Synthetic method of pyrrolo [2, 1-f] [1, 2, 4] triazine-4 (3H)-ketone

Abstract

The embodiment of the invention discloses a synthetic method of pyrrolo [2, 1-f] [1, 2, 4] triazine-4 (3H)-ketone. The synthesis method comprises the following steps: taking 2, 5-dimethoxytetrahydrofuran and tert-butyloxycarboryl hydrazine as initial raw materials, and sequentially carrying out Clawson-Kass pyrrole synthesis reaction, formylation reaction, deprotection group reaction and cyclization reaction to prepare pyrrolo [2, 1-f] [1, 2, 4] triazine-4 (3H)-ketone. Reagents and solvents used in the method are cheap and easy to obtain, reaction conditions of key steps are mild, a reliable technical scheme is provided for industrial production, and the method is a synthesis method with large-scale preparation value and has good application value.

Description

Technical Field

[0001] The embodiments of the present invention relate to the technical field of organic synthesis, and particularly to a method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one. Background Art

[0002] The pyrrolo[2,1-f][1,2,4]triazine structure is a class of electron-rich heterocyclic nitrogen compounds that can bind to targets through a variety of weak interactions, including hydrogen bonds, dipole-dipole interactions, hydrophobic effects, van der Waals forces, and π-π stacking interactions. In recent years, the application value of this structural unit has gradually emerged in drug discovery and occupies an important position in marketed drugs. Its application research mainly focuses on the fields of anti-tumor drugs, immunity, and stress-related diseases. For example, Avapritinib (BLU-285) developed by Blueprint Medicines Corporation was approved for marketing by the US Food and Drug Administration (FDA) on January 9, 2020. It can potently and precisely inhibit the PDGFRα D842V and KIT D816V mutations and is used to treat patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) with the PDGFRα D84V mutation. Multiple drugs targeting FGFR, IGF1R, and EGFR in clinical research by Bristol Myers Squibb Company. And a novel immunosuppressant targeting JAK3 developed by BioCryst Pharmaceuticals, Inc.

[0003] Pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and the drug structure containing pyrrolo[2,1-f][1,2,4]triazine are as follows:

[0004]

[0005]

[0006] As a key intermediate for constructing the molecular skeleton of pyrrolo[2,1-f][1,2,4]triazine drugs, the development of its synthesis process is of great significance in the field of medicinal chemistry. The first reported synthesis route by the Klein research group in 1994 used 2-pyrrolecarboxaldehyde 2 as the starting material, introduced the N-1 amino group and C-2 cyano group through hydroxylamine sulfonic acid, and then constructed the intermediate 4 by the strategy of hydrolyzing the cyano group to amide (see Synthesis Route 1a). Although this classic route provides a preparation method for trace samples (milligram level) for medicinal chemistry research, it has significant limitations: four steps of reaction require multiple intermediate separations and purifications (column chromatography), and the final overall yield is only 15.3%. This synthesis mode with difficult intermediate purification and low yield is difficult to meet the strict requirements of industrial production for atom economy, process efficiency, and environmental friendliness.

[0007] In the process of BioCryst's research and development of a novel JAK3-targeted immunosuppressant, to prepare Compound 1, commercial raw materials 2,5-dimethoxytetrahydrofuran 6 and Boc-hydrazine (tert-butoxycarbonyl hydrazine) were used as starting materials. A method was adopted to introduce a cyano group through chlorosulfonyl isocyanate (CSI) and DMF, and then hydrolyze it to formamide to prepare the key intermediate 10 (see Synthetic Route 1b). However, the efficiency of introducing the cyano group by this method is low, and intermediate 8 needs to be purified by column chromatography. Although this route optimized the purification efficiency of some intermediates by recrystallization instead of column chromatography, there are still many deficiencies: complex functional group transformation steps, excessive consumption of reagents and solvents, and only a 25.3% overall yield, which seriously restricts the low-cost large-scale production of Compound 1 and its industrial application prospects.

[0008] The reported synthetic routes of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1) are as follows:

[0009]

[0010] In view of the above research background, it is of great significance to develop a synthetic route that combines safety, economy and has the potential for process scale-up. Summary of the Invention

[0011] Therefore, the embodiments of the present invention provide a method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one. By using chlorosulfonyl isocyanate (CSI) to introduce an amide in one step, the present invention has established an efficient synthesis and simple purification method for the key intermediate (Compound 9), greatly improving the preparation efficiency of the target product, reducing the material and labor costs, and having a high safety factor, providing a solid technical foundation for large-scale production.

[0012] To achieve the above object, the embodiments of the present invention provide the following technical solutions:

[0013] A method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, using 2,5-dimethoxytetrahydrofuran and tert-butoxycarbonyl hydrazine as starting materials, successively carrying out the Clauson-Kaas pyrrole synthesis reaction, formamidation reaction, deprotection reaction and cyclization reaction to obtain pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, namely Compound 1. The synthetic route is as follows:

[0014]

[0015] Further, the Clauson-Kaas pyrrole synthesis reaction is carried out in the presence of a solvent and a catalyst;

[0016] Or, the solvent is tetrahydrofuran or 1,4-dioxane;

[0017] Or, the catalyst is hydrochloric acid with a concentration of 6M - 12M;

[0018] Or, the molar ratio of 2,5-dimethoxytetrahydrofuran, tert-butoxycarbonyl hydrazine to hydrogen chloride is 1.0 - 1.3:1.0:0.06 - 0.03;

[0019] The temperature of the Clauson-Kaas pyrrole synthesis reaction is 80 - 100 °C.

[0020] Further, the solvent is 1,4-dioxane, and the catalyst is hydrochloric acid with a concentration of 10M - 12M.

[0021] Further, the formylation reaction includes: at -25 - 5 °C, mixing compound 7, isocyanatosulfonyl chloride and a solvent, adding an alkali solution to adjust the pH of the system to 8 - 9, and after adding, naturally warming up to 0 - 25 °C;

[0022] Or, the solvent is acetonitrile or tetrahydrofuran;

[0023] Or, the alkali solution is an aqueous solution of sodium hydroxide or potassium hydroxide, with a mass concentration of 10% - 50%, and the molar amount of sodium hydroxide or potassium hydroxide is 3.5 - 4.0 times that of compound 7;

[0024] Or, the molar ratio of compound 7 to isocyanatosulfonyl chloride is 1.0:1.0 - 1.2.

[0025] Further, the formylation reaction includes: at -5 - 5 °C, mixing compound 7, isocyanatosulfonyl chloride and a solvent, controlling the temperature not exceeding 5 °C, adding an alkali to adjust the pH of the system to 8 - 9, controlling the temperature not exceeding 10 °C, and after adding, naturally warming up to 20 - 25 °C.

[0026] Further, the deprotection reaction is carried out in the presence of an acid solution and a solvent;

[0027] Or, the acid solution includes an ethyl acetate solution of hydrogen chloride, a methanol solution of hydrogen chloride or a 1,4-dioxane solution of hydrogen chloride;

[0028] Or, the solvent is selected from any one or more of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran;

[0029] Or, the molar ratio of compound 9 to hydrogen chloride is 1.0:2.0 - 4.0;

[0030] Or, the temperature of the deprotection reaction is below 25 °C.

[0031] Further, the cyclization reaction is carried out in the presence of a cyclizing reagent, a base and a solvent;

[0032] Alternatively, the cyclizing reagent is trimethyl orthoformate or triethyl orthoformate;

[0033] Alternatively, the base is sodium carbonate or sodium bicarbonate;

[0034] Alternatively, the solvent is methanol or ethanol;

[0035] Alternatively, the molar ratio of the compound 9, the base and the cyclizing reagent is 1.0:0.5 - 1.0:3.0 - 8.0;

[0036] Alternatively, the temperature of the cyclization reaction is 60 - 85 °C.

[0037] Furthermore, the base is sodium carbonate.

[0038] The embodiments of the present invention have the following advantages:

[0039] The present invention uses 2,5 - dimethoxytetrahydrofuran and Boc - hydrazine as starting materials, and innovatively adopts the one - step formylation mediated by chlorosulfonyl isocyanate (CSI) as the key reaction to achieve the high - efficiency synthesis of key intermediates. By optimizing the reaction parameters (temperature, molar ratio, reaction time) and the intermediate purification scheme, the atom economy and operation continuity of the process are significantly improved. Verified by process scale - up, the total yield of the target product in the multi - hundred - gram - scale experiment is as high as 60.7% (HPLC purity 99.51%). Compared with the existing methods, the reagents and solvents used in this route are cheap and easily available, and the reaction conditions of the key steps are mild (-5 - 25 °C), providing a reliable technical solution for industrial production and being a synthesis method with large - scale preparation value. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only exemplary, and for those of ordinary skill in the art, other implementation drawings can be obtained according to the provided drawings without creative efforts.

[0041] Figure 1 1H NMR of compound 1 provided in Example 1 of the present invention 1 1H NMR;

[0042] Figure 2 13C NMR of compound 1 provided in Example 1 of the present invention 13 13C NMR;

[0043] Figure 3 HRMS of compound 1 provided in Example 1 of the present invention

[0044] Figure 4 The analysis method and purity detection result of Compound 1 provided in Embodiment 1 of the present invention. Detailed implementation manners

[0045] The following specific embodiments illustrate the implementation manners of the present invention. Those skilled in the art can easily understand the other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0046] Embodiment 1

[0047] This embodiment provides a synthesis method of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one:

[0048] Step 1. Synthesis of tert-butyl (1H-pyrrol-1-yl)carbamate (7)

[0049] Add 2,5-dimethoxytetrahydrofuran (550.00 g, 4.16 mol, 1.10 eq.) to a solution of Boc-hydrazine (500.00 g, 3.78 mol, 1.00 eq.) in 1,4-dioxane (3.00 L, 6.00 V). Start mechanical stirring and control the internal temperature at 20 - 25 °C. Slowly add 12 M concentrated hydrochloric acid (9.45 ml, 113.4 mmol, 0.03 eq.) to the reaction system over 15 min. After addition, turn on the electric heating mantle to heat the reaction system to control the internal temperature at 87 - 92 °C, and keep stirring for 6 h to complete the reaction. Turn off the heating, and let the reaction system cool down naturally to 65 °C. Add sodium bicarbonate (12.71 g, 0.15 mol, 0.04 eq.) and stir for 30 min to quench the reaction. Continue to cool down to 45 °C, and concentrate 1,4-dioxane in the reaction system under reduced pressure. The remaining residue volume is about 3.00 V. Add n-heptane (2.00 L, 4.00 V) to the reaction flask, continue to stir at room temperature for 4 - 5 h for crystallization, and filter under reduced pressure. Wash the filter cake with n-heptane (0.50 L, 1.00 V) and dry to obtain a pale yellow solid 7 (544.60 g, 2.99 mol, 79.0%). HPLC purity = 98.25%; R f = 0.85 [silica gel TLC, V(EtOAc)∶V(petroleum ether) = 1∶1]; 1 1H NMR (600 MHz, DMSO-d6) δ 10.27 (br, 1H), 6.68 (t, J = 2.3 Hz, 2H), 5.96 (t, J = 2.3 Hz, 2H), 1.43 (s, 9H);13 C NMR (150 MHz, DMSO-d6) δ 154.67, 121.95, 121.95, 106.22, 106.22, 80.10, 27.95, 27.95, 27.95; HRMS (ESI) m / z: calculated for C9H 14 N2O2 [M + H] + 182.1128, found 182.1129.

[0050] Step 2. Synthesis of tert-butyl (2-carbamoyl-1H-pyrrol-1-yl)carbamate (9)

[0051] Add acetonitrile (4.36 L, 8V), compound 7 (544.60 g, 2.99 mol) to a three-necked reaction flask in sequence under nitrogen protection. Start mechanical stirring, cool the reaction system to 0 - 5 °C, and slowly add isocyanatochlorosulfate (260.3 mL, 2.99 mol, 1.0 eq) dropwise to the reaction system, controlling the temperature not to exceed 5 °C, which takes 1 h. After addition, continue to keep the temperature for reaction for 0.5 h. Add an aqueous KOH solution (KOH dosage 652.96 g, 11.66 mol, 3.9 eq, W KOH / W (KOH+water) = 10%) dropwise to the reaction system, controlling the temperature not to exceed 10 °C. After addition, the pH of the reaction system is 8 - 9 at this time, and it is naturally heated to 20 - 25 °C and stirred for another 1 h, and a large amount of yellow solid precipitates. Filter by vacuum under reduced pressure, wash the filter cake with water (1.64 L, 3V), and dry it in vacuo at 65 °C to obtain a pale yellow solid 9 (544.60 g, 2.42 mol, 80.9%). HPLC purity = 99.13%; R f = 0.7 [silica gel TLC, V(DCM)∶V(MeOH) = 20∶1, 1.0 mL + 1 drops NH3 . H2O]; 1 1H NMR (600 MHz, DMSO-d6) δ 9.91 (br, 1H), 7.38 (br, 1H), 6.91–6.81 (m, 2H), 6.76 (dd, J = 4.1, 1.8 Hz, 1H), 5.97 (dd, J = 4.1, 2.8 Hz, 1H), 1.40 (s, 10H); 13 13C NMR (150 MHz, DMSO-d6) δ 161.48, 155.38, 127.65, 124.20, 111.49, 104.78, 79.80, 28.01, 28.01, 28.01. HRMS (ESI) m / z: calculated for C 10 H 15N3O3[M+Na] + 248.1006, found 248.1004.

[0052] Steps three and four, synthesis of 1-amino-1H-pyrrole-2-carboxamide hydrochloride (11) and pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1)

[0053] Add ethyl acetate (2.72 L, 5V) and compound 9 (544.60 g, 2.42 mol) successively to a three-necked reaction flask. Start mechanical stirring, cool the reaction system to 0 - 5 °C, and slowly add a 4M HCl ethyl acetate solution (1.21 L, 4.84 mol) to the reaction system while controlling the temperature not to exceed 25 °C, which takes 1.5 h. After addition, allow the temperature to rise to 20 - 25 °C naturally and continue stirring for 2 h. A large amount of solid precipitates. Filter under reduced pressure, wash the filter cake with ethyl acetate (272.30 mL, 0.5V), and drain. The obtained compound 11 can be directly used for the next cyclization reaction without further operation. R f = 0.55 [silica gel TLC, V(DCM)∶V(MeOH) = 20∶1, 1.0 mL + 1 drops NH3 . H2O]; 1 1H NMR (600 MHz, DMSO-d6) δ 9.55 (br, 3H), 8.12 (br, 1H), 7.46 (br, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.92 (dd, J = 4.3, 1.9 Hz, 1H), 6.10 (dd, J = 4.2, 2.8 Hz, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 162.95, 123.89, 121.33, 111.55, 106.11. HRMS (ESI) m / z: calculated for C5H8N3O [M + H] + 126.0662, found 126.0663.

[0054] To the reaction flask, the obtained compound 11, methanol (1.63 L, 3V), trimethyl orthoformate (794.26 mL, 7.26 mol, 3.00 eq.) were added in sequence. The mechanical stirring was started, and solid sodium carbonate (153.91 g, 1.45 mol, 0.60 eq.) was added in batches. The temperature was raised to 70 °C and refluxed for 1 h. After the reaction system was cooled to 40 °C, methanol (1.63 L, 3V) and activated carbon (5.44 g) were added. The temperature was further raised to 70 °C and refluxed for decolorization for 1 h. Then it was cooled to 40 °C, dichloromethane (1.63 L, 3V) was added, and it was filtered through a pad of diatomaceous earth while hot. The filter cake was washed with methanol / dichloromethane (V:V = 2:1, 1.63 L, 3V). The filtrates were combined and concentrated to dryness under reduced pressure to obtain the crude product of compound 1. It was slurried and purified with ethyl acetate (2.18 L, 4V) at 20 - 25 °C for 2 h, filtered under reduced pressure, and the filter cake was washed with ethyl acetate (272.30 mL, 0.5V), and dried to obtain a pale yellow solid 1 (310.4 g, 2.30 mol, 95.0%). HPLC purity = 99.51%; R f = 0.75 [silica gel TLC, V(DCM)∶V(MeOH) = 20∶1, 1.0 mL + 1 drops NH3 . H2O]; 1 1H NMR (600 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.57–7.54 (m, 1H), 6.85 (dd, J = 4.2, 1.5 Hz, 1H), 6.52 (dd, J = 4.2, 2.7 Hz, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 154.63, 139.01, 120.81, 120.05, 109.86, 106.90. HRMS (ESI) m / z: calculated for C6H5N3O [M + H] + 136.0505, found 136.0503.

[0055] Example 2

[0056] This example provides a method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one:

[0057] Step 1. Synthesis of tert-butyl (1H-pyrrol-1-yl)carbamate (7)

[0058] To a solution of Boc-hydrazine (500.00 g, 3.78 mol, 1.00 eq.) in tetrahydrofuran (3.00 L, 6.00 V), add 2,5-dimethoxytetrahydrofuran (550.00 g, 4.16 mol, 1.10 eq.). Start mechanical stirring, control the internal temperature at 20 - 25 °C, and slowly add 12 M concentrated hydrochloric acid (9.45 ml, 113.4 mmol, 0.03 eq.) dropwise to the reaction system over 15 min. After addition, start heating with an electric heating mantle to control the internal temperature of the reaction system at 87 - 92 °C, and keep stirring and reacting for 6 h to complete the reaction. Turn off the heating, let the reaction system cool naturally to 65 °C, add sodium bicarbonate (12.71 g, 0.15 mol, 0.04 eq.), and stir for 30 min to quench the reaction. Continue to cool to 45 °C, and concentrate the tetrahydrofuran in the reaction system under reduced pressure. The remaining residue volume is about 3.00 V. Add n-heptane (2.00 L, 4.00 V) to the reaction flask, continue to cool to room temperature and stir for crystallization for 4 - 5 h, filter under reduced pressure, wash the filter cake with n-heptane (0.50 L, 1.00 V), and dry to obtain a dark yellow solid 7 (475.7 g, 2.61 mol, 69.0%). HPLC purity = 95.21%.

[0059] Step 2. Synthesis of tert-butyl (2-carbamoyl-1H-pyrrol-1-yl)carbamate (9)

[0060] Add tetrahydrofuran (3.81 L, 8 V) and compound 7 (475.7 g, 2.61 mol) to a three-necked reaction flask in sequence under nitrogen protection. Start mechanical stirring, cool the reaction system to -25 °C, and slowly add isocyanatochlorosulfate (227.3 mL, 2.61 mol, 1.0 eq) dropwise to the reaction system, controlling the temperature not exceeding 5 °C over 1 h. After addition, continue to keep the reaction at the same temperature for 0.5 h. Add an aqueous KOH solution (the amount of KOH is 555.52 g, 9.92 mol, 3.8 eq, KOH / W (KOH+water) W = 10%) dropwise to the reaction system, controlling the temperature not exceeding 10 °C. After addition, the pH of the reaction system is 8 - 9 at this time, and it is allowed to warm up naturally to 20 - 25 °C, and continue to stir for 1 h to precipitate a large amount of yellow solid. Filter under reduced pressure, wash the filter cake with water (1.64 L, 3 V), and dry in vacuo at 65 °C to obtain a pale yellow solid 9 (411.53 g, 1.83 mol, 70.1%). HPLC purity = 95.60%.

[0061] Steps 3 and 4. Synthesis of 1-amino-1H-pyrrole-2-carboxamide hydrochloride (11) and pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1)

[0062] Add tetrahydrofuran (2.06 L, 5 V) and compound 9 (411.53 g, 1.83 mol) to a three-necked reaction flask in sequence. Start mechanical stirring, cool the reaction system to 0 - 5 °C, and slowly add a 1,4-dioxane solution of 4 M HCl (0.92 L, 3.66 mol) dropwise to the reaction system, controlling the temperature not to exceed 25 °C, which takes 1.5 h. After addition, allow the temperature to rise to 20 - 25 °C naturally, and continue stirring for 2 h. A large amount of solid precipitates. Filter under reduced pressure, wash the filter cake with tetrahydrofuran (205.8 mL, 0.5 V), and filter dry. The obtained compound 11 can be directly used for the next cyclization reaction without further operation.

[0063] Add the compound 11 obtained in the previous step, ethanol (1.24 L, 3 V), and triethyl orthoformate (0.91 L, 5.49 mol, 3.00 eq.) to the reaction flask in sequence. Start mechanical stirring, add solid sodium carbonate (116.4 g, 1.1 mol, 0.60 eq.) in batches, and heat to 85 - 90 °C for reflux reaction for 1 h. After the reaction system is cooled to 40 °C, add ethanol (1.24 L, 3 V) and activated carbon (4.11 g), continue heating to 85 °C for reflux decolorization for 1 h, then cool to 40 °C, add dichloromethane (1.24 L, 3 V), filter while hot with diatomaceous earth as a pad, wash the filter cake with ethanol / dichloromethane (V:V = 2:1, 1.24 L, 3 V), combine the filtrates, concentrate to dryness under reduced pressure to obtain the crude product of compound 1. Pulverize and purify with ethyl acetate (1.65 L, 4 V) at 20 - 25 °C for 2 h, filter under reduced pressure, wash the filter cake with ethyl acetate (205.8 mL, 0.5 V), and dry to obtain a pale yellow solid 1 (234.5 g, 1.74 mol, 95.1%). HPLC purity = 99.31%.

[0064] Example 3

[0065] This example provides a method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one:

[0066] Step 1. Synthesis of tert-butyl (1H-pyrrol-1-yl)carbamate (7)

[0067] To a solution of Boc-hydrazine (500.00 g, 3.78 mol, 1.00 eq.) in 1,4-dioxane (3.00 L, 6.00 V), add 2,5-dimethoxytetrahydrofuran (550.00 g, 4.16 mol, 1.10 eq.). Start mechanical stirring and control the internal temperature at 20 - 25 °C. Slowly add 6 M hydrochloric acid (18.9 ml, 113.4 mmol, 0.03 eq.) dropwise to the reaction system over 15 min. After addition, start heating with an electric heating mantle to control the internal temperature of the reaction system at 87 - 92 °C and stir for 6 h to complete the reaction. Turn off the heating and let the reaction system cool naturally to 65 °C. Add sodium bicarbonate (12.71 g, 0.15 mol, 0.04 eq.) and stir for 30 min to quench the reaction. Continue to cool to 45 °C and concentrate the 1,4-dioxane in the reaction system under reduced pressure (which can be recycled and reused for this reaction). The remaining residue has a volume of approximately 3.00 V. Add n-heptane (2.00 L, 4.00 V) to the reaction flask and continue to stir at room temperature for 4 - 5 h to crystallize. Filter under reduced pressure, wash the filter cake with n-heptane (0.50 L, 1.00 V), and dry to obtain yellow solid 7 (482.6 g, 2.65 mol, 70.1%). HPLC purity = 96.16%.

[0068] Step 2. Synthesis of tert-butyl (2-carbamoyl-1H-pyrrol-1-yl)carbamate (9)

[0069] Add acetonitrile (4.36 L, 8 V) and compound 7 (482.6 g, 2.65 mol) to a three-necked reaction flask under nitrogen protection. Start mechanical stirring and cool the reaction system to -5 - 0 °C. Slowly add isocyanatothionyl chloride (230.7 mL, 2.65 mol, 1.0 eq) dropwise to the reaction system, controlling the temperature not to exceed 5 °C over 1 h. After addition, continue to stir at the same temperature for 0.5 h. Add an aqueous NaOH solution (NaOH dosage 402.8 g, 10.07 mol, 3.8 eq, NaOH / W (NaOH+water) = 10%) dropwise to the reaction system, controlling the temperature not to exceed 10 °C. After addition, the pH of the reaction system is 8 - 9 at this time. Let it warm up naturally to 20 - 25 °C and continue to stir for 1 h, during which a large amount of yellow solid precipitates. Filter under reduced pressure, wash the filter cake with water (1.45 L, 3 V), and dry in vacuo at 65 °C to obtain pale yellow solid 9 (471.6 g, 2.09 mol, 78.9%). HPLC purity = 96.2%.

[0070] Steps 3 and 4. Synthesis of 1-amino-1H-pyrrole-2-carboxamide hydrochloride (11) and pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1)

[0071] Isopropanol (2.36 L, 5V) and compound 9 (471.6 g, 2.09 mol) were successively added to a three-necked reaction flask. The mechanical stirring was started, and the reaction system was cooled to 0 - 5 °C. A 1,4-dioxane solution of 4 M HCl (1.05 L, 4.18 mol) was slowly added dropwise to the reaction system, controlling the temperature not to exceed 25 °C, and it took 1.5 h. After the addition was completed, the temperature was naturally raised to 20 - 25 °C, and stirring was continued for 2 h, during which a large amount of solid was precipitated. The mixture was filtered under reduced pressure, and the filter cake was washed with 1,4-dioxane (235.6 mL, 0.5V), and then dried by suction. The obtained compound 11 was directly used for the next cyclization reaction without further treatment.

[0072] To the reaction flask were successively added the compound 11 obtained in the previous step, ethanol (1.42 L, 3V), and triethyl orthoformate (1.04 L, 6.27 mol, 3.00 eq.). The mechanical stirring was started, and solid sodium carbonate (132.9 g, 1.25 mol, 0.60 eq.) was added in batches. The temperature was raised to 70 °C and refluxed for 1 h. After the reaction system was cooled to 40 °C, ethanol (1.42 L, 3V) and activated carbon (4.71 g) were added. The temperature was further raised to 70 °C and refluxed for 1 h for decolorization. Then it was cooled to 40 °C, and dichloromethane (1.42 L, 3V) was added. The mixture was filtered through a pad of diatomaceous earth while hot, and the filter cake was washed with methanol / dichloromethane (V:V = 2:1, 1.42 L, 3V). The filtrates were combined and concentrated to dryness under reduced pressure to obtain the crude compound 1. It was slurried and purified with ethyl acetate (1.89 L, 4V) at 20 - 25 °C for 2 h, filtered under reduced pressure, and the filter cake was washed with ethyl acetate (23.8 mL, 0.5V), and then dried to obtain a pale yellow solid 1 (254.18 g, 1.88 mol, 90.0%). HPLC purity = 98.20%.

[0073] Experimental Example 1

[0074] Optimization of Reaction Conditions for Clauson-Kaas Pyrrole Synthesis a

[0075]

[0076] Table 1

[0077]

[0078] a Reaction conditions: Boc-hydrazine (13.2 g, 0.1 mol, 1.0 eq.), compound 6 (14.5 g, 0.11 mol, 1.1 eq.), acid (0.025 - 6.5 equiv.) and solvent (79.2 mL, 6V) were mixed and stirred at 90 - 110 °C for 6 - 30 h. b Oil bath. c Isolated yield obtained by crystallization. dDifficult to purify.

[0079] The results showed that when acetic acid was used as the acidic catalyst, the reaction conversion was slow and the time was long, resulting in the generation of more large-polarity impurities and difficult separation of the product (Table 1, entry 1). While using p-toluenesulfonic acid with stronger acidity, compound 7 could be obtained in moderate yield, but it was necessary to remove the residual p-toluenesulfonic acid through extraction and washing operations, and quickly remove the larger-polarity impurities by silica gel column chromatography. The complexity of the post-treatment led to poor process continuity, and the unstable product quality affected the conversion rate of the next reaction (Table 1, entry 2). When different concentrations of hydrochloric acid were used (Table 1, entries 3, 4, 5), it was found that a catalytic amount of hydrochloric acid could promote the reaction to proceed completely, and as the concentration of hydrochloric acid increased, the reaction time was significantly shortened and the yield was also improved to a certain extent.

[0080] Test Example 2

[0081] Optimization of the One-Step Formamidation Reaction Conditions Mediated by Chlorosulfonyl Isocyanate (CSI) a

[0082]

[0083] Table 2

[0084]

[0085] a Reaction conditions: At 0 °C or -25 °C, compound 7 (18.2 g, 0.1 mol, 1.0 eq.), CSI (1.0 equiv.) and solvent (145.6 mL, 8V) were mixed, and then a 10% alkaline solution was added dropwise at the corresponding temperature to adjust the pH value of the reaction system to 8-9. After the addition was completed, the temperature was naturally raised to 0 °C or 20-25 °C, and stirring was continued for 1-24 h. b The isolated yield obtained by crystallization.

[0086] The results showed that at -25 °C, chlorosulfonyl isocyanate (CSI) was added dropwise to the acetonitrile solution of compound 7, and 10% aqueous sodium carbonate solution was added dropwise at this temperature. Then it was naturally warmed to 0 °C and hydrolyzed for 24 h to obtain compound 9 in a yield of 48.5% (Table 2, entry 1). When adding dropwise chlorosulfonyl isocyanate (CSI) and subsequent hydrolysis reaction were carried out at 0 °C (ice-water bath), a significant increase in the yield of compound 9 was found (Table 2, entry 2). Although there was a fluctuation of about 5 °C in the reaction temperature during the addition of CSI, it did not affect the product yield, indicating that the addition reaction of compound 7 and CSI could occur smoothly at 0 °C. Further findings showed that the hydrolysis temperature and basic strength of the sulfonamide bond in intermediate 9' affected the yield of compound 9. When adding dropwise chlorosulfonyl isocyanate (CSI) at 0 °C (ice-water bath), adjusting the pH value of the system to 8 - 9 with the alkali solution, and naturally warming to 20 - 25 °C, sodium hydroxide and potassium hydroxide could efficiently hydrolyze into compound 9 (Table 2, entry 3, 4, 5).

[0087] Test Example 3

[0088] Optimization of Deprotection Reaction and Cyclization Reaction Conditions a

[0089]

[0090] In the patent report of BioCryst, trifluoroacetic acid was used to remove the Boc protecting group. Our small-scale experiment found that this method caused compound 1 to show dark brown color and was difficult to decolorize, seriously affecting the appearance of the product. The research found that by using a solution of hydrogen chloride in organic solvents (such as ethyl acetate, methanol, 1,4-dioxane) for deprotection, after the reaction ended, it was directly filtered and separated, and compound 11 could be obtained in the yield of a quantitative reaction. After the cyclization reaction ended, simple decolorization treatment was carried out with activated carbon, and then purified by slurrying with ethyl acetate to obtain a pale yellow solid, effectively improving the appearance of compound 1.

[0091] Table 3

[0092]

[0093] a Reaction conditions: Compound 11 (16.1 g, 0.1 mol, 1.0 eq.), HC(OMe)3 (2.0 - 30.0 equiv.), NaHCO3 (1.2 eq.) or Na2CO3 (0.6 eq.) and solvent (32.2 mL, 3V) were mixed and reacted at 70 - 79 °C. b Solvent-free reaction. c Oil bath. d Purified by slurrying with ethyl acetate. e No reaction occurred.

[0094] The results showed that the usage amount of trimethyl orthoformate was optimized, reduced from 30.0 eq. reported in the literature to 3.0 eq., and by adding sodium bicarbonate or sodium carbonate, the reaction time was greatly shortened and the synthesis efficiency was improved.

[0095] Although the present invention has been described in detail with general descriptions and specific examples above, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of the present invention claimed.

Claims

1. A method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, characterized in that, Using 2,5-dimethoxytetrahydrofuran and tert-butoxycarbonylhydrazine as starting materials, the Clauson-Kaas pyrrole synthesis reaction, formamidation reaction, deprotection reaction and cyclization reaction are carried out in sequence to obtain pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, that is, compound 1. The synthesis route is as follows:

2. The synthesis method of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 1, characterized in that, The Clauson-Kaas pyrrole synthesis reaction is carried out in the presence of a solvent and a catalyst; Or, the solvent is tetrahydrofuran or 1,4-dioxane; Or, the catalyst is hydrochloric acid with a concentration of 6M to 12M; Or, the molar ratio of 2,5-dimethoxytetrahydrofuran, tert-butoxycarbonylhydrazine to hydrogen chloride is 1.0 to 1.3:1.0:0.06 to 0.03; The temperature of the Clauson-Kaas pyrrole synthesis reaction is 80 to 100 °C.

3. The synthesis method of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 2, characterized in that, The solvent is 1,4-dioxane and the catalyst is hydrochloric acid with a concentration of 10M to 12M.

4. The method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 1, wherein, The formamidation reaction includes: at -25 to 5 °C, mixing compound 7, isocyanatochlorosulfate and a solvent, adding an alkali solution to adjust the pH of the system to 8 to 9, and after adding, naturally warming up to 0 to 25 °C; Or, the solvent is acetonitrile or tetrahydrofuran; Or, the alkali solution is an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution with a mass concentration of 10% to 50%, and the molar amount of sodium hydroxide or potassium hydroxide is 3.5 to 4.0 times that of compound 7; Or, the molar ratio of compound 7 to isocyanatochlorosulfate is 1.0:1.0 to 1.

2.

5. The method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 4, characterized in that The formamidation reaction includes: at -5 to 5 °C, mixing compound 7, isocyanatochlorosulfate and a solvent, controlling the temperature not exceeding 5 °C, adding an alkali to adjust the pH of the system to 8 to 9, controlling the temperature not exceeding 10 °C, and after adding, naturally warming up to 20 to 25 °C.

6. The method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 1, characterized in that, The deprotection reaction is carried out in the presence of an acid solution and a solvent; Or, the acid solution includes ethyl acetate solution of hydrogen chloride, methanol solution of hydrogen chloride or 1,4-dioxane solution of hydrogen chloride; Or, the solvent is selected from any one or more of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran; Or, the molar ratio of compound 9 to hydrogen chloride is 1.0:2.0 to 4.0; Or, the temperature of the deprotection reaction is below 25 °C.

7. The synthesis method of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 1, characterized in that, The cyclization reaction is carried out in the presence of a cyclization reagent, a base and a solvent; Or, the cyclization reagent is trimethyl orthoformate or triethyl orthoformate; Or, the base is sodium carbonate or sodium bicarbonate; Or, the solvent is methanol or ethanol; Or, the molar ratio of compound 9, the base to the cyclization reagent is 1.0:0.5 to 1.0:3.0 to 8.0; Or, the temperature of the cyclization reaction is 60 to 85 °C.

8. The method for synthesizing pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one according to claim 7, characterized in that, The base is sodium carbonate.

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