CN112194661A - Preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine - Google Patents
Preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine Download PDFInfo
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Abstract
The invention discloses a preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine, wherein 4-amino-pyrrolo [2,1-f ] [1,2,4] triazine reacts with iodine-containing substances and oxidants to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine; the iodine-containing substance is iodine or hydroiodide; the oxidant is at least one of potassium hydrogen persulfate composite salt, hydrogen peroxide, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide, sodium hypochlorite, ammonium persulfate and sodium persulfate. The preparation method of the invention enables the preparation to be simpler, and 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine can be obtained in one step; the preparation method has the characteristics of easily obtained and cheap raw materials, simple process, mild reaction conditions, high product yield, high utilization rate of iodine atoms and the like.
Description
Technical Field
The invention relates to the technical field of chemical synthetic drugs, in particular to a novel preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine.
Background
Reddesivir (Remdesivir) is a nucleoside compound developed by Gilidae, USA, and is a broad-spectrum antiviral drug. Previous studies have demonstrated that Reidesciclovir has some efficacy against Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), and the drug has also been used in clinical trials against Ebola virus infection. Because the new coronavirus has a similar structure with the coronavirus such as SARS and MERS, the effect target of the Redexilvir on the new coronavirus can be presumed to be effective as well. In vitro experiments show that the Reidesciclovir has good inhibition effect on the new coronavirus.
Reidesciclovir is a synthetic drug and has been reported in synthetic lines, wherein the main synthetic steps were performed according to the method published in 2016 in Nature (2016, 531, 381-385). The method has 6 steps in total, most of the steps relate to asymmetric synthesis, and the reaction conditions are harsh, wherein in the first step, D-ribonate is used as a raw material to react with 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine, and the yield is lower. Since 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine is an important raw material for synthesizing the ridciclovir, methods for synthesizing the compound are still few, and the method of the patent (WO 2016069826) is mainly adopted at present. The method prepares 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine by reacting N-iodosuccinimide with 4-aminopyrrolo [2,1-f ] [1,2,4] triazine in a solvent of N, N-dimethylformamide, but the yield of the reaction product is not high and impurities are more. Although a new report (CN 111423443A) has recently been made on the improvement of the above method, i.e. the reaction of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine with iodine or iodine chloride and then N-iodosuccinimide in the solvent N, N-dimethylformamide to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine, the method consumes more iodine-containing substances and is more costly. Therefore, the development of a plurality of new methods for preparing the 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine has better application prospect.
Synthetic route of Reidesciclovir:
disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine, so that the preparation method is simpler, meets the reaction requirement of green chemistry, and can obtain the 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine by one step; the preparation method has the characteristics of easily obtained and cheap raw materials, simple process, mild reaction conditions, high product yield and the like.
The invention is realized by the following technical scheme:
the invention provides a preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine, which comprises the following steps:
4-amino pyrrolo [2,1-f ] [1,2,4] triazine reacts with iodine-containing substances and oxidizing agents to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine;
the iodine-containing substance is iodine or hydroiodide;
the oxidant is at least one of potassium hydrogen persulfate composite salt, hydrogen peroxide, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide, sodium hypochlorite, ammonium persulfate and sodium persulfate.
Preferably, the preparation method comprises the following steps:
(1) under the protective atmosphere, dispersing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine in a solvent, adding iodine, stirring uniformly, reacting or adding hydroiodide, stirring uniformly, adding an oxidant, reacting, and finally adding water and sodium thiosulfate to finish the reaction to obtain a reaction solution;
(2) and (2) adding sodium bicarbonate into the reaction liquid obtained in the step (1) for crystallization or extracting with ethyl acetate to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine.
Preferably, in the step (1), the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the hydroiodide and the oxidant is 1 (1-5) to (1-5).
More preferably, the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine to the hydroiodide to the oxidant is 1:1 (1-2).
Preferably, the hydroiodide is at least one of sodium iodide, potassium iodide, ammonium iodide, lithium iodide and tetramethylammonium iodide.
Preferably, the oxidant is oxone complex salt. The invention optimizes the type of the oxidant, and the selection of the oxidant influences the utilization rate of iodine atoms and the yield of products; if the oxidant is not properly selected, the oxidant not only oxidizes iodine anions in the reaction, but also destroys amino structures in raw materials and products, so that the yield of the products is reduced, and therefore, the choice of the oxidant is very important.
More preferably, the hydroiodide is at least one of sodium iodide and potassium iodide.
Preferably, in the step (1), the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, iodine and oxidant is 1 (0.5-3) to (0.5-5).
More preferably, the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine to the iodine to the oxidant is 1:0.5 (0.5-2).
Preferably, in the step (1), the solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, acetonitrile, tetrahydrofuran, benzene, dimethyl sulfoxide, methanol, ethanol, dichloromethane and ethyl acetate.
More preferably, the solvent is at least one of N, N-dimethylformamide, methanol and ethanol.
Preferably, in the step (1), 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is dispersed in a solvent, hydroiodide is added and uniformly stirred, and then an oxidant is added for reaction at the reaction temperature of-5-20 ℃ for 0.5-10 hours.
More preferably, the reaction temperature is 0 ℃ and the reaction time is 2-8 hours.
Preferably, in the step (1), 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is dispersed in a solvent, iodine is added, the mixture is stirred uniformly and is reacted for 0.5-5 hours, and then an oxidant is added for reaction for 1-5 hours; the reaction temperature is-5-20 ℃.
More preferably, adding iodine, stirring uniformly, reacting for 0.5-2 hours, and then adding an oxidant for reacting for 1-3 hours; the reaction temperatures were all 0 ℃.
The invention has the beneficial effects that:
1. the invention provides a novel synthesis method of 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine, which can realize one-step reaction to obtain the 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine.
2. The preparation process of the invention uses cheap raw materials and reaction solvents which are easy to obtain, and the iodine atom in the iodinating reagent has high utilization rate in the reaction, thus reducing the cost for preparing the 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine.
3. The method has mild reaction conditions, produces fewer byproducts, and has simple post-treatment without complex purification process; high reaction yield and high product purity, and is suitable for large-scale production.
Drawings
FIG. 1 shows the NMR spectra of 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine prepared in example 4 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As described in the background, 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine is currently prepared mainly by the method of the patent (WO 2016069826). The method prepares 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine by reacting N-iodosuccinimide with 4-aminopyrrolo [2,1-f ] [1,2,4] triazine in a solvent of N, N-dimethylformamide, but the yield of the reaction product is not high and impurities are more. There has been a recent report (CN 111423443 a) of an improvement of the above method: 4-amino pyrrolo [2,1-f ] [1,2,4] triazine is reacted with iodine or iodine chloride to produce most of the iodinated product, and the unreacted material is reacted with N-iodosuccinimide. The reaction formula is as follows:
the utilization rate of iodine atoms in the iodinating reagent used in the method is low (1.6 molar equivalent is needed), the utilization rate of the iodine atoms is 35-61%, the economic effect of the iodine atoms is poor, the cost is increased, the price of N-iodosuccinimide is high, the toxicity is high, and potential safety hazards are easy to generate in the preparation process. Therefore, a simpler preparation method is needed for preparing the 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine, and the selected reagent is easy to obtain, low in cost and free of potential safety hazard.
Based on the above, the invention provides a preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine, which can be divided into the following two methods:
the first method comprises the following steps: reacting 4-aminopyrrolo [2,1-f ] [1,2,4] triazine with a hydroiodide and an oxidizing agent to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine, wherein the reaction formula is as follows:
the second method comprises the following steps: the 4-amino pyrrolo [2,1-f ] [1,2,4] triazine firstly reacts with iodine molecules and then reacts with an oxidant to obtain the 4-amino-7-iodine pyrrolo [2,1-f ] [1,2,4] triazine, and the reaction formula is as follows:
the principle of the invention is as follows:
in the first method, cheap oxidant is used to react with hydroiodide to generate active molecular iodine, and then the active molecular iodine reacts with 4-aminopyrrolo [2,1-f ] [1,2,4] triazine to obtain a product; in the second method, molecular iodine firstly reacts with 4-amino pyrrolo [2,1-f ] [1,2,4] triazine to obtain more 4-amino-7-iodine pyrrolo [2,1-f ] [1,2,4] triazine products, meanwhile, by-product iodine negative ions generated in the reaction are oxidized into molecular iodine through an oxidant to continue the reaction, and the completion of the reaction is promoted. Compared with the patent (CN 111423443A), the utilization rate of iodine atoms of iodine-containing substances in the two methods is greatly improved to 100 percent at most, so that the novel method for preparing the 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine meets the reaction requirement of green chemistry.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments. If the experimental conditions not specified in the examples are specified, the conditions are generally conventional or recommended by the reagent company; reagents, consumables, and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Under nitrogen, 3.5g (26.1mmol) of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine and 4.3g (26.1mmol,1.0equiv) of potassium iodide were added to 15mL of methanol, and the mixture was stirred well. The temperature is reduced to 0 ℃, 16.0g (26.1mmol,1.0equiv) of Oxone (Oxone) is added in equal portions, and the reaction is continued for 3 hours while feeding. 100mL of water and 6.5g of sodium thiosulfate were added, and then the pH of the reaction solution was adjusted to be alkaline with a saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate, and the organic phase was washed, dried, filtered and the solvent was removed under reduced pressure to give 6.0g of 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine (purity > 98%, yield 88%).
It is composed of1The H NMR data are as follows:1H-NMR(400MHz,DMSO-d6):7.91(s,1H),7.90-7.70(br,2H),7.00(d,J＝3.5Hz,1H),6.84(d,J＝3.6Hz,1H)。
example 2
Under nitrogen, 35g (0.261mol) of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine and 86g (0.522mol,2.0equiv) of potassium iodide were added to 150mL of methanol, and the mixture was stirred well. The temperature is reduced to 0 ℃, 160g (0.261mol,1.0equiv) of Oxone complex salt (Oxone) are added in equal portions, and the reaction is continued for 7 hours to end. 1000mL of water and 65g of sodium thiosulfate were added, and then the pH of the reaction solution was adjusted to be alkaline with a saturated sodium bicarbonate solution. Stirring, filtering, pulping the filtered solid with water and ethanol, filtering, and vacuum drying to obtain 61.1g 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine (purity greater than 96%, yield 90%).
It is composed of1The H NMR data are as follows:1H-NMR(400MHz,DMSO-d6):7.91(s,1H),7.90-7.70(br,2H),7.00(d,J＝3.5Hz,1H),6.84(d,J＝3.6Hz,1H)。
example 3
Under nitrogen, 3.5g (26.1mmol) of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine are added to 15mL of methanol and stirred uniformly. The temperature was reduced to 0 ℃ and 3.3g (13.1mmol,0.5equiv) of molecular iodine was added in equal portions and reacted at 0 ℃ for 2 h. An equal amount of 8.0g (13.1mmol,0.5equiv) of Oxone complex salt (Oxone) was added in portions at the same temperature and the reaction was continued for 2 h. 100mL of water and 6.5g of sodium thiosulfate were added, and then the pH of the reaction solution was adjusted to be alkaline with a saturated sodium bicarbonate solution. Stirring, filtering, pulping the filtered solid with water and ethanol, filtering, and vacuum drying to obtain 5.8g 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine (purity greater than 96%, yield 85%).
It is composed of1The H NMR data are as follows:1H-NMR(400MHz,DMSO-d6):7.91(s,1H),7.90-7.70(br,2H),7.00(d,J＝3.5Hz,1H),6.84(d,J＝3.6Hz,1H)。
example 4
70g (0.522mol) of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine are added to 250mL of methanol under nitrogen protection and stirred uniformly. The temperature was lowered to 0 ℃ and 66g (0.261mol,0.5equiv) of molecular iodine was added in equal portions and reacted at 0 ℃ for 2 h. 160g (0.261mol,0.5equiv) of Oxone complex salt (Oxone) were added in equal portions at the same temperature, and the reaction was continued for 3 hours. 1800mL of water and 65g of sodium thiosulfate were added, and then the pH of the reaction solution was adjusted to basic with a saturated sodium bicarbonate solution. Stirring, filtering, pulping the filtered solid with water and ethanol, filtering, and vacuum drying to obtain 125g of 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine (purity is more than 96%, yield is 92%).
It is composed of1The H NMR data are as follows:1H-NMR(400MHz,DMSO-d6) 7.91(s,1H),7.90-7.70(br,2H),7.00(d, J ═ 3.5Hz,1H),6.84(d, J ═ 3.6Hz,1H), see fig. 1.
The utilization rate of iodine atoms in the present invention means the ratio of the number of iodine atoms utilized in the reaction to the total number of iodine atoms, and therefore the utilization rates of iodine atoms in examples 1,3 and 4 are all 100%, and the utilization rate of iodine atoms in example 2 is 50%.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine is characterized by comprising the following steps:
4-amino pyrrolo [2,1-f ] [1,2,4] triazine reacts with iodine-containing substances and oxidizing agents to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine;
the iodine-containing substance is iodine or hydroiodide;
the oxidant is at least one of potassium hydrogen persulfate composite salt, hydrogen peroxide, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide, sodium hypochlorite, ammonium persulfate and sodium persulfate.
2. The method of claim 1, comprising the steps of:
(1) under the protective atmosphere, dispersing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine in a solvent, adding iodine, stirring uniformly, reacting or adding hydroiodide, stirring uniformly, adding an oxidant, reacting, and finally adding water and sodium thiosulfate to finish the reaction to obtain a reaction solution;
(2) and (2) adding sodium bicarbonate into the reaction liquid obtained in the step (1) for crystallization or extracting with ethyl acetate to obtain 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine.
3. The preparation method according to claim 2, wherein in the step (1), the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the hydroiodide and the oxidant is 1 (1-5) to (1-5); preferably, the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine to the hydroiodide to the oxidant is 1:1 (1-5).
4. The method according to any one of claims 1 to 3, wherein the hydroiodide is at least one of sodium iodide, potassium iodide, ammonium iodide, lithium iodide, and tetramethylammonium iodide.
5. The method according to claim 4, wherein the hydroiodide is at least one of sodium iodide and potassium iodide.
6. The method according to claim 2, wherein in the step (1), the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, iodine and the oxidant is 1 (0.5-3) to (0.5-5); preferably, the molar ratio of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine to the iodine to the oxidant is 1:0.5 (0.5-5).
7. The method according to claim 2, wherein in the step (1), the solvent is at least one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, acetonitrile, tetrahydrofuran, benzene, dimethylsulfoxide, methanol, ethanol, dichloromethane, and ethyl acetate.
8. The preparation method according to claim 2, wherein in the step (1), 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is dispersed in a solvent, hydroiodide is added and uniformly stirred, and then an oxidant is added for reaction at the temperature of-5 to 20 ℃ for 0.5 to 10 hours; preferably, the reaction temperature is 0 ℃ and the reaction time is 2-8 hours.
9. The preparation method according to claim 2, wherein in the step (1), 4-aminopyrrolo [2,1-f ] [1,2,4] triazine is dispersed in a solvent, iodine is added, the mixture is uniformly stirred and reacted for 0.5-5 hours, then an oxidant is added for reaction for 1-5 hours, and the reaction temperature is-5-20 ℃; preferably, the iodine is added, the mixture is uniformly stirred and reacted for 0.5-2 hours, then the oxidant is added for reaction for 1-3 hours, and the reaction temperature is 0 ℃.
10. The production method according to claim 1 or 2, wherein the oxidizing agent is oxone complex salt.
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| CN114920615A (en) * | 2022-06-02 | 2022-08-19 | 上海凌凯医药科技有限公司 | Iodination method and production system of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine or derivatives thereof |
| CN115124539A (en) * | 2022-07-29 | 2022-09-30 | 河南豫辰药业股份有限公司 | Preparation method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine |
| CN115124539B (en) * | 2022-07-29 | 2024-02-27 | 河南豫辰药业股份有限公司 | Preparation method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine |
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