A method for preparing tetraenoxyestrone

Abstract

This invention discloses a method for preparing tetraenestrol, comprising the following steps: S1. Etherification reaction: In a solvent and in the presence of a catalyst, compound I is etherified with methanol to generate compound II, yielding a solution of compound II; S2. Grignard reaction: The solution of compound II obtained in S1 is reacted with a Grignard reagent to generate compound III, yielding a solution of compound III; S3. Hydrolysis reaction: In the presence of an acid, the solution of compound III obtained in S2 is hydrolyzed to generate compound IV, yielding a solution of compound IV; S4. Dehydrogenation reaction: In the presence of a dehydrogenation reagent, the solution of compound IV obtained in S3 is dehydrogenated to generate compound V, yielding tetraenestrol. This preparation route features simple reaction operation, high overall yield, and high product purity, reducing the overall production cost.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, and more specifically relates to a method for preparing tetraethrinone. Background Technology

[0002] Altrenogest, also known as allenogen, is a synthetic trienic-C21 steroidal progestin belonging to the 19-nortestosterone class. It is an orally active progestin. In veterinary medicine, altrenogest is used to induce estrus in mares and sows, primarily as an animal contraceptive, such as for dolphins and poultry like pigs.

[0003] Tetraethrin has the following structure:

[0004]

[0005] Currently, there are several routes for the synthesis of tetraethrin:

[0006] Route 1: Patent CN106946961 reports a method for preparing tetraethrinone. This route uses estradiol-4,9,11-triene-3,17-dione as a raw material, protects and deprotects the 3-position, and then uses allyl magnesium chloride to perform a Grignard reaction on the side chain. This route seems simple, but it has obvious drawbacks: when using a triene as a raw material to protect the 3-position, the reaction is difficult and incomplete due to the relatively stable 4,9,11(12) conjugated structure formed in the triene; moreover, the Grignard reaction is carried out in the same system, and the residual alcohol after deprotection will directly affect the Grignard reaction effect.

[0007]

[0008] Route 2: Patent CN106810584 reports a method for preparing tetraethrinone. This route uses ketal for 3-position protection. This route has the problem that incomplete or excessive hydrolysis of the ketal will produce byproducts Δ4,9 (as shown in formula VI below). The polarity of this impurity is similar to that of the product, and it is difficult to remove in subsequent purification. Multiple purifications are required, resulting in a low overall yield.

[0009]

[0010] Overall, existing technologies involve complex operating procedures, large byproducts, difficulty in removing impurities, and low overall yield, resulting in high production costs and hindering commercial production. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the background art above and provide a method for preparing tetraethrin to improve the yield and product purity.

[0012] To solve the above-mentioned technical problems, the technical solution proposed by this invention is as follows:

[0013] A method for preparing tetraethrin includes the following steps:

[0014] S1. Etherification reaction: In a solvent and in the presence of a catalyst, compound I is etherified with methanol to generate compound II, resulting in a solution of compound II.

[0015]

[0016] S2. Grignard reaction: The solution of compound II obtained in S1 is reacted with a Grignard reagent to produce compound III, resulting in a solution of compound III;

[0017]

[0018] S3. Hydrolysis reaction: In the presence of acid, the solution of compound III obtained in S2 is hydrolyzed to generate compound IV, resulting in a solution of compound IV;

[0019]

[0020] S4. Dehydrogenation reaction: In the presence of a dehydrogenating agent, the solution of compound IV obtained in S3 undergoes a dehydrogenation reaction to generate compound V, yielding tetraethrinone;

[0021]

[0022] As a further improvement, the solvent used in the etherification reaction described in S1 is selected from at least one of methanol, acetone, chloroform, dichloromethane, tetrahydrofuran, or 1,4-dioxane; and / or

[0023] The catalyst is selected from at least one of acetyl chloride, benzoyl chloride, oxalyl chloride, chloroacetyl chloride, or trichloroacetyl chloride.

[0024] As a further improvement, methanol is used as the etherifying agent and reaction solvent in S1, and acetyl chloride is used as the catalyst.

[0025] As a further improvement, the solvent used in the Grignard reaction described in S2 is selected from at least one of dichloromethane, toluene, tetrahydrofuran, or anhydrous diethyl ether; and / or

[0026] The Grignard reagent is selected from at least one of allyl magnesium bromide or allyl magnesium chloride.

[0027] As a further improvement, tetrahydrofuran is used as the reaction solvent in S2, and allyl magnesium chloride is used as the Grignard reagent.

[0028] As a further improvement, the solvent used in the hydrolysis reaction described in S3 is at least one of acetone, acetonitrile, methanol, or ethanol; and / or

[0029] The acid is selected from at least one of hydrochloric acid, sulfuric acid, potassium bisulfate, sodium bisulfate, phosphoric acid, or oxalic acid.

[0030] As a further improvement, acetonitrile is used as the reaction solvent and potassium hydrogen sulfate is used as the acid in S3.

[0031] As a further improvement, the solvent used in the dehydrogenation reaction described in S4 is selected from at least one of dichloromethane, chloroform, or acetone; and / or

[0032] The dehydrogenating agent is selected from at least one of 2,3-dichloro-5,6-dicyanobenzoquinone or tetrachlorobenzoquinone.

[0033] As a further improvement, dichloromethane is used as the reaction solvent in S4, and 2,3-dichloro-5,6-dicyanobenzoquinone is used as the dehydrogenation reagent.

[0034] As a further improvement:

[0035] In S1, after the reactants have reacted completely, the reaction solution is poured into an aqueous sodium carbonate solution and stirred. Then, it is extracted with dichloromethane and separated to obtain an organic phase. The dichloromethane in the organic phase is replaced with tetrahydrofuran to obtain a tetrahydrofuran solution of compound II; and / or

[0036] In S2, after the reactants have reacted completely, the reaction is quenched with ammonium chloride solution. After separation, an organic phase is obtained. The tetrahydrofuran in the organic phase is replaced with acetonitrile to obtain an acetonitrile solution of compound III; and / or

[0037] In S3, after the reactants have reacted completely, the reaction is terminated with an aqueous sodium carbonate solution. The mixture is then concentrated, and water and dichloromethane are added. The layers are separated to obtain the organic phase, which is then washed with water to obtain a dichloromethane solution of compound IV; and / or

[0038] In S4, after the raw materials have reacted completely, the mixture is filtered. An aqueous solution of sodium metabisulfite is added to the organic phase and reacted. The mixture is then filtered again, and the filtrate is separated into layers to obtain the organic phase. The organic phase is concentrated and crystallized, and then recrystallized using ethyl acetate to obtain tetraethrinone.

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0040] The method for preparing tetraenestrol of the present invention uses compound I as the starting material, and proceeds through etherification, Grignard reaction, hydrolysis, and dehydrogenation. During the post-processing of each intermediate, centrifugation, drying, and discharge are unnecessary; only the intermediate solution needs to be obtained for continuous feeding into the next reaction step, avoiding material loss in intermediate operations. This can be understood as a one-pot preparation of tetraenestrol. Simultaneously, by using specific solvents and reagents in each step, and employing specific post-processing methods after the raw material reaction, the yield and purity of each product are high, especially with low content of the byproduct Δ4,9-. Furthermore, the byproducts do not affect the next reaction step, resulting in high overall yield and high purity of the final product. Therefore, this preparation route features simple reaction operation, high overall yield, and high product purity, reducing the overall production cost. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0042] Figure 1 This is the HPLC chromatogram of Example 3;

[0043] Figure 2 This is the HNMR spectrum of tetraethrin from Example 4;

[0044] Figure 3 This is the HPLC chromatogram of tetraethrin from Example 4. Detailed Implementation

[0045] To facilitate understanding of the present invention, the present invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of protection of the present invention is not limited to the following specific embodiments.

[0046] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention.

[0047] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be purchased from the market or prepared by existing methods.

[0048] In some embodiments, the method for preparing tetraethrin of the present invention includes the following steps:

[0049] S1. Etherification reaction :

[0050] Starting with compound I (4,9-property), an etherification reaction was carried out in an inert atmosphere in the presence of an etherifying agent and a catalyst to generate compound II, resulting in a solution of compound II.

[0051]

[0052] In some specific embodiments, the solvent for the etherification reaction is selected from at least one of methanol, acetone, chloroform, dichloromethane, tetrahydrofuran, and 1,4-dioxane. Methanol is preferred as the etherifying agent. The use of methanol as both the etherifying agent and solvent significantly improves the yield and purity of intermediate II compared to the use of ketal protection in conventional processes.

[0053] In some specific embodiments, the catalyst is selected from at least one of acetyl chloride, benzoyl chloride, oxalyl chloride, chloroacetyl chloride, and trichloroacetyl chloride, preferably acetyl chloride, and preferably the catalyst is added dropwise to the reaction system.

[0054] In some specific embodiments, the reaction temperature of the etherification reaction is -30 to 20°C, preferably 0 to 5°C, and the reaction time is 0.5 to 4 hours.

[0055] In some specific embodiments, after the reactants have reacted completely, the reaction solution is poured into an aqueous sodium carbonate solution and stirred at 10–20°C for 0.5–1.5 hours. Then, it is extracted with dichloromethane and separated to obtain the organic phase. The dichloromethane is then replaced with tetrahydrofuran (using tetrahydrofuran as a solvent in the Grignard reaction can improve the reaction yield and purity), yielding a tetrahydrofuran solution of compound II. Because hydrogen chloride acts as a catalyst in the reaction system, the aqueous sodium carbonate solution terminates the reaction. Furthermore, by pouring the reaction solution into an alkaline aqueous solution, the materials are kept in an alkaline environment throughout. Compound II exhibits good stability under alkaline conditions and will not deteriorate.

[0056] S2. Grignard reaction :

[0057] In an inert atmosphere, a solution of compound II is subjected to a Grignard reaction in the presence of a Grignard reagent to generate compound III, resulting in a solution of compound III.

[0058]

[0059] In some specific embodiments, the solvent for the Grignard reaction is selected from at least one of dichloromethane, toluene, tetrahydrofuran, and anhydrous diethyl ether, preferably tetrahydrofuran.

[0060] In some specific embodiments, the Grignard reagent is selected from at least one of allyl magnesium bromide and allyl magnesium chloride, preferably allyl magnesium chloride.

[0061] In some specific embodiments, a solution of compound III is added dropwise to a solvent and a Grignard reagent to carry out the reaction. In some specific embodiments, the Grignard reaction is carried out at a temperature of -10 to 40°C, preferably 15 to 18°C, for a reaction time of 0.5 to 1 hour.

[0062] In some specific embodiments, the reaction is quenched with ammonium chloride solution (stirring for 0.5 to 1 hour), and after separation, an organic phase is obtained. Tetrahydrofuran is replaced with acetonitrile to obtain an acetone solution of compound III.

[0063] S3. Hydrolysis reaction :

[0064] In an inert atmosphere, a solution of compound III is hydrolyzed in the presence of acid to generate compound IV, resulting in a solution of compound IV.

[0065]

[0066] Compared to the traditional process using ketal protection, this step reduces various impurities in the side reactions. In particular, if the ketal reaction is incomplete, a large amount of raw material remains. If hydrolysis is excessive, a byproduct Δ4,9- will be generated. The hydrolysate from this step is an important prerequisite for the final purification and preparation of high-purity tetraethrin.

[0067] In some specific embodiments, the solvent for the hydrolysis reaction is at least one of acetone, acetonitrile, methanol and ethanol, preferably acetonitrile, and the product contains the lowest content of Δ4,9-.

[0068] In some specific embodiments, the acid used for hydrolysis is selected from at least one of hydrochloric acid, sulfuric acid, potassium bisulfate, sodium bisulfate, phosphoric acid, and oxalic acid. Potassium bisulfate is preferred because it results in the lowest content of impurities in the product, especially Δ4,9- compounds. Using other acids may lead to incomplete or excessive hydrolysis, resulting in more Δ4,9- compounds and lower purity. Potassium bisulfate is preferably added in the form of an aqueous solution with a mass concentration of 16.5%–23%, and the volume / mL is 1.8 to 2.5 times the mass / g of the starting material Δ4,9- compounds.

[0069] In some specific embodiments, the hydrolysis reaction temperature is 0–40°C, preferably 16–22°C, and the reaction time is 1–2 hours.

[0070] In some specific embodiments, after the reactants have reacted completely, the reaction is terminated with an aqueous sodium carbonate solution, then concentrated, water and dichloromethane are added, the mixture is separated into layers, and the organic phase is washed with water, which is a dichloromethane solution of compound IV.

[0071] S4. Dehydrogenation reaction :

[0072] In an inert atmosphere, a solution of compound IV is subjected to a dehydrogenation reaction in the presence of a dehydrogenating agent to produce compound V (tetraethestrol).

[0073]

[0074] In some specific embodiments, the solvent for the dehydrogenation reaction is selected from at least one of dichloromethane, trichloromethane, and acetone, with dichloromethane being preferred.

[0075] In some specific embodiments, the dehydrogenating agent is selected from 2,3-dichloro-5,6-dicyanobenzoquinone or tetrachlorobenzoquinone, preferably 2,3-dichloro-5,6-dicyanobenzoquinone.

[0076] In some specific embodiments, the dehydrogenation reaction temperature is -10 to 30°C, preferably 18 to 22°C, and the reaction time is 0.5 to 1.5 h.

[0077] In some specific embodiments, after the raw materials have reacted completely, the mixture is filtered. An aqueous solution of sodium metabisulfite is added to the organic phase, and the mixture is filtered again. The filtrate separates into layers, yielding the organic phase. The organic phase is concentrated and crystallized to obtain crude tetraethrinone. The aqueous solution of sodium metabisulfite is added to react with a dehydrogenating agent in a redox reaction, washing away any residual dehydrogenating agent from the solution.

[0078] In some specific embodiments, crude tetraethrin can be purified by recrystallization from ethyl acetate, resulting in high yield and high purity.

[0079] Generally, byproducts or impurities generated during a one-pot reaction may affect subsequent reactions, such as reducing the yield of the next reaction or increasing the amount of byproducts. However, in this invention, the above steps employ specific solvents and reagents (ethanol + acetyl chloride for etherification, tetrahydrofuran + allyl magnesium chloride for Grignard reaction, acetonitrile + potassium hydrogen sulfate for hydrolysis, and dichloromethane + 2,3-dichloro-5,6-dicyanobenzoquinone for dehydrogenation), and specific post-treatment methods are used after the raw materials have reacted. This results in high yields and high purity of products in each step, especially low content of the byproduct Δ4,9-, and the byproducts or impurities generated do not affect subsequent reactions, thus achieving high overall yield and high purity of the final product.

[0080] The present application will be further described in detail below with reference to the embodiments. The tetraethione in the following embodiments is synthesized by the following process route:

[0081]

[0082] Example 1

[0083] Preparation of intermediate II:

[0084] In a dry 2L three-necked reaction flask under nitrogen protection, 500g of methanol and 100g of compound I (4,9-form) were added. 100g of acetyl chloride was weighed into a constant-pressure dropping funnel. The mixture was purged with nitrogen three times and cooled to 0–5°C. Acetyl chloride was slowly added dropwise to the etherification reaction flask, maintaining the temperature at 5–10°C. After addition, the reaction was maintained at 0–5°C for 2 hours. TLC showed complete reaction of the starting materials. The reaction solution was poured into an aqueous sodium carbonate solution for precipitation, and stirred at 10–20°C for 1 hour. 200ml of dichloromethane was added for extraction, and the mixture was separated to obtain the organic phase. The organic phase was concentrated under reduced pressure at 50°C, and 100ml of tetrahydrofuran was added for displacement to obtain a tetrahydrofuran solution of compound II (water content less than 0.10%), which was directly added to the next reaction step.

[0085] Example 2

[0086] Preparation of intermediate III:

[0087] Add 15g of magnesium shavings and 190g of tetrahydrofuran to a 2000L three-necked reaction flask. Under nitrogen protection, purge three times, start stirring, and slowly add 80g of a mixture of 3-chloropropene and 200g of tetrahydrofuran dropwise, controlling the addition temperature at 10-25℃. After the addition is complete, maintain the reaction at 10-20℃ for 1 hour, then control the temperature to 10-20℃. Add a tetrahydrofuran solution of compound II obtained in Example 1 dropwise. After the addition is complete, maintain the reaction at 15-18℃ for 1 hour until the reactants have reacted completely. Slowly add 210ml of 20% ammonium chloride solution to the reaction system to quench the reaction. Stir at room temperature for 1 hour, allow to stand and separate the phases. Extract the aqueous phase once with 100ml of tetrahydrofuran. Combine the organic phases, concentrate under reduced pressure at 50℃, and add 150ml of acetonitrile for concentration and replacement to obtain an acetonitrile solution of intermediate III, which is directly added to the next reaction.

[0088] Example 3

[0089] Preparation of intermediate IV:

[0090] 800 g of acetonitrile was added to the acetonitrile solution of intermediate III obtained in Example 2. Under nitrogen protection, the mixture was purged three times. Potassium bisulfate aqueous solution was slowly added. After the addition was complete, the reaction was maintained at 16–22 °C for 1.5 hours until the reactants were fully reacted. The reaction was terminated by adding sodium carbonate aqueous solution. The mixture was concentrated to a small volume under reduced pressure at ≤55 °C. 800 g of water and 900 g of dichloromethane were added, and the mixture was stirred for 5 minutes, allowed to stand for 15 minutes, and allowed to separate into layers. The organic phase was temporarily stored. The aqueous phase was extracted twice with dichloromethane, 450 g each time, stirred for 5 minutes, and allowed to stand for 15 minutes. All organic phases were combined. The mixture was washed twice with drinking water, 350 g each time, stirred for approximately 5 minutes, and allowed to stand for approximately 30 minutes. The organic layer was then separated. This yielded a dichloromethane solution of intermediate IV. The HPLC chromatogram is shown below. Figure 1The HPLC purity was 98.4% (calculated by peak area normalization), and the content of Δ4,9- compound (RRT≈0.922) was 0.7%; it was directly added to the next reaction.

[0091] HPLC detection conditions: column: 4.6×250mm ZORBAXCN 5μm, mobile phase: n-hexane:isopropanol = 90:10, flow rate: 1.5ml / min, wavelength: 235nm, injection volume: 10μl, time: at least 40min.

[0092] Based on this embodiment, the following comparative experiments were conducted (Table 1). The only difference is the acid and solvent used. The purity and impurity content of the products are listed in Table 1.

[0093] Table 1

[0094]

[0095] The volume is defined as: the volume of the acid solution (mL) / the mass of the starting material (g) = 1.

[0096] Example 4

[0097] Preparation of crude tetraethrin:

[0098] A dichloromethane solution of intermediate IV prepared in Example 3 was added to a 2L three-necked reaction flask. Under nitrogen protection, the mixture was purged three times, stirred, and the temperature was adjusted to 15-20℃. 2,3-Dichloro-5,6-dicyanobenzoquinone was slowly added to the reaction system. After the addition was complete, the reaction was maintained at 18-22℃ for 1 hour until the reactants reacted completely. After the reaction was complete, the mixture was filtered. The filter cake was washed twice with 200g*2 dichloromethane. The organic phase was transferred to the reaction flask, and 160ml of a 10% sodium metabisulfite aqueous solution was added. The mixture was stirred for 10 minutes and allowed to stand for 15 minutes. A large amount of solid precipitated in the system. The mixture was filtered, and the filtrate was allowed to separate into layers. The organic phase was transferred to the reaction flask, and 120ml of a 10% sodium metabisulfite aqueous solution was added. The mixture was stirred for 5 minutes and allowed to stand for 10 minutes. A large amount of solid precipitated in the system. The mixture was filtered, and the filtrate was allowed to separate into layers. The aqueous phase was discarded. The organic phase was transferred to a reaction flask and concentrated and crystallized: The mixture was concentrated to dryness under reduced pressure at ≤50℃, then 100g of isopropyl ether was added for displacement, and the concentration was continued under reduced pressure at ≤50℃ until a paste-like consistency was reached. A large amount of crystalline solid precipitated from the system. Concentration under reduced pressure was stopped, and the temperature was slowly lowered to 0-5℃ for crystallization over 2 hours. The mixture was filtered and dried to obtain 87g of solid, with a yield of 87% (based on the initial 4,9- compound) and a purity ≥98%.

[0099] Example 5

[0100] Product Refinement:

[0101] Add 800g of ethyl acetate to a 2L single-necked flask and heat to 50-60℃. Add 87g of crude tetraethrin obtained in Example 4 and stir to dissolve. Filter hot, collect the filtrate, concentrate under reduced pressure at ≤55℃ until approximately 2-3 volumes remain, then stop concentration, cool to 13-16℃ and stir for 1 hour, then stir at -5~0℃ for 2 hours. Filter to obtain 81g of white crystalline solid, with a purification yield of 93%. The HNMR spectrum of the product is shown below. Figure 2 The HPLC chromatogram of the product is as follows: Figure 3 The HPLC purity was 99.8%, with the largest impurity being Δ4,9- (retention time 17.810, content approximately 0.10%–0.15%), meeting the quality standards. The overall yield based on the initial 4,9- compound was 81%.

[0102] The HPLC detection conditions were as follows: column: 4.6×250mm ZORBAXCN 5μm, mobile phase: n-hexane:isopropanol = 96:4, flow rate: 1ml / min, wavelength: 235nm, injection volume: 10μl, and time: at least 40min.

[0103] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Therefore, any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention should fall within the protection scope of the present invention.

Claims

1. A method for preparing tetraestradiol, characterized by, Includes the following steps: S1. Etherification reaction: In a solvent and in the presence of a catalyst, compound I is etherified with an etherifying agent to generate compound II. In S1, methanol is used as the etherifying agent and the reaction solvent, and acetyl chloride is used as the catalyst. After the reactants have reacted, the reaction solution is poured into an aqueous sodium carbonate solution and stirred. Then, it is extracted with dichloromethane and separated to obtain an organic phase. The dichloromethane in the organic phase is replaced with tetrahydrofuran to obtain a tetrahydrofuran solution of compound II. S2. Grignard reaction: The tetrahydrofuran solution of compound II obtained in S1 is reacted with a Grignard reagent to produce compound III. In S2, tetrahydrofuran is used as the reaction solvent and allyl magnesium chloride is used as the Grignard reagent. After the reactants have reacted completely, the reaction is quenched with ammonium chloride solution. After separation, an organic phase is obtained. The tetrahydrofuran in the organic phase is replaced with acetonitrile to obtain an acetonitrile solution of compound III. S3. Hydrolysis reaction: In the presence of acid, the acetonitrile solution of compound III obtained in S2 is hydrolyzed to generate compound IV; in S3, acetonitrile is used as the reaction solvent and potassium bisulfate is used as the acid, which is added in the form of an aqueous solution of potassium bisulfate with a mass concentration of 16.5%~23% and a volume / mL that is 1.8 to 2.5 times the mass / g of compound I; after the reactants have reacted completely, the reaction is terminated with an aqueous solution of sodium carbonate, then concentrated, water and dichloromethane are added, the layers are separated, the organic phase is obtained and washed with water to obtain a dichloromethane solution of compound IV; S4. Dehydrogenation reaction: In the presence of a dehydrogenating agent, the dichloromethane solution of compound IV obtained in S3 is subjected to a dehydrogenation reaction to generate compound V; in S4, dichloromethane is used as the reaction solvent and 2,3-dichloro-5,6-dicyanobenzoquinone is used as the dehydrogenating agent. After the reactants have reacted completely, the mixture is filtered, and an aqueous solution of sodium metabisulfite is added to the organic phase for reaction. The mixture is filtered again, and the filtrate is separated into layers to obtain the organic phase. The organic phase is concentrated and crystallized, and then recrystallized with ethyl acetate to obtain pure tetraethrinone. 。

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