Method for preparing CYP11a1 inhibitor

Abstract

Provided in the present invention is a method for preparing a CYP11A1 inhibitor (a compound of formula (E)). The method has readily available raw materials, simple steps, convenient post-treatment, low costs, high intermediate stability, and high purity and yield, and is suitable for large-scale industrial production.

Description

Preparation method of CYP11A1 inhibitor TECHNICAL FIELD

[0001] The present application relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of a CYP11A1 inhibitor, and belongs to the technical field of pharmaceutical chemistry. BACKGROUND

[0002] Prostate cancer has been the second most common tumor in men, second only to lung cancer, with about 1.4 million new cases and 370,000 deaths worldwide in 2020. Age is a known risk factor for prostate cancer. The incidence of prostate cancer is showing a significant upward trend, with an incidence of about 15.6 / 100,000 people in 2020, more than 110,000 new cases, and more than 50,000 deaths, which has become an important disease affecting the health of middle-aged and elderly men. Currently, only about 1 / 3 of newly diagnosed patients are clinically localized prostate cancer, and most are in the middle and late stages when discovered, with poor overall prognosis.

[0003] It is currently believed that the mechanism of prostate cancer is mainly related to androgens and the AR pathway. The AR signaling pathway is regulated by the hypothalamic-pituitary-gonadal axis. The hypothalamus produces luteinizing hormone (LH) releasing hormone (LHRH), which causes the anterior pituitary to produce luteinizing hormone, which stimulates the testes to produce androgens. In addition, the hypothalamus produces corticotropin-releasing hormone (CRH), which causes the anterior pituitary to produce adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce androgens. Androgens promote the maturation and translocation of AR to the nucleus, thereby binding to androgen response elements and stimulating the transcription of androgen-responsive genes, leading to the development and progression of prostate cancer.

[0004] Studies have shown that steroid hormones are one of the key factors driving prostate cancer, and cytochrome P450 11A1 (CYP11A1) is an important rate-limiting enzyme in the process of steroid synthesis, targeting CYP11A1 provides an effective means to inhibit the production of steroid hormones.

[0005] CYP11A1 is a mitochondrial enzyme that functions to catalyze the conversion of cholesterol to pregnenolone. After treatment with CYP17A1 inhibitors (abiraterone), patients have increased AR expression, increased proportion of AR mutations, increased levels of steroid hormones such as progesterone in the body, and increased affinity for mutant AR, further activating the AR pathway, which is speculated to be one of the mechanisms of resistance to abiraterone. By inhibiting the activity of CYP11A1 enzyme, the production of all steroid hormones and hormone precursors that can activate the AR signaling pathway can be inhibited, thereby treating prostate cancer.

[0006] MK-5684 (also known as ODM-208) is a potential "first-in-class" CYP11A1 specific oral non-steroidal inhibitor discovered and developed by Orion Corporation, which is developed for the treatment of hormone-dependent cancers such as prostate cancer. By inhibiting the activity of CYP11A1 enzyme, MK-5684 can inhibit the production of all steroid hormones and hormone precursors that can activate the androgen receptor (AR) signaling pathway. This is particularly relevant to patients with AR ligand binding domain (LBD) activating somatic point mutations, which is one of the mechanisms of resistance of mCRPC to hormone therapy.

[0007] ODM-208 has a significant effect on blocking the production of steroid hormones in mCRPC male patients previously treated with abiraterone / enzalutamide and taxanes. Good antitumor activity is observed in patients with specific AR mutations.

[0008] PCT / CN2024 / 083998 provides a CYP11A1 inhibitor, wherein the following formula (E) compound is described, which has excellent CYP11A1 inhibitory activity,

[0009] The preparation method of the above formula (E) compound described in the patent has the following disadvantages: many reaction conditions are not conducive to production scale-up, the stability of intermediates is poor, the purification is difficult, and the total yield is low; not only the cost is high, but also it is difficult to realize large-scale production. SUMMARY

[0010] The present application provides a preparation method of a compound of formula (A-2), comprising the following reaction:

[0011] wherein,

[0012] R1 is: OH, OTs or OTf,

[0013] R2 is: OTs, OTf, Cl, Br or I.

[0014] The present application provides a preparation method of a compound of formula (A-4), comprising the following reaction:

[0015] wherein, R3 is Cl, Br, I, OTs or OTf, and R4 is OTs or OTf.

[0016] The present application provides a preparation method of a compound of formula (A-6), comprising the following reaction:

[0017] wherein, R5 is Cl, Br, I or R6 is OTs or OTf.

[0018] The present application provides a preparation method of a compound of formula (A), which comprises the following reaction:

[0019] wherein R1 is OTs or OTf;

[0020] Optionally, in some embodiments, R1 is OTs, the reaction is carried out in the presence of p-toluenesulfonyl chloride; the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of N,N-diisopropylethylamine, triethylamine; the reaction solvent used in the reaction is selected from at least one of dichloromethane, n-heptane, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol methyl ether, acetonitrile, toluene, 1,2-dichloroethane, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably at least one of dichloromethane, toluene; the reaction temperature of the reaction is 10-40°C, preferably at room temperature.

[0021] Optionally, in some embodiments, R1 is OTf, the reaction is carried out in the presence of N-phenylbis(trifluoromethylsulfonyl)imide or trifluoromethanesulfonic anhydride, preferably in the presence of N-phenylbis(trifluoromethylsulfonyl)imide; the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of potassium carbonate, triethylamine; the reaction solvent used in the reaction is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, sulfolane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, preferably at least one of dimethyl sulfoxide, N,N-dimethylformamide; the reaction temperature of the reaction is -20-20°C, preferably 5±5°C.

[0022] The present application provides a preparation method of a compound of formula (A1c), which comprises the following reaction:

[0023] wherein, R0 is Cl, Br, I, OTs or OTf;

[0024] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, potassium carbonate, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, lithium acetate, potassium pivalate, sodium pivalate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably at least one of triethylamine, N,N-diisopropylethylamine;

[0025] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, preferably at least one of dimethyl sulfoxide, N,N-dimethylformamide;

[0026] Optionally, in some embodiments, the reaction of formula (A1a) to prepare formula (A1c) is carried out at a reaction temperature of 30-100°C, preferably 50±5°C.

[0027] The present application provides a preparation method of a compound of formula (A), which comprises the following reaction:

[0028] wherein, R1 is OTs or OTf, and R2 is OTs, OTf, Cl, Br or I;

[0029] Optionally, in some embodiments, R1 is OTs, R2 is Cl, Br or I, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of N,N-diisopropylethylamine, triethylamine; the reaction solvent used in the reaction is selected from at least one of dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, preferably at least one of dimethylsulfoxide, N,N-dimethylformamide; the reaction temperature of the reaction is 30-100°C, preferably 50±5°C.

[0030] Optionally, in some embodiments, R1, R2 are both OTs, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of N,N-diisopropylethylamine, triethylamine; the reaction solvent used in the reaction is selected from at least one of dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, preferably at least one of dimethylsulfoxide, N,N-dimethylformamide; the reaction temperature of the reaction is 30-100°C, preferably 50±5°C.

[0031] The present application provides a preparation method of a compound of formula (A2b), which comprises the following reaction:

[0032] wherein R1 is OTs or OTf, R2 is OTs, OTf, Cl, Br or I;

[0033] Optionally, in some embodiments, R1 is OTs, R2 is Cl, the reaction is carried out in the presence of p-toluenesulfonyl chloride; the reaction is carried out in the presence of a base selected from at least one of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of N,N-diisopropylethylamine, triethylamine; the reaction solvent used in the reaction is selected from at least one of dichloromethane, n-heptane, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol methyl ether, acetonitrile, toluene, 1,2-dichloroethane, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably at least one of dichloromethane, toluene; the reaction temperature of the reaction is 10-100°C, preferably 40±5°C;

[0034] Optionally, in some embodiments, R1, R2 are both OTs, the reaction is carried out in the presence of p-toluenesulfonic anhydride; the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of N,N-diisopropylethylamine, triethylamine; the reaction solvent used in the reaction is selected from at least one of dichloromethane, n-heptane, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol methyl ether, acetonitrile, toluene, 1,2-dichloroethane, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably at least one of dichloromethane, toluene; the reaction temperature of the reaction is 10-60°C, preferably 40±5°C.

[0035] The present application provides a preparation method of a compound of formula (A2b-2), which comprises the following reaction:

[0036] wherein R3 is Cl, Br or I, and R1 is OTs or OTf;

[0037] Optionally, in some embodiments, R3 is Cl, Br or I, R1 is OTs, the reaction is carried out in the presence of p-toluenesulfonyl chloride; the reaction is carried out in the presence of a base selected from at least one of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of N,N-diisopropylethylamine, triethylamine; the reaction solvent used in the reaction is selected from at least one of dichloromethane, n-heptane, 1,4-dioxane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol methyl ether, acetonitrile, toluene, 1,2-dichloroethane, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably at least one of dichloromethane, toluene; the reaction temperature of the reaction is 10-80°C, preferably 20±5°C.

[0038] The present application also provides a preparation method of a compound of formula (A), comprising the following steps:

[0039] wherein, R0 is Cl, Br, I, OTs or OTf, and R1 is OTs or OTf.

[0040] The present application also provides another preparation method of a compound of formula (A), comprising the following steps:

[0041] wherein, R1 is OTs or OTf, and R2 is OTs, OTf, Cl, Br or I.

[0042] The present application also provides another preparation method of a compound of formula (A), comprising the following steps:

[0043] wherein, R1 is OTs or OTf, and R3 is Cl, Br or I.

[0044] The present application also provides a preparation method of a compound of formula (B), comprising the following reaction:

[0045] wherein, the base is selected from at least one of triethylamine, 4-dimethylaminopyridine, pyridine, N,N-diisopropylethylamine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of triethylamine, 4-dimethylaminopyridine, pyridine.

[0046] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of hydrogen chloro zirconocene, copper bromide, copper chloride, copper sulfate, copper acetate, copper trifluoromethanesulfonate, (1,5-cyclooctadiene)chloro rhodium (I) dimer, (1,5-cyclooctadiene)chloro iridium (I) dimer, preferably at least one of hydrogen chloro zirconocene, copper trifluoromethanesulfonate.

[0047] Optionally, in some embodiments, the reaction is carried out at a temperature of 0-80°C, preferably 30±5°C.

[0048] The present application also provides a method for preparing a compound of formula (B), comprising the following reaction:

[0049] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of 2,2,6,6-tetramethylpiperidinyl lithium, lithium diisopropylamide, sodium amide, potassium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, phenyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, isopropylmagnesium chloride, preferably at least one of 2,2,6,6-tetramethylpiperidinyl lithium, lithium diisopropylamide.

[0050] Optionally, in some embodiments, the reaction is carried out in the presence of a boron reagent selected from at least one of bis[(pinacolato)boron]methane, 2,2'-methylenebis[5,5-dimethyl-1,3,2-dioxaborinane], bis(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)methane, preferably bis[(pinacolato)boron]methane.

[0051] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of tetrahydrofuran, n-heptane, n-hexane, diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, toluene, preferably at least one of tetrahydrofuran, cyclopentyl methyl ether.

[0052] Optionally, in some embodiments, the reaction is carried out at a temperature of -80 to -20°C, preferably -70 to -60°C. The present application also provides a method for preparing a compound of formula (C), comprising the following reaction:

[0053] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, lithium acetate, potassium pivalate, sodium pivalate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine, piperidine, 2,6-dimethylpyridine, imidazole, morpholine, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of potassium carbonate, potassium bicarbonate, potassium phosphate, potassium acetate;

[0054] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of bis-bis[(1,2,3)-1-phenyl-2-propenyl]dipalladium, NiCl2, NiCl2 diglyme, Ni(COD)2, Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd2(dba)3, Pd(TFA)2, Pd(MeCN)2Cl 2、 Pd(PhCN)2Cl2, PEPPSI-iPr, PdCl2[P(Cy)3]2, allylpalladium(II) chloride dimer, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, preferably at least one of allylpalladium(II) chloride dimer, bis-bis[(1,2,3)-1-phenyl-2-propenyl]dipalladium;

[0055] Optionally, in some embodiments, the reaction is carried out in the presence of a ligand selected from at least one of Ph3P, RuPhos, SPhos, DavePhos, XPhos, BrettPhos, XantPhos, Cy-cBRIDP, CataCixum PtB, dppf, dppb, Ad2nBuP, preferably at least one of XPhos, XantPhos, SPhos;

[0056] Optionally, in some embodiments, the reaction solvent employed in the reaction is selected from at least one of 2-methyltetrahydrofuran, water, methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, t-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl t-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, dithiane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably at least one of 2-methyltetrahydrofuran, 1,4-dioxane.

[0057] Optionally, in some embodiments, the reaction temperature of the reaction is 50-120 °C, preferably 65±5 °C. The present application also provides a method for preparing a compound of formula (D), comprising the following reaction:

[0058] wherein n is 1 or 2; X is selected from HCl, TsOH, MsOH, trifluoroacetic acid, phosphoric acid, sulfuric acid, ethanedisulfonic acid or camphorsulfonic acid;

[0059] Optionally, in some embodiments, the reaction is carried out in the presence of hydrochloric acid; the reaction solvent used in the reaction is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, water, methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, t-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl t-butyl ether, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, dithiane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, chloroform, preferably at least one of tetrahydrofuran, acetonitrile; the reaction temperature of the reaction is 10-80 °C, preferably 40±5 °C;

[0060] Optionally, in some embodiments, the reaction is carried out in the presence of p-toluenesulfonic acid; the reaction solvent used in the reaction is selected from at least one of isopropanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, n-butanol, t-butanol, t-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl t-butyl ether, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, dithiane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, chloroform, preferably at least one of tetrahydrofuran, isopropanol; the reaction temperature of the reaction is 10-80 °C, preferably 65±5 °C;

[0061] Optionally, in some embodiments, the reaction is carried out in the presence of methanesulfonic acid; the reaction solvent used in the reaction is selected from at least one of isopropanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, n-butanol, t-butanol, t-amyl alcohol, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl t-butyl ether, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, dimethyl sulfoxide, dithiane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, chloroform, preferably at least one of tetrahydrofuran isopropanol; the reaction temperature of the reaction is 10-100 °C, preferably 50±5 °C.

[0062] The present application also provides a method for preparing a compound of formula (E), comprising the following reaction:

[0063] wherein n is 1 or 2; X is selected from HCl, TsOH, MsOH, trifluoroacetic acid, phosphoric acid, sulfuric acid, ethanedisulfonic acid or camphorsulfonic acid;

[0064] Optionally, in some embodiments, the reaction is carried out in the presence of an activating agent selected from at least one of HOBt, DMAP, 4-PPY, HOAt, HOSu, NHPI, NHNI, preferably at least one of HOBt, DMAP;

[0065] Optionally, in some embodiments, the reaction is carried out in the presence of a condensing agent selected from at least one of EDCI, DCC, DIC, CDI, NDSC, EEDQ, IIDQ, BBDI, TCT, DMTMM, CDMT, PyBOP, PyBrOP, TBTU, HBTU, COMU, HATU, DPP-Cl, DECP, DPPA, MPTA, BOP-Cl, T3P, TCFH, preferably at least one of EDCI, HATU, T3P;

[0066] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, pyridine, piperidine, 2,6-dimethylpyridine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of triethylamine, N,N-diisopropylethylamine, pyridine;

[0067] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of tetrahydrofuran, acetonitrile, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, preferably at least one of tetrahydrofuran, acetonitrile;

[0068] Optionally, in some embodiments, X is HCI, the reaction solvent used in the reaction is selected from at least one of tetrahydrofuran, acetonitrile, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, preferably tetrahydrofuran, the reaction temperature of the reaction is 0-60°C, preferably 35±5°C;

[0069] Optionally, in some embodiments, X is HCI, the reaction solvent used in the reaction is selected from at least one of acetonitrile, tetrahydrofuran, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, preferably acetonitrile, the reaction temperature of the reaction is 0-80°C, preferably 25±5°C;

[0070] Optionally, in some embodiments, X is MsOH, the reaction solvent used in the reaction is selected from at least one of N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, acetone, 4-methyl-2-pentanone, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, preferably at least one of tetrahydrofuran, N,N-dimethylacetamide, the reaction temperature of the reaction is 0-100°C, preferably 15±5°C.

[0071] The present application also provides a preparation method of a compound of formula (F), comprising the following reaction:

[0072] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dimethylsulfoxide, acetone, isopropanol, water, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, tert-butyl alcohol, tert-amyl alcohol, ethyl acetate, isopropyl acetate, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, chloroform, trifluoroethanol, n-hexane, and a mixed solution of ethanol and water, preferably a mixed solution of ethanol and water or a mixed solution of acetone and dimethylsulfoxide;

[0073] Optionally, in some embodiments, the reaction temperature of the reaction is 20-100°C, preferably 45±5°C. The present application also provides a method for preparing a compound of formula (E), comprising the following steps:

[0074] wherein n is 1 or 2; X is selected from HCl, TsOH, MsOH, trifluoroacetic acid, phosphoric acid, sulfuric acid, ethanedisulfonic acid or camphorsulfonic acid.

[0075] The present application also provides a method for preparing a compound of formula (E), comprising the following steps:

[0076] wherein R1 is OTs or OTf; n is 1 or 2; X is selected from HCl, TsOH, MsOH, trifluoroacetic acid, phosphoric acid, sulfuric acid, ethanedisulfonic acid or camphorsulfonic acid.

[0077] The present application also provides a compound of formula (A1) or a salt thereof, and a compound of formula (D1), formula (D2), formula (D3):

[0078] Abbreviations and key terms of the present application:

[0079] Technical effects of the present application:

[0080] 1. The starting materials are easy to obtain, and the steps are simple. The entire synthesis process is purified by crystallization, without using silica gel column chromatography or other preparative chromatography methods, and the post-treatment is convenient.

[0081] 2. The intermediates have good stability, high purity, high yield, low preparation cost, and are suitable for large-scale industrial production. DETAILED DESCRIPTION

[0082] The present application is further described in detail below in conjunction with the examples, but is not limited thereto. Any equivalent replacement in the art according to the disclosure of the present application is within the scope of the present application.

[0083] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shift (δ) is given in units of 10-6 (ppm). The determination of NMR is carried out by (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0084] MS was determined using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0085] HPLC was determined using Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 μM);

[0086] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used in thin layer chromatography is 0.15 mm-0.20 mm, and the specification of the product separated and purified by thin layer chromatography is 0.4 mm-0.5 mm.

[0087] The known starting materials of the present application can be synthesized by using or according to the methods known in the art, or can be purchased from Titan Technology, Anjieji Chemical, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0088] Example A1 Preparation of compound A1:

[0089] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl 4-methylbenzenesulfonate (compound A1)

[0090] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl

[0091] 4-methylbenzenesulfonate (compound A1)

[0092] First step: 5-hydroxy-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (A1c)

[0093] 5-hydroxy-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one (A1c)

[0094] Into a reaction flask, 336.29 g of 5-trifluoromethylisoindoline hydrochloride (A1b), 0.75 L of dimethyl sulfoxide, and 424.85 g of N,N-diisopropylethylamine were added under nitrogen protection, and then the reaction was warmed up. While controlling the temperature at 50±5 °C, 229.85 g of a mixture of (2-chloromethyl)-5-hydroxy-4H-pyran-4-one (A1a) and 500 ml of dimethyl sulfoxide were added dropwise into the reaction solution. After completion of the addition, the reaction was continued at 50±5 °C. After the reaction was completed, 45.05 g of acetic acid and 150 ml of acetonitrile were added into the reaction solution, and then 1.1 L of purified water was added dropwise into the reaction solution while controlling the temperature at 50±5 °C. After completion of the addition, a large amount of solid was precipitated, and the stirring was continued at 50±5 °C for about 0.5 hours. The reaction solution was cooled to 20±5 °C and reacted for about 1 hour. After filtration, the filter cake was washed with a mixed solution of acetonitrile and purified water, and then the filter cake was dried under reduced pressure to obtain Compound A1c as a brown solid (404.59 g, yield 90.7%).

[0095] 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.48 (d, 2H), 7.46 (s, 1H) 7.30 (d, 1H), 6.56 (s, 1H), 4.09 (s, 4H), 3.80 (s, 2H).

[0096] LCMS m / z = 312.2 [M+1].

[0097] Second step: 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl 4-methylbenzenesulfonate (Compound A1)

[0098] Into a reaction flask, 336.29 g of 5-trifluoromethylisoindoline hydrochloride (A1b), 0.75 L of dimethyl sulfoxide, and 424.85 g of N,N-diisopropylethylamine were added under nitrogen protection, and then the reaction was warmed up. While controlling the temperature at 50±5 °C, 229.85 g of a mixture of (2-chloromethyl)-5-hydroxy-4H-pyran-4-one (A1a) and 500 ml of dimethyl sulfoxide were added dropwise into the reaction solution. After completion of the addition, the reaction was continued at 50±5 °C. After the reaction was completed, 45.05 g of acetic acid and 150 ml of acetonitrile were added into the reaction solution, and then 1.1 L of purified water was added dropwise into the reaction solution while controlling the temperature at 50±5 °C. After completion of the addition, a large amount of solid was precipitated, and the stirring was continued at 50±5 °C for about 0.5 hours. The reaction solution was cooled to 20±5 °C and reacted for about 1 hour. After filtration, the filter cake was washed with a mixed solution of acetonitrile and purified water, and then the filter cake was dried under reduced pressure to obtain Compound A1c as a brown solid (404.59 g, yield 90.7%).

[0099] 1H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.84(d,2H),7.63(s,1H)7.57(d,1H),7.49(m,3H),6.50(s,1H),4.04(s,4H),3.85(s,2H),2.43(s,3H).

[0100] LCMS m / z = 466.0 [M+1].

[0101] Example A1-1 Preparation of compound A1:

[0102] 4-Oxo-6-((5-(trifluoromethyl)isoindoline-2-yl)methyl)-4H-pyran-3-yl-4-methylbenzenesulfonate (Compound A1)

[0103] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl

[0104] 4-methylbenzenesulfonate(Compound A1)

[0105] Step 1: 6-(chloromethyl)-4-oxo-4H-pyran-3-yl-4-methylbenzenesulfonate (A2b)

[0106] 6-(chloromethyl)-4-oxo-4H-pyran-3-yl 4-methylbenzenesulfonate(A2b)

[0107] 10.03 g of (2-chloromethyl)-5-hydroxy-4H-pyran-4-one (A1a) was dissolved in 100 ml of dichloromethane, 13.02 g of p-toluenesulfonyl chloride was added, followed by 7.66 g of triethylamine. After the addition was complete, the reaction was carried out at 20 ± 5 °C. After the reaction was complete, 100 ml of water was added, and the mixture was extracted and separated. The organic phase was washed once with 100 ml of 10% citric acid solution, and then washed once with 100 ml of 10% sodium bicarbonate solution. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After complete concentration, 100 ml of methyl tert-butyl ether was added to the residue, the mixture was slurried, filtered, and the filter cake was dried to give compound A2b, a pale yellow solid (17.85 g, yield 91.1%).

[0108] 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),7.90(d,2H),7.36(d,2H),6.44(s,1H),4.31(s,2H),2.45(s,3H).

[0109] LCMS m / z = 314.9 [M+1].

[0110] Second Step: 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl 4-methylbenzenesulfonate (Compound A1)

[0111] To 1.51 g of 5-trifluoromethylisoindoline hydrochloride (A1b) in 5 ml of dimethyl sulfoxide was added 1.92 g of N,N-diisopropylethylamine. To 2.02 g of 6-(chloromethyl)-4-oxo-4H-pyran-3-yl 4-methylbenzenesulfonate (A2b) in 5 ml of dimethyl sulfoxide was added, and the mixture was added dropwise to the dimethyl sulfoxide solution of A1b. After the addition was completed, the temperature was raised to 50±5°C and the reaction was allowed to proceed. After the reaction was completed, 1 ml of acetic acid, 4 ml of acetonitrile and 10 ml of water were added to the reaction solution, and the temperature was lowered to precipitate crystals. The crystals were filtered, washed with water, and then slurried with 10 ml of methyl tert-butyl ether. The crystals were filtered, washed with methyl tert-butyl ether, and dried to obtain Compound A1 as a white solid (2.42 g, yield 81.0%).

[0112] Example A1-2 Preparation of Compound A1:

[0113] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl 4-methylbenzenesulfonate (Compound A1)

[0114] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl

[0115] 4-methylbenzenesulfonate (Compound A1)

[0116] First Step: 6-(chloromethyl)-4-oxo-4H-pyran-3-yl 4-methylbenzenesulfonate (A2b)

[0117] 6-(chloromethyl)-4-oxo-4H-pyran-3-yl 4-methylbenzenesulfonate (A2b)

[0118] 10.06 g of kojic acid (A3a) was added to 100 ml of dichloromethane, and then 29.52 g of p-toluenesulfonyl chloride and 17.88 g of triethylamine were added. After the addition was completed, the reaction was allowed to proceed at room temperature for 3 hours, and then the temperature was increased to 40±5°C and the reaction was allowed to proceed for 2 hours. After the completion of the reaction, 100 ml of water was added to the reaction solution, and the extraction was performed. The organic phase was washed once with 100 ml of 10% citric acid solution, and then washed once with 100 ml of 10% sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness. To the residue, 100 ml of methyl tert-butyl ether was added to make a slurry, and then filtered. The filter cake was dried to obtain compound A2b as a light yellow solid (17.44 g, yield 78.3%).

[0119] Second Step: 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl 4-methylbenzenesulfonate (Compound A1)

[0120] 7.89 g of 5-trifluoromethylisoindoline hydrochloride (A1b) was added to 25 ml of dimethyl sulfoxide, and then 10.30 g of N,N-diisopropylethylamine was added. 10.04 g of 6-(chloromethyl)-4-oxo-4H-pyran-3-yl 4-methylbenzenesulfonate (A2b) was dissolved in 25 ml of dimethyl sulfoxide, and then the solution was added dropwise to the dimethyl sulfoxide solution of A1b. After the addition was completed, the temperature was increased to 50±5°C and the reaction was allowed to proceed. After the completion of the reaction, 5 ml of acetic acid, 20 ml of acetonitrile, and 50 ml of water were added to the reaction solution, and then the temperature was decreased to precipitate crystals. The crystals were filtered, and then the filter cake was washed with water. The filter cake was made into a slurry with methyl tert-butyl ether, and then filtered. The filter cake was washed with methyl tert-butyl ether, and then dried to obtain compound A1 as a white solid (12.25 g, yield 83.0%).

[0121] Example A1-3 Preparation of Compound A1

[0122] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl

[0123] 4-methylbenzenesulfonate(Compound A1)

[0124] 4-methylbenzenesulfonate(Compound A1)

[0125] First Step: (4-oxo-5-(toluoyloxy)-4H-pyran-2-yl)methyl 4-methylbenzenesulfonate (A4a)

[0126] (4-oxo-5-(tosyloxy)-4H-pyran-2-yl)methyl 4-methylbenzenesulfonate(A4a)

[0127] 10.02 g of kojic acid was added to 150 ml of dichloromethane, 68.99 g of p-toluenesulfonic anhydride was added, and then 36.55 g of N,N-diisopropylethylamine was added, and after the addition, it was reacted at 20±5°C for 3 hours, and then the temperature was increased to 40±5°C and reacted for 2 hours. After the reaction was completed, 150 ml of water was added and extracted and separated, and the organic phase was washed once with 150 ml of sodium bicarbonate solution and then washed once with 150 ml of 10% citric acid solution, and the organic phase was dried with anhydrous sodium sulfate. After filtering and concentrating the filtrate, 100 ml of n-heptane and 50 ml of ethyl acetate were added and stirred to form a slurry, filtered, and the filter cake was dried to obtain compound A4a as a light yellow solid (22.95 g, 72.4%).

[0128] 1 H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.87 (d, 2H), 7.79 (d, 2H), 7.36 (m, 4H), 6.32 (s, 1H), 4.82 (s, 2H), 2.46 (d, 6H).

[0129] LCMS m / z = 451.0 [M+1].

[0130] Second step: 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl 4-methylbenzenesulfonate (Compound A1)

[0131] 5.48 g of 5-trifluoromethylisoindoline hydrochloride (A1b) was added to 50 ml of dimethyl sulfoxide, 7.21 g of N,N-diisopropylethylamine was added, and then 10.01 g of (4-oxo-5-(tosyloxy)-4H-pyran-2-yl)methyl 4-methylbenzenesulfonate (A4a) was added, and after the addition, the temperature was increased to 50±5°C and reacted. After the reaction was completed, 5 ml of acetic acid, 20 ml of acetonitrile, and 50 ml of water were added to the reaction solution, and then the temperature was decreased to precipitate crystals, which were filtered, washed with water, and then slurried with methyl tert-butyl ether, filtered, and the filter cake was washed with methyl tert-butyl ether, and the dried filter cake was obtained as compound A1 as a white solid (8.85 g, yield 85.7%).

[0132] Preparation of Compound A2 according to Scheme A2:

[0133] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl trifluoromethanesulfonate (Compound A2)

[0134] 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl trifluoromethanesulfonate (Compound A2)

[0135] 62.08 g of 5-hydroxy-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyrane-4- one (A1c) was added into 600 ml of N,N-dimethylformamide, and then 82.68 g of potassium carbonate was added. After cooling under nitrogen protection, 85.4 g of N-phenyl bis(trifluoromethylsulfonyl)imide was added at 5±5°C. After the addition, the reaction was carried out at 5±5°C. After the reaction, water was added to quench the reaction, and a large amount of solid was precipitated in the reaction solution. The reaction solution was stirred at 15±5°C, and the solid was filtered, washed with water, and then dissolved in 150 ml of toluene at 60±5°C. After the complete dissolution, the reaction was carried out by cooling. After the cooling to 15±5°C, 100 ml of n-hexane was added to the reaction solution, and then the reaction was carried out by cooling at 15±5°C. The reaction solution was filtered, washed with n-hexane, and then dried to obtain A2, a gray solid (72.70 g, yield 82.3%).

[0136] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.63 (s, 1H), 7.57-7.59 (d, 1H), 7.47-7.49 (d, 1H), 6.74 (s, 1H), 4.08 (s, 4H), 3.92 (s, 2H).

[0137] LCMS m / z = 444.0 [M+1].

[0138] Preparation of the compound of formula (B) according to Example B:

[0139] tert-butyl ((1r,4r)-4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclohexyl)carbamate (compound of formula (B))

[0140] tert-butyl ((1r,4r)-4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclohexyl)carbamate (compound of formula (B))

[0141] Example B-1 (Method 1):

[0142] 50L reaction kettle was added 10L toluene, stirring was started, 2000g trans-1-(Boc-amino)-4-ethynylcyclohexane (B1a), 462g hydrochloride zirconocene, 181g triethylamine and 4585g neopentyl glycol borane were added under nitrogen protection; after addition, the reaction was heated, and the temperature was controlled at 30±5℃ under nitrogen protection; after the reaction was completed, 3L acetone was added dropwise into the reaction solution at 30±10℃ to quench the reaction, and the reaction was maintained at 30±10℃ for 1 hour; then 10L 10% citric acid aqueous solution and 10L isopropyl acetate were slowly added, and the mixture was extracted and separated at 30±5℃; the organic phase was washed once with 10% citric acid aqueous solution at 30±5℃, and then washed with saturated sodium bicarbonate aqueous solution at 30±5℃; the organic phase was dried with anhydrous sodium sulfate, filtered to remove sodium sulfate, and then concentrated to dryness under reduced pressure; 5L acetonitrile was added, and the mixture was concentrated to dryness under reduced pressure at 50℃; after concentration, 10L acetonitrile was added, and the mixture was dissolved by heating to 60℃; after complete dissolution, 10L purified water was slowly added to crystallize, and the mixture was stirred at 30±5℃ for 1 hour; the mixture was filtered, washed with 30±5℃ purified water, and dried under vacuum; the compound of formula (B) was obtained as a white solid (2506g, yield 79.65%, content 98.86%).

[0143] 1 H NMR (400 MHz, CDCl3) δ 6.56 (dd, 1H), 5.41 (d, 1H), 4.35 (s, 1H), 3.35 (s, 1H), 2.04 (m, 3H), 1.81 (m, 2H), 1.43 (s, 9H), 1.26 (s, 12H), 1.15 (m, 4H).

[0144] LCMS m / z = 214.1 [M-56-82+1].

[0145] Preparation of the compound of formula (B) according to Example B-2:

[0146] tert-butyl ((1r,4r)-4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclohexyl)carbamate (compound of formula (B))

[0147] tert-butyl ((1r,4r)-4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclohexyl)carbamate (compound of formula (B))

[0148] Method two:

[0149] Into a reaction vessel was added THF (4.0 L, 4 V) and 2,2,6,6-tetramethylpiperidine (0.67 kg, 1.2 eq.) under nitrogen protection. The temperature was controlled at -60 to -50 °C, and n-butyllithium (1.90 L, 1.2 eq.) was slowly added dropwise into the reaction solution. After the addition was completed, the mixture was stirred for 0.5 h. The temperature was controlled at -70 to -60 °C, and bis[(pinacolato)boron]methane (1.27 kg, 1.2 eq.) was added into the reaction solution. After the addition was completed, the mixture was stirred for 0.5 h. The temperature was controlled at -70 to -60 °C, and a solution of trans-4-(BOC-amino)cyclohexylcarboxaldehyde (B2a) (0.90 kg, 1.0 eq.) was added into the reaction solution. After the addition was completed, the mixture was continuously stirred at -70 to -60 °C for 30 to 50 mins.

[0150] Work-up: 1.0 L of water was slowly added dropwise into the reaction solution; 5.0 L of water and 5.0 L of methyl tert-butyl ether were added into the reaction solution, and the mixture was allowed to stand and separate. The organic phase was washed once with saturated sodium chloride solution, and the organic phase was collected. After the organic phase was concentrated under pressure to 2 L, 5.0 L of acetonitrile was added, and the mixture was stirred to dissolve the solid at 55 to 60 °C. The temperature was controlled at 45 to 60 °C, and 6.0 L of water was slowly added into the reaction solution. After the addition was completed, the mixture was slowly cooled to 10 to 30 °C, and the mixture was stirred at 10 to 30 °C to precipitate crystals. The crystals were filtered to obtain 2.22 kg of wet product.

[0151] Re-crystallization: the wet product (2.22 kg) was added into 4.0 L of acetonitrile, and the mixture was stirred to dissolve the solid at 60 to 65 °C. 5.0 L of water was slowly added into the reaction solution (solid was gradually precipitated), and the mixture was slowly cooled to 10 to 30 °C. The mixture was stirred at 10 to 30 °C to precipitate crystals. The crystals were filtered, and the filter cake was washed twice with water. The filter cake was dried under reduced pressure to obtain 857.40 g of white solid (yield 61.64%) of the compound of formula (B).

[0152] 1 H NMR (400 MHz, CDC13) δ = 6.53 (dd, J = 6.3, 18.2 Hz, 1H), 5.33 (br d, J = 9.4 Hz, 1H), 4.38 (br d, J = 1.6 Hz, 1H), 3.53 - 3.10 (m, 1H), 2.09 - 1.91 (m, 3H), 1.88 - 1.73 (m, 2H), 1.44 (s, 9H), 1.31 - 1.03 (m, 16H).

[0153] Example C Preparation of the compound of formula (C):

[0154] tert-Butyl ((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindol-2-yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)carbamate (compound of formula (C))

[0155] tert-butyl((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)carbamate (compound of formula (C))

[0156] Method 1:

[0157] Into a 100 L reactor, 28 L of 2-methyltetrahydrofuran and 14 L of purified water were added; after the addition was completed, stirring was started, and 2.802 kg of 4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyrane-3-yl 4-methylbenzenesulfonate (A1), 2.285 kg of tert-butyl ((1r,4r)-4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)cyclohexyl)carbamate (B), and 2.500 kg of potassium carbonate were added. Oxygen was removed under nitrogen for about 2 h. Under nitrogen protection, a suspension of bis[(1,2,3)-1-phenyl-2-propenyl]palladium(II) and 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl in 2-methyltetrahydrofuran (15.65 g of bis[(1,2,3)-1-phenyl-2-propenyl]palladium(II), 57.42 g of 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl, and 0.5 L of 2-methyltetrahydrofuran) was added. The temperature was raised to 65±5°C, and the reaction was carried out under nitrogen protection and temperature control at 65±5°C. After the reaction was completed, the reaction liquid was kept at 65±5°C for 30 min, and then separated into two layers. The upper organic layer was retained. Sodium chloride solution (2.8 kg of sodium chloride dissolved in 14 L of purified water) was added to the organic layer. The temperature was controlled at 65±5°C, and stirring was carried out for 30 min. After standing for 1 h, the upper organic layer was separated. Under nitrogen protection, 0.144 kg of tributylphosphine was added to the organic layer, and stirring was carried out at 65±5°C for about 1 h. The reaction was carried out by lowering the temperature to 20±5°C, and the product was crystallized for about 0.5 h. Then, 28 L of n-heptane was added to the reaction liquid, and the temperature was controlled at 20±5°C for crystallization. The liquid was filtered, and the filter cake was washed with n-heptane. The filter cake was dried under reduced pressure, and the product was collected. The compound of formula (C) was obtained as a white solid, with a weight of 2.880 kg, a yield of 92.3%, and a purity of 99.2%.

[0158] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.62 (s, 1H), 7.56-7.58 (d, 1H) 7.46-7.48 (d, 1H), 6.69-6.71 (br s, 1H), 6.60-6.66 (m, 1H), 6.35 (s, 1H), 6.07-6.11 (d, 1H), 4.03 (s, 4H), 3.81 (s, 2H), 3.17 (m, 1H), 1.95-1.98 (m, 1H), 1.72-1.82 (m, 4H), 1.38 (s, 9H), 1.14-1.25 (m, 4H).

[0159] LCMS m / z = 463.0 [M+56+1].

[0160] Method two:

[0161] 41.62 g of tert-butyl ((1 r, 4r)-4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)vinyl)cyclohexyl)carbamate (B), 35.30 g of 4-oxo-6-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-3-yl trifluoromethanesulfonate (A2), 32.60 g of potassium carbonate, 70 ml of water, 350 ml of 1,4-dioxane were added into a reaction flask, after adding, the liquid surface was blown with nitrogen for about 1 h to remove oxygen, then 5.68 g of [1,1 '- bis(diphenylphosphino)ferrocene] palladium dichloride was added, after adding, the reaction was heated, and the reaction was carried out at 50±5°C; after the reaction was completed, the heating was turned off, and the reaction liquid was concentrated under reduced pressure; after the volume was reduced to half, 400 ml of water and 500 ml of ethyl acetate were added, the liquid was separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After the concentration was completed, column purification was carried out, the product point was collected, and after concentration, 50 ml of n-heptane and 20 ml of ethyl acetate were added to the residual solid, after adding, the liquid was stirred and pulped at 20±5°C, filtered, and the filter cake was dried to obtain the compound of formula (C), which was a gray solid (19.58 g, yield 47.8%).

[0162] Preparation of compound D1 of Example D1 :

[0163] 5-((E)-2-((1 r, 4r)-4-aminocyclohexyl)vinyl)-2-(5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one dihydrochloride (compound D1)

[0164] 5-((E)-2-((1 r,4r)-4-aminocyclohexyl)vinyl)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one Dihydrochloride (Compound D1)

[0165] 100L reaction kettle was charged with 22.4L of tetrahydrofuran, and stirring was started. Then, 2.800kg of tert-butyl ((1 r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)carbamate (C) was added. After the addition was completed, the temperature was lowered to 10±5°C, and 5.6L of hydrochloric acid was added to the reaction solution while controlling the temperature below 40°C. After the addition was completed, the temperature was raised to 40±5°C, and the reaction was carried out while maintaining the temperature. After the reaction was completed, 22.4L of tetrahydrofuran was added to the reaction solution, and the temperature was lowered to 5±5°C. The product was crystallized while maintaining the temperature at 5±5°C, and the filtrate was filtered. The filter cake was washed with tetrahydrofuran and then dried under reduced pressure. The product was collected, and Compound D1 was obtained as a white solid, having a weight of 2.322kg, a yield of 87.5%, and a purity of 99.81%.

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.15-8.26 (m, 2H), 7.80 (s, 1H) 7.72-7.74 (d, 1H), 7.61-7.63 (d, 1H), 6.66-6.71 (m, 2H), 6.10-6.15 (d, 1H), 4.74 (s, 4H), 4.59 (s, 2H), 2.95 (s, 1H), 1.78-2.02 (m, 5H), 1.19-1.42 (m, 4H).

[0167] LCMS m / z = 419.1 [M-73+1].

[0168] Example D2 Preparation of Compound D2:

[0169] 5-((E)-2-((1 r,4r)-4-aminocyclohexyl)vinyl)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one Dihydrochloride (Compound D1)

[0170] 5-((E)-2-((1 r,4r)-4-aminocyclohexyl)vinyl)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one di(p-toluenesulfonate) (Compound D2)

[0171] 3.00 g of tert-butyl ((1 r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)- 4H-pyran-3-yl)vinyl)cyclohexyl)carbamate (C) was added 24 ml of isopropyl alcohol, 9 ml of water, 4.43 g of p-toluenesulfonic acid monohydrate, and the reaction was warmed up. The reaction was performed at 65 ± 5°C. After the reaction, the reaction was cooled down, and 30 ml of isopropyl acetate was added at 25 ± 5°C. The reaction was cooled down to 5 ± 5°C, and the compound D2 was precipitated. The precipitate was filtered, washed with isopropyl acetate, and dried to obtain the compound D2 as a white solid (3.52 g, 79.8%).

[0172] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.73-7.80 (m, 5H), 7.61-7.63 (d, 1H) 7.46-7.48 (d, 4H), 7.10-7.12 (d, 4H), 6.65-6.71 (m, 1H), 6.60 (s, 1H), 6.11-6.15 (d, 1H), 4.75 (s, 4H), 4.59 (s, 2H), 2.98 (s, 1H), 2.29 (s, 6H), 1.94-2.06 (m, 3H), 1.77-1.80 (m, 2H), 1.16-1.41 (m, 4H).

[0173] LCMS m / z = 419.1 [M-344+1].

[0174] Example D3 Preparation of Compound D3

[0175] 5-((E)-2-((1 r,4r)-4-aminocyclohexyl)vinyl)-2-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one di(p-toluenesulfonate) (Compound D2)

[0176] 5-((E)-2-((1r,4r)-4-aminocyclohexyl)vinyl)-2-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-4-one dimethyl sulfonate (Compound D3)

[0177] 10.02 g of tert-butyl ((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)carbamate (C) was added with 100 ml of isopropanol, 8.38 g of methanesulfonic acid, and the reaction was warmed up. After the reaction was completed, the heating was turned off, and the reaction was cooled to 25±5°C. The mixture was stirred to precipitate crystals, which were filtered, washed with isopropanol, and dried to obtain Compound D3 as a gray solid (10.61 g, yield 90.1%).

[0178] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.81 (s, 4H), 7.62-7.75 (m, 2H) 6.66-6.72 (m, 1H), 6.61 (s, 1H), 6.12-6.16 (d, 1H), 4.74 (s, 4H), 4.57 (s, 2H), 2.98 (s, 1H), 2.34 (s, 6H), 1.96-2.07 (m, 3H), 1.72-1.81 (m, 2H), 1.16-1.42 (m, 4H).

[0179] LCMS m / z = 419.1 [M-192+1].

[0180] Preparation of the compound of formula (E):

[0181] N-((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)cyclopropanecarboxamide (Compound of formula (E))

[0182] N-((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)cyclopropanecarboxamide (Compound of formula (E))

[0183] Method one:

[0184] 100L reaction kettle was charged with 22.5L tetrahydrofuran, stirring was started, 2.250kg 5-((E)-2-((1r,4r)-4-aminocyclohexyl)vinyl)-2-(5-(trifluoromethyl)isoindol-2-yl)methyl)-4H-pyr an-4-one dihydrochloride (D1), 0.743kg 1-hydroxybenzotriazole, 1.055kg 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.482kg cyclopropanecarboxylic acid. Under nitrogen protection, 2.963kg N,N-diisopropylethylamine was added. After the addition was completed, the reaction was warmed up and controlled at 35±5°C. After the reaction was completed, 45L purified water was added to the reaction solution, and the reaction was cooled down and controlled at 10±5°C for crystallization. The filtrate was filtered, and the filter cake was washed once with purified water and once with a mixture of 3L acetone and 9L purified water. The material was collected to obtain 2.05kg of compound of formula (E) with a yield of 92% and a purity of 99.375%.

[0185] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.90-7.92 (d, 1H), 7.62 (s, 1H) 7.56-7.58 (d, 1H), 7.46-7.48 (d, 1H), 6.61-6.67 (m, 1H), 6.36 (s, 1H), 6.09-6.13 (d, 1H), 4.04 (s, 4H), 3.81 (s, 2H), 3.46-3.54 (m, 1H), 2.00-2.03 (m, 1H), 1.82-1.84 (m, 2H), 1.74-1.76 (m, 2H), 1.48-1.55 (m, 1H), 1.13-1.28 (m, 4H), 0.58-0.67 (m, 4H).

[0186] LCMS m / z = 487.1 [M+1].

[0187] Method two:

[0188] 2.01 g of 5-((E)-2-((1 r,4r)-4-aminocyclohexyl)vinyl)-2-(5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one dihydrochloride (D1), 20 ml of acetonitrile, 2.70 g of N,N- diisopropylethylamine, 0.65 g of 1-hydroxybenzotriazole, 0.99 g of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.44 g of cyclopropanecarboxylic acid were added into a reaction bottle, and the reaction was carried out at 25±5°C; after the reaction was completed, 40 ml of water was added to quench the reaction, and after stirring at 25±5°C for 1 h, the filter cake was washed with water and then with acetonitrile, and the filter cake was dried to obtain the compound of formula (E), which was a white solid (1.81 g, 91.4%).

[0189] Example E-2 Preparation of the compound of formula (E):

[0190] N-((1 r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3- yl)vinyl)cyclohexyl)cyclopropanecarboxamide (compound of formula (E))

[0191] N-((1 r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-4H-pyran-3- yl)vinyl)cyclohexyl)cyclopropanecarboxamide (compound of formula (E))

[0192] 4.01 g of 5-((E)-2-((1 r,4r)-4-aminocyclohexyl)vinyl)-2-(5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-4-one dimethanesulfonate (D3), 33 ml of N,N-dimethylacetamide, 0.76 g of cyclopropanecarboxylic acid, 4.30 g of N,N-diisopropylethylamine, 1.86 g of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.35 g of 1- hydroxybenzotriazole were added, and the reaction was carried out at 15±5°C; after the reaction was completed, 60 ml of purified water was added to the reaction solution, and the filter cake was washed with water and dried to obtain the compound of formula (E), which was a gray solid (2.85 g, yield 89.3%).

[0193] Example F Preparation of the compound of formula (F):

[0194] Into a 100 L reactor, was placed 6.75 L of dimethyl sulfoxide, 2.00 kg of N-((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)cyclopropanecarboxamide (E), and 22.5 L of acetone. The reaction was warmed and the temperature was controlled at 45±5 °C. The reaction solution was filtered while hot, and the filtrate was transferred to a 100 L reactor and warmed. The reaction was dissolved at 45±5 °C. At 45±5 °C, about 2.4 kg of p-toluenesulfonic acid in acetone (0.87 kg of p-toluenesulfonic acid monohydrate was dissolved in 8.7 kg of acetone to prepare) was added dropwise to the reaction solution. 23 g of N-((1r,4r)-4-((E)-2-(4-oxo-6-((5-(trifluoromethyl)isoindolin-2- yl)methyl)-4H-pyran-3-yl)vinyl)cyclohexyl)cyclopropanecarboxamide (E) seed crystals were added to the reaction solution. After the addition was completed, the temperature was controlled at 45±5 °C and the reaction solution was stirred for about 10 min to crystallize. The remaining 7.17 kg of p-toluenesulfonic acid in acetone was added dropwise to the reaction solution at 45±5 °C. After the addition was completed, the temperature was controlled at 45±5 °C and the reaction solution was stirred for about 0.5 h to crystallize. The temperature was lowered and the reaction solution was stirred at 15±5 °C for 1 h to crystallize. After the crystallization was completed, the reaction solution was filtered, and the filter cake was washed with acetone and then dried under reduced pressure to obtain the compound of formula (F) as a white solid, 2.479 kg in weight, with a yield of 91.5% and a purity of 99.85%.

[0195] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.91-7.93 (m, 1H), 7.81 (s, 1H), 7.74-7.76 (d, 1H) 7.61-7.63 (d, 1H), 7.44-7.46 (d, 2H), 7.08-7.10 (d, 2H), 6.66-6.72 (m, 1H), 6.61 (s, 1H), 6.11-6.15 (d, 1H), 4.78 (s, 4H), 4.62 (s, 2H), 3.48-3.51 (m, 1H), 2.28 (s, 3H), 2.02-2.04 (m, 1H), 1.74-1.84 (m, 4H), 1.48-1.54 (m, 1H), 1.20-1.25 (m, 4H), 0.59-0.65 (m, 4H).

[0196] LCMS m / z = 487.1 [M+1].

Claims

1. A method for preparing a compound of formula (A-2), comprising the following reaction: wherein, R1 is OH, OTs or OTf, R2 is OTs, OTf, Cl, Br or I.

2. A method for preparing a compound of formula (A-4), comprising the following reaction: wherein R3 is Cl, Br, I, OTs or OTf, and R4 is OTs or OTf.

3. A method for preparing a compound of formula (A-6), comprising the following reaction: wherein R5is CI, Br, I or R6 is OTs or OTf.

4. A method for preparing a compound of formula (B), comprising the following reaction: wherein, The base is selected from at least one of triethylamine, 4-dimethylaminopyridine, pyridine, N,N-diisopropylethylamine, piperidine, 2,6-lutidine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of triethylamine, 4-dimethylaminopyridine or pyridine.

5. A method for preparing a compound of formula (B), comprising the following reaction:

6. A method for preparing a compound of formula (C), comprising the following reaction:

7. A method for preparing a compound of formula (D), comprising the following reaction: wherein n is 1 or 2; and X is selected from HCI, TsOH, MsOH, trifluoroacetic acid, phosphoric acid, sulfuric acid, ethanedisulfonic acid or camphorsulfonic acid.

8. A method for preparing a compound of formula (E), comprising the following reaction: wherein X is HCI or TsOH or MsOH.

9. A method for preparing a compound of formula (F), comprising the following reaction: The reaction solvent used in the reaction is selected from at least one of dimethyl sulfoxide, acetone, isopropanol, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, t-butanol, t-amyl alcohol, ethyl acetate, isopropyl acetate, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl t-butyl ether, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, chloroform, trifluoroethanol, n-hexane, and a mixed solution of ethanol and water, preferably a mixed solution of ethanol and water or a mixed solution of acetone and dimethyl sulfoxide. The base is selected from at least one of triethylamine, 4-dimethylaminopyridine, pyridine, N,N-diisopropylethylamine, piperidine, 2,6-lutidine, triethylenediamine, imidazole, N-methylimidazole, morpholine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, preferably at least one of triethylamine, 4-dimethylaminopyridine or pyridine. n is 1 or 2; and X is selected from HCI, TsOH, MsOH, trifluoroacetic acid, phosphoric acid, sulfuric acid, ethanedisulfonic acid or camphorsulfonic acid. X is HCI or TsOH or MsOH. The reaction solvent used in the reaction is selected from at least one of dimethyl sulfoxide, acetone, isopropanol, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, t-butanol, t-amyl alcohol, ethyl acetate, isopropyl acetate, 4-methyl-2-pentanone, n-heptane, 1,4-dioxane, methyl t-butyl ether, cyclopentyl methyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, toluene, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, chloroform, trifluoroethanol, n-hexane, and a mixed solution of ethanol and water, preferably a mixed solution of ethanol and water or a mixed solution of acetone and dimethyl sulfoxide.

10. A compound of formula (Al) or a salt thereof, and a compound of formula (D1), formula (D2), formula (D3):

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