Preparation method of anti-herpes virus medicine

Abstract

The invention relates to a preparation method of an antiviral drug Priteelivir. According to the preparation method, a cheap commercial raw material compound shown in a formula 1 is adopted, a compound shown in a formula 3 is synthesized by utilizing acrylonitrile to form a heterocyclic ring, an ester group is hydrolyzed in an alkaline environment to obtain a compound shown in a formula 4, and then the compound shown in the formula 4 and a compound shown in a formula 5 are subjected to an amidation reaction to synthesize the target product Priteelivir. The method has the advantages of simplicity in operation, mild reaction conditions, high yield and simplicity and convenience in post-treatment, and is suitable for industrial batch production.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and relates to a preparation method of an anti-herpes virus drug. Specifically, it relates to a preparation method 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), 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 are resistant 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 preparation method 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. To this end, an object of the present invention is to provide a preparation method of an anti-herpes virus drug Pritelivir. Compared with the prior art, the preparation method of the present invention uses inexpensive commercially available raw materials (the compound shown in Formula 1) (the raw material procurement cost is about 3 - 10 yuan / g), uses acrylonitrile to form a heterocycle to synthesize the compound shown in Formula 3, hydrolyzes the ester group in an alkaline environment to obtain the compound shown in Formula 4, and then conducts an amidation reaction with the compound shown in Formula 5 to synthesize the target product Pritelivir.

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

[0007] (1) Contact the compound represented by Formula 1 with the compound represented by Formula 2 to obtain the compound represented by Formula 3;

[0008] (2) Contact the compound represented by Formula 3 with LiOH to obtain the compound represented by Formula 4;

[0009] (3) Contact the compound represented by Formula 4 with the compound represented by Formula 5, a condensing agent, and an organic base to obtain the compound Pritelivir represented by Formula I,

[0010]

[0011] The condensing agent is any one selected from HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-hydroxybenzotriazole), or DCC (1,3-dicyclohexylcarbodiimide);

[0012] 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).

[0013] The inventors found that by using the preparation method of the present invention, starting from the compound represented by Formula 1, the compound represented by Formula 2 (acrylonitrile), methanol, and the compound represented by Formula 5, and going through a total of 3 steps of reactions, the compound Pritelivir represented by Formula I can be successfully synthesized.

[0014] 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. If necessary, 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.

[0015] 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 of" means two or more, unless otherwise specifically defined.

[0016] According to the embodiments of the present invention, the methods for preparing the compound represented by Formula 3, the compound represented by Formula 4, and the compound represented by Formula I may further have at least one of the following additional technical features:

[0017] 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 compounds shown in Formula 3, the compounds shown in Formula 4, and the raw materials of the compounds 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: 5462-71-5, the CAS of the compound shown in Formula 2 is: 107-13-1, and the CAS of the compound shown in Formula 5 is: 348086-68-0.

[0018] According to an embodiment of the present invention, in step (1), the contact mode between the compound shown in Formula 1 and the compound shown in Formula 2 is not particularly limited. Thereby, the efficiency of the contact reaction between the compound shown in Formula 1 and the compound shown in Formula 2 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.

[0019] According to an embodiment of the present invention, in step (1), the following steps are included: at room temperature, in a reaction flask, the compound shown in Formula 1 and the compound shown in Formula 2 are dissolved in methanol, the reaction solution is stirred at room temperature for 2.5 to 4 hours, then heated to 50 °C to 60 °C, and then stirred continuously for 3.5 to 5 hours. The reaction solution is filtered, the filtrate is concentrated under reduced pressure to obtain a solid, and then the solid is dried in vacuo to obtain the compound shown in Formula 3. Thereby, the efficiency of the contact reaction between the compound shown in Formula 1 and the compound shown in Formula 2 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 molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 is 1:(1.2 to 1.8), and preferably the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 is 1:1.5. Thereby, 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 weight-to-volume ratio of the compound shown in Formula 1 to methanol is 1:(8 to 15), and preferably the weight-to-volume ratio of the compound shown in Formula 1 to methanol is 1:10. 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 stirred at room temperature for 3 hours, then heated to 55 °C, and then stirred continuously for 4 hours.

[0023] According to a specific embodiment of the present invention, in step (1), the following steps are included: at room temperature, in a reaction flask, the compound shown in formula 1 (6.0 g, 34.25 mmol) and the compound shown in formula 2 (2.73 g, 51.37 mmol) are dissolved in methanol (60 mL). The reaction solution is stirred at room temperature for 3 hours, then heated to 55 °C and stirred continuously for 4 hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to obtain a solid. Then the solid is dried in vacuo to obtain the compound shown in formula 3, with a yield of 7.30 g and a yield of 93.8%.

[0024] According to the embodiment of the present invention, in step (2), the contact mode between the compound shown in formula 3 and LiOH is not particularly limited. Thereby, the efficiency of the contact reaction between the compound shown in formula 3 and LiOH can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in formula 4 by this method can be further improved.

[0025] According to the embodiment of the present invention, in step (2), the following steps are included: at 0 °C, the compound shown in formula 3 is dissolved in THF, and 2M LiOH solution is added. After the reaction solution is heated to 40 °C, it is kept warm and stirred for 1 hour and 45 minutes to 3 hours. TLC shows that the compound shown in formula 3 has completely reacted. After the reaction solution is cooled to room temperature, ethyl acetate is added for extraction. After liquid separation, an appropriate amount of 2M HCl solution is added to the aqueous phase to adjust the pH to about 5, and then post-treatment is carried out. Finally, it is concentrated under reduced pressure and dried in vacuo to obtain the compound shown in formula 4. Thereby, the efficiency of the contact reaction between the compound shown in formula 3 and LiOH can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in formula 4 by this method can be further improved.

[0026] According to the embodiment of the present invention, in step (2), the molar ratio of the compound shown in formula 3 to LiOH is 1:(1.3 - 2.0), and preferably the molar ratio of the compound shown in formula 3 to LiOH is 1:1.5. Thereby, the efficiency of preparing the compound shown in formula 4 by this method can be further improved.

[0027] According to the embodiment of the present invention, in step (2), the preferred time for keeping warm and stirring the reaction is 2 hours.

[0028] According to a specific embodiment of the present invention, in step (2), the following steps are included: at 0 °C, dissolve the compound shown in formula 3 (60.0 g, 264.0 mmol) in THF (60 mL), add 2 M LiOH solution (198 mL, 396.0 mmol), raise the temperature of the reaction solution to 40 °C and then keep stirring for 2 hours. TLC shows that the compound shown in formula 3 has completely reacted. After the reaction solution is cooled to room temperature, add ethyl acetate (200 mL) for extraction. After liquid separation, adjust the aqueous phase to pH about 5 by adding an appropriate amount of 2 M HCl solution, and extract with ethyl acetate (2 × 400 ml) and dichloromethane (400 ml) respectively. After combining the organic phases, dry over anhydrous Na2SO4, concentrate under reduced pressure and dry in vacuo to obtain the compound shown in formula 4, with a yield of 39.0 g and a yield of 69.3%.

[0029] According to the embodiment of the present invention, in step (3), the contact mode of the compound shown in formula 4 with the compound shown in formula 5, the condensing agent and the organic base is not particularly limited. Thus, the efficiency of the contact reaction of the compound shown in formula 4 with the compound shown in formula 5, 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 I by this method can be further improved.

[0030] According to the embodiment of the present invention, in step (3), the following steps are included: at room temperature, under N2 protection, in a reaction vessel, dissolve the compound shown in formula 4 and the compound shown in formula 5 in DMF, add a condensing agent and an organic base, then raise the temperature of the reaction solution to 30 °C and continue stirring and reacting for 9 to 12 hours. The reaction solution is concentrated in vacuo, water 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 for 0.5 hour, and the solid obtained by filtration is further dried in vacuo to obtain the compound shown in formula I. Thus, the efficiency of the contact reaction of the compound shown in formula 4 with the compound shown in formula 5, 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 I by this method can be further improved.

[0031] According to the embodiment of the present invention, in step (3), the condensing agent is any one selected from HATU, HOBt, or DCC, and preferably the condensing agent is selected from HATU.

[0032] According to the embodiment of the present invention, in step (3), the organic base is any one selected from Et3N, DIPEA, DBU, or DMAP, and preferably the condensing agent is selected from Et3N or DIPEA.

[0033] According to an embodiment of the present invention, in step (3), the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5, the condensing agent, and the organic base is (1.0 - 1.2):1:(1.5 - 2.5):(1.5 - 3.0), and preferably the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5, the condensing agent, and the organic base is 1.05:1:2.0:2.0. Thus, the efficiency of preparing the compound shown in Formula I by this method can be further improved.

[0034] According to a specific embodiment of the present invention, in step (3), preferably the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5, HATU, and Et3N is 1.05:1:2.0:2.0.

[0035] According to a specific embodiment of the present invention, in step (3), preferably the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5, HATU, and DIPEA is 1.05:1:2.0:2.0.

[0036] According to an embodiment of the present invention, in step (3), 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.

[0037] According to an embodiment of the present invention, in step (3), preferably, the reaction is stirred for 10 hours.

[0038] According to a specific embodiment of the present invention, in step (3), the following steps are included: at room temperature, under N2 protection, in a reaction vessel, dissolve the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) in DMF (210 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 60 mL), dropwise add water (120 mL) to precipitate the solid, after filtering and collecting the precipitated solid, purify it by slurrying with a petroleum ether / ethyl acetate mixed solvent (120 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 I, with a yield of 29.89 g and a yield of 74.3%. Determination: purity 99.5% (HPLC).

[0039] Alternatively, according to a specific embodiment of the present invention, in step (3), the following steps are included: At room temperature, under N2 protection, in a reaction vessel, dissolve the compound shown in formula 4 (22.39 g, 0.105 mol) and the compound shown in formula 5 (20.73 g, 0.1 mol) in DMF (210 mL), add HATU (76.05 g, 0.2 mol) and DIPEA (25.85 g, 0.2 mol), then raise the temperature of the reaction solution to 30 °C and continue stirring for 10 hours. The reaction solution is concentrated in vacuo (remaining approximately 60 mL), water (120 mL) is added dropwise to precipitate a solid. After the precipitated solid is collected by filtration, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate (120 mL, the volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour. The solid obtained by filtration is then dried in vacuo to obtain the compound shown in formula I, with a yield of 29.86 g and a yield of 74.2%. Determination: purity 99.5% (HPLC).

[0040] According to a specific embodiment of the present invention, the synthetic route of the compound Pritelivir shown in formula I can be as follows:

[0041]

[0042] Compared with the prior art, the preparation method of Pritelivir described in the present invention has at least the following beneficial effects:

[0043] 1. Compared with the prior art, the preparation method described in the present invention uses inexpensive commercially available raw materials (the compound shown in formula 1) (the raw material procurement cost is about 3 - 10 yuan / g), uses acrylonitrile to form a heterocycle to synthesize the compound shown in formula 3, hydrolyzes the ester group in a basic environment to obtain the compound shown in formula 4, and then carries out an amidation reaction with the compound shown in formula 5 to synthesize the target product Pritelivir.

[0044] 2. Compared with the existing technical methods, the significant advantages of the present invention are as follows: There are mainly two kinds of synthesis literatures of the compound shown in Formula 3. One is the Suzuki reaction of heteroaryl boronic acid and haloaryl (US 7105553 B2), which requires a catalyst and an anaerobic condition; the other is the substitution reaction of trimethyltin heteroaryl and haloaryl (US2004 / 0006076A1). The disadvantage of this method is that trimethyltin is used as a leaving group. Even after the final product is post-treated, a certain amount of tin substances will still remain, which is toxic and very unfavorable for drug molecules. In addition, after the removal of trimethyltin, halo trimethyltin is formed, and the post-treatment is troublesome. Liquid-liquid extraction is often prone to emulsification. Even when a saturated KF aqueous solution or Py-HF solution is added, it is still necessary to stir for at least one hour, and then perform conventional post-treatment and purification after filtration through diatomaceous earth. This method uses acrylonitrile to form a heterocycle, with mild reaction conditions, high yield, and simple post-treatment. In addition, the purification method of the compound shown in Formula 4 obtained in Step 2 is simple, and the compound shown in Formula I obtained in Step 3 is purified by slurrying. The post-treatment of the whole route is simple and has good economy. In summary, this method has the advantages of simple operation, mild reaction conditions, high yield, and simple post-treatment, and is suitable for industrial batch production. Detailed Embodiments

[0045] The embodiments of the present invention are 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 to the present invention. For those not specified in the embodiments regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications. For the reagents or instruments not indicated by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0046] Example 1 Synthesis of the Compound Shown in Formula 3

[0047] At room temperature, in a reaction flask, the compound shown in Formula 1 (6.0 g, 34.25 mmol) and the compound shown in Formula 2 (acrylonitrile, 2.73 g, 51.37 mmol) were dissolved in methanol (60 mL). The reaction solution was stirred at room temperature for 3 hours, then heated to 55 °C and stirred for another 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was then dried under vacuum to obtain the compound shown in Formula 3, with a yield of 7.30 g and a yield of 93.8%.

[0048] LC-MS (APCI): m / z = 228.1 (M + 1) + .

[0049] 1H-NMR(400MHz, DMSO, δ / ppm): 3.65 (s, 3H), 3.76 (s, 2H), 7.34 - 7.41 (m, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.87 - 7.91 (m, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 8.68 (d, J = 4.2 Hz, broad, 1H).

[0050] Synthesis of the compound shown in Formula 3 in Example 2

[0051] At room temperature, in a reaction flask, dissolve the compound shown in Formula 1 (6.0 g, 34.25 mmol) and the compound shown in Formula 2 (2.18 g, 41.10 mmol) in methanol (48 mL). Keep the reaction solution stirring at room temperature for 2.5 hours, then raise the temperature to 50 °C and continue stirring for 3.5 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure to dryness, and dry it in vacuo to obtain the compound shown in Formula 3, with a yield of 7.04 g and a yield of 90.4%.

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

[0053] At room temperature, in a reaction flask, dissolve the compound shown in Formula 1 (6.0 g, 34.25 mmol) and the compound shown in Formula 2 (acrylonitrile, 3.27 g, 61.65 mmol) in methanol (90 mL). Keep the reaction solution stirring at room temperature for 4 hours, then raise the temperature to 60 °C and continue stirring for 5 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure to dryness, and dry it in vacuo to obtain the compound shown in Formula 3, with a yield of 7.26 g and a yield of 93.3%.

[0054] Synthesis of the compound shown in Formula 4 in Example 4

[0055] At 0 °C, dissolve the compound shown in Formula 3 (60.0 g, 264.0 mmol) in THF (60 mL), add 2 M LiOH solution (198 mL, 396.0 mmol). After the reaction solution is heated to 40 °C, keep stirring for 2 hours. TLC shows that the compound shown in Formula 3 has completely reacted. After the reaction solution is cooled to room temperature, add ethyl acetate (200 mL) for extraction. After liquid separation, adjust the aqueous phase to pH about 5 by adding an appropriate amount of 2 M HCl solution, and extract with ethyl acetate (2 × 400 ml) and dichloromethane (400 ml) respectively. Combine the organic phases, dry over anhydrous Na2SO4, concentrate under reduced pressure and dry in vacuo to obtain the compound shown in Formula 4, with a yield of 39.0 g and a yield of 69.3%.

[0056] LC-MS (APCI): m / z = 214.1 (M + 1) + .

[0057] 1 H-NMR (400 MHz, DMSO, δ / ppm): 3.75 (s, 2H), 7.44 - 7.50 (m, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.99 (td, J1 = 7.7 Hz, J2 = 1.9 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.14 (d, J - 8.3 Hz, 2H), 8.77 (dt, J1 = 4.0 Hz, J2 = 0.9 Hz, 1H).

[0058] Example 5 Synthesis of the compound shown in Formula 4

[0059] At 0 °C, dissolve the compound shown in Formula 3 (60.0 g, 264.0 mmol) in THF (60 mL), add 2 M LiOH solution (172 mL, 343.2 mmol), warm the reaction mixture to 40 °C and continue stirring for 1 hour and 45 minutes. TLC shows that the compound shown in Formula 3 has completely reacted. After the reaction mixture is cooled to room temperature, add ethyl acetate (200 mL) for extraction. After liquid separation, adjust the aqueous phase to pH about 5 with an appropriate amount of 2 M HCl solution, and extract with ethyl acetate (2 × 400 ml) and dichloromethane (400 ml) respectively. Combine the organic phases, dry over anhydrous Na2SO4, concentrate under reduced pressure and dry in vacuo to obtain the compound shown in Formula 4, with a yield of 37.8 g and a yield of 67.1%.

[0060] Example 6 Synthesis of the compound shown in Formula 4

[0061] At 0 °C, dissolve the compound shown in Formula 3 (60.0 g, 264.0 mmol) in THF (100 mL), add 2 M LiOH solution (264 mL, 528.0 mmol), warm the reaction mixture to 40 °C and continue stirring for 3 hours. TLC shows that the compound shown in Formula 3 has completely reacted. After the reaction mixture is cooled to room temperature, add ethyl acetate (250 mL) for extraction. After liquid separation, adjust the aqueous phase to pH about 5 with an appropriate amount of 2 M HCl solution, and extract with ethyl acetate (2 × 500 ml) and dichloromethane (500 ml) respectively. Combine the organic phases, dry over anhydrous Na2SO4, concentrate under reduced pressure and dry in vacuo to obtain the compound shown in Formula 4, with a yield of 38.8 g and a yield of 69.0%.

[0062] Comparative Example 1 Synthesis of the compound shown in Formula 4

[0063] At 0 °C, dissolve the compound shown in Formula 3 (60.0 g, 264.0 mmol) in THF (60 mL), add 2 M LiOH solution (138.6 mL, 277.2 mmol), warm the reaction mixture to 40 °C and stir for an additional 2 hours. TLC shows that the compound shown in Formula 3 has completely reacted. After the reaction mixture is cooled to room temperature, extract with ethyl acetate (200 mL). After liquid separation, adjust the aqueous phase to pH about 5 with an appropriate amount of 2 M HCl solution, and extract with ethyl acetate (2 × 400 mL) and dichloromethane (400 mL) respectively. Combine the organic phases, dry over anhydrous Na2SO4, concentrate under reduced pressure and dry in vacuo to obtain the compound shown in Formula 4, with a yield of 36.8 g and a yield of 65.3%.

[0064] It can be seen that when the molar ratio of the compound shown in Formula 3 to LiOH is changed to 1:1.05 and the reaction is stirred for 2 hours, the efficiency (yield) of preparing the compound shown in Formula 4 is not further improved.

[0065] Preparation of the compound Pritelivir of Formula I in Example 7

[0066] Under N2 protection at room temperature, in a reaction vessel, dissolve the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) in DMF (210 mL), add HATU (76.05 g, 0.2 mol) and Et3N (20.24 g, 0.2 mol), then warm the reaction mixture to 30 °C and continue stirring for 10 hours. Concentrate the reaction mixture under vacuum (remaining about 60 mL), add water dropwise (120 mL) to precipitate the solid. Filter and collect the precipitated solid, and purify it by trituration with a mixed solvent of petroleum ether / ethyl acetate (120 mL, volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour. Vacuum dry the solid obtained by filtration to obtain the compound shown in Formula I, with a yield of 29.89 g and a yield of 74.3%. Determination: purity 99.5% (HPLC).

[0067] LC-MS (APCI): m / z = 403.1 (M + 1) + 。

[0068] 1 1H-NMR (400 MHz, DMSO δ / ppm): 2.39 (s, 3H), 3.65 (s, 3H), 4.16 (s, 2H), 7.29 - 7.27 (m, 1H), 7.33 (d, J = 8 Hz, 2H), 7.59 (s, 2H), 7.83 - 7.97 (m, 2H), 7.98 (d, J = 8.0 Hz, 2H), 8.62 (m, 1H).

[0069] Preparation of the compound Pritelivir of Formula I in Example 8

[0070] Under nitrogen protection at room temperature, in a reaction vessel, the compound of Formula 4 (21.32 g, 0.1 mol) and the compound of Formula 5 (20.73 g, 0.1 mol) were dissolved in DMF (210 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 for 9 hours. The reaction solution was concentrated in vacuo (remaining about 60 mL), water (120 mL) was added dropwise to precipitate the solid. The precipitated solid was collected by filtration, and then triturated and purified with a mixed solvent of petroleum ether / ethyl acetate (120 mL, volume ratio of petroleum ether to ethyl acetate was 4:1) for 0.5 hour. The solid obtained by filtration was dried in vacuo to obtain the compound of Formula I, with a yield of 29.58 g and a yield of 73.5%. Determination: purity 99.5% (HPLC).

[0071] Preparation of the compound Pritelivir of Formula I in Example 9

[0072] Under nitrogen protection at room temperature, in a reaction vessel, the compound of Formula 4 (25.59 g, 0.12 mol) and the compound of Formula 5 (20.73 g, 0.1 mol) were dissolved in DMF (250 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 for 12 hours. The reaction solution was concentrated in vacuo (remaining about 60 mL), water (120 mL) was added dropwise to precipitate the solid. The precipitated solid was collected by filtration, and then triturated and purified with a mixed solvent of petroleum ether / ethyl acetate (120 mL, volume ratio of petroleum ether to ethyl acetate was 6:1) for 0.5 hour. The solid obtained by filtration was dried in vacuo to obtain the compound of Formula I, with a yield of 29.78 g and a yield of 74.0%. Determination: purity 99.4% (HPLC).

[0073] Preparation of the compound Pritelivir of Formula I in Example 10

[0074] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) were dissolved in DMF (210 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 in vacuo (remaining about 60 mL), water (120 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 (120 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 I, with a yield of 29.86 g and a yield of 74.2%. Determination: purity 99.5% (HPLC).

[0075] Preparation of the compound Pritelivir shown in Formula I in Example 11

[0076] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) were dissolved in DMF (210 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 60 mL), water (120 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 (120 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 I, with a yield of 29.50 g and a yield of 73.3%. Determination: purity 99.2% (HPLC).

[0077] Preparation of the compound Pritelivir shown in Formula I in Example 12

[0078] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) were dissolved in DMF (210 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 60 mL), water (120 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 (120 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 in vacuo to obtain the compound shown in Formula I, with a yield of 29.66 g and a yield of 73.7%. Determination: purity 99.4% (HPLC).

[0079] Preparation of the compound Pritelivir shown in Formula I in Example 13

[0080] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) were dissolved in DMF (210 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 in vacuo (remaining about 60 mL), water (120 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 (120 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 in vacuo to obtain the compound shown in Formula I, with a yield of 29.38 g and a yield of 73.0%. Determination: purity 99.3% (HPLC).

[0081] Preparation of the compound Pritelivir shown in Formula I in Comparative Example 2

[0082] At room temperature, under N2 protection, in a reaction vessel, the compound shown in Formula 4 (22.39 g, 0.125 mol) and the compound shown in Formula 5 (20.73 g, 0.1 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 for another 12 hours. The reaction solution was concentrated in vacuo (remaining about 60 mL), water (120 mL) was added dropwise to precipitate the solid. After the precipitated solid was collected by filtration, it was triturated and purified with a mixed solvent of petroleum ether / ethyl acetate (120 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 in vacuo to obtain the compound shown in Formula I, with a yield of 29.74 g and a yield of 73.9%. Determination: purity 99.3% (HPLC).

[0083] It can be seen that when the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5, HATU, and Et3N was changed to 1.25:1:2.8:3.2 and stirred for 12 hours, the efficiency (yield) of preparing the compound shown in Formula I was not further improved.

[0084] 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 any one or more embodiments or examples in a suitable manner. 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.

[0085] 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 method for preparing Pritelivir, characterized in that, Comprising: (1) Contacting the compound shown by formula 1 with the compound shown by formula 2 to obtain the compound shown by formula 3; (2) Contacting the compound shown by formula 3 with LiOH to obtain the compound shown by formula 4; (3) Contacting the compound shown by formula 4 with the compound shown by formula 5, a condensing agent, and an organic base to obtain the compound Pritelivir shown by formula I, 2. The method according to claim 1, characterized in that In step (1), it includes the following steps: at room temperature, in a reaction flask, dissolving the compound shown by formula 1 and the compound shown by formula 2 in methanol, keeping the reaction solution stirred at room temperature for 2.5 to 4 hours, then heating to 50 °C to 60 °C, and continuing to stir for 3.5 to 5 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure to obtain a solid, and then vacuum-dry the solid to obtain the compound shown by formula 3.

3. The method according to claim 2, wherein In step (1), the molar ratio of the compound shown by formula 1 to the compound shown by formula 2 is 1:(1.2 to 1.8), and preferably the molar ratio of the compound shown by formula 1 to the compound shown by formula 2 is 1:1.5; Optionally, in step (1), the weight-to-volume ratio of the compound shown by formula 1 to methanol is 1:(8 to 15), and preferably the weight-to-volume ratio of the compound shown by formula 1 to methanol is 1:10; Optionally, in step (1), preferably the reaction solution is kept stirred at room temperature for 3 hours, then heated to 55 °C, and continued to stir for 4 hours.

4. The method according to claim 1, characterized in that In step (2), it includes the following steps: at 0 °C, dissolving the compound shown by formula 3 in THF, adding a 2M LiOH solution, heating the reaction solution to 40 °C and keeping it warm and continuing to stir for 1 hour and 45 minutes to 3 hours. TLC shows that the compound shown by formula 3 has completely reacted. After the reaction solution is cooled to room temperature, add ethyl acetate for extraction. After liquid separation, add an appropriate amount of 2M HCl solution to the aqueous phase to adjust the pH to about 5, and then perform post-treatment. Finally, concentrate under reduced pressure and dry in vacuo to obtain the compound shown by formula 4.

5. The method according to claim 4, wherein In step (2), the molar ratio of the compound shown by formula 3 to LiOH is 1:(1.3 to 2.0), and preferably the molar ratio of the compound shown by formula 3 to LiOH is 1:1.5; Optionally, in step (2), preferably the time for keeping warm and stirring the reaction is 2 hours.

6. The method according to claim 1, characterized in that, In step (3), it includes the following steps: at room temperature, under N2 protection, in a reaction vessel, dissolving the compound shown by formula 4 and the compound shown by formula 5 in DMF, adding a condensing agent and an organic base, then heating the reaction solution to 30 °C, and continuing to stir and react for 9 to 12 hours. The reaction solution is concentrated in vacuo, and water is added dropwise to precipitate a solid. After collecting the precipitated solid by filtration, it is slurried and purified with a mixed solvent of petroleum ether / ethyl acetate for 0.5 hour. The solid obtained by filtration is then vacuum-dried to obtain the compound shown by formula I.

7. The method according to claim 1 or claim 6, characterized in that The condensing agent is any one selected from HATU, HOBt, or DCC, and preferably the condensing agent is selected from HATU; Optionally, the organic base is any one selected from Et3N, DIPEA, DBU, or DMAP, and preferably the organic base is selected from Et3N or DIPEA.

8. The method according to claim 6, wherein In step (3), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, the condensing agent, and the organic base is (1.0 - 1.2):1:(1.5 - 2.5):(1.5 - 3.0), and preferably the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, the condensing agent, and the organic base is 1.05:1:2.0:2.

0.

9. The method according to claim 8, wherein In step (3), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, HATU, and Et3N is 1.05:1:2.0:2.0; Or, in step (3), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, HATU, and DIPEA is 1.05:1:2.0:2.0; Optionally, in step (3), 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 (3), it is preferred to stir the reaction for 10 hours.

10. The method according to claim 1, wherein In step (1), the following steps are included: At room temperature, in a reaction flask, dissolve the compound shown in Formula 1 (6.0 g, 34.25 mmol) and the compound shown in Formula 2 (2.73 g, 51.37 mmol) in methanol (60 mL). Keep the reaction solution stirred at room temperature for 3 hours, then raise the temperature to 55 °C and continue stirring for 4 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure to obtain a solid, and then vacuum dry the solid to obtain the compound shown in Formula 3, with a yield of 7.30 g and a yield of 93.8%; In step (2), the following steps are included: At 0 °C, dissolve the compound shown in Formula 3 (60.0 g, 264.0 mmol) in THF (60 mL), add 2 M LiOH solution (198 mL, 396.0 mmol), and after the reaction solution is heated to 40 °C, keep stirring for 2 hours. TLC shows that the compound shown in Formula 3 has completely reacted. After the reaction solution is cooled to room temperature, add ethyl acetate (200 mL) for extraction. After liquid separation, adjust the pH of the aqueous phase to about 5 by adding an appropriate amount of 2 M HCl solution, and extract with ethyl acetate (2 × 400 ml) and dichloromethane (400 ml) respectively. After combining the organic phases, dry with anhydrous Na2SO4, concentrate under reduced pressure and dry in vacuo to obtain the compound shown in Formula 4, with a yield of 39.0 g and a yield of 69.3%; In step (3), the following steps are included: Under N2 protection at room temperature, in a reaction vessel, dissolve the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) in DMF (210 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 and continue stirring for 10 hours. The reaction solution is concentrated in vacuo (remaining about 60 mL), water (120 mL) is added dropwise to precipitate the solid. After the precipitated solid is collected by filtration, it is purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (120 mL, volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour. The solid obtained by filtration is then dried in vacuo to obtain the compound shown in Formula I, with a yield of 29.89 g and a yield of 74.3%. Determination: purity 99.5% (HPLC); Or, in step (3), the following steps are included: Under N2 protection at room temperature, in a reaction vessel, dissolve the compound shown in Formula 4 (22.39 g, 0.105 mol) and the compound shown in Formula 5 (20.73 g, 0.1 mol) in DMF (210 mL), add HATU (76.05 g, 0.2 mol) and DIPEA (25.85 g, 0.2 mol), then raise the temperature of the reaction solution to 30 °C and continue stirring for 10 hours. The reaction solution is concentrated in vacuo (remaining about 60 mL), water (120 mL) is added dropwise to precipitate the solid. After the precipitated solid is collected by filtration, it is purified by pulping with a mixed solvent of petroleum ether / ethyl acetate (120 mL, volume ratio of petroleum ether to ethyl acetate is 5:1) for 0.5 hour. The solid obtained by filtration is then dried in vacuo to obtain the compound shown in Formula I, with a yield of 29.86 g and a yield of 74.2%. Determination: purity 99.5% (HPLC).

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