A method for preparing oxazole compounds

Abstract

The application provides a preparation method of an oxazole compound. The application provides a preparation method of compound 7, which comprises the following steps: under a solvent-free condition, compound 6 is subjected to a ring-closing reaction with halogenated acetone to obtain compound 7. The oxazole compound prepared by the preparation method of the application is an important isomer in defamisir, and can be used for qualitative and quantitative analysis of impurities in defamisir, so that the quality standard of defamisir is improved.

Description

Technical Field

[0001] This invention relates to a method for preparing oxazole compounds. Background Technology

[0002] Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by red, swollen, and cracked skin, accompanied by intense itching. Worldwide, up to 10% of adults and 20% of children suffer from atopic dermatitis, and according to publicly available data, more than 60% of AD cases are mild to moderate.

[0003] The prevalence of atopic dermatitis in China has been increasing over the past decade, affecting people of all ages. The Chinese Guidelines for the Diagnosis and Treatment of Atopic Dermatitis (2020 Edition) indicate that data from 12 cities in my country show a prevalence of 12.94% in children aged 1-7 years and 30.48% in infants aged 1-12 months.

[0004] PDE4 inhibitors increase intracellular cAMP concentration by inhibiting the hydrolysis of cAMP by PDE4. High levels of cAMP can activate protein kinase A (PKA) and cAMP-activated exchange protein 1 / 2 (Epac1 / 2), thereby regulating multiple signaling pathways. On one hand, activated PKA phosphorylates cAMP response element-binding protein (CREB), activating transcription factor 1 (ATF-1), and cAMP-responsive element modulator (CREM), thereby increasing anti-inflammatory cytokines. On the other hand, activated PKA regulates the transcriptional activity of the nuclear factor-κB (NF-κB) pathway by competitively recruiting CREB-binding protein (CBP) or its homolog p300, leading to a reduction in pro-inflammatory cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-31, and tumor necrosis factor-alpha (TNF-α). Furthermore, PKA activation can interfere with Bcl-6-mediated synthesis of pro-inflammatory cytokines and the proliferation of immune cells. Simultaneously, the Epac1 / 2-mediated alternative pathway is activated upon elevated cAMP levels, interacting with the small GTPase protein Rap to inhibit the synthesis of pro-inflammatory cytokines and cell proliferation. Since PDE4 is expressed in various types of immune-active cells, PDE4 inhibitors can modulate both innate and adaptive immune systems.

[0005] Difamilast is a nonsteroidal, locally active anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor discovered by Otsuka. It was first approved for marketing in Japan in September 2021 for the treatment of mild to moderate Alzheimer's disease in children aged 2 years and older and adults.

[0006] According to data, there are currently 20 PDE4 inhibitors under development globally for atopic dermatitis. Of these, two have been approved for marketing: Otsuka's Difamilast and Pfizer's Cresaborole, which received FDA approval in December 2016. Additionally, Arcutis Biopharmaceuticals' Roflumilast cream / ARQ151 is currently in Phase III trials.

[0007] Pfizer's nonsteroidal PDE4 inhibitor crisaborole (trade name: Eucrisa) was approved for marketing in July 2020 for the topical treatment of mild to moderate atopic dermatitis in patients aged 2 years and older, becoming the first nonsteroidal topical PDE4 inhibitor in China. Summary of the Invention

[0008] The main technical problem solved by this invention is to overcome the lack of research on the preparation methods of oxazole compounds in the prior art, and to provide a method for preparing oxazole compounds. The oxazole compounds of this invention are important isomers of defamiclast, and can be used for the qualitative and quantitative analysis of impurities in defamiclast, thereby improving the quality standards of defamiclast.

[0009] The present invention provides a method for preparing compound 7, which includes the following steps: under solvent-free conditions, compound 6 undergoes a cyclization reaction with haloacetone to obtain compound 7;

[0010] ,

[0011] Where R is Cl, Br, or I.

[0012] In one particular scheme, R is Cl.

[0013] In one embodiment, in the preparation method of compound 7, the haloacetone is chloroacetone, preferably 1,3-dichloroacetone.

[0014] In one embodiment, the molar ratio of compound 6 to haloacetone in the preparation method of compound 7 is 1:(1~3), for example 1:2.

[0015] In one embodiment, the preparation method of compound 7 involves a cyclization reaction at a temperature of 100-150°C, for example, 130°C.

[0016] The progress of the ring-closing reaction is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the reactants in the reaction solution. The preferred time for the ring-closing reaction is 0.5-3 hours, for example, 1 hour.

[0017] In one embodiment, the post-processing in the preparation of compound 7 includes the following steps: cooling the mixture to room temperature, adding water to precipitate the solid, filtering, drying to obtain a crude product, and recrystallizing to obtain compound 7.

[0018] The recrystallization is preferably performed using the following steps: recrystallizing the crude product using an antisolvent method; the positive solvent is ethanol, and the antisolvent is n-heptane.

[0019] In one embodiment, the preparation of compound 7 comprises the following steps: at 130°C, compound 6 is reacted with haloacetone in a molar ratio of 1:(1~3) in a ring-closing reaction.

[0020] The preparation method of compound 7 may further include the following steps: in the presence of sodium alkoxide, compound 5 is subjected to an amino-ester exchange reaction in an ammonia-alcohol solution to obtain compound 6;

[0021] .

[0022] In one embodiment, during the preparation of compound 6, the concentration of the ammonia-ethanol solution is 5-10 mol / L, preferably 7 mol / L. The ammonia-ethanol solution is preferably an ammonia-methanol solution.

[0023] In one embodiment, during the preparation of compound 6, the mass-to-volume ratio of compound 5 to the ammonia solution is 0.1 to 0.5 g / mL, for example, 0.25 g / mL.

[0024] In one embodiment, during the preparation of compound 6, the molar ratio of compound 5 to sodium alkoxide is 1:(0.05~0.15), for example, 1:0.1.

[0025] In one embodiment, the reaction temperature during the preparation of compound 6 is 30-70°C, for example, 50°C.

[0026] The preparation of compound 6 is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the reactants in the reaction solution. The preferred reaction time for the preparation of compound 6 is 0.5-3 h, for example, 2 h.

[0027] In one embodiment, the reaction for preparing compound 6 comprises the following steps: at 50°C, compound 5 and sodium alkoxide undergo an amino-ester exchange reaction at a molar ratio of 1:(0.05~0.15).

[0028] The preparation method of compound 7 further includes the following steps: in an organic solvent, in the presence of a base, compound 4 reacts with a haloisopropane to obtain compound 5.

[0029] .

[0030] In one embodiment, the organic solvent used in the preparation of compound 5 is an amide solvent, such as N,N-dimethylformamide.

[0031] In one embodiment, during the preparation of compound 5, the mass-to-volume ratio of compound 4 to the organic solvent is 0.05~0.5 g / mL, for example, 0.2 g / mL.

[0032] In one embodiment, during the preparation of compound 5, the base is a metal carbonate, preferably an alkali metal carbonate, such as potassium carbonate.

[0033] In one embodiment, during the preparation of compound 5, the molar ratio of compound 4 to the base is 1:(1~3), for example, 1:2.

[0034] In one embodiment, in the preparation of compound 5, the haloisopropane is bromoisopropane.

[0035] In one embodiment, during the preparation of compound 5, the molar ratio of compound 4 to the haloisopropane is 1:(1~2), for example, 1:1.4.

[0036] In one embodiment, the reaction temperature for preparing compound 5 is 50-90°C, for example, 80°C.

[0037] The preparation process of compound 5 is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the reactants in the reaction solution. The preparation time of compound 5 is preferably 1-5 h, for example, 2 h.

[0038] In one embodiment, the post-processing of the preparation method of compound 5 includes the following post-processing steps: adding water, extraction, drying, and purification.

[0039] Preferably, the water added is used to dissolve the reaction system completely.

[0040] The extraction is preferably performed using an ester solvent, such as ethyl acetate;

[0041] The drying process preferably uses anhydrous sodium sulfate.

[0042] The purification is preferably column purification, wherein the developing solvent for column purification can be a conventional developing solvent in the art, such as petroleum ether and ethyl acetate.

[0043] In one embodiment, the preparation of compound 5 comprises the following steps: at 80°C, in N,N-dimethylformamide, compound 4 and haloisopropane are reacted in a molar ratio of 1:(1~3) in the presence of potassium carbonate; after the reaction is completed, water is added to the reaction solution to dissolve it, the mixture is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain compound 5.

[0044] The preparation method of compound 7 may further include the following steps: in an organic solvent, in the presence of a catalyst, compound 3 is reduced with hydrogen to obtain compound 4;

[0045] .

[0046] In one embodiment, the organic solvent used in the preparation of compound 4 is an alcohol solvent, such as ethanol.

[0047] In one embodiment, during the preparation of compound 4, the mass-to-volume ratio of compound 3 to the organic solvent is 0.05~0.5 g / mL, for example, 0.11 g / mL.

[0048] In the preparation of compound 4, the catalyst is a conventional catalyst used in the art for reduction reactions, preferably palladium on carbon.

[0049] In one embodiment, during the preparation of compound 4, the mass ratio of compound 3 to the catalyst is (5~8):1, for example, 6.5:1.

[0050] In one embodiment, the reaction is carried out at room temperature during the preparation of compound 4.

[0051] The preparation process of compound 4 is monitored using conventional detection methods in the art, generally with the disappearance or cessation of reaction of one of the raw materials in the reaction solution as the reaction endpoint. The preferred preparation time for compound 4 is 10-15 hours, for example, 12 hours.

[0052] In one embodiment, the preparation of compound 4 further includes the following post-processing steps: concentration and filtration.

[0053] In one embodiment, the preparation of compound 4 preferably comprises the following steps: in the presence of palladium on carbon, in ethanol, the reduction of compound 3 with hydrogen to obtain compound 4.

[0054] The preparation method of compound 7 further includes the following steps: in an organic solvent, in the presence of a base, compound 2 reacts with ClCF2COONa to obtain compound 3;

[0055] .

[0056] In one embodiment, the organic solvent used in the preparation of compound 3 is an amide solvent, such as N,N-dimethylformamide.

[0057] In one embodiment, during the preparation of compound 3, the mass-to-volume ratio of compound 2 to the organic solvent is 50-100 g / L, for example, 70 g / L.

[0058] In one embodiment, during the preparation of compound 3, the base is an alkali metal carbonate, preferably cesium carbonate.

[0059] In one embodiment, during the preparation of compound 3, the molar ratio of compound 2 to the base is 1:(1~2), for example, 1:1.1.

[0060] In one embodiment, during the preparation of compound 3, the molar ratio of compound 2 to ClCF2COONa is 1:(1~2), for example, 1:1.4.

[0061] In one embodiment, the reaction in the preparation of compound 3 is carried out at 50-90°C, for example, 80°C.

[0062] The preparation process of compound 3 is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the reactants in the reaction solution. The preferred preparation time for compound 3 is 10-15 h, for example, 12 h.

[0063] In one embodiment, the preparation of compound 3 further includes the following post-processing steps: cooling, adding water, extraction, drying, and purification.

[0064] The cooling is preferably performed by cooling the reaction system to room temperature;

[0065] The extraction is preferably performed using an ester solvent, such as ethyl acetate;

[0066] The drying process preferably uses anhydrous sodium sulfate.

[0067] The purification is preferably column purification, wherein the developing solvent for column purification can be a conventional developing solvent in the art, such as petroleum ether and ethyl acetate.

[0068] In one embodiment, the preparation of compound 3 comprises the following steps: at 80°C, in N,N-dimethylformamide, compound 2 and ClCF2COONa are subjected to a substitution reaction in a molar ratio of 1:(1~3) in the presence of cesium carbonate; after the reaction is completed, water is added to the reaction solution to dissolve it, the mixture is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain compound 3.

[0069] In one embodiment, the preparation method of compound 7 further includes a preparation method of compound 2: in an organic solvent, in the presence of a base, compound 1 reacts with benzyl bromide to obtain compound 2;

[0070] .

[0071] In this invention, the above-mentioned reaction conditions are conventional conditions and operations in the art. The present invention particularly prefers the following conditions and operations:

[0072] In one embodiment, the organic solvent used in the preparation of compound 2 is a nitrile solvent, such as acetonitrile.

[0073] In one embodiment, during the preparation of compound 2, the mass-to-volume ratio of compound 1 to the organic solvent is 50-100 g / L, for example, 75 g / L.

[0074] In one embodiment, during the preparation of compound 2, the base is a metal carbonate, preferably an alkali metal carbonate, such as potassium carbonate.

[0075] In one embodiment, during the preparation of compound 2, the molar ratio of compound 1 to the base is 1:(1.5~2.5), for example, 1:1.8.

[0076] In one embodiment, during the preparation of compound 2, the molar ratio of compound 1 to benzyl bromide is 1:(1~1.5), for example, 1:1.1.

[0077] In one embodiment, the reaction in the preparation of compound 2 is carried out at 50-90°C, for example, 70°C.

[0078] The preparation process of compound 2 is monitored using conventional detection methods in the art, and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The preferred preparation time for compound 2 is 10-15 hours, for example, 12 hours.

[0079] In one embodiment, the preparation of compound 2 further includes the following post-processing steps: adjusting the pH to 5-6, extraction, drying, concentration, and purification.

[0080] The pH-adjusting reagent is preferably hydrochloric acid, such as 2N hydrochloric acid;

[0081] The extraction is preferably performed using an ester solvent, such as ethyl acetate;

[0082] The drying process preferably uses anhydrous sodium sulfate.

[0083] The purification is preferably column purification, wherein the eluent for column purification can be petroleum ether and ethyl acetate (1:0~10:1).

[0084] In one embodiment, the preparation of compound 2 preferably comprises the following steps: at 70°C, in acetonitrile, compound 1 and benzyl bromide are reacted in a molar ratio of 1:(1~1.5) in the presence of potassium carbonate.

[0085] The present invention also provides a method for preparing compound 2, which includes the following steps:

[0086] In an organic solvent, in the presence of a base, compound 1 reacts with benzyl bromide to give compound 2;

[0087] .

[0088] The conditions and procedures for preparing compound 2 can be as described above.

[0089] This invention provides a method for preparing the compound shown in Formula I, which is method 1, 2, or 3 as follows:

[0090] Method 1: The preparation method of the compound shown in Formula I includes the following steps:

[0091] Step 1: Prepare compound 2 from compound 1;

[0092] Step 2: Prepare compound 3 from compound 2;

[0093] Step 3: Prepare compound 4 from compound 3;

[0094] Step 4: Prepare compound 5 from compound 4;

[0095] Step 5: Prepare compound 6 from compound 5;

[0096] Step 6: Prepare compound 7 from compound 6;

[0097] Step 7: Prepare compound 8 from compound 7;

[0098] Step 8: Prepare compound 9 from compound 8;

[0099] Step 9: Prepare the compound shown in Formula I using compound 9;

[0100] ;

[0101] Method 2: The preparation method of the compound shown in Formula I includes the following steps:

[0102] The preparation method of compound 2 mentioned above;

[0103] And, the method for preparing compound 2 obtained by the above-described method for preparing compound 2 to further prepare the compound shown in formula I;

[0104] Method 3: The preparation method of the compound shown in Formula I includes the following steps:

[0105] The preparation method of compound 7 mentioned above;

[0106] And, the preparation method of compound 7 obtained by the above preparation method for compound 7, further preparing the compound shown in formula I.

[0107] In Scheme 1, the reaction conditions and operations for steps 1 to 6 can be the same as described above.

[0108] In Scheme 1, step 7 may include the following steps: in an organic solvent, compound 7 and the alkali metal salt of phthalimide undergo a substitution reaction to obtain compound 8.

[0109] In one embodiment, in step 7, the organic solvent is an amide solvent, preferably N,N-dimethylformamide.

[0110] In one embodiment, in step 7, the mass-to-volume ratio of compound 7 to the organic solvent is 0.1~0.5 g / mL, for example, 0.195 g / mL.

[0111] In one embodiment, in step 7, the alkali metal salt of phthalimide is potassium phthalimide.

[0112] In one embodiment, in step 7, the molar ratio of compound 7 to the phthalimide alkali metal salt is 1:(1~1.5), for example, 1:1.3.

[0113] In step 7, the temperature of the substitution reaction is 50~100℃, for example 80℃.

[0114] In one embodiment, in step 7, the reaction progress is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The reaction time in step 7 is preferably 1-5 hours, for example, 3 hours.

[0115] In one embodiment, the reaction in step 7 further includes the following post-processing steps: cooling, adding water to induce crystallization, filtering to obtain the filter cake, and drying.

[0116] In one embodiment, the cooling process involves lowering the reaction system to room temperature, such as 25°C.

[0117] In one embodiment, during the water crystallization, the mass-to-volume ratio of compound 7 to water is 0.1~0.5 g / mL, for example, 0.195 g / mL;

[0118] In one embodiment, the drying process involves forced-air drying at 40-60 °C (e.g., 50 °C).

[0119] In one embodiment, step 7 preferably includes the following steps: at 80°C, in N,N-dimethylformamide, the compound 7 and the phthalimide alkali metal salt undergo a substitution reaction at a molar ratio of 1:(1~1.5); after the reaction is completed, the reaction system is cooled to room temperature, water is added to precipitate crystals, the filter cake is filtered, and then dried at 40-60°C to obtain the compound 8.

[0120] In Scheme 1, step 8 may include the following steps: in the presence of a deprotecting agent, in an organic solvent, compound 8 undergoes a deprotection reaction to obtain compound 9.

[0121] In one embodiment, in step 8, the organic solvent is a furan solvent, such as 2-methyltetrahydrofuran.

[0122] In one embodiment, in step 8, the mass-to-volume ratio of compound 8 to the organic solvent is 0.01~0.2 g / mL, for example, 0.07 g / mL.

[0123] In one embodiment, in step 8, the deprotecting agent is methylamine, wherein the deprotecting agent is preferably reacted in the form of an aqueous solution.

[0124] In step 8, the amount of the deprotecting agent used is the conventional amount used in the art, for example, the molar ratio of compound 8 to the deprotecting agent is 1:(5~15), for example 1:11.

[0125] In one embodiment, the reaction temperature in step 8 is 50~80℃, for example 65℃.

[0126] In one embodiment, in step 8, the reaction progress is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The reaction time in step 8 is preferably 0.5 to 3 hours, for example, 2 hours.

[0127] In one embodiment, the reaction in step 8 includes the following post-processing steps: settling, washing with water, concentration, heating to dissolve, adding acid to crystallize, cooling, filtering, and drying.

[0128] The solvent used for dissolving is preferably 2-methyltetrahydrofuran;

[0129] The preferred method for acid crystallization is to add concentrated hydrochloric acid.

[0130] The mass ratio of compound 8 to the acid is (1~5):1, for example 3:1;

[0131] In one embodiment, step 8 includes the following steps: at 65°C, compound 8 and the deprotecting reagent undergo a deprotection reaction at a molar ratio of 1:(5~15); after the reaction is completed, the reaction solution is washed with water and concentrated, then dissolved in 2-methyltetrahydrofuran at 50°C, concentrated hydrochloric acid is added to crystallize, filtered and dried to obtain compound 9.

[0132] In Scheme 1, step 9 may include the following steps: in an organic solvent, in the presence of a base and a condensing agent, compound 9 reacts with 2-ethoxybenzoic acid via a condensation reaction to obtain the compound shown in Formula I.

[0133] In one embodiment, in step 9, the organic solvent is an ester solvent, such as ethyl acetate.

[0134] In one embodiment, in step 9, the mass-to-volume ratio of compound 9 to the organic solvent is 0.1~0.5 g / mL, for example, 0.18 g / mL.

[0135] In one embodiment, in step 9, the base is a tertiary amine organic base, preferably triethylamine.

[0136] In one embodiment, in step 9, the molar ratio of compound 9 to the base is 1:(1~2), for example, 1:1.6.

[0137] In one embodiment, in step 9, the molar ratio of compound 9 to 2-ethoxybenzoic acid is 1:(1~3), for example, 1:2.

[0138] In one embodiment, in step 9, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0139] In one embodiment, in step 9, the molar ratio of compound 9 to the condensing agent is 1:(1~1.5), for example, 1:1.1.

[0140] In step 9, the reaction temperature is preferably 15~35℃, for example 20~30℃.

[0141] In one embodiment, in step 9, the reaction progress is monitored using conventional detection methods in the art (e.g., LC-MS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The reaction time in step 9 is preferably 0.5-3 hours, for example, 2 hours.

[0142] In one embodiment, step 9 includes the following steps: mixing compound 9 with an organic solvent and ethyl acetoacetate to obtain a mixture, and adding 2-ethoxybenzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the mixture.

[0143] The reaction in step 9 includes the following post-processing steps: acid washing (e.g., washing with 3%~3.3% hydrochloric acid solution), alkali washing (e.g., washing with 3%~5% sodium hydroxide solution), concentration, and recrystallization.

[0144] The recrystallization preferably includes the following steps: decolorizing and recrystallizing the concentrate in a mixed solvent of ethanol and water to obtain the compound shown in Formula I.

[0145] In one embodiment, step 9 comprises the following steps: mixing compound 9 with triethylamine in ethyl acetate at a molar ratio of 1:(1~2) to obtain a mixture, and adding 2-ethoxybenzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the mixture for a condensation reaction.

[0146] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0147] The reagents and raw materials used in this invention are all commercially available.

[0148] The positive and progressive effects of this invention are as follows:

[0149] This invention can synthesize intermediate compound 7, an important isomer of defamisate, in high yield and is suitable for industrial production;

[0150] This invention can obtain compound 2 in good yield;

[0151] This invention synthesizes an important isomer of defamiclast through a specific reaction route design, which can be used for the qualitative and quantitative analysis of impurities in defamiclast, thereby improving the quality standards of defamiclast. Detailed Implementation

[0152] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0153] Synthesis steps:

[0154]

[0155] Example 1: Preparation of Compound 2

[0156]

[0157] 300g of compound 1 and 4L of acetonitrile were added to a reaction flask. 455g of potassium carbonate was added under stirring, followed by 336g of benzyl bromide. The mixture was stirred at 70°C for 12 hours. The pH was adjusted to 5-6 with 2N dilute hydrochloric acid. 6L of water was added and stirred. 4L of ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (PE:EA = 1:0-10:1) to obtain 150g of product (compound 2), with a yield of 33.5%.

[0158] Example 2: Preparation of Compound 3

[0159]

[0160] 140 g of compound 2 was dissolved in 2 L of DMF, 200 g of cesium carbonate and 117 g of ClCF2COONa were added, and the mixture was stirred at 80 °C for 12 h. LCMS showed that about 32% of the product was present. The mixture was cooled to room temperature, 6 L of water was added, and the mixture was stirred until dissolved. 2 L of ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (PE:EA = 1:0~20:1) to give 65 g of product (compound 3), with a yield of 39.2%.

[0161] Example 3: Preparation of Compound 4

[0162]

[0163] 65 g of compound 3 was dissolved in 600 mL of ethanol, and 10 g of wet palladium on carbon was added. The mixture was then purged three times with a hydrogen balloon, and the reaction was carried out at room temperature for 12 h. After filtration and rotary evaporation, 46.8 g of product (compound 4) was obtained, with a yield of 100%.

[0164] Example 4: Preparation of Compound 5

[0165]

[0166] 46.8 g of compound 4 was dissolved in 400 mL of DMF, 55.7 g of potassium carbonate and 37 g of bromoisopropane were added, and the mixture was stirred at 80 °C for 2 h. LC-MS showed that the reaction was complete. 500 mL of water was added and stirred until dissolved. 600 mL of ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (PE:EA = 1:0~20:1) to give 50 g of product (compound 5), with a yield of 91%.

[0167] Example 5: Preparation of Compound 6

[0168]

[0169] 25g of compound 5 was added to an autoclave, along with 100mL of 7M ammonia-methanol solution and 0.5g of sodium methoxide. The mixture was stirred at 50°C for 2 hours, and the reaction was confirmed to be complete by LC-MS. The mixture was concentrated to 50mL, and then 200mL of purified water was added dropwise. After the reaction was complete, the mixture was stirred in an ice-water bath for 2 hours, filtered, and the filter cake was dried at 50°C to obtain 22.1g of off-white solid (compound 6), with a yield of 94.1%.

[0170] Example 6: Preparation of Compound 7

[0171]

[0172] Add 22g of compound 6 to a reaction flask, add 22.8g of 1,3-dichloropropanone, heat to 130℃ and stir for 1 hour; LC-MS detects complete reaction; cool to 20℃, add 400mL of purified water, filter, rinse the filter cake with water, and dry the crude product at 50℃ using a forced-air drying method.

[0173] Add 40 mL of anhydrous ethanol to the crude product, heat to 70 °C, stir to dissolve, add 80 mL of n-heptane dropwise, slowly cool to 10 °C, stir for 3 hours, filter, and dry the filter cake under vacuum at 50 °C to obtain 19.6 g of off-white solid (compound 7), yield 69.2%.

[0174] Example 7: Preparation of Compound 8

[0175]

[0176] 19.5 g of compound 7 was added to a reaction flask, followed by 100 mL of DMF and 14.8 g of potassium phthalimide. The mixture was heated to 80 °C and stirred for 3 hours. The reaction was confirmed by LC-MS. The mixture was then cooled to 25 °C, and 100 mL of purified water was added dropwise. After the reaction was complete, the mixture was stirred for 2 hours, filtered, and the filter cake was dried at 50 °C with a forced air drying process to obtain 24.2 g of light gray solid (compound 8), with a yield of 92.1%.

[0177] Example 8: Preparation of Compound 9

[0178]

[0179] 24.0 g of compound 8 was added to a reaction flask, along with 48 g of methylamine aqueous solution (40% concentration) and 100 mL of 2-methyltetrahydrofuran. The mixture was heated to 65 °C and stirred for 2 hours. The reaction was confirmed by LC-MS, and the mixture was allowed to stand for phase separation. The organic phase was washed once with 95 mL of purified water. The organic phase was concentrated to dryness, and then 240 mL of 2-methyltetrahydrofuran was added. The mixture was heated to 50 °C, and 7.2 g of concentrated hydrochloric acid was added. After stirring for 0.5 hours, the mixture was cooled to 0–10 °C in an ice-water bath and stirred for 3 hours. The mixture was then filtered and dried under vacuum at 50 °C to obtain 16.8 g of an off-white solid (compound 9), with a yield of 89.9%.

[0180] Example 9: Preparation of Formula I

[0181]

[0182] Add 6.3 g of compound 9, 35 mL of ethyl acetate, and 3.1 g of triethylamine (1.6 eq) to the reaction flask; incubate at 20-30 °C and stir for 1 h. Then add 6.1 g of 2-ethoxybenzoic acid (2.0 eq) and 3.96 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 eq), and continue stirring for another 1 h. The reaction was confirmed to be complete by LC-MS; add 54 mL of purified water and 5.2 mL of 35%–38% concentrated hydrochloric acid and stir; separate the liquid from the organic phase, add 54 mL of purified water and 5.4 g of 25% sodium hydroxide solution, stir, separate the liquid from the organic phase, and evaporate the organic phase to dryness.

[0183] Add 16 mL of ethanol, 6.4 mL of purified water, and 2 mL of 25% sodium hydroxide solution to the evaporated organic phase, then add 0.06 g of activated carbon. Heat to reflux, stir for 0.5 hours, filter, wash the filter cake with 4 mL of ethanol, slowly cool the filtrate to 5-10 °C, keep it at this temperature and stir for 1 hour, filter again, and obtain a white solid (compound of formula I). ​​Dry under vacuum at 50 °C to obtain 6 g, yield 71.4%. MS = 447.18 (M+1).

[0184] 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.25 (dd, J = 7.8, 1.8 Hz,1H), 7.90 – 7.81 (m, 2H), 7.65 (s, 1H), 7.46 – 7.40 (m, 1H), 7.14 – 7.00 (m,2H), 6.96 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 75.1 Hz, 1H), 4.71 – 4.61 (m,3H), 4.20 (q, J = 7.0 Hz, 2H), 1.52 (t, J = 7.0 Hz, 3H), 1.41 (d, J = 6.1 Hz, 6H).

Claims

1. A method for preparing compound 7, characterized in that, It includes the following steps: under solvent-free conditions, compound 6 undergoes a cyclization reaction with haloacetone to obtain compound 7; The haloacetone is 1,3-dichloroacetone; The temperature for the ring-closing reaction is 100~150℃; ， Where R stands for Cl.

2. The method for preparing compound 7 as described in claim 1, characterized in that, It satisfies one or more of the following conditions (1)-(3): (1) In the preparation method of compound 7, the molar ratio of compound 6 to haloacetone is 1:(1~3). (2) In the preparation method of compound 7, the temperature of the cyclization reaction is 130°C; (3) The post-processing of the preparation method of compound 7 includes the following post-processing steps: cooling the mixture to room temperature, adding water to precipitate the solid, filtering, drying to obtain the crude product, recrystallizing to obtain compound 7.

3. The method for preparing compound 7 as described in claim 2, characterized in that, In the preparation method of compound 7, the molar ratio of compound 6 to haloacetone is 1:

2.

4. The method for preparing compound 7 as described in claim 2, characterized in that, The preparation of compound 7 comprises the following steps: at 130°C, compound 6 and haloacetone undergo a cyclization reaction at a molar ratio of 1:(1~3).

5. The method for preparing compound 7 as described in claim 1, characterized in that, The preparation method of compound 7 further includes the following steps: in the presence of sodium alkoxide, compound 5 is subjected to an amino-ester exchange reaction in an ammonia-alcohol solution to obtain compound 6; 。 6. The method for preparing compound 7 as described in claim 5, characterized in that, It satisfies one or more of the following conditions (1)-(4): (1) In the preparation of compound 6, the concentration of the ammonia solution is 5~10 mol / L; (2) In the preparation of compound 6, the mass-to-volume ratio of compound 5 to the ammonia solution is 0.1~0.5 g / mL; (3) In the preparation of compound 6, the molar ratio of compound 5 to sodium alkoxide is 1:(0.05~0.15). (4) In the preparation of compound 6, the reaction temperature is 30~70℃.

7. The method for preparing compound 7 as described in claim 6, characterized in that, It satisfies one or more of the following conditions (1)-(5): (1) In the preparation of compound 6, the concentration of the ammonia solution is 7 mol / L; (2) In the preparation of compound 6, the ammonia solution is an ammonia-methanol solution; (3) In the preparation of compound 6, the mass-to-volume ratio of compound 5 to the ammonia solution is 0.25 g / mL; (4) In the preparation of compound 6, the molar ratio of compound 5 to sodium alkoxide is 1:0.1; (5) In the preparation of compound 6, the reaction temperature is 50°C.

8. The method for preparing compound 7 as described in claim 6, characterized in that... The reaction for preparing compound 6 comprises the following steps: at 50°C, compound 5 and sodium alkoxide undergo ammonolysis at a molar ratio of 1:(0.05~0.15).

9. The method for preparing compound 7 as described in claim 5, characterized in that, The preparation method of compound 7 further includes the following steps: in an organic solvent, in the presence of a base, compound 4 reacts with a haloisopropane to obtain compound 5. 。 10. The method for preparing compound 7 as described in claim 9, characterized in that, It satisfies one or more of the following conditions (1)-(8): (1) In the preparation of compound 5, the organic solvent is an amide solvent; (2) In the preparation of compound 5, the mass-to-volume ratio of compound 4 to the organic solvent is 0.05~0.5 g / mL; (3) In the preparation of compound 5, the base is a metal carbonate; (4) In the preparation of compound 5, the molar ratio of compound 4 to the base is 1:(1~3). (5) In the preparation of compound 5, the haloisopropane is brominated isopropane; (6) In the preparation of compound 5, the molar ratio of compound 4 to haloisopropane is 1:(1~2). (7) The reaction temperature for preparing compound 5 is 50~90℃; (8) The post-processing in the preparation of compound 5 includes the following post-processing steps: adding water, extraction, drying and purification.

11. The method for preparing compound 7 as described in claim 10, characterized in that, It satisfies one or more of the following conditions (1)-(6): (1) In the preparation of compound 5, the organic solvent is N,N-dimethylformamide; (2) In the preparation of compound 5, the mass-to-volume ratio of compound 4 to the organic solvent is 0.2 g / mL; (3) In the preparation of compound 5, the base is an alkali metal carbonate; (4) In the preparation of compound 5, the molar ratio of compound 4 to the base is 1:2; (5) In the preparation of compound 5, the molar ratio of compound 4 to haloisopropane is 1:1.4; (6) The reaction temperature for preparing compound 5 is 80°C.

12. The method for preparing compound 7 as described in claim 11, characterized in that, In the preparation of compound 5, the base is potassium carbonate.

13. The method for preparing compound 7 as described in claim 10 or 11, characterized in that, The preparation of compound 5 comprises the following steps: at 80°C, in N,N-dimethylformamide, compound 4 and haloisopropane are subjected to a substitution reaction in a molar ratio of 1:(1~3) in the presence of potassium carbonate; after the reaction is completed, water is added to the reaction solution to dissolve it, the solution is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and obtained by column chromatography to obtain compound 5.

14. The method for preparing compound 7 as described in claim 9, characterized in that, The preparation method of compound 7 further includes the following steps: in an organic solvent, in the presence of a catalyst, compound 3 is reduced with hydrogen to obtain compound 4; 。 15. The method for preparing compound 7 as described in claim 14, characterized in that, It satisfies one or more of the following conditions (1)-(5): (1) In the preparation of compound 4, the organic solvent is an alcohol solvent; (2) In the preparation of compound 4, the mass-to-volume ratio of compound 3 to the organic solvent is 0.05~0.5 g / mL; (3) In the preparation of compound 4, the catalyst is palladium on carbon; (4) In the preparation of compound 4, the mass ratio of compound 3 to the catalyst is (5~8):1; (5) The post-processing of compound 4 includes the following post-processing steps: concentration and filtration.

16. The method for preparing compound 7 as described in claim 15, characterized in that, It satisfies one or more of the following conditions (1)-(3): (1) In the preparation of compound 4, the organic solvent is ethanol; (2) In the preparation of compound 4, the mass-to-volume ratio of compound 3 to the organic solvent is 0.11 g / mL; (3) In the preparation of compound 4, the mass ratio of compound 3 to the catalyst is 6.5:

1.

17. The method for preparing compound 7 as described in claim 15 or 16, characterized in that, The preparation of compound 4 comprises the following steps: in the presence of palladium on carbon, in ethanol, the reduction of compound 3 with hydrogen gas yields compound 4.

18. The method for preparing compound 7 as described in claim 14, characterized in that, The preparation method of compound 7 further includes the following steps: in an organic solvent, in the presence of a base, compound 2 reacts with ClCF2COONa to obtain compound 3; 。 19. The method for preparing compound 7 as described in claim 18, characterized in that, It satisfies one or more of the following conditions (1)-(7): (1) In the preparation of compound 3, the organic solvent is an amide solvent; (2) In the preparation of compound 3, the mass-to-volume ratio of compound 2 to the organic solvent is 50-100 g / L; (3) In the preparation of compound 3, the base is an alkali metal carbonate; (4) In the preparation of compound 3, the molar ratio of compound 2 to the base is 1:(1~2). (5) In the preparation of compound 3, the molar ratio of compound 2 to ClCF2COONa is 1:(1~2). (6) In the preparation of compound 3, the reaction temperature is 50~90℃; (7) The post-processing of the preparation of compound 3 includes the following post-processing steps: cooling, adding water, extraction, drying and purification.

20. The method for preparing compound 7 according to claim 19, characterized in that, It satisfies one or more of the following conditions (1)-(6): (1) In the preparation of compound 3, the organic solvent is N,N-dimethylformamide; (2) In the preparation of compound 3, the mass-to-volume ratio of compound 2 to the organic solvent is 70 g / L; (3) In the preparation of compound 3, the base is cesium carbonate; (4) In the preparation of compound 3, the molar ratio of compound 2 to the base is 1:1.1; (5) In the preparation of compound 3, the molar ratio of compound 2 to ClCF2COONa is 1:1.4; (6) In the preparation of compound 3, the reaction temperature is 80°C.

21. The method for preparing compound 7 as described in claim 19 or 20, characterized in that, The preparation of compound 3 comprises the following steps: at 80°C, in N,N-dimethylformamide, compound 2 and ClCF2COONa are subjected to a substitution reaction in a molar ratio of 1:(1~3) in the presence of cesium carbonate; after the reaction is completed, water is added to the reaction solution to dissolve it, the mixture is extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain compound 3.

22. The method for preparing compound 7 as described in claim 18, characterized in that, The method for preparing compound 7 also includes a method for preparing compound 2: in an organic solvent, in the presence of a base, compound 1 reacts with benzyl bromide to obtain compound 2; 。 23. The method for preparing compound 7 as described in claim 22, characterized in that, It satisfies one or more of the following conditions (1)-(7): (1) In the preparation of compound 2, the organic solvent is a nitrile solvent; (2) In the preparation of compound 2, the mass-to-volume ratio of compound 1 to the organic solvent is 50~100 g / L; (3) In the preparation of compound 2, the base is a metal carbonate; (4) In the preparation of compound 2, the molar ratio of compound 1 to the base is 1:(1.5~2.5). (5) In the preparation of compound 2, the molar ratio of compound 1 to benzyl bromide is 1:(1~1.5). (6) In the preparation of compound 2, the reaction temperature is 50~90℃; (7) The post-processing of compound 2 includes the following post-processing steps: adjusting pH to 5-6, extraction, drying, concentration and purification.

24. The method for preparing compound 7 as described in claim 23, characterized in that, It satisfies one or more of the following conditions (1)-(6): (1) In the preparation of compound 2, the organic solvent is acetonitrile; (2) In the preparation of compound 2, the mass-to-volume ratio of compound 1 to the organic solvent is 75 g / L; (3) In the preparation of compound 2, the base is an alkali metal carbonate; (4) In the preparation of compound 2, the molar ratio of compound 1 to the base is 1:1.8; (5) In the preparation of compound 2, the molar ratio of compound 1 to benzyl bromide is 1:1.1; (6) In the preparation of compound 2, the reaction temperature is 70°C.

25. The method for preparing compound 7 as described in claim 24, characterized in that, In the preparation of compound 2, the base is potassium carbonate.

26. The method for preparing compound 7 as described in claim 23 or 24, characterized in that, The preparation of compound 2 comprises the following steps: at 70°C, in acetonitrile, compound 1 and benzyl bromide are reacted in a molar ratio of 1:(1~1.5) in the presence of potassium carbonate.

27. A method for preparing a compound of Formula I, characterized in that, The method is as follows: Method 1: The preparation method of the compound shown in Formula I includes the following steps: Step 1: Prepare compound 2 from compound 1; Step 2: Prepare compound 3 from compound 2; Step 3: Prepare compound 4 from compound 3; Step 4: Prepare compound 5 from compound 4; Step 5: Prepare compound 6 from compound 5; Step 6: Compound 7 was prepared by reacting compound 6 with 1,3-dichloroacetone under solvent-free conditions at 100-150°C; Step 7: Prepare compound 8 from compound 7; Step 8: Prepare compound 9 from compound 8; Step 9: Prepare the compound shown in Formula I using compound 9; 。 28. The method for preparing the compound of formula I as described in claim 27, characterized in that, It satisfies one or more of the following conditions: (1) Step 7 includes the following steps: in an organic solvent, compound 7 and phthalimide alkali metal salt undergo a substitution reaction to obtain compound 8; (2) Step 8 includes the following steps: in the presence of a deprotecting agent, in an organic solvent, compound 8 undergoes a deprotection reaction to give compound 9; (3) Step 9 includes the following steps: in an organic solvent, in the presence of a base and a condensing agent, compound 9 reacts with 2-ethoxybenzoic acid by a condensation reaction to obtain the compound shown in Formula I.

29. The method for preparing the compound of formula I as described in claim 28, characterized in that, It satisfies one or more of the following conditions: (1) In step 7, the organic solvent is an amide solvent; (2) In step 7, the mass-to-volume ratio of compound 7 to the organic solvent is 0.1~0.5 g / mL; (3) In step 7, the alkali metal salt of phthalimide is potassium phthalimide; (4) In step 7, the molar ratio of compound 7 to the phthalimide alkali metal salt is 1:(1~1.5). (5) In step 7, the temperature of the substitution reaction is 50~100℃; (6) The post-reaction treatment in step 7 includes the following post-reaction steps: cooling, adding water to crystallize, filtering to obtain filter cake and drying; (7) In step 8, the organic solvent is a furan solvent; (8) In step 8, the mass-to-volume ratio of compound 8 to the organic solvent is 0.01~0.2 g / mL; (9) In step 8, the deprotection agent is methylamine; (10) In step 8, the reaction temperature is 50~80℃; (11) The post-reaction treatment of step 8 includes the following post-reaction steps: standing, washing with water, concentration, heating to dissolve, adding acid to crystallize, cooling, filtering, and drying; (12) In step 9, the organic solvent is an ester solvent; (13) In step 9, the mass-to-volume ratio of compound 9 to the organic solvent is 0.1~0.5 g / mL; (14) In step 9, the base is a tertiary amine organic base; (15) In step 9, the molar ratio of compound 9 to the base is 1:(1~2). (16) In step 9, the molar ratio of compound 9 to 2-ethoxybenzoic acid is 1:(1~3). (17) In step 9, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (18) In step 9, the molar ratio of compound 9 to condensing agent is 1:(1~1.5). (19) In step 9, the reaction temperature is 15~35℃; (20) In step 9, the reaction includes the following steps: mixing compound 9 with an organic solvent and ethyl acetoacetate to obtain a mixture, and adding 2-ethoxybenzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the mixture.

30. The method for preparing the compound of Formula I as described in claim 29, characterized in that, It satisfies one or more of the following conditions: (1) In step 7, the organic solvent is N,N-dimethylformamide; (2) In step 7, the mass-to-volume ratio of compound 7 to the organic solvent is 0.195 g / mL; (3) In step 7, the molar ratio of compound 7 to the phthalimide alkali metal salt is 1:1.3; (4) In step 7, the temperature of the substitution reaction is 80°C; (5) In step 8, the organic solvent is 2-methyltetrahydrofuran; (6) In step 8, the mass-to-volume ratio of compound 8 to the organic solvent is 0.07 g / mL; (7) In step 8, the deprotecting agent is reacted in the form of an aqueous solution; (8) In step 8, the reaction temperature is 65°C; (9) In step 9, the organic solvent is ethyl acetate; (10) In step 9, the mass-to-volume ratio of compound 9 to the organic solvent is 0.18 g / mL; (11) In step 9, the base is triethylamine; (12) In step 9, the molar ratio of compound 9 to the base is 1:1.6; (13) In step 9, the molar ratio of compound 9 to 2-ethoxybenzoic acid is 1:2; (14) In step 9, the molar ratio of compound 9 to the condensing agent is 1:1.1; (15) In step 9, the reaction temperature is 20~30℃.

31. The method for preparing the compound of Formula I as described in claim 29 or 30, characterized in that, It satisfies one or more of the following conditions: Step 7 includes the following steps: at 80°C, in N,N-dimethylformamide, the compound 7 and the phthalimide alkali metal salt undergo a substitution reaction at a molar ratio of 1:(1~1.5); after the reaction is completed, the reaction system is cooled to room temperature, water is added to precipitate crystals, the filter cake is filtered, and then dried at 40-60°C to obtain the compound 8; Step 8 includes the following steps: at 65°C, compound 8 undergoes a deprotection reaction with the aqueous methylamine solution; after the reaction is completed, the reaction solution is washed and concentrated with water, dissolved in 2-methyltetrahydrofuran at 50°C, crystallized by adding concentrated hydrochloric acid, filtered and dried to obtain compound 9. Step 9 includes the following steps: in ethyl acetate, compound 9 is mixed with triethylamine at a molar ratio of 1:(1~2) to obtain a mixture, and 2-ethoxybenzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the mixture to carry out a condensation reaction.

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