Synthesis process of anti-herpes virus medicine

Abstract

The invention relates to a synthesis process of an anti-herpes virus drug. The invention relates to a synthesis process of an antiviral drug Priteelivir. According to the synthesis process disclosed by the invention, cheap commercial raw materials N-methylthiourea and chloroacetone are used as initial raw materials, and the target product Priteelivir is synthesized through four chemical reactions, namely heterocyclic ring formation, amide condensation, sulfonylation reaction and reductive amination reaction. The method simplifies synthesis steps, is excellent in overall yield, has the advantages of simple operation process and cheap purification, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and relates to a synthesis process of an anti-herpes virus drug. Specifically, it relates to a synthesis process of an anti-herpes virus drug, Pritelivir. Background Art

[0002] Pritelivir is a novel and highly active small molecule inhibitor of herpes simplex virus (HSV). It is an innovative anti-herpes virus drug developed by Bayer AG and is currently in the clinical phase 3 research stage. Pritelivir is active against both HSV-1 and HSV-2, and is also active against viruses that have developed resistance to commercially available drugs. Pritelivir can be used to treat adult patients with mucocutaneous HSV infections who are immunocompromised and resistant to acyclovir (a nucleoside analogue). Pritelivir has a different antiviral mechanism of action compared to the nucleoside analogue acyclovir. Nucleoside analogues terminate ongoing DNA strand elongation by inhibiting viral DNA polymerase, while Pritelivir blocks de novo synthesis of viral DNA by inhibiting the helicase-primase complex. In addition, it does not need to be activated by viral thymidine kinase in HSV-infected cells, so it also has a protective effect on uninfected cells. Pritelivir has a powerful antiviral effect that can overcome drug resistance and has the potential to treat life-threatening HSV-1 and HSV-2 infections, including herpes simplex encephalitis. The chemical structural formula of Pritelivir is shown in Formula I:

[0003]

[0004] However, the current synthesis process for the anti-herpes virus drug Pritelivir still needs to be improved. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems in the related art to some extent. For this purpose, an object of the present invention is to provide a synthesis process of an anti-herpes virus drug, Pritelivir. Compared with the prior art, the synthesis process of the present invention uses commercially available inexpensive starting materials, the compound shown in Formula 1 (N-methylthiourea) and the compound shown in Formula 2 (chloroacetone), as starting materials, and synthesizes the target product Pritelivir through four chemical reactions, namely, heterocyclic formation, amide condensation, sulfonylation reaction, and reductive amination reaction.

[0006] In one aspect of the present invention, the present invention provides a synthesis process of an anti-herpes virus drug, Pritelivir. According to an embodiment of the present invention, the synthesis process includes:

[0007] (1) Contact the compound shown in Formula 1 with the compound shown in Formula 2 and pyridine to obtain the compound shown in Formula 3;

[0008] (2) Contact the compound shown in Formula 3 with the compound shown in Formula 4, a condensing agent, and an organic base to obtain the compound shown in Formula 5;

[0009] (3) Contact the compound shown in Formula 5 with thionyl chloride and chlorosulfonic acid to obtain the compound shown in Formula 6;

[0010] (4) Contact the compound shown in Formula 6 with an ammonia-methanol solution to obtain the compound Pritelivir shown in Formula I,

[0011]

[0012] The condensing agent in the present invention is any one selected from HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-hydroxybenzotriazole), or DCC (1,3-dicyclohexylcarbodiimide);

[0013] The organic base is any one selected from Et3N, DIPEA (N,N-diisopropylethylamine), DBU (dicycloimidazole, or 1,8-diazabicyclo(5,4,0)-7-undecene), or DMAP (4-dimethylaminopyridine).

[0014] The inventors found that by using the synthesis process described in the present invention, starting from the compound shown in Formula 1 (N-methylthiourea) and the compound shown in Formula 2 (chloroacetone), after a total of 4 steps of reactions, the compound Pritelivir shown in Formula I can be successfully synthesized and prepared.

[0015] The term "contact" used herein should be understood in a broad sense, which can be any way that enables at least two reactants to undergo a chemical reaction, for example, it can be mixing the two reactants under appropriate conditions. According to need, the reactants to be contacted can be mixed under stirring. Thus, the type of stirring is not particularly limited, for example, it can be mechanical stirring, that is, stirring under the action of mechanical force.

[0016] In this article, the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, "a plurality" means two or more, unless otherwise clearly and specifically defined.

[0017] According to an embodiment of the present invention, the method for preparing the compound shown in Formula 3, the compound shown in Formula 5, the compound shown in Formula 6, and the compound shown in Formula I may further have at least one of the following additional technical features:

[0018] According to an embodiment of the present invention, the chemical reaction described in the present invention can be carried out according to any method known in the art. The sources of the raw materials of the compound shown in Formula 3, the compound shown in Formula 5, the compound shown in Formula 6, and the compound shown in Formula I are not particularly limited, and they can be prepared by any known method or obtained commercially. For example, the CAS of the compound shown in Formula 1 is: 598-52-7, and the CAS of the compound shown in Formula 2 is: 78-95-5.

[0019] According to an embodiment of the present invention, in step (1), the contact mode of the compound shown in Formula 1 with the compound shown in Formula 2 and pyridine is not particularly limited. Thereby, the efficiency of the contact reaction of the compound shown in Formula 1 with the compound shown in Formula 2 and pyridine can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 3 by this method can be further improved.

[0020] According to an embodiment of the present invention, in step (1), the following steps are included: placing the compound shown in Formula 1 and the compound shown in Formula 2 in a reaction flask, adding an appropriate amount of methanol to dissolve, cooling to about 0 °C, slowly dropping pyridine, after dropping, slowly heating the reaction solution to 40 °C, continuing to stir and react for 6 to 7 hours, then cooling to 0 °C and continuing to stir for 2 to 3 hours, filtering the reaction solution, washing the solid with cold ethanol, and drying under reduced pressure to obtain the compound shown in Formula 3. Thereby, the efficiency of the contact reaction of the compound shown in Formula 1 with the compound shown in Formula 2 and pyridine can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 3 by this method can be further improved.

[0021] According to an embodiment of the present invention, in step (1), the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 and pyridine is (1.0 to 1.2):1:(1.0 to 1.2), and preferably the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 and pyridine is 1.05:1:1.05. Thereby, the efficiency of preparing the compound shown in Formula 3 by this method can be further improved.

[0022] According to an embodiment of the present invention, preferably in step (1), the reaction solution is slowly heated to 40 °C, and continues to stir and react for 6.5 hours, then cools to 0 °C and continues to stir for 2.5 hours.

[0023] According to a specific embodiment of the present invention, in step (1), the following steps are included: Place the compound shown in Formula 1 (9.46 g, 105.0 mmol) and the compound shown in Formula 2 (9.25 g, 100.0 mmol) in a reaction flask, add an appropriate amount of methanol (100 mL) to dissolve, cool down to about 0 °C, slowly dropwise add pyridine (8.31 g, 105.0 mmol). After the addition is complete, slowly warm up the reaction solution to 40 °C, continue stirring and reacting for 6.5 hours, then cool down to 0 °C and continue stirring for 2.5 h. Filter the reaction solution, wash the solid with cold ethanol (0 °C, 50 mL), and then dry it under reduced pressure to obtain the compound shown in Formula 3, with a yield of 10.60 g and a yield of 82.7%.

[0024] According to an embodiment of the present invention, in step (2), the contact manner of the compound shown in Formula 3 with the compound shown in Formula 4, the condensing agent, and the organic base is not particularly limited. Thereby, the efficiency of the contact reaction of the compound shown in Formula 3 with the compound shown in Formula 4, the condensing agent, and the organic base can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 5 by this method can be further improved.

[0025] According to an embodiment of the present invention, in step (2), the following steps are included: Under N2 protection at room temperature, in a reaction vessel, dissolve the compound shown in Formula 3 and the compound shown in Formula 4 in DMF, add a condensing agent and an organic base, then warm up the reaction solution to 30 °C, continue stirring and reacting for 9 - 12 hours. The reaction solution is concentrated under vacuum, and water is added dropwise to precipitate a solid. After the precipitated solid is filtered and collected, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate for 0.5 hour, and the solid obtained by filtration is then dried under vacuum to obtain the compound shown in Formula 5. Thereby, the efficiency of the contact reaction of the compound shown in Formula 3 with the compound shown in Formula 4, the condensing agent, and the organic base can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 5 by this method can be further improved.

[0026] According to an embodiment of the present invention, in step (2), the condensing agent is any one selected from HATU, HOBt, or DCC, and preferably the condensing agent is selected from HATU.

[0027] According to an embodiment of the present invention, in step (2), the organic base is any one selected from Et3N, DIPEA, DBU, or DMAP, and preferably the condensing agent is selected from Et3N or DIPEA.

[0028] According to an embodiment of the present invention, in step (2), the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, the condensing agent, and the organic base is 1:(1.0 - 1.2):(1.5 - 2.5):(1.5 - 3.0), and preferably the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, the condensing agent, and the organic base is 1:1.05:2.0:2.0. Thereby, the efficiency of preparing the compound shown in Formula 5 by this method can be further improved.

[0029] According to a specific embodiment of the present invention, in step (2), preferably the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, HATU, and Et3N is 1:1.05:2.0:2.0.

[0030] According to a specific embodiment of the present invention, in step (2), preferably the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, HATU, and DIPEA is 1:1.05:2.0:2.0.

[0031] According to an embodiment of the present invention, in step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (4 - 6):1, and preferably the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 5:1.

[0032] According to an embodiment of the present invention, in step (2), preferably the reaction is stirred for 10 hours.

[0033] According to a specific embodiment of the present invention, in step (2), the following steps are included: at room temperature, under N2 protection, in a reaction vessel, dissolve the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (22.39 g, 0.105 mol) in DMF (200 mL), add HATU (76.05 g, 0.2 mol) and Et3N (20.24 g, 0.2 mol), then raise the temperature of the reaction solution to 30 °C, continue stirring for 10 hours, concentrate the reaction solution under vacuum (remaining about 40 mL), dropwise add water (80 mL) to precipitate the solid, after filtering and collecting the precipitated solid, purify it by pulping with a petroleum ether / ethyl acetate mixed solvent (80 mL, the volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour, and then vacuum dry the filtered solid to obtain the compound shown in Formula 5, with a yield of 24.19 g and a yield of 74.8%.

[0034] According to an embodiment of the present invention, in step (3), the contact mode of the compound shown in Formula 5 with thionyl chloride (sulfur oxychloride) and chlorosulfonic acid is not particularly limited. Thereby, the efficiency of the contact reaction of the compound shown in Formula 5 with thionyl chloride and chlorosulfonic acid can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 6 by this method can be further improved.

[0035] According to an embodiment of the present invention, in step (3), the following steps are included: at room temperature, the compound shown in formula 5 is slowly added to a mixed solution containing thionyl chloride and chlorosulfonic acid, and the reaction solution is heated to reflux for 45 to 52 hours. After the reaction solution is naturally cooled to room temperature, it is poured into rapidly stirred ice water, and solid sodium carbonate is slowly added to adjust the pH of the solution to about 8. Dichloromethane is added for extraction, and after combining the organic phases, saturated brine is added for washing, followed by drying with sodium sulfate and concentration to obtain the compound shown in formula 6. Thereby, the efficiency of the contact reaction between the compound shown in formula 5 and thionyl chloride and chlorosulfonic acid can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in formula 6 by this method can be further increased.

[0036] According to an embodiment of the present invention, in step (3), the molar ratio of the compound shown in formula 5 to thionyl chloride and chlorosulfonic acid is 1:(2.0 - 3.0):(4.0 - 6.0), and preferably the molar ratio of the compound shown in formula 5 to thionyl chloride and chlorosulfonic acid is 1:2.5:5.0. Thereby, the efficiency of preparing the compound shown in formula 6 by this method can be further increased.

[0037] According to an embodiment of the present invention, in step (3), it is preferred to reflux for 48 hours.

[0038] According to a specific embodiment of the present invention, in step (3), the following steps are included: at room temperature, the compound shown in formula 5 (32.34 g, 0.1 mol) is slowly added to a mixed solution containing thionyl chloride (29.74 g, 0.25 mol) and chlorosulfonic acid (58.27 g, 0.5 mol), and the reaction solution is heated to reflux for 48 hours. After the reaction solution is naturally cooled to room temperature, it is poured into 800 mL of rapidly stirred ice water, and solid sodium carbonate is slowly added to adjust the pH of the solution to about 8. Dichloromethane (400×3 mL) is added for extraction, and after combining the organic phases, saturated brine (600 mL) is added for washing, followed by drying with sodium sulfate and concentration to obtain the compound shown in formula 6, with a yield of 35.61 g and a yield of 84.4%.

[0039] According to an embodiment of the present invention, in step (4), the contact mode between the compound shown in formula 6 and ammonia methanol is not particularly limited. Thereby, the efficiency of the contact reaction between the compound shown in formula 6 and ammonia methanol can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in formula I by this method can be further increased.

[0040] According to an embodiment of the present invention, in step (4), the following steps are included: at -10°C, a 7M ammonia methanol solution is added dropwise to a pressure-resistant bottle containing the compound shown in Formula 6 dissolved in tetrahydrofuran. The reaction solution is slowly heated to 0°C and stirred for another 2 hours. The reaction solution is concentrated under reduced pressure. After collecting the residue, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate for 0.5 hours. The solid obtained by filtration is then dried under vacuum to obtain the compound shown in Formula I. Thereby, the efficiency of the contact reaction between the compound shown in Formula 6 and ammonia methanol can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula I by this method can be further improved.

[0041] According to an embodiment of the present invention, in step (4), the molar ratio of the compound shown in Formula 6 to ammonia methanol is 1:2.0. Thereby, the efficiency of preparing the compound shown in Formula I by this method can be further improved.

[0042] According to a specific embodiment of the present invention, in step (4), the following steps are included: at -10°C, a 7M ammonia methanol solution (5.4 mL, 37.92 mmol) is added dropwise to a pressure-resistant bottle containing the compound shown in Formula 6 (8.0 g, 18.96 mmol) dissolved in tetrahydrofuran (40 mL). The reaction solution is slowly heated to 0°C and stirred for another 2 hours. The reaction solution is concentrated under reduced pressure. After collecting the residue, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (30 mL, the volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hours. The solid obtained by filtration is then dried under vacuum to obtain the compound shown in Formula I, with a yield of 6.77 g and a yield rate of 88.7%. Determination: purity 99.6% (HPLC).

[0043] According to a specific embodiment of the present invention, the synthetic route of the compound Pritelivir shown in Formula I can be as follows:

[0044]

[0045] Compared with the prior art, the synthetic process of Pritelivir described in the present invention has at least the following beneficial effects:

[0046] 1. Compared with the prior art, the synthetic process of the present invention uses commercially available and inexpensive raw materials, the compound shown in Formula 1 (N-methylthiourea) and the compound shown in Formula 2 (chloroacetone), as starting materials, and synthesizes the target product Pritelivir through four chemical reactions, namely heterocyclic formation, amide condensation, sulfonylation reaction, and reductive amination reaction.

[0047] 2. Compared with the prior art methods, the significant advantages of the present invention are as follows: (1) In step 1 of the present invention, the synthesis of substituted amino heterocycles provides direct raw materials for subsequent amide condensation reactions. Compared with the prior art US2004 / 0006076 A1 which needs to first construct halogenated heterocycles and then convert them into substituted amino groups, step 1 of the present invention not only shortens one reaction step but also reduces possible reaction sites (sulfonamide groups), improves the reaction yield, and lays a foundation for subsequent purification (pulping). (2) In step 4 of the present invention, ammonia methanol is used as a reaction reagent. Compared with ammonia water, this method not only has excellent yield but also simplifies the post-treatment (avoiding the steps of adding organic solvents for extraction that may be required when using ammonia water). In summary, this method simplifies the synthesis steps and has an excellent overall yield. Using pulping purification as a purification means has the advantages of simple operation process and low purification cost, and is suitable for large-scale industrial production. Detailed Description of the Invention

[0048] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as a limitation of the present invention. For those not specified in the embodiments regarding specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0049] Synthesis of the compound shown in Formula 3 in Example 1

[0050] The compound shown in Formula 1 (9.46 g, 105.0 mmol) and the compound shown in Formula 2 (9.25 g, 100.0 mmol) were placed in a reaction flask, dissolved in an appropriate amount of methanol (100 mL), cooled to about 0 °C, and pyridine (8.31 g, 105.0 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to 40 °C and stirred for 6.5 hours, then cooled to 0 °C and stirred for another 2.5 h. The reaction solution was filtered, and the solid was washed with cold ethanol (0 °C, 50 mL) and dried under reduced pressure to obtain the compound shown in Formula 3, with a yield of 10.60 g and a yield of 82.7%.

[0051] LC-MS (APCI): m / z = 129.0 (M + 1) + .

[0052] Synthesis of the compound shown in Formula 3 in Example 2

[0053] Place the compound shown in Formula 1 (9.01 g, 100.0 mmol) and the compound shown in Formula 2 (9.25 g, 100.0 mmol) in a reaction flask, add an appropriate amount of methanol (100 mL) to dissolve, cool down to about 0 °C, slowly add dropwise pyridine (7.91 g, 100.0 mmol). After the addition is complete, slowly warm the reaction solution to 40 °C, continue stirring and reacting for 6 hours, then cool to 0 °C and continue stirring for 2 h. Filter the reaction solution, wash the solid with cold ethanol (0 °C, 50 mL), and then dry it under reduced pressure to obtain the compound shown in Formula 3, with a yield of 10.45 g and a yield of 81.5%.

[0054] Synthesis of the compound shown in Formula 3 in Example 3

[0055] Place the compound shown in Formula 1 (10.82 g, 120.0 mmol) and the compound shown in Formula 2 (9.25 g, 100.0 mmol) in a reaction flask, add an appropriate amount of methanol (100 mL) to dissolve, cool down to about 0 °C, slowly add dropwise pyridine (9.49 g, 120.0 mmol). After the addition is complete, slowly warm the reaction solution to 40 °C, continue stirring and reacting for 7 hours, then cool to 0 °C and continue stirring for 3 h. Filter the reaction solution, wash the solid with cold ethanol (0 °C, 50 mL), and then dry it under reduced pressure to obtain the compound shown in Formula 3, with a yield of 10.58 g and a yield of 82.5%.

[0056] Synthesis of the compound shown in Formula 5 in Example 4

[0057] Under N2 protection at room temperature, in a reaction vessel, dissolve the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (22.39 g, 0.105 mol) in DMF (200 mL), add HATU (76.05 g, 0.2 mol) and Et3N (20.24 g, 0.2 mol), then warm the reaction solution to 30 °C and continue stirring for 10 hours. The reaction solution is concentrated under vacuum (remaining about 40 mL), and water (80 mL) is added dropwise to precipitate a solid. The precipitated solid is collected by filtration, slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (8 mL, volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour, and the solid obtained by filtration is then dried under vacuum to obtain the compound shown in Formula 5, with a yield of 24.19 g and a yield of 74.8%.

[0058] LC-MS (APCI): m / z = 324.1 (M + 1) + 。

[0059] Synthesis of the compound shown in Formula 5 in Example 5

[0060] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (21.32 g, 0.1 mol) were dissolved in DMF (200 mL), HATU (57.04 g, 0.15 mol) and Et3N (15.18 g, 0.15 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 9 hours. The reaction solution was concentrated under vacuum (remaining about 40 mL), water (80 mL) was added dropwise to precipitate a solid. After the precipitated solid was collected by filtration, it was purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (80 mL, the volume ratio of petroleum ether to ethyl acetate was 4:1) for 0.5 hours. The solid obtained by filtration was then dried under vacuum to obtain the compound shown in Formula 5, with a yield of 23.87 g and a yield of 73.8%.

[0061] Synthesis of the compound shown in Formula 5 in Example 6

[0062] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.12 mol) and the compound shown in Formula 4 (25.59 g, 0.12 mol) were dissolved in DMF (240 mL), HATU (95.06 g, 0.25 mol) and Et3N (30.36 g, 0.3 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 12 hours. The reaction solution was concentrated under vacuum (remaining about 40 mL), water (80 mL) was added dropwise to precipitate a solid. After the precipitated solid was collected by filtration, it was purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (80 mL, the volume ratio of petroleum ether to ethyl acetate was 6:1) for 0.5 hours. The solid obtained by filtration was then dried under vacuum to obtain the compound shown in Formula 5, with a yield of 24.13 g and a yield of 74.6%.

[0063] Synthesis of the compound shown in Formula 5 in Example 7

[0064] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (22.39 g, 0.105 mol) were dissolved in DMF (200 mL), HATU (76.05 g, 0.2 mol) and DIPEA (25.85 g, 0.2 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 10 hours. The reaction solution was concentrated under vacuum (remaining about 40 mL), water (80 mL) was added dropwise to precipitate a solid. After the precipitated solid was collected by filtration, it was purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (80 mL, the volume ratio of petroleum ether to ethyl acetate was 5:1) for 0.5 hours. The solid obtained by filtration was then dried under vacuum to obtain the compound shown in Formula 5, with a yield of 24.09 g and a yield of 74.5%.

[0065] Synthesis of the compound shown in Formula 5 of Example 8

[0066] Under nitrogen protection at room temperature, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (22.39 g, 0.105 mol) were dissolved in DMF (200 mL), HOBt (27.02 g, 0.2 mol) and DIPEA (25.85 g, 0.2 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 10 hours. The reaction solution was concentrated in vacuo (remaining about 40 mL), water (80 mL) was added dropwise to precipitate a solid. After the precipitated solid was collected by filtration, it was slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (80 mL, volume ratio of petroleum ether to ethyl acetate was 5:1) for 0.5 hour. The solid obtained by filtration was then dried in vacuo to obtain the compound shown in Formula 5, with a yield of 24.00 g and a yield of 74.2%.

[0067] Synthesis of the compound shown in Formula 5 of Example 9

[0068] Under nitrogen protection at room temperature, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (22.39 g, 0.105 mol) were dissolved in DMF (200 mL), HOBt (27.02 g, 0.2 mol) and DBU (30.45 g, 0.2 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 10 hours. The reaction solution was concentrated in vacuo (remaining about 40 mL), water (80 mL) was added dropwise to precipitate a solid. After the precipitated solid was collected by filtration, it was slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (80 mL, volume ratio of petroleum ether to ethyl acetate was 5:1) for 0.5 hour. The solid obtained by filtration was then dried in vacuo to obtain the compound shown in Formula 5, with a yield of 23.93 g and a yield of 74.0%.

[0069] Synthesis of the compound shown in Formula 5 of Example 10

[0070] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (22.39 g, 0.105 mol) were dissolved in DMF (200 mL), DCC (41.27 g, 0.2 mol) and DMAP (24.43 g, 0.2 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 10 hours. The reaction solution was concentrated under vacuum (remaining about 40 mL), water (80 mL) was added dropwise to precipitate the solid. After the precipitated solid was collected by filtration, it was purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (80 mL, the volume ratio of petroleum ether to ethyl acetate was 5:1) for 0.5 hour. The solid obtained by filtration was then dried under vacuum to obtain the compound shown in Formula 5, with a yield of 23.96 g and a yield of 74.1%.

[0071] Synthesis of the compound shown in Formula 5 in Comparative Example 1

[0072] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 3 (12.82 g, 0.1 mol) and the compound shown in Formula 4 (26.66 g, 0.125 mol) were dissolved in DMF (280 mL), HATU (106.47 g, 0.28 mol) and Et3N (32.38 g, 0.32 mol) were added, then the reaction solution was heated to 30 °C and stirred continuously for 12 hours. The reaction solution was concentrated under vacuum (remaining about 40 mL), water (80 mL) was added dropwise to precipitate the solid. After the precipitated solid was collected by filtration, it was purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (80 mL, the volume ratio of petroleum ether to ethyl acetate was 5:1) for 0.5 hour. The solid obtained by filtration was then dried under vacuum to obtain the compound shown in Formula I, with a yield of 24.08 g and a yield of 74.5%.

[0073] It can be seen that when the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, HATU, and Et3N was changed to 1:1.25:2.8:3.2 and stirred and reacted for 12 hours, the efficiency (yield) of preparing the compound shown in Formula 5 was not further improved.

[0074] Synthesis of the compound shown in Formula 6 in Example 11

[0075] At room temperature, the compound shown in Formula 5 (32.34 g, 0.1 mol) was slowly added to a mixed solution containing thionyl chloride (29.74 g, 0.25 mol) and chlorosulfonic acid (58.27 g, 0.5 mol). The reaction solution was heated under reflux for 48 hours. After the reaction solution was naturally cooled to room temperature, it was poured into 800 mL of ice water under rapid stirring. Solid sodium carbonate was slowly added to adjust the pH of the solution to about 8. Dichloromethane (400×3 mL) was added for extraction. After combining the organic phases, saturated brine (600 mL) was added for washing. It was dried over sodium sulfate and concentrated to obtain the compound shown in Formula 6, with a yield of 35.61 g and a yield of 84.4%.

[0076] LC-MS(APCI): m / z = 422.1 (M+1) + 。

[0077] Example 12 Synthesis of the compound shown in Formula 6

[0078] At room temperature, the compound shown in Formula 5 (32.34 g, 0.1 mol) was slowly added to a mixed solution containing thionyl chloride (23.79 g, 0.2 mol) and chlorosulfonic acid (46.62 g, 0.4 mol). The reaction solution was heated under reflux for 45 hours. After the reaction solution was naturally cooled to room temperature, it was poured into 800 mL of ice water under rapid stirring. Solid sodium carbonate was slowly added to adjust the pH of the solution to about 8. Dichloromethane (400×3 mL) was added for extraction. After combining the organic phases, saturated brine (600 mL) was added for washing. It was dried over sodium sulfate and concentrated to obtain the compound shown in Formula 6, with a yield of 34.89 g and a yield of 82.7%.

[0079] Example 13 Synthesis of the compound shown in Formula 6

[0080] At room temperature, the compound shown in Formula 5 (32.34 g, 0.1 mol) was slowly added to a mixed solution containing thionyl chloride (35.69 g, 0.3 mol) and chlorosulfonic acid (69.92 g, 0.6 mol). The reaction solution was heated under reflux for 52 hours. After the reaction solution was naturally cooled to room temperature, it was poured into 800 mL of ice water under rapid stirring. Solid sodium carbonate was slowly added to adjust the pH of the solution to about 8. Dichloromethane (400×3 mL) was added for extraction. After combining the organic phases, saturated brine (600 mL) was added for washing. It was dried over sodium sulfate and concentrated to obtain the compound shown in Formula 6, with a yield of 35.52 g and a yield of 84.2%.

[0081] Example 14 Preparation of the compound Pritelivir shown in Formula I

[0082] At -10 °C, 7M ammonia methanol solution (5.4 mL, 37.92 mmol) was added dropwise to a pressure-resistant flask containing the compound shown in Formula 6 (8.0 g, 18.96 mmol) dissolved in tetrahydrofuran (40 mL). The reaction solution was slowly warmed to 0 °C and stirred for an additional 2 hours. The reaction solution was concentrated under reduced pressure. After collecting the residue, it was triturated and purified with a mixed solvent of petroleum ether / ethyl acetate (30 mL, volume ratio of petroleum ether to ethyl acetate was 5:1) for 0.5 hours. The solid obtained by filtration was then dried under vacuum to obtain the compound shown in Formula I, with a yield of 6.77 g and a yield of 88.7%. Determination: purity 99.6% (HPLC).

[0083] LC-MS (APCI): m / z = 403.1 (M+1) + 。

[0084] 1 1H-NMR (400 MHz, DMSO δ / ppm): 2.38 (s, 3H), 3.64 (s, 3H), 4.16 (s, 2H), 7.29 - 7.27 (m, 1H), 7.33 (d, J = 8 Hz, 2H), 7.58 (s, 2H), 7.82 - 7.96 (m, 2H), 7.99 (d, J = 8.0 Hz, 2H), 8.62 (m, 1H).

[0085] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0086] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A synthetic process of Pritelivir, characterized in that, Comprising: (1) Contacting the compound shown in Formula 1 with the compound shown in Formula 2 and pyridine to obtain the compound shown in Formula 3; (2) Contacting the compound shown in Formula 3 with the compound shown in Formula 4, a condensing agent, and an organic base to obtain the compound shown in Formula 5; (3) Contacting the compound shown in Formula 5 with thionyl chloride and chlorosulfonic acid to obtain the compound shown in Formula 6; (4) Contacting the compound shown in Formula 6 with an ammonia methanol solution to obtain the compound Pritelivir shown in Formula I, 2. The method according to claim 1, characterized in that, In step (1), it includes the following steps: placing the compound shown in Formula 1 and the compound shown in Formula 2 in a reaction flask, adding an appropriate amount of methanol to dissolve, cooling to about 0 °C, slowly dropping pyridine, after dropping, slowly warming the reaction solution to 40 °C, continuing to stir and react for 6 - 7 hours, then cooling to 0 °C and continuing to stir for 2 - 3 hours, filtering the reaction solution, washing the solid with cold ethanol and drying under reduced pressure to obtain the compound shown in Formula 3.

3. The method according to claim 2, wherein In step (1), the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 and pyridine is (1.0 - 1.2):1:(1.0 - 1.2), preferably the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 and pyridine is 1.05:1:1.05; Optionally, in step (1), preferably the reaction solution is slowly warmed to 40 °C, continuing to stir and react for 6.5 hours, then cooling to 0 °C and continuing to stir for 2.5 hours.

4. The method according to claim 1, wherein In step (2), it includes the following steps: under N2 protection at room temperature, in a reaction vessel, dissolving the compound shown in Formula 3 and the compound shown in Formula 4 in DMF, adding a condensing agent and an organic base, then warming the reaction solution to 30 °C, continuing to stir and react for 9 - 12 hours, concentrating the reaction solution under vacuum, slowly adding water dropwise to precipitate a solid, filtering and collecting the precipitated solid, slurrying and purifying with a mixed solvent of petroleum ether / ethyl acetate for 0.5 hour, and drying the filtered solid under vacuum to obtain the compound shown in Formula 5.

5. The method according to claim 1 or claim 4, characterized in that, The condensing agent is any one selected from HATU, HOBt, or DCC, preferably the condensing agent is selected from HATU; Optionally, the organic base is any one selected from Et3N, DIPEA, DBU, or DMAP, preferably the organic base is selected from Et3N or DIPEA.

6. The method according to claim 4, characterized in that, In step (2), the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, the condensing agent, and the organic base is 1:(1.0 - 1.2):(1.5 - 2.5):(1.5 - 3.0), preferably the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, the condensing agent, and the organic base is 1:1.05:2.0:2.0; Optionally, in step (2), preferably the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, HATU, and Et3N is 1:1.05:2.0:2.0; Or, optionally, in step (2), preferably the molar ratio of the compound shown in Formula 3 to the compound shown in Formula 4, HATU, and DIPEA is 1:1.05:2.0:2.0; Optionally, in step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (4 - 6):1, and preferably the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 5:1; Optionally, in step (2), it is preferred to stir and react for 10 hours.

7. The method according to claim 1, wherein In step (3), the following steps are included: at room temperature, the compound shown in Formula 5 is slowly added to a mixed solution containing thionyl chloride and chlorosulfonic acid, the reaction solution is heated to reflux for 45 - 52 hours, after the reaction solution is naturally cooled to room temperature, it is poured into rapidly stirred ice water, solid sodium carbonate is slowly added to adjust the pH of the solution to about 8, dichloromethane is added for extraction, after combining the organic phases, saturated brine is added for washing, dried over sodium sulfate and concentrated to obtain the compound shown in Formula 6.

8. The method according to claim 7, wherein In step (3), the molar ratio of the compound shown in Formula 5 to thionyl chloride and chlorosulfonic acid is 1:(2.0 - 3.0):(4.0 - 6.0), and preferably the molar ratio of the compound shown in Formula 5 to thionyl chloride and chlorosulfonic acid is 1:2.5:5.0; Optionally, in step (3), it is preferred to reflux and react for 48 hours.

9. The method according to claim 1, wherein In step (3), the following steps are included: at -10°C, a 7M ammonia-methanol solution is added dropwise to a pressure-resistant flask containing the compound shown in Formula 6 dissolved in tetrahydrofuran, the reaction solution is slowly warmed to 0°C and stirred for another 2 hours, the reaction solution is concentrated under reduced pressure, after collecting the residue, it is slurried and purified with a petroleum ether / ethyl acetate mixed solvent for 0.5 hour, the solid obtained by filtration is then dried under vacuum to obtain the compound shown in Formula I; Optionally, in step (4), the molar ratio of the compound shown in Formula 6 to ammonia-methanol is 1:2.

0.

10. The method according to claim 1, characterized in that, In step (1), the following steps are included: The compound shown in Formula 1 (9.46 g, 105.0 mmol) and the compound shown in Formula 2 (9.25 g, 100.0 mmol) are placed in a reaction flask, an appropriate amount of methanol (100 mL) is added for dissolution, the temperature is lowered to about 0°C, pyridine (8.31 g, 105.0 mmol) is slowly added dropwise, after the addition is complete, the reaction solution is slowly warmed to 40°C and stirred and reacted for 6.5 hours, then cooled to 0°C and stirred for another 2.5 hours, the reaction solution is filtered, the solid is washed with cold ethanol (0°C, 50 mL) and dried under reduced pressure to obtain the compound shown in Formula 3, with a yield of 10.60 g and a yield of 82.7%; In step (2), the following steps are included: Under N2 protection at room temperature, in a reaction vessel, the compound shown in formula 3 (12.82 g, 0.1 mol) and the compound shown in formula 4 (22.39 g, 0.105 mol) are dissolved in DMF (200 mL), HATU (76.05 g, 0.2 mol) and Et3N (20.24 g, 0.2 mol) are added, then the reaction solution is heated to 30 °C and stirred continuously for 10 hours. The reaction solution is concentrated under vacuum (remaining about 40 mL), water (80 mL) is added dropwise to precipitate the solid. After the precipitated solid is collected by filtration, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (80 mL, volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour. The solid obtained by filtration is then dried under vacuum to obtain the compound shown in formula 5, with a yield of 24.19 g and a yield of 74.8%; In step (3), the following steps are included: At room temperature, the compound shown in formula 5 (32.34 g, 0.1 mol) is slowly added to a mixed solution containing thionyl chloride (29.74 g, 0.25 mol) and chlorosulfonic acid (58.27 g, 0.5 mol). The reaction solution is heated to reflux for 48 hours. After the reaction solution is naturally cooled to room temperature, it is poured into 800 mL of ice water under rapid stirring, solid sodium carbonate is slowly added to adjust the pH of the solution to about 8, extracted with dichloromethane (400×3 mL), the organic phases are combined and washed with saturated brine (600 mL), dried over sodium sulfate and concentrated to obtain the compound shown in formula 6, with a yield of 35.61 g and a yield of 84.4%; In step (4), the following steps are included: At -10 °C, 7M ammonia methanol solution (5.4 mL, 37.92 mmol) is added dropwise to a pressure-resistant flask containing the compound shown in formula 6 (8.0 g, 18.96 mmol) dissolved in tetrahydrofuran (40 mL). The reaction solution is slowly heated to 0 °C and stirred continuously for 2 hours. The reaction solution is concentrated under reduced pressure. After the residue is collected, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (30 mL, volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour. The solid obtained by filtration is then dried under vacuum to obtain the compound shown in formula I, with a yield of 6.77 g and a yield of 88.7%. Determination: Purity 99.6% (HPLC).

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