Method for producing hepatitis B virus nucleocapsid inhibitor

Abstract

The present invention relates to a method for preparing a hepatitis B virus nucleocapsid inhibitor. Specifically, the method of the present invention provides a new method for preparing the compound of formula I (where each group is as defined in the specification) by optimizing the process. This method can significantly improve the yield, improve the purity of the product, and significantly reduce genotoxic impurities in the product. The present invention also discloses a new intermediate for preparing the compound of formula I. [Formula 1] JPEG2024525966000047.jpg4953

Description

[Technical Field]

[0001] The present invention relates to the fields of medicine and fine chemical engineering, and in particular to a method for preparing a Hepatitis B virus nucleocapsid inhibitor and to new intermediates for the preparation of said inhibitor. [Background technology]

[0002] [ka] The compound series represented by Formula I is a hepatitis B virus nucleocapsid inhibitor, developed by Shanghai Zhimeng Pharmaceutical Technology Co., Ltd., and is a new drug for hepatitis B virus currently undergoing clinical trials. Currently, commercially available hepatitis B drugs can only inhibit hepatitis B virus replication and delay the progression of liver cirrhosis, but few can achieve the goal of curing chronic hepatitis B. Formula I compounds improve the functional cure rate of chronic hepatitis B by inhibiting the formation of HBV virus nucleocapsid, and preclinical research results have shown excellent safety and efficacy.

[0003] Therefore, the development and optimization of the manufacturing process for the above compounds is of great significance in reducing their production costs, promoting their commercialization, and enabling more patients to benefit from them sooner. Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide a method for preparing the compound of formula I, which has high yield, mild conditions, high product purity, few side reactions, convenient operation, and avoids the use of genotoxic intermediates.

[0005] It is also an object of the present invention to provide new intermediates for the preparation of compounds of formula I, namely compounds of formula II and III.

[0006] In a first aspect of the present invention, there is provided a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, or a tautomer, or stereoisomer, or a racemate thereof, comprising the steps of: 1) In the presence of a catalyst, a compound of formula II is subjected to ring formation to give a compound of formula I. [ka] (wherein R1, R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, a substituted or unsubstituted C1-C6 alkyl group, an amino group, a hydroxy group, and a nitro group, and the substitution means being substituted with one or more (e.g., 2, 3, 4, or 5) substituents selected from the group consisting of halogen, a nitro group, an amino group, and a hydroxy group. R6 is selected from the group consisting of hydrogen, deuterium, halogen, amino group, and hydroxy group. n is 0, 1, 2, 3 or 4. Q is selected from the group consisting of a C6-C10 aryl group which is unsubstituted or substituted with one or more halogens, and a 6-10 membered heteroaryl group which is unsubstituted or substituted with one or more halogens and contains 1-3 heteroatoms selected from N, O and S. X is a halogen.

[0007] In another preferred embodiment, the stereoisomer according to formula I is the R configuration. In another preferred embodiment, the stereoisomer according to formula I is the S-configuration. In another preferred embodiment, the R isomer has a structure represented by the following formula IR: [ka] (wherein each group is as defined above).

[0008] In another preferred embodiment, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, deuterium and halogen. In another preferred embodiment, n is 0. In another preferred embodiment, Q is a halogen-substituted C6-C10 aryl group, preferably a halogen-substituted phenyl group, simultaneously a phenyl group substituted with deuterium and halogen. In another preferred embodiment, X is bromine or iodine.

[0009] In another preferred embodiment, in step 1), the catalyst is a substance selected from the group consisting of copper(I) iodide, copper(I) chloride, copper(I) bromide, copper sulfate, copper powder, copper(I) oxide, copper(I) hydroxide, copper(I) acetate, copper citrate, copper methanesulfonate, copper fluoroborate, copper basic carbonate, copper gluconate, copper(I) tartrate, copper acetylacetonate, copper 8-hydroxyquinoline, copper(I) thiocyanate, copper(I) nitrate, copper(I) cyanide, copper oxalate, copper phosphate, copper(I) trifluoromethanesulfonate, copper formate, copper selenide, copper dichloro(1,10-phenanthroline), (1,10-phenanthroline)(trifluoromethyl)copper, CuTC, or a hydrate thereof. In the present invention, CuTC is copper(I) thiophene-2-carboxylate.

[0010] In another preferred embodiment, step 1) is carried out in the presence of a catalyst and a ligand selected from the following group: [ka]

[0011] In another preferred embodiment, in step 1), the catalyst is copper powder. In another preferred embodiment, in step 1), the molar ratio of the catalyst to the compound of formula II is 0.2-3, preferably 0.4-2, more preferably 0.6-1.5, and most preferably 0.8-1.2. In another preferred embodiment, step 1) is carried out at 40-150°C, preferably 50-130°C, more preferably 60-110°C.

[0012] In another preferred embodiment, the reaction time in step 1) is 0.1-36 h, preferably 0.3-10 h, more preferably 0.4-5 h. In another preferred embodiment, in step 1), the catalyst is selected from the group consisting of cuprous oxide, cuprous chloride, cuprous iodide, or a combination thereof.

[0013] In another preferred embodiment, step 1) is carried out in the presence of a catalyst and a ligand, and 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). 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).

[0014] In another preferred embodiment, step 1) is carried out in the presence of a base. In another preferred embodiment, in step 1), the base is selected from the group consisting of 1,5-diazabicyclo[5.4.0]undecene-5, 1,8-diazabicycloundecene-7 (DBU), cesium carbonate, sodium carbonate, potassium carbonate, sodium t-butoxide, potassium t-butoxide, potassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or a combination thereof. In another preferred embodiment, in step 1), the molar ratio of the base to the compound of formula II is 0.5-5.0, preferably 1.0-2.0.

[0015] In another preferred embodiment, the compound of formula I is [ka] is selected from the group consisting of:

[0016] In another preferred embodiment, the method further comprises the following step before step 1): 2) Reacting the compound of formula III with a halogenating agent to give the compound of formula II. [ka] (In the compound of formula III, R1, R2, R3, R4, R5, R6, n, X, and Q are as defined in claim 1.)

[0017] In another preferred embodiment, in step 2), the halogenating 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 gas, N-chlorosuccinimide, N-bromosuccinimide (NBS), or a combination thereof. In another preferred embodiment, in step 2), the molar ratio of the halogenating reagent to the compound of formula III is 0.8-2, preferably 0.9-1.8, more preferably 1.1-1.5.

[0018] In another preferred embodiment, step 2) is carried out at 40-100°C, preferably 50-90°C, more preferably 55-85°C. In another preferred embodiment, step 2) is carried out in a solvent selected from the group consisting of acetonitrile, dimethylformamide, or a combination thereof, preferably acetonitrile.

[0019] In another preferred embodiment, the production method further comprises the following step before step 2): 3) reacting the formula IV compound with a carbonylation reagent to give the formula IV-1 isocyanate intermediate; 4) The isocyanate intermediate of formula IV-1 obtained in step 3) is reacted in situ with an aminating reagent without separation to obtain a compound of formula III. [ka] (In the formula IV compound and formula IV-1 isocyanate intermediate, R1, R2, R3, R4, R5, R6, n, and Q are as defined in claim 1.)

[0020] In another preferred embodiment, the compound of formula IV is in the R configuration. In another preferred embodiment, in step 3), the carbonylation reagent is selected from the group consisting of triphosgene, CDI, potassium isocyanate, or a combination thereof; and / or In step 4), the aminating reagent is selected from the group consisting of aqueous ammonia, ammonia gas, an organic solution of ammonia, or a combination thereof.

[0021] In another preferred embodiment, in step 3), the carbonylation reagent is triphosgene. In another preferred embodiment, in step 2), the molar ratio of the carbonylation reagent to the compound of formula IV is 0.2-2, preferably 0.25-1.5, more preferably 0.3-1.2.

[0022] In another preferred embodiment, step 3) and / or step 4) are carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, imidazole, or a combination thereof. In another preferred embodiment, in step 3) and / or step 4), the base is pyridine. 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, preferably 1.0-4.0, more preferably 2.0-3.5.

[0023] In another preferred embodiment, the molar ratio of the aminating reagent to the compound of formula IV is 1.0-30, preferably 3-20, more preferably 8.0-15. In another preferred embodiment, step 3) and / or step 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 a combination thereof. In another preferred embodiment, step 3) and / or step 4) are carried out in dichloromethane.

[0024] In another preferred embodiment, step 3) is carried out at -40-40°C, preferably -30-30°C, more preferably -20-20°C. In another preferred embodiment, step 4) is carried out at -40 to 10°C, preferably -30 to 5°C, more preferably -20 to 0°C. In another preferred embodiment, step 4) involves quenching the reaction with water at 10-40°C.

[0025] In a second aspect of the present invention, there is provided an intermediate of formula II: [ka] (R1, R2, R3, R4, R5, R6, n, X and Q are as defined in the first aspect of the invention.)

[0026] In another preferred embodiment, the intermediate of formula II is [ka] is selected from the group consisting of:

[0027] In a third aspect of the present invention, there is provided an intermediate of formula III: [ka] (R1, R2, R3, R4, R5, R6, n and Q are as defined in the first aspect of the invention.)

[0028] In another preferred embodiment, the intermediate of formula III is [ka] is selected from the group consisting of:

[0029] In a fourth aspect of the present invention, there is provided the use of an intermediate of formula II according to the second aspect of the present invention or an intermediate of formula III according to the third aspect of the present invention for the preparation of a compound of formula I according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemate thereof.

[0030] Of course, it is understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0031] After extensive research and process optimization, the inventors have obtained a new method for preparing the compound of formula I and a new intermediate for preparing the compound of formula I. This method has high yields, 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 the present invention generates urea from an aniline-based key intermediate, which is then cyclized by Ullmann reaction to synthesize the hepatitis B virus nucleocapsid inhibitor of the present invention. Based on this, the inventors have completed the present invention.

[0032] term In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I, preferably Cl, Br or I.

[0033] In the present invention, the term "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a neopentyl group, a t-pentyl group, or a similar group. In the present invention, the term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as a phenyl group and a naphthyl group. The term "plurality" means two, three or four.

[0034] The term "6-10 membered heteroaryl group" refers to an aromatic heterocycle containing 1-3 heteroatoms selected from N, O, and S and 3-9 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted. The term "room temperature" refers to 10-40°C, preferably 15-30°C, more preferably 20-30°C.

[0035] Formula I compound [ka] (R1, R2, R3, R4, R5, R6, n, and Q are as defined above.)

[0036] The compound of formula I produced by the synthesis method of the present invention has significantly higher yield and higher purity, and the synthetic procedures are simple, eliminating high-risk procedures such as nitration, and at the same time avoiding processes that are not suitable for large-scale production, such as column chromatography. The intermediates in the last three steps of synthesizing the compound were all negative when detected by AMES, indicating that they are not genotoxic. The risk of genotoxic impurities in the compound exceeding the standard is reduced.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a medicament-appropriate salt formed between a compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic and organic salts. One type of suitable salt is a salt formed between a compound of the present invention and an acid. Acids suitable 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, propanoic 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.

[0038] Another type of suitable salt is a salt formed by a compound of the present invention with a base, such as an alkali metal salt (e.g., sodium salt, potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., ammonium salts of lower alkanols and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, t-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, trihydroxyethylamine, and the amine salts formed from morpholine, piperazine, and lysine, respectively.

[0039] Existing synthesis methods compound [ka] Taking the above as an example and referring to the disclosure of Example 6 of WO2017173999 A1, the compound can be prepared as follows: [ka]

[0040] As shown in Example 6 of WO2017173999 A1, step 3 requires nitration using concentrated nitric acid as a solvent in acetic anhydride, which is a severe reaction condition. The nitration reaction generates a large amount of heat and there is a risk of repeated nitration, which is unfavorable for large-scale production and poses a hidden risk in the subsequent production despite its high safety.

[0041] As shown in Example 6 of WO2017173999 A1, four steps are required for the final ring-closure reaction from intermediate 26, and the yields of the four steps are low, at 65.3%, 32.6%, 69.3%, and 24.9%, respectively. Furthermore, the final step requires purification by column chromatography to obtain the product, which is unsuitable for large-scale production.

[0042] As shown in Example 6 of WO2017173999 A1, in the above manufacturing route, intermediates 27, 28, and 29 produced in steps 3-5 all contain nitrobenzene or o-phenylenediamine structures, which pose potential risks. All intermediates in the drug substance must be strictly controlled by developing ppm-level analytical methods, as residual intermediates will affect the quality control of the drug substance and, if not thoroughly removed, will not meet strict clinical requirements, which is disadvantageous for the large-scale production of safe and standard-compliant clinical samples.

[0043] The synthetic method of the present invention The difference from the above existing synthesis method is that compound 4 [ka] For example, the present invention uses the synthetic route shown below. [ka]

[0044] The process includes the following steps: 1) Compound 24 and compound 31 are converted into compound 32 in the presence of p-toluenesulfonic acid as a catalyst; 2) reducing compound 32 to compound 33 with hydrogen gas over a Raney nickel catalyst; 3) Resolving racemic compound 33 by chiral chromatography or supercritical fluid chromatography (SFC) or other resolution means to obtain optically pure compound 34; 4) Compound 17 is produced from compound 34, triphosgene, and aqueous ammonia in the presence of pyridine; 5) Compound 17 is converted to compound 9 in the presence of pyridinium p-toluenesulfonate as a catalyst; 6) Compound 9 is converted to compound 4 in a catalyst of copper powder and DBU; Step 1) is carried out in a single or combination of solvents, including but not limited to toluene, xylene, methanol, ethanol, or combinations thereof, with toluene being preferred.

[0045] The acid in step 1) includes, but is not limited to, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, and is preferably p-toluenesulfonic acid. The amount of acid used in step 1) is such that the mass ratio to compound 31 is 0.1-1, preferably 0.25.

[0046] The amount of compound 24 used in step 1) is 0.90 eq. to 1.5 eq., preferably 1.2 eq., in terms of molar ratio to compound 31. The temperature in step 1) is 60-120°C, preferably 110-120°C.

[0047] The reduction of the nitro group in step 2) may be carried out using a reducing agent such as iron powder, zinc powder, hydrosulfide, or tin dichloride, or by catalytic hydrogenation. The catalyst used in the catalytic hydrogenation of the nitro group in step 2) includes, but is not limited to, palladium on carbon, platinum on carbon, Raney nickel, palladium hydroxide on carbon, with Raney nickel being preferred.

[0048] In step 2), when catalytic hydrogenation of the nitro group is carried out with Raney nickel, the mass ratio thereof to compound 32 is 0.1-0.5, preferably 0.3. Step 2) is carried out in a single or combination of solvents, including but not limited to ethanol, methanol, ethyl acetate, toluene, xylene, methyltetrahydrofuran, tetrahydrofuran and water, with ethyl acetate being preferred.

[0049] Of course, the compounds of formula IV of the present invention (eg, compound 33) may be prepared by the above-described preparation methods, may be prepared by methods known in the art, or may be commercially available.

[0050] Compared with the above-mentioned existing synthetic methods, the synthetic method of the present invention optimizes the original step 3 and subsequent processes to obtain compound of Formula I, represented by compound 4. The yields of the three-step reactions are 90.86%, 86.9%, and 83.5%, respectively, for a total yield of 65.9%. This total yield is significantly improved over the 44.6% total yield of the four-step reactions in the previous literature racemic synthesis (yields of 70%, 93.8%, 90%, and 75.4%, respectively). In the synthetic method of the present invention, intermediates 17 and 9 were found to be free of any structural warnings, effectively avoiding the impact of residual related impurities on compound of Formula I, represented by compound 4. The final three steps of this method avoid the need for purification by column chromatography, effectively improving purification efficiency. At the same time, this method avoids high safety risks, such as nitration, in the original synthetic process, making it more advantageous for large-scale production. This method has the advantages of high yield, controllable impurities, convenient operation, and suitability for kilogram-scale production.

[0051] Formula II Compounds and Formula III Compounds [ka] (R1, R2, R3, R4, R5, R6, n, X, and Q are as defined above.) [ka] (R1, R2, R3, R4, R5, R6, n, and Q are as defined above.)

[0052] It has been identified that most of the compounds of formula II and III of the present invention do not contain warning structures such as primary aniline and nitrobenzene, which is very advantageous for the quality control of the target product, the compound of formula I.

[0053] Compared with existing technologies, the present invention has the following main advantages: (1) The process has the advantages of high yield, safe process operation, easy scalability, mild conditions, and no need for column chromatographic separation in the chemical synthesis step. The process also has the advantage of low cost. (2) The process avoids the use of intermediates with warning structures, effectively reducing the difficulty of controlling impurities in the manufacturing process and final products.

[0054] The present invention will be further described below with reference to specific examples. It is understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which no specific conditions are described were generally carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0056] Example 1 Synthesis of Compound 32 [ka] Toluene (303 kg), compound 31 (35 kg), and p-toluenesulfonic acid (7 kg) were added to an autoclave at room temperature, and the mixture was heated to 105-115 °C and stirred for 1 hour to remove water. The temperature was then lowered to 60-80 °C, and compound 24 (28.33 kg) was added to the autoclave. The mixture was then heated to 110-120 °C and refluxed for 12 hours to remove water. The temperature was then lowered to 78-80 °C, and excess p-toluenesulfonic acid (180 g) and compound 24 (505 g) were added. The mixture was then refluxed for 7-8 hours to remove water. HPLC monitoring indicated that most of compound 31 was completely converted. The reaction mixture was then cooled to 50-55 °C, and methanol (35.4 kg) was added. The mixture was stirred for 2 hours, cooled, filtered, and the resulting cake was washed with a small amount of toluene / methanol solution. After drying the cake, 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

[0057] Example 2 Synthesis of Compound 33 [ka] At room temperature, a reaction flask was charged with ethyl acetate (8 L), compound 32 (178.3 g, 1.0 eq.), triethylamine (80 mL), and Raney nickel (48 g, 27%). The reaction mixture was purged with hydrogen gas three times and allowed to react at room temperature for 8 h. HPLC monitoring indicated complete conversion of compound 32. After filtration, 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

[0058] Example 3 Resolution of Compound 33 [ka] 5 g of racemic compound 33 was taken and separated by chiral chromatography using methanol as the main mobile phase. Chiral separation gave 1.3 g of compound 34 (ee > 99%) and 1.78 g of compound 34-S.

[0059] Example 4 Synthesis of Compound 17 [ka] A solution of triphosgene (BTC) (170.75 g, 0.58 mol) in dichloromethane (6 L) was placed at -10°C. A solution of compound 34 (600 g, 1.15 mol) in dichloromethane (4.8 L) was slowly added dropwise to the triphosgene dichloromethane solution. The mixture was stirred for 30 minutes. A solution of pyridine (273.07 g, 3.45 mol) in dichloromethane (1.2 L) was added dropwise at -5°C or below. After the addition was complete, the mixture was stirred for 20 minutes. Aqueous ammonia (0.9 L) was added dropwise at -5°C or below, followed by stirring for at least 30 minutes. HPLC showed the reaction was complete, and the mixture was washed twice with water and then concentrated. The resulting product was dissolved in ethyl acetate and mixed with n-heptane. The cake was collected and dried by heating to give 590 g of compound 17, with a yield of 90.86% and a purity of 98.45%. MS: [M+H] + = 563.01 / 565.02

[0060] Example 5 Synthesis of Compound 9 [ka] Compound 17 (190 g, 0.337 mol) was dissolved in acetonitrile (1.3 L) and PPTS (i.e., pyridinium p-toluenesulfonate) (42.3 g, 0.168 mol) and NIS (i.e., N-iodosuccinimide) (90.88 g, 0.4 mol) were added. After overnight reaction at 56 °C, a large amount of solid precipitated. After passing HPLC detection, the mixture was cooled to 20-30 °C and washed with 5% sodium sulfite solution. The solid was collected by suction filtration and washed with MTBE (methyl tert-butyl ether). After drying by heating, 202 g of compound 9 was obtained in 86.9% yield and 98.75% purity. MS: [M+H] + =689.84 / 691.84

[0061] Example 6 Synthesis of Compound 4 [ka] 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]undecene-5 (48.5 g, 0.319 mol) were added. The mixture was reacted at 106 °C for 2 hours. After passing the HPLC monitoring, activated carbon was added. The mixture was filtered and the filtrate was collected. The filtrate was added to 7% aqueous acetic acid and stirred for 20 minutes. The mixture was suction filtered and the cake was collected. The resulting 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 organic phase was dried over anhydrous sodium sulfate and concentrated to remove the organic solvent. The mixture was mixed in acetone, filtered, and the cake was collected and dried to obtain 136 g of compound 4, with a yield of 83.5% and a purity of 99.33%. MS: [M+H] +=562.5 / 563.4; 1 H NMR (600 MHz, DMSO-d6) δ 10.48 - 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 = 7.8 Hz, 1H), 6.64 (s, 1H), 6.61 (dd, J = 8.0, 1.6 Hz, 1H), 6.03 (d, J = 1.8 Hz, 1H), 4.30 - 4.21 (m, 2H), 3.70 (dt, J = 14.3, 7.3 Hz, 1H), 2.92 (dt, J = 14.3, 7.3 Hz, 1H), 2.69 (dt, J = 14.5, 7.4 Hz, 1H), 2.62 (dt, J = 14.1, 7.0 Hz, 1H).

[0062] Example 7 Synthesis of Compound 4 [ka] 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 as monitored by HPLC, the mixture was cooled to room temperature and separated into 50 mL of water and 50 mL of ethyl acetate. 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 mixed with a mixture of ethyl acetate and petroleum ether to obtain the finished product, compound 4 (520 mg, purity 95.15%, yield 65%). MS: [M+H]+ = 562.1 / 564.1

[0063] In the present invention, the ligand L19 is N 1 ,N 2 -Bis[(thiophen-2-yl)methyl]oxalamide (N 1 ,N 2- bis(thiophen-2-ylmethyl)oxalamide).

[0064] Compared to Example 3 of WO2017173999 A1, a common intermediate (compound 34 in this patent) is required to undergo a total of four steps, namely nitration, hydrolysis, reduction, and CDI cyclization, to complete the final cyclization reaction. The yields of the four steps are 70%, 94%, 90%, and 75%, respectively, for a total yield of 44%, resulting in a long synthesis process and low yield. Furthermore, the final step requires purification by column chromatography to obtain the product, which is unsuitable for large-scale production. The synthetic route described in this patent requires only three steps, and the total synthesis yield can reach up to 66%. Both production efficiency and total yield are significantly improved.

[0065] Compared with Example 3 of WO2017173999 A1, the intermediates used in the last three steps are similar to those in Example 6 of the patent, both of which contain nitrobenzene and o-phenylenediamine structures, posing potential risks. All related intermediates in the drug substance require the development of ppm-level analytical methods for strict control. This route is unfavorable for the large-scale production of safe, standard-compliant clinical samples. The synthetic route of this patent avoids the use of compounds containing similar structures, and compounds 17 and 9 tested negative in the Ames test, demonstrating better safety. The corresponding production control is also easier.

[0066] Example 8 Synthesis of Compound 4 [ka] 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 as monitored by HPLC, the mixture was cooled to room temperature and separated into 50 mL of water and 50 mL of ethyl acetate. 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 mixed with a mixture of ethyl acetate and petroleum ether to obtain the finished product, compound 4 (650 mg, purity 99.76%, yield 80%). MS: [M+H]+ = 562.0 / 564.1

[0067] In the present invention, the ligand L21 is N 1 ,N 2 -bis[(furan-2-yl)methyl]oxalamide (N 1 ,N 2 - bis(furan-2-ylmethyl)oxalamide).

[0068] A comparison summary of Examples 6-8 of the present invention with Example 3 (Comparative Example 1) and Example 6 (Comparative Example 2) of WO2017173999 A1 is shown in the table below. [Table 1]

[0069] Example 9 Synthesis of Compound 35 [ka] Compound 17 (1.5 g, 2.66 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), followed by the addition of NBS (570 mg, 3.19 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium sulfite (20 mL x 2) and saturated aqueous sodium bicarbonate (20 mL x 2). 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. LCMS: [M+H] + = 644.1

[0070] Example 10 Synthesis of Compound 4 [ka] Compound 35 (100 mg, 0.155 mmol, 1.0 eq) was dissolved in DMSO (2 mL), followed by cuprous iodide (29.6 mg, 0.155 mmol, 1.0 eq) and DBU (47.6 mg, 0.310 mmol, 2.0 eq). The atmosphere was purged with nitrogen gas three times, and the reaction mixture was stirred at 120 °C for 21 h under nitrogen gas protection. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), washed with aqueous citric acid (5%, 10 mL × 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, purity 99%) as a white solid. LCMS: [M+H] + = 562.1 1H NMR (400 MHz, CDCl3) δ 9.88 - 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)

[0071] Example 11 Synthesis of Compound 37 [ka] 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 added, and the reaction mixture was stirred at room temperature for 10 minutes. Palladium on carbon (10%, 300 mg) was added, and the mixture was heated 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 flash 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

[0072] Example 12 Synthesis of Compound 38 [ka] 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 poured into saturated aqueous sodium bicarbonate until the pH reached 8. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (neutral aluminum oxide, 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

[0073] Example 13 Synthesis of Compound 39 [ka] Compound 38 (1.5 g, 8.523 mmol, 1.0 eq) was dissolved in acetic acid (24 mL) and then concentrated hydrochloric acid (48 mL) was added. After cooling to -5 °C, 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 h, followed by the dropwise addition of a solution of stannous chloride (4.0 g, 21.307 mmol, 2.5 eq) in concentrated hydrochloric acid (9 mL), maintaining the reaction temperature between 0 °C and 5 °C throughout the addition. After the addition was complete, the reaction mixture was stirred between 0 °C and 5 °C for 40 min. The mixture was filtered and the solid was washed with chilled concentrated aqueous hydrochloric acid. The solid was collected and lyophilized to give compound 39 (1.74 g, 87%) as a white solid. LCMS: [M+H] + =191.0

[0074] Example 14 Synthesis of Compound 40 [ka] Compound 39 (1.74 g, 7.647 mmol, 1.0 eq) was dissolved in ethanol (8 mL), followed by the addition of 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 h. 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, concentrated, and petroleum ether (30 mL) was added to the residue and stirred for 0.5 h. The solid was filtered, 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

[0075] Example 15 Synthesis of Compound 42 [ka] DMF (692 mg, 9.473 mmol, 2.2 eq) was cooled to 0 °C, and then phosphoryl chloride (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 0.5 hours, and then a solution of compound 40 (1.34 g, 4.306 mmol, 1.0 eq) in DMF (9 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was warmed to room temperature and stirred for 40 minutes, then heated to 70 °C and stirred for 5 hours. After cooling to room temperature, the reaction mixture was poured into ice water. After filtration, the solid was collected and azeotroped with toluene to remove water. The resulting 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

[0076] Example 16 Synthesis of Compound 43 [ka] 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, purity 80%) as a white solid. LCMS: [M+H] + =555.0

[0077] Example 17 Synthesis of Compound 44 [ka] 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 h, cooled to room temperature, and the pH of the mixture was adjusted to 9 with aqueous sodium carbonate (2 N) and then diluted with ethyl acetate (100 mL). The filtrate was filtered, washed with water and 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

[0078] Example 18 Synthesis of Compound 21 [ka] Compound 44 (0.9 g, 1.717 mmol, 1.0 eq) was dissolved in tetrahydrofuran (35 mL) and cooled to 0°C. Triphosgene (0.25 g, 0.858 mmol, 0.5 eq) was added, and the mixture was warmed to room temperature and stirred at room temperature for 2 hours. After cooling to 0°C, aqueous ammonia (2.5 mL) was added. The reaction mixture was warmed to room temperature and stirred for half an hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and 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

[0079] Example 19 Synthesis of Compound 13 [ka] 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 h. After cooling to room temperature, the reaction mixture was adjusted to pH 8 with aqueous sodium sulfite (0.2 N) and concentrated to remove acetonitrile. The residue was diluted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting 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

[0080] Example 20 Synthesis of Compound 5 [ka] 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 with water and 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

[0081] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. After reading the above content of the present invention, it should be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

1. A method for producing a compound of formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemate thereof, comprising the following step 1), and further comprising the following step 2) before step 1): 1) In the presence of a catalyst, a compound of formula II is subjected to ring formation to give a compound of formula I. 【Chemical 1】 2) reacting the compound of formula III with a halogenating reagent to obtain the compound of formula II, wherein the halogenating reagent is selected from the group consisting of N-iodosuccinimide (NIS), N-bromosuccinimide, N-chlorosuccinimide, N-bromosuccinimide (NBS), or a combination thereof. 【Chemistry 2】 (However, R １ , R ２ , R ３ , R ４ and R ５ are each independently selected from the group consisting of hydrogen, deuterium, and halogen. R ６ is hydrogen. n is 0, 1, 2, 3 or 4; Q is selected from the group consisting of C6-C10 aryl groups unsubstituted or substituted with one or more halogens. X is a halogen.

2. 2. The method of claim 1, wherein in step 1), the catalyst is selected from the group consisting of copper(I) iodide, copper(I) chloride, copper(I) bromide, copper sulfate, copper powder, copper(I) oxide, copper(I) hydroxide, copper(I) acetate, copper citrate, copper methanesulfonate, copper fluoroborate, copper basic carbonate, copper gluconate, copper(I) tartrate, copper acetylacetonate, 8-hydroxyquinoline copper, copper(I) thiocyanate, copper(I) nitrate, copper(I) cyanide, copper oxalate, copper phosphate, copper(I) trifluoromethanesulfonate, copper formate, copper selenide, dichloro(1,10-phenanthroline)copper, (1,10-phenanthroline)(trifluoromethyl)copper, CuTC, or a combination thereof, or a hydrate thereof.

3. Compounds of formula I are 【Chemistry 3】 The method according to claim 1, wherein the compound is selected from the group consisting of:

4. 2. The method according to claim 1, wherein in step 2), the halogenating reagent is selected from the group consisting of N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), or a combination thereof.

5. 10. The method of claim 1, wherein before step 2), the method further comprises the following steps: 3) reacting the formula IV compound with a carbonylating reagent to give the formula IV-1 isocyanate intermediate; 4) The isocyanate intermediate of formula IV-1 obtained in step 3) is reacted in situ with an aminating reagent without isolation to give the compound of formula III. 【Chemistry 4】 (In the Formula IV compound and the Formula IV-1 isocyanate intermediate, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , n and Q are as defined in claim 1.

6. In step 3), the carbonylation reagent is selected from the group consisting of triphosgene, CDI, potassium isocyanate, or a combination thereof; and / or In step 4), the aminating reagent is selected from the group consisting of aqueous ammonia, ammonia gas, an organic solution of ammonia, or a combination thereof. The manufacturing method according to claim 5 .

7. An intermediate of formula II. 【Chemistry 5】 (R １ , R ２ , R ３ , R ４ , R ５ , R ６ , n, X and Q are as defined in claim 1.

8. The intermediate described in claim 7, wherein the intermediate is selected from the group consisting of: 【Chemistry 6】

9. An intermediate of formula III: 【Chemistry 7】 (R １ , R ２ , R ３ , R ４ , R ５ , R ６ , n and Q are as defined in claim 1.

10. Use of an intermediate of formula II according to claim 7 or an intermediate of formula III according to claim 9, characterized in that it is used for the preparation of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a stereoisomer thereof, or a racemate thereof.

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