Preparation method of IDH1 mutant inhibitor

Abstract

The invention belongs to the technical field of medicine preparation, and discloses a preparation method of an IDH1 mutant inhibitor, which comprises the following steps: by taking 3-nitro-4-fluorobenzaldehyde and triethyl phosphorylacetate as raw materials, carrying out HWE reaction, substitution reaction, hydrogenation pressurization reaction, cyclization reaction and hydrolysis reaction in sequence to obtain (R)-3-(1-(1, 2, 3, 4-tetrahydro-2H-1, 2, 4-tetrahydro-2H-1, 2, 4-tetrahydro-2H-1, 2, 4-tetrahydro-2H-1, 2, 4-tetrahydro-2H-1, 2, 4- The preparation method comprises the following steps: firstly, preparing (R)-3-(1-(1, 2, 3, 4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy) phenyl) amino)-1H-benzo [d] imidazole-5-yl) propionic acid in a crystal form A, and then carrying out a crystal transformation process to prepare (R)-3-(1-(1, 2, 3, 4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy) phenyl) amino)-1H-benzo [d] imidazole-5-yl) propionic acid in a crystal form B; wherein the crude product obtained by the HWE reaction is subjected to pulping treatment and impurity removal, and then is used for the reaction of the next step. Compared with a direct leaching mode, the crude product pulping mode has the advantages that impurities can be better removed, the purity of an intermediate product is improved, and the purity of the finally obtained target product is further improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and in particular, relates to a method for preparing an IDH1 mutant inhibitor. Background Art

[0002] Isocitrate dehydrogenase (IDH) is an important enzyme in the citric acid cycle, which catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., 2-α-ketoglutarate, α-KG). The protein encoded by the IDH1 gene is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes, which contains a PTS-1 peroxidase targeting signal sequence. The presence of this enzyme in the oxisome suggests a role in the regeneration of internal NADPH.

[0003] Non-mutant, such as wild-type IDH, catalyzes the oxidative decarboxylation of isocitrate while reducing NAD + (NADP + ) to NADP(NADPH), as follows:

[0004] Isocitrate + NAD + (NADP + )→α-KG+CO2+NADP(NADPH)+H +

[0005] Currently, IDH 1 / 2 mutant proteins (IDH 1 / 2m) have been found in a variety of tumors, including glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma, melanoma, prostate cancer, and angioimmunoblastic T-cell lymphoma. Among gliomas, more than 70% of non-primary glioblastomas have IDH1 mutations, and 92.7% of IDH1 mutant tumors have arginine replaced by histidine (i.e., IDH1 R132H).

[0006] IDH mutant protein has a new protein function, which is to catalyze the reduction of α-KG to produce the oncogene 2-hydroxyglutarate (2-HG). The production of 2-HG has been reported to contribute to the formation and development of cancer. The level of 2-HG produced in normal cells is very low, but cells with IDH mutations can produce high levels of 2-HG. High levels of 2-HG can also be found in tumors with IDH mutations.

[0007] Therefore, inhibition of mutant IDH and its new activity is a potential approach for cancer treatment, and there is a need to obtain inhibitors of IDH mutants to inhibit their new role in producing 2-HG.

[0008] Malignant tumors are major diseases that threaten human health and are difficult to cure. They are the main cause of death and a public health issue. Surgical treatment is an effective treatment for early solid tumors, but most cancer patients are already in the advanced stage when they are discovered, and the treatment options and efficacy are relatively limited. In recent years, with the development of targeted drugs and immune-related therapies, the treatment effect of advanced tumors has been greatly improved, but some tumor types, such as unresectable or metastatic bile duct cancer patients, still lack effective therapeutic drugs. Therefore, new drugs still need to be developed to benefit more patients.

[0009] More specifically, isocitrate dehydrogenase (IDH) contains three members in human cells: IDH1, IDH2, and IDH3. Among them, IDH1 is present in the cytoplasm and peroxisomes, and IDH2 and IDH3 are present in mitochondria. IDH1 and IDH2 enzymes are encoded by IDH1 and IDH2 genes, and mutations in IDH1 and IDH2 genes can be seen in a variety of human cancers. In malignant tumors such as bile duct cancer, glioma, and chondrosarcoma with IDH1 mutations, it can be seen that the content of the cancer metabolite 2-HG is increased. The structure of 2-HG is similar to α-KG, and it can competitively inhibit multiple α-KG-dependent dioxygenases, including lysine histone demethylase and DNA demethylase, causing abnormal histone and DNA demethylation, thereby blocking cell differentiation and causing tumor development. IDH1 and IDH2 mutations have gradually become important targets for anti-tumor.

[0010] Most IDH1 gene mutations occur at the arginine 132 (R132) residue. Malignant tumors with IDH1 mutations that have been found so far include hematologic tumors such as acute myeloid leukemia (AML), as well as solid tumors, mainly gliomas, chondrosarcomas, and cholangiocarcinomas. The IDH1 mutation rate in cholangiocarcinoma is about 20%, and about 13%-18% of intrahepatic cholangiocarcinomas have IDH1 mutations, with even higher mutation rates. 50-70% of chondrosarcoma patients have IDH1 and IDH2 mutations (mainly IDH1 mutations), and about 80% of grade II-III gliomas and secondary glioblastomas have IDH1 mutations. In addition, IDH1 mutations can also occur in other solid tumors with lower frequencies, such as prostate cancer, paraganglioma, and melanoma. Preclinical efficacy experiments have shown that IDH1 inhibitors can cause a decrease in 2-HG production, restore cell differentiation, and inhibit tumor growth by inhibiting IDH1 mutations in tumors. Clinical trials have also shown that IDH1 inhibitors can reduce the level of 2-HG in the blood of patients with AML, cholangiocarcinoma, and chondrosarcoma with IDH1 mutations, exerting their pharmacodynamic effects. IDH1 small molecule inhibitors are becoming a targeted drug for IDH1 mutations that pharmaceutical companies are focusing on developing.

[0011] The currently marketed small molecule IDH1 inhibitor is Ivosidenib (AG-120) developed by Agios Pharmaceuticals. It was approved by the U.S. FDA in 2018 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with IDH1 mutations. In 2019, it was approved by the U.S. FDA to add an indication for the treatment of newly diagnosed adult AML patients with IDH1 mutations who are ≥75 years old or cannot use intensive induction chemotherapy due to comorbidities (Ivosidenib label, 2019). On August 25, 2021, Ivosidenib was launched in the United States for the treatment of IDH1-mutated cholangiocarcinoma; in addition to the indications of AML and intrahepatic cholangiocarcinoma, Ivosidenib is also exploring multiple tumor types related to IDH1 gene mutations, including myelodysplastic syndrome and solid tumors (including glioma, chondrosarcoma, etc.). On December 1, 2022, FORMA's Olutasidenib (FT-2102) was approved by the FDA for the treatment of adult relapsed or refractory (R / R) acute myeloid leukemia (AML) with IDH1 mutation.

[0012] Other selective IDH1 inhibitors under clinical development include Novartis' IDH-305, Bayer's BAY-1436032, and Daiichi Sankyo's DS-1001, which have entered Phase I or Phase II early clinical trials.

[0013] AU2019296173A1 discloses the specific structure of an IDH1 mutant inhibitor, KY100001. This compound is an innovative drug for targeted anti-tumor therapy independently developed by Kunming Pharmaceutical Group Co., Ltd. in my country. It has been approved by the State Food and Drug Administration for Phase I clinical trial research in November 2020 and is intended to be used to treat intrahepatic bile duct carcinoma, brain glioma and chondrosarcoma. The chemical name of KY100001 is (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-(trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid, and its English chemical name is (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-(trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid, and its structural formula is as follows:

[0014]

[0015] However, in the research on the preparation of the IDH1 mutant inhibitor KY100001, it is necessary to explore a KY100001 preparation method that is suitable for industrial production and has a short process flow, simple operation, improved product purity, low cost, safety and environmental protection.

[0016] In view of this, the present invention is proposed. Summary of the invention

[0017] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for preparing an IDH1 mutant inhibitor, which can effectively improve the purity of the target product by improving the purity of the intermediate product in the preparation process and is suitable for industrial production.

[0018] In order to solve the above technical problems, the basic concept of the technical solution adopted by the present invention is:

[0019] A method for preparing an IDH1 mutant inhibitor comprises the following steps:

[0020] (1) mixing 3-nitro-4-fluorobenzaldehyde and triethyl phosphoacetate in a solvent system, and performing HWE reaction under the condition of adding a catalyst, filtering to obtain a crude product of (E)-3-nitro-4-fluorophenyl-ethyl acrylate; adding a solvent to the crude product of (E)-3-nitro-4-fluorophenyl-ethyl acrylate for slurrying, and then filtering to obtain (E)-3-nitro-4-fluorophenyl-ethyl acrylate;

[0021] (2) dissolving the (E)-3-nitro-4-fluorophenyl-ethyl acrylate obtained in step (1) and (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine in a solvent, carrying out a substitution reaction under alkaline and heating conditions, quenching with hot water, adding seed crystals after cooling, and continuing to cool to 0-5° C. for crystallization, and then filtering to obtain (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate;

[0022] (3) the (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate obtained in step (2) is subjected to a hydrogenation pressure reaction in a solvent system using palladium-carbon as a catalyst to obtain (R,E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate;

[0023] (4) the (R,E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate obtained in step (3) is subjected to a cyclization reaction with 4-trifluoromethoxyphenyl isothiocyanate and a condensation reagent in a solvent system to obtain (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propionic acid ethyl ester;

[0024] (5) the (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid ethyl ester obtained in step (4) is subjected to a hydrolysis reaction in a solvent system in the presence of an alkaline reagent to obtain (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid;

[0025] (6) The (R)-3-(1-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid obtained in step (5) is dissolved in a solvent under heating conditions, and the insoluble matter is removed by filtration; then, the solid is heated again until it is completely dissolved, the temperature is lowered to 60 to 70°C, a crystal seed of Form B is added, and the temperature is maintained at 60 to 70°C for crystallization, and then a mixed solution of ethanol and water is added, the temperature is lowered to 20 to 30°C and maintained, and the crystallization is stirred; after filtration and drying, Form B of (R)-3-(1-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid is obtained.

[0026] In step (1) of the preparation method of the present invention, the raw material 3-nitro-4-fluorobenzaldehyde and triethyl phosphoacetate are subjected to Horner-Wadsworth-Emmons (HWE) reaction in a solvent system, and after the reaction is completed, a crude product is obtained by suction filtration. The crude product is pulped and filtered again to obtain an intermediate product M1 that can be used for the next step of the reaction, i.e. (E)-3-nitro-4-fluorophenyl-ethyl acrylate. The pulping treatment can effectively remove impurities and improve the purity of the intermediate product M1, which is conducive to ensuring the purity of the target product finally obtained. When the crystal is converted in step (6), the B crystal seed is added when the temperature is lowered to 60-70°C, which makes it easier to accurately control the timing of adding the seed, which is particularly suitable for industrial production processes.

[0027] Furthermore, in step (1), the solvent added when the crude product is pulped is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate and butyl acetate;

[0028] Preferably, beating at 25-35° C. for 0.5-1.0 h;

[0029] Preferably, the ratio between the mass of the 3-nitro-4-fluorobenzaldehyde and the volume of the pulping solvent is 1 kg:5-7L.

[0030] In the above scheme, the crude product is slurried at room temperature. After testing, by controlling the process parameters of the slurrying operation within the above range, an intermediate product M1 with an HPLC purity close to or reaching 100% can be obtained. At the same time, the yield of the step (1) reaction is higher than 90%, achieving high purity of the intermediate product M1 and high yield of the reaction, thereby improving the purity and reaction yield of the target product.

[0031] Furthermore, in step (1), the reaction temperature of the HWE reaction is 50-60° C., and the reaction time is 5-10 h;

[0032] Preferably, the reaction temperature is 50-55° C., and the reaction time is 5-6 h.

[0033] In the above scheme, the reaction temperature of the HWE reaction is increased to 50-60°C, and the reaction time can be shortened from 17 hours to 5-10 hours. By significantly shortening the reaction time, the preparation efficiency of the target product, that is, the IDH1 mutant inhibitor KY100001, can be improved, especially when applied to industrial production, the production cycle can be shortened, which helps to reduce production costs and meet market demand.

[0034] Furthermore, in step (1), the molar ratio of 3-nitro-4-fluorobenzaldehyde to triethyl phosphoacetate is 1.0:1.0-1.05; the solvent used to form the solvent system is tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dichloromethane, toluene or xylene; and the catalyst used is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydride and potassium hydride.

[0035] Specifically, in step (1) of the preparation method of the present invention, a solvent, 3-nitro-4-fluorobenzaldehyde and triethyl phosphoacetate are added to a reaction kettle to form a solvent system, and after sufficient mixing, an aqueous solution of the catalyst is added dropwise to the above-mentioned solvent system. After the addition is completed, the temperature is raised to 50-60°C and stirred for reaction for 5-10 hours, then the temperature is lowered to 50°C, water is added dropwise to the reaction system, and then the temperature is lowered to 25-35°C, and stirred at 25-35°C for 2.0 hours, and the crude product is filtered to obtain the crude product. The crude product is pulped with a pulping solvent at room temperature of 25-35°C for 0.5 hours, and then filtered to obtain the intermediate product M1. The reaction formula of step (1) is as follows:

[0036]

[0037] Furthermore, in step (2) of the preparation method, hot water at a temperature of 50 to 60° C. is added for extraction;

[0038] Preferably, the substitution reaction is carried out at 70-75°C for 5-6 hours, then the temperature is lowered to 55°C, and hot water at a temperature of 50-60°C is added;

[0039] More preferably, after adding hot water, the mixture is allowed to stand for separation, and then the aqueous phase is removed by separation, while the organic phase is retained; the process of adding hot water and then separating the liquids is repeated at least three times, preferably three times.

[0040] In the present invention, hot water is added after the substitution reaction is completed, and the mixture is mixed and then separated, which can also play the effect of washing the product to remove impurities. According to the material characteristics, hot water quenching can avoid material loss in the above washing process, ensure the reaction yield, and is more conducive to industrial production.

[0041] Furthermore, in step (2), seed crystals are added when the system temperature drops to 40-50°C, preferably at 45-48°C;

[0042] Preferably, after adding the seed crystals, the temperature is maintained for crystallization for 1.0 h, then the temperature is lowered to 0-5° C. for crystallization for 2.0 h, and (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-acrylate is obtained by suction filtration.

[0043] In the present invention, the intermediate product M2, i.e., (R, E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalene-1-yl)amino)phenyl)-ethyl acrylate, can be obtained through the substitution reaction of step (2). After the substitution reaction is completed, the temperature is lowered to a certain extent, and then hot water is added under a solvent system and the liquid is separated at least three times, and then the temperature is further lowered, and then the seed crystals of the intermediate product M2 are added for crystallization for a period of time, and then the temperature is further lowered for crystallization. By washing with hot water and two crystallization stages at different temperatures, impurities can be well removed without causing a decrease in yield. According to testing, the yield of step (2) can reach 91.61%, and the HPLC purity of the intermediate product M2 obtained is 100%.

[0044] Furthermore, in step (2), the molar ratio of (E)-3-nitro-4-fluorophenyl-ethyl acrylate to (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine is 1.0:1.0-1.05; the solvent used is n-hexane, n-heptane, ethyl acetate, isopropyl acetate or butyl acetate; and an alkaline environment is formed by adding potassium carbonate.

[0045] Specifically, in step (2) of the preparation method of the present invention, the intermediate product M1, (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine and solvent are added to the reaction kettle, fully mixed, and then potassium carbonate is added, the temperature is raised to 70-75°C for reaction for 5-6 hours, the temperature is lowered to 55°C, hot water is added dropwise to the reaction system, the reaction system is allowed to stand for stratification, the aqueous phase is removed, and the operation of adding hot water and then separating the liquids is repeated twice, then the temperature is lowered to 40-50°C, seed crystals are added, the system temperature is maintained at 40-50°C, stirred and crystallized for 1.0 hour, the temperature is further lowered to 0-5°C, stirred and crystallized for 2.0 hours, and filtered to dryness to obtain the intermediate product M2. The reaction formula of step (2) is as follows:

[0046]

[0047] Furthermore, in step (3) of the preparation method, wet palladium carbon is added as a catalyst, and the mass ratio of the (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate to wet palladium carbon is 1.0:0.025-0.075, preferably 1.0:0.025-0.030;

[0048] The reaction temperature of the hydrogenation pressure reaction is 20-35°C, the pressure is 0.5-1.0MPa, and the reaction time is 4-10h;

[0049] Preferably, the reaction temperature is 25-30° C., the pressure is 0.8-1.0 MPa, and the reaction time is 4-6 h.

[0050] In the present invention, by exploring and optimizing various process parameters, especially the continuous adjustment and optimization of palladium carbon dosage, reaction time and reaction pressure, it is found that without affecting the quality of the product, the reaction time can be reduced from 16.5h to 4-10h, which is significantly shortened, which is conducive to improving production efficiency. At the same time, since the amount of palladium carbon can be reduced to 2.5%-3.0% of the mass of the intermediate product M2, the cost of using palladium carbon is greatly reduced. In addition, the reaction pressure can be reduced from 2.8MPa of the prior art to 0.8-1.0MPa, and the safety risk is also greatly reduced, which is more suitable for industrial production. After testing, after the above improvements, the quality and yield of the final target product are not affected.

[0051] Furthermore, when performing the hydrogenation pressure reaction, the hydrogen pressure is maintained at 0.8-1.0 MPa, the reaction is stirred at 25-35° C. for 4-8 hours, and then the temperature is lowered to 20-30° C. and stirred for 0.5-1.0 hour to terminate the reaction;

[0052] Preferably, the temperature is first lowered to 25-30° C. and stirred for 0.5 h, and then lowered to 20-25° C. and stirred for 0.5 h to terminate the reaction.

[0053] In the above scheme, during the reaction process, the reaction temperature is lowered to 20-30° C. and the reaction is continued under pressure and stirring, which is conducive to the complete reaction, improves the reaction yield, and reduces the impurity level.

[0054] Furthermore, in step (3), the solvent used to form the solvent system is tetrahydrofuran, methyl tert-butyl ether, ethanol, methanol, 1,4-dioxane, acetonitrile or toluene.

[0055] Specifically, in step (3) of the preparation method of the present invention, the intermediate product M2, wet palladium carbon and tetrahydrofuran (THF) are added to the autoclave in sequence, and then the autoclave is sealed. Next, the autoclave is replaced with nitrogen three times, and then hydrogen is replaced three times, and hydrogen is introduced into the autoclave, and the hydrogen pressure is maintained at 0.5-1.0MPa, and the temperature is stirred at 25-35°C for 4-8h, and then the temperature is lowered to 25-30°C and stirred for 0.5h, and then the temperature is lowered to 20-25°C and stirred for 0.5h. Then, the stirring is turned off, the nitrogen is replaced three times, and the autoclave is opened again to transfer the reaction solution. The reaction solution is filtered through a Buchner funnel covered with diatomaceous earth, the filtrate is collected, the filter cake is rinsed with THF, and the elution is collected and combined with the filtrate to obtain the intermediate product M3 (i.e., (R, E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalene-1-yl)amino)phenyl)-ethyl acrylate) THF solution, which is directly used in the next step reaction. The reaction formula of step (3) is as follows:

[0056]

[0057] Furthermore, in step (4) of the preparation method, the reaction temperature of the cyclization reaction is 30 to 65° C.; after the cyclization reaction is completed, a purification treatment is performed, including:

[0058] a) performing reduced pressure concentration at 40-50° C. to remove the reaction solvent;

[0059] b) cooling the reaction system to 20-30° C., adding methyl tert-butyl ether and water, stirring to dissolve, standing to separate, separating and removing the aqueous phase, and retaining the organic phase;

[0060] c) adding water to the organic phase for washing, removing the aqueous phase by separation, and retaining the organic phase;

[0061] d) adding a hydrochloric acid solution to the organic phase at 20 to 30° C., stirring, standing and separating the layers, removing the aqueous phase by separation, and retaining the organic phase; the concentration of the hydrochloric acid solution is preferably 0.1 to 0.2 M, more preferably 0.15 M;

[0062] e) adding water to the organic phase for washing, separating and removing the aqueous phase, and retaining the organic phase;

[0063] f) adding a sodium bicarbonate aqueous solution to the organic phase at 20 to 30° C., stirring, standing and separating the layers, removing the aqueous phase by separation, and retaining the organic phase; the concentration of the sodium bicarbonate aqueous solution is preferably 0.1 to 0.2 M, more preferably 0.15 M;

[0064] g) adding water to the organic phase for washing, removing the aqueous phase by separation, and retaining the organic phase;

[0065] h) the organic phase is concentrated under reduced pressure at 30-40° C.;

[0066] i) adding anhydrous ethanol and continuing to concentrate under reduced pressure at 40-50° C.;

[0067] j) adding 95% ethanol aqueous solution to dissolve the oily substance and then cooling to 10-25° C. to obtain an ethanol aqueous solution of the intermediate product;

[0068] k) adding the ethanol aqueous solution of the intermediate product dropwise into water at 5 to 15° C. under stirring, continuing stirring after the addition is completed, and filtering to obtain a filter cake;

[0069] l) The filter cake was concentrated under reduced pressure to a constant weight to obtain ethyl (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoate.

[0070] In the above scheme, the product obtained by the cyclization reaction in the solvent system is a viscous oily substance, which is not convenient for transfer and storage, and is not convenient for the next step of reaction. In the present invention, after the above-mentioned purification treatment, the intermediate product M4 (i.e., (R)-3-(1-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazole-5-yl)ethyl propionate) obtained is a light yellow solid with good properties, which is convenient for transfer to the next step of reaction. At the same time, the intermediate product M4 is subjected to a separate separation and purification, which can also effectively improve the yield of this step and the purity of the intermediate product M4 obtained. After testing, the yield of this step is 87.16%, and the HPLC purity of the intermediate product M4 obtained is greater than 97%.

[0071] Furthermore, in step (4), the molar ratio of (R,E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate, 4-trifluoromethoxyphenyl isothiocyanate and condensing agent is 1.0:(0.97-1.02):2.0; the condensing agent is one of HOBT, HATU, EDCI, CDI and T3P; the reaction time of the cyclization reaction is 8-12h; and the solvent used to form the solvent system is tetrahydrofuran, 1,2-dichloroethane, toluene, N,N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether, acetonitrile or 1,4-dioxane.

[0072] Specifically, in step (4) of the preparation method of the present invention, the THF solution of the intermediate product M3 is added to the high-low temperature jacketed kettle at one time, stirred and heated to 30-35°C, the internal temperature is controlled to be 30-35°C, and then the THF solution of 4-trifluoromethoxyphenyl isothiocyanate diluted with THF is added dropwise to the high-low temperature jacketed kettle. After the dropwise addition is completed, the internal temperature is maintained at 30-35°C, and the reaction is performed for 2 hours to obtain the intermediate state. Then EDCI is added to the reaction system at one time, the temperature is raised to 60-65°C, and the reaction is stirred for 8-12 hours.

[0073] Then, the purification treatment is carried out. First, the internal temperature is controlled at 40-50°C, and the reaction solvent is removed by decompression and concentration until no liquid is dripped. Then the temperature is lowered to 20-30°C, and methyl tert-butyl ether and water are added alternately. After stirring and dissolving, the mixture is allowed to stand for 20-30 minutes, and the lower aqueous phase is removed by separation. Water is added to the organic phase and stirred for 10-20 minutes, and the mixture is allowed to stand for 20-30 minutes. The lower aqueous phase is removed by separation, and the washing is performed twice. After that, stirring is turned on, the internal temperature is controlled at 20-30°C, 0.1-0.2M hydrochloric acid solution is added, stirred for 10-15 minutes, and the mixture is allowed to stand for 30-35 minutes. The lower aqueous phase is removed by separation. Water is added to the organic phase and stirred for 10-20 minutes, and the mixture is allowed to stand for 30-35 minutes. The lower aqueous phase is removed by separation, and the washing is performed twice.

[0074] Then, control the internal temperature at 20-30°C, add 0.1-0.2M sodium bicarbonate aqueous solution, stir for 10-15min, let stand for 20-30min, separate and remove the lower aqueous phase. Add water to the organic phase and stir for 10-15min, let stand for 20-30min, separate and remove the lower aqueous phase, and wash twice. After that, control the external temperature at 30-40°C, and concentrate under reduced pressure until no liquid drips. Add anhydrous ethanol, control the external temperature at 40-50°C, and concentrate under reduced pressure until no liquid drips. Turn off the vacuum, add 95% ethanol to the reactor, dissolve the oil and then cool to 10-25°C to obtain a 95% ethanol solution of the intermediate product M4 for standby use.

[0075] Add water to another reaction kettle, control the temperature at 5-15°C, set the stirring speed ≥150 rpm, and then slowly drop the 95% ethanol solution of the intermediate product M4 into 5-15°C water to precipitate a white solid. Continue stirring for 10-20 minutes after the dropwise addition is complete, and then filter. The filter cake is concentrated under reduced pressure at 25-35°C to a constant weight to obtain the intermediate product M4. The reaction formula of step (4) is as follows:

[0076]

[0077] Furthermore, in step (5) of the preparation method, after the hydrolysis reaction, the system is filtered to obtain a filter cake, the filter cake is slurried with a mixed solution of ethanol and isopropyl acetate, and then filtered again to obtain (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazole-5-yl)propanoic acid;

[0078] Preferably, the mixture is stirred and slurried at 45 to 50° C. for 1 to 1.5 hours, then cooled to 10 to 25° C. and stirred for 2 hours, and then filtered again;

[0079] Preferably, in the mixed solution of ethanol and isopropyl acetate, the volume ratio of ethanol to isopropyl acetate is 1-2:2-3, preferably 1:2;

[0080] Preferably, the ratio between the feed mass of the (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid ethyl ester and the volume of the mixed solution of ethanol and isopropyl acetate used for pulping is 1 kg:2.5 to 5.0 L.

[0081] In step (5) of the preparation method of the present invention, a refining process of beating the filter cake and then filtering it again is added, which effectively removes the existing impurities and ensures the quality of the product of this step, especially the purity. The product obtained in this step is a crude product of KY100001, and its HPLC purity is 100% after testing, and the yield of the reaction is 90.34%. Preferably, in the previous step (2), the intermediate product M1 is dissolved in isopropyl acetate. At the same time, the hydrolysis reaction is carried out in a solvent system formed by ethanol in this step, and a mixed solution of ethanol and isopropyl acetate is used in the subsequent beating, without introducing a new solvent, which reduces the control pressure of the residual solvent.

[0082] Furthermore, in step (5), the molar ratio of the (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid ethyl ester to the alkaline reagent is 1.0:1.5-2.0; the hydrolysis reaction temperature is 25-35°C, and the reaction time is 4-6h; and the solvent used to form the solvent system is tetrahydrofuran, ethanol, methanol, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, acetonitrile or 2-methyltetrahydrofuran.

[0083] In the present invention, through small-scale research and kilogram-level scale-up research, the above-mentioned hydrolysis reaction is carried out in a 30-100L reactor, and the heat exchange effect and the stirring effect are significantly improved, which has a good promoting effect on the reaction rate of the hydrolysis reaction. Therefore, according to the results of multiple batches of kilogram-level scale-up research, this step of hydrolysis reaction can be completely reacted in only 4-6 hours, which effectively shortens the reaction time.

[0084] Specifically, in step (5) of the preparation method of the present invention, the intermediate product M4 is dissolved in ethanol, and an aqueous sodium hydroxide solution is added dropwise to the above solution at 25 to 35°C, and the reaction is stirred at 25 to 35°C for 4 to 6 hours. Then, the system temperature is controlled to 20 to 30°C, and a 1M hydrochloric acid aqueous solution is slowly added dropwise to adjust the pH to 5 to 6. After the addition is completed, the internal temperature is maintained at 20 to 30°C and stirred for 2.0 hours. Filter, stir and slurry the filter cake with a mixed solution of ethanol and isopropyl acetate at 45 to 50°C for 1.0 to 1.5 hours, then cool to 10 to 25°C and stir for 2.0 to 2.5 hours, and filter to obtain the crude product of KY100001. The reaction formula of step (5) is as follows:

[0085]

[0086] Furthermore, in step (6) of the preparation method, the temperature for heating and dissolving is 70-75° C., and insoluble matter is removed by hot filtration; thereafter, heating is performed again until the solid is completely dissolved;

[0087] Preferably, after heating again until the solid is completely dissolved, the temperature is controlled at 70-75° C., ethanol is added dropwise to the system, and the ratio between the mass of the desired (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid to the volume of ethanol is 1 kg:2.0-2.5 L; then the temperature is lowered to 60-70° C. and a crystal seed of Form B is added;

[0088] More preferably, after adding the B crystal seed, the temperature is maintained at 60-70°C and stirred for crystallization for 1.0-2.0h; after adding a mixed solution of ethanol and water and cooling to 10-30°C, stirring and crystallization are continued for 1.0h.

[0089] In the above scheme, seed crystals of crystal form B (R)-3-(1-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazole-5-yl)propionic acid are added when the temperature is lowered to 60-70°C, which simplifies the operability of the crystallization process and is easier to implement in the industrial production process, making the preparation method of the present invention more suitable for industrial production. During the crystallization process, the crystallization is first stirred for 2.0 hours at a relatively high temperature of 60-70°C, and then a mixed solution of ethanol and water is added, and the temperature is lowered to continue crystallization, which can shorten the overall crystallization time and does not affect the yield of the target product. After testing, the HPLC purity of the target product obtained in this step is 100%, and the yield is 98%.

[0090] Furthermore, in step (6), the solvent used for dissolving is at least one of dimethyl sulfoxide, isopropanol, ethanol, methanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, and tetrahydrofuran; and in the mixed solution of ethanol and water, the volume ratio of ethanol to water is 2:1.

[0091] Specifically, in step (6) of the preparation method of the present invention, the crude KY100001 obtained in step (5), as well as dimethyl sulfoxide (DMSO) and ethanol are added to the reactor, stirred and heated to 70-75°C until the solid is completely dissolved. Then filter while hot to remove insoluble matter, collect the filtrate into the reactor, and heat again until the solid is completely dissolved. Control the system temperature to 75°C, add ethanol dropwise thereto, and maintain the system clear. Then slowly cool to 60-70°C, add B crystal seed to the system, maintain the system temperature at 60-70°C, stir and crystallize for 2.0h, then add a mixed solution of ethanol and water to the system, cool to 10-30°C, stir and crystallize for 1.0h, and finally filter and dry to obtain the target product, that is, the B crystal form IDH1 mutant inhibitor KY100001.

[0092] After adopting the above technical scheme, the present invention has the following beneficial effects compared with the prior art.

[0093] 1. The starting materials and reagents used in the process route are all commercial products, cheap and easy to obtain. The technical scheme of the synthesis reaction is reasonable and the process flow has been simplified.

[0094] 2. After the reaction of each step is completed, conventional post-treatment and purification are performed without the need for chromatography column purification, and the impurities in the intermediate products and target products are reduced, and the quality is controllable; after testing, the purity of multiple intermediate products is 100% or close to 100%, and the yield of each step reaction is more than 85%, ensuring the high purity and high yield of the final target product.

[0095] 3. In the hydrogenation pressure reaction, the reaction can be completed within a relatively small reaction pressure range of 0.5 to 1.0 MPa, which effectively reduces the safety risk of industrial production, especially when applied to industrial production. At the same time, the amount of wet palladium carbon used in the hydrogenation pressure reaction is reduced to 2.5% to 7.5% of the mass of the intermediate product M2. By reducing the use of palladium carbon, the production cost is greatly reduced, and mass production can be carried out to meet the needs of clinical trial research drugs, which is suitable for industrial scale-up production to meet future commercialization.

[0096] 4. By optimizing the process parameters in each step of the reaction, the duration of some reaction steps can be shortened without affecting the product quality and purity, as well as the reaction yield, thereby achieving the goal of improving production efficiency.

[0097] The specific embodiments of the present invention are described in further detail below. DETAILED DESCRIPTION

[0098] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments will be described clearly and completely below. The following embodiments are used to illustrate the present invention, but are not used to limit the scope of the present invention. The chemical reagents used in the embodiments of the present invention are all conventional chemical reagents in the art. Unless otherwise specified, they are purchased from Sinopharm Chemical Reagent Co., Ltd.

[0099] In the following embodiments:

[0100] The intermediate product M1 is (E)-3-nitro-4-fluorophenyl-ethyl acrylate;

[0101] The intermediate product M2 is (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate;

[0102] The intermediate product M3 is (R,E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate;

[0103] Intermediate product M4 is (R)-ethyl 3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoate;

[0104] KY100001 is (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid.

[0105] Example 1

[0106] In this example, the preparation of the B-type IDH1 mutant inhibitor KY100001 was carried out according to the following steps, wherein the room temperature was 25-35°C.

[0107] (1) The intermediate product M1 is prepared by HWE reaction as follows:

[0108] In a clean and dry 50L glass reactor, solvent THF (9.0L), 3-nitro-4-fluorobenzaldehyde (3.0kg, 17.74mol) and triethyl phosphoacetate (4.18kg, 18.63mol) were added, mixed thoroughly, and then an aqueous solution of potassium carbonate (obtained by dissolving 4.9kg, 35.48mol of potassium carbonate in 9.0L of water) was added dropwise. The temperature of the reaction liquid was controlled to be 25±10°C during the addition. After the addition was completed, the addition port was closed, the cooling circulation system of the condenser was opened, the reflux valve on the condenser was opened, the temperature was raised to 55°C and stirred for reaction for 6h, then cooled to 50°C, water (21.0L) was added dropwise to the reaction system, and then cooled to room temperature, and stirred at room temperature for 2.0h, filtered to dryness to obtain a crude intermediate product M1, the crude product was slurried with ethanol (21.0L) at room temperature for 0.5h, and filtered to obtain the intermediate product M1 as a light yellow needle-shaped solid, a total of 3.82kg.

[0109] The yield of this step was 90.02%, and the HPLC purity of the intermediate product M1 was 100%.

[0110] (2) The intermediate product M2 is prepared by substitution reaction, as follows:

[0111] In a clean and dry 50L glass reactor, the intermediate product M1 (3.0kg, 12.54mol) obtained in step (1) and (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine (1.94kg, 13.17mol) were added and dissolved in isopropyl acetate (18.0L), mixed thoroughly, and then potassium carbonate powder (1.73kg, 12.54mol) was added; the cooling circulation system of the condenser was turned on, the reflux valve on the condenser was opened, the temperature was raised to 73°C for reaction for 6h, the temperature was lowered to 55°C, 55°C hot water (18.0L) was added dropwise to the reaction system, the mixture was allowed to stand for stratification, the aqueous phase was removed, and the operation of adding 55°C hot water for washing and then separating the liquids was repeated twice. The temperature was lowered to 48°C, and seed crystals of the intermediate product M2 were added. The system temperature was maintained at 48°C and stirred for crystallization for 1.0 h. The temperature was further lowered to 0°C, and stirred for crystallization for 2.0 h. The intermediate product M2 was obtained by filtering to dryness as a yellow needle-shaped solid, a total of 4.21 kg.

[0112] The yield of this step was 91.61%, and the HPLC purity of the intermediate product M2 was 100%.

[0113] (3) The intermediate product M3 is prepared by hydrogenation and pressure reaction, as follows:

[0114] The intermediate product M2 (3.0 kg, 8.19 mol) obtained in step (2), wet palladium carbon ((Pd: 10%, water: 56.77%); 116 g, 3.9 wt%) and THF (30.0 L) were added to a 100 L autoclave in sequence. After the addition, the autoclave was sealed. The autoclave was replaced with nitrogen three times, and then replaced with hydrogen three times. After that, hydrogen was introduced into the autoclave, and the hydrogen pressure was maintained at 0.9 ± 0.1 MPa. The reaction was stirred at 30 ° C for 5.0 h, then cooled to 25 ° C and stirred for 0.5 h, and then cooled to 20 ° C and stirred for 0.5 h; the stirring was turned off, and the nitrogen was replaced three times; the autoclave was opened and the reaction solution was transferred out. The reaction solution was filtered through a Buchner funnel covered with diatomaceous earth (3000 g), and the filtrate was collected; the filter cake was rinsed twice with THF, each time using 3000 ml of THF, the rinse liquid was collected and combined with the filtrate to finally obtain a THF solution of the intermediate product M3, which was directly used in the next reaction. Calculated based on a 100% yield, the THF solution of the intermediate product M3 contained a total of 8.19 mol of the intermediate product M3.

[0115] (4) The intermediate product M4 is prepared by cyclization reaction, as follows:

[0116] The THF solution of the intermediate product M3 obtained in step (3) (containing a total of 2.67 kg, 7.89 mol of the intermediate product M3) was measured and added to a 100L high and low temperature jacketed reactor at one time, stirring was turned on, and the temperature was raised to 33°C. 4-trifluoromethoxyphenyl isothiocyanate (1.68 kg, 7.65 mol) was weighed and THF (13.5 L) was added thereto for dilution to obtain a THF solution of 4-trifluoromethoxyphenyl isothiocyanate. The internal temperature of the high and low temperature jacketed reactor was controlled to be 35°C, and the THF solution of 4-trifluoromethoxyphenyl isothiocyanate was added dropwise to the high and low temperature jacketed reactor; after the addition was completed, the internal temperature was maintained at 35°C and the reaction was performed for 2 hours to obtain an intermediate state. Samples were taken and retained for use in the subsequent reaction process by TLC analysis to monitor whether there was an intermediate state remaining in the product. Then EDCI (3.02 kg, 15.78 mol) was added to the reaction system at one time, the temperature was raised to 60°C, and the reaction was stirred for 12 hours.

[0117] Continue to purify in the above-mentioned 100L high and low temperature jacketed kettle, first control the internal temperature to 45°C, concentrate under reduced pressure until no liquid drips, then cool the reaction system to 25°C, alternately add methyl tert-butyl ether (29.0L) and water (29.0L, 11V), wherein the amount of methyl tert-butyl ether and water added each time is 4 to 5L respectively. After stirring and dissolving, let stand for 25 minutes, and separate the lower aqueous phase. Add water (29.0L) to the organic phase, stir for 15 minutes, let stand for 25 minutes, separate the lower aqueous phase, and repeat the operation of adding water (29.0L) to wash and separate the liquid once. Turn on stirring, control the internal temperature to 25°C, add 0.2M hydrochloric acid solution (29.0L), stir for 10 minutes, let stand for 35 minutes, and separate the lower aqueous phase. Water (29.0 L) was added to the organic phase, stirred for 10 min, allowed to stand for 35 min, the lower aqueous phase was removed by separation, and the operation of adding water (29.0 L) for washing and separation was repeated once.

[0118] Control the internal temperature at 25°C, add 0.2M sodium bicarbonate aqueous solution (29.0L), stir for 10min, let stand for 20min, separate and remove the lower aqueous phase. Add water (29.0L) to the organic phase, stir for 10min, let stand for 20min, separate and remove the lower aqueous phase, and repeat the operation of adding water (29.0L) for washing and separation once. Control the external temperature at 30°C, and concentrate under reduced pressure until no liquid drips; then add anhydrous ethanol (25.0L), control the external temperature at 40°C, and concentrate under reduced pressure until no liquid drips. Turn off the vacuum, add 95% ethanol (25.0L) to the 100L high and low temperature jacketed kettle, dissolve the oil and then cool to 25°C to obtain a 95% ethanol solution of the intermediate product M4 for standby use.

[0119] Add water (360.0L) to a 500L reactor, cool to 10°C, set the stirring speed to 180 rpm; slowly drop the obtained 95% ethanol solution of the intermediate product M4 into 10°C water to precipitate a white solid; continue stirring for 20 minutes after the dropwise addition is complete, and then filter. The obtained filter cake is concentrated under reduced pressure at 25°C to a constant weight to obtain the intermediate product M4, which is a light yellow solid, a total of 3.6kg.

[0120] The yield of this step is 87.16%, and the HPLC purity of the intermediate product M4 is greater than 97%.

[0121] (5) The crude product of KY100001 was prepared by hydrolysis reaction as follows:

[0122] Take the intermediate product M4 (2.0kg, 3.82mol) obtained in step (4) and dissolve it in ethanol (20.0L). At room temperature, add an aqueous solution of sodium hydroxide (obtained by dissolving 305.6g of sodium hydroxide, 7.64mol in 4.0L of water) dropwise to the above solution, maintain room temperature and stir for 5.0h; control the system temperature to 25°C, slowly add 1M hydrochloric acid aqueous solution, adjust the pH value to 6, maintain the internal temperature at 25°C after the addition is complete, and stir for 2.0h. Filter, stir and beat the filter cake with a mixed solution of ethanol and isopropyl acetate (volume ratio of 1:2, 6.0L) at 45°C for 1.0h, then cool to 10°C and stir for 2.0h, and filter to obtain the crude product of KY100001, which is a light yellow solid, a total of 1.71kg.

[0123] The yield of this step was 90.34%, and the HPLC purity of the crude KY100001 was 100%.

[0124] (6) Preparation of KY100001 of crystal form B, specifically as follows:

[0125] The crude KY100001 obtained in step (5) (1.0 kg, 2.96 mol), DMSO (1.0 L) and ethanol (2.0 L) were added to a 30 L glass reactor, stirred and heated to 70 ° C until the solid was completely dissolved, filtered while hot to remove insoluble matter, the filtrate was collected in the reactor, and heated again until the solid was completely dissolved; the system temperature was controlled to 75 ° C, ethanol (2.0 L) was added dropwise to the system, and the system was kept clear. The temperature was slowly lowered to 70 ° C, the seed crystal of the B crystal form KY100001 was added to the system, and the system temperature was maintained at 65 ° C and stirred for crystallization for 2.0 h, and then a mixed solution of ethanol and water (volume ratio of 2: 1, 10.0 L) was added dropwise to the system, and the temperature was lowered to 20 ° C and stirred for crystallization for 2.0 h; after filtration and drying, the B crystal form IDH1 mutant inhibitor KY100001 was obtained as an off-white solid, a total of 0.98 kg.

[0126] The yield of this step was 98%, and the HPLC purity of the obtained KY100001 was 100%.

[0127] Example 2

[0128] In this example, the preparation of the B-type IDH1 mutant inhibitor KY100001 was carried out according to the following steps, wherein the room temperature was 25-35°C.

[0129] (1) The intermediate product M1 is prepared by HWE reaction as follows:

[0130] Add solvent THF (30ml), 3-nitro-4-fluorobenzaldehyde (10.0g, 0.059mol) and triethyl phosphoacetate (13.9g, 0.062mol) to a three-necked flask, mix thoroughly, and then drop an aqueous solution of potassium carbonate (obtained by dissolving 16.4g of potassium carbonate, 0.118mol in 30ml of water). During the dropwise addition, control the temperature of the reaction liquid to be 25±10°C. After the dropwise addition is completed, heat to 60°C and stir to react for 5.0h, then cool to 48°C, add water (70ml) to the reaction system, cool to room temperature, and maintain stirring at room temperature for 2.0h, filter to dryness to obtain the crude intermediate product M1. The crude product is slurried with ethanol (60ml) at room temperature for 0.5h, and filtered to obtain the intermediate product M1, which is a light yellow needle-shaped solid, a total of 13.153g.

[0131] The yield of this step was 93.0%, and the HPLC purity of the intermediate product M1 was 99.9%.

[0132] (2) The intermediate product M2 is prepared by substitution reaction, as follows:

[0133] In a three-necked flask, add the intermediate product M1 (10.0 g, 0.042 mol) obtained in step (1) and (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine (6.46 g, 0.0439 mol), dissolve in isopropyl acetate (60 mL), mix thoroughly, and then add potassium carbonate powder (5.78 g, 0.042 mol); heat to 72 ° C for 6 h, cool to 55 ° C, add 55 ° C hot water (60 mL) to the reaction system, let stand for stratification, remove the aqueous phase, and repeat the operation of adding 55 ° C hot water for washing and then separating the liquids twice. Cool to 46 ° C, add the seed crystal of the intermediate product M2, maintain the system temperature at 46 ° C, stir and crystallize for 1.0 h, continue to cool to 0 ° C, stir and crystallize for 2.0 h; filter to dryness to obtain the intermediate product M2, which is a yellow needle-shaped solid, a total of 13.969 g.

[0134] The yield of this step was 91.12%, and the HPLC purity of the intermediate product M2 was 100%.

[0135] (3) The intermediate product M3 is prepared by hydrogenation and pressure reaction, as follows:

[0136] The intermediate product M2 (10.0 g, 0.027 mol) obtained in step (2), wet palladium carbon ((Pd: 10%, water: 56.77%); 0.25 g, 2.5 wt%) and THF (100 mL) were added to the autoclave in sequence. After the addition, the autoclave was sealed. The autoclave was replaced with nitrogen three times, and then replaced with hydrogen three times. After that, hydrogen was introduced into the autoclave, and the hydrogen pressure was maintained at 0.9±0.1 MPa. The reaction was stirred at 30°C for 6.0 h, and then the temperature was slowly lowered to 20°C and stirred for 0.5 h. The stirring was turned off, and the nitrogen was replaced three times; the autoclave was opened and the reaction liquid was transferred out. The reaction solution was filtered through a Buchner funnel covered with diatomaceous earth (50 g), and the filtrate was collected; the filter cake was rinsed twice with THF, each time using 100 mL of THF, the eluate was collected and combined with the filtrate, and finally a THF solution of the intermediate product M3 was obtained, wherein the HPLC purity of the intermediate product M3 was 98.87%, which was directly used in the next reaction. Calculated according to a yield of 100%, the THF solution of the intermediate product M3 contained a total of 0.027 mol of the intermediate product M3.

[0137] (4) The intermediate product M4 is prepared by cyclization reaction, as follows:

[0138] The THF solution of the intermediate product M3 obtained in step (3) (containing a total of 9.23g of the intermediate product M3, 0.027mol) was added to a 500mL three-necked flask at one time, stirred, and heated to 30°C. Weigh 4-trifluoromethoxyphenyl isothiocyanate (5.8g, 0.0268mol), add THF (60mL) to dilute it, and obtain a THF solution of 4-trifluoromethoxyphenyl isothiocyanate. Control the internal temperature at 35°C, and add the THF solution of 4-trifluoromethoxyphenyl isothiocyanate dropwise to the three-necked flask; after the addition is complete, maintain the internal temperature at 35°C, and react for 2 hours to obtain an intermediate state. Take a sample and keep it. Then add EDCI (10.46g, 0.055mol) to the reaction system at one time, heat it to 65°C, and stir the reaction for 10h.

[0139] Continue to carry out purification treatment in the above three-necked flask, first control the internal temperature to 45°C, concentrate under reduced pressure until no liquid drips, then cool the reaction system to room temperature, alternately add methyl tert-butyl ether (90mL) and water (90mL, 10V), wherein the amount of methyl tert-butyl ether and water added each time is 13-15mL respectively. After stirring and dissolving, let it stand for 30min, and separate the lower aqueous phase. Add water (90mL) to the organic phase, stir for 20min, let it stand for 30min, separate the lower aqueous phase, and repeat the operation of adding water (90mL) to wash and separate the liquid once. Turn on stirring, control the internal temperature to 25°C, add 0.2M hydrochloric acid solution (90mL), stir for 15min, let it stand for 35min, separate the lower aqueous phase. Add water (90mL) to the organic phase, stir for 20min, let it stand for 35min, separate the lower aqueous phase, and repeat the operation of adding water (90mL) to wash and separate the liquid once.

[0140] Control the internal temperature at 25°C, add 0.2M sodium bicarbonate aqueous solution (90mL), stir for 15min, let stand for 30min, separate and remove the lower aqueous phase. Add water (90mL) to the organic phase, stir for 15min, let stand for 30min, separate and remove the lower aqueous phase, and repeat the operation of adding water (90mL) for washing and separation. Control the external temperature at 35°C, and concentrate under reduced pressure until no liquid drips; then add anhydrous ethanol (83mL, 9V), control the external temperature at 45°C, and concentrate under reduced pressure until no liquid drips. Turn off the vacuum, add 95% ethanol (83mL) to the three-necked flask, dissolve the oil and then cool to 10°C to obtain a 95% ethanol solution of the intermediate product M4 for standby use.

[0141] Add water (550mL, 60V) to a 1000mL three-necked flask, cool to 5°C, set the stirring speed to ≥150 rpm; slowly drop the obtained 95% ethanol solution of the intermediate product M4 into 5°C water to precipitate a white solid; continue stirring for 20 minutes after the dropwise addition is complete, and then filter. The obtained filter cake is concentrated under reduced pressure at 30°C to a constant weight to obtain the intermediate product M4, which is a light yellow solid, a total of 12.738g.

[0142] The yield of this step is 89.21%, and the HPLC purity of the intermediate product M4 is greater than 97%.

[0143] (5) The crude product of KY100001 was prepared by hydrolysis reaction as follows:

[0144] Take the intermediate product M4 (10g, 0.019mol) obtained in step (4) and dissolve it in ethanol (40mL). At room temperature, add an aqueous solution of sodium hydroxide (obtained by dissolving 1.5g of sodium hydroxide, 0.038mol in 20mL of water) dropwise to the above solution, maintain room temperature and stir for 5.0h; control the system temperature to 25°C, slowly add 1M hydrochloric acid aqueous solution, adjust the pH value to 6, maintain the internal temperature at 25°C after the addition, and stir for 2.0h. Filter, stir and beat the filter cake with a mixed solution of ethanol and isopropyl acetate (volume ratio of 1:2, 25mL) at 45°C for 1.0h, then cool to 10°C and stir for 2.0h, and filter to obtain the crude product of KY100001, which is a light yellow solid, totaling 8.830g.

[0145] The yield of this step was 93.23%, and the HPLC purity of the crude KY100001 was 99.97%.

[0146] (6) Preparation of KY100001 of crystal form B, specifically as follows:

[0147] The crude KY100001 obtained in step (5) (8.0 g, 0.0161 mol), DMSO (8 mL) and ethanol (16 mL) were added to a 100 mL three-necked flask, and the mixture was stirred and heated to 70°C until the solid was completely dissolved. The insoluble matter was removed by hot filtration, and the filtrate was collected in a three-necked flask, and heated again until the solid was completely dissolved. The system temperature was controlled to 75°C, and ethanol (16 mL) was added dropwise to the system, and the system was kept clear. The temperature was slowly lowered to 65°C, and the seed crystals of the B crystal form KY100001 were added to the system, and the system temperature was maintained at 65°C for stirring and crystallization for 2.0 h. A mixed solution of ethanol and water (volume ratio of 2:1, 40 mL) was then added dropwise to the system, and the temperature was lowered to 20°C for stirring and crystallization for 2.0 h. After filtration and drying, the B crystal form IDH1 mutant inhibitor KY100001 was obtained as an off-white solid, a total of 7.56 g.

[0148] The yield of this step was 94.50%, and the HPLC purity of the obtained KY100001 was 100%.

[0149] Example 3

[0150] In this example, the preparation of the B-type IDH1 mutant inhibitor KY100001 is carried out according to the following steps, wherein the room temperature is 25-35°C.

[0151] (1) The intermediate product M1 is prepared by HWE reaction as follows:

[0152] Solvent THF (1.5L), 3-nitro-4-fluorobenzaldehyde (500g, 2.958mol) and triethyl phosphoacetate (696.0g, 3.106mol) were added to a 10L glass reactor, mixed thoroughly, and then an aqueous solution of potassium carbonate (817.7g, 5.916mol of potassium carbonate was dissolved in 1.5L of water) was added dropwise, and the temperature of the reaction liquid was controlled to be 25±10°C during the addition. After the addition was completed, the temperature was raised to 55°C and stirred for 6.0h, then cooled to 48°C, water (4.5L) was added dropwise to the reaction system, and then cooled to room temperature, and stirred at room temperature for 2.0h, and filtered to dryness to obtain the crude intermediate product M1. The crude product was slurried in ethanol (3.5L) at room temperature for 0.5h, and the intermediate product M1 was obtained by suction filtration, which was a light yellow needle-shaped solid, a total of 667.06g.

[0153] The yield of this step was 94.33%, and the HPLC purity of the intermediate product M1 was 100%.

[0154] (2) The intermediate product M2 is prepared by substitution reaction, as follows:

[0155] In a 10L glass reactor, add the intermediate product M1 (500g, 2.092mol) obtained in step (1) and (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine (323.0g, 2.196mol), dissolve in isopropyl acetate (3.0L), mix thoroughly, and then add potassium carbonate powder (289.1g, 2.092mol); heat to 75°C for reaction for 6h, cool to 60°C, drop 60°C hot water (3.0L) into the reaction system, let stand for stratification, remove the aqueous phase, repeat the operation of adding 60°C hot water for washing and then separating the liquids twice. Cool to 45°C, add seed crystals of the intermediate product M2, maintain the system temperature at 45°C and stir for crystallization for 1.0h, continue to cool to 5°C, stir for crystallization for 2.0h; filter to dryness to obtain the intermediate product M2, which is a yellow needle-shaped solid, a total of 690.02g.

[0156] The yield of this step was 90.10%, and the HPLC purity of the intermediate product M2 was 100%.

[0157] (3) The intermediate product M3 is prepared by hydrogenation and pressure reaction, as follows:

[0158] The intermediate product M2 (100 g, 0.273 mol) obtained in step (2), wet palladium carbon ((Pd: 10%, water: 56.77%); 2.5 g, 2.5 wt%) and THF (1000 mL) were added to a 3 L autoclave in sequence. After the addition, the autoclave was sealed. The autoclave was replaced with nitrogen three times, and then replaced with hydrogen three times. After that, hydrogen was introduced into the autoclave, and the hydrogen pressure was maintained at 0.9 ± 0.1 MPa. The reaction was stirred at 30 ° C for 6 h, and then the temperature was slowly lowered to 20 ° C and stirred for 0.5 h. The stirring was turned off, and the nitrogen was replaced three times; the autoclave was opened and the reaction liquid was transferred out. The reaction solution was filtered through a Buchner funnel covered with diatomaceous earth (500 g), and the filtrate was collected; the filter cake was rinsed twice with THF, each time using 1000 mL of THF, the eluate was collected and combined with the filtrate to finally obtain a THF solution of the intermediate product M3, which was directly used in the next reaction. Calculated based on a 100% yield, the THF solution of the intermediate product M3 contained a total of 0.273 mol of the intermediate product M3.

[0159] (4) The intermediate product M4 is prepared by cyclization reaction, as follows:

[0160] The THF solution of the intermediate product M3 obtained in step (3) (containing a total of 92.3g of the intermediate product M3, 0.273mol) was added to a 10L glass reactor at one time, stirred, and heated to 35°C. Weigh 4-trifluoromethoxyphenyl isothiocyanate (57.9g, 0.265mol), add THF (600mL) to dilute it, and obtain a THF solution of 4-trifluoromethoxyphenyl isothiocyanate. Control the internal temperature at 35°C, and drop the THF solution of 4-trifluoromethoxyphenyl isothiocyanate into a three-necked flask; after the addition is complete, keep the internal temperature at 35°C, and react for 2 hours to obtain an intermediate state. Take a sample and keep it. Then add EDCI (104.6g, 0.546mol) to the reaction system at one time, heat it to 60°C, and stir the reaction for 12h.

[0161] Continue to carry out purification treatment in the glass reactor, first control the internal temperature to 45°C, concentrate under reduced pressure until no liquid drips, then cool to room temperature, alternately add methyl tert-butyl ether (920mL) and water (920mL, 10V), wherein the amount of methyl tert-butyl ether and water added each time is 130-160mL respectively. After stirring and dissolving, let it stand for 20min, and separate the lower aqueous phase. Add water (920mL) to the organic phase, stir for 15min, let it stand for 20min, separate the lower aqueous phase, and repeat the operation of adding water (920mL) to wash and separate the liquid once. Turn on the stirring, control the internal temperature to 25°C, add 0.2M hydrochloric acid solution (920mL), stir for 10min, let it stand for 35min, separate the lower aqueous phase. Add water (920mL) to the organic phase, stir for 10min, let it stand for 35min, separate the lower aqueous phase, and repeat the operation of adding water (920mL) to wash and separate the liquid once.

[0162] Control the internal temperature at 25°C, add 0.2M sodium bicarbonate aqueous solution (920mL), stir for 15min, let stand for 20min, separate and remove the lower aqueous phase. Add water (920mL) to the organic phase, stir for 15min, let stand for 20min, separate and remove the lower aqueous phase, and repeat the operation of adding water (920mL) for washing and separation once. Control the external temperature at 35°C, and concentrate under reduced pressure until no liquid drips; then add anhydrous ethanol (830mL, 9V), control the external temperature at 45°C, and concentrate under reduced pressure until no liquid drips. Turn off the vacuum, add 95% ethanol (830mL) to the 10L glass reactor, dissolve the oil and cool to 15°C to obtain a 95% ethanol solution of the intermediate product M4 for standby use.

[0163] Add water (4.6L, ​​50V) to another 10L glass reactor, cool to 5°C, set the stirring speed ≥ 250 rpm; slowly drop the obtained 95% ethanol solution of the intermediate product M4 into 5°C water to precipitate a white solid; continue stirring for 10 minutes after the dropwise addition is complete, and then filter. The obtained filter cake is concentrated under reduced pressure at 25°C to a constant weight to obtain the intermediate product M4, which is a light yellow solid, a total of 125.99g.

[0164] The yield of this step is 88.23%, and the HPLC purity of the intermediate product M4 is greater than 97%.

[0165] (5) The crude product of KY100001 was prepared by hydrolysis reaction as follows:

[0166] Take the intermediate product M4 (120g, 0.229mol) obtained in step (4) and dissolve it in ethanol (480mL). At room temperature, add an aqueous solution of sodium hydroxide (obtained by dissolving 18.3g of sodium hydroxide, 0.459mol in 240mL of water) dropwise to the above solution, maintain room temperature and stir for 5.0h; control the system temperature to 25°C, slowly add 1M hydrochloric acid aqueous solution, adjust the pH value to 6, maintain the internal temperature at 25°C after the addition is complete, and stir for 2.0h. Filter, stir and slurry the filter cake with a mixed solution of ethanol and isopropyl acetate (volume ratio of 1:2, 360mL) at 45°C for 1.0h, then cool to 15°C and stir for 2.0h, and filter to obtain the crude product of KY100001, which is a light yellow solid, a total of 108.44g.

[0167] The yield of this step was 95.42%, and the HPLC purity of the crude KY100001 was 99.96%.

[0168] (6) Preparation of KY100001 of crystal form B, specifically as follows:

[0169] The crude KY100001 obtained in step (5) (100 g, 0.202 mol), DMSO (100 mL) and ethanol (200 mL) were added to a 2000 mL three-necked flask, and the mixture was stirred and heated to 70°C until the solid was completely dissolved. The insoluble matter was removed by hot filtration, and the filtrate was collected in a three-necked flask, and heated again until the solid was completely dissolved; the system temperature was controlled to 75°C, and ethanol (200 mL) was added dropwise to the system, and the system was kept clear. The temperature was slowly lowered to 70°C, and the seed crystals of the B crystal form KY100001 were added to the system, and the system temperature was maintained at 70°C for stirring and crystallization for 2.0 h, and then a mixed solution of ethanol and water (volume ratio of 2:1, 500 mL) was added dropwise to the system, and the temperature was lowered to 20°C for stirring and crystallization for 2.0 h; after filtration and drying, the B crystal form IDH1 mutant inhibitor KY100001 was obtained as an off-white solid, a total of 96.75 g.

[0170] The yield of this step was 96.75%, and the HPLC purity of the obtained KY100001 was 99.97%.

[0171] Comparative Example 1

[0172] In this comparative example, the preparation method described in Example 1 and Example 4 in the patent document with publication number TW202128153A was used to prepare the B-type KY100001.

[0173] According to the test, the yield of the intermediate product M1 prepared by the HWE reaction was 86.22%, and the HPLC purity of the intermediate product M1 was 94.89%.

[0174] The yield of the intermediate product M2 prepared by the substitution reaction was 75.10%, and the HPLC purity of the intermediate product M2 was 97.56%.

[0175] The yield of the crude KY100001 prepared by the hydrolysis reaction was 78.43%, and the HPLC purity of the obtained crude KY100001 was 97.01%.

[0176] The final crystallization yield was 74.99%, and the target product, i.e., crystalline form B of KY100001, had an HPLC purity of 97.86%.

[0177] By comparing this comparative example with Example 1, it can be seen that the scheme of Example 1 significantly improves the yield of each reaction step, and the purity of the reaction product of each step is also higher than that in this comparative example. It shows that the preparation method of the present invention can improve the yield of each step in the reaction process, thereby improving the yield of the target product, and can produce KY100001 with higher purity.

[0178] Comparative Example 2

[0179] In this comparative example, an intermediate product M3 is prepared according to steps (1) to (3) in Example 3, and the intermediate product M3 is further used to prepare a crude product of KY100001, wherein the difference from step (4) in Example 3 is that no purification treatment is performed. Specifically, the steps after step (3) are as follows:

[0180] (4) Add the THF solution of the intermediate product M3 obtained in step (3) (calculated based on the yield of the previous step of 100%, wherein the intermediate product M3 obtained in step (3) is 92.3 g, 0.273 mol) into a 10L glass reactor at one time, start stirring, and heat to 35°C. Weigh 4-trifluoromethoxyphenyl isothiocyanate (57.9 g, 0.265 mol), add THF (600 mL) to dilute it, and obtain a THF solution of 4-trifluoromethoxyphenyl isothiocyanate. Control the internal temperature at 35°C, and add the THF solution of 4-trifluoromethoxyphenyl isothiocyanate dropwise into the three-necked flask; after the addition is completed, keep the internal temperature at 35°C and react for 2 hours to obtain the intermediate state. Then, EDCI (104.6 g, 0.546 mol) was added to the reaction system at once, the temperature was raised to 60° C., and the reaction was stirred for 12 h. EDCI was removed by filtration to obtain a THF solution of the intermediate product M4. Based on a yield of 100%, a total of 142.8 g (0.273 mol) of the intermediate product M4 was obtained.

[0181] (5) The THF solution of the intermediate product M4 obtained in step (4) (containing a total of 142.8 g, 0.273 mol of the intermediate product M4) was added to a 10L glass reactor at once, and an aqueous solution of sodium hydroxide (obtained by dissolving 21.8 g, 0.546 mol of sodium hydroxide in 290 mL of water) was added dropwise to the above solution at room temperature, and the reaction was maintained at room temperature and stirred for 5.0 h; the system temperature was controlled to 25°C, and a 1M hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH value to 6. After the addition was completed, the internal temperature was maintained at 25°C and stirred for 2.0 h. Filter to obtain a crude product of KY100001, which was a light yellow solid, with a total of 110.18 g.

[0182] It was calculated that, without purifying the intermediate product M4 in step (4), the yield of the hydrolysis reaction in step (5) was only 81.53%, which was significantly lower than the yield of step (5) in Example 3. It was tested that the purity of the crude KY100001 obtained was 92.21%, which was significantly lower than the purity of the crude KY100001 obtained in step (5) in Example 3. It can be seen that the step (4) of the preparation method of the present invention adds the operation of purifying the intermediate product M4, which effectively improves the subsequent reaction yield and product purity.

[0183] Test Example 1

[0184] This test example refers to step (1) in Example 1 to prepare the intermediate product M1, only the reaction temperature is changed, and the other operation steps and process parameters are kept the same. The intermediate product M1 obtained is tested, and the results are shown in Table 1 below.

[0185] Table 1

[0186] Reaction temperature (℃) Yield (%) HPLC purity (%) 20 50.2 52.4 30 60.3 64.4 50 83.0 85.6 55 90.33 99.91 60 91.6 100.0

[0187] It can be seen from the above test data that the reaction temperature in step (1) is controlled at 50-60°C, the reaction yield can reach more than 80%, and the HPLC purity of the obtained intermediate product can reach more than 85%. Further increasing the reaction temperature to 55-60°C can achieve a yield higher than 90%, and an HPLC purity close to 100%. Therefore, in the preparation method of the present invention, the reaction temperature in step (1) is controlled at 50-60°C, preferably controlled at 55-60°C.

[0188] Test Example 2

[0189] This test example refers to steps (1) to (3) in Example 3 to prepare the intermediate product M3, only the amount of wet palladium carbon added in step (3) is changed, and the other operating steps and process parameters are kept the same. The obtained intermediate product M3 is tested, and the results are shown in Table 2 below.

[0190] Table 2

[0191] Wet palladium carbon dosage (g) Palladium carbon mass relative to M2 ratio (wt%) HPLC purity (%) 2.5 2.5 98.8 3.0 3.0 98.4 4.0 4.0 97.4 5.0 5.0 96.1 7.5 7.5 95.7 8.0 8.0 92.5 10.0 10.0 74.6

[0192] As can be seen from the above test data, the amount of wet palladium carbon in step (3) is controlled to 2.5% to 7.5% of the mass of the intermediate product M2, and the HPLC purity of the intermediate product M3 obtained can reach more than 95%. The amount of wet palladium carbon is further controlled to be 2.5% to 3.0% of the mass of the intermediate product M2, and the HPLC purity of the intermediate product M3 can be further improved to higher than 98%. Therefore, in the preparation method of the present invention, the amount of wet palladium carbon in step (3) is controlled to be 2.5% to 7.5% of the mass of the intermediate product M2, preferably controlled to be 2.5% to 3.0% of the mass of the intermediate product M2.

[0193] Test Example 3

[0194] This test example refers to steps (1) to (3) in Example 1 to prepare the intermediate product M3, only the hydrogen pressure in step (3) is changed, and the other operating steps and process parameters are kept the same. The obtained intermediate product M3 is tested, and the results are shown in Table 3 below.

[0195] Table 3

[0196] Hydrogen pressure (MPa) HPLC purity (%) 0.3 72.3 0.5 97.1 0.8 98.0 1.0 97.6 2.0 95.3 2.8 91.1

[0197] It can be seen from the above test data that the HPLC purity of the intermediate product M3 obtained by controlling the hydrogen pressure in step (3) to 0.5-1.0 MPa can reach more than 97%. Further controlling the hydrogen pressure to 0.8-1.0 MPa, the HPLC purity of the intermediate product M3 can be further increased to higher than 97.5%. Therefore, in the preparation method of the present invention, the hydrogen pressure in step (3) is controlled to 0.5-1.0 MPa, preferably 0.8-1.0 MPa.

[0198] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. A method for preparing an IDH1 mutant inhibitor, characterized in that: The following steps are involved: (1) mixing 3-nitro-4-fluorobenzaldehyde and triethyl phosphoacetate in a solvent system, and performing HWE reaction under the condition of adding a catalyst, filtering to obtain a crude product of (E)-3-nitro-4-fluorophenyl-ethyl acrylate; adding a solvent to the crude product of (E)-3-nitro-4-fluorophenyl-ethyl acrylate for slurrying, and then filtering to obtain (E)-3-nitro-4-fluorophenyl-ethyl acrylate; (2) dissolving the (E)-3-nitro-4-fluorophenyl-ethyl acrylate obtained in step (1) and (R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine in a solvent, carrying out a substitution reaction under alkaline and heating conditions, quenching with hot water, adding seed crystals after cooling, and continuing to cool to 0-5° C. for crystallization, and then filtering to obtain (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate; (3) the (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate obtained in step (2) is subjected to a hydrogenation pressure reaction in a solvent system using palladium-carbon as a catalyst to obtain (R,E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate; (4) the (R,E)-3-(3-amino-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate obtained in step (3) is subjected to a cyclization reaction with 4-trifluoromethoxyphenyl isothiocyanate and a condensation reagent in a solvent system to obtain (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propionic acid ethyl ester; (5) the (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid ethyl ester obtained in step (4) is subjected to a hydrolysis reaction in a solvent system in the presence of an alkaline reagent to obtain (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid; (6) The (R)-3-(1-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid obtained in step (5) is dissolved in a solvent under heating conditions, and the insoluble matter is removed by filtration; then, the solid is heated again until it is completely dissolved, the temperature is lowered to 60 to 70° C., a crystal seed of Form B is added, and the temperature is maintained at 60 to 70° C. for crystallization, and then a mixed solution of ethanol and water is added, the temperature is lowered to 20 to 30° C. and the temperature is maintained for stirring and crystallization; after filtration and drying, Form B of (R)-3-(1-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid is obtained.

2. The method for preparing the IDH1 mutant inhibitor according to claim 1, characterized in that: In step (1), the solvent added when the crude product is pulped is at least one of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate and butyl acetate; Preferably, beating at 25-35° C. for 0.5-1.0 h; Preferably, the ratio between the mass of the 3-nitro-4-fluorobenzaldehyde and the volume of the pulping solvent is 1 kg:5-7L.

3. The method for preparing an IDH1 mutant inhibitor according to claim 1 or 2, characterized in that: In step (1), the reaction temperature of the HWE reaction is 50-60° C., and the reaction time is 5-10 h; Preferably, the reaction temperature is 55-60° C. and the reaction time is 5-6 h.

4. The method for preparing an IDH1 mutant inhibitor according to any one of claims 1 to 3, characterized in that: In step (2), hot water at a temperature of 50 to 60° C. is added for quenching; Preferably, the substitution reaction is carried out at 70-75°C for 5-6 hours, then cooled to 55-60°C, and then hot water at 50-60°C is added; More preferably, after adding hot water, the mixture is allowed to stand for separation, and then the aqueous phase is removed by separation, while the organic phase is retained; the process of adding hot water and then separating the liquids is repeated at least three times, preferably three times.

5. The method for preparing an IDH1 mutant inhibitor according to any one of claims 1 to 4, characterized in that: In step (2), seed crystals are added when the system temperature drops to 40-50°C, preferably at 45-48°C; Preferably, after adding the seed crystals, the temperature is maintained for crystallization for 1.0 to 1.5 hours, and then the temperature is lowered to 0 to 5° C. for crystallization for 2.0 to 2.5 hours, and (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-acrylate is obtained by suction filtration.

6. The method for preparing an IDH1 mutant inhibitor according to any one of claims 1 to 5, characterized in that: In step (3), wet palladium carbon is added as a catalyst, and the mass ratio of the (R,E)-3-(3-nitro-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenyl)-ethyl acrylate to wet palladium carbon is 1.0:0.025-0.075, preferably 1.0:0.025-0.030; The reaction temperature of the hydrogenation pressure reaction is 20-35°C, the pressure is 0.5-1.0MPa, and the reaction time is 4-10h; Preferably, the reaction temperature is 25-30° C., the pressure is 0.8-1.0 MPa, and the reaction time is 4-6 h.

7. The method for preparing the IDH1 mutant inhibitor according to claim 6, characterized in that: When conducting hydrogenation pressure reaction, maintain the pressure at 0.8-1.0 MPa, stir the reaction at 25-35°C for 4-8 hours, then cool to 20-30°C and stir for 0.5-1.0 hour to terminate the reaction; Preferably, the temperature is first lowered to 25-30° C. and stirred for 0.5 h, and then lowered to 20-25° C. and stirred for 0.5 h to terminate the reaction.

8. The method for preparing an IDH1 mutant inhibitor according to any one of claims 1 to 7, characterized in that: In step (4), the reaction temperature of the cyclization reaction is 30 to 65° C. After the cyclization reaction is completed, a purification treatment is performed, including: a) performing reduced pressure concentration at 40-50° C. to remove the reaction solvent; b) cooling the reaction system to 20-30° C., adding methyl tert-butyl ether and water, stirring to dissolve, standing to separate, separating and removing the aqueous phase, and retaining the organic phase; c) adding water to the organic phase for washing, removing the aqueous phase by separation, and retaining the organic phase; d) adding a hydrochloric acid solution to the organic phase at 20 to 30° C., stirring, standing and separating the layers, removing the aqueous phase by separation, and retaining the organic phase; the concentration of the hydrochloric acid solution is preferably 0.1 to 0.2 M, more preferably 0.15 M; e) adding water to the organic phase for washing, removing the aqueous phase by separation, and retaining the organic phase; f) adding a sodium bicarbonate aqueous solution to the organic phase at 20 to 30° C., stirring, standing and separating the layers, removing the aqueous phase by separation, and retaining the organic phase; the concentration of the sodium bicarbonate aqueous solution is preferably 0.1 to 0.2 M, more preferably 0.15 M; g) adding water to the organic phase for washing, removing the aqueous phase by separation, and retaining the organic phase; h) the organic phase is concentrated under reduced pressure at 30-40° C.; i) adding anhydrous ethanol and continuing to concentrate under reduced pressure at 40-50° C.; j) adding 95% ethanol aqueous solution to dissolve the oily substance and then cooling to 10-25° C. to obtain an ethanol aqueous solution of the intermediate product; k) adding the ethanol aqueous solution of the intermediate product dropwise into water at 5 to 15° C. under stirring, continuing stirring after the addition is completed, and filtering to obtain a filter cake; l) The filter cake was concentrated under reduced pressure to a constant weight to obtain ethyl (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoate.

9. The method for preparing an IDH1 mutant inhibitor according to any one of claims 1 to 8, characterized in that: In step (5), after the hydrolysis reaction, the system is filtered to obtain a filter cake, the filter cake is slurried with a mixed solution of ethanol and isopropyl acetate, and then filtered again to obtain (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazole-5-yl)propionic acid; Preferably, the mixture is stirred and slurried at 45 to 50° C. for 1 to 1.5 hours, then cooled to 10 to 25° C. and stirred for 2 to 2.5 hours, and then filtered again; Preferably, in the mixed solution of ethanol and isopropyl acetate, the volume ratio of ethanol to isopropyl acetate is 1-2:2-3; Preferably, the ratio between the feed mass of the (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid ethyl ester and the volume of the mixed solution of ethanol and isopropyl acetate used for pulping is 1 kg:2.5 to 5.0 L.

10. The method for preparing an IDH1 mutant inhibitor according to any one of claims 1 to 9, characterized in that: In step (6), the temperature for heating and dissolving is 70-75° C., and the insoluble matter is removed by hot filtration; thereafter, the mixture is heated again until the solid is completely dissolved; Preferably, after heating again until the solid is completely dissolved, the temperature is controlled at 70-75° C., ethanol is added dropwise to the system, and the ratio between the mass of the desired (R)-3-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-((4-trifluoromethoxy)phenyl)amino)-1H-benzo[d]imidazol-5-yl)propanoic acid to the volume of ethanol is 1 kg:2.0-2.5 L, and then the temperature is lowered to 60-70° C. to add Form B seed crystals; More preferably, after adding the B crystal seed, the temperature is maintained at 60-70°C and the crystallization is stirred for 1.0-2.0 hours; after adding a mixed solution of ethanol and water and cooling to 10-30°C, the crystallization is continued by stirring for 2.0-3.0 hours.

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