CN116751136A

CN116751136A - Novel preparation method of oxo-pyridine compound and key intermediate

Info

Publication number: CN116751136A
Application number: CN202310738580.3A
Authority: CN
Inventors: 朱绪成; 黄龙; 曾燕群
Original assignee: Chengdu Shibeikang Biological Medicine Technology Co ltd
Current assignee: Chengdu Shibeikang Biological Medicine Technology Co ltd
Priority date: 2023-06-21
Filing date: 2023-06-21
Publication date: 2023-09-15
Anticipated expiration: 2043-06-21
Also published as: CN116751136B

Abstract

The invention relates to a novel route for preparing oxo-pyridine compounds shown in a formula (I) and key intermediates thereof. The novel route provided by the invention can greatly reduce the generation of isomer impurities, improve the selectivity of reaction chirality and N/O-alkylation selectivity, improve the yield, especially has the meaning of chemical resolution on the novel structure of R1 which is a non-hydrogen group, and the obtained crude product does not need to carry out chiral purification (SFC) with high cost, has the advantages of reduced cost, short production period, energy conservation and environmental protection, is suitable for preparing the medicaments for treating and/or preventing diseases related to the FXI a receptor, and provides a new thought for preparing the medicaments for treating and/or preventing cerebrovascular arterial diseases and/or peripheral arterial diseasesAnd (5) a road.

Description

Novel preparation method of oxo-pyridine compound and key intermediate

Technical Field

The invention belongs to the field of pharmaceutical chemistry preparation, and particularly relates to a novel preparation method of an oxo-pyridine compound and a key intermediate thereof.

Background

Thromboembolic disorders are diseases caused by abnormal blood clots formed in blood vessels during survival of humans and animals. Drugs of FXIa target, which have been studied as a hotspot of anticoagulants in recent years, can block endogenous pathways and inhibit amplification of the coagulation cascade, thereby having an antithrombotic effect. Wherein, based on BAY-2433334 anticoagulants of Bayer pharmacy, shi Beikang is subjected to a great deal of structural modification and technological research, and aims to provide a variety which has better effect and is more suitable for industrialized amplified production.

Particularly, in the preparation research process of anticoagulant derivative drugs shown in the following formula (I), the compound patent of Bayer pharmacy and the technological patent method thereof are difficult to obtain high-yield and high-purity crude drugs.

。

Patent WO 2014/154794 and WO 2017/005725 disclose the synthesis of such compounds starting from 2, 5-dimethoxypyridine, using a linear synthesis strategy to synthesize the target compound through nine steps, not only in a lengthy route, but also in a high racemization easily, with a low overall yield, wherein the crude product has a synthesis step yield of only 70% and is a racemate, requiring cumbersome post-treatment and purification procedures, and separating isomers by HPLC or chiral Supercritical Fluid Chromatography (SFC), which is time-consuming and expensive, and not suitable for industrial scale-up.

In patent CN 111770917A, a polymerization type synthesis strategy is disclosed, the main synthesis steps are shown below, key intermediates of the compound of formula (XVI-CF 3)/(XVI-Cl) and the compound of formula (XIX) are respectively synthesized, crude products of the compound 1/the compound 2 are generated through condensation reaction, and then impurities are separated through chemical purification and forward chromatography. The total reaction is subjected to six steps, the longest step is four, the reaction period is shortened, and the crude product is filtered and the solvent is evaporated, and then the crude product of the crude drug in an amorphous form is obtained at a high ee-value of 85% ee to 93% ee.

Although the polymeric synthetic route of this patent is overall superior to the linear synthetic strategy, when R ¹ When a substituent exists at a position, particularly when alkyl is substituted, a product with high chiral purity cannot be obtained by a chemical synthesis method even if a CN 111770917A synthesis thought is adopted, and an ee-value still needs to be obtained by chromatographic column resolution>98% of the product. Combining the above factors, the difficulty in subsequent purification and risk in product quality control of the series of compounds represented by the above formula (I) remains a technical problem to be solved.

Disclosure of Invention

In order to solve the technical problems in the prior art and improve the yield and ee value, the invention is more suitable for industrial production, and discloses a novel preparation method for oxo-pyridine compounds and a key intermediate thereof.

In one aspect, the present invention provides an intermediate of formula (II):

wherein:

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

X is selected from halogen atoms.

Further, in the intermediate represented by the above formula (II) or a pharmaceutically acceptable salt thereof:

and/or R ² 、R ³ 、R ⁴ 、R ⁵ Independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.

Further, in the intermediate shown in the formula (II) or the pharmaceutically acceptable salt thereof, the intermediate shown in the formula (II) comprises the following structure:

，

wherein R is ² 、R ³ 、R ⁴ 、R ⁵ The definition of the term "is the same as the definition of the term" corresponding to "above.

Further, the hydrogen in the structure of any of the intermediates described above may be substituted with at least 1 deuterium.

Further, the above intermediates include the following compounds:

、/>、、/>。

furthermore, the invention also provides application of any intermediate or pharmaceutically acceptable salt thereof in preparing standard substances, reference substances or medicines for treating or preventing vascular arterial diseases.

In another aspect, the present invention also provides a method for preparing an oxopyridine compound represented by the formula (i), comprising the following reaction steps:

wherein,,

R ^x selected from fluorine, chlorine or trifluoromethyl;

R ¹ selected from alkyl, cycloalkyl or deuterated alkyl, cycloalkyl;

Step 1: reacting an intermediate shown in a formula (II) or a pharmaceutically acceptable salt thereof with a compound shown in a formula (III) to obtain a compound shown in a formula (IV);

step 2: carrying out hydrolysis reaction on the compound of the formula (IV) to obtain a compound of the formula (V);

step 3: the compound of formula (V) undergoes condensation reaction to obtain the compound of formula (I).

Further preferably, in the above method:

R ¹ selected from methyl or deuterated methyl;

Further, the above step 1 includes the following reaction conditions:

the reaction conditions include a base selected from an organic base or an inorganic base; preferably, the base comprises any one or more than two of tetramethylguanidine, triethylamine, DBU, DIPEA, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide; more preferably, the base comprises any one or more than two of tetramethylguanidine, triethylamine, DBU, DIPEA, potassium carbonate and cesium carbonate;

the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isopropanol, ethanol, acetone, DMF, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;

optionally, the molar ratio of the compound of formula (ii) to the base in step 1 is 1:1 to 3, preferably 1:2;

optionally, the reaction temperature in the step 1 is 0 ℃ to 60 ℃, preferably 20 ℃ to 40 ℃, and more preferably 26 to 32 ℃;

optionally, the reaction time in the step 1 is 1 to 10 hours, preferably 4 to 6 hours.

Further, the above step 2 includes the following reaction conditions:

the reaction conditions include an acid selected from an organic acid or an inorganic acid; preferably, the acid comprises any one or more than two of hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid and hydrobromic acid; more preferably, the base comprises any one or more of hydrochloric acid, trifluoroacetic acid and sulfuric acid;

the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isotetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, methanol, ethanol, isopropanol and DMF;

optionally, the molar ratio of compound of formula (IV) to acid in step 2 is 1:30, preferably 10:20, a step of;

optionally, the reaction temperature in the step 2 is-20 ℃ to 40 ℃, preferably-10 ℃ to 10 ℃, more preferably-5 ℃ to 5 ℃;

optionally, the reaction time in the step 2 is 1-8 hours, preferably 2-4 hours.

Further, the above step 3 includes the following reaction conditions:

the reaction conditions include a base selected from an organic base or an inorganic base; preferably, the base comprises any one or more than two of triethylamine, DBU, DIPEA, tetramethyl guanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide; more preferably, the base comprises any one or more than two of triethylamine, DBU, DIPEA, tetramethyl guanidine, potassium carbonate and cesium carbonate;

the reaction conditions include condensing agent and ligand; preferably, the condensing agent and the ligand comprise any one or more than two of EDCI, HOBT and HATU, HBTU, DCC, CDI, T3P, DPP-Cl, HCTU, TBTU, DMAP; more preferably, the base comprises any one or more than two of EDCI, HOBT, HATU, HBTU;

the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isotetrahydrofuran, DCM, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, ethanol, isopropanol, DMF and DMAC;

optionally, the molar ratio of compound of formula (V) to base in step 3 is 1:1 to 5, preferably 1:3, a step of;

optionally, the reaction temperature in the step 3 is 0 ℃ to 60 ℃, preferably 20 ℃ to 40 ℃, and more preferably 26 to 32 ℃;

optionally, the reaction time in the step 3 is 1 to 10 hours, preferably 4 to 6 hours.

Term interpretation:

"alkyl" refers to lower alkyl, specifically containing a C1-C16 saturated branched or straight chain alkyl. The alkyl moiety in "alkylcarbonyl" is to be interpreted identically.

"cycloalkyl" means a C3-C10 cycloalkyl group, preferably a C3-C6 cycloalkyl group.

"halogen" means fluorine, chlorine, bromine, iodine.

The terms "above" and "below" include the same.

DBU:1, 8-diazabicyclo undec-7-ene

DIPEA: isopropyl ethylamine

T3P: 1-propylphosphoric acid cyclic anhydride

DPP-Cl: diphenylphosphinoyl chloride

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

HOBT 1-hydroxybenzotriazole

HBTU benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate

HATU 2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate

DCC N, N' -dicyclohexylcarbodiimide

Compared with the prior art, the invention has the following advantages:

the synthetic route of the invention can improve the ratio of N-alkylation to O-alkylation to a certain extent, and meanwhile, the intermediate formula (V) with the ee-value higher than 99% is obtained through chemical resolution of the intermediate formula (V) compound; finally obtaining a target compound shown in a formula (I) through condensation reaction; the ee value of formula (I) is maintained above 99%. So that the chemical resolution method of the compound of the formula (I) can be applied in the process of technical amplification without resolution by high chiral Supercritical Fluid Chromatography (SFC).

Detailed Description

The present invention will be described in further detail with reference to the following examples and test examples, which are only for the purpose of illustrating the technical aspects of the present invention, but are not to be construed as limiting the present invention, and any equivalent substitution in the art according to the present disclosure is intended to be within the scope of the present invention.

The compounds of the present invention, stereoisomers or pharmaceutically acceptable salts thereof may be prepared by the synthetic routes of the examples, and the conventional conditions of the reaction starting materials and reaction solvents may be adjusted according to the substituents or salt-forming requirements, which may be accomplished by one skilled in the art based on the present disclosure. In addition, the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified, and the eluting solvent may be a single or mixed eluting solvent determined by combining the reaction solvent with common knowledge or common means of a person skilled in the art.

The structure of the compound is nuclear magnetic resonance ¹ H NMR) or liquid mass spectrometry (LC-MS).

The liquid chromatography-mass spectrometer (LC-MS) is Agilent G6120B (matched with liquid phase Agilent 1260); nuclear magnetic resonance apparatus ¹ H NMR) of Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance ¹ H NMR) shift [ ]δ) Given in parts per million (ppm), the internal standard is Tetramethylsilane (TMS), the chemical shift is 10 ^-6 (ppm) is given as a unit.

The term "room temperature" according to the invention means a temperature between 10 and 30 ℃.

The mixed solvent used in the examples of the present invention refers to a volume ratio unless otherwise specified.

The term "20ml ethyl acetate" according to the invention: the n-heptane 1:2 solvent "refers to 20ml of the mixed solvent (ethyl acetate: n-heptane 1:2, v/v)". Similar writing is similarly interpreted.

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) butyramide) -2-fluoro-N-methylbenzamide (compound 1):

step 1: preparation of (R) -4- (2-bromobutyramide) -2-fluorobenzoic acid tert-butyl ester

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

ESI-MS:m/z=360.1(M+H) ⁺ 。

Step 2: 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) butanamide) -2-fluorobenzoic acid tert-butyl ester

2.0g (5.39 mmol) of 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one, 50ml of isopropanol and 20ml of acetone were mixed, 1.87mg (16.24 mmol) of tetramethylguanidine was added, and stirring was performed for 5 minutes, 2.33mg (6.48 mmol) of tert-butyl (R) -4- (2-bromobutyramide) -2-fluorobenzoate was added, and the reaction was stirred at room temperature overnight. After the completion of the reaction, saturated ammonium chloride was added to terminate the reaction, ethyl acetate was added to extract, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4.60mg of crude product. Column chromatography, eluent (ethyl acetate: petroleum ether=1:2) and collection of the product afforded 2.58g of a white solid. The yield thereof was found to be 73.7% and the purity thereof was found to be 97.82%.

ESI-MS:m/z=650.2(M+H) ⁺ 。

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) butyramide) -2-fluorobenzoic acid

2.58g (3.97 mmol) of tert-butyl (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyryl) -2-fluorobenzoate was taken and dissolved in 25mL of acetonitrile, the temperature was reduced to about 0℃for monitoring at an internal temperature, 25mL of concentrated hydrochloric acid was slowly added dropwise, TLC was used for detection of completion of the reaction after 0.5H, water was added to terminate the reaction, EA extraction was added, and the organic phase was washed successively with saturated sodium bicarbonate, water, saturated brine, anhydrous sodium sulfate was dried, and the solvent was evaporated to dryness to give 2.36g of crude product. To the crude product, 15ml of ethyl acetate was added, and the mixture was stirred well, the solids were removed by filtration, and the mother liquor was concentrated and then 20ml of ethyl acetate was used: n-heptane 1:2 solvent was stirred at room temperature for 2 hours, filtered, the filter cake was washed with n-heptane and dried in vacuo to give 2.06g of a white solid in 87.3% yield, 99.36% ee-value and 98.20% purity.

ESI-MS:m/z=594.1(M+H) ⁺ 。

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) butyramide) -2-fluoro-N-methylbenzamide

1.0g (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) butyryl) -2-fluorobenzoic acid was dissolved in 10mL of DMAC, 226mg (3.35 mmol) of methylamine hydrochloride, 953mg (2.52 mmol) of HBTU were added, the temperature was lowered to about 5℃and monitored by internal temperature, 1.1g (8.38 mmol) of DIPEA was slowly added dropwise, after maintaining the reaction at 5-10℃for 1 hour, TLC detection was complete, 30mL of water was slowly added to terminate the reaction, and after stirring and beating for 1 hour, a solid was obtained by filtration, and after air-blast drying, 1.06g of crude product was obtained. Then 20ml of ethyl acetate: n-heptane 1:2 solvent was stirred at room temperature for 2 hours, filtered, the filter cake was washed with n-heptane and dried in vacuo to give 860mg of a white solid with a yield of 84.3%, ee-value 99.27% and purity 98.32%.

ESI-MS:m/z=607.2(M+H) ⁺ 。

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)。

Example 2: preparation of the 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) butyramide) -2-fluoro-N- (methyl-d 3) benzamide

The preparation method is the same as that of example 1, and the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 2 can be prepared in a yield of 87%, an ee-value of 99.22% and a purity of 98.02%.

ESI-MS:m/z=610.2(M+H) ⁺ 。

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)。

Example 3: preparation of Compound 3

The preparation method is the same as that of example 1, and the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (trifluoromethyl) benzoate, so that the title compound 3 with an ee-value of 99.17% and a purity of 97.62% can be obtained.

ESI-MS:m/z=657.2(M+H) ⁺ 。

¹ H 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)。

Example 4: preparation of Compound 4

The preparation method is the same as that of example 1, the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (trifluoromethyl) benzoate, and the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 4 can be prepared, wherein the ee-value is 98.92%, and the purity is 98.50%.

ESI-MS:m/z=660.2(M+H) ⁺ 。

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 = 7.2 Hz, 3H)。

Example 5: preparation of Compound 5

The preparation method is the same as that of example 1, and the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-chlorobenzoate, so that the title compound 5 can be prepared, wherein the ee-value is 98.89%, and the purity is 98.49%.

ESI-MS:m/z=623.1(M+H) ⁺ 。

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)。

Example 6: preparation of Compound 6

The preparation method is the same as that of example 1, the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-chlorobenzoate, and the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 6 can be prepared, wherein the ee-value is 98.96%, and the purity is 98.32%.

ESI-MS:m/z=626.1(M+H) ⁺ 。

¹ H 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 = 7.2 Hz, 3H)。

Example 7: preparation of Compound 7

The preparation method is the same as that of example 1, and the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (methoxy) benzoate, so that the title compound 7 can be obtained, wherein the ee-value is 98.68%, and the purity is 98.65%.

ESI-MS:m/z=619.2(M+H) ⁺ 。

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)。

Example 8: preparation of Compound 8

The preparation method is the same as that of example 1, the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (methoxy) benzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 8 can be prepared, wherein the ee-value is 98.68%, and the purity is 98.95%.

ESI-MS:m/z=622.2(M+H) ⁺ 。

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)。

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) butyramide) -2-fluoro-N-methylbenzamide (compound 1):

compound 1 was synthesized according to the synthetic strategy disclosed in patent CN 111770917A and finally purified to give the title compound 1 having an ee-value 82.12% and purity of 96.26%. Since the crystallization process of compound 1 cannot form a synergistic crystal of the enantiomer, the chiral isomer of compound 1 (R-configuration compound 1) cannot be removed in the refinement process.

By the route provided by this patent, as in example 1, intermediate formula (V) with ee-value higher than 98% was obtained by chemical resolution of structural formula (V), thereby achieving the target API of high ee value and high chemical purity of compound 1.

The nuclear magnetism and mass spectrum data for intermediates produced by the methods of the examples above for compounds 1-7 are shown in the following table:

the above embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or color changes made in the main design concept and spirit of the present invention are still consistent with the present invention, and all the technical problems to be solved are included in the scope of the present invention.

Claims

1. An intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof:

,

in:

R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, halogen, alkoxy or haloalkyl;

X is selected from F, Cl, Br or I.

2. The intermediate or pharmaceutically acceptable salt thereof according to claim 1, characterized in that,

The R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl;

and/or X is independently selected from Cl or Br.

3. The intermediate or pharmaceutically acceptable salt thereof according to claim 1, wherein the intermediate of formula (II) includes the following structure:

,

The definitions of R ² , R ³ , R ⁴ and R ⁵ are the same as those in claims 1 to 2.

4. The intermediate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that the hydrogen in the structure of the intermediate can be replaced by at least one deuterium.

5. The intermediate or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the intermediate includes the following compounds:

,/> ,/> , .

6. The use of the intermediate according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use in standard substances, reference substances or in the preparation of drugs for the treatment or prevention of vascular and arterial diseases.

7. A method for preparing oxopyridine compounds represented by formula (I), characterized in that the method includes the following reaction steps:

in,

R ^x is selected from fluorine, chlorine or trifluoromethyl;

R ¹ is selected from alkyl or deuterated alkyl;

Step 1: react the intermediate represented by formula (II) or its pharmaceutically acceptable salt with the compound of formula (III) to obtain the compound of formula (IV);

Step 2: The compound of formula (IV) undergoes a hydrolysis reaction to obtain the compound of formula (V);

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

8. The method of claim 7, wherein step 1 includes the following reaction conditions:

The reaction conditions include a base, the base is selected from organic bases or inorganic bases;

The reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent includes any one or two of isopropyl alcohol, ethanol, acetone, DMF, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane Mix the above;

Optionally, the molar ratio of the compound of formula (II) to the base in step 1 is 1:1~3;

Optionally, the reaction temperature in step 1 is 0°C to 60°C;

Optionally, the reaction time of step 1 is 1 to 10 hours.

9. The method of claim 7, wherein step 2 includes the following reaction conditions:

The reaction conditions include an acid, and the acid is selected from organic acids or inorganic acids; preferably, the acid includes any one or a mixture of two or more of hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, and hydrobromic acid. ;

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

Optionally, the molar ratio of the compound of formula (IV) to the acid in step 2 is 1:30;

Optionally, the reaction temperature in step 2 is -20°C ~ 40°C;

Optionally, the reaction time of step 2 is 1 to 8 hours.

10. The method of claim 7, wherein step 3 includes the following reaction conditions:

The reaction conditions include a base; preferably, the base includes triethylamine, DBU, DIPEA, tetramethylguanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, Any one or a mixture of two or more of sodium hydroxide and potassium hydroxide;

The reaction conditions include a condensing agent and a ligand; preferably, the condensing agent and 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;

The reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvents include isotetrahydrofuran, DCM, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, ethanol, isopropanol, DMF, DMAC Any one or a mixture of two or more;

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

Optionally, the reaction temperature in step 3 is 0°C to 60°C;

Optionally, the reaction time of step 3 is 1 to 10 hours.