阅读说明：本技术 异鸟嘌呤核苷中间体、其制备方法、异鸟嘌呤核苷化合物、其制备方法和其下游产品 (Isoguanosine intermediates, process for producing the same, isoguanosine compounds, process for producing the same, and downstream products thereof ) 是由 孙波 姚峰 于 2019-11-04 设计创作，主要内容包括：本发明涉及药物合成技术领域,具体而言,涉及异鸟嘌呤核苷中间体、其制备方法、异鸟嘌呤核苷化合物、其制备方法和其下游产品。一种异鸟嘌呤核苷中间体,其包括如式(1)所示化合物、其药学上可接受的盐、其溶剂化物、其多晶型物和其互变异构体中的至少一种,<Image he="410" wi="676" file="DDA0002258970380000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R为直链烷烃基团。通过该异鸟嘌呤核苷中间体使得最终的异鸟嘌呤核苷化合物具有良好的脂溶性能够大量进入细胞,提升细胞摄取率,提升该化合物的生物利用度,同时,使得该化合物抗酶降解效果好,提升该化合物的治疗效果。该中间体的制备方法极大程度降低了异构体的生成,较大地提高了转化率以及降低了中间体的纯化难度,便于规模化生产。(The invention relates to the technical field of drug synthesis, in particular to an isoguanosine intermediate, a preparation method thereof, an isoguanosine compound, a preparation method thereof and downstream products thereof. An isoguanine nucleoside intermediate, which comprises at least one of a compound shown as a formula (1), pharmaceutically acceptable salt thereof, solvate thereof, polymorphic substance thereof and tautomer thereof, wherein R is a linear alkane group. The final isoguanosine compound has good lipid solubility and can enter cells in a large amount through the isoguanosine intermediate, the cell uptake rate is improved, the bioavailability of the compound is improved, meanwhile, the compound has good anti-enzymatic degradation effect, and the treatment effect of the compound is improved. TheThe preparation method of the intermediate greatly reduces the generation of isomers, greatly improves the conversion rate, reduces the purification difficulty of the intermediate and is convenient for large-scale production.)

1. An isoguanine nucleoside intermediate, characterized in that it comprises at least one of the compounds represented by formula (1), the pharmaceutically acceptable salts, the solvates, the polymorphs and the tautomers thereof,

wherein R is a linear alkane group.

2. An isoguanine nucleoside intermediate according to claim 1, wherein R is an unsubstituted linear alkane group, preferably an unsubstituted linear alkane group having a number of C equal to or greater than 8, more preferably any one of a dodecane hydrocarbon group, a tetradecane hydrocarbon group and a hexadecane hydrocarbon group.

3. An isoguanine nucleoside intermediate according to claim 1, wherein the isoguanine nucleoside intermediate is selected from any one of the following compounds:

4. a process for the preparation of an isoguanine nucleoside intermediate according to any one of claims 1 to 3, comprising: carrying out substitution reaction on 2, 6-di-amino-purine nucleoside and halogenated alkane to form the compound shown in the formula (1).

5. The process according to claim 4, wherein the preparation of the isoguanosine intermediate comprises: reacting the 2, 6-di-amino-purine nucleoside with hydroxide to form an active intermediate, and then reacting with the halogenated alkane to form the compound shown in the formula (1);

preferably, the hydroxide is used in an amount of 1 to 1.5 molar equivalents of the 2, 6-di-amino-purine nucleoside;

preferably, the hydroxide comprises at least one of sodium hydroxide and potassium hydroxide, preferably potassium hydroxide;

preferably, the preparation of the reactive intermediate comprises: mixing the 2, 6-di-amino-purine nucleoside with an organic solvent, controlling the temperature of the mixed solution to be between 40 and 100 ℃, and reacting with hydroxide in a protective gas atmosphere for 1 to 3 to form the active intermediate;

preferably, the temperature is controlled to be 50-80 ℃, and optimally 60 ℃;

preferably, 5-10 liters of said organic solvent is added per kilogram of said 2, 6-di-amino-purine nucleoside;

preferably, the organic solvent comprises a polar solvent;

more preferably, the polar solvent includes any one of DMF, DMSO, and DME, more preferably DMF;

preferably, the preparation of the isoguanine nucleoside intermediate further comprises: mixing the active intermediate with the halogenated alkane at the temperature of 40-100 ℃, and then keeping the temperature to react for 5-12 hours to form a crude intermediate product;

preferably, the haloalkane is used in an amount of 1-1.5 molar equivalents of the 2, 6-di-amino-purine nucleoside;

preferably, the halogenated alkane is any one of brominated alkane, chlorinated alkane and iodoalkane, and is preferably brominated alkane; most preferably 1-bromotetradecane;

more preferably, the mixing of the reactive intermediate with the haloalkane comprises adding the haloalkane dropwise to a reaction solution forming the reactive intermediate;

preferably, the preparation of the isoguanine nucleoside intermediate further comprises: after the active intermediate reacts with the halogenated alkane, the formed crude intermediate product is purified;

preferably, the purification treatment comprises: mixing the crude intermediate product with an alcohol solvent for crystallization,

preferably, 10-30 kg of alcohol solvent is added per kg of said 2, 6-di-amino-purine nucleoside, preferably 15-25 kg, more preferably 20 kg.

6. An isoguanine nucleoside compound, characterized in that it comprises at least one of the compounds represented by the formula (2), the pharmaceutically acceptable salts thereof, the solvates thereof, the polymorphs thereof and the tautomers thereof,

wherein R is a linear alkane group.

7. An isoguanine nucleoside compound according to claim 6, wherein R is an unsubstituted linear alkane group, preferably an unsubstituted linear alkane group having a number of C equal to or greater than 8, more preferably any one of a dodecane hydrocarbon group, a tetradecane hydrocarbon group and a hexadecane hydrocarbon group;

preferably, the isoguanine nucleoside compound is selected from any one of the following compounds:

8. the process for producing an isoguanine nucleoside compound according to claim 6 or 7, comprising: the compound represented by the formula (2) is produced by reacting an isoguanosine intermediate as described in any one of claims 1 to 3 or an isoguanosine intermediate produced by the production method as described in claim 4 or 5 in a diazotization-hydrolysis reaction system.

9. The preparation method according to claim 8, wherein the diazotization-hydrolysis reaction system is an organic acid-diazonium salt aqueous solution;

preferably, the organic acid in the aqueous organic acid-diazonium salt solution is a monobasic organic acid, more preferably formic acid or acetic acid, most preferably acetic acid;

preferably, the diazonium salt in the organic acid-diazonium salt aqueous solution is NaNO₂More preferably 1M NaNO₂An aqueous solution of (a);

preferably, the preparation of the isoguanine nucleoside compound further comprises: mixing the isoguanosine intermediate with organic acid, and cooling the temperature of the reaction solution to 0-15 ℃; preferably 5-10 ℃; optimally 5 ℃;

then mixing the reaction solution with a diazonium salt aqueous solution, and keeping the temperature to react for 2 to 5 hours;

preferably, the weight ratio of the organic acid to the isoguanosine intermediate is 10-20:1, preferably 10-15:1, most preferably 10: 1;

preferably, 2-10L of 1M NaNO is added per kg of said isoguanine nucleoside intermediate₂The aqueous solution is added correspondingly, preferably 4-8 liters, most preferably 5 liters;

preferably, the preparation of the isoguanine nucleoside compound further comprises: purifying a crude product formed by the isoguanosine intermediate in a diazotization-hydrolysis reaction system;

preferably, the purification comprises purification by crystallization of the crude product with an alcoholic solvent;

preferably, the alcohol solvent is a monohydric alcohol solvent, more preferably a methanol solvent or an ethanol solvent, most preferably an ethanol solvent; further preferably, the ethanol solvent is 70-80% by volume;

preferably, 20 to 40 kg of alcohol solvent, preferably 25 to 35kg, most preferably 30kg, is added per kg of said isoguanosine intermediate during the purification.

10. A downstream product of an isoguanosine compound produced by using an isoguanosine intermediate as described in any one of claims 1 to 3 or an isoguanosine intermediate as described in claim 4 or 5 or an isoguanosine compound as described in claim 6 or 7 or an isoguanosine compound as described in claim 8 or 9.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to an isoguanosine intermediate, a preparation method thereof, an isoguanosine compound, a preparation method thereof and downstream products thereof.

Background

In recent years, with the development of the genomic medicines, antisense oligonucleotide medicines have been rapidly developed, and the reason for this is that they have the following advantages compared with the conventional medicines: 1) the specificity is stronger. A15-mer antisense oligonucleotide contains 30-45 hydrogen bonds, while low molecular weight conventional drugs (200- & ltu & gt 600u) generally form only 1-4 bonds with a target; 2) the amount of information is large. The genetic information is from DNA-RNA-protein, it is very accurate to block the synthesis of a certain protein with complementary oligonucleotides; 3) the antisense medicine takes nucleic acid as a target spot, and is easier to reasonably design a new medicine compared with a protein as the target spot. By acting upstream of the transmission of genetic information, lower doses are required and fewer side effects are likely.

With the advance of technical research, research on antisense drugs is being flourished. Several scientific research units in China are developing research on antisense drugs, and several antisense oligonucleotide products are in preclinical test stages, but the existing antisense compounds have poor lipid solubility, cannot enter cells well and cannot be taken up, so that the bioavailability is low, and meanwhile, the existing antisense compounds have poor anti-enzymatic degradation effect and further cause the reduction of the treatment effect of the antisense compounds. Particularly, when the intermediate of the antisense compound is synthesized, the conversion rate is low, the purification difficulty of the synthesized intermediate is high, the yield of the intermediate is further reduced, and the yield of the final product, namely the antisense compound, is also low.

In view of this, the invention is particularly proposed.

Disclosure of Invention

The present invention aims to provide an isoguanosine intermediate, a method for producing the same, an isoguanosine compound, a method for producing the same, and downstream products thereof. The isoguanine nucleoside intermediate provided by the invention has good lipid solubility, so that the finally formed isoguanine nucleoside compound also has good lipid solubility and good enzyme degradation resistance effect, and meanwhile, the preparation method of the isoguanine nucleoside intermediate greatly reduces the generation of isomers, greatly improves the conversion rate, reduces the purification difficulty of the intermediate and is convenient for large-scale production.

The invention is realized by the following steps:

in a first aspect, the embodiments of the present invention provide an isoguanine nucleoside intermediate, which includes at least one of a compound represented by formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a polymorph thereof, and a tautomer thereof,

wherein R is a linear alkane group.

In an alternative embodiment, R is an unsubstituted linear alkane group, preferably an unsubstituted linear alkane group having a number of C ≧ 8, and more preferably any one of a dodecane group, a tetradecane group, and a hexadecane group.

In alternative embodiments, the isoguanine nucleoside intermediate is selected from any one of the following compounds:

in a second aspect, embodiments of the present invention provide a method of preparing an isoguanine nucleoside intermediate as in any one of the preceding embodiments, comprising: carrying out substitution reaction on 2, 6-di-amino-purine nucleoside and halogenated alkane to form the compound shown in the formula (1).

In an alternative embodiment, the preparation of the isoguanine nucleoside intermediate comprises: reacting 2, 6-di-amino-purine nucleoside with hydroxide to form an active intermediate, and then reacting with halogenated alkane to form a compound shown in a formula (1);

preferably, the hydroxide is used in an amount of 1 to 1.5 molar equivalents of the 2, 6-di-amino-purine nucleoside;

preferably, the hydroxide comprises at least one of sodium hydroxide and potassium hydroxide, preferably potassium hydroxide;

preferably, the preparation of the reactive intermediate comprises: mixing 2, 6-di-amino-purine nucleoside with an organic solvent, controlling the temperature of the mixed solution between 40 and 100 ℃, and reacting with hydroxide for 1 to 3 hours in a protective gas atmosphere to form an active intermediate;

preferably, the temperature is controlled to be 50-80 ℃, and optimally 60 ℃;

preferably, 5-10 liters of organic solvent is added per kg of 2, 6-di-amino-purine nucleoside;

preferably, the organic solvent comprises a polar solvent;

more preferably, the polar solvent includes any one of DMF, DMSO, and DME, more preferably DMF;

preferably, the preparation of the isoguanine nucleoside intermediate further comprises: mixing the active intermediate with halogenated alkane at the temperature of 40-100 ℃, and then keeping the temperature to react for 5-12 hours to form an intermediate crude product;

preferably, the haloalkane is used in an amount of 1-1.5 molar equivalents of the 2, 6-di-amino-purine nucleoside;

preferably, the halogenated alkane is any one of brominated alkane, chlorinated alkane and iodoalkane, and is preferably brominated alkane; most preferably 1-bromotetradecane;

more preferably, the mixing of the reactive intermediate with the haloalkane comprises adding the haloalkane dropwise to a reaction liquid in which the reactive intermediate is formed;

preferably, the preparation of the isoguanine nucleoside intermediate further comprises: after the reaction of the active intermediate and the halogenated alkane, the formed intermediate crude product is purified;

preferably, the purification treatment comprises: mixing the intermediate crude product with an alcohol solvent for crystallization,

preferably, 10-30 kg of alcohol solvent is added per kg of 2, 6-di-amino-purine nucleoside, preferably 15-25 kg, more preferably 20 kg.

In a third aspect, embodiments of the present invention provide isoguanine nucleoside compounds, including at least one of compounds represented by formula (2), pharmaceutically acceptable salts thereof, solvates thereof, polymorphs thereof, and tautomers thereof,

wherein R is a linear alkane group.

In an alternative embodiment, R is an unsubstituted linear alkane group, preferably an unsubstituted linear alkane group having a number of C ≧ 8, more preferably any one of a dodecane group, a tetradecane group, and a hexadecane group;

preferably, the isoguanine nucleoside compound is selected from any one of the following compounds:

in a fourth aspect, embodiments of the present invention provide a method for preparing an isoguanine nucleoside compound, comprising: the isoguanosine intermediate according to any one of the above-mentioned embodiments or the isoguanosine intermediate produced by the production method according to any one of the above-mentioned embodiments is reacted in a diazotization-hydrolysis reaction system to form a compound represented by the formula (2).

In an alternative embodiment, the diazotization-hydrolysis reaction system is an organic acid-diazonium salt aqueous solution;

preferably, the organic acid in the aqueous organic acid-diazonium salt solution is a monobasic organic acid, more preferably formic acid or acetic acid, most preferably acetic acid;

preferably, the diazonium salt in the organic acid-diazonium salt aqueous solution is NaNO₂More preferably 1M NaNO₂An aqueous solution of (a);

preferably, the preparation of the isoguanine nucleoside compound further comprises: mixing the isoguanosine intermediate with organic acid, and cooling the temperature of the reaction solution to 0-15 ℃; preferably 5-10 ℃; optimally 5 ℃;

then mixing the reaction solution with a diazonium salt aqueous solution, and keeping the temperature to react for 2 to 5 hours;

preferably, the weight ratio of organic acid to isoguanine nucleoside intermediate is 10-20:1, preferably 10-15:1, most preferably 10: 1;

preferably, 2-10 liters of 1M NaNO are added per kg of isoguanine nucleoside intermediate₂The aqueous solution is added correspondingly, preferably 4-8 liters, most preferably 5 liters;

preferably, the preparation of the isoguanine nucleoside compound further comprises: purifying a crude product formed by the isoguanosine intermediate in a diazotization-hydrolysis reaction system;

preferably, the purification comprises purification by crystallization of the crude product with an alcoholic solvent;

preferably, the alcohol solvent is a monohydric alcohol solvent, more preferably a methanol solvent or an ethanol solvent, most preferably an ethanol solvent; further preferably, the ethanol solvent is 70-80% by volume;

preferably, 20 to 40 kg of alcohol solvent, preferably 25 to 35kg, most preferably 30kg, is added per kg of isoguanosine intermediate during the purification.

In a fifth aspect, embodiments of the present invention provide downstream products of isoguanosine compounds, which are prepared using the isoguanosine intermediate of any of the preceding embodiments or the isoguanosine intermediate prepared by the preparation method of any of the preceding embodiments or the isoguanosine compound prepared by the preparation method of any of the preceding embodiments.

The invention has the following beneficial effects: the isoguanine nucleoside intermediate provided by the invention has good fat solubility, so that the finally obtained isoguanine nucleoside compound has good fat solubility and can enter cells in a large amount, the cellular uptake rate is improved, the bioavailability of the compound is improved, meanwhile, the compound has good anti-enzymatic degradation effect, and the treatment effect of the compound is improved. The preparation method of the intermediate greatly reduces the generation of isomers, greatly improves the conversion rate, reduces the purification difficulty of the intermediate and is convenient for large-scale production.

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 diagram showing the results of high performance liquid chromatography detection of an isoguanine nucleoside intermediate provided in example 1 of the present invention;

FIG. 2 is a diagram showing the results of high performance liquid chromatography detection of an isoguanine nucleoside compound provided in example 1 of the present invention;

FIG. 3 shows the high performance liquid purity of compound B in the downstream product of isoguanosine compound provided in example 1 of the present invention;

FIG. 4 shows the high performance liquid purity of Compound C in the downstream product of isoguanosine compound provided in example 1 of the present invention;

FIG. 5 shows the high performance liquid purity of compound D in the downstream product of isoguanosine compound provided in example 1 of the present invention;

FIG. 6 shows the purity of the phosphorus spectrum of compound D in the downstream product of isoguanosine compound provided 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.

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

The invention provides an isoguanine nucleoside intermediate, which comprises at least one of a compound shown as a formula (1), pharmaceutically acceptable salt, solvate, polymorphic substance and tautomer thereof,

wherein R is a linear alkane group. R is an unsubstituted linear alkane group, preferably an unsubstituted linear alkane group having a number of C.gtoreq.8, more preferably any one of a dodecane group, a tetradecane group and a hexadecane group. The adoption of the functional group can ensure that the intermediate can ensure that the finally formed isoguanine nucleoside compound has good anti-enzymatic degradation effect.

Further, the isoguanine nucleoside intermediate is selected from any one of the following compounds:

. The compound can ensure that the isoguanine nucleoside intermediate has good fat solubility and enzyme degradation resistance.

The embodiment of the invention also provides a preparation method of the isoguanine nucleoside intermediate, which comprises the following steps:

carrying out substitution reaction on 2, 6-di-amino-purine nucleoside and halogenated alkane to form the compound shown in the formula (1).

Specifically, 2, 6-di-amino-purine nucleosides are reacted with hydroxide to form an activated intermediate; specifically, 2, 6-di-amino-purine nucleoside is mixed with an organic solvent, then the temperature of the mixed solution is controlled between 40 ℃ and 100 ℃, and the mixed solution reacts with hydroxide for 1 to 3 hours under the atmosphere of protective gas to form an active intermediate;

preferably, the temperature is controlled to be 50-80 ℃, and optimally 60 ℃;

preferably, 5-10 liters of organic solvent is added per kg of 2, 6-di-amino-purine nucleoside;

preferably, the organic solvent comprises a polar solvent;

more preferably, the polar solvent includes any one of DMF, DMSO, and DME, and more preferably DMF.

It will be appreciated that the organic solvent of choice is those familiar to those skilled in the art, as long as it is capable of achieving dissolution of the reactant 2, 6-di-amino-purine nucleoside, while reagents which do not react with inorganic bases are all useful in the present invention.

By adopting the conditions, the stable formation of the active intermediate can be ensured, the safety of the production process is ensured, safety accidents are not easy to happen, and the operation conditions are easy to realize.

Further, the hydroxide is used in an amount of 1 to 1.5 molar equivalents of the 2, 6-di-amino-purine nucleoside;

preferably, the hydroxide comprises at least one of sodium hydroxide and potassium hydroxide, preferably potassium hydroxide. The hydroxide is used as a reaction raw material, so that the yield of the isoguanine nucleoside intermediate can be ensured, the production safety can be ensured, and when the hydroxide is used, the reaction condition is easy to control, and the industrial production is facilitated. If the substances with strong alkalinity such as sodium hydrogen or potassium alcoholate are used as reactants, the reaction conditions are not easy to control, safety accidents are easy to happen, and the industrial production is not facilitated, meanwhile, the substances with strong alkalinity such as sodium hydrogen can react with the hydroxyl groups at other sites of the 2, 6-di-amino-purine nucleoside to form multi-substitution or 3 'and 5' substitution, so that more impurities are formed, the yield of the isoguanine nucleoside intermediate is reduced, and the purity of the isoguanine nucleoside intermediate is also reduced. On the other hand, if a base having a weak basicity such as ammonia water is used as a reaction raw material, the reaction yield is lowered, which is not favorable for industrial production. Finally, the hydroxide is used as a reaction raw material, so that the generation of isomers of the isoguanine nucleoside intermediate is greatly reduced, the conversion rate is greatly improved, the purification difficulty of the isoguanine nucleoside intermediate is reduced, and the large-scale production is facilitated.

Then, the active intermediate reacts with halogenated alkane to form an isoguanine nucleoside intermediate; specifically, the active intermediate is mixed with halogenated alkane at the temperature of 40-100 ℃, and then the temperature is maintained for reaction for 5-12 hours to form an intermediate crude product;

preferably, the haloalkane is used in an amount of 1-1.5 molar equivalents of the 2, 6-di-amino-purine nucleoside;

preferably, the halogenated alkanes are brominated alkanes, chlorinated alkanes and iodoalkanes, preferably brominated alkanes; most preferably 1-bromotetradecane;

more preferably, the mixing of the reactive intermediate with the haloalkane comprises adding the haloalkane dropwise to a reaction liquid in which the reactive intermediate is formed;

by adopting the method, the reactive intermediate can be ensured to react with the halogenated alkane, the formation of the isoguanine nucleoside intermediate is ensured, the yield of the isoguanine nucleoside intermediate is ensured, and the finally formed compound is ensured to have good performance.

Further, the preparation of the isoguanine nucleoside intermediate also comprises: after the reaction of the active intermediate and the halogenated alkane, the formed intermediate crude product is purified;

preferably, the purification treatment comprises: mixing the intermediate crude product with an alcohol solvent for crystallization,

preferably, 10-30 kg of alcohol solvent is added per kg of 2, 6-di-amino-purine nucleoside, preferably 15-25 kg, more preferably 20 kg.

The crude product of the intermediate is crystallized and purified, so that the purity of the isoguanine nucleoside intermediate is ensured, excessive impurities cannot be formed in the subsequent reaction process, the purity of the final product is ensured, and the performance of the final product is further ensured.

Accordingly, the embodiment of the present invention further provides an isoguanine nucleoside compound, which includes at least one of the compound shown in formula (2), a pharmaceutically acceptable salt thereof, a solvate thereof, a polymorph thereof and a tautomer thereof,

wherein R is a linear alkane group. The adoption of the straight-chain alkane group is beneficial to improving the fat solubility of the compound and the bioavailability of the compound, and simultaneously, the enzyme degradation resistance effect of the compound can be improved, and if the straight-chain alkane group is replaced by other groups, the fat solubility can be reduced or the enzyme degradation resistance effect can be reduced.

Preferably, R is an unsubstituted linear alkane group, preferably an unsubstituted linear alkane group having a number of C.gtoreq.8, more preferably any one of a dodecane group, a tetradecane group and a hexadecane group. The number of carbon in the linear alkane group is controlled, so that the performance of the compound is guaranteed, if the carbon number is too low, the anti-enzymatic degradation effect is reduced, if the carbon number is too high, the synthesis is not facilitated, the yield is low, the separation is not easy, and the performance of the compound is reduced. And the straight-chain alkane group is unsubstituted alkane, so that the fat solubility and the enzyme degradation resistance effect are further ensured.

Preferably, the isoguanine nucleoside compound is selected from any one of the following compounds:

. By adopting the isoguanine nucleoside compound, the good enzyme degradation resistant effect can be ensured, and the treatment effect of the compound is improved.

The invention also provides a preparation method of the isoguanine nucleoside compound, which comprises the following steps: the isoguanosine intermediate according to any one of the above-mentioned embodiments or the isoguanosine intermediate produced by the production method according to any one of the above-mentioned embodiments is reacted in a diazotization-hydrolysis reaction system to form a compound represented by the formula (2).

Wherein, the diazotization-hydrolysis reaction system is organic acid-diazonium salt aqueous solution;

preferably, the organic acid in the aqueous organic acid-diazonium salt solution is a monobasic organic acid, more preferably formic acid or acetic acid, most preferably acetic acid;

preferably, the diazonium salt in the organic acid-diazonium salt aqueous solution is NaNO₂More preferably 1M NaNO₂An aqueous solution of (a).

By adopting the reaction system, the 6 th amino group can be specifically converted into the carbonyl group, the target product modified by the specific target group can be generated at high selectivity, the yield of the compound is improved, the generation of isomers is greatly reduced, the conversion rate is greatly improved, the purification difficulty of the final product is reduced, and the large-scale production is facilitated.

Further, the preparation of the isoguanine nucleoside compound includes: mixing the isoguanosine intermediate with organic acid, and cooling the temperature of the reaction solution to 0-15 ℃; preferably 5-10 ℃; optimally 5 ℃;

then mixing the reaction solution with a diazonium salt aqueous solution, and keeping the temperature to react for 2 to 5 hours;

preferably, the weight ratio of organic acid to isoguanine nucleoside intermediate is 10-20:1, preferably 10-15:1, most preferably 10: 1;

preferably, 2-10 liters of 1M NaNO are added per kg of isoguanine nucleoside intermediate₂The aqueous solution is added correspondingly, preferably in the range from 4 to 8 liters, most preferably 5 liters.

The compound shown in the formula (2) is synthesized by the method, so that the formation of isomers can be further reduced, and the yield of the compound is ensured.

Further, the preparation of the isoguanine nucleoside compound further comprises: purifying a crude product formed by the isoguanosine intermediate in a diazotization-hydrolysis reaction system;

preferably, the purification comprises purification by crystallization of the crude product with an alcoholic solvent;

preferably, the alcohol solvent is a monohydric alcohol solvent, more preferably a methanol solvent or an ethanol solvent, most preferably an ethanol solvent; further preferably, the ethanol solvent is 70-80% by volume;

preferably, 20 to 40 kg of alcohol solvent, preferably 25 to 35kg, most preferably 30kg, is added per kg of isoguanosine intermediate during the purification.

The purification by adopting the method is convenient for industrial implementation, ensures the purification effect and ensures that the purified compound has good performance.

The present invention also provides a downstream product of an isoguanosine compound produced by using the isoguanosine intermediate according to any one of the above-mentioned embodiments or the isoguanosine intermediate produced by the production method according to any one of the above-mentioned embodiments or the isoguanosine compound produced by the production method according to any one of the above-mentioned embodiments.