Estetrol intermediate compound B, preparation method of estetrol intermediate compound A and preparation method of estetrol

Abstract

The invention provides an estetrol intermediate compound B as shown in a formula (I), a preparation method of the compound B and a method for preparing a compound A and estetrol from the compound B. According to the present invention, estrone is adopted as the starting material, the compound B is constructed through the olefin etherification reaction, the compound A is obtained through the oxidation reaction, and the target product compound A can be obtained through the two-step reaction, such that the synthesis route is shortened, the synthesis steps are simplified, the total yield of the reaction can achieve 82%, and the purity of the obtained compound A is more than 98%. According to the route, the reaction yield and efficiency are improved, and the obtained compound is high in purity, low in cost, beneficial to large-scale industrial production and wide in commercial application prospect. (I).

Description

Technical Field

[0001] This application relates to the field of steroidal chemical drug technology, and in particular to a method for preparing estradiol intermediate compound B, estradiol intermediate compound A, and estradiol itself. Background Technology

[0002] Estradiol is a naturally occurring estrogen, primarily synthesized by the fetal liver and secreted into the maternal bloodstream during pregnancy. Compared to estradiol, estradiol has lower biological activity and a unique metabolic pathway. In recent years, it has attracted attention due to its potential medical applications. Studies have also shown that it has less stimulating effects on the endometrium and mammary glands, potentially reducing the risk of side effects from long-term use. Therefore, there is a broad market demand for estradiol. Existing technologies report various methods for preparing estradiol, all using estrone as a starting material to construct the key estradiol intermediate compound A (Δ... 15 (-estradiol) or compound A protected at position 3, and then through a series of chemical transformations, estradiol is obtained.

[0003]

[0004] In its patent WO 2023001866, NewChem SPA used estrone as a starting material and proceeded through five steps: esterification, ketalization, bromination, elimination, and hydrolysis, to obtain the target product compound A with a 65% overall yield and 95% purity. This route is relatively mature, but it involves a long process and has poor atom economy.

[0005]

[0006] In its patent WO 2025 / 046071 A1, ESTETRA SRL also used estradiol as a starting material, undergoing a three-step reaction involving silyl ether protection, substitution, and elimination to obtain compound A, which is protected at the 3-position with a silicon group. This compound then underwent a series of transformations to obtain estradiol. However, this route requires elimination reactions at temperatures of at least 100°C, resulting in high energy consumption and demanding equipment requirements.

[0007]

[0008] Furthermore, the methods for preparing compound A or its derivatives reported above are lengthy and have low yields. Therefore, in order to meet market demand, it is of great significance to prepare the key intermediate compound A of estradiol in a simple and efficient manner, and then synthesize estradiol. Summary of the Invention

[0009] In view of this, this application provides a method for preparing compound B, estradiol intermediate compound A, and estradiol. The synthetic route provided by this application is simple in steps, has high yield, and high purity of the target product.

[0010] This application provides compound B, represented by formula (Ⅰ):

[0011] (I);

[0012] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

[0013] In some specific implementations, R is preferably a C1-C8 alkyl group or a C6-C6 alkyl group. 10 The aryl-substituted C1-C8 alkyl group, more preferably a C1-C6 alkyl group or a C6-C8 alkyl group. 10 The alkyl group is an aryl-substituted C1-C6 alkyl group, most preferably a C1-C5 alkyl group or a phenyl-substituted C1-C5 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, benzyl, phenethyl, etc. In this application, the alkyl group can be a straight-chain alkyl group, a branched alkyl group, or a cycloalkyl group, and there are no particular limitations on this. Similarly, the aromatic group can be a phenyl, naphthyl, or biphenyl group, and there are no particular limitations on this.

[0014] This application provides a method for preparing the estradiol intermediate compound B represented by formula (I), comprising the following steps:

[0015] Under the action of a catalyst and an optional dehydrating agent, the estradiol represented by formula (III) undergoes an etherification reaction with the alcohol compound represented by formula (IV) to give compound B represented by formula (I);

[0016] (Ⅲ); R-OH (IV);

[0017] (I);

[0018] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

[0019] The reaction process is as follows:

[0020]

[0021] This application uses estradiol as a raw material and reacts it with an alcohol compound represented by formula (IV) via an enyl etherification reaction to prepare compound B. This application does not impose any particular limitation on the alcohol compound represented by formula (IV), wherein R has the definition described above, which will not be repeated here. Accordingly, the alcohol compound can be methanol, ethanol, propanol, isopropanol, butanol, benzyl alcohol, phenethyl alcohol, etc., preferably ethanol. In this application, the enyl etherification reaction is carried out under the action of a catalyst, which includes, but is not limited to, p-toluenesulfonic acid, sulfuric acid, and pyridine hydrochloride, and can be one or more of these. When the catalyst is a combination of multiple substances, this application does not impose any particular limitation on the specific proportion of each substance. In this application, the enyl etherification reaction is carried out under the action of a dehydrating agent, which includes, but is not limited to, trimethyl orthoformate, triethyl orthoformate, and tripropyl orthoformate, and can be one or more of these. When the dehydrating agent is a combination of multiple substances, this application does not impose any particular limitation on the specific proportion of each substance. In some specific implementations, the etherification reaction is carried out in a solvent, which is an aprotic solvent, including but not limited to dichloromethane, trichloromethane, ethyl acetate, toluene, tetrahydrofuran, etc., and may be one or more of these, with dichloromethane being preferred. In some specific implementations, the mass ratio of the estradiol to the volume ratio of the solvent is 1 kg:1 L to 30 L, preferably 1 kg:1 L to 10 L, and more preferably 1 kg:1 L to 5 L.

[0022] In some specific implementations, the weight ratio of the estrone, alcohol compound, catalyst and dehydrating agent is 1:1~30:0.05~1:1~3, preferably 1:1~10:0.1~0.5:1~2.5, and more preferably 1:1~5:0.1~0.2:1~2.

[0023] Specifically, this application disperses estrone and a catalyst in a solvent, then adds an alcohol compound and a dehydrating agent to react. After the reaction is complete, an alkali is added to quench the reaction, and after post-treatment, compound B is obtained. In some specific implementations, the reaction temperature is 5℃~80℃, preferably 5℃~60℃, more preferably 10℃~50℃, and most preferably 20℃~40℃; the reaction time is 2h~6h, preferably 3h~5h. In some specific implementations, the alkali includes, but is not limited to, triethylamine, pyridine, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, etc., and can be one or more of these. When the alkali is a combination of multiple substances, this application does not have a special limitation on the specific proportion of each substance. In some specific implementations, the weight ratio of estrone to alkali is 1:0.1~1, preferably 1:0.2~0.6.

[0024] After quenching the reaction, dichloromethane and water were added to the resulting reaction solution to separate the phases. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain estradiol intermediate compound B.

[0025] This application also provides a method for preparing estradiol intermediate compound A, wherein compound B represented by formula (I) is converted into estradiol intermediate compound A represented by formula (II) under the action of an oxidizing agent;

[0026] (I); (II);

[0027] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

[0028] The reaction pathway is as follows:

[0029]

[0030] This application uses compound B as a raw material to prepare estradiol intermediate compound A. Specifically, this application first disperses compound B in a solvent, and then adds an oxidant to carry out an oxidative dehydrogenation reaction.

[0031] In some specific implementations, the solvent includes, but is not limited to, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, and N,N-dimethylacetamide, and may be one or more of these. When the solvent is a combination of multiple substances, this application does not impose any special restrictions on the specific proportions of each substance. In some specific implementations, the solvent is preferably N,N-dimethylformamide. In some specific implementations, the mass ratio of compound B to the volume ratio of the solvent is 1 kg:1 L to 30 L, preferably 1 kg:1 L to 20 L, and more preferably 1 kg:1 L to 15 L.

[0032] In some specific implementations, the oxidant includes, but is not limited to, 2-iodobenzoic acid (IBX), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), and tetrachlorobenzoquinone, and may be one or more of these. When the oxidant is a combination of multiple substances, this application does not impose any special restrictions on the proportions of each specific substance. In some specific implementations, the oxidant is preferably tetrachlorobenzoquinone. In some specific implementations, the weight ratio of compound B to the oxidant is 1:0.8~3, preferably 1:1~2.

[0033] In some specific implementations, the reaction temperature is 0℃~120℃, preferably 30℃~90℃, more preferably 40℃~70℃, and most preferably 50℃~60℃. In some specific implementations, the reaction time is 4h~36h, preferably 10h~35h, and more preferably 20h~30h.

[0034] After the reaction is complete, the reaction is quenched by adding an aqueous sodium sulfite solution to the obtained reaction solution, followed by extraction with water and dichloromethane. The organic phase is collected, concentrated to dryness, and dried to obtain crude compound A. After obtaining crude compound A, it is preferably post-treated to obtain pure compound A. In some specific implementations, the post-treatment specifically involves adding a mixture of organic solvent and water to the crude compound A, stirring, filtering, and drying to obtain pure compound A. In some specific implementations, the organic solvent includes, but is not limited to, acetone, methanol, and ethanol. In some specific implementations, the volume ratio of compound A to organic solvent is 1:1 to 5, preferably 1:2 to 4. In some specific implementations, the stirring temperature is 20℃ to 40℃, preferably 30℃; the stirring time is 1h to 3h, preferably 2h.

[0035] Specifically, this application uses estrone as a starting material to construct compound B through an etherification reaction, and then obtains compound A through an oxidation reaction. The reaction route is as follows:

[0036]

[0037] This application also provides a method for preparing estradiol, comprising the following steps:

[0038] Compound B, represented by formula (Ⅰ), is converted into estradiol intermediate compound A, represented by formula (Ⅱ), under the action of an oxidizing agent.

[0039] (I); (II);

[0040] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl;

[0041] The intermediate compound A of estradiol was converted into estradiol.

[0042] After preparing the estradiol intermediate compound A according to the method described above, it is converted into estradiol according to methods commonly used by those skilled in the art. This application does not impose any special restrictions on it.

[0043] This application uses estrone as a starting material to construct compound B through an etherification reaction, followed by an oxidation reaction to obtain compound A. The target product compound A can be obtained in just two steps, shortening the synthetic route and simplifying the synthetic steps. Furthermore, the overall yield can reach 82%, and the purity of the obtained compound A is greater than 98%. This route improves reaction yield and efficiency, yields high-purity compounds, and is low-cost, making it suitable for large-scale industrial production and possessing broad commercial application prospects. Attached Figure Description

[0044] Figure 1 This is an LC-MS chromatogram of the product obtained in Example 1 of this application;

[0045] Figure 2 This is an LC-MS chromatogram of the product obtained in Example 4 of this application;

[0046] Figure 3 This is the HPLC chromatogram of the product obtained in Example 4 of this application;

[0047] Figure 4 This is the HPLC chromatogram of the product obtained in Example 5 of this application;

[0048] Figure 5 This is the HPLC chromatogram of the product obtained in Example 6 of this application;

[0049] Figure 6 This is the HPLC chromatogram of the product obtained in Example 7 of this application. Detailed Implementation

[0050] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0051] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0052] It should be understood that the order of steps or the sequence of actions is not important as long as this application remains operational. Furthermore, two or more steps or actions may be performed simultaneously.

[0053] The use of any and all instances or exemplary language such as “e.g.” or “including” herein is merely intended to better illustrate the application and does not constitute a limitation on the scope of the application unless the claims are made. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of this application.

[0054] Furthermore, the numerical ranges and parameters used to define this application are approximate values, and the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any numerical value inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise explicitly stated, it should be understood that all ranges, quantities, values, and percentages used in this disclosure are modified with the word "approximately." Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range.

[0055] This application provides compound B, an intermediate of estradiol, represented by formula (Ⅰ):

[0056] (I);

[0057] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

[0058] This application provides a method for preparing the estradiol intermediate compound B represented by formula (I), comprising the following steps:

[0059] Under the action of a catalyst and an optional dehydrating agent, the estradiol represented by formula (III) undergoes an etherification reaction with the alcohol compound represented by formula (IV) to give compound B represented by formula (I);

[0060] (Ⅲ); R-OH (IV);

[0061] (I);

[0062] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

[0063] This application provides a method for preparing estradiol intermediate compound A, wherein compound B represented by formula (I) is converted into estradiol intermediate compound A represented by formula (II) under the action of an oxidizing agent;

[0064] (I); (II);

[0065] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

[0066] This application also provides a method for preparing estradiol, comprising the following steps:

[0067] Compound B, represented by formula (Ⅰ), is converted into estradiol intermediate compound A, represented by formula (Ⅱ), under the action of an oxidizing agent.

[0068] (I); (II);

[0069] Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl;

[0070] The intermediate compound A of estradiol was converted into estradiol.

[0071] Specifically, this application uses estrone as a starting material to construct compound B through an etherification reaction, and then obtains compound A through an oxidation reaction. The reaction route is as follows:

[0072]

[0073] This application yields the target product compound A through a two-step reaction, shortening the synthetic route and simplifying the synthetic steps. The overall yield reaches 82%, and the purity of compound A is greater than 98%. This route improves reaction yield and efficiency, yields a high-purity compound, and is cost-effective, making it suitable for large-scale industrial production and possessing broad commercial application prospects.

[0074] The present application is further illustrated below with reference to embodiments. The scope of protection of the present application is not limited to the following embodiments.

[0075] Example 1: Preparation of compound B

[0076] 1 kg of estradiol, 150 g of p-toluenesulfonic acid, 5 L of dichloromethane, 1.5 kg of anhydrous ethanol, and 1.1 kg of triethyl orthoformate were added to a reaction flask and stirred at 30 °C for 4 h. 250 g of triethylamine was added to the system, and stirring continued for 60 min. 2 L of dichloromethane and 2 L of water were added to the reaction mixture, the layers separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound B, with a yield of approximately 108%.

[0077] The reaction pathway is as follows:

[0078]

[0079] In compound B, R is an ethyl group.

[0080] For LC-MS analysis of compound B, see [link to LC-MS analysis]. Figure 1 The test results are shown in Table 1.

[0081] Table 1. LC-MS data of compound B prepared in Example 1

[0082]

[0083] Example 2: Preparation of compound B

[0084] 100 g estrone, 10 g p-toluenesulfonic acid, 300 ml chloroform, 200 g benzyl alcohol, and 150 g triethyl orthoformate were added to a reaction flask and stirred at 40 °C for 3 h. 30 g pyridine was added to the system, and stirring continued for 60 min. 200 ml dichloromethane and 200 ml water were added to the reaction mixture, the layers separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound B, with a yield of approximately 127%.

[0085] The reaction pathway is as follows:

[0086]

[0087] In compound B, R is benzyl.

[0088] Example 3: Preparation of Compound B

[0089] Add 500g estrone, 100g pyridine hydrochloride, 4000ml dichloromethane, 2500g methanol, and 750g triethyl orthoformate to a reaction flask, and stir at 35°C for 5 hours. Add 100g sodium hydroxide to the system and continue stirring for 60 minutes. Add 1500ml dichloromethane and 1500ml water to the reaction solution, allow the layers to separate, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound B in approximately 100% yield.

[0090] The reaction pathway is as follows:

[0091]

[0092] In compound B, R is a methyl group.

[0093] Example 4: Preparation of Compound A

[0094] 500g of compound B prepared in Example 1, 5L of N,N-dimethylformamide, and 500g of tetrachlorobenzoquinone were added to a reaction flask, and the mixture was stirred at 60°C for 20h. The reaction was quenched with an aqueous sodium sulfite solution, and the mixture was extracted with 10L of water and 10L of dichloromethane. The organic phase was collected, concentrated to dryness under reduced pressure, and dried at 60°C to obtain crude compound A. 1L of acetone and 1L of water were added to crude compound A, and the mixture was stirred at 30°C for 2h. The mixture was then filtered and dried at 60°C to obtain compound A. The reaction route is as follows:

[0095]

[0096] For LC-MS analysis of compound A, see [link to LC-MS analysis]. Figure 2 The test results are shown in Table 2; for HPLC analysis of estradiol intermediate compound A, please refer to [reference needed]. Figure 3 The test results are shown in Table 3. It can be seen that the purity of estradiol intermediate compound A is about 98.4%, the yield is 76%, and the total yield based on the starting material estradiol is 82%.

[0097] Table 2 LC-MS data of compound A prepared in Example 4

[0098]

[0099] Table 3. HPLC data of compound A prepared in Example 4.

[0100]

[0101] Example 5: Preparation of Compound A

[0102] 1 kg of compound B prepared in Example 1, 30 L of dimethyl sulfoxide, and 3 kg of DDQ were added to a reaction flask, and the mixture was stirred at 55 °C for 25 h. The reaction was quenched by adding sodium sulfite aqueous solution, and the mixture was extracted with 50 L of water and 50 L of dichloromethane. The organic phase was collected, concentrated to dryness under reduced pressure, and dried at 60 °C to obtain crude compound A. 5 L of methanol and 5 L of water were added to crude compound A, and the mixture was stirred at 30 °C for 2 h. The mixture was then filtered and dried at 60 °C to obtain compound A.

[0103] For HPLC analysis of compound A, see [link to HPLC analysis]. Figure 4 The test results are shown in Table 4. It can be seen that the purity of estradiol intermediate compound A is about 98.3%, the yield of this step is 74%, and the total yield based on the starting material estradiol is 80%.

[0104] Table 4. HPLC data of compound A prepared in Example 5

[0105]

[0106] Example 6: Preparation of Compound A

[0107] 100g of compound B prepared in Example 1, 0.5L of dioxane, and 200g of IBX were added to a reaction flask, and the mixture was stirred at 50°C for 30h. The reaction was quenched with an aqueous sodium sulfite solution, and the mixture was extracted with 0.5L of water and 0.5L of dichloromethane. The organic phase was collected, concentrated to dryness under reduced pressure, and dried at 60°C to obtain crude compound A. 0.3L of ethanol and 0.3L of water were added to crude compound A, and the mixture was stirred at 30°C for 2h. The mixture was then filtered and dried at 60°C to obtain compound A.

[0108] For HPLC analysis of compound A, see [link to HPLC analysis]. Figure 5 The test results are shown in Table 5. It can be seen that the purity of estradiol intermediate compound A is about 98.1%, the yield of this step is 71%, and the total yield based on the starting material estradiol is 77%.

[0109] Table 5. HPLC data of compound A prepared in Example 6.

[0110]

[0111] Example 7: Preparation of Compound A

[0112] 100 g of compound B prepared in Example 1, 1 L of tetrahydrofuran, and 80 g of tetrachlorobenzoquinone were added to a reaction flask and the mixture was stirred at 60 °C for 23 h. The reaction was quenched by adding sodium sulfite aqueous solution, and the mixture was extracted with 1 L of water and 0.5 L of dichloromethane. The organic phase was collected, concentrated to dryness under reduced pressure, and dried at 60 °C to obtain crude compound A. 0.2 L of acetone and 0.2 L of water were added to crude compound A, and the mixture was stirred at 30 °C for 2 h. The mixture was then filtered and dried at 60 °C to obtain compound A.

[0113] For HPLC analysis of compound A, see [link to HPLC analysis]. Figure 6 The test results are shown in Table 6. It can be seen that the purity of estradiol intermediate compound A is about 98.4%, the yield of this step is 75%, and the total yield based on the starting material estradiol is 81%.

[0114] Table 6. HPLC data of compound A prepared in Example 7

[0115]

[0116] Therefore, the synthetic route provided in this application is relatively short, the steps are simple, and the yield and purity are high.

[0117] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in this application, based on the technical solution and inventive concept of this application, should be included within the scope of protection of this application.

Claims

1. Compound B, the intermediate of estradiol shown in formula (Ⅰ): （Ⅰ）； in, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

2. The estradiol intermediate compound B according to claim 1, characterized in that, R is a C1-C5 alkyl or a C1-C5 alkyl group substituted with a phenyl group.

3. The estradiol intermediate compound B according to claim 2, characterized in that, R is ethyl or benzyl.

4. A method for preparing the estradiol intermediate compound B shown in formula (Ⅰ), comprising the following steps: Under the action of a catalyst and an optional dehydrating agent, the estradiol represented by formula (III) undergoes an etherification reaction with the alcohol compound represented by formula (IV) to give compound B represented by formula (I); (Ⅲ); R-OH (IV); （Ⅰ）； Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

5. The preparation method according to claim 4, characterized in that, The alcohol compound is one or more of C1-C5 fatty alcohols or phenyl-substituted C1-C5 fatty alcohols; The catalyst is one or more of p-toluenesulfonic acid, sulfuric acid, and pyridine hydrochloride; The dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, and tripropyl orthoformate. The solvent for the etherification reaction is one or more of dichloromethane, trichloromethane, ethyl acetate, toluene, and tetrahydrofuran; The weight ratio of the estrone, alcohol, catalyst, and dehydrating agent is 1:1~30:0.05~1:1~3.

6. The preparation method according to claim 4, characterized in that, The etherification reaction is carried out at a temperature of 5℃ to 80℃ for a time of 2h to 6h.

7. A method for preparing an estradiol intermediate compound A, characterized in that, Compound B, represented by formula (Ⅰ), is converted into estradiol intermediate compound A, represented by formula (Ⅱ), under the action of an oxidizing agent. （Ⅰ）； （Ⅱ）； Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl.

8. The preparation method according to claim 6, characterized in that, The oxidant is one or more of 2-iodobenzoic acid, 2,3-dichloro-5,6-dicyanobenzoquinone and tetrachlorobenzoquinone; The weight ratio of compound B to oxidant is 1:0.8~3.

9. The preparation method according to claim 6, characterized in that, The reaction temperature for the transformation is 0℃~120℃, and the reaction time is 4h~36h.

10. A method for preparing estradiol, characterized in that, Includes the following steps: Compound B, represented by formula (Ⅰ), is converted into estradiol intermediate compound A, represented by formula (Ⅱ), under the action of an oxidizing agent. （Ⅰ）； （Ⅱ）； Wherein, R is C1~C 10 Alkyl or C6~C 20 aryl-substituted C1~C 10 alkyl; The intermediate compound A of estradiol was converted into estradiol.

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