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Isoguanosine intermediate, preparation method thereof, isoguanosine compound, preparation method thereof and downstream product thereof

A technology of purine nucleoside intermediates and purine nucleoside compounds, which is applied in the field of drug synthesis, can solve the problems of low conversion rate, difficult purification of intermediates, and poor resistance to enzymatic degradation, so as to reduce the generation of isomers and improve Effect of cell uptake rate and ease of large-scale production

Active Publication Date: 2020-02-07
SHANGHAI ZHAOWEI TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Several domestic scientific research institutes are conducting research on antisense drugs, and some antisense oligonucleotide products are in the preclinical test stage, but the existing antisense compounds are poorly fat-soluble and cannot enter cells well. Cannot be ingested, which leads to low bioavailability. At the same time, existing antisense compounds are poorly resistant to enzymatic degradation, which further reduces the therapeutic effect of antisense compounds
Especially when synthesizing antisense compound intermediates, the conversion rate is low, and the purification of the synthesized intermediates is difficult, which further reduces the yield of the intermediates, which in turn leads to the low yield of the final product antisense compounds

Method used

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  • Isoguanosine intermediate, preparation method thereof, isoguanosine compound, preparation method thereof and downstream product thereof
  • Isoguanosine intermediate, preparation method thereof, isoguanosine compound, preparation method thereof and downstream product thereof
  • Isoguanosine intermediate, preparation method thereof, isoguanosine compound, preparation method thereof and downstream product thereof

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preparation example Construction

[0064] The embodiment of the present invention also provides a method for preparing the above-mentioned isoguanosine intermediate, comprising the following steps:

[0065] Substitution reaction of 2,6-di-amino-purine nucleoside and halogenated alkanes to form the compound represented by formula (1).

[0066] Specifically, 2,6-di-amino-purine nucleoside is reacted with hydroxide to form an active intermediate; specifically, 2,6-di-amino-purine nucleoside is mixed with an organic solvent, and then the mixed solution is The temperature is controlled between 40-100 ° C, and then reacted with hydroxide for 1-3 hours under a protective gas atmosphere to form an active intermediate;

[0067] Preferably, the temperature is controlled at 50-80°C, the most optimal is 60°C;

[0068] Preferably, 5-10 liters of organic solvent is added corresponding to every kilogram of 2,6-di-amino-purine nucleoside;

[0069] Preferably, the organic solvent comprises a polar solvent;

[0070] More pref...

Embodiment 1

[0108] This embodiment provides a kind of isoguanosine intermediate, its structural formula is as shown in formula (3);

[0109] Formula (3), its high liquid analysis diagram see figure 1 .

[0110] This embodiment also provides a preparation method of the isoguanosine intermediate shown in the above formula (3), comprising the following steps:

[0111] Synthesize isoguanosine intermediate according to the following formula:

[0112]

[0113] The specific operation is as follows;

[0114] Weigh 13kg of 2,6-diaminopurine nucleoside (CAS No.: 2096-10-8) and dissolve it in 1300L DMF, heat the reaction solution to 60°C, add 0.52kg of KOH under the protection of argon, and stir at 60°C for 2 Hour. Then, 19.2 kg of 1-bromotetradecane was added dropwise to the system, and after the drop was completed, the reaction was stirred at 60°C. React until the product no longer increases. Concentrate in vacuo at 65 DEG C until not dripping, and the residual solid is crystallized in ...

Embodiment 2

[0132] This embodiment provides an isoguanosine intermediate, the structural formula of which is shown in formula (5);

[0133]

[0134] This embodiment also provides a preparation method of the isoguanosine intermediate shown in the above formula (5), comprising the following steps:

[0135] Synthesize isoguanosine intermediate according to the following formula:

[0136]

[0137] The specific operation is as follows;

[0138] Weigh 13kg of 2,6-diaminopurine nucleoside (CAS No.: 2096-10-8) and dissolve it in 1300L DMF, heat the reaction solution to 60°C, add 0.52kg of KOH under the protection of argon, and stir at 60°C for 2 Hour. Then, 17.2 kg of 1-bromododecane was added dropwise to the system, and the reaction was stirred at 60° C. after the drop was completed. React until the product no longer increases. Then concentrated in vacuo at 65°C until no dripping, the residual solid was crystallized in ethanol (80% by volume of ethanol, and 260kg of ethanol was used) t...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to an isoguanosine intermediate, a preparation method of the isoguanosine intermediate, an isoguanosine compound, a preparation method thereof and a downstream product thereof. An isoguanosine intermediate includes at least one of compounds represented by formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a polymorph thereof, and a tautomer thereof, where R is a straight-chain alkane group. According to the present invention, through the isoguanosine intermediate, the final isoguanosine compound has good lipid solubility, and can enter cells in a large amount, such that the cell uptake rate is improved, the bioavailability of the compound is improved, the anti-enzyme degradation effect of the compound is good, 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.

Description

technical field [0001] The present invention relates to the technical field of drug synthesis, in particular, to an isoguanosine intermediate, a preparation method thereof, an isoguanosine nucleoside compound, a preparation method thereof and downstream products thereof. Background technique [0002] In recent years, with the development of genomic medicines, antisense oligonucleotide drugs have been rapidly developed. The reason is that they have the following advantages over traditional drugs: 1) Stronger specificity. A 15-mer antisense oligonucleotide contains 30-45 hydrogen bonds, while low-molecular traditional drugs (200-600u) generally only form 1-4 bonds with the target; 2) The amount of information is large. Genetic information is from DNA-RNA-protein, and it is very accurate to block the synthesis of a certain protein with complementary oligonucleotides; 3) antisense drugs target nucleic acid, which is easier to rationally design new drugs than proteins . Since i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167C07H1/00
CPCC07H1/00C07H19/167
Inventor 孙波姚峰
Owner SHANGHAI ZHAOWEI TECH DEV
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