TWI823531B - Preparation methods of imidazolinone derivatives or stereoisomers thereof and intermediates thereof - Google Patents

Abstract

The invention relates to a preparation method of an imidazolinone derivative or its stereoisomer and an intermediate thereof. The preparation method is simple to operate, has high reaction yield and high product purity, and is suitable for industrial production.

Description

Preparation method of imidazolinone derivatives or stereoisomers thereof and intermediates thereof body

The invention relates to a preparation method of an imidazolinone derivative or its stereoisomer and its intermediates.

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).

The patent (application number: PCT/CN2021/087912) describes a new type of 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 method for preparing imidazolinone derivatives or their stereoisomers and their intermediates. The preparation method has the advantages of low cost, high yield, and is more suitable for industrial production.

In one or more embodiments of the present invention, a method for preparing an imidazolinone derivative of formula (I-1) or a stereoisomer thereof is provided, which includes the following steps:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；R₂為H、氰基、=O、羧基、-C(=O)NR_2aR_2b、C_1-6烷氧基、C_1-6烷基、鹵素、-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烷氧基任選地被1個或者多個選自鹵素和氘的取代基取代；R_2a和R_2b各自獨立地為H、C_1-6烷基或者3元至5元環烷基，其中所述C_1-6烷基任選地進一步被1個或者多個選自OH、D、鹵素、C_1-6烷基和C_1-6烷氧基的取代基取代；或者，R_2a和R_2b與其相連的原子一起形成5元至6元雜環基，所述5元至6元雜環基含有1、2或3個選自N、O和S的雜原子，所述5元至6元雜環基任選地進一步被1個或者多個選自C_1-6烷基、OH和鹵素的取代基取代；R₃為鹵素或者C_1-6烷基，所述C_1-6烷基任選地進一步被1至3個選自D和鹵素的取代基取代； m為0或者1；n為0、1或2；x和y各自獨立為1、2或者3；n為1時，R₀為H或者甲基，R₂為甲氧基或者-S(=O)₂Me，R₃為甲基。其中，Me為甲基。 The compound of formula (Ia-1) is reacted with an oxidizing agent in a reaction solvent under inorganic and/or organic base conditions to prepare a compound of formula (I-1); wherein: R ₀ is H, C _1-6 alkyl or Cyclopropyl, the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from halogen and deuterium; R ₁ is

, and R ₁ 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 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; the C _1-6 alkyl, -C(=O)OC _1-6 alkyl or C _1-6 alkoxy is optionally replaced by 1 or more selected from halogen and deuterium Substituted with substituents; 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 substituted by 1 or more Substituted with a substituent selected from OH, D, halogen, C _1-6 alkyl and C _1-6 alkoxy; alternatively, R _2a and R _2b together with the atoms to which they are connected form a 5- to 6-membered heterocyclyl group, The 5- to 6-membered heterocyclyl group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclyl group is optionally further composed of 1 or more heteroatoms selected from C _1-6 alkyl, OH and halogen substituents are substituted; R ₃ is halogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 to 3 selected from D and halogen. Substituent substitution; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3; when n is 1, R ₀ is H or methyl, R ₂ is methoxy or -S(=O) ₂ Me, R ₃ is methyl. Among them, Me is methyl.

In one or more embodiments of the present invention, a method for preparing the imidazolinone derivative of formula (I) or its stereoisomer is provided, which includes the following steps:

The compound of formula (I-a) is reacted with an oxidizing agent in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I).

In one or more embodiments of the present invention, the compound of formula (Ia) is reacted with an oxidizing agent in DMSO solution under inorganic alkali conditions to prepare the compound of formula (I); the oxidizing agent is selected from H ₂ O ₂ .

In one or more embodiments of the present invention, the molar ratio of inorganic base and/or organic base, oxidizing agent and the compound of formula (I-a) is (0.2-1.5): (1.5-5): 1; the inorganic The molar ratio of alkali and/or organic base, the oxidizing agent and the compound of formula (I-a-1) is (0.2-1.5): (1.5-5):1.

In one or more embodiments of the present invention, the reaction temperature of the above reaction step is between room temperature and 60°C, preferably between room temperature and 40°C.

In one or more embodiments of the present invention, the compound of the above formula (Ia-1) is prepared by the following reaction steps:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；R₂為H、氰基、=O、羧基、-C(=O)NR_2aR_2b、C_1-6烷氧基、C_1-6烷基、鹵素、-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烷氧基任選地被1個或者多個選自鹵素和氘的取代基取代；R_2a和R_2b各自獨立地為H、C_1-6烷基或者3元至5元環烷基，其中所述C_1-6烷基任選地進一步被1個或者多個選自OH、D、鹵素、C_1-6烷基和C_1-6烷氧基的取代基取代；或者，R_2a和R_2b與其相連的原子一起形成5元至6元雜環基，所述5元至6元雜環基含有1、2或3個選自N、O和S的雜原子，所述5元至6元雜環基任選地進一步被1個或者多個選自C_1-6烷基、OH和鹵素的取代基取代；R₃為鹵素或者C_1-6烷基，所述C_1-6烷基任選地進一步被1至3個選自D和鹵素的取代基取代； m為0或者1；n為0、1或2；x和y各自獨立為1、2或者3；n為1時，R₀為H或者甲基，R₂為甲氧基或者-S(=O)₂Me，R₃為甲基。 The compound of formula (I-c1-1) and/or the compound of formula (I-c2-1) reacts with the compound of formula (Ib-1) in a reaction solvent under inorganic base and/or organic base conditions to prepare the formula ( Ia-1) Compounds, wherein: R ₀ is H, C _1-6 alkyl or cyclopropyl, and the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from halogen and deuterium Replacement; R ₁ is

, and R ₁ 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 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; the C _1-6 alkyl, -C(=O)OC _1-6 alkyl or C _1-6 alkoxy is optionally replaced by 1 or more selected from halogen and deuterium Substituted with substituents; 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 substituted by 1 or more Substituted with a substituent selected from OH, D, halogen, C _1-6 alkyl and C _1-6 alkoxy; alternatively, R _2a and R _2b together with the atoms to which they are connected form a 5- to 6-membered heterocyclyl group, The 5- to 6-membered heterocyclyl group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclyl group is optionally further composed of 1 or more heteroatoms selected from C _1-6 alkyl, OH and halogen substituents are substituted; R ₃ is halogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 to 3 selected from D and halogen. Substituent substitution; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3; when n is 1, R ₀ is H or methyl, R ₂ is methoxy or -S(=O) ₂ Me, R ₃ is methyl.

R _q1 is selected from C _1-6 alkyl or C _3-6 cycloalkyl.

In one or more embodiments of the present invention, the compound of the above formula (Ia) is prepared by the following reaction steps:

The compound of formula (I-c1) and/or the compound of formula (I-c2) reacts with the compound of formula (I-b) in a reaction solvent under inorganic base and/or organic base conditions to prepare a compound of formula (I-a).

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 inorganic base or organic base conditions to prepare the formula (I-a) Compound.

In one or more embodiments of the present invention, the molar ratio of the compound of formula (I-c1) and/or the compound of formula (I-c2), the inorganic base and/or the organic base and the compound of formula (I-b) is 1: (1-5): (0.5-2); the compound of formula (I-c1-1) and/or the compound of formula (I-c2-1), the inorganic base and/or organic base and the compound of formula ( The molar ratio of compound I-b) is 1: (1-5): (0.5-2).

In one or more embodiments of the present invention, in the above steps, during the addition of inorganic base and/or organic base, the temperature of the reaction solution is controlled to be -10°C to 10°C, preferably -5°C to 0°C.

In one or more embodiments of the present invention, the reaction temperature of the above reaction step is between 15°C and 45°C, preferably at room temperature.

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.

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:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；m為0或者1；x和y各自獨立為1、2或者3；R_q1選自C_1-6烷基或者C_3-6環烷基。 The compound of formula (Id-1) is reacted by adding an oxidant in the reaction solvent to prepare the compound of formula (I-c1-1) and the compound of formula (I-c2-1), wherein: R ₀ is H, C _1-6 alkane group or cyclopropyl, the C _1-6 alkyl group is optionally further substituted by 1 or more substituents selected from halogen and deuterium; R ₁ is

, and R ₁ is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; m is 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.

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:

The compound of formula (I-d) is reacted by adding an oxidant in the reaction solvent to prepare the compound of formula (I-c1) and the compound of formula (I-c2).

In one or more embodiments of the present invention, the compound of formula (Id) is reacted with an oxidant in a solvent of alcohol and/or H ₂ O to prepare a compound of formula (I-c1) and a compound of formula (I-c2); The oxidizing agent is selected from Oxone or mCPBA.

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.

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 to 50°C for reaction, and the preferred reaction temperature is 25°C to 35°C.

In one or more embodiments of the present invention, the compound of the above formula (Id-1) is prepared by the following reaction steps:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；m為0或者1；x和y各自獨立為1、2或者3；R_q1選自C_1-6烷基或者C_3-6環烷基。 The compound of formula (Ie-1) and reagent I are reacted in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (Id-1). The reagent I is selected from ethyl iodide and diethyl sulfate. , one of diethyl carbonate, ethyl bromide, acetaldehyde, acetic acid, methanol, ethyl triflate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal Or more, wherein: R ₀ is H, C _1-6 alkyl or cyclopropyl, the C _1-6 alkyl is optionally further substituted by 1 or more substituents selected from halogen and deuterium; R ₁ for

, and R ₁ is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; m is 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.

In one or more embodiments of the present invention, the compound of the above formula (Id) is prepared by the following reaction steps:

The compound of formula (I-e) and the reagent I are reacted in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-d). The reagent I is selected from ethyl iodide, diethyl sulfate, and diethyl carbonate. One or more of ester, bromoethane, acetaldehyde, acetic acid, methanol, ethyl triflate, ethyl p-toluenesulfonate and N,N-dimethylformamide diethyl acetal.

In one or more embodiments of the present invention, the compound of formula (I-e) and iodoethane are reacted in an aprotic solvent under inorganic base conditions to prepare the compound of formula (I-d).

In one or more embodiments of the present invention, the molar ratio of the inorganic base and/or organic base, reagent I and the compound of formula (I-e) is (1-4): (1-5): 1; the inorganic base The molar ratio of the organic base, the reagent I and the compound of formula (I-e-1) is (1-4): (1-5): 1.

In one or more embodiments of the present invention, the reaction temperature of the above reaction step is from 20°C to 40°C, preferably from 25°C to 35°C.

In one or more embodiments of the present invention, the compound of the above formula (Ie-1) is prepared by the following reaction steps:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；m為0或者1；x和y各自獨立為1、2或者3；R_q1選自C_1-6烷基或者C_3-6環烷基。 The compound of formula (If-1) and the azide reagent are reacted in the reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (Ie-1), wherein: R ₁ is

, and R ₁ is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; m is 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.

In one or more embodiments of the present invention, the compound of the above formula (Ie) is prepared by the following reaction steps:

The compound of formula (I-f) and the azide reagent are reacted in a reaction solvent under the conditions of inorganic base and/or organic base to prepare the compound of formula (I-e).

In one or more embodiments of the present invention, the azide reagent is selected from one or more of diphenyl phosphate azide, azidotrimethylsilane, sodium azide and hydrazoic acid.

In one or more embodiments of the present invention, a compound of formula (I-f) and an azide reagent are reacted in an aprotic solvent under alkaline conditions to prepare a compound of formula (I-e); the azide reagent is selected from DPPA .

In one or more embodiments of the present invention, in order to prevent the temperature from being too high, during the addition of the azide reagent, the temperature of the reaction solution is controlled to be below 30°C.

In one or more embodiments of the present invention, the molar ratio of the inorganic base and/or organic base, the azide reagent and the compound of formula (I-f) is (1-4): (1-3): 1; The molar ratio of the inorganic base and/or organic base, the azide reagent and the compound of formula (I-f-1) is (1-4): (1-3): 1.

In one or more embodiments of the present invention, in the above reaction step, after the addition is completed, and after the complete conversion of the compound of formula (I-f) is detected, the reaction solution can be further heated to 60°C to 80°C, and bubbles begin to emerge, Control the internal temperature at 80°C to 100°C until the bubbles are completely released, then raise the temperature to 95°C to 105°C for reaction.

In one or more embodiments of the present invention, the compound of the above formula (If-1) is prepared by the following reaction steps:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；m為0或者1；x和y各自獨立為1、2或者3；R_q1選自C_1-6烷基或者C_3-6環烷基；R_q2選自C_1-6烷基或者C_3-6環烷基；R_q3選自鹵素；Q選自一分子或多分子的無機酸，所述無機酸優選為鹽酸、硫酸、磷酸、氫溴酸、高氯酸或者氫碘酸。 The compound of formula (Ih-1) and the compound of formula (Ig-1) are reacted in a reaction solvent under inorganic base and/or organic base conditions to prepare a compound of formula (If-1), wherein: R ₁ is

, and R ₁ is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; m is 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 acid, and the inorganic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, perchloric acid or hydriodic acid.

In one or more embodiments of the present invention, the compound of the above formula (If) 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).

In one or more embodiments of the present invention, 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 inorganic base conditions; subsequently, the inorganic base is added The aqueous solution continues to react to prepare a compound of formula (If).

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) and the compound of formula (I-h) is (1-3): (1-1.2): 1; so The molar ratio of the inorganic base and/or organic base, the compound of formula (I-g-1) and the compound of formula (I-h-1) is (1-3): (1-1.2): 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 in a reaction solvent under the conditions of inorganic base and/or organic base. After the completion of the reaction is detected by HPLC, an aqueous solution of the inorganic base is added. The reaction continues, and the molar ratio of the inorganic base and the compound of formula (I-h) is (2-5):1.

In one or more embodiments of the present invention, after the addition of the inorganic base and/or the organic base is completed and the completion of the reaction is detected, the reaction liquid is concentrated under reduced pressure to remove most of the solvent, and then the sodium hydroxide aqueous solution is added to the reaction liquid, React at 60°C to 70°C.

In one or more embodiments of the present invention, the reaction solvent is selected from the group consisting of tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, toluene, isopropyl alcohol, 1,4-dioxane, and N,N-dimethylformamide. , N,N-dimethylacetamide, dimethylstyrene, methyltetrahydrofuran, H ₂ O, one or more of dichloromethane and tert-butanol.

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.

It should be noted that the reaction time is appropriately adjusted according to the amount of reaction raw materials, as long as the reaction can proceed normally and the reaction is completed.

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 tetrahydrogen and cesium hydroxide; The organic base is selected from sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene , one or more of 4-dimethylaminopyridine and sodium tert-amyloxide.

In one or more embodiments of the present invention, the oxidizing agent 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.

In one or more embodiments of the present invention, a method for preparing the imidazolinone derivative of formula (I) or its stereoisomer is provided, which includes the following steps:

The first step: react the compound of formula (Ih) and the compound of formula (Ig) in an aprotic solvent or a mixed solvent of aprotic solvent/H ₂ O under the condition of inorganic base; then, add an aqueous solution of inorganic base to continue the reaction to prepare The compound of formula (If); the second step: the compound of formula (If) and the azide reagent are reacted in an aprotic solvent under basic conditions to prepare the compound of formula (Ie); the above-mentioned azide reagent is selected from DPPA; The third step: react the compound of formula (Ie) and ethyl iodide in an aprotic solvent under inorganic base conditions to prepare the compound of formula (Id); the fourth step: react the compound of formula (Id) with alcohol and/or H ₂ O In the solvent, add an oxidizing agent for reaction to prepare the compound of formula (I-c1) and the 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) The compound of formula (Ib) reacts with the compound of formula (Ib) in an aprotic solvent under the condition of inorganic base or organic base to prepare the compound of formula (Ia); Step 6: The compound of formula (Ia) is reacted in DMSO solution under the condition of inorganic base , add an oxidizing agent to react, and prepare the compound of formula (I); the above-mentioned oxidizing agent is selected from H ₂ O ₂ .

In one or more embodiments of the present invention, an intermediate for preparing the compound of formula (I) or a stereoisomer thereof is provided, wherein the intermediate is selected from:

，且R₁任選地進一步被1或2個選自D、鹵素、氰基、羥基、C_1-6烷基和C_1-6烷氧基的取代基取代；R₂為H、氰基、=O、羧基、-C(=O)NR_2aR_2b、C_1-6烷氧基、C_1-6烷基、鹵素、-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烷氧基任選地被1個或者多個選自鹵素和氘的取代基取代； R_2a和R_2b各自獨立地為H、C_1-6烷基或者3元至5元環烷基，其中所述C_1-6烷基任選地進一步被1個或者多個選自OH、D、鹵素、C_1-6烷基和C_1-6烷氧基的取代基取代；或者，R_2a和R_2b與其相連的原子一起形成5元至6元雜環基，所述5元至6元雜環基含有1、2或3個選自N、O和S的雜原子，所述5元至6元雜環基任選地進一步被1個或者多個選自C_1-6烷基、OH和鹵素的取代基取代；R₃為鹵素或者C_1-6烷基，所述C_1-6烷基任選地進一步被1至3個選自D和鹵素的取代基取代；m為0或者1；n為0、1或2；x和y各自獨立為1、2或者3；n為1時，R₀為H或者甲基，R₂為甲氧基或者-S(=O)₂Me，R₃為甲基。 Wherein: 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 is

, and R ₁ 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 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; the C _1-6 alkyl, -C(=O)OC _1-6 alkyl or C _1-6 alkoxy is optionally replaced by 1 or more selected from halogen and deuterium Substituted with substituents; 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 substituted by 1 or more Substituted with a substituent selected from OH, D, halogen, C _1-6 alkyl and C _1-6 alkoxy; alternatively, R _2a and R _2b together with the atoms to which they are connected form a 5- to 6-membered heterocyclyl group, The 5- to 6-membered heterocyclyl group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclyl group is optionally further composed of 1 or more heteroatoms selected from C _1-6 alkyl, OH and halogen substituents are substituted; R ₃ is halogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally further substituted by 1 to 3 selected from D and halogen. Substituent substitution; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3; 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 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.

或者

In one or more embodiments of the present invention, an intermediate for preparing the compound of formula (I) or a stereoisomer thereof is provided, wherein the intermediate is selected from:

or

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, where 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 superheavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, mirror image isomers and configurational isomers.

"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may but may not occur, and the description includes the circumstances in which the event or condition occurs and the circumstances in which it does not occur. What happened. For example, "heterocyclyl optionally substituted by alkyl" means that the alkyl group may but not necessarily be present. This description includes the case where the heterocyclyl is substituted by an alkyl group, and the case where the heterocyclyl is not substituted by an alkyl group. condition.

Base refers to a compound that ionizes ^OH- in an aqueous solution; or a compound that can accept a proton; the inorganic base described in the present invention such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, hydroxide Cesium etc.

The organic base mentioned in the present invention refers to containing nitrogen atoms, such as amine compounds and nitrogen-containing heterocyclic compounds. Non-limiting examples: sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, Grignard reagent, quaternary ammonium hydroxide, pyridine, lithium amide compounds (such as lithium diisopropylamide (LDA), lithium hexamethyldisilamide (LiHMDS), etc.). The organic bases selected in the present invention include sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecane -7-ene, 4-dimethylaminopyridine and sodium tert-amyloxide, etc.

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 to these.

DMSO: dimethylsulfoxide; DTT: dithiothreitol; ATP: adenosine triphosphate; DNA: deoxyribonucleotide.

IC50: refers to the concentration of the compound when the activity of DNA-PK kinase is inhibited by 50%; HPLC: high performance liquid chromatography.

Example

Example 1

Compound 1 : 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino) -2-Fluoro-5-methylbenzamide (4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- 2-yl)amino)-2-fluoro-5-methylbenzamide)

Step 1: 1c : 2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid (2-(methylthio)-4-((tetrahydro- 2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid)

Add 20L tetrahydrofuran to the 50-liter (L) reaction kettle, then add 10L deionized water, and then add 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester 1a (5.000 kilograms (kg), 1.0 Equivalent (eq.)) and tetrahydro-2H-pyran-4-amine hydrochloride 1b (3.166kg, 1.07eq.), a large amount of solid was not dissolved. Potassium carbonate solid (5.934kg, 2.0eq.) was slowly added in batches, the internal temperature increased from 16°C to 32°C, and after stirring at room temperature for 3 hours (h), the reaction was completed by HPLC. After the reaction solution was distilled under reduced pressure at 45°C to remove most of the tetrahydrofuran, the prepared sodium hydroxide aqueous solution (3.0kg sodium hydroxide dissolved in 10L deionized water) was added to the reaction kettle. The reaction solution warmed up slightly, and then the reaction solution was heated to 60°C and reacted for 5 hours. A large amount of solids in the reaction solution dissolved and gradually approached clarity. A sample was sent to HPLC to detect that the reaction was completed. 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. After continuing to add concentrated hydrochloric acid dropwise, a large amount of white solid precipitated until the pH value was adjusted to 3. Continue to 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 (6.5kg, yield 112.1%).

LCMS m/z(ESI)=270.1[M+1].

¹ H NMR(400MHz,DMSO-d6)δ 13.32(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).

Second step: 1d : 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (2-(methylthio) -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Add 15L N,N-dimethylacetamide to the 50L reaction kettle, and then add 2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxy Acid 1c (2.900kg, 1.0eq.), a large amount of solid is not dissolved, then add triethylamine (1.140kg, 1.05eq.), the solid gradually dissolves, the reaction liquid turns yellow, then slowly add diphenyl azidophosphate (3.112 kg, 1.05eq.), if there is a temperature rise phenomenon, control the dropping temperature below 30°C. After the addition is completed, stir at room temperature for 2 hours. After HPLC detects the complete conversion of 1c , the reaction solution is heated to 65°C and bubbles begin to appear. Control The internal temperature is between 80°C and 100°C until the bubbles are completely released, then the temperature is raised to 100°C for 2 hours. After the HPLC detection reaction is completed, add 30L of deionized water to the reaction kettle, and a large amount of solid will precipitate. Stir for 0.5h and then centrifuge and filter. The filter cake is rinsed with 10L of deionized water. Centrifuge until no obvious droplets drip out, then take out the filter cake. Dry in a blast drying oven at 60°C for 8 hours to obtain an off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one 1d (2.583kg, yield 90.1%).

LCMS m/z(ESI)=267.1[M+1].

¹ H NMR(400MHz, DMSO-d6)δ 11.30(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).

The third step: 1e : 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ( 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Add 15L N,N-dimethylformamide into the 50L reaction kettle, and then add the raw material 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-di Hydrogen-8H-purin-8- one 1d (3.00kg, 1.0eq.), a large amount of solid is not dissolved, showing a white suspension, then weigh the sodium hydroxide solid (901.2g, 2.0eq.), add it at room temperature In the reaction kettle, the solid gradually dissolved and turned into a yellow transparent solution. The internal temperature is about 30°C, and then slowly add ethyl iodide dropwise. If there is an obvious temperature rise, control the temperature at 30±5°C. After the dropwise addition is completed, stir at room temperature for 3 hours. HPLC detects the completion of the reaction. Pour 30L of ice water into the reaction solution. A large amount of solid will precipitate. Stir for 0.5h and then centrifuge and filter. Rinse the filter cake with 10L of deionized water. Centrifuge until no droplets drip out. Store the filter cake at 60°C. Dry in a blast drying oven for 8 hours to obtain an 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].

¹ H NMR(400MHz, DMSO-d6)δ 8.38-8.37(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).

Step 4: 7-ethyl-2-(methanesulfonyl)-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-one)

7-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-one)

Add 16L methanol to the 50L reaction kettle, and then add 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 solids were not dissolved, then 2L of purified water was added, some solids were not dissolved; then peroxymonosulfonic acid was slowly added in five batches at room temperature Potassium (Oxone) (2.920kg, 0.7eq.) has an exothermic phenomenon. The reaction solution gradually changes from a white turbid liquid to a yellow turbid liquid, and then back to a white turbid liquid again. Control the temperature between 35±5℃; react for 2 hours Afterwards, the reaction was confirmed to be completed by HPLC (remaining raw material <3%). The reaction solution was cooled to 0±5°C. After stirring for 0.5h, the reaction solution was filtered (the filter cake contained a large amount of product and unreacted remaining peroxymonosulfonic acid. Sulfate after the reaction of potassium and potassium peroxymonosulfonate); the filter cake was stirred and washed with 10L methylene chloride, filtered after 0.5h, the filter cake was stirred again with 10L methylene chloride, filtered after 0.5h, and the two washes were combined The dichloromethane phase; after distilling the solvent (dichloromethane) under normal pressure at 50°C, the residue was pulped with 10L n-hexane for 0.5h and then filtered. The filter cake was dried in a blast drying oven at 40°C for 5h. Obtain 7-ethyl-2-(methanesulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8- one 1f and 7-ethyl A mixture of 1 g of base-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8- one (1.940kg, Yield 92.0%).

1f : LCMS m/z(ESI)=327.1[M+1].

1g : LCMS m/z(ESI)=311.1[M+1].

Step 5: 4-((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-methylbenzonitrile)

Add 2L methylene chloride to the 5L reaction kettle, then add the mixture of raw material 1f and 1g (100g, 1.0eq.) to the reaction kettle. The raw material is completely dissolved and becomes a colorless solution, and then add 1h (47.8g, 1.0eq.) .), the solid dissolved and the reaction liquid turned brown-black. Cool the reaction solution to -5°C to 0°C, and slowly add potassium tert-butoxide (107g, 3.0eq., powder solid) in batches. There will be an obvious temperature rise. Control the temperature at -5°C to 0°C, and solids will precipitate. , the reaction solution becomes viscous. Slowly raise the temperature to room temperature. After reacting at room temperature for 3 hours, the reaction is completed by HPLC (the peak area of the compound at 1 hour is <2%). Add 100 ml of pure water to the reaction kettle. After stirring for 0.5 hours, add 200 ml of methanol (the solution is not clear and separated. ), then add a mixed solution of dichloromethane/methanol (500ml, DCM:MeOH=10:1), and then add 2L of purified water. The lower solid is completely dissolved. After stirring for 1 hour, separate the liquids. The organic phase was filtered through diatomaceous earth and concentrated under reduced pressure (there was no flowing methylene chloride in the bottle). The solid was slurried with ethyl acetate (1L) and then filtered again. The filtrate was a black solution and the filter cake was an off-white solid. The filter cake was washed with 1 L of ethyl acetate, and the eluate was a colorless solution. The filter cake was dried in a blast drying oven at 60°C for 2 hours. Obtain 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2 -Fluoro-5-methylbenzonitrile 1i (95g, yield 75%).

LCMS m/z(ESI)=397.2[M+1].

¹ H NMR(400MHz, DMSO-d6)δ 8.79(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).

¹⁹ F NMR (400MHz, DMSO-d6) δ 111.805.

Step 6: Compound 1 : 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- ethyl)amino)-2-fluoro-5-methylbenzamide (4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro- 7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide)

Add 9.5L dimethyl styrene into the 50L reaction kettle, and then add the 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.), then add aqueous potassium carbonate solution (243.3g, 1.0eq.). in 100ml pure water), slowly add hydrogen peroxide (600ml, 3.0eq., 30% aqueous solution) dropwise at room temperature. There will be an obvious temperature rise. Control the temperature between 30±10°C until the dropwise addition is completed. The reaction solution was heated to 40°C and reacted for 2 hours. The reaction was completed by HPLC. After the reaction solution was cooled to room temperature, 30L of pure water was added. A large amount of solid precipitated. After stirring for 1 hour, it was centrifuged and filtered. The filtrate was an orange solution, and the filter cake was an off-white solid. The filter cake was dried in a forced air drying oven at 60°C for 8 hours. Obtained off-white solid 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )-2-fluoro-5-methylbenzamide compound 1 (700g, yield 95.6%, purity >90%).

LCMS m/z(ESI)=415.2[M+1] ⁺ .

HRMS m/z(ESI)=415.1904[M+1] ⁺ and 437.1713[M+Na] ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ 8.51(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).

¹⁹ F NMR (400MHz, DMSO-d6) δ 115.501.

¹³ C NMR (400MHz, DMSO-d6)δ 165.255,165.232,159.960,157.530,154.717,151.987,150.132,142.998,142.882,124.104,124.077,116.809,115.69 1,107.716,107.430,67.004,49.728,36.202,29.934,17.791 ,13.892.

Example 2

The difference between this embodiment and Example 1 mainly lies in the first step. The implementation process of the first step in this embodiment is as follows: 2-(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 acid)

Prepare the compound according to the first step of preparation method of Example 1, the difference is: the reaction solvent is 15L N,N-dimethylformamide and 5L deionized water, and the raw material is 4-chloro-2-(methylthio)pyrimidine -5-Carboxylic acid ethyl ester 1a (4.500kg, 19.3mol) and tetrahydro-2H-pyran-4-amine hydrochloride 1b (2.656kg, 19.3mol), the base is sodium hydroxide solid (772g, 19.3mol) ), the aqueous solution of the inorganic base is sodium hydroxide aqueous solution (1.93kg sodium hydroxide is dissolved in 8L deionized water). The reaction was completed, and after post-treatment and drying, a white solid 2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c was obtained.

Example 3

The difference between this embodiment and Example 1 mainly lies in the first step. The implementation process of the first step in this embodiment is as follows: 1c : 2-(methylthio)4-((tetrahydro-2H-pyran-4- 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid

Prepare the compound according to the first step of preparation method of Example 1, the difference is: the reaction solvent is 15L acetone, 3L deionized water and 15L N,N-dimethylacetamide, and the raw material is 4-chloro-2-(methylsulfide) ethyl)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 (7.435 kg, 77.37mol), the aqueous solution of the inorganic base is potassium hydroxide aqueous solution (6.511kg potassium hydroxide is dissolved in 20L deionized water). The reaction was completed, and after post-treatment and drying, a white solid 2-(methylthio)4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 1c was obtained.

Example 4

The difference between this embodiment and Embodiment 1 mainly lies in the second step. The implementation process of the second step in this embodiment is as follows:

Second step: 1d : 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (2-(methylthio) -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Prepare the compound according to the second step of the preparation method of Example 1, the difference is: the reaction solvent is 14L dimethyl styrene, and the raw material is 2-(methylthio)-4-((tetrahydro-2H-pyran-4- Base)amino)pyrimidine-5-carboxylic acid 1c (3.45kg, 12.81mol), the base is N,N-diisopropylethylamine (1.656kg, 12.81mol), the azide reagent is azidotrimethyl Silane (1.476kg, 12.81mol). The reaction is completed, and after post-treatment and drying, an off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one is obtained. 1d .

Example 5

The difference between this embodiment and Embodiment 1 mainly lies in the second step. The implementation process of the second step in this embodiment is as follows:

Second step: 1d : 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (2-(methylthio) -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Prepare the compound according to the second step of the preparation method of Example 1, the difference is: the reaction solvent is 18L acetonitrile, and the raw material is 2-(methylthio)-4-((tetrahydro-2H-pyran-4-yl)amino) Pyrimidine-5-carboxylic acid 1c (2.56kg, 9.51mol.), base is 1,8-diazabicyclo[5.4.0]undec-7-ene (5.788kg, 38.02mol.), azidation The reagent is sodium azide (1.855kg, 28.53mol). The reaction is completed, and after post-treatment and drying, an off-white solid 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one is obtained. 1d .

Example 6

The difference between this embodiment and Embodiment 1 mainly lies in the third step. The implementation process of the third step in this embodiment is as follows:

The third step: 1e : 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ( 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Prepare with reference to the third step preparation method of the compound of Example 1, the difference is: the reaction solvent is 45L ethanol, the raw material is 2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-Dihydro-8H-purin-8- one 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). The reaction was completed, and after post-treatment and drying, an off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- was obtained. Purin-8-one 1e .

Example 7

The difference between this embodiment and Embodiment 1 mainly lies in the third step. The implementation process of the third step in this embodiment is as follows:

The third step: 1e : 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ( 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Prepare the compound according to the third step of the preparation method of Example 1, the difference is: the reaction solvent is 16L acetonitrile and 8L H ₂ O, and the raw material is 2-(methylthio)-9-(tetrahydro-2H-pyran-4- base)-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). The reaction was completed, and after post-treatment and drying, an off-white solid 7-ethyl-2-(methylthio)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- was obtained. Purin-8-one 1e .

Example 8

The difference between this embodiment and Embodiment 1 mainly lies in the fourth step. The implementation process of the fourth step in this embodiment is as follows: 1f : 7-ethyl-2-(methanesulfonyl)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one (7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one)

1g : 7-ethyl-2-(methylsulfenyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one(7 -ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Prepare the compound according to the fourth step of the preparation method of Example 1. The difference is: the reaction solvent is 20L tert-butyl alcohol and 2L pure water, and the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H- Pyran-4-yl)-7,9-dihydro-8H-purin-8- one 1e (2.53kg, 8.59mol), the oxidizing agent is m-chloroperoxybenzoic acid (mCPBA) (0.741kg, 4.295mol). The reaction is completed, and after post-treatment and drying, 7-ethyl-2-(methanesulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one 1f and 7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8- Mixture of ketones 1g .

Example 9

The difference between this embodiment and Embodiment 1 mainly lies in the fourth step. The implementation process of the fourth step in this embodiment is as follows: 1f : 7-ethyl-2-(methanesulfonyl)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one (7-ethyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one)

1g : 7-ethyl-2-(methylsulfenyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one(7 -ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one)

Prepare the compound according to the fourth step of the preparation method of Example 1. The difference is: the reaction solvent is 25L isopropyl alcohol and 10L pure water, and the raw material is 7-ethyl-2-(methylthio)-9-(tetrahydro-2H- Pyran-4-yl)-7,9-dihydro-8H-purin-8- one 1 (3.27kg, 11.11mol), the oxidizing agent is sodium periodate (4.75kg, 22.22mol). The reaction is completed, and after post-treatment and drying, 7-ethyl-2-(methanesulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one 1f and 7-ethyl-2-(methylsulfinyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8- Mixture of ketones 1g .

Example 10

The difference between this embodiment and Embodiment 1 mainly lies in the fifth step. The implementation process of the fifth step in this embodiment is as follows: 1i : 4-((7-ethyl-8-oxo-9-(tetrahydro-2H -pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile (4-((7-ethyl-8-oxo -9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile)

Prepare the compound according to the fifth step of the preparation method of Example 1, the difference is: the reaction solvent is 1L acetonitrile, the raw material is a mixture of 1f and 1g (100g, 1.0eq.) and 1h (75.08g, 0.5eq.), the base is N , N-diisopropylethylamine (129.25g, 1.0eq). The reaction is completed, and after post-treatment and drying, 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine- 2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i .

Example 11

The difference between this embodiment and Embodiment 1 mainly lies in the fifth step. The implementation process of the fifth step in this embodiment is as follows: 1i : 4-((7-ethyl-8-oxo-9-(tetrahydro-2H -pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile (4-((7-ethyl-8-oxo -9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile)

Prepare according to the fifth step preparation method of the compound of Example 1, the difference is: the reaction solvent is 3L toluene, the raw material is a mixture of 1f and 1g (100g, 1.0eq.), 1h (300.32g, 2eq.), the alkali is hydroxide Potassium (280.53g, 5.0eq). The reaction is completed, and after post-treatment and drying, 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine- 2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i .

Example 12

The difference between this embodiment and Example 1 mainly lies in the sixth step. The implementation process of the sixth step in this embodiment is as follows: Compound 1 : 4-((7-ethyl-8-oxo-9-(tetrahydro- 2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (4-((7-ethyl-8 -oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide)

Prepare with reference to the sixth step of the preparation method of the compound of Example 1, the difference is: the reaction solvent is 10L tetrahydrofuran, and the raw material is 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4) -base)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzonitrile 1i (1kg, 2.52 mol), the base is sodium hydroxide aqueous solution (20.16g , 0.504mol dissolved in 100ml pure water), the oxidant is N-fluorobenzenesulfonamide (1.192kg, 3.78mol), the reaction is completed, and after post-treatment and drying, an off-white solid 4-((7-ethyl -8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzyl Amide compound 1 .

The specification of the present invention describes specific embodiments in detail. Those skilled in the art should realize that the above embodiments are exemplary and should not be construed as limitations of the present invention. At the same time, the above-mentioned embodiments presented in this application can be freely combined within the reasonable scope 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, without departing from the principle of the present invention, the technical solution obtained by making several improvements and modifications to the present invention also falls within the protection scope of the patent application of the present invention.

Claims (8)

A method for preparing an imidazolinone derivative of formula (I) or a stereoisomer thereof, wherein: the compound of formula (I) is prepared through the following reaction steps:

The compound of formula (Ia) is reacted with an oxidizing agent in dimethylsulfur dioxide (DMSO) solution under inorganic alkali conditions to prepare the compound of formula (I); the oxidizing agent is selected from hydrogen peroxide (H ₂ O ₂ ) . A method for preparing a compound of formula (Ia), wherein: the compound of formula (Ia) is prepared through the following reaction steps:

The compound of formula (I-c1), the compound of formula (I-c2) and the compound of formula (Ib) are reacted in an aprotic solvent under inorganic base or organic base conditions to prepare the formula (Ia) compound. A method for preparing a compound of formula (I-c1) and a compound of formula (I-c2), wherein: the compound of formula (I-c1) and the compound of formula (I-c2) are prepared by the following steps:

The compound of formula (Id) is reacted with an oxidizing agent in a solvent of alcohol and/or H ₂ O to prepare the compound of formula (I-c1) and the compound of formula (I-c2); the oxidizing agent is selected from the group consisting of Potassium oxymonosulfonate (Oxone) or meta-chloroperoxybenzoic acid (mCPBA). A method for preparing a compound of formula (Id), wherein: the compound of formula (Id) is prepared by the following method:

The compound of formula (Ie) and the reagent I are reacted in an aprotic solvent under inorganic base conditions to prepare the compound of formula (Id); the reagent I is selected from iodoethane. The preparation method of the compound of formula (Id) according to claim 4, wherein: the compound of formula (Ie) is prepared by the following method:

The compound of formula (If) and an azidation reagent are reacted in an aprotic solvent under alkaline conditions to prepare the compound of formula (Ie); the azidation reagent is selected from diphenyl phosphate azide (DPPA ). The preparation method of the compound of formula (Id) according to claim 5, wherein: the compound of formula (If) is prepared by the following method:

The compound of formula (Ih) and the compound of formula (Ig) are reacted in an aprotic solvent or a mixed solvent of an aprotic solvent and H ₂ O under inorganic base conditions; after the reaction is completed, the aprotic solvent is removed under reduced pressure Or a mixed solvent of an aprotic solvent and H ₂ O, and then adding the aqueous solution of the inorganic base to continue the reaction to prepare the compound of formula (If). A method for preparing an imidazolinone derivative of formula (I) or a stereoisomer thereof, wherein:

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 an aprotic solvent and H ₂ O under inorganic base conditions; then, the aqueous solution of the inorganic base is added to continue the reaction, Prepare a compound of formula (If); The second step: react the compound of formula (If) and an azide reagent in an aprotic solvent under alkaline conditions to prepare a compound of formula (Ie); the azide reagent Selected from DPPA; the third step: the compound of formula (Ie) and ethyl iodide react in an aprotic solvent under inorganic base conditions to prepare the compound of formula (Id); the fourth step: the compound of formula (Id) In a solvent of alcohol and/or H ₂ O, an oxidizing agent is added for reaction 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 fifth step: the formula ( The compound I-c1), the compound of formula (I-c2) and the compound of formula (Ib) are reacted in an aprotic solvent under the conditions of inorganic base or organic base to prepare the compound of formula (Ia); the sixth step: the The compound of formula (Ia) is reacted with an oxidizing agent in a DMSO solution under inorganic alkali conditions to prepare the compound of formula (I); the oxidizing agent is selected from H ₂ O ₂ . An intermediate for preparing the compound of formula (I) described in claim 1 or a stereoisomer thereof, wherein the intermediate is selected from:

or