Preparation method of steroid compound

Abstract

The invention discloses a preparation method of a steroid compound. Specifically, the invention discloses a preparation method of (3S, 10R, 13S)-10, 13-dimethyl-17-(4-methyl-1H-imidazole-1-yl)-2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15-dodecahydro-1H-cyclopentadiene [a] phenanthrene-3-ol, and a preparation method of the (3S, 10R, 13S)-10, 13-dimethyl-17-(4-methyl-1H-imidazole-1-yl)-2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15-dodecahydro-1H-cyclopentadiene [a] Compared with the prior art, the method disclosed by the invention has the advantages of few reaction steps, simplicity in operation, low cost, high yield, greenness, environmental friendliness and the like, and the final product does not need column chromatography purification, is more suitable for large-scale production and is beneficial to popularization.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol. Background Art

[0002] Prostate cancer is a multi-stage progressive disease. Almost all prostate cancers will develop into lethal metastatic castration-resistant prostate cancer (mCRPC) in the advanced stage, seriously threatening male health. The androgen / androgen receptor (AR) signaling pathway plays a crucial role in mCRPC patients and has become an important research field for the treatment of mCRPC.

[0003] YXG-158 is the first reported compound with a dual mechanism of action of AR degradation and inhibition of androgen synthase (CYP17A1) (J. Med. Chem. 2023, 66, 9972-9991). While inhibiting androgen synthesis, it can simultaneously degrade AR. Compared with AR antagonists or androgen synthase inhibitors, it can more completely and thoroughly block the androgen / AR signaling pathway. YXG-158 exhibits potent anti-tumor activity in two mouse xenograft tumor models sensitive and resistant to enzalutamide, and can be used for the treatment of enzalutamide-sensitive and resistant mCRPC patients.

[0004] Compound I, with the chemical name (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, is a key intermediate in the preparation method of YXG-158. Currently, its main synthetic route is as follows:

[0005]

[0006] Using dehydroepiandrosterone acetate 1 as the starting material, the Vilsmeier-Haack reaction was carried out to obtain compound 2 (WO2012083112A2), followed by an addition-elimination reaction with 4-methylimidazole to obtain compound 3 (WO2023131310A1). Subsequently, decarbonylation was carried out using palladium on carbon to obtain compound 4, and finally, the ester group was hydrolyzed in a methanol solution of sodium methoxide to obtain compound I. The whole reaction has four steps. In the first step, the high-risk reagent phosphorus oxychloride needs to be used, and a large amount of waste acid is generated during the post-treatment of the reaction. In the third step, a large amount of palladium on carbon is used, resulting in high cost and a large amount of solid waste, and the yield is low. The whole synthesis process is cumbersome and requires column chromatography purification, which is not conducive to industrial production.

[0007] Therefore, there is an urgent need for a method for synthesizing the YXG-158 intermediate (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol that is environmentally friendly, simple to operate, has a high yield, and is suitable for large-scale production. Summary of the Invention

[0008] To solve the above problems, the present invention provides a method for synthesizing the YXG-158 intermediate (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol that is environmentally friendly, simple to operate, has a high yield, and is suitable for large-scale production.

[0009] In the first aspect of the present invention, a method for preparing (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol is provided, including the following reaction steps:

[0010]

[0011] Under the action of a catalyst, compound 5 and 4-methylimidazole undergo an Ullmann coupling reaction under alkaline conditions to obtain (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, that is, compound I;

[0012] Wherein the catalyst includes monovalent copper and its ligand.

[0013] In a preferred embodiment, the molar ratio of the compound 5 to 4-methylimidazole is 1:(1 to 5), preferably 1:(1 to 2), more preferably 1:(1 to 1.5).

[0014] In a preferred embodiment, the basic condition of the reaction is provided by a base selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, anhydrous sodium acetate, potassium phosphate, or a combination thereof.

[0015] In another preferred embodiment, the basic condition is provided by potassium carbonate.

[0016] In a preferred embodiment, the molar ratio of the compound 5 to the base is 1:(1 to 5); preferably 1:(1 to 4); more preferably 1:(1 to 3).

[0017] In a preferred embodiment, the monovalent copper is selected from the group consisting of cuprous iodide, cuprous chloride, cuprous bromide, or a combination thereof.

[0018] In a preferred embodiment, the ligand is selected from the group consisting of 8-hydroxyquinoline, 2-hydroxyquinoline, 6-hydroxyquinoline, proline, sarcosine, N,N-dimethylglycine hydrochloride, 2-pipecolic acid, 2-acetylcyclohexanone, or a combination thereof.

[0019] In another preferred embodiment, the monovalent copper is cuprous iodide.

[0020] In another preferred embodiment, the ligand is 8-hydroxyquinoline.

[0021] In a preferred embodiment, the molar ratio of the compound 5 of formula 5 to the monovalent copper is 1:(0.01 to 1), preferably 1:(0.01 to 0.5), more preferably 1:(0.01 to 0.2).

[0022] In a preferred embodiment, the molar ratio of the compound 5 to the ligand is 1:(0.01 to 1.2), preferably 1:(0.01 to 0.8), more preferably 1:(0.05 to 0.6).

[0023] In a preferred embodiment, the reaction is carried out in the presence of a solvent, and the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, 1,4-dioxane, acetonitrile, or a combination thereof.

[0024] In another preferred embodiment, the solvent is N,N-dimethylformamide.

[0025] In another preferred embodiment, the mass-volume ratio of the compound 5 to the solvent is 1:(1 to 12), preferably 1:(1 to 10), more preferably 1:(2 to 8).

[0026] In a preferred embodiment, the temperature of the reaction is 80 to 200 °C, preferably 80 to 180 °C, more preferably 100 to 160 °C;

[0027] The reaction time is 8 to 48 hours, preferably 8 to 38 hours, more preferably 16 to 28 hours.

[0028] In another preferred embodiment, the reaction further comprises the following steps: removing the isomers of compound I from the crude reaction product by a purification method

[0029] In another preferred embodiment, the purification method is selected from the group consisting of: salting out, liberation, trituration, or a combination thereof.

[0030] In another preferred embodiment, the purification method is a combination of salting out, liberation and trituration, and comprises the following steps:

[0031] S1. Adding ammonia water and water to the reaction solution after the reaction is completed, filtering, and drying to obtain dry solid 1;

[0032] S2. Triturating dry solid 1 with acetone, filtering, and drying at 50 to 65 °C to obtain dry solid 2;

[0033] S2. Triturating dry solid 2 with 2 to 5 M sodium hydroxide, filtering, and drying to obtain dry solid 3;

[0034] S3. Dissolving dry solid 3 in a mixed solvent of dichloromethane and methanol, adding 1 to 3 M hydrochloric acid, filtering, and drying to obtain the hydrochloride salt of compound I;

[0035] S4. Dissolving the hydrochloride salt of compound I obtained in S3 in methanol, adding 2 to 5 M sodium hydroxide, filtering, and drying to obtain the crude product of compound I;

[0036] S5. Then triturating the crude product of compound I with anhydrous methanol 2 to 5 times, filtering, and drying under vacuum at 60 to 70 °C to obtain the pure product of compound I.

[0037] In another preferred embodiment, the purification method is trituration, and comprises the following steps: dispersing the reaction product in a trituration solvent and triturating 1 to 8 times.

[0038] In another preferred embodiment, the number of trituration times is 2 to 5 times.

[0039] In another preferred embodiment, the trituration solvent is selected from the group consisting of: acetone, anhydrous methanol, ethanol, methyl tert-butyl ether, acetonitrile, isopropanol, ethyl acetate, tetrahydrofuran, or a combination thereof.

[0040] In another preferred embodiment, the trituration solvent is anhydrous methanol.

[0041] In another preferred example, the volume of the beating solvent is 2 to 30 times (v / w), preferably 5 to 20 times, more preferably 8 to 15 times the mass of the crude product.

[0042] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Brief Description of the Drawings

[0043] Figure 1 The high performance liquid chromatography (HPLC) chromatogram of Compound I of the present invention is shown.

[0044] Figure 2 The chiral high performance liquid chromatography (HPLC) chromatogram of Compound I of the present invention is shown. Detailed Description of the Invention

[0045] Through long-term and in-depth research and extensive screening, the inventors have for the first time developed a method for preparing the YXG-158 intermediate (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol with fewer reaction steps and being green and environmentally friendly. The method of the present invention is simple to operate, low in cost, high in yield, does not require column chromatography purification, and is suitable for large-scale production. Based on this, the inventors have completed the present invention.

[0046] Abbreviations

[0047] TLC: Thin Layer Chromatography

[0048] HPLC: High Performance Liquid Chromatography

[0049] DCM: Dichloromethane

[0050] MeOH: Methanol

[0051] MTBE: Methyl tert-butyl ether

[0052] Main advantages of the present invention:

[0053] 1. Compared with the prior art, the method of the present invention has the advantages of fewer reaction steps (shortened from 4 steps to 1 step), simple operation, low cost, high yield, and being more green and environmentally friendly.

[0054] 2. Compared with the prior art, the end product of the present invention does not require column chromatography purification, is more suitable for large-scale production, and is conducive to promotion.

[0055] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight percentage and weight parts.

[0056] Example 1

[0057] Dissolve compound 5 (50 g, 0.126 mol, 1 eq), 8-hydroxyquinoline (1.8 g, 0.0126 mol, 0.1 eq), copper(I) iodide (1.2 g, 0.006 mol, 0.05 eq), potassium carbonate (43.4 g, 0.314 mol, 2.5 eq) and 4-methylimidazole (12.3 g, 0.151 mol, 1.2 eq) in N,N-dimethylformamide (300 mL, 6V), protect with argon, slowly heat up to 155 °C, react for 20 h, and monitor the reaction process by TLC (methylene chloride:methanol = 20:1).

[0058] After the reaction is completed, cool the system to room temperature, then add ammonia water (80 mL) and water (300 mL). At this time, a large amount of solid precipitates. After stirring for 1 h, filter, wash the filter cake three times with water, drain, transfer to a bottle, slurry with acetone (350 mL, 7V) for 2 h, filter, wash the filter cake once with 20 mL of acetone, dry at 55 °C for 4 h. The dried solid is slurried with 200 mL of 4M sodium hydroxide aqueous solution for 1 h to further remove copper salts, filter, and dry.

[0059] Then dissolve all the dried solid in methylene chloride:methanol = 7:1 (350 mL:50 mL), add 350 mL of 2M hydrochloric acid aqueous solution, stir vigorously for 4 h, and gradually precipitate solid. Filter, wash the filter cake once with 20 mL of methylene chloride and twice with 20 mL of water. Then collect the filter cake and place it in a vacuum drying oven at 65 °C for 12 h. Then dissolve the solid in 180 mL of methanol, stir until clear, and then slowly add 180 mL of 4M sodium hydroxide aqueous solution, stir for 40 min. At this time, a large amount of grayish-white solid precipitates. Filter with a Buchner funnel, wash the filter cake three times with water, collect the filter cake and place it in a vacuum drying oven at 65 °C for drying, to obtain 23.756 g of crude product, with a total yield of 53.62%.

[0060] NMR shows that the ratio of compound I to isomer I-1 in the obtained crude product is 1:0.05, that is, the purity of compound I is 95.24% and the isomer content is 4.76%. Use HPLC to accurately verify the purity of compound I in the crude product. HPLC shows that the purity of compound I is 91.2% and the content of isomer I-1 is 8.8%.

[0061] Then it was slurried with 280 mL (12 V) of anhydrous methanol for 1.5 h, filtered through a Buchner funnel. When no filtrate was dripping, the filter cake was collected. Then it was slurried with anhydrous methanol for the second and third times, repeating the above operation. Finally, the filter cake was placed in a vacuum drying oven at 65 °C to obtain 15.3 g of pure compound I, which was a grayish-white solid. The total yield was 34%, and the purity by HPLC was 97.4732%. See Figure 1 and Table 1.

[0062] NMR showed that the ratio of compound I to isomer I-1 in the obtained pure product was 1:0.00. Further verification was carried out using chiral HPLC. Chiral HPLC showed that the purity of compound I was 99.818% and the content of isomer I-1 was 0.182%. See Figure 2 and Table 2.

[0063] HPLC conditions: Detection wavelength, 254 nm, mobile phase, 0.1% methanol solution, Agilent ZORBAX RX-C18 5 μm 4.6 * 250 mm.

[0064] 1 1H NMR (600 MHz, CDCl3) δ 7.67 (s, 1H), 6.81 (s, 1H), 5.69 (s, 1H), 5.40 (s, 1H), 3.56 (s, 1H), 2.34 (s, 1H), 2.29 (s, 5H), 2.05 (t, J = 13.0 Hz, 2H), 1.96 (s, 1H), 1.87 (s, 2H), 1.78 - 1.65 (m, 5H), 1.61 (d, J = 6.8 Hz, 2H), 1.54 (d, J = 11.8 Hz, 1H), 1.12 (d, J = 8.4 Hz, 1H), 1.08 (s, 3H), 1.02 (s, 3H).

[0065] Table 1. Report form of chromatographic peak area percentage of compound I

[0066]

[0067] Table 2. Report form of chromatographic peak area percentage of compound I

[0068]

[0069] Example 2

[0070] Dissolve compound 5 (5 g, 12.5 mmol, 1 eq), 8-hydroxyquinoline (0.182 g, 1.25 mmol, 0.1 eq), cuprous iodide (0.12 g, 0.628 mmol, 0.05 eq), potassium carbonate (4.34 g, 31.25 mmol, 2.5 eq) and 4-methylimidazole (1.24 g, 15 mmol, 1.2 eq) in N,N-dimethylformamide (30 mL, 6V), protect with argon, slowly heat up to 155 °C, react for 20 h, and monitor the reaction process by TLC (methylene chloride:methanol = 20:1).

[0071] After the reaction is completed, cool the system to room temperature, then add ammonia water (8 mL) and water (30 mL). At this time, a large amount of solid precipitates. After stirring for 1 h, filter, wash the filter cake with water three times, drain, transfer to a bottle, slurry with acetone (35 mL, 7V) for 2 h, filter, wash the filter cake with 2 mL of acetone once, dry at 55 °C for 4 h. The dried solid is slurried with 20 mL of 4M sodium hydroxide aqueous solution for 1 h to further remove copper salts, filter and dry. Then dissolve all the dried solid in methylene chloride:methanol = 7:1 (35 mL:5 mL), add 35 mL of 2M hydrochloric acid aqueous solution, stir vigorously for 4 h, and gradually precipitate solid. Filter, wash the filter cake with 2 mL of methylene chloride once and 2 mL of water twice in sequence. Then collect the filter cake and place it in a vacuum drying oven at 65 °C for drying for 12 h to obtain 2.95 g of crude product, which is an off-white solid. The total yield is 60.2%. NMR shows that the ratio of compound I to compound I-1 in the obtained crude product is 3:1.

[0072] Example 3

[0073] Dissolve compound 5 (1 g, 2.5 mmol, 1.0 eq), 8-hydroxyquinoline (72.9 mg, 0.5 mmol, 0.2 eq), cuprous iodide (47.8 mg, 0.25 mmol, 0.1 eq), potassium carbonate (868 mg, 6.28 mmol, 2.5 eq) and 4-methylimidazole (247 mg, 3.015 mol, 1.2 eq) in N,N-dimethylformamide (4 mL, 4V), protect with argon, slowly heat up to 155 °C, react for 24 h, and monitor the reaction process by TLC (methylene chloride:methanol = 20:1).

[0074] After the reaction was completed, the reaction system was cooled to room temperature, 15 mL of saturated ammonium chloride and 15 mL of (DCM:MeOH = 20:1) were added and stirred. The flocculants were filtered through diatomaceous earth, and the filter cake was washed three times with 5 mL of (DCM:MeOH = 20:1). The filtrate was transferred to a separatory funnel for extraction. The aqueous layer was extracted twice with 15 mL of (DCM:MeOH = 20:1). The organic layers were combined, washed three times with saturated ammonium chloride, once with saturated sodium chloride, once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0.3 - 2% DCM / MeOH) to obtain 20 mg of the crude product, with an overall yield of 60%. NMR showed that the ratio of compound I to compound I-1 was 3:1.

[0075] Example 4

[0076] Compound 5 (20 g, 0.05 mol, 1.0 eq), N,N-dimethylglycine hydrochloride (2.8 g, 0.02 mol, 0.4 eq), copper(I) iodide (1.9 g, 0.01 mol, 0.2 eq), potassium carbonate (28 g, 0.1 mol, 2.0 eq) and 4-methylimidazole (4.4 g, 0.055 mol, 1.1 eq) were dissolved in N,N-dimethylformamide (120 mL, 6V), protected with argon, slowly heated to 155 °C, and reacted for 24 h. The reaction progress was monitored by TLC (dichloromethane:methanol = 20:1).

[0077] After the reaction was completed, the reaction system was cooled to room temperature, then 32 mL of ammonia water and 120 mL of water were added. A large amount of solid precipitated at this time. After stirring for 1 h, the mixture was filtered, and the filter cake was washed three times with water. Then the filter cake was rinsed successively with 400 mL of DCM and 150 mL of (DCM:MeOH = 20:1). The rinsing solutions were combined, then 32 mL of ammonia water and 120 mL of water were added and stirred for 30 min. Subsequently, it was extracted three times with 140 mL of DCM:MeOH = 20:1. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and finally slurried with 130 mL of methyl tert-butyl ether for 1 h. After filtration, the filter cake was washed three times with 20 mL of methyl tert-butyl ether. The filter cake was collected and dried in a vacuum drying oven at 65 °C to obtain 8.68 g of the crude product, which was a grayish-white solid, with an overall yield of 50%. NMR showed that the ratio of compound I to compound I-1 in the crude product was 3:1.

[0078] Example 5

[0079] Dissolve compound 5 (5 g, 12.5 mmol, 1 eq), 8-hydroxyquinoline (0.73 g, 2.5 mmol, 0.2 eq), cuprous iodide (240 mg, 1.25 mmol, 0.1 eq), anhydrous sodium acetate (2.57 g, 31.25 mmol, 2.5 eq) and 4-methylimidazole (1.3 g, 15 mmol, 1.2 eq) in N,N-dimethylformamide (30 mL, 6V), protect with argon, slowly heat to 155 °C, react for 24 h, and monitor the reaction progress by TLC (dichloromethane:methanol = 20:1).

[0080] After the reaction is completed, cool the system to room temperature, add saturated ammonium chloride (15 mL), 15 mL (DCM:MeOH = 20:1), stir, filter the floccules through diatomaceous earth, wash the filter cake three times with DCM:MeOH = 20:1, transfer the filtrate to a separatory funnel for extraction, extract the aqueous layer twice with 15 mL (DCM:MeOH = 20:1), combine the organic layers, wash three times with saturated ammonium chloride, wash once with saturated sodium chloride, wash once with water, dry over anhydrous sodium sulfate, filter, concentrate, slurry twice with 25 mL of MTBE for 1 h each time, filter, wash the filter cake three times with MTBE, collect the filter cake and dry it in a vacuum drying oven at 65 °C to obtain 0.88 g of the product, with a total yield of 20%. NMR shows that the ratio of compound I to compound I-1 in the product is 3:1.

[0081] Example 6

[0082] Repeat the operation of Example 3, the only difference is using sarcosine instead of 8-hydroxyquinoline as the ligand, with a total yield of 14.9%. NMR shows that the ratio of compound I to compound I-1 in the product is 3:1.

[0083] Example 7

[0084] Repeat the operation of Example 3, the only difference is using dimethyl sulfoxide instead of N,N-dimethylformamide as the solvent, with a total yield of 2.26%. NMR shows that the ratio of compound I to compound I-1 in the product is 3:1.

[0085] Example 8

[0086] Repeat the operation of Example 4, the only difference is using 10-hydroxybenzo[h]quinoline instead of 8-hydroxyquinoline as the ligand, and the result shows that almost no product is formed.

[0087] Example 9

[0088] Repeat the operation of Example 4, the only difference is using 1,10-phenanthroline instead of 8-hydroxyquinoline as the ligand, and the result shows that almost no product is formed.

[0089] Example 10

[0090] In this example, the method for preparing compound YXG-158 from compound I is shown by the following synthetic route.

[0091]

[0092] Synthesize compound 5

[0093] Under argon protection, compound I (21 g, 0.0596 mol, 1 eq) was suspended in anhydrous dichloromethane (420 mL, 20 V), triethylamine (24.85 mL, 3.0 eq) was added, and the mixture was stirred at room temperature for 15 min. Methanesulfonyl chloride (9.2 mL, 2.0 eq) was slowly added dropwise, and bubbles were generated. After the addition was complete, the solution became clear. The reaction was carried out at 25 °C, and the reaction progress was monitored by TLC (dichloromethane:methanol = 20:1). After the reaction was completed in 2 h, it was transferred to an ice bath, and the reaction was quenched by adding water under the ice bath. Then, it was extracted with dichloromethane successively. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 5 as a foamy yellow oil, HPLC = 91.958%. It was directly fed into the next step at a 100% yield.

[0094] 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.80 (s, 1H), 5.69 (d, J = 1.3 Hz 1H), 5.47 (d, J = 4.8 Hz 1H), 4.60 - 4.69 (m, 1H), 3.04 (s, 3H), 2.28 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H).

[0095] Synthesize compound 6

[0096] Under the protection of argon, the above-mentioned foamy yellow oily product was dissolved in anhydrous dichloromethane (210 mL, 10V) and stirred in an ice bath. Then, trimethylsilyl azide (54.8 mL, 0.4173 mol, 7 eq) was added, and the mixture was stirred for 5 min. Boron trifluoride diethyl ether complex (45 mL, 0.3577 mol, 6 eq) was added dropwise. After the addition was complete, the mixture was stirred for 10 min and transferred to a reaction at 25 °C. The reaction process was monitored by TLC (dichloromethane: methanol = 20:1). After 12 h, the reaction was monitored by HPLC until completion. The system was transferred to an ice bath, and a 30% methanol solution of sodium methoxide (12 eq) was slowly added dropwise to quench the reaction. The solution gradually became white and turbid with bubbles, and the bubbles gradually dissipated during stirring. After the addition was complete, the mixture was stirred in an ice bath for 40 min and then transferred to room temperature and stirred for 24 h. TLC was used to spot the plate, and the bound state had been converted to the free state product. A small amount of the reaction solution was taken and extracted with water. The dichloromethane layer was injected into HPLC with a purity of 94%. Then, it was extracted with water and dichloromethane. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated at room temperature (22 °C) to obtain compound 6, which was used in the next step of the reaction in 100% yield.

[0097] 1 H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 6.84 (s, 1H), 5.92 - 5.88 (m, 1H), 5.42 (d, J = 4.9 Hz 1H), 3.27 - 3.17 (m, 1H), 2.39 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0098] Synthesis of compound 7

[0099] Under the protection of argon, the above-mentioned concentrated compound 6 was dissolved in tetrahydrofuran: water = 4:1 (210 mL: 52.5 mL), triphenylphosphine (23.4553 g, 0.0894 mol, 1.5 eq) was added, and the mixture was transferred to an oil bath and heated to 60 °C for reaction. The reaction process was monitored by TLC (dichloromethane: methanol = 20:1 for the raw material, dichloromethane: methanol = 10:1 for the product). After 7 h, the solvent was concentrated by rotary evaporation, then dichloromethane was added, and 2M hydrochloric acid was added dropwise in an ice bath to adjust the pH to strongly acidic, and a large amount of white solid precipitated. Then, water and dichloromethane were added for extraction. The aqueous layer was collected and 2M sodium hydroxide was added dropwise in an ice bath to adjust the pH to strongly basic, and a large amount of solid precipitated again. The solid was filtered, and the filter cake was washed three times with water and dried in vacuo at 55 °C for 12 h to obtain the crude product of compound 7. Then, it was slurried with 6V methyl tert-butyl ether for 1 h, and after drying, 14.6 g of white solid of compound 7 was obtained, HPLC = 97.454%, and the overall yield of three steps was 69.7%.

[0100] 1H NMR (600 MHz, DMSO) δ 7.69 (s, 1H), 7.04 (s, 1H), 5.73 (s, 1H), 5.41 (s, 1H), 2.10 (s, 3H), 0.99 (d, J=12.6 Hz, 3H), 0.97 (s, 3H).

[0101] Synthesis of compound YXG-158

[0102] Under argon protection, compound 7 (6.0 g, 0.017 mmol, 1 eq) and 4-dimethylaminopyridine (208 mg, 0.0017 mmol, 0.1 eq) were dissolved in anhydrous dichloromethane and stirred in an ice bath. Then, triethylamine (4.0 mL, 0.029 mmol, 1.5 eq) was added. After stirring for 5 min, 4-fluorobenzoyl chloride (2.6 mL, 0.022 mmol, 1.2 eq) was added. After the addition was complete, the mixture was stirred at room temperature and monitored by TLC (dichloromethane:methanol = 20:1). After the reaction was completed in 2 h, water was added, and then extracted with DCM. The organic layers were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a foamy solid. Then, it was recrystallized from 6V anhydrous ethanol to obtain 6.2 g of a white solid of compound YXG-158, HPLC = 99.302%, and the yield was 72%.

[0103] 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.0 Hz, 1H), 7.92 (dd, J=8.7, 5.6 Hz, 2H), 7.70 (s, 1H), 7.30 (t, J=8.9 Hz, 2H), 7.06 (s, 1H), 5.74 (s, 1H), 5.38 (d, J=4.3 Hz, 1H), 3.72 (dd, J=12.0, 4.2 Hz, 1H), 2.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H).

[0104] All documents mentioned in the present invention are incorporated herein by reference as if each individual document was specifically and individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A method for preparing (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, characterized in that, It includes the following reaction steps: Under the action of a catalyst, compound 5 and 4-methylimidazole undergo an Ullmann coupling reaction under alkaline conditions to obtain (3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, namely compound I; Wherein the catalyst includes monovalent copper and its ligand.

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound 5 to 4-methylimidazole is 1:(1-5), preferably 1:(1-2), more preferably 1:(1-1.5).

3. The preparation method according to claim 1, wherein The reaction alkaline conditions are provided by a base selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, anhydrous sodium acetate, potassium phosphate, or a combination thereof.

4. The preparation method according to claim 1, characterized in that, The molar ratio of compound 5 to the base is 1:(1-5); preferably 1:(1-4); more preferably 1:(1-3).

5. The preparation method according to claim 1, characterized in that, The monovalent copper is selected from the group consisting of cuprous iodide, cuprous chloride, cuprous bromide, or a combination thereof.

6. The preparation method according to claim 1, characterized in that, The ligand is selected from the group consisting of 8-hydroxyquinoline, 2-hydroxyquinoline, 6-hydroxyquinoline, proline, sarcosine, N,N-dimethylglycine hydrochloride, 2-pipecolic acid, 2-acetylcyclohexanone, or a combination thereof.

7. The preparation method according to claim 5, characterized in that, The molar ratio of the compound of formula 5 to monovalent copper is 1:(0.01-1), preferably 1:(0.01-0.5), more preferably 1:(0.01-0.2).

8. The preparation method according to claim 5, characterized in that, The molar ratio of compound 5 to the ligand is 1:(0.01-1.2), preferably 1:(0.01-0.8), more preferably 1:(0.05-0.6).

9. The preparation method according to claim 1, characterized in that, The reaction is carried out in the presence of a solvent, and the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, acetonitrile, or a combination thereof.

10. The preparation method according to claim 1, characterized in that, The reaction temperature is 80-200 °C, preferably 80-180 °C, more preferably 100-160 °C; The reaction time is 8-48 hours, preferably 8-38 hours, more preferably 16-28 hours.

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