A method for preparing estrogen receptor inhibitor indazole compounds

Abstract

The present invention discloses a method for preparing an estrogen receptor inhibitor indazole compound, and belongs to the technical field of drug synthesis. The preparation method is that the intermediate compound 9 is sequentially subjected to sulfonylation reaction, Miyaura coupling reaction, Suzuki coupling reaction, and deprotection reaction to prepare the estrogen receptor inhibitor indazole compound. The present invention adopts a chiral synthesis method to retain the chiral characteristics of the target product, and at the same time changes the protecting group THP of the original synthetic route into a dimethylaminosulfonyl group, optimizes the chiral separation and purification method of the original route, and solves the bottleneck of the process amplification of the original route. In addition, the present invention pre-places the reaction step of potential genotoxic impurities to the starting material, so that the quality controllability of the reaction is greatly improved. In addition, the reaction conditions are relatively mild, and there are no ultra-low temperature and highly dangerous experimental conditions. The reaction yield of each step is also significantly improved, which is conducive to reducing production costs for large-scale industrial production. Compound 9: Target product:

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing an estrogen receptor inhibitor indazole compound. Background Art

[0002] According to statistics, the number of new breast cancer cases worldwide will increase from 2.08 million to 2.5 million from 2018 to 2022, increasing at a rate of 6% per year. In 2015, the number of new breast cancer patients in China exceeded 300,000, increasing at a rate of 2% per year. After a lot of scientific research, the pathogenesis of breast cancer has been verified, and estrogen receptors as markers of breast cancer have received widespread attention in the development and identification of breast cancer. Breast cancer can be divided into estrogen receptor-positive breast cancer and estrogen receptor-negative breast cancer based on estrogen receptor expression. Among them, estrogen receptor (ER)-positive breast cancer accounts for about 75% of breast cancer patients.

[0003] For the treatment of estrogen receptor (ER)-positive breast cancer, the current standard treatment is endocrine therapy. Among them, the representative aromatase inhibitor (AI) letrozole and ER modulator (SERM) tamoxifen can make the 5-year survival rate of patients with in situ ER-positive breast cancer reach 85%. Among all breast cancer patients, 30% of patients will metastasize. Patients with metastatic ER-positive breast cancer also use endocrine therapy, and the 5-year survival rate is low, only 27%. In addition, patients receiving endocrine therapy will eventually develop drug resistance, among which 20%-40% of resistant patients are due to ERa mutations that lead to drug resistance independent of estrogen. For drug resistance caused by mutations, the current first-line drug for clinical treatment is the selective estrogen receptor downregulator fulvestrant, which has shown good effects in the treatment of breast cancer resistant to hormone therapy. However, fulvestrant has the disadvantages of poor pharmacokinetic properties and low bioavailability for the treatment of AI-resistant ER-mutated breast cancer. Therefore, this treatment plan is not the best for AI-resistant ER-mutated breast cancer during clinical treatment. Therefore, there is still unmet clinical need for estrogen receptor (ER)-positive breast cancer, and a new generation of drug molecules is urgently needed to be launched to solve the current clinical drug use dilemma.

[0004] Currently, a new generation of non-covalent estrogen receptor antagonists are being developed for the treatment of ER-positive breast cancer. The molecules are in Phase I clinical trials for the treatment of ER-positive and HER2-negative breast cancer. For the above-mentioned new generation of non-covalent estrogen receptor antagonists, only WO2022001971A1 patent reports its synthesis route as follows:

[0005]

[0006] After experimental verification, this synthetic route has the following disadvantages:

[0007] (1) The total yield is only about 5%, the yield is extremely low, the cost is high, and it is not suitable for scale-up production in the process;

[0008] (2) In the process of preparing the starting materials, the multi-step reaction operating conditions are harsh, requiring a low temperature of below -70°C, making the process scale-up difficult, and using n-butyl lithium reagents, which is highly dangerous during process scale-up;

[0009] (3) The preparation of the target molecule requires chiral column separation and purification, which limits the magnitude of purification and separation and makes the process scale-up extremely difficult;

[0010] (4) The potential genotoxic impurity 3-fluoro-1-iodopropane is used in the reaction process, and the quality controllability of the potential genotoxic impurity in the product is poor;

[0011] The above problems have greatly affected the industrial development and cost control of target molecules. Summary of the invention

[0012] In view of this, the technical problem to be solved by the present invention is to provide a preparation method of indazole compounds of estrogen receptor inhibitors. The preparation method retains the chiral characteristics of the target product by chiral synthesis, optimizes the chiral separation and purification method of the original route, and has mild and easy-to-control reaction conditions, simple synthesis steps, easy product purification, and is suitable for industrial production.

[0013] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0014] The present invention provides a method for preparing an estrogen receptor inhibitor indazole compound, comprising the following steps:

[0015] 1) Compound 9 is subjected to a sulfonylation reaction with perfluorobutylsulfonyl fluoride in the presence of a basic catalyst to prepare compound 10;

[0016] 2) Compound 10 is mixed with bis-pinacol borate, a palladium catalyst, a phosphorus ligand and an organic base and subjected to a Miyaura coupling reaction to prepare compound 11;

[0017] 3) Compound 11 is mixed with compound 12, an aqueous solution of an alkaline compound, and a palladium catalyst, and subjected to a Suzuki coupling reaction, and then salified with methanesulfonic acid to prepare compound 13;

[0018] 4) Compound 13 was subjected to a deprotection reaction and salified with methanesulfonic acid to prepare an estrogen receptor inhibitor indazole compound 14.

[0019] .

[0020] The above preparation method specifically comprises the following steps: the intermediate compound 9 is subjected to sulfonylation reaction, Miyaura coupling reaction, Suzuki coupling reaction and deprotection reaction in sequence to obtain the estrogen receptor inhibitor indazole compound.

[0021] The present invention replaces the THP substituent on the indazole ring in the original route with a dimethylaminosulfonyl group because the introduction of the THP substituent will increase a chiral center in the compound, increasing the difficulty of separation and purification, while the dimethylaminosulfonyl group as a substituent avoids the operation of chiral column separation and improves the purification and separation efficiency.

[0022] Preferably, in the present invention, the alkaline catalyst in step 1) is selected from one or more of NaHMDS, KHMDS, KOtBu, and LiHMDS; more preferably, it is NaHMDS or LiHMDS; further preferably, it is LiHMDS.

[0023] The alkaline catalyst requires low temperature conditions when used. In some specific embodiments of the present invention, LiHMDS is added at -25°C to -20°C.

[0024] Preferably, the molar ratio of compound 9, the basic catalyst and perfluorobutylsulfonyl fluoride is 1:(1-2):(1-2); more preferably 1:(1-1.2):(1.1-1.5); further preferably 1:1.1:1.3.

[0025] Preferably, the solvent of the reaction is selected from one or more of tetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether; in some specific embodiments of the present invention, the solvent of the reaction is selected from tetrahydrofuran.

[0026] In the present invention, low temperature is conducive to the sulfonylation reaction. After the sulfonylation agent is added to the reaction system, the system is controlled to react at a relatively low temperature.

[0027] Preferably, the reaction temperature is -5°C to 10°C.

[0028] After the reaction in step 1) is completed, post-treatments such as quenching, extraction, and washing are also included.

[0029] The present invention has no particular limitation on the above-mentioned quenching, extraction and washing solvents, which may be quenching, extraction and washing solvents well known to those skilled in the art.

[0030] In some specific embodiments of the present invention, the quenching is performed with a sodium chloride aqueous solution, preferably with a concentration of 10 wt %, the extraction is preferably performed with ethyl acetate, and the washing is preferably performed with a sodium bicarbonate aqueous solution and a sodium chloride aqueous solution.

[0031] In the above preparation method, in step 2), compound 10 is dissolved in an organic solvent, and bis-pinacol borate, phosphorus ligand and organic base are sequentially added to the system, followed by a palladium catalyst. After the system is heated and reacted, compound 11 is obtained by recrystallization.

[0032] Preferably, the palladium catalyst in step 2) is selected from one or more of bis(triphenylphosphine)palladium dichloride, palladium dichloride, palladium acetate, and tris(dibenzylideneacetone)dipalladium.

[0033] Preferably, the phosphorus ligand is selected from one or more of triphenylphosphine, tributylphosphine, tri-tert-butylphosphine and tricyclohexylphosphine.

[0034] Preferably, the organic base is selected from one or more of KOAc, PhOK, K2CO3, and PivOK; more preferably K2CO3 or PivOK. In some specific embodiments of the present invention, the organic base is selected from PivOK.

[0035] Preferably, the molar ratio of the compound 10 to the bis-pinacol borate, the phosphorus ligand, the organic base, and the palladium catalyst is 1: (1-1.5): (0.01-0.05): (1.5-3.5): (0.005-0.02); more preferably 1: (1.1-1.3): (0.01-0.03): (1.5-2.5): (0.005-0.015); further preferably 1: 1.2: 0.02: 2: 0.01.

[0036] Preferably, the reaction temperature is 75°C to 80°C.

[0037] After the reaction in step 2) is completed, post-treatments such as quenching, washing, recrystallization, and decolorization are also included.

[0038] The present invention has no particular limitation on the above-mentioned solvents for quenching, washing and recrystallization, and the solvents for quenching, washing and recrystallization may be any solvents well known to those skilled in the art.

[0039] In some specific embodiments of the present invention, the quenching is performed with an aqueous sodium bicarbonate solution (preferably at a concentration of 5 wt%), the washing is preferably performed with an aqueous solution of (L)-N-acetylcysteine, a 5 wt% aqueous sodium bicarbonate solution, or a 5 wt% aqueous sodium chloride solution, and the recrystallization is preferably performed with isopropyl acetate and n-heptane, and the preferred volume ratio of the isopropyl acetate to n-heptane is 1:3.

[0040] The present invention has no particular limitation on the above decolorization method, and it can be a decolorization method well known to those skilled in the art.

[0041] In some specific embodiments of the present invention, the decolorization is preferably carried out using activated carbon.

[0042] In the process of preparing compound 13 of the present invention, the Suzuki coupling reaction uses chiral compound 12 and compound 11 to cross-couple under the action of palladium catalyst to obtain a non-salt compound of compound 13.

[0043] The present invention retains the chiral characteristics of the target product, the estrogen receptor inhibitor indazole compound, through a chiral synthesis method, optimizes the chiral separation and purification method of the original route, and solves the bottleneck of process amplification of the original route.

[0044] After the above Suzuki coupling reaction is completed, methanesulfonic acid is added to the reaction system so that the product after the coupling reaction is salified and precipitated to prepare compound 13.

[0045] Preferably, the alkaline compound in step 3) is selected from one or more of potassium carbonate, potassium hydroxide and potassium phosphate. In some specific embodiments of the present invention, the alkaline compound is selected from potassium hydroxide.

[0046] Preferably, the palladium catalyst is selected from palladium acetate or palladium dichloride.

[0047] Preferably, the molar ratio of compound 11, compound 12, alkaline compound and palladium catalyst is 1: (0.9~1.1): (2.0~6.0): (0.005~0.03); more preferably 1.0: (0.9-1): (3-5) (0.005-0.015); further preferably 1: 0.95: 4: 0.01.

[0048] Preferably, the solvent of the reaction is selected from one or more of toluene, 2-methyltetrahydrofuran, tetrahydrofuran. More preferably, the solvent of the reaction is selected from toluene.

[0049] Preferably, the reaction temperature is 85°C to 90°C.

[0050] After the Suzuki coupling reaction in step 3) is completed, post-treatments such as extraction, washing, palladium removal, and recrystallization are also included.

[0051] The present invention has no particular limitation on the above-mentioned extraction, washing and recrystallization solvents, and they may be extraction, washing and recrystallization solvents well known to those skilled in the art.

[0052] In some specific embodiments of the present invention, the extraction is preferably carried out using tert-butyl methyl ether and water, the washing is preferably carried out using an aqueous solution of sodium carbonate (3 wt%), an aqueous solution of (L)-N-acetylcysteine, or a 5 wt% aqueous solution of sodium chloride, and the recrystallization solvent is preferably methanesulfonic acid, so that it forms a salt to precipitate compound 13.

[0053] The present invention has no particular limitation on the palladium removal method, and the palladium removal method may be a palladium removal method well known to those skilled in the art.

[0054] In some specific embodiments of the present invention, the palladium removal post-treatment preferably adopts a method of adding modified palladium-removing silica gel and activated carbon and then filtering to remove the residual palladium catalyst in the solution.

[0055] In the above preparation method, in step 4), compound 13 is dissolved, an organic acid is added dropwise at low temperature, and then the temperature is raised to perform a deprotection reaction, and then methanesulfonic acid is added, and a crude compound 14 is obtained by post-treatment, and then recrystallization is performed to obtain compound 14. After the deprotection reaction is completed, methanesulfonic acid is added again to precipitate the salt, because the mesylate of the compound has a better degree of crystallization, a higher purity, and easier quality control.

[0056] Preferably, in the deprotection reaction in step 4), an organic acid is used;

[0057] Preferably, the organic acid is selected from one or more of trifluoromethanesulfonic acid, trifluoroacetic acid and methanesulfonic acid; more preferably trifluoromethanesulfonic acid.

[0058] In some specific embodiments of the present invention, trifluoromethanesulfonic acid is added dropwise to the reaction system at 0-10° C. The purpose of adding at low temperature is to avoid acid-base reaction between the organic acid and the target intermediate, which will cause violent heat release and affect the product quality of the intermediate 14.

[0059] Preferably, the molar ratio of the organic acid to compound 13 is (2-10):1; more preferably (5-7):1; further preferably 6:1.

[0060] Preferably, the temperature of the deprotection reaction is 15°C to 20°C.

[0061] After the deprotection reaction in step 4) is completed, post-treatments such as quenching, extraction, and washing are also included.

[0062] The present invention has no particular limitation on the above-mentioned quenching, extraction and washing solvents, which may be quenching, extraction and washing solvents well known to those skilled in the art.

[0063] In some specific embodiments of the present invention, the quenching is preferably performed using an aqueous sodium carbonate solution, the extraction is preferably performed using dichloromethane and water, and the washing is preferably performed using an aqueous sodium carbonate solution and deionized water.

[0064] After the above post-treatment is completed, the deprotected product is reacted with methanesulfonic acid to form a salt, and the solid is washed out to prepare compound 14.

[0065] Preferably, in the present invention, the compound 14 in step 4) is purified and post-treated to obtain a pure product of the estrogen receptor inhibitor indazole compound.

[0066] The purpose of refining is to purify the synthesized product or intermediate compound. In the present invention, there is no particular limitation on the refining method, which can be quenching, extraction, recrystallization, filtration, washing, pulping purification, column chromatography and other refining methods well known to those skilled in the art.

[0067] Preferably, the refining is selected from recrystallization.

[0068] Preferably, the recrystallization solvent is selected from a mixed solvent of organic solvent 1 and organic solvent 2.

[0069] In the above recrystallization, compound 14 is specifically dissolved in organic solvent 1, the temperature is raised until compound 14 is completely dissolved, organic solvent 2 is added, and then the temperature is slowly lowered to room temperature to obtain product compound 14 by crystallization.

[0070] The room temperature may be 10°C to 30°C, preferably 15°C to 20°C.

[0071] Preferably, the organic solvent 1 is selected from one or more of dimethyl sulfoxide, tetrahydrofuran and DMF.

[0072] Preferably, the organic solvent 2 is selected from one or more of isopropyl acetate, n-heptane and acetone.

[0073] In some specific embodiments of the present invention, the recrystallization solvent is preferably a mixed solution of dimethyl sulfoxide and isopropyl acetate.

[0074] In some specific embodiments of the present invention, the above recrystallization is preferably performed by dissolving compound 14 in dimethyl sulfoxide at a dissolving temperature of 50°C to 60°C.

[0075] In the present invention, the estrogen receptor inhibitor indazole compound is prepared and synthesized from the intermediate compound 9. The intermediate compound 9 is prepared from 4-bromoindazole as a starting material by sequentially undergoing THP protection reaction, fluorination reaction, THP deprotection reaction, amino protection reaction, coupling reaction, reduction reaction, iodination reaction, and ring-closing reaction.

[0076] The present invention also provides a method for preparing compound 9, comprising the following steps:

[0077] 1) Perform THP protection reaction on 4-bromoindazole to prepare compound 1;

[0078] 2) Compound 1 is mixed with N-fluorobisbenzenesulfonamide under the action of an organic base and subjected to a fluorination reaction to prepare Compound 2;

[0079] 3) Compound 2 is subjected to deprotection reaction to prepare compound 3;

[0080] 4) Compound 3 is subjected to a sulfonylation reaction with dimethylaminosulfonyl chloride in the presence of an organic base to prepare compound 4;

[0081] 5) Compound 4 is mixed with compound 5, a palladium catalyst, cuprous iodide, and an organic base and subjected to a coupling reaction to prepare compound 6;

[0082] 6) Compound 6 is mixed with palladium hydroxide on carbon and subjected to reduction reaction under a hydrogen atmosphere to prepare compound 7;

[0083] 7) Compound 7 is subjected to iodination reaction with N-iodosuccinimide under the catalysis of trifluoromethanesulfonic acid to prepare compound 8;

[0084] 8) Compound 8 is mixed with isopropylmagnesium chloride-lithium chloride complex and subjected to a ring-closing reaction to prepare compound 9.

[0085] .

[0086] Preferably, in the step 1), 4-bromoindazole, pyridinium p-toluenesulfonate and 3,4-dihydropyran are mixed and subjected to THP protection reaction.

[0087] In the above THP protection reaction, 3,4-dihydropyran is catalyzed by pyridinium p-toluenesulfonate to obtain a tetrahydropyranyl group for THP protection.

[0088] In the above preparation method, pyridinium p-toluenesulfonate is used as a potential genotoxic impurity, and the reaction step of the potential genotoxic impurity is pre-placed to the starting material, so that the quality controllability of the reaction is greatly improved, thereby increasing the reaction yield.

[0089] Preferably, the molar ratio of 4-bromoindazole, pyridinium p-toluenesulfonate and 3,4-dihydropyran is 1:(0.01-0.03):(3-5); more preferably 1:(0.015-0.025):(3-3.5); in some specific embodiments of the present invention, the above molar ratio is 1:0.02:3.2.

[0090] Preferably, the solvent of the reaction is selected from one or more of n-heptane, toluene, n-heptane, and toluene; more preferably, it is a mixed solution of n-heptane and toluene.

[0091] Preferably, the reaction temperature is 30°C to 50°C, more preferably 35°C to 45°C. In some specific embodiments of the present invention, the reaction temperature is 40°C.

[0092] After the reaction in step 1) is completed, post-treatments such as washing and recrystallization are also included.

[0093] The present invention has no particular limitation on the washing and recrystallization solvents, which may be washing and recrystallization solvents well known to those skilled in the art.

[0094] In some specific embodiments of the present invention, the washing is performed with an aqueous sodium bicarbonate solution, preferably a 5 wt % aqueous sodium bicarbonate solution, and the recrystallization is preferably performed with n-heptane.

[0095] In the above step 2), compound 1 is dissolved in an organic solvent, an organic base is added dropwise at low temperature, and then N-fluorobisbenzenesulfonamide (NFSI) is added in batches. After a certain reaction time, compound 2 is obtained by post-treatment.

[0096] Preferably, the organic base in step 2) is selected from one or more of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, and lithium hexamethyldisilazide; more preferably lithium diisopropylamide. In some specific embodiments of the present invention, LDA is added dropwise to the system at a rate of 50 to 100 ml / min at 0 to 5°C.

[0097] The above-mentioned method of adding NFSI in batches at low temperature is because it avoids the violent local reaction that affects the product quality of compound 2.

[0098] Preferably, the molar ratio of the compound 1 to the organic base and N-fluorobisbenzenesulfonamide is 1:(1-2):(1-2); more preferably 1:(1-1.1):(1-1.2); further preferably 1:1.05:1.1.

[0099] Preferably, the solvent of the reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether;

[0100] Preferably, the mixing temperature is -40°C to -20°C;

[0101] Preferably, the reaction temperature is -60°C to -10°C.

[0102] After the reaction in step 2) is completed, post-treatments such as quenching, extraction, washing, and recrystallization are also included.

[0103] The present invention has no particular limitation on the above-mentioned quenching, extraction, washing and recrystallization solvents, which may be quenching, extraction, washing and recrystallization solvents well known to those skilled in the art.

[0104] In some specific embodiments of the present invention, the quenching is performed using an aqueous sodium hydroxide solution, preferably a 5 wt% aqueous sodium hydroxide solution, the extraction is preferably performed using methyl tert-butyl ether, the washing is preferably performed using saturated brine, and the recrystallization is preferably performed using isopropanol.

[0105] Then, compound 2 is deprotected. Preferably, compound 2 is dissolved in an organic solvent, and an acid solution is added dropwise at a low temperature of -5°C to 5°C. After a certain reaction time, a crude compound 3 is obtained by post-treatment, and compound 3 is obtained by purification.

[0106] Preferably, the acidic conditions for the deprotection reaction in step 3) are provided by one or more of concentrated hydrochloric acid, trifluoroacetic acid, and hydrobromic acid. In some specific embodiments of the present invention, the reaction of removing the THP protecting group is carried out in concentrated hydrochloric acid, preferably at a concentration of 37 wt%.

[0107] Preferably, the pH value of the reaction system is 1-3; more preferably 1-2.

[0108] Preferably, the solvent of the reaction is one or more of methanol, ethanol, isopropanol, and acetonitrile;

[0109] Preferably, the reaction temperature is 10°C to 20°C.

[0110] The present invention has no particular limitation on the purification method after the completion of the above reaction, and it can be a purification method well known to those skilled in the art.

[0111] In some specific embodiments of the present invention, the above purification method is selected from pulping purification, and the solvent for pulping purification is selected from a mixed solution of methyl tert-butyl ether and n-heptane.

[0112] In the above preparation method, compound 3 is preferably dissolved in an organic solvent, an organic base is added at low temperature, dimethylaminosulfonyl chloride is slowly added dropwise at a certain dropping speed, and then the reaction is carried out, and then compound 4 is obtained by post-treatment.

[0113] Compared with THP (tetrahydropyranyl) on the indazole ring in the original synthetic route, the dimethylaminosulfonyl group has a stronger leaving ability, is easier to carry out deprotection reaction, and has simpler post-processing.

[0114] In the present invention, the organic base in step 4) is preferably selected from one or more of triethylenediamine, pyridine and 4-dimethylaminopyridine; more preferably triethylenediamine.

[0115] In some specific embodiments of the present invention, triethylenediamine is added to the reaction system at 0-5°C, and dimethylaminosulfonyl chloride is added dropwise at a rate of 50 ml / min to avoid excessive local acylation reaction that affects the quality of the product.

[0116] Preferably, the molar ratio of the compound 3 to the organic base and dimethylaminosulfonyl chloride is 1:(1-1.5):(1-1.5); more preferably 1:1.3:1.2.

[0117] Preferably, the reaction temperature is 5°C to 20°C.

[0118] After the reaction in step 4) is completed, post-treatment such as recrystallization is also included.

[0119] The present invention has no particular limitation on the solvent for the recrystallization, and the solvent may be any solvent known to those skilled in the art.

[0120] In some specific embodiments of the present invention, the recrystallization is preferably performed by first adding water to precipitate the crude product of compound 4, then adding isopropanol with a dissolving temperature of 70°C to 80°C, then cooling to room temperature (10~30°C) to precipitate the solid, and filtering to obtain the pure product of compound 4.

[0121] Preferably, the palladium catalyst in step 5) is selected from one or more of bis(triphenylphosphine)palladium(II) dichloride, palladium acetate, and palladium dichloride;

[0122] Preferably, the organic base is selected from one or more of triethylamine, pyridine, and 4-dimethylaminopyridine;

[0123] Preferably, the molar ratio of compound 4 to compound 5 is 1:(1-1.5); more preferably 1:(1-1.3); further preferably 1:1.2.

[0124] Preferably, the molar ratio of the compound 4 to the palladium catalyst, cuprous iodide and the organic base is 1: (0.01-0.03): (0.01-0.03): (2-4); more preferably 1: (0.01-0.03): (0.01-0.03): (2.5-3.5); further preferably 1: 0.01: 0.02: 3;

[0125] Preferably, the reaction temperature is 70°C to 80°C.

[0126] After the reaction in step 5) is completed, post-treatments such as extraction, washing, and purification are also included.

[0127] The present invention has no particular limitation on the above-mentioned extraction and washing solvents, and they can be any solvent well known to those skilled in the art.

[0128] In some specific embodiments of the present invention, the extraction is preferably carried out using methyl tert-butyl ether, and the washing is carried out using ammonia water, preferably a mixed solution of 5 wt% and saturated brine.

[0129] The present invention has no particular limitation on the above purification method, which may be a method well known to those skilled in the art.

[0130] In some specific embodiments of the present invention, the purification is selected from pulping purification, and the solvent for the pulping purification is a mixed solution of isopropanol and water or a mixed solution of methanol and water.

[0131] Preferably, the isopropanol:water=2:1 (volume ratio).

[0132] Preferably, the methanol:water=3:1 (volume ratio).

[0133] In the above preparation method, compound 6 is dissolved in an organic solvent, palladium hydroxide carbon is added, hydrogen is introduced for reaction, and then post-processed to obtain compound 7. Preferably, the mass ratio of compound 6 to palladium hydroxide carbon in step 6) is 1: (0.05-0.2); more preferably 1: 0.1.

[0134] Preferably, the hydrogen pressure is 0.8-1.5 MPa; more preferably 1.0 MPa.

[0135] Preferably, the solvent of the reaction is selected from methanol and / or tetrahydrofuran; more preferably, it is a mixed solution of methanol and tetrahydrofuran.

[0136] Preferably, the reaction temperature is 20°C to 30°C;

[0137] Preferably, the reaction time is 15 to 20 h.

[0138] In the above preparation method, compound 6 is dissolved in an organic solvent, and trifluoromethanesulfonic acid and N-iodosuccinimide (NIS) are added in sequence to react to obtain compound 8.

[0139] Preferably, the molar ratio of compound 7 to N-iodosuccinimide and trifluoromethanesulfonic acid in step 7) is 1:(1-2):(0.5-1.5); more preferably 1:(1-1.2):(1-1.5). In some specific embodiments of the present invention, the molar ratio is 1:1:1.5.

[0140] Preferably, the solvent of the reaction is selected from one or more of acetonitrile, tetrahydrofuran, 1,4-dioxane, and acetone;

[0141] Preferably, the reaction temperature is 15°C to 20°C.

[0142] After the reaction in step 7) is completed, post-treatments such as extraction, washing, and purification are also included.

[0143] The present invention has no particular limitation on the above-mentioned extraction and washing solvents, and they can be any solvent well known to those skilled in the art.

[0144] In some specific embodiments of the present invention, the extraction is preferably carried out using methyl tert-butyl ether, and the washing is preferably carried out using an aqueous solution of sodium bicarbonate, an aqueous solution of sodium sulfite, or an aqueous solution of sodium chloride.

[0145] The present invention has no particular limitation on the above purification method, which may be a method well known to those skilled in the art.

[0146] In some specific embodiments of the present invention, the purification method is selected from pulping purification, and the solvent for the pulping purification is preferably a mixed solution of isopropanol and water.

[0147] Preferably, the isopropanol:water=3:1 (volume ratio).

[0148] Preferably, in the present invention, the molar ratio of compound 8 to isopropylmagnesium chloride lithium chloride complex in step 8) is 1:(1-2); more preferably 1:(1.3-1.7); further preferably 1:1.5.

[0149] Preferably, the solvent of the reaction is selected from one or more of toluene, n-heptane, tetrahydrofuran, and 1,4-dioxane;

[0150] Preferably, the reaction temperature is 0°C to 15°C.

[0151] After the reaction in step 8) is completed, post-treatments such as quenching, extraction, washing, and purification are also included.

[0152] The present invention has no particular limitation on the solvents for the quenching, extraction and washing, and the solvents may be any solvent known to those skilled in the art.

[0153] In some specific embodiments of the present invention, the quenching solvent is preferably hydrochloric acid, the extraction solvent is preferably ethyl acetate, and the washing solvent is preferably a sodium chloride aqueous solution.

[0154] The present invention has no particular limitation on the above purification method, which may be a method well known to those skilled in the art.

[0155] In some specific embodiments of the present invention, the purification method is preferably pulping purification.

[0156] Preferably, the solvent for pulping purification is selected from ethyl acetate and methyl tert-butyl ether.

[0157] Preferably, the ethyl acetate: methyl tert-butyl = 1:2 (volume ratio).

[0158] The intermediate compound 9 obtained by post-treatment is used to synthesize estrogen receptor inhibitor indazole compounds.

[0159] The preparation method of the target product estrogen receptor inhibitor indazole compound or intermediate compound 9 of the present invention has mild overall conditions and simple steps, and does not require ultra-low temperature experimental conditions and the use of a large amount of hazardous chemical reagents.

[0160] Compared with the prior art, the preparation method of the estrogen receptor inhibitor indazole compound provided by the present invention is that the intermediate compound 9 is sequentially subjected to sulfonylation reaction, Miyaura coupling reaction, Suzuki coupling reaction, and deprotection reaction to prepare the estrogen receptor inhibitor indazole compound. The present invention adopts a chiral synthesis method to retain the chiral characteristics of the target product, and at the same time changes the protecting group THP of the original synthetic route into a dimethylaminosulfonyl group, optimizes the chiral separation and purification method of the original route, and solves the bottleneck of the process amplification of the original route. In addition, compared with the original synthetic route, the present invention pre-places the potential genotoxic impurity reaction step to the starting material, so that the quality controllability of the reaction is greatly improved. The reaction conditions of each step in the preparation method are relatively mild, and there are no ultra-low temperature and highly dangerous experimental conditions, and the reaction yield of each step is also significantly improved, which is conducive to reducing production costs for large-scale industrial production. DETAILED DESCRIPTION

[0161] In order to further illustrate the present invention, the preparation method of the estrogen receptor inhibitor indazole compound provided by the present invention is described in detail below with reference to the examples. Example

[0162] (I) Synthesis of compound 1

[0163] At 15°C, pyridinium p-toluenesulfonate (38.28 g, 0.15 mol) and 3,4-dihydropyran (2.05 kg, 24.3 mol) were added to a stirred mixed solution of 4-bromoindazole (1.50 kg, 7.61 mol) in n-heptane (6.0 L) and toluene (6.0 L), and the mixture was stirred at 40°C for 9 hours. The mixture was cooled to 25°C, washed 3 times with 5 wt% sodium bicarbonate (aq, 7.5 L*3), and then washed once with water (7.5 L). The organic phase was dried with 1.0 kg of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until no liquid was evaporated. n-heptane (1.3 L) was added and stirred at 0-10°C for 12 hours to precipitate solids. The resulting suspension was filtered under reduced pressure through a Buchner funnel, the filter cake was collected, and vacuum dried to obtain white solid compound 1 (1.62 kg, yield 75.5%). 1H NMR (400 MHz, MeOD) δ = 8.37 (d, J = 0.6 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.28‒ 7.24 (m, 1H), 7.22 ‒ 7.16 (m, 1H), 5.74 ‒ 5.68 (m, 1H), 4.11 (tdd, J = 2.3,4.3, 11.5 Hz, 1H), 3.85 ‒ 3.76 (m, 1H), 2.25 ‒ 2.11 (m, 2H), 2.09 ‒ 2.00 (m,1H), 1.86 ‒ 1.62 (m, 3H).

[0164] (II) Synthesis of Compound 2

[0165] At 0-5°C, a solution of lithium diisopropylamide (LDA) in tetrahydrofuran / n-heptane (2 mol / L, 1.87 L, 3.74 mol) was added dropwise at a rate of 50-100 ml / min to a solution of compound 1 (1.00 kg, 3.56 mol) in tetrahydrofuran (8.0 L) under stirring. After the addition was completed, the temperature was naturally raised to about 5-10°C after stirring for 1 hour. The temperature was lowered to -40°C, and N-fluorobisbenzenesulfonamide (NFSI) (1.23 kg, 3.91 mol) was added in 5 batches between -40 and -20°C. After the addition was completed, the cold bath was removed, and after 1 hour, it was monitored at about -30 to -20°C that most of the raw materials had been converted. NaOH (aq, 5 wt%, 10.0 L) was added to slowly quench, keeping the temperature below 10°C. Extract with methyl tert-butyl ether (5.0 L*3). The combined organic phase was washed with saturated brine (2.0 L), dried over 1.0 kg of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.1 kg of crude product. 1.0 L of isopropanol was added and stirred at 15°C for 12 hours. The resulting suspension was filtered under reduced pressure through a Buchner funnel, the filter cake was collected, and vacuum dried to obtain compound 2 as a yellow solid (0.72 kg, yield 67.7%). 1 H NMR (400 MHz, MeOD) δ = 7.53 ‒ 7.43(m, 1H), 7.27 ‒ 7.23 (m, 1H), 7.20 ‒ 7.13 (m, 1H), 5.87 ‒ 5.76 (m, 1H), 4.12‒ 4.03 (m, 1H), 3.80 (dt, J = 2.9, 11.1 Hz, 1H), 2.51 ‒ 2.36 (m, 1H), 2.21 ‒2.12 (m, 1H), 2.09 ‒ 1.99 (m, 1H), 1.91 ‒ 1.68 (m, 3H).

[0166] (III) Synthesis of compound 3

[0167] Concentrated hydrochloric acid (aq, 37 wt%, 50 ml, 0.6 mol) was added dropwise to a stirred solution of compound 2 (7.00 kg, 23.4 mol) in methanol (15.0 liters), and the mixture was stirred at 15°C for 0.5 hours. The reaction solution was concentrated under reduced pressure until no liquid dripped out, and about 7.5 kg of crude product was obtained. A mixed solution of 3.0 liters of methyl tert-butyl ether and 12.0 liters of n-heptane was added and stirred at 15°C for 12 hours. The resulting suspension was filtered under reduced pressure through a Buchner funnel, the filter cake was collected, and vacuum dried to obtain compound 3 as a yellow solid (4.50 kg, yield 89.4%). 1 H NMR (400 MHz, MeOD) δ = 7.46 ‒ 7.40 (m, 1H), 7.34 ‒ 7.26 (m, 2H).

[0168] (IV) Synthesis of Compound 4

[0169] At 0-5°C, triethylenediamine (1.02 kg, 9.09 mol) was added to a solution of compound 3 (1.50 kg, 6.98 mol) in acetonitrile (15.0 L), and dimethylaminosulfonyl chloride (900.0 ml, 8.40 mol) was added dropwise at a rate of 50 ml / min. After the addition was completed, the temperature was naturally raised and stirred for 2 hours. Water (30.0 L) was added to the reaction solution and stirred at 15°C for 0.5 hour. About 2.2 kg of yellow solid was obtained by filtration. After vacuum drying, 4.5 L of isopropanol was added, the temperature was raised to 70-80°C and stirred for 2 hours to dissolve completely, and the temperature was naturally lowered to 25°C and stirred overnight. The resulting suspension was filtered under reduced pressure through a Buchner funnel, the filter cake was collected, and vacuum dried to obtain a yellow-white solid compound 4 (1.8 kg, purity 92%). 1 H NMR (400 MHz, DMSO-d6) δ = 7.96(dd, J = 1.9, 8.6 Hz, 1H), 7.73 ‒ 7.67 (m, 1H), 7.65 ‒ 7.59 (m, 1H), 2.91 (s,6H)

[0170] (V) Synthesis of Compound 6

[0171] Under nitrogen protection, bis(triphenylphosphine)palladium(II)dichloride (65.36 g, 93.12 mmol), cuprous(I) iodide (35.47 g, 186.25 mmol) and triethylamine (3.24 liters, 23.28 mol) were added to a solution of compound 4 (2.50 kg, 7.76 mol) and compound 5 (2.08 kg, 9.31 mol) in acetonitrile (17.5 liters), and the mixture was heated to 70-75°C and stirred for 13 hours. After cooling to room temperature, methyl tert-butyl ether (10 liters) was added to the reaction solution and stirred, and ammonia water (5 wt%, 5 liters) and saturated brine (5 liters) were added. After stirring for 0.5 hour, the mixture was allowed to stand. The organic phase obtained after separation was washed with a mixed solution of ammonia water (5 wt%, 5 liters) and saturated brine (5 liters) for 0.5 hour. The organic phase obtained after separation was concentrated under reduced pressure to obtain 4.1 kg of crude product. Isopropanol / water = 2:1 mixture (7 L) was added and stirred at room temperature for 16 hours. The mixture was filtered and the filter cake was washed once with methanol / water = 3:1 (3 L) by slurrying. The filter cake was vacuum dried to obtain yellow solid compound 6 (2.90 kg, yield 80.4%). 1 H NMR (400 MHz, DMSO-d6)δ = 7.99 ‒ 7.89 (m, 1H), 7.74 ‒ 7.65 (m, 1H), 7.55 ‒ 7.45 (m, 1H), 3.79 ‒3.68 (m, 3H), 3.51 ‒ 3.38 (m, 1H), 3.16 (br s, 3H), 2.95 ‒ 2.89 (m, 6H), 2.86 (d, J = 7.3 Hz, 1H), 2.83 ‒ 2.71 (m, 2H), 2.70 ‒ 2.58 (m, 1H). LCMS (ESI) m / z:465.0 [M+H] + .

[0172] (VI) Synthesis of Compound 7

[0173] To a mixed solution of compound 6 (500.00 g, 1.07 mol) in methanol (5 L) and tetrahydrofuran (0.5 L) was added wet palladium hydroxide on carbon (50 wt%, 50 g) at 25°C, and the mixture was stirred at 25°C for 16 hours under a hydrogen (1 MPa) atmosphere. The reaction solution was filtered through diatomaceous earth, the filter cake was washed, and the filtrate was concentrated under reduced pressure to obtain a gray oil compound 7 (501.00 g, yield 99.2%). 1H NMR (400 MHz, CDCl3) δ = 7.77 (dd, J = 1.9, 8.6 Hz, 1H), 7.44 ‒7.36 (m, 1H), 7.01 (d, J = 7.3 Hz, 1H), 3.61 (s, 3H), 3.16 (br d, J = 4.1 Hz,4H), 2.94 (s, 6H), 2.87 (br t, J = 7.1 Hz, 2H), 2.72 ‒ 2.56 (m, 1H), 2.19 ‒1.95 (m, 1H), 1.70 ‒ 1.47 (m, 4H). LCMS (ESI) m / z: 469.2 [M+H] + .

[0174] (VII) Synthesis of Compound 8

[0175] At 10-20°C, trifluoromethanesulfonic acid (509 ml, 5.76 mol) was slowly added to a solution of compound 7 (2.7 kg, 5.76 mol) in acetonitrile (13.5 L), and then solid NIS (1.94 kg, 8.65 mol) was added in batches. The mixture was stirred at 15-20°C for 16 hours under nitrogen protection. After the reaction was completed, methyl tert-butyl ether (10 L) was added to the reaction solution, and a mixed aqueous solution of 10% sodium bicarbonate and 10% sodium sulfite (20 L) was added under stirring, and stirred for 0.5 hours. After standing and separating the liquids, the obtained organic phase was washed twice with a 10% sodium chloride aqueous solution (10 L * 2), and the organic phase was concentrated under reduced pressure to obtain a brown oil compound 8. Add a mixed solution of isopropanol / water = 3:1 (10 L) and stir at 15°C for 2 hours. The resulting filter cake was filtered and washed thoroughly with a mixture of isopropanol and water = 3:1 (3 L), and dried in vacuo to obtain a white solid compound 8 (2.9 kg, yield 81.7%). 1 H NMR (400 MHz, CDCl3) δ = 7.91 (d, J = 9.0 Hz, 1H), 7.67 ‒ 7.56 (m, 1H), 3.78 ‒ 3.67 (m,3H), 3.37 ‒ 3.19 (m, 4H), 3.09 ‒ 3.01 (m, 8H), 2.91 ‒ 2.69 (m, 1H), 2.29 ‒2.09 (m, 1H), 1.95 ‒ 1.78 (m, 1H), 1.76 ‒ 1.62 (m, 3H). LCMS (ESI) m / z: 595.0[M+H] + .

[0176] (VIII) Synthesis of Compound 9

[0177] At 0°C, under nitrogen protection, a tetrahydrofuran solution of isopropylmagnesium chloride lithium chloride complex (1.3 mol / L, 6.31 L, 7.57 mol, 1.5 eq) was added dropwise to a toluene (30 L) solution of compound 8 (3.0 kg, 5.05 mol), and the mixture was stirred at 0-15°C for 16 hours under nitrogen protection. The reaction solution was added to hydrochloric acid (1 M, 12 L in total) in batches at 0-15°C to quench (pH = 2-3), and then ethyl acetate (10 L) was added to assist dissolution. After standing and separating the liquids, the obtained aqueous phase was extracted once with ethyl acetate (5 L), and the combined organic phase was washed twice with 10% sodium chloride aqueous solution (10 L * 2), and concentrated under reduced pressure to obtain a crude product. A mixture of ethyl acetate / methyl tert-butyl ether = 1:2 (volume ratio) (4 L) was added and stirred at 15°C for 1 hour. The filter cake was filtered and vacuum dried to obtain white solid compound 9 (2.06 kg, yield 85.4%). 1 H NMR (400 MHz, CDCl3) δ = 8.02 ‒7.79 (m, 2H), 3.82 ‒ 3.64 (m, 1H), 3.38 ‒ 3.26 (m, 1H), 3.24 ‒ 3.12 (m, 1H), 3.04 (s, 6H), 2.42 ‒ 2.03 (m, 3H), 1.83 ‒ 1.64 (m, 2H), 1.60 (s, 1H). LCMS(ESI) m / z: 408.0 [M+H] + .

[0178] (IX) Synthesis of Compound 10

[0179] At -25~-20°C, under nitrogen protection, a tetrahydrofuran solution of lithium hexamethyldisilazide (1 mol / L, 4.32 L, 4.32 mol, 1.1 eq) was added dropwise to a tetrahydrofuran (16 L) solution of compound 9 (1.6 kg, 3.93 mol), and the mixture was stirred at -25~-20°C for 1 hour under nitrogen protection. Perfluorobutylsulfonyl fluoride (1.54 kg, 896.75 mL, 5.11 mol, 1.3 eq) was added dropwise within 0.5 hours in this temperature range. The mixture was heated to -5~10°C and stirred at this temperature for 12 hours. The reaction solution was added to a sodium chloride aqueous solution (10 wt%, 15 L) under stirring at 10~15°C and stirred for 0.5 hours. Ethyl acetate (4 L) was added and stirred for 10 minutes. After standing and separating the liquids, the obtained organic phase was washed twice with an aqueous sodium bicarbonate solution (5 wt %, 5 L), and then washed once with a 10% aqueous sodium chloride solution (5 L), dried over 1.0 kg of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain compound 10, which was directly used in the next step. 1H NMR (400 MHz, CDCl3) δ = 7.96 (dd, J =2.0, 9.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 3.79 ‒ 3.67 (m, 1H), 3.35 ‒ 3.28(m, 2H), 3.06 ‒ 3.04 (m, 6H), 2.43 (quin, J = 7.1 Hz, 2H), 2.34 ‒ 2.20 (m,1H), 2.14 ‒ 2.06 (m, 2H). LCMS (ESI) m / z: 690.0 [M+H] + .

[0180] (X) Synthesis of Compound 11

[0181] Under nitrogen protection, bis(triphenylphosphine)palladium(II) chloride (27.59 g, 39.31 mmol, 0.01 eq) was added to a solution of compound 10 (2.71 kg, 3.93 mol) in isopropyl acetate (27 L). The mixture was stirred at 10-15°C for 5 minutes, then bis(triphenylphosphine)palladium(II) chloride (27.59 g, 39.31 mmol, 0.01 eq) was added, and the mixture was heated to 75-80°C and stirred for 16 hours. After cooling to room temperature, sodium bicarbonate aqueous solution (5 wt%, 10 liters) was added to the reaction solution, stirred for 0.5 hours, and allowed to stand for separation. To the obtained organic phase, a premixed sodium bicarbonate aqueous solution (5 wt%, 20 liters) of (L)-N-acetylcysteine ​​(800 grams) was added. After stirring for 0.5 hours, the solution was allowed to stand for separation. The obtained organic phase was washed twice with 5% sodium bicarbonate aqueous solution (20 liters + 10 liters), and then washed twice with 5 wt% sodium chloride aqueous solution (5 liters * 2). Activated carbon (800 grams) was added to the organic phase obtained after separation, and the mixture was stirred at 50-60°C for 2 hours, cooled and filtered. The obtained filtrate was dried over 1.0 kg of anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried under reduced pressure to obtain a crude product (3.0 kg). Isopropyl acetate / n-heptane = 1:3 mixed solution (15 liters) was added to the crude product, and it was completely dissolved at 60-70°C, and the temperature was naturally reduced to 20-25°C to precipitate a white solid. The filter cake obtained after filtration was vacuum dried to obtain white solid compound 11 (1.60 kg, content 83%). 1H NMR (400 MHz, CDCl3) δ = 7.82 (dd, J = 2.2, 8.8 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 3.60 (q, J = 11.1 Hz, 2H), 3.04 (s, 6H), 2.89 (t, J= 7.1 Hz, 2H), 2.31 (quin, J = 7.1 Hz, 2H), 2.08 - 2.01 (m, 2H), 1.31 (s,12H). LCMS (ESI) m / z: 518.0 [M+H] + .

[0182] (XI) Synthesis of Compound 13

[0183] Under nitrogen protection, potassium hydroxide (910.97 g, 16.24 mol, 4 eq) aqueous solution (4.2 L), compound 12 (1.17 kg, 3.86 mol, 0.95 eq) and DPPF (45.01 g, 81.18 mmol, 0.02 eq) were added to a toluene (21 L) solution of compound 11 (2.10 kg, 4.06 mol). The mixture was stirred at 10-15 °C for 10 minutes, and palladium (II) acetate (9.11 g, 40.59 mmol, 0.01 eq) was added, and the mixture was heated to 85-90 °C and stirred for 16 hours. After cooling to room temperature, tert-butyl methyl ether (5 liters) and water (10 liters) were added to the reaction solution. After stirring for 10 minutes, the mixture was allowed to stand for separation. A sodium carbonate aqueous solution (3 wt%, 15 liters) was added to the organic phase and stirred for 0.5 hours. After standing for separation, a premixed sodium carbonate aqueous solution (3 wt%, 15 liters) of (L)-N-acetylcysteine ​​(1.2 kg) was added. After stirring for 10 minutes, the mixture was allowed to stand for separation. The organic phase was washed twice with a 3 wt% sodium carbonate aqueous solution (15 liters + 10 liters), and then washed once with a 5 wt% sodium chloride aqueous solution (10 liters), dried over 2.0 kg of anhydrous sodium sulfate, and filtered. Modified palladium-removing silica gel (SiliaMetS Thiol, 800 g) and activated carbon (800 g) were added to the filtrate. The mixture was stirred at 50-60°C for 2 hours, cooled and filtered, and the filter cake was washed with tert-butyl methyl ether (2 liters * 2). The filtrate and washing solution were combined and concentrated under reduced pressure to obtain a crude product (2.9 kg). The crude product was dissolved in tert-butyl methyl ether (6 L) and added dropwise to a stirred solution of methanesulfonic acid (380 g) in tert-butyl methyl ether (26 L) over 40 minutes. During the addition, a yellow solid precipitated and the temperature was maintained at 15-25°C. After stirring for 1 hour, the mixture was filtered through a Buchner funnel and the filter cake was vacuum dried to obtain a yellow solid powder of compound 12 (2.50 kg, 96.6% purity, 82% content). 1H NMR (400 MHz, DMSO-d6) d = 9.79 (br d, J = 3.5 Hz, 1H),8.03 (dd, J = 1.3, 6.7 Hz, 1H), 7.79 ‒ 7.69 (m, 2H), 7.10 (d, J = 8.9 Hz, 1H),4.59 (q, J = 5.8 Hz, 1H), 4.53 ‒ 4.43 (m, 2H), 3.83 ‒ 3.62 (m, 1H), 3.61 ‒ 3.45(m, 3H), 3.45 ‒ 3.13 (m, 4H), 3.04 ‒ 2.94 (m, 3H), 2.92 (s, 6H), 2.39 ‒ 2.29 (m, 6H), 2.14 ‒ 1.90 (m, 5H). LCMS (ESI) m / z: 614.2 [M+H] + .

[0184] (XII) Synthesis of Compound 14

[0185] The compound 13 (2.50 kg, 3.52 mol) obtained in the previous step was dissolved in dichloromethane (10-15 L), and the residual tert-butyl methyl ether was removed by azeotropic removal using a rotary evaporator to obtain a yellow foamy solid. Under nitrogen protection, trifluoromethanesulfonic acid (3.17 kg, 21.13 mol, 1.87 L, 6 eq) was added dropwise to the treated dichloromethane (12.5 L) solution of TFX06-4 at 0-10 ° C for 1 hour. The mixture was heated to 15-20 ° C and stirred for 16 hours. If the reaction was not complete, trifluoromethanesulfonic acid (264.31 g, 1.76 mol, 155.48 ml, 0.5 eq) was added. The mixture was heated to 15-20 ° C and stirred for 5 hours. The reaction solution was allowed to stand at 15°C for 10 minutes, most of the supernatant (about 80%) was removed and discarded, and sodium carbonate aqueous solution (15 wt%, 10 liters) and 10 liters of dichloromethane were slowly added to the reactor and stirred for 0.5 hours, and then allowed to stand for separation. The obtained organic phase was fully washed with sodium carbonate aqueous solution (5 wt%, 5 liters * 2), and then fully washed with deionized water (5 liters * 3). The obtained organic phase was concentrated and dried under reduced pressure to obtain a crude product (1.76 kg). Acetone (7.65 liters) was added to 1.53 kg of the crude product to dissolve it, and methanesulfonic acid (290.30 g, 215 ml, 3.02 mol, 1 eq) was added dropwise to the crude solution at 0-15°C for 30 minutes, and the mixed solution was stirred at 10-15°C for 16 hours to precipitate a yellow solid. The solution was filtered through a Buchner funnel, and the filter cake was washed with acetone (1 L*2). The filter cake was vacuum dried to obtain yellow solid compound 14 (1.48 kg, 97.0% purity, 94% content).

[0186] 13. Synthesis of target molecules

[0187] The intermediate compound 14 (370 g) was suspended in dimethyl sulfoxide (1920 ml), heated to 60-65 ° C and stirred continuously until completely dissolved. Isopropyl acetate (13.2 L) was added dropwise at 50-65 ° C for 1 hour, and stirred at 60-65 ° C for 1 hour. The mixture was naturally cooled to 15-20 ° C to precipitate solids, which lasted for 16 hours. Filtered under reduced pressure through a Buchner funnel, and the collected filter cake was washed twice with isopropyl acetate (4 L × 2). The obtained filter cake was added with acetone (16.4 L) and slurried at 55-60 ° C for 16 hours. Cooled to 15-20 ° C, filtered under reduced pressure through a Buchner funnel, and the collected filter cake was added with acetone (22 L) and slurried at 55-60 ° C for 16 hours. Cooled to 15-20 ° C, filtered under reduced pressure through a Buchner funnel, and the collected filter cake was vacuum dried at 50-55 ° C for 16 hours (pressure: ≤0.01 MPa). The finished product 1736g TFX06 was obtained; yield: 73.6%. 1H NMR (400 MHz, DMSO-d6) δ =12.55 (s, 1H), 9.81 (br s, 1H), 8.04 (br s, 1H), 7.87 - 7.49 (m, 2H), 7.23(dd, J = 2.0, 8.7 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.59 (br d, J = 4.8 Hz,1H), 4.47 (br d, J = 4.6 Hz, 2H), 4.06 - 3.35 (m, 5H), 3.32 - 3.24 (m, 2H), 3.23 - 2.87 (m, 3H), 2.47 - 2.23 (m, 6H), 2.15 - 1.91 (m, 5H). LCMS (ESI) m / z:507.2 [M+H] + .

[0188] In summary, the preparation method of the present invention has more advantages in chiral separation than the original synthesis route, the product purification is easy, the reaction conditions are mild and easy to control, the synthesis steps are simple, the production cost is greatly reduced, and it is suitable for large-scale industrial production.

[0189] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing an estrogen receptor inhibitor indazole compound, It is characterized in that include Follow these steps: 1) Compound 9 is subjected to a sulfonylation reaction with perfluorobutylsulfonyl fluoride in the presence of a basic catalyst. Preparation of compound 10; 2) Compound 10 is mixed with bis-pinacol borate, a palladium catalyst, a phosphorus ligand and an organic base and subjected to a Miyaura coupling reaction to prepare compound 11; 3) Compound 11 is mixed with compound 12, an aqueous solution of an alkaline compound, and a palladium catalyst, and subjected to a Suzuki coupling reaction, and then salified with methanesulfonic acid to prepare compound 13; 4) Compound 13 was subjected to a deprotection reaction and salified with methanesulfonic acid to prepare an estrogen receptor inhibitor indazole compound 14; ； The alkaline catalyst in step 1) is selected from one or more of NaHMDS, KHMDS, and LiHMDS; The palladium catalyst in step 2) is selected from one or more of bis(triphenylphosphine)palladium dichloride, palladium dichloride, palladium acetate, and tris(dibenzylideneacetone)dipalladium; The phosphorus ligand in step 2) is selected from one or more of triphenylphosphine, tributylphosphine, tri-tert-butylphosphine, and tricyclohexylphosphine; The organic base in step 2) is selected from KOAc, PhOK, K 2 CO 3 , PivOK or more; The alkaline compound in step 3) is selected from one or more of potassium carbonate, potassium hydroxide and potassium phosphate; The palladium catalyst in step 3) is selected from palladium acetate or palladium dichloride.

2. The preparation method according to claim 1, It is characterized in that In the step 1), the molar ratio of compound 9, the alkaline catalyst and perfluorobutylsulfonyl fluoride is 1:(1-2):(1-2); The solvent for the reaction in step 1) is selected from one or more of tetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether; The reaction temperature in step 1) is -5°C to 10°C.

3. The preparation method according to claim 1, It is characterized in that In the step 2), the molar ratio of compound 10 to bis-pinacol borate, phosphorus ligand, organic base and palladium catalyst is 1: (1-1.5): (0.01-0.05): (1.5-3.5): (0.005-0.02); The reaction temperature of step 2) is 75°C to 80°C.

4. The preparation method according to claim 1, It is characterized in that The molar ratio of compound 11, compound 12, basic compound and palladium catalyst in step 3) is 1: (0.9-1.1): (2.0-6.0): (0.005-0.03); The solvent for the reaction in step 3) is selected from one or more of toluene, 2-methyltetrahydrofuran, and tetrahydrofuran; The reaction temperature in step 3) is 85°C to 90°C.

5. The preparation method according to claim 1, It is characterized in that The deprotection reaction in step 4) uses an organic acid; The organic acid is selected from one or more of trifluoromethanesulfonic acid, trifluoroacetic acid, and methanesulfonic acid; The molar ratio of the organic acid to the compound 13 is (2-10):1; The temperature of the deprotection reaction is 15°C to 20°C.

6. The preparation method according to claim 1, It is characterized in that The compound 14 in step 4) is purified and post-treated to obtain a pure product of an estrogen receptor inhibitor indazole compound; The refining is selected from recrystallization; The recrystallization solvent is selected from a mixed solvent of organic solvent 1 and organic solvent 2; The organic solvent 1 is selected from one or more of dimethyl sulfoxide, tetrahydrofuran, and DMF; The organic solvent 2 is selected from one or more of isopropyl acetate, n-heptane and acetone.

7. A method for preparing compound 9, It is characterized in that The following steps are involved: 1) Perform THP protection reaction on 4-bromoindazole to prepare compound 1; 2) Compound 1 is mixed with N-fluorobisbenzenesulfonamide, and subjected to a fluorination reaction under the action of an organic base to prepare compound 2; 3) Compound 2 is subjected to deprotection reaction to prepare compound 3; 4) Compound 3 is subjected to a sulfonylation reaction with dimethylaminosulfonyl chloride in the presence of an organic base to prepare compound 4; 5) Compound 4 is mixed with compound 5, a palladium catalyst, cuprous iodide, and an organic base and subjected to a coupling reaction to prepare compound 6; 6) Compound 6 is mixed with palladium hydroxide on carbon and subjected to reduction reaction under a hydrogen atmosphere to prepare compound 7; 7) Compound 7 is subjected to iodination reaction with N-iodosuccinimide under the catalysis of trifluoromethanesulfonic acid to prepare compound 8; 8) Compound 8 is mixed with isopropylmagnesium chloride lithium chloride complex and subjected to a ring-closing reaction to prepare compound 9; ； The organic base in step 2) is selected from one or more of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, and lithium hexamethyldisilazide; The organic base in step 4) is selected from one or more of triethylenediamine, pyridine, and 4-dimethylaminopyridine; The palladium catalyst in step 5) is selected from one or more of bis(triphenylphosphine)palladium(II) dichloride, palladium acetate, and palladium dichloride; The organic base in step 5) is selected from one or more of triethylamine, pyridine and 4-dimethylaminopyridine.

8. The preparation method according to claim 7, It is characterized in that The reaction in step 1) is to mix 4-bromoindazole, pyridinium p-toluenesulfonate and 3,4-dihydropyran and perform THP protection reaction; The molar ratio of 4-bromoindazole, pyridinium p-toluenesulfonate and 3,4-dihydropyran is 1: (0.01-0.03): (3-5); The solvent of the reaction is selected from one or more of n-heptane, toluene, n-heptane, and toluene; The reaction temperature is 30°C to 50°C.

9. The preparation method according to claim 7, It is characterized in that In the step 2), the molar ratio of compound 1 to the organic base and N-fluorobisbenzenesulfonamide is 1:(1-2):(1-2); The solvent for the reaction in step 2) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether; The reaction temperature of step 2) is -60°C to -10°C.

10. The preparation method according to claim 7, It is characterized in that The deprotection reaction in step 3) is carried out in an acidic environment; The acidic environment is provided by one or more of concentrated hydrochloric acid, trifluoroacetic acid, and hydrobromic acid; The pH value of the reaction system is 1.0-3.0; The solvent of the reaction is one or more of methanol, ethanol, isopropanol and acetonitrile; The reaction temperature is 10°C to 20°C.

11. The preparation method according to claim 7, It is characterized in that The molar ratio of compound 3 to organic base and dimethylaminosulfonyl chloride in step 4) is 1:(1-1.5):(1-1.5); The reaction temperature of step 4) is -10°C to 20°C.

12. The preparation method according to claim 7, It is characterized in that The molar ratio of compound 4 to compound 5 in step 5) is 1:(1-1.5); The molar ratio of compound 5 to palladium catalyst, cuprous iodide and organic base in step 5) is 1:(0.01-0.03):(0.01-0.03):(2-4); The reaction temperature in step 5) is 70°C to 80°C.

13. The preparation method according to claim 7, It is characterized in that The mass ratio of compound 6 to palladium hydroxide carbon in step 6) is 1: (0.05-0.2); The hydrogen pressure is 0.8-1.5 MPa; The solvent of the reaction is selected from methanol and / or tetrahydrofuran; The reaction temperature is 20°C to 30°C; The reaction time is 15 to 20 h.

14. The preparation method according to claim 7, It is characterized in that The molar ratio of compound 7 to N-iodosuccinimide and trifluoromethanesulfonic acid in step 7) is 1:(1-2):(0.5-1.5); The solvent of the reaction is selected from one or more of acetonitrile, tetrahydrofuran, 1,4-dioxane, and acetone; The reaction temperature is 15°C to 20°C.

15. The preparation method according to claim 7, It is characterized in that The molar ratio of compound 8 to isopropylmagnesium chloride lithium chloride complex in step 8) is 1:(1-2); The solvent of the reaction is selected from one or more of toluene, n-heptane, tetrahydrofuran, and 1,4-dioxane; The reaction temperature is 0°C to 15°C.

Images