Synthesis method of 8, 9-dehydroestrone

Abstract

The invention discloses a synthesis method of 8, 9-dehydroestrone. The invention discloses a preparation method of 8, 9-dehydroestrone, which comprises the following steps: (1) in the presence of an acid catalyst, in an aprotic solvent, carrying out a deprotecting group-isomerization reaction on a compound 5 to obtain a compound 6; and (2) in the presence of a catalyst, in an aprotic solvent, carrying out an addition reaction on the compound 6 and a hydrogen source reagent to obtain the 8, 9-dehydroestrone. The method has one or more advantages as follows: raw materials are cheap, reaction steps are simple, the reaction yield of each step is high, post-treatment is simple and convenient, conditions are mild, operation is controllable, and the method is suitable for amplification.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing 8,9-dehydroxyphenestrol ketone. BACKGROUND

[0002] In 1941, the first conjugated estrogen (CE) was marketed by American Wyeth-Ayerst Company under the trade name of Premarin. The drug was extracted from pregnant mare's urine, and the main components were estrogen, equilenin and equilin, and other estrogen derivatives and their sulfate salts. It is widely used in hormone replacement therapy (HRT), and can relieve menopausal symptoms and osteoporosis caused by estrogen deficiency.

[0003] Due to the problems of unstable quality and limited supply in natural extraction method, Duramed Company marketed synthetic conjugated estrogen drugs Cenestin and Enjuvia in 1999 and 2004, respectively, which are mixtures of 9 and 10 steroidal estrogens. The difference between them is that Enjuvia contains more 8,9-dehydroxyphenestrol sodium sulfate.

[0004] It is difficult to scale up the synthesis of 8,9-dehydroxyphenestrol with pharmaceutical purity. The main reason is that its structure is unstable, the double bond is easy to migrate to form isomers, and the configuration of some chiral sites (such as 14 position) on the skeleton is also easy to change to form isomers. The only effective synthesis method at present uses isomerization of equilin (Raijmakers, P. H. U. S. Patent 5739363, 1998; Shackleton. C. H. L., Organic Letters, 2001, P2547), but equilin is very expensive. Some methods of total synthesis obtain racemates, which cannot be used for medicine, and the yield is also low (Quinkert, G., Helvetica Chimica Acta, 1995, P1345; Douglas, G. H. Journal of the Chemical Society, 1963, P5072). Therefore, it is of great significance to develop an efficient, controllable and scalable synthesis route of 8,9-dehydroxyphenestrol. SUMMARY

[0005] The technical problem this invention aims to solve is to overcome the deficiency in existing technologies regarding the lack of efficient, controllable, and scale-up synthetic routes for 8,9-dehydroestradiol. To this end, this invention provides a method for preparing 8,9-dehydroestradiol, which has one or more of the following advantages: inexpensive raw materials, simple reaction steps, high yields in each step, convenient post-processing, mild conditions, controllable operation, and suitability for scale-up. The entire route uses 11α-hydroxy-androst-1,4-diene-3,17-dione as the starting material and efficiently synthesizes 8,9-dehydroestradiol through six steps (overall yield up to 58%).

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] This invention provides a method for preparing 8,9-dehydroestradiol ketone, which includes the following steps:

[0008] In the presence of a catalyst and in an aprotic solvent, compound 6 and a hydrogen source reagent undergo an addition reaction to give 8,9-dehydroestradiol ketone.

[0009]

[0010] In certain preferred embodiments of the present invention, certain conditions, operations, or materials in the preparation method of 8,9-dehydroestradiol ketone have the following definitions, and conditions, operations, or materials not mentioned are the same as those described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention"). Other aspects of the present invention are referred to using the same abbreviations as this invention and will not be described in detail hereafter.

[0011] In one embodiment of the present invention, the catalyst is a catalyst for catalytic hydrogenation.

[0012] In one embodiment of the present invention, the catalyst is composed of an active component and a support;

[0013] The active component is preferably one or more of a transition metal, its oxide, and its hydroxide;

[0014] The carrier is preferably activated carbon.

[0015] In one aspect of the present invention, the catalyst is selected from one or more of Pd / C, Pd(OH)2 / C, and Pt / C;

[0016] The catalyst is preferably Pd / C, more preferably 1%-20% Pd / C, such as 5% Pd / C or 10% Pd / C.

[0017] In one embodiment of the present invention, the molar ratio of the active component in the catalyst to the compound 6 is (0.01-0.5):1, preferably (0.01-0.02):1, for example 0.0156:1.

[0018] In one aspect of the present invention, the aprotic solvent is an aromatic solvent or a haloalkanes solvent;

[0019] The aromatic solvent is preferably benzene, toluene, or chlorobenzene;

[0020] The preferred halogenated hydrocarbon solvent is dichloromethane.

[0021] In one embodiment of the present invention, the volume-to-mass ratio of the aprotic solvent to compound 6 is 1-60 mL / g, preferably 20-30 mL / g, for example 22.5 mL / g.

[0022] In one aspect of the present invention, the hydrogen source reagent is selected from one or more of trialkylsilane, hydrogen, cyclohexene, and ammonium formate;

[0023] The trialkylsilane is preferably triethylsilane.

[0024] In one embodiment of the present invention, the molar ratio of the hydrogen source reagent to the compound 6 is (1-30):1, preferably (10-30):1, for example 18.8:1.

[0025] In one aspect of this invention, the progress of the addition reaction is monitored using conventional detection methods in the art (e.g., HPLC, LC-MS, or TLC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the reactants in the reaction solution. The preferred reaction time for the addition reaction is 1-20 hours, for example, 6 hours.

[0026] In one aspect of the present invention, the temperature of the addition reaction is -5 to 25°C, preferably -5 to 5°C, for example 0°C.

[0027] In one embodiment of the present invention, the addition reaction is carried out under normal pressure.

[0028] In one aspect of the present invention, the method for preparing 8,9-dehydroestradiol ketone includes the following steps:

[0029] The compound 6, the aprotic solvent, and the hydrogen source reagent were mixed, a catalyst was added, and an addition reaction was carried out to obtain 8,9-dehydroestradiol ketone.

[0030] In one embodiment of the present invention, the method for preparing 8,9-dehydroestradiol ketone further includes one or more of the following post-processing steps:

[0031] The catalyst is removed, the organic phase is washed, and the mixture is concentrated and purified.

[0032] The catalyst removal step preferably uses diatomaceous earth filtration to remove the catalyst.

[0033] The washing and organic phase removal step preferably uses dichloromethane for washing;

[0034] The purification step preferably uses the crude product obtained by column chromatography or recrystallization purification and concentration steps;

[0035] The column chromatography preferably uses petroleum ether and ethyl acetate as eluents.

[0036] In one aspect of the present invention, the method for preparing 8,9-dehydroestradiol ketone further includes the following steps:

[0037] Preparation steps of compound 6: In the presence of an acid catalyst and in an aprotic solvent, compound 5 was subjected to a deprotection-isomerization reaction to obtain compound 6;

[0038]

[0039] Where PG is C 1-6 alkyl.

[0040] In one embodiment of the present invention, in the preparation step of compound 6, PG is methyl.

[0041] In one embodiment of the present invention, in the preparation step of compound 6, the acid catalyst is one or both of a strong protic acid and a strong Lewis acid;

[0042] The strong protic acid is preferably a hydrohalic acid or a sulfonic acid; the hydrohalic acid is preferably HI; the sulfonic acid is preferably CF3SO3H.

[0043] The strong Lewis acid is preferably BBr3.

[0044] In one embodiment of the present invention, in the preparation step of compound 6, the acid catalyst is BBr3; the BBr3 is preferably used in solution form, more preferably in the form of a haloalkane solvent solution of BBr3, such as a 0.1-10 mol / L dichloromethane solution, and further, for example, a 1 mol / L dichloromethane solution.

[0045] In one embodiment of the present invention, in the preparation step of compound 6, the molar ratio of the acid catalyst to compound 5 is (0.5-5):1, preferably (0.5-2):1, for example 1:1.

[0046] In one embodiment of the present invention, in the preparation step of compound 6, the aprotic solvent is an aromatic solvent; the aromatic solvent is preferably one or more of toluene, benzene, and chlorobenzene.

[0047] In one embodiment of the present invention, in the preparation step of compound 6, the volume-to-mass ratio of the aprotic solvent to compound 5 is (1-60) mL / g, preferably (30-40) mL / g, for example 36 mL / g.

[0048] In one embodiment of the present invention, in the preparation step of compound 6, the progress of the deprotection-isomerization reaction is monitored using conventional detection methods in the art (e.g., HPLC, LC-MS, or TLC), and the reaction endpoint is generally defined as the content of compound 5 in the reaction solution falling below 1% or compound 5 ceasing to react. The reaction time of the deprotection-isomerization reaction is preferably 1-2 hours.

[0049] In one embodiment of the present invention, in the preparation step of compound 6, the temperature of the deprotection-isomerization reaction is -80-25°C, preferably -80-0°C, for example -78°C.

[0050] In one embodiment of the present invention, in the preparation step of compound 6, the deprotection-isomerization reaction is carried out under normal pressure.

[0051] In one embodiment of the present invention, the preparation step of compound 6 includes the following steps:

[0052] Compound 5 and the aprotic solvent were mixed, an acid catalyst was added, and the mixture was subjected to a deprotection-isomerization reaction to obtain compound 6.

[0053] In one embodiment of the present invention, the preparation step of compound 6 further includes one or more of the following post-processing steps:

[0054] The mixture was brought back to room temperature, washed with alkali to obtain the organic phase, dried, concentrated, and purified.

[0055] The step of alkali washing to obtain the organic phase preferably uses a saturated sodium bicarbonate solution for washing.

[0056] The purification step preferably uses the crude product obtained by column chromatography or recrystallization purification and concentration steps.

[0057] In one embodiment of the present invention, the preparation step of compound 6 further includes the following steps:

[0058] Preparation steps of compound 5: In the presence of a palladium catalyst and an oxidant, compound 4A is oxidized in an organic solvent to obtain compound 5;

[0059]

[0060] Where PG is C 1-6 alkyl.

[0061] In one embodiment of the present invention, in the preparation step of compound 5, PG is methyl.

[0062] In one embodiment of the present invention, in the preparation step of compound 5, the palladium catalyst is selected from one or more of palladium acetate, tris(dibenzylacetone)palladium, and bis(acetonitrile)dichloropalladium.

[0063] In one embodiment of the present invention, in the preparation step of compound 5, the molar ratio of the palladium catalyst to compound 4A is (0.1-1):1, for example 0.38:1.

[0064] In one embodiment of the present invention, in the preparation step of compound 5, the oxidant is O2.

[0065] In one aspect of the present invention, in the preparation step of compound 5, when the oxidant is O2, the oxidation reaction is carried out under an oxygen atmosphere; the partial pressure of the oxygen atmosphere is preferably 0.5-10 atm, for example 1 atm.

[0066] In one aspect of the present invention, in the preparation step of compound 5, when the oxidant is O2, the amount of O2 used is the conventional amount used in the art and there is no need to limit it in particular, as long as it does not affect the occurrence of the oxidation reaction; the amount of O2 used is generally in great excess.

[0067] In one embodiment of the present invention, in the preparation step of compound 5, the organic solvent is selected from one or more of dialkyl sulfoxide solvents, amide solvents, and hexaalkylphosphotriamine solvents;

[0068] The sulfoxide solvent is preferably dimethyl sulfoxide;

[0069] The amide solvent is preferably a dialkylformamide solvent or a lactam solvent;

[0070] The preferred dialkylformamide solvent is N,N-dimethylformamide;

[0071] The lactam solvent is preferably N-methylpyrrolidone;

[0072] The hexaalkylphosphoric triamine solvent is preferably hexamethylphosphoric triamine (HMPA).

[0073] In one embodiment of the present invention, in the preparation step of compound 5, the molar volume ratio of compound 4A to the organic solvent is 0.05-1 mol / L, for example 0.2 mol / L.

[0074] In one embodiment of the present invention, in the preparation step of compound 5, compound 4A is...

[0075] In one embodiment of the present invention, in the preparation step of compound 5, the progress of the oxidation reaction is monitored using conventional detection methods in the art (e.g., HPLC, LC-MS, or TLC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The reaction time of the oxidation reaction is preferably 1-6 hours, for example, 4 hours.

[0076] In one embodiment of the present invention, in the preparation step of compound 5, the temperature of the oxidation reaction is 15-40°C, for example 25°C.

[0077] In one embodiment of the present invention, in the preparation step of compound 5, the oxidation reaction is carried out under an oxygen atmosphere.

[0078] In one embodiment of the present invention, the preparation step of compound 5 includes the following steps:

[0079] The crude product containing compound 4A was mixed with the organic solvent, and a palladium catalyst was added to rapidly replace the gas in the reaction system with oxygen. Compound 4A was then oxidized to obtain compound 5.

[0080] In one embodiment of the present invention, the preparation step of compound 5 further includes one or more of the following post-processing steps:

[0081] The process involves dilution, filtration to obtain the filtrate, washing the filtrate with water to obtain the organic phase, drying, concentration, and purification.

[0082] The dilution step preferably uses ethyl acetate to dilute the reaction system;

[0083] The purification step preferably uses the crude product obtained by column chromatography or recrystallization purification and concentration steps.

[0084] In one embodiment of the present invention, the preparation step of compound 5 further includes the following steps:

[0085] Preparation steps of compound 4A: In the presence of a non-nucleophilic strong base and a silanizing agent, in an aprotic solvent, compound 4A is obtained by silylation reaction.

[0086]

[0087] Where PG is C 1-6 alkyl.

[0088] In one embodiment of the present invention, in the preparation step of compound 4A, PG is methyl.

[0089] In one embodiment of the present invention, in the preparation step of compound 4A, compound 4A is...

[0090] In one embodiment of the present invention, in the preparation step of compound 4A, the non-nucleophilic strong base is a non-nucleophilic organometallic compound, preferably a dialkylamino metal compound, more preferably a dialkylamino alkali metal compound, such as lithium diisopropylamino.

[0091] In one aspect of the present invention, the non-nucleophilic organometallic compound is used in solution form, preferably in the form of an ether solvent and / or an alkane solvent solution of the non-nucleophilic organometallic compound, for example, a 1-3 mol / L THF and n-hexane mixed solution; wherein the volume ratio of THF to n-hexane solution in the mixed solution is preferably 1:1;

[0092] Preferably, the solution of the non-nucleophilic organometallic compound is a 2 mol / L solution of diisopropylaminolithium; the solvent of the diisopropylaminolithium solution is preferably THF and / or n-hexane.

[0093] In one embodiment of the present invention, in the preparation step of compound 4A, the molar ratio of the non-nucleophilic strong base to compound 4 is (1-10):1, preferably (1-3):1, for example 2:1.

[0094] In one embodiment of the present invention, in the preparation step of compound 4A, the silanizing agent is... The halogen is preferably chlorine;

[0095] The silanizing agent is preferably one or more of trimethylchlorosilane, triethylchlorosilane, and tert-butyldimethylchlorosilane.

[0096] In one embodiment of the present invention, in the preparation step of compound 4A, the molar ratio of the silanizing agent to compound 4 is (1-4):1; for example, 2:1.

[0097] In one embodiment of the present invention, in the preparation step of compound 4A, the aprotic solvent is a drying solvent.

[0098] In one aspect of the present invention, in the preparation step of compound 4A, the aprotic solvent is one or both of ether solvents and haloalkanes solvents;

[0099] The ether solvent is preferably a cyclic ether solvent or a C-type solvent. 1-6 Alkyl-OC 1-6 alkyl;

[0100] The cyclic ether solvent is preferably tetrahydrofuran or methyltetrahydrofuran;

[0101] The C 1-6 Alkyl-OC 1-6 The alkyl group is preferably methyl tert-butyl ether;

[0102] The preferred halogenated hydrocarbon solvent is dichloromethane.

[0103] In one embodiment of the present invention, in the preparation step of compound 4A, the molar volume ratio of compound 4 to the aprotic solvent is 0.05-1 mol / L, preferably 0.1-0.4 mol / L, for example 0.2 mol / L.

[0104] In one embodiment of the present invention, during the preparation step of compound 4A, the progress of the silyl etherification reaction is monitored using conventional detection methods in the art (e.g., HPLC, LC-MS, or TLC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The preferred reaction time for the silyl etherification reaction is 0.5-5 hours, for example, 1 hour.

[0105] In one embodiment of the present invention, in the preparation step of compound 4A, the temperature of the silanization reaction is 0-25°C, for example, 25°C.

[0106] In one embodiment of the present invention, in the preparation step of compound 4A, the silanization reaction is carried out under an inert gas atmosphere; the inert gas is preferably argon.

[0107] In one embodiment of the present invention, the silanization reaction is carried out under normal pressure during the preparation step of compound 4A.

[0108] In one aspect of the present invention, the preparation steps of compound 4A include the following steps:

[0109] Under an argon atmosphere, compound 4 and the aprotic solvent are mixed, and after an ice bath, the non-nucleophilic strong base is added. After 10-20 min (e.g., 15 min), the silanizing agent is added, and a silanization reaction occurs at 0-25 °C to obtain compound 4A.

[0110] In one embodiment of the present invention, the preparation step of compound 4A further includes one or more of the following post-processing steps:

[0111] Extraction, washing, drying, and vacuum drying;

[0112] The post-processing is preferably performed by directly drying the sample and then using it directly for subsequent reactions.

[0113] In one embodiment of the present invention, the preparation step of compound 4A further includes the following steps:

[0114] Preparation steps of compound 4:

[0115] Step (A): In the presence of a dehydrating agent, in an aprotic solvent, compound 1 undergoes an elimination reaction to give compound 2;

[0116] The dehydrating agent is preferably one or more of phosphorus pentachloride, phosphorus trichloride, and thionyl chloride;

[0117] The aprotic solvent is preferably a dry aprotic solvent;

[0118] The aprotic solvent is preferably one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, chloroform, dichloromethane, and 1,2-dichloroethane;

[0119] The preferred temperature for the elimination reaction is -80℃ to 25℃;

[0120] The elimination reaction time is preferably 1-8 hours;

[0121] The volume-to-mass ratio of the aprotic solvent to compound 1 is preferably 1-20 mL / g;

[0122] The preferred molar ratio of the dehydrating agent to compound 1 is (1-4):1;

[0123] Step (A) preferably includes the following post-processing steps:

[0124] The reaction solution was poured into water for hydrolysis, filtered, the filter cake was washed with water until neutral, and dried to obtain crude compound 2, which could be used directly in the next step or further purified by column chromatography or recrystallization.

[0125] Step (B): In the presence of a reducing agent and in an organic solvent, compound 2 undergoes an aromatization reaction to give compound 3;

[0126] The reducing agent is preferably one or more of zinc powder, iron powder, and magnesium powder;

[0127] The organic solvent is preferably one or more selected from pyridine, piperidine, N,N-dimethylformamide, hexamethylphosphoric triamine and N-methylpyrrolidone;

[0128] The preferred temperature for the aromatization reaction is 100℃-140℃;

[0129] The aromatization reaction is preferably carried out over a period of 1-10 hours.

[0130] The volume-to-mass ratio of the organic solvent to compound 2 is preferably 1-20 mL / g;

[0131] The preferred mass ratio of the reducing agent to compound 2 is (1-10):1;

[0132] Step (B) preferably includes the following post-processing steps:

[0133] Cool to room temperature, let stand, pour off the supernatant by decantation, wash the solid three times with acetone, combine the organic phases, add dilute hydrochloric acid to acidity (pH<3), add water for water precipitation, filter, wash the filter cake with water, dry to obtain crude compound 3, which can be used directly for the next step or further purified by column chromatography or recrystallization.

[0134] Step (C): In the presence of an alkylating agent and an inorganic base, in a polar aprotic solvent, compound 3 undergoes a substitution reaction to give compound 4;

[0135] The alkylating agent is preferably one or more selected from dimethyl sulfate, iodomethane, diethyl sulfate, and iodoethane;

[0136] The inorganic base is preferably one or more selected from NaOH, KOH, K2CO3 and Cs2CO3;

[0137] The polar aprotic solvent is preferably one or more of acetone, acetonitrile, and tetrahydrofuran;

[0138] The preferred temperature for the elimination-substitution reaction is 70℃-90℃;

[0139] The substitution reaction is preferably carried out over a period of 0.5 to 2 hours.

[0140] The preferred volume-to-mass ratio of the polar aprotic solvent to compound 3 is 1-20 mL / g;

[0141] The preferred molar ratio of compound 3, the alkylating agent, and the base is 1:(1-3):(2-6);

[0142] Step (C) preferably includes the following post-processing steps:

[0143] Acidification, extraction, washing with water, separation, drying, concentration, and then purification by column chromatography;

[0144] Alternatively, after adding a large amount of water and separating the solid, the solid can be dried and recrystallized.

[0145]

[0146] Where PG is C 1-6 alkyl.

[0147] In one embodiment of the present invention, in the preparation step of compound 4, PG is methyl.

[0148] This invention also provides a method for preparing compound 4A, which includes the following steps:

[0149] In the presence of a nonnucleophilic strong base and a silanizing agent, in an aprotic solvent, compound 4 undergoes a silyl etherification reaction to give compound 4A;

[0150]

[0151] Where PG is C 1-6 alkyl;

[0152] The conditions, operations, materials, and steps in the preparation method of compound 4A are as described in any of the aforementioned technical solutions for the preparation steps of compound 4A.

[0153] The present invention also provides a method for preparing compound 5, which includes the following steps:

[0154] In the presence of a palladium catalyst and an oxidant, compound 4A was oxidized in an organic solvent to give compound 5.

[0155]

[0156] Where PG is C 1-6 alkyl;

[0157] The conditions, operations, materials, and steps in the preparation method of compound 5 are as described in any of the aforementioned technical solutions for the preparation steps of compound 5.

[0158] The present invention also provides a method for preparing compound 6, which includes the following steps:

[0159] In the presence of an acid catalyst and in an aprotic solvent, compound 5 undergoes a deprotection-isomerization reaction to give compound 6;

[0160]

[0161] Where PG is C 1-6 alkyl;

[0162] The conditions, operations, materials, and steps in the preparation method of compound 6 are as described in any of the aforementioned technical solutions for the preparation steps of compound 6.

[0163] This invention also provides a preparation route for 8,9-dehydroestradiol ketone, which includes the following steps:

[0164]

[0165] Where PG is C 1-6 alkyl.

[0166] In one aspect of the present invention, the preparation route of 8,9-dehydroestradiol ketone includes the following steps:

[0167] (1) Preparation steps of compound 4:

[0168] Step (A): In the presence of a dehydrating agent, in an aprotic solvent, compound 1 undergoes an elimination reaction to give compound 2;

[0169] The dehydrating agent is preferably one or more of phosphorus pentachloride, phosphorus trichloride, and thionyl chloride;

[0170] The aprotic solvent is preferably a dry aprotic solvent;

[0171] The aprotic solvent is preferably one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, chloroform, dichloromethane, and 1,2-dichloroethane;

[0172] The preferred temperature for the elimination reaction is -80℃ to 25℃;

[0173] The elimination reaction time is preferably 1-8 hours;

[0174] The volume-to-mass ratio of the aprotic solvent to compound 1 is preferably 1-20 mL / g;

[0175] The preferred molar ratio of the dehydrating agent to compound 1 is (1-4):1;

[0176] Step (A) preferably includes the following post-processing steps:

[0177] The reaction solution was poured into water for hydrolysis, filtered, the filter cake was washed with water until neutral, and dried to obtain crude compound 2, which could be used directly in the next step or further purified by column chromatography or recrystallization.

[0178] Step (B): In the presence of a reducing agent and in an organic solvent, compound 2 undergoes an aromatization reaction to give compound 3;

[0179] The reducing agent is preferably one or more of zinc powder, iron powder, and magnesium powder;

[0180] The organic solvent is preferably one or more selected from pyridine, piperidine, N,N-dimethylformamide, hexamethylphosphoric triamine and N-methylpyrrolidone;

[0181] The preferred temperature for the aromatization reaction is 100℃-140℃;

[0182] The aromatization reaction is preferably carried out over a period of 1-10 hours.

[0183] The volume-to-mass ratio of the organic solvent to compound 2 is preferably 1-20 mL / g;

[0184] The preferred mass ratio of the reducing agent to compound 2 is (1-10):1;

[0185] Step (B) preferably includes the following post-processing steps:

[0186] Cool to room temperature, let stand, pour off the supernatant by decantation, wash the solid three times with acetone, combine the organic phases, add dilute hydrochloric acid to acidity (pH<3), add water for water precipitation, filter, wash the filter cake with water, dry to obtain crude compound 3, which can be used directly for the next step or further purified by column chromatography or recrystallization.

[0187] Step (C): In the presence of an alkylating agent and an inorganic base, in a polar aprotic solvent, compound 3 undergoes a substitution reaction to give compound 4;

[0188] The alkylating agent is preferably one or more selected from dimethyl sulfate, iodomethane, diethyl sulfate, and iodoethane;

[0189] The inorganic base is preferably one or more selected from NaOH, KOH, K2CO3 and Cs2CO3;

[0190] The polar aprotic solvent is preferably one or more of acetone, acetonitrile, and tetrahydrofuran;

[0191] The preferred temperature for the elimination-substitution reaction is 70℃-90℃;

[0192] The substitution reaction is preferably carried out over a period of 0.5 to 2 hours.

[0193] The preferred volume-to-mass ratio of the polar aprotic solvent to compound 3 is 1-20 mL / g;

[0194] The preferred molar ratio of compound 3, the alkylating agent, and the base is 1:(1-3):(2-6);

[0195] Step (C) preferably includes the following post-processing steps:

[0196] Acidification, extraction, washing with water, separation, drying, concentration, and then purification by column chromatography;

[0197] Alternatively, after adding a large amount of water and separating the solid, the solid can be dried and recrystallized.

[0198]

[0199] (2) In the presence of a nonnucleophilic strong base and a silanizing agent, in an aprotic solvent, compound 4 was silanized to give compound 4A.

[0200]

[0201] (3) In the presence of a palladium catalyst and an oxidant, in an organic solvent, compound 4A is oxidized to give compound 5;

[0202]

[0203] (4) In the presence of an acid catalyst and in an aprotic solvent, compound 5 undergoes a deprotection-isomerization reaction to give compound 6;

[0204]

[0205] (5) In the presence of a catalyst, in an aprotic solvent, compound 6 and a hydrogen source reagent undergo an addition reaction to give 8,9-dehydroestradiol ketone.

[0206]

[0207] The conditions, operations, and materials for each step are as described in any of the aforementioned technical solutions for the corresponding preparation steps.

[0208] This invention also provides a compound 4A:

[0209]

[0210] Where PG is C 1-6 alkyl.

[0211] In one embodiment of the present invention, compound 4A is... The present invention also provides a compound 5:

[0212]

[0213] Where PG is C 1-6 alkyl.

[0214] In one embodiment of the present invention, compound 5 is... The present invention also provides a compound 6:

[0215]

[0216] The present invention also provides the use of compound 4 in the preparation of compound 4A;

[0217]

[0218] Where PG is C 1-6 alkyl.

[0219] The present invention also provides the use of compound 4A in the preparation of compound 5;

[0220]

[0221] Where PG is C 1-6 alkyl.

[0222] The present invention also provides the use of compound 4 in the preparation of compound 5;

[0223]

[0224] Where PG is C 1-6 alkyl.

[0225] The present invention also provides the use of compound 6 in the preparation of 8,9-dehydroestradiol ketone;

[0226]

[0227] Unless otherwise specified, the terms used in this invention may be defined as follows:

[0228] The expression "molar ratio of compound A to compound B" refers to the ratio of the amount of substance of compound A to the amount of substance of compound B; for example, a molar ratio of 10:1 means that the amount of substance of compound A to the amount of substance of compound B is 10:1. The rules and meanings for similar expressions are similar and will not be repeated here.

[0229] The expression "molar volume ratio of compound A to organic solvent B" refers to the ratio of the amount of substance of compound A (in mol) to the volume of organic solvent B (in L). For example, a molar volume ratio of 1 mol / L means that the amount of substance of compound A and the volume of organic solvent B are 1 mol / L. The rules and meanings for similar expressions are similar and will not be repeated here.

[0230] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0231] The reagents and raw materials used in this invention are all commercially available.

[0232] The positive and progressive effects of this invention are as follows:

[0233] The method for synthesizing 8,9-dehydroestradiol ketone derivatives disclosed in this invention uses inexpensive and readily available 11α-hydroxy-androst-1,4-diene-3,17-dione as a starting material. Through A-ring aromatization, D-ring double bond introduction, conjugated double bond migration, and selective hydrogenation, 8,9-dehydroestradiol ketone is finally synthesized. This invention has advantages such as low raw material cost, simple reaction steps, high yields in each step (most steps exceeding 90%), simple post-processing, mild conditions, controllable operation, and the ability to achieve large-scale preparation. It provides key technical support for the development and production of conjugated estrogen drugs and has significant application value in the field of drugs for the treatment and prevention of menopausal syndrome, osteoporosis, and other related diseases in women. Detailed Implementation

[0234] The present invention is further illustrated below by way of examples, but these examples do not limit the invention to the scope of the embodiments described. Experimental methods not specifically described in the following examples were performed according to conventional methods and conditions, or as selected according to the product instructions. All reagents used in this application are commercially available and can be used without further purification.

[0235] Example 1 Synthesis of 1,4,9(11)androstriene-3,17-dione

[0236]

[0237] 450 mg of 11α-hydroxyandrost-1,4-diene-3,17-dione was placed in a reaction flask, 7.5 mL of dried tetrahydrofuran was added, and 620 mg of PCl5 was added in portions at -78 °C. The mixture was stirred for 6 h, and the reaction was monitored by TLC until complete. The mixture was poured into 200 mL of water, filtered, and the filter cake was dissolved in 10 mL of dichloromethane. The mixture was washed twice with water, dried over anhydrous sodium sulfate, and subjected to rapid column chromatography to obtain 420 mg of 1,4,9(11)androstriene-3,17-dione, with a yield of 94%.

[0238] 1,4,9(11)androstriene-3,17-dione: 1 H NMR (400MHz, CDCl3) δ7.17(d,J=10.2Hz,1H),6.26(dd,J=10.2,1.8Hz,1H),6.06(s,1H),5.56(s,1H),2.72-2.62(m,1H),2.47(ddd,J=13.5,9.0,4. 7Hz,3H),2.32-2.24(m,1H),2.19-2.02(m,4H),1.61(ddd,J=11.7,10.7, 3.8Hz,1H),1.48-1.39(m,4H),1.23(dd,J=13.9,4.7Hz,1H),0.89(s,3H).

[0239] Example 2 Synthesis of 9,11-dehydroestradiol

[0240]

[0241] 1 g of zinc powder was placed in a reaction flask, 2 mL of pyridine and 400 mg of 1,4,9(11)androstriene-3,17-dione were added, and the mixture was refluxed at 130 °C for 8 h. The reaction was monitored by TLC until it was complete. The mixture was cooled to room temperature, allowed to stand, and the supernatant was poured off by decantation. The solid was washed three times with 10 mL of acetone. The organic phases were combined, and the pH was adjusted to weakly acidic by adding dilute hydrochloric acid. 20 mL of water was added, and the mixture was filtered. The filter cake was dissolved in 60 mL of ethyl acetate, washed twice with water, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate and subjected to rapid column chromatography to obtain 370 mg of white solid 9,11-dehydroestradiol ketone, with a yield of 92%.

[0242] 9,11-Dehydroestradiol: 1 H NMR (400MHz, CDCl3) δ7.49(d,J=8.7Hz,1H),6.65(dd,J=8.6,2.7Hz,1H),6.57(d,J=2.5Hz,1H),6.17-6.09(m,1H),4.89(s, 1H),2.96-2.77(m,2H),2.58-2.46(m,1H),2.38-2.10(m,6H),1.74-1.57(m,2H),1.45(qd,J=12.4,5.6Hz,1H),0.94(s,3H).

[0243] Post-processing operations not described in detail in subsequent examples shall be performed in accordance with the conventional methods of Example 1 (e.g., extraction using an ethyl acetate / water system, drying using anhydrous sodium sulfate, and column chromatography eluent using a petroleum ether / ethyl acetate mixture).

[0244] Example 3 Synthesis of 9,11-dehydroestradiol methyl ether

[0245]

[0246] 280 mg of 9,11-dehydroestradiol ketone was added to a reaction flask, along with 5 mL of acetone, 0.3 mL of dimethyl sulfate, and 0.5 mL of NaOH (5N). The mixture was heated to 80 °C and reacted under TLC for 1 h until complete. After cooling to room temperature, the acetone was removed under reduced pressure, and the mixture was dissolved in 10 mL of dichloromethane. The solution was washed three times with water, dried over anhydrous sodium sulfate, concentrated, and dried under vacuum. Rapid column chromatography yielded 260 mg of a white solid, 9,11-dehydroestradiol ketone methyl ether, in 93% yield.

[0247] 9,11-Dehydroestradiol methyl ether: 1H NMR (400MHz, CDCl3) δ7.53(d,J=8.8Hz,1H),6.73(dd,J=8.8,2.7Hz,1H),6.62(d,J=2.6Hz,1H),6.17-6.08(m,1H),3.79(s,3H),2.99-2.8 1(m,2H),2.52(ddd,J=13.6,9.6,4.3Hz,1H),2.38-2.10(m,6H),1.66(dd,J=11.5,7.9Hz,2H),1.46(qd,J=12.4,5.7Hz,1H),0.93(s,3H).

[0248] Example 4 Synthesis of 9,11-15,16-didehydroestradiol methyl ether

[0249]

[0250] 280 mg of compound 9,11-dehydroestradiol methyl ether was weighed into a Schlenk flask. Under an argon atmosphere, 5 mL of dry tetrahydrofuran solution was added to the reaction flask, which was then placed in an ice bath. 1 mL of diisopropylaminolithium (2 min THF / n-hexanes) was added dropwise. After 15 min, 0.26 mL of trimethylchlorosilane was added dropwise. The mixture was then moved to room temperature (25 °C), and the reaction was monitored by TLC for 1 h until it was complete. The mixture was then directly dried under vacuum pump to obtain a yellow oily crude compound 4A, which could be used directly in the next reaction without purification.

[0251] Add 5 mL of DMSO to the crude intermediate compound 4A, then add 30 wt% (relative to the amount of 9,11-dehydroestradiol methyl ether) of Pd(OAc)₂ (84 mg). Quickly replace the gas in the system with oxygen (using a balloon to store the gas at a pressure of approximately 1 atm), and stir vigorously at room temperature. After 4 hours, TLC showed complete substrate conversion. Add 50 mL of ethyl acetate, filter to remove insoluble matter, wash the filtrate three times with water, dry the organic phase with anhydrous Na₂SO₄, concentrate, and purify by column chromatography to give 250 mg of white solid 9,11-15,16-didehydroestradiol methyl ether, with a two-step yield of 90%.

[0252] 9,11-15,16-Didehydroestradiol methyl ether: 1H NMR (400MHz, CDCl3) δ7.64(d,J=5.5Hz,1H),7.55(d,J=8.8Hz,1H),6.75(dd,J=8.7,2.4Hz,1H),6.64(s,1H),6.29–6.20(m,1H),6.15(dd,J=5.8,2 .9Hz,1H),3.80(s,3H),3.04-2.85(m,2H),2.49(dt,J=24.0,12.2Hz,3H) ,2.26(dd,J=27.8,9.4Hz,2H),1.55(qd,J=12.4,5.7Hz,1H),1.11(s,3H).

[0253] Example 5 Synthesis of 8,9-14,15-didehydroestradiolone

[0254]

[0255] 280 mg of 9,11-15,16-bisdehydroestradiol methyl ether was weighed and dissolved in 10 mL of dichloromethane. 1 mL of 1 mol / L BBr3 solution (dichloromethane as solvent) was added, and the reaction was carried out at -78 °C. The reaction was stopped when the content of the starting material was lower than 1% by HPLC monitoring. At room temperature, 10 mL of saturated sodium bicarbonate solution was added and the mixture was washed twice. The oil phase was dried over anhydrous sodium sulfate, concentrated, and dried under vacuum. Column chromatography yielded 248 mg of white solid 8,9-14,15-bisdehydroestradiol ether, with a yield of 89%.

[0256] 8,9-14,15-Didehydroestradiol: 1 H NMR (400MHz, CDCl3) δ7.51(d,J=8.8Hz,1H),6.71(dd,J=8.8,2.7Hz,1H),6.61(d,J=2.6Hz,1H),6.14–6.09(m,1 H),2.95-2.82(m,2H),2.56-2.44(m,1H),2.34-2.10(m,4H),1.71-1.61(m,2H),1.51-1.36(m,1H),0.92(s,3H).

[0257] Example 6 Synthesis of 8,9-Dehydroestradiol

[0258]

[0259] 80 mg of 8,9-14,15-bisdehydroestradiol was dissolved in a mixed solution of 1.8 mL benzene and 0.9 mL triethylsilane. 5 mg of Pd / C (10% content) was added, and the reaction was carried out at 0 °C. The reaction was monitored by TLC for 6 h until complete. The palladium on carbon was removed by diatomaceous earth filtration. The mixture was washed three times with 5 mL dichloromethane, and the organic phases were combined. The solvent was concentrated and evaporated to dryness. The mixture was then subjected to rapid column chromatography (PE:EA = 20:1) to give 70 mg of white solid 8,9-bisdehydroestradiol, with a yield of 91%.

[0260] 8,9-Dehydroestradiol: 1 H NMR(400MHz,(CD3)2CO)δ7.12(d,J=8.1Hz,1H),6.72-6.62(m,2H),2.79-2.63(m,3H),2 .61-2.50(m,3H),2.36-2.06(m,4H),2.04-2.01(m,1H),1.82-1.62(m,2H),0.99(s,3H).

Claims

1. A method for preparing 8,9-dehydroestradiol ketone, comprising the following steps: Step (1) Preparation of compound 6: In the presence of an acid catalyst, in an aprotic solvent, compound 5 is deprotected and isomerized to obtain compound 6; Where PG is C 1-6 alkyl; In step (2), in the presence of a catalyst, in an aprotic solvent, compound 6 and a hydrogen source reagent undergo an addition reaction to give 8,9-dehydroestradiol ketone.

2. The method for preparing 8,9-dehydroestradiol ketone as described in claim 1, characterized in that, Step (1) satisfies one or more of the following conditions: (1) PG is methyl; (2) The acid catalyst is one or both of strong protic acid and strong Lewis acid; The strong protic acid is preferably a hydrohalic acid or a sulfonic acid; the hydrohalic acid is preferably HI; the sulfonic acid is preferably CF3SO3H. The strong Lewis acid is preferably BBr3; Preferably, the acid catalyst is BBr3; the BBr3 is preferably used in solution form, more preferably in the form of a haloalkanes solvent solution of BBr3, such as a 0.1-10 mol / L dichloromethane solution, and further, for example, a 1 mol / L dichloromethane solution; (3) The molar ratio of the acid catalyst to the compound 5 is (0.5-5):1, for example 1:1; (4) The aprotic solvent is an aromatic solvent; preferably, the aromatic solvent is one or more of toluene, benzene, and chlorobenzene; (5) The volume-to-mass ratio of the aprotic solvent to compound 5 is (1-60) mL / g, for example, 36 mL / g; (6) The temperature of the deprotection-isomerization reaction is -80 to 25°C, for example -78°C; (7) The preparation steps of compound 6 include the following steps: Compound 5 was mixed with the aprotic solvent, an acid catalyst was added, and the mixture was subjected to a deprotection-isomerization reaction to obtain compound 6. (8) The preparation steps of compound 6 further include one or more of the following post-processing steps: The mixture was brought back to room temperature, washed with alkali to obtain the organic phase, dried, concentrated, and purified. The step of alkali washing to obtain the organic phase preferably uses a saturated sodium bicarbonate solution for washing. The purification step preferably uses the crude product obtained by column chromatography or recrystallization purification and concentration steps; and or, Step (2) satisfies one or more of the following conditions: (1) The catalyst is a catalyst used for catalytic hydrogenation; (2) The catalyst is composed of an active component and a support; the active component is preferably one or more of a transition metal, its oxide and its hydroxide; the support is preferably activated carbon; Preferably, the catalyst is selected from one or more of Pd / C, Pd(OH)2 / C, and Pt / C; More preferably, the catalyst is Pd / C, for example, 1%-20% Pd / C; (3) The molar ratio of the active component to the compound 6 in the catalyst is (0.01-0.5):1, preferably (0.01-0.02):1, for example 0.0156:1; (4) The aprotic solvent is an aromatic solvent or a haloalkanes solvent; The aromatic solvent is preferably benzene, toluene, or chlorobenzene; The preferred halogenated hydrocarbon solvent is dichloromethane; (5) The volume-to-mass ratio of the aprotic solvent to the compound 6 is 1-50 mL / g, preferably 20-30 mL / g, for example 22.5 mL / g; (6) The hydrogen source reagent is selected from one or more of trialkylsilane, hydrogen, cyclohexene and ammonium formate; the trialkylsilane is preferably triethylsilane; (7) The molar ratio of the hydrogen source reagent to the compound 6 is (1-30):1, preferably (10-30):1, for example 18.8:1; (8) The temperature of the addition reaction is -5 to 25°C, preferably -5 to 5°C, for example 0°C; (9) The preparation method of the 8,9-dehydroestradiol ketone includes the following steps: The compound 6, the aprotic solvent and the hydrogen source reagent were mixed, a catalyst was added, and an addition reaction was carried out to obtain 8,9-dehydroestradiol ketone. (10) The method for preparing 8,9-dehydroestradiol ketone further includes one or more of the following post-processing steps: The catalyst is removed, the organic phase is washed, and the mixture is concentrated and purified. The catalyst removal step preferably uses diatomaceous earth filtration to remove the catalyst. The washing and organic phase removal step preferably uses dichloromethane for washing; The purification step preferably uses the crude product obtained by column chromatography or recrystallization purification and concentration steps; The column chromatography preferably uses petroleum ether and ethyl acetate as eluents.

3. The method for preparing 8,9-dehydroestradiol ketone as described in claim 1, characterized in that, The preparation steps of compound 6 further include the following steps: Preparation steps of compound 5: In the presence of a palladium catalyst and an oxidant, compound 4A is oxidized in an organic solvent to obtain compound 5; Where PG is C 1-6 alkyl; Preferably, the preparation steps of compound 5 satisfy one or more of the following conditions: (1) PG is methyl; (2) The palladium catalyst is selected from one or more of palladium acetate, tris(dibenzylacetone)dipalladium, and bis(acetonitrile)dichloropalladium; (3) The molar ratio of the palladium catalyst to the compound 4A is (0.1-1):1, for example, 0.38:1; (4) In the preparation step of compound 5, the oxidant is O2; Preferably, when the oxidant is O2, the oxidation reaction is carried out in an oxygen atmosphere; the partial pressure of the oxygen atmosphere is preferably 0.5-10 atm, for example 1 atm; (5) The organic solvent is selected from one or more of dialkyl sulfoxide solvents, amide solvents, and hexaalkylphosphoric triamine solvents; The sulfoxide solvent is preferably dimethyl sulfoxide; The amide solvent is preferably a dialkylformamide solvent or a lactam solvent; The preferred dialkylformamide solvent is N,N-dimethylformamide; The lactam solvent is preferably N-methylpyrrolidone; The hexaalkylphosphoric triamine solvent is preferably hexamethylphosphoric triamine; (6) The molar volume ratio of the compound 4A to the organic solvent is 0.05-1 mol / L, for example 0.2 mol / L; (7) Compound 4A is (8) The temperature of the oxidation reaction is 15-40℃, for example 25℃; (9) The oxidation reaction is carried out in an oxygen atmosphere; (10) The preparation steps of compound 5 include the following steps: The crude product containing compound 4A was mixed with the organic solvent, and a palladium catalyst was added to rapidly replace the gas in the reaction system with oxygen. Compound 4A was then oxidized to obtain compound 5. (11) The preparation steps of compound 5 further include one or more of the following post-processing steps: The process involves dilution, filtration to obtain the filtrate, washing the filtrate with water to obtain the organic phase, drying, concentration, and purification. The dilution step preferably uses ethyl acetate to dilute the reaction system; The purification step preferably uses the crude product obtained by column chromatography or recrystallization purification and concentration steps.

4. The method for preparing 8,9-dehydroestradiol ketone as described in claim 3, characterized in that, The preparation steps of compound 5 further include the following steps: Preparation steps of compound 4A: In the presence of a non-nucleophilic strong base and a silanizing agent, in an aprotic solvent, compound 4A is obtained by silylation reaction. Where PG is C 1-6 alkyl; Preferably, the preparation steps of compound 4A satisfy one or more of the following conditions: (1) PG is methyl; (2) Compound 4A is (3) The non-nucleophilic strong base is a non-nucleophilic organometallic compound, preferably a dialkylamino metal compound, more preferably a dialkylamino alkali metal compound, such as lithium diisopropylamino; preferably, the non-nucleophilic organometallic compound is used in solution form, more preferably in the form of an ether solvent and / or an alkane solvent solution of the non-nucleophilic organometallic compound, such as a 1-3 mol / L THF and n-hexane mixed solution; (4) The molar ratio of the non-nucleophilic strong base to the compound 4 is (1-10):1, preferably (1-3):1, for example 2:1; (5) The silanizing agent is The halogen is preferably chlorine; The silanizing agent is preferably one or more selected from trimethylchlorosilane, triethylchlorosilane, and tert-butyldimethylchlorosilane; (6) The molar ratio of the silanizing agent to compound 4 is (1-4):1; for example, 2:1; (7) The aprotic solvent is a dry solvent; (8) The aprotic solvent is one or both of ether solvents and halocarbon solvents; The ether solvent is preferably a cyclic ether solvent or a C-type solvent. 1-6 Alkyl-OC 1-6 alkyl; The cyclic ether solvent is preferably tetrahydrofuran or methyltetrahydrofuran; The C 1-6 Alkyl-OC 1-6 The alkyl group is preferably methyl tert-butyl ether; The preferred halogenated hydrocarbon solvent is dichloromethane; (9) The molar volume ratio of compound 4 to the aprotic solvent is 0.05-1 mol / L, for example 0.2 mol / L; (10) The temperature of the silylation reaction is 0-25°C, for example 25°C; (11) The silylation reaction is carried out under an inert gas atmosphere; the inert gas is preferably argon. (12) The preparation steps of compound 4A include the following steps: Under an argon atmosphere, compound 4 and the aprotic solvent were mixed, and after an ice bath, the non-nucleophilic strong base was added. After 10-20 min, the silanizing reagent was added, and a silanization reaction was carried out at 0-25 °C to obtain compound 4A. (13) The preparation steps of compound 4A further include one or more of the following post-processing steps: Extraction, washing, drying, and vacuum drying; The post-processing is preferably performed by directly drying the sample and then using it directly for subsequent reactions.

5. The method for preparing 8,9-dehydroestradiol ketone as described in claim 4, characterized in that, The preparation steps of compound 4A further include the following steps: Preparation steps of compound 4: Step (A): In the presence of a dehydrating agent, in an aprotic solvent, compound 1 undergoes an elimination reaction to give compound 2; The dehydrating agent is preferably one or more of phosphorus pentachloride, phosphorus trichloride, and thionyl chloride; The aprotic solvent is preferably a dry aprotic solvent; The aprotic solvent is preferably one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, chloroform, dichloromethane, and 1,2-dichloroethane; The preferred temperature for the elimination reaction is -80℃ to 25℃; The elimination reaction time is preferably 1-8 hours; The volume-to-mass ratio of the aprotic solvent to compound 1 is preferably 1-20 mL / g; The preferred molar ratio of the dehydrating agent to compound 1 is (1-4):1; Step (A) preferably includes the following post-processing steps: The reaction solution was poured into water for hydrolysis, filtered, the filter cake was washed with water until neutral, and dried to obtain crude compound 2, which could be used directly in the next step or further purified by column chromatography or recrystallization. Step (B): In the presence of a reducing agent and in an organic solvent, compound 2 undergoes an aromatization reaction to give compound 3; The reducing agent is preferably one or more of zinc powder, iron powder, and magnesium powder; The organic solvent is preferably one or more selected from pyridine, piperidine, N,N-dimethylformamide, hexamethylphosphoric triamine and N-methylpyrrolidone; The preferred temperature for the aromatization reaction is 100℃-140℃; The aromatization reaction is preferably carried out over a period of 1-10 hours. The volume-to-mass ratio of the organic solvent to compound 2 is preferably 1-20 mL / g; The preferred mass ratio of the reducing agent to compound 2 is (1-10):1; Step (B) preferably includes the following post-processing steps: Cool to room temperature, let stand, pour off the supernatant by decantation, wash the solid three times with acetone, combine the organic phases, add dilute hydrochloric acid to acidity (pH<3), add water for water precipitation, filter, wash the filter cake with water, dry to obtain crude compound 3, which can be used directly for the next step or further purified by column chromatography or recrystallization. Step (C): In the presence of an alkylating agent and an inorganic base, in a polar aprotic solvent, compound 3 undergoes a substitution reaction to give compound 4; The alkylating agent is preferably one or more selected from dimethyl sulfate, iodomethane, diethyl sulfate, and iodoethane; The inorganic base is preferably one or more selected from NaOH, KOH, K2CO3 and Cs2CO3; The polar aprotic solvent is preferably one or more of acetone, acetonitrile, and tetrahydrofuran; The preferred temperature for the elimination-substitution reaction is 70℃-90℃; The substitution reaction is preferably carried out over a period of 0.5 to 2 hours. The preferred volume-to-mass ratio of the polar aprotic solvent to compound 3 is 1-20 mL / g; The preferred molar ratio of compound 3, the alkylating agent, and the base is 1:(1-3):(2-6); Step (C) preferably includes the following post-processing steps: Acidification, extraction, washing with water, separation, drying, concentration, and then purification by column chromatography; Alternatively, after adding a large amount of water and separating the solid, the solid can be dried and recrystallized. Where PG is C 1-6 alkyl.

6. A method for preparing compound 6, comprising the following steps: In the presence of an acid catalyst and in an aprotic solvent, compound 5 undergoes a deprotection-isomerization reaction to give compound 6; Where PG is C 1-6 alkyl; The conditions, operations, materials, and steps in the preparation method of compound 6 are as described in any corresponding technical solution of claims 1-5.

7. A method for preparing compound 5, comprising the following steps: In the presence of a palladium catalyst and an oxidant, compound 4A was oxidized in an organic solvent to give compound 5. Where PG is C 1-6 alkyl; The conditions, operations, materials, and steps in the preparation method of compound 5 are as described in any corresponding technical solution of claims 1-5; Preferably, the preparation method of compound 5 further includes the following steps: Preparation steps of compound 4A: In the presence of a non-nucleophilic strong base and a silanizing agent, in an aprotic solvent, compound 4A is obtained by silylation reaction. Where PG is C 1-6 alkyl; The conditions, operations, materials, and steps in the preparation of compound 4A are as described in any corresponding technical solution of claims 1-5.

8. A preparation route for 8,9-dehydroestradiol ketone, comprising the following steps: Where PG is C 1-6 alkyl.

9. A compound, wherein the compound is compound 4A, compound 5, or compound 6; wherein compound 4A is: in, PG is C 1-6 alkyl; Preferably, compound 4A is Compound 5 is: Where PG is C 1-6 alkyl; Preferably, compound 5 is Compound 6 is:

10. Use of compound 6 in the preparation of 8,9-dehydroestradiol ketone;

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