CN114524816A - Preparation method of 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine - Google Patents

Abstract

The invention discloses a preparation method of a key intermediate 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine of Reidexilvir, which is characterized in that pyrrolo [2,1-f ] [1,2,4] triazine-4-amine and an iodine simple substance are used for preparing the 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine under the condition of an oxidant. An iodine/oxidant system is selected as an iodine reagent, so that the using amount of iodine is greatly reduced, the yield can reach 91%, and the purity of a product is more than 99%; compared with the prior art, the process greatly reduces the production cost, has higher economic benefit and is suitable for industrial production.

Description

Preparation method of 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine

The technical field is as follows:

the invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of a key intermediate 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine of Reidesvir.

Background

One kind of nucleotide analogue prodrug developed by Reidsievir Jilide company, which can triphosphorylate in human body and inhibit RNA-dependent RNA synthetase (RdRp) to block the replication of virus RNA, has excellent broad-spectrum antiviral activity, and can inhibit SARS, Ebola coronavirus and other coronavirus (bioRxiv. 2020). Currently, the Reidcisvir is clinically researched in a plurality of countries, and the Reidcisvir is proved to have safety and activity on the COVID-19 coronavirus. United states FDA approval was obtained at 22/10/2020, and reidcivir became the first approved drug in the united states for patients with new coronary pneumonia (COVID-19). In addition, the drug has been approved for marketing in Japan and the United kingdom for the treatment of hospitalized patients with novel coronavirus pneumonia (COVID-19).

Triazinamine derivatives are important intermediates for synthesizing prodrugs, and nucleoside drugs such as Reidesciclovir and the like can be prepared through multi-step reactions (J.Med.chem.2017,60,1648). The Rudesiwei molecular structure consists of three parts of a ribonic acid mother nucleus, pyrrolotriazine and a phosphamidophenoxy ester side chain. The compound of formula I (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine) is a key intermediate for the synthesis of Reidesciclovir.

Specific synthetic methods for compounds of formula I are disclosed in various patents such as WO2015069939A1/WO20170275290A1, which are shown below:

the method takes DMF as a solvent, and the compound of the formula II reacts with N-iodosuccinimide (NIS) at the temperature of 0 ℃ or room temperature to obtain the compound of the formula I. The NIS has higher raw material cost, so that great restriction is brought to the scale-up production; DMF is selected as a solvent, the three wastes are large, and diiodo byproducts are easily generated in the reaction process, so that the high-purity 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine is difficult to obtain, and the process is not suitable for industrial production.

With the marketing of the Reidesvir drugs, the research on the activity of triazine amine derivatives and the related applications thereof will be more and more concerned by medicinal chemists, wherein the market demand of a Reidesvir key intermediate 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine will be continuously expanded, so that a feasible synthetic route which has simple research and development process, low cost, easy separation and purification and is suitable for large-scale production is required.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a method for synthesizing 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine, which aims to solve the defects that the use cost is high, a diiodo byproduct is easily generated in the reaction process, and the high-purity 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine is difficult to obtain and is not suitable for industrial production in the conventional process of 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine.

In one aspect, the invention provides a process for the preparation of a compound of formula I:

and reacting the compound shown in the formula II with iodine elementary substance under the condition of an oxidant to generate the compound shown in the formula I.

In some embodiments, the oxidizing agent is selected from one or more of sodium hypochlorite, iodic acid, hydrogen peroxide, carbamide peroxide, or potassium peroxymonosulfonate;

in some embodiments, the oxidizing agent is selected from one or more of iodic acid, hydrogen peroxide, or carbamide peroxide;

in some embodiments, the oxidizing agent is iodic acid;

in some embodiments, the solvent used is selected from one or more of methanol/water, ethanol/water, 1, 2-dichloroethane, or isopropyl acetate;

in some embodiments, the solvent used is isopropyl acetate;

in some embodiments, the molar ratio of the compound of formula II to elemental iodine is in the range of 1: 0.4 to 0.8;

in some embodiments, the molar ratio of the compound of formula II to the oxidizing agent is in the range of 1: 0.1 to 0.5;

in some embodiments, the reaction temperature ranges from 20 to 60 ℃.

Advantageous effects

The invention aims to overcome the defects of high cost, high three wastes and difficult obtainment of high-purity products of the existing synthesis process of 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine; the market price of iodine is half that of N-iodosuccinimide (NIS); an iodine/oxidant system is selected as an iodination reagent, the yield is greatly improved (the yield is improved from 61 percent to 91 percent) compared with that of the iodination reagent, the iodine consumption is also greatly reduced (the equivalent is reduced from 2.4 to about 0.5), and the product purity can reach as high as 99.8 percent; the selected solvent can be recycled and reused, and compared with the existing process, the production cost is greatly reduced. In conclusion, the technical scheme provided by the invention is suitable for industrial production and has higher economic benefit.

Drawings

For a clearer explanation of the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the description of the embodiments or the prior art will be briefly introduced, and it is obvious that the drawings in the following description are some embodiments of the present invention.

FIG. 1 shows the final product of example 1 of the present invention¹H-NMR spectrum;

FIG. 2 is a GC spectrum of the final product of example 1 of the present invention;

FIG. 3 is a MS spectrum of the final product of example 1 of the present invention.

Detailed Description

The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Example 1

Preparation of a Compound of formula I:

isopropyl acetate (16.9kg) was added to a 50L reactor, and the compound of formula II (1500g, 11.18mol, 1.0eq.) was added with stirring and stirred uniformly to give an off-white suspension. Adding iodine simple substance (1702.8g, 6.71mol, 0.6eq.) at one time at room temperature, heating to 30 ℃, dropwise adding iodic acid (786.8g, 4.48mol, 0.4eq., dissolved in 1.5L of water) solution, heating to 45 ℃, keeping the temperature for reaction for 10h, and detecting by LC-MS to show that the raw materials are completely reacted. And dropwise adding a 15% sodium sulfite solution into the reaction system until the system becomes milky white. And after the detection is qualified, cooling to room temperature, stirring overnight, concentrating under reduced pressure to remove isopropyl acetate, cooling to room temperature, adjusting the pH value to 10-11 with 20% NaOH solution, performing suction filtration, leaching and drying a filter cake with water, and recrystallizing and purifying tetrahydrofuran/n-heptane to obtain 2644g of the compound shown in the formula I as an off-white solid with the yield of 91%.

¹H-NMR(400MHz，DMSO)(ppm)：7.9230(s，1H)，7.8026(s，2H)，7.0101～6.9990(d，J＝4.44Hz，1H)，6.8473～68362(d，J＝4.44Hz，1H)；(ESI-TOF)m/z：[M+H]+calcd for C₆H₅N₄I: 260 of a solvent; found: 261; the purity was 99.85% by GC.

Comparative example 1

The results of the iodine dosage, oxidant, temperature and solvent observations are given in table 1 with reference to the procedure of example 1.

TABLE 1

Claims (9)

1. A process for the preparation of a compound of formula I, characterized in that:

and reacting the compound shown in the formula II with iodine elementary substance under the condition of an oxidant to generate the compound shown in the formula I.

2. The method of claim 1, wherein: the oxidant is selected from one or more of sodium hypochlorite, iodic acid, hydrogen peroxide, carbamide peroxide or potassium peroxymonosulfonate.

3. The production method according to claim 1 or claim 2, characterized in that: the oxidant is one or more selected from iodic acid, hydrogen peroxide or carbamide peroxide.

4. The production method according to claim 1 or claim 2, characterized in that: the oxidant is iodic acid.

5. The production method according to claim 1, characterized in that: the solvent is selected from one or more of methanol/water, ethanol/water, 1, 2-dichloroethane or isopropyl acetate.

6. The production method according to claim 1 or claim 5, characterized in that: the solvent used is isopropyl acetate.

7. The method of claim 1, wherein: the molar ratio of the compound shown in the formula II to the iodine simple substance is 1: 0.4-0.8.

8. The method of claim 1, wherein: the molar ratio of the compound shown in the formula II to the oxidant is 1: 0.1-0.5.

9. The method of claim 1, wherein: the reaction temperature range is 20-60 ℃.

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