WO2024251276A1 - 氧代吡啶类化合物的新型制备方法及关键中间体和应用 - Google Patents

氧代吡啶类化合物的新型制备方法及关键中间体和应用 Download PDF

Info

Publication number
WO2024251276A1
WO2024251276A1 PCT/CN2024/098225 CN2024098225W WO2024251276A1 WO 2024251276 A1 WO2024251276 A1 WO 2024251276A1 CN 2024098225 W CN2024098225 W CN 2024098225W WO 2024251276 A1 WO2024251276 A1 WO 2024251276A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
preparation
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/098225
Other languages
English (en)
French (fr)
Inventor
周广林
黄龙
朱绪成
曾燕群
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Shibeikang Biomedical Technology Co Ltd
Original Assignee
Chengdu Shibeikang Biomedical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN202310679927.1A external-priority patent/CN116621742B/zh
Priority claimed from CN202310738580.3A external-priority patent/CN116751136B/zh
Priority claimed from CN202310757873.6A external-priority patent/CN116535392B/zh
Application filed by Chengdu Shibeikang Biomedical Technology Co Ltd filed Critical Chengdu Shibeikang Biomedical Technology Co Ltd
Priority to KR1020267000750A priority Critical patent/KR20260021743A/ko
Publication of WO2024251276A1 publication Critical patent/WO2024251276A1/zh
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of pharmaceutical chemistry and preparation thereof, and specifically relates to a novel preparation method of oxopyridine compounds and key intermediates and applications thereof.
  • Rx is selected from fluorine, chlorine or trifluoromethyl
  • Patents WO 2014/154794 and WO 2017/005725 disclose that the synthesis of such compounds uses 2,5-dimethoxypyridine as the starting material and a linear synthesis strategy to synthesize the target compound in nine steps. Not only is the route lengthy, but it is also prone to high racemization and has a low overall yield, with the yield of the crude product synthesis step being only 70%. It requires cumbersome post-processing and purification procedures, and separation of isomers by HPLC or chiral supercritical fluid chromatography (SFC), which is time-consuming and expensive and is not suitable for industrial scale-up production.
  • SFC supercritical fluid chromatography
  • Patent CN 111770917 A discloses a polymerization synthesis strategy.
  • the crude product synthesis steps are shown in the figure below.
  • the crude products of compound 1/compound 2 are generated through condensation reaction.
  • the total reaction undergoes six steps, with the longest step being four steps, which shortens the reaction cycle and focuses on optimizing the enantioselectivity and N/O-alkylation selectivity of the crude product synthesis step.
  • the condensate is filtered to obtain amorphous compound 1/compound 2 crude products with a high ee-value of 85% ee to 93% ee.
  • a preferred N-alkylation is obtained over the unwanted O-alkylation at a ratio of N-alkylation:O-alkylation of 9:1 to 10:1.
  • the condensation step of the crude product synthesis still has great limitations, such as: (1) low conversion rate.
  • the yield of the condensation step of the crude product synthesis of compound 1 and compound 2 is only 70% and 75% respectively, and the yield of the alternative method is as low as 61% (paragraphs 0095 to 0097 of the specification).
  • the total conversion rate of the six steps is 2.3%.
  • the yield is only 20% to 25% (paragraph 0054 of the specification); (2) the proportion of isomers is relatively large.
  • the ee value of the crude product is optimized to 85% to 93%, there are still 7% to 15% isomer impurities, and it is necessary to purify it with an organic solvent to obtain a purified crude product with an ee value of >99%, and then obtain the target crystals through a crystallization process; (3) the N/O-alkylation selectivity is poor.
  • the ratio of crude N-alkylation: O-alkylation reaches (9 to 10): 1, there is still an unsatisfactory O/N conversion rate of about 10%, which not only leads to a low conversion rate, but also produces more O-alkylated impurities, which increases the difficulty of subsequent purification and the risk of product quality control.
  • the present invention discloses a novel preparation method for oxopyridine compounds and key intermediates and applications thereof.
  • the present invention provides an intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from TsO-, X, R 7 O-;
  • Ts is p-toluenesulfonyl, and
  • X is selected from F, Cl, Br or I;
  • R 2 is selected from -NHR 8 , -OC(CH 3 ) 3 ;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl;
  • R 7 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl;
  • R 8 is selected from hydrogen, alkyl or cycloalkyl
  • Ts is p-toluenesulfonyl
  • R 2 is selected from -NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl;
  • X is selected from F, Cl, Br or I;
  • R 2 is selected from NHR 8 , R 8 is selected from hydrogen, alkyl or cycloalkyl;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl;
  • R7 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl.
  • R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.
  • the intermediate includes the structure shown in formula (IV-a):
  • R 3 , R 4 , R 5 and R 6 have the same meanings as above.
  • the hydrogen in the structure of any of the above intermediates may be replaced by at least one deuterium.
  • the present invention provides a method for preparing the intermediate represented by the above formula (II) or a pharmaceutically acceptable salt thereof, wherein the synthesis of the intermediate comprises the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as any of the corresponding definitions above.
  • preparation method of the intermediate represented by the above formula (II) includes method A, method B or method C:
  • Method A The intermediate represented by formula (III) is obtained by reacting the compound represented by formula (III-a) with p-toluenesulfonyl chloride under alkaline conditions.
  • Method B The intermediate represented by formula (IV) is obtained by reacting the compound represented by formula (III-a-5) with a halogenated carboxylic acid.
  • R 3 , R 4 , R 5 , and R 6 are defined as any of the above corresponding definitions;
  • the hydroxyl protecting agent described in the above method C includes any one of trifluoromethanesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenemethylsulfonyl chloride and benzenesulfonyl chloride.
  • the reaction solvent of the synthesis step is selected from an organic solvent; preferably, the organic solvent includes but is not limited to any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and dichloromethane, or a mixture of two or more thereof;
  • the molar ratio of the compound of formula (III-a) to the organic base in the synthesis step is 1:0.5 to 8, preferably 1:1 to 3;
  • reaction temperature of the synthesis step is 0°C to 60°C, preferably 10 to 30°C;
  • reaction time of the synthesis step is 1 to 10 hours, preferably 4 to 6 hours.
  • the above method B includes the following reaction conditions:
  • the reaction conditions include an organic base; preferably, the organic base includes triethylamine, pyridine, DBU or DIPEA;
  • the reaction conditions include an organic solvent; the organic solvent includes tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, DMF or acetonitrile;
  • the reaction conditions include a condensing agent; the condensing agent includes 1-propylphosphoric anhydride, DCC or EDCI;
  • the reaction temperature is -10°C to 10°C for 5-60 minutes, and then 10°C to 50°C for 10-600 minutes; preferably Select 0°C to 5°C for 10 minutes, and then react at room temperature for 30 minutes.
  • the preparation method of the compound of formula (III-a) comprises the following steps:
  • the D-2-aminobutyric acid shown in formula (III-a-1) is subjected to a diazo reaction with sodium nitrite in an acetic acid environment to obtain a compound of formula (III-a-2);
  • the compound of formula (III-a-2) and the compound of formula (III-a-3) are subjected to an amide condensation reaction in the presence of a base and an acid anhydride to obtain a compound of formula (III-a-4);
  • the compound of formula (III-a-4) is hydrolyzed to obtain the compound of formula (III-a).
  • D-2-aminobutyric acid is dissolved in acetic acid, sodium nitrite is added at 0-5°C, and stirred at 0-5°C for 6-10h;
  • the molar ratio of D-2-aminobutyric acid to sodium nitrite is 1:1.8-2.3, preferably 1:2.
  • the method comprises: mixing the compound of formula (III-a-2) and the compound of formula (III-a-3) in a molar ratio of 1.3-1.8:1, adding a base and anhydride at -10-0°C, stirring at 0-5°C for 5-15 minutes, and then stirring at room temperature for 20-60 minutes.
  • the molar ratio of the compound of formula (III-a-2) to the compound of formula (III-a-3) is 1.3-1.8:1, preferably 1.5:1.
  • reaction conditions are stirring at 0-5°C for 5-13 min, and then stirring at room temperature for 20-40 min.
  • the present invention also provides the use of any of the above intermediates or pharmaceutically acceptable salts thereof as standard products, reference products, in the preparation of oxopyridine compounds represented by formula (I), or in the preparation of drugs for treating or preventing vascular arterial diseases.
  • the present invention also provides a method for preparing an oxopyridine compound represented by formula (I), wherein the preparation
  • the preparation method comprises reacting an intermediate represented by formula (II) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI) to obtain a compound represented by formula (I);
  • R 1 is selected from TsO-, X, R 7 O-;
  • Ts is p-toluenesulfonyl, and
  • X is selected from F, Cl, Br or I;
  • R 8 is selected from hydrogen, alkyl or cycloalkyl
  • R 9 is selected from fluorine, chlorine or trifluoromethyl
  • Ts is selected from p-toluenesulfonyl
  • R 10 is selected from alkyl, cycloalkyl or deuterated alkyl, cycloalkyl;
  • R 9 is selected from fluorine, chlorine or trifluoromethyl
  • Step 2 hydrolyzing the compound of formula (VII) to obtain the compound of formula (VIII);
  • Step 3 The compound of formula (VIII) undergoes condensation reaction to obtain a compound of formula (I-a);
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, alkoxy, or haloalkyl;
  • R7 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-nitrobenzenemethylsulfonyl or benzenesulfonyl.
  • R 9 is selected from fluorine, chlorine or trifluoromethyl
  • Ts is selected from p-toluenesulfonyl
  • R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.
  • the method 1 comprises a base, and the base is selected from an organic base or an inorganic base; preferably, the base comprises any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, DBU, DIPEA, and pyridine, or a mixture of two or more thereof; more preferably, the base comprises any one of potassium carbonate, cesium carbonate, tetramethylguanidine, triethylamine, DBU, and DIPEA, or a mixture of two or more thereof;
  • the reaction solvent of the method 1 is selected from an organic solvent; preferably, the organic solvent includes any one of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, and DMF, or a mixture of two or more thereof;
  • the molar ratio of the compound of formula (III) to the base is 1:1 to 3, preferably 1:2;
  • reaction temperature of the method 1 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26 to 32°C;
  • the above method 1 comprises the steps of synthesizing the compound of formula (III):
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same as any of the corresponding definitions above.
  • the base is selected from an organic base; preferably, the organic base includes triethylamine, pyridine, tetramethylguanidine, DMAP, DBU or DIPEA, more preferably triethylamine or pyridine;
  • the reaction solvent of the synthesis step is selected from an organic solvent; preferably, the organic solvent includes but is not limited to any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and dichloromethane, or a mixture of two or more thereof;
  • the molar ratio of the compound of formula (III-a) to the organic base in the synthesis step is 1:0.5 to 8, preferably 1:1 to 3;
  • reaction temperature of the synthesis step is 0°C to 60°C, preferably 10 to 30°C;
  • the preparation method of the compound of formula (III-a) comprises the following steps:
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same as any corresponding definitions above;
  • Step 1 The compound of formula (III-a-2) and the compound of formula (III-a-3) undergo condensation reaction to obtain a compound of formula (III-a-4);
  • Step 2 The compound of formula (III-a-4) undergoes hydrolysis reaction under alkaline conditions to obtain the compound of formula (III-a).
  • step 1 of preparing the compound of formula (III-a) comprises the following reaction conditions:
  • the conditions of the condensation reaction include a condensation agent, preferably, the condensation agent includes T3P or DPP-Cl;
  • the conditions of the condensation reaction also include an organic base; preferably, the organic base includes triethylamine, pyridine, tetramethylguanidine, DBU or DIPEA; more preferably triethylamine or pyridine;
  • the solvent for the condensation reaction is an organic solvent; preferably, the organic solvent includes any one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, DMF, acetonitrile, and ethyl acetate, or a mixture of two or more thereof;
  • the condensation reaction temperature is 0°C to 60°C, preferably 10 to 30°C;
  • the condensation reaction time is 1 to 10 hours, preferably 2 to 4 hours.
  • step 2 of preparing the compound of formula (III-a) comprises the following reaction conditions:
  • the hydrolysis reaction includes an inorganic base; preferably, the inorganic base includes potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate; more preferably potassium carbonate;
  • 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 1:1-10, preferably 1:1-2; the mixed solvent includes methanol and water, ethanol and water, tetrahydrofuran and water, or DMSO and water, preferably methanol and water;
  • the molar ratio of the compound of formula (III-a-4) to the inorganic base in the hydrolysis reaction is 1:1 to 10, preferably 1:1 to 3;
  • the temperature of the hydrolysis reaction is 0°C to 60°C, preferably 10 to 30°C;
  • the hydrolysis reaction time is 1 to 10 hours, preferably 5 to 7 hours.
  • the molar ratio of the compound of formula (V) to the base is 1:1-3, the reaction temperature is 0°C-60°C, and the reaction time is 1-10 hours.
  • the method three includes a base, and the base is selected from an organic base or an inorganic base; preferably, the base includes any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, DBU, DIPEA, and pyridine, or a mixture of two or more thereof; more preferably, the base includes any one of potassium carbonate, cesium carbonate, tetramethylguanidine, triethylamine, DBU, and DIPEA, or a mixture of two or more thereof;
  • the reaction solvent of the method three is selected from an organic solvent; preferably, the organic solvent includes any one of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, ethanol, acetone, and DMF, or a mixture of two or more thereof;
  • the molar ratio of the compound of formula (V) to the base is 1:1 to 3, preferably 1:2;
  • reaction temperature of the method three is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26°C to 32°C;
  • reaction time of the method three is 1 to 10 hours, preferably 4 to 6 hours.
  • R 10 is selected from methyl or deuterated methyl
  • R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.
  • step 1 of the above method 2 includes the following reaction conditions:
  • the reaction conditions include a base, and the base 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, potassium hydroxide, or a mixture of two or more thereof; more preferably, the base includes any one of tetramethylguanidine, triethylamine, DBU, DIPEA, potassium carbonate, cesium carbonate, or a mixture of two or more thereof;
  • reaction time of step 1 is 1 to 10 hours, preferably 4 to 6 hours.
  • the reaction conditions include an acid, and the acid is 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;
  • reaction time of step 2 is 1 to 8 hours, preferably 2 to 4 hours.
  • the reaction conditions include a base, which is selected from an organic base or an inorganic base; preferably, the base includes triethylamine, DBU, DIPEA, tetramethylguanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, any one or a mixture of two or more thereof; more preferably, the base comprises triethylamine, DBU, DIPEA, tetramethylguanidine, potassium carbonate, cesium carbonate any one or a mixture of two or more thereof;
  • 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;
  • step 3 the molar ratio of the compound of formula (VIII) to the base is 1:1 to 5, preferably 1:3;
  • reaction temperature of step 3 is 0°C to 60°C, preferably 20°C to 40°C, more preferably 26°C to 32°C;
  • reaction time of step 3 is 1 to 10 hours, preferably 4 to 6 hours.
  • the oxopyridine compounds of formula (I) obtained by the above method 1, method 2, and method 3 have at least any of the following characteristics: (1) the enantioselective ee value is 98% or more, preferably 99% or more; (2) the N/O-alkylation selectivity ratio is 30-40:1 or more; (3) the single-step yield is 85% or more, preferably 90% or more; (4) the production cycle is short, no complicated post-treatment is required, and it is suitable for industrial scale-up production; (5) the product purity is 98% or more.
  • the oxopyridine compounds of formula (I) obtained by the above methods 1, 2 and 3 can be crystallized by a crystallization method, such as the crystallization method in patent CN111770917A, to obtain high-quality crystal products even higher than the crystal quality in the patent.
  • Alkyl refers to a lower alkyl group, specifically a C1-C16 saturated branched or straight chain alkyl group.
  • alkyl part of “alkylcarbonyl” shall be interpreted in the same manner.
  • cycloalkyl group refers to a C3-C10 cycloalkyl group, preferably a C3-C6 cycloalkyl group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • DIAD diisopropyl azodicarboxylate
  • TMAD azodicarbonamide
  • DTBAD di-tert-butyl azodicarboxylate.
  • ADDP azodicarbonyl dipyridine.
  • DBU 1,8-diazabicycloundec-7-ene.
  • DIPEA isopropylethylamine.
  • T3P 1-propylphosphoric anhydride.
  • DPP-Cl diphenylphosphinyl chloride.
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • DCC N,N'-dicyclohexylcarbodiimide.
  • the present invention has the following advantages:
  • the new preparation route of the present invention can improve the total conversion rate, enantioselectivity and N/O-alkylation selectivity, which has absolute advantages.
  • a conversion rate of N/O ratio of 30 to 40:1 or more can be obtained, and O-alkylation impurities are less.
  • the ratio of N-alkylation: O-alkylation in the crude product is (9 to 10): 1, which contains more O-alkylation impurities, and the purification of such isomerization impurities is extremely difficult.
  • the synthetic route of the present application has low difficulty in subsequent purification, which is beneficial to the subsequent crystallization yield and improves the stability of the crystallization refining process control.
  • the yield of the crude product prepared by the single-step condensation reaction is increased to more than 85% to 98%, and the total yield of the route is more than 60% to 70%, while the total yield in the prior art is only 20% to 25%. Therefore, the conversion rate of the synthetic route is high, the production cycle is greatly shortened, complex post-processing is avoided, costs are saved, and it is conducive to industrialized production.
  • the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts can be prepared by selecting the synthetic routes of the embodiments, and the conventional conditions of the reaction raw materials and the reaction solvent can be adjusted according to the needs of the substituents or the salt formation, which can be realized by those skilled in the art based on the disclosure of the present invention.
  • the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified, and the elution solvent can be determined as a single or mixed elution solvent in combination with the reaction solvent and the common knowledge or common means of those skilled in the art unless otherwise specified.
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).
  • the liquid spectrometer-mass spectrometer was Agilent G6120B (used with Agilent 1260 liquid phase); the nuclear magnetic resonance ( 1 H NMR) was Bruker AVANCE-400 or Bruker AVANCE-800.
  • the measurement solvent was DMSO, the internal standard was tetramethylsilane (TMS), and the chemical shift was given in 10 -6 (ppm).
  • room temperature in the present invention means a temperature between 10 and 30°C.
  • the mixed solvents used in the embodiments of the present invention refer to volume ratios unless otherwise specified.
  • 20 ml of ethyl acetate: n-heptane 1:2 solvent in the present invention refers to 20 ml of a mixed solvent (ethyl acetate: n-heptane 1:2, v/v)". Similar expressions are interpreted similarly.
  • Step 1 Preparation of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate
  • Step 3 Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl p-toluenesulfonate
  • the crude product can be crystallized into a high-quality target product according to the crystallization method in patent CN111770917A.
  • the preparation method is the same as the preparation method of Example 1, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one in step 4 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one to obtain the crude title compound 2 with a yield of 90%, an ee value of 98.61%, and an N/O-alkylation conversion ratio of 35:1 at the reaction endpoint.
  • the crude product can be crystallized into a high-quality target product according to the crystallization method in patent CN111770917A.
  • the preparation method is the same as the preparation method of Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced by 4-amino-2-methoxy-benzamide to obtain the crude title compound 3.
  • the final synthesis step yield is 90%, the ee-value is 98.39%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as the preparation method of Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced by 4-amino-2-fluoro-N-methylbenzamide to obtain the crude title compound 4.
  • the final synthesis step yield is 90%, the ee-value is 99.02%, and the N/O-alkylation conversion ratio at the reaction endpoint is 40:1.
  • the preparation method is the same as that of Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide to obtain the crude title compound 5.
  • the final synthesis step yield is 89%, the ee-value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 40:1.
  • the preparation method is the same as the preparation method of Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced by 4-amino-2-trifluoromethyl-benzamide to obtain the crude title compound 6.
  • the final synthesis step yield is 89%, the ee-value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as the preparation method of Example 1, except that 4-amino-2-fluorobenzamide in step 1 is replaced by 4-amino-2-chloro-benzamide to obtain the crude title compound 7.
  • the final synthesis step yield is 92%, the ee-value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 35:1.
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same as any corresponding definitions in the summary of the invention.
  • 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)butyramido)-2-fluorobenzoate
  • 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)butyramido)-2-fluorobenzoic acid
  • the organic phase is washed with saturated sodium bicarbonate, water, and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent is evaporated to obtain 2.36g 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. After the mother liquor was concentrated, 20 ml of ethyl acetate: n-heptane (1:2) was added and stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with n-heptane. The filter cake was 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%.
  • 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)butyramido)-2-fluoro-N-methylbenzamide
  • the preparation method is the same as that of Example 8, except that the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 5 with a yield of 87%, an ee-value of 99.22% and a purity of 98.02%.
  • the preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced with tert-butyl 4-amino-2-(trifluoromethyl)benzoate to obtain the title compound 8 with an ee value of 99.17% and a purity of 97.62%.
  • the preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-(trifluoromethyl)benzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 9 with an ee value of 98.92% and a purity of 98.50%.
  • the preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced with tert-butyl 4-amino-2-chlorobenzoate to obtain the title compound 10 with an ee value of 98.89% and a purity of 98.49%.
  • the preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-chlorobenzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 11 with an ee value of 98.96% and a purity of 98.32%.
  • the preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced with tert-butyl 4-amino-2-(methoxy)benzoate to obtain the title compound 12 with an ee value of 98.68% and a purity of 98.65%.
  • the preparation method is the same as that of Example 8, except that tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-(methoxy)benzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride to obtain the title compound 13 with an ee value of 98.68% and a purity of 98.95%.
  • Examples 16-22 provide a type of intermediate and an oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is trifluoromethanesulfonyl, and the specific synthesis route is as follows:
  • Step 2 Preparation of (R)-1-((4-carbamoyl-3-fluorophenyl)amino)-1-oxobutan-2-yl acetate
  • Step 4 Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl trifluoromethanesulfonate
  • the crude product can be crystallized to obtain high-quality target product.
  • the preparation method is the same as the preparation method of Example 16, except that the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one, that is, R 9 is replaced by trifluoromethyl to chlorine, to obtain a crude compound 2 with a yield of 90%, an ee value of 98.61%, and an N/O-alkylation conversion ratio of 35:1 at the reaction end point.
  • the crude product can be crystallized to obtain high-quality target product.
  • the preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxy-benzamide, i.e., R 6 is replaced by methoxy from fluorine, to obtain a crude compound 3.
  • the final synthesis step yield is 90%, the ee value is 98.39%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as the preparation method of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide, i.e., R2 is replaced by amino group by N-methyl group, to obtain a crude compound 4, with a final synthesis step yield of 90%, an ee value of 99.02%, and an N/O-alkylation conversion ratio of 40:1 at the reaction endpoint.
  • the preparation method is the same as that of Example 16, except that the 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, i.e., R2 is replaced by amino by N-(methyl-d3), to obtain a crude compound 5, with a final synthesis step yield of 89%, an ee value of 98.87%, and an N/O-alkylation conversion ratio of 40:1 at the reaction endpoint.
  • the preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide, i.e., R 6 is replaced by trifluoromethyl from fluorine, to obtain a crude compound 6.
  • the final synthesis step yield is 89%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as that of Example 16, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide, i.e., R 6 is replaced by chlorine from fluorine, to obtain a crude compound 7.
  • the final synthesis step yield is 92%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 35:1.
  • Embodiments 23-29 provide a type of intermediate and an oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is a mesyl group, as follows:
  • steps 1-3 and step 5 of this embodiment are consistent with those of embodiment 16, except that:
  • Step 4 Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl methanesulfonate
  • the crude product can be crystallized to obtain high-quality target product.
  • the preparation method is the same as the preparation method of Example 23, except that the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one, that is, R9 is replaced by trifluoromethyl to chlorine, to obtain a crude compound 2 with a yield of 90%, an ee value of 98.61%, and an N/O-alkylation conversion ratio of 35:1 at the reaction end point.
  • the crude product can be crystallized to obtain high-quality target product.
  • the preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxy-benzamide, i.e., R 6 is replaced by methoxy from fluorine, to obtain a crude compound 3.
  • the final synthesis step yield is 90%, the ee value is 98.39%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as the preparation method of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide, i.e., R2 is replaced by amino to N-methyl, to obtain a crude compound 4.
  • the final synthesis step yield is 90%, the ee value is 99.02%, and the N/O-alkylation conversion ratio at the reaction endpoint is 40:1.
  • the preparation method is the same as that of Example 23, except that the 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, i.e., R2 is replaced by amino by N-(methyl-d3), to obtain a crude compound 5, with a final synthesis step yield of 89%, an ee value of 98.87%, and an N/O-alkylation conversion ratio of 40:1 at the reaction endpoint.
  • the preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide, i.e., R 6 is replaced by trifluoromethyl from fluorine, to obtain a crude compound 6.
  • the final synthesis step yield is 89%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as that of Example 23, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide, i.e., R 6 is replaced by chlorine from fluorine, to obtain a crude compound 7.
  • the final synthesis step yield is 92%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 35:1.
  • Examples 30-36 provide a type of intermediate and an oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is p-nitrobenzenemethylsulfonyl, as follows:
  • steps 1-3 and step 5 of this embodiment are consistent with those of embodiment 16, except that:
  • Step 4 Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl p-nitrobenzenesulfonate
  • the preparation method is the same as the preparation method of Example 30, except that the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one in step 5 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridine-2(1H)-one, that is, R9 is replaced by trifluoromethyl to chlorine, to obtain a crude compound 2 with a yield of 90%, an ee value of 98.61%, and an N/O-alkylation conversion ratio of 35:1 at the reaction end point.
  • the crude product can be crystallized to obtain high-quality target product.
  • the preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxy-benzamide, i.e., R 6 is replaced by methoxy from fluorine, to obtain a crude compound 3.
  • the final synthesis step yield is 90%, the ee value is 98.39%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as the preparation method of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide, i.e., R2 is replaced by amino by N-methyl, to obtain a crude compound 4, with a final synthesis step yield of 90%, an ee value of 99.02%, and an N/O-alkylation conversion ratio of 40:1 at the reaction endpoint.
  • the preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide, i.e., R 6 is replaced by trifluoromethyl from fluorine, to obtain a crude compound 6.
  • the final synthesis step yield is 89%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as that of Example 30, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzamide, i.e., R 6 is replaced by chlorine from fluorine, to obtain a crude compound 7.
  • the final synthesis step yield is 92%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 35:1.
  • Examples 37-43 provide a type of intermediate and an oxopyridine compound of formula (I) synthesized therefrom, wherein R 7 is a benzenesulfonyl group, specifically as follows:
  • steps 1-3 and step 5 of this embodiment are consistent with those of embodiment 16, except that:
  • Step 4 Preparation of (R)-1-((4-amino-3-fluorophenyl)amino)-1-oxobutan-2-yl methanesulfonate
  • the crude product can be crystallized to obtain high-quality target product.
  • the preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-methoxy-benzamide, i.e., R6 is replaced by methoxy from fluorine, to obtain a crude compound 3.
  • the final synthesis step yield is 90%, the ee value is 98.39%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.
  • the preparation method is the same as the preparation method of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide, i.e., R2 is replaced from amino to N-methyl, to obtain a crude compound 4.
  • the final synthesis step yield is 90%, the ee value is 99.02%, and the N/O-alkylation conversion ratio at the reaction endpoint is 40:1.
  • the preparation method is the same as the preparation method of Example 37, except that the 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, that is, R2 is replaced by amino by N-(methyl-d3), to obtain a crude compound 5, with a final synthesis step yield of 89%, an ee value of 98.87%, and an N/O-alkylation conversion ratio of 40:1 at the reaction endpoint.
  • the preparation method is the same as that of Example 37, except that 4-amino-2-fluorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-N-methylbenzamide, i.e., R 6 is replaced by trifluoromethyl from fluorine, to obtain a crude compound 6.
  • the final synthesis step yield is 89%, the ee value is 98.87%, and the N/O-alkylation conversion ratio at the reaction endpoint is 30:1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种制备式(Ⅰ)所示氧代吡啶类化合物的新型路线及其关键中间体。所述新型路线能极大程度降低异构体杂质的产生，提高反应手性的选择性和N/O-烷基化选择性，产率提高，粗品无需再提纯，成本减少，生产周期短，节能环保，适于用于制备治疗和/或预防与FXIa受体相关的疾病的药物，尤其为制备治疗和/或预防脑血管动脉疾病和/或外周动脉疾病的药物提供了新的思路。

Description

氧代吡啶类化合物的新型制备方法及关键中间体和应用 技术领域
本发明属于药物化学及其制备领域，具体涉及到一种氧代吡啶类化合物的新型制备方法及其关键中间体和应用。
背景技术
血栓栓塞病是人类和动物在存活期间，由血管内形成的异常血凝块造成的疾病。凝血因子XI(FXI)是维持内源性途径所必需的一种血浆丝氨酸蛋白酶原，激活后生成活化的凝血因子XIa(FXIa)，在凝血级联反应放大过程中发挥关键作用。在凝血级联反应中，凝血酶可反馈激活FXI，活化的FXIa又促使凝血酶的大量产生，从而使凝血级联反应放大。因此，针对FXIa靶点的药物可阻断内源性途径并抑制凝血级联反应的放大，从而具有抗血栓形成的作用。近年来研究表明，相比直接的FXa抑制剂，抑制FXIa可能会出血风险更小，是抗栓防治的新靶点。其中，拜耳制药的BAY-2433334抗凝血药物因出血少引起了本领域的热烈关注。
关于BAY-2433334抗凝血药物，拜耳制药的化合物专利CN108026072B重点披露了两个氧代吡啶类化合物，分别如下：
该类分子结构复杂，合成难度大，且异构体不容易拆分，放大生产极具挑战。成都施贝康进行了大量结构改造和工艺研究，旨在提供效果更好、更适合工业化放大生产的品种。尤其在如下式(I)所示的抗凝血衍生药物的制备研究过程中发现，采用拜耳制药的化合物专利及其工艺专利方法均难以获得高收率和高纯度原料药。
Rx选自氟、氯或三氟甲基；
R1选自烷基或氘代烷基；
R2、R3、R4、R5独立地选自氢、卤素、烷氧基或卤代烷基。
专利WO 2014/154794和WO 2017/005725披露了该类化合物的合成以2,5-二甲氧基吡啶为起始原料，采用线性合成策略经九步合成目标化合物，不仅路线冗长，而且容易高外消旋化，总收率低，其中粗品合成步收率仅为70％，需要繁琐的后处理和纯化程序，并通过HPLC或手性超临界流体色谱法(SFC)分离异构体，耗时且昂贵，不适用工业化放大生产。
专利CN 111770917 A中公开了聚合式合成策略，粗品合成步如下图所示，分别合成关键中间体式(XVI-CF3)/(XVI-Cl)化合物和式(XIX)化合物后，经缩合反应生成化合物1/化合物2的粗品。总反应经历六步，最长四步，缩短了反应周期，并重点优化了粗品合成步的对映选择性和N/O-烷基化选择性，缩合物在过滤和蒸发溶剂后以85％ee至93％ee的高ee-值获得非晶形式的化合物1/化合物2粗品，此外，以9:1至10:1的N-烷基化:O-烷基化的比率获得优于不想要的O-烷基化的优选的N-烷基化。
虽然该专利的聚合式合成路线整体优于线性合成策略，但是其粗品合成的缩合步仍存在很大局限，如：(1)转化率低，化合物1、化合物2的粗品合成的缩合步收率分别仅为70％、75％，替代性方法收率低至61％(说明书第0095～0097段)，六个步骤的总 收率仅为20％～25％(说明书第0054段)；(2)异构体占比较大，虽然粗品ee值优化至了85％～93％，但仍存在7％～15％的异构体杂质，并需再经过有机溶剂纯化才能获得＞99％ee值的提纯粗品，再通过结晶工艺获得目标晶体；(3)N/O-烷基化选择性不佳，虽然粗品N-烷基化：O-烷基化的比率达到了(9～10)：1，但仍存在10％左右的不理想的O/N转换率，不仅导致转化率低，而且产生较多O-烷基化杂质，加重后续纯化难度和产品质量控制风险。
因此，如何提高氧代吡啶类化合物的抗凝血产品质量、降低杂质控制风险，提高产品转化率和纯度，缩短生产周期，降低成本，更适用于工业化放大生产，是目前该领域亟待解决的技术难题。
发明内容
为了解决现有技术存在的技术问题，本发明公开了一种用于氧代吡啶类化合物的新型制备方法及其关键中间体和应用。
一方面，本发明提供了一种如式(II)所示的中间体或其药学上可接受的盐：
式(II)中：
R1选自TsO-、X、R7O-；Ts为对甲苯磺酰基，X选自F、Cl、Br或I；
R2选自-NHR8、-OC(CH3)3；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基；
R8选自氢、烷基或环烷基；
式(II)不为
进一步地，所述中间体具有式(Ⅲ)、式(Ⅳ)或式(V)所示的结构：
式(III)中，
Ts为对甲苯磺酰基；
R2选自-NHR8，R8选自氢、烷基或环烷基；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
式(Ⅳ)中：
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
X选自F、Cl、Br或I；
式(Ⅴ)中：
R2选自NHR8，R8选自氢、烷基或环烷基；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基。
进一步地，式(III)所示的中间体或其药学上可接受的盐中：
所述R2选自-NHR8，R8选自氢、甲基、乙基、丙基、环丙基、环丙甲基或叔丁基；
和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基。
进一步地，上述式(Ⅳ)所示的中间体或其药学上可接受的盐中：
和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基。
进一步地，式(V)所示的中间体或其药学上可接受的盐中：
R8选自氢、甲基、乙基、丙基、环丙基、环丙甲基或叔丁基；
和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基。
进一步地，上述式(Ⅳ)所示的中间体或其药学上可接受的盐中，所述式(Ⅳ)中 间体包括式(Ⅳ-a)所示的结构：
式(Ⅳ-a)中，R3、R4、R5、R6的定义同上述相应定义。
进一步地，上述任一中间体的结构中的氢可被至少1个氘取代。
进一步地，所述中间体选自如下化合物：

进一步地，本发明提供上述式(II)所示中间体或其药学上可接受的盐的制备方法，所述中间体的合成包括如下步骤：
其中，R1、R2、R3、R4、R5、R6的定义同上述任一相应定义。
进一步地，上述式(II)所示中间体的制备方法包括方法A、方法B或方法C：
方法A：由式(III-a)化合物与对甲苯磺酰氯在碱性条件反应获得式(III)所示中间体，
其中，R2、R3、R4、R5、R6的定义同上述任一相应定义；
方法B：由式(III-a-5)化合物与卤代羧酸反应获得式(IV)所示中间体，
其中，X选自F、Cl、Br或I；R3、R4、R5、R6的定义同上述任一相应定义；
方法C：由式(III-a)化合物在碱性条件下与羟基保护试剂进行酯化反应，得到式(V)所示中间体，
其中，R2、R3、R4、R5、R6、R7的定义同上述任一相应定义。
进一步地，上述方法B的卤代羧酸选自如下结构的溴代羧酸：
进一步地，上述方法C所述的羟基保护试剂包括三氟甲磺酰氯、甲磺酰氯、对硝基苯甲磺酰氯和苯磺酰氯中的任一种。
进一步地，上述方法A和/或方法C包括如下反应条件：
所述碱选自有机碱；优选地，所述有机碱包括三乙胺、吡啶、DMAP、四甲基胍、DBU或DIPEA，更优选为三乙胺或吡啶；
所述合成步骤的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括但不限于四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF、乙腈、二氯甲烷中的任一种或两种以上混合；
任选地，所述合成步骤的式(III-a)化合物与有机碱的摩尔比例为1：0.5～8，优选为1：1～3；
任选地，所述合成步骤的反应温度为0℃～60℃，优选为10～30℃；
任选地，所述合成步骤的反应时间为1～10小时，优选为4～6小时。
进一步地，上述方法B包括如下反应条件：
所述反应条件包括有机碱；优选地，所述有机碱包括三乙胺、吡啶、DBU或DIPEA；
所述反应条件包括有机溶剂；所述有机溶剂包括四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、DMF或乙腈；
所述反应条件包括缩合剂；所述缩合剂包括1-丙基磷酸酐、DCC或EDCI；
所述反应温度为-10℃至10℃反应5-60分钟，再10℃至50℃反应10-600分钟；优 选0℃至5℃反应10分钟，再室温反应30分钟。
进一步地，上述式(III-a)化合物的制备方法包括如下步骤：
将如式(III-a-1)所示的D-2-氨基丁酸式在醋酸环境中与亚硝酸钠进行重氮反应，得到式(III-a-2)化合物；
将式(III-a-2)化合物与式(III-a-3)化合物在碱、酸酐的存在下，进行酰胺缩合反应，得到式(III-a-4)化合物；
将式(III-a-4)化合物进行水解，得到式(III-a)化合物。
进一步地，在制备式(III-a-2)化合物的步骤中，将D-2-氨基丁酸在醋酸中溶解，在0-5℃下加入亚硝酸钠，并于0-5℃下搅拌6-10h；
任选地，D-2-氨基丁酸与亚硝酸钠的摩尔比为1：1.8-2.3，优选为1：2。
进一步地，在由式(III-a-2)化合物制备式(III-a-4)化合物的所述酰胺缩合反应中，包括：将所述式(III-a-2)化合物与所述式(III-a-3)化合物按照摩尔比为1.3-1.8：1混合，于-10-0℃下加入碱和酸酐后，于0-5℃搅拌5-15min，随后室温搅拌反应20-60min。
任选地，所述式(III-a-2)化合物与式(III-a-3)化合物的摩尔比为1.3-1.8：1，优选为1.5：1。
任选地，反应条件为0-5℃下搅拌5-13min后，室温搅拌20-40min。
另一方面，本发明还提供上述任一中间体或其药学上可接受的盐用于标准品、对照品、制备式(I)所示氧代吡啶类化合物、或在制备治疗或预防血管动脉疾病的药物中的应用。
另一方面，本发明还提供一种式(I)所示氧代吡啶类化合物的制备方法，所述制 备方法包括式(Ⅱ)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(I)化合物；
式(II)中：
R1选自TsO-、X、R7O-；Ts为对甲苯磺酰基，X选自F、Cl、Br或I；
R2选自-NHR8、-OC(CH3)3；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基；
R8选自氢、烷基或环烷基；
R9选自氟、氯或三氟甲基；
式(II)不为
进一步地，上述式(I)所示氧代吡啶类化合物的制备方法，其包括以下步骤：所述制备方法包括：
当式(II)中的R2选自-OC(CH3)3时，式(II)所示中间体结构为式(II-a)，所述制备方法包括以下步骤：
其中，
R1选自TsO-、X、R7O-；Ts为对甲苯磺酰基，X选自F、Cl、Br或I；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基；
R8选自氢、烷基或环烷基；
R9选自氟、氯或三氟甲基；
步骤1：式(Ⅱ-a)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(VII)化合物；
步骤2：式(VII)化合物发生水解反应得到式(VIII)化合物；
步骤3：式(VIII)化合物发生缩合反应得到式(I)化合物。
进一步地，上述式(I)所示氧代吡啶类化合物的制备方法，其选自方法一、方法二或方法三；
方法一：所述制备方法包括式(III)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(I)化合物，
其中，
Ts选自对甲苯磺酰基；
R2选自-NHR8，R8选自氢、烷基或环烷基；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R9选自氟、氯或三氟甲基；
方法二：
其中，
R10选自烷基、环烷基或氘代烷基、环烷基；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R9选自氟、氯或三氟甲基；
X选自F、Cl、Br或I；
步骤1：式(IV)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(VII)化合物；
步骤2：式(VII)化合物发生水解反应得到式(VIII)化合物；
步骤3：式(VIII)化合物发生缩合反应得到式(I-a)化合物；
方法三：
将式(V)所示的中间体与式(VI)化合物在碱性条件下进行亲核取代反应，获得式(I)化合物；
其中，
R9选自氟、氯或三氟甲基；
R2选自NHR8，R8选自氢、烷基或环烷基；
R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基。
进一步地，上述方法一中：
R9选自氟、氯或三氟甲基；
Ts选自对甲苯磺酰基；
R2选自NHR8，其中：R8选自氢、甲基、乙基、丙基、环丙基、环丙甲基或叔丁基；
和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基。
进一步地，上述方法一包括如下反应条件：
所述方法一包括碱，所述碱选自有机碱或无机碱；优选地，所述碱包括碳酸钠、碳酸钾、碳酸铯、碳酸氢钾、碳酸氢钠、氢氧化锂、氢氧化钠、氢氧化钾、四甲基胍、三乙胺、DBU、DIPEA、吡啶中的任一种或两种以上混合；更优选地，所述碱包括碳酸钾、碳酸铯、四甲基胍、三乙胺、DBU、DIPEA中的任一种或两种以上混合；
所述方法一的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF中的任一种或两种以上混合；
任选地，所述方法一中式(III)化合物与碱的摩尔比为1：1～3，优选为1：2；
任选地，所述方法一的反应温度为0℃～60℃，优选为20℃～40℃，更优选为26～32℃；
任选地，所述方法一的反应时间为1～10小时，优选为4～6小时。
进一步地，上述方法一包括式(III)化合物的合成步骤：
由式(III-a)化合物与对甲苯磺酰氯在碱性条件反应获得：
其中，R2、R3、R4、R5、R6的定义同上述任一相应定义。
进一步地，上述式(III)化合物的合成步骤包括如下反应条件：
所述碱选自有机碱；优选地，所述有机碱包括三乙胺、吡啶、四甲基胍、DMAP、DBU或DIPEA，更优选为三乙胺或吡啶；
所述合成步骤的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括但不限于四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF、乙腈、二氯甲烷中的任一种或两种以上混合；
任选地，所述合成步骤的式(III-a)化合物与有机碱的摩尔比例为1：0.5～8，优选为1：1～3；
任选地，所述合成步骤的反应温度为0℃～60℃，优选为10～30℃；
任选地，所述合成步骤的反应时间为1～10小时，优选为4～6小时。
进一步地，上述式(III-a)化合物的制备方法包括如下步骤：
其中，R2、R3、R4、R5、R6的定义同上述任一相应定义；
步骤1：式(III-a-2)化合物与式(III-a-3)化合物发生缩合反应获得式(III-a-4)化合物；
步骤2：式(III-a-4)化合物在碱性条件下发生水解反应获得所述式(III-a)化合物。
进一步地，上述制备式(III-a)化合物的步骤1缩合反应包括如下反应条件：
所述缩合反应的条件包括缩合剂，优选地，所述缩合剂包括T3P或DPP-Cl；
所述缩合反应的条件还包括有机碱；优选地，所述有机碱包括三乙胺、吡啶、四甲基胍、DBU或DIPEA；更优选为三乙胺或吡啶；
所述缩合反应的溶剂为有机溶剂；优选地，所述有机溶剂包括四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF、乙腈、乙酸乙酯中的任一种或两种以上混合；
任选地，所述缩合反应的温度为0℃～60℃，优选为10～30℃；
任选地，所述缩合反应的时间为1～10小时，优选为2～4小时。
进一步地，上述制备式(III-a)化合物的步骤2水解反应包括如下反应条件：
所述水解反应包括无机碱；优选地，所述无机碱包括碳酸钾、碳酸钠、碳酸铯、碳酸氢钾或碳酸氢钠；更优选为碳酸钾；
所述水解反应的溶剂为有机溶剂与水的混合溶剂；优选地，所述混合溶剂中有机溶剂与水的体积比为1:1～10，优选为1:1～2；所述混合溶剂包括甲醇与水、乙醇与水、四氢呋喃与水、或DMSO与水，优选甲醇与水；
任选地，所述水解反应的式(III-a-4)化合物与无机碱的摩尔比例为1：1～10，优选为1：1～3；
任选地，所述水解反应的温度为0℃～60℃，优选为10～30℃；
任选地，所述水解反应的时间为1～10小时，优选为5～7小时。
进一步地，方法三中，在由式(V)所示的中间体制备式(I)化合物的所述亲核取代反应中，式(V)化合物与碱的摩尔比为1：1-3，反应温度为0℃-60℃，反应时间为1-10小时。
进一步地，上述方法三包括如下反应条件：
所述方法三包括碱，所述碱选自有机碱或无机碱；优选地，所述碱包括碳酸钠、碳酸钾、碳酸铯、碳酸氢钾、碳酸氢钠、氢氧化锂、氢氧化钠、氢氧化钾、四甲基胍、三乙胺、DBU、DIPEA、吡啶中的任一种或两种以上混合；更优选地，所述碱包括碳酸钾、碳酸铯、四甲基胍、三乙胺、DBU、DIPEA中的任一种或两种以上混合；
所述方法三的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF中的任一种或两种以上混合；
任选地，所述方法三中式(V)化合物与碱的摩尔比为1：1～3，优选为1：2；
任选地，所述方法三的反应温度为0℃～60℃，优选为20℃～40℃，更优选为26℃～32℃；
任选地，所述方法三的反应时间为1～10小时，优选为4～6小时。
进一步优选地，上述方法二中：
R10选自甲基或氘代甲基；
和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基。
进一步地，上述方法二的步骤1包括如下反应条件：
所述反应条件包括碱，所述碱选自有机碱或无机碱；优选地，所述碱包括四甲基胍、三乙胺、DBU、DIPEA、吡啶、碳酸钠、碳酸钾、碳酸铯、碳酸氢钾、碳酸氢钠、氢氧化锂、氢氧化钠、氢氧化钾中的任一种或两种以上混合；更优选地，所述碱包括四甲基胍、三乙胺、DBU、DIPEA、碳酸钾、碳酸铯中的任一种或两种以上混合；
所述反应条件的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括异丙醇、乙醇、丙酮、DMF、四氢呋喃、2-甲基四氢呋喃、二氧六环中的任一种或两种以上混合；
任选地，所述步骤1中式(IV)化合物与碱的摩尔比为1：1～3，优选为1：2；
任选地，所述步骤1的反应温度为0℃～60℃，优选为20℃～40℃，更优选为26℃～32℃；
任选地，所述步骤1的反应时间为1～10小时，优选为4～6小时。
进一步地，上述方法二的步骤2包括如下反应条件：
所述反应条件包括酸，所述酸选自有机酸或无机酸；优选地，所述酸包括盐酸、三氟乙酸、硫酸、磷酸、醋酸、氢溴酸中的任一种或两种以上混合；更优选地，所述碱包括盐酸、三氟乙酸、硫酸中的任一种或两种以上混合；
所述反应条件的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括异四氢呋喃、2-甲基四氢呋喃、二氧六环、丙酮、甲醇、乙醇、异丙醇、DMF中的任一种或两种以上混合；
任选地，所述步骤2中式(VII)化合物与酸的摩尔比为1：30，优选为10：20；
任选地，所述步骤2的反应温度为-20℃～40℃，优选为-10℃～10℃，更优选为-5℃～5℃；
任选地，所述步骤2的反应时间为1～8小时，优选为2～4小时。
进一步地，上述方法二的步骤3包括如下反应条件：
所述反应条件包括碱，所述碱选自有机碱或无机碱；优选地，所述碱包括三乙胺、 DBU、DIPEA、四甲基胍、吡啶、碳酸钠、碳酸钾、碳酸铯、碳酸氢钾、碳酸氢钠、氢氧化锂、氢氧化钠、氢氧化钾中的任一种或两种以上混合；更优选地，所述碱包括三乙胺、DBU、DIPEA、四甲基胍、碳酸钾、碳酸铯中的任一种或两种以上混合；
所述反应条件包括缩合剂和配体；优选地，所述缩合剂及配体包括EDCI，HOBT、HATU、HBTU、DCC、CDI、T3P、DPP-Cl、HCTU、TBTU、DMAP中的任一种或两种以上混合；更优选地，所述碱包括EDCI，HOBT、HATU、HBTU中的任一种或两种以上混合；
所述反应条件的反应溶剂选自有机溶剂；优选地，所述有机溶剂包括异四氢呋喃、DCM、2-甲基四氢呋喃、二氧六环、乙腈、丙酮、乙醇、异丙醇、DMF、DMAC中的任一种或两种以上混合；
任选地，所述步骤3中式(VIII)化合物与碱的摩尔比为1：1～5，优选为1：3；
任选地，所述步骤3的反应温度为0℃～60℃，优选为20℃～40℃，更优选为26℃～32℃；
任选地，所述步骤3的反应时间为1～10小时，优选为4～6小时。
进一步地，上述方法一、方法二、方法三所得式(Ⅰ)所示氧代吡啶类化合物至少具备如下任一特征：(1)对映选择性的ee值为98％以上，优选为99％以上；(2)N/O-烷基化选择性比例达到30～40:1以上；(3)单步收率85％以上，优选90％以上；(4)生产周期短，无需复杂的后处理，适合工业化放大生产；(5)产品纯度98％以上。
进一步地，上述方法一、方法二和方法三所得式(Ⅰ)所示氧代吡啶类化合物可以采用结晶方法，如专利CN111770917A中成晶方法获得高品质甚至高于该专利中晶体品质的晶体产物。
术语解释：
“烷基”指低级烷基，具体为含有C1-C16饱和支链或直链烷基。“烷基羰基”中的烷基部分作相同解释。
“环烷基”指含C3-C10环烷基，优选C3-C6环烷基。
“卤素”指氟、氯、溴、碘。
“以上”、“以下”包含本数。
DMAP：4-二甲氨基吡啶。
DEAD：偶氮二甲酸二乙酯。
DIAD：偶氮二甲酸二异丙酯。
TMAD：偶氮二甲酰胺。
DTBAD：偶氮二甲酸二叔丁酯。
ADDP：偶氮二甲酰二哌啶。
DBU：1,8-二氮杂二环十一碳-7-烯。
DIPEA：异丙基乙胺。
T3P：1-丙基磷酸酐。
DPP-Cl：二苯基次膦酰氯。
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
HOBT:1-羟基苯并三唑。
HBTU:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐。
HATU:2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
DCC:N,N'-二环己基碳二亚胺。
DMF:N,N-二甲基甲酰胺。
相对于现有技术，本发明具有以下优势：
1、通过本发明的新制备路线合成式(Ⅰ)化合物，可以提高总转化率以及对映选择性和N/O-烷基化选择性有绝对优势，特别是在用更温和的碱和更易得的溶剂选择上，可以获得N/O比例达到30～40:1以上的转化率，O-烷基化杂质较少，而现有技术中，粗品中的N-烷基化：O-烷基化的比率为(9～10)：1，含有较多的O-烷基化杂质，而这种异构化杂质的纯化是极其困难的。对比可见，本申请的合成路线，后续纯化难度低，有利于后续结晶收率，提高结晶精制过程控制的稳定性。
2、更令人惊喜的是，通过本发明制备式(Ⅰ)化合物的过程，可获得更高非晶型形式的ee-值的式(Ⅰ)，在萃取和蒸发溶剂后以98％ee以上、甚至99％ee以上的ee-值获得非晶形式的式(Ⅰ)的化合物。而现有技术中ee值最高仅能优化到85～93％，仍存在7～15％的异构体杂质。由此可见，通过本申请的合成路线，由于所得粗品中异构体杂质的含量仅存在1～2％，无需通过复杂的手性异构体纯化过程，可直接获得＞98％ee值的粗品，再通过结晶工艺即可获得目标晶体，极大的简化了除杂步骤，避免复杂的后处理，节约成本，并有利于工业化放大生产。
3、单步缩合反应制备粗品的收率提高到85％～98％以上，路线总收率60～70％以上，而现有技术中的总收率仅为20～25％。因此，该合成路线的转化率高，生产周期大幅缩短，避免复杂的后处理，节约成本，并有利于工业化放大生产。
具体实施方式
以下将结合实施例和试验例对本发明作进一步的详细描述，本发明的实施例和试验例仅用于说明本发明的技术方案，并非对本发明的限制，凡依照本发明公开的内容所作的任何本领域的等同置换，均属于本发明的保护范围。
本发明的化合物、其立体异构体或药学上可接受的盐均可选择实施例的合成路线进行制备，并根据取代基或成盐的需要，对反应原料和反应溶剂的常规条件加以调整，这些都是本领域的技术人员在本发明公开内容的基础上可以实现的。此外，本发明的柱层析在没有特别说明的情况下指硅胶柱层析，洗脱溶剂在没有特别说明的情况下可以结合反应溶剂与本领域技术人员的公知常识或者常用手段确定单一或者混合洗脱溶剂。
化合物的结构是核磁共振(1H NMR)或液质联用(LC-MS)来确定的。
液质联用仪(LC-MS)为安捷伦G6120B(与液相Agilent 1260配用)；核磁共振仪(1H NMR)为Bruker AVANCE-400或Bruker AVANCE-800，核磁共振(1H NMR)位移(δ)以百万分之一(ppm)的单位给出，测定溶剂为DMSO，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。
本发明的术语“室温”是指温度处于10～30℃之间。
本发明实施例所用混合溶剂没有特别说明的情况下指体积比。
本发明术语“20ml乙酸乙酯：正庚烷1:2溶剂”指20ml混合溶剂(乙酸乙酯：正庚烷1:2，v/v)”。类似写法做类似解释。
第一部分实施例：实施例1-7
实施例1：(S)-2-氟-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧吡啶-1(2H)-基)丁酰胺基)苯甲酰胺(化合物1)的制备：
步骤1：(R)-1-((4-氨基甲酰基-3-氟苯基)氨基)-1-氧代丁-2-基乙酸酯的制备
取1.03g(7.05mmol)(R)-2-乙酰氧基丁酸，溶于20ml四氢呋喃中，加入720mg(4.70mmol)4-氨基-2-氯苯甲酰胺，冷却至0℃以下，加入1.12g(14.1mmol)吡啶，然后滴加用10ml四氢呋喃稀释的4.50g(14.1mmol)1-丙基磷酸酐(50％乙酸乙酯溶液)，加毕，0～5℃搅拌10分钟，室温搅拌反应30分钟。反应完成，加入水终止反应，加入EA萃取，有机相依次用5％柠檬酸洗，饱和碳酸氢钠洗，水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品。向粗品中加入10ml乙酸乙酯：正庚烷1:1溶剂室温搅拌2小时，过滤，正庚烷洗涤滤饼，滤饼真空干燥得到白色固体，收率86.1％，ee-值99.56％，纯度96.20％。
ESI-MS:m/z＝283.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.76(s,1H),8.08–7.77(m,1H),7.92–7.88(m,1H),7.76(s,2H),7.60-7.56(m,1H),4.56(m,1H),2.25(s,3H),1.98–1.88(m,2H),0.88(t,3H)。
步骤2：(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺的制备
取1.5g(5.32mmol)(R)-1-((4-氨基甲酰基-3-氟苯基)氨基)-1-氧代丁-2-基乙酸酯，溶于10ml甲醇和15ml的水混合溶剂中，加入2.20g(15.96mmol)碳酸钾，室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，体系析出大量白色固体，继续加入50ml水后搅拌打浆1h，过滤得到白色固体，滤饼真空干燥得到白色固体，收率87.3％，ee-值98.87％，纯度96.82％。
ESI-MS:m/z＝241.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),8.08–7.77(m,1H),7.92–7.88(m,1H),7.78(s,2H),7.60-7.56(m,1H),5.52(s,1H),4.56(m,1H),2.01–1.88(m,2H),0.88(t,3H)。
步骤3：(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基对甲苯磺酸酯的制备
取860mg(3.58mmol)(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺，溶于10m二氯甲烷中，加入723mg(7.16mmol)三乙胺和88mg(0.72mmol)DMAP，最后0℃左右滴加3.95mmol对甲基苯磺酸的5m二氯甲烷溶液，保持室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，有机相用二氯甲烷萃取干燥后浓缩得到粗品，用约8ml乙酸乙酯溶解后冷却析晶得到淡黄色固体，收率86.6％，ee-值98.52％，纯度95.65％。
ESI-MS:m/z＝395.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),8.08-7.97(m,1H),7.96(s,2H),7.78-7.75(m,3H),7.60-7.56(m,1H),7.50-7.45(m,2H),4.56-4.52(m,1H),2.43(s,3H),2.01-1.88(m,2H),0.88(t,3H)。
步骤4：化合物1的制备
取200mg(0.539mmol)4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，加入25ml单口瓶，以5ml二氧六环溶解搅拌，加入150mg(1.08mmol)碳酸钾，以及62mg(0.539mmol)四甲基胍，搅拌5分钟，加入0.648mmol(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基对甲苯磺酸酯，升温到35℃搅拌反应，直至TLC监测反应完成，N/O-烷基化转化比例为40：1，加入饱和氯化铵终止反应，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品，收率95.8％，ee-值99.24％。
ESI-MS:m/z＝593.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H)。
粗品按照专利CN111770917A中成晶方法可以获得高品质目标产物。
实施例2：化合物2的制备
制备方法同实施例1的制备方法，将步骤4的4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮替换为4-(5-氯-2-(4-氯-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，即可制得标题化合物2粗品，收率90％，ee-值98.61％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝559.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H)。
粗品按照专利CN111770917A中成晶方法可以获得高品质目标产物。
实施例3：化合物3的制备
制备方法同实施例1的制备方法，将步骤1的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-甲氧基-苯甲酰胺，即可制得标题化合物3粗品，最后合成步收率90％，ee-值98.39％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝605.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(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)。
实施例4：化合物4的制备
制备方法同实施例1的制备方法，将步骤1的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-甲基苯甲酰胺，即可制得标题化合物4粗品，最后合成步收率90％，ee-值99.02％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例5：化合物5的制备
制备方法同实施例1的制备方法，将步骤1的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-(甲基-d3)苯甲酰胺，即可制得标题化合物5粗品，最后合成步收率89％，ee-值98.87％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝610.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),9.14(d,J＝1.1Hz,1H),8.06(d,J＝3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J＝8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J＝7.1Hz,2H),0.78(t,J＝7.2Hz,3H)。
实施例6：化合物6的制备
制备方法同实施例1的制备方法，将步骤1的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-三氟甲基-苯甲酰胺，即可制得标题化合物6粗品，最后合成步收率89％，ee-值98.87％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝643.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.51(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)。
实施例7：化合物7的制备
制备方法同实施例1的制备方法，将步骤1的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氯-苯甲酰胺，即可制得标题化合物7粗品，最后合成步收率92％，ee-值98.87％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H)。
以上实施例所包含的中间体及其核磁和质谱数据如下表1所示：
表1

上述中间体的制备采用实施例1相同的制备思路，也正如各实施例1-实施例7所记载，即各实施例1-实施例7制备路线的步骤3所得产物。各中间体制备方法总结如下：
由式(III-a)化合物与对甲苯磺酰氯在碱性条件反应获得：
其中，R2、R3、R4、R5、R6的定义同发明内容中任一相应定义。
可以理解，上述各实施例1-实施例7所使用到的具体式(III-a-3)化合物，本领域技术人员可以根据本领域常规技术手段容易获得，在此不再赘述。
第二部分实施例：实施例8-15
实施例8：(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟-N-甲基苯甲酰胺(化合物4)的制备：
步骤1：(R)-4-(2-溴丁酰胺)-2-氟苯甲酸叔丁酯的制备
取441mg(2.64mmol)(R)-2-溴-3-丙酸，溶于4ml四氢呋喃中，加入372mg(1.76mmol)4-氨基-2-氟苯甲酸叔丁酯，冷却至0℃以下，加入654mg(8.27mmol)吡啶，然后滴加用2ml四氢呋喃稀释的2.24g(3.52mmol)1-丙基磷酸酐(50％乙酸乙酯溶液)，加毕，0～5℃搅拌10分钟，室温搅拌反应30分钟。反应完成，加入水终止反应，加入EA萃取，有机相依次用5％柠檬酸洗，饱和碳酸氢钠洗，水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到608mg粗品。向粗品中加入5ml乙酸乙酯室温搅拌2小时，过滤，乙酸乙酯洗涤滤饼，滤饼真空干燥得到白色固体，收率74.0％，纯度97.55％。
ESI-MS:m/z＝360.1(M+H)+。
步骤2：(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟苯甲酸叔丁酯的制备
取2.0g(5.39mmol)4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，50ml异丙醇，20ml丙酮混合，加入1.87mg(16.24mmol)四甲基胍，搅拌5分钟，加入2.33mg(6.48mmol)(R)-4-(2-溴丁酰胺)-2-氟苯甲酸叔丁酯，室温搅拌反应过夜。反应完成，加入饱和氯化铵终止反应，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到4.60mg粗品。柱层析，洗脱剂(乙酸乙酯：石油醚＝1:2)，收集产物得到2.58g白色固体。收率73.7％，纯度为97.82％。
ESI-MS:m/z＝650.2(M+H)+。
步骤3：(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟苯甲酸的制备
取2.58g(3.97mmol)(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟苯甲酸叔丁酯用25mL乙腈溶解，降温到0℃左右内温监控，缓慢滴加25mL浓盐酸，TLC检测0.5h后反应完全，加入水终止反应，加入EA萃取，有机相依次用，饱和碳酸氢钠洗，水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到2.36g粗品。向粗品中加入15ml乙酸乙酯充分搅拌溶解，过滤除去固体，母液浓缩后再用20ml乙酸乙酯：正庚烷1:2溶剂室温搅拌2小时，过滤，正庚烷洗涤滤饼，滤饼真空干燥得到2.06g白色固体，收率87.3％，ee-值99.36％，纯度98.20％。
ESI-MS:m/z＝594.1(M+H)+。
步骤4：(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟-N-甲基苯甲酰胺的制备
取1.0g(1.675mmol)(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟苯甲酸用10mL DMAC溶解，加入226mg(3.35mmol)甲胺盐酸盐，953mg(2.52mmol)HBTU，降温到5℃左右内温监控，缓慢滴加1.1g(8.38mmol)DIPEA，保持5-10℃反应1h后，TLC检测反应完全，缓慢加入30ml水终止反应，体系逐渐析出灰白色固体颗粒，搅拌打浆1h后，过滤得到固体，鼓风干燥后得到1.06g粗品。再用20ml乙酸乙酯：正庚烷1:2溶剂室温 搅拌2小时，过滤，正庚烷洗涤滤饼，滤饼真空干燥得到860mg白色固体，收率84.3％，ee-值99.27％，纯度98.32％。
ESI-MS:m/z＝607.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例9：(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟-N-(甲基-d3)苯甲酰胺(化合物5)的制备
制备方法同实施例8的制备方法，将步骤4的甲胺盐酸盐替换成氘代甲胺盐酸盐，即可制得标题化合物5，收率87％，ee-值99.22％，纯度为98.02％。
ESI-MS:m/z＝610.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),9.14(d,J＝1.1Hz,1H),8.06(d,J＝3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J＝8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J＝7.1Hz,2H),0.78(t,J＝7.2Hz,3H)。
实施例10：化合物8的制备
制备方法同实施例8的制备方法，将步骤1的4-氨基-2-氟苯甲酸叔丁酯替换成4-氨基-2-(三氟甲基)苯甲酸叔丁酯，即可制得标题化合物8，ee-值99.17％，纯度为97.62％。
ESI-MS:m/z＝657.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.18–8.12(m,1H),7.98–7.90(m,2H),7.85(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.53(t,J＝7.8Hz,1H),3.26(s,3H),2.77(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例11：化合物9的制备
制备方法同实施例8的制备方法，将步骤1的4-氨基-2-氟苯甲酸叔丁酯替换成4-氨基-2-(三氟甲基)苯甲酸叔丁酯，将步骤4的甲胺盐酸盐替换成氘代甲胺盐酸盐即可制得标题化合物9，ee-值98.92％，纯度为98.50％。
ESI-MS:m/z＝660.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.15(d,J＝1.1Hz,1H),8.19–8.12(m,1H),7.98–7.91(m,2H),7.85(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.53(t,J＝7.8Hz,1H),3.26(s,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例12：化合物10的制备
制备方法同实施例8的制备方法，将步骤1的4-氨基-2-氟苯甲酸叔丁酯替换成4-氨基-2-氯苯甲酸叔丁酯，即可制得标题化合物10，ee-值98.89％，纯度为98.49％。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.16–8.10(m,1H),7.96–7.88(m,2H),7.84(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.26(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例13：化合物11的制备
制备方法同实施例8的制备方法，将步骤1的4-氨基-2-氟苯甲酸叔丁酯替换成4-氨基-2-氯苯甲酸叔丁酯，将步骤4的甲胺盐酸盐替换成氘代甲胺盐酸盐，即可制得标题化合物11，ee-值98.96％，纯度为98.32％。
ESI-MS:m/z＝626.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.81(s,1H),9.16(d,J＝1.1Hz,1H),8.16–8.10(m,1H),7.96–7.89(m,2H),7.84(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.26(s,3H),2.18–2.06(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例14：化合物12的制备
制备方法同实施例8的制备方法，将步骤1的4-氨基-2-氟苯甲酸叔丁酯替换成4-氨基-2-(甲氧基)苯甲酸叔丁酯，即可制得标题化合物12，ee-值98.68％，纯度为98.65％。
ESI-MS:m/z＝619.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.86(s,3H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例15：化合物13的制备
制备方法同实施例8的制备方法，将步骤1的4-氨基-2-氟苯甲酸叔丁酯替换成4-氨基-2-(甲氧基)苯甲酸叔丁酯，将步骤4的甲胺盐酸盐替换成氘代甲胺盐酸盐，即可制得标题化合物13，ee-值98.68％，纯度为98.95％。
ESI-MS:m/z＝622.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.81(s,1H),9.17(d,J＝1.1Hz,1H),8.13–8.08(m,1H),7.89–7.81(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.53(t,J＝7.8Hz,1H),3.86(s,3H),3.25(s,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
对比例1：(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟-N-甲基苯甲酰胺(化合物4)的制备：
按照专利CN 111770917 A中公开的合成策略，合成化合物4，最终精制可制得标题化合物4，其ee-值82.12％，纯度为96.26％。由于化合物4的结晶过程不能形成对映异构体的协同晶体，未能在精致过程中除去化合物4的手性异构体(R构型化合物4)。
而通过本专利提供的路线，如实施例8，通过对结构式(VIII)的化学拆分的方法得到ee-值高于98％的中间体式(VIII)，从而达到化合物4的高ee值及高化学纯度的目标API。
以上实施例8-14的化合物按实施例方法所产生的中间体的核磁及质谱数据如下表2所示：
表2
第三部分实施例：实施例16-43
第三部分第一组实施例
实施例16-22，提供一种类型的中间体及其由其合成的式(I)所示氧代吡啶类化合物，其中R7为三氟甲磺酰基的，具体合成路线如下：
实施例16：化合物1的制备：
步骤1：(R)-2-乙酰氧基丁酸
取5.0g(48.49mmol)D-2-氨基丁酸用20g(mmol)醋酸溶解，冷却至5℃以下，分批加入6.7g(97.09mmol)亚硝酸钠，控制温度在0～5℃以下，约30分钟加料完毕，0～5℃搅拌反应液6-10h；随后，反应液加入3V体积的水后，用乙酸乙酯萃取三次，合并有机相；有机相再用大量水洗，再用碳酸氢钠溶液将醋酸完全洗掉后，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到7.5g油状物，无需纯化直接用于下一步。
ESI-MS:m/z＝147.1(M+H)+。
步骤2：(R)-1-((4-氨基甲酰基-3-氟苯基)氨基)-1-氧代丁-2-基乙酸酯的制备
取1.03g(7.05mmol)(R)-2-乙酰氧基丁酸，溶于20ml四氢呋喃中，加入720mg(4.70mmol)4-氨基-2-氟苯甲酰胺，冷却至0℃以下，加入1.12g(14.1mmol)吡啶，然后滴加用10ml四氢呋喃稀释的4.50g(14.1mmol)1-丙基磷酸酐(50％乙酸乙酯溶液)，加毕，0～5℃搅拌10分钟，室温搅拌反应30分钟。反应完成，加入水终止反应，加入 EA萃取，有机相依次用5％柠檬酸洗，饱和碳酸氢钠洗，水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品。向粗品中加入10ml的有机溶剂混合液(乙酸乙酯：正庚烷按照体积比1:1混合)室温搅拌2小时，过滤，正庚烷洗涤滤饼，滤饼真空干燥得到白色固体，收率76.1％，ee值99.56％，纯度96.20％。
ESI-MS:m/z＝283.1(M+H)+。
步骤3：(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺的制备
取1.5g(5.32mmol)(R)-1-((4-氨基甲酰基-3-氟苯基)氨基)-1-氧代丁-2-基乙酸酯，溶于10ml甲醇和15ml的水混合溶剂中，加入2.20g(15.96mmol)碳酸钾，室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，体系析出大量白色固体，继续加入50ml水后搅拌打浆1h，过滤得到白色固体，滤饼真空干燥得到白色固体，收率87.3％，ee值98.87％，纯度96.82％。
ESI-MS:m/z＝241.1(M+H)+。
步骤4：(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基三氟甲磺酸酯的制备
取860mg(3.58mmol)(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺，溶于10m二氯甲烷中，加入723mg(7.16mmol)三乙胺和88mg(0.72mmol)4-二甲氨基吡啶(DMAP)，最后0℃左右滴加678mg(3.95mmol)三氟甲磺酸5ml二氯甲烷溶液，保持室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，有机相用二氯甲烷萃取干燥后浓缩得到粗品，用约8ml乙酸乙酯溶解后冷却析晶得到淡黄色固体，收率86.6％，ee值98.52％，纯度95.65％。
ESI-MS:m/z＝373.1(M+H)+。
步骤5：化合物1的制备
取200mg(0.539mmol)4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，加入25ml单口瓶，以5ml二氧六环溶解搅拌，加入150mg(1.08mmol)碳酸钾，以及62mg(0.539mmol)四甲基胍，搅拌5分钟，加入0.648mmol(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基三氟甲磺酸酯，升温到35℃搅拌反应，直至TLC监测反应完成，N/O-烷基化转化比例为40：1，加入饱和氯化铵终止反应，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品，收率95.8％，ee值98.51％。
ESI-MS:m/z＝593.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s, 3H),2.18–2.00(m,2H),0.78(t,3H)。
将粗品进行结晶处理，即可获得高品质目标产物。
实施例17：化合物2的制备
制备方法同实施例16的制备方法，将步骤5的4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮替换为4-(5-氯-2-(4-氯-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，即将R9由三氟甲基替换成氯，可制得化合物2粗品，收率90％，ee值98.61％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝559.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H)。
将粗品进行结晶处理，即可获得高品质目标产物。
实施例18：化合物3的制备
制备方法同实施例16的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-甲氧基-苯甲酰胺，即将R6由氟替换成甲氧基，可制得化合物3粗品，最后合成步收率90％，ee值98.39％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝605.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(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)。
实施例19：化合物4的制备
制备方法同实施例16的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-甲基苯甲酰胺，即将R2由氨基替换成N-甲基，可制得化合物4粗品，最后合成步收率90％，ee值99.02％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例20：化合物5的制备
制备方法同实施例16的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-(甲基-d3)苯甲酰胺，即将R2由氨基替换成N-(甲基-d3)，可制得化合物5粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝610.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),9.14(d,J＝1.1Hz,1H),8.06(d,J＝3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J＝8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J＝7.1Hz,2H),0.78(t,J＝7.2Hz,3H)。
实施例21：化合物6的制备
制备方法同实施例16的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-三氟甲基-N-甲基苯甲酰胺，即将R6由氟替换成三氟甲基，可制得化合物6粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝643.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.51(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)。
实施例22：化合物7的制备
制备方法同实施例16的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氯-苯甲酰胺，即将R6由氟替换成氯，可制得化合物7粗品，最后合成步收率92％，ee值98.87％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H)。
本实施例16-22所包含的中间体及其核磁和质谱数据如下表3所示：
表3.实施例16-22所涉及的中间体及其核磁、质谱数据

第三部分第二组实施例
实施例23-29，提供一种类型的中间体及其由其合成的式(I)所示氧代吡啶类化合物，其中R7为甲磺酰基，具体如下：
实施例23：(S)-2-氟-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧吡啶-1(2H)-基)丁酰胺基)苯甲酰胺(化合物1)的制备：
其中，本实施例的步骤1-3以及步骤5与实施例16一致，不同之处在于：
步骤4：(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基甲磺酸酯的制备
取860mg(3.58mmol)(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺，溶于10m二氯甲烷中，加入723mg(7.16mmol)三乙胺和88mg(0.72mmol)DMAP，最后0℃左右滴加3.95mmol甲磺酸的5m二氯甲烷溶液，保持室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，有机相用二氯甲烷萃取干燥后浓缩得到粗品，用约8ml乙酸乙酯溶解后冷却析晶得到淡黄色固体，收率86.6％，ee值98.52％，纯度95.65％。
ESI-MS:m/z＝319.1(M+H)+。
步骤5：化合物1的制备
取200mg(0.539mmol)4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，加入25ml单口瓶，以5ml二氧六环溶解搅拌，加入150mg(1.08mmol)碳酸钾，以及62mg(0.539mmol)四甲基胍，搅拌5分钟，加入0.648mmol(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基甲磺酸酯，升温到35℃搅拌反应，直至TLC监测反应完成，N/O-烷基化转化比例为40：1，加入饱和氯化铵终止反应，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品，收率95.8％，ee值99.78％。
ESI-MS:m/z＝593.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H)。
将粗品进行结晶处理，即可获得高品质目标产物。
实施例24：化合物2的制备
制备方法同实施例23的制备方法，将步骤5的4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮替换为4-(5-氯-2-(4-氯-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，即将R9由三氟甲基替换成氯，可制得化合物2粗品，收率90％，ee值98.61％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝559.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).
将粗品进行结晶处理，即可获得高品质目标产物。
实施例25：化合物3的制备
制备方法同实施例23的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-甲氧基-苯甲酰胺，即将R6由氟替换成甲氧基，可制得化合物3粗品，最后合成步收率90％，ee值98.39％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝605.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(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)。
实施例26：化合物4的制备
制备方法同实施例23的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-甲基苯甲酰胺，即将R2由氨基替换成N-甲基，可制得化合物4粗品，最后合成步收率90％，ee值99.02％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例27：化合物5的制备
制备方法同实施例23的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-(甲基-d3)苯甲酰胺，即将R2由氨基替换成N-(甲基-d3)，可制得化合物5粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝610.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),9.14(d,J＝1.1Hz,1H),8.06(d,J＝3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J＝8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J＝7.1Hz,2H),0.78(t,J＝7.2Hz,3H)。
实施例28：化合物6的制备
制备方法同实施例23的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-三氟甲基-N-甲基苯甲酰胺，即将R6由氟替换成三氟甲基，可制得化合物6粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝643.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.51(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)。
实施例29：化合物7的制备
制备方法同实施例23的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氯-苯甲酰胺，即将R6由氟替换成氯，可制得化合物7粗品，最后合成步收率92％，ee值98.87％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H)。
本实施例23-29所包含的中间体及其核磁和质谱数据如表4所示：
表4.实施例23-29所涉及的中间体及其核磁、质谱数据

第三部分第三组实施例
实施例30-36，提供一种类型的中间体及其由其合成的式(I)所示氧代吡啶类化合物，其中R7为对硝基苯甲磺酰基，具体如下：
实施例30：(S)-2-氟-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧吡啶-1(2H)-基)丁酰胺基)苯甲酰胺(化合物1)的制备：
其中，本实施例的步骤1-3以及步骤5与实施例16一致，不同之处在于：
步骤4：(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基对硝基苯磺酸酯的制备
取860mg(3.58mmol)(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺，溶于10m二氯甲烷中，加入723mg(7.16mmol)三乙胺和88mg(0.72mmol)DMAP，最后0℃左右滴加802mg(3.95mmol)对硝基苯甲磺酸的5ml二氯甲烷溶液，保持室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，有机相用二氯甲烷萃取干燥后浓缩得到粗品，用约8ml乙酸乙酯溶解后冷却析晶得到淡黄色固体，收率86.6％，ee值98.52％，纯度95.65％。
ESI-MS:m/z＝426.1(M+H)+。
步骤5：化合物1的制备
取200mg(0.539mmol)4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，加入25ml单口瓶，以5ml二氧六环溶解搅拌，加入150mg(1.08mmol)碳酸钾，以及62mg(0.539mmol)四甲基胍，搅拌5分钟，加入0.648mmol(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基对硝基苯磺酸酯，升温到35℃搅拌反应，直至TLC监测反应完成，N/O-烷基化转化比例为40：1，加入饱和氯化铵终止反应，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品，收率95.8％，ee值98.51％。
ESI-MS:m/z＝593.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H)。
将粗品进行结晶处理，即可获得高品质目标产物。
实施例31：化合物2的制备
制备方法同实施例30的制备方法，将步骤5的4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮替换为4-(5-氯-2-(4-氯-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，即将R9由三氟甲基替换成氯，可制得化合物2粗品，收率90％，ee值98.61％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝559.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H)。
将粗品进行结晶处理，即可获得高品质目标产物。
实施例32：化合物3的制备
制备方法同实施例30的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-甲氧基-苯甲酰胺，即将R6由氟替换成甲氧基，可制得化合物3粗品，最后合成步收率90％，ee值98.39％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝605.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(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)。
实施例33：化合物4的制备
制备方法同实施例30的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-甲基苯甲酰胺，即将R2由氨基替换成N-甲基，可制得化合物4粗品，最后合成步收率90％，ee值99.02％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例34：化合物5的制备
制备方法同实施例30的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-(甲基-d3)苯甲酰胺，即将R2由氨基替换成N-(甲基-d3)，可制得化合物5粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝610.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),9.14(d,J＝1.1Hz,1H),8.06(d,J＝3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J＝8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J＝7.1Hz,2H),0.78(t,J＝7.2Hz,3H)。
实施例35：化合物6的制备
制备方法同实施例30的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-三氟甲基-N-甲基苯甲酰胺，即将R6由氟替换成三氟甲基，可制得化合物6粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝643.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.51(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)。
实施例36：化合物7的制备
制备方法同实施例30的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氯-苯甲酰胺，即将R6由氟替换成氯，可制得化合物7粗品，最后合成步收率92％，ee值98.87％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H)。
本实施例30-36所包含的中间体及其核磁和质谱数据如表5所示：
表5.实施例30-36所涉及的中间体及其核磁、质谱数据

第三部分第四组实施例
实施例37-43，提供一种类型的中间体及其由其合成的式(I)所示氧代吡啶类化合物，其中R7为苯磺酰基，具体如下：
实施例37：(S)-2-氟-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧吡啶-1(2H)-基)丁酰胺基)苯甲酰胺(化合物1)的制备：
其中，本实施例的步骤1-3以及步骤5与实施例16一致，不同之处在于：
步骤4：(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基甲磺酸酯的制备
取860mg(3.58mmol)(R)-2-氟-4-(2-羟基丁酰胺)苯甲酰胺，溶于10m二氯甲烷中，加入723mg(7.16mmol)三乙胺和88mg(0.72mmol)DMAP，最后0℃左右滴加625mg(3.95mmol)苯磺酸的5ml二氯甲烷溶液，保持室温搅拌反应过夜。TLC监测反应完成后，缓慢加入20ml水终止反应，有机相用二氯甲烷萃取干燥后浓缩得到粗品，用约8ml乙酸乙酯溶解后冷却析晶得到淡黄色固体，收率86.6％，ee值98.52％，纯度95.65％。
ESI-MS:m/z＝381.1(M+H)+。
步骤5：化合物1的制备
取200mg(0.539mmol)4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，加入25ml单口瓶，以5ml二氧六环溶解搅拌，加入150mg(1.08mmol)碳酸钾，以及62mg(0.539mmol)四甲基胍，搅拌5分钟，加入246mg(0.648mmol)(R)-1-((4-氨基-3-氟苯基)氨基)-1-氧代丁-2-基苯磺酸酯，升温到35℃搅拌反应，直至TLC监测反应完成，N/O-烷基化转化比例为40：1，加入饱和氯化铵终止反应，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂得到粗品，收率92.8％，ee值98.51％。
ESI-MS:m/z＝593.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.78(s,1H),9.14(s,1H),7.88–7.77(m,3H),7.72–7.61(m,2H),7.55(d,2H),7.37(dd,1H),7.13(s,1H),6.54(s,1H),5.52(dd,1H),3.25(s,3H),2.18–2.00(m,2H),0.78(t,3H)。
将粗品进行结晶处理，即可获得高品质目标产物。
实施例38：化合物2的制备
制备方法同实施例37的制备方法，将步骤5的4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮替换为4-(5-氯-2-(4-氯-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基吡啶-2(1H)-酮，即将R9由三氟甲基替换成氯，可制得化合物2粗品，收率90％，ee值98.61％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝559.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.15(d,1H),7.98–7.72(m,5H),7.59–7.28(m,3H),7.15(s,1H),6.52(s,1H),5.52(dd 1H),3.28(s,3H),2.15-2.03(m,2H),0.78(t,3H).
将粗品进行结晶处理，即可获得高品质目标产物。
实施例39：化合物3的制备
制备方法同实施例37的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-甲氧基-苯甲酰胺，即将R6由氟替换成甲氧基，可制得化合物3粗品，最后合成步收率90％，ee值98.39％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝605.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),9.14(d,1H),7.95–7.73(m,4H),7.56(m,2H),7.46(d,1H),7.19(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)。
实施例40：化合物4的制备
制备方法同实施例37的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-甲基苯甲酰胺，即将R2由氨基替换成N-甲基，可制得化合物4粗品，最后合成步收率90％，ee值99.02％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.16(d,J＝1.1Hz,1H),8.13–8.06(m,1H),7.89–7.80(m,2H),7.79(d,J＝2.0Hz,1H),7.70–7.60(m,2H),7.37(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.52(t,J＝7.8Hz,1H),3.25(s,3H),2.76(d,J＝4.6Hz,3H),2.18–2.02(m,2H),0.78(t,J＝7.2Hz,3H)。
实施例41：化合物5的制备
制备方法同实施例37的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氟-N-(甲基-d3)苯甲酰胺，即将R2由氨基替换成N-(甲基-d3)，可制得化合物5粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为40：1。
ESI-MS:m/z＝610.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),9.14(d,J＝1.1Hz,1H),8.06(d,J＝3.4Hz,1H),7.92–7.81(m,2H),7.81–7.76(m,1H),7.70–7.60(m,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.13(s,1H),6.54(s,1H),5.51(d,J＝8.6Hz,1H),3.25(s,3H),2.19–1.99(m,J＝7.1Hz,2H),0.78(t,J＝7.2Hz,3H)。
实施例42：化合物6的制备
制备方法同实施例37的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-三氟甲基-N-甲基苯甲酰胺，即将R6由氟替换成三氟甲基，可制得化合物6粗品，最后合成步收率89％，ee值98.87％，反应终点N/O-烷基化转化比例为30：1。
ESI-MS:m/z＝643.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.80(s,1H),9.13(s,1H),8.12(d,1H),8.02–7.72(m,5H),7.54-7.51(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)。
实施例43：化合物7的制备
制备方法同实施例37的制备方法，将步骤2的4-氨基-2-氟苯甲酰胺替换成4-氨基-2-氯-苯甲酰胺，即将R6由氟替换成氯，可制得化合物7粗品，后合成步收率92％，ee值98.87％，反应终点N/O-烷基化转化比例为35：1。
ESI-MS:m/z＝623.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),9.11(s,1H),7.91–7.66(m,4H),7.58–7.25(m,3H),7.15(s,1H),6.51(s,1H),5.53(dd 1H),3.26(s,3H),2.88(d,3H),2.12-2.01(m,2H),0.79(t,3H)。
本实施例37-43所包含的中间体及其核磁和质谱数据如表6所示:
表6.实施例37-43所涉及的中间体及其核磁、质谱数据

上述实施例仅为本发明的优选实施方式之一，不应当用于限制本发明的保护范围，但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色，其所解决的技术问题仍然与本发明一致的，均应当包含在本发明的保护范围之内。

Claims (18)

  1. 一种如式(II)所示的中间体或其药学上可接受的盐：
    式(II)中：
    R1选自TsO-、X、R7O-；Ts为对甲苯磺酰基，X选自F、Cl、Br或I；
    R2选自-NHR8、-OC(CH3)3；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基；
    R8选自氢、烷基或环烷基；
    式(II)不为
  2. 根据权利要求1所述的中间体或其药学上可接受的盐，其中，所述中间体具有式(Ⅲ)、式(Ⅳ)或式(V)所示的结构：
    式(III)中，
    R2选自-NHR8，R8选自氢、烷基或环烷基；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    式(Ⅳ)中：
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    X选自F、Cl、Br或I；
    式(Ⅴ)中：
    R2选自NHR8，R8选自氢、烷基或环烷基；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基。
  3. 根据权利要求2所述的中间体或其药学上可接受的盐，其中，式(III)中，
    所述R2选自-NHR8，R8选自氢、甲基、乙基、丙基、环丙基、环丙甲基或叔丁基；
    和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基；
    式(Ⅳ)中，
    所述R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基，
    和/或X独立地选自Cl或Br；
    式(V)中，
    R8选自氢、甲基、乙基、丙基、环丙基、环丙甲基或叔丁基；
    和/或R3、R4、R5、R6独立地选自氢、氟、氯、甲氧基、乙氧基或三氟甲基。
  4. 根据权利要求3所述的中间体或其药学上可接受的盐，其中所述中间体包括式(Ⅳ-a)所示的结构：
    式(Ⅳ-a)中，R3、R4、R5、R6的定义同权利要求3相应定义。
  5. 根据权利要求2所述的中间体或其药学上可接受的盐，其中所述中间体的结构中的氢可被至少1个氘取代。
  6. 根据权利要求2所述的中间体或其药学上可接受的盐，其中所述中间体包括如下化合物：
  7. 权利要求1-6任一项所述中间体或其药学上可接受的盐的制备方法，所述中间体的合成包括方法A、方法B或方法C：
    方法A：由式(III-a)化合物与对甲苯磺酰氯在碱性条件反应获得式(III)所示中 间体，
    其中，R2、R3、R4、R5、R6的定义同权利要求1-6任一相应定义；
    方法B：由式(III-a-5)化合物与卤代羧酸反应获得式(IV)所示中间体，
    其中，X选自F、Cl、Br或I；R3、R4、R5、R6的定义同权利要求1-6任一相应定义；
    方法C：由式(III-a)化合物在碱性条件下与羟基保护试剂进行酯化反应，得到式(V)所示中间体，
    其中，R2、R3、R4、R5、R6、R7的定义同权利要求1-6任一相应定义。
  8. 根据权利要求7所述的制备方法，其中所述方法A和/或方法C包括如下反应条件：
    所述碱选自有机碱；
    所述合成步骤的反应溶剂选自有机溶剂；
    任选地，所述合成步骤的式(III-a)化合物与有机碱的摩尔比为1：0.5-8；
    任选地，所述合成步骤的反应温度为0℃-60℃；
    任选地，所述合成步骤的反应时间为1-10小时。
  9. 根据权利要求8所述的制备方法，其中，
    所述有机碱包括三乙胺、吡啶、四甲基胍、DMAP、DBU、DIPEA中的任一种或两 种以上混合；
    所述有机溶剂包括但不限于二氯甲烷、四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF、乙腈中的任一种或两种以上混合；
    或所述式(III-a)化合物与有机碱的摩尔比为1：1-3；
    或所述反应温度为10-30℃；
    或所述反应时间为为4-6小时。
  10. 根据权利要求7所述的制备方法，其中所述式(III-a)化合物的制备包括如下步骤：
    其中，R2、R3、R4、R5、R6的定义同上述任一相应定义；
    步骤1：式(III-a-2)化合物与式(III-a-3)化合物发生缩合反应获得式(III-a-4)化合物；
    步骤2：式(III-a-4)化合物在碱性条件下发生水解反应获得所述式(III-a)化合物。
  11. 根据权利要求10所述的制备方法，其中所述步骤1的缩合反应包括如下反应条件：
    所述缩合反应包括缩合剂，所述缩合剂包括T3P或DPP-Cl；
    所述缩合反应包括有机碱，所述有机碱包括三乙胺、吡啶、四甲基胍、DBU或DIPEA；
    所述缩合反应的溶剂为有机溶剂；优选地，所述有机溶剂包括四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF、乙腈、乙酸乙酯中的任一种或两种以上混合；
    任选地，所述缩合反应的温度为0℃～60℃；
    任选地，所述缩合反应的时间为1～10小时；
    和/或，所述步骤2的水解反应包括如下反应条件：
    所述水解反应包括无机碱，所述无机碱包括碳酸钾、碳酸钠、碳酸铯、碳酸氢钾或碳酸氢钠；
    所述水解反应的溶剂为有机溶剂与水的混合溶剂，所述混合溶剂中有机溶剂与水的体积比为1:1～10；
    任选地，所述水解反应的式(III-a-4)化合物与无机碱的摩尔比例为1：1～10；
    任选地，所述水解反应的温度为0℃～60℃；
    任选地，所述水解反应的时间为1～10小时。
  12. 权利要求1-6任一项所述中间体或其药学上可接受的盐用于标准品、对照品、制备式(I)所示氧代吡啶类化合物、或在制备治疗或预防血管动脉疾病的药物中的应用。
  13. 一种式(I)所示氧代吡啶类化合物的制备方法，所述制备方法包括式(Ⅱ)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(I)化合物；
    式(II)中：
    R1选自TsO-、X、R7O-；Ts为对甲苯磺酰基，X选自F、Cl、Br或I；
    R2选自-NHR8、-OC(CH3)3；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基；
    R8选自氢、烷基或环烷基；
    R9选自氟、氯或三氟甲基；
    式(II)不为
  14. 根据权利要求13所述的式(I)所示氧代吡啶类化合物的制备方法，其中，所 述制备方法包括：
    当式(II)中的R2选自-OC(CH3)3时，式(II)所示中间体结构为式(II-a)，所述制备方法包括以下步骤：
    其中，
    R1选自TsO-、X、R7O-；Ts为对甲苯磺酰基，X选自F、Cl、Br或I；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基；
    R8选自氢、烷基或环烷基；
    R9选自氟、氯或三氟甲基；
    步骤1：式(Ⅱ-a)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(VII)化合物；
    步骤2：式(VII)化合物发生水解反应得到式(VIII)化合物；
    步骤3：式(VIII)化合物发生缩合反应得到式(I)化合物。
  15. 根据权利要求13所述的式(I)所示氧代吡啶类化合物的制备方法，其中所述制备方法选自方法一、方法二或方法三；
    方法一：所述制备方法包括式(III)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(I)化合物，
    其中，
    R2选自-NHR8，R8选自氢、烷基或环烷基；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R9选自氟、氯或三氟甲基；
    方法二：
    其中，
    R10选自烷基、环烷基或氘代烷基、环烷基；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R9选自氟、氯或三氟甲基；
    X选自F、Cl、Br或I；
    步骤1：式(IV)所示的中间体或其药学上可接受的盐和式(VI)化合物反应获得式(VII)化合物；
    步骤2：式(VII)化合物发生水解反应得到式(VIII)化合物；
    步骤3：式(VIII)化合物发生缩合反应得到式(I-a)化合物；
    方法三：
    将式(V)所示的中间体与式(VI)化合物在碱性条件下进行亲核取代反应，获得式(I)化合物；
    其中，
    R9选自氟、氯或三氟甲基；
    R2选自NHR8，R8选自氢、烷基或环烷基；
    R3、R4、R5、R6独立地选自氢、卤素、烷氧基或卤代烷基；
    R7选自三氟甲磺酰基、甲磺酰基、对硝基苯甲磺酰基或苯磺酰基。
  16. 根据权利要求15所述的式(I)所示氧代吡啶类化合物的制备方法，其中所述方法一和/或方法三包括如下反应条件：
    反应条件包括碱，所述碱选自有机碱或无机碱；
    反应溶剂选自有机溶剂；
    任选地，式(III)化合物或式(V)化合物与碱的摩尔比为1：1-3；
    任选地，反应温度为0℃至60℃；
    任选地，反应时间为1-10小时。
  17. 根据权利要求16所述的式(I)所示氧代吡啶类化合物的制备方法，其中，
    所述碱包括碳酸钠、碳酸钾、碳酸铯、碳酸氢钾、磷酸钾，磷酸氢二钾、磷酸二氢钾、碳酸氢钠、氢氧化锂、氢氧化钠、氢氧化钾、四甲基胍、三乙胺、DBU、DIPEA、吡啶中的任一种或两种以上混合；
    所述有机溶剂包括四氢呋喃、2-甲基四氢呋喃、异丙醇、乙醇、丙酮、DMF、二氧六环中的任一种或两种以上混合；
    或所述式(III)化合物或式(V)化合物与碱的摩尔比为1：2；
    或所述反应温度为为20℃至40℃；
    或所述反应时间为4-6小时。
  18. 根据权利要求15所述的式(I)所示氧代吡啶类化合物的制备方法，其中所述方法二包括如下反应条件：
    所述步骤1包括如下反应条件，
    所述步骤1包括碱，所述碱选自有机碱或无机碱；
    所述步骤1的反应溶剂选自有机溶剂，所述有机溶剂包括异丙醇、乙醇、丙酮、DMF、四氢呋喃、2-甲基四氢呋喃、二氧六环中的任一种或两种以上混合；
    任选地，所述步骤1中式(IV)化合物与碱的摩尔比为1：1-3；
    任选地，所述步骤1的反应温度为0℃-60℃；
    任选地，所述步骤1的反应时间为1-10小时；
    或者，所述步骤2包括如下反应条件，
    所述步骤2包括酸，所述酸包括盐酸、三氟乙酸、硫酸、磷酸、醋酸、氢溴酸中的任一种或两种以上混合；
    所述步骤2的反应溶剂选自有机溶剂，所述有机溶剂包括异四氢呋喃、2-甲基四氢呋喃、二氧六环、丙酮、甲醇、乙醇、异丙醇、DMF中的任一种或两种以上混合；
    任选地，所述步骤2中式(VII)化合物与酸的摩尔比为1：30；
    任选地，所述步骤2的反应温度为-20℃至40℃；
    任选地，所述步骤2的反应时间为1-8小时；
    或者，所述步骤3包括如下反应条件，
    所述步骤3包括碱，所述碱包括三乙胺、DBU、DIPEA、四甲基胍、吡啶、碳酸钠、碳酸钾、碳酸铯、碳酸氢钾、碳酸氢钠、氢氧化锂、氢氧化钠、氢氧化钾中的任一种或两种以上混合；
    所述步骤3包括缩合剂和配体，所述缩合剂及配体包括EDCI，HOBT、HATU、HBTU、DCC、CDI、T3P、DPP-Cl、HCTU、TBTU、DMAP中的任一种或两种以上混合；
    所述步骤3的反应溶剂选自有机溶剂，所述有机溶剂包括异四氢呋喃、DCM、2-甲基四氢呋喃、二氧六环、乙腈、丙酮、乙醇、异丙醇、DMF、DMAC中的任一种或两种以上混合；
    任选地，所述步骤3中式(VIII)化合物与碱的摩尔比为1：1-5；
    任选地，所述步骤3的反应温度为0℃至60℃；
    任选地，所述步骤3的反应时间为1-10小时。
PCT/CN2024/098225 2023-06-09 2024-06-07 氧代吡啶类化合物的新型制备方法及关键中间体和应用 Pending WO2024251276A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020267000750A KR20260021743A (ko) 2023-06-09 2024-06-07 옥소피리딘 화합물의 신규 제조방법, 핵심 중간체 및 그 용도

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202310679927.1 2023-06-09
CN202310679927.1A CN116621742B (zh) 2023-06-09 2023-06-09 氧代吡啶类化合物的新型制备方法及关键中间体
CN202310738580.3A CN116751136B (zh) 2023-06-21 2023-06-21 氧代吡啶类化合物的新型制备方法及关键中间体
CN202310738580.3 2023-06-21
CN202310757873.6A CN116535392B (zh) 2023-06-26 2023-06-26 一种氧代吡啶类化合物的制备方法及中间体和应用
CN202310757873.6 2023-06-26

Publications (1)

Publication Number Publication Date
WO2024251276A1 true WO2024251276A1 (zh) 2024-12-12

Family

ID=93795093

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/098225 Pending WO2024251276A1 (zh) 2023-06-09 2024-06-07 氧代吡啶类化合物的新型制备方法及关键中间体和应用

Country Status (2)

Country Link
KR (1) KR20260021743A (zh)
WO (1) WO2024251276A1 (zh)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014154794A1 (de) 2013-03-28 2014-10-02 Bayer Pharma Aktiengesellschaft Substituierte oxopyridin-derivate und ihre verwendung bei der behandlung von herz-kreislauf-erkrankungen
WO2017005725A1 (en) 2015-07-09 2017-01-12 Bayer Pharma Aktiengesellschaft Substituted oxopyridine derivatives
CN111770917A (zh) 2018-03-15 2020-10-13 拜耳股份公司 两种4-{[(2s)-2-{4-[5-氯-2-(1h-1,2,3-三唑-1-基)苯基]-5-甲氧基-2-氧代吡啶-1(2h)-基}丁酰基]氨基}-2-氟苯甲酰胺衍生物的制备方法
CN116082303A (zh) * 2022-12-21 2023-05-09 成都施贝康生物医药科技有限公司 新型氧代吡啶类化合物及其中间体和应用
CN116535392A (zh) * 2023-06-26 2023-08-04 成都施贝康生物医药科技有限公司 一种氧代吡啶类化合物的制备方法及中间体和应用
CN116621742A (zh) * 2023-06-09 2023-08-22 成都施贝康生物医药科技有限公司 氧代吡啶类化合物的新型制备方法及关键中间体
CN116751136A (zh) * 2023-06-21 2023-09-15 成都施贝康生物医药科技有限公司 氧代吡啶类化合物的新型制备方法及关键中间体
CN116903585A (zh) * 2022-04-13 2023-10-20 天津药物研究院有限公司 一种氧代吡啶衍生物及其在医药上的应用
CN116969918A (zh) * 2022-04-29 2023-10-31 上海美悦生物科技发展有限公司 氟取代的吡啶酮类衍生物及其药物组合物、制备方法和用途

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014154794A1 (de) 2013-03-28 2014-10-02 Bayer Pharma Aktiengesellschaft Substituierte oxopyridin-derivate und ihre verwendung bei der behandlung von herz-kreislauf-erkrankungen
WO2017005725A1 (en) 2015-07-09 2017-01-12 Bayer Pharma Aktiengesellschaft Substituted oxopyridine derivatives
CN108026072B (zh) 2015-07-09 2021-08-17 拜耳制药股份公司 取代的氧代吡啶衍生物
CN111770917A (zh) 2018-03-15 2020-10-13 拜耳股份公司 两种4-{[(2s)-2-{4-[5-氯-2-(1h-1,2,3-三唑-1-基)苯基]-5-甲氧基-2-氧代吡啶-1(2h)-基}丁酰基]氨基}-2-氟苯甲酰胺衍生物的制备方法
CN116903585A (zh) * 2022-04-13 2023-10-20 天津药物研究院有限公司 一种氧代吡啶衍生物及其在医药上的应用
CN116969918A (zh) * 2022-04-29 2023-10-31 上海美悦生物科技发展有限公司 氟取代的吡啶酮类衍生物及其药物组合物、制备方法和用途
CN116082303A (zh) * 2022-12-21 2023-05-09 成都施贝康生物医药科技有限公司 新型氧代吡啶类化合物及其中间体和应用
CN116621742A (zh) * 2023-06-09 2023-08-22 成都施贝康生物医药科技有限公司 氧代吡啶类化合物的新型制备方法及关键中间体
CN116751136A (zh) * 2023-06-21 2023-09-15 成都施贝康生物医药科技有限公司 氧代吡啶类化合物的新型制备方法及关键中间体
CN116535392A (zh) * 2023-06-26 2023-08-04 成都施贝康生物医药科技有限公司 一种氧代吡啶类化合物的制备方法及中间体和应用

Also Published As

Publication number Publication date
KR20260021743A (ko) 2026-02-13

Similar Documents

Publication Publication Date Title
CN104159898B (zh) 用于制备取代的5‑氟‑1h‑吡唑并吡啶类化合物的方法
CN116751136B (zh) 氧代吡啶类化合物的新型制备方法及关键中间体
CN116535392B (zh) 一种氧代吡啶类化合物的制备方法及中间体和应用
WO2016199031A1 (en) Process for preparation of apremilast and its intermediates
JP2020528064A (ja) Ｌｆａ−１拮抗薬リフィテグラストを調製および精製するためのプロセス
JP2019523273A (ja) ベリノスタットの多形形態、およびその調製のためのプロセス
KR100794955B1 (ko) 트란스-4-아미노-1-시클로헥산카르복실산 유도체의 제조방법
CN116621742A (zh) 氧代吡啶类化合物的新型制备方法及关键中间体
CN116621728A (zh) 氧代吡啶类化合物的新型制备方法及关键中间体
CN109923107B (zh) 用于制备吲哚甲酰胺化合物的方法
JP4541140B2 (ja) 新塩類
CN116874387B (zh) 氧代吡啶类化合物的新型制备方法及关键中间体
WO2024251276A1 (zh) 氧代吡啶类化合物的新型制备方法及关键中间体和应用
JP2019532075A (ja) 重水素化イミダゾリジンジオン系化合物を調製する方法
CN116730861A (zh) 氧代吡啶类化合物的新型制备方法及关键中间体
KR100900177B1 (ko) 트리테르펜 유도체의 제조 방법
JP7834210B2 (ja) ジャクチニブ二塩酸塩一水和物の製造プロセス
CN100404543C (zh) 一种合成吡利霉素的中间体及其制备方法和用途
JP2025519918A (ja) ジャクチニブ二塩酸塩一水和物の製造プロセス
NO311935B1 (no) Nye heteroaryloksyetylaminer, anvendelse, fremgangsmåte for fremstilling derav og farmasöytiske preparater inneholdende dem
CN107365299B (zh) 一种达比加群酯的制备方法及其中间体
CN101687859A (zh) 阿呋唑嗪及其盐的制备工艺
CN120665002A (zh) 一种3-氨基吡咯烷-1-羧酸叔丁酯的制备方法及其应用
CN115368283A (zh) 一种手性结构或非手性结构的顺式-3-氟-4-羟基吡咯烷及其衍生物的制备方法
WO2026037241A1 (zh) 异吲哚啉类化合物制备方法、其中间体及其中间体的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24818802

Country of ref document: EP

Kind code of ref document: A1

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112025027164

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 1020267000750

Country of ref document: KR

Free format text: ST27 STATUS EVENT CODE: A-0-1-A10-A15-NAP-PA0105 (AS PROVIDED BY THE NATIONAL OFFICE)

WWE Wipo information: entry into national phase

Ref document number: 1020267000750

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2024818802

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024818802

Country of ref document: EP

Effective date: 20260109

WWE Wipo information: entry into national phase

Ref document number: 2025135036

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2024818802

Country of ref document: EP

Effective date: 20260109

ENP Entry into the national phase

Ref document number: 2024818802

Country of ref document: EP

Effective date: 20260109

WWE Wipo information: entry into national phase

Ref document number: 11202508306S

Country of ref document: SG

WWP Wipo information: published in national office

Ref document number: 11202508306S

Country of ref document: SG

ENP Entry into the national phase

Ref document number: 2024818802

Country of ref document: EP

Effective date: 20260109

ENP Entry into the national phase

Ref document number: 2024818802

Country of ref document: EP

Effective date: 20260109

WWP Wipo information: published in national office

Ref document number: 1020267000750

Country of ref document: KR