New preparation method and key intermediates of oxopyridine compounds

Abstract

The present invention relates to a novel route for preparing oxopyridine compounds represented by formula (I) and key intermediates thereof. The novel route provided by the present invention can greatly reduce the generation of isomeric impurities, improve the selectivity of reaction chirality and N / O-alkylation selectivity, improve the yield, eliminate the need for further purification of crude products, reduce costs, shorten the production cycle, and be energy-saving and environmentally friendly. The novel route is suitable for preparing drugs for treating and / or preventing diseases related to FXIa receptors, and in particular, provides a new idea for preparing drugs for treating and / or preventing cerebrovascular arterial diseases and / or peripheral arterial diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and its preparation, specifically relating to a novel preparation method for oxopyridine compounds and its key intermediates. Background Technology

[0002] Thromboembolism is a disease in humans and animals caused by abnormal blood clots forming within blood vessels during survival. Coagulation factor XI (FXI) is a plasma serine protease protease essential for maintaining the intrinsic pathway. Upon activation, it generates activated coagulation factor XIa (FXIa), playing a crucial role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback-activate FXI, and activated FXIa further promotes the production of large amounts of thrombin, thus amplifying the coagulation cascade. Therefore, drugs targeting FXIa can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thereby exerting an antithrombotic effect. Recent studies have shown that inhibiting FXIa may carry a lower bleeding risk compared to direct FXa inhibitors, making it a novel target for antithrombotic prevention and treatment. Among these, Bayer's anticoagulant BAY-2433334 has attracted significant attention in the field due to its low bleeding rate.

[0003] Regarding the anticoagulant drug BAY-2433334, Bayer Pharmaceuticals' compound patent CN108026072B highlights two oxopyridine compounds, as follows:

[0004] .

[0005] These molecules have complex structures, are difficult to synthesize, and their isomers are not easily separated, making large-scale production extremely challenging. Patents WO 2014 / 154794 and WO 2017 / 005725 disclose the synthesis of these compounds using 2,5-dimethoxypyridine as the starting material and employing a linear synthesis strategy to synthesize the target compound in nine steps. This route is not only lengthy but also prone to high racemization, resulting in low overall yields. The crude product synthesis step yields only 70%, requiring cumbersome post-processing and purification procedures. Isomers are separated by HPLC or chiral supercritical fluid chromatography (SFC), which is time-consuming and expensive, making it unsuitable for industrial-scale production.

[0006] Patent CN 111770917 A discloses a polymerization synthesis strategy. The crude product synthesis steps are as follows: after synthesizing the key intermediates (XVI-CF3) / (XVI-Cl) and (XIX) compounds respectively, a condensation reaction is carried out to generate crude compounds 1 / 2. The total reaction involves six steps, with a maximum of four steps, shortening the reaction cycle. The enantioselectivity and N / O-alkylation selectivity of the crude product synthesis steps are optimized. After filtration and solvent evaporation, the condensate yields amorphous crude compounds 1 / 2 with a high ee-value of 85%ee to 93%ee. In addition, a preferred N-alkylation ratio of 9:1 to 10:1 is obtained, which is superior to unwanted O-alkylation.

[0007]

[0008] Although the polymeric synthesis route of this patent is generally superior to the linear synthesis strategy, the condensation step of its crude product synthesis still has significant limitations, such as: (1) low conversion rate, with the condensation step yields of compounds 1 and 2 being only 70% and 75% respectively, and alternative methods yielding as low as 61% (paragraphs 0095-0097 of the specification), and the total yield of the six steps being only 20%-25% (paragraph 0054 of the specification); (2) a large proportion of isomers, although the ee value of the crude product has been optimized to 85%-90%. 3%, but there are still 7%~15% isomer impurities, and it is necessary to purify it with organic solvents to obtain a crude product with a ee value of >99%, and then obtain the target crystal through crystallization process; (3) The N / O-alkylation selectivity is not good. Although the ratio of N-alkylation to O-alkylation of crude product reaches (9~10):1, there is still an undesirable O / N conversion rate of about 10%, which not only leads to low conversion rate, but also generates more O-alkylation impurities, which aggravates the difficulty of subsequent purification and the risk of product quality control.

[0009] Therefore, how to improve the quality of anticoagulant products made from 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 production are the technical challenges that urgently need to be solved in this field. Summary of the Invention

[0010] In order to solve the technical problems existing in the prior art, the present invention discloses a novel preparation method for oxopyridine compounds and its key intermediates.

[0011] On the one hand, the present invention provides an intermediate of formula (II) or a pharmaceutically acceptable salt thereof:

[0012] ,in:

[0013] Ts represents p-toluenesulfonyl group;

[0014] R 2 Selected from NHR 7 , where: R 7 Selected from hydrogen, alkyl, or cycloalkyl;

[0015] R 3 、R 4 、R 5 、R 6 It is independently selected from hydrogen, halogen, alkoxy or haloalkyl.

[0016] Furthermore, in the intermediate shown in formula (II) above, or its pharmaceutically acceptable salt:

[0017] The R 2 Selected from NHR 7 , where: R 7 Selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, or tert-butyl;

[0018] and / or R 3 、R 4 、R 5 、R 6 It is independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy, or trifluoromethyl.

[0019] Furthermore, the hydrogen in the structure of any of the above intermediates can be replaced by at least one deuterium.

[0020] Furthermore, the above intermediates include the following compounds:

[0021] .

[0022] Furthermore, the present invention also provides the use of any of the above intermediates or their pharmaceutically acceptable salts for use as standards, reference standards or oxopyridine compounds of formula (I).

[0023] Furthermore, the present invention provides a method for preparing the intermediate shown in formula (II) above or a pharmaceutically acceptable salt thereof, comprising the following synthetic steps: reacting the compound of formula (II-a) with p-toluenesulfonyl chloride under basic conditions to obtain:

[0024]

[0025] Among them, R 2 、R 3 、R 4 、R 5 、R 6 The definition is the same as any corresponding definition in equation (II) above.

[0026] Furthermore, the preparation method of the intermediate shown in formula (II) above or its pharmaceutically acceptable salt includes the following reaction conditions:

[0027] The base is selected from organic bases; preferably, the organic base includes triethylamine, pyridine, DMAP, tetramethylguanidine, DBU or DIPEA, more preferably triethylamine or pyridine;

[0028] The reaction solvent in the synthesis step is selected from organic solvents; preferably, the organic solvent includes, but is not limited to, any one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and dichloromethane.

[0029] Optionally, the molar ratio of the compound of formula (II-a) to the organic base in the synthesis step is 1:0.5 to 8, preferably 1:1 to 3;

[0030] Optionally, the reaction temperature of the synthesis step is 0℃~60℃, preferably 10~30℃;

[0031] Optionally, the reaction time for the synthesis step is 1 to 10 hours, preferably 4 to 6 hours.

[0032] On the other hand, the present invention also provides a method for preparing an oxopyridine compound of formula (I), comprising reacting an intermediate of formula (II) or a pharmaceutically acceptable salt thereof with a compound of formula (III) to obtain a compound of formula (I).

[0033]

[0034] in,

[0035] R 1 Selected from fluorine, chlorine, or trifluoromethyl;

[0036] Ts is selected from p-toluenesulfonyl group;

[0037] R 2 Selected from NHR 7 , where: R 7 Selected from hydrogen, alkyl, or cycloalkyl;

[0038] R 3 、R 4 、R 5 、R 6 It is independently selected from hydrogen, halogen, alkoxy or haloalkyl.

[0039] More preferably, in the above method:

[0040] R 1 Selected from fluorine, chlorine, or trifluoromethyl;

[0041] Ts is selected from p-toluenesulfonyl group;

[0042] R 2 Selected from NHR 7 , where: R 7 Selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, or tert-butyl;

[0043] and / or R 3 、R 4 、R 5 、R 6 It is independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy, or trifluoromethyl.

[0044] Furthermore, the preparation method of the oxopyridine compound shown in formula (I) above includes the following reaction conditions:

[0045] The reaction conditions of the above method include a base, which is selected from organic or inorganic bases; preferably, the base includes any one or a mixture of two or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, DBU, DIPEA, and pyridine; more preferably, the base includes any one or a mixture of two or more of potassium carbonate, cesium carbonate, tetramethylguanidine, triethylamine, DBU, and DIPEA.

[0046] The reaction solvent in the above method is selected from organic solvents; preferably, the organic solvent includes any one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, and DMF.

[0047] Optionally, in the above method, the molar ratio of compound (II) to base is 1:1 to 3, preferably 1:2;

[0048] Optionally, the reaction temperature of the above method is 0℃~60℃, preferably 20℃~40℃, and more preferably 26℃~32℃;

[0049] Optionally, the reaction time of the above method is 1 to 10 hours, preferably 4 to 6 hours.

[0050] Furthermore, the oxopyridine compound of formula (I) obtained by the above preparation method shall have at least one of the following characteristics: (1) an enantioselectivity 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-processing, and suitable for industrial scale-up production; (5) a product purity of 98% or more.

[0051] Furthermore, the oxopyridine compound of formula (Ⅰ) obtained by the above preparation method can be crystallized using the crystallization method in patent CN111770917A to obtain crystal products of high quality or even higher quality than those in the patent.

[0052] Furthermore, the preparation method of the oxopyridine compound shown in formula (I) includes the synthetic steps of the compound of formula (II): the compound of formula (II-a) is obtained by reacting p-toluenesulfonyl chloride under alkaline conditions.

[0053]

[0054] Among them, R 2 、R 3 、R 4 、R 5 、R 6 The definition is the same as any of the corresponding definitions mentioned above.

[0055] Furthermore, the synthetic steps of the above-mentioned compound (II) include the following reaction conditions:

[0056] The base is selected from organic bases; preferably, the organic base includes triethylamine, pyridine, tetramethylguanidine, DBU or DIPEA, more preferably triethylamine or pyridine;

[0057] The reaction solvent in the synthesis step is selected from organic solvents; preferably, the organic solvent includes, but is not limited to, any one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, and acetonitrile.

[0058] Optionally, the molar ratio of the compound of formula (II-a) to the organic base in the synthesis step is 1:0.5 to 8, preferably 1:1 to 3;

[0059] Optionally, the reaction temperature of the synthesis step is 0℃~60℃, preferably 10~30℃;

[0060] Optionally, the reaction time for the synthesis step is 1 to 10 hours, preferably 4 to 6 hours.

[0061] Furthermore, the preparation method of the above-mentioned compound (II-a) includes the following steps:

[0062]

[0063] Among them, R 2 、R 3 、R 4 、R 5 、R 6 The definition is the same as any of the corresponding definitions above;

[0064] Step 1: Compound (Ⅳ-1) undergoes a condensation reaction with compound (Ⅴ) to obtain compound (II-b);

[0065] Step 2: Compound (II-b) undergoes hydrolysis under alkaline conditions to obtain compound (II-a).

[0066] Furthermore, step 1 above includes the following reaction conditions:

[0067] The conditions for the condensation reaction include a condensing agent, preferably, the condensing agent includes T3P or DPP-Cl;

[0068] The conditions for the condensation reaction also include an organic base; preferably, the organic base includes triethylamine, pyridine, tetramethylguanidine, DBU or DIPEA, more preferably triethylamine or pyridine;

[0069] The solvent for the condensation reaction is an organic solvent; preferably, the organic solvent includes any one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and ethyl acetate.

[0070] Optionally, the temperature of the condensation reaction is 0°C to 60°C, preferably 10°C to 30°C;

[0071] Optionally, the condensation reaction takes 1 to 10 hours, preferably 2 to 4 hours.

[0072] Furthermore, step 2 above includes the following reaction conditions:

[0073] The conditions for the hydrolysis reaction include an inorganic base; preferably, the inorganic base includes potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, or sodium bicarbonate; more preferably, potassium carbonate.

[0074] The solvent for the hydrolysis reaction is a mixture of an organic solvent and water; preferably, the volume ratio of the organic solvent to water in the mixture is 1:1 to 10, more preferably 1:1 to 2; the mixture includes methanol and water, ethanol and water, tetrahydrofuran and water, or DMSO and water, preferably methanol and water;

[0075] Optionally, the molar ratio of the compound of formula (V) to the inorganic base in the hydrolysis reaction is 1:1 to 10, preferably 1:1 to 3;

[0076] Optionally, the temperature of the hydrolysis reaction is 0℃~60℃, preferably 10℃~30℃;

[0077] Optionally, the hydrolysis reaction takes 1 to 10 hours, preferably 5 to 7 hours.

[0078] Terminology Explanation:

[0079] "Alkyl" refers to lower alkyl groups, specifically those containing C1-C16 saturated branched or straight-chain alkyl groups. The alkyl portion in "alkyl carbonyl" is interpreted in the same way.

[0080] "Cycloalkyl" refers to cycloalkyl groups containing C3-C10 cycloalkyl groups, preferably C3-C6 cycloalkyl groups.

[0081] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0082] "Above" and "below" include the number itself.

[0083] DEAD: Diethyl azodicarbonate.

[0084] DIAD: Diisopropyl azodicarbonate.

[0085] TMAD: Azodicarbonamide.

[0086] DTBAD: Di-tert-butyl azodicarbonate.

[0087] ADDP: Azodicarbonylpiperidine.

[0088] DBU: 1,8-diazabicycloundec-7-ene.

[0089] DIPEA: Isopropyl ethylamine.

[0090] T3P: 1-Propylphosphocyclic anhydride.

[0091] DPP-Cl: Diphenylphosphine chloride.

[0092] Compared with the prior art, the present invention has the following advantages:

[0093] The novel preparation route of this invention can synthesize compound (I), which has an absolute advantage in improving the overall conversion rate, enantioselectivity and N / O-alkylation selectivity. In particular, it can achieve a conversion rate of N / O ratio of 30 to 40:1 or higher by using a milder base and a more readily available solvent, which is beneficial to the subsequent crystallization yield and improves the stability of the crystallization purification process control.

[0094] Even more excitingly, through the process of preparing compound (I) of the present invention, a higher ee-value of compound (I) in amorphous form can be obtained. After extraction and evaporation of solvent, amorphous compound (I) in amorphous form can be obtained with an ee-value of more than 98% ee or even more than 99% ee.

[0095] The yield of crude product prepared by single-step condensation reaction is increased to over 85%~98%, and the total yield of 4 steps is over 60%~70%. The conversion rate is high, the production cycle is greatly shortened, complex post-processing is avoided, costs are saved, and it is conducive to industrial scale-up production. Detailed Implementation

[0096] The present invention will be further described in detail below with reference to 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 made in the art based on the content disclosed in the present invention shall fall within the protection scope of the present invention.

[0097] The compounds, their stereoisomers, or pharmaceutically acceptable salts of this invention can be prepared using the synthetic routes described in the embodiments. The conventional conditions of the reactants and reaction solvents can be adjusted according to the needs of substituents or salt formation; these are all achievable by those skilled in the art based on the disclosure of this invention. Furthermore, unless otherwise specified, column chromatography in this invention refers to silica gel column chromatography, and the elution solvent, unless otherwise specified, can be determined as a single or mixed elution solvent by combining the reaction solvent with common knowledge or methods known to those skilled in the art.

[0098] The structure of the compound is determined by nuclear magnetic resonance (NMR). 1 The determination was made by ¹H NMR or liquid chromatography-mass spectrometry (LC-MS).

[0099] The liquid chromatography-mass spectrometry (LC-MS) system is an Agilent G6120B (compatible with an Agilent 1260 liquid chromatography system); the nuclear magnetic resonance (NMR) system is... 1 HNMR) is Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance (NMR) 1 H NMR) displacement ( d The concentration is given in parts per million (ppm), the solvent is DMSO, the internal standard is tetramethylsilane (TMS), and the chemical shift is expressed in 10⁻⁶ ppm. -6 (ppm) is given as the unit.

[0100] In this invention, the term "room temperature" refers to a temperature between 10 and 30°C.

[0101] 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)butamido)benzamide (compound 1):

[0102]

[0103] Step 1: Preparation of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutyl-2-yl acetate

[0104] Dissolve 1.03 g (7.05 mmol) of (R)-2-acetoxybutyric acid in 20 mL of tetrahydrofuran. Add 720 mg (4.70 mmol) of 4-amino-2-chlorobenzamide, cool to below 0 °C, add 1.12 g (14.1 mmol) of pyridine, and then dropwise add 4.50 g (14.1 mmol) of 1-propylphosphonic anhydride (50% ethyl acetate solution) diluted in 10 mL of tetrahydrofuran. After the addition is complete, stir at 0–5 °C for 10 minutes, and then stir at room temperature for 30 minutes. When the reaction is complete, add water to terminate the reaction, extract with EA, and wash the organic phase successively with 5% citric acid, saturated sodium bicarbonate, water, saturated brine, and dry with anhydrous sodium sulfate. Evaporate the solvent to obtain the crude product. Add 10 ml of ethyl acetate: n-heptane 1:1 solvent to the crude product and stir at room temperature for 2 hours. Filter, wash the filter cake with n-heptane, and dry the filter cake under vacuum to obtain a white solid with a yield of 86.1%, ee- value of 99.56%, and purity of 96.20%.

[0105] ESI-MS: m / z = 283.1 (M+H) + .

[0106] 1 H NMR (400 MHz, 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).

[0107] Step 2: Preparation of (R)-2-fluoro-4-(2-hydroxybutyramide)benzamide

[0108] 1.5 g (5.32 mmol) of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutyl-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 overnight at room temperature. After the reaction was completed by TLC monitoring, 20 mL of water was slowly added to terminate the reaction. A large amount of white solid precipitated from the system. 50 mL of water was added, and the mixture was stirred and slurried for 1 hour. The mixture was filtered to obtain a white solid, 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%.

[0109] ESI-MS: m / z = 241.1 (M+H) + .

[0110] 1H NMR (400 MHz, 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).

[0111] Step 3: Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutyl-2-yl p-toluenesulfonate

[0112] 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 3.95 mmol of p-toluenesulfonic acid in dichloromethane was added dropwise at approximately 0 °C. The reaction was stirred overnight at room temperature. After the reaction was completed by TLC monitoring, 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, cooled, and crystallized to obtain a pale yellow solid. The yield was 86.6%, the ee-value was 98.52%, and the purity was 95.65%.

[0113] ESI-MS: m / z = 395.1 (M+H) + .

[0114] 1 H NMR (400 MHz, 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).

[0115] Step 4: Preparation of Compound 1

[0116] Take 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, add it to a 25 ml single-necked flask, dissolve and stir with 5 ml of dioxane, add 150 mg (1.08 mmol) of potassium carbonate and 62 mg (0.539 mmol) of tetramethylguanidine, stir for 5 minutes, add 0.648 mmol of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobut-2-yl p-toluenesulfonate, heat to 35 °C and stir until the reaction is complete as monitored by TLC, the N / O-alkylation conversion ratio is 40:1, add saturated ammonium chloride to terminate the reaction, add ethyl acetate to extract, wash the organic phase with water, wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent to obtain crude product, yield 95.8%, ee- value 99.24%.

[0117] ESI-MS: m / z = 593.2 (M+H) + .

[0118] 1 H NMR (400 MHz, 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).

[0119] The crude product can be crystallized using the crystallization method described in patent CN111770917A to obtain the high-quality target product.

[0120] Example 2: Preparation of compound 2:

[0121]

[0122] The preparation method is the same as that in 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 product of 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.

[0123] ESI-MS: m / z = 559.1 (M+H) + .

[0124] 1 H NMR (400 MHz, 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).

[0125] The crude product can be crystallized using the crystallization method described in patent CN111770917A to obtain the high-quality target product.

[0126] Example 3: Preparation of compound 3:

[0127]

[0128] The preparation method is the same as that in Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced with 4-amino-2-methoxy-benzamide to obtain the crude product of title compound 3. The final synthesis yield is 90%, the ee- value is 98.39%, and the N / O-alkylation conversion ratio at the reaction endpoint is 30:1.

[0129] ESI-MS: m / z = 605.1 (M+H) + .

[0130] 1 H NMR (400 MHz, 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 (dd, 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).

[0131] Example 4: Preparation of compound 4:

[0132]

[0133] The preparation method is the same as that in Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced with 4-amino-2-fluoro-N-methylbenzamide to obtain the crude product of title compound 4. The final synthesis yield is 90%, the ee- value is 99.02%, and the N / O-alkylation conversion ratio at the reaction endpoint is 40:1.

[0134] ESI-MS: m / z = 623.1 (M+H) + .

[0135] 1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.13 – 8.06 (m, 1H), 7.89 – 7.80 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 –7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.25 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02(m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0136] Example 5: Preparation of compound 5:

[0137]

[0138] The preparation method is the same as that in Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced with 4-amino-2-fluoro-N-(methyl-d3)benzamide to obtain the crude product of title compound 5. The final synthesis yield is 89%, the ee- value is 98.87%, and the N / O-alkylation conversion ratio at the reaction endpoint is 40:1.

[0139] ESI-MS: m / z = 610.2(M+H) + .

[0140] 1H NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.06 (d, J = 3.4 Hz, 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, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.51 (d, J = 8.6 Hz, 1H), 3.25 (s, 3H), 2.19 – 1.99 (m, J = 7.1 Hz, 2H), 0.78(t, J = 7.2 Hz, 3H).

[0141] Example 6: Preparation of compound 6:

[0142]

[0143] The preparation method is the same as that in Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced with 4-amino-2-trifluoromethyl-benzamide to obtain the crude product of title compound 6. The final synthesis yield is 89%, the ee- value is 98.87%, and the N / O-alkylation conversion ratio at the reaction endpoint is 30:1.

[0144] ESI-MS: m / z = 643.1 (M+H) + .

[0145] 1 H NMR (400 MHz, DMSO-d6) δ:10.80 (s, 1H), 9.13 (s, 1H), 8.12 (d,1H), 8.02 – 7.72 (m, 5H), 7.54-7.51 (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).

[0146] Example 7: Preparation of compound 7:

[0147]

[0148] The preparation method is the same as that in Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced with 4-amino-2-chloro-benzamide to obtain the crude product of title compound 7. The final synthesis yield is 92%, the ee- value is 98.87%, and the N / O-alkylation conversion ratio at the reaction endpoint is 35:1.

[0149] ESI-MS: m / z = 623.1 (M+H) + .

[0150] 1 H NMR (400 MHz, 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).

[0151] The intermediates included in the embodiments of the present invention and their NMR and mass spectrometry data are shown in the table below:

[0152]

[0153] The preparation of the above intermediates follows the same approach as in Example 1, and is the product obtained in step 3 of the preparation route described in each example. The preparation methods for each intermediate are summarized below:

[0154] Compound (II) is obtained by reacting compound (II-a) with p-toluenesulfonyl chloride under alkaline conditions:

[0155]

[0156] Among them, R 2 、R 3 、R 4 、R 5 、R 6 The definition is the same as any corresponding definition in the invention description.

[0157] It is understood that the specific formula (V) compounds used in the above embodiments can be easily obtained by those skilled in the art using conventional techniques, and will not be described in detail here.

[0158] The above embodiments are merely one of the preferred embodiments of the present invention and should not be used to limit the scope of protection of the present invention. Any modifications or refinements made to the main design concept and spirit of the present invention that are not of substantial significance, but solve the same technical problem as the present invention, should be included within the scope of protection of the present invention.

Claims

1. An intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof: ,in: Ts is p-toluenesulfonyl; R 2 Selected from NHR 7 , where: R 7 is selected from hydrogen, methyl, ethyl, propyl or tert-butyl; R 3 , R 4 , R 5 are independently selected from hydrogen; R 6 is selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

2. The intermediate or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The hydrogen in the structure of the intermediate may be replaced by at least one deuterium.

3. The intermediate or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The intermediates include the following compounds:

4. A method for preparing the intermediate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The synthesis of the intermediate comprises the following steps: a compound of formula (II-a) is reacted with p-toluenesulfonyl chloride under alkaline conditions to obtain: ， Among them, R 2 , R 3 , R 4 , R 5 , R 6 The definition is the same as any corresponding definition in claims 1 to 2.

5. A method for preparing an oxopyridine compound represented by formula (I), characterized in that: The method comprises reacting an intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof with a compound represented by formula (III) to obtain a compound represented by formula (I), ， in, R 1 is selected from fluorine, chlorine or trifluoromethyl; R 2 Selected from NHR 7 , where: R 7 is selected from hydrogen, methyl, ethyl, propyl or tert-butyl; R 3 , R 4 , R 5 are independently selected from hydrogen; R 6 is selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

6. The method according to claim 5, characterized in that The method comprises the following reaction conditions: The reaction conditions of the method include a base, which is selected from an organic base or an inorganic base; The reaction solvent of the method is selected from organic solvents.

7. The method according to claim 6, characterized in that The base is selected from 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 is selected from any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, and dioxane, or a mixture of two or more thereof.

8. The method according to claim 6, characterized in that In the method, the molar ratio of the compound of formula (II) to the base is 1:1-3.

9. The method according to claim 8, characterized in that The molar ratio of the compound of formula (II) to the base is 1:

2.

10. The method according to claim 5, characterized in that The reaction temperature of the method is 0°C to 60°C.

11. The method according to claim 10, characterized in that The reaction temperature is 20°C to 40°C.

12. The method according to claim 5, characterized in that The reaction time of the method is 1 to 10 hours.

13. The method according to claim 12, characterized in that The reaction time is 4 to 6 hours.

14. The method according to any one of claims 5 to 13, characterized in that: The method further comprises the step of synthesizing a compound of formula (II): The compound of formula (II) is obtained by reacting a compound of formula (II-a) with p-toluenesulfonyl chloride under alkaline conditions: ， Among them, R 2 , R 3 , R 4 , R 5 , R 6 The definition is the same as any corresponding definition in claims 5 to 13.

15. The method according to claim 14, characterized in that The synthesis steps of the compound of formula (II) include the following reaction conditions: The base is selected from organic bases; The reaction solvent of the synthesis step is selected from an organic solvent; The molar ratio of the compound of formula (II-a) to the organic base in the synthesis step is 1:0.5-8; The reaction temperature of the synthesis step is 0°C to 60°C; The reaction time of the synthesis step is 1 to 10 hours.

16. The method according to claim 15, characterized in that The reaction conditions of the synthesis step of the compound of formula (II) are: The organic base is selected from any one of trimethylamine hydrochloride, triethylamine, pyridine, tetramethylguanidine, DBU, and DIPEA, or a mixture of two or more thereof; The organic solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, and acetonitrile, or a mixture of two or more thereof; The molar ratio of the compound of formula (II-a) to the organic base is 1:1-3; The reaction temperature is 10-30°C; The reaction time is 4 to 6 hours.

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