WO2023025160A1 - Preparation process for imidazolinone derivative, and intermediate thereof - Google Patents

Preparation process for imidazolinone derivative, and intermediate thereof Download PDF

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Publication number
WO2023025160A1
WO2023025160A1 PCT/CN2022/114328 CN2022114328W WO2023025160A1 WO 2023025160 A1 WO2023025160 A1 WO 2023025160A1 CN 2022114328 W CN2022114328 W CN 2022114328W WO 2023025160 A1 WO2023025160 A1 WO 2023025160A1
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compound
formula
preparation process
alkyl
prepare
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PCT/CN2022/114328
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French (fr)
Chinese (zh)
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许学珍
楚洪柱
魏用刚
何吕学
雷飞全
朱丹
刘兆军
孙毅
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成都百裕制药股份有限公司
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Priority to CN202280034777.2A priority Critical patent/CN117321057A/en
Publication of WO2023025160A1 publication Critical patent/WO2023025160A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6

Definitions

  • the invention relates to a preparation process of imidazolinone derivatives or their stereoisomers and intermediates thereof.
  • DNA-dependent protein kinase is a DNA-PK enzyme complex composed of Ku70/Ku80 heterodimer and DNA-dependent protein kinase catalytic subunit (DNA-PKcs).
  • the patent (application number: PCT/CN2021/087912) describes a novel DNA-PK inhibitor represented by formula (I-1), which has a good inhibitory effect on DNA-PK activity and has the potential to prepare anti-tumor drugs .
  • the object of the present invention is to provide a new imidazolinone derivative or its stereoisomer preparation process and its intermediate.
  • the preparation process has the advantages of low cost, high yield and is more suitable for industrial production.
  • a preparation process for imidazolinone derivatives of formula (I-1) or stereoisomers thereof comprising the following steps:
  • the compound of formula (I-a-1) is reacted with an oxidizing agent in the reaction solvent under the condition of inorganic base and/or organic base, and the compound of formula (I-1) is prepared;
  • R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
  • R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
  • R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
  • n 0 or 1
  • n 0, 1 or 2;
  • x and y are each independently 1, 2 or 3;
  • R 0 is H or methyl
  • R 3 is methyl
  • the compound of formula (I-a) is reacted with an oxidizing agent in a reaction solvent under the condition of inorganic base and/or organic base to prepare the compound of formula (I).
  • the compound of formula (Ia) is reacted with an oxidizing agent in DMSO solution under the condition of inorganic alkali to prepare the compound of formula (I); the oxidizing agent is selected from H 2 O 2 .
  • the molar ratio of the inorganic base and/or organic base, the oxidizing agent and the compound of formula (I-a) is (0.2-1.5): (1.5-5): 1; the inorganic base And/or the molar ratio of the organic base, the oxidizing agent and the compound of formula (I-a-1) is (0.2-1.5):(1.5-5):1.
  • the reaction temperature in the above reaction step is at room temperature - 60°C, preferably at room temperature - 40°C.
  • the above compound of formula (I-a-1) is prepared by the following reaction steps:
  • R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
  • R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
  • R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
  • n 0 or 1
  • n 0, 1 or 2;
  • x and y are each independently 1, 2 or 3;
  • R 0 is H or methyl
  • R 3 is methyl
  • R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  • the above compound of formula (I-a) is prepared by the following reaction steps:
  • the compound of formula (I-c1) and/or the compound of formula (I-c2) is reacted with the compound of formula (I-b) in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-a).
  • the compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (I-b) are reacted in an aprotic solvent under the conditions of inorganic base or organic base to prepare the compound of formula (I-a) Compounds.
  • the molar ratio of the above-mentioned formula (I-c1) compound and/or formula (I-c2) compound, inorganic base and/or organic base and formula (I-b) compound is 1:( 1-5): (0.5-2); said compound of formula (I-c1-1) and/or compound of formula (I-c2-1), said inorganic base and/or organic base and said compound of formula (I-b )
  • the molar ratio of the compound is 1:(1-5):(0.5-2).
  • the temperature of the reaction solution is controlled to be -10°C-10°C, preferably -5°C-0°C.
  • the reaction temperature of the above reaction step is 15°C-45°C, preferably at room temperature.
  • the solid obtained after the reaction is beaten with a beating solvent, and the beating solvent is selected from one or more of ethyl acetate, methyl tert-butyl ether, isopropyl acetate and n-heptane .
  • the above-mentioned compound of formula (I-c1-1) and compound of formula (I-c2-1) are prepared by the following reaction steps:
  • Formula (I-d-1) compound is in reaction solvent, adds oxidant reaction, prepares formula (I-c1-1) compound and formula (I-c2-1) compound,
  • R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • n 0 or 1
  • x and y are each independently 1, 2 or 3;
  • R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  • the above-mentioned compound of formula (I-c1) and compound of formula (I-c2) are prepared by the following reaction steps:
  • the compound of the formula (I-d) is reacted by adding an oxidizing agent in a reaction solvent to prepare the compound of the formula (I-c1) and the compound of the formula (I-c2).
  • the compound of formula (Id) is reacted with an oxidizing agent in an alcohol and/or H 2 O solvent to prepare a compound of formula (I-c1) and a compound of formula (I-c2);
  • the oxidizing agent is selected from Oxone or mCPBA.
  • the molar ratio of the oxidant to the compound of formula (I-d) is (0.5-2): 1; the molar ratio of the oxidant to the compound of formula (I-d-1) is (0.5- 2): 1.
  • the reaction solution in the above reaction step, after the oxidant is added, can be kept at 20°C-50°C for reaction, preferably at a reaction temperature of 25°C-35°C.
  • the above compound of formula (I-d-1) is prepared by the following reaction steps:
  • the compound of formula (I-e-1) and reagent I are reacted under the conditions of inorganic base and/or organic base in the reaction solvent to prepare the compound of formula (I-d-1), and the reagent I is selected from iodoethane, diethyl sulfate One of , diethyl carbonate, bromoethane, acetaldehyde, acetic acid, methanol, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal or more,
  • R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • n 0 or 1
  • x and y are each independently 1, 2 or 3;
  • R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  • the compound of formula (I-e) and reagent I are reacted under conditions of inorganic base and/or organic base in a reaction solvent to prepare the compound of formula (I-d), and said reagent I is selected from ethyl iodide, diethyl sulfate, diethyl carbonate One or more of esters, bromoethane, acetaldehyde, acetic acid, methanol, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal.
  • the compound of formula (I-e) is reacted with ethyl iodide in an aprotic solvent under inorganic base conditions to prepare the compound of formula (I-d).
  • the molar ratio of the inorganic base and/or organic base, reagent I to the compound of formula (I-e) is (1-4):(1-5):1; the inorganic base and The molar ratio of/or the organic base, the reagent I to the compound of formula (I-e-1) is (1-4):(1-5):1.
  • the reaction temperature in the above reaction step is 20°C-40°C, preferably 25°C-35°C.
  • the above compound of formula (I-e-1) is prepared by the following reaction steps:
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • n 0 or 1
  • x and y are each independently 1, 2 or 3;
  • R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  • the compound of formula (I-f) is reacted with the azidation reagent in a reaction solvent under the condition of inorganic base and/or organic base to prepare the compound of formula (I-e).
  • the azidation reagent is selected from one or more of diphenylphosphoryl azide, azidotrimethylsilane, sodium azide and azide.
  • the compound of formula (I-f) and the azidation reagent are reacted in an aprotic solvent under basic conditions to prepare the compound of formula (I-e); the azidation reagent is selected from DPPA.
  • the temperature of the reaction solution is controlled below 30°C.
  • the molar ratio of inorganic base and/or organic base, azidation reagent and formula (I-f) compound is (1-4):(1-3):1;
  • the molar ratio of the base and/or organic base, the azidation reagent and the compound of formula (I-f-1) is (1-4):(1-3):1.
  • the reaction solution in the above reaction step, after the addition of the feed is completed, after the complete conversion of the compound of formula (I-f) is detected, the reaction solution can be further heated to 60-80°C, and bubbles begin to emerge, and the control The internal temperature is 80°C-100°C, until the bubbles are completely released, then the temperature is raised to 95-105°C for reaction.
  • the above compound of formula (I-f-1) is prepared by the following reaction steps:
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • n 0 or 1
  • x and y are each independently 1, 2 or 3;
  • R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl
  • R q2 is selected from C 1-6 alkyl or C 3-6 cycloalkyl
  • R q3 is selected from halogen
  • Q is selected from one or more molecules of inorganic acids, preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, perchloric acid or hydroiodic acid.
  • the above compound of formula (I-f) is prepared by the following reaction steps:
  • the compound of formula (I-h) and the compound of formula (I-g) are reacted in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-f).
  • the compound of formula (Ih) and the compound of formula (Ig) are reacted under inorganic base conditions in an aprotic solvent or a mixed solvent of aprotic solvent/H 2 O; subsequently, adding an inorganic base
  • the aqueous solution continues to react to prepare the compound of formula (If).
  • the molar ratio of the inorganic base and/or organic base, the compound of formula (I-g) to the compound of formula (I-h) is (1-3): (1-1.2): 1;
  • the molar ratio of the inorganic base and/or organic base, the compound of formula (I-g-1) to the compound of formula (I-h-1) is (1-3):(1-1.2):1.
  • the compound of formula (I-h) and the compound of formula (I-g) are reacted under the conditions of inorganic base and/or organic base in the reaction solvent, after the completion of the reaction detected by HPLC, the aqueous solution of inorganic base is added Continue the reaction, the molar ratio of the inorganic base to the compound of formula (I-h) is (2-5):1.
  • the reaction solution is concentrated under reduced pressure to remove most of the solvent, and then the aqueous sodium hydroxide solution is added to the reaction solution, React at 60-70°C.
  • the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, toluene, isopropanol, 1,4-dioxane, N,N-dimethylformamide, One or more of N,N-dimethylacetamide, dimethyl sulfoxide, methyl tetrahydrofuran, H 2 O, dichloromethane and tert-butanol.
  • the reaction solvent is selected from alcohol and H 2 O
  • the volume ratio of the alcohol to H 2 O is (10-4):1.
  • reaction time can be properly adjusted according to the amount of reaction raw materials, so that the reaction can proceed normally and the reaction can be completed.
  • the inorganic base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium aluminum hydride and cesium hydroxide species;
  • the organic base is selected from sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7
  • the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, sodium periodate, tert-butyl hydroperoxide, oxygen, N-fluorobiphenyl One or more of sulfonamide, ammonium molybdate/hydrogen peroxide, and ozone.
  • the first step the compound of formula (Ih) and the compound of formula (Ig) are reacted in an aprotic solvent or a mixed solvent of aprotic solvent/H 2 O under the condition of an inorganic base; subsequently, an aqueous solution of an inorganic base is added to continue the reaction to prepare A compound of formula (If);
  • the second step the compound of formula (I-f) and the azidation reagent react in an aprotic solvent under basic conditions to prepare the compound of formula (I-e); the above-mentioned azidation reagent is selected from DPPA;
  • Step 3 the compound of formula (I-e) reacts with ethyl iodide in an aprotic solvent under inorganic base conditions to prepare the compound of formula (I-d);
  • the fourth step the compound of formula (Id) is reacted with an oxidizing agent in alcohol and/or H 2 O solvent to prepare the compound of formula (I-c1) and compound of formula (I-c2); the above-mentioned oxidizing agent is selected from Oxone or mCPBA ;
  • the fifth step the compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (I-b) are reacted in an aprotic solvent under the conditions of inorganic base or organic base to prepare the compound of formula (I-a);
  • Step 6 The compound of formula (Ia) is reacted in DMSO solution under the condition of inorganic alkali by adding an oxidizing agent to obtain the compound of formula (I); the above-mentioned oxidizing agent is selected from H 2 O 2 .
  • R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
  • R1 is And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
  • R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
  • R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
  • n 0 or 1
  • n 0, 1 or 2;
  • x and y are each independently 1, 2 or 3;
  • R 0 is H or methyl
  • R 3 is methyl
  • R q2 is selected from C 1-6 alkyl or C 3-6 cycloalkyl
  • R q3 is selected from halogen
  • R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14
  • Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Optional or “optionally” or “optional” or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group.
  • Alkali refers to the compound that ionizes out OH- in aqueous solution; Or the compound that can accept proton; Inorganic base of the present invention such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, hydroxide cesium, etc.
  • the organic bases mentioned in the present invention refer to nitrogen atoms, such as amine compounds and nitrogen-containing heterocyclic compounds.
  • nitrogen atoms such as amine compounds and nitrogen-containing heterocyclic compounds.
  • LDA lithium diisopropylamide
  • LiHMDS lithium hexamethyldisilazide
  • organic bases selected in the present invention such as sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecyl -7-ene, 4-dimethylaminopyridine and sodium tert-amylate, etc.
  • DMSO dimethyl sulfoxide
  • ATP adenosine triphosphate
  • DNA Deoxyribonucleotides.
  • IC50 refers to the concentration of the compound when the activity of DNA-PK kinase is inhibited by 50%;
  • the prepared aqueous sodium hydroxide solution (3.0 kg of sodium hydroxide dissolved in 10 L of deionized water) was added into the reaction kettle. The temperature of the reaction solution was slightly raised, and then the temperature of the reaction solution was raised to 60° C. for 5 hours. A large amount of solids in the reaction solution were dissolved and gradually became clear, and the reaction was completed by sending samples to HPLC for detection. Subsequently, the reaction solution was cooled to room temperature, and concentrated hydrochloric acid was slowly added dropwise. A large number of bubbles were generated, the solid gradually dissolved, and the reaction solution became clear.
  • the internal temperature is about 30°C, and then slowly add iodoethane dropwise, there is a significant temperature rise phenomenon, control the temperature at 30 ⁇ 5°C, after the dropwise addition is completed, stir at room temperature for 3 hours.
  • HPLC detected that the reaction was complete, poured 30L of ice water into the reaction solution, a large amount of solids precipitated, stirred for 0.5h and then centrifugally filtered, the filter cake was rinsed with 10L of deionized water, and after centrifugation until no liquid dripped out, the filter cake was placed at 60°C Dry in a blast oven for 8 hours to obtain off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- Purin-8-one 1e (2.810kg, yield 84.8%).
  • the temperature of the reaction solution was raised to 40° C. for 2 h. The completion of the reaction was detected by HPLC. After the reaction solution was cooled to room temperature, 30L of pure water was added, and a large amount of solids were precipitated. After stirring for 1 h, it was centrifugally filtered. The filtrate was an orange solution, and the filter cake was an off-white solid. The filter cake was dried in a blast oven at 60°C for 8 hours.
  • the reaction solvent was 15L N,N-dimethylformamide and 5L deionized water, and the raw materials were 4-chloro-2-(methylthio)pyrimidine-5-carboxylate ethyl ester 1a (4.500kg, 19.3mol) and four Hydrogen-2H-pyran-4-amine hydrochloride 1b (2.656kg, 19.3mol), the base is sodium hydroxide solid (772g, 19.3mol), the aqueous solution of inorganic base is sodium hydroxide aqueous solution (1.93kg sodium hydroxide dissolved in 8L deionized water).
  • 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c was obtained as a white solid after work-up and drying.
  • the reaction solvent is 15L acetone, 3L deionized water and 15L N,N-dimethylacetamide
  • the raw material is ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 1a (6.0kg, 25.79mol ) and tetrahydro-2H-pyran-4-amine hydrochloride 1b (4.258kg, 30.94mol)
  • the base is sodium tert-butoxide (7.435kg, 77.37mol)
  • the aqueous solution of inorganic base is potassium hydroxide aqueous solution (6.511 kg potassium hydroxide dissolved in 20L deionized water).
  • 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c was obtained as a white solid after work-up and drying.
  • the reaction solvent is 14L dimethyl sulfoxide, and the raw material is 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c (3.45kg, 12.81 mol.), the base is N,N-diisopropylethylamine (1.656kg, 12.81mol), and the azidation reagent is azidotrimethylsilane (1.476kg, 12.81mol).
  • the off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one was obtained after post-treatment and drying 1d.
  • the reaction solvent is 18L acetonitrile
  • the raw material is 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c (2.56kg, 9.51mol), base It is 1,8-diazabicyclo[5.4.0]undec-7-ene (5.788kg, 38.02mol.), and the azide reagent is sodium azide (1.855kg, 28.53mol).
  • the off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one was obtained after post-treatment and drying 1d.
  • the reaction solvent is 45L ethanol
  • the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8- Ketone 1d (3.89kg, 14.61mol)
  • the base is potassium tert-butoxide (1.639kg, 14.61mol)
  • the reagent I is ethyl iodide (2.279kg, 14.61mol).
  • the off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- Purin-8-one 1e.
  • the reaction solvent is 16L acetonitrile and 8L H 2 O
  • the starting material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H - Purin-8-one 1d (1.58kg, 5.93mol)
  • the base is triethylamine (1.20kg, 11.86mol)
  • the reagent I is diethyl carbonate (1.75kg, 14.825mol).
  • the off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- Purin-8-one 1e.
  • the reaction solvent is 20L tert-butanol and 2L purified water
  • the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H - Purin-8-one 1e (2.53 kg, 8.59 mol)
  • the oxidizing agent is m-chloroperoxybenzoic acid (mCPBA) (0.741 kg, 4.295 mol).
  • the reaction solvent is 25L isopropanol and 10L purified water, and the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2 H-pyran-4-yl)-7,9-dihydro- 8H-purin-8-one 1e (3.27kg, 11.11mol), the oxidizing agent is sodium periodate (4.75kg, 22.22mol).
  • the reaction solvent is 1L acetonitrile
  • the raw material is the mixture of 1f and 1g (100g, 1.0eq.) and 1h (75.08g, 0.5eq.)
  • the base is N,N-diisopropylethylamine (129.25g, 1.0eq) .
  • post-treatment and drying yielded 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine- 2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i.
  • the reaction solvent was 3L toluene
  • the raw material was the mixture of 1f and 1g (100g, 1.0eq.), 1h (300.32g, 2eq.)
  • the base was potassium hydroxide (280.53g, 5.0eq).
  • post-treatment and drying yielded 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine- 2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i.
  • the reaction solvent is 10L tetrahydrofuran
  • the starting material is 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2 -yl)amino)-2-fluoro-5-methylbenzonitrile 1i (1kg, 2.52mol)
  • the base is aqueous sodium hydroxide solution (20.16g, 0.504mol.

Abstract

Provided are a preparation process for an imidazolinone derivative or a stereoisomer thereof, and an intermediate thereof. The preparation process involves simple operations, has high reaction yield, achieves high product purity, and is suitable for industrialized production. Also provided is a preparation process for the intermediate.

Description

一种咪唑啉酮衍生物的制备工艺及其中间体A kind of preparation technology of imidazolinone derivative and its intermediate 技术领域technical field
本发明涉及一种咪唑啉酮衍生物或者其立体异构体的制备工艺及其中间体。The invention relates to a preparation process of imidazolinone derivatives or their stereoisomers and intermediates thereof.
背景技术Background technique
DNA依赖的蛋白激酶(DNA-dependent protein kinase，DNA-PK)是由Ku70/Ku80异二聚体和DNA依赖的蛋白激酶催化亚基(DNA-PKcs)构成的DNA-PK酶复合物。DNA-dependent protein kinase (DNA-PK) is a DNA-PK enzyme complex composed of Ku70/Ku80 heterodimer and DNA-dependent protein kinase catalytic subunit (DNA-PKcs).
专利(申请号：PCT/CN2021/087912)描述了式(I-1)所示的一种新型的DNA-PK抑制剂，对DNA-PK活性具有良好的抑制作用，具有制备抗肿瘤药物的潜力。The patent (application number: PCT/CN2021/087912) describes a novel DNA-PK inhibitor represented by formula (I-1), which has a good inhibitory effect on DNA-PK activity and has the potential to prepare anti-tumor drugs .
Figure PCTCN2022114328-appb-000001
Figure PCTCN2022114328-appb-000001
发明内容Contents of the invention
本发明的目的是提供一种新的咪唑啉酮衍生物或者其立体异构体的制备工艺及其中间体。该制备工艺具有成本低、收率高、更适于工业化生产的优势。The object of the present invention is to provide a new imidazolinone derivative or its stereoisomer preparation process and its intermediate. The preparation process has the advantages of low cost, high yield and is more suitable for industrial production.
本发明的一个或多个实施方式中，提供一种式(I-1)的咪唑啉酮衍生物或者其立体异构体的制备工艺，包括以下步骤：In one or more embodiments of the present invention, a preparation process for imidazolinone derivatives of formula (I-1) or stereoisomers thereof is provided, comprising the following steps:
Figure PCTCN2022114328-appb-000002
Figure PCTCN2022114328-appb-000002
式(I-a-1)化合物在反应溶剂中，无机碱和/或有机碱条件下，加入氧化剂反应，制备得到式(I-1)化合物；The compound of formula (I-a-1) is reacted with an oxidizing agent in the reaction solvent under the condition of inorganic base and/or organic base, and the compound of formula (I-1) is prepared;
其中：in:
R 0为H、C 1-6烷基或者环丙基，所述C 1-6烷基任选地进一步被1个或者多个选自卤素和氘的取代基取代； R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
R 1为
Figure PCTCN2022114328-appb-000003
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷 基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000003
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
R 2为H、氰基、＝O、羧基、-C(＝O)NR 2aR 2b、C 1-6烷氧基、C 1-6烷基、卤素、-S(＝O) 2R 2a或者-C(＝O)OC 1-6烷基；所述C 1-6烷基、-C(＝O)OC 1-6烷基或者C 1-6烷氧基任选地被1个或者多个选自卤素和氘的取代基取代； R 2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1-6 alkoxy, C 1-6 alkyl, halogen, -S(=O) 2 R 2a Or -C(=O)OC 1-6 alkyl; said C 1-6 alkyl, -C(=O)OC 1-6 alkyl or C 1-6 alkoxy is optionally replaced by 1 or Multiple substituents selected from halogen and deuterium are substituted;
R 2a和R 2b各自独立地为H、C 1-6烷基或者3至5元环烷基，其中所述C 1-6烷基任选地进一步被1个或者多个选自OH、D、卤素、C 1-6烷基和C 1-6烷氧基的取代基取代； R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
或者，R 2a和R 2b与其相连的原子一起形成5至6元杂环基，所述5至6元杂环基含有1、2或3个选自N、O和S的杂原子，所述5至6元杂环基任选地进一步被1个或者多个选自C 1-6烷基、OH和卤素的取代基取代； Alternatively, R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
R 3为卤素或者C 1-6烷基，所述C 1-6烷基任选地进一步被1至3个选自D和卤素的取代基取代； R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
m为0或者1；m is 0 or 1;
n为0、1或2；n is 0, 1 or 2;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
n为1时，R 0为H或者甲基，R 2为甲氧基或者-S(＝O) 2Me，R 3为甲基。 When n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2 Me, and R 3 is methyl.
本发明的一个或多个实施方式中，提供一种式(I)的咪唑啉酮衍生物或者其立体异构体的制备工艺，包括以下步骤：In one or more embodiments of the present invention, there is provided a preparation process of imidazolinone derivatives of formula (I) or stereoisomers thereof, comprising the following steps:
Figure PCTCN2022114328-appb-000004
Figure PCTCN2022114328-appb-000004
式(I-a)化合物在反应溶剂中，无机碱和/或有机碱条件下，加入氧化剂反应，制备得到式(I)化合物。The compound of formula (I-a) is reacted with an oxidizing agent in a reaction solvent under the condition of inorganic base and/or organic base to prepare the compound of formula (I).
本发明的一个或多个实施方式中，式(I-a)化合物在DMSO溶液中，无机碱条件下，加入氧化剂反应，制备得到式(I)化合物；所述的氧化剂选自H 2O 2。 In one or more embodiments of the present invention, the compound of formula (Ia) is reacted with an oxidizing agent in DMSO solution under the condition of inorganic alkali to prepare the compound of formula (I); the oxidizing agent is selected from H 2 O 2 .
本发明的一个或多个实施方式中，无机碱和/或有机碱、氧化剂和所述式(I-a)化合物的摩尔比为(0.2-1.5)：(1.5-5)：1；所述无机碱和/或有机碱、所述氧化剂和所述式(I-a-1)化合物的摩尔比为(0.2-1.5)：(1.5-5)：1。In one or more embodiments of the present invention, the molar ratio of the inorganic base and/or organic base, the oxidizing agent and the compound of formula (I-a) is (0.2-1.5): (1.5-5): 1; the inorganic base And/or the molar ratio of the organic base, the oxidizing agent and the compound of formula (I-a-1) is (0.2-1.5):(1.5-5):1.
本发明的一个或多个实施方式中，上述反应步骤的反应温度在室温-60℃下反应，优选在室温-40℃。In one or more embodiments of the present invention, the reaction temperature in the above reaction step is at room temperature - 60°C, preferably at room temperature - 40°C.
本发明的一个或多个实施方式中，上述式(I-a-1)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-a-1) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000005
Figure PCTCN2022114328-appb-000005
式(I-c1-1)化合物和/或式(I-c2-1)化合物，与式(I-b-1)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-a-1)化合物，Formula (I-c1-1) compound and/or formula (I-c2-1) compound, react with formula (I-b-1) compound in reaction solvent, under inorganic base and/or organic base condition, prepare formula ( I-a-1) compounds,
其中：in:
R 0为H、C 1-6烷基或者环丙基，所述C 1-6烷基任选地进一步被1个或者多个选自卤素和氘的取代基取代； R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
R 1为
Figure PCTCN2022114328-appb-000006
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000006
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
R 2为H、氰基、＝O、羧基、-C(＝O)NR 2aR 2b、C 1-6烷氧基、C 1-6烷基、卤素、-S(＝O) 2R 2a或者-C(＝O)OC 1-6烷基；所述C 1-6烷基、-C(＝O)OC 1-6烷基或者C 1-6烷氧基任选地被1个或者多个选自卤素和氘的取代基取代； R 2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1-6 alkoxy, C 1-6 alkyl, halogen, -S(=O) 2 R 2a Or -C(=O)OC 1-6 alkyl; said C 1-6 alkyl, -C(=O)OC 1-6 alkyl or C 1-6 alkoxy is optionally replaced by 1 or Multiple substituents selected from halogen and deuterium are substituted;
R 2a和R 2b各自独立地为H、C 1-6烷基或者3至5元环烷基，其中所述C 1-6烷基任选地进一步被1个或者多个选自OH、D、卤素、C 1-6烷基和C 1-6烷氧基的取代基取代； R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
或者，R 2a和R 2b与其相连的原子一起形成5至6元杂环基，所述5至6元杂环基含有1、2或3个选自N、O和S的杂原子，所述5至6元杂环基任选地进一步被1个或者多个选自C 1-6烷基、OH和卤素的取代基取代； Alternatively, R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
R 3为卤素或者C 1-6烷基，所述C 1-6烷基任选地进一步被1至3个选自D和卤素的取代基取代； R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
m为0或者1；m is 0 or 1;
n为0、1或2；n is 0, 1 or 2;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
n为1时，R 0为H或者甲基，R 2为甲氧基或者-S(＝O) 2Me，R 3为甲基。 When n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2 Me, and R 3 is methyl.
R q1选自C 1-6烷基或者C 3-6环烷基。 R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
本发明的一个或多个实施方式中，上述式(I-a)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-a) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000007
Figure PCTCN2022114328-appb-000007
式(I-c1)化合物和/或式(I-c2)化合物，与式(I-b)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-a)化合物。The compound of formula (I-c1) and/or the compound of formula (I-c2) is reacted with the compound of formula (I-b) in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-a).
本发明的一个或多个实施方式中，式(I-c1)化合物、式(I-c2)化合物和式(I-b)化合物在非质子溶剂中，无机碱或者有机碱条件下反应，制备得到式(I-a)化合物。In one or more embodiments of the present invention, the compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (I-b) are reacted in an aprotic solvent under the conditions of inorganic base or organic base to prepare the compound of formula (I-a) Compounds.
本发明的一个或多个实施方式中，上述式(I-c1)化合物和/或式(I-c2)化合物、无机碱和/或有机碱和式(I-b)化合物的摩尔比为1：(1-5)：(0.5-2)；所述式(I-c1-1)化合物和/或式(I-c2-1)化合物、所述无机碱和/或有机碱和所述式(I-b)化合物的摩尔比为1：(1-5)：(0.5-2)。In one or more embodiments of the present invention, the molar ratio of the above-mentioned formula (I-c1) compound and/or formula (I-c2) compound, inorganic base and/or organic base and formula (I-b) compound is 1:( 1-5): (0.5-2); said compound of formula (I-c1-1) and/or compound of formula (I-c2-1), said inorganic base and/or organic base and said compound of formula (I-b ) The molar ratio of the compound is 1:(1-5):(0.5-2).
本发明的一个或多个实施方式中，上述步骤中，无机碱和/或有机碱加入过程中，控制反应液温度为-10℃-10℃.优选-5℃-0℃。In one or more embodiments of the present invention, in the above steps, during the addition of the inorganic base and/or the organic base, the temperature of the reaction solution is controlled to be -10°C-10°C, preferably -5°C-0°C.
本发明的一个或多个实施方式中，上述反应步骤的反应温度在15℃-45℃下反应，优选在室温下反应。In one or more embodiments of the present invention, the reaction temperature of the above reaction step is 15°C-45°C, preferably at room temperature.
本发明的一个或多个实施方式中，反应后所得固体用打浆溶剂进行打浆，打浆溶剂选自乙酸乙酯、甲基叔丁基醚、醋酸异丙酯和正庚烷中的一种或多种。In one or more embodiments of the present invention, the solid obtained after the reaction is beaten with a beating solvent, and the beating solvent is selected from one or more of ethyl acetate, methyl tert-butyl ether, isopropyl acetate and n-heptane .
本发明的一个或多个实施方式中，上述式(I-c1-1)化合物和式(I-c2-1)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above-mentioned compound of formula (I-c1-1) and compound of formula (I-c2-1) are prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000008
Figure PCTCN2022114328-appb-000008
式(I-d-1)化合物在反应溶剂中，加入氧化剂反应，制备得到式(I-c1-1)化合物和式(I-c2-1)化合物，Formula (I-d-1) compound is in reaction solvent, adds oxidant reaction, prepares formula (I-c1-1) compound and formula (I-c2-1) compound,
其中：in:
R 0为H、C 1-6烷基或者环丙基，所述C 1-6烷基任选地进一步被1个或者多个选自卤素和氘的取代基取代； R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
R 1为
Figure PCTCN2022114328-appb-000009
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000009
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
m为0或者1；m is 0 or 1;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
R q1选自C 1-6烷基或者C 3-6环烷基。 R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
本发明的一个或多个实施方式中，上述式(I-c1)化合物和式(I-c2)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above-mentioned compound of formula (I-c1) and compound of formula (I-c2) are prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000010
Figure PCTCN2022114328-appb-000010
式(I-d)化合物在反应溶剂中，加入氧化剂反应，制备得到式(I-c1)化合物和式(I-c2)化合物。The compound of the formula (I-d) is reacted by adding an oxidizing agent in a reaction solvent to prepare the compound of the formula (I-c1) and the compound of the formula (I-c2).
本发明的一个或多个实施方式中，式(I-d)化合物在醇和/或H 2O的溶剂中，加入氧化剂反应，制备得到式(I-c1)化合物和式(I-c2)化合物；所述的氧化剂选自Oxone或者mCPBA。 In one or more embodiments of the present invention, the compound of formula (Id) is reacted with an oxidizing agent in an alcohol and/or H 2 O solvent to prepare a compound of formula (I-c1) and a compound of formula (I-c2); The oxidizing agent is selected from Oxone or mCPBA.
本发明的一个或多个实施方式中，氧化剂与式(I-d)化合物的摩尔比为(0.5-2)：1；所述氧化剂与所述式(I-d-1)化合物的摩尔比为(0.5-2)：1。In one or more embodiments of the present invention, the molar ratio of the oxidant to the compound of formula (I-d) is (0.5-2): 1; the molar ratio of the oxidant to the compound of formula (I-d-1) is (0.5- 2): 1.
本发明的一个或多个实施方式中，上述反应步骤中，氧化剂加毕后，可以使反应液保持在20℃-50℃反应，优选反应温度25℃-35℃。In one or more embodiments of the present invention, in the above reaction step, after the oxidant is added, the reaction solution can be kept at 20°C-50°C for reaction, preferably at a reaction temperature of 25°C-35°C.
本发明的一个或多个实施方式中，上述式(I-d-1)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-d-1) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000011
Figure PCTCN2022114328-appb-000011
式(I-e-1)化合物和试剂Ⅰ在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-d-1)化合物，所述试剂Ⅰ选自碘乙烷、硫酸二乙酯、碳酸二乙酯、溴乙烷、乙醛、乙酸、甲醇、三氟甲磺酸乙酯、对甲苯磺酸乙酯和N,N-二甲基甲酰胺二乙基缩醛中的一种或多种，The compound of formula (I-e-1) and reagent I are reacted under the conditions of inorganic base and/or organic base in the reaction solvent to prepare the compound of formula (I-d-1), and the reagent I is selected from iodoethane, diethyl sulfate One of , diethyl carbonate, bromoethane, acetaldehyde, acetic acid, methanol, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal or more,
其中：in:
R 0为H、C 1-6烷基或者环丙基，所述C 1-6烷基任选地进一步被1个或者多个选自卤素和氘的取代基取代； R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
R 1为
Figure PCTCN2022114328-appb-000012
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000012
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
m为0或者1；m is 0 or 1;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
R q1选自C 1-6烷基或者C 3-6环烷基。 R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
本发明的一个或多个实施方式中，上述式(I-d)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-d) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000013
Figure PCTCN2022114328-appb-000013
式(I-e)化合物和试剂Ⅰ在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-d)化合物，所述试剂Ⅰ选自碘乙烷、硫酸二乙酯、碳酸二乙酯、溴乙烷、乙醛、乙酸、甲醇、三氟甲磺酸乙酯、对甲苯磺酸乙酯和N,N-二甲基甲酰胺二乙基缩醛中的一种或多种。The compound of formula (I-e) and reagent I are reacted under conditions of inorganic base and/or organic base in a reaction solvent to prepare the compound of formula (I-d), and said reagent I is selected from ethyl iodide, diethyl sulfate, diethyl carbonate One or more of esters, bromoethane, acetaldehyde, acetic acid, methanol, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal.
本发明的一个或多个实施方式中，式(I-e)化合物和碘乙烷在非质子溶剂中，无机碱条件下反应，制备得到式(I-d)化合物。In one or more embodiments of the present invention, the compound of formula (I-e) is reacted with ethyl iodide in an aprotic solvent under inorganic base conditions to prepare the compound of formula (I-d).
本发明的一个或多个实施方式中，无机碱和/或有机碱、试剂Ⅰ与式(I-e)化合物的摩尔比为(1-4)：(1-5)：1；所述无机碱和/或有机碱、所述试剂Ⅰ与所述式(I-e-1)化合物的摩尔比为(1-4)：(1-5)：1。In one or more embodiments of the present invention, the molar ratio of the inorganic base and/or organic base, reagent I to the compound of formula (I-e) is (1-4):(1-5):1; the inorganic base and The molar ratio of/or the organic base, the reagent I to the compound of formula (I-e-1) is (1-4):(1-5):1.
本发明的一个或多个实施方式中，上述反应步骤的反应温度在20℃-40℃，优选25℃-35℃。In one or more embodiments of the present invention, the reaction temperature in the above reaction step is 20°C-40°C, preferably 25°C-35°C.
本发明的一个或多个实施方式中，上述式(I-e-1)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-e-1) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000014
Figure PCTCN2022114328-appb-000014
式(I-f-1)化合物和叠氮化试剂在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-e-1)化合物，The compound of formula (I-f-1) and the azidation reagent are reacted under the conditions of inorganic base and/or organic base in the reaction solvent to prepare the compound of formula (I-e-1),
其中：in:
R 1为
Figure PCTCN2022114328-appb-000015
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000015
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
m为0或者1；m is 0 or 1;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
R q1选自C 1-6烷基或者C 3-6环烷基。 R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
本发明的一个或多个实施方式中，上述式(I-e)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-e) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000016
Figure PCTCN2022114328-appb-000016
式(I-f)化合物和叠氮化试剂在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-e)化合物。The compound of formula (I-f) is reacted with the azidation reagent in a reaction solvent under the condition of inorganic base and/or organic base to prepare the compound of formula (I-e).
本发明的一个或多个实施方式中，所述叠氮化试剂选自叠氮磷酸二苯酯、叠氮基三甲基硅烷、叠氮化钠和叠氮酸中的一种或多种。In one or more embodiments of the present invention, the azidation reagent is selected from one or more of diphenylphosphoryl azide, azidotrimethylsilane, sodium azide and azide.
本发明的一个或多个实施方式中，式(I-f)化合物和叠氮化试剂在非质子溶剂中，碱性条件下反应，制备得到式(I-e)化合物；所述的叠氮化试剂选自DPPA。In one or more embodiments of the present invention, the compound of formula (I-f) and the azidation reagent are reacted in an aprotic solvent under basic conditions to prepare the compound of formula (I-e); the azidation reagent is selected from DPPA.
本发明的一个或多个实施方式中，为防止温度过高，叠氮化试剂加入过程中，控制反应液温度在30℃以下。In one or more embodiments of the present invention, in order to prevent the temperature from being too high, during the process of adding the azide reagent, the temperature of the reaction solution is controlled below 30°C.
本发明的一个或多个实施方式中，无机碱和/或有机碱、叠氮化试剂和式(I-f)化合物的摩尔比为(1-4)：(1-3)：1；所述无机碱和/或有机碱、所述叠氮化试剂和所述式(I-f-1)化合物的摩尔比为(1-4)：(1-3)：1。In one or more embodiments of the present invention, the molar ratio of inorganic base and/or organic base, azidation reagent and formula (I-f) compound is (1-4):(1-3):1; The molar ratio of the base and/or organic base, the azidation reagent and the compound of formula (I-f-1) is (1-4):(1-3):1.
本发明的一个或多个实施方式中，上述反应步骤中，加料完毕后，待检测到式(I-f)化合物完全转化后，反应液可以进一步加热至60-80℃，开始有气泡冒出，控制内温于80℃-100℃，直至气泡完全放出后，升温至95-105℃反应。In one or more embodiments of the present invention, in the above reaction step, after the addition of the feed is completed, after the complete conversion of the compound of formula (I-f) is detected, the reaction solution can be further heated to 60-80°C, and bubbles begin to emerge, and the control The internal temperature is 80°C-100°C, until the bubbles are completely released, then the temperature is raised to 95-105°C for reaction.
本发明的一个或多个实施方式中，上述式(I-f-1)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-f-1) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000017
Figure PCTCN2022114328-appb-000017
式(I-h-1)化合物和式(I-g-1)化合物在反应溶剂中，无机碱和/或有机碱条件下 反应，制备得到式(I-f-1)化合物，Formula (I-h-1) compound and formula (I-g-1) compound are reacted under inorganic base and/or organic base condition in reaction solvent, prepare formula (I-f-1) compound,
其中：in:
R 1为
Figure PCTCN2022114328-appb-000018
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000018
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
m为0或者1；m is 0 or 1;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
R q1选自C 1-6烷基或者C 3-6环烷基， R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl,
R q2选自C 1-6烷基或者C 3-6环烷基； R q2 is selected from C 1-6 alkyl or C 3-6 cycloalkyl;
R q3选自卤素； R q3 is selected from halogen;
Q选自一分子或多分子的无机酸，所述无机酸优选盐酸、硫酸、磷酸、氢溴酸、高氯酸或者氢碘酸。Q is selected from one or more molecules of inorganic acids, preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, perchloric acid or hydroiodic acid.
本发明的一个或多个实施方式中，上述式(I-f)化合物通过如下反应步骤制备而得：In one or more embodiments of the present invention, the above compound of formula (I-f) is prepared by the following reaction steps:
Figure PCTCN2022114328-appb-000019
Figure PCTCN2022114328-appb-000019
式(I-h)化合物和式(I-g)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-f)化合物。The compound of formula (I-h) and the compound of formula (I-g) are reacted in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-f).
本发明的一个或多个实施方式中，式(I-h)化合物和式(I-g)化合物在非质子溶剂或者非质子溶剂/H 2O的混合溶剂中，无机碱条件下反应；随后，加入无机碱的水溶液继续反应，制备得到式(I-f)化合物。 In one or more embodiments of the present invention, the compound of formula (Ih) and the compound of formula (Ig) are reacted under inorganic base conditions in an aprotic solvent or a mixed solvent of aprotic solvent/H 2 O; subsequently, adding an inorganic base The aqueous solution continues to react to prepare the compound of formula (If).
本发明的一个或多个实施方式中，无机碱和/或有机碱、式(I-g)化合物与式(I-h)化合物的摩尔比为(1-3)：(1-1.2)：1；所述无机碱和/或有机碱、所述式(I-g-1)化合物与所述式(I-h-1)化合物的摩尔比为(1-3)：(1-1.2)：1。In one or more embodiments of the present invention, the molar ratio of the inorganic base and/or organic base, the compound of formula (I-g) to the compound of formula (I-h) is (1-3): (1-1.2): 1; The molar ratio of the inorganic base and/or organic base, the compound of formula (I-g-1) to the compound of formula (I-h-1) is (1-3):(1-1.2):1.
本发明的一个或多个实施方式中，式(I-h)化合物和式(I-g)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，经HPLC检测反应完成后，加入无机碱的水溶液继续反应，无机碱与式(I-h)化合物的摩尔比为(2-5)：1。In one or more embodiments of the present invention, the compound of formula (I-h) and the compound of formula (I-g) are reacted under the conditions of inorganic base and/or organic base in the reaction solvent, after the completion of the reaction detected by HPLC, the aqueous solution of inorganic base is added Continue the reaction, the molar ratio of the inorganic base to the compound of formula (I-h) is (2-5):1.
本发明的一个或多个实施方式中，无机碱和/或有机碱加毕后，经检测反应完成后，反应液减压浓缩除去大部分溶剂，然后将氢氧化钠水溶液加入到反应液中，于60-70℃反应。In one or more embodiments of the present invention, after the addition of the inorganic base and/or the organic base is completed, after the detection reaction is completed, the reaction solution is concentrated under reduced pressure to remove most of the solvent, and then the aqueous sodium hydroxide solution is added to the reaction solution, React at 60-70°C.
本发明的一个或多个实施方式中，反应溶剂选自四氢呋喃、甲醇、乙醇、乙腈、丙酮、甲苯、异丙醇、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲基四氢呋喃、H 2O、二氯甲烷和叔丁醇中的一种或多种。 In one or more embodiments of the present invention, the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, toluene, isopropanol, 1,4-dioxane, N,N-dimethylformamide, One or more of N,N-dimethylacetamide, dimethyl sulfoxide, methyl tetrahydrofuran, H 2 O, dichloromethane and tert-butanol.
本发明的一个或多个实施方式中，当反应溶剂选自醇和H 2O时，所述醇与H 2O的体积比为(10-4)：1。 In one or more embodiments of the present invention, when the reaction solvent is selected from alcohol and H 2 O, the volume ratio of the alcohol to H 2 O is (10-4):1.
需要说明的是，反应时间根据反应原料量适当调整，能使反应正常进行并完成反应即可。It should be noted that the reaction time can be properly adjusted according to the amount of reaction raw materials, so that the reaction can proceed normally and the reaction can be completed.
本发明的一个或多个实施方式中，无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、氢氧化钡、四氢铝锂和氢氧化铯中的一种或多种；有机碱选自叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和叔戊醇钠中的一种或多种。In one or more embodiments of the present invention, the inorganic base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium aluminum hydride and cesium hydroxide species; the organic base is selected from sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7 One or more of -ene, 4-dimethylaminopyridine and sodium tert-amylate.
本发明的一个或多个实施方式中，氧化剂选自双氧水、间氯过氧苯甲酸、过氧单磺酸钾、高碘酸钠、叔丁基过氧化氢、氧气、N-氟代双苯磺酰胺、钼酸铵/双氧水、臭氧中的一种或多种。In one or more embodiments of the present invention, the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, sodium periodate, tert-butyl hydroperoxide, oxygen, N-fluorobiphenyl One or more of sulfonamide, ammonium molybdate/hydrogen peroxide, and ozone.
本发明的一个或多个实施方式中，提供一种式(I)的咪唑啉酮衍生物或者其立体异构体的制备工艺，包括如下步骤：In one or more embodiments of the present invention, there is provided a preparation process of imidazolinone derivatives of formula (I) or stereoisomers thereof, comprising the following steps:
Figure PCTCN2022114328-appb-000020
Figure PCTCN2022114328-appb-000020
第一步：式(I-h)化合物和式(I-g)化合物在非质子溶剂或者非质子溶剂/H 2O的 混合溶剂中，无机碱条件下反应；随后，加入无机碱的水溶液继续反应，制备得到式(I-f)化合物； The first step: the compound of formula (Ih) and the compound of formula (Ig) are reacted in an aprotic solvent or a mixed solvent of aprotic solvent/H 2 O under the condition of an inorganic base; subsequently, an aqueous solution of an inorganic base is added to continue the reaction to prepare A compound of formula (If);
第二步：式(I-f)化合物和叠氮化试剂在非质子溶剂中，碱性条件下反应，制备得到式(I-e)化合物；上述的叠氮化试剂选自DPPA；The second step: the compound of formula (I-f) and the azidation reagent react in an aprotic solvent under basic conditions to prepare the compound of formula (I-e); the above-mentioned azidation reagent is selected from DPPA;
第三步：式(I-e)化合物和碘乙烷在非质子溶剂中，无机碱条件下反应，制备得到式(I-d)化合物；Step 3: the compound of formula (I-e) reacts with ethyl iodide in an aprotic solvent under inorganic base conditions to prepare the compound of formula (I-d);
第四步：式(I-d)化合物在醇和/或H 2O的溶剂中，加入氧化剂反应，制备得到式(I-c1)化合物和式(I-c2)化合物；上述的氧化剂选自Oxone或者mCPBA； The fourth step: the compound of formula (Id) is reacted with an oxidizing agent in alcohol and/or H 2 O solvent to prepare the compound of formula (I-c1) and compound of formula (I-c2); the above-mentioned oxidizing agent is selected from Oxone or mCPBA ;
第五步：式(I-c1)化合物、式(I-c2)化合物和式(I-b)化合物在非质子溶剂中，无机碱或者有机碱条件下反应，制备得到式(I-a)化合物；The fifth step: the compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (I-b) are reacted in an aprotic solvent under the conditions of inorganic base or organic base to prepare the compound of formula (I-a);
第六步：式(I-a)化合物在DMSO溶液中，无机碱条件下，加入氧化剂反应，制备得到式(I)化合物；上述的氧化剂选自H 2O 2。 Step 6: The compound of formula (Ia) is reacted in DMSO solution under the condition of inorganic alkali by adding an oxidizing agent to obtain the compound of formula (I); the above-mentioned oxidizing agent is selected from H 2 O 2 .
本发明的一个或多个实施方式中，提供一种用于制备上述式(I)化合物的中间体或者其立体异构体，其中该中间体选自：In one or more embodiments of the present invention, there is provided an intermediate or a stereoisomer thereof for the preparation of the compound of formula (I), wherein the intermediate is selected from:
Figure PCTCN2022114328-appb-000021
Figure PCTCN2022114328-appb-000021
其中：in:
R 0为H、C 1-6烷基或者环丙基，所述C 1-6烷基任选地进一步被1个或者多个选自卤素和氘的取代基取代； R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
R 1为
Figure PCTCN2022114328-appb-000022
且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代； R1 is
Figure PCTCN2022114328-appb-000022
And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
R 2为H、氰基、＝O、羧基、-C(＝O)NR 2aR 2b、C 1-6烷氧基、C 1-6烷基、卤素、-S(＝O) 2R 2a或者-C(＝O)OC 1-6烷基；所述C 1-6烷基、-C(＝O)OC 1-6烷基或者C 1-6烷氧基任选地被1个或 者多个选自卤素和氘的取代基取代； R 2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1-6 alkoxy, C 1-6 alkyl, halogen, -S(=O) 2 R 2a Or -C(=O)OC 1-6 alkyl; said C 1-6 alkyl, -C(=O)OC 1-6 alkyl or C 1-6 alkoxy is optionally replaced by 1 or Multiple substituents selected from halogen and deuterium are substituted;
R 2a和R 2b各自独立地为H、C 1-6烷基或者3至5元环烷基，其中所述C 1-6烷基任选地进一步被1个或者多个选自OH、D、卤素、C 1-6烷基和C 1-6烷氧基的取代基取代； R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
或者，R 2a和R 2b与其相连的原子一起形成5至6元杂环基，所述5至6元杂环基含有1、2或3个选自N、O和S的杂原子，所述5至6元杂环基任选地进一步被1个或者多个选自C 1-6烷基、OH和卤素的取代基取代； Alternatively, R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
R 3为卤素或者C 1-6烷基，所述C 1-6烷基任选地进一步被1至3个选自D和卤素的取代基取代； R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
m为0或者1；m is 0 or 1;
n为0、1或2；n is 0, 1 or 2;
x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
n为1时，R 0为H或者甲基，R 2为甲氧基或者-S(＝O) 2Me，R 3为甲基； When n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2 Me, R 3 is methyl;
R q2选自C 1-6烷基或者C 3-6环烷基； R q2 is selected from C 1-6 alkyl or C 3-6 cycloalkyl;
R q3选自卤素； R q3 is selected from halogen;
R q1选自C 1-6烷基或者C 3-6环烷基。 R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
本发明的一个或多个实施方式中，提供一种用于制备上述式(I)化合物的中间体或者其立体异构体，其中该中间体选自：In one or more embodiments of the present invention, there is provided an intermediate or a stereoisomer thereof for the preparation of the compound of formula (I), wherein the intermediate is selected from:
Figure PCTCN2022114328-appb-000023
Figure PCTCN2022114328-appb-000023
Figure PCTCN2022114328-appb-000024
或者
Figure PCTCN2022114328-appb-000025
Figure PCTCN2022114328-appb-000024
or
Figure PCTCN2022114328-appb-000025
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group. Condition.
碱指在水溶液中电离出OH-的化合物；或者能够接受质子的化合物；本发明所述的无机碱如碳酸钾，碳酸钠，碳酸铯，氢氧化钠，氢氧化钾，氢氧化钡，氢氧化铯等。Alkali refers to the compound that ionizes out OH- in aqueous solution; Or the compound that can accept proton; Inorganic base of the present invention such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, hydroxide cesium, etc.
本发明所述的有机碱指含有氮原子，例如胺类化合物和含氮杂环化合物。非限定性实施例：甲醇钠，乙醇钾，叔丁醇钾，丁基锂，苯基锂，格氏试剂，氢氧化季铵盐，吡啶，胺基锂化合物(例如二异丙基胺基锂(LDA)，六甲基二硅胺基锂(LiHMDS)等)。本发明所选取的有机碱如叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和叔戊醇钠等。The organic bases mentioned in the present invention refer to nitrogen atoms, such as amine compounds and nitrogen-containing heterocyclic compounds. Non-limiting examples: sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, Grignard reagents, quaternary ammonium hydroxides, pyridine, lithium amides such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), etc.). The organic bases selected in the present invention such as sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecyl -7-ene, 4-dimethylaminopyridine and sodium tert-amylate, etc.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;
DTT：二硫苏糖醇；DTT: dithiothreitol;
ATP：三磷酸腺苷；ATP: adenosine triphosphate;
DNA：脱氧核糖核苷酸。DNA: Deoxyribonucleotides.
IC50：是指DNA-PK激酶的活性受到50％抑制时化合物的浓度；IC50: refers to the concentration of the compound when the activity of DNA-PK kinase is inhibited by 50%;
MPLC：中压硅胶柱色谱。MPLC: medium pressure silica gel column chromatography.
实施例Example
实施例1Example 1
4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲酰胺化合物14-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2- Fluoro-5-methylbenzamide compound 1
4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide
Figure PCTCN2022114328-appb-000026
Figure PCTCN2022114328-appb-000026
第一步：first step:
2-(甲硫基)4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c
2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid
向50L反应釜中加入20L四氢呋喃，再加入10L去离子水，随后加入4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯1a(5.000kg,1.0eq.)和四氢-2H-吡喃-4-胺盐酸盐1b(3.166kg,1.07eq.)，大量固体不溶解。分批缓慢加入碳酸钾固体(5.934kg，2.0eq.)，内温由16℃上升至32℃，室温搅拌3h后，经HPLC检测反应完成。反应液于45℃减压蒸馏除去大部分四氢呋喃后，将配制好的氢氧化钠水溶液(3.0kg氢氧化钠溶于10L去离子水中)加入到反应釜中。反应液略有升温，然后将反应液升温至60℃反应5h，反应液中大量固体溶解，逐渐接近澄清，送样HPLC检测反应完成。随后，将反应液降温至室温，缓慢滴加浓盐酸，有大量气泡产生，固体逐渐溶解，反应液变澄清，继续滴加浓盐酸后，大量白色固体析出，直至调节pH值于3后，继续搅拌0.5h，复测pH至仍是3后，离心机过滤，滤饼于40℃鼓风干燥箱中干燥5h后，得到 白色固体2-(甲硫基)-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c(6.5kg，收率112.1％)。Add 20L tetrahydrofuran to the 50L reactor, then add 10L deionized water, then add 4-chloro-2-(methylthio)pyrimidine-5-carboxylate ethyl ester 1a (5.000kg, 1.0eq.) and tetrahydro- 2H-pyran-4-amine hydrochloride 1b (3.166kg, 1.07eq.), a lot of solids did not dissolve. Potassium carbonate solid (5.934kg, 2.0eq.) was slowly added in batches, and the internal temperature rose from 16°C to 32°C. After stirring at room temperature for 3 hours, the reaction was detected by HPLC. After the reaction solution was distilled off under reduced pressure at 45°C to remove most of the tetrahydrofuran, the prepared aqueous sodium hydroxide solution (3.0 kg of sodium hydroxide dissolved in 10 L of deionized water) was added into the reaction kettle. The temperature of the reaction solution was slightly raised, and then the temperature of the reaction solution was raised to 60° C. for 5 hours. A large amount of solids in the reaction solution were dissolved and gradually became clear, and the reaction was completed by sending samples to HPLC for detection. Subsequently, the reaction solution was cooled to room temperature, and concentrated hydrochloric acid was slowly added dropwise. A large number of bubbles were generated, the solid gradually dissolved, and the reaction solution became clear. Stir for 0.5h, retest the pH until it is still 3, filter with a centrifuge, and dry the filter cake in a blast drying oven at 40°C for 5h to obtain a white solid 2-(methylthio)-4-((tetrahydro-2H -pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c (6.5 kg, yield 112.1%).
LCMS m/z(ESI)＝270.1[M+1].LCMS m/z(ESI)＝270.1[M+1].
1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),8.53(s,1H),8.38-8.36(d,2H),4.24-4.19(m,2H),3.87-3.84(m,2H),3.47-3.45(m,2H),2.46(s,3H),1.95-1.90(m,2H),1.56-1.50(m,2H). 1 H NMR (400MHz,DMSO-d6)δ13.32(s,1H),8.53(s,1H),8.38-8.36(d,2H),4.24-4.19(m,2H),3.87-3.84(m, 2H),3.47-3.45(m,2H),2.46(s,3H),1.95-1.90(m,2H),1.56-1.50(m,2H).
第二步：Step two:
2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1d
2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
向50L反应釜中加入15L N,N-二甲基乙酰胺，然后加入2-(甲硫基)-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c(2.900kg,1.0eq.)，大量固体未溶解，然后加入三乙胺(1.140kg,1.05eq.)，固体逐渐溶解，反应液呈黄色，然后缓慢加入叠氮磷酸二苯酯(3.112kg,1.05eq.)，有升温现象，控制滴加温度在30℃以下，加料完毕后，室温搅拌2h，HPLC检测1c完全转化后，反应液加热至65℃，开始有气泡冒出，控制内温于80℃-100℃，直至气泡完全放出后，升温至100℃反应2h。HPLC检测反应完成后，向反应釜中加入30L去离子水，大量固体析出，搅拌0.5h后离心过滤，滤饼用10L去离子水淋洗，离心至无明显液滴滴出后，取出滤饼于60℃鼓风干燥箱中干燥8h，得到类白色固体2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d(2.583kg，收率90.1％)。Add 15L N,N-dimethylacetamide to the 50L reactor, then add 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxy Acid 1c (2.900kg, 1.0eq.), a large amount of solids were not dissolved, then triethylamine (1.140kg, 1.05eq.) was added, the solids gradually dissolved, the reaction solution was yellow, and then diphenylphosphoryl azide (3.112 kg, 1.05eq.), there is a phenomenon of temperature rise, control the dropping temperature below 30°C, after the addition is complete, stir at room temperature for 2h, after HPLC detects that 1c is completely converted, the reaction solution is heated to 65°C, bubbles begin to emerge, control the Warm at 80°C-100°C until the bubbles are completely released, then raise the temperature to 100°C for 2 hours. After the HPLC detection reaction is completed, add 30L deionized water to the reaction kettle, a large amount of solids are precipitated, stir for 0.5h and then centrifugally filter, rinse the filter cake with 10L deionized water, centrifuge until no obvious droplets drip out, then take out the filter cake Dry in a blast oven at 60°C for 8 hours to obtain off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-keto 1d (2.583 kg, yield 90.1%).
LCMS m/z(ESI)＝267.1[M+1].LCMS m/z(ESI)＝267.1[M+1].
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.10(s,1H),4.43-4.34(m,1H),3.98-3.94(m,2H),3.46-3.32(m,2H),2.50(s,3H),2.49-2.42(m,2H),1.67-1.62(m,2H). 1 H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.10(s,1H),4.43-4.34(m,1H),3.98-3.94(m,2H),3.46-3.32(m, 2H),2.50(s,3H),2.49-2.42(m,2H),1.67-1.62(m,2H).
第三步：third step:
7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e7-Ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1e
7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
向50L反应釜中加入15L N,N-二甲基甲酰胺，再加入原料7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d(3.00kg,1.0eq.)，大量固体未溶解，呈白色悬浊液，再称量氢氧化钠固体(901.2g,2.0eq.)，于室温加入到反应釜，固体逐渐溶解，呈黄色透明溶液。内温于30℃左右，之后再缓慢滴加碘乙烷，有明显升温现象，控制温度于30±5℃，滴加完成后，室温搅拌3h。HPLC检测反 应完成，向反应液中倒入冰水30L，大量固体析出，搅拌0.5h后离心过滤，滤饼用10L去离子水淋洗，离心至无液滴滴出后，滤饼于60℃鼓风干燥箱中干燥8h，得到类白色固体7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e(2.810kg,收率84.8％)。Add 15L N,N-dimethylformamide to the 50L reactor, and then add the raw material 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7 , 9-dihydro-8H-purin-8-one 1d (3.00kg, 1.0eq.), a large amount of undissolved solid, white suspension, and then weigh the sodium hydroxide solid (901.2g, 2.0eq.), Add it to the reaction kettle at room temperature, the solid gradually dissolves, and it becomes a yellow transparent solution. The internal temperature is about 30°C, and then slowly add iodoethane dropwise, there is a significant temperature rise phenomenon, control the temperature at 30±5°C, after the dropwise addition is completed, stir at room temperature for 3 hours. HPLC detected that the reaction was complete, poured 30L of ice water into the reaction solution, a large amount of solids precipitated, stirred for 0.5h and then centrifugally filtered, the filter cake was rinsed with 10L of deionized water, and after centrifugation until no liquid dripped out, the filter cake was placed at 60°C Dry in a blast oven for 8 hours to obtain off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- Purin-8-one 1e (2.810kg, yield 84.8%).
LCMS m/z(ESI)＝295.1[M+1].LCMS m/z(ESI)＝295.1[M+1].
1H NMR(400MHz,DMSO-d6)δ8.38-8.37(d,1H),4.46-4.40(m,1H),3.99-3.94(m,2H),3.88-3.83(m,2H),3.47-3.41(m,2H),2.50(s,3H),2.50-2.43(m,2H),1.69-1.64(m,2H),1.25-1.21(t,3H). 1 H NMR (400MHz,DMSO-d6)δ8.38-8.37(d,1H),4.46-4.40(m,1H),3.99-3.94(m,2H),3.88-3.83(m,2H),3.47- 3.41(m,2H),2.50(s,3H),2.50-2.43(m,2H),1.69-1.64(m,2H),1.25-1.21(t,3H).
第四步：the fourth step:
7-乙基-2-(甲磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1f7-Ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1f
7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
7-乙基-2-(甲基亚磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1g7-Ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1g
7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
向50L反应釜的中加入16L甲醇,然后将原料7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e(2.0kg,1.0eq.)加入到反应釜，部分固体不溶解，再加入2L纯净水，部分固体未溶解；然后于室温分五批缓慢加入过氧单磺酸钾(Oxone)(2.920kg,0.7eq.),有放热现象，反应液由白色浑浊液逐渐变为黄色浑浊液，然后再次变回白色浑浊液，控制温度于35±5℃之间；反应2h后，经HPLC检测确认反应完成(原料剩余<3％)，将反应液降温至0±5℃，搅拌0.5h后，过滤反应液(滤饼含有大量产物、未反应剩余的过氧单磺酸钾及过氧单磺酸钾反应后的硫酸盐)；滤饼用10L二氯甲烷搅洗，0.5h后过滤，滤饼再次用10L二氯甲烷搅洗，0.5h后过滤，合并两次洗涤的二氯甲烷相；50℃常压蒸馏除去溶剂(二氯甲烷)后，剩余物用10L正己烷打浆0.5h后过滤，滤饼于40℃在鼓风干燥箱中干燥5h。得到7-乙基-2-(甲磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1f和7-乙基-2-(甲基亚磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1g的混合物(1.940kg,收率92.0％)。Add 16L of methanol to the 50L reactor, and then feed the raw material 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H -Purin-8-one 1e (2.0kg, 1.0eq.) was added to the reaction kettle, some of the solids were not dissolved, then 2L of purified water was added, some of the solids were not dissolved; then potassium peroxymonosulfonate was slowly added in five batches at room temperature (Oxone) (2.920kg, 0.7eq.), there is exothermic phenomenon, the reaction liquid gradually changes from white turbid liquid to yellow turbid liquid, and then turns back to white turbid liquid again, control the temperature between 35±5°C; react for 2h Afterwards, detect through HPLC and confirm that reaction is finished (raw material remaining＜3%), reaction solution is cooled to 0 ± 5 ℃, after stirring 0.5h, filter reaction solution (filter cake contains a large amount of product, unreacted remaining peroxymonosulfonic acid Potassium and potassium peroxymonosulfonate reacted sulfate); the filter cake was stirred and washed with 10L dichloromethane, filtered after 0.5h, the filter cake was stirred again with 10L dichloromethane, filtered after 0.5h, and the two washings were combined The dichloromethane phase; after the solvent (dichloromethane) was distilled off under normal pressure at 50°C, the residue was slurried with 10L n-hexane for 0.5h and then filtered, and the filter cake was dried in a blast oven at 40°C for 5h. 7-Ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1f and 7-ethyl -2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1g mixture (1.940kg, yield 92.0%).
1f:LCMS m/z(ESI)＝327.1[M+1].1f:LCMS m/z(ESI)＝327.1[M+1].
1g:LCMS m/z(ESI)＝311.1[M+1].1g:LCMS m/z(ESI)＝311.1[M+1].
第五步：the fifth step:
4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5- 甲基苯甲腈1i4-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2- Fluoro-5-methylbenzonitrile 1i
4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile
向5L反应釜中加入2L二氯甲烷，然后再将原料1f及1g的混合物(100g,1.0eq.)加入到反应釜，原料完全溶解，呈无色溶液，然后再加入1h(47.8g，1.0eq.)，固体溶解，反应液呈棕黑色。将反应液降温至-5-0℃，分批缓慢加入叔丁醇钾(107g,3.0eq.,粉末固体)，有明显的升温现象，控制温度于-5-0℃，有固体析出，反应液变粘稠。缓慢升温至室温，于室温反应3h后，经HPLC检测反应完成(化合物1h峰面积<2％)，向反应釜加入纯净水100ml，搅拌0.5h后，加入甲醇200ml(溶液未澄清分层)，再加入二氯甲烷/甲醇(500ml,DCM:MeOH＝10:1)的混合溶液，再加入2L纯净水，下层固体完全溶解，搅拌1h后，分液。有机相经硅藻土过滤后，减压浓缩(瓶中无流动性二氯甲烷)，固体用乙酸乙酯(1L)打浆，然后再次过滤，滤液呈黑色溶液，滤饼为类白色固体。滤饼用1L乙酸乙酯淋洗，洗脱液呈无色溶液，滤饼于60℃在鼓风干燥箱中干燥2h。得到4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i(95g,收率75％)。Add 2L of dichloromethane to the 5L reactor, then add the mixture of raw material 1f and 1g (100g, 1.0eq.) eq.), the solid dissolved, and the reaction solution was brownish black. Cool the reaction solution to -5-0°C, slowly add potassium tert-butoxide (107g, 3.0eq., powder solid) in batches, there is an obvious temperature rise, control the temperature at -5-0°C, solids are precipitated, and the reaction The liquid becomes viscous. Slowly warming up to room temperature, after reacting at room temperature for 3 hours, the reaction was detected by HPLC (compound 1h peak area<2%), 100ml of pure water was added to the reaction kettle, after stirring for 0.5h, 200ml of methanol was added (the solution was not clarified and layered), A mixed solution of dichloromethane/methanol (500ml, DCM:MeOH=10:1) was added, and 2L of purified water was added to completely dissolve the solid in the lower layer. After stirring for 1 h, the liquid was separated. After the organic phase was filtered through celite, it was concentrated under reduced pressure (there was no fluid dichloromethane in the bottle), the solid was slurried with ethyl acetate (1 L), and then filtered again. The filtrate was a black solution, and the filter cake was an off-white solid. The filter cake was rinsed with 1L of ethyl acetate, and the eluent was a colorless solution. The filter cake was dried at 60°C in a forced air drying oven for 2 hours. 4-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2 -Fluoro-5-methylbenzonitrile 1i (95 g, yield 75%).
LCMS m/z(ESI)＝397.2[M+1].LCMS m/z(ESI)＝397.2[M+1].
1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.31(s,1H),8.22-8.19(d,1H),4.49-4.41(m,1H),4.00-3.96(m,2H),3.87-3.83(m,2H),3.46-3.39(m,2H),2.57-2.52(m,2H),2.32(s,3H),1.71-1.67(m,2H),1.27-1.23(t,3H). 1 H NMR (400MHz,DMSO-d6)δ8.79(s,1H),8.31(s,1H),8.22-8.19(d,1H),4.49-4.41(m,1H),4.00-3.96(m, 2H),3.87-3.83(m,2H),3.46-3.39(m,2H),2.57-2.52(m,2H),2.32(s,3H),1.71-1.67(m,2H),1.27-1.23( t,3H).
19F NMR(400MHz,DMSO-d6)δ111.805. 19 F NMR (400MHz, DMSO-d6) δ111.805.
第六步：Step six:
4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲酰胺化合物14-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2- Fluoro-5-methylbenzamide compound 1
4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide
向50L反应釜中加入9.5L二甲基亚砜，然后再加入原料4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i(700g，1.0eq.)，然后再加入碳酸钾水溶液(243.3g,1.0eq.溶于100ml纯水中)，于室温缓慢滴加双氧水(600ml,3.0eq.,30％的水溶液)，有明显的升温现象，控制温度于30±10℃之间，直至滴加完毕。反应液升温至40℃反应2h。经HPLC检测反应完成，反应液降温至室温后，加入30L纯净水，大量固体析出，搅拌1h后，离心过 滤。滤液呈橙色溶液，滤饼为类白色固体。滤饼于60℃在鼓风干燥箱中干燥8h。得到类白色固体4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲酰胺化合物1(700g,收率95.6％，纯度＞90％)。In the 50L reactor, add 9.5L dimethyl sulfoxide, then add raw material 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8, 9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i (700g, 1.0eq.), and then add potassium carbonate aqueous solution (243.3g, 1.0eq. In 100ml of pure water), slowly add hydrogen peroxide (600ml, 3.0eq., 30% aqueous solution) dropwise at room temperature, there will be obvious heating phenomenon, control the temperature between 30±10°C until the dropwise addition is completed. The temperature of the reaction solution was raised to 40° C. for 2 h. The completion of the reaction was detected by HPLC. After the reaction solution was cooled to room temperature, 30L of pure water was added, and a large amount of solids were precipitated. After stirring for 1 h, it was centrifugally filtered. The filtrate was an orange solution, and the filter cake was an off-white solid. The filter cake was dried in a blast oven at 60°C for 8 hours. 4-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino was obtained as an off-white solid )-2-fluoro-5-methylbenzamide compound 1 (700g, yield 95.6%, purity>90%).
LCMS m/z(ESI)＝415.2[M+1] +. LCMS m/z (ESI) = 415.2[M+1] + .
HRMS m/z(ESI)＝415.1904[M+1] +&437.1713[M+Na] +. HRMS m/z(ESI)＝415.1904[M+1] + &437.1713[M+Na] + .
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.24(s,1H),7.93-7.89(d,1H),7.56-7.54(d,1H),7.46(s,1H),7.38-7.37(d,1H),4.48-4.40(m,1H),3.97-3.96(m,2H),3.86-3.42(m,2H),3.46-3.39(m,2H),2.59-2.50(m,2H),2.30(s,3H),1.71-1.67(m,2H),1.26-1.23(t,3H). 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.24(s,1H),7.93-7.89(d,1H),7.56-7.54(d,1H),7.46(s,1H) ,7.38-7.37(d,1H),4.48-4.40(m,1H),3.97-3.96(m,2H),3.86-3.42(m,2H),3.46-3.39(m,2H),2.59-2.50( m,2H),2.30(s,3H),1.71-1.67(m,2H),1.26-1.23(t,3H).
19F NMR(400MHz,DMSO-d6)δ115.501. 19 F NMR (400MHz, DMSO-d6) δ115.501.
13C NMR(400MHz,DMSO-d6)δ165.255,165.232,159.960,157.530,154.717,151.987,150.132,142.998,142.882,124.104,124.077,116.809,115.691,107.716,107.430,67.004,49.728,36.202,29.934,17.791,13.892. 13 C NMR(400MHz,DMSO-d6)δ165.255,165.232,159.960,157.530,154.717,151.987,150.132,142.998,142.882,124.104,124.077,116.809,115.691,107.716,107.430,67.004,49.728,36.202,29.934,17.791, 13.892.
实施例2Example 2
本实施例与实施例1的区别主要在于第一步，本实施例中第一步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the first step, and the implementation process of the first step in the present embodiment is as follows:
2-(甲硫基)4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c
2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid
参照实施例1化合物的第一步制备方法制备，区别在于：Prepare with reference to the first step preparation method of the compound of Example 1, the difference is:
反应溶剂为15L N,N-二甲基甲酰胺和5L去离子水，原料为4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯1a(4.500kg,19.3mol)和四氢-2H-吡喃-4-胺盐酸盐1b(2.656kg,19.3mol)，碱为氢氧化钠固体(772g，19.3mol)，无机碱的水溶液为氢氧化钠水溶液(1.93kg氢氧化钠溶于8L去离子水中)。反应完成，后处理及干燥后得到白色固体2-(甲硫基)-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c。The reaction solvent was 15L N,N-dimethylformamide and 5L deionized water, and the raw materials were 4-chloro-2-(methylthio)pyrimidine-5-carboxylate ethyl ester 1a (4.500kg, 19.3mol) and four Hydrogen-2H-pyran-4-amine hydrochloride 1b (2.656kg, 19.3mol), the base is sodium hydroxide solid (772g, 19.3mol), the aqueous solution of inorganic base is sodium hydroxide aqueous solution (1.93kg sodium hydroxide dissolved in 8L deionized water). After the reaction was completed, 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c was obtained as a white solid after work-up and drying.
实施例3Example 3
本实施例与实施例1的区别主要在于第一步，本实施例中第一步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the first step, and the implementation process of the first step in the present embodiment is as follows:
2-(甲硫基)4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c
2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid
参照实施例1化合物的第一步制备方法制备，区别在于：Prepare with reference to the first step preparation method of the compound of Example 1, the difference is:
反应溶剂为15L丙酮、3L去离子水和15L N,N-二甲基乙酰胺，原料为4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯1a(6.0kg,25.79mol)和四氢-2H-吡喃-4-胺盐酸盐1b(4.258kg,30.94mol)，碱为叔丁醇钠(7.435kg，77.37mol)，无机碱的水溶液为氢氧化钾水溶液(6.511kg氢氧化钾溶于20L去离子水中)。反应完成，后处理及干燥后得到白色固体2-(甲硫基)-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c。The reaction solvent is 15L acetone, 3L deionized water and 15L N,N-dimethylacetamide, and the raw material is ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 1a (6.0kg, 25.79mol ) and tetrahydro-2H-pyran-4-amine hydrochloride 1b (4.258kg, 30.94mol), the base is sodium tert-butoxide (7.435kg, 77.37mol), and the aqueous solution of inorganic base is potassium hydroxide aqueous solution (6.511 kg potassium hydroxide dissolved in 20L deionized water). After the reaction was completed, 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c was obtained as a white solid after work-up and drying.
实施例4Example 4
本实施例与实施例1的区别主要在于第二步，本实施例中第二步的实施过程如下：第二步：The difference between the present embodiment and embodiment 1 mainly lies in the second step, and the implementation process of the second step in the present embodiment is as follows: the second step:
2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1d
2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
参照实施例1化合物的第二步制备方法制备，区别在于：Prepare with reference to the second step preparation method of the compound of Example 1, the difference is:
反应溶剂为14L二甲基亚砜，原料为2-(甲硫基)-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c(3.45kg,12.81mol.)，碱为N,N-二异丙基乙胺(1.656kg,12.81mol)，叠氮化试剂为叠氮基三甲基硅烷(1.476kg,12.81mol)。反应完成，后处理及干燥后得到类白色固体2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d。The reaction solvent is 14L dimethyl sulfoxide, and the raw material is 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c (3.45kg, 12.81 mol.), the base is N,N-diisopropylethylamine (1.656kg, 12.81mol), and the azidation reagent is azidotrimethylsilane (1.476kg, 12.81mol). After the reaction was completed, the off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one was obtained after post-treatment and drying 1d.
实施例5Example 5
本实施例与实施例1的区别主要在于第二步，本实施例中第二步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the second step, and the implementation process of the second step in the present embodiment is as follows:
第二步：Step two:
2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1d
2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
参照实施例1化合物的第二步制备方法制备，区别在于：Prepare with reference to the second step preparation method of the compound of Example 1, the difference is:
反应溶剂为18L乙腈，原料为2-(甲硫基)-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸1c(2.56kg,9.51mol)，碱为1,8-二氮杂二环[5.4.0]十一碳-7-烯(5.788kg,38.02mol.)，叠氮化试剂为叠氮化钠(1.855kg,28.53mol)。反应完成，后处理及干燥后得到类白色固体2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d。The reaction solvent is 18L acetonitrile, the raw material is 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c (2.56kg, 9.51mol), base It is 1,8-diazabicyclo[5.4.0]undec-7-ene (5.788kg, 38.02mol.), and the azide reagent is sodium azide (1.855kg, 28.53mol). After the reaction was completed, the off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one was obtained after post-treatment and drying 1d.
实施例6Example 6
本实施例与实施例1的区别主要在于第三步，本实施例中第三步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the third step, and the implementation process of the third step in the present embodiment is as follows:
第三步：third step:
7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e7-Ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1e
7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
参照实施例1化合物的第三步制备方法制备，区别在于：Prepare with reference to the third step preparation method of the compound of Example 1, the difference is:
反应溶剂为45L乙醇，原料为7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d(3.89kg,14.61mol)，碱为叔丁醇钾(1.639kg,14.61mol)，试剂Ⅰ为碘乙烷(2.279kg,14.61mol)。反应完成，后处理及干燥后得到类白色固体7 -乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e。The reaction solvent is 45L ethanol, and the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8- Ketone 1d (3.89kg, 14.61mol), the base is potassium tert-butoxide (1.639kg, 14.61mol), and the reagent I is ethyl iodide (2.279kg, 14.61mol). After the reaction was completed, the off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- Purin-8-one 1e.
实施例7Example 7
本实施例与实施例1的区别主要在于第三步，本实施例中第三步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the third step, and the implementation process of the third step in the present embodiment is as follows:
第三步：third step:
7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e7-Ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1e
7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
参照实施例1化合物的第三步制备方法制备，区别在于：Prepare with reference to the third step preparation method of the compound of Example 1, the difference is:
反应溶剂为16L乙腈和8L H 2O，原料为7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1d(1.58kg,5.93mol)，碱为三乙胺(1.20kg,11.86mol)，试剂Ⅰ为碳酸二乙酯(1.75kg,14.825mol)。反应完成，后处理及干燥后得到类白色固体7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e。 The reaction solvent is 16L acetonitrile and 8L H 2 O, and the starting material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H - Purin-8-one 1d (1.58kg, 5.93mol), the base is triethylamine (1.20kg, 11.86mol), and the reagent I is diethyl carbonate (1.75kg, 14.825mol). After the reaction was completed, the off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- Purin-8-one 1e.
实施例8Example 8
本实施例与实施例1的区别主要在于第四步，本实施例中第四步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the fourth step, and the implementation process of the fourth step in this embodiment is as follows:
7-乙基-2-(甲磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1f7-Ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1f
7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
7-乙基-2-(甲基亚磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1g7-Ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1g
7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
参照实施例1化合物的第四步制备方法制备，区别在于：Prepare with reference to the fourth step preparation method of the compound of Example 1, the difference is:
反应溶剂为20L叔丁醇和2L纯净水，原料为7-乙基-2-(甲硫基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e(2.53kg,8.59mol)，氧化剂为间氯过氧苯甲酸(mCPBA)(0.741kg,4.295mol)。反应完成，后处理及干燥后得到7-乙基-2-(甲磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1f和7-乙基-2-(甲基亚磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1g的混合物。The reaction solvent is 20L tert-butanol and 2L purified water, and the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H - Purin-8-one 1e (2.53 kg, 8.59 mol), the oxidizing agent is m-chloroperoxybenzoic acid (mCPBA) (0.741 kg, 4.295 mol). After the reaction was completed, 7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8 was obtained after work-up and drying - Ketone 1f and 7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1g mixture.
实施例9Example 9
本实施例与实施例1的区别主要在于第四步，本实施例中第四步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the fourth step, and the implementation process of the fourth step in this embodiment is as follows:
7-乙基-2-(甲磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1f7-Ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1f
7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
7-乙基-2-(甲基亚磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1g7-Ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1g
7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one
参照实施例1化合物的第四步制备方法制备，区别在于：Prepare with reference to the fourth step preparation method of the compound of Example 1, the difference is:
反应溶剂为25L异丙醇和10L纯净水，原料为7-乙基-2-(甲硫基)-9-(四氢-2 H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1e(3.27kg,11.11mol)，氧化剂为高碘酸钠(4.75kg,22.22mol)。反应完成，后处理及干燥后得到7-乙基-2-(甲磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1f和7-乙基-2-(甲基亚磺酰基)-9-(四氢-2H-吡喃-4-基)-7,9-二氢-8H-嘌呤-8-酮1g的混合物。The reaction solvent is 25L isopropanol and 10L purified water, and the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2 H-pyran-4-yl)-7,9-dihydro- 8H-purin-8-one 1e (3.27kg, 11.11mol), the oxidizing agent is sodium periodate (4.75kg, 22.22mol). After the reaction was completed, 7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8 was obtained after work-up and drying - Ketone 1f and 7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1g mixture.
实施例10Example 10
本实施例与实施例1的区别主要在于第五步，本实施例中第五步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the fifth step, and the implementation process of the fifth step in the present embodiment is as follows:
4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i4-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2- Fluoro-5-methylbenzonitrile 1i
4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile
参照实施例1化合物的第五步制备方法制备，区别在于：Prepare with reference to the fifth step preparation method of the compound of Example 1, the difference is:
反应溶剂为1L乙腈，原料为1f及1g的混合物(100g,1.0eq.)和1h(75.08g，0.5eq.)，碱为N,N-二异丙基乙胺(129.25g,1.0eq)。反应完成，后处理及干燥后得到4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i。The reaction solvent is 1L acetonitrile, the raw material is the mixture of 1f and 1g (100g, 1.0eq.) and 1h (75.08g, 0.5eq.), the base is N,N-diisopropylethylamine (129.25g, 1.0eq) . After completion of the reaction, post-treatment and drying yielded 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine- 2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i.
实施例11Example 11
本实施例与实施例1的区别主要在于第五步，本实施例中第五步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the fifth step, and the implementation process of the fifth step in the present embodiment is as follows:
4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i4-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2- Fluoro-5-methylbenzonitrile 1i
4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile
参照实施例1化合物的第五步制备方法制备，区别在于：Prepare with reference to the fifth step preparation method of the compound of Example 1, the difference is:
反应溶剂为3L甲苯，原料为1f及1g的混合物(100g,1.0eq.)，1h(300.32g，2eq.)，碱为氢氧化钾(280.53g,5.0eq)。反应完成，后处理及干燥后得到4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i。The reaction solvent was 3L toluene, the raw material was the mixture of 1f and 1g (100g, 1.0eq.), 1h (300.32g, 2eq.), and the base was potassium hydroxide (280.53g, 5.0eq). After completion of the reaction, post-treatment and drying yielded 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine- 2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i.
实施例12Example 12
本实施例与实施例1的区别主要在于第六步，本实施例中第六步的实施过程如下：The difference between this embodiment and embodiment 1 mainly lies in the sixth step, and the implementation process of the sixth step in this embodiment is as follows:
4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲酰胺化合物14-((7-Ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2- Fluoro-5-methylbenzamide compound 1
4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-flu oro-5-methylbenzamide4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-flu oro-5- methylbenzamide
参照实施例1化合物的第六步制备方法制备，区别在于：Prepare with reference to the sixth step preparation method of the compound of Example 1, the difference is:
反应溶剂为10L四氢呋喃，原料为4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲腈1i(1kg，2.52mol)，碱为氢氧化钠水溶液(20.16g,0.504mol.溶于100ml纯水中)，氧化剂为N-氟代双苯磺酰胺(1.192kg,3.78mol)，反应完成，后处理及干燥后得到类白色固体4-((7-乙基-8-氧代-9-(四氢-2H-吡喃-4-基)-8,9-二氢-7H-嘌呤-2-基)氨基)-2-氟-5-甲基苯甲酰胺化合物1。The reaction solvent is 10L tetrahydrofuran, and the starting material is 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2 -yl)amino)-2-fluoro-5-methylbenzonitrile 1i (1kg, 2.52mol), the base is aqueous sodium hydroxide solution (20.16g, 0.504mol. dissolved in 100ml pure water), the oxidizing agent is N- Fluorinated bisbenzenesulfonamide (1.192kg, 3.78mol), the reaction was completed, after treatment and drying, an off-white solid 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran) was obtained -4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide Compound 1.
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制。同时，本申请中呈现的上述实施例，可以在本领域技术人员理解的合理范围内，进行自由组合，这些组合也将落在本发明的保护范围内。对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The description of the present invention describes specific implementations in detail, and those skilled in the art should recognize that the above implementations are exemplary and should not be construed as limitations on the present invention. At the same time, the above-mentioned embodiments presented in the present application can be freely combined within a reasonable range understood by those skilled in the art, and these combinations will also fall within the protection scope of the present invention. For those skilled in the art, on the premise of not departing from the principles of the present invention, some improvements and modifications are made to the present invention, and the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (32)

  1. 一种式(I-1)的咪唑啉酮衍生物或者其立体异构体的制备工艺，其特征在于：A preparation process for imidazolinone derivatives of formula (I-1) or stereoisomers thereof, characterized in that:
    Figure PCTCN2022114328-appb-100001
    Figure PCTCN2022114328-appb-100001
    式(I-a-1)化合物在反应溶剂中，无机碱和/或有机碱条件下，加入氧化剂反应，制备得到式(I-1)化合物；The compound of formula (I-a-1) is reacted with an oxidizing agent in the reaction solvent under the condition of inorganic base and/or organic base, and the compound of formula (I-1) is prepared;
    其中：in:
    R 0为H、C 1-6烷基或者环丙基，所述C 1-6烷基任选地进一步被1个或者多个选自卤素和氘的取代基取代； R 0 is H, C 1-6 alkyl or cyclopropyl, and the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium;
    R 1为
    Figure PCTCN2022114328-appb-100002
    且R 1任选地进一步被1或2个选自D、卤素、氰基、羟基、C 1-6烷基和C 1-6烷氧基的取代基取代；     R1 is
    Figure PCTCN2022114328-appb-100002
    And R is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy;
    R 2为H、氰基、＝O、羧基、-C(＝O)NR 2aR 2b、C 1-6烷氧基、C 1-6烷基、卤素、-S(＝O) 2R 2a或者-C(＝O)OC 1-6烷基；所述C 1-6烷基、-C(＝O)OC 1-6烷基或者C 1-6烷氧基任选地被1个或者多个选自卤素和氘的取代基取代； R 2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1-6 alkoxy, C 1-6 alkyl, halogen, -S(=O) 2 R 2a Or -C(=O)OC 1-6 alkyl; said C 1-6 alkyl, -C(=O)OC 1-6 alkyl or C 1-6 alkoxy is optionally replaced by 1 or Multiple substituents selected from halogen and deuterium are substituted;
    R 2a和R 2b各自独立地为H、C 1-6烷基或者3至5元环烷基，其中所述C 1-6烷基任选地进一步被1个或者多个选自OH、D、卤素、C 1-6烷基和C 1-6烷氧基的取代基取代； R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further selected from OH, D , halogen, C 1-6 alkyl and C 1-6 alkoxy substituents;
    或者，R 2a和R 2b与其相连的原子一起形成5至6元杂环基，所述5至6元杂环基含有1、2或3个选自N、O和S的杂原子，所述5至6元杂环基任选地进一步被1个或者多个选自C 1-6烷基、OH和卤素的取代基取代； Alternatively, R 2a and R 2b form a 5 to 6 membered heterocyclic group together with the atoms connected to them, and the 5 to 6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, said The 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkyl, OH and halogen;
    R 3为卤素或者C 1-6烷基，所述C 1-6烷基任选地进一步被1至3个选自D和卤素的取代基取代； R 3 is halogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen;
    m为0或者1；m is 0 or 1;
    n为0、1或2；n is 0, 1 or 2;
    x和y各自独立为1、2或者3；x and y are each independently 1, 2 or 3;
    n为1时，R 0为H或者甲基，R 2为甲氧基或者-S(＝O) 2Me，R 3为甲基。 When n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2 Me, and R 3 is methyl.
  2. 根据权利要求1所述的制备工艺，其特征在于：所述式(I-1)化合物选自式I化合物，所述式I化合物通过如下反应步骤制备而得：The preparation process according to claim 1, characterized in that: the compound of formula (I-1) is selected from the compound of formula I, and the compound of formula I is prepared by the following reaction steps:
    Figure PCTCN2022114328-appb-100003
    Figure PCTCN2022114328-appb-100003
    式(I-a)化合物在反应溶剂中，无机碱和/或有机碱条件下，加入氧化剂反应，制备得到式(I)化合物。The compound of formula (I-a) is reacted with an oxidizing agent in a reaction solvent under the condition of inorganic base and/or organic base to prepare the compound of formula (I).
  3. 根据权利要求2所述的制备工艺，其特征在于：式(I-a)化合物在DMSO溶 液中，无机碱条件下，加入氧化剂反应，制备得到式(I)化合物；所述的氧化剂选自H 2O 2。 The preparation process according to claim 2, characterized in that: the compound of formula (Ia) is reacted with an oxidizing agent in DMSO solution under the condition of inorganic alkali to prepare the compound of formula (I); the oxidizing agent is selected from H2O 2 .
  4. 根据权利要求1-3任一项所述的制备工艺，其特征在于：所述无机碱和/或有机碱、所述氧化剂和所述式(I-a)化合物的摩尔比为(0.2-1.5)：(1.5-5)：1；The preparation process according to any one of claims 1-3, characterized in that: the molar ratio of the inorganic base and/or organic base, the oxidizing agent and the compound of formula (I-a) is (0.2-1.5): (1.5-5): 1;
    所述无机碱和/或有机碱、所述氧化剂和所述式(I-a-1)化合物的摩尔比为(0.2-1.5)：(1.5-5)：1。The molar ratio of the inorganic base and/or organic base, the oxidizing agent and the compound of formula (I-a-1) is (0.2-1.5):(1.5-5):1.
  5. 一种式(I-a-1)化合物的制备工艺，其特征在于：式(I-a-1)化合物通过如下反应步骤制备而得，A preparation process for a compound of formula (I-a-1), characterized in that: the compound of formula (I-a-1) is prepared through the following reaction steps,
    Figure PCTCN2022114328-appb-100004
    Figure PCTCN2022114328-appb-100004
    式(I-c1-1)化合物和/或式(I-c2-1)化合物，与式(I-b-1)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-a-1)化合物，Formula (I-c1-1) compound and/or formula (I-c2-1) compound, react with formula (I-b-1) compound in reaction solvent, under inorganic base and/or organic base condition, prepare formula ( I-a-1) compounds,
    其中，所述R 0、R 1、R 2、R 3、n定义与权利要求1的定义一致， Wherein, the definitions of R 0 , R 1 , R 2 , R 3 , and n are consistent with those in claim 1,
    其中，R q1选自C 1-6烷基或者C 3-6环烷基。 Wherein, R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  6. 根据权利要求5所述的制备工艺，其特征在于：所述式(I-a-1)化合物选自式(I-a)化合物，所述式(I-a)化合物通过如下反应步骤制备而得：The preparation process according to claim 5, characterized in that: the compound of formula (I-a-1) is selected from the compound of formula (I-a), and the compound of formula (I-a) is prepared by the following reaction steps:
    Figure PCTCN2022114328-appb-100005
    Figure PCTCN2022114328-appb-100005
    式(I-c1)化合物和/或式(I-c2)化合物，与式(I-b)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-a)化合物。The compound of formula (I-c1) and/or the compound of formula (I-c2) is reacted with the compound of formula (I-b) in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-a).
  7. 根据权利要求6所述的制备工艺，其特征在于：式(I-c1)化合物、式(I-c2)化合物和式(I-b)化合物在非质子溶剂中，无机碱或者有机碱条件下反应，制备得到式(I-a)化合物。The preparation process according to claim 6, characterized in that: the compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (I-b) react in an aprotic solvent under inorganic or organic base conditions, The compound of formula (I-a) is prepared.
  8. 根据权利要求5-7任一项所述的制备工艺，其特征在于：所述式(I-c1)化合物和/或式(I-c2)化合物、所述无机碱和/或有机碱和所述式(I-b)化合物的摩尔比为 1：(1-5)：(0.5-2)；According to the preparation process described in any one of claims 5-7, it is characterized in that: the compound of formula (I-c1) and/or the compound of formula (I-c2), the inorganic base and/or organic base and the The molar ratio of the compound of formula (I-b) is 1: (1-5): (0.5-2);
    所述式(I-c1-1)化合物和/或式(I-c2-1)化合物、所述无机碱和/或有机碱和所述式(I-b)化合物的摩尔比为1：(1-5)：(0.5-2)。The mol ratio of described formula (I-c1-1) compound and/or formula (I-c2-1) compound, described inorganic base and/or organic base and described formula (I-b) compound is 1: (1- 5): (0.5-2).
  9. 一种式(I-c1-1)化合物和式(I-c2-1)化合物的制备工艺，其特征在于：其通过如下反应步骤制备而得，A preparation process for a compound of formula (I-c1-1) and a compound of formula (I-c2-1), characterized in that: it is prepared through the following reaction steps,
    Figure PCTCN2022114328-appb-100006
    Figure PCTCN2022114328-appb-100006
    式(I-d-1)化合物在反应溶剂中，加入氧化剂反应，制备得到式(I-c1-1)化合物和式(I-c2-1)化合物，Formula (I-d-1) compound is in reaction solvent, adds oxidant reaction, prepares formula (I-c1-1) compound and formula (I-c2-1) compound,
    其中，所述R 0、R 1定义与权利要求1的定义一致，R q1选自C 1-6烷基或者C 3-6环烷基。 Wherein, the definitions of R 0 and R 1 are consistent with those of claim 1, and R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  10. 根据权利要求9所述的制备工艺，其特征在于：所述式(I-c1-1)化合物和所述式(I-c2-1)化合物选自式(I-c1)化合物和式(I-c2)化合物，所述式(I-c1)化合物和式(I-c2)化合物通过以下步骤制备而得：The preparation process according to claim 9, characterized in that: the compound of the formula (I-c1-1) and the compound of the formula (I-c2-1) are selected from the compound of the formula (I-c1) and the compound of the formula (I -c2) compound, the compound of the formula (I-c1) and the compound of the formula (I-c2) are prepared by the following steps:
    Figure PCTCN2022114328-appb-100007
    Figure PCTCN2022114328-appb-100007
    式(I-d)化合物在反应溶剂中，加入氧化剂反应，制备得到式(I-c1)化合物和式(I-c2)化合物。The compound of the formula (I-d) is reacted by adding an oxidizing agent in a reaction solvent to prepare the compound of the formula (I-c1) and the compound of the formula (I-c2).
  11. 根据权利要求10所述的制备工艺，其特征在于：式(I-d)化合物在醇和/或H 2O的溶剂中，加入氧化剂反应，制备得到式(I-c1)化合物和式(I-c2)化合物；所述的氧化剂选自Oxone或者mCPBA。 The preparation process according to claim 10, characterized in that: the compound of formula (Id) is reacted with an oxidizing agent in alcohol and/or H2O solvent to prepare the compound of formula (I-c1) and formula (I-c2) compound; the oxidizing agent is selected from Oxone or mCPBA.
  12. 根据权利要求9-11中任一项所述的制备工艺，其特征在于：所述氧化剂与所述式(I-d)化合物的摩尔比为(0.5-2)：1；The preparation process according to any one of claims 9-11, characterized in that: the molar ratio of the oxidizing agent to the compound of formula (I-d) is (0.5-2): 1;
    所述氧化剂与所述式(I-d-1)化合物的摩尔比为(0.5-2)：1。The molar ratio of the oxidizing agent to the compound of formula (I-d-1) is (0.5-2):1.
  13. 一种式(I-d-1)化合物的制备工艺，其特征在于：其通过如下反应步骤制备 而得，A preparation process for a compound of formula (I-d-1), characterized in that: it is prepared through the following reaction steps,
    Figure PCTCN2022114328-appb-100008
    Figure PCTCN2022114328-appb-100008
    式(I-e-1)化合物和试剂Ⅰ在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-d-1)化合物，所述试剂Ⅰ选自碘乙烷、硫酸二乙酯、碳酸二乙酯、溴乙烷、乙醛、乙酸、甲醇、三氟甲磺酸乙酯、对甲苯磺酸乙酯和N,N-二甲基甲酰胺二乙基缩醛中的一种或多种，The compound of formula (I-e-1) and reagent I are reacted under the conditions of inorganic base and/or organic base in the reaction solvent to prepare the compound of formula (I-d-1), and the reagent I is selected from iodoethane, diethyl sulfate One of , diethyl carbonate, bromoethane, acetaldehyde, acetic acid, methanol, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal or more,
    其中，所述R 0、R 1定义与权利要求1的定义一致；R q1选自C 1-6烷基或者C 3-6环烷基。 Wherein, the definitions of R 0 and R 1 are consistent with those of claim 1; R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  14. 根据权利要求13所述的制备工艺，其特征在于：所述式(I-d-1)化合物选自式(I-d)化合物，所述式(I-d)化合物通过以下方法制备得到：The preparation process according to claim 13, characterized in that: the compound of formula (I-d-1) is selected from the compound of formula (I-d), and the compound of formula (I-d) is prepared by the following method:
    Figure PCTCN2022114328-appb-100009
    Figure PCTCN2022114328-appb-100009
    式(I-e)化合物和试剂Ⅰ在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-d)化合物，所述试剂Ⅰ选自碘乙烷、硫酸二乙酯、碳酸二乙酯、溴乙烷、乙醛、乙酸、甲醇、三氟甲磺酸乙酯、对甲苯磺酸乙酯和N,N-二甲基甲酰胺二乙基缩醛中的一种或多种。The compound of formula (I-e) and reagent I are reacted under conditions of inorganic base and/or organic base in a reaction solvent to prepare the compound of formula (I-d), and said reagent I is selected from ethyl iodide, diethyl sulfate, diethyl carbonate One or more of esters, bromoethane, acetaldehyde, acetic acid, methanol, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal.
  15. 根据权利要求14所述的制备工艺，其特征在于：式(I-e)化合物和碘乙烷在非质子溶剂中，无机碱条件下反应，制备得到式(I-d)化合物。The preparation process according to claim 14, characterized in that: the compound of formula (I-e) reacts with ethyl iodide in an aprotic solvent under inorganic alkali conditions to prepare the compound of formula (I-d).
  16. 根据权利要求13-15中的任一项所述的制备工艺，其特征在于：所述无机碱和/或有机碱、所述试剂Ⅰ与所述式(I-e-1)化合物的摩尔比为(1-4)：(1-5)：1，According to the preparation process described in any one of claims 13-15, it is characterized in that: the molar ratio of the inorganic base and/or organic base, the reagent I and the compound of formula (I-e-1) is ( 1-4):(1-5):1,
    所述无机碱和/或有机碱、所述试剂Ⅰ与所述式(I-e)化合物的摩尔比为(1-4)：(1-5)：1。The molar ratio of the inorganic base and/or organic base, the reagent I to the compound of formula (I-e) is (1-4):(1-5):1.
  17. 根据权利要求13所述的制备工艺，其特征在于：式(I-e-1)化合物通过如下反应步骤制备而得，The preparation process according to claim 13, characterized in that: the compound of formula (I-e-1) is prepared through the following reaction steps,
    Figure PCTCN2022114328-appb-100010
    Figure PCTCN2022114328-appb-100010
    式(I-f-1)化合物和叠氮化试剂在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-e-1)化合物，The compound of formula (I-f-1) and the azidation reagent are reacted under the conditions of inorganic base and/or organic base in the reaction solvent to prepare the compound of formula (I-e-1),
    其中，所述R 1定义与权利要求1的定义一致；R q1选自C 1-6烷基或者C 3-6环烷基。 Wherein, the definition of R 1 is consistent with the definition of claim 1; R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl.
  18. 根据权利要求17所述的制备工艺，其特征在于：所述式(I-e-1)化合物选自式(I-e)化合物，所述式(I-e)化合物通过以下方法制备而得：The preparation process according to claim 17, characterized in that: the compound of formula (I-e-1) is selected from the compound of formula (I-e), and the compound of formula (I-e) is prepared by the following method:
    Figure PCTCN2022114328-appb-100011
    Figure PCTCN2022114328-appb-100011
    式(I-f)化合物和叠氮化试剂在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-e)化合物。The compound of formula (I-f) is reacted with the azidation reagent in a reaction solvent under the condition of inorganic base and/or organic base to prepare the compound of formula (I-e).
  19. 根据权利要求17或18所述的制备工艺，其特征在于：所述叠氮化试剂选自叠氮磷酸二苯酯、叠氮基三甲基硅烷、叠氮化钠和叠氮酸中的一种或多种。The preparation process according to claim 17 or 18, characterized in that: the azidation reagent is selected from one of diphenylphosphoryl azide, azidotrimethylsilane, sodium azide and azide one or more species.
  20. 根据权利要求18所述的制备工艺，其特征在于：式(I-f)化合物和叠氮化试剂在非质子溶剂中，碱性条件下反应，制备得到式(I-e)化合物；所述的叠氮化试剂选自DPPA。The preparation process according to claim 18, characterized in that: the compound of formula (I-f) and the azidation reagent react in an aprotic solvent under basic conditions to prepare the compound of formula (I-e); the azidation Reagents are selected from DPPA.
  21. 根据权利要求17-20中的任一项所述的制备工艺，其特征在于：所述无机碱和/或有机碱、所述叠氮化试剂和所述式(I-f)化合物的摩尔比为(1-4)：(1-3)：1；According to the preparation process described in any one of claims 17-20, it is characterized in that: the molar ratio of the inorganic base and/or organic base, the azidation reagent and the compound of formula (I-f) is ( 1-4):(1-3):1;
    所述无机碱和/或有机碱、所述叠氮化试剂和所述式(I-f-1)化合物的摩尔比为(1-4)：(1-3)：1。The molar ratio of the inorganic base and/or organic base, the azidation reagent and the compound of formula (I-f-1) is (1-4):(1-3):1.
  22. 根据权利要求17所述的制备工艺，其特征在于：式(I-f-1)化合物通过如下反应步骤制备而得，The preparation process according to claim 17, characterized in that: the compound of formula (I-f-1) is prepared through the following reaction steps,
    Figure PCTCN2022114328-appb-100012
    Figure PCTCN2022114328-appb-100012
    式(I-h-1)化合物和式(I-g-1)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-f-1)化合物，The compound of formula (I-h-1) and the compound of formula (I-g-1) are reacted under the conditions of inorganic base and/or organic base in the reaction solvent to prepare the compound of formula (I-f-1),
    其中，所述R 1定义与权利要求1的定义一致， Wherein, the definition of R1 is consistent with the definition of claim 1,
    其中，R q2选自C 1-6烷基或者C 3-6环烷基；R q3选自卤素；R q1选自C 1-6烷基或者C 3 -6环烷基， Wherein, R q2 is selected from C 1-6 alkyl or C 3-6 cycloalkyl; R q3 is selected from halogen; R q1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl,
    Q选自一分子或多分子的无机酸，所述无机酸优选盐酸、硫酸、磷酸、氢溴酸、高氯酸或者氢碘酸。Q is selected from one or more molecules of inorganic acids, preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, perchloric acid or hydroiodic acid.
  23. 根据权利要求22所述的制备工艺，其特征在于：所述式(I-f-1)化合物选自式(I-f)化合物，所述式(I-f)化合物通过以下方法制备而得：The preparation process according to claim 22, characterized in that: the compound of formula (I-f-1) is selected from the compound of formula (I-f), and the compound of formula (I-f) is prepared by the following method:
    Figure PCTCN2022114328-appb-100013
    Figure PCTCN2022114328-appb-100013
    式(I-h)化合物和式(I-g)化合物在反应溶剂中，无机碱和/或有机碱条件下反应，制备得到式(I-f)化合物。The compound of formula (I-h) and the compound of formula (I-g) are reacted in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-f).
  24. 根据权利要求23所述的制备工艺，其特征在于：式(I-h)化合物和式(I-g)化合物在非质子溶剂或者非质子溶剂/H 2O的混合溶剂中，无机碱条件下反应；反应完成后，减压除去溶剂，再加入无机碱的水溶液继续反应，制备得到式(I-f)化合物。 The preparation process according to claim 23, characterized in that: the compound of formula (Ih) and the compound of formula (Ig) are reacted under inorganic alkali conditions in an aprotic solvent or a mixed solvent of aprotic solvent/H 2 O; the reaction is completed Finally, the solvent is removed under reduced pressure, and then an aqueous solution of an inorganic base is added to continue the reaction to prepare a compound of formula (If).
  25. 根据权利要求22-24中的任一项所述的制备工艺，其特征在于：所述无机碱和/或有机碱、所述式(I-g-1)化合物与所述式(I-h-1)化合物的摩尔比为(1-3)：(1-1.2)：1，The preparation process according to any one of claims 22-24, characterized in that: the inorganic base and/or organic base, the compound of formula (I-g-1) and the compound of formula (I-h-1) The molar ratio is (1-3): (1-1.2): 1,
    所述无机碱和/或有机碱、所述式(I-g)化合物与所述式(I-h)化合物的摩尔比为(1-3)：(1-1.2)：1。The molar ratio of the inorganic base and/or organic base, the compound of formula (I-g) to the compound of formula (I-h) is (1-3):(1-1.2):1.
  26. 根据权利要求1-25任一项所述的制备工艺，其特征在于：所述反应溶剂选自 四氢呋喃、甲醇、乙醇、乙腈、丙酮、甲苯、异丙醇、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲基四氢呋喃、H 2O、二氯甲烷和叔丁醇中的一种或多种。 According to the preparation process described in any one of claims 1-25, it is characterized in that: the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, toluene, isopropanol, 1,4-dioxane, One or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyl tetrahydrofuran, H 2 O, dichloromethane and tert-butanol.
  27. 根据权利要求26所述的制备工艺，其特征在于：当所述反应溶剂选自醇和H 2O时，所述醇与H 2O的体积比为10-4：1。 The preparation process according to claim 26, characterized in that: when the reaction solvent is selected from alcohol and H 2 O, the volume ratio of the alcohol to H 2 O is 10-4:1.
  28. 根据权利要求1-27任一项所述的制备工艺，其特征在于：所述无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、氢氧化钡、四氢铝锂和氢氧化铯中的一种或多种；所述有机碱选自叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、4-二甲氨基吡啶和叔戊醇钠中的一种或多种。According to the preparation process described in any one of claims 1-27, it is characterized in that: the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium aluminum hydride and one or more of cesium hydroxide; the organic base is selected from sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazepine One or more of bicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine and sodium tert-amylate.
  29. 根据权利要求1-27任一项所述的制备工艺，其特征在于：所述氧化剂选自双氧水、间氯过氧苯甲酸、过氧单磺酸钾、高碘酸钠、叔丁基过氧化氢、氧气、N-氟代双苯磺酰胺、钼酸铵/双氧水、臭氧中的一种或多种。According to the preparation process described in any one of claims 1-27, it is characterized in that: the oxidizing agent is selected from hydrogen peroxide, m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, sodium periodate, tert-butyl peroxide One or more of hydrogen, oxygen, N-fluorobisbenzenesulfonamide, ammonium molybdate/hydrogen peroxide, and ozone.
  30. 一种式(I)的咪唑啉酮衍生物或者其立体异构体的制备工艺，其特征在于：A preparation process for imidazolinone derivatives of formula (I) or stereoisomers thereof, characterized in that:
    Figure PCTCN2022114328-appb-100014
    Figure PCTCN2022114328-appb-100014
    第一步：式(I-h)化合物和式(I-g)化合物在非质子溶剂或者非质子溶剂/H 2O的混合溶剂中，无机碱条件下反应；随后，加入无机碱的水溶液继续反应，制备得到式(I-f)化合物； The first step: the compound of formula (Ih) and the compound of formula (Ig) are reacted in an aprotic solvent or a mixed solvent of aprotic solvent/H 2 O under the condition of an inorganic base; subsequently, an aqueous solution of an inorganic base is added to continue the reaction to prepare A compound of formula (If);
    第二步：式(I-f)化合物和叠氮化试剂在非质子溶剂中，碱性条件下反应，制备 得到式(I-e)化合物；所述的叠氮化试剂选自DPPA；Second step: the compound of formula (I-f) and the azidation reagent react in an aprotic solvent under basic conditions to prepare the compound of formula (I-e); the azide reagent is selected from DPPA;
    第三步：式(I-e)化合物和碘乙烷在非质子溶剂中，无机碱条件下反应，制备得到式(I-d)化合物。The third step: the compound of formula (I-e) reacts with ethyl iodide in an aprotic solvent under the condition of inorganic base to prepare the compound of formula (I-d).
    第四步：式(I-d)化合物在醇和/或H 2O的溶剂中，加入氧化剂反应，制备得到式(I-c1)化合物和式(I-c2)化合物；所述的氧化剂选自Oxone或者mCPBA； The fourth step: the compound of formula (Id) is reacted with an oxidizing agent in alcohol and/or H 2 O solvent to prepare the compound of formula (I-c1) and compound of formula (I-c2); the oxidizing agent is selected from Oxone or mCPBA;
    第五步：式(I-c1)化合物、式(I-c2)化合物和式(I-b)化合物在非质子溶剂中，无机碱或者有机碱条件下反应，制备得到式(I-a)化合物；The fifth step: the compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (I-b) are reacted in an aprotic solvent under the conditions of inorganic base or organic base to prepare the compound of formula (I-a);
    第六步：式(I-a)化合物在DMSO溶液中，无机碱条件下，加入氧化剂反应，制备得到式(I)化合物；所述的氧化剂选自H 2O 2。 Step 6: The compound of formula (Ia) is reacted in DMSO solution under the condition of inorganic alkali by adding an oxidizing agent to obtain the compound of formula (I); the oxidizing agent is selected from H 2 O 2 .
  31. 一种用于制备权利要求1-30任一项所述的式(I-1)化合物的中间体或者其立体异构体，其中该中间体选自：An intermediate or a stereoisomer thereof for preparing the compound of formula (I-1) described in any one of claims 1-30, wherein the intermediate is selected from:
    Figure PCTCN2022114328-appb-100015
    Figure PCTCN2022114328-appb-100015
  32. 一种用于制备权利要求1-30任一项所述的式(I)化合物的中间体或者其立体异构体，其中该中间体选自：An intermediate or a stereoisomer thereof for preparing the compound of formula (I) described in any one of claims 1-30, wherein the intermediate is selected from:
    Figure PCTCN2022114328-appb-100016
    Figure PCTCN2022114328-appb-100016
    Figure PCTCN2022114328-appb-100017
    或者
    Figure PCTCN2022114328-appb-100018
    Figure PCTCN2022114328-appb-100017
    or
    Figure PCTCN2022114328-appb-100018
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