CN112159447B

CN112159447B - Intermediate for synthesizing 2-chloroadenosine, synthesis process thereof and synthesis process of 2-chloroadenosine

Info

Publication number: CN112159447B
Application number: CN202011079654.XA
Authority: CN
Inventors: 吴法浩; 李钢; 高仰哲; 王志航
Original assignee: Nanjing Redwood Fine Chemical Co ltd
Current assignee: Nanjing Redwood Fine Chemical Co ltd
Priority date: 2020-10-10
Filing date: 2020-10-10
Publication date: 2022-03-08
Anticipated expiration: 2040-10-10
Also published as: CN112159447A

Abstract

The invention relates to the technical field of organic synthesis, in particular to an intermediate for synthesizing 2-chloroadenosine, a synthesis process thereof and a synthesis process of 2-chloroadenosine. The synthesis process of the intermediate for synthesizing 2-chloroadenosine comprises the following steps: 2, 6-dichloropurine and tetraacetyl ribose are subjected to condensation reaction under the catalysis of 4-dimethylaminopyridine to form 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside. The synthesis process has the advantages of simple operation, small catalyst consumption, low cost, less pollution, easy industrial realization and higher yield and purity of the synthesized 2-chloroadenosine.

Description

Intermediate for synthesizing 2-chloroadenosine, synthesis process thereof and synthesis process of 2-chloroadenosine

Technical Field

The invention relates to the technical field of organic synthesis, in particular to an intermediate for synthesizing 2-chloroadenosine, a synthesis process thereof and a synthesis process of 2-chloroadenosine.

Background

2-chloroadenosine, 2-chloro-6-aminopurine nucleoside, is an adenosine receptor agonist which can effectively inhibit the expression of tumor metastasis associated genes mtal and mRNA, and then has an inhibitory effect on various cancer cells, and thus is one of anticancer agents newly developed in recent years. Meanwhile, the compound is also a drug intermediate of traditional Chinese medicine, and 2-chloroadenosine can be used for synthesizing an anti-leukemia drug-cladribine. Therefore, the synthesis of 2-chloroadenosine is of great significance.

In the prior art, various approaches for synthesizing 2-chloroadenosine exist, but the existing synthesis method has a plurality of problems: for example, the adopted catalyst is a heavy metal catalyst, the catalyst is large in dosage, harsh in reaction conditions, high in cost and pollution, and the yield and purity of the synthesized 2-chloroadenosine are low. For example, the synthesis method of using tetraacetyl ribose, 2-chloroadenine and tin tetrachloride as a catalyst to react to form 2', 3', 5', triacetyl nucleoside, and then reacting with ammonia-methanol to form 2-chloroadenosine has a yield of only about 62%, uses tin tetrachloride as a catalyst, is highly polluting and costly, and is also not easy to purchase 2-chloroadenine and costly. For example, tetraacetyl ribose and 2, 6-dichloropurine react under the catalytic action of trifluoromethanesulfonic acid to form 2', 3', 5' -tri-O-acetyl-2, 6-dichloropurine nucleoside, and then react with ammonia-methanol to form 2-chloroadenosine, the reaction adopts trifluoromethanesulfonic acid as a catalyst, the price is high, the production cost of 2-chloroadenosine is increased, meanwhile, the catalyst is large in dosage, the cost is difficult to control, the industrial production is not facilitated, and the purity and the yield of the 2-chloroadenosine formed by the process are low.

In view of this, the invention is particularly proposed.

Disclosure of Invention

The invention aims to provide an intermediate for synthesizing 2-chloroadenosine, a synthesis process thereof and a synthesis process of the 2-chloroadenosine. The synthesis process provided by the embodiment of the invention has the advantages of simple operation, less catalyst consumption, low cost, less pollution and easy industrial realization, and the yield and the purity of the synthesized 2-chloroadenosine are higher.

The invention is realized by the following steps:

in a first aspect, embodiments of the present invention provide a synthesis process for an intermediate used in the synthesis of 2-chloroadenosine, comprising: 2, 6-dichloropurine and tetraacetyl ribose are subjected to condensation reaction under the catalysis of 4-dimethylaminopyridine to form 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside.

In alternative embodiments, the step of forming the 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside comprises: mixing the 2, 6-dichloropurine, the tetraacetyl ribose, the 4-dimethylaminopyridine and a solvent, heating and refluxing for condensation reaction, and cooling and crystallizing a reaction solution after the reaction is finished.

In alternative embodiments, the solvent is an aromatic solvent; preferably toluene;

preferably, 3.5-5 ml of toluene is added per gram of said 2, 6-dichloropurine;

preferably, the conditions of the condensation reaction are: the reaction temperature is 100 ℃ and 130 ℃, and the reaction time is 1.5-2.5 hours.

In alternative embodiments, the molar ratio of the 2, 6-dichloropurine to the tetraacetyl ribose is 1:1 to 1.2;

preferably, the mass ratio of the 2, 6-dichloropurine to the 4-dimethylaminopyridine is 1: 0.004-0.02.

In a second aspect, the present embodiment also provides a process for synthesizing 2-chloroadenosine, comprising the above process for synthesizing an intermediate for 2-chloroadenosine;

preferably, the method comprises the following steps: forming 2-chloroadenosine using the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside;

preferably, the step of forming the 2-chloroadenosine using the 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside comprises: and (2) sequentially carrying out hydrolysis reaction and ammoniation reaction on the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside.

In an alternative embodiment, the step of hydrolysis reaction comprises: mixing the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside, a first alcohol solvent and an alkaline substance, and reacting at 20-30 ℃;

preferably, the basic substance comprises a sodium alkoxide, preferably sodium methoxide;

preferably, the step of the synthesis process further comprises: carrying out post-treatment on the reaction system after the hydrolysis reaction before the ammoniation reaction;

preferably, the step of post-processing comprises: and after the hydrolysis reaction is finished, diluting the reaction system, and cooling and crystallizing.

In an alternative embodiment, 3.5 to 6 ml of the first alcohol solvent is added per gram of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside, and the molar ratio of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside to the basic substance is 1:1 to 1.3.

In an alternative embodiment, the step of ammoniation reaction comprises: mixing 2, 6-dichloropurine nucleoside formed by hydrolysis reaction with ammonia water and reacting at 20-30 ℃;

preferably, the step of the synthesis process further comprises: purifying the reaction mixed liquid formed after the ammoniation reaction;

preferably, the purification treatment comprises: the reaction mixture is mixed with a second glycol solvent and crystallized.

In an alternative embodiment, 2 to 4 ml of aqueous ammonia is added per gram of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside and 1 to 1.5 ml of a second glycol solvent is added per gram of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside.

In a third aspect, embodiments of the present invention provide an intermediate for the synthesis of 2-chloroadenosine, which is synthesized by the synthesis process of an intermediate for the synthesis of 2-chloroadenosine described in any one of the preceding embodiments.

The invention has the following beneficial effects: according to the embodiment of the invention, 2, 6-dichloropurine and tetraacetyl ribose are used as reaction raw materials, and 4-dimethylaminopyridine is used as a catalyst, so that the cost for synthesizing 2-chloroadenosine is reduced, a heavy metal catalyst is not used, the pollution is reduced, the dosage of the catalyst is reduced, the reaction condition is easy to realize, and the industrial production is facilitated. Meanwhile, the yield and the purity of the subsequent 2-chloroadenosine are improved by adopting the reaction of the 2, 6-dichloropurine, the tetraacetyl ribose and the 4-dimethylaminopyridine.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.

FIG. 1 is a process flow diagram for the synthesis of 2-chloroadenosine according to example 1 of the present invention;

FIG. 2 is a diagram showing the results of HPLC analysis of 2-chloroadenosine synthesized in example 1 of the present invention;

FIG. 3 is a graph showing the results of HPLC analysis of 2,3,5-4 triacetyl-2, 6 dichloropurine nucleoside synthesized in example 1 of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

This example provides an intermediate for the synthesis of 2-chloroadenosine and a process for the synthesis of 2-chloroadenosine, which synthesizes 2-chloroadenosine according to the following synthetic pathway:

specifically, the method comprises the following steps:

s1, carrying out condensation reaction to form an intermediate;

2, 6-dichloropurine and tetraacetyl ribose are subjected to condensation reaction under the catalysis of 4-dimethylaminopyridine (hereinafter, abbreviated as DMAP) to form 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside. The embodiment of the invention adopts the cheap commercialized 2, 6-dichloropurine, tetraacetyl ribose and DMAP, which is beneficial to reducing the production cost and difficulty of synthesizing 2-chloroadenosine, and simultaneously adopts the DMAP as the catalyst, thereby avoiding the use of heavy metal catalyst, reducing the residue of heavy metal, avoiding the subsequent removal of heavy metal and improving the synthesis purity. Meanwhile, DMAP is adopted as the catalyst, so that the using amount of the catalyst is reduced, the reaction condition is milder, and the industrial implementation is facilitated. Moreover, the inventor also finds that the yield and the purity of the prepared 2-chloroadenosine can be remarkably improved by adopting DMAP to catalyze the condensation reaction of the 2, 6-dichloropurine and the tetraacetylribose, and the yield and the purity of the 2-chloroadenosine can be remarkably reduced by adopting other catalysts.

Specifically, the step of forming the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside comprises: and mixing the 2, 6-dichloropurine, the tetraacetyl ribose, the 4-dimethylaminopyridine and a solvent, heating and refluxing for condensation reaction, and after the reaction is finished, cooling and crystallizing the reaction liquid, wherein the cooling and crystallizing is to naturally cool the reaction liquid to room temperature (about 25 ℃) so as to separate out 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside in the reaction liquid, and then obtain the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside.

Wherein the solvent is an aromatic solvent; preferably toluene; 3.5-5 ml of toluene is added for each gram of the 2, 6-dichloropurine; the molar ratio of the 2, 6-dichloropurine to the tetraacetyl ribose is 1: 1-1.2; the mass ratio of the 2, 6-dichloropurine to the 4-dimethylaminopyridine is 1: 0.004-0.02; the conditions of the condensation reaction are as follows: the reaction temperature is 100 ℃ and 130 ℃, and the reaction time is 1.5-2.5 hours. The condensation reaction can be ensured by adopting the conditions, the formation of 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside can be ensured, the formation of 2-chloroadenosine is further facilitated, and the synthesis yield and purity of the 2-chloroadenosine are improved.

S2, hydrolysis reaction;

and mixing the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside, a first alcohol solvent and an alkaline substance for hydrolysis reaction to form the 4, 2, 6-dichloropurine nucleoside. Wherein, the alkaline substance comprises sodium alkoxide, preferably sodium methoxide; the temperature of the hydrolysis reaction is 20-30 ℃; 3.5-6 ml of first alcohol solvent is correspondingly added to each gram of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside, and the molar ratio of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside to the alkaline substance is 1: 1-1.3.

The adoption of the conditions can ensure the hydrolysis reaction, is favorable for operators to control the reaction conditions, avoids the local reaction, further ensures the synthesis yield and purity of the subsequent 2-chloroadenosine, and is favorable for industrialization. Particularly, the first alcohol solvent and the alkaline substance are adopted, so that the reaction condition is milder, and the industrial operation is facilitated.

It should be noted that, in the embodiments of the present invention, only examples are provided in which the first alcohol solvent and the basic substance are methanol and sodium methoxide, respectively, but other alcohol solvents and sodium alkoxides capable of performing hydrolysis reaction are also within the scope of the embodiments of the present invention.

And then carrying out post-treatment on the reaction system after the hydrolysis reaction, specifically, diluting the reaction system and cooling and crystallizing the reaction system after the hydrolysis reaction is finished. Specifically, the reaction system is diluted by water, and simultaneously, the reaction system can be cooled by adding water, so that effective components in the reaction system are crystallized and separated out, and the subsequent 2-chloroadenosine is obtained.

S3, ammoniation reaction;

mixing 2, 6-dichloropurine nucleoside formed by hydrolysis reaction with ammonia water and reacting at 20-30 ℃; 2-4 ml of ammonia water is correspondingly added to each gram of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside. By adopting the reaction conditions, the ammonification reaction can be ensured, and the yield and the purity of the 2-chloroadenosine can be improved.

Then, purifying the reaction mixed liquid formed after the ammoniation reaction; specifically, the reaction mixture is concentrated, mixed with a second glycol solvent, and crystallized. And 1-1.5 ml of a second glycol solvent is added per gram of the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside. As the second glycol solvent, an alcohol solvent such as methanol, ethanol or propanol can be used.

According to the embodiment of the invention, sodium alkoxide is adopted for hydrolysis reaction, and then ammonia water is utilized for ammoniation reaction, so that compared with ammonia-alcohol solution (such as ammonia-methanol solution), the subsequent steps provided by the embodiment of the invention are easier to operate and realize, and the purity and yield of 2-rate adenosine are improved.

The embodiment of the invention also provides 2-chloroadenosine, which is synthesized by the synthesis process.

The features and properties of the present invention are described in further detail below with reference to examples.

Example 1

Referring to fig. 1, this example provides a process for synthesizing 2-chloroadenosine, including the following steps:

s1, condensation reaction;

189g of 2.6-dichloropurine is added into 750ml of toluene, 318g of tetraacetyl ribose and 0.9g of dmap are added, the temperature is increased to 110 ℃ for reflux for 2h, and after the reaction is finished, the reaction solution is cooled to normal temperature for crystallization to obtain 436.6g of 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside, the yield is 97.5 percent, and the purity is 99.8 percent. The high liquid analysis was carried out, and the detection results are shown in FIG. 3.

S2, hydrolysis reaction;

2,3, 5-triacetyl-2, 6-dichloropurine nucleoside (426.6g) synthesized in S1 was added to 1700ml of methanol, 62g of sodium methoxide was then added thereto, and the mixture was reacted at 25 ℃ for 5 hours, after the reaction was completed, 1.5L of water was added thereto, and the temperature was lowered to 0 ℃ to crystallize 2.6-dichloropurine nucleoside (300.0 g).

S3, ammoniation reaction;

2.6-dichloropurine nucleoside (302.3g) synthesized from S2 was added to 600ml of ammonia water, aminated at 25 ℃ for 12 hours, concentrated to a small volume after amination, and crystallized by adding 300ml of methanol to give 2-chloroadenosine (272.4 g).

272.4g of 2-chloroadenosine was obtained in the present example, and the yield was calculated to be 90.3%, and the purity of 2-chloroadenosine prepared in the present example was 99.3% according to FIG. 2, which is shown by high liquid analysis of 2-chloroadenosine prepared in the present example.

Examples 2 to 12

Examples 2-12 2-chloroadenosine was synthesized according to the synthesis provided in example 1, except that the operating conditions were varied, as specified in tables 1-3 below:

TABLE 1 DMAP Change in amount

TABLE 2 variation of the proportions

TABLE 3 ratio and temperature Change

Comparative example:

2-chloroadenosine was synthesized according to the synthesis procedure provided in example 1, except for the type and amount of catalyst and the starting materials, see in particular tables 4-9:

table 42.6-dichloropurine: the mass ratio of the catalyst is 1:0.005

Catalyst and process for preparing same	Yield of	Purity of
			P-toluenesulfonic acid	64％	74.2％
DCC	57％	78.8％
			DMAP	90.6	98.9％
Trifluoromethanesulfonic acid	49.5％	68.8％

Table 52.6-dichloropurine: the mass ratio of the catalyst is 1:0.01

Table 62.6-dichloropurine: the mass ratio of the catalyst is 1:0.015

Catalyst and process for preparing same	Yield of	Purity of
			P-toluenesulfonic acid	68％	91.2％
DCC	65％	77.4％
			DMAP	90.3％	99.0％
Trifluoromethanesulfonic acid	62.4％	82.7％

Table 72.6-dichloropurine: the mass ratio of the catalyst is 1:0.02

Catalyst and process for preparing same	Yield of	Purity of
			P-toluenesulfonic acid	71％	91.2％
DCC	67％	83.1％
			DMAP	90.5％	99.1％
Trifluoromethanesulfonic acid	63％	91.6％

TABLE 8 DMAP amounts used

TABLE 9 differences in raw materials

Raw materials	Yield of	Purity of
			2-chloroadenine	75.7％	91.4％

As can be seen from tables 4 to 7, the synthesis raw materials and the synthesis conditions are the same as those in example 1, and in the case of using the same proportion of catalyst, only changing the catalyst can cause the yield and purity of 2-chloroadenosine to be obviously reduced, which shows that the catalyst of the present application can obviously improve the yield and purity of 2-chloroadenosine.

On the other hand, as is clear from Table 8, the yield and purity of 2-chloroadenosine were significantly reduced by changing the amount of the catalyst used in example 1, in the same manner as in example 1, and in the same catalyst.

As can be seen from Table 9, the type, amount and synthesis conditions of the catalyst were the same as those of example 1, and the yield and purity of 2-chloroadenosine were significantly reduced by replacing 2.6-dichloropurine of example 1 with 2-chloroadenine, which demonstrates that the raw material provided by the examples of the present invention specifically acts on the catalyst to improve the synthesis yield and purity of 2-chloroadenosine.

In conclusion, the embodiment of the invention adopts 2, 6-dichloropurine and tetraacetyl ribose as reaction raw materials and 4-dimethylaminopyridine as a catalyst, so that the cost for synthesizing 2-chloroadenosine is reduced, a heavy metal catalyst is avoided, pollution is reduced, the dosage of the catalyst is reduced, the reaction condition is easy to realize, and the industrial production is facilitated. Meanwhile, the yield and the purity of the 2-chloroadenosine can be improved by adopting the 2, 6-dichloropurine, the tetraacetyl ribose and the 4-dimethylaminopyridine to react to form the 2-chloroadenosine.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A process for the synthesis of an intermediate for the synthesis of 2-chloroadenosine, comprising: 2, 6-dichloropurine and tetraacetyl ribose are subjected to condensation reaction under the catalytic action of 4-dimethylaminopyridine to form 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside; wherein the mass ratio of the 2, 6-dichloropurine to the 4-dimethylaminopyridine is 1: 0.004-0.02.

2. The process of synthesizing an intermediate for the synthesis of 2-chloroadenosine according to claim 1, wherein the step of forming the 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside comprises: mixing the 2, 6-dichloropurine, the tetraacetyl ribose, the 4-dimethylaminopyridine and a solvent, heating and refluxing for condensation reaction, and cooling and crystallizing a reaction solution after the reaction is finished.

3. The process of claim 2, wherein the solvent is an aromatic solvent.

4. The process for the synthesis of an intermediate for the synthesis of 2-chloroadenosine according to claim 2, wherein the solvent is toluene; and 3.5-5 ml of toluene is added for each gram of the 2, 6-dichloropurine.

5. A synthesis process of an intermediate for the synthesis of 2-chloroadenosine according to claim 2, characterized in that the conditions of condensation reaction are: the reaction temperature is 100 ℃ and 130 ℃, and the reaction time is 1.5-2.5 hours.

6. The process for the synthesis of an intermediate for the synthesis of 2-chloroadenosine according to any one of claims 1-5, wherein the molar ratio of the 2, 6-dichloropurine to the tetraacetylribose is 1: 1-1.2.

7. A process for the synthesis of 2-chloroadenosine, comprising the synthesis of an intermediate for the synthesis of 2-chloroadenosine according to any one of claims 1 to 6.

8. The process for the synthesis of 2-chloroadenosine according to claim 7, comprising: forming 2-chloroadenosine using the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside;

wherein the step of forming the 2-chloroadenosine using the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside comprises: and (2) sequentially carrying out hydrolysis reaction and ammoniation reaction on the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside.

9. The process for the synthesis of 2-chloroadenosine according to claim 8, wherein the step of hydrolysis reaction comprises: mixing the 2,3, 5-triacetyl-2, 6-dichloropurine nucleoside, the first alcohol solvent and the alkaline substance, and reacting at 20-30 ℃.

10. The process of synthesizing 2-chloroadenosine of claim 9, wherein the basic substance comprises sodium alkoxide.

11. The process for the synthesis of 2-chloroadenosine according to claim 10, wherein said sodium alkoxide is sodium methoxide.

12. The process of synthesizing 2-chloroadenosine of claim 8, wherein the step of synthesizing process further comprises: carrying out post-treatment on the reaction system after the hydrolysis reaction before the ammoniation reaction; wherein the post-processing step comprises: and after the hydrolysis reaction is finished, diluting the reaction system, and cooling and crystallizing.

13. The process for the synthesis of 2-chloroadenosine according to claim 9, wherein 3.5-6 ml of a first alcohol solvent is added per gram of said 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside, and the molar ratio of said 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside to said basic substance is 1: 1-1.3.

14. The process for the synthesis of 2-chloroadenosine according to claim 8, wherein the step of ammoniation reaction comprises: the 2, 6-dichloropurine nucleoside formed by the hydrolysis reaction is mixed with ammonia water and reacted at 20-30 ℃.

15. The process of synthesizing 2-chloroadenosine of claim 14, wherein the step of synthesizing further comprises: purifying the reaction mixed liquid formed after the ammoniation reaction;

wherein, the purification treatment comprises: the reaction mixture is mixed with a second glycol solvent and crystallized.

16. The process for the synthesis of 2-chloroadenosine according to claim 14, wherein 2-4 ml of ammonia water is added per gram of 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside and 1-1.5 ml of a second glycol solvent is added per gram of 2,3, 5-triacetyl-2, 6 dichloropurine nucleoside.