Preparation method of 19-hydroxyestradione and intermediate compound prepared by preparation method

Abstract

The invention provides a preparation method of 19-hydroxyestradione and an intermediate compound prepared by the preparation method. According to the method, 19-hydroxy-4-androstenedione is used as a raw material, and the 19-hydroxyestradione is prepared through four steps of reactions including sulfur condensation reaction, ketalation reaction, desulfurization and hydrolysis reaction. According to the preparation method disclosed by the invention, the synthesis of the 19-hydroxyestradienone is realized through a relatively simple and convenient route and shorter reaction steps, the use of a chromium oxidizing agent which is relatively serious in environmental pollution is avoided in the route, the safe industrial production is easy, and another feasible way is provided for commercial production of the 19-hydroxyestradienone.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly to a preparation method of 19-hydroxyestrone and an intermediate compound prepared thereby. Background Art

[0002] 19-Hydroxyestrone drugs have been found to be competitive inhibitors of human placental aromatase, with obvious inhibitory effects. The Ki value is 12.5 nM, but they do not cause time-dependent enzyme inactivation. Aromatase inhibitors can specifically cause aromatase inactivation, block the aromatization reaction, inhibit estrogen production, and reduce the estrogen level in the blood, thereby achieving the purpose of treating breast cancer. They are mostly used for postmenopausal advanced breast cancer patients who have failed anti-estrogen (tamoxifen) treatment.

[0003] Mitsuteru Numazawa et al. reported a synthesis method of 19-hydroxyestrone in the literature J. Med. Chem. 1991, 34, 2496 - 2504. Using 19-hydroxy-4-androstenedione as the raw material, after the thioketal reaction, the 19-hydroxy group was protected with a silyl ether, then desulfurized with sodium amide to obtain the silyl ether of 19-hydroxyestrenol, and then oxidized and deprotected to obtain 19-hydroxyestrone.

[0004]

[0005] Soonsin S. Oh and Cecil H. Robinson et al. reported in the literature J. Chem. soc. perkin trans I, 1994, 16, 2237 - 2244 that using 19-hydroxy-4-androstenedione as the raw material, after the thioketal reaction, the 19-hydroxy group was protected with dihydropyran, and then 19-hydroxyestrone was prepared by desulfurization, oxidation and deprotection.

[0006]

[0007] In the above synthesis routes, during the reductive desulfurization, the 17-ketone is inevitably reduced to 17-alcohol at the same time. Therefore, in the subsequent steps, it is necessary to oxidize the 17-alcohol back to 17-ketone again. And in order to avoid the oxidation of the 19-hydroxy group during the oxidation process, it is also necessary to protect the 19-hydroxy group in advance. It can be seen that due to the mutual influence among the 3-position thioketal, the 19-hydroxy group and the 17-ketone group, the current process route of 19-hydroxyestrone is relatively cumbersome and requires five chemical reactions. Moreover, during the oxidation reaction, Jones reagent is usually used for oxidation, and chromium salts have great harm to the environment, which limits the route in industrial production to a certain extent.

[0008] Therefore, it is urgent to study a new preparation method of 19-hydroxyestrone to simplify the production steps and avoid environmental pollution. Summary of the Invention

[0009] In view of this, the present invention provides a preparation method of 19-hydroxyestrone, which realizes the synthesis of 19-hydroxyestrone with a relatively simpler route and shorter reaction steps, and avoids the use of chromium oxidants that cause greater environmental pollution in the route.

[0010] In a first aspect, the present invention provides a preparation method of 19-hydroxyestrone, and the 19-hydroxyestrone has a structure shown in formula (Ⅰ):

[0011]

[0012] The 19-hydroxyestrone is prepared by hydrolysis of a 19-hydroxyestrone ketal; wherein, the preparation method of the 19-hydroxyestrone ketal includes the following steps:

[0013] Step 1: 19-Hydroxy-4-androstenedione undergoes a thioacetalization reaction to obtain a thioacetal;

[0014] Step 2: The thioacetal obtained in Step 1 undergoes a ketalization reaction to obtain a thioacetal ketal;

[0015] Step 3: The thioacetal ketal obtained in Step 2 undergoes a desulfurization reaction to obtain a 19-hydroxyestrone ketal.

[0016] That is, in the present invention, the preparation of the 19-hydroxyestrone is realized with reference to the following reaction flow chart:

[0017]

[0018] Step 1: 19-Hydroxy-4-androstenedione shown in formula (Ⅱ) undergoes a thioacetalization reaction to obtain a thioacetal shown in formula (Ⅲ);

[0019] Step 2: The thioacetal shown in formula (Ⅲ) undergoes a ketalization reaction to obtain a thioacetal ketal shown in formula (Ⅳ);

[0020] Step 3: The thioacetal ketal shown in formula (Ⅳ) undergoes a desulfurization reaction to obtain a 19-hydroxyestrone ketal shown in formula (Ⅴ);

[0021] Step 4: The 19-hydroxyestrone ketal shown in formula (Ⅴ) undergoes a hydrolysis reaction to obtain 19-hydroxyestrone shown in formula (Ⅰ).

[0022] Based on the above technical solutions, preferably, in Step 1, the 19-hydroxy-4-androstenedione undergoes a thioacetalization reaction with 1,2-ethanedithiol in a tetrahydrofuran solution using boron trifluoride diethyl etherate as a catalyst to obtain a thioacetal shown in formula (Ⅲ).

[0023] Based on the above technical solutions, preferably, the molar ratio of 19-hydroxy-4-androstenedione, ethanedithiol, and boron trifluoride diethyl etherate is 1:(1.4 - 2.0):(0.3 - 0.6); the mass-volume ratio of 19-hydroxy-4-androstenedione to tetrahydrofuran is 1 g:(8 - 12) ml.

[0024] Based on the above technical solutions, preferably, in step two, the thioacetal shown in formula (III) undergoes a ketalization reaction with ethylene glycol using p-toluenesulfonic acid as a catalyst and triethyl orthoformate as a water scavenger to obtain a thioketal shown in formula (IV).

[0025] Based on the above technical solutions, preferably, the molar ratio of the thioacetal, p-toluenesulfonic acid, and ethylene glycol is 1:(0.18 - 0.26):(32 - 48); the volume ratio of triethyl orthoformate to ethylene glycol is 1:(0.9 - 1.4).

[0026] Based on the above technical solutions, preferably, in step three, the thioketal shown in formula (IV) undergoes a desulfurization reaction using tetrahydrofuran as a solvent under the combined action of liquid ammonia and sodium metal to obtain a 19-hydroxyestrone ketal shown in formula (V).

[0027] Based on the above technical solutions, preferably, the molar ratio of the thioketal to sodium metal is 1:(4.7 - 7.2); the mass-volume ratio of the thioketal to liquid ammonia and tetrahydrofuran is 1 g:(16 - 24) ml:(8 - 12) ml.

[0028] Based on the above technical solutions, preferably, in step four, the 19-hydroxyestrone ketal shown in formula (V) undergoes a hydrolysis reaction using tetrahydrofuran as a solvent and hydrochloric acid as a catalyst to obtain 19-hydroxyestrone shown in formula (I).

[0029] Based on the above technical solutions, preferably, the molar ratio of the 19-hydroxyestrone ketal to hydrochloric acid is 1:(3.2 - 4.8); the volume ratio of hydrochloric acid to tetrahydrofuran is 1:(1.4 - 2.0).

[0030] In the second aspect, the present invention relates to a new compound, and the structural formula of the compound is shown in formula (IV):

[0031]

[0032] The preparation method of 19-hydroxyestrone provided by the present invention and the intermediate compound prepared thereby have the following beneficial effects compared with the prior art:

[0033] The preparation method of 19-hydroxyestrone of the present invention is efficient, economical and environmentally friendly. By adopting protection strategies such as thioacetalization and ketalization, sensitive functional groups are effectively protected, enabling the reaction to proceed under mild conditions, reducing the generation of by-products, and improving the selectivity and yield of the target product. In addition, this method avoids the use of more expensive or toxic reagents that may be used in traditional processes, reducing production costs and potential environmental hazards. Overall, this method simplifies the production process, improves production efficiency, and ensures product quality, which is of great value for promoting the research and development and production of related drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0035] Figure 1 1H-NMR spectrum of the thioacetal prepared in Example 1 provided by the present invention;

[0036] Figure 2 Mass spectrum (MS) of the thioacetal prepared in Example 1 provided by the present invention;

[0037] Figure 3 1H-NMR spectrum of the thioacetal ketal prepared in Example 1 provided by the present invention;

[0038] Figure 4 Mass spectrum (MS) of the thioacetal ketal prepared in Example 1 provided by the present invention;

[0039] Figure 5 1H-NMR spectrum of 19-hydroxyestrone prepared in Example 1 provided by the present invention;

[0040] Figure 6 Mass spectrum (MS) of 19-hydroxyestrone prepared in Example 1 provided by the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0041] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0042] The present invention will be further described below in conjunction with specific embodiments, and the protection scope of the present invention is not limited by the following embodiments. The sources of the main materials involved in the embodiments are all conventional commercially available products.

[0043] The relevant tests in the following embodiments are all carried out with reference to the following methods:

[0044] HPLC method 1:

[0045] Chromatographic column: InfinityLab Poroshell 120 EC-C18 (4.6×150 mm, 4-Micron), Agilent.

[0046] Mobile phase: water and acetonitrile gradient.

[0047] Time Water (%) Acetonitrile (%) Flow rate (ml / min) 0 50 50 1.00 15 50 50 1.00 20 0 100 1.00 40 0 100 1.00 41 50 50 1.00

[0048] Flow rate: 1 mL / min;

[0049] Detector: ultraviolet detector (VWD), signal polarity: positive; wavelength: 205 nm; column oven temperature: 40 °C; injection volume: 10 μL; acquisition time: 41 min;

[0050] HPLC method 2:

[0051] Chromatographic column: InfinityLab Poroshell 120 EC-C18 (4.6×150 mm, 4-Micron), Agilent.

[0052] Mobile phase: water and acetonitrile gradient.

[0053] Time Water (%) Acetonitrile (%) Flow rate (ml / min) 0 25 75 1.00 15 25 75 1.00 20 0 100 1.00 40 0 100 1.00 45 25 75 1.00

[0054] Flow rate: 1 mL / min;

[0055] Detector: ultraviolet detector (VWD), signal polarity: positive; wavelength: 205 nm; column oven temperature: 40 °C; injection volume: 10 μL; acquisition time: 45 min.

[0056] Example 1

[0057] Step 1, thioketalization reaction to prepare the thioketal as shown in formula (Ⅲ)

[0058] Under nitrogen protection, 2 L of tetrahydrofuran, 200 g of 19-hydroxy-4-androstenedione, and 80 mL of ethanedithiol were added to a 5-L reaction flask. The mixture was stirred, and 60 mL of a boron trifluoride etherate solution with a mass concentration of 48% was slowly added dropwise. After the addition was complete, the reaction solution was kept at 20 °C for 4 h until the raw materials were completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 3 / 1).

[0059] The reaction solution was slowly poured into 2 L of water, stirred for 1 - 2 h, filtered, and dried under reduced pressure at 40 - 50 °C to obtain 240 g of a off-white thioacetal, with a molar yield of 96% and a purity of 95.22% (HPLC method 1).

[0060] 1 H NMR (600 MHz, CDCl3) δ 5.84 (s, 1H), 3.93 (d, J = 12.0 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H, 3.37 - 3.36 (m, 2H) 3.27 - 3.22 (m, 1H), 2.46 - 2.36 (m, 2H), 2.21 - 2.14 (m, 4H), 2.08 - 2.03 (m, 1H), 1.93 - 1.87 (m, 2H), 1.81 - 1.79 (m, 1H), 1.76 - 1.70 (m, 2H), 1.69 - 1.63 (m, 1H), 1.55 - 1.46 (m, 1H), 1.42 - 1.18 (m, 6H), 1.07 - 1.02 (m, 1H), 1.01 - 0.96 (m, 1H), 0.87 (s, 3H). MS [M + H] + = 379.2.

[0061] Step 2: Ketal reaction to prepare the thioacetal ketal as shown in formula (IV)

[0062] Under nitrogen protection, 200 g of the thioacetal, 20 g of p-toluenesulfonic acid, 1 L of triethyl orthoformate, and 1.2 L of ethylene glycol were added to a 5-L reaction flask. The mixture was stirred and reacted at 20 - 25 °C for 8 h until the raw materials were completely converted as shown by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 2:1).

[0063] The reaction solution was slowly poured into 2 L of 1N aqueous sodium hydroxide solution, stirred for 1 h, filtered, and dried under reduced pressure at 40 °C to obtain 200 g of a off-white thioacetal ketal, with a molar yield of 89.7% and a purity of 97.46% (HPLC method 2).

[0064] 11H NMR (600 MHz, CDCl3) δ 5.84 (s, 1H), 3.95 - 3.91 (m, 2H), 3.85 - 3.81 (m, 2H), 3.62 (d, J = 12.0 Hz, 1H), 3.36 - 3.35 (m, 2H), 3.27 - 3.22 (m, 1H), 2.41 (t, J = 12.0 Hz, 1H), 2.17 - 2.13 (m, 3H), 1.99 - 1.94 (m, 1H), 1.80 - 1.75 (m, 2H), 1.70 - 1.63 (m, 3H), 1.51 - 1.48 (m, 2H), 1.42 - 1.35 (m, 5H), 1.31 - 1.25 (m, 3H), 1.01 - 0.93 (m, 2H), 0.85 (s, 3H). MS [M + H] + = 423.2.

[0065] Step 3: Desulfurization reaction to prepare the 19-hydroxyestrone ketal as shown in formula (V)

[0066] Under nitrogen protection, in a 10 L reaction flask, add 2 L of tetrahydrofuran and 4 L of liquid ammonia, and cool down to -65 °C. Add 200 g of the thioketal, stir to dissolve, and slowly add 65 g of metallic sodium in portions. Keep the reaction at -65 °C for 0.5 h until the raw material is completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 2 / 1).

[0067] Add 2 L of dichloromethane to the reaction solution, stir to remove ammonia gas. Separate the layers, wash the organic phase with water until neutral, dry it, concentrate it nearly to dryness, add 1 L of ethanol, stir at 50 °C for 1 h, cool down to 0 °C and stir for 1 h, filter, and dry under reduced pressure at 40 °C to obtain 145 g of off-white 19-hydroxyestrone ketal, with a molar yield of 92.3% and a purity of 96.52% (HPLC method 2).

[0068] Step 4: Hydrolysis reaction to prepare 19-hydroxyestrone as shown in formula (I)

[0069] Under nitrogen protection, in a 3 L reaction flask, add 1 L of tetrahydrofuran, 100 g of 19-hydroxyestrone ketal, and 600 mL of 2N hydrochloric acid, and keep the reaction at 20 °C for 4 h until the raw material is completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 3 / 1).

[0070] Slowly add 1 L of water dropwise to the reaction solution, stir for 1 h, filter to obtain the crude product of 19-hydroxyestrone. Add 500 mL of ethanol to the crude product, stir at 50 °C for 1 h, cool down to 0 °C and stir for 1 h, filter, and dry under reduced pressure at 40 °C to obtain 78 g of off-white 19-hydroxyestrone, with a molar yield of 90% and a purity of 98.75% (HPLC method 2).

[0071] 1 1H NMR (600 MHz, CDCl3) δ 5.74 (brs, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.56 (d, J = 12.0 Hz, 1H), 2.46 - 2.42 (m, 1H), 2.20 - 2.13 (m, 2H), 2.09 - 2.01 (m, 2H), 1.98 - 1.91 (m, 3H), 1.88 - 1.86 (m, 1H), 1.81 - 1.68 (m, 4H), 1.61 - 1.60 (m, 1H), 1.55 - 1.49 (m, 1H), 1.42 - 1.31 (m, 2H), 1.28 - 1.18 (m, 4H), 1.03 - 0.99 (m, 1H), 0.88 (s, 3H). MS [M - H2O + H] + = 271.

[0072] Example 2

[0073] Step 1: Thioacetalization reaction to prepare the thioacetal as shown in formula (Ⅲ)

[0074] Under nitrogen protection, in a 5 L reaction flask, add 1.6 L of tetrahydrofuran, 200 g of 19 - hydroxy - 4 - androstenedione, and 64 mL of ethanedithiol. Stir, and slowly add dropwise 48 mL of a boron trifluoride diethyl ether solution with a mass concentration of 48%. After the addition is complete, keep the reaction solution at 25 °C for 5 h until the raw materials are completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 3 / 1).

[0075] Slowly pour the reaction solution into 2 L of water, stir for 2 h, filter, and dry under reduced pressure at 50 °C to obtain 232.2 g of a pale - white thioacetal, with a molar yield of 92.76% and a purity of 94.68% (HPLC method 1).

[0076] Step 2: Ketalization reaction to prepare the thioacetal ketal as shown in formula (Ⅳ)

[0077] Under nitrogen protection, in a 5 L reaction flask, add 230 g of the thioacetal, 18.9 g of p - toluenesulfonic acid, 1.2 L of triethyl orthoformate, and 980 ml of ethylene glycol. Stir and react at 25 °C for 10 h until the raw materials are completely converted as shown by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 2:1).

[0078] Slowly pour the reaction solution into 2 L of 1N aqueous sodium hydroxide solution, stir for 2 h, filter, and dry under reduced pressure at 50 °C to obtain 218.4 g of a pale - white thioacetal ketal, with a molar yield of 85.06% and a purity of 96.54% (HPLC method 2).

[0079] Step 3: Desulfurization reaction to prepare the 19 - hydroxyestrone ketal as shown in formula (Ⅴ)

[0080] Under nitrogen protection, in a 10 L reaction flask, 1.67 L of tetrahydrofuran and 3.34 L of liquid ammonia were added, and the temperature was lowered to -65 °C. 209 g of the thioacetal compound was added and stirred until dissolved. 53.5 g of metallic sodium was slowly added in portions. The reaction was carried out at -60 °C for 1 h until the raw materials were completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 2 / 1).

[0081] 2 L of dichloromethane was added to the reaction solution, and the mixture was stirred to expel ammonia gas. The layers were separated, and the organic phase was washed with water until neutral, dried, concentrated nearly to dryness, 1 L of ethanol was added, and the mixture was stirred at 60 °C for 1 h, then cooled to 10 °C and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 50 °C to obtain 154 g of off-white 19-hydroxyestrenone ketal, with a molar yield of 93.66% and a purity of 96.22% (HPLC method 2).

[0082] Step 4: Hydrolysis reaction to prepare 19-hydroxyestrenone as shown in formula (I)

[0083] Under nitrogen protection, 670 ml of tetrahydrofuran, 170 g of 19-hydroxyestrenone ketal, and 820 mL of 2N hydrochloric acid were added to a 3 L reaction flask, and the reaction was carried out at 25 °C for 5 h until the raw materials were completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 3 / 1).

[0084] 1 L of water was slowly added dropwise to the reaction solution, and the mixture was stirred for 1 h and then filtered to obtain the crude product of 19-hydroxyestrenone. 500 mL of ethanol was added to the crude product, and the mixture was stirred at 60 °C for 1 h, then cooled to 10 °C and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 50 °C to obtain 131.1 g of off-white 19-hydroxyestrenone, with a molar yield of 88.9% and a purity of 98.15% (HPLC method 2).

[0085] Example 3

[0086] Step 1: Thiolation reaction to prepare the thioacetal compound as shown in formula (III)

[0087] Under nitrogen protection, 2.4 L of tetrahydrofuran, 200 g of 19-hydroxy-4-androstenedione, and 96 mL of ethanedithiol were added to a 5 L reaction flask, and the mixture was stirred. 72 mL of a boron trifluoride diethyl ether solution with a mass concentration of 48% was slowly added dropwise. After the addition was complete, the reaction solution was kept at 22 °C for 4.5 h until the raw materials were completely converted as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 3 / 1).

[0088] The reaction solution was slowly poured into 2 L of water, stirred for 1 h, filtered, and dried under reduced pressure at 45 °C to obtain 237.5 g of off-white thioacetal compound, with a molar yield of 94.87% and a purity of 95.53% (HPLC method 1).

[0089] Step 2: Ketal reaction to prepare the thioacetal shown in formula (IV)

[0090] Under nitrogen protection, in a 5 L reaction flask, add 200 g of thioacetal, 23.7 g of p-toluenesulfonic acid, 1 L of triethyl orthoformate, and 1.4 L of ethylene glycol. Stir and react at 25 °C for 9 h until TLC (developing agent: petroleum ether / ethyl acetate, v / v = 2:1) shows that the raw materials are completely converted.

[0091] Slowly pour the reaction solution into 2 L of 1N aqueous sodium hydroxide solution, stir for 2 h, filter, and dry under reduced pressure at 50 °C to obtain 198.6 g of off-white thioacetal, with a molar yield of 88.95% and a purity of 97.51% (HPLC method 2).

[0092] Step 3: Desulfurization reaction to prepare the 19-hydroxyestrone ketal shown in formula (V)

[0093] Under nitrogen protection, in a 10 L reaction flask, add 2.16 L of tetrahydrofuran and 4.32 L of liquid ammonia, and cool to -65 °C. Add 180 g of thioacetal, stir to dissolve, and slowly add 70.7 g of metallic sodium in batches. Keep the temperature at -60 °C and react for 0.8 h until TLC (developing agent: petroleum ether / ethyl acetate, v / v = 2 / 1) monitors that the raw materials are completely converted.

[0094] Add 1.6 L of dichloromethane to the reaction solution, stir to remove ammonia gas. Separate the layers, wash the organic phase with water until neutral, dry, concentrate until nearly dry, add 800 ml of ethanol, stir at 55 °C for 1 h, cool to 5 °C and stir for 1 h, filter, and dry under reduced pressure at 40 °C to obtain 130.5 g of off-white 19-hydroxyestrone ketal, with a molar yield of 92.15% and a purity of 96.8% (HPLC method 2).

[0095] Step 4: Hydrolysis reaction to prepare 19-hydroxyestrone shown in formula (I)

[0096] Under nitrogen protection, in a 3 L reaction flask, add 1.45 L of tetrahydrofuran, 100 g of 19-hydroxyestrone ketal, and 722.5 mL of 2N hydrochloric acid. Keep the temperature at 20 °C and react for 5 h until TLC (developing agent: petroleum ether / ethyl acetate, v / v = 3 / 1) monitors that the raw materials are completely converted.

[0097] Slowly add 1 L of water dropwise to the reaction solution, stir for 1 h, filter to obtain the crude product of 19-hydroxyestrone. Add 500 mL of ethanol to the crude product, stir at 60 °C for 1 h, cool to 8 °C and stir for 1 h, filter, and dry under reduced pressure at 50 °C to obtain 78.5 g of off-white 19-hydroxyestrone, with a molar yield of 90.49% and a purity of 98.84% (HPLC method 2).

[0098] Comparative Example 1

[0099] The difference from Example 1 is that in Step 1, the boron trifluoride ether solution is replaced with titanium tetrachloride solution. The yield is 84.2% and the purity is 88.8%.

[0100] The possible reason for this may be that the activity of titanium tetrachloride as a Lewis acid catalyst is different from that of boron trifluoride, showing different catalytic efficiencies in the thio - condensation reaction. Moreover, due to the relatively large hydrolysis tendency of titanium tetrachloride, side reactions or incomplete reactions may be introduced, affecting the purity of the final product.

[0101] Comparative Example 2

[0102] The difference from Example 1 is that in Step 3, the reaction temperature is set at - 40°C. The yield is 82.3% and the purity is 89.8%.

[0103] The possible reason for this may be that although the reaction rate can be accelerated when the temperature reaches - 40°C, it may also lead to an increase in side reactions. And at a higher temperature, sodium metal may be more reactive, resulting in unnecessary side reactions and reducing the product selectivity and purity.

[0104] Comparative Example 3

[0105] The difference from Example 1 is that in Step 4, 4N hydrochloric acid is used instead of 2N hydrochloric acid. The yield is 91.4% and the purity is 91.1%.

[0106] The possible reason for this may be that excessive acid may cause other side reactions, such as further hydrolysis of the ester group or protonation of other functional groups. At the same time, high - concentration acid may also cause certain degradation of the product, especially under long - term exposure.

[0107] The above - mentioned is only the preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 19-hydroxyestrenone, characterized in that: The structure of the 19-hydroxyestrenone is shown in formula (I): The 19-hydroxyestrenone is prepared by hydrolyzing 19-hydroxyestrenone ketal; wherein the preparation method of the 19-hydroxyestrenone ketal comprises the following steps: Step 1, 19-hydroxy-4-androstenedione is subjected to a sulfur condensation reaction to obtain a sulfur condensation product; Step 2: The sulfur condensate of step 1 is subjected to a ketal reaction to obtain a sulfur condensate ketal; Step 3: The condensed ketal product of step 2 is subjected to a desulfurization reaction to obtain 19-hydroxyestrenone ketal product.

2. The method for preparing 19-hydroxyestrenone according to claim 1, characterized in that: The 19-hydroxyestrenone ketal is subjected to a hydrolysis reaction using tetrahydrofuran as a solvent and hydrochloric acid as a catalyst to obtain 19-hydroxyestrenone as shown in formula (I).

3. The method for preparing 19-hydroxyestrenone according to claim 2, characterized in that: The molar ratio of the 19-hydroxyestrenone ketal to hydrochloric acid is 1:(3.2-4.8); the volume ratio of the hydrochloric acid to tetrahydrofuran is 1:(1.4-2.0).

4. The method for preparing 19-hydroxyestrenone according to claim 1, characterized in that: In step 1, the 19-hydroxy-4-androstenedione undergoes a condensation reaction with ethanedithiol in a tetrahydrofuran solution with boron trifluoride ether as a catalyst to obtain a condensation product.

5. The method for preparing 19-hydroxyestrenone according to claim 4, characterized in that: The molar ratio of the 19-hydroxy-4-androstenedione, ethanedithiol and boron trifluoride etherate is 1:(1.4-2.0):(0.3-0.6); the mass volume ratio of the 19-hydroxy-4-androstenedione to tetrahydrofuran is 1g:(8-12)ml.

6. The method for preparing 19-hydroxyestrenone according to claim 1, characterized in that: In step 2, the condensate undergoes ketal reaction with ethylene glycol using p-toluenesulfonic acid as a catalyst and triethyl orthoformate as a water scavenger to obtain a ketal.

7. The method for preparing 19-hydroxyestrenone according to claim 6, characterized in that: The molar ratio of the condensate, p-toluenesulfonic acid and ethylene glycol is 1:(0.18-0.26):(32-48); the volume ratio of the triethyl orthoformate to the ethylene glycol is 1:(0.9-1.4).

8. The method for preparing 19-hydroxyestrenone according to claim 1, characterized in that: In step 3, the thioketal product is subjected to a desulfurization reaction under the combined action of liquid ammonia and metallic sodium with tetrahydrofuran as solvent to obtain 19-hydroxyestrenone ketal product.

9. The method for preparing 19-hydroxyestrenone according to claim 8, characterized in that: The molar ratio of the thioacetal to metallic sodium is 1:(4.7-7.2); the mass volume ratio of the thioacetal to liquid ammonia and tetrahydrofuran is 1g:(16-24)ml:(8-12)ml.

10. A compound, characterized in that The structural formula of the compound is shown in formula (IV):

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