A preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine

Abstract

The invention provides a novel preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine. The method adopts a compound NT01 and a compound NT02 to react under the catalysis of a zeolite molecular sieve to prepare 4-aminopyrrolo[2,1-f][1,2,4]triazine. The method has the advantages of simple operation process, high reaction yield, short reaction time and low production cost.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine. Background Art

[0002] The riboside compounds of the base pyrrolo[1,2-f][1,2,4]triazine-4-amine have a wide range of biological activities and have been shown to have inhibitory effects on a variety of viruses such as Ebola virus, respiratory syncytial virus, Hendra virus, and coronavirus.

[0003] The structure of this type of nucleoside compound is very similar to that of natural nucleosides and cannot be recognized by viruses. It can inhibit the activity of viral DNA polymerase and reverse transcriptase and compete with nucleotides to be incorporated into the viral DNA chain, thereby terminating or inhibiting the extension and synthesis of the viral DNA chain, inhibiting the replication of the virus and exerting an antiviral effect. Remdesivir is one of the many pyrrolo[1,2-f][1,2,4]triazine-4-amine nucleoside compounds and is a broad-spectrum antiviral compound.

[0004] At present, there are few reports on the synthesis route of remdesivir, and its key step is the connection of the D-ribonucleic acid lactone fragment and the heterocyclic fragment. The literature J.Med.Chem.2017,60,1648-1661 and CN107074902 reported its related synthesis. Its synthesis route is as follows:

[0005]

[0006]

[0007] CN111574523A also reported that 4-aminopyrrolo[2,1-f][1,2,4]triazine was used as an intermediate to replace the X-substituted heterocyclic fragment compound 2 to prepare remdesivir, which has the advantages of high yield and mild reaction conditions.

[0008] According to the public route, 4-aminopyrrolo[2,1-f][1,2,4]triazine (Formula I) is a key intermediate used in the preparation of remdesivir.

[0009]

[0010] CN 111533747 A discloses a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine in one pot by using pyrrole as raw material, chlorosulfonic acid isocyanate as cyanation reagent, O-[4-nitro-2-(trifluoromethyl)phenyl]hydroxylamine as amination reagent and formamidine acetate as cyclization reagent. The method has complicated operation, a yield of about 66%, a low yield and large pollution of three wastes.

[0011] CN110092787A discloses a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine in an ethanol solution by heating 1-amino-1H-pyrrole-2-carbonitrile hydrochloride with formamidine acetate and K3PO4 for 16 hours of reflux reaction with a yield of 55.9%. The route is as follows:

[0012]

[0013] This method has low yield and long reaction time.

[0014] WO2007056170 discloses a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine as follows:

[0015] This method has a long reaction step, harsh conditions, cumbersome operation, more three wastes, and a low total yield. It is not suitable for industrial scale-up production. In addition, the last step of the reaction is to convert 1-amino-1H-pyrrole-2-carbonitrile hydrochloride into the target compound 4-aminopyrrolo[2,1-f][1,2,4]triazine. The reaction time is as long as 18 hours, and the post-processing is cumbersome. In addition, this method uses a large amount of potassium phosphate, which is converted into phosphate solid waste in production, causing great environmental pollution and difficult treatment, and is not suitable for industrial production applications.

[0016] 4-Aminopyrrolo[2,1-f][1,2,4]triazine is a key intermediate for preparing nucleoside compounds of base pyrrolo[1,2-f][1,2,4]triazine-4-amine, including remdesivir. However, there are few publicly available index methods for 4-aminopyrrolo[2,1-f][1,2,4]triazine, and the existing methods have problems such as low yield, long reaction time, and severe environmental pollution. It is particularly important to develop a preparation method of pyrrolo[1,2-f][1,2,4]triazine-4-amine with high yield and suitable for industrial production. Summary of the invention

[0017] In order to solve the above problems existing in the prior art, the present invention provides a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine with high yield, short reaction time and low pollution.

[0018] Specifically, the present invention provides a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine, comprising reacting compound nt01 with compound nt02 to obtain compound I:

[0019]

[0020] Preferably, in the process of preparing compound I by reacting compound nt01 with compound nt02, compound nt01 reacts with compound nt02 to first generate transition state compound nt03, and then compound nt03 is converted into compound I:

[0021]

[0022] In the above method, further preferably, the molar feed ratio of compound nt01 to compound nt02 is 1:1 to 1:2.

[0023] Furthermore, the reaction of compound nt01 and compound nt02 is carried out under the catalysis of a catalyst, and the catalyst is a zeolite molecular sieve.

[0024] Further preferably, the zeolite molecular sieve is a medium-silicon zeolite molecular sieve and a high-silicon zeolite molecular sieve; wherein the Si / Al in the medium-silicon zeolite molecular sieve is 2.0-5.0, including but not limited to M type, β type, HY type, and the Si / Al in the high-silicon zeolite molecular sieve is 10-100, including but not limited to H-ZSM-5 type and H-ZSM-11 type; more preferably, the catalyst of the present invention is an H-ZSM-5 molecular sieve catalyst or a HY type molecular sieve catalyst.

[0025] The amount of the catalyst zeolite molecular sieve used is preferably 0.3-500 g / mole of compound nt01, more preferably 10-400 g / mole of compound nt01, and further preferably 100-200 g / mole of compound nt01.

[0026] In the above reaction, it is further preferred that compound nt01 and compound nt02 are reacted in a suitable solvent such as toluene, ethanol or DMF solution under the catalysis of zeolite molecular sieve. Preferably, the reaction temperature is 100-200°C and the reaction time is 0.5-5 hours. It is further preferred that after the reaction, compound I obtained by the reaction is purified by recrystallization with ethyl acetate to obtain high-purity compound I.

[0027] In a second aspect of the present invention, a method for preparing remdesivir is provided, comprising (1) preparing compound I by the method described in the present invention, and (2) converting compound I into remdesivir. The method for converting compound 1 into remdesivir in step (2) can be prepared according to methods disclosed in the art, such as J.Med.Chem.2017, 60, 1648-1661 and methods disclosed in CN107074902 or CN111574523A.

[0028] The present invention provides a new route for preparing compound I, which has simple process, convenient operation, easy to obtain starting materials, and can improve the reaction yield to more than 80%, and greatly shorten the reaction time. In addition, the present invention uses zeolite molecular sieve as a catalyst, especially H-ZSM-5 molecular sieve catalyst or HY type molecular sieve catalyst, which is not only conducive to promoting the reaction, shortening the reaction time, and improving the reaction efficiency, but also the catalyst used can be recycled and reused, which greatly saves production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The technical solution of the present application is further described below in conjunction with the accompanying drawings and embodiments.

[0030] Figure 1 is the HPLC spectrum of Compound I prepared by the method of Example 1 of the present invention;

[0031] HPLC test data are as follows:

[0032] <Peak table>

[0033] Detector A220nm

[0034] Peak Retention time area high Resolution (USP) Theoretical Plate Number (USP) area% 1 2.096 4229 218 -- 352 0.019 2 3.277 3328 137 1.912 277 0.015 3 4.429 13065 255 1.163 220 0.058 4 9.279 3717 247 6.036 8093 0.017 5 10.604 22323065 1254979 2.983 7928 99.437 6 12.205 102135 5158 3.150 8165 0.455 total 22449539 1260993 100.000 . DETAILED DESCRIPTION

[0035] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application may be combined with each other.

[0036] Unless otherwise specified, the reagents and starting materials used in the present invention can be prepared by methods known in the art or purchased from the market; the catalyst zeolite molecular sieve used can be purchased from the market.

[0037] Example 1: Preparation of 4-aminopyrrolo[2,1-f][1,2,4]triazine

[0038] In a 200mL stainless steel reactor, 5.5g nt01 (0.05mol), 3.0g nt02 (0.05mol), 100mL toluene and 6.0g powdered HY zeolite molecular sieve catalyst were added respectively. Then 5bar nitrogen was filled. The reactor was stirred at 150°C for 1 hour. After the reaction, the reaction mixture was filtered, the filtrate was washed with water, and then concentrated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 5.9g of the product with a yield of 88%, HPLC: 99.4%, and the HPLC spectrum is as shown below. Figure 1 The recovered catalyst can be recycled after washing and drying.

[0039] Example 2: Preparation of 4-aminopyrrolo[2,1-f][1,2,4]triazine

[0040] In a 200mL stainless steel reactor, 5.5g nt01 (0.05mol), 3.6g nt02 (0.06mol), 60mL ethanol and 6.0g powdered H-ZSM-5 molecular sieve catalyst were added respectively. Then 5bar nitrogen was filled. The reactor was stirred at 110°C for 2.5 hours. After the reaction was completed, the reaction mixture was filtered. After the filtrate was concentrated to dryness, the residue was dissolved in ethyl acetate and washed with water. After the mother liquor was concentrated to dryness, the residue was recrystallized from ethyl acetate again to obtain 5.7g of product, with a yield of 85%, HPLC: 99.7%. The recovered catalyst can be recycled after washing and drying. The catalyst was recycled 3 times, and the reaction results are shown in the table below.

[0041] Under the same reaction conditions as above, HY zeolite molecular sieve catalyst was used instead of H-ZSM-5 molecular sieve catalyst, and the catalyst was recycled 3 times. The reaction results are shown in Table 1 below.

[0042] Table 1: Reaction results of recycling the catalyst 3 times

[0043] catalyst HY type zeolite molecular sieve H-ZSM-5 zeolite molecular sieve First use yield 88％ 84％ First cycle yield 85％ 83％ Second cycle yield 82％ 81％ The third cycle yield 83％ 80％

[0044] As can be seen from the above table, the two catalysts were recycled three times under the conditions used. From the results, the yield was slightly reduced, but the activity was basically maintained at a good level.

[0045] Example 3: Preparation of 4-aminopyrrolo[2,1-f][1,2,4]triazine

[0046] In a 200mL stainless steel reactor, 5.5g nt01 (0.05mol), 3.6g nt02 (0.06mol), 60mL DMF and 6.0g powdered HY type zeolite molecular sieve catalyst were added respectively. Then 5bar nitrogen was filled. The reactor was stirred at 150℃ for 1 hour. After the reaction was completed, the reaction mixture was filtered. After the filtrate was concentrated to dryness, the residue was dissolved in ethyl acetate and washed with water. After the mother liquor was concentrated to dryness, the residue was recrystallized from ethyl acetate again to obtain 5.5g of product, with a yield of 82%, HPLC: 99.6%. The recovered catalyst can be recycled after solvent washing and drying.

[0047] Example 4: Preparation of 4-aminopyrrolo[2,1-f][1,2,4]triazine

[0048] In a 200mL stainless steel reactor, 5.5g nt01 (0.05mol), 4.5g nt02 (0.075mol), and 60mL DMF were added respectively. Then 5bar nitrogen was filled. The reactor was stirred at 150°C for 24 hours. After the reaction was completed, HPLC monitoring showed that there was still a large amount of raw materials remaining in the reaction, and the product was relatively mixed.

[0049] Based on the above ideal embodiments of this application, the relevant staff can make various changes and modifications without departing from the technical concept of this application through the above description. The technical scope of this application is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula I, characterized in that: The method comprises reacting compound nt01 with compound nt02 to obtain compound I: Wherein, the reaction of the compound nt01 and the compound nt02 is carried out under the catalysis of a catalyst, and the catalyst is a zeolite molecular sieve.

2. The method according to claim 1, characterized in that In the process of preparing compound I by reacting compound nt01 with compound nt02, compound nt01 reacts with compound nt02 to first generate transition state compound nt03, and then compound nt03 is converted into compound I:

3. The method according to claim 1, characterized in that The molar feed ratio of compound nt01 to compound nt02 is 1:1 to 1:

2.

4. The method according to claim 1, characterized in that The zeolite molecular sieves are medium-silicon zeolite molecular sieves and high-silicon zeolite molecular sieves, wherein the Si / Al ratio of the medium-silicon zeolite molecular sieve is 2.0-5.0, and the Si / Al ratio of the high-silicon zeolite molecular sieve is 10-100.

5. The method according to claim 1, characterized in that The catalyst is an H-ZSM-5 molecular sieve catalyst or a HY type molecular sieve catalyst.

6. The method according to claim 1, characterized in that The reaction solvent is toluene, ethanol or DMF.

7. The method according to claim 1, characterized in that: The reaction time is 0.5 to 5 hours.

8. The method according to any one of claims 1 to 7, characterized in that: The method also includes purifying the compound I obtained by the reaction by recrystallization with ethyl acetate.

9. A method for preparing remdesivir, characterized in that: The method comprises any one of claims 1 to 8.

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