WO2023025160A1 - Procédé de préparation d'un dérivé d'imidazolinone et intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un dérivé d'imidazolinone et intermédiaire de celui-ci Download PDF

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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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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/zh
Publication of WO2023025160A1 publication Critical patent/WO2023025160A1/fr

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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.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un dérivé d'imidazolinone ou d'un stéréoisomère de celui-ci, et un intermédiaire de celui-ci. Le procédé de préparation implique des opérations simples, a un rendement de réaction élevé, permet d'obtenir une pureté de produit élevée, et est approprié pour une production industrialisée. L'invention concerne également un procédé de préparation de l'intermédiaire.
PCT/CN2022/114328 2021-08-23 2022-08-23 Procédé de préparation d'un dérivé d'imidazolinone et intermédiaire de celui-ci WO2023025160A1 (fr)

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