Preparation method of chloranoron and intermediate thereof

Abstract

The invention provides a preparation method of chloranoron and an intermediate compound 6 thereof, the preparation method of the compound 6 comprises the following steps: reacting a compound 3 with a cyanation reagent, and then hydrolyzing under an acidic condition to generate a compound 4, and the compound 4 obtained by the method is basically 17beta-CN and is free of 17alpha-CN. Then, the compound 4 is subjected to nucleophilic addition reaction of 3-position carbonyl and 17-position cyano of the compound 4 with a Grignard reagent, and a target compound 6 is generated. According to the preparation method of the compound 6 provided by the invention, the reaction yield of each step is relatively high, the obtained crude product can be directly used for next-step reaction or used for next-step reaction after simple pulping and purification, and the preparation method is suitable for industrial large-scale production. R1 and R2 in structural formula 3 of # imgabs0 # imgabs1 # jointly form structure of # imgabs2 # imgabs3 #

Description

Technical Field

[0001] The invention belongs to the field of organic compound synthesis, and more specifically, relates to a method for preparing a raw material drug, julannolon and an intermediate thereof. Background Art

[0002] The gamma-aminobutyric acid type A (GABAA) receptors and N-methyl-D-aspartate (NMDA) receptors in the brain play the role of inhibiting and stimulating the generation of nerve impulses by brain neurons, respectively. Julannolon is a new generation of positive allosteric modulators of GABAA receptors, which can simultaneously regulate the functions of GABAA receptors located inside and outside the synapses, and restore the balance between the activity of GABAA receptors and NMDA receptors in the brain. Therefore, Julannolon has the potential to treat mental illnesses including depression. Previously, the drug was granted breakthrough therapy designation by the FDA for the treatment of major depression.

[0003] Zuranolone, whose Chinese chemical name is 1-[(3α,5β)-3-hydroxy-3-methyl-20-oxo-19-demethylpregnane-21-yl]-1H-pyrazole-4-carbonitrile, has a CAS number of 1632051-40-1 and a molecular structure of:

[0004]

[0005] Prior art WO2014169833A1 discloses a method for preparing chrysanolone as shown in the following route 1.

[0006]

[0007] This route uses 19-nor-4-androstenedione as a raw material, and successively undergoes hydrogenation, methylation, wittig reaction, hydroboration-oxidation reaction, oxidation reaction, bromination and 4-cyanopyrazole substitution to obtain the raw material drug zhulannolon. In this route, the products obtained by methylation reaction, Wittig reaction and oxidation reaction of hydroxyl group all need to be purified by chromatography column, especially in the process of oxidizing compound SA-E to obtain SA-F, it is necessary to use highly toxic PCC reagent, and the yield of this step is only about 62%. Therefore, route 1 reported in the prior art has the defects of low preparation efficiency, complicated process operation and high toxicity, which greatly increases the production cost and industrialization difficulty of zhulannolon.

[0008] Therefore, it is of great significance to develop a synthetic route with high yield, simple post-processing and operational arrangement. Summary of the invention

[0009] In view of the defects of the preparation method of Zhulanolone in the prior art, the present invention provides a preparation method of Zhulanolone intermediate (Compound 6), which does not use highly toxic reagents, has a high yield in each step, and the obtained crude product does not need to be purified by chromatography column, and can be used for the next step reaction after simple purification, which is very suitable for industrial large-scale production. To achieve the purpose of the present invention, the present invention adopts the following technical scheme:

[0010] A method for preparing compound 6, The following steps are involved:

[0011] Compound 3 first reacts with a cyanation reagent and then hydrolyzes under acidic conditions to generate compound 4. The reaction formula is as follows:

[0012]

[0013] In structural formula 3, R1 and R2 together form a structure:

[0014] In another more preferred embodiment, R1 and R2 in Structural Formula 3 together form a structure:

[0015] In another preferred embodiment, the cyanation agent is selected from p-toluenesulfonylmethyl isocyanide, zinc cyanide, trimethylsilyl cyanide, or a combination thereof. In another more preferred embodiment, the cyanation agent is selected from p-toluenesulfonylmethyl isocyanide.

[0016] In another preferred embodiment, the cyanation agent is selected from p-toluenesulfonylmethyl isocyanide, zinc cyanide, trimethylsilyl cyanide, or a combination thereof, more preferably, p-toluenesulfonylmethyl isocyanide.

[0017] In another preferred embodiment, the molar ratio of the cyanation reagent to the compound 3 is 1 to 3:1, more preferably 1.3 to 2.0:1.

[0018] In another preferred embodiment, a base is also present in the reaction system of the compound 3 and the cyanation reagent. In another preferred embodiment, the base is selected from potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, or a combination thereof, preferably potassium tert-butoxide. In another preferred embodiment, the molar ratio of the base to the compound 3 is 2 to 8:1, more preferably 4 to 7:1.

[0019] In another preferred embodiment, the acid used for hydrolysis under acidic conditions is selected from formic acid, acetic acid, hydrobromic acid and hydrochloric acid.

[0020] In another preferred embodiment, the solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane and isopropyl ether, more preferably, ethylene glycol dimethyl ether.

[0021] In another preferred embodiment, the reaction temperature of compound 3 and the cyanation reagent is -10 to 40°C, more preferably 0 to 25°C.

[0022] In another preferred embodiment, the preparation method of compound 6 further comprises the following steps:

[0023] Compound 4 reacts with a methylating agent to generate compound 5. The reaction formula is as follows:

[0024]

[0025] In another preferred embodiment, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide or methyllithium, more preferably methylmagnesium bromide.

[0026] In another preferred embodiment, the reaction of compound 4 with the methylating agent is carried out in the presence of methylaluminum bis(2,6-di-tert-butyl-4-anisole) (MAD) or methylaluminum bis(2,4,6-tri-tert-butyl-phenol) (MAT), more preferably MAD.

[0027] In another preferred embodiment, compound 4 reacts with a methylating agent in the presence of MAD or MAT, comprising the following steps:

[0028] (a) Compound 4 reacts with MAD or MAT at -78 to -50°C to form a complex;

[0029] (b) adding a methylating agent to the reaction solution of step (a), and reacting at -78 to -50°C until the complex is completely converted to generate compound 5.

[0030] In another preferred embodiment, the preparation method of compound 6 further comprises the following steps:

[0031] Compound 5 reacts with a methylating agent to generate compound 6. The reaction formula is as follows:

[0032]

[0033] In another more preferred embodiment, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

[0034] In another more preferred embodiment, the molar ratio of compound 5 to the methylating agent is 1:1-8, more preferably, 1:3-4.

[0035] In another preferred embodiment, the solvent used in the reaction is selected from toluene, tetrahydrofuran, hexamethylphosphoramide, isopropyl ether and dimethyl sulfoxide or a combination thereof, more preferably tetrahydrofuran.

[0036] In another preferred embodiment, the preparation method of compound 3 comprises the following steps:

[0037] Compound 2 reacts with an alcohol reagent to generate compound 3. The reaction formula is as follows:

[0038]

[0039] In structural formula 3, R1 and R2 together form a structure:

[0040] In another preferred embodiment, the alcohol reagent is selected from ethylene glycol, propylene glycol or neopentyl glycol. In another more preferred embodiment, the alcohol reagent is selected from ethylene glycol.

[0041] In another preferred embodiment, the acid is selected from p-toluenesulfonic acid and / or pyridine p-toluenesulfonate. In another more preferred embodiment, the acid is selected from pyridine p-toluenesulfonic acid.

[0042] In another preferred embodiment, the dehydrating agent is selected from trimethyl orthoformate and / or trimethyl orthoacetate, more preferably, trimethyl orthoacetate.

[0043] In another preferred embodiment, the preparation method of compound 2 comprises the following steps:

[0044] Compound 1 undergoes a hydrogenation reduction reaction to generate compound 2.

[0045] The reaction formula is as follows:

[0046]

[0047] In another preferred embodiment, the hydrogenation reduction reaction is carried out in the presence of a hydrogen source, a catalyst, and optionally an acid.

[0048] In another preferred embodiment, the hydrogen source is selected from hydrogen. In another preferred embodiment, the catalyst is selected from palladium carbon, platinum carbon or palladium calcium carbonate.

[0049] In another preferred embodiment, the acid is selected from formic acid, acetic acid, hydrobromic acid, hydrochloric acid, proline, and a combination thereof, more preferably, hydrobromic acid.

[0050] In another preferred embodiment, the preparation method of compound 6 provided by the present invention comprises the following steps:

[0051] Compound 5 reacts with a methylating agent to generate compound 6. The reaction formula is as follows:

[0052]

[0053] In another preferred embodiment, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

[0054] In another preferred embodiment, the preparation method of compound 6 provided by the present invention comprises the following steps:

[0055] Compound 4 reacts with a methylating agent to generate compound 5. The reaction formula is as follows:

[0056] as well as

[0057] Compound 5 reacts with a methylating agent to generate compound 6. The reaction formula is as follows:

[0058]

[0059] In another preferred embodiment, the methylating agent used for the reaction of compound 4 with the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

[0060] In another preferred embodiment, the methylating agent used for the reaction of compound 5 with the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

[0061] In another preferred embodiment, the preparation method of compound 6 provided by the present invention comprises the following steps:

[0062] (1) Compound 1 is reduced to obtain compound 2;

[0063] (2) Compound 2 reacts with ethylene glycol to generate compound 3-1;

[0064] (3) Compound 3-1 first reacts with a cyanation reagent and then hydrolyzes under acidic conditions to generate compound 4;

[0065] (4) Compound 4 reacts with a methylating agent to generate compound 5;

[0066] (5) Compound 5 reacts with a methylating agent to generate compound 6,

[0067] The reaction formula is as follows:

[0068]

[0069] The present invention also provides a method for preparing chrysanthemine, comprising the following steps:

[0070] (A) According to the above preparation method, compound 6 was prepared;

[0071] (B) Compound 6 is brominated to generate Compound 7; and

[0072] (C) Compound 7 reacts with 4-cyanopyrazole to generate chrysanolone,

[0073] The reaction formula is as follows:

[0074]

[0075] In another preferred embodiment, step (B) and step (C) are carried out according to the prior art, such as the method disclosed in WO2014169833A.

[0076] The present invention also provides a compound, the structural formula of the compound is as follows:

[0077] BRIEF DESCRIPTION OF THE DRAWINGS

[0078] The manufacturer of the nuclear magnetic resonance instrument used in the present invention for nuclear magnetic resonance detection is Bruker, and the model is AVANCE III 300; the manufacturer of the mass spectrometer used is Agilent, and the models are 6120 and 1290;

[0079] Figure 1 This is a chiral HPLC chromatogram of the reaction solution containing compound 4 obtained in Example 3a, in which only 17β-CN configuration products are present, and no 17α-CN configuration products are observed.

[0080] Figure 2 In route A, after compound 1 reacts with methanol to form methyl ether (compound A) at the 3-position carbonyl, cyanation at the 17-position is performed in a similar manner to that in Example 3a. The chiral HPLC chromatogram of the reaction solution containing compound B is obtained, wherein the ratio of the 17β-CN configuration product to the 17α-CN configuration product is about 1.4 / 1.

[0081] Figure 3 is the NMR carbon spectrum of compound 5 obtained in the present invention;

[0082] Figure 4 is the H NMR spectrum of compound 5 obtained in the present invention;

[0083] Figure 5 is the mass spectrum of compound 5 obtained in the present invention;

[0084] Figure 6 is the NMR carbon spectrum of compound 6 obtained in the present invention;

[0085] Figure 7 is the H NMR spectrum of compound 6 obtained in the present invention;

[0086] Figure 8 is the mass spectrum of compound 6 obtained in the present invention;

[0087] Fig. 9 is the NMR carbon spectrum of Zuranolone obtained in the present invention;

[0088] Fig.10 is the H NMR spectrum of Zuranolone obtained in the present invention;

[0089] Fig.11 is the mass spectrum of Zuranolone obtained in the present invention; DETAILED DESCRIPTION

[0090] In some specific embodiments of the present invention, the preparation method of the julannolon intermediate compound 6 of the present invention comprises the following steps:

[0091] (1) Compound 1 is subjected to hydrogen reduction to obtain compound 2;

[0092] (2) Compound 2 reacts with an alcohol reagent to generate compound 3;

[0093] (3) Compound 3 first reacts with a cyanation reagent and then hydrolyzes under acidic conditions to generate compound 4;

[0094] (4) Compound 4 reacts with a methylating agent to generate compound 5;

[0095] (5) Compound 5 reacts with a methylating agent to generate compound 6,

[0096] The reaction formula is as follows:

[0097]

[0098] In structural formula 3, R1 and R2 together form a structure:

[0099] The alcohol reagent is selected from ethylene glycol, propylene glycol or neopentyl glycol.

[0100] In step (1), the hydrogenation reduction reaction of compound 1 is carried out in the presence of a hydrogen source and a catalyst and optionally an acid. Available hydrogen sources include but are not limited to hydrogen. When hydrogen is used, the hydrogen pressure in the reaction vessel is preferably 0.1 to 1 MPa, more preferably 0.3 to 0.5 MPa. Available catalysts include but are not limited to palladium carbon, platinum carbon, and palladium calcium carbonate. The amount of catalyst used is the conventional amount used in this field for such reactions, and its weight ratio to the substrate compound 1 is preferably 0.01 to 0.1:1. The role of the acid is to increase the reaction selectivity of the hydrogenation of the double bond at the 4,5-position, so that the proportion of the 5β-H target product is higher. Available acids include but are not limited to formic acid, acetic acid, hydrobromic acid, hydrochloric acid and proline. The acid is a catalytic amount, for example, its molar ratio to compound 1 is 0.01 to 0.1:1. The reduction reaction temperature is preferably 5 to 50°C, more preferably 15 to 30°C.

[0101] The solvent used in the hydrogenation reduction reaction of this step is a common solvent for such reactions in the art, including but not limited to tetrahydrofuran, methanol, ethanol, 2-methyltetrahydrofuran, isopropanol or a combination thereof, preferably tetrahydrofuran. The volume ratio of compound 1 to the solvent is preferably 1 g / 2 to 30 mL, preferably 1 g / 10 to 15 mL.

[0102] In this step, the reaction is completed by TLC detection, the reaction solution is filtered, the filtrate is concentrated, and the obtained residue is slurried with methyl tert-butyl ether to obtain the target compound that can be used for the next step reaction.

[0103] In step (2), the carbonyl group of compound 2 reacts with an alcohol reagent to form an acetal. The alcohol reagent can be both a solvent and a reaction reagent. For example, when ethylene glycol or propylene glycol is used as the alcohol reagent, other solvents that do not affect the acetalization reaction may also be present in the reaction system. The amount of ethylene glycol or propylene glycol used is 2 to 50 mL / 1 g, preferably 3 to 10 mL / 1 g, in terms of volume weight ratio to compound 2. When neopentyl glycol is used, the reaction system uses a solvent that does not affect the etherification reaction, and the amount used is the conventional amount used in this field for such reactions, for example, the molar ratio to compound 2 is 5 to 20:1. Acid and a water scavenger are also present in the system in which compound 2 reacts with ethylene glycol, propylene glycol or neopentyl glycol. The acid acts as a catalyst, and the acid that can be used in this step includes but is not limited to p-toluenesulfonic acid, citric acid and / or pyridine p-toluenesulfonate. The amount of acid used is a catalytic amount, and the molar ratio to compound 2 is preferably 0.01 to 0.1:1. The function of the dehydrating agent is to remove the water generated by the etherification reaction and shorten the reaction time. Available dehydrating agents include but are not limited to trimethyl orthoformate or trimethyl orthoacetate. The amount of the dehydrating agent is the conventional amount used in this field for such reactions, for example, the molar ratio of the dehydrating agent to compound 2 is 1 to 5:1, preferably 1.5 to 2:1. The reaction temperature of this step is the conventional temperature used in this field for such reactions, for example, 10 to 80°C, preferably 50 to 60°C.

[0104] In some preferred embodiments of the present invention, after the reaction is completed by TLC detection, the reaction is quenched with a base (e.g., triethylamine), extracted with an organic solvent and water, the organic phase is concentrated, and the residue is slurried with an alcohol (e.g., methanol) to obtain the target product which is directly used in the next reaction.

[0105] In step (3), the reaction of compound 3 with a cyanation agent is carried out under alkaline conditions. The cyanation agent used includes but is not limited to p-toluenesulfonylmethyl isocyanide and zinc cyanide. The amount of the cyanation agent used is the conventional amount used in this field for such reactions, for example, the molar ratio of the cyanation agent to compound 3 is preferably 1 to 3:1, more preferably 1.3 to 2.0:1. The base used includes but is not limited to potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, and potassium methoxide. The amount of the base used is a molar ratio of 2 to 8:1 to compound 3, more preferably 4 to 7:1. The solvent used in this step includes but is not limited to tetrahydrofuran, ether, ethylene glycol dimethyl ether, 1,4-dioxane and isopropyl ether, more preferably ethylene glycol dimethyl ether. The amount of the solvent used is a volume weight ratio of 5 to 50 mL / 1 g to compound 3, more preferably 8 to 20 mL / 1 g. In this step, the reaction temperature of compound 3 and the cyanation reagent is -10 to 40°C, preferably 0 to 25°C.

[0106] After TLC monitoring shows that the conversion of compound 3 is completed, water and an organic solvent are added to the reaction solution for extraction. After the obtained organic phase is washed with water, an acidic aqueous solution is added thereto to make the system pH 1 to 3, and the acetal bond is hydrolyzed under stirring at room temperature. The hydrolysis conditions (the acid and temperature used) are the common conditions (the acid and temperature used) for such reactions in the art. The acid used for hydrolysis includes but is not limited to formic acid, acetic acid, hydrobromic acid and hydrochloric acid.

[0107] In some preferred embodiments of the present invention, the reaction solution after hydrolysis is allowed to stand for stratification, the obtained organic phase is washed with alkaline water and water in sequence, concentrated, and the residue is slurried with alcohol (such as methanol) to obtain the target compound which is directly used in the next reaction.

[0108] In step (4), the reaction of compound 4 with a methylating agent is carried out in the presence of MAD or MAT. The methylating agent includes but is not limited to methylmagnesium bromide, methylmagnesium iodide or methyllithium. The amount of the methylating agent used is the conventional amount used in the art for such reactions. The molar ratio of compound 4 to the methylating agent is preferably 1:1 to 5, more preferably 1:1.2 to 1.8. The amount of MAD or MAT used is also the conventional amount used in the art for such reactions, and the molar ratio of compound 4 to MAD or MAT is preferably 1:1 to 3, more preferably, 1:1.0 to 1.1. The solvent used in this step includes but is not limited to toluene, dichloromethane, tetrahydrofuran, ether, hexamethylphosphoramide, isopropyl ether and dimethyl sulfoxide or a combination thereof, more preferably dichloromethane.

[0109] The reaction of compound 4 with a methylating agent in the presence of MAD or MAT comprises the steps of: (a) reacting compound 4 with MAD or MAT under stirring at -78 to -50°C (for example, for 0.5 to 2 hours) to form a complex; (b) adding a methylating agent to the reaction solution of step (a), and reacting at -78 to -50°C under stirring (for example, for 2 to 5 hours) until the complex is completely converted to generate compound 5.

[0110] In step (a), MAD or MAT coordinates with the carbonyl group of compound 4 to form a MAD-ketone complex or a MAT-ketone complex, and the stereo configuration of the compound is controlled by means of its larger steric hindrance. In step (b), the methylating agent acts as a nucleophilic addition agent to react with the 3-carbonyl group of the complex to generate an intermediate metal salt (e.g., magnesium salt *-OMgBr, where * represents the site connected to the 3-carbon), and the intermediate metal salt is hydrolyzed under acidic conditions to generate compound 5.

[0111] In some preferred embodiments of the present invention, the methylating agent is quenched with a saturated ammonium chloride solution, filtered, the filtrate is extracted with an organic solvent, the organic layer is concentrated to dryness under reduced pressure, and the residue is slurried with isopropyl ether to obtain the target compound.

[0112] The methylating agent used in step (5) includes but is not limited to methylmagnesium bromide, methylmagnesium iodide, and methyllithium. The amount of the methylating agent used is the conventional amount used in the art for such reactions, for example, the molar ratio of compound 5 to the methylating agent is 1:1 to 8, more preferably, 1:3 to 4. The solvent used in the reaction of this step includes but is not limited to tetrahydrofuran, hexamethylphosphoramide, isopropyl ether and dimethyl sulfoxide or a combination thereof. The reaction temperature of compound 3 and the methylating agent is 40 to 70°C, more preferably 60 to 70°C.

[0113] The methylating agent can be added dropwise to the solution of compound 5 at room temperature. After the addition is complete, the reaction solution is heated to 60-70°C. After TLC monitoring shows that the conversion of compound 5 is complete, the reaction solution is cooled to -15-5°C, an acidic aqueous solution is added thereto to make the pH of the system 1-3, and stirred at room temperature for 1-5 hours to allow the intermediate metal salt to be hydrolyzed under acidic conditions to generate compound 6. The acid used includes but is not limited to hydrochloric acid solution, sulfuric acid solution and phosphoric acid solution. The reaction solution is extracted, and the obtained organic phase is washed with water and concentrated. The residue is slurried with alcohol to obtain the target compound that can be used for the next step of the reaction.

[0114] In the synthesis process of compound 4, the inventors of the present application initially used methanol to react with compound 1 to perform 3-carbonyl etherification reaction, and then performed 17-position cyanation and deprotection to obtain compound 4. The reaction formula (route A) and the specific preparation process are as follows:

[0115]

[0116] Step (1): Into a 500 ml four-necked flask, at 20°C, under magnetic stirring and nitrogen protection, first add 100 ml of methanol, 10 g of compound 1 (36.7 mmol), and 15.4 g of trimethyl orthoacetate (128.5 mmol, 3.5 eq). After the addition is complete, add 0.02 g of p-toluenesulfonic acid, keep warm and stir for 3 h, then drop 10 ml of purified water into it, continue to keep warm for 1 h, TLC (n-hexane / ethyl acetate = 5:1) shows that the reaction is complete, add 1 ml of triethylamine to adjust the pH to >7, drop 100 ml of purified water into it, cool to 2°C, filter, and obtain 9.5 g of (17β)-3-methoxyestradiol-3,5-diene-17-one (compound A), with a molar yield of 90.1% and a HPLC purity of 99.7%.

[0117] Step (2): In a 500 ml four-necked bottle, 50 ml of tetrahydrofuran, 9.7 g of potassium tert-butoxide (86.8 mmol, 2.5 eq) and 10.0 g of compound A (purity 99.3%, 34.7 mmol) were first added to a 500 ml four-necked bottle at 0 ° C., under magnetic stirring and nitrogen protection. After the addition was completed, a 50 ml tetrahydrofuran solution of 13.5 g of p-methylbenzenesulfonylmethyl isocyanide (69.4 mmol, 2.0 eq) was added dropwise to the above mixture, and the mixture was stirred for 3 h. TLC (n-hexane / ethyl acetate = 5:1) showed that the reaction was complete. Hydrochloric acid was slowly added dropwise to the above mixture so that the pH of the system was about 2 and the addition was stopped. The mixture was stirred at 25 ° C. for 3 h. EtOAc was then added, and the organic layer was washed with water and brine, concentrated, and slurried with methanol to obtain 8.9 g of compound B (a mixture of 17β-CN configuration and 17α-CN configuration), with a molar yield of 89.6% and a HPLC purity of 99.0%.

[0118] Step (3): Into a 500 ml four-necked bottle, at 25° C., under magnetic stirring and nitrogen protection, first add 100 ml of tetrahydrofuran and 10.0 g of compound B (purity 98.8%, 34.9 mmol), then add 0.5 g of palladium carbon and 0.2 g of 40% hydrobromic acid, in a hydrogen environment (provided by a hydrogen balloon), stir at 25° C. for 12 h, TLC (n-hexane / ethyl acetate = 3:1) shows that the reaction is complete, add 2 ml of 5% sodium bicarbonate solution to adjust the system pH to about 7, filter the mixture through a diatomaceous earth pad, filter, concentrate, and slurry with methyl tert-butyl ether to obtain 9.7 g of compound 4' (a mixture of 17β-CN configuration (i.e., compound 4) and 17α-CN configuration), with a molar yield of 96.6% and a HPLC purity of 99.2%.

[0119] The chiral HPLC chromatogram of the obtained compound B is as follows: Figure 2As shown, the structural formulas of the two configurations of the products (17β-CN and 17α-CN) are as follows:

[0120]

[0121] The structural formulas of the 17β-CN configuration product and the 17α-CN configuration product of compound 4' are as follows:

[0122]

[0123] According to the preparation method of the present invention, that is, using compound 1 as the starting material, the chiral HPLC of the reaction solution containing compound 4 (see the specific examples 1a-4c below) is obtained by sequentially reacting compound 2 and compound 3. Figure 1 Among them, only 17β-CN was present, and 17α-CN was not found.

[0124] Comparison of chiral HPLC chromatograms of the reaction solution containing compound B in route A ( Figure 2 ) and the chiral HPLC chromatogram of the reaction solution containing compound 4 in Example 3a of the present invention ( Figure 1 ) It can be seen that in route A, compound A containing an ether structure is used to react with a cyanation reagent, and the ratio of the 17β-CN configuration product to the 17α-CN configuration product in the reaction solution containing compound B is about 1.4 / 1. In Example 3a of the present invention, compound 3 containing an acetal structure is used to react with a cyanation reagent, and the reaction solution containing compound 4 obtained only contains a 17β-CN configuration product (target compound), and no 17α-CN configuration product is found. The reason why the 17β-CN product obtained in Example 3a of the present invention is absolutely dominant is presumably because the 3-carbonyl group is protected by ethylene glycol, which further affects the spatial structure of the steroid itself, and then affects the chirality of the 17 position, so that the 17β-CN product is preferentially generated when it reacts with the cyanation reagent.

[0125] The method for preparing compound 7 from compound 6 and finally preparing chrysanolone can be prepared by referring to the prior art (for example, the method disclosed in WO2014 / 169833A1).

[0126] In the description of the present invention, "room temperature" refers to 4-40°C, for example, 15-35°C, 15-35°C, 25-28°C.

[0127] Compared with the prior art, the preparation method of chrysanolone and its intermediates provided by the present invention has the following beneficial effects:

[0128] 1. The preparation method of the chrysanolone of the present invention uses cheap, low-toxic or non-toxic and readily available reagents;

[0129] 2. The preparation method of Zhulannolon of the present invention has a simple process route, high product purity in each reaction step, few side reactions, relatively high yields, and relatively simple post-treatments. The crude product does not require column chromatography purification and can be directly used in the next step reaction after pulping and purification, which is suitable for industrial large-scale production;

[0130] 3. The preparation method of the chrysanolone of the present invention is guided by "green chemistry" and provides a variety of simple and practical purification methods for the chrysanolone intermediate and the raw material drug.

[0131] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually based on conventional conditions.

[0132] Unless otherwise specified, the reagents used in the following examples are commercially available.

[0133] Example 1a

[0134] Preparation of (5β)-estrane-3,17-dione (Compound 2)

[0135] In a 500 ml four-necked flask, 100 ml of tetrahydrofuran and 10.0 g of 19-nor-4-androstenedione (compound 1, 36.7 mmol) were first added under magnetic stirring at 25 ° C., followed by the addition of 0.2 g of palladium carbon and 0.2 g of 40% hydrobromic acid. The mixture was stirred at 25 ° C. for 12 h in a hydrogen environment. TLC (n-hexane / ethyl acetate = 3:1) showed that the reaction was complete. 2 ml of 5% sodium bicarbonate solution was added to adjust the pH to about 7, filtered, and the filtrate was concentrated. The filter cake was slurried with n-heptane, filtered, and dried to obtain 9.5 g of (5β)-estrane-3,17-dione (compound 2) with a molar yield of 93.4% and a HPLC purity of 99.0%.

[0136] Example 1b

[0137] Preparation of (5β)-estrane-3,17-dione (Compound 2)

[0138] In a 500 ml four-necked bottle, 150 ml of tetrahydrofuran and 10.0 g of 19-nor-4-androstenedione (compound 1, 36.7 mmol) were first added under magnetic stirring at 25 ° C., followed by the addition of 0.2 g of palladium calcium carbonate and 0.3 g of 40% hydrobromic acid. After stirring at 25 ° C. for 12 h in a hydrogen environment, TLC detection (n-hexane / ethyl acetate = 3:1) showed that the reaction was complete, and 2 ml of 5% sodium bicarbonate solution was added to adjust the pH to about 7, filtered, and the filtrate was concentrated. The filter cake was slurried with n-heptane, filtered, and dried to obtain 9.2 g of (5β)-estrane-3,17-dione (compound 2), with a molar yield of 90.6% and a HPLC purity of 99.2%.

[0139] Example 1c

[0140] Preparation of (5β)-estrane-3,17-dione (Compound 2)

[0141] In a 500 ml four-necked bottle, 150 ml of tetrahydrofuran and 10.0 g of 19-nor-4-androstenedione (compound 1, 36.7 mmol) were first added under magnetic stirring at 25 ° C., followed by the addition of 0.5 g of palladium carbon and 0.5 g of 40% hydrobromic acid. After stirring at 25 ° C. for 12 h in a hydrogen environment, TLC detection (n-hexane / ethyl acetate = 3:1) showed that the reaction was complete, and 2 ml of 5% sodium bicarbonate solution was added to adjust the pH to about 7, filtered, and the filtrate was concentrated. The filter cake was slurried with n-heptane, filtered, and dried to obtain 9.4 g of (5β)-estrane-3,17-dione (compound 2) with a molar yield of 92.9% and a HPLC purity of 99.5%.

[0142] Example 2a

[0143] Preparation of 3-acetal-estrane-3,17-dione (Compound 3-1)

[0144]

[0145] In a 500 ml four-necked bottle, 40 ml of ethylene glycol, 6.6 g of trimethyl orthoacetate (54.9 mmol, 1.5 eq) and 10.0 g of (5β)-estrane-3,17-dione (compound 2, HPLC purity 99.5%, 36.3 mmol) were first added at 50 ° C. under magnetic stirring and nitrogen protection, and then 0.04 g of pyridine p-toluenesulfonate was added. Stirring at 50 ° C. for 3 h, TLC detection (n-hexane / ethyl acetate = 3:1) showed that the reaction was complete, 0.1 ml of triethylamine was added to quench the reaction, and then ethyl acetate and water were added. The layers were allowed to stand and the organic layer was concentrated. The residue was slurried with methanol, filtered, and dried to obtain 10.3 g of 3-acetal-estrane-3,17-dione (compound 3-1), with a molar yield of 88.2% and a HPLC purity of 99.0%.

[0146] Example 2b

[0147] Preparation of 3-acetal-estrane-3,17-dione (Compound 3-1)

[0148] In a 500 ml four-necked flask, 50 ml of ethylene glycol, 7.9 g of trimethyl orthoacetate (65.8 mmol, 1.8 eq) and 10.0 g of (5β)-estrane-3,17-dione (compound 2, HPLC purity 99.5%, 36.3 mmol) were first added at 50 ° C., magnetic stirring and nitrogen protection, and then 0.04 g of pyridine p-toluenesulfonate was added. Stirring at 50 ° C. for 3 h, TLC detection (n-hexane / ethyl acetate = 3:1) showed that the reaction was complete, 0.1 ml of triethylamine was added to quench the reaction, and then ethyl acetate and water were added. The stratification was allowed to stand, and the organic layer was concentrated. The resulting residue was slurried with methanol, filtered, and dried to obtain 10.8 g of 3-acetal-estrane-3,17-dione (compound 3-1), with a molar yield of 92.6% and a HPLC purity of 99.2%.

[0149] Example 2c

[0150] Preparation of 3-acetal-estrane-3,17-dione (Compound 3-2)

[0151]

[0152] In a 500 ml four-necked bottle, 40 ml of propylene glycol, 7.9 g of trimethyl orthoacetate (65.8 mmol, 1.8 eq) and 10.0 g of (5β)-estrane-3,17-dione (compound 2, HPLC purity 99.5%, 36.3 mmol) were first added at 60 ° C. under magnetic stirring and nitrogen protection, and then 0.06 g of pyridine p-toluenesulfonate was added. Stirring at 60 ° C. for 3 h, TLC detection (n-hexane / ethyl acetate = 3:1) showed that the reaction was complete, 0.1 ml of triethylamine was added to quench the reaction, and then ethyl acetate and water were added. The stratification was allowed to stand, and the organic layer was concentrated. The resulting residue was slurried with methanol, filtered, and dried to obtain 10.9 g of 3-acetal-estrane-3,17-dione (compound 3-2), with a molar yield of 89.1% and a HPLC purity of 98.6%.

[0153] Example 3a

[0154] Preparation of 17β-estrane-3-one-17-carbonitrile (Compound 4)

[0155] In a 500ml four-necked bottle, add 100ml of ethylene glycol dimethyl ether and 10.0g of 3-acetal-estrane-3,17-dione (compound 3-1, HPLC purity 99.2%, 31.2mmol), followed by the addition of 28.2g of potassium tert-butoxide (251.3mmol, 8eq) in 50ml of tert-butanol solution. After the addition was completed, 9.2g of p-toluenesulfonylmethyl isocyanide (47.1mmol, 1.5eq) in 50ml of ethylene glycol dimethyl ether solution was added dropwise to the above mixture, stirred for 3h at room temperature, and TLC detection (n-hexane / ethyl acetate = 5:1) showed that the reaction was complete. After adding dichloromethane and water, the mixture was allowed to stand for stratification. Hydrochloric acid was added dropwise to the organic layer until the pH of the system was about 2. The addition was stopped, stirred at 25°C for 3h, and the organic layer was washed with 5% sodium bicarbonate solution and water, concentrated, and the residue was slurried with methanol, filtered, and dried to obtain 6.7g 17β-estrane-3-one-17-carbonitrile (Compound 4), molar yield 74.3%, HPLC purity 98.8%. The chiral HPLC chromatogram of the reaction solution containing Compound 4 is shown in Figure 1 .

[0156] Example 3b

[0157] Preparation of 17β-estrane-3-one-17-carbonitrile (Compound 4)

[0158] In a 500ml four-necked bottle, at 0℃, magnetic stirring and nitrogen protection, add 150ml of ethylene glycol dimethyl ether and 10.0g 3-acetal-estrane-3,17-dione (compound 3-1, HPLC purity 99.2%, 31.2mmol), followed by the addition of 21.1g of potassium tert-butoxide (188.1mmol, 6eq) in 40ml of tert-butanol solution. After the addition was completed, 9.2g of p-toluenesulfonylmethyl isocyanide (47.1mmol, 1.5eq) in 50ml of ethylene glycol dimethyl ether solution was added dropwise to the above mixture, stirred for 3h at room temperature, and TLC detection (n-hexane / ethyl acetate = 5:1) showed that the reaction was complete. After adding dichloromethane and water, the mixture was allowed to stand for stratification. Hydrochloric acid was added dropwise to the organic layer until the pH of the system was about 2. The addition was stopped, stirred at 25°C for 3h, and the organic layer was washed with 5% sodium bicarbonate solution and water, and concentrated. The residue was slurried with methanol, filtered, and dried to obtain 6.5g 17β-estrane-3-one-17-carbonitrile (Compound 4), molar yield 71.9%, HPLC purity 98.5%.

[0159] Example 3c

[0160] Preparation of 17β-estrane-3-one-17-carbonitrile (Compound 4)

[0161] In a 500ml four-necked bottle, add 140ml of ethylene glycol dimethyl ether and 10.5g of 3-acetal-estrane-3,17-dione (compound 3-2, HPLC purity 98.6%, 31.2mmol), followed by the addition of 21.1g of potassium tert-butoxide (188.1mmol, 6eq) in 60ml of tert-butanol solution. After the addition was completed, 5.6g of trimethylsilyl cyanide (56.5mmol, 1.8eq) was added dropwise to the above mixture, stirred for 3h at room temperature, and TLC detection (n-hexane / ethyl acetate = 5:1) showed that the reaction was complete. After adding dichloromethane and water, the mixture was allowed to stand for stratification. Hydrochloric acid was slowly added dropwise to the organic layer until the pH of the system was about 2. The addition was stopped, stirred at 25°C for 3h, allowed to stand for stratification, and the organic layer was washed with 5% sodium bicarbonate solution and water, concentrated, and the residue was slurried with methanol, filtered, and dried to obtain 6.3g of 17β-estrane-3-one-17-nitrile (compound 4), with a molar yield of 70.2% and a HPLC purity of 99.2%.

[0162] Example 4a

[0163] Preparation of (3α,5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5)

[0164] In a 500ml four-necked bottle, under -60°C, magnetic stirring and nitrogen protection, 10.0g 17β-estrane-3-one-17-carbonitrile (Compound 4, HPLC purity 99.2%, 34.80mmol) in 100ml dichloromethane solution was dripped into MAD solution (35.7mmol, 1.02eq). After the addition was completed, the reaction mixture was stirred at -60°C for 1 hour. Then, 1M MeMgBr (38.5mL, 38.5mmol, 1.1eq) was slowly dripped into the above mixture at -60°C in a nitrogen atmosphere, and the reaction mixture was stirred at this temperature for 3 hours. TLC detection (n-hexane / ethyl acetate = 2:1) showed that the reaction was complete. Then, saturated ammonium chloride solution was added dropwise to the above mixture so that the pH of the system was 7 and the dripping was stopped. EtOAc was then added, and the organic layer was washed with brine and concentrated. The residue was slurried with isopropyl ether, filtered, and dried to give 9.6 g of (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5) with a molar yield of 90.5% and a HPLC purity of 98.9%.

[0165] Example 4b

[0166] Preparation of (3α,5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5)

[0167] In a 500ml four-necked bottle, under -60°C, magnetic stirring and nitrogen protection, 10.0g 17β-estrane-3-one-17-carbonitrile (Compound 4, HPLC purity 99.2%, 34.8mmol) in 100ml dichloromethane solution was dripped into MAD solution (35.7mmol, 1.02eq). After the addition was completed, the reaction mixture was stirred at -60°C for 1 hour. Then, 1M MeMgBr (45.5mL, 45.5mmol, 1.3eq) was slowly dripped into the above mixture at -60°C in a nitrogen atmosphere, and the reaction mixture was stirred at this temperature for 3 hours. TLC detection (n-hexane / ethyl acetate = 2:1) showed that the reaction was complete. Then, saturated ammonium chloride solution was added dropwise to the above mixture so that the pH of the system was 7 and the dripping was stopped. EtOAc was then added, and the organic layer was washed with brine and concentrated. The residue was slurried with isopropyl ether, filtered, and dried to give 9.4 g of (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5) with a molar yield of 89.0% and a HPLC purity of 99.3%.

[0168] Example 4c

[0169] Preparation of (3α,5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5)

[0170] In a 500ml four-necked bottle, under -65°C, magnetic stirring and nitrogen protection, 10.0g 17β-estrane-3-one-17-nitrile (Compound 4, HPLC purity 99.2%, 34.8mmol) in 100ml anhydrous toluene solution was dripped into MAT solution (38.5mmol, 1.1eq). After the addition was completed, the reaction mixture was stirred at -65°C for 1 hour. Then, in a nitrogen atmosphere at -65°C, 1.3M methyl lithium (35mL, 45.5mmol, 1.3eq) was slowly dripped into the above mixture, and the reaction mixture was stirred at this temperature for 3 hours. TLC detection (n-hexane / ethyl acetate = 2:1) showed that the reaction was complete. Then saturated ammonium chloride solution was added dropwise to the above mixture so that the system pH was 7 when the dripping was stopped. EtOAc was then added, and the organic layer was washed with brine and concentrated. The residue was slurried with isopropyl ether, filtered, and dried to give 9.3 g of (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5) with a molar yield of 87.6% and a HPLC purity of 98.8%.

[0171] Example 5a

[0172] Preparation of (3α,5β)-3-hydroxy-3-methyl-19-demethylpregnane-20-one (Compound 6)

[0173] In a 500ml four-necked bottle, under magnetic stirring and nitrogen protection, 50ml of tetrahydrofuran and 10.0g (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5, HPLC purity 99.3%, 32.9mmol) were first added. Then 1M MeMgBr (99.6mL, 99.6mmol, 3.0eq) was added, and the reaction mixture was stirred at 70°C for 12 hours. After TLC detection (n-hexane / ethyl acetate = 2:1) showed that the reaction was completed, the heating of the reaction solution was stopped and the temperature was lowered to -10°C, and 2N hydrochloric acid solution was slowly added dropwise to the above mixture so that the pH of the system was about 2, and the addition was stopped, and the temperature was raised to 25°C and stirred for 3h. EtOAc was then added, and the organic layer was washed with 5% sodium bicarbonate solution and brine. The organic layer was concentrated, and the residue was slurried with isopropyl ether, filtered, and dried to obtain 8.6 g of 5β-19-desmethylpregnane-3,20-dione (Compound 6) with a molar yield of 80.8% and a HPLC purity of 98.5%.

[0174] Example 5b

[0175] Preparation of (3α,5β)-3-hydroxy-3-methyl-19-demethylpregnane-20-one (Compound 6)

[0176] In a 500ml four-necked bottle, under magnetic stirring and nitrogen protection, 50ml of tetrahydrofuran and 10.0g (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyanide (Compound 5, HPLC purity 99.3%, 32.9mmol) were first added. Then 1M MeMgBr (116.2mL, 116.2mmol, 3.5eq) was added, and the reaction mixture was stirred at 70°C for 12 hours. After TLC detection (n-hexane / ethyl acetate = 2:1) showed that the reaction was completed, the heating of the reaction solution was stopped and the temperature was lowered to -10°C, and 2N hydrochloric acid solution was slowly added dropwise to the above mixture so that the pH of the system was about 2, and the addition was stopped, and the temperature was raised to 25°C and stirred for 3h. EtOAc was then added, and the organic layer was washed with 5% sodium bicarbonate solution and brine. The organic layer was concentrated, and the residue was slurried with isopropyl ether, filtered, and dried to obtain 8.8 g of 5β-19-desmethylpregnane-3,20-dione (Compound 6) with a molar yield of 83.1% and a HPLC purity of 99.0%.

[0177] Example 5c

[0178] Preparation of (3α,5β)-3-hydroxy-3-methyl-19-demethylpregnane-20-one (Compound 6)

[0179] In a 500ml four-necked bottle, under magnetic stirring and nitrogen protection, 50ml of tetrahydrofuran and 10.0g of (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-17-cyano (Compound 5, purity 99.3%, 32.9mmol) were first added. Then 1.3M methyl lithium (102.2mL, 132.8mmol, 4eq) was added, and the reaction mixture was stirred at 65°C for 12 hours. After TLC (n-hexane / ethyl acetate = 2:1) showed that the reaction was complete, the heating of the reaction solution was stopped and the temperature was lowered to -10°C, and 2N hydrochloric acid solution was slowly added dropwise to the above mixture so that the pH of the system was about 2, and the addition was stopped, and the temperature was raised to 25°C and stirred for 3h. EtOAc was then added, and the organic layer was washed with 5% sodium bicarbonate solution and water. The organic layer was concentrated, and the residue was slurried with isopropyl ether, filtered, and dried to obtain 8.3 g of 5β-19-desmethylpregnane-3,20-dione (Compound 6) with a molar yield of 78.6% and a HPLC purity of 99.2%.

[0180] Example 6

[0181] Preparation of (3α,5β)-21-bromo-3-hydroxy-3-methyl-19-demethylpregnane-20-one (Compound 7)

[0182] In a 500ml four-necked bottle, 200ml methanol, 0.05ml HBr and 10.0g (3α, 5β)-3-hydroxy-3-methyl-19-demethylpregnane-20-one (compound 6, purity 99.2%, 31.1mmol) were first added at 15°C, magnetic stirring and nitrogen protection. After the addition was completed, 5.5g liquid bromine (34.5mmol, 1.1eq) was dropped into the above mixture, stirred at 15°C for 3h, and TLC (n-hexane / ethyl acetate = 5:1) showed that the reaction was complete. EtOAc and sodium bicarbonate solution were then added, and the organic layer was washed with water, concentrated, and the residue was slurried with isopropyl ether, filtered, and dried to obtain 9.7g (3α, 5β)-21-bromo-3-hydroxy-3-methyl-19-demethylpregnane-20-one (compound 7), with a molar yield of 78.5% and a HPLC purity of 99.0%.

[0183] Example 7

[0184] Preparation of 1-[(3α,5β)-3-hydroxy-3-methyl-20-oxo-19-demethylpregnane-21-yl]-1H-pyrazole-4-carbonitrile (zuranolone)

[0185] Into a 500 ml four-necked flask, 200 ml of tetrahydrofuran, 10.4 g of potassium carbonate (75.6 mmol, 3 eq), 2.6 g of 4-cyanopyrazole (27.7 mmol, 1.1 eq) and 10.0 g of (3α, 5β)-21-bromo-3-hydroxy-3-methyl-19-demethylpregnane-20-one (compound 7, 99.0%, 24.9 mmol) were added at 15 ° C. under magnetic stirring and nitrogen protection, and the mixture was stirred for 12 h at 15 ° C. TLC detection (n-hexane / ethyl acetate = 5:1) showed that the reaction was completed. EtOAc was then added, and the organic layer was washed with water, concentrated, slurried twice with ethyl acetate, filtered, and dried to give 7.6 g of 1-[(3α,5β)-3-hydroxy-3-methyl-20-oxo-19-demethylpregnane-21-yl]-1H-pyrazole-4-carbonitrile (zuranolone) with a molar yield of 73.9% and a HPLC purity of 99.2%.

[0186] The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. The above embodiment of the present invention can also be modified in various ways. That is, all simple, equivalent changes and modifications made according to the claims and the description of the present invention application fall within the protection scope of the claims of the present invention patent.

Claims

1. A method for preparing compound 6, It is characterized in that The preparation method shown comprises the following steps: Compound 3 is first reacted with a cyanation reagent and then hydrolyzed under acidic conditions to generate compound 4. The reaction formula is as follows: In structural formula 3, R1 and R2 together form a structure: Preferably, the cyanation agent is selected from p-toluenesulfonylmethyl isocyanide, zinc cyanide, trimethylsilyl cyanide, or a combination thereof, more preferably, p-toluenesulfonylmethyl isocyanide.

2. The preparation method according to claim 1, characterized in that: In the reaction system of compound 2 and cyanation reagent, there is also a base. Preferably, the base is selected from potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, or a combination thereof, more preferably potassium tert-butoxide.

3. The preparation method according to claim 1 or 2, characterized in that: The preparation method further comprises the following steps: Compound 4 reacts with a methylating agent to generate compound 5. The reaction formula is as follows: Preferably, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide or methyllithium, more preferably methylmagnesium bromide.

4. The preparation method according to claim 3, characterized in that: The reaction of compound 4 with the methylating agent is carried out in the presence of methylaluminum bis(2,6-di-tert-butyl-4-anisole) or methylaluminum bis(2,4,6-tri-tert-butyl-phenol). More preferably, the reaction of compound 5 with a methylating agent in the presence of methylaluminum bis(2,6-di-tert-butyl-4-anisole) or methylaluminum bis(2,4,6-tri-tert-butyl-phenol) comprises the following steps: (a) Compound 2 reacts with methylaluminum bis(2,6-di-tert-butyl-4-anisole) or methylaluminum bis(2,4,6-tri-tert-butyl-phenol) at -78 to -50°C to form a complex; (b) adding a methylating agent to the reaction solution of step (a), and reacting at -78 to -50°C until the complex is completely converted to generate compound 5.

5. The preparation method according to claim 3, characterized in that: The preparation method further comprises the following steps: Compound 5 reacts with a methylating agent to generate compound 6. The reaction formula is as follows: Preferably, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

6. The preparation method according to claim 1, characterized in that: The preparation method of the compound 3 comprises the following steps: Compound 2 reacts with an alcohol reagent to generate compound 3. The reaction formula is as follows: In structural formula 3, R1 and R2 together form a structure: The alcohol reagent is selected from ethylene glycol, propylene glycol or neopentyl glycol.

7. The preparation method according to claim 6, characterized in that: The preparation method of the compound 2 comprises the following steps: Compound 1 undergoes a hydrogenation reduction reaction to generate compound 2. The reaction formula is as follows:

8. A method for preparing compound 6, characterized in that: The preparation method comprises the following steps: Compound 5 reacts with a methylating agent to generate compound 6. The reaction formula is as follows: Preferably, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

9. A method for preparing compound 6, characterized in that: The preparation method comprises the following steps: Compound 4 reacts with a methylating agent to generate compound 5. The reaction formula is as follows: Preferably, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide, and Compound 5 reacts with a methylating agent to generate compound 6. The reaction formula is as follows: Preferably, the methylating agent is selected from methylmagnesium bromide, methylmagnesium iodide, methyllithium, or a combination thereof, more preferably methylmagnesium bromide.

10. A method for preparing compound 6, characterized in that: The preparation method comprises the following steps: (1) Compound 1 is subjected to hydrogen reduction to generate compound 2; (2) Compound 2 reacts with ethylene glycol to generate compound 3-1; (3) Compound 3-1 is first reacted with a cyanation reagent and then hydrolyzed under acidic conditions to generate compound 4; (4) Compound 4 reacts with a methylating agent to generate compound 5; (5) Compound 5 reacts with a methylating agent to generate compound 6, The reaction formula is as follows:

11. A method for preparing chrysanthemidoron, characterized in that: The preparation method comprises the following steps: (A) preparing compound 6 according to the method according to any one of claims 1 to 10; (B) compound 6 is subjected to bromination reaction to generate compound 7; and (C) Compound 7 reacts with 4-cyanopyrazole to generate chrysanolone, The reaction formula is as follows:

12. A compound, characterized in that The structural formula of the compound is as follows:

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