtain an intermediate A after the reaction is finished;

b)1 part of the intermediate A is recrystallized by using 5 to 20 parts (mass number) of mixed solvent, and the mixed solvent consists of isopropanol and methanol in a mass ratio of 5: 1; recrystallizing and purifying to obtain an intermediate B;

c) and (3) carrying out ammonolysis reaction on the intermediate B at the reaction temperature, and carrying out post-treatment after the reaction is finished to obtain the 5-deoxy-D-ribose.

Wherein, the acylation reaction in the step a) refers to the reaction of 2, 3-O-isopropylidene-D-furan type methyl glucoside and an acylating agent, and the acylating agent is formed by mixing glacial acetic acid and acetic anhydride in a mass ratio of 5: 5. After the reaction is finished, distilling to recover acetic acid and acetic anhydride to obtain a crude product, namely an intermediate A;

recrystallizing and purifying the crude product A in the step B) by using an isopropanol-methanol mixed solvent to obtain an intermediate B. Specifically, 1 part of the intermediate A is recrystallized by using 5 to 20 parts (mass number) of mixed solvent, the mixed solvent is composed of 5: 1 (mass ratio) of isopropanol and methanol, the intermediate A is heated to the reflux temperature by using the mixed solvent, stirred, filtered by using a G4 filter plate (the aperture is 3-4 μm), insoluble substances are filtered out, the filtrate is cooled to 5 to 10 ℃ to be crystallized and separated out for more than 12 hours, filtered and dried, and the product intermediate B is obtained.

The ammonolysis reaction in the step c) refers to the dissociation reaction of the intermediate B in ammonia-methanol. Specifically, 1 part of the intermediate B is reacted in 5 to 20 parts (by mass) of ammonia-methanol at about 25 ℃. The ammonia-methanol solution is prepared by introducing 25 parts of liquid ammonia (or ammonia gas) into 100 parts of methanol at 0 deg.C and mixing.

Further, the post-treatment of the ammonolysis reaction in the step C) means that after the ammonolysis reaction, the reaction liquid is firstly subjected to vacuum distillation at 35 ℃, 5 times of mass of methanol is added into the residue C, the mixture is cooled to 10 ℃ and filtered, and the filtrate is distilled at 35 ℃ and the vacuum degree of 0.98MPa-0.99MPa to remove the solvent, so that colorless to light yellow slurry liquid, namely 5-deoxy-D-ribose is obtained. Product characterization, [ alpha ]]_D ²⁵＝+11(C4， H₂O)；MS(m/z)：M⁺: 134.0662 (relative molecular mass 134.0567), and the content is 99.1-99.3%.

Compared with the prior art, the invention has the advantages that: the preparation method is simple, the raw materials are easy to obtain, the process conditions are mild, the cost is lower, and the industrial production is facilitated.

Detailed Description

The present invention will be further described with reference to the following examples.

Example 1

Adding 50ml of glacial acetic acid and 50ml of acetic anhydride into a 500ml reaction bottle, then adding 30g of 2, 3-O-isopropylidene-D-furan type methyl glucoside, heating to 120 ℃, carrying out reflux reaction for 7.5 hours to carry out acylation reaction on the 2, 3-O-isopropylidene-D-furan type methyl glucoside, and after the reaction is finished, carrying out reduced pressure distillation to remove the glacial acetic acid and the acetic anhydride to obtain a viscous oily intermediate A crude product, wherein the crude product is about 30.05 g.

And (II) adding 30.05G of the crude intermediate A into a mixed solution formed by 125G of isopropanol and 25G of methanol, heating to reflux, keeping the reflux for 45 minutes, stopping heating, slowly cooling, filtering by using a G4 filter plate (the pore diameter is 3-4 mu m) when the temperature is reduced to 25 ℃, filtering out insoluble substances, cooling the filtrate to 5-10 ℃, crystallizing and separating out for more than 12 hours, filtering, and drying to obtain 27.32G of intermediate B and white crystals with the content of 99.5%.

And step three, introducing 25 parts by mass of liquid ammonia (or ammonia gas) into 100 parts by mass of methanol at 0 ℃ to prepare ammonia-methanol. 20.00g of intermediate B was added to 100g of ammonia-methanol, and the reaction was carried out at 25 ℃ for 24 hours with stirring. After the reaction is finished, heating to 35 ℃ for vacuum distillation, adding 5 times mass number of methanol into the distillation residue C, cooling to 10 ℃, filtering, distilling the filtrate at 35 ℃ under the vacuum degree of 0.98MPa-0.99MPa to remove the solvent, and obtaining 15.23g of colorless slurry liquid, namely 5-deoxy-D-ribose. Product characterization, [ alpha ]]_D ²⁵＝+11(C4，H₂O)；MS(m/z)：M⁺: 134.0662 (relative molecular mass 134.0567), content 99.1%.

Example 2

Step (one) is the same as example 1

And (II) adding 30.05G of the crude intermediate A into a mixed solution formed by 500G of isopropanol and 100G of methanol, heating to reflux, keeping the reflux for 120 minutes, stopping heating, slowly cooling, filtering by using a G4 filter plate (the pore diameter is 3-4 mu m) when the temperature is reduced to 25 ℃, filtering out insoluble substances, cooling the filtrate to 5-10 ℃, crystallizing and separating out for more than 12 hours, filtering, and drying to obtain 25.65G of intermediate B and white crystals with the content of 99.8%.

And step three, introducing 25 parts by mass of liquid ammonia (or ammonia gas) into 100 parts by mass of methanol at 0 ℃ to prepare ammonia-methanol. 20.00g of intermediate B was added to 400g of ammonia-methanol, and the reaction was carried out at 25 ℃ for 24 hours with stirring. After the reaction is finished, heating to 35 ℃ for vacuum distillation, adding 5 times mass number of methanol into the residue C, cooling to 10 ℃, filtering, distilling the filtrate at 35 ℃ under the vacuum degree of 0.98MPa-0.99MPa to remove the solvent, and obtaining 14.88g of colorless slurry liquid, namely 5-deoxy-D-ribose. Product characterization, [ α ] D25 ═ 11(C4, H2O); MS (m/z): m +: 134.0662 (relative molecular mass 134.0567), content 99.3%.

Claims

1. A method for preparing high-purity 5-deoxy-D-ribose, which is characterized by comprising the following steps:

Further, the post-treatment of the ammonolysis reaction in the step C) means that after the ammonolysis reaction, the reaction liquid is firstly subjected to vacuum distillation at 35 ℃, 5 times of mass of methanol is added into the residue C, the mixture is cooled to 10 ℃ and filtered, and the filtrate is distilled at 35 ℃ and the vacuum degree of 0.98MPa-0.99MPa to remove the solvent, so that colorless to light yellow slurry liquid, namely 5-deoxy-D-ribose is obtained.