A process for the synthesis of oestrone from androsta-1,4-diene-3,17-dione

Abstract

The present application relates to a kind of from androsta 1, 4-diene-3, 17-dione starting synthesis of estren and the method of a kind of compound thereof.Especially, the present application provides a kind of preparation method of estren shown in formula I, comprising the following steps: in inert solvent, androsta-1, 4-diene-3, 17-dione (II) with reagent R4VX carries out demethylation aromatization reaction step directly to obtain estren (I);Wherein, the definition of reaction substrate, reagent and reaction condition is as claimed in claim or specification.The method is simple in operation, and good in selectivity, and product purity is high, suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthetic chemistry, and specifically relates to a method for synthesizing estradiol from androstened 1,4-diene-3,17-dione. Background Technology

[0002] Estradiol is a representative compound of endogenous estrogen-like substances. It is not only a raw material for pharmaceuticals and veterinary drugs, but also an important synthetic precursor for other estrogen-like drugs. Since its discovery, estradiol has attracted considerable attention from chemists due to its broad application prospects and its low abundance and difficulty in obtaining it in nature. Many synthetic methods for estradiol and related compounds have been reported, details of which can be found in relevant reports (PF Morand, JM Lyall, ...). Chem. Revs., 1968, 68, 1, 85-124). Industrially, dehydroepiandrosterone (3) was once used as a raw material via C 19 -Methyl oxidation (biological or chemical conversion), C3-hydroxy oxidation, C1- and C4-dehydrogenation, C 19 -A series of reactions including decarbonylation and A-ring aromatization synthesizes estradiolone. Huang-Minlon and Inhoffen were the chemists who initially envisioned the direct synthesis of estrone from androstened 1,4-diene-3,17-dione (ADD). Unfortunately, when they treated analogues of androstened 1,4-diene-3,17-dione with acid, they only obtained products from the dienone-phenol rearrangement reaction (Inhoffen, H., Huang-Minlon, ...). Natural sciences , 1938, 26, 756). Subsequently, Inhoffen et al. of the Sinning Company developed a thermal elimination aromatization method, but it not only had low yields but was also inconvenient to operate (Inhoffen, HH, Zühlsdorff, G., Chem. Ber ., 1941, 74, 1911; Inhoffen, HH, US Patent, 2,361,847 (1944); Wilds, AL, Djerassi, C., J. Am. Chem. Soc ., 1946, 2125). Heating compound 2 to 325 o At C, the yield was only 5%; when heated to 380°C in dihydronaphthalene, the yield was even lower. oAt C, the reported yield can reach 20%. Later, when Djerassi repeated the experiment, he only obtained 10% estrone, but when heated to 535°C in mineral oil, he could obtain a 20% yield of the product. Tsuda et al. discovered that androstenediol 1,4,9(11)-trien-3,17-dione(7) could be obtained in 70% yield by refluxing zinc powder with pyridine or ethylene glycol solvent. 9 -Estradiolone, but under these reaction conditions, the yield of androstenedione 1,4-diene-3,17-dione (ADD) is only 4% (Tsuda, K., Ohki, E., Nozoe, S., J. Org. Chem .,1963,28, 783). In 1964, Dryden et al. of Searle discovered that androstenedione-1,4-diene-3,17-dione and 17-monoacetal could be reacted with lithium metal and biphenyl in refluxed tetrahydrofuran, followed by deprotection, to yield estradiol in a total yield of 55-58%. Further optimization yielded up to 75% in the laboratory (Dryden, HL, Jr., Webber, GM, Belgian Patent, 1964, 644, 104). Chemical Abstracts ., 63, 8452 (1965); Dryden, HL,Jr., Webber, GM, Weiczorek, J., J. Am. Chem. Soc (1964, 86, 742). This method, when industrialized, yields approximately 65%. In 1999, Pivnitsky et al. first used sodium bis(2-methoxyethoxyaluminum hydride) (NaAIH2(OCH2CH2OMe)2, Red-All) to reduce androsterone-1,4-diene-3,17-dione to give the corresponding androsterone-1,4-diene-3,17-diol (8), with a 3α- to 3β-hydroxyl ratio of 4:6. The reduction product 8 was reacted in toluene at a reaction temperature of 100 °C. o C reacts with 5 moles of n-butyllithium to give estradiol (Vasiljeva, LL, Detain, PM, Kochev, DM, Lapitskay, MA, Pivnitsky, KK). Russian Chemical Bulletin , 1999, 48, 3, 595). However, the use of metal reagents presents operational inconveniences and safety hazards, leading to safety restrictions on the production of estrone using this technique. To avoid the use of metal reagents, the inventors previously discovered a demethylation aromatization reaction of androstened 1,4-diene-3,17-dione initiated by triphenylphosphine / iodine, which can be applied to the synthesis of estrone (Tian Weisheng, Shi Yong, Wang Yun, Chinese Patent: CN 107602650, 2018, A, granted in 2019. This patent has not been effectively maintained due to the impact of the "pandemic" and the retirement of the patent holder). This patent shows that, at the gram-scale laboratory level, the best yield of the invented technique can reach 70% (silica gel column separation yield), but as a practical technique, it still suffers from low reaction selectivity and difficulties in product purification. Based on this technology, Zizhu Company has also made some improvements (Li Zhifeng, Ding Xiaoyong, Jiang Shengming, Chinese Patent, Application No. 202310643359 X, Publication No. CN 118724992 A, 2024.10.01), characterized by replacing the triphenylphosphine and iodine reagents found in the reaction with acids or Lewis acids and some chemical reagents such as sodium thiolate and quaternary ammonium salts. Although the improved patented technology further proves the rationality of the design idea of ​​the androster 1,4-diene-3,17-diketone demethylation aromatization reaction through the "dual activation" strategy, this patented technology still fails to solve the problems of poor reaction selectivity and difficulty in sample purification.

[0003] Therefore, there is an urgent need in this field to develop a method for synthesizing estrone with high selectivity and high product purity. Summary of the Invention

[0004] The main objective of this invention is to provide a method for synthesizing estradiolone from androstened 1,4-diene-3,17-dione, which is simple, efficient and suitable for industrial production.

[0005] A first aspect of the present invention provides a method for preparing estradiol ketone as shown in Formula I, comprising the following steps: In an inert solvent, in the presence of an insoluble solid base and an iodomethane trapping agent, compound II undergoes a demethylation and aromatization reaction with reagent R4VX to obtain compound I. in, R4 is each independently composed of 3 or 4 substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, phenyloxy, phenyl, 5-6 heteroaryl, benzyl, halogen; said R4 is optionally substituted by 1-3 Ra selected from the group consisting of: halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, phenyl; V is selected from the following group: phosphorus (P), arsine (As), nitrogen (N); X is one or two halogens; The total number of substituents R4 and X is 5.

[0006] In another preferred embodiment, when R4 has 3 substituents, the number of X is 2, and when R4 has 4 substituents, the number of X is 1.

[0007] In another preferred embodiment, when R4 has four substituents, one of the substituents is different from the other three substituents; In another preferred embodiment, when V is phosphorus or arsine, R4 is a C1-C6 alkoxy, phenoxy, or substituted phenoxy group, wherein the substitution is selected from one or more of Ra.

[0008] In another preferred embodiment, the step is as follows: in an inert solvent, in the presence of an insoluble solid base, a molecular sieve, and an iodomethane trapping agent, compound II undergoes a demethylation aromatization reaction with the reaction reagent R4VX to obtain compound I; each group is as defined above.

[0009] In another preferred embodiment, the step is as follows: in an inert solvent, in the presence of an iodomethane trapping agent, compound II undergoes a demethylation aromatization reaction with the reaction reagent R4VX to obtain compound I; each group is as defined above.

[0010] In another preferred embodiment, the inert solvent is one or more aprotic organic solvents selected from the group consisting of aromatic solvents, alkane solvents, ether solvents, and halogenated solvents; the aromatic solvent is preferably one or more of benzene, toluene, and xylene (e.g., o-xylene, p-xylene, m-xylene); the alkane solvent is one or more of cyclohexane, n-hexane, cyclopentane, and petroleum ether; the ether solvent is one or more of aromatic ethers such as diaryl ethers. The chlorinated hydrocarbon solvent is preferably tetrachloroethane, dichloroethane, dichloromethane, etc.; the organic solvent is more preferably one or more of o-xylene, p-xylene, m-xylene, toluene, and tetrachloroethane.

[0011] In another preferred embodiment, the insoluble solid base is selected from the group consisting of: disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, potassium carbonate, lithium carbonate, quaternary ammonium salts, quaternary ammonium bases, anion exchange resins, or combinations thereof.

[0012] In another preferred embodiment, the iodomethane capturing agent is selected from the group consisting of organophosphorus reagents, organoarsine reagents, thioether reagents, diphenyl sulfides, anisole, or combinations thereof.

[0013] In another preferred embodiment, the iodomethane capturing agent is selected from the group consisting of: organophosphorus reagents, such as triphenylphosphine; organoarsine reagents, such as triphenylarsine; sulfide reagents, such as dimethyl sulfide, diphenyl sulfide, anisole, etc.

[0014] In another preferred embodiment, the molar ratio of the reagent R4VX, the insoluble solid base, and the iodomethane capturing reagent is 1:(0.5~1.5):(1~3):(1~3).

[0015] In another preferred embodiment, the molar ratio of the reagent R4VX, the insoluble solid base, and the iodomethane capturing reagent is 1:1.1:1.1, 1:1.5:1.5, 1:1.8:1.8, 1:2.0:2.0, 1:2.3:2.3, 1:2.5:2.5, or 1:3.0:3.0.

[0016] In another preferred embodiment, the molar ratio of compound II to reagent R4VX is 1:(1~1.5).

[0017] In another preferred embodiment, the molar ratio of compound II to the iodomethane capturing agent is 1:(0.5~1); and / or The molar ratio of compound II to the insoluble solid base is 1:(1~2).

[0018] In another preferred embodiment, the weight ratio of compound II to molecular sieve is 1:(0.5~2).

[0019] In another preferred embodiment, the volume molar ratio of the inert solvent to compound II is 0.1 mL / g to 100 mL / g.

[0020] In another preferred embodiment, the volume molar ratio of the inert solvent to the compound of formula II is 10 mL / g to 30 mL / g (e.g., 17 mL / g, 22 mL / g).

[0021] In another preferred embodiment, the reaction temperature of the method is 40~150℃.

[0022] In another preferred embodiment, the reaction temperature of the method is 60°C to 120°C (e.g., 60°C, 80°C, 100°C, 120°C).

[0023] In another preferred embodiment, the reaction time of the method is 3 to 30 hours.

[0024] In another preferred embodiment, the step further includes a post-processing step: after the reaction is completed, the reaction is quenched with a saturated sodium thiosulfate aqueous solution, and the compound of formula I can be separated.

[0025] In another preferred embodiment, the compound of formula I is recrystallized to obtain a high-purity compound of formula I.

[0026] In another preferred embodiment, the preparation method of the reaction reagent R4VX includes the following steps: (a) Provide a reaction precursor 1 containing R4 and V groups and a reaction precursor 2 containing X; (b) Dissolve the reaction precursor 1 containing R4 and V groups from step (a) in an aprotic organic solvent and react it with the reaction precursor 2 to obtain the reaction reagent R4VX.

[0027] In another preferred embodiment, the X-containing reaction precursor 2 may optionally be dissolved in an aprotic organic solvent.

[0028] In another preferred embodiment, the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, or combinations thereof.

[0029] In another preferred embodiment, when R4VX is a chlorotriphenylphosphine salt (R4 is three phenyl groups, one chlorine group, V is phosphorus, and X is elemental chlorine), the preparation method is to dissolve triphenylphosphine in dichloromethane, add oxalyl chloride to react, remove the solvent after the reaction is completed, wash with cyclohexane and dry to obtain the desired reagent.

[0030] In another preferred embodiment, when R4VX is an iodotri-p-methylphenylphosphine salt (R4 is three p-methylphenyl groups, one iodine group, V is phosphorus, and X is elemental iodine), the preparation method is to dissolve the tri-p-methylphenylphosphine in dichloromethane, then control the temperature at 0°C, gradually add iodine or a dichloromethane solution of iodine to the reaction, and after the reaction is complete, remove the solvent, wash with cyclohexane, and dry to obtain the desired reagent.

[0031] In another preferred embodiment, when R4VX is methyltriphenylphosphine iodide (R4 is three phenyl groups, one methyl group, V equals phosphorus, and X is elemental iodine), the preparation method is to dissolve triphenylphosphine in dichloromethane, then control the temperature at 0°C, gradually add iodine or a dichloromethane solution of iodine to the reaction, and after the reaction is complete, remove the solvent, wash with cyclohexane, and dry to obtain the desired reagent.

[0032] In another preferred embodiment, when R4VX is iodotriphenylarsine iodide (R4 is three phenyl groups, one iodine group, V equals arsine, and X is elemental iodine), the preparation method is described in relevant literature (Steinkopf; Schwen). Chem. Ber. , 1921, 54, 1452; Bhattacharya; Singh, Indian J. Chem., Section A (Inorganic, Physical, Theoretical and Analytical, 1979, 18, 515). Triphenylarsine reacts with iodine in petroleum ether to give the reagent triphenylarsine iodide.

[0033] In another preferred embodiment, when R4VX is an iodinated quaternary ammonium salt (R4 is three identical alkyl groups and one other alkyl group, V is equal to nitrogen, and X is elemental iodine), it is prepared by reacting the corresponding tertiary amine with a haloalkane, or the corresponding haloquaternary ammonium salt can be purchased directly for use.

[0034] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0035] Through extensive and in-depth research, the inventors further optimized the reaction reagents and other conditions, developing a simpler method for preparing estrone with good reaction stability, high selectivity, and high product purity. Based on this, the present invention was completed.

[0036] the term In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0037] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0038] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pteropentyl, or similar groups. The similar term "C1-C4 alkyl" has a similar definition.

[0039] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc. Similar terms such as "C1-C4 alkoxy" have similar definitions.

[0040] In this invention, the term "substituted phenyl" refers to the presence of one or more substituent groups, such as methyl, ethyl, fluorine, chlorine, alkoxy, acyloxy, nitro, sulfone, etc., at the ortho, meta, and para positions of the benzene ring.

[0041] In this invention, the term "aryl" refers to a monocyclic or bicyclic system consisting of a specific number of carbon atoms that obeys Hückel's rule. It should be understood that when "aryl" in this invention refers to a bicyclic system, it includes not only the case where all rings are aromatic rings, but also the case where only one ring is an aromatic ring and the other ring is a non-aromatic aliphatic ring.

[0042] In this invention, the term "substituted phenoxy" refers to the presence of one or more substituent groups, such as methyl, ethyl, fluorine, chlorine, alkoxy, acyloxy, nitro, sulfone, etc., at the ortho, meta, and para positions of the benzene ring.

[0043] In this invention, the term "heteroaryl" refers to a cyclic group with a specific number of cyclic atoms, containing at least one cyclic heteroatom (N, O, or S), and possessing aromaticity. Unless otherwise defined, the "heteroaryl" in this invention includes not only monocyclic heteroaryl systems but also polycyclic heteroaryl systems, such as bicyclic heteroaryl, tricyclic heteroaryl, and tetracyclic heteroaryl. When the "heteroaryl" is a polycyclic heteroaryl system, at least one ring is aromatic, and the other rings can be aromatic or non-aromatic. The heteroatom can be located in an aromatic ring or a non-aromatic ring. Polycyclic heteroaryl systems include not only fused ring systems but also bridged ring and spiro ring systems.

[0044] In this invention, the term "5-6 heteroaryl" refers to a cyclic group having 5-6 cyclic atoms, at least one of which is a heteroatom and is aromatic.

[0045] In this invention, the term "optionally" means that when there is a series of candidate groups to choose from, some of them can be selected, or none can be selected.

[0046] In this invention, "each independently" means that when several substituents defined at the same time are selected from the same series of candidate groups, they do not affect each other, and they may be the same or different.

[0047] In this invention, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0048] In this invention, the term "1-6" refers to having 1, 2, 3, 4, 5 or 6, and other similar terms each have a similar meaning independently.

[0049] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0050] Preparation method of compound of formula I of the present invention The embodiments of this invention specifically describe the preparation method of the compound with structure (I) of this invention, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art.

[0051] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0052] The present invention provides a method for synthesizing estrone: in an aprotic organic solvent (anhydrous, residual protonated substances (such as alcohols, thiols and amines) and acids, amides and enols), compound ADD (2), key reaction reagent R4VX, a solid base insoluble in the reaction solvent and iodomethane trapping reagent are reacted at 40-150°C to obtain compound 1 (estrone). The R4VX reaction reagent, wherein R is the same or different alkyl, alkoxy, phenyl, substituted phenyl, phenoxy, substituted phenoxy, benzyl, aromatic heterocyclic group, or halogen; V is phosphorus, arsene, nitrogen, etc.; and X is halogen. Various trimethylarylphosphine derivatives exhibit superior reactivity in this invention.

[0053] The solid bases that are insoluble in the reaction solvent include: disodium hydrogen phosphate (potassium), sodium carbonate (potassium, lithium), quaternary ammonium salts, quaternary ammonium bases, and anion exchange resins, etc.

[0054] The iodomethane capturing reagents are mainly organophosphorus reagents, such as triphenylphosphine; organoarsine reagents, such as triphenylarsine; and sulfide reagents, such as dimethyl sulfide, diphenyl sulfide, and anisole.

[0055] The aprotic organic solvent can be a conventional organic solvent used in this type of aromatization reaction in the art, as long as it does not affect the reaction. Preferably, it is one or more of aromatic solvents, alkane solvents, ether solvents, and halogenated solvents. The aromatic solvents are preferably one or more of benzene, toluene, and xylene (e.g., o-xylene, p-xylene, m-xylene). The alkane solvents are one or more of cyclohexane, n-hexane, cyclopentane, and petroleum ether. The ether solvents are one or more of diaryl ethers and other aromatic ethers. The chlorinated hydrocarbon solvents are preferably tetrachloroethane, dichloroethane, dichloromethane, etc.; the organic solvents are more preferably one or more of o-xylene, p-xylene, m-xylene, toluene, and tetrachloroethane.

[0056] The molar ratio of compound 2, reagent R4VX, insoluble solid base, and iodomethane capturing agent is preferably 1:(0.5-1.5):(1-3):(1-3) (e.g., 1:1.1:1.1, 1:1.5:1.5, 1:1.8:1.8, 1:2.0:2.0, 1:2.3:2.3, 1:2.5:2.5, 1:3.0:3.0) in this invention.

[0057] The amount of organic solvent used can be the amount conventional for this type of reaction in the art, sufficient to dissolve all other reactants except the solid base. For example, the volume molar ratio of the organic solvent to compound 2 is 0.1 mL / g to 100 mL / g, and preferably 10 mL / g to 30 mL / g (e.g., 17 mL / g, 22 mL / g) in this invention.

[0058] The temperature of the aromatization reaction can be the conventional temperature for this type of aromatization reaction in the art, such as 40 to 150°C, and preferably 60 to 120°C (e.g., 60°C, 80°C, 100°C, 120°C) in this invention.

[0059] The synthesis method involves mixing ADD (2) with the reagent in the organic solvent to obtain compound 1.

[0060] The process of the aromatization reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR). The reaction endpoint is generally defined as when compound 2 disappears or stops reacting. The reaction time varies from 3 to 30 hours (e.g., 4 hours, 5 hours, 6 hours, ...).

[0061] The synthesis method may further include the following post-processing step: after the reaction is completed, the mixture is quenched with a saturated sodium thiosulfate aqueous solution to separate compound 1.

[0062] 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.

[0063] The reagents and raw materials used in this invention are either commercially available or provided by the patent applicant.

[0064] The features of this invention are: 1. Because the quality and dosage of all reaction reagents are accurately controlled, the reaction conditions are easily controlled and the reaction stability is increased; 2. The optimized reaction selectivity is significantly improved. For example, under the original reaction conditions, the yield ratios of estrone to reaction byproducts 10 and 11 were 70%:7.5%:7.5%, and sometimes byproduct 12 was also separated. Under the conditions of this patent application, the yield ratios of estrone to reaction byproducts 10 and 11 were 88%:2.5%:trace, and no byproduct 12 was found; 3. The post-processing operation is simple and suitable for industrial production. The pure estrone sample obtained by the previously authorized patent technology needs to be separated and purified by silica gel column chromatography, while the post-processing of the product of this patent application only requires a simple crystallization operation. This technology is based on the demethylation aromatization reaction of androstenedione 1,4-diene-3,17-dione initiated by triphenylphosphine / iodine, as discovered by the patent applicant, and is further extended and applied to the efficient synthesis of estrone. This technology involves reacting androstenedione 1,4-diene-3,17-dione (ADD) with a freshly prepared reagent of the general formula "R4VX" in a nonpolar solvent to obtain estrone in a yield of over 85%. The synthetic method described in this invention is simple to operate, has controllable conditions, and achieves high yield. Compared with the current industrial technique of using metal reducing agents to reduce 1,4-diene-3,17-dione (ADD) to synthesize estrone, the advantages of this invention are: 1. It avoids the use of metal reagents, eliminating safety hazards; 2. It reduces two reaction steps; 3. It improves the reaction yield. Compared with the applicant's previous patent method, the advantages are: 1. The operation procedure is simpler, more convenient and controllable; 2. The reaction selectivity is significantly improved, making the purification of the reaction product simple and easy to industrialize; 3. The synthesis yield and purity are significantly improved.

[0065] Compared with the prior art, the main advantages of the present invention are: (1) The synthesis method described in this invention is simple and controllable, with mild reaction conditions, and is suitable for industrial production.

[0066] (2) The method described in this invention has excellent reaction selectivity, high reaction yield, and convenient product purification.

[0067] (3) The method described in this invention can achieve a maximum yield of 88%, providing a feasible technology for the synthesis of estradiol.

[0068] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed according to the conditions described in the conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0070] Example 1 Compound 2 (2.84 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol), triphenylphosphine (2.62 g, 10 mmol), and reagents ( p -MePh)3PI2 (5.58 g, 10 mmol) was reacted in 50 mL of tetrachloroethane at 120 °C for 5 hours. TLC showed that the starting material was essentially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Solvent crystallization of the crude product yielded compound 1, 2.33 g, with a yield of 86% and a purity of 95–98%.

[0071] Example 2 Compound 2 (2.84 g, 10 mmol), sodium carbonate (0.53 g, 5 mmol), triphenylarsine (3.06 g, 10 mmol), and Ph3PBr2 (4.22 g, 10 mmol) were placed in 50 mL of tetrachloroethane and heated to 120 °C for 6 hours. TLC showed that the starting materials were essentially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 2.2 g, with a yield of 81% and a purity of 95–98%.

[0072] Example 3 Compound 2 (2.84 g, 10 mmol), disodium hydrogen phosphate (1.42 g, 10 mmol), and reagent Ph3MePI (4.04 g, 10 mmol) were placed in 50 mL of tetrachloroethane and heated to 120 °C for 5 hours. TLC showed that the starting material was substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 1.76 g, with a yield of 65% and a purity of 95–98%.

[0073] Example 4 Compound 2 (2.84 g, 10 mmol), dipotassium hydrogen phosphate (1.74 g, 10 mmol), triphenylarsine (3.06 g, 10 mmol), and reagent Ph3PCl2 (3.33 g, 10 mmol) were placed in 50 mL of tetrachloroethane and heated to 80 °C for 10 hours. TLC showed that the starting material was substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 1.87 g, with a yield of 67% and a purity of 95–98%.

[0074] Example 5 (without insoluble solid alkali) Compound 2 (2.84 g, 10 mmol), diphenyl sulfide (1.86 g, 10 mmol), and reagent Ph3AsI2 (5.60 g, 10 mmol) were placed in 50 mL of tetrachloroethane and heated to 120 °C for 5 hours. TLC showed that the starting material was substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 1.32 g, with a yield of 60% and a purity of 95–98%.

[0075] Example 6 Compound 2 (2.84 g, 10 mmol), lithium carbonate (0.74 g, 10 mmol), anisole (1.24 g, 10 mmol), and reagent Ph3MePI (4.04 g, 10 mmol) were placed in 50 mL of dichloroethane and heated to 120 °C for 5 hours. TLC showed that the starting material was essentially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 1.80 g, with a yield of 68% and a purity of 95–98%.

[0076] Example 7 Compound 2 (2.84 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol), molecular sieve (2 g), triphenylphosphine (2.62 g, 10 mmol), and Ph3PI2 (5.16 g, 10 mmol) were placed in 50 mL of toluene and heated to 100 °C for 8 hours. TLC showed that the starting materials were substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 2.4 g, with a yield of 89% and a purity of 95–98%.

[0077] Example 8 Compound 2 (2.84 g, 10 mmol), lithium carbonate (0.74 g, 10 mmol), molecular sieve (1.5 g), anisole (1.24 g, 10 mmol), and reagent Ph3AsI2 (5.6 g, 10 mmol) were placed in 50 mL of toluene and heated to 100 °C for 8 hours. TLC showed that the starting material was substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 2.33 g, with a yield of 85% and a purity of 95–98%.

[0078] Example 9 Compound 2 (2.84 g, 10 mmol), lithium carbonate (0.74 g, 10 mmol), triphenylarsine (3.06 g, 10 mmol), and reagent Ph3MeNI (3.87 g, 10 mmol) were placed in 80 mL of cyclohexane and heated to 100 °C for 8 hours. TLC showed that the starting material was essentially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The reaction was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 1.89 g, with a yield of 70% and a purity of 95–98%.

[0079] Example 10 Compound 2 (2.84 g, 10 mmol), dipotassium hydrogen phosphate (1.74 g, 10 mmol), triphenylarsine (3.06 g, 10 mmol), and reagent Ph3MeNI (3.87 g, 10 mmol) were placed in 80 mL of dichloroethane and heated to 100 °C for 8 hours. TLC showed that the starting material was substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The mixture was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to give compound 1, 1.92 g, with a yield of 72% and a purity of 95–98%.

[0080] Example 11 Compound 2 (2.84 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol), triphenylphosphine (2.62 g, 10 mmol), and reagents ( p -MePh)3PI2 (8.37g, 15mmol) in 80 mL petroleum ether (90-100 o In step C), the reaction was heated to 100°C for 8 hours. TLC showed that the starting material was basically completely converted. Heating was stopped, and the mixture was cooled to room temperature. The mixture was then quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized in a solvent to give compound 1, 2.32 g, with a yield of 86% and a purity of 95-98%.

[0081] Example 12 Compound 2 (2.84 g, 10 mmol), disodium hydrogen phosphate (1.20 g, 10 mmol), triphenylarsine (3.06 g, 10 mmol), and reagent Ph3AsI2 (5.6 g, 10 mmol) were placed in 50 mL of tetrachloroethane and heated to 100 °C for 8 hours. TLC showed that the starting material was substantially completely converted. Heating was stopped, and the mixture was cooled to room temperature. The solution was quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized from the solvent to obtain compound 1, 2.16 g, with a yield of 80% and a purity of 95–98%.

[0082] Example 13 Compound 2 (2.84 g, 10 mmol), disodium hydrogen phosphate (1.20 g, 10 mmol), triphenylarsine (3.06 g, 10 mmol), and reagents ( p -NO2Ph)3PI2 (9.77g, 10mmol) in 80 mL petroleum ether (90-100 o In step C), the reaction was heated to 100°C for 8 hours. TLC showed that the starting material was basically completely converted. Heating was stopped, and the mixture was cooled to room temperature. The mixture was then quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized in a solvent to give compound 1, 2.02 g, with a yield of 75% and a purity of 95–98%.

[0083] Example 14 Compound 2 (2.84 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol), triphenylphosphine (2.62 g, 10 mmol), and reagents ( p -MeO2CPh)3PI2 (10.35g, 15mmol) in 80 mL petroleum ether (90-100o In step C), the reaction was heated to 100°C for 8 hours. TLC showed that the starting material was basically completely converted. Heating was stopped, and the mixture was cooled to room temperature. The mixture was then quenched with a saturated sodium thiosulfate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then crystallized in a solvent to give compound 1, 1.94 g, with a yield of 72% and a purity of 95–98%.

[0084] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing estradiol ketone as shown in Formula I, characterized in that, Includes the following steps: In an inert solvent, in the presence of an insoluble solid base and an iodomethane trapping agent, compound II undergoes a demethylation and aromatization reaction with reagent R4VX to obtain compound I. in, R4 is each independently composed of 3 or 4 substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, phenyloxy, phenyl, 5-6 heteroaryl, benzyl, halogen; said R4 is optionally substituted by 1-3 Ra selected from the group consisting of: halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, phenyl; V is selected from the following group: phosphorus (P), arsine (As), nitrogen (N); X is one or two halogens; The total number of substituents R4 and X is 5.

2. The preparation method according to claim 1, characterized in that, The inert solvent is one or more of the following aprotic organic solvents: aromatic solvents, alkane solvents, ether solvents, and halogenated solvents; the aromatic solvent is preferably one or more of benzene, toluene, and xylene (e.g., o-xylene, p-xylene, m-xylene); the alkane solvent is one or more of cyclohexane, n-hexane, cyclopentane, and petroleum ether; the ether solvent is one or more of aromatic ethers such as diaryl ethers; the chlorinated hydrocarbon solvent is preferably tetrachloroethane, dichloroethane, dichloromethane, etc.; the organic solvent is more preferably one or more of o-xylene, p-xylene, m-xylene, toluene, and tetrachloroethane.

3. The preparation method according to claim 1, characterized in that, The insoluble solid base is selected from the group consisting of: disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, potassium carbonate, lithium carbonate, quaternary ammonium salts, quaternary ammonium bases, anion exchange resins, or combinations thereof.

4. The preparation method according to claim 1, characterized in that, The iodomethane capturing reagent is selected from the group consisting of organophosphorus reagents, organoarsine reagents, thioether reagents, diphenyl sulfides, anisole, or combinations thereof.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the reagent R4VX, the insoluble solid base and the iodomethane capture reagent is 1:(0.5~1.5):(1~3):(1~3).

6. The preparation method according to claim 1, characterized in that, The molar ratio of compound II to reagent R4VX is 1:(1~1.5).

7. The preparation method according to claim 1, characterized in that, The molar ratio of compound II to the iodomethane capturing agent is 1:(0.5~1); and / or The molar ratio of compound II to the insoluble solid base is 1:(1~2).

8. The preparation method according to claim 1, characterized in that, The volume molar ratio of the inert solvent to compound II is 0.1 mL / g to 100 mL / g.

9. The preparation method according to claim 1, characterized in that, The reaction temperature of the method is 40~150℃.

10. The preparation method according to claim 1, characterized in that, The preparation method of the reaction reagent R4VX includes the following steps: (a) Provide a reaction precursor 1 containing R4 and V groups and a reaction precursor 2 containing X; (b) Dissolve the reaction precursor 1 containing R4 and V groups from step (a) in an aprotic organic solvent and react it with the reaction precursor 2 to obtain the reaction reagent R4VX.

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