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

Abstract

The present invention provides a method for preparing compound I by reacting compound nt01 with compound nt02 using a fixed-bed catalysis method. Compared with the prior art, the method provided by the present invention has the advantages of simple operation, not only avoiding the filtration operation after the reaction, but also being able to precisely control the residence time of the materials on the catalyst surface, reducing side reactions, and significantly improving the reaction yield.

Description

Technical Field

[0001] This application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine. Background Art

[0002] Riboside compounds of base pyrrolo[1,2-f][1,2,4]triazin-4-amine have a wide range of biological activities and have been proven to have inhibitory effects on various viruses such as Ebola virus, respiratory syncytial virus, Hendra virus, and coronavirus.

[0003] The structures of such nucleoside compounds are very similar to natural nucleosides and cannot be recognized by viruses. They can inhibit the activities of viral DNA polymerase and reverse transcriptase and competitively incorporate nucleotides into the viral DNA chain, thereby terminating or inhibiting the extension and synthesis of the viral DNA chain, and inhibiting the replication of the virus to play an antiviral role. Remdesivir is one of many riboside compounds of pyrrolo[1,2-f][1,2,4]triazin-4-amine and is a broad-spectrum antiviral compound.

[0004] Currently, there are few reports on the synthetic route of Remdesivir, and its key step is the connection of the D-ribonic acid lactone fragment and the heterocyclic fragment. Literature J.Med.Chem.2017,60,1648-1661 and CN107074902 reported its related synthesis. The synthetic route is as follows:

[0005]

[0006]

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

[0008] Judging from the disclosed route, 4-aminopyrrolo[2,1-f][1,2,4]triazine (such as 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 by using pyrrole as a raw material, using isocyanatochlorosulfonic acid as a cyanating reagent, O-[4-nitro-2-(trifluoromethyl)phenyl]hydroxylamine as an aminating reagent, and acetic formamidine as a cyclizing reagent in one-pot. This method has complex operations, a yield of about 66%, a relatively low yield, and serious three-waste pollution.

[0011] CN110092787A discloses that in an ethanol solution, 1-amino-1H-pyrrole-2-carbonitrile hydrochloride reacts with acetic formamidine and K 3 PO 4 , and the reaction is heated under reflux for 16 h to prepare 4-aminopyrrolo[2,1-f][1,2,4]triazine with a yield of 55.9%. The route is as follows:

[0012]

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

[0014] WO2007056170 discloses the following method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine:

[0015]

[0016] This method has long reaction steps, harsh conditions, cumbersome operations, a large amount of three-wastes, and a relatively low overall yield. It is not suitable for industrial scale-up production. Moreover, when the last step reaction converts 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 h and the post-treatment is cumbersome. In addition, this method uses a large amount of potassium phosphate, which is converted into phosphate solid waste in production, causing serious environmental pollution and difficult to handle, and is not suitable for industrial production applications.

[0017] 4-aminopyrrolo[2,1-f][1,2,4]triazine is a key intermediate for preparing riboside compounds of base pyrrolo[1,2-f][1,2,4]triazin-4-amine including remdesivir. However, there are few currently disclosed 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 serious environmental pollution. Therefore, it is particularly important to develop a preparation method for pyrrolo[1,2-f][1,2,4]triazin-4-amine with high yield and suitable for industrial production. SUMMARY OF THE INVENTION

[0018] 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, few side reactions, and simple operations.

[0019] Specifically, the present invention provides a method for preparing 4-aminopyrrolo[2,1-f][1,2,4]triazine, which includes reacting compound nt01 with compound nt02 under the catalysis of a fixed bed to obtain compound I:

[0020]

[0021] Preferably, the reaction of compound nt01 with compound nt02 under the catalysis of a fixed bed means catalyzing the reaction of compound nt01 with compound nt02 by placing a catalyst in a multiphase fixed bed.

[0022] Further preferably, the catalyst is a zeolite molecular sieve catalyst.

[0023] More preferably, the zeolite molecular sieve is a medium-silica zeolite molecular sieve and a high-silica zeolite molecular sieve; wherein, in the medium-silica zeolite molecular sieve, Si / Al = 2.0 - 5.0, including but not limited to M-type, β-type, H-Y type, and in the high-silica zeolite molecular sieve, Si / Al = 10 - 100, including but not limited to H-ZSM-5 type, H-ZSM-11 type.

[0024] More preferably, the catalyst of the present invention is an H-ZSM-5 molecular sieve catalyst or an H-Y type molecular sieve catalyst, and the H-ZSM-5 molecular sieve catalyst or the H-Y type molecular sieve catalyst catalyzes the reaction in the form of a fixed bed.

[0025] Furthermore, the particle size of the catalyst particles for catalysis in the form of a fixed bed is 2 - 5 mm.

[0026] Further preferably, the molar feed ratio of compound nt01 to compound nt02 is 1:1 - 1:2; preferably 1:1 - 1:1.2.

[0027] Further preferably, in the above reaction, compound nt01 and compound nt02 react under the catalysis of a fixed bed in a suitable solvent such as toluene, ethanol or DMF solution; wherein, preferably, the zeolite molecular sieve catalyst (particularly preferably the H-ZSM-5 molecular sieve catalyst or the H-Y type molecular sieve catalyst) catalyzes the reaction of compound nt01 with compound nt02 in the form of a fixed bed; further preferably, after compound nt01 and compound nt02 are added to the reaction solution, the reaction solution is fed by a high-pressure infusion pump, and after passing through a preheating zone, the reaction solution enters the fixed bed catalyst bed layer for catalytic reaction; more preferably, the reaction temperature is 100 - 150 °C, and most preferably, the reaction temperature is 120 - 130 °C.

[0028] The reaction vessel for the fixed-bed catalytic reaction can be appropriately selected according to the test scale and requirements. For example, a continuous-flow micro-reactor can be selected for convenient investigation of the reaction results in the laboratory; if it is for production, a large fixed-bed catalytic device can be selected. The flow rate of the feed of the reaction solution through the high-pressure infusion pump is related to the reaction device, and those skilled in the art can adjust it according to the reaction device; for example, when a continuous-flow micro-reactor is selected, the flow rate can be selected from 1 to 5 mL / min.

[0029] In the present invention, the diameter of the catalyst fixed-bed layer is preferably 1.5 to 2.5 cm, and the height is 4 to 6 cm; more preferably, the diameter of the catalyst fixed-bed layer is preferably 1.5 cm, and the height is 5 cm.

[0030] Furthermore, after the reaction is completed, the obtained compound I is recrystallized with ethyl acetate for purification to obtain high-purity compound I.

[0031] In the second aspect of the present invention, a preparation method of remdesivir is also provided, including:

[0032] (1) Preparing compound I by the method described in the present invention;

[0033] (2) Converting compound I into remdesivir.

[0034] Among them, the method for converting compound I into remdesivir in step (2) can be prepared according to the methods already disclosed in the art, such as the methods disclosed in J.Med.Chem.2017,60,1648 - 1661 and CN107074902 or CN111574523A, etc.

[0035] The present invention provides a method for preparing compound I by reacting compound nt01 with compound nt02 using a fixed-bed catalytic method. First, compared with the prior art, the fixed-bed catalytic method provided by the present invention is simple to operate, not only avoiding the filtration operation after the reaction; it can also accurately control the residence time of the materials on the catalyst surface, reduce side reactions, and significantly improve the reaction yield.

[0036] Secondly, the route for preparing compound I provided by the present invention has a simple process, is convenient to operate, and the starting materials are easily obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The technical solutions of the present application will be further described below with reference to the drawings and embodiments.

[0038] Figure 1 is the HPLC chromatogram of compound I prepared by the method of Example 1 of the present invention;

[0039] The HPLC detection data is as follows:

[0040] <Peak Table>

[0041] Detector A at 220 nm

[0042] Detailed implementation manners

[0043] It should be noted that, without conflict, the embodiments in this application and the features in the embodiments can be combined with each other.

[0044] Unless otherwise specified, the reagents and starting materials used in the present invention can be prepared by known methods in the art or obtained through market purchase; the zeolite molecular sieve used as the catalyst is obtained through market purchase.

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

[0046] In this example, a continuous flow microreactor was used. The reactor was made of 316L stainless steel. The diameter of the catalyst fixed bed was 1.5 cm and the height was 5 cm. The H-Y zeolite molecular sieve catalyst (Si / Al ratio of 2.6) was loaded, and the particle size of the catalyst was 2 mm. 5.5 g of compound nt01 (0.05 mol) and 3.0 g of compound nt02 (0.05 mol) were dissolved in 60 mL of ethanol. The reaction solution was fed at a flow rate of 1 mL / min through a high-pressure infusion pump. The reaction solution entered the fixed bed catalyst bed after passing through the preheating zone, then passed through the back pressure valve into the cooling zone, and finally entered the collection tank. The reaction temperature was 120 °C. After the collected reaction solution was concentrated to dryness, the residue was recrystallized with ethyl acetate to obtain 6.2 g of the product, with a yield of 93%, HPLC: 99.9%. The HPLC chromatogram is as Figure 1 shown.

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

[0048] The same reaction device as in Example 1 was used, and the H-ZSM-5 molecular sieve catalyst with a particle size of 3 mm (Si / Al ratio of 18) was loaded. 5.5 g of compound nt01 (0.05 mol) and 3.0 g of compound nt02 (0.05 mol) were dissolved in 60 mL of DMF. The reaction solution was fed at a flow rate of 2 mL / min through a high-pressure infusion pump. The reaction solution entered the fixed bed catalyst bed after passing through the preheating zone, then passed through the back pressure valve into the cooling zone, and finally entered the collection tank. The reaction temperature was 150 °C. After the collected reaction solution was concentrated to dryness, the residue was recrystallized with ethyl acetate to obtain 6.1 g of the product, with a yield of 91%, HPLC: 99.8%.

[0049] Example 3: Preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine

[0050] Using the same reaction apparatus as in Example 1, a H-ZSM-5 type molecular sieve catalyst with a particle size of 2 mm (Si / Al ratio of 18) was loaded. 5.5 g of compound nt01 (0.05 mol) and 3.6 g of compound nt02 (0.06 mol) were dissolved in 60 mL of toluene. The reaction solution was fed at a flow rate of 3 mL / min through a high-pressure liquid delivery pump. After passing through the preheating zone, the reaction solution entered the fixed-bed catalyst bed layer, then passed through the back pressure valve into the cooling zone, and finally entered the collection tank. The reaction temperature was 150 °C. After the collected reaction solution was concentrated to dryness, the residue was recrystallized with ethyl acetate to obtain 6.37 g of compound I, with a yield of 95% and HPLC: 99.9%.

[0051] Example 4: Preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine

[0052] Using the same reaction apparatus as in Example 1, a H-ZSM-11 type molecular sieve catalyst with a particle size of 2 mm was loaded. 5.5 g of compound nt01 (0.05 mol) and 3.0 g of compound nt02 (0.05 mol) were dissolved in 60 mL of ethanol. The reaction solution was fed at a flow rate of 5 mL / min through a high-pressure liquid delivery pump. After passing through the preheating zone, the reaction solution entered the fixed-bed catalyst bed layer, then passed through the back pressure valve into the cooling zone, and finally entered the collection tank. The reaction temperature was 100 °C. After the collected reaction solution was concentrated to dryness, the residue was recrystallized with ethyl acetate to obtain 6.1 g of compound I, with a yield of 91% and HPLC: 99.8%.

[0053] Inspired by the above ideal embodiments according to the present application, through the above description, relevant staff can completely make various changes and modifications without departing from the technical idea of this application. 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 represented by formula I, characterized in that, it comprises reacting compound nt01 with compound nt02 under fixed-bed catalysis to obtain compound I: wherein the catalyst is zeolite molecular sieve, and the zeolite molecular sieve is medium-silica zeolite molecular sieve or high-silica zeolite molecular sieve.

2. The method according to claim 1, characterized in that, the reacting of compound nt01 with compound nt02 under fixed-bed catalysis means catalyzing the reaction of compound nt01 with compound nt02 by placing the catalyst in a multiphase fixed bed.

3. The method according to claim 1, characterized in that, in the medium-silica zeolite molecular sieve, Si / Al = 2.0 - 5.0, and in the high-silica zeolite molecular sieve, Si / Al = 10 - 100.

4. The method according to claim 1, characterized in that, the catalyst is medium-silica zeolite molecular sieve, wherein in the medium-silica zeolite molecular sieve, Si / Al = 2.0 - 5.

0.

5. The method according to claim 1, characterized in that, the catalyst is high-silica zeolite molecular sieve, wherein in the high-silica zeolite molecular sieve, Si / Al = 10 - 100.

6. The method according to claim 1, characterized in that, the catalyst is H-ZSM-5 molecular sieve catalyst or H-Y type molecular sieve catalyst, and the H-ZSM-5 molecular sieve catalyst or H-Y type molecular sieve catalyst catalyzes the reaction in the form of a fixed bed.

7. The method according to any one of claims 1 - 6, characterized in that, the molar feed ratio of compound nt01 to compound nt02 is 1:1 - 1:

2.

8. The method according to any one of claims 1 - 6, characterized in that, the reaction solvent is toluene, ethanol or DMF.

9. The method according to any one of claims 1 - 6, characterized in that, after adding compound nt01 and compound nt02 to the reaction solvent, the reaction solution is fed by a high-pressure infusion pump, and after passing through the preheating zone, the reaction solution enters the fixed-bed catalyst bed layer for catalytic reaction.

10. The method according to claim 8, characterized in that, the catalytic reaction temperature is 100 - 150 °C.

11. The method according to any one of claims 1 - 6, characterized in that, it further comprises purifying the obtained compound I by recrystallization with ethyl acetate.

12. A method for preparing remdesivir, characterized in that, it comprises the method according to any one of claims 1 - 11, wherein compound I is a key intermediate for preparing remdesivir.

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