Preparation method of azvudine and its intermediate

Abstract

The present invention discloses a preparation method of azvudine and its intermediates. The present invention provides a preparation method of a compound represented by Formula IX, which comprises the following steps: in a solvent, under the action of an inorganic salt, a phase transfer catalyst and m-chloroperoxybenzoic acid, reacting a compound represented by Formula VIII with m-chlorobenzoic acid as shown below, and crystallizing to obtain the compound represented by Formula IX. The preparation method provided by the present invention avoids toxic and harmful and / or dangerous reagents and harsh reaction conditions in the GMP steps, significantly improves the total yield, and significantly improves the reaction repeatability and scalability, and is more suitable for industrial synthesis.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical synthesis processes, and particularly relates to a method for preparing azvudine and its intermediates. Background Art

[0002] Azvudine, chemical name: 1-(4-azido-2-deoxy-2-fluoro-β-D-ribofuranosyl)cytosine, is a nucleoside reverse transcriptase inhibitor and can be used to treat AIDS and novel coronavirus infection. Its molecular formula is as follows:

[0003]

[0004] Currently, the main synthesis methods of azvudine are as follows:

[0005] 1. Smith DB, et al. The design, synthesis, and antiviral activity of 4'-azidocytidine analogues against hepatitis C virus replication: the discovery of 4'-azidoarabinocytidine. J Med Chem. 2009;52(1):219-223. reported that using 4'-azido-uridine as the raw material, 2,2'-epoxyuridine was first synthesized through a dehydration reaction, followed by fluorination to obtain 2-fluorouridine, and then the final product azvudine was obtained through chlorination and ammonolysis with phosphorus oxychloride. The authors also reported another synthesis method in the article, using 2-fluorouridine as the raw material to first synthesize 4'-azido-uridine, and then obtaining 4-imidazolyl nucleoside through a one-pot method of chlorination with phosphorus oxychloride and imidazole substitution, and finally obtaining the final product through ammonolysis. Both methods reported in the article first chlorinated and then ammonolyzed to obtain the final product. During the ammonolysis process, it was also necessary to remove the protecting group, and reagents such as phosphorus oxychloride with relatively serious pollution were used during the reaction process.

[0006] 2. CN101177442A reported a method to obtain 4'-azidouridine from fluorosugar through multiple steps, followed by chlorination, ammonolysis, and simultaneous removal of the protecting group. This reaction process is relatively simpler than the previous method, but it also uses phosphorus oxychloride with relatively serious pollution, uses a silver reagent in the penultimate step, resulting in higher costs and easy introduction of Ag heavy metal, and the purification of the final product is cumbersome and the yield is low, which is not suitable for large-scale industrial production.

[0007] 3. CN114149475A reported a 4'-azido uridine nucleoside. After deprotection (ammonolysis or alcoholysis), it reacts with hexamethyldisilazane and acetamide to prepare azvudine. This method is simple to operate, but the yield is relatively low. The total yield of the two steps is 42 - 54%. SUMMARY OF THE INVENTION

[0008] The technical problem to be solved by the present invention is to overcome the technical defects of the existing preparation methods of azvudine, such as low total yield, use of toxic, harmful, dangerous or expensive reagents, harsh reaction conditions, and / or poor reaction reproducibility and scalability, which are not suitable for large-scale synthesis. Therefore, a preparation method of azvudine and its intermediates is provided. Compared with the existing preparation methods, the preparation method provided by the present invention avoids the use of toxic, harmful and / or dangerous reagents and harsh reaction conditions in the GMP steps, significantly improves the total yield, significantly improves the reaction reproducibility and scalability, and is more suitable for industrial synthesis.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] The present invention provides a preparation method of a compound shown in Formula IX, which comprises the following steps: in a solvent, under the action of an inorganic salt, a phase transfer catalyst and m-chloroperoxybenzoic acid, reacting a compound shown in Formula VIII with m-chlorobenzoic acid as shown below, and crystallizing to obtain a compound shown in Formula IX;

[0011]

[0012] wherein, R a is benzoyl or trifluoroacetyl.

[0013] The conditions of the preparation method of the compound shown in Formula IX can be the conventional conditions of such reactions in the art. The present invention preferably adopts the following conditions: the solvent can be a mixed solvent of water and halogenated hydrocarbon solvents. The halogenated hydrocarbon solvent can be one or more of DCM (dichloromethane), DCE (1,2-dichloroethane) and chloroform. Among them, in the mixed solvent of water and halogenated hydrocarbon solvents, the volume ratio of water to halogenated hydrocarbon solvent can be 10 - 3:5, such as 4:5. The amount of the solvent used only needs to not affect the reaction.

[0014] The inorganic salt can be one or more of phosphates, sodium dihydrogen phosphates and disodium hydrogen phosphates, preferably disodium hydrogen phosphate, and more preferably sodium hydrogen phosphate.

[0015] The phase transfer catalyst can be tetrabutylammonium hydrogen sulfate.

[0016] The molar ratio of the inorganic salt to the compound represented by Formula VIII may be 2 to 6:1, such as 4:1. The inorganic salt may be added in batches, for example, in two batches. For instance, the first batch is added with 0.4 - 0.6 times the equivalent amount of the total amount of the inorganic salt, and the second batch is added with the remaining amount.

[0017] The molar ratio of the phase transfer catalyst to the compound represented by Formula VIII may be 1 to 2:1, such as 1.35:1.

[0018] The molar ratio of m-chlorobenzoic acid to the compound represented by Formula VIII may be 1 to 2:1, such as 1.1:1.

[0019] The molar ratio of m-chloroperbenzoic acid to the compound represented by Formula VIII may be 2 to 8:1, such as 6:1. The m-chloroperbenzoic acid may be added in batches, for example, in two batches. For instance, the first batch is added with 0.5 - 0.8 times the equivalent amount of the total amount of m-chloroperbenzoic acid, and the second batch is added with the remaining amount.

[0020] The temperature of the reaction may be 20 - 30 °C.

[0021] The reaction time may be conventional in the art, as long as the reaction is completed. The reaction is considered complete when no more product is formed.

[0022] The compound represented by Formula IX preferably includes the following steps: To a mixture of a solvent, the first part of the inorganic salt, the phase transfer catalyst, the compound represented by Formula VIII, and m-chlorobenzoic acid, the first part of m-chloroperbenzoic acid is added in batches under temperature control for reaction. After the temperature-controlled reaction, the second part of the inorganic salt and the second part of m-chloroperbenzoic acid are added again for the said reaction. Among them, the said temperature control preferably means controlling the temperature at 20 - 30 °C. The said first part of the inorganic salt is preferably 0.4 - 0.6 times the equivalent amount of the total amount of the inorganic salt. The said first part of m-chloroperbenzoic acid is preferably 0.5 - 0.8 times the equivalent amount of the total amount of m-chloroperbenzoic acid.

[0023] The solvent for crystallization may be an alkane solvent, and the alkane solvent may be n-heptane.

[0024] The temperature of crystallization may be 20 - 30 °C.

[0025] After the reaction, post-treatment may also be included. The post-treatment preferably includes the following steps: quenching the reaction solution after the reaction with a sodium sulfite solution (such as an 18% sodium sulfite solution), performing solid-liquid separation (such as filtration), washing the filter cake with a chlorinated hydrocarbon solvent (such as dichloromethane), allowing the filtrate to stand for liquid separation, adjusting the pH of the organic phase to 8-9 (such as adjusting the pH value with sodium carbonate), performing liquid separation, then washing the organic phase with a sodium bicarbonate solution (such as a 5% sodium bicarbonate solution) (such as washing 3 times), washing with water, concentrating the organic phase to remove part of the solvent, to obtain a concentrated solution of the compound shown in Formula IX.

[0026] The above crystallization preferably performs crystallization on the concentrated solution of the compound shown in Formula IX. The volume ratio of the concentrated solution to the crystallization solvent can be 1:2 - 1:4. After crystallization, solid-liquid separation is performed, and the filter cake is dried in vacuo to obtain the compound product shown in Formula IX.

[0027] The present invention provides a preparation method of azvudine, which includes the following steps:

[0028] In a solvent, the compound shown in Formula IX obtained by the preparation method of the compound shown in Formula IX as described above and ammonia are subjected to the following reaction to obtain azvudine;

[0029]

[0030] The said R a is benzoyl or trifluoroacetyl.

[0031] The conditions of the preparation method of the said azvudine can be the conventional conditions for such reactions in the art. The present invention preferably adopts the following conditions:

[0032] The temperature of the said reaction is 20 - 30 °C.

[0033] The reaction time can be conventional in the art, as long as the reaction is completed, and the reaction is considered completed when the product is no longer generated.

[0034] After the said reaction, post-treatment may also be included. The post-treatment may include the following steps: removing the solvent under reduced pressure, adding water, washing the aqueous phase with ethyl acetate, concentrating the aqueous phase under reduced pressure, and filtering to obtain azvudine.

[0035] In a certain embodiment, the preparation method of the compound shown in Formula IX also includes the preparation method of the compound shown in Formula VIII, which includes the following steps: in a solvent, under the action of a base, the compound shown in Formula VII and an amino protecting reagent are subjected to the following reaction to obtain the compound shown in Formula VIII;

[0036]

[0037] Among them, the amino protecting reagent is benzoyl chloride, benzoic anhydride, trifluoroacetyl chloride or trifluoroacetic anhydride, where R a is benzoyl or trifluoroacetyl.

[0038] The conditions for the preparation method of the compound shown in Formula VIII can be the conventional conditions for such reactions in the art. The present invention preferably adopts the following conditions:

[0039] The solvent can be a halogenated alkane solvent, such as DCM, DCE or chloroform. The amount of the solvent used only needs to not affect the reaction.

[0040] The base can be an organic base, such as pyridine, triethylamine or diisopropylamine.

[0041] The molar ratio of the base to the compound shown in Formula VII can be 2 - 5:1, such as 4:1.

[0042] The molar ratio of the compound shown in Formula VII to the amino protecting reagent can be 1.5 - 3:1, such as 2:1.

[0043] The reaction can further include DMAP (4 - dimethylaminopyridine). The molar ratio of DMAP to the compound shown in Formula VII can be 1:5 - 20, such as 1:10.

[0044] The temperature of the reaction can be -5 - 5°C.

[0045] The reaction time can be conventional in the art, as long as the reaction is completed. The reaction is considered completed when the product no longer forms.

[0046] After the reaction, post - treatment can also be included. The post - treatment can include the following steps: adding dichloromethane to the reaction solution after the reaction, adjusting the pH to 6 - 7 (for example, adjusting the pH value with 0.2N hydrochloric acid), separating the liquid, washing the organic phase successively with water, washing with sodium bicarbonate solution (such as saturated sodium bicarbonate solution) and water, concentrating the obtained organic phase to remove part of the solvent, to obtain a concentrated solution of the compound shown in Formula VIII.

[0047] After the reaction, crystallization can also be included. The solvent for crystallization can be an aromatic hydrocarbon solvent, and the aromatic hydrocarbon solvent can be toluene. The temperature for crystallization can be 20 - 30°C. The crystallization preferably crystallizes the concentrated solution of the compound shown in Formula VIII. After crystallization, solid - liquid separation is carried out, and the filter cake is dried under reduced pressure to obtain the product of the compound shown in Formula VIII.

[0048] In one embodiment, the method for preparing the compound represented by Formula IX may further include a method for preparing the compound of Formula VII, which comprises the following steps: In a solvent, react the compound represented by Formula VI with sodium azide and iodine chloride as shown below to obtain the compound represented by Formula VII;

[0049]

[0050] The conditions for the method for preparing the compound represented by Formula VII may be conventional conditions for such reactions in the art. The present invention preferably adopts the following conditions:

[0051] The solvent may be an ether solvent, such as tetrahydrofuran. The amount of the solvent used only needs to not affect the reaction. Generally, the water content of the solvent needs to be controlled not to exceed 0.10%. If the water content in the solvent is higher than 0.10%, the solvent needs to be repeatedly concentrated to control the water content not to exceed 0.10%.

[0052] The molar ratio of sodium azide to the compound represented by Formula VI may be 1-3:1, such as 2.5:1.

[0053] The molar ratio of iodine chloride to the compound represented by Formula VI may be 1-2:1, such as 1.7:1.

[0054] The molar ratio of iodine chloride to sodium azide is 5:8.

[0055] The reaction time may be conventional in the art, as long as the reaction is completed, and the reaction is considered completed when the product is no longer generated.

[0056] The reaction temperature may be -5 - 5°C.

[0057] The reaction is monitored by TLC to determine whether it is completed. If not, sodium azide and iodine chloride need to be added additionally until the reaction is complete.

[0058] After the reaction, post-treatment may also be included; the post-treatment may include the following steps: quenching with a sodium thiosulfate solution (such as quenching with 20% sodium thiosulfate), extracting with ethyl acetate, washing the organic phase with saturated sodium chloride solution, concentrating under reduced pressure, adding dichloromethane twice and then concentrating under reduced pressure to obtain a concentrated solution of the compound represented by Formula VII.

[0059] After the reaction, crystallization may also be included. The solvent for crystallization may be an alkane solvent, and the alkane solvent may be n-heptane. The crystallization temperature may be 0 - 10°C. The crystallization preferably crystallizes the concentrated solution of the compound represented by Formula VII. After crystallization, solid-liquid separation is carried out, and the filter cake is dried under vacuum to obtain the compound product represented by Formula VII.

[0060] In one embodiment, the method for preparing the compound represented by Formula IX may further include a method for preparing the compound represented by Formula VI, which comprises the following steps: reacting the compound represented by Formula V with sodium methoxide in a solvent to obtain the compound represented by Formula VI;

[0061]

[0062] The conditions for the method for preparing the compound represented by Formula VI may be conventional conditions for such reactions in the art. The present invention preferably adopts the following conditions:

[0063] The solvent may be an alcohol solvent or an ether solvent, such as methanol or tetrahydrofuran. The amount of the solvent used only needs to not affect the reaction.

[0064] The molar ratio of sodium methoxide to the compound represented by Formula V may be 2 to 5:1, such as 3.5:1.

[0065] The temperature of the reaction may be 0 - 10 °C.

[0066] The reaction time may be conventional in the art, as long as the reaction is completed. The reaction is considered completed when the product no longer forms.

[0067] After the reaction is completed, it may further include post-treatment; the post-treatment may include the following steps: adding water to the reaction solution after the reaction is completed, concentrating under reduced pressure, filtering, washing the filter cake with water, extracting the filtrate with ethyl acetate, adjusting the pH of the aqueous phase to 7 - 8 (such as adjusting the pH with sodium bisulfite), extracting with ethyl acetate, and concentrating the organic phase to remove the solvent to obtain the compound represented by Formula VI.

[0068] In one embodiment, the method for preparing the compound represented by Formula IX may further include a method for preparing the compound represented by Formula V, which comprises the following steps: reacting the compound represented by Formula IV, imidazole, triphenylphosphine and iodine in a solvent as shown below to obtain the compound represented by Formula V;

[0069]

[0070] The conditions for the method for preparing the compound represented by Formula V may be conventional conditions for such reactions in the art. The present invention preferably adopts the following conditions:

[0071] The solvent may be an ether solvent, such as tetrahydrofuran, such as anhydrous tetrahydrofuran. The amount of the solvent used only needs to not affect the reaction.

[0072] The molar ratio of imidazole to the compound represented by Formula IV may be 1 to 3:1, such as 2:1.

[0073] The molar ratio of the triphenylphosphine to the compound represented by Formula IV may be 1 to 3:1, such as 1.5:1.

[0074] The molar ratio of the iodine to the compound represented by Formula IV may be 1 to 3:1, such as 1.5:1.

[0075] The temperature of the reaction may be 20 - 30 °C.

[0076] The time of the reaction may be conventional in the art, as long as the reaction is completed, and the reaction is considered completed when the product no longer forms.

[0077] After the reaction is completed, post-treatment may also be included. The post-treatment may include the following steps: quenching with a sodium sulfite solution (such as quenching with a 5% sodium sulfite solution), concentrating under reduced pressure, extracting with ethyl acetate, and concentrating the organic phase under reduced pressure to obtain a concentrated solution of the compound represented by Formula V.

[0078] Among them, after the reaction is completed, crystallization may also be included. The solvent for the crystallization may be an ester solvent, and the ester solvent may be ethyl acetate. The temperature of the crystallization may be 0 - 10 °C. The crystallization preferably crystallizes the concentrated solution of the compound represented by Formula V. After crystallization, solid-liquid separation is performed, and the filter cake is dried under vacuum to obtain the compound product represented by Formula V.

[0079] In one embodiment, the method for preparing the compound represented by Formula IX may further include a method for preparing the compound IV, which includes the following steps: reacting the compound represented by Formula III with an ammonia-methanol solution to obtain the compound represented by Formula IV;

[0080]

[0081] wherein, R a is benzoyl or trifluoroacetyl.

[0082] The conditions for the method for preparing the compound represented by Formula IV may be conventional conditions for such reactions in the art. The present invention preferably uses the following conditions:

[0083] The concentration of the ammonia-methanol solution may be 7 mol / L.

[0084] The temperature of the reaction may be 25 - 35 °C.

[0085] The time of the reaction may be conventional in the art, as long as the reaction is completed, and the reaction is considered completed when the product no longer forms.

[0086] When R a is benzoyl, the time of the reaction may be 50 - 60 hours.

[0087] When R aWhen it is trifluoroacetyl group, the reaction time can be 15 - 20 hours.

[0088] After the reaction, post-treatment may be included. The post-treatment may include the following steps: controlling the temperature of the reaction solution after the reaction at 40 - 50 °C and concentrating it under reduced pressure to dryness, mixing it with an alcohol solvent (such as methanol), cooling it to 25 - 35 °C, then mixing it with a halogenated alkane solvent (such as dichloromethane), controlling the temperature at 0 - 10 °C, stirring (such as for 2 - 4 hours), performing solid-liquid separation, and drying the filter cake under vacuum to obtain the compound shown in Formula IV.

[0089] In a certain embodiment, the preparation method of the compound shown in Formula IX may further include the preparation method of the compound III, which includes the following steps:

[0090] (1) React the amino R a -protected cytosine, hexamethyldisilazane and ammonium sulfate; obtain a mixture;

[0091] (2) In a solvent, react the compound shown in Formula II with the mixture obtained in step (1) to obtain the compound shown in Formula III;

[0092]

[0093] wherein, the R a is benzoyl group or trifluoroacetyl group.

[0094] The conditions for the preparation method of the compound shown in Formula III can be the conventional conditions for such reactions in the art. The present invention preferably uses the following conditions:

[0095] In step (1), the molar ratio of the amino R a -protected cytosine to the compound shown in Formula IV can be 1 - 3:1, such as 2:1.

[0096] In step (1), the molar ratio of hexamethyldisilazane to the compound shown in Formula IV can be 10 - 20:1, such as 14:1.

[0097] In step (1), the molar ratio of ammonium sulfate to the compound shown in Formula IV can be 1 - 2:1, such as 1.3:1.

[0098] In step (1), the reaction temperature is 130 - 140 °C.

[0099] In step (2), the solvent can be a halogenated hydrocarbon solvent, such as dichloromethane.

[0100] In step (2), the reaction temperature is 65 - 75 °C.

[0101] The time of the reaction can be conventional in the art, as long as the reaction is completed, and the reaction is considered completed when the product is no longer generated.

[0102] After the reaction, post-treatment may also be included. The post-treatment may include the following steps: cooling to 0 - 10°C, adding water (after addition, stirring at 20 - 30°C for 4 - 10 hours), filtering, washing the organic phase with water, concentrating under reduced pressure, and crystallizing with an alkane solvent (such as n-heptane) to obtain the compound shown in Formula III.

[0103] In one embodiment, the method for preparing the compound shown in Formula IX may further include a method for preparing the compound II, which includes the following steps: in a solvent, reacting the compound shown in Formula I with a hydrobromic acid - glacial acetic acid solution to obtain the compound shown in Formula II;

[0104]

[0105] The conditions for the method for preparing the compound shown in Formula II can be conventional conditions for such reactions in the art. The present invention preferably uses the following conditions:

[0106] The solvent can be a halogenated hydrocarbon solvent, such as dichloromethane.

[0107] The concentration of the hydrobromic acid - glacial acetic acid solution is 33% (mass percentage concentration).

[0108] The temperature of the reaction is 15 - 25°C.

[0109] The time of the reaction can be conventional in the art, as long as the reaction is completed, and the reaction is considered completed when the product is no longer generated.

[0110] After the reaction, post-treatment may also be included. The post-treatment may include the following steps: adding water for liquid separation, washing the organic phase with water, adjusting the pH ≥ 7 (for example, adjusting with 5% sodium bicarbonate), and removing the solvent from the organic phase to obtain the compound shown in Formula II.

[0111] The obtained compound shown in Formula II can be directly used for preparing the compound shown in Formula III without further purification.

[0112] The present invention provides a method for preparing azvudine, which includes the following steps:

[0113]

[0114] wherein, R a is benzoyl or trifluoroacetyl;

[0115] The operations and conditions of each step of the reaction in the preparation method can be the same as those of the corresponding reactions in any of the above embodiments of the present invention.

[0116] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0117] The reagents and raw materials used in the present invention are all commercially available.

[0118] The positive and progressive effects of the present invention are as follows: The preparation method provided by the present invention avoids toxic, harmful and / or dangerous reagents and harsh reaction conditions, significantly improves the total yield, significantly improves the reaction repeatability and scalability, and is more suitable for industrial synthesis. Detailed implementation mode

[0119] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0120] Example 1: Synthesis of Compound III

[0121]

[0122] Under stirring, 300 g of Compound I and 3 L of dichloromethane were added to Reactor 1, the temperature was controlled at 15 - 25 °C, and 840 g of 33% hydrobromic acid - glacial acetic acid solution was added dropwise. After the addition was completed, the reaction was carried out under insulation for 14 - 18 hours. After the reaction was completed, 3 L of water was added dropwise while controlling the temperature, and after standing for liquid separation, the organic phase was washed with 33 L of water, neutralized with 5% sodium bicarbonate to pH ≥ 7, and after liquid separation, the organic phase was concentrated until no liquid flowed out to obtain Compound II.

[0123] The amino - protected cytosine (1.29 mol, 2.0 equivalents), 900 g of hexamethyldisilazane, and 69 g of ammonium sulfate were added to Reactor 2, and the temperature was raised to 130 - 140 °C for reaction for 10 hours.

[0124] 15 L of chloroform was added to Reactor 1, stirred to obtain a homogeneous solution, and the obtained solution was transferred to Reactor 2. The reactor was heated to 65 - 75 °C and kept at this temperature for reaction for 16 hours. The temperature was lowered to 0 - 10 °C, and 1.5 L of water was slowly added dropwise. After the addition was completed, the temperature was slowly raised to 20 - 30 °C and kept stirring for 4 - 10 hours. Filtered, the filtrate was layered, and the organic layer was washed with 1.5 L of water. The organic phase was concentrated under reduced pressure to 0.6 - 0.9 L, the temperature was controlled at 20 - 30 °C, and 3 L of n - heptane was added dropwise. After the addition was completed, it was stirred under controlled temperature for 2 - 3 hours. Filtered, the filter cake was rinsed with n - heptane and dried in vacuo to obtain a white solid Compound III.

[0125] R a When it is benzoyl, the yield is 92.3%, MS: 558.0 (M + H + )

[0126] R a When R is trifluoroacetyl, the yield is 88.4%, MS: 549.9 (M+H + ).

[0127] Example 2: Synthesis of Compound IV

[0128]

[0129] 100 g of Compound III and 1 L of ammonia-methanol solution (7 mol / L) were added to the reaction kettle, and the temperature was controlled at 25-35 °C for reaction. After the reaction was completed (when R a is benzoyl, the reaction time is 50-60 hours; when R a is trifluoroacetyl, the reaction time is 15-20 hours), the temperature was controlled at 40-50 °C and concentrated under reduced pressure to dryness. 100 mL of methanol was added to the reaction kettle, stirred until dissolved, cooled to 25-35 °C, and 1 L of dichloromethane was added dropwise. After the addition was completed, the temperature was lowered to 0-10 °C and stirred for 2-4 hours. Filtered, the filter cake was washed with dichloromethane and dried in vacuo to obtain a white solid compound IV. MS: 245.9 (M+H + ), molar yield 93.2% (when R a is benzoyl), 93.4% (when R a is trifluoroacetyl).

[0130] Example 3: Synthesis of Compound V

[0131]

[0132] 100 g of Compound IV, 55.3 g of imidazole (2.0 equivalents), 160 g of triphenylphosphine (1.5 equivalents), and 500 mL of anhydrous tetrahydrofuran were added to the reaction kettle, and the temperature was adjusted to 20-30 °C. At 20-30 °C, a solution of 155 g of iodine (1.5 equivalents) dissolved in 500 mL of tetrahydrofuran was added dropwise to the reaction kettle. After the addition was completed, the reaction was maintained for 3-5 hours. Quenched with 5% sodium sulfite solution, after quenching, concentrated under reduced pressure to 900-1100 mL. Extracted with ethyl acetate (500 mL * 3), the organic phase was concentrated under reduced pressure to 400-500 mL, cooled to 0-10 °C, and stirred for 2-3 hours. Filtered, the filter cake was rinsed with cold ethyl acetate and dried in vacuo to obtain a white solid compound V, 234 g, MS: 355.8 (M+H + ), content 51.0%, yield 82.3%.

[0133] Example 4: Synthesis of Compound VII

[0134]

[0135] Method 1:

[0136] Add 100 g of Compound V (net content) and 1 L of methanol to the reaction kettle. While controlling the temperature at 0 - 10°C, slowly add 53 g of sodium methoxide dropwise. After addition, react at 0 - 10°C for 14 - 16 hours. While controlling the temperature at 0 - 10°C, slowly add 1 L of water dropwise, concentrate under reduced pressure to 900 - 1000 mL, filter, and rinse the filter cake with 200 mL of water. Extract the filtrate with ethyl acetate (500 mL * 2), and discard the organic phase. Adjust the pH of the aqueous phase to 7 - 8 with sodium bisulfite, and extract with ethyl acetate (500 mL * 3). After washing the organic phase with 500 mL of saturated brine, concentrate to dryness to obtain Compound VI.

[0137] Then add 1000 mL of tetrahydrofuran, concentrate to 400 - 600 mL, and detect that the water content is not higher than 0.10%; if the water content is higher than 0.1%, then repeatedly concentrate with the addition of tetrahydrofuran until the water content is not higher than 0.10%. Cool to room temperature, add 47 g of sodium azide to the reaction kettle; and cool to -5 - 5°C. While controlling the temperature at -5 - 5°C, slowly add 78 g of iodine chloride dropwise. After the addition is complete, keep the temperature and react for 1 - 2 hours. TLC shows that the reaction is complete. If not, supplement sodium azide and iodine chloride (mass ratio: sodium azide: iodine chloride = 5:8) until the reaction is complete. After the reaction is complete, quench with 20% sodium thiosulfate, and extract with ethyl acetate (500 mL * 3). Wash the combined organic phase with saturated sodium chloride solution (500 mL * 2). Concentrate the organic phase under reduced pressure to about 200 mL, add 1000 mL of dichloromethane, concentrate under reduced pressure to about 200 mL, add 1000 mL of dichloromethane, and concentrate under reduced pressure to about 200 mL. While stirring, add 500 mL of n - heptane dropwise, cool to 0 - 10°C, keep the temperature and stir for 2 - 3 hours. Filter, rinse the filter cake with n - heptane, and dry in vacuo at 30 - 40°C to obtain 56.9 g of a white solid Compound VII, MS: 396.8 (M + H + ), and the total yield of the two - step reaction is 51.0%.

[0138] Method 2: Add 100 g of Compound V (net content) and 1 L of tetrahydrofuran to the reaction kettle. While controlling the temperature at 0 - 10°C, slowly add 53 g of sodium methoxide dropwise. After addition, react at 0 - 10°C for 14 - 16 hours. While controlling the temperature at 0 - 10°C, slowly add 1 L of water dropwise, concentrate under reduced pressure to 900 - 1000 mL, filter, and rinse the filter cake with 200 mL of water. Extract the filtrate with ethyl acetate (500 mL * 2), and discard the organic phase. Adjust the pH of the aqueous phase to 7 - 8 with sodium bisulfite, and extract with ethyl acetate (500 mL * 3). After washing the organic phase with 500 mL of saturated brine, concentrate to dryness to obtain Compound VI.

[0139] Subsequently, 1000 mL of tetrahydrofuran was added, and the mixture was concentrated to 400 - 600 mL. The water content was detected to be no higher than 0.10%; if the water content was higher than 0.1%, it was repeatedly concentrated by adding tetrahydrofuran until the water content was no higher than 0.10%. It was cooled to room temperature, and 47 g of sodium azide was added to the reaction kettle; and it was cooled to -5 - 5 °C. While controlling the temperature at -5 - 5 °C, 78 g of iodine chloride was slowly added dropwise. After the addition was completed, the reaction was kept warm for 1 - 2 hours, and TLC showed that the reaction was completed. If not completed, sodium azide and iodine chloride were added (mass ratio: sodium azide: iodine chloride = 5:8) until the reaction was complete. After the reaction was completed, it was quenched with 20% sodium thiosulfate and extracted with ethyl acetate (500 mL * 3). The combined organic phases were washed with saturated sodium chloride solution (500 mL * 2). The organic phase was concentrated under reduced pressure to about 200 mL, 1000 mL of dichloromethane was added, and it was concentrated under reduced pressure to about 200 mL. 1000 mL of dichloromethane was added, and it was concentrated under reduced pressure to about 200 mL. 500 mL of n - heptane was added dropwise with stirring, the temperature was lowered to 0 - 10 °C, and it was kept warm and stirred for 2 - 3 hours. It was filtered, the filter cake was rinsed with n - heptane, and dried in vacuo at 30 - 40 °C to obtain 85.0 g of a white solid compound VII, and the total molar yield of the two steps was 76.2%.

[0140] Example 5: Synthesis of Compound VIII

[0141]

[0142] 100 g of compound VII, 102 g of triethylamine (4.0 equivalents), 3.11 g of 4 - dimethylaminopyridine, and 1000 mL of dichloromethane were added to the reaction kettle and cooled to -5 - 5 °C. While controlling the temperature at -5 - 5 °C, 2.0 equivalents of acyl chloride or acid anhydride were slowly added dropwise. After the addition was completed, the reaction was kept warm for 1 - 2 hours. 1000 mL of dichloromethane was added to the reaction kettle, and the pH was adjusted to 6 - 7 with 0.2 N hydrochloric acid. The layers were separated, and the organic phase was washed successively with 500 mL of water, 500 mL of saturated sodium bicarbonate solution, and 500 mL of water. The organic phase was concentrated under reduced pressure to 800 - 900 mL, 1000 mL of toluene was added, and it was concentrated under reduced pressure to 900 - 1000 mL. It was cooled to 20 - 30 °C, kept warm and stirred for 2 - 4 hours, filtered, and the filter cake was rinsed with 300 mL of toluene and dried under reduced pressure to obtain a white solid.

[0143] Molar yield: 85.1% (R a = benzoyl), MS: 604.8 (M + H + ),

[0144] Molar yield: 82.0% (R a = trifluoroacetyl), MS: 588.8 (M + H + ).

[0145] Example 6: Synthesis of Compound IX

[0146]

[0147] 100 g of compound VIII, 400 g of water, 500 mL of dichloromethane, 2.2 equivalents of disodium hydrogen phosphate, 1.35 equivalents of tetrabutylammonium hydrogen sulfate, and 1.1 equivalents of m-chlorobenzoic acid were added to a reaction kettle. The temperature was adjusted to 20 - 30 °C, and under temperature control, 4.0 eq of m-chloroperbenzoic acid was added in batches. After addition, the mixture was stirred at 20 - 30 °C for 0.5 h. Under temperature control at 20 - 30 °C, 1.9 equivalents of disodium hydrogen phosphate were added, and 2.0 equivalents of m-chloroperbenzoic acid were added in batches. After addition, the reaction was carried out with heat preservation for 15 - 16 h. After the reaction was completed, it was quenched with 18% sodium sulfite solution, filtered, and the filter cake was rinsed with dichloromethane. The filtrate was allowed to stand, separated, and the organic phase was adjusted to pH 8 - 9 with sodium carbonate and then separated. The organic phase was washed with 5% sodium bicarbonate solution (500 mL * 3) and washed with 500 mL of water. The organic phase was concentrated to 200 - 300 mL, cooled to 20 - 30 °C, 800 mL of n-heptane was added dropwise, stirred with heat preservation, filtered, the filter cake was washed with 200 mL of n-heptane, and dried in vacuo to obtain a white solid compound IX.

[0148] Molar yield: 85.1% (R a = benzoyl), MS: 634.9 (M + H + ), purity (HPLC): 98.5%;

[0149] Molar yield: 79.2% (R a = trifluoroacetyl), MS: 618.9 (M + H + ), purity (HPLC): 98.2%.

[0150] Example 7: Synthesis of Azvudine

[0151]

[0152] 100 g of compound IX and 500 mL of methanol were added to a reaction kettle. The temperature was adjusted to 20 - 30 °C, and ammonia gas was introduced under temperature control until the reaction was complete. Then it was concentrated under reduced pressure until no liquid flowed out. 500 mL of water and 500 mL of ethyl acetate were added, and the temperature was raised to 35 - 45 °C. After separation, the aqueous phase was washed with ethyl acetate (500 mL * 2), and the combined organic phase was extracted with 300 mL of water. The aqueous phases were combined, and under temperature control not higher than 40 °C, it was concentrated under reduced pressure to 0.5 - 1 L and then filtered. The filter cake was rinsed with ethyl acetate to obtain a pale yellow solid.

[0153] Molar yield: 82.5% (R a = benzoyl), purity (HPLC): 99.35%,

[0154] Molar yield: 85.2% (Ra = trifluoroacetyl group), purity (HPLC): 99.42%,

[0155] MS: 286.9 (M+H + )。

Claims

1. A method for preparing a compound represented by Formula IX, characterized in that, It includes the following steps: In a solvent, under the action of an inorganic salt, a phase transfer catalyst, and m-chloroperbenzoic acid, the compound shown in Formula VIII and m-chlorobenzoic acid are subjected to the following reaction, and then crystallization is carried out to obtain the compound shown in Formula IX; wherein, R a is benzoyl or trifluoroacetyl; The inorganic salt is disodium hydrogen phosphate; The molar ratio of the m-chloroperbenzoic acid to the compound shown in Formula VIII is 6-8:1; The molar ratio of the inorganic salt to the compound shown in Formula VIII is 4-6:

1.

2. The preparation method of the compound shown by Formula IX as described in Claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The solvent is a mixed solvent of water and a halogenated hydrocarbon solvent; (2) The phase transfer catalyst is tetrabutylammonium hydrogensulfate; (3) The molar ratio of the inorganic salt to the compound shown in Formula VIII is 4:1; (4) The molar ratio of the phase transfer catalyst to the compound shown in Formula VIII is 1-2:1; (5) The molar ratio of the m-chlorobenzoic acid to the compound shown in Formula VIII is 1-2:1; (6) The molar ratio of the m-chloroperbenzoic acid to the compound shown in Formula VIII is 6:1; (7) The temperature of the reaction is 20-30 °C; (8) The solvent for the crystallization is an alkane solvent.

3. The preparation method of the compound represented by Formula IX according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The halogenated hydrocarbon solvent is one or more of DCM, DCE, and chloroform; (2) The volume ratio of the water to the halogenated hydrocarbon solvent is 10-3:5; (3) The molar ratio of the phase transfer catalyst to the compound shown in Formula VIII is 1.35:1; (4) The molar ratio of the m-chlorobenzoic acid to the compound shown in Formula VIII is 1.1:1; (5) The m-chloroperbenzoic acid is added in batches; (6) The solvent for the crystallization is n-heptane; (7) The temperature of the crystallization is 20-30 °C.

4. The preparation method of the compound shown by Formula IX according to claim 3, characterized in that, It satisfies one or more of the following conditions: (1) The volume ratio of the water to the halogenated hydrocarbon solvent is 4:5; (2) The inorganic salt is added in batches; (3) The m-chloroperbenzoic acid is added in two batches. The first batch is added with 0.5-0.8 times the equivalent amount of the total amount of m-chloroperbenzoic acid, and the second batch is added with the remaining amount; (4) The crystallization is carried out on the concentrated solution of the compound shown in Formula IX; the volume ratio of the concentrated solution to the crystallization solvent is 1:2-1:

4.

5. The preparation method of the compound shown in Formula IX as described in claim 4, characterized in that, The inorganic salt is added in two batches. The first batch is added with 0.4-0.6 times the equivalent amount of the total amount of the inorganic salt, and the second batch is added with the remaining amount.

6. The preparation method of the compound shown by Formula IX according to any one of claims 1-5, characterized in that, It also includes the preparation method of the compound shown in Formula VIII, which includes the following steps: In a solvent, under the action of a base, the compound shown in Formula VII and an amino protecting reagent are subjected to the following reaction to obtain the compound shown in Formula VIII; Among them, the amino protecting reagent is benzoyl chloride, benzoic anhydride, trifluoroacetyl chloride or trifluoroacetic anhydride, where R a is benzoyl or trifluoroacetyl.

7. The preparation method of the compound shown in Formula IX according to claim 6, characterized in that, In the preparation method of the compound shown in Formula VIII, the reaction satisfies one or more of the following conditions: (1) The solvent is a halogenated alkane solvent; (2) The base is an organic base; (3) The molar ratio of the base to the compound shown in Formula VII is 2-5:1; (4) The molar ratio of the compound shown in Formula VII to the amino protecting reagent is 1.5-3:1; (5) The reaction also includes DMAP; the molar ratio of DMAP to the compound shown in Formula VII is 1:5 to 20; (6) The temperature of the reaction is -5 - 5 °C.

8. The preparation method of the compound shown by Formula IX as described in Claim 7, characterized in that, In the method for preparing the compound shown in Formula VIII, the reaction satisfies one or more of the following conditions: (1) The solvent is DCM, DCE or chloroform; (2) The base is pyridine, triethylamine or diisopropylamine; (3) The molar ratio of the base to the compound shown in Formula VII is 4:1; (4) The molar ratio of the compound shown in Formula VII to the amino protecting reagent is 2:1; (5) The molar ratio of DMAP to the compound shown in Formula VII is 1:9 to 10.

9. The preparation method of the compound shown by Formula IX as described in Claim 6, characterized in that, It also includes a method for preparing the compound VII, which includes the following steps: In a solvent, react the compound shown in Formula VI, sodium azide and iodine chloride as shown below to obtain the compound shown in Formula VII; 10. The preparation method of the compound shown by formula IX as described in claim 9, characterized in that, In the method for preparing the compound VII, the reaction satisfies one or more of the following conditions: (1) The solvent is an ether solvent; (2) The molar ratio of sodium azide to the compound shown in Formula VI is 1 - 3:1; (3) The molar ratio of iodine chloride to the compound shown in Formula VI is 1 - 2:1; (4) The molar ratio of iodine chloride to sodium azide is 5:8; (5) The temperature of the reaction is -5 - 5 °C.

11. The method for preparing the compound represented by Formula IX according to claim 10, characterized in that, In the method for preparing the compound VII, the reaction satisfies one or more of the following conditions: (1) The solvent is tetrahydrofuran; (2) The molar ratio of sodium azide to the compound shown in Formula VI is 2.4 - 2.6:1; (3) The molar ratio of iodine chloride to the compound shown in Formula VI is 1.6 - 1.8:

1.

12. The preparation method of the compound represented by Formula IX according to claim 9, characterized in that, It also includes a method for preparing the compound VI, which includes the following steps: In a solvent, react the compound shown in Formula V and sodium methoxide to obtain the compound shown in Formula VI; 13. The preparation method of the compound represented by Formula IX as described in claim 12, characterized in that, In the method for preparing the compound VI, the reaction satisfies one or more of the following conditions: (1) The solvent is an alcohol solvent or an ether solvent; (2) The molar ratio of sodium methoxide to the compound shown in Formula V is 2 - 5:1; (3) The temperature of the reaction is 0 - 10 °C.

14. The preparation method of the compound represented by Formula IX according to claim 13, characterized in that, In the method for preparing the compound VI, the reaction satisfies one or two of the following conditions: (1) The solvent is methanol or tetrahydrofuran; (2) The molar ratio of sodium methoxide to the compound shown in Formula V is 3.4 - 3.6:

1.

15. The preparation method of the compound shown by formula IX as described in claim 12, characterized in that, It also includes a method for preparing the compound V, which includes the following steps: In a solvent, react the compound shown in Formula IV, imidazole, triphenylphosphine and iodine as shown below to obtain the compound shown in Formula V; 16. The preparation method of the compound represented by Formula IX as described in claim 15, characterized in that, In the method for preparing the compound V, the reaction satisfies one or more of the following conditions: (1) The solvent is an ether solvent; (2) The molar ratio of imidazole to the compound shown in Formula IV is 1 - 3:1; (3) The molar ratio of triphenylphosphine to the compound shown in Formula IV is 1 - 3:1; (4) The molar ratio of the iodine to the compound shown in Formula IV is 1 to 3:1; (5) The temperature of the reaction is 20 - 30 °C.

17. The preparation method of the compound represented by Formula IX as described in claim 16, characterized in that, In the method for preparing the compound V, the reaction satisfies one or more of the following conditions: (1) The solvent is tetrahydrofuran; (2) The molar ratio of the imidazole to the compound shown in Formula IV is 2:1; (3) The molar ratio of the triphenylphosphine to the compound shown in Formula IV is 1.5:1; (4) The molar ratio of the iodine to the compound shown in Formula IV is 1.5:

1.

18. The preparation method of the compound represented by Formula IX as described in claim 15, characterized in that, It also includes a method for preparing the compound IV, which comprises the following steps: reacting the compound shown in Formula III with an ammonia - methanol solution as shown below to obtain the compound shown in Formula IV; Among them, R a is benzoyl or trifluoroacetyl.

19. The method for preparing the compound represented by Formula IX according to claim 18, characterized in that, In the method for preparing the compound IV, the reaction satisfies one or more of the following conditions: (1) The concentration of the ammonia - methanol solution is 7 mol / L; (2) The temperature of the reaction is 25 - 35 °C; (3) When R a is benzoyl, the reaction time is 50 - 60 hours; (4) When R a is trifluoroacetyl group, the reaction time is 15 - 20 hours.

20. The method for preparing the compound represented by Formula IX according to claim 18, characterized in that, It also includes a method for preparing the compound III, which comprises the following steps: (1) React the amino R a protected cytosine, hexamethyldisilazane and ammonium sulfate; obtain a mixture; (2) In a solvent, reacting the compound shown in Formula II with the mixture from step (1) as shown below to obtain the compound shown in Formula III; Among them, the R a is benzoyl or trifluoroacetyl.

21. The preparation method of the compound represented by Formula IX as described in claim 20, characterized in that, In the method for preparing the compound III, the reaction satisfies one or more of the following conditions: (1) The amino group R a The molar ratio of the amino-protected cytosine to the compound shown in Formula II is 1 to 3:1; (2) The molar ratio of the hexamethyldisilazane to the compound shown in Formula II is 5 to 20:1; (3) The molar ratio of the ammonium sulfate to the compound shown in Formula II is 1 to 2:1; (4) In step (1), the temperature of the reaction is 130 - 140 °C; (5) In step (2), the solvent is a halogenated hydrocarbon solvent; (6) In step (2), the temperature of the reaction is 65 - 75 °C.

22. The preparation method of the compound represented by Formula IX according to claim 21, characterized in that, In the method for preparing the compound III, the reaction satisfies one or more of the following conditions: (1) The amino group R a The molar ratio of the protected cytosine to the compound shown in Formula II is 2:1; (2) The molar ratio of the hexamethyldisilazane to the compound shown in Formula II is 8 to 10:1; (3) The molar ratio of the ammonium sulfate to the compound shown in Formula II is 1.2 to 1.4:1; (4) In step (2), the solvent is dichloromethane.

23. The preparation method of the compound represented by Formula IX as described in claim 20, characterized in that, It also includes a method for preparing the compound II, which comprises the following steps: reacting the compound shown in Formula I with a hydrogen bromide - glacial acetic acid solution in a solvent as shown below to obtain the compound shown in Formula II; 24. The preparation method of the compound represented by Formula IX as described in claim 23, characterized in that, In the method for preparing the compound II, the reaction satisfies one or more of the following conditions: (1) The solvent is a halogenated hydrocarbon solvent; (2) The concentration of the hydrogen bromide - glacial acetic acid solution is 33%; (3) The temperature of the reaction is 15 - 25 °C.

25. The preparation method of the compound represented by Formula IX according to claim 24, characterized in that, In the method for preparing the compound II, the solvent is dichloromethane.

26. A preparation method of azvudine, characterized in that, It comprises the following steps: (1) Preparing the compound shown in Formula IX according to the preparation method of the compound shown in Formula IX as described in any one of claims 1 - 25; (2) In a solvent, reacting the compound shown in Formula IX with ammonia as shown below to obtain azvudine; The said R a is benzoyl or trifluoroacetyl.

27. The preparation method of azvudine according to claim 26, wherein, The temperature of the reaction is 20 - 30 °C.

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