A process for the preparation of an inhibitor of hepatitis b virus nucleocapsid

Abstract

The present invention relates to a process for the preparation of an inhibitor of hepatitis B virus core. In particular, the process of the present invention provides a novel process for the preparation of a compound of formula (I) (each group is as defined in the specification) by optimisation of the process. The process can significantly improve the yield, improve the purity of the product and can significantly reduce genotoxic impurities in the product. The present invention also discloses novel intermediates for the preparation of a compound of formula (I).

Description

Technical Field

[0001] This invention relates to the fields of pharmaceuticals and fine chemicals, specifically to a method for preparing a hepatitis B virus nucleocapsid inhibitor and a novel intermediate for the preparation of the inhibitor. Background Technology

[0002]

[0003] The compounds represented by Formula I are hepatitis B virus nucleocapsid inhibitors, developed by Shanghai Zhimeng Pharmaceutical Technology Co., Ltd., and represent a new class of hepatitis B drugs currently in clinical trials. Currently marketed hepatitis B drugs can control hepatitis B virus replication to a limited extent and slow the progression of cirrhosis, but few can achieve a cure for chronic hepatitis B. Compounds of Formula I improve the functional cure rate of chronic hepatitis B by inhibiting HBV nucleocapsid formation, and preclinical studies have shown that they have good safety and efficacy.

[0004] Therefore, developing and optimizing the preparation process of the above-mentioned compounds is of great significance for reducing their production costs, promoting their marketization, and enabling more patients to benefit from them as soon as possible. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing compound I with high yield, mild conditions, high product purity, low side reactions, convenient operation, and avoidance of using genotoxic intermediates.

[0006] Another objective of this invention is to provide a novel intermediate for the preparation of compounds of formula I, namely compounds of formula II and formula III.

[0007] A first aspect of the present invention provides a method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemic mixture thereof, comprising the following steps:

[0008]

[0009] 1) In the presence of a catalyst, compound II is cyclized to obtain compound I;

[0010] R1, R2, R3, R4 and R5 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, amino, hydroxyl, nitro, where substitution refers to being substituted by one or more (e.g. 2, 3, 4 or 5) substituents selected from the group consisting of: halogen, nitro, amino, hydroxyl.

[0011] R6 is selected from the following group: hydrogen, deuterium, halogen, amino, hydroxyl;

[0012] n is 0, 1, 2, 3 or 4;

[0013] Q is selected from the following group: C6-C10 aryl groups substituted or unsubstituted with one or more halogens, and 6-10 heteroaryl groups substituted or unsubstituted with one or more halogens containing 1-3 heteroatoms selected from N, O and S.

[0014] X is a halogen.

[0015] In another preferred embodiment, the stereoisomer described in Formula I is an R isomer.

[0016] In another preferred embodiment, the stereoisomer described in Formula I is an S-isomer.

[0017] In another preferred embodiment, the R isomer has the structure shown by the following formula IR:

[0018]

[0019] The groups are as defined above.

[0020] In another preferred embodiment, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, deuterium and halogen.

[0021] In another preferred example, n is 0.

[0022] In another preferred embodiment, Q is a halogen-substituted C6-C10 aryl group, preferably a halogen-substituted phenyl group or a phenyl group co-substituted with deuterium and halogen.

[0023] In another preferred embodiment, X is bromine or iodine.

[0024] In another preferred embodiment, in step 1), the catalyst is selected from the group consisting of: cuprous iodide, cuprous chloride, cuprous bromide, copper sulfate, copper powder, cuprous oxide, cuprous hydroxide, cuprous acetate, copper citrate, copper methanesulfonate, copper fluoroborate, basic copper carbonate, copper gluconate, cuprous tartrate, copper acetylacetone, 8-hydroxyquinoline copper, cuprous thiocyanate, cuprous nitrate, cuprous cyanide, copper oxalate, copper phosphate, cuprous trifluoromethanesulfonate, copper formate, copper selenide, copper dichloro(1,10-phenanthroline)copper, (1,10-phenanthroline)(trifluoromethyl)copper, CuTC, or combinations thereof.

[0025] In this invention, CuTC refers to cuprous thiophene-2-carboxylate (I).

[0026] In another preferred embodiment, step 1) is carried out in the presence of a catalyst and a ligand selected from the group consisting of:

[0027]

[0028] In another preferred embodiment, in step 1), the catalyst is copper powder.

[0029] In another preferred embodiment, in step 1), the molar ratio of the catalyst to the compound of formula II is 0.2-3, more preferably 0.4-2, more preferably 0.6-1.5, and most preferably 0.8-1.2.

[0030] In another preferred embodiment, step 1) is performed at 40-150°C, more preferably 50-130°C, and even more preferably 60-110°C.

[0031] In another preferred embodiment, the reaction time of step 1) is 0.1-36 h, more preferably 0.3-10 h, and even more preferably 0.4-5 h.

[0032] In another preferred embodiment, in step 1), the catalyst is selected from the group consisting of cuprous oxide, cuprous chloride, cuprous iodide, or combinations thereof.

[0033] In another preferred embodiment, step 1) is carried out in the presence of a catalyst and a ligand, wherein the molar ratio of the catalyst to the compound of formula II is 0.0001-1 (preferably 0.001-0.5, more preferably 0.005-0.2, and most preferably 0.01-0.1);

[0034] The molar ratio of the catalyst to the ligand is 0.2-5.0 (preferably 0.5-2.0, more preferably 0.8-1.2).

[0035] In another preferred embodiment, step 1) is carried out in the presence of an alkali.

[0036] In another preferred embodiment, in step 1), the base is selected from the group consisting of 1,5-diazabicyclo[5.4.0]undec-5-ene, 1,8-diazabicycloundec-7-ene (DBU), cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, or combinations thereof.

[0037] In another preferred embodiment, in step 1), the molar ratio of the base to the compound of formula II is 0.5-5.0, more preferably 1.0-2.0.

[0038] In another preferred embodiment, the compound of formula I is selected from the group consisting of:

[0039] In another preferred embodiment, prior to step 1), the method further includes the following steps:

[0040]

[0041] 2) Reacting compound III with a halogenating agent to obtain compound II;

[0042] In the compound of formula III, R1, R2, R3, R4, R5, R6, n, X and Q are as defined in claim 1.

[0043] In another preferred embodiment, in step 2), the halogenated reagent is selected from the group consisting of N-iodosuccinimide (NIS), iodine, 1,3-diiodo-5,5-dimethylhydantoin, N-bromosuccinimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, chlorine, N-chlorosuccinimide, N-bromosuccinimide (NBS), or combinations thereof.

[0044] In another preferred embodiment, in step 2), the molar ratio of the halogenated reagent to the compound of formula III is 0.8-2, more preferably 0.9-1.8, and even more preferably 1.1-1.5.

[0045] In another preferred embodiment, step 2) is performed at 40-100°C, preferably 50-90°C, and more preferably 55-85°C.

[0046] In another preferred embodiment, step 2) is carried out in a solvent selected from the group consisting of acetonitrile, dimethylformamide, or combinations thereof, preferably acetonitrile.

[0047] In another preferred embodiment, prior to step 2), the preparation method further includes the following steps:

[0048] 3) The compound of formula IV is reacted with a carbonylating agent to obtain the isocyanate intermediate of formula IV-1;

[0049]

[0050] 4) The isocyanate intermediate of formula IV-1 obtained in step 3) is reacted directly with an amination reagent in the system without separation to obtain compound of formula III;

[0051] In the compounds of formula IV and the isocyanate intermediates of formula IV-1, R1, R2, R3, R4, R5, R6, n and Q are as defined in claim 1.

[0052] In another preferred embodiment, the compound of formula IV is an R isomer.

[0053] In another preferred embodiment, in step 3), the carbonylating agent is selected from the group consisting of triphosgene, CDI, potassium isocyanate, or combinations thereof; and / or

[0054] In step 4), the amination reagent is selected from the group consisting of ammonia water, ammonia gas, organic solutions of ammonia, or combinations thereof.

[0055] In another preferred embodiment, in step 3), the carbonylating agent is triphosgene.

[0056] In another preferred embodiment, in step 3), the molar ratio of the carbonylating agent to the compound of formula IV is 0.2-2, more preferably 0.25-1.5, and even more preferably 0.3-1.2.

[0057] In another preferred embodiment, steps 3) and / or 4) are carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, imidazole, or combinations thereof.

[0058] In another preferred embodiment, in step 3) and / or step 4), the base is pyridine.

[0059] In another preferred embodiment, in step 3) and / or step 4), the molar ratio of the base to the compound of formula IV is 0.5-5, more preferably 1.0-4.0, and even more preferably 2.0-3.5.

[0060] In another preferred embodiment, the molar ratio of the amination reagent to the compound of formula IV is 1.0-30, more preferably 3-20, and even more preferably 8.0-15.

[0061] In another preferred embodiment, steps 3) and / or 4) are carried out in a solvent selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, dioxane, toluene, xylene, ethyl acetate, acetonitrile, ethylene glycol dimethyl ether, or combinations thereof.

[0062] In another preferred embodiment, steps 3) and / or 4) are carried out in dichloromethane.

[0063] In another preferred embodiment, step 3) is performed at -40-40°C, preferably -30-30°C, and more preferably -20-20°C.

[0064] In another preferred embodiment, step 4) is performed at -40-10°C, more preferably -30-5°C, and even more preferably -20-0°C.

[0065] In another preferred embodiment, step 4) involves quenching the reaction with water between 10-40°C.

[0066] A second aspect of the present invention provides an intermediate of Formula II.

[0067]

[0068] R1, R2, R3, R4, R5, R6, n, X, and Q are as defined in the first aspect of this invention.

[0069] In another preferred embodiment, the intermediate shown in Formula II is selected from the following group:

[0070] A third aspect of the present invention provides an intermediate of Formula III.

[0071]

[0072] R1, R2, R3, R4, R5, R6, n, and Q are as defined in the first aspect of this invention.

[0073] In another preferred embodiment, the intermediate shown in Formula III is selected from the group consisting of:

[0074] A fourth aspect of the present invention provides the use of an intermediate of Formula II as described in the second aspect of the present invention or an intermediate of Formula III as described in the third aspect of the present invention for preparing a compound of Formula I as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemic mixture thereof.

[0075] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0076] Through long-term and in-depth research, the inventors have obtained a new method for preparing compound I and a new intermediate for preparing compound I by optimizing the process. This method offers high yield, high product purity, mild conditions, safe and convenient operation, and avoids the generation of genotoxic intermediates in the last three steps. Specifically, the method of this invention starts from a key aniline intermediate, forms a urea, and then uses the Ullmann reaction to cyclize and synthesize the hepatitis B virus nucleocapsid inhibitor of this invention. Based on this, the inventors completed this invention.

[0077] the term

[0078] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0079] In this invention, the term "halogen" refers to F, Cl, Br or I, preferably Cl, Br or I.

[0080] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0081] In this invention, the term "C6-C10 aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0082] The term "multiple" refers to 2, 3, or 4.

[0083] The term "6-10-membered heteroaryl" refers to an aromatic heterocycle containing 1-3 heteroatoms selected from N, O, and S and 3-9 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0084] The term "room temperature" refers to 10-40°C, preferably 15-30°C, and even more preferably 20-30°C.

[0085] Formula I compound

[0086]

[0087] R1, R2, R3, R4, R5, R6, n, and Q are defined above.

[0088] The compound of formula I obtained by the synthetic method described in this invention exhibits significantly higher yield and purity. Furthermore, the synthetic process is simple, avoiding high-risk operations such as nitration, and circumventing the use of column chromatography and other processes unsuitable for large-scale production. The final three intermediates in the synthesis of this compound were all negative for genotoxicity by AMES testing, thus reducing the risk of excessive genotoxic impurities in the compound.

[0089] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0090] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0091] Existing synthesis methods

[0092] With compounds For example, referring to the disclosure of Example 6 of WO2017173999 A1, the compound was prepared as follows:

[0093]

[0094] As shown in Example 6 of WO2017173999 A1, step 3 requires acetic anhydride as a solvent and concentrated nitric acid for nitration, resulting in relatively harsh reaction conditions. The nitration reaction generates a large amount of heat and carries the potential risk of multiple nitrations, which is detrimental to scale-up production and poses significant safety hazards in later stages of production.

[0095] As shown in Example 6 of WO2017173999 A1, the final cyclization reaction requires four steps starting from intermediate 26. The yields of the four steps are 65.3%, 32.6%, 69.3%, and 24.9%, respectively, which are relatively low. Furthermore, the final step requires column chromatography purification to obtain the product, making it unsuitable for large-scale production.

[0096] As shown in Example 6 of WO2017173999 A1, in the above preparation route, intermediates 27, 28, and 29 generated in steps 3-5 all contain nitrobenzene or o-phenylenediamine structures, posing a potential risk. Any intermediate in the active pharmaceutical ingredient requires the development of ppm-level analytical methods and strict control. Residues of these intermediates can affect the quality control of the active pharmaceutical ingredient. If not completely removed, it will fail to meet stringent clinical requirements and hinder the large-scale preparation of safe and compliant clinical samples.

[0097] Synthesis method of the present invention

[0098] Unlike the existing synthetic methods mentioned above, compound 4 is used. For example, the present invention adopts the following synthetic route:

[0099]

[0100] Includes the following steps:

[0101] 1) Compound 24 and compound 31 react with p-toluenesulfonic acid to form compound 32;

[0102] 2) Compound 32 was reduced to compound 33 by hydrogen under the catalysis of Raney nickel;

[0103] 3) The racemic compound 33 was separated by chiral chromatography, supercritical fluid chromatography (SFC), or other separation methods to obtain chiral pure compound 34;

[0104] 4) Compound 34 reacts with triphosgene and ammonia in the presence of pyridine to form compound 17;

[0105] 5) Compound 17 was converted to compound 9 by pyridine p-toluenesulfonate catalysis;

[0106] 6) Compound 9 reacts with copper powder and DBU as catalysts to form compound 4;

[0107] Step 1) is carried out in a single solvent or a combination of solvents, including but not limited to toluene, xylene, methanol, ethanol, or combinations thereof. Toluene is preferred.

[0108] The acid in step 1) includes, but is not limited to, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid, with p-toluenesulfonic acid being preferred.

[0109] In step 1), the amount of acid used relative to the mass ratio of compound 31 is 0.1-1, preferably 0.25.

[0110] In step 1), the molar ratio of compound 24 to compound 31 is 0.90 eq.-1.5 eq., preferably 1.2 eq.

[0111] The temperature in step 1) is 60-120℃, preferably 110-120℃.

[0112] In step 2), the reduction of nitro groups can be achieved using reducing agents such as iron powder, zinc powder, sodium hydrosulfite, and tin dichloride, or by catalytic hydrogenation.

[0113] The catalysts used in the catalytic hydrogenation reaction of the nitro group in step 2) include, but are not limited to, palladium on carbon, platinum on carbon, Raney nickel, palladium hydroxide on carbon, and preferably Raney nickel.

[0114] In step 2), if Raney nickel is used for the catalytic hydrogenation of nitro, its mass ratio to compound 32 is 0.1-0.5, preferably 0.3.

[0115] Step 2) is carried out in a single solvent or a combination of solvents, including but not limited to ethanol, methanol, ethyl acetate, toluene, xylene, methyltetrahydrofuran, tetrahydrofuran and water, preferably ethyl acetate.

[0116] It should be understood that the compounds of formula IV of the present invention (such as compound 33) can be prepared by the above-described preparation method, or by methods known in the prior art, or may be commercially available products.

[0117] Compared with the existing synthetic methods described above, the synthetic method of this invention obtains the compound of formula I represented by compound 4 by optimizing the original step 3) and subsequent processes. The yields of the three-step reaction are 90.86%, 86.9%, and 83.5%, respectively, with an overall yield of 65.9%. The overall yield is significantly improved compared to the 44.6% overall yield of the four-step reaction for the synthesis of racemates in previous literature (yields of 70%, 93.8%, 90%, and 75.4%, respectively). In the synthetic method of this invention, intermediates 17 and 9 were tested and found to be free of warning structures, effectively avoiding the influence of related impurities on the compound of formula I represented by compound 4. The last three steps of this method avoid the use of column chromatography for purification, effectively improving purification efficiency. This method also avoids high-risk operations such as nitration in the original synthetic process, making it more suitable for scale-up production. This method has the advantages of high yield, controllable impurities, convenient operation, and suitability for kilogram-scale preparation.

[0118] Compounds of Formula II and Compounds of Formula III

[0119]

[0120] R1, R2, R3, R4, R5, R6, n, X, and Q are defined as above.

[0121]

[0122] R1, R2, R3, R4, R5, R6, n, and Q are defined above.

[0123] Upon examination, it was found that most of the compounds of formula II and formula III of this invention do not contain warning structures such as primary aniline or nitrobenzene, which is very beneficial for the quality control of the target product, formula I.

[0124] Compared with the prior art, the present invention has the following main advantages:

[0125] (1) The preparation method has the advantages of high yield, safe process operation, easy scale-up, mild conditions, and no need for column chromatography separation in the chemical synthesis steps; the preparation method also has the advantage of low cost;

[0126] (2) The method described above can avoid the use of intermediates with warning structures, effectively reducing the difficulty of impurity control in the preparation process and the final product.

[0127] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0128] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0129] Example 1: Synthesis of Compound 32

[0130]

[0131] At room temperature, toluene (303 kg), compound 31 (35 kg), and p-toluenesulfonic acid (7 kg) were added sequentially to a reaction vessel. The mixture was heated to 105–115 °C and stirred to remove water for 1 hour. The temperature was then lowered to 60–80 °C, and compound 24 (28.33 kg) was added to the reaction vessel. The temperature was raised to 110–120 °C, and the mixture was refluxed to remove water for 12 hours. The temperature was then lowered to 78–80 °C, and additional p-toluenesulfonic acid (180 g) and compound 24 (505 g) were added. The mixture was heated and refluxed for another 7–8 hours to remove water. HPLC control showed that most of compound 31 was completely converted. The reaction system was then cooled to 50–55 °C, methanol (35.4 kg) was added, and the mixture was stirred for 2 hours. After cooling, the mixture was filtered, and the resulting filter cake was washed with a small amount of toluene / methanol solution. After drying, 40.5 kg of compound 32 was obtained, with a yield of 72.5% and an HPLC purity of 98%. MS: [M+H] + =551.4 / 553.4

[0132] Example 2: Synthesis of compound 33

[0133]

[0134] At room temperature, ethyl acetate (8 L), compound 32 (178.3 g, 1.0 eq.), triethylamine (80 mL), and Raney nickel (48 g, 27%) were added to a reaction flask. The reaction system was purged with hydrogen three times and reacted at room temperature for 8 h. HPLC control showed complete conversion of compound 32. The mixture was filtered, and the filtrate was concentrated to give 160.4 g of compound 33. The yield was 95.1%, and the HPLC purity was 98.2%. MS: [M+H] + =521.5 / 523.5

[0135] Example 3: Resolution of compound 33

[0136]

[0137] 5 g of racemic compound 33 was separated by chiral chromatography with methanol as the main mobile phase. Chiral separation yielded 1.3 g of compound 34 (ee > 99%) and 1.78 g of compound 34-S.

[0138] Example 4 Synthesis of Compound 17

[0139]

[0140] Prepare a triphosgene (BTC) solution (170.75 g, 0.58 mol) in 6 L of dichloromethane at -10 °C. Slowly add a 4.8 L solution of compound 34 (600 g, 1.15 mol) in dichloromethane to the above triphosgene solution in dichloromethane. Stir for 30 minutes. At -5 °C, add a 1.2 L solution of pyridine (273.07 g, 3.45 mol) in dichloromethane, stirring for another 20 minutes after the addition is complete. At -5 °C, add 0.9 L of ammonia solution, continuing stirring for at least 30 minutes.

[0141] HPLC showed the reaction was complete. After washing twice with water, the solution was concentrated. The product was dissolved in ethyl acetate and then slurried with n-heptane. The filter cake was collected, dried, and 590 g of compound 17 was obtained, yield: 90.86%, purity: 98.45%. MS: [M+H] + =563.01 / 565.02

[0142] Example 5: Synthesis of Compound 9

[0143]

[0144] Compound 17 (190 g, 0.337 mol) was dissolved in acetonitrile (1.3 L), and PPTS (pyridine p-toluenesulfonate) (42.3 g, 0.168 mol) and NIS (N-iodosuccinimide) (90.88 g, 0.4 mol) were added. After reacting overnight at 56 °C, a large amount of solid precipitated. After passing HPLC analysis, the mixture was cooled to 20-30 °C and washed with 5% sodium sulfite solution. The solid was collected by filtration and washed with MTBE (methyl tert-butyl ether). After drying, 202 g of compound 9 was obtained, yield: 86.9%, purity: 98.75%. MS: [M+H] + =689.84 / 691.84

[0145] Example 6 Synthesis of Compound 4

[0146]

[0147] Compound 9 (200 g, 0.29 mol) was dissolved in DMSO (1.6 L), and copper powder (18.5 g, 0.29 mol) and 1,5-diazabicyclo[5.4.0]undec-5-ene (48.5 g, 0.319 mol) were added. The reaction was carried out at 106 °C for 2 hours. After passing HPLC monitoring, activated carbon was added. The mixture was filtered, and the filtrate was collected. The filtrate was added to a 7% aqueous acetic acid solution and stirred for 20 minutes. The mixture was then filtered, and the filter cake was collected. The obtained filter cake was dissolved in ethyl acetate and THF. The organic phase was washed with 7% dilute acetic acid and 7% sodium bicarbonate (2.0 L), respectively. The obtained organic phase was dried with anhydrous sodium sulfate. The organic solvent was removed by concentration. The mixture was slurried in acetone, filtered, and the filter cake was collected and dried to give 136 g of compound 4, yield: 83.5%, purity: 99.33%.

[0148] MS:[M+H] + =562.5 / 563.4; 1 H NMR(600MHz,DMSO-d6)δ10.48–10.43(m,2H),8.73(s,1H),7.93–7.87(m,2H), 7.75–7.69(m,2H),7.67–7.60(m,2H),7.33–7.26(m,2H),6.73(d,J=7.8Hz,1H ),6.64(s,1H),6.61(dd,J=8.0,1.6Hz,1H),6.03(d,J=1.8Hz,1H),4.30–4.21 (m,2H),3.70(dt,J=14.3,7.3Hz,1H),2.92(dt,J=14.3,7.3Hz,1H),2.69(dt,J =14.5,7.4Hz,1H),2.62(dt,J=14.1,7.0Hz,1H).

[0149] Example 7 Synthesis of Compound 4

[0150]

[0151] Compound 9 (1 g, 1.45 mmol), cuprous oxide (10 mg, 0.07 mmol), ligand L19 (20 mg, 0.07 mmol), and cesium carbonate (1.89 g, 5.79 mmol) were dissolved in dimethyl sulfoxide and reacted at 75 °C for 24 hours. After the reaction was completed under HPLC monitoring, the mixture was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added, followed by separation. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried and concentrated to obtain the crude product. The crude product was slurried in a mixed solution of ethyl acetate and petroleum ether to obtain the final product of compound 4 (520 mg, purity 95.15%, yield 65%). MS: [M+H]+ = 562.1 / 564.1

[0152] In this invention, ligand L19 is N 1 N 2 -bis[(2-thienyl)methyl]oxalamide (N 1 N 2 -bis(thiophen-2-ylmethyl)oxalamide).

[0153] Compared to Example 3 of WO2017173999 A1, the synthesis route, starting from a common intermediate (compound 34 in this patent), requires four steps: nitration, hydrolysis, reduction, and CDI ring closure to achieve the final ring-closure reaction. The yields of the four steps are 70%, 94%, 90%, and 75%, respectively, with an overall yield of 44%. This synthesis is lengthy and yields are low. Furthermore, the final step requires column chromatography purification to obtain the product, making it unsuitable for large-scale production. The synthetic route described in this patent requires only three steps, with a maximum overall yield of 66%. Both production efficiency and overall yield are significantly improved.

[0154] Compared to Example 3 of WO2017173999 A1, the intermediates used in its last three steps are similar to those in Example 6 of the same patent, all containing nitrobenzene or o-phenylenediamine, which carries a potential risk. Related intermediates in the active pharmaceutical ingredient require the development of ppm-level analytical methods and strict control. Such a route is not conducive to the large-scale preparation of safe and compliant clinical samples. The synthetic route of this patent avoids the use of compounds containing similar structures; compounds 17 and 9 are negative in the Ames test, indicating better safety. Correspondingly, production control becomes simpler.

[0155] Example 8 Synthesis of Compound 4

[0156]

[0157] Compound 9 (1.0 g, 1.45 mmol), cuprous chloride (7.17 mg, 0.072 mmol), ligand L21 (18 mg, 4.35 mmol), and cesium carbonate (1.416 g, 4.35 mmol) were dissolved in dimethyl sulfoxide (10 mL) and reacted at 70 °C for 16 hours. After the reaction was completed under HPLC monitoring, the mixture was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried and concentrated to obtain the crude product. The crude product was slurried in a mixed solution of ethyl acetate and petroleum ether to obtain compound 4 as the final product (650 mg, purity 99.76%, yield 80%). MS: [M+H]+=562.0 / 564.1

[0158] In this invention, ligand L21 is N 1N 2 -Bis[(2-furanyl)methyl]oxalamide (N 1 N 2 -bis(furan-2-ylmethyl)oxalamide).

[0159] The following table summarizes the comparison between Examples 6-8 of the present invention and Examples 3 (Comparative Example 1) and 6 (Comparative Example 2) of WO2017173999 A1.

[0160] Synthetic steps from compound 34 to the product 3 3 3 4 4 Overall synthetic yield from compound 34 to the product 65.9％ 51.3％ 63.2％ 44.6％ 3.7％

[0161] Example 9 Synthesis of Compound 35

[0162]

[0163] Compound 17 (1.5 g, 2.66 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), and then NBS (570 mg, 3.19 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (40 mL), and then washed with saturated sodium sulfite aqueous solution (20 mL x 2) and saturated sodium bicarbonate aqueous solution (20 mL x 2), respectively. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 35 (1.7 g, 99%) as a yellow solid.

[0164] LCMS:[M+H] + =644.1

[0165] Example 10 Synthesis of Compound 4

[0166]

[0167] Compound 35 (100 mg, 0.155 mmol, 1.0 eq) was dissolved in DMSO (2 mL), followed by the sequential addition of cuprous iodide (29.6 mg, 0.155 mmol, 1.0 eq) and DBU (47.6 mg, 0.310 mmol, 2.0 eq). After three nitrogen purgings, the reaction mixture was stirred at 120 °C for 21 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 5% citric acid aqueous solution (10 mL x 2) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 20) to give compound 4 (34 mg, 99% purity) as a white solid. LCMS: [M+H] + =562.1

[0168] 1H NMR (400MHz, CDCl3) δ9.88-9.48(m,2H),7.85(s,1H),7.62-7.52(m,6H),7.14-7.10(m,2H),6.79-6 .63(m,3H),5.90(s,1H),4.43-4.26(m,2H),3.96-3.80(m,1H),3.08-2.96(m,1H),2.78-2.68(m,2H)

[0169] Example 11 Synthesis of Compound 37

[0170]

[0171] Compound 36 (2.5 g, 19.51 mmol, 1.0 eq) was dissolved in methanol (30 mL). Ammonium formate (6.2 g, 97.55 mmol, 5.0 eq) was then added, and the reaction mixture was stirred at room temperature for 10 minutes. Palladium on carbon (10%, 300 mg) was added to the reaction mixture, and the temperature was raised to 70 °C and stirred for 20 minutes. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 37 (1.5 g, 78%) as a colorless oil. LCMS: [M+H] + =99.2

[0172] Example 12 Synthesis of Compound 38

[0173]

[0174] Compound 37 (3.7 g, 37.693 mmol, 1.0 eq) was dissolved in chloroform (75 mL), and then tetrabutylammonium tribromide (19 g, 39.578 mmol, 1.05 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated sodium bicarbonate aqueous solution until the pH reached 8. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (neutral alumina, petroleum ether / ethyl acetate = 20 / 1 to 12 / 1) to give compound 38 (2.6 g, 39%) as a brown solid. LCMS: [M+H] + =176.0

[0175] Example 13 Synthesis of Compound 39

[0176]

[0177] Compound 38 (1.5 g, 8.523 mmol, 1.0 eq) was dissolved in acetic acid (24 mL), followed by the addition of concentrated hydrochloric acid (48 mL). The mixture was cooled to -5 °C, and then a solution of sodium nitrite (0.7 g, 10.227 mol, 1.2 eq) in water (9 mL) was added dropwise. The reaction mixture was stirred at -5 °C for 0.5 hours, followed by the addition of stannous chloride (4.0 g, 21.307 mmol, 2.5 eq) in concentrated hydrochloric acid (9 mL), maintaining the temperature between 0 °C and 5 °C during the addition. After the addition was complete, the reaction mixture was stirred between 0 °C and 5 °C for 40 minutes. The mixture was filtered, and the solid was washed with cooled concentrated hydrochloric acid solution. The solid was collected and freeze-dried to give compound 39 (1.74 g, 87%) as a white solid. LCMS: [M+H] + =191.0

[0178] Example 14 Synthesis of Compound 40

[0179]

[0180] Compound 39 (1.74 g, 7.647 mmol, 1.0 eq) was dissolved in ethanol (8 mL), followed by compound 41 (1.05 g, 7.647 mmol, 1.0 eq) and potassium acetate (0.75 g, 7.647 mmol, 1.0 eq). The reaction mixture was stirred at 88 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether (30 mL) was added to the residue and stirred for half an hour. The mixture was filtered, and the resulting solid was washed with petroleum ether and dried under vacuum to give compound 40 (1.34 g, 56%) as a brown solid. LCMS: [M+H] + =311.1

[0181] Example 15 Synthesis of Compound 42

[0182]

[0183] DMF (692 mg, 9.473 mmol, 2.2 eq) was cooled to 0 °C, and then phosphorus oxychloride (1.45 g, 9.473 mmol, 2.2 eq) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0 °C for half an hour. Then, a DMF (9 mL) solution of compound 40 (1.34 g, 4.306 mmol, 1.0 eq) was added dropwise to the above reaction mixture. After the addition was complete, the mixture was heated to room temperature and stirred for 40 minutes, then heated to 70 °C and stirred for 5 hours. The mixture was cooled to room temperature, and then poured into ice water. After filtration, the solid was collected and azeotropically purified with toluene. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give compound 42 (1.0 g, 66%) as a white solid. LCMS: [M+H] + =349.0

[0184] Example 16 Synthesis of Compound 43

[0185]

[0186] Compound 42 (1.0 g, 2.863 mmol, 1.0 eq) was dissolved in toluene (100 mL), followed by the addition of compound 24 (0.77 g, 3.436 mmol, 1.2 eq) and p-toluenesulfonic acid monohydrate (0.27 g, 1.432 mmol, 0.5 eq). The reaction mixture was stirred at 148 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 43 (1.27 g, 80%) as a white solid. LCMS: [M+H] + =555.0

[0187] Example 17 Synthesis of Compound 44

[0188]

[0189] Compound 43 (1.27 g, 2.286 mmol, 1.0 eq) was dissolved in ethanol (40 mL), followed by the addition of stannous chloride (10.84 g, 57.166 mmol, 25.0 eq). The reaction mixture was stirred at 90 °C for 1.5 hours, cooled to room temperature, and the pH of the reaction mixture was adjusted to 9 with an aqueous sodium carbonate solution (2 N). The solution was then diluted with ethyl acetate (100 mL). The mixture was filtered, and the filtrate was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 44 (1.1 g, 91%) as a white solid. LCMS: [M+H] + =525.1

[0190] Example 18 Synthesis of Compound 21

[0191]

[0192] Compound 44 (0.9 g, 1.717 mmol, 1.0 eq) was dissolved in tetrahydrofuran (35 mL) and then cooled to 0 °C. Triphosgene (0.25 g, 0.858 mmol, 0.5 eq) was added, and the mixture was brought to room temperature and stirred for 2 hours. The mixture was then cooled to 0 °C, and ammonia (2.5 mL) was added. The reaction mixture was brought to room temperature and stirred for half an hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 21 (0.95 g, 97%) as a white solid. LCMS: [M+H] + =568.1

[0193] Example 19: Synthesis of Compound 13

[0194]

[0195] Compound 21 (950 mg, 1.675 mmol, 1.0 eq) was dissolved in acetonitrile (35 mL), followed by the addition of p-toluenesulfonic acid monohydrate (64 mg, 0.335 mmol, 0.2 eq) and NIS (565 mg, 2.513 mmol, 1.5 eq). The reaction mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the pH of the reaction mixture was adjusted to 8 with an aqueous sodium sulfite solution (0.2 N), and then concentrated to remove the acetonitrile. The residue was diluted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 5) to give compound 13 (605 mg, 52%) as a brown solid. LCMS: [M+H] + =693.9

[0196] Example 20 Synthesis of Compound 5

[0197]

[0198] Compound 13 (400 mg, 0.576 mmol, 1.0 eq) was dissolved in DMSO (30 mL), followed by the addition of DBU (175 mg, 1.152 mmol, 2.0 eq) and cuprous iodide (109 mg, 0.576 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL), washed successively with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1 to 30 / 1) to give compound 5 (244 mg, purity 99.34%, yield 75%) as a yellow solid. LCMS: [M+H] + =566.1

[0199] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemic mixture thereof, characterized in that, Includes the following steps: 1) In the presence of a catalyst, compound II is cyclized to obtain compound I; Before step 1), the method further includes the following steps: 2) Reacting compound III with a halogenating agent to obtain compound II; The halogenated reagent is selected from the group consisting of N-iodosuccinimide (NIS), N-chlorosuccinimide, N-bromosuccinimide (NBS), or combinations thereof; Among them, R1, R2, R3, R4 and R5 are each independently selected from the following group: hydrogen, deuterium, halogen; R6 is hydrogen; n is 0, 1, 2, or 3; Q is a C6-C10 aryl group that is substituted with or unsubstituted with one or more halogens; X is selected from the following group: Cl, Br, I.

2. The preparation method according to claim 1, characterized in that, In step 1), the catalyst is selected from the group consisting of copper iodide, cuprous iodide, copper chloride, cuprous chloride, copper bromide, cuprous bromide, copper sulfate, copper powder, copper oxide, cuprous oxide, copper hydroxide, cuprous hydroxide, copper acetate, cuprous acetate, copper citrate, copper methanesulfonate, copper fluoroborate, basic copper carbonate, copper gluconate, copper tartrate, cuprous tartrate, copper acetylacetone, 8-hydroxyquinoline copper, copper thiocyanate, cuprous thiocyanate, copper nitrate, cuprous nitrate, copper cyanide, cuprous cyanide, copper oxalate, copper phosphate, copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, copper formate, copper selenide, copper dichloro(1,10-phenanthroline)copper, (1,10-phenanthroline)(trifluoromethyl)copper, CuTC, or combinations thereof.

3. The preparation method according to claim 1, characterized in that, Compounds of Formula I are selected from the following group: , , , , , , , .

4. The preparation method according to claim 1, characterized in that, In step 2), the halogenated reagent is selected from the group consisting of N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), or combinations thereof.

5. The preparation method according to claim 1, characterized in that, Before step 2), the preparation method further includes the following steps: 3) The compound of formula IV is reacted with a carbonylating agent to obtain the isocyanate intermediate of formula IV-1; 4) The isocyanate intermediate of formula IV-1 obtained in step 3) is reacted directly with an amination reagent in the system without separation to obtain compound of formula III; In the compounds of formula IV and the isocyanate intermediates of formula IV-1, R1, R2, R3, R4, R5, R6, n and Q are as defined in claim 1.

6. The preparation method according to claim 5, characterized in that, In step 3), the carbonylating agent is selected from the group consisting of triphosgene, CDI, potassium isocyanate, or combinations thereof; and / or In step 4), the amination reagent is selected from the group consisting of ammonia water, ammonia gas, organic solutions of ammonia, or combinations thereof.

7. An intermediate as shown in Formula II, , R1, R2, R3, R4, R5, R6, n, X, and Q are as defined in claim 1.

8. The intermediate as described in claim 7, characterized in that, The intermediate is selected from the group consisting of: , , , , , , , .

9. An intermediate as shown in Formula III, ， R1, R2, R3, R4, R5, R6, n, and Q are as defined in claim 1.

10. Use of the intermediate shown in Formula II according to claim 7, characterized in that, Used to prepare the compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemic mixture thereof.

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