A method for preparing the CYP11B2 inhibitor BAXDROSTAT

Abstract

This invention relates to a method for preparing the CYP11B2 inhibitor BAXDROSTAT. Specifically, this invention provides two preparation methods. Method 1: Baxdrostat is obtained by condensing 4-halo-6,7-dihydroisoquinoline-8(5H)-one with S-tert-butylsulfinamide aldehyde ketone, followed by reduction with sodium borohydride, then reaction with pinacol diboronate, followed by Suzuki coupling reaction, deprotection, and reaction with propionyl chloride. Method 2: The product (S)-N-(4-halo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonylimide from step 2 of Method 1 is first deprotected, then reacted with 6-bromo-1-methyl-3,4-dihydroquinoline-2(1H)-one via Suzuki coupling reaction, and then reacted with allyl chloride.

Description

TECHNICAL FIELD

[0001] The present invention belongs to the field of chemical medicine synthesis and relates to two methods of preparing the CYP11B2 inhibitor BAXDROSTAT. BACKGROUND

[0002] Aldosterone, secreted by the zona glomerulosa region of the human adrenal cortex, is a mineralocorticoid that maintains water and salt balance by regulating sodium reabsorption in the kidney. Excessive aldosterone inappropriately activates the mineralocorticoid receptor, which increases plasma volume and leads to elevated blood pressure. In addition, excessive aldosterone levels cause myocardial and vascular interstitial fibrosis, leading to ventricular and vascular remodeling, and induce leukocyte infiltration causing coronary and myocardial damage, arrhythmia. Aldosterone synthase (AS, encoded by the CYP11B2 gene) controls the synthesis of aldosterone and has been a pharmacological target for the treatment of hypertension for decades. Since the enzyme that produces aldosterone and the enzyme that produces cortisol are 93% identical, it has been difficult to develop a drug that inhibits aldosterone production without affecting cortisol. CYP11B2 produces aldosterone through a three-step sequence. Starting from 11-deoxycorticosterone (DOC), initial hydroxylation at C-11 provides corticosterone, which is hydroxylated at C-18 to provide 18-hydroxycorticosterone. 18-hydroxycorticosterone then undergoes a final C-18 oxidation (alcohol to aldehyde) to provide aldosterone. Importantly, CYP11B2 is the only enzyme that catalyzes the final oxidation to produce aldosterone.

[0003] One was initially discovered to be a potent inhibitor of aldosterone synthase (CYP11B2), with the ability to lower aldosterone, but also strongly inhibited 11 -hydroxylase (CYP-11B1) and lower blood cortisol, and for this reason ultimately discontinued for the treatment of hypertension. Subsequent work by researchers has focused on improving its selectivity for aldosterone synthase. The Whitehead group designed and synthesized a series of pyridinoimidazole and benzopyrazole compounds by replacing the original benzene ring with a pyridine ring. A review of the literature on CYP11B2 showed several other screening approaches that utilized pyridine and imidazole metal binding pharmacophores (MBGs) to provide modest selectivity. These approaches were subsequently developed into selective inhibitors. While maintaining the high selectivity imparted by the optimized MBG, researchers used modifications to the rest of the scaffold to enhance potency.

[0004] Baxdrostat is a small-molecule, highly selective aldosterone synthase inhibitor that selectively inhibits aldosterone synthase without blocking mineralocorticoid receptors. Preclinical and phase I studies have shown that Baxdrostat has very high selectivity (100:1) for aldosterone synthase compared to cortisol synthase. Aldosterone synthase is produced only in a small subset of cells in the adrenal glands; it is not produced in other parts of the body, thus off-target effects are not expected. Results from the BrigHTN phase 2 study showed that the aldosterone synthase inhibitor (ASI) Baxdrostat significantly reduced blood pressure in patients with refractory hypertension. Patients treated with Baxdrostat 2 mg experienced a reduction in systolic blood pressure exceeding 20 mmHg; after adjusting for the placebo group, the Baxdrostat 2 mg group showed a mean reduction of 11.0 mmHg in systolic blood pressure. These results were published concurrently in the *New England Journal of Medicine*. Researchers in the BrigHTN phase 2 study also measured patients' plasma Baxdrostat levels, serum and urinary aldosterone levels, and serum cortisol activity. All three dosage groups of Baxdrostat showed a decrease in 24-hour urinary aldosterone levels, but no change in serum cortisol levels. This means that Baxdrostat reduced aldosterone levels and increased plasma renin activity without lowering cortisol, supporting its biological effects and selectivity. Summary of the Invention

[0005] In view of the above, the preparation of the CYP11B2 inhibitor BAXDROSTAT is very important. The inventors have developed two preparation methods for the CYP11B2 inhibitor BAXDROSTAT through experimental research.

[0006] The compounds described in this invention are prepared using the following two routes:

[0007] Option 1

[0008]

[0009] (S,Z)-N-(4-halo-6,7-dihydroisoquinoline-8(5H)-one) and S-tert-butylsulfinamide were obtained by aldehyde-ketone condensation reaction of the raw material 4-halo-6,7-dihydroisoquinoline-8(5H)-one with S-tert-butylsulfinamide.

[0010] The compound was obtained by reduction with sodium borohydride to give (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonylimide;

[0011] (S)-N-(4-halo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonamide reacts with pinacol diborane to give compound (S)-N-tert-butylsulfonamide-6,7-dihydroisoquinoline-8(5H)-4-pinacol borate;

[0012] Further reaction with 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one by Suzuki coupling reaction gives compound (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)tert-butylsulfonimidate;

[0013] The product in step 4) is subjected to de-tert-butylsulfonyl protection to give (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one;

[0014] Finally, the amino group in compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one reacts with propionyl chloride to give the target compound Baxdrostat.

[0015] Scheme II

[0016]

[0017] The product of step 2 in Scheme I, (S)-N-(4-halo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonamide, is first subjected to de-amino tert-butylsulfonyl protection to give compound (R)-4-halo-5,6,7,8-tetrahydroisoquinolin-8-amine;

[0018] The de-amino protected (R)-4-halo-5,6,7,8-tetrahydroisoquinolin-8-amine reacts to give compound (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine with pinacol diborane;

[0019] The compound obtained in step 2) is subjected to Suzuki coupling reaction with 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one to give (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one;

[0020] Finally, the amino group in compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one reacts with allyl chloride to give the target compound Baxdrostat. Specific embodiments

[0021] The application will be further described in conjunction with the following examples which do not limit the scope of the application in any way.

[0022] Example 1

[0023]

[0024] Step A

[0025] Compound 4-bromo-6,7-dihydroisoquinoline-8(5H)-one (1.56 g, 6.9 mmol) and (S)-tert-butylsulfmamide (2.51 g, 20.7 mmol) were dissolved in tetrahydrofuran 20 mL, ethyl titanate (10.08 mL, 48.28 mmol) was added and the reaction was stirred at 65 °C for 48 h. The reaction was cooled to room temperature, ethyl acetate and water were added and stirred for 15 min. The solid obtained was filtered off. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain crude (S,Z)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfmide which was used directly in the next step.

[0026] Step B

[0027] Compound (S,Z)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfmide (1.98 g, 6 mmol) was dissolved in tetrahydrofuran 15 mL and cooled to -45 °C. Sodium borohydride (0.34 g, 9.0 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with ice water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to obtain compound (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfmide (755 mg, yield 38%). LC / MS (ESI): m / z = 331.2 [M+H] + .

[0028] Step C

[0029] To a mixture of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)- / er / -butylsulfmide (0.66 g, 2 mmol), bis(pinacolato)diboron (1.05 g, 2.1 mmol), AcOK (0.578 g, 6 mmol) in toluene (10 mL) was added Pd(dppf)Cl2(0.144 g, 0.2 mmol). The mixture was degassed and stirred at 130 °C for 3 h. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (15 mL) and water (10 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) eluted with 30-40% ethyl acetate in petroleum ether to give (S)-N-ter / -butylsulfonamide-6,7-dihydroisoquinoline-8(5H)-4-boronic acid pinacol ester (0.45 g, yield 60%). LC / MS (ESI): m / z = 378.3 [M+H] + .

[0030] Step D

[0031] To a reaction flask was added compound 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.29 g, 1.2 mmol), (S)-N-ter / -butylsulfonamide-6,7-dihydroisoquinoline-8(5H)-4-boronic acid pinacol ester (0.42 g, 1.26 mmol), dichlorobis(triphenylphosphine)palladium (84 mg, 0.12 mmol), copper(I)iodide (38 mg, 0.2 mmol), triethylamine (1.01 g, 10.0 mmol) and N,N-dimethylformamide 15 mL. Nitrogen was bubbled through the mixture for 3 times and stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and water, and the organic phase was extracted with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography to give compound (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl) / er / -butylsulfonamide (0.37 g, yield 74%) as a yellow solid. LC / MS (ESI): m / z = 411.5 [M+H] + .

[0032] Step E

[0033] Compound (S)-2-methyl-N-((R)-4-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)- 5,6,7,8-tetrahydroisoquinolin-8-yl)tert-butylsulfinamide (0.33 g, 0.80 mmol) was dissolved in dichloromethane 1 mL, trifluoroacetic acid 1 mL was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase preparative column to give compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-l- methyl-3,4-dihydroquinolin-2(lH)-one (0.24 g, 97% yield). LC / MS (ESI): m / z = 307.1 [M+H] + .

[0034] Step F

[0035] To a reaction flask was added (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-l- methyl-3,4-dihydroquinolin-2(lH)-one (100 mg, 0.33 mmol), triethylamine (51 mg, 0.5 mmol), 4 mL tetrahydrofuran, and the reaction was cooled in an ice water bath before slowly adding a solution of propionyl chloride (46.25 mg, 0.5 mmol) in 0.5 mL tetrahydrofuran dropwise. After the addition was complete, the reaction was stirred for an additional 4 hours. The reaction was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the target compound Baxdrostat (46 mg, 38% yield). LC / MS (ESI): m / z = 363.1 [M+H]+. H NMR (400 MHz, CDC13) ppm 1.22 (t, 3 H) 1.79 (s, 3 H) 2.07 (s, 1 H) 2.28 (q, 2 H) 2.43-2.68 (m, 2 H) 2.71 (t, 2 H) 2.82-3.12 (m, 2 H) 3.40 (s, 3 H) 5.34 (d, 1 H) 5.78 (d, 1 H) 7.05 (d, 1 H) 7.09 (s, 1 H) 7.17 (d, 1 H) 8.28 (s, 1 H) 8.49 (s, 1 H)

[0036] Example 2

[0037]

[0038] Step A

[0039] Compound (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-yl)-tert-butylsulfinamide (1.65 g, 5 mmol) was dissolved in dichloromethane 20 mL, trifluoroacetic acid 20 mL was added, the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase preparative column to give compound (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (1.07 g, yield 94%). LC / MS (ESI): m / z = 226.0 [M+H] + .

[0040] Step B

[0041] To a mixture of (R)-4-bromo-5,6,7,8-tetrahydroisoquinoline-8-amine (0.86 g, 3.8 mmol), bis(pinacolato)diboron (2 g, 4 mmol), AcOK (1.10 g, 11.4 mmol) in toluene (10 mL) was added Pd(dppf)Cl2(0.27 g, 0.38 mmol). The mixture was degassed and stirred at 130 °C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (10 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) eluted with 30-40% ethyl acetate in petroleum ether to give (R)-8-amino-5,6,7,8-tetrahydroisoquinoline-4-boronic acid pinacol ester (0.68 g, yield 65%). LC / MS (ESI): m / z = 274.1 [M+H] + .

[0042] Step C

[0043] To a reaction flask was added compound 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.72 g, 3.0 mmol), (R)-8-amino-5,6,7,8-tetrahydroisoquinoline-4-boronic acid pinacol ester (0.99 g, 3.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (210 mg, 0.3 mmol), potassium phosphate monohydrate (204 mg, 0.9 mmol) dissolved in dioxane and water (9:1, 30 mL). Nitrogen was replaced for 3 times, stirred at 90 °C overnight. Cooled to room temperature, the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate. The resulting organic phase was washed with water and saturated brine again, dried over anhydrous sodium sulfate, the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to give compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.81 g, yield 88%). LC / MS (ESI): m / z = 307.1 [M+H]+ The target compound Baxdrostat was prepared in the next step using a similar method as the last step in Example 1.

[0044] Example 3

[0045]

[0046] Step A

[0047] Compound 4-bromo-6,7-dihydroisoquinoline-8(5H)-one (1.88 g, 6.9 mmol) and (S)-tert-butylsulfmamide (2.51 g, 20.7 mmol) were dissolved in tetrahydrofuran 20 mL, ethyl titanate (10.08 mL, 48.28 mmol) was added, the reaction was stirred at 65 °C for 48 hours. Cooled to room temperature, ethyl acetate and water were added, stirred for 15 minutes, the resulting solid was removed by filtration. The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product (S,Z)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfmide, which was used directly in the next step. LC / MS (ESI): m / z = 376.2 [M+H] + .

[0048] Step B

[0049] Compound (S,Z)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfmide (2.26 g, 6 mmol) was dissolved in tetrahydrofuran 15 mL, cooled to -45 °C. Sodium borohydride (0.36 g, 9.0 mmol) was added, and the reaction was stirred at room temperature for 18 hours. Quenched with ice water, extracted with dichloromethane. The resulting organic phase was washed with saturated brine again, dried with anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to obtain compound (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfmide (1.04 g, yield 46%). LC / MS (ESI): m / z = 378.0 [M+H] + .

[0050] Step C

[0051] To a mixture of (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfmide (0.76 g, 2 mmol), bis(pinacolato)diboron (1.05 g, 2.1 mmol), AcOK (0.578 g, 6 mmol) in toluene (10 mL) was added Pd(dppf)Cl2(0.144 g, 0.2 mmol). The mixture was degassed and stirred at 130 °C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (15 mL) and water (10 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) eluted with 30-40% ethyl acetate in petroleum ether to give (S)-N-tert-butylsulfonamide-6,7-dihydroisoquinoline-8(5H))-4-boronic acid pinacol ester (0.51 g, yield 68%). LC / MS (ESI): m / z = 378.2 [M+H] + .

[0052] The next three steps were prepared to give the target compound Baxdrostat in the same way as in Example 1.

[0053] Example 4

[0054]

[0055] Step A

[0056] Compound (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfmide (1.89 g, 5 mmol) was dissolved in dichloromethane 20 mL, trifluoroacetic acid 20 mL was added, the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase preparative column to give compound (R)-4-iodo-5,6,7,8-tetrahydroisoquinoline-8-amine (1.32 g, yield 96%). LC / MS (ESI): m / z = 274.0 [M+H] + .

[0057] Step B

[0058] To a mixture of (R)-4-iodo-5,6,7,8-tetrahydroisoquinoline-8-amine (1.04 g, 3.8 mmol), bis(pinacolato)diboron (2 g, 4 mmol), AcOK (1.10 g, 11.4 mmol) in toluene (10 mL) was added Pd(dppf)Cl2(0.27 g, 0.38 mmol). The mixture was degassed and stirred at 130 °C for 3 h. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (10 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) eluted with 30-40% ethyl acetate in petroleum ether to give (R)-8-amino-5,6,7,8-tetrahydroisoquinoline-4-boronic acid pinacol ester (0.75 g, yield 72%). LC / MS (ESI): m / z = 274.1 [M+H] + H NMR (400 MHz, CDC13) ppm 1.22 (t, 3 H) 1.79 (s, 3 H) 2.07 (s, 1 H) 2.28 (q, 2 H) 2.43 - 2.68 (m, 2 H) 2.71 (t, 2 H) 2.82 - 3.12 (m, 2 H) 3.40 (s, 3 H) 5.34 (d, 1 H) 5.78 (d, 1 H) 7.05 (d, 1 H) 7.09 (s, 1 H) 7.17 (d, 1 H) 8.28 (s, 1 H) 8.49 (s, 1 H)

[0059] The next two steps were prepared using the same method as in Example 2 to give the target compound Baxdrostat.

[0060] The above examples are only used to illustrate the embodiments of the present application, but the present application is not limited to the above examples only. The present application can have various changes and improvements without departing from the spirit and scope of the present application, and these changes and improvements all fall within the scope of the present application claimed, the scope of the present application is defined by the claims and their equivalents.

Claims

1. A process for the preparation of the CYP11B2 inhibitor BAXDROSTAT, characterized in that, The process comprises the following specific steps: 1) Aldehyde ketone condensation reaction of raw material 4-bromo-6,7- dihydroisoquinoline-8(5H)-ketone with S-tert-butylsulfonamide to obtain (S,Z)-N-(4- bromo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonylimide; 2) Reduction by sodium borohydride to obtain compound (S)-N-(4-bromo-6,7- dihydroisoquinoline-8(5H))-tert-butylsulfonylimide; 3) Reaction of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonyl imide with bis(pinacolato)diboron to obtain compound (S)-N-tert-butylsulfonylimide-6,7- dihydroisoquinoline-8(5H))-4-pinacolboronate; 4) Further Suzuki coupling reaction with 6-bromo-1-methyl-3,4-dihydroquinoline- 2(1H)-ketone to obtain compound (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-6-yl)-5,6,7,8-tetrahydroisoquinoline-8-yl)tert-butylsulfonylimide; 5) The product in step 4) is subjected to tert-butylsulfonyl protecting group removal to obtain (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinoline-4-yl)-1-methyl-3,4- dihydroquinoline-2(1H)-ketone; 6) Finally, reaction of the amino group in compound (R)-6-(8-amino-5,6,7,8- tetrahydroisoquinoline-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-ketone with propionyl chloride to obtain target compound Baxdrostat; In step 1), the reaction temperature is selected from 20-240°C, and the reaction time is selected from 0.5-72h; the solvent used is selected from one or more of toluene, carbon tetrachloride, chlorobenzene, diphenyl ether, n-hexane, n-heptane, n-pentane, petroleum ether, benzene, THF, 2-Me-THF, DME, MTBE, diethyl ether, butyl ether, isopropyl ether, DMA, DMSO; the auxiliary reagent used is selected from one or both of ethyl titanate or isopropyl titanate; the product is selected from crude product for use, and the purification is selected from column chromatography, slurry, Prep-TLC, Prep-HPLC or recrystallization.

2. A process for the preparation of a CYP11B2 inhibitor BAXDROSTAT as claimed in claim 1, wherein, In step 2), the reaction temperature is selected from -78-150°C, and the reaction time is selected from 0-72h; the solvent used is selected from one or more of toluene, carbon tetrachloride, chlorobenzene, diphenyl ether, n-hexane, n-heptane, n-pentane, petroleum ether, benzene, THF, 2-Me-THF, DME, MTBE, diethyl ether, butyl ether, isopropyl ether, DMA, DMSO, water, methanol, ethanol, isopropyl alcohol; Lewis acid is added or not; the product is selected from crude product for use, and the purification is selected from column chromatography, slurry, Prep-TLC, Prep-HPLC or recrystallization.

3. The method for preparing the CYP11B2 inhibitor BAXDROSTAT as described in claim 1, characterized in that, Step 3) reaction temperature is selected from 10-200 °C, reaction time is selected from 0-72 h, solvent is selected from one or two of diethyl ether, acetonitrile, THF, DMF, DME, 1,4-dioxane, NMP, DMA, DMSO, benzene, toluene; catalyst used in the reaction can be selected from one or more of bis(triphenylphosphine)-palladium dichloride, bis(triphenylphosphine)ferrocene palladium dichloride, bis(triphenylphosphine)ferrocene palladium dichloride dichloromethane complex, Pd2(dba)3, pd(dppe)Cl2; base used in the reaction is selected from one of triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, CsCO3, KOAc, NaOAc, K2CO3, tBuOK, tBuONa; purification is selected from column chromatography, trituration, Prep-TLC, Prep-HPLC or recrystallization.

4. The method for preparing the CYP11B2 inhibitor BAXDROSTAT as described in claim 1, characterized in that, Suzuki coupling reaction temperature is selected from 10-200 °C, reaction time is selected from 0-72 h, solvent is selected from one or two of diethyl ether, acetonitrile, THF, DMF, DME, 1,4-dioxane, NMP, DMA, DMSO, benzene, toluene; catalyst used in the reaction can be selected from one or more of bis(triphenylphosphine)-palladium dichloride, bis(triphenylphosphine)ferrocene palladium dichloride, bis(triphenylphosphine)ferrocene palladium dichloride dichloromethane complex, Pd2(dba)3, pd(dppe)Cl2, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)ferrocene nickel dichloride, base used in the reaction is selected from one of triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, CsCO3, KOAc, NaOAc, K2CO3, Na2CO3, Li2CO3, tBuOK, tBuONa, K3PO4, NaOH, KOH, Ba(OH)2; purification is selected from column chromatography, trituration, Prep-TLC, Prep-HPLC or recrystallization.

5. The method for preparing the CYP11B2 inhibitor BAXDROSTAT as described in claim 1, characterized in that, De-tert-butylsulfinyl reaction temperature is selected from 10-200 °C, reaction time is selected from 0-72 h, solvent is selected from one or two of DCM, 1,2-dichloroethane, chlorobenzene, acetonitrile, THF, 2-MeTHF, DMF, DME, 1,4-dioxane, NMP, DMAC, DMSO; acid used is selected from one or two of trifluoroacetic acid, hydrochloric acid; product is selected from crude down, purification is selected from column chromatography, trituration, Prep-TLC, Prep-HPLC or recrystallization.

6. The method for preparing the CYP11B2 inhibitor BAXDROSTAT as described in claim 1, characterized in that, The reaction temperature for the last step is selected from -50-100 °C, the reaction time is selected from 0-24 h, the solvent is selected from one or more of DCM, 1,2-dichloroethane, chlorobenzene, acetonitrile, THF, 2-MeTHF, DMF, DME, 1,4-dioxane, NMP, DMAC, DMSO, the base used is selected from one or more of triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, DMAP, CsCO3, KOAc, NaOAc, K2CO3, Na2CO3, the reaction quencher is selected from one or more of methanol, ethanol, isopropanol, or H2O; product purification is selected from column chromatography, trituration, Prep-TLC, Prep-HPLC, or recrystallization.

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