New method for preparing oxopyridine compound, and key intermediate and use

Abstract

A new route for preparing an oxopyridine compound as represented by formula (I) and a key intermediate thereof. The new route can greatly reduce the generation of isomer impurities, improve the selectivity of the reaction chirality and the selectivity of N / O-alkylation, increase the yield, avoid re-purification of a crude product, and reduce the cost, has a short production period, and is energy-saving and environmentally-friendly, and suitable for preparing a drug for treating and / or preventing diseases related to FXIa receptors, and particularly provides a new idea for preparing a drug for treating and / or preventing cerebrovascular artery diseases and / or peripheral artery diseases.

Description

New preparation method of oxopyridine compounds, key intermediates and applications Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and its preparation, and specifically relates to a novel preparation method of oxopyridine compounds and key intermediates and applications thereof. Background Art

[0002] Thromboembolic disease is a condition in humans and animals caused by abnormal blood clots that form within blood vessels during life. Coagulation factor XI (FXI) is a plasma serine protease essential for maintaining the intrinsic pathway. Upon activation, it generates activated coagulation factor XIa (FXIa), which plays a key role in the amplification of the coagulation cascade. During the coagulation cascade, thrombin can activate FXI, and activated FXIa in turn promotes the production of large amounts of thrombin, thereby amplifying the coagulation cascade. Therefore, drugs targeting FXIa can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thereby exerting anti-thrombotic effects. Recent studies have shown that FXIa inhibition may reduce the risk of bleeding compared to direct FXa inhibitors, making it a new target for anti-thrombotic prevention and treatment. Bayer Pharmaceuticals' BAY-2433334 anticoagulant drug has attracted significant attention in the field due to its reduced bleeding risk.

[0003] Regarding the anticoagulant drug BAY-2433334, Bayer Pharmaceuticals' compound patent CN108026072B focuses on disclosing two oxopyridine compounds, which are as follows:

[0004] This type of molecule has a complex structure, is difficult to synthesize, and isomers are not easily separated, making scaled-up production extremely challenging. Chengdu Shibeikang has conducted extensive structural modification and process research, aiming to provide products with better efficacy and better suited for industrial scale-up production. In particular, during the preparation research of the anticoagulant derivative drug represented by formula (I) below, it was found that it was difficult to obtain high-yield and high-purity APIs using Bayer Pharmaceuticals' patented compound and process methods.

[0005] Rx is selected from fluoro, chloro or trifluoromethyl;

[0006] R1 is selected from alkyl or deuterated alkyl;

[0007] R2, R3, R4, and R5 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl.

[0008] Patents WO 2014 / 154794 and WO 2017 / 005725 disclose the synthesis of this class of compounds using 2,5-dimethoxypyridine as the starting material and a linear synthesis strategy to synthesize the target compound in nine steps. This route is not only lengthy but also prone to high racemization and low overall yield. The yield of the crude product synthesis step is only 70%, requiring cumbersome post-processing and purification procedures, and separation of isomers by HPLC or chiral supercritical fluid chromatography (SFC), which is time-consuming and expensive, making it unsuitable for industrial scale-up production.

[0009] Patent CN 111770917 A discloses a polymerization-based synthesis strategy. The crude product synthesis steps are shown in the figure below. After synthesizing the key intermediate compounds of formula (XVI-CF3) / (XVI-Cl) and formula (XIX), crude compounds 1 / 2 are generated through a condensation reaction. The overall reaction involves six steps, with the longest step being four, which shortens the reaction cycle. The enantioselectivity and N / O-alkylation selectivity of the crude product synthesis step are optimized. After filtration and solvent evaporation, the condensate is filtered, yielding crude amorphous compounds 1 / 2 with high ee values ​​of 85% to 93%. Furthermore, a 9:1 to 10:1 N-alkylation:O-alkylation ratio is achieved, resulting in a preferred N-alkylation over undesired O-alkylation.

[0010] Although the polymerization synthesis route of this patent is better than the linear synthesis strategy as a whole, the condensation step of its crude product synthesis still has great limitations, such as: (1) low conversion rate. The yield of the condensation step of the crude product synthesis of compound 1 and compound 2 is only 70% and 75% respectively, and the yield of the alternative method is as low as 61% (paragraphs 0095 to 0097 of the specification). The total yield of the six steps is only 20% to 25% (paragraph 0054 of the specification); (2) the proportion of isomers is large. Although the ee value of the crude product is optimized to 85% to 9 3%, but there are still 7% to 15% isomer impurities, and it needs to be purified by organic solvent to obtain a purified crude product with an ee value of >99%, and then the target crystals are obtained through a crystallization process; (3) The N / O-alkylation selectivity is poor. Although the ratio of crude N-alkylation: O-alkylation reaches (9 to 10): 1, there is still an unsatisfactory O / N conversion rate of about 10%, which not only leads to a low conversion rate, but also produces more O-alkylated impurities, increasing the difficulty of subsequent purification and the risk of product quality control.

[0011] Therefore, how to improve the quality of anticoagulant products of oxopyridine compounds, reduce the risk of impurity control, increase product conversion rate and purity, shorten the production cycle, reduce costs, and make them more suitable for industrial scale-up production is a technical problem that needs to be solved urgently in this field.

[0012] Summary of the Invention

[0013] In order to solve the technical problems existing in the prior art, the present invention discloses a novel preparation method for oxopyridine compounds, key intermediates and applications thereof.

[0014] In one aspect, the present invention provides an intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0015] In formula (II):

[0016] R 1 Selected from TsO-, X, R 7 O-; Ts is p-toluenesulfonyl, X is selected from F, Cl, Br or I;

[0017] R 2 Selected from -NHR 8 、-OC(CH3)3;

[0018] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0019] R 7 is selected from trifluoromethanesulfonyl, methylsulfonyl, p-nitrobenzenemethylsulfonyl or phenylsulfonyl;

[0020] R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0021] Formula (II) is not

[0022] Furthermore, the intermediate has a structure represented by formula (III), formula (IV) or formula (V):

[0023] In formula (III),

[0024] Ts is p-toluenesulfonyl;

[0025] R 2 Selected from -NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0026] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0027] In formula (IV):

[0028] R3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0029] X is selected from F, Cl, Br or I;

[0030] In formula (V):

[0031] R 2 Selected from NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0032] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0033] R 7 Selected from trifluoromethanesulfonyl, methylsulfonyl, p-nitrobenzenemethylsulfonyl or phenylsulfonyl.

[0034] Furthermore, in the intermediate represented by formula (III) or a pharmaceutically acceptable salt thereof:

[0035] The R 2 Selected from -NHR 8 , R 8 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0036] and / or R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0037] Furthermore, in the intermediate represented by the above formula (IV) or a pharmaceutically acceptable salt thereof:

[0038] and / or R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0039] Furthermore, in the intermediate represented by formula (V) or a pharmaceutically acceptable salt thereof:

[0040] R 8 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0041] and / or R3 、R 4 、R 5 、R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0042] Furthermore, in the intermediate represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, the intermediate of formula (IV) includes a structure represented by formula (IV-a):

[0043] In formula (IV-a), R 3 、R 4 、R 5 、R 6 The definitions of are the same as above.

[0044] Furthermore, the hydrogen in the structure of any of the above intermediates may be replaced by at least one deuterium.

[0045] Furthermore, the intermediate is selected from the following compounds:

[0046] Furthermore, the present invention provides a method for preparing the intermediate represented by the above formula (II) or a pharmaceutically acceptable salt thereof, wherein the synthesis of the intermediate comprises the following steps:

[0047] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 has the same meaning as any of the corresponding definitions above.

[0048] Furthermore, the preparation method of the intermediate represented by the above formula (II) includes method A, method B or method C:

[0049] Method A: The intermediate represented by formula (III) is obtained by reacting the compound of formula (III-a) with p-toluenesulfonyl chloride under alkaline conditions.

[0050] Among them, R 2 、R 3 、R 4 、R 5 、R 6 has the same meaning as any of the corresponding definitions above;

[0051] Method B: The intermediate represented by formula (IV) is obtained by reacting the compound represented by formula (III-a-5) with a halogenated carboxylic acid.

[0052] wherein X is selected from F, Cl, Br or I; R 3 、R 4 、R 5 、R 6 has the same meaning as any of the corresponding definitions above;

[0053] Method C: The compound of formula (III-a) is subjected to an esterification reaction with a hydroxyl protecting agent under alkaline conditions to obtain an intermediate represented by formula (V).

[0054] Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 has the same meaning as any of the corresponding definitions above.

[0055] Furthermore, the halogenated carboxylic acid in the above method B is selected from the bromocarboxylic acid of the following structure:

[0056] Furthermore, the hydroxyl protecting agent described in the above method C includes any one of trifluoromethanesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenemethylsulfonyl chloride and benzenesulfonyl chloride.

[0057] Furthermore, the above method A and / or method C includes the following reaction conditions:

[0058] The base is selected from an organic base; preferably, the organic base includes triethylamine, pyridine, DMAP, tetramethylguanidine, DBU or DIPEA, more preferably triethylamine or pyridine;

[0059] The reaction solvent of the synthesis step is selected from an organic solvent; preferably, the organic solvent includes but is not limited to any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and dichloromethane, or a mixture of two or more thereof;

[0060] Optionally, the molar ratio of the compound of formula (III-a) to the organic base in the synthesis step is 1:0.5 to 8, preferably 1:1 to 3;

[0061] Optionally, the reaction temperature of the synthesis step is 0°C to 60°C, preferably 10°C to 30°C;

[0062] Optionally, the reaction time of the synthesis step is 1 to 10 hours, preferably 4 to 6 hours.

[0063] Furthermore, the above method B includes the following reaction conditions:

[0064] The reaction conditions include an organic base; preferably, the organic base includes triethylamine, pyridine, DBU or DIPEA;

[0065] The reaction conditions include an organic solvent; the organic solvent includes tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, DMF or acetonitrile;

[0066] The reaction conditions include a condensing agent; the condensing agent includes 1-propylphosphoric anhydride, DCC or EDCI;

[0067] The reaction temperature is -10°C to 10°C for 5-60 minutes, then 10°C to 50°C for 10-600 minutes; preferably 0°C to 5°C for 10 minutes, then room temperature for 30 minutes.

[0068] Furthermore, the preparation method of the compound of formula (III-a) comprises the following steps:

[0069] The D-2-aminobutyric acid represented by formula (III-a-1) is subjected to a diazo reaction with sodium nitrite in an acetic acid environment to obtain a compound represented by formula (III-a-2);

[0070] The compound of formula (III-a-2) and the compound of formula (III-a-3) are subjected to an amide condensation reaction in the presence of a base and an acid anhydride to obtain a compound of formula (III-a-4);

[0071] The compound of formula (III-a-4) is hydrolyzed to obtain the compound of formula (III-a).

[0072] Furthermore, in the step of preparing the compound of formula (III-a-2), D-2-aminobutyric acid is dissolved in acetic acid, sodium nitrite is added at 0-5°C, and stirred at 0-5°C for 6-10 hours;

[0073] Optionally, the molar ratio of D-2-aminobutyric acid to sodium nitrite is 1:1.8-2.3, preferably 1:2.

[0074] Furthermore, in the amide condensation reaction of preparing the compound of formula (III-a-4) from the compound of formula (III-a-2), the method includes: mixing the compound of formula (III-a-2) and the compound of formula (III-a-3) in a molar ratio of 1.3-1.8:1, adding a base and anhydride at -10-0°C, stirring at 0-5°C for 5-15 minutes, and then stirring at room temperature for 20-60 minutes.

[0075] Optionally, the molar ratio of the compound of formula (III-a-2) to the compound of formula (III-a-3) is 1.3-1.8:1, preferably 1.5:1.

[0076] Optionally, the reaction conditions are stirring at 0-5°C for 5-13 min, and then stirring at room temperature for 20-40 min.

[0077] On the other hand, the present invention also provides the use of any of the above intermediates or pharmaceutically acceptable salts thereof as a standard, a reference substance, in the preparation of oxopyridine compounds represented by formula (I), or in the preparation of drugs for treating or preventing vascular arterial diseases.

[0078] On the other hand, the present invention also provides a method for preparing an oxopyridine compound represented by formula (I), which comprises reacting an intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI) to obtain a compound represented by formula (I);

[0079] In formula (II):

[0080] R 1 Selected from TsO-, X, R 7 O-; Ts is p-toluenesulfonyl, X is selected from F, Cl, Br or I;

[0081] R 2 Selected from -NHR 8 、-OC(CH3)3;

[0082] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0083] R 7 is selected from trifluoromethanesulfonyl, methylsulfonyl, p-nitrobenzenemethylsulfonyl or phenylsulfonyl;

[0084] R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0085] R 9 selected from fluorine, chlorine or trifluoromethyl;

[0086] Formula (II) is not

[0087] Furthermore, the preparation method of the oxopyridine compound represented by the above formula (I) comprises the following steps:

[0088] When R in formula (II) 2 When -OC(CH3)3 is selected, the intermediate structure represented by formula (II) is formula (II-a), and the preparation method comprises the following steps:

[0089] in,

[0090] R 1 Selected from TsO-, X, R 7 O-; Ts is p-toluenesulfonyl, X is selected from F, Cl, Br or I;

[0091] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0092] R 7 is selected from trifluoromethanesulfonyl, methylsulfonyl, p-nitrobenzenemethylsulfonyl or phenylsulfonyl;

[0093] R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0094] R 9 selected from fluorine, chlorine or trifluoromethyl;

[0095] Step 1: reacting the intermediate represented by formula (II-a) or a pharmaceutically acceptable salt thereof with a compound of formula (VI) to obtain a compound of formula (VII);

[0096] Step 2: hydrolyzing the compound of formula (VII) to obtain the compound of formula (VIII);

[0097] Step 3: The compound of formula (VIII) undergoes condensation reaction to obtain the compound of formula (I).

[0098] Furthermore, the preparation method of the oxopyridine compound represented by the above formula (I) is selected from method 1, method 2 or method 3;

[0099] Method 1: The preparation method comprises reacting an intermediate represented by formula (III) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI) to obtain a compound represented by formula (I).

[0100] in,

[0101] Ts is selected from p-toluenesulfonyl;

[0102] R 2 Selected from -NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0103] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0104] R 9selected from fluorine, chlorine or trifluoromethyl;

[0105] Method 2:

[0106] in,

[0107] R 10 is selected from alkyl, cycloalkyl or deuterated alkyl, cycloalkyl;

[0108] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0109] R 9 selected from fluorine, chlorine or trifluoromethyl;

[0110] X is selected from F, Cl, Br or I;

[0111] Step 1: reacting the intermediate represented by formula (IV) or a pharmaceutically acceptable salt thereof with the compound of formula (VI) to obtain the compound of formula (VII);

[0112] Step 2: hydrolyzing the compound of formula (VII) to obtain the compound of formula (VIII);

[0113] Step 3: The compound of formula (VIII) undergoes condensation reaction to obtain the compound of formula (Ia);

[0114] Method 3:

[0115] The intermediate represented by formula (V) is subjected to a nucleophilic substitution reaction with the compound represented by formula (VI) under alkaline conditions to obtain the compound represented by formula (I);

[0116] in,

[0117] R 9 selected from fluorine, chlorine or trifluoromethyl;

[0118] R 2 Selected from NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl;

[0119] R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0120] R 7 Selected from trifluoromethanesulfonyl, methylsulfonyl, p-nitrobenzenemethylsulfonyl or phenylsulfonyl.

[0121] Furthermore, in the above method 1:

[0122] R 9 selected from fluorine, chlorine or trifluoromethyl;

[0123] Ts is selected from p-toluenesulfonyl;

[0124] R 2 Selected from NHR 8 , where: R 8 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0125] and / or R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0126] Furthermore, the above method 1 includes the following reaction conditions:

[0127] The method 1 includes a base, and the base is selected from an organic base or an inorganic base; preferably, the base includes any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, DBU, DIPEA, and pyridine, or a mixture of two or more thereof; more preferably, the base includes any one of potassium carbonate, cesium carbonate, tetramethylguanidine, triethylamine, DBU, and DIPEA, or a mixture of two or more thereof;

[0128] The reaction solvent of the method 1 is selected from an organic solvent; preferably, the organic solvent includes any one of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, and DMF, or a mixture of two or more thereof;

[0129] Optionally, in the method 1, the molar ratio of the compound of formula (III) to the base is 1:1 to 3, preferably 1:2;

[0130] Optionally, the reaction temperature of the method 1 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26°C to 32°C;

[0131] Optionally, the reaction time of the method 1 is 1 to 10 hours, preferably 4 to 6 hours.

[0132] Furthermore, the above method 1 includes the steps of synthesizing the compound of formula (III):

[0133] The compound of formula (III-a) is reacted with p-toluenesulfonyl chloride under alkaline conditions to obtain:

[0134] Among them, R 2 、R3 、R 4 、R 5 、R 6 has the same meaning as any of the corresponding definitions above.

[0135] Furthermore, the synthesis steps of the compound of formula (III) above include the following reaction conditions:

[0136] The base is selected from an organic base; preferably, the organic base includes triethylamine, pyridine, tetramethylguanidine, DMAP, DBU or DIPEA, more preferably triethylamine or pyridine;

[0137] The reaction solvent of the synthesis step is selected from an organic solvent; preferably, the organic solvent includes but is not limited to any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and dichloromethane, or a mixture of two or more thereof;

[0138] Optionally, the molar ratio of the compound of formula (III-a) to the organic base in the synthesis step is 1:0.5 to 8, preferably 1:1 to 3;

[0139] Optionally, the reaction temperature of the synthesis step is 0°C to 60°C, preferably 10°C to 30°C;

[0140] Optionally, the reaction time of the synthesis step is 1 to 10 hours, preferably 4 to 6 hours.

[0141] Furthermore, the preparation method of the compound of formula (III-a) comprises the following steps:

[0142] Among them, R 2 、R 3 、R 4 、R 5 、R 6 has the same meaning as any of the corresponding definitions above;

[0143] Step 1: The compound of formula (III-a-2) and the compound of formula (III-a-3) undergo condensation reaction to obtain the compound of formula (III-a-4);

[0144] Step 2: The compound of formula (III-a-4) undergoes hydrolysis reaction under alkaline conditions to obtain the compound of formula (III-a).

[0145] Furthermore, the condensation reaction in step 1 of the above-mentioned preparation of the compound of formula (III-a) includes the following reaction conditions:

[0146] The conditions of the condensation reaction include a condensing agent, preferably, the condensing agent includes T3P or DPP-Cl;

[0147] The conditions of the condensation reaction further include an organic base; preferably, the organic base includes triethylamine, pyridine, tetramethylguanidine, DBU or DIPEA; more preferably triethylamine or pyridine;

[0148] The solvent for the condensation reaction is an organic solvent; preferably, the organic solvent includes any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and ethyl acetate, or a mixture of two or more thereof;

[0149] Optionally, the condensation reaction temperature is 0°C to 60°C, preferably 10°C to 30°C;

[0150] Optionally, the condensation reaction time is 1 to 10 hours, preferably 2 to 4 hours.

[0151] Furthermore, the hydrolysis reaction in step 2 of the above-mentioned preparation of the compound of formula (III-a) includes the following reaction conditions:

[0152] The hydrolysis reaction includes an inorganic base; preferably, the inorganic base includes potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate; more preferably potassium carbonate;

[0153] The solvent for the hydrolysis reaction is a mixed solvent of an organic solvent and water; preferably, the volume ratio of the organic solvent to water in the mixed solvent is 1:1 to 10, preferably 1:1 to 2; the mixed solvent includes methanol and water, ethanol and water, tetrahydrofuran and water, or DMSO and water, preferably methanol and water;

[0154] Optionally, the molar ratio of the compound of formula (III-a-4) to the inorganic base in the hydrolysis reaction is 1:1 to 10, preferably 1:1 to 3;

[0155] Optionally, the temperature of the hydrolysis reaction is 0°C to 60°C, preferably 10°C to 30°C;

[0156] Optionally, the hydrolysis reaction time is 1 to 10 hours, preferably 5 to 7 hours.

[0157] Furthermore, in method three, in the nucleophilic substitution reaction for preparing the compound of formula (I) from the intermediate represented by formula (V), the molar ratio of the compound of formula (V) to the base is 1:1-3, the reaction temperature is 0°C-60°C, and the reaction time is 1-10 hours.

[0158] Furthermore, the above method 3 includes the following reaction conditions:

[0159] The method three includes a base, and the base is selected from an organic base or an inorganic base; preferably, the base includes any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, DBU, DIPEA, and pyridine, or a mixture of two or more thereof; more preferably, the base includes any one of potassium carbonate, cesium carbonate, tetramethylguanidine, triethylamine, DBU, and DIPEA, or a mixture of two or more thereof;

[0160] The reaction solvent of the method three is selected from an organic solvent; preferably, the organic solvent includes any one of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, and DMF, or a mixture of two or more thereof;

[0161] Optionally, in the method three, the molar ratio of the compound of formula (V) to the base is 1:1 to 3, preferably 1:2;

[0162] Optionally, the reaction temperature of the method three is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26°C to 32°C;

[0163] Optionally, the reaction time of the method three is 1 to 10 hours, preferably 4 to 6 hours.

[0164] Further preferably, in the above method 2:

[0165] R 10 is selected from methyl or deuterated methyl;

[0166] and / or R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0167] Furthermore, step 1 of the above method 2 includes the following reaction conditions:

[0168] The reaction conditions include a base, which is selected from an organic base or an inorganic base; preferably, the base includes any one of tetramethylguanidine, triethylamine, DBU, DIPEA, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide, or a mixture of two or more thereof; more preferably, the base includes any one of tetramethylguanidine, triethylamine, DBU, DIPEA, potassium carbonate, and cesium carbonate, or a mixture of two or more thereof;

[0169] The reaction solvent of the reaction conditions is selected from an organic solvent; preferably, the organic solvent includes any one of isopropanol, ethanol, acetone, DMF, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane, or a mixture of two or more thereof;

[0170] Optionally, in step 1, the molar ratio of the compound of formula (IV) to the base is 1:1 to 3, preferably 1:2;

[0171] Optionally, the reaction temperature of step 1 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26°C to 32°C;

[0172] Optionally, the reaction time of step 1 is 1 to 10 hours, preferably 4 to 6 hours.

[0173] Furthermore, step 2 of the above method 2 includes the following reaction conditions:

[0174] The reaction conditions include an acid selected from an organic acid or an inorganic acid; preferably, the acid includes any one of hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, and hydrobromic acid, or a mixture of two or more thereof; more preferably, the base includes any one of hydrochloric acid, trifluoroacetic acid, and sulfuric acid, or a mixture of two or more thereof;

[0175] The reaction solvent of the reaction conditions is selected from an organic solvent; preferably, the organic solvent includes any one of isotetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, methanol, ethanol, isopropanol, DMF, or a mixture of two or more thereof;

[0176] Optionally, in step 2, the molar ratio of the compound of formula (VII) to the acid is 1:30, preferably 10:20;

[0177] Optionally, the reaction temperature of step 2 is -20°C to 40°C, preferably -10°C to 10°C, more preferably -5°C to 5°C;

[0178] Optionally, the reaction time of step 2 is 1 to 8 hours, preferably 2 to 4 hours.

[0179] Furthermore, step 3 of the above method 2 includes the following reaction conditions:

[0180] The reaction conditions include a base, which is selected from an organic base or an inorganic base; preferably, the base includes any one of triethylamine, DBU, DIPEA, tetramethylguanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide, or a mixture of two or more thereof; more preferably, the base includes any one of triethylamine, DBU, DIPEA, tetramethylguanidine, potassium carbonate, and cesium carbonate, or a mixture of two or more thereof;

[0181] The reaction conditions include a condensing agent and a ligand; preferably, the condensing agent and the ligand include any one of EDCI, HOBT, HATU, HBTU, DCC, CDI, T3P, DPP-Cl, HCTU, TBTU, and DMAP, or a mixture of two or more thereof; more preferably, the base includes any one of EDCI, HOBT, HATU, and HBTU, or a mixture of two or more thereof;

[0182] The reaction solvent of the reaction conditions is selected from an organic solvent; preferably, the organic solvent includes any one of isotetrahydrofuran, DCM, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, ethanol, isopropanol, DMF, DMAC, or a mixture of two or more thereof;

[0183] Optionally, in step 3, the molar ratio of the compound of formula (VIII) to the base is 1:1 to 5, preferably 1:3;

[0184] Optionally, the reaction temperature of step 3 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26°C to 32°C;

[0185] Optionally, the reaction time of step 3 is 1 to 10 hours, preferably 4 to 6 hours.

[0186] Furthermore, the oxopyridine compounds of formula (I) obtained by the above-mentioned methods 1, 2, and 3 have at least any of the following characteristics: (1) an enantioselective ee value of 98% or more, preferably 99% or more; (2) an N / O-alkylation selectivity ratio of 30 to 40:1 or more; (3) a single-step yield of 85% or more, preferably 90% or more; (4) a short production cycle, no need for complex post-treatment, and suitable for industrial scale-up production; (5) a product purity of 98% or more.

[0187] Furthermore, the oxopyridine compounds of formula (I) obtained by the above methods 1, 2 and 3 can be crystallized using a crystallization method, such as the crystallization method in patent CN111770917A, to obtain high-quality crystal products even higher than the crystal quality in the patent.

[0188] Explanation of terms:

[0189] "Alkyl" refers to a lower alkyl group, specifically a C1-C16 saturated branched or straight chain alkyl group. The alkyl portion of "alkylcarbonyl" shall be interpreted similarly.

[0190] "Cycloalkyl" refers to a C3-C10 cycloalkyl group, preferably a C3-C6 cycloalkyl group.

[0191] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0192] “Above” and “below” include the number itself.

[0193] DMAP: 4-dimethylaminopyridine.

[0194] DEAD: diethyl azodicarboxylate.

[0195] DIAD: diisopropyl azodicarboxylate.

[0196] TMAD: azodicarbonamide.

[0197] DTBAD: di-tert-butyl azodicarboxylate.

[0198] ADDP: azodicarbonyl dipyridine.

[0199] DBU: 1,8-diazabicycloundec-7-ene.

[0200] DIPEA: isopropylethylamine.

[0201] T3P: 1-propylphosphoric anhydride.

[0202] DPP-Cl: diphenylphosphinyl chloride.

[0203] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0204] HOBT: 1-hydroxybenzotriazole.

[0205] HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0206] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0207] DCC: N,N'-dicyclohexylcarbodiimide.

[0208] DMF: N,N-dimethylformamide.

[0209] Compared with the prior art, the present invention has the following advantages:

[0210] 1. The novel preparation route of the present invention for synthesizing the compound of formula (I) can improve the overall conversion rate, enantioselectivity, and N / O-alkylation selectivity, which has absolute advantages. In particular, when using milder bases and more readily available solvents, a conversion rate of N / O ratios of 30 to 40:1 or higher can be achieved, with fewer O-alkylated impurities. In the prior art, the ratio of N-alkylation to O-alkylation in the crude product is (9 to 10):1, containing a large amount of O-alkylated impurities, and the purification of such isomerized impurities is extremely difficult. By comparison, the synthetic route of the present application has low subsequent purification difficulty, which is beneficial to the subsequent crystallization yield and improves the stability of the crystallization refining process control.

[0211] 2. What is even more surprising is that, through the process of preparing the compound of formula (I) of the present invention, a higher ee-value of the amorphous form of formula (I) can be obtained. After extraction and evaporation of the solvent, the amorphous form of the compound of formula (I) is obtained with an ee-value of more than 98% ee, or even more than 99% ee. In the prior art, the ee value can only be optimized to 85-93% at most, and there are still 7-15% isomeric impurities. It can be seen that through the synthesis route of the present application, since the content of isomeric impurities in the obtained crude product is only 1-2%, there is no need to go through a complicated chiral isomer purification process, and a crude product with an ee value of >98% can be directly obtained, and then the target crystal can be obtained through a crystallization process, which greatly simplifies the impurity removal step, avoids complicated post-processing, saves costs, and is conducive to industrial scale-up production.

[0212] 3. The yield of the crude product prepared by the single-step condensation reaction is increased to over 85% to 98%, and the overall yield of the route is over 60% to 70%, while the overall yield in the existing technology is only 20% to 25%. Therefore, this synthetic route has a high conversion rate, significantly shortens the production cycle, avoids complex post-processing, saves costs, and is conducive to industrial scale-up production. DETAILED DESCRIPTION

[0213] The present invention will be further described in detail below in conjunction with embodiments and test examples. The embodiments and test examples of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Any equivalent substitutions in the art made in accordance with the contents disclosed in the present invention shall fall within the scope of protection of the present invention.

[0214] The compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof can be prepared by selecting the synthetic routes described in the examples. Conventional conditions for the reaction starting materials and reaction solvents can be adjusted based on the desired substituents or salt formation. These conditions can be implemented by those skilled in the art based on the disclosure of the present invention. Furthermore, column chromatography in the present invention, unless otherwise specified, refers to silica gel column chromatography. The elution solvent, unless otherwise specified, can be determined using a combination of the reaction solvent, common knowledge, or commonly used methods employed by those skilled in the art, to determine a single or mixed elution solvent.

[0215] The structure of the compound is determined by NMR ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0216] The liquid chromatography-mass spectrometer (LC-MS) was Agilent G6120B (used with Agilent 1260 liquid chromatography); the nuclear magnetic resonance instrument ( 1 H NMR) was performed on a Bruker AVANCE-400 or Bruker AVANCE-800, and nuclear magnetic resonance ( 1H NMR) shifts (δ) are given in parts per million (ppm) using DMSO as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are expressed in 10 -6 The units are given in ppm.

[0217] The term "room temperature" in the present invention refers to a temperature between 10 and 30°C.

[0218] The mixed solvents used in the embodiments of the present invention refer to volume ratios unless otherwise specified.

[0219] The term "20 ml of ethyl acetate:n-heptane 1:2 solvent" in the present invention refers to 20 ml of a mixed solvent (ethyl acetate:n-heptane 1:2, v / v)". Similar expressions shall be interpreted similarly.

[0220] Part I Examples: Examples 1-7

[0221] Example 1: Preparation of (S)-2-fluoro-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)benzamide (Compound 1):

[0222] Step 1: Preparation of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate

[0223] 1.03 g (7.05 mmol) of (R)-2-acetoxybutyric acid was dissolved in 20 ml of tetrahydrofuran, and 720 mg (4.70 mmol) of 4-amino-2-chlorobenzamide was added. The mixture was cooled to below 0°C, and 1.12 g (14.1 mmol) of pyridine was added. Then, 4.50 g (14.1 mmol) of 1-propylphosphonic anhydride (50% ethyl acetate solution) diluted with 10 ml of tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred at 0-5°C for 10 minutes and then at room temperature for 30 minutes. After the reaction was complete, water was added to terminate the reaction, and EA was added for extraction. The organic phase was washed sequentially with 5% citric acid, saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a crude product. To the crude product was added 10 ml of ethyl acetate:n-heptane (1:1) solvent, stirred at room temperature for 2 hours, filtered, and the filter cake was washed with n-heptane. The filter cake was vacuum dried to obtain a white solid with a yield of 86.1%, an ee value of 99.56%, and a purity of 96.20%.

[0224] ESI-MS: m / z = 283.1 (M+H) + .

[0225] 1H NMR(400MHz,DMSO-d6)δ:10.76(s,1H),8.08–7.77(m,1H),7.92–7.88(m,1H),7.76( s,2H),7.60-7.56(m,1H),4.56(m,1H),2.25(s,3H),1.98–1.88(m,2H),0.88(t,3H).

[0226] Step 2: Preparation of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide

[0227] 1.5 g (5.32 mmol) of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate was dissolved in a mixture of 10 ml of methanol and 15 ml of water. 2.20 g (15.96 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 ml of water was slowly added to terminate the reaction. A large amount of white solid precipitated from the system. After further addition of 50 ml of water, stirring and slurrying was performed for 1 hour. The white solid was filtered and the filter cake was dried under vacuum to obtain a white solid with a yield of 87.3%, an ee value of 98.87%, and a purity of 96.82%.

[0228] ESI-MS: m / z = 241.1 (M+H) + .

[0229] 1 H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),8.08–7.77(m,1H),7.92–7.88(m,1H),7.78( s,2H),7.60-7.56(m,1H),5.52(s,1H),4.56(m,1H),2.01–1.88(m,2H),0.88(t,3H).

[0230] Step 3: Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl p-toluenesulfonate

[0231] 860 mg (3.58 mmol) of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide was dissolved in 10 mL of dichloromethane. 723 mg (7.16 mmol) of triethylamine and 88 mg (0.72 mmol) of DMAP were added. Finally, a 5 mL solution of p-toluenesulfonic acid in dichloromethane (3.95 mmol) was added dropwise at approximately 0°C. The reaction was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 mL of water was slowly added to terminate the reaction. The organic phase was extracted with dichloromethane, dried, and concentrated to obtain the crude product. The crude product was dissolved in approximately 8 mL of ethyl acetate and cooled to crystallize to obtain a pale yellow solid. The yield was 86.6%, the ee value was 98.52%, and the purity was 95.65%.

[0232] ESI-MS: m / z = 395.1 (M+H) + .

[0233] 1 H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),8.08-7.97(m,1H),7.96(s,2H),7.78-7.75(m,3H),7.60- 7.56(m,1H),7.50-7.45(m,2H),4.56-4.52(m,1H),2.43(s,3H),2.01-1.88(m,2H),0.88(t,3H).

[0234] Step 4: Preparation of compound 1

[0235] 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one was added to a 25 ml single-necked bottle and dissolved in 5 ml of dioxane with stirring. 150 mg (1.08 mmol) of potassium carbonate and 62 mg (0.539 mmol) of tetramethylguanidine were added and stirred for 5 minutes. 0.648 mmol of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl p-toluenesulfonate was added and the temperature was raised to 35°C with stirring until the reaction was complete as monitored by TLC. The N / O-alkylation conversion ratio was 40:1. Saturated ammonium chloride was added to terminate the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain the crude product with a yield of 95.8% and an ee value of 99.24%.

[0236] ESI-MS: m / z = 593.2 (M+H) + .

[0237] 1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H) ),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H).

[0238] The crude product can be crystallized according to the method described in patent CN111770917A to obtain high-quality target product.

[0239] Example 2: Preparation of Compound 2

[0240] The preparation method is the same as that of Example 1, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 4 is replaced with 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one to obtain the crude title compound 2 with a yield of 90%, an ee value of 98.61%, and an N / O-alkylation conversion ratio of 35:1 at the reaction endpoint.

[0241] ESI-MS: m / z = 559.1 (M+H) + .

[0242] 1 H NMR(400MHz, DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).

[0243] The crude product can be crystallized according to the method described in patent CN111770917A to obtain high-quality target product.

[0244] Example 3: Preparation of Compound 3

[0245] The preparation method was the same as that of Example 1, except that 4-amino-2-fluorobenzamide in step 1 was replaced with 4-amino-2-methoxybenzamide to obtain the crude title compound 3. The final synthesis step yield was 90%, the ee value was 98.39%, and the N / O-alkylation conversion ratio at the reaction endpoint was 30:1.

[0246] ESI-MS: m / z = 605.1 (M+H) + .

[0247] 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(d d,1H),7.14(s,1H),6.53(s,1H),5.54(dd,1H),3.86(s,3H),3.25(s,3H),2.16-2.04(m,2H),0.78(t,3H).

[0248] Example 4: Preparation of Compound 4

[0249] The preparation method was the same as that of Example 1, except that 4-amino-2-fluorobenzamide in step 1 was replaced with 4-amino-2-fluoro-N-methylbenzamide to obtain the crude title compound 4. The final synthesis step yield was 90%, the ee value was 99.02%, and the N / O-alkylation conversion ratio at the reaction endpoint was 40:1.

[0250] ESI-MS: m / z = 623.1 (M+H) + .

[0251] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06( m,1H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0252] Example 5: Preparation of Compound 5

[0253] The preparation method is the same as that of Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide to obtain the crude title compound 5. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction endpoint is 40:1.

[0254] ESI-MS: m / z = 610.2 (M+H) + .

[0255] 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),9.14(d,J=1.1Hz,1H),8.06(d,J=3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H), 7.37(dd,J=8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J=8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J=7.1Hz,2H),0.78(t,J=7.2Hz,3H).

[0256] Example 6: Preparation of Compound 6

[0257] The preparation method was the same as that of Example 1, except that 4-amino-2-fluorobenzamide in step 1 was replaced with 4-amino-2-trifluoromethyl-benzamide to obtain the crude title compound 6. The final synthesis step yield was 89%, the ee value was 98.87%, and the N / O-alkylation conversion ratio at the reaction endpoint was 30:1.

[0258] ESI-MS: m / z = 643.1 (M+H) + .

[0259] 1 H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.5 1(m,2H),7.14(s,1H),6.54(s,1H),5.51(dd,1H),3.25(s,3H),2.23–2.03(m,2H),0.79(t,3H).

[0260] Example 7: Preparation of Compound 7

[0261] The preparation method was the same as that of Example 1, except that 4-amino-2-fluorobenzamide in step 1 was replaced with 4-amino-2-chlorobenzamide to obtain the crude title compound 7. The final synthesis step yield was 92%, the ee value was 98.87%, and the N / O-alkylation conversion ratio at the reaction endpoint was 35:1.

[0262] ESI-MS: m / z = 623.1 (M+H) + .

[0263] 1 H NMR(400MHz, DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H).

[0264] The intermediates included in the above examples and their NMR and mass spectrometry data are shown in Table 1 below:

[0265] Table 1

[0266] The preparation of the above intermediates adopts the same preparation concept as Example 1, as described in Examples 1 to 7, that is, the products obtained in step 3 of the preparation routes of Examples 1 to 7. The preparation methods of each intermediate are summarized as follows:

[0267] The compound of formula (III-a) is reacted with p-toluenesulfonyl chloride under alkaline conditions to obtain:

[0268] Among them, R 2 、R 3 、R 4 、R 5 、R 6 The definition of is the same as any corresponding definition in the Summary of the Invention.

[0269] It can be understood that the specific compounds of formula (III-a-3) used in the above Examples 1 to 7 can be easily obtained by those skilled in the art according to conventional techniques in the art, and will not be described in detail here.

[0270] Part II Examples: Examples 8-15

[0271] Example 8: Preparation of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)-2-fluoro-N-methylbenzamide (Compound 4):

[0272] Step 1: Preparation of (R)-tert-butyl 4-(2-bromobutyramide)-2-fluorobenzoate

[0273] 441 mg (2.64 mmol) of (R)-2-bromo-3-propionic acid was dissolved in 4 ml of tetrahydrofuran, and 372 mg (1.76 mmol) of tert-butyl 4-amino-2-fluorobenzoate was added. The mixture was cooled to below 0°C, and 654 mg (8.27 mmol) of pyridine was added. Then, 2.24 g (3.52 mmol) of 1-propylphosphoric anhydride (50% ethyl acetate solution) diluted with 2 ml of tetrahydrofuran was added dropwise. After the addition, the mixture was stirred at 0-5°C for 10 minutes and then at room temperature for 30 minutes. After the reaction was complete, water was added to terminate the reaction. EA was added for extraction. The organic phase was washed sequentially with 5% citric acid, saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to yield 608 mg of crude product. 5 ml of ethyl acetate was added to the crude product, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was then dried under vacuum to yield a white solid with a yield of 74.0% and a purity of 97.55%.

[0274] ESI-MS: m / z = 360.1 (M+H) + .

[0275] Step 2: Preparation of (S)-tert-butyl 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-fluorobenzoate

[0276] 2.0 g (5.39 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one was mixed with 50 ml of isopropanol and 20 ml of acetone. 1.87 mg (16.24 mmol) of tetramethylguanidine was added and stirred for 5 minutes. 2.33 mg (6.48 mmol) of (R)-tert-butyl 4-(2-bromobutyramide)-2-fluorobenzoate was added and the mixture was stirred at room temperature overnight. After completion, the reaction was terminated by adding saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to yield 4.60 mg of crude product. The product was collected by column chromatography using an eluent of ethyl acetate:petroleum ether = 1:2 to obtain 2.58 g of a white solid. The yield was 73.7% and the purity was 97.82%.

[0277] ESI-MS: m / z = 650.2 (M+H) + .

[0278] Step 3: Preparation of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-fluorobenzoic acid

[0279] 2.58 g (3.97 mmol) of (S)-tert-butyl 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-fluorobenzoate was dissolved in 25 mL of acetonitrile, cooled to about 0°C and the internal temperature was monitored. 25 mL of concentrated hydrochloric acid was slowly added dropwise. The reaction was complete after 0.5 h according to TLC detection. Water was added to terminate the reaction, and EA was added for extraction. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 2.36 g of a crude product. 15 ml of ethyl acetate was added to the crude product, stirred thoroughly to dissolve, and the solid was removed by filtration. The mother liquor was concentrated and then stirred with 20 ml of ethyl acetate:n-heptane (1:2) at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with n-heptane. The filter cake was vacuum dried to obtain 2.06 g of a white solid with a yield of 87.3%, an ee value of 99.36%, and a purity of 98.20%.

[0280] ESI-MS: m / z = 594.1 (M+H) + .

[0281] Step 4: Preparation of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-fluoro-N-methylbenzamide

[0282] 1.0 g (1.675 mmol) of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-fluorobenzoic acid was dissolved in 10 mL of DMAC, and 226 mg (3.35 mmol) of methylamine hydrochloride and 953 mg (2.52 mmol) of HBTU were added. The temperature was cooled to about 5°C and the internal temperature was monitored. 1.1 g (8.38 mmol) of DIPEA was slowly added dropwise. The reaction was maintained at 5-10°C for 1 h. After TLC detection, the reaction was complete. 30 ml of water was slowly added to terminate the reaction. Off-white solid particles gradually precipitated from the system. After stirring and beating for 1 h, the solid was filtered and air-dried to obtain 1.06 g of a crude product. The mixture was stirred at room temperature for 2 hours with 20 ml of ethyl acetate:n-heptane (1:2) and filtered. The filter cake was washed with n-heptane and dried under vacuum to obtain 860 mg of a white solid with a yield of 84.3%, an ee value of 99.27%, and a purity of 98.32%.

[0283] ESI-MS: m / z = 607.2 (M+H) + .

[0284] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06( m,1H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0285] Example 9: Preparation of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)-2-fluoro-N-(methyl-d3)benzamide (Compound 5)

[0286] The preparation method is the same as that of Example 8, except that the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 5 with a yield of 87%, an ee value of 99.22%, and a purity of 98.02%.

[0287] ESI-MS: m / z = 610.2 (M+H) + .

[0288] 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),9.14(d,J=1.1Hz,1H),8.06(d,J=3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H), 7.37(dd,J=8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J=8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J=7.1Hz,2H),0.78(t,J=7.2Hz,3H).

[0289] Example 10: Preparation of Compound 8

[0290] The preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced with tert-butyl 4-amino-2-(trifluoromethyl)benzoate to obtain the title compound 8 with an ee value of 99.17% and a purity of 97.62%.

[0291] ESI-MS: m / z = 657.2 (M+H) + .

[0292] 1 H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.18–8.12( m,1H),7.98–7.90(m,2H),7.85(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.53(t,J=7.8Hz,1H),3. 26(s,3H),2.77(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0293] Example 11: Preparation of Compound 9

[0294] The preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-(trifluoromethyl)benzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 9 with an ee value of 98.92% and a purity of 98.50%.

[0295] ESI-MS: m / z = 660.2 (M+H) + .

[0296] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.15(d,J=1.1Hz,1H),8.19–8.12(m,1H),7.98–7.91(m,2H),7.85(d,J=2.0Hz,1H),7.70–7.60(m, 2H),7.37(dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.53(t,J=7.8Hz,1H),3.26(s,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0297] Example 12: Preparation of Compound 10

[0298] The preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced with tert-butyl 4-amino-2-chlorobenzoate to obtain the title compound 10 with an ee value of 98.89% and a purity of 98.49%.

[0299] ESI-MS: m / z = 623.1 (M+H) + .

[0300] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.16–8.10( m,1H),7.96–7.88(m,2H),7.84(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 26(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0301] Example 13: Preparation of Compound 11

[0302] The preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-chlorobenzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 11 with an ee value of 98.96% and a purity of 98.32%.

[0303] ESI-MS: m / z = 626.1 (M+H) + .

[0304] 1 H NMR(400MHz, DMSO-d6)δ:10.81(s,1H),9.16(d,J=1.1Hz,1H),8.16–8.10(m,1H),7.96–7.89(m,2H),7.84(d,J=2.0Hz,1H),7.70–7.60(m, 2H),7.37(dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3.26(s,3H),2.18–2.06(m,2H),0.78(t,J=7.2Hz,3H).

[0305] Example 14: Preparation of Compound 12

[0306] The preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced with tert-butyl 4-amino-2-(methoxy)benzoate to obtain the title compound 12 with an ee value of 98.68% and a purity of 98.65%.

[0307] ESI-MS: m / z = 619.2 (M+H) + .

[0308] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06(m,1 H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J=8 .5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3.86(s,3H), 3.25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0309] Example 15: Preparation of Compound 13

[0310] The preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-(methoxy)benzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 13 with an ee value of 98.68% and a purity of 98.95%.

[0311] ESI-MS: m / z = 622.2 (M+H) + .

[0312] 1H NMR(400MHz, DMSO-d6)δ:10.81(s,1H),9.17(d,J=1.1Hz,1H),8.13–8.08(m,1H),7.89–7.81(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7 .37(dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.53(t,J=7.8Hz, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.18–2.02 (m, 2H), 0.78 (t, J = 7.2Hz, 3H).

[0313] Comparative Example 1: Preparation of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)-2-fluoro-N-methylbenzamide (Compound 4):

[0314] Compound 4 was synthesized according to the synthesis strategy disclosed in patent CN 111770917 A and purified to obtain the title compound 4 with an ee value of 82.12% and a purity of 96.26%. Since the crystallization process of compound 4 failed to form co-enantiomer crystals, the chiral isomer of compound 4 (R-configured compound 4) was not removed during the purification process.

[0315] Through the route provided by this patent, such as Example 8, an intermediate formula (VIII) with an ee-value higher than 98% is obtained by chemical resolution of structural formula (VIII), thereby achieving the target API of high ee value and high chemical purity of compound 4.

[0316] The NMR and mass spectrometry data of the intermediates produced by the compounds of Examples 8-14 above according to the methods of the examples are shown in Table 2 below:

[0317] Table 2

[0318] Part III Examples: Examples 16-43

[0319] Part III: First Group of Examples

[0320] Examples 16-22 provide a type of intermediate and the oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 For trifluoromethanesulfonyl, the specific synthetic route is as follows:

[0321] Example 16: Preparation of Compound 1:

[0322] Step 1: (R)-2-Acetoxybutyric acid

[0323] 5.0 g (48.49 mmol) of D-2-aminobutyric acid was dissolved in 20 g (mmol) of acetic acid and cooled to below 5°C. 6.7 g (97.09 mmol) of sodium nitrite was added in batches. The temperature was controlled below 0-5°C. The addition was completed in about 30 minutes. The reaction solution was stirred at 0-5°C for 6-10 hours. Subsequently, 3V volume of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined. The organic phases were washed with plenty of water, and the acetic acid was completely washed off with sodium bicarbonate solution. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 7.5 g of an oily product, which was used directly in the next step without purification.

[0324] ESI-MS: m / z = 147.1 (M+H) + .

[0325] Step 2: Preparation of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate

[0326] 1.03 g (7.05 mmol) of (R)-2-acetoxybutyric acid was dissolved in 20 ml of tetrahydrofuran, and 720 mg (4.70 mmol) of 4-amino-2-fluorobenzamide was added. The mixture was cooled to below 0°C, and 1.12 g (14.1 mmol) of pyridine was added. Then, 4.50 g (14.1 mmol) of 1-propylphosphoric anhydride (50% ethyl acetate solution) diluted with 10 ml of tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred at 0-5°C for 10 minutes and then at room temperature for 30 minutes. After the reaction was complete, water was added to terminate the reaction, and EA was added for extraction. The organic phase was washed sequentially with 5% citric acid, saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a crude product. To the crude product was added 10 ml of an organic solvent mixture (ethyl acetate: n-heptane in a volume ratio of 1:1) and stirred at room temperature for 2 hours. The mixture was filtered, and the filter cake was washed with n-heptane. The filter cake was vacuum dried to obtain a white solid with a yield of 76.1%, an ee value of 99.56%, and a purity of 96.20%.

[0327] ESI-MS: m / z = 283.1 (M+H) + .

[0328] Step 3: Preparation of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide

[0329] 1.5 g (5.32 mmol) of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate was dissolved in a mixture of 10 ml of methanol and 15 ml of water. 2.20 g (15.96 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 ml of water was slowly added to terminate the reaction. A large amount of white solid precipitated from the system. After further addition of 50 ml of water, stirring and slurrying was performed for 1 hour. The white solid was filtered and the filter cake was dried under vacuum to obtain a white solid with a yield of 87.3%, an ee value of 98.87%, and a purity of 96.82%.

[0330] ESI-MS: m / z = 241.1 (M+H) + .

[0331] Step 4: Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl trifluoromethanesulfonate

[0332] 860 mg (3.58 mmol) of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide was dissolved in 10 mL of dichloromethane, and 723 mg (7.16 mmol) of triethylamine and 88 mg (0.72 mmol) of 4-dimethylaminopyridine (DMAP) were added. Finally, 678 mg (3.95 mmol) of trifluoromethanesulfonic acid (5 mL) in dichloromethane was added dropwise at approximately 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 mL of water was slowly added to terminate the reaction. The organic phase was extracted with dichloromethane, dried, and concentrated to obtain a crude product. The crude product was dissolved in approximately 8 mL of ethyl acetate and cooled to obtain a pale yellow solid for crystallization. The yield was 86.6%, the ee value was 98.52%, and the purity was 95.65%.

[0333] ESI-MS: m / z = 373.1 (M+H) + .

[0334] Step 5: Preparation of Compound 1

[0335] 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one was added to a 25 ml single-necked bottle and dissolved in 5 ml of dioxane with stirring. 150 mg (1.08 mmol) of potassium carbonate and 62 mg (0.539 mmol) of tetramethylguanidine were added and stirred for 5 minutes. 0.648 mmol of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl trifluoromethanesulfonate was added and the temperature was raised to 35°C with stirring until the reaction was complete as monitored by TLC. The N / O-alkylation conversion ratio was 40:1. Saturated ammonium chloride was added to terminate the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain the crude product with a yield of 95.8% and an ee value of 98.51%.

[0336] ESI-MS: m / z = 593.2 (M+H) + .

[0337] 1 H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61( m,2H),7.55(d,2H),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s, 3H),2.18–2.00(m,2H),0.78(t,3H).

[0338] The crude product can be crystallized to obtain high-quality target product.

[0339] Example 17: Preparation of Compound 2

[0340] The preparation method is the same as that of Example 16, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, that is, R 9 By replacing the trifluoromethyl group with chlorine, the crude compound 2 was obtained with a yield of 90%, an ee value of 98.61%, and an N / O-alkylation conversion ratio of 35:1 at the reaction end point.

[0341] ESI-MS: m / z = 559.1 (M+H) + .

[0342] 1 H NMR(400MHz, DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).

[0343] The crude product can be crystallized to obtain high-quality target product.

[0344] Example 18: Preparation of Compound 3

[0345] The preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxybenzamide, that is, R 6 By replacing fluorine with methoxy, crude compound 3 can be obtained. The final synthesis step yield is 90%, the ee value is 98.39%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0346] ESI-MS: m / z = 605.1 (M+H) + .

[0347] 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(d d,1H),7.14(s,1H),6.53(s,1H),5.54(dd,1H),3.86(s,3H),3.25(s,3H),2.16-2.04(m,2H),0.78(t,3H).

[0348] Example 19: Preparation of Compound 4

[0349] The preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide. 2 By replacing the amino group with an N-methyl group, the crude compound 4 was obtained. The final synthesis step yield was 90%, the ee value was 99.02%, and the N / O-alkylation conversion ratio at the reaction endpoint was 40:1.

[0350] ESI-MS: m / z = 623.1 (M+H) + .

[0351] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06( m,1H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0352] Example 20: Preparation of Compound 5

[0353] The preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, that is, R 2 By replacing the amino group with N-(methyl-d3), the crude compound 5 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 40:1.

[0354] ESI-MS: m / z = 610.2 (M+H) + .

[0355] 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),9.14(d,J=1.1Hz,1H),8.06(d,J=3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H), 7.37(dd,J=8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J=8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J=7.1Hz,2H),0.78(t,J=7.2Hz,3H).

[0356] Example 21: Preparation of Compound 6

[0357] The preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide. 6By replacing fluorine with trifluoromethyl, crude compound 6 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0358] ESI-MS: m / z = 643.1 (M+H) + .

[0359] 1 H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.5 1(m,2H),7.14(s,1H),6.54(s,1H),5.51(dd,1H),3.25(s,3H),2.23–2.03(m,2H),0.79(t,3H).

[0360] Example 22: Preparation of Compound 7

[0361] The preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide. 6 By replacing fluorine with chlorine, crude compound 7 can be obtained. The final synthesis step yield is 92%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 35:1.

[0362] ESI-MS: m / z = 623.1 (M+H) + .

[0363] 1 H NMR(400MHz, DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H).

[0364] The intermediates included in Examples 16-22 and their NMR and mass spectrometry data are shown in Table 3 below:

[0365] Table 3. Intermediates involved in Examples 16-22 and their NMR and mass spectrometry data

[0366] Part III Second Group of Examples

[0367] Examples 23-29 provide a type of intermediate and the oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is a methylsulfonyl group, specifically as follows:

[0368] Example 23: Preparation of (S)-2-fluoro-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)benzamide (Compound 1):

[0369] Steps 1-3 and step 5 of this embodiment are consistent with those of Example 16, except that:

[0370] Step 4: Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl methanesulfonate

[0371] 860 mg (3.58 mmol) of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide was dissolved in 10 mL of dichloromethane. 723 mg (7.16 mmol) of triethylamine and 88 mg (0.72 mmol) of DMAP were added. Finally, a 5 mL solution of methanesulfonic acid (3.95 mmol) was added dropwise at approximately 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 mL of water was slowly added to terminate the reaction. The organic phase was extracted with dichloromethane, dried, and concentrated to obtain the crude product. The crude product was dissolved in approximately 8 mL of ethyl acetate and cooled to crystallize to obtain a pale yellow solid. The yield was 86.6%, the ee value was 98.52%, and the purity was 95.65%.

[0372] ESI-MS: m / z = 319.1 (M+H) + .

[0373] Step 5: Preparation of Compound 1

[0374] 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one was added to a 25 ml single-necked bottle and dissolved in 5 ml of dioxane with stirring. 150 mg (1.08 mmol) of potassium carbonate and 62 mg (0.539 mmol) of tetramethylguanidine were added and stirred for 5 minutes. 0.648 mmol of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl methanesulfonate was added and the temperature was raised to 35°C with stirring until the reaction was complete as monitored by TLC. The N / O-alkylation conversion ratio was 40:1. Saturated ammonium chloride was added to terminate the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain the crude product with a yield of 95.8% and an ee value of 99.78%.

[0375] ESI-MS: m / z = 593.2 (M+H) + .

[0376] 1 H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H) ),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H).

[0377] The crude product can be crystallized to obtain high-quality target product.

[0378] Example 24: Preparation of Compound 2

[0379] The preparation method is the same as that of Example 23, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, that is, R 9 By replacing the trifluoromethyl group with chlorine, the crude compound 2 was obtained with a yield of 90%, an ee value of 98.61%, and an N / O-alkylation conversion ratio of 35:1 at the reaction end point.

[0380] ESI-MS: m / z = 559.1 (M+H) + .

[0381] 1 H NMR(400MHz, DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).

[0382] The crude product can be crystallized to obtain high-quality target product.

[0383] Example 25: Preparation of Compound 3

[0384] The preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxybenzamide. 6 By replacing fluorine with methoxy, crude compound 3 can be obtained. The final synthesis step yield is 90%, the ee value is 98.39%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0385] ESI-MS: m / z = 605.1 (M+H) + .

[0386] 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(d d,1H),7.14(s,1H),6.53(s,1H),5.54(dd,1H),3.86(s,3H),3.25(s,3H),2.16-2.04(m,2H),0.78(t,3H).

[0387] Example 26: Preparation of Compound 4

[0388] The preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide. 2 By replacing the amino group with an N-methyl group, the crude compound 4 was obtained. The final synthesis step yield was 90%, the ee value was 99.02%, and the N / O-alkylation conversion ratio at the reaction endpoint was 40:1.

[0389] ESI-MS: m / z = 623.1 (M+H) + .

[0390] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06( m,1H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0391] Example 27: Preparation of Compound 5

[0392] The preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, that is, R 2 By replacing the amino group with N-(methyl-d3), the crude compound 5 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 40:1.

[0393] ESI-MS: m / z = 610.2 (M+H) + .

[0394] 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),9.14(d,J=1.1Hz,1H),8.06(d,J=3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H), 7.37(dd,J=8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J=8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J=7.1Hz,2H),0.78(t,J=7.2Hz,3H).

[0395] Example 28: Preparation of Compound 6

[0396] The preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide. 6By replacing fluorine with trifluoromethyl, crude compound 6 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0397] ESI-MS: m / z = 643.1 (M+H) + .

[0398] 1 H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.5 1(m,2H),7.14(s,1H),6.54(s,1H),5.51(dd,1H),3.25(s,3H),2.23–2.03(m,2H),0.79(t,3H).

[0399] Example 29: Preparation of Compound 7

[0400] The preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide. 6 By replacing fluorine with chlorine, crude compound 7 can be obtained. The final synthesis step yield is 92%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 35:1.

[0401] ESI-MS: m / z = 623.1 (M+H) + .

[0402] 1 H NMR(400MHz, DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H).

[0403] The intermediates contained in Examples 23-29 and their NMR and mass spectrometry data are shown in Table 4:

[0404] Table 4. Intermediates involved in Examples 23-29 and their NMR and mass spectrometry data

[0405] Part III: The third group of embodiments

[0406] Examples 30-36 provide a type of intermediate and the oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is p-nitrobenzenemethylsulfonyl, specifically as follows:

[0407] Example 30: Preparation of (S)-2-fluoro-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)benzamide (Compound 1):

[0408] Steps 1-3 and step 5 of this embodiment are consistent with those of Example 16, except that:

[0409] Step 4: Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl p-nitrobenzenesulfonate

[0410] 860 mg (3.58 mmol) of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide was dissolved in 10 mL of dichloromethane. 723 mg (7.16 mmol) of triethylamine and 88 mg (0.72 mmol) of DMAP were added. Finally, a solution of 802 mg (3.95 mmol) of p-nitrobenzenesulfonic acid in 5 mL of dichloromethane was added dropwise at approximately 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 mL of water was slowly added to terminate the reaction. The organic phase was extracted with dichloromethane, dried, and concentrated to obtain a crude product. The crude product was dissolved in approximately 8 mL of ethyl acetate and cooled for crystallization to obtain a pale yellow solid with a yield of 86.6%, an ee value of 98.52%, and a purity of 95.65%.

[0411] ESI-MS: m / z = 426.1 (M+H) + .

[0412] Step 5: Preparation of Compound 1

[0413] 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one was added to a 25 ml single-necked bottle and dissolved in 5 ml of dioxane with stirring. 150 mg (1.08 mmol) of potassium carbonate and 62 mg (0.539 mmol) of tetramethylguanidine were added and stirred for 5 minutes. 0.648 mmol of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl-p-nitrobenzenesulfonate was added and the temperature was raised to 35°C with stirring until the reaction was complete as monitored by TLC. The N / O-alkylation conversion ratio was 40:1. Saturated ammonium chloride was added to terminate the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain the crude product with a yield of 95.8% and an ee value of 98.51%.

[0414] ESI-MS: m / z = 593.2 (M+H) + .

[0415] 1 H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H) ),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H).

[0416] The crude product can be crystallized to obtain high-quality target product.

[0417] Example 31: Preparation of Compound 2

[0418] The preparation method is the same as that of Example 30, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, that is, R 9 By replacing the trifluoromethyl group with chlorine, the crude compound 2 was obtained with a yield of 90%, an ee value of 98.61%, and an N / O-alkylation conversion ratio of 35:1 at the reaction end point.

[0419] ESI-MS: m / z = 559.1 (M+H) + .

[0420] 1 H NMR(400MHz, DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).

[0421] The crude product can be crystallized to obtain high-quality target product.

[0422] Example 32: Preparation of Compound 3

[0423] The preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxybenzamide. 6 By replacing fluorine with methoxy, crude compound 3 can be obtained. The final synthesis step yield is 90%, the ee value is 98.39%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0424] ESI-MS: m / z = 605.1 (M+H) + .

[0425] 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(d d,1H),7.14(s,1H),6.53(s,1H),5.54(dd,1H),3.86(s,3H),3.25(s,3H),2.16-2.04(m,2H),0.78(t,3H).

[0426] Example 33: Preparation of Compound 4

[0427] The preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide. 2 By replacing the amino group with an N-methyl group, the crude compound 4 was obtained. The final synthesis step yield was 90%, the ee value was 99.02%, and the N / O-alkylation conversion ratio at the reaction endpoint was 40:1.

[0428] ESI-MS: m / z = 623.1 (M+H) + .

[0429] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06( m,1H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0430] Example 34: Preparation of Compound 5

[0431] The preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, that is, R 2 By replacing the amino group with N-(methyl-d3), the crude compound 5 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 40:1.

[0432] ESI-MS: m / z = 610.2 (M+H) + .

[0433] 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),9.14(d,J=1.1Hz,1H),8.06(d,J=3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H), 7.37(dd,J=8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J=8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J=7.1Hz,2H),0.78(t,J=7.2Hz,3H).

[0434] Example 35: Preparation of Compound 6

[0435] The preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide. 6By replacing fluorine with trifluoromethyl, crude compound 6 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0436] ESI-MS: m / z = 643.1 (M+H) + .

[0437] 1 H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.5 1(m,2H),7.14(s,1H),6.54(s,1H),5.51(dd,1H),3.25(s,3H),2.23–2.03(m,2H),0.79(t,3H).

[0438] Example 36: Preparation of Compound 7

[0439] The preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide. 6 By replacing fluorine with chlorine, crude compound 7 can be obtained. The final synthesis step yield is 92%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 35:1.

[0440] ESI-MS: m / z = 623.1 (M+H) + .

[0441] 1 H NMR(400MHz, DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H).

[0442] The intermediates contained in Examples 30-36 and their NMR and mass spectrometry data are shown in Table 5:

[0443] Table 5. Intermediates involved in Examples 30-36 and their NMR and mass spectrometry data

[0444] Part III. Fourth Group of Examples

[0445] Examples 37-43 provide a type of intermediate and the oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is a benzenesulfonyl group, specifically as follows:

[0446] Example 37: Preparation of (S)-2-fluoro-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzamide (Compound 1):

[0447] Steps 1-3 and step 5 of this embodiment are consistent with those of Example 16, except that:

[0448] Step 4: Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl methanesulfonate

[0449] 860 mg (3.58 mmol) of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide was dissolved in 10 mL of dichloromethane. 723 mg (7.16 mmol) of triethylamine and 88 mg (0.72 mmol) of DMAP were added. Finally, a solution of 625 mg (3.95 mmol) of benzenesulfonic acid in 5 mL of dichloromethane was added dropwise at approximately 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, 20 mL of water was slowly added to terminate the reaction. The organic phase was extracted with dichloromethane, dried, and concentrated to obtain the crude product. The crude product was dissolved in approximately 8 mL of ethyl acetate and cooled to crystallize to obtain a pale yellow solid with a yield of 86.6%, an ee value of 98.52%, and a purity of 95.65%.

[0450] ESI-MS: m / z = 381.1 (M+H) + .

[0451] Step 5: Preparation of Compound 1

[0452] 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one was added to a 25 ml single-necked bottle and dissolved in 5 ml of dioxane with stirring. 150 mg (1.08 mmol) of potassium carbonate and 62 mg (0.539 mmol) of tetramethylguanidine were added and stirred for 5 minutes. 246 mg (0.648 mmol) of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-ylbenzenesulfonate was added and the temperature was raised to 35°C with stirring until the reaction was complete as monitored by TLC. The N / O-alkylation conversion ratio was 40:1. Saturated ammonium chloride was added to terminate the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain the crude product with a yield of 92.8% and an ee value of 98.51%.

[0453] ESI-MS: m / z = 593.2 (M+H) + .

[0454] 1 H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H) ),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H).

[0455] The crude product can be crystallized to obtain high-quality target product.

[0456] Example 38: Preparation of Compound 2

[0457] The preparation method is the same as that of Example 37, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, that is, R 9 By replacing the trifluoromethyl group with chlorine, the crude compound 2 was obtained with a yield of 90%, an ee value of 98.61%, and an N / O-alkylation conversion ratio of 35:1 at the reaction end point.

[0458] ESI-MS: m / z = 559.1 (M+H) + .

[0459] 1 H NMR(400MHz, DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).

[0460] The crude product can be crystallized to obtain high-quality target product.

[0461] Example 39: Preparation of Compound 3

[0462] The preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxybenzamide. 6 By replacing fluorine with methoxy, crude compound 3 can be obtained. The final synthesis step yield is 90%, the ee value is 98.39%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0463] ESI-MS: m / z = 605.1 (M+H) + .

[0464] 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(d d,1H),7.14(s,1H),6.53(s,1H),5.54(dd,1H),3.86(s,3H),3.25(s,3H),2.16-2.04(m,2H),0.78(t,3H).

[0465] Example 40: Preparation of Compound 4

[0466] The preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide. 2 By replacing the amino group with an N-methyl group, the crude compound 4 was obtained. The final synthesis step yield was 90%, the ee value was 99.02%, and the N / O-alkylation conversion ratio at the reaction endpoint was 40:1.

[0467] ESI-MS: m / z = 623.1 (M+H) + .

[0468] 1 H NMR(400MHz, DMSO-d6)δ:10.82(s,1H),9.16(d,J=1.1Hz,1H),8.13–8.06( m,1H),7.89–7.80(m,2H),7.79(d,J=2.0Hz,1H),7.70–7.60(m,2H),7.37( dd,J=8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J=7.8Hz,1H),3. 25(s,3H),2.76(d,J=4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J=7.2Hz,3H).

[0469] Example 41: Preparation of Compound 5

[0470] The preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, that is, R 2 By replacing the amino group with N-(methyl-d3), the crude compound 5 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 40:1.

[0471] ESI-MS: m / z = 610.2 (M+H) + .

[0472] 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),9.14(d,J=1.1Hz,1H),8.06(d,J=3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H), 7.37(dd,J=8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J=8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J=7.1Hz,2H),0.78(t,J=7.2Hz,3H).

[0473] Example 42: Preparation of Compound 6

[0474] The preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide. 6By replacing fluorine with trifluoromethyl, crude compound 6 can be obtained. The final synthesis step yield is 89%, the ee value is 98.87%, and the N / O-alkylation conversion ratio at the reaction end is 30:1.

[0475] ESI-MS: m / z = 643.1 (M+H) + .

[0476] 1 H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.5 1(m,2H),7.14(s,1H),6.54(s,1H),5.51(dd,1H),3.25(s,3H),2.23–2.03(m,2H),0.79(t,3H).

[0477] Example 43: Preparation of Compound 7

[0478] The preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide. 6 By replacing fluorine with chlorine, crude compound 7 can be obtained with a subsequent synthesis step yield of 92%, an ee value of 98.87%, and an N / O-alkylation conversion ratio of 35:1 at the reaction endpoint.

[0479] ESI-MS: m / z = 623.1 (M+H) + .

[0480] 1 H NMR(400MHz, DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H).

[0481] The intermediates contained in Examples 37-43 and their NMR and mass spectrometry data are shown in Table 6:

[0482] Table 6. Intermediates involved in Examples 37-43 and their NMR and mass spectrometry data

[0483] The above embodiment is only one of the preferred implementation methods of the present invention and should not be used to limit the scope of protection of the present invention. Any changes or modifications that have no substantive meaning made to the main design concept and spirit of the present invention, as long as the technical problems solved are still consistent with the present invention, should be included in the scope of protection of the present invention.

Claims

1. An intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof: In formula (II): R 1 Selected from TsO-, X, R 7 O-; Ts is p-toluenesulfonyl, and X is selected from F, Cl, Br or I; R 2 Selected from -NHR 8 、-OC(CH3)3; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 7 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl; R 8 is selected from hydrogen, alkyl or cycloalkyl; Formula (II) is not 2. The intermediate or pharmaceutically acceptable salt thereof according to claim 1, wherein: The intermediate has a structure shown in formula (III), formula (IV) or formula (V): In formula (III), R 2 Selected from -NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; In formula (IV): R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; X is selected from F, Cl, Br or I; In formula (V): R 2 Selected from NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 7 Selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl.

3. The intermediate or pharmaceutically acceptable salt thereof according to claim 2, wherein: In formula (III), The R 2 Selected from -NHR 8 , R 8 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl; and / or R 3 , R 4 , R 5 , R 6 independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl; In formula (IV), The R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl, and / or X is independently selected from Cl or Br; In formula (V), R 8 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl; and / or R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

4. The intermediate or a pharmaceutically acceptable salt thereof according to claim 3, wherein the intermediate comprises a structure represented by formula (IV-a): In formula (IV-a), R 3 , R 4 , R 5 , R 6 The definition is the same as that of claim 3. 5 . The intermediate or a pharmaceutically acceptable salt thereof according to claim 2 , wherein hydrogen in the structure of the intermediate may be substituted by at least one deuterium.

6. The intermediate according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the intermediate comprises the following compound:

7. A method for preparing the intermediate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the synthesis of the intermediate comprises method A, method B or method C: Method A: The compound of formula (III-a) is reacted with p-toluenesulfonyl chloride under alkaline conditions to obtain the compound of formula (III) Interstitial, in, R 2 , R 3 , R 4 , R 5 , R 6 The meaning is the same as any corresponding definition in claims 1 to 6; Method B: The intermediate represented by formula (IV) is obtained by reacting the compound represented by formula (III-a-5) with a halogenated carboxylic acid. wherein X is selected from F, Cl, Br or I; R 3 , R 4 , R 5 , R 6 The meaning is the same as any corresponding definition in claims 1 to 6; Method C: The compound of formula (III-a) is subjected to an esterification reaction with a hydroxyl protecting agent under alkaline conditions to obtain an intermediate of formula (V). Among them, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The definition is the same as any corresponding definition in claims 1-6.

8. The preparation method according to claim 7, wherein the method A and / or method C comprises the following reaction conditions: The base is selected from organic bases; The reaction solvent of the synthesis step is selected from an organic solvent; Optionally, the molar ratio of the compound of formula (III-a) to the organic base in the synthesis step is 1:0.5-8; Optionally, the reaction temperature of the synthesis step is 0°C-60°C; Optionally, the reaction time of the synthesis step is 1-10 hours.

9. The preparation method according to claim 8, wherein: The organic base includes any one or two of triethylamine, pyridine, tetramethylguanidine, DMAP, DBU, DIPEA Mixture of more than one species; The organic solvent includes but is not limited to any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile or a mixture of two or more thereof; Or the molar ratio of the compound of formula (III-a) to the organic base is 1:1-3; Or the reaction temperature is 10-30°C; Or the reaction time is 4-6 hours.

10. The preparation method according to claim 7, wherein the preparation of the compound of formula (III-a) comprises the following steps: in, R 2 , R 3 , R 4 , R 5 , R 6 has the same meaning as in any of the corresponding definitions above; Step 1: The compound of formula (III-a-2) and the compound of formula (III-a-3) undergo condensation reaction to obtain a compound of formula (III-a-4); Step 2: The compound of formula (III-a-4) undergoes hydrolysis reaction under alkaline conditions to obtain the compound of formula (III-a).

11. The preparation method according to claim 10, wherein the condensation reaction in step 1 comprises the following reaction conditions: The condensation reaction includes a condensation agent, and the condensation agent includes T3P or DPP-Cl; The condensation reaction includes an organic base, and the organic base includes triethylamine, pyridine, tetramethylguanidine, DBU or DIPEA; The solvent for the condensation reaction is an organic solvent; preferably, the organic solvent includes any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and ethyl acetate, or a mixture of two or more thereof; Optionally, the condensation reaction temperature is 0°C to 60°C; Optionally, the condensation reaction time is 1 to 10 hours; And / or, the hydrolysis reaction in step 2 includes the following reaction conditions: The hydrolysis reaction includes an inorganic base, and the inorganic base includes potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate; The solvent of the hydrolysis reaction is a mixed solvent of an organic solvent and water, and the volume ratio of the organic solvent to water in the mixed solvent is 1:1 to 10; Optionally, the molar ratio of the compound of formula (III-a-4) to the inorganic base in the hydrolysis reaction is 1:1 to 10; Optionally, the temperature of the hydrolysis reaction is 0°C to 60°C; Optionally, the hydrolysis reaction time is 1 to 10 hours.

12. Use of the intermediate according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as a standard substance, a reference substance, in the preparation of an oxopyridine compound of formula (I), or in the preparation of a drug for treating or preventing vascular arterial diseases.

13. A method for preparing an oxopyridine compound of formula (I), the method comprising reacting an intermediate of formula (II) or a pharmaceutically acceptable salt thereof with a compound of formula (VI) to obtain a compound of formula (I); In formula (II): R 1 Selected from TsO-, X, R 7 O-; Ts is p-toluenesulfonyl, and X is selected from F, Cl, Br or I; R 2 Selected from -NHR 8 、-OC(CH3)3; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 7 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl; R 8 is selected from hydrogen, alkyl or cycloalkyl; R 9 is selected from fluorine, chlorine or trifluoromethyl; Formula (II) is not 14. The method for preparing the oxopyridine compound of formula (I) according to claim 13, wherein: The preparation method comprises: When R in formula (II) 2 When -OC(CH3)3 is selected, the intermediate structure shown in formula (II) is formula (II-a), and the preparation method comprises the following steps: in, R 1 Selected from TsO-, X, R 7 O-; Ts is p-toluenesulfonyl, and X is selected from F, Cl, Br or I; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 7 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl; R 8 is selected from hydrogen, alkyl or cycloalkyl; R 9 is selected from fluorine, chlorine or trifluoromethyl; Step 1: reacting the intermediate represented by formula (II-a) or a pharmaceutically acceptable salt thereof with the compound of formula (VI) to obtain the compound of formula (VII); Step 2: hydrolyzing the compound of formula (VII) to obtain the compound of formula (VIII); Step 3: The compound of formula (VIII) undergoes condensation reaction to obtain the compound of formula (I).

15. The method for preparing the oxopyridine compound of formula (I) according to claim 13, wherein the preparation method is selected from method 1, method 2 or method 3; Method 1: The preparation method comprises reacting an intermediate represented by formula (III) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI) to obtain a compound represented by formula (I). in, R 2 Selected from -NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 9 is selected from fluorine, chlorine or trifluoromethyl; Method 2: in, R 10 is selected from alkyl, cycloalkyl or deuterated alkyl, cycloalkyl; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 9 is selected from fluorine, chlorine or trifluoromethyl; X is selected from F, Cl, Br or I; Step 1: reacting the intermediate represented by formula (IV) or a pharmaceutically acceptable salt thereof with the compound represented by formula (VI) to obtain the compound represented by formula (VII); Step 2: hydrolyzing the compound of formula (VII) to obtain the compound of formula (VIII); Step 3: The compound of formula (VIII) undergoes a condensation reaction to obtain a compound of formula (Ia); Method 3: The intermediate represented by formula (V) is subjected to a nucleophilic substitution reaction with the compound represented by formula (VI) under alkaline conditions to obtain a compound represented by formula (I); in, R 9 is selected from fluorine, chlorine or trifluoromethyl; R 2 Selected from NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl; R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy or haloalkyl; R 7 Selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl.

16. The method for preparing the oxopyridine compound of formula (I) according to claim 15, wherein the method 1 and / or the method 3 comprises the following reaction conditions: The reaction conditions include a base selected from an organic base or an inorganic base; The reaction solvent is selected from an organic solvent; Optionally, the molar ratio of the compound of formula (III) or the compound of formula (V) to the base is 1:1-3; Optionally, the reaction temperature is 0°C to 60°C; Optionally, the reaction time is 1-10 hours.

17. The method for preparing the oxopyridine compound of formula (I) according to claim 16, wherein: The base includes any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, DBU, DIPEA, and pyridine, or a mixture of two or more thereof; The organic solvent includes any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, and dioxane, or a mixture of two or more thereof; Or the molar ratio of the compound of formula (III) or the compound of formula (V) to the base is 1:2; Or the reaction temperature is 20°C to 40°C; Or the reaction time is 4-6 hours.

18. The method for preparing the oxopyridine compound of formula (I) according to claim 15, wherein the second method comprises the following reaction conditions: The step 1 includes the following reaction conditions: The step 1 comprises a base, wherein the base is selected from an organic base or an inorganic base; The reaction solvent of step 1 is selected from an organic solvent, and the organic solvent includes any one of isopropanol, ethanol, acetone, DMF, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane, or a mixture of two or more thereof; Optionally, in step 1, the molar ratio of the compound of formula (IV) to the base is 1:1-3; Optionally, the reaction temperature of step 1 is 0°C-60°C; Optionally, the reaction time of step 1 is 1-10 hours; Alternatively, the step 2 comprises the following reaction conditions, The step 2 comprises an acid, wherein the acid comprises any one of hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, and hydrobromic acid, or a mixture of two or more thereof; The reaction solvent of step 2 is selected from an organic solvent, and the organic solvent includes any one of isotetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, methanol, ethanol, isopropanol, and DMF, or a mixture of two or more thereof; Optionally, in step 2, the molar ratio of the compound of formula (VII) to the acid is 1:30; Optionally, the reaction temperature of step 2 is -20°C to 40°C; Optionally, the reaction time of step 2 is 1-8 hours; Alternatively, the step 3 comprises the following reaction conditions, The step 3 comprises a base, and the base comprises any one of triethylamine, DBU, DIPEA, tetramethylguanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture of two or more thereof; The step 3 comprises a condensing agent and a ligand, wherein the condensing agent and the ligand comprise any one of EDCI, HOBT, HATU, HBTU, DCC, CDI, T3P, DPP-Cl, HCTU, TBTU, and DMAP, or a mixture of two or more thereof; The reaction solvent of step 3 is selected from an organic solvent, and the organic solvent includes any one of isotetrahydrofuran, DCM, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, ethanol, isopropanol, DMF, and DMAC, or a mixture of two or more thereof; Optionally, in step 3, the molar ratio of the compound of formula (VIII) to the base is 1:1-5; Optionally, the reaction temperature of step 3 is 0°C to 60°C; Optionally, the reaction time of step 3 is 1-10 hours.