Preparation method of oxazole compound

Abstract

The invention provides a preparation method of an oxazole compound. The invention provides a preparation method of a compound 7. The preparation method comprises the following step: under a solvent-free condition, carrying out ring closing reaction on a compound 6 and halogenated acetone to obtain the compound 7. The oxazole compound prepared by the preparation method disclosed by the invention is an important isomer in the defamilast, and can be used for qualitative and quantitative analysis of impurities in the defamilast, so that the quality standard of the defamilast is improved. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing oxazole compounds. Background Art

[0002] Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by redness, swelling, cracking, and severe itching of the skin. Worldwide, up to 10% of adults and 20% of children suffer from atopic dermatitis, and according to public data, mild to moderate AD patients account for more than 60%.

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

[0004] PDE4 inhibitors increase the intracellular cAMP concentration by inhibiting the hydrolysis of cAMP by PDE4. High levels of cAMP can activate protein kinase A (PKA) and exchange protein activated by cAMP1 / 2 (Epac1 / 2), thereby regulating multiple signaling pathways. On the one hand, activated PKA phosphorylates cAMP response element-binding protein (CREB), activating transcription factor 1 (ATF-1) and cAMP response 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 homologous protein p300, leading to a reduction in proinflammatory cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-31, and tumor necrosis factor alpha (TNF-α). In addition, PKA activation can also interfere with the synthesis of proinflammatory cytokines and the proliferation of immune cells mediated by Bcl-6. At the same time, the Epac1 / 2-mediated bypass pathway is activated after the increase of cAMP levels, interacting with the small GTPase protein Rap, inhibiting the synthesis of proinflammatory cytokines and cell proliferation. Since PDE4 is expressed in many types of immune-competent cells, PDE4 inhibitors can regulate the innate and adaptive immune systems.

[0005] Difamilast is a non-steroidal, topical 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 AD in children aged 2 years and above and adults.

[0006] According to data, there are currently 20 PDE4 inhibitors under development for atopic dermatitis worldwide. Among them, two have been approved for marketing, in addition to Otsuka's Difamilast, there is also Crisaborole developed by Pfizer, which was approved by the FDA in December 2016. In addition, Arcutis Biopharmaceuticals' Roflumilast Cream / Roflumilast / ARQ151 is currently in Phase III trials.

[0007] Pfizer's non-steroidal PDE4 inhibitor Crisaborole (trade name: Eucrisa) was approved for marketing in July 2020 for topical treatment of mild to moderate atopic dermatitis in patients aged 2 years and above, becoming China's first non-hormonal topical PDE4 inhibitor. Summary of the invention

[0008] The main technical problem solved by the present invention is to overcome the lack of research on the preparation method of oxazole compounds in the prior art, and to provide a preparation method of oxazole compounds. The oxazole compound of the present invention is an important isomer in defamilastat, which can be used for qualitative and quantitative analysis of impurities in defamilastat, thereby improving the quality standard of defamilastat.

[0009] The present invention provides a method for preparing compound 7, which comprises the following steps: in a solvent-free condition, compound 6 and halogenated acetone undergo a ring-closing reaction to obtain compound 7;

[0010] ,

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

[0012] In one embodiment, R is Cl.

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

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

[0015] In one embodiment, in the method for preparing compound 7, the temperature of the ring-closure reaction is 100-150°C, for example, 130°C.

[0016] The progress of the ring-closing reaction is monitored by conventional detection methods in the art (eg, LC-MS), and the end point of the reaction is generally when one of the raw materials disappears or ceases to react in the reaction solution. The ring-closing reaction time is preferably 0.5-3 h, for example, 1 h.

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

[0018] The recrystallization preferably comprises the following steps: adopting an anti-solvent method to recrystallize the crude product; the positive solvent is ethanol and the anti-solvent is n-heptane.

[0019] In one embodiment, the preparation of the compound 7 comprises the following steps: at 130° C., the compound 6 and the halogenated acetone are subjected to a ring-closing reaction in a molar ratio of 1:(1-3).

[0020] The preparation method of the compound 7 may also include the following steps: in the presence of sodium alcoholate, subjecting the compound 5 to an amine ester exchange reaction in an ammonia alcohol solution to obtain the compound 6;

[0021] .

[0022] In a certain embodiment, in the preparation of the compound 6, the concentration of the ammonia alcohol solution is 5-10 mol / L, preferably 7 mol / L. The ammonia alcohol solution is preferably an ammonia methanol solution.

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

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

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

[0026] The progress of the preparation of the compound 6 is monitored by conventional detection methods in the art (eg, LC-MS), and the end point of the reaction is generally the disappearance or no-reaction of one of the raw materials in the reaction solution. The reaction time for the preparation of the compound 6 is preferably 0.5-3 h, for example, 2 h.

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

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

[0029] .

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

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

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

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

[0034] In a certain embodiment, in the preparation of compound 5, the isopropyl halide is isopropyl bromide.

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

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

[0037] The progress of the preparation of the compound 5 is monitored by conventional detection methods in the art (eg, LC-MS), and the end point of the reaction is generally the disappearance of one of the raw materials in the reaction solution or the end of the reaction. The preparation time of the compound 5 is preferably 1-5 h, for example, 2 h.

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

[0039] Wherein, the adding of water preferably dissolves the reaction system;

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

[0041] The drying is preferably carried out using anhydrous sodium sulfate;

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

[0043] In a certain scheme, the preparation of the compound 5 comprises the following steps: at 80° C., in N,N-dimethylformamide, the compound 4 reacts with the halogenated isopropyl in a molar ratio of 1:(1-3) in the presence of potassium carbonate; after the reaction, water is added to the reaction solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain the compound 5.

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

[0045] .

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

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

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

[0049] In a certain embodiment, in the preparation of the compound 4, the mass ratio of the compound 3 to the catalyst is (5-8):1, for example, 6.5:1.

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

[0051] The progress of the preparation of the compound 4 is monitored by conventional detection methods in the art, and generally the disappearance or no-reaction of one of the raw materials in the reaction solution is taken as the reaction endpoint. The preparation time of the compound 4 is preferably 10-15 hours, for example 12 hours.

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

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

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

[0055] .

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

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

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

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

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

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

[0062] The progress of the preparation of the compound 3 is monitored by conventional detection methods in the art (eg, LC-MS), and the end point of the reaction is generally the disappearance of one of the raw materials in the reaction solution or the end of the reaction. The preparation time of the compound 3 is preferably 10-15 h, for example, 12 h.

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

[0064] The cooling preferably cools the reaction system to room temperature;

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

[0066] The drying is preferably carried out using anhydrous sodium sulfate;

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

[0068] In a certain scheme, the preparation of the compound 3 comprises the following steps: at 80°C, in N,N-dimethylformamide, the 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, water is added to the reaction solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain the compound 3.

[0069] In one embodiment, the preparation method of compound 7 also includes the 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 the present invention, the above reaction conditions are conventional conditions and operations in the art, and the present invention particularly prefers the following conditions and operations:

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

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

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

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

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

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

[0078] The progress of the preparation of the compound 2 is monitored by conventional detection methods in the art, and generally the disappearance or no-reaction of one of the raw materials in the reaction solution is taken as the reaction endpoint. The preparation time of the compound 2 is preferably 10-15 hours, for example 12 hours.

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

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

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

[0082] The drying is preferably carried out using anhydrous sodium sulfate;

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

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

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

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

[0087] .

[0088] The conditions and operations for the preparation of compound 2 can be as described above.

[0089] The present invention provides a method for preparing a compound represented by formula I, which is the following method 1, 2 or 3:

[0090] Method 1: The method for preparing the compound represented by formula I comprises the following steps:

[0091] Step 1: Compound 2 is prepared from compound 1;

[0092] Step 2: Compound 3 is prepared via compound 2;

[0093] Step 3: Compound 4 is prepared via compound 3;

[0094] Step 4: Compound 5 is prepared via compound 4;

[0095] Step 5: Compound 6 is prepared via compound 5;

[0096] Step 6: Compound 7 is prepared via compound 6;

[0097] Step 7: Compound 8 is prepared via compound 7;

[0098] Step 8: Compound 9 is prepared via compound 8;

[0099] Step 9: Prepare the compound represented by formula I through compound 9;

[0100] ;

[0101] Method 2: The preparation method of the compound represented by formula I comprises the following steps:

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

[0103] and, a method for preparing a compound of formula I by further preparing compound 2 obtained by the method for preparing compound 2 above;

[0104] Method 3: The preparation method of the compound represented by formula I comprises the following steps:

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

[0106] And, a method for further preparing the compound represented by formula I from compound 7 obtained by the method for preparing compound 7 above.

[0107] In Scheme 1, the reaction conditions and operations of Step 1 to Step 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 alkali metal salt of phthalimide are subjected to 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 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 alkali metal salt of phthalimide is 1:(1-1.5), for example, 1:1.3.

[0113] In step 7, the temperature of the substitution reaction is 50-100°C, for example 80°C.

[0114] In one embodiment, in step 7, the progress of the reaction is monitored by conventional detection methods in the art (e.g., LC-MS), and the disappearance or no-reaction of one of the raw materials in the reaction solution is generally used as the reaction endpoint. The reaction time of step 7 is preferably 1-5 h, for example, 3 h.

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

[0116] In one embodiment, the cooling is to reduce the temperature of the reaction system to room temperature, such as 25°C;

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

[0118] In a certain embodiment, the drying is carried out by forced air drying at 40-60°C (eg 50°C).

[0119] In a certain scheme, step 7 preferably comprises the following steps: at 80°C, in N,N-dimethylformamide, the compound 7 and the alkali metal salt of phthalimide are subjected to a substitution reaction in a molar ratio of 1:(1-1.5); after the reaction is completed, the reaction system is cooled to room temperature, water is added for crystallization, and the filter cake is dried at 40-60°C after filtering 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 is subjected to 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 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 in the art, for example, the molar ratio of the compound 8 to the deprotecting agent is 1:(5-15), for example 1:11.

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

[0126] In one embodiment, in step 8, the progress of the reaction is monitored by conventional detection methods in the art (e.g., LC-MS), and the disappearance or no-reaction of one of the raw materials in the reaction solution is generally used as the reaction endpoint. The reaction time of step 8 is preferably 0.5 to 3 h, for example, 2 h.

[0127] In one embodiment, the reaction of step 8 includes the following post-treatment steps: standing, washing with water, concentrating, heating to dissolve, adding acid to crystallize, cooling, filtering, and drying.

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

[0129] The acid addition crystallization is preferably performed by adding concentrated hydrochloric acid;

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

[0131] In a certain scheme, step 8 comprises the following steps: at 65°C, the compound 8 and the deprotection reagent are subjected to a deprotection reaction at a molar ratio of 1:(5-15); after the reaction, the reaction solution is washed with water and concentrated, and then dissolved in 2-methyltetrahydrofuran at 50°C, concentrated hydrochloric acid is added for crystallization, and the solution is filtered and dried to obtain the 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 is subjected to a condensation reaction with 2-ethoxybenzoic acid to obtain a compound of 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 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 the 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 condensation agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0139] In one embodiment, in step 9, the molar ratio of the 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°C, such as 20-30°C.

[0141] In one embodiment, in step 9, the progress of the reaction is monitored by conventional detection methods in the art (e.g., LC-MS), and the disappearance or no-reaction of one of the raw materials in the reaction solution is generally used as the reaction endpoint. The reaction time in step 9 is preferably 0.5-3 h, for example, 2 h.

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

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

[0144] The recrystallization preferably comprises the following steps: decolorizing and recrystallizing the concentrate in a mixed solvent of ethanol and water to obtain the compound represented by formula I.

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

[0146] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0147] The reagents and raw materials used in the present invention are commercially available.

[0148] The positive and progressive effects of the present invention are:

[0149] The present invention can synthesize the intermediate compound 7 of the important isomer in defamilastat with high yield and is suitable for industrial production;

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

[0151] The invention synthesizes important isomers in defamilastat by designing a specific reaction route, and can be used for qualitative and quantitative analysis of impurities in defamilastat, thereby improving the quality standard of defamilastat. DETAILED DESCRIPTION

[0152] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0153] Synthesis steps:

[0154]

[0155] Example 1: Preparation of Compound 2

[0156]

[0157] Add 300 g of compound 1 and 4 L of acetonitrile to the reaction bottle, add 455 g of potassium carbonate under stirring, then add 336 g of benzyl bromide, and stir at 70 ° C for 12 h; add 2N dilute hydrochloric acid to adjust the pH to 5-6, add 6 L of water and stir, add 4 L of ethyl acetate to extract, dry the organic phase with anhydrous sodium sulfate, spin dry, and purify by column (PE: EA = 1: 0-10: 1) to obtain 150 g of product (compound 2) with a yield of 33.5%.

[0158] Example 2: Preparation of Compound 3

[0159]

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

[0161] Example 3: Preparation of Compound 4

[0162]

[0163] Dissolve 65g of compound 3 in 600mL of ethanol, add 10g of wet palladium carbon, replace with hydrogen balloon three times, react at room temperature for 12h. Filter and spin dry to obtain 46.8g of product (compound 4), 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 isopropyl bromide were added, and the mixture was stirred at 80°C for 2 h. LCMS showed that the reaction was complete. 500 mL of water was added and stirred to dissolve the mixture. 600 mL of ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (PE:EA=1:0~20:1) to obtain 50 g of the product (compound 5) with a yield of 91%.

[0167] Example 5: Preparation of Compound 6

[0168]

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

[0170] Example 6: Preparation of Compound 7

[0171]

[0172] Add 22 g of compound 6 to a reaction bottle, add 22.8 g of 1,3-dichloroacetone, heat to 130°C and stir for 1 hour; LC-MS detection shows that the reaction is complete; cool to 20°C, add 400 mL of purified water dropwise, filter, rinse the filter cake with water, and dry the crude product at 50°C.

[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 in vacuum at 50 °C to obtain 19.6 g of an off-white solid (compound 7), with a yield of 69.2%.

[0174] Example 7: Preparation of Compound 8

[0175]

[0176] 19.5 g of compound 7 was added to a reaction bottle, and 100 mL of DMF and 14.8 g of potassium phthalimide were added in sequence. The temperature was raised to 80°C and stirred for 3 hours. The reaction was completed after LC-MS detection. The temperature was lowered to 25°C, and 100 mL of purified water was added dropwise. After completion, the reaction was stirred for 2 hours, filtered, and the filter cake was dried at 50°C to obtain 24.2 g of a 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 bottle, and 48 g of methylamine aqueous solution (concentration of 40%) and 100 mL of 2-methyltetrahydrofuran were added. The temperature was raised to 65°C and stirred for 2 hours. The reaction was completed by LC-MS detection, and the mixture was allowed to stand for stratification. The organic phase was washed once with 95 mL of purified water. The organic phase was concentrated to dryness, and 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 hour, the mixture was cooled to 0-10°C in an ice-water bath, stirred for 3 hours, and filtered. The mixture was dried in a vacuum oven 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 6.3g of compound 9, 35mL of ethyl acetate and 3.1g of triethylamine (1.6eq) to the reaction flask; stir at 20-30℃ for 1h. Add 6.1g of 2-ethoxybenzoic acid (2.0eq) and 3.96g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1eq) and continue to stir at 1h. LC-MS detection shows that the reaction is complete; add 54mL of purified water and 5.2mL of 35%~38% concentrated hydrochloric acid and stir; separate the liquids, add 54mL of purified water and 5.4g of 25% sodium hydroxide solution to the organic phase, stir and separate the liquids, 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, rinse the filter cake with 4 mL of ethanol, slowly cool the filtrate to 5-10°C, keep warm and stir for 1 hour, filter, and obtain a white solid (Formula I compound), which is vacuum dried at 50°C to obtain 6 g, with a yield of 71.4%. MS = 447.18 (M+1), 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: The method comprises the following steps: in the absence of solvent, compound 6 and halogenated acetone undergo a ring-closing reaction to obtain compound 7; ， Wherein, R is Cl, Br or I.

2. The method for preparing compound 7 according to claim 1, characterized in that: It satisfies one or more of the following conditions (1)-(4): (1) In the preparation method of compound 7, R is Cl; (2) In the preparation method of compound 7, the halogenated acetone is chloroacetone, preferably 1,3-dichloroacetone; (3) In the preparation method of the compound 7, the molar ratio of the compound 6 to the halogenated acetone is 1:(1-3), for example 1:2; (4) In the preparation method of compound 7, the temperature of the ring-closing reaction is 100-150°C, for example, 130°C; (5) The post-treatment of the preparation method of the compound 7 comprises the following post-treatment steps: cooling the mixture to room temperature, adding water to precipitate solids, filtering, drying to obtain a crude product, and recrystallizing to obtain the compound 7; Preferably, The preparation of the compound 7 comprises the following steps: at 130° C., the compound 6 and the halogenated acetone are subjected to a ring-closing reaction in a molar ratio of 1:(1-3).

3. The method for preparing compound 7 according to claim 1, characterized in that: The preparation method of the compound 7 further comprises the following steps: in the presence of sodium alcoholate, subjecting the compound 5 to an amine ester exchange reaction in an ammonia alcohol solution to obtain the compound 6; ； Preferably, it satisfies one or more of the following conditions (1)-(4): (1) In the preparation of the compound 6, the concentration of the ammonia alcohol solution is 5-10 mol / L, preferably 7 mol / L; wherein the ammonia alcohol solution is preferably an ammonia methanol solution; (2) In the preparation of the compound 6, the mass volume ratio of the compound 5 to the amino alcohol solution is 0.1-0.5 g / mL, for example 0.25 g / mL; (3) In the preparation of the compound 6, the molar ratio of the compound 5 to the sodium alkoxide is 1:(0.05-0.15), for example 1:0.1; (4) In the preparation of the compound 6, the reaction temperature is 30-70°C, for example 50°C; More preferably, The reaction for preparing the compound 6 comprises the following steps: at 50° C., the compound 5 and the sodium alcoholate are subjected to an aminolysis reaction at a molar ratio of 1:(0.05-0.15).

4. The method for preparing compound 7 according to claim 3, characterized in that: The preparation method of the compound 7 further comprises the following steps: in an organic solvent, in the presence of a base, compound 4 reacts with a halogenated isopropyl to obtain compound 5, ； Preferably, it satisfies one or more of the following conditions (1)-(8): (1) In the preparation of the compound 5, the organic solvent is an amide solvent, such as N,N-dimethylformamide; (2) In the preparation of the compound 5, the mass volume ratio of the compound 4 to the organic solvent is 0.05-0.5 g / mL, for example 0.2 g / mL; (3) In the preparation of the compound 5, the base is a metal carbonate, preferably an alkali metal carbonate, such as potassium carbonate; (4) In the preparation of the compound 5, the molar ratio of the compound 4 to the base is 1:(1-3), for example 1:2; (5) In the preparation of compound 5, the isopropyl halide is isopropyl bromide; (6) In the preparation of the compound 5, the molar ratio of the compound 4 to the haloisopropyl is 1:(1-2), for example, 1:1.4; (7) The reaction temperature for preparing the compound 5 is 50-90°C, for example 80°C; (8) The post-treatment in the preparation of compound 5 includes the following post-treatment steps: adding water, extraction, drying and purification; More preferably, The preparation of the compound 5 comprises the following steps: at 80° C., in N,N-dimethylformamide, the compound 4 and the halogenated isopropyl are subjected to a substitution reaction in a molar ratio of 1:(1-3) in the presence of potassium carbonate; after the reaction, water is added to the reaction solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain the compound 5.

5. The method for preparing compound 7 according to claim 4, characterized in that: The preparation method of the compound 7 may further include the following steps: in an organic solvent, in the presence of a catalyst, compound 3 is subjected to a reduction reaction with hydrogen to obtain compound 4; ； Preferably, 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, such as ethanol; (2) In the preparation of the compound 4, the mass volume ratio of the compound 3 to the organic solvent is 0.05-0.5 g / mL, for example 0.11 g / mL; (3) In the preparation of compound 4, the catalyst is palladium on carbon; (4) In the preparation of the compound 4, the mass ratio of the compound 3 to the catalyst is (5-8):1, for example, 6.5:1; (5) The post-processing of the preparation of compound 4 includes the following post-processing steps: concentration and filtration; More preferably, The preparation of the compound 4 comprises the following steps: in the presence of palladium carbon in ethanol, the compound 3 is reduced with hydrogen to obtain the compound 4.

6. The method for preparing compound 7 according to claim 5, characterized in that: The preparation method of the compound 7 further comprises the following steps: in an organic solvent, in the presence of a base, the compound 2 reacts with ClCF2COONa to obtain the compound 3; ； Preferably, it satisfies one or more of the following conditions (1)-(7): (1) In the preparation of the compound 3, the organic solvent is an amide solvent, such as N,N-dimethylformamide; (2) In the preparation of the compound 3, the mass volume ratio of the compound 2 to the organic solvent is 50-100 g / L, for example 70 g / L; (3) In the preparation of the compound 3, the base is an alkali metal carbonate, preferably cesium carbonate; (4) In the preparation of the compound 3, the molar ratio of the compound 2 to the base is 1:(1-2), for example 1:1.1; (5) In the preparation of the compound 3, the molar ratio of the compound 2 to the ClCF2COONa is 1:(1-2), for example, 1:1.4; (6) In the preparation of the compound 3, the reaction temperature is 50-90°C, for example 80°C; (7) The post-treatment of the preparation of compound 3 includes the following post-treatment steps: cooling, adding water, extraction, drying and purification; More preferably, The preparation of the compound 3 comprises the following steps: at 80° C., in N,N-dimethylformamide, the 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, water is added to the reaction solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and subjected to column chromatography to obtain the compound 3.

7. The method for preparing compound 7 according to claim 6, characterized in that: The preparation method of the compound 7 also includes the preparation method of the compound 2: in an organic solvent, in the presence of a base, the compound 1 reacts with benzyl bromide to obtain the compound 2; ； Preferably, it satisfies one or more of the following conditions (1)-(8): (1) In the preparation of the compound 2, the organic solvent is a nitrile solvent, such as acetonitrile; (2) In the preparation of the compound 2, the mass volume ratio of the compound 1 to the organic solvent is 50-100 g / L, for example, 75 g / L; (3) In the preparation of the compound 2, the base is a metal carbonate, preferably an alkali metal carbonate, such as potassium carbonate; (4) In the preparation of the compound 2, the molar ratio of the compound 1 to the base is 1:(1.5-2.5), for example 1:1.8; (5) In the preparation of the compound 2, the molar ratio of the compound 1 to the benzyl bromide is 1:(1-1.5), for example 1:1.1; (6) In the preparation of the compound 2, the reaction temperature is 50-90°C, for example 70°C; (7) The post-treatment of the preparation of compound 2 includes the following post-treatment steps: adjusting the pH to 5-6, extraction, drying, concentration and purification; More preferably, The preparation of the compound 2 preferably comprises the following steps: the compound 1 is reacted with benzyl bromide at a molar ratio of 1:(1-1.5) in acetonitrile at 70°C in the presence of potassium carbonate.

8. A method for preparing compound 2, characterized in that: It includes the following steps: In an organic solvent, in the presence of a base, compound 1 reacts with benzyl bromide to obtain compound 2; ， The conditions and operations of the preparation method of compound 2 can be as described in claim 7.

9. A method for preparing a compound of formula I, characterized in that: It is method 1, 2 or 3 as follows: Method 1: The preparation method of the compound represented by formula I comprises the following steps: Step 1: Compound 2 is prepared from compound 1; Step 2: Compound 3 is prepared via compound 2; Step 3: Compound 4 is prepared via compound 3; Step 4: Compound 5 is prepared via compound 4; Step 5: Compound 6 is prepared via compound 5; Step 6: Compound 7 is prepared via compound 6; Step 7: Compound 8 is prepared via compound 7; Step 8: Compound 9 is prepared via compound 8; Step 9: Prepare the compound represented by formula I through compound 9; ； Method 2: The preparation method of the compound represented by formula I comprises the following steps: The method for preparing compound 2 as claimed in claim 7; and, a method for preparing a compound of formula I further prepared from compound 2; Method 3: The preparation method of the compound represented by formula I comprises the following steps: A method for preparing compound 7 according to any one of claims 1 to 7; And, the preparation method of compound 7 further preparing the compound shown in formula I.

10. The method for preparing the compound of formula I as claimed in claim 9, characterized in that: It meets one or more of the following conditions: (1) Step 7 comprises the following steps: in an organic solvent, compound 7 and an alkali metal salt of phthalimide undergo a substitution reaction to obtain compound 8; (2) Step 8 comprises the following steps: in the presence of a deprotecting agent, in an organic solvent, compound 8 is subjected to a deprotection reaction to obtain compound 9; (3) Step 9 comprises the following steps: in an organic solvent, in the presence of a base and a condensing agent, compound 9 is subjected to a condensation reaction with 2-ethoxybenzoic acid to obtain a compound of formula I; Preferably, it satisfies one or more of the following conditions: (1) In step 7, the organic solvent is an amide solvent, preferably N,N-dimethylformamide; (2) In step 7, the mass volume ratio of the compound 7 to the organic solvent is 0.1-0.5 g / mL, for example 0.195 g / mL; (3) In step 7, the alkali metal salt of phthalimide is potassium phthalimide; (4) In the step 7, the molar ratio of the compound 7 to the alkali metal salt of phthalimide is 1:(1-1.5), for example, 1:1.3; (5) In step 7, the temperature of the substitution reaction is 50-100°C, for example, 80°C; (6) The post-reaction treatment of step 7 includes the following post-treatment steps: cooling, adding water for crystallization, filtering to obtain a filter cake, and drying; (7) In step 8, the organic solvent is a furan solvent, such as 2-methyltetrahydrofuran; (8) In step 8, the mass volume ratio of the compound 8 to the organic solvent is 0.01-0.2 g / mL, for example 0.07 g / mL; (9) In step 8, the deprotection reagent is methylamine, wherein the deprotection reagent is preferably reacted in the form of an aqueous solution; (10) In step 8, the reaction temperature is 50-80°C, for example 65°C; (11) The post-reaction treatment of step 8 includes the following post-treatment steps: standing, washing, concentrating, heating to dissolve, adding acid to crystallize, cooling, filtering, and drying; (12) In step 9, the organic solvent is an ester solvent, such as ethyl acetate; (13) In step 9, the mass volume ratio of the compound 9 to the organic solvent is 0.1-0.5 g / mL, for example 0.18 g / mL; (14) In step 9, the base is a tertiary amine organic base, preferably triethylamine; (15) In the step 9, the molar ratio of the compound 9 to the base is 1:(1-2), for example 1:1.6; (16) In the step 9, the molar ratio of the compound 9 to the 2-ethoxybenzoic acid is 1:(1-3), for example 1:2; (17) In step 9, the condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (18) In step 9, the molar ratio of the compound 9 to the condensing agent is 1:(1-1.5), for example 1:1.1; (19) In step 9, the reaction temperature is preferably 15-35°C, for example 20-30°C; (20) In step 9, the reaction comprises the following steps: mixing compound 9 with an organic solvent and ethyl acetoacetate to obtain a mixed solution, and adding 2-ethoxybenzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the mixed solution; More preferably, it satisfies one or more of the following conditions: Step 7 comprises the following steps: at 80°C, in N,N-dimethylformamide, the compound 7 and the alkali metal salt of phthalimide are subjected to substitution reaction at a molar ratio of 1:(1-1.5); after the reaction, the reaction system is cooled to room temperature, water is added for crystallization, and the filter cake is dried at 40-60°C after filtration to obtain the compound 8; Alternatively, the step 8 comprises the following steps: at 65° C., the compound 8 is subjected to a deprotection reaction with the methylamine aqueous solution; after the reaction is completed, the reaction solution is washed with water and concentrated, and then dissolved in 2-methyltetrahydrofuran at 50° C., concentrated hydrochloric acid is added for crystallization, and the solution is filtered and dried to obtain the compound 9; Alternatively, step 9 comprises the following steps: in ethyl acetate, the compound 9 is mixed with triethylamine at a molar ratio of 1:(1-2) to obtain a mixed solution, and 2-ethoxybenzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the mixed solution for condensation reaction.

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