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 their key intermediates. This novel route significantly reduces the generation of isomeric impurities, improves reaction chiral selectivity and N / O-alkylation selectivity, and enhances yield. It is particularly effective for chemical resolution of novel structures in which R1 is a non-hydrogen group. The resulting crude product eliminates the need for costly chiral purification (SFC), reducing costs, shortening production cycles, and being energy-efficient and environmentally friendly. The novel route is suitable for use in the preparation of drugs for the treatment and / or prevention of diseases associated with the FXIa receptor, particularly providing a novel approach for the preparation of drugs for the treatment and / or prevention of cerebrovascular arterial disease and / or peripheral arterial disease. #imgabs0#

Description

Technical Field

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

[0002] Thromboembolic disease is a condition in humans and animals caused by abnormal blood clots forming within blood vessels during life. Drugs targeting FXIa can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thereby exerting anti-thrombotic effects. This target has become a hot topic in recent anticoagulant research. Chengdu Shibeikang has conducted extensive structural modification and process research based on Bayer Pharmaceuticals' BAY-2433334 anticoagulant, aiming to develop a product with improved efficacy and better suitability for industrial scale-up.

[0003] In particular, during the research process for the preparation of anticoagulant derivative drugs represented by the following formula (I), it was found that it was difficult to obtain high-yield and high-purity APIs using Bayer Pharmaceuticals' patented compound and process patents.

[0004] .

[0005] 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, resulting in a low overall yield. The crude product synthesis step yield is only 70%, and the product is a racemate, 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.

[0006] Patent CN 111770917 A discloses a polymerization-based synthesis strategy. The main synthetic steps are as follows: After synthesizing the key intermediates (XVI-CF3) / (XVI-Cl) and (XIX), a condensation reaction is performed to produce crude Compound 1 / Compound 2. These are then chemically purified and impurities are separated by normal phase chromatography. The total reaction involves six steps, the longest being four, which shortens the reaction cycle. After filtration and solvent evaporation, the crude amorphous API is obtained with a high ee value of 85% to 93%.

[0007]

[0008] Although the polymerization synthesis route of this patent is better than the linear synthesis strategy as a whole, when R 1When substituents are present at these positions, particularly alkyl substitutions, chemical synthesis is still not feasible to obtain high-chirally pure products, even using the synthetic approach described in CN 111770917 A. Chromatographic column separation is still required to obtain products with an ee value >98%. Taking all of these factors into account, the subsequent purification difficulty and product quality control risks of this series of compounds represented by formula (I) above remain urgent technical challenges. Summary of the Invention

[0009] In order to solve the technical problems existing in the prior art, improve the yield and ee value, and make it more suitable for industrial production, the present invention discloses a novel preparation method for oxopyridine compounds and key intermediates thereof.

[0010] In one aspect, the present invention provides an intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0011] ,in:

[0012] R 2 、R 3 、R 4 、R 5 are independently selected from hydrogen, halogen, alkoxy or haloalkyl.

[0013] X is selected from halogen atoms.

[0014] Furthermore, in the intermediate represented by the above formula (II) or a pharmaceutically acceptable salt thereof:

[0015] and / or R 2 、R 3 、R 4 、R 5 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0016] Furthermore, in the intermediate represented by the above formula (II) or a pharmaceutically acceptable salt thereof, the intermediate of formula (II) includes the following structure:

[0017] ,

[0018] where R 2 、R 3 、R 4 、R 5 The definitions of , are the same as those above.

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

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

[0021] 、 、 、 .

[0022] Furthermore, the present invention also provides use of any of the above intermediates or pharmaceutically acceptable salts thereof as a standard substance, a reference substance, or in the preparation of a drug for treating or preventing vascular arterial diseases.

[0023] On the other hand, the present invention also provides a method for preparing an oxopyridine compound represented by formula (I), comprising the following reaction steps:

[0024] in,

[0025] R x selected from fluorine, chlorine or trifluoromethyl;

[0026] R 1 is selected from alkyl, cycloalkyl or deuterated alkyl, cycloalkyl;

[0027] R 2 、R 3 、R 4 、R 5 are independently selected from hydrogen, halogen, alkoxy or haloalkyl.

[0028] Step 1: reacting the intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof with the compound represented by formula (III) to obtain the compound represented by formula (IV);

[0029] Step 2: The compound of formula (IV) undergoes hydrolysis to obtain the compound of formula (V);

[0030] Step 3: The compound of formula (V) undergoes condensation reaction to obtain the compound of formula (I).

[0031] Further preferably, in the above method:

[0032] R 1 is selected from methyl or deuterated methyl;

[0033] and / or R 2 、R 3 、R 4 、R 5 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

[0034] Furthermore, the above step 1 includes the following reaction conditions:

[0035] 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;

[0036] 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;

[0037] Optionally, in step 1, the molar ratio of the compound of formula (II) to the base is 1:1 to 3, preferably 1:2;

[0038] Optionally, the reaction temperature of step 1 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26 to 32°C;

[0039] Optionally, the reaction time of step 1 is 1 to 10 hours, preferably 4 to 6 hours.

[0040] Furthermore, the above step 2 includes the following reaction conditions:

[0041] 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;

[0042] 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;

[0043] Optionally, in step 2, the molar ratio of the compound of formula (IV) to the acid is 1:30, preferably 10:20;

[0044] 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;

[0045] Optionally, the reaction time of step 2 is 1 to 8 hours, preferably 2 to 4 hours.

[0046] Furthermore, the above step 3 includes the following reaction conditions:

[0047] 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;

[0048] 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;

[0049] 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;

[0050] Optionally, in step 3, the molar ratio of the compound of formula (V) to the base is 1:1 to 5, preferably 1:3;

[0051] Optionally, the reaction temperature of step 3 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26 to 32°C;

[0052] Optionally, the reaction time of step 3 is 1 to 10 hours, preferably 4 to 6 hours.

[0053] Explanation of terms:

[0054] "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.

[0055] "Cycloalkyl" refers to a C3-C10 cycloalkyl group, preferably a C3-C6 cycloalkyl group.

[0056] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0057] “Above” and “below” include the number itself.

[0058] DBU: 1,8-diazabicycloundec-7-ene

[0059] DIPEA: Isopropylethylamine

[0060] T3P: 1-propylphosphonic acid cyclic anhydride

[0061] DPP-Cl: diphenylphosphinyl chloride

[0062] EDCI:1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0063] HOBT: 1-Hydroxybenzotriazole

[0064] HBTU:Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0065] HATU:2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0066] DCC: N,N'-dicyclohexylcarbodiimide

[0067] Compared with the prior art, the present invention has the following advantages:

[0068] The synthetic route of the present invention can improve the N-alkylation:O-alkylation ratio to a certain extent. At the same time, by chemically resolving the intermediate compound of formula (V), an intermediate compound of formula (V) with an ee value exceeding 99% is obtained. Finally, the target compound of formula (I) is obtained through a condensation reaction, maintaining an ee value of formula (I) exceeding 99%. This allows the chemical resolution method of the compound of formula (I) to be applied in a scaled-up process, eliminating the need for expensive chiral supercritical fluid chromatography (SFC) resolution. DETAILED DESCRIPTION

[0069] 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 replacements 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.

[0070] 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.

[0071] The structure of the compound was determined by NMR ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0072] The liquid chromatography-mass spectrometer (LC-MS) was Agilent G6120B (used with Agilent 1260 liquid chromatography); the nuclear magnetic resonance instrument ( 1 HNMR) was Bruker AVANCE-400 or Bruker AVANCE-800, and nuclear magnetic resonance ( 1 H NMR) shift ( d ) are given in parts per million (ppm), the internal standard is tetramethylsilane (TMS), and the chemical shifts are expressed in 10 -6 The units are given in ppm.

[0073] The term "room temperature" in the present invention refers to a temperature between 10 and 30°C.

[0074] The mixed solvents used in the embodiments of the present invention refer to volume ratios unless otherwise specified.

[0075] The term "20 ml of a solvent of ethyl acetate:n-heptane in a ratio of 1:2" in the present invention refers to 20 ml of a mixed solvent (ethyl acetate:n-heptane in a ratio of 1:2, v / v)". Similar expressions shall be interpreted similarly.

[0076] 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)butanamido)-2-fluoro-N-methylbenzamide (Compound 1):

[0077]

[0078] Step 1: Preparation of (R)-tert-butyl 4-(2-bromobutyramide)-2-fluorobenzoate

[0079] 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-propylphosphonic anhydride (50% ethyl acetate solution) diluted in 2 ml of tetrahydrofuran was added dropwise. After addition, the mixture was stirred at 0-5°C for 10 minutes and then at room temperature for 30 minutes. After completion of the reaction, 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 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 and dried under vacuum to yield a white solid with a yield of 74.0% and a purity of 97.55%.

[0080] ESI-MS: m / z=360.1(M+H) + .

[0081] 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

[0082] 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 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 obtain 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%.

[0083] ESI-MS: m / z=650.2 (M+H) + .

[0084] 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

[0085] 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. 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 dryness to obtain 2.36 g of a crude product. 15 ml of ethyl acetate was added to the crude product and stirred thoroughly to dissolve. 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 dried under vacuum 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%.

[0086] ESI-MS: m / z=594.1(M+H) + .

[0087] 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

[0088] 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 while monitoring the internal temperature. 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 slurrying for 1 h, the solid was filtered and air-dried to obtain 1.06 g of crude product. The reaction 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%.

[0089] ESI-MS: m / z=607.2 (M+H) + .

[0090] 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).

[0091] Example 2: Preparation of Compound 2(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

[0092]

[0093] The preparation method is the same as that of Example 1, except that methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 2 with a yield of 87%, an ee value of 99.22%, and a purity of 98.02%.

[0094] ESI-MS: m / z=610.2 (M+H) + .

[0095] 1 H 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).

[0096] Example 3: Preparation of Compound 3

[0097]

[0098] The preparation method was the same as that of Example 1, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 was replaced with tert-butyl 4-amino-2-(trifluoromethyl)benzoate to obtain the title compound 3 with an ee value of 99.17% and a purity of 97.62%.

[0099] ESI-MS: m / z=657.2 (M+H) + .

[0100] 1H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.18 – 8.12 (m, 1H), 7.98 – 7.90 (m, 2H), 7.85 (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), 5.53 (t, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.77 (d, J = 4.6 Hz, 3H), 2.18 – 2.02(m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0101] Example 4: Preparation of Compound 4

[0102]

[0103] The preparation method was the same as that of Example 1, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 was replaced with tert-butyl 4-amino-2-(trifluoromethyl)benzoate, and methylamine hydrochloride in step 4 was replaced with deuterated methylamine hydrochloride to obtain the title compound 4 with an ee value of 98.92% and a purity of 98.50%.

[0104] ESI-MS: m / z=660.2 (M+H) + .

[0105] 1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.15 (d, J = 1.1 Hz, 1H), 8.19 – 8.12 (m, 1H), 7.98 – 7.91 (m, 2H), 7.85 (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), 5.53 (t, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2Hz, 3H).

[0106] Example 5: Preparation of Compound 5

[0107]

[0108] The preparation method is the same as that of Example 1, 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 5 with an ee value of 98.89% and a purity of 98.49%.

[0109] ESI-MS: m / z=623.1(M+H) + .

[0110] 1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.16 – 8.10 (m, 1H), 7.96 – 7.88 (m, 2H), 7.84 (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), 3.26 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02(m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0111] Example 6: Preparation of Compound 6

[0112]

[0113] The preparation method is the same as that of Example 1, 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 6 with an ee value of 98.96% and a purity of 98.32%.

[0114] ESI-MS: m / z=626.1(M+H) + .

[0115] 1H NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.16 – 8.10 (m, 1H), 7.96 – 7.89 (m, 2H), 7.84 (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), 3.26 (s, 3H), 2.18 – 2.06 (m, 2H), 0.78 (t, J = 7.2Hz, 3H).

[0116] Example 7: Preparation of Compound 7

[0117]

[0118] The preparation method was the same as that of Example 1, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 was replaced with tert-butyl 4-amino-2-(methoxy)benzoate to obtain the title compound 7 with an ee value of 98.68% and a purity of 98.65%.

[0119] ESI-MS: m / z=619.2 (M+H) + .

[0120] 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), 3.86 (s, 3H), 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).

[0121] Example 8: Preparation of Compound 8

[0122]

[0123] The preparation method was the same as that of Example 1, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 was replaced with tert-butyl 4-amino-2-(methoxy)benzoate, and methylamine hydrochloride in step 4 was replaced with deuterated methylamine hydrochloride to obtain the title compound 8 with an ee value of 98.68% and a purity of 98.95%.

[0124] ESI-MS: m / z=622.2 (M+H) + .

[0125] 1 H NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 9.17 (d, J = 1.1 Hz, 1H), 8.13 – 8.08 (m, 1H), 7.89 – 7.81 (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), 5.53 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.18 – 2.02 (m, 2H),0.78 (t, J = 7.2 Hz, 3H).

[0126] 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)butanamido)-2-fluoro-N-methylbenzamide (Compound 1):

[0127]

[0128] Compound 1 was synthesized according to the synthetic strategy disclosed in patent CN 111770917 A and purified to yield the title compound 1 with an ee value of 82.12% and a purity of 96.26%. Because the crystallization of compound 1 failed to form co-enantiomer crystals, the chiral isomer of compound 1 (R-configured compound 1) was not removed during the purification process.

[0129] Through the route provided by this patent, such as Example 1, an intermediate formula (V) with an ee-value higher than 98% is obtained by chemically splitting the structural formula (V), thereby achieving the target API of high ee value and high chemical purity of compound 1.

[0130] The NMR and mass spectrometry data of the intermediates produced by the above Example compounds 1-7 according to the Example method are shown in the following table:

[0131]

[0132] 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. A method for preparing an oxopyridine compound represented by formula (I), characterized in that: The method comprises the following reaction steps: ， in, R x Selected from trifluoromethyl; R 1 is selected from methyl or deuterated methyl; R 2 、R 3 、R 4 are independently selected from hydrogen; R 5 selected from fluorine, chlorine, trifluoromethyl or methoxy; X is selected from bromine; Step 1: reacting the intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof with the compound represented by formula (III) to obtain the compound represented by formula (IV); Step 2: The compound of formula (IV) undergoes hydrolysis to obtain the compound of formula (V); Step 3: The compound of formula (V) undergoes a condensation reaction to obtain a compound of formula (I); The step 1 includes the following reaction conditions: The reaction conditions include a base selected from tetramethylguanidine; The reaction solvent of the reaction conditions is selected from a mixture of isopropyl alcohol and acetone; In step 1, the molar ratio of the compound of formula (II) to the base is 1:1-3; The reaction temperature of step 1 is 0°C to 60°C; The reaction time of step 1 is 1 to 10 hours; The step 2 includes the following reaction conditions: The reaction conditions include an acid selected from concentrated hydrochloric acid; The reaction solvent of the reaction conditions is selected from acetonitrile; The reaction temperature of step 2 is -20°C to 40°C; The step 3 includes the following reaction conditions: The reaction conditions include a base selected from DIPEA; The reaction conditions include a condensing agent and a ligand, wherein the condensing agent and the ligand are selected from HBTU; The reaction solvent of the reaction conditions is selected from DMAC; In step 3, the molar ratio of the compound of formula (V) to the base is 1:1-5; The reaction temperature of step 3 is 0°C to 60°C.

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