Novel Preparation Method of Oxopyridine Compounds and Key Intermediates

Abstract

The present invention relates to a novel route for preparing oxopyridine compounds shown in formula (I) and their key intermediates. The novel route provided by the present invention can greatly reduce the generation of isomeric impurities, improve the chiral selectivity of the reaction and the N / O-alkylation selectivity, increase the yield, eliminate the need for further purification of the crude product, reduce the cost, shorten the production cycle, save energy and protect the environment, and is suitable for use in the preparation of drugs for treating and / or preventing diseases related to the FXIa receptor, especially providing a new idea for the preparation of drugs for treating and / or preventing cerebrovascular arterial diseases and / or peripheral arterial diseases.

Description

Technical Field

[0001] The present invention belongs to the fields of medicinal chemistry and its preparation, and particularly relates to a novel preparation method of oxopyridine compounds and their key intermediates. Background Art

[0002] Thromboembolic diseases are diseases caused by abnormal blood clots formed in blood vessels during the survival of humans and animals. Coagulation factor XI (FXI) is a plasma serine protease zymogen necessary to maintain the intrinsic pathway. After activation, it generates activated coagulation factor XIa (FXIa), which plays a key role in the amplification process of the coagulation cascade reaction. In the coagulation cascade reaction, thrombin can feedback activate FXI, and the activated FXI promotes the large production of thrombin, thus amplifying the coagulation cascade reaction. Therefore, drugs targeting the FXIa target can block the intrinsic pathway and inhibit the amplification of the coagulation cascade reaction, thereby having an antithrombotic effect. In recent years, studies have shown that compared with direct FXa inhibitors, inhibiting FXIa may have a lower bleeding risk and is a new target for antithrombotic prevention and treatment. Among them, the anticoagulant drug BAY-2433334 of Bayer Pharma has attracted great attention in this field due to its low bleeding.

[0003] Regarding the anticoagulant drug BAY-2433334, the compound patent CN108026072B of Bayer Pharma discloses two oxopyridine compounds, which are as follows:

[0004] 。

[0005] The molecular structure of this type is complex, with a large synthesis difficulty, and the isomers are not easy to separate, making large-scale production extremely challenging. Patents WO 2014 / 154794 and WO 2017 / 005725 disclose the synthesis of this type of compound starting from 2,5-dimethoxypyridine and adopting a linear synthesis strategy to synthesize the target compound in nine steps. Not only is the route lengthy, but also it is prone to high racemization, with a low overall yield. The yield of the crude product synthesis step is only 70%. It requires cumbersome post-treatment and purification procedures, and the isomers are separated by HPLC or chiral supercritical fluid chromatography (SFC), which is time-consuming and expensive and not suitable for industrial scale-up production.

[0006] The polymeric synthesis strategy is disclosed in Patent CN 111770917 A. The crude product synthesis steps are shown as follows. After separately synthesizing the key intermediate compounds of formula (XVI-CF3) / (XVI-Cl) and formula (XIX), the crude products of compound 1 / compound 2 are generated through a condensation reaction. The total reaction undergoes six steps, with the longest being four steps, shortening the reaction cycle. And the enantioselectivity and N / O-alkylation selectivity of the crude product synthesis step are emphatically optimized. After filtration and evaporation of the solvent, the crude products of compound 1 / compound 2 in amorphous form are obtained with a high ee-value of 85%ee to 93%ee. In addition, a preferred N-alkylation with a ratio of N-alkylation:O-alkylation of 9:1 to 10:1 is obtained, which is superior to the unwanted O-alkylation.

[0007]

[0008] Although the overall polymeric synthesis route of this patent is superior to the linear synthesis strategy, there are still great limitations in the condensation step of its crude product synthesis. For example: (1) The conversion rate is low. The yields of the condensation steps for the synthesis of the crude products of compound 1 and compound 2 are only 70% and 75% respectively, and the yield of the alternative method is as low as 61% (paragraphs 0095 - 0097 of the specification), and the total yield of the six steps is only 20% - 25% (paragraph 0054 of the specification); (2) The proportion of isomers is relatively large. Although the ee value of the crude product is optimized to 85% - 93%, there are still 7% - 15% of isomer impurities, and it is necessary to further purify with organic solvents to obtain a purified crude product with an ee value > 99%, and then obtain the target crystal through a crystallization process; (3) The N / O-alkylation selectivity is not good. Although the ratio of N-alkylation:O-alkylation of the crude product reaches (9 - 10):1, there is still about 10% of the undesirable O / N conversion rate, which not only leads to a low conversion rate, but also generates more O-alkylation impurities, increasing the difficulty of subsequent purification and the risk of product quality control.

[0009] Therefore, how to improve the quality of anticoagulant products of oxopyridine compounds, reduce the risk of impurity control, increase the conversion rate and purity of products, shorten the production cycle, reduce costs, and be more suitable for industrial scale-up production is an urgent technical problem 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 its pharmaceutically acceptable salt:

[0012] , wherein:

[0013] R 1Selected from hydrogen, or substituted or unsubstituted alkylcarbonyl;

[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 Independently selected from hydrogen, halogen, alkoxy or haloalkyl.

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

[0017] R 1 Selected from hydrogen or acetyl;

[0018] And / or R 2 Selected from NHR 7 , where: R 7 Selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0019] And / or R 3 、R 4 、R 5 、R 6 Independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0020] Furthermore, in the intermediate represented by the above formula (II) or its pharmaceutically acceptable salt, the intermediate of formula (II) includes the following structures:

[0021] Or ,

[0022] Where R 2 、R 3 、R 4 、R 5 、R 6 Is defined as any of the above corresponding definitions.

[0023] Furthermore, the hydrogen in the structure of any of the above intermediates can be substituted by at least 1 deuterium.

[0024] Furthermore, the above intermediate includes the following compounds:

[0025] .

[0026] Furthermore, the present invention also provides the use of any of the above intermediates or their pharmaceutically acceptable salts as reference standards, reference substances or for the preparation of the oxopyridine compounds represented by formula (I).

[0027] The present invention also provides a method for preparing the above intermediate or its pharmaceutically acceptable salt, comprising the following steps:

[0028] (1) When R 1 is a substituted or unsubstituted alkylcarbonyl, the compound of formula (II) is obtained by a condensation reaction of the compound of formula (IV) and the compound of formula (V):

[0029]

[0030] wherein, the definitions of R 2 , R 3 , R 4 , R 5 , R 6 are the same as the corresponding definitions in any of the above;

[0031] When R 1 is hydrogen, the compound of formula (II) is obtained by a hydrolysis reaction of the compound of formula (II-b) under alkaline conditions:

[0032]

[0033] wherein, the definitions of R 2 , R 3 , R 4 , R 5 , R 6 are the same as the corresponding definitions in any of the above.

[0034] Furthermore, the method for preparing the above intermediate or its pharmaceutically acceptable salt comprises the following reaction conditions:

[0035] When R 1 is a substituted or unsubstituted alkylcarbonyl:

[0036] The above reaction conditions include a base, and the base is selected from organic bases 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, pyridine; more preferably, the base includes any one or a mixture of two or more of potassium carbonate, cesium carbonate, tetramethylguanidine, triethylamine, DBU, DIPEA;

[0037] The reaction solvent of the above method is selected from organic solvents; preferably, the organic solvents include any one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, dioxane;

[0038] Optionally, the molar ratio of the compound of formula (II) to the base in the above method is 1:1 to 3, preferably 1:2;

[0039] Optionally, the reaction temperature of the above method is 0 °C to 60 °C, preferably 20 °C to 40 °C, more preferably 26 to 32 °C;

[0040] Optionally, the reaction time of the above method is 1 to 10 hours, preferably 4 to 6 hours;

[0041] When R 1 is hydrogen:

[0042] The reaction solvent of the above method is an organic solvent; preferably, the organic solvent includes one or more of tetrahydrofuran, dichloromethane, DMF, and acetonitrile;

[0043] Optionally, the above method includes a phosphorus ligand; preferably, the phosphorus ligand includes triphenylphosphine or tributylphosphine;

[0044] Optionally, the above method includes an azo reagent; preferably, the azo reagent includes DEAD, DIAD, TMAD, DTBAD, or ADDP;

[0045] Optionally, the reaction temperature of the above method is -10 °C to 50 °C, preferably 0 to 25 °C;

[0046] Optionally, the reaction time of the above method is 2 to 15 hours, preferably 6 to 10 hours.

[0047] On the other hand, the present invention provides a method for preparing an oxopyridine compound represented by formula (I), which includes reacting an intermediate represented by formula (II-a) or a pharmaceutically acceptable salt thereof with a compound of formula (III) to obtain a compound of formula (I),

[0048]

[0049] wherein,

[0050] R x is selected from fluorine, chlorine, or trifluoromethyl;

[0051] R 2 is selected from NHR 7 , wherein: R 7 is selected from hydrogen, alkyl, or cycloalkyl;

[0052] R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl.

[0053] Further preferably, in the above method:

[0054] The R 2 is selected from NHR 7 , where: R 7 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0055] and / or R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0056] Furthermore, the preparation method of the oxopyridine compound shown in the above formula (I) includes the following reaction conditions:

[0057] The reaction solvent of the above method is an organic solvent; preferably, the organic solvent includes one or more mixtures of tetrahydrofuran, dichloromethane, DMF, and acetonitrile;

[0058] Optionally, the above method includes a phosphorus ligand; preferably, the phosphorus ligand includes triphenylphosphine or tributylphosphine;

[0059] Optionally, the above method includes an azo reagent; preferably, the azo reagent includes DEAD, DIAD, TMAD, DTBAD or ADDP;

[0060] Optionally, the reaction temperature of the above method is -10°C to 50°C, preferably 0 to 25°C;

[0061] Optionally, the reaction time of the above method is 2 to 15 hours, preferably 6 to 10 hours.

[0062] Furthermore, the crude product of the oxopyridine compound shown in the above formula (I) obtained by the above preparation method has at least any one of the following characteristics: (1) the ee value of enantioselectivity is above 98%, preferably above 99%; (2) the N / O-alkylation selectivity ratio reaches above 30 to 40:1; (3) the single-step yield is above 85%, preferably above 90%; (4) the production cycle is short, no complex post-treatment is required, and it is suitable for industrial scale-up production. (5) The product purity is above 98%.

[0063] Furthermore, the oxopyridine compound shown in the above formula (I) obtained by the above preparation method can obtain a crystal product with high quality or even higher crystal quality than that in the patent CN111770917A by the crystallization method.

[0064] Even further, the synthesis of the compound of formula (II-a) in the above method includes the following steps:

[0065]

[0066] Among them, R 2 , R 3 , R 4 , R 5 , R 6 are defined as any of the corresponding definitions above;

[0067] Step 1: The compound of formula (IV-1) undergoes a condensation reaction with the compound of formula (V) to obtain the compound of formula (II-b);

[0068] Step 2: The compound of formula (II-b) undergoes a hydrolysis reaction under basic conditions to obtain the compound of formula (II-a).

[0069] Furthermore, the above Step 1 includes the following reaction conditions:

[0070] The conditions for the condensation reaction include a condensing agent. Preferably, the condensing agent includes T3P or DPP-Cl;

[0071] 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;

[0072] 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, ethyl acetate;

[0073] Optionally, the temperature of the condensation reaction is 0°C to 60°C, preferably 10 to 30°C;

[0074] Optionally, the time of the condensation reaction is 1 to 10 hours, preferably 2 to 4 hours.

[0075] Furthermore, the above Step 2 includes the following reaction conditions:

[0076] 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;

[0077] 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;

[0078] Optionally, the molar ratio of the compound of formula (II-b) to the inorganic base in the hydrolysis reaction is 1:1 to 10, preferably 1:1 to 3;

[0079] Optionally, the temperature of the hydrolysis reaction is 0°C to 60°C, preferably 10 to 30°C;

[0080] Optionally, the time of the hydrolysis reaction is 1 to 10 hours, preferably 5 to 7 hours.

[0081] Term Explanation:

[0082] "Alkyl" refers to lower alkyl, specifically a saturated branched or straight-chain alkyl containing C1-C16. The alkyl part in "alkylcarbonyl" is interpreted in the same way.

[0083] "Cycloalkyl" refers to a cycloalkyl containing C3-C10, preferably C3-C6.

[0084] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0085] "Above" and "below" include the recited number.

[0086] DEAD: Diethyl azodicarboxylate.

[0087] DIAD: Diisopropyl azodicarboxylate.

[0088] TMAD: Azodicarbonamide.

[0089] DTBAD: Di-tert-butyl azodicarboxylate.

[0090] ADDP: Dipiperidyl azodicarboxylate.

[0091] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene.

[0092] DIPEA: N,N-Diisopropylethylamine.

[0093] T3P: 1-Propylphosphonic anhydride cyclic.

[0094] DPP-Cl: Diphenylphosphinous chloride.

[0095] Compared with the prior art, the present invention has the following advantages:

[0096] By synthesizing the compound of formula (I) through the new preparation route of the present invention, the total conversion rate can be improved, and there is an absolute advantage in enantioselectivity and N / O-alkylation selectivity. Especially in the selection of milder bases and more readily available solvents, a conversion rate with an N / O ratio reaching 30 to 40:1 or more can be obtained, which is beneficial to the subsequent crystallization yield and improves the stability of the control in the crystallization and purification process.

[0097] More surprisingly, in the process of preparing the compound of formula (I) by the present invention, the compound of formula (I) with a higher ee-value in the amorphous form can be obtained. After extraction and evaporation of the solvent, the compound of formula (I) in the amorphous form is obtained with an ee-value of more than 98% ee, even more than 99% ee.

[0098] The yield of the crude product prepared by the one-step condensation reaction is increased to more than 85% - 98%, and the total yield of the three steps is more than 60 - 70%. The conversion rate is high, the production cycle is greatly shortened, complex post-treatment is avoided, the cost is saved, and it is beneficial to industrial scale-up production. Detailed implementation manners

[0099] The present invention will be further described in detail below in combination with examples and test examples. The examples and test examples of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the present invention. Any equivalent substitution in the art made in accordance with the content disclosed in the present invention belongs to the protection scope of the present invention.

[0100] The compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention can be prepared by selecting the synthetic route of the examples, and the conventional conditions of the reaction raw materials and reaction solvents can be adjusted according to the needs of substituents or salt formation. These can all be achieved by those skilled in the art based on the disclosed content of the present invention. In addition, the column chromatography of the present invention refers to silica gel column chromatography without special instructions, and the elution solvent can be determined as a single or mixed elution solvent by combining the reaction solvent with the common knowledge or common means of those skilled in the art without special instructions.

[0101] The structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography - mass spectrometry (LC-MS).

[0102] The liquid chromatography - mass spectrometer (LC-MS) is Agilent G6120B (used in combination with liquid phase Agilent 1260); the nuclear magnetic resonance spectrometer ( 1 HNMR) is Bruker AVANCE-400 or Bruker AVANCE-800. The nuclear magnetic resonance ( 1 H NMR) chemical shift ( δ δ) is given in units of parts per million (ppm). The measurement solvent is DMSO, and the internal standard is tetramethylsilane (TMS). The chemical shift is given in units of 10 -6 δ (ppm).

[0103] The term "room temperature" in the present invention refers to a temperature between 10 and 30 °C.

[0104] 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)butanamido)benzamide (Compound 1):

[0105]

[0106] Step 1: Preparation of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate

[0107] Take 1.03 g (7.05 mmol) of (R)-2-acetoxybutyric acid, dissolve it 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-propylphosphoric anhydride (50% ethyl acetate solution) diluted with 10 ml of tetrahydrofuran. After addition, stir at 0 - 5 °C for 10 minutes and at room temperature for 30 minutes. After the reaction is completed, add water to terminate the reaction, extract with EA. The organic phase is washed successively with 5% citric acid, saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated 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 vacuum dry the filter cake to obtain a white solid with a yield of 86.1%, ee-value of 99.56%, and purity of 96.20%.

[0108] ESI-MS: m / z = 283.1 (M + H) + 。

[0109] 1 1H 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).

[0110] Step 2: Preparation of (R)-2-fluoro-4-(2-hydroxybutanamido)benzamide

[0111] Take 1.5 g (5.32 mmol) of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate, dissolve it in a mixed solvent of 10 ml of methanol and 15 ml of water, add 2.20 g (15.96 mmol) of potassium carbonate, and stir the reaction at room temperature overnight. After monitoring the completion of the reaction by TLC, slowly add 20 ml of water to terminate the reaction. A large amount of white solid precipitates in the system. Continue to add 50 ml of water and stir and slurry for 1 h. Filter to obtain a white solid. The filter cake is dried in vacuo to obtain a white solid with a yield of 87.3%, an ee-value of 98.87%, and a purity of 96.82%.

[0112] ESI-MS: m / z = 241.1 (M+H) + 。

[0113] 1 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).

[0114] Step 3: 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)

[0115] Take 200 mg (0.833 mmol) of (R)-2-fluoro-4-(2-hydroxybutanamido)benzamide, 280 mg (0.758 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, dissolve in 5 ml of tetrahydrofuran. After adding 350 mg (1.73 mmol) of tributylphosphine to dissolve in the system, then add dropwise 343 mg (1.73 mmol) of dibenzyl azodicarboxylate, and stir the reaction at room temperature for 5 h. After monitoring the completion of the reaction by TLC, the N / O-alkylation conversion ratio is 40:1. Add saturated ammonium chloride to terminate the reaction, then add ethyl acetate for extraction. The organic phase is washed successively with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated to obtain the crude product of Compound 1 with a yield of 85.8% and an ee value of 99.24%.

[0116] ESI-MS: m / z = 593.2 (M+H) + 。

[0117] 1 1H 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).

[0118] The crude product can obtain a high-quality target product according to the crystallization method in Patent CN111770917A.

[0119] Example 2: Preparation of Compound 2:

[0120]

[0121] The preparation method is the same as that of Example 1. Replace 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in Step 3 with 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, and the crude product of the title compound 2 can be obtained, with a yield of 88%, an ee-value of 98.61%, and the conversion ratio of the reaction end point N / O-alkylation being 35:1.

[0122] ESI-MS: m / z = 559.1 (M + H) + .

[0123] 1 1H 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).

[0124] The crude product can obtain a high-quality target product according to the crystallization method in Patent CN111770917A.

[0125] Example 3: Preparation of Compound 3:

[0126]

[0127] 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.

[0128] ESI-MS: m / z=605.1(M+H) + .

[0129] 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).

[0130] Example 4: Preparation of Compound 4:

[0131]

[0132] 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.

[0133] ESI-MS: m / z=623.1(M+H) + .

[0134] 11H 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).

[0135] Example 5: Preparation of Compound 5:

[0136]

[0137] The preparation method was the same as that of Example 1. Replace 4-amino-2-fluorobenzamide in Step 1 with 4-amino-2-fluoro-N-(methyl-d3)benzamide to obtain the crude title compound 5. The yield of the final synthesis step was 89%, the ee value was 98.87%, and the conversion ratio of the reaction end point N / O-alkylation was 40:1.

[0138] ESI-MS: m / z = 610.2 (M+H) + .

[0139] 1 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).

[0140] Example 6: Preparation of Compound 6:

[0141]

[0142] The preparation method is the same as that of Example 1. Replace 4-amino-2-fluorobenzamide in Step 1 with 4-amino-2-trifluoromethyl-benzamide to obtain the crude title compound 6. The yield of the final synthesis step is 89%, the ee-value is 99.87%, and the conversion ratio of N / O-alkylation at the reaction end point is 30:1.

[0143] ESI-MS: m / z = 643.1 (M+H) + 。

[0144] 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).

[0145] Example 7: Preparation of Compound 7:

[0146]

[0147] The preparation method is the same as that of Example 1. Replace 4-amino-2-fluorobenzamide in Step 1 with 4-amino-2-chloro-benzamide to obtain the crude title compound 7. The yield of the final synthesis step is 92%, the ee-value is 98.81%, and the conversion ratio of N / O-alkylation at the reaction end point is 35:1.

[0148] ESI-MS: m / z = 623.1 (M+H) + 。

[0149] 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).

[0150] The intermediates included in the embodiments of the present invention and their NMR and mass spectrometry data are shown in the following table:

[0151]

[0152] The above intermediates are prepared using the same preparation idea as in Example 1. As recorded in each example, the preparation ideas of compounds II-4, II-6, II-8, II-10, and II-12 are the same as that of compound II-1, and they are prepared by the condensation reaction of the compound of formula (VI-1) with the corresponding compound of formula (V); the preparation ideas of compounds II-3, II-5, II-7, II-9, and II-11 are the same as that of compound II-2, and they are obtained by the hydrolysis reaction of compounds II-4, II-6, II-8, II-10, and II-12 under alkaline conditions. The preparation methods of each intermediate are summarized as follows:

[0153] When R in the compound of formula (II) 1 is methylcarbonyl, that is, when it is the compound of formula (II-b), it is obtained by the condensation reaction of the compound of formula (Ⅵ-1) with the compound of formula (V):

[0154]

[0155] Among them,

[0156] R 2 is selected from NHR 7 wherein: R 7 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0157] R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0158] When R in the compound of formula (II) 1 is hydrogen, that is, when it is the compound of formula (II-a), it is obtained by the hydrolysis reaction of the compound of formula (II-b) under alkaline conditions:

[0159]

[0160] Among them,

[0161] R 2 is selected from NHR 7 wherein: R 7selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl;

[0162] R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0163] The reaction conditions of the above method for preparing the intermediate are the same as those correspondingly recorded in the invention content of this application.

[0164] It can be understood that those skilled in the art can easily obtain the specific compound of formula (V) used in the above embodiments by conventional technical means in the art, and will not be elaborated here.

[0165] The above embodiments are only one of the preferred embodiments of the present invention and should not be used to limit the protection scope of the present invention. Any modifications or polishings made without substantial significance in the main design concept and spirit of the present invention, as long as the technical problems solved are still consistent with those of the present invention, should be included in the protection scope of the present invention.

Claims

1. An intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof: , Wherein: R 1 selected from hydrogen or acetyl; R 2 selected from NHR 7 wherein: R 7 is selected from hydrogen or methyl; R 3 、R 4 、R 5 are hydrogen; R 6 Selected from fluorine, chlorine, methoxy or trifluoromethyl.

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

3. The intermediate according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The intermediate includes the following compounds: 。 4. Use of the intermediate according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for preparing an oxopyridine compound represented by formula (I): ， Wherein, R x selected from fluorine, chlorine or trifluoromethyl; R 2 selected from NHR 7 , wherein: R 7 is selected from hydrogen or methyl; R 3 、R 4 、R 5 are hydrogen; R 6 Selected from fluorine, chlorine, methoxy or trifluoromethyl.

5. A process for preparing the intermediate according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that, The method includes the following steps: (1) When R 1 is an acetyl group, the compound of formula (II) is obtained by a condensation reaction of a compound of formula (IV) and a compound of formula (V): ， wherein, R 2 , R 3 , R 4 , R 5 , R 6 are defined in the same way as the corresponding definitions in any one of claims 1 to 3; (2) When R 1 is hydrogen, the compound of formula (II) is obtained by hydrolysis of the compound of formula (II-b) under alkaline conditions: ， Among them, R 2 , R 3 , R 4 , R 5 , R 6 has the same definition as the corresponding definition in any one of claims 1 to 3.

6. A method for preparing an oxopyridine compound represented by formula (I), characterized in that, The method includes reacting an intermediate represented by formula (Ⅱ-a) or a pharmaceutically acceptable salt thereof with a compound of formula (Ⅲ) to obtain a compound of formula (I), ， Wherein, R x selected from fluorine, chlorine or trifluoromethyl; R 2 selected from NHR 7 , wherein: R 7 is selected from hydrogen or methyl; R 3 、R 4 、R 5 are hydrogen; R 6 Selected from fluorine, chlorine, methoxy or trifluoromethyl.

7. The method according to claim 6, wherein The method includes the following reaction conditions: The reaction solvent is an organic solvent, a phosphorus ligand and an azo reagent are added during the reaction process, the reaction temperature is -10°C to 50°C, and the reaction time is 2 to 15 hours.

8. According to the method of claim 7, characterized in that, The organic solvent is selected from one or more mixtures of tetrahydrofuran, dichloromethane, DMF, and acetonitrile; Or the phosphorus ligand is selected from triphenylphosphine or tributylphosphine; Or the azo reagent is selected from DEAD, DIAD, TMAD, DTBAD, or ADDP; Or the reaction temperature is 0°C to 25°C; Or the reaction time is 6 to 10 hours.

9. The method according to any one of claims 6 to 8, characterized in that The method includes the synthesis step of compound (II-a): ， Among them, R 2 , R 3 , R 4 , R 5 , R 6 are defined in the same way as the corresponding definitions in any one of claims 6 to 8; Step 1: A condensation reaction occurs between a compound of formula (Ⅳ-1) and a compound of formula (Ⅴ) to obtain a compound of formula (II-b); Step 2: The compound of formula (II-b) undergoes a hydrolysis reaction under alkaline conditions to obtain the compound of formula (II-a).

10. The method according to claim 9, wherein The synthesis step of the compound of formula (II-a) includes the following reaction conditions: In step 1: The conditions for the condensation reaction include a condensing agent; The conditions for the condensation reaction further include an organic base; The solvent for the condensation reaction is an organic solvent; The temperature of the condensation reaction is 0°C to 60°C; The time of the condensation reaction is 1 to 10 hours; In step 2: The conditions for the hydrolysis reaction include an inorganic base; The solvent for the hydrolysis reaction is a mixed solvent of an organic solvent and water; The molar ratio of the compound of formula (V) to the inorganic base in the hydrolysis reaction is 1:1 to 10; The temperature of the hydrolysis reaction is 0°C to 60°C; The time of the hydrolysis reaction is 1 to 10 hours.

11. According to the method of claim 10, characterized in that, In step 1: The condensing agent is selected from T3P or DPP-Cl; The organic base is selected from triethylamine, pyridine, tetramethylguanidine, DBU, or DIPEA; The organic solvent is selected from any one or more mixtures of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and ethyl acetate; In step 2: The inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, or sodium bicarbonate; The volume ratio of the organic solvent to water in the mixed solvent is 1:1 to 10; The mixed solvent is selected from methanol and water, ethanol and water, tetrahydrofuran and water, or DMSO and water.

12. According to the method of claim 11, characterized in that, In step 1: The temperature of the reaction is 10 to 30°C; The time of the reaction is 2 to 4 hours.

13. The method according to claim 11, wherein: In step 2: The molar ratio of the compound of formula (V) to the inorganic base is 1:1 to 3; The temperature of the reaction is 10 to 30 °C; The time of the reaction is 5 to 7 hours.

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