Method for removing brominated impurities from estetrol or derivatives thereof
By catalyzing the debromination reaction in the presence of a metal catalyst and a hydrogen-providing compound, the problem of difficult removal of brominated impurities in estetrol or its derivatives is solved, and a purification effect with high yield and high purity is achieved.
Patent Information
- Application Number
- CN202510919767.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-04
- Publication Date
- 2025-10-17
AI Technical Summary
It is difficult to effectively remove brominated byproduct impurities at the 2- and 4-positions of the estrone skeleton in estetrol or its derivatives using existing technologies, resulting in large purification losses and low yields of target compounds.
In the presence of a metal catalyst and a hydrogen-providing compound, brominated impurities in estetrol or its derivatives are converted into target products through a catalytic debromination reaction, and the target products are purified by a method under mild conditions.
The method realizes the removal of brominated impurities in estetrol or its derivatives with high yield and high purity, avoids multiple recrystallizations and column chromatography, and reduces solvent usage and environmental pollution.
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Figure CN120795053A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to a method for purifying organic compounds, and more particularly, relates to a method for removing brominated impurities from estetrol. Background Art
[0002] Estretrol is a biogenic estrogen produced endogenously by the fetal liver during human pregnancy. It is also known as estradiol. Its chemical name is estradiol-1,3,5(10)-triene-3,15α,16α,17β-tetrol, and its structural formula is as follows:
[0003]
[0004] On April 16, 2021, Mayne Pharma announced that the U.S. FDA has approved Nextstellis (drospirenone and estradiol) combination tablets for pregnancy prevention. Nextstellis (drospirenone and estradiol) combination tablets are the first new estrogen approved by the FDA in over 50 years. Other important uses of estradiol include contraception, treatment of autoimmune diseases, prevention and treatment of breast and colon tumors, enhancement of libido, skin care, and wound healing.
[0005] Nambara et al., Steroids, 1976, Vol. 27, P111-121 reported a method for synthesizing estetrol using estrone (compound of formula I) as a starting material (Route 1):
[0006]
[0007] Route 1
[0008] The conversion of estrone (Formula I) to estetrol (Formula VI) in Route 1 involves bromination and debromination steps. When the present inventors repeated this method, they discovered that in the bromination step, in addition to the target product, Formula II, brominated byproducts at positions 2 and 4 of the estrone skeleton are also generated, with relatively high levels (typically 0.1 to 7.0%). These byproducts are difficult to remove using conventional purification methods (e.g., recrystallization and column chromatography), and multiple purification operations are required to remove these impurities from the target compound, resulting in significant purification losses and low yields. Furthermore, the inventors discovered that if the product obtained from the bromination step is not purified, the brominated byproducts subsequently undergo debromination (forming a double bond) at position 16, acetylation, reduction, reacetylation, oxidation, and deacetylation with the target product. The brominated byproducts then generate corresponding byproducts that are also difficult to separate and remove from the corresponding target product using conventional purification methods.
[0009] Accordingly, there is a need for a method for removing the 2- and / or 4-bromo byproduct impurity of the estrone skeleton from estetrol or a derivative thereof. SUMMARY
[0010] It is an object of the present invention to provide a method for removing the impurities of the compounds of formula IM1 and / or IM2 from estetrol or a derivative thereof, a compound of formula IM, said method comprising the steps of:
[0011] The estetrol or a derivative thereof, containing the compounds of formula IM1 and / or IM2, is catalytically debrominated in a solvent in the presence of a metal catalyst and a compound providing hydrogen, wherein the compounds of formula IM1 and / or IM2 are converted into estetrol or a derivative thereof, according to the following reaction scheme:
[0012]
[0013] In the structural formulae IM1, IM2 and IM, R1, R2, R3 and R4 are each independently selected from H or a hydroxyl protecting group, and the metal catalyst is selected from a palladium containing catalyst.
[0014] In another preferred embodiment, the hydroxyl protecting group is selected from an acyl group, a sulfonyl group, an alkyl group, a benzyl group (Bn), a p-oxyl benzyl group or a silyl group.
[0015] In another preferred embodiment, the acyl group is selected from an acetyl group (Ac), a propionyl group, a pivaloyl group, a benzoyl group (Bz) or a p-toluoyl group.
[0016] In another preferred embodiment, the sulfonyl group is selected from a methylsulfonyl group, a phenylsulfonyl group, a p-toluenesulfonyl group.
[0017] In another preferred embodiment, the alkyl group is selected from a C1-C6 alkyl group.
[0018] In another preferred embodiment, the silyl group is selected from a trimethylsilyl group or a dimethylsilyl group.
[0019] In another more preferred embodiment, the hydroxyl protecting group is selected from an acetyl group.
[0020] In another preferred embodiment, in the structural formulae IM1, IM2 and IM, R1, R2, R3 and R4 are each independently selected from H or Ac.
[0021] In another preferred embodiment, in the structural formulae IM1, IM2 and IM, R1, R2, R3 and R4 are each selected from Ac, or R1 and R4 are selected from Ac and R2 and R3 are selected from H, or R1, R2, R3 and R4 are each selected from H.
[0022] In another preferred embodiment, the weight content of the compound of formula IMl and the compound of formula IM2 in the estetrol or its derivatives containing the impurities is each independently 0% to 10.0%, more preferably 0.1% to 7.0%.
[0023] In another preferred embodiment, the solvent is selected from the group consisting of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, toluene, acetone, or a combination thereof, or a mixture of tetrahydrofuran and water.
[0024] In another preferred embodiment, the debromination temperature is 0 to 70°C.
[0025] In another preferred embodiment, the debromination time is 5 to 36 hours.
[0026] In another preferred embodiment, the palladium catalyst is selected from the group consisting of palladium dichloride, palladium on carbon, palladium hydroxide on carbon, or a combination thereof.
[0027] In another preferred embodiment, the hydrogen-providing compound is selected from the group consisting of sodium triacetylborohydride, sodium borohydride, sodium formate, ammonium formate, formic acid, triethylsilane, ethyl formate, hydrogen, or a combination thereof.
[0028] In another preferred embodiment, the metal catalyst is selected from palladium on carbon, and the hydrogen-providing compound is selected from formic acid, sodium borohydride or triethylsilane.
[0029] In another preferred embodiment, the molar ratio of estetrol or its derivatives to the hydrogen source compound is 1:0.1 to 12, more preferably 1:0.5 to 10.
[0030] In another preferred embodiment, the mass ratio of estetrol or its derivatives to the metal catalyst is 1:0.001 to 0.1, more preferably 1:0.01 to 0.05.
[0031] In another preferred embodiment, the method further comprises, after the debromination reaction is completed, filtering the reaction solution, concentrating, and slushing with a mixture of methanol and water to obtain estetrol or its derivatives.
[0032] In another preferred embodiment, the volume ratio of methanol to water in the mixture of methanol and water is 1:3 to 6.
[0033] In another preferred embodiment, before the reaction solution is filtered, the method further comprises a step of quenching the reaction.
[0034] The present application also provides the following compounds, the structural formula of which is shown as follows:
[0035]
[0036] The method for removing the impurity compounds of formula IM1 and / or formula IM2 from estetrol or its derivatives provided by the present application does not require high-pressure hydrogenation equipment and can remove the 2-position and 4-position bromination by-product impurities of the estrone skeleton under mild conditions at each intermediate and final product stage of the synthesis of estetrol. BRIEF DESCRIPTION OF DRAWINGS
[0037] Figure 1a HPLC spectrum of the compound of formula IM-a before purification in Example 1 to Example 4 of the present application;
[0038] Figure 1b HPLC spectrum of the compound of formula IM-a after purification in Example 1 of the present application;
[0039] Figure 2 HPLC spectrum of the compound of formula IM-a after purification in Example 2 of the present application;
[0040] Figure 3 HPLC spectrum of the compound of formula IM-a after purification in Example 3 of the present application;
[0041] Figure 4 HPLC spectrum of the compound of formula IM-a after purification in Example 4 of the present application;
[0042] Figure 5a HPLC spectrum of the compound of formula IM-b before purification in Example 5 to Example 7 of the present application;
[0043] Figure 5b HPLC spectrum of the compound of formula IM-b after purification in Example 5 of the present application;
[0044] Figure 6 HPLC spectrum of the compound of formula IM-b after purification in Example 6 of the present application;
[0045] Figure 7 HPLC spectrum of the compound of formula IM-b after purification in Example 7 of the present application;
[0046] Figure 8a HPLC spectrum of the compound of formula IM-c before purification in Example 8 to Example 9 of the present application;
[0047] Figure 8b HPLC spectrum of the compound of formula IM-c after purification in Example 8 of the present application;
[0048] Figure 9 HPLC spectrum of the compound of formula IM-c after purification in Example 9 of the present application;
[0049] Figure 10 NMR hydrogen spectrum of the compound of formula II-a;
[0050] Figure 11 NMR of compound of formula II-b;
[0051] Figure 12 NMR of compound of formula IM1-a;
[0052] Figure 13 NMR of compound of formula IM2-a;
[0053] Figure 14 NMR of compound of formula IM1-b;
[0054] Figure 15 NMR of compound of formula IM2-b. DETAILED DESCRIPTION
[0055] Nambara et al., Steroids, 1976, Vol. 27, P111-121 reported a method for synthesizing estetrol (compound of formula VI) using estrone (compound of formula I) as starting material. The inventors of the present application repeated the method and found that in the bromination step, in addition to the target product compound of formula II, 2-bromo and 4-bromo byproducts of estrone skeleton were also generated. These byproducts were difficult to remove by conventional purification methods (e.g. recrystallization and column chromatography), and removing the impurities from the target compound required multiple purification operations, resulting in large loss of the target compound and low yield. The inventors also found that if the product obtained in the bromination step was not purified or the impurities were not completely removed, the bromination byproducts would subsequently react with other reactants together with the target product, resulting in the presence of 2-bromo and 4-bromo byproducts of estrone skeleton in the subsequently obtained intermediate products and final products, which were difficult to remove. The inventors of the present application found through in-depth research that the bromine of these bromination byproducts could be removed and converted into the corresponding target product, such as estetrol or its derivatives, by a specific reduction system. On this basis, the present application was completed.
[0056] Compounds of formula IM1 and compounds of formula IM2
[0057] The inventors of the present application prepared estetrol according to the above-mentioned route 1 disclosed by Nambara et al. The inventors found that the product obtained in the bromination step involved in the conversion of estrone (compound of formula I) to estetrol (compound of formula VI) contained two obvious impurities, which were difficult to remove by conventional purification methods (e.g. recrystallization and column chromatography) or required multiple purifications in the removal process, resulting in large loss of the target product. The inventors separated the two impurities through multiple purifications and named them as “compound of formula II-a” and “compound of formula II-b”. They were characterized and structurally analyzed, and their structures were determined as follows:
[0058]
[0059] In the case of not removing or incompletely removing the impurities of the compound of formula II-a and the compound of formula II-b, they will be derived into other bromo impurities in the subsequent steps. For example, in the final estratetraenol (compound of formula VI) product, there are two obvious impurities, which are as same as the compound of formula II-a and the compound of formula II-b, and are difficult to be removed by the conventional purification method, or in the removal process, multiple purifications are required, resulting in a large loss of the target product. The inventors isolated the two impurities by multiple purifications, named as “compound of formula IM1-b” and “compound of formula IM2-b”, and characterized and analyzed their structures, which are determined as follows:
[0060]
[0061] In the case of not removing or incompletely removing the impurities of the compound of formula II-a and the compound of formula II-b, the inventors also found that there are two obvious impurities in the obtained compound of formula V, which are as same as the compound of formula II-a and the compound of formula II-b, and are difficult to be removed by the conventional purification method, or in the removal process, multiple purifications are required, resulting in a large loss of the target product. The inventors tried to isolate these impurities by multiple purifications, but found that these impurities are more difficult to be isolated than the aforementioned compound of formula II-a, the compound of formula II-b, the compound of formula IM1-b and the compound of formula IM2-b. According to the reaction process of route 1, the inventors speculated that the main impurities obtained may be as shown in the following structural formula IM1-c and structural formula IM2-c. In order to facilitate the purification and isolation of these impurities, the inventors acetylated the compound of formula V containing these impurities with acetic anhydride, and finally isolated the compounds as shown in the following structural formula IM1-a and structural formula IM2-a, and characterized them. According to the structures of the impurity compounds confirmed after derivation, the inventors further determined that the structures of the impurities contained in the compound of formula V are indeed as shown in the structural formula IM1-c and the structural formula IM2-c, respectively.
[0062]
[0063] The nuclear magnetic resonance hydrogen spectrum data of the above-mentioned compound of formula II-a, the compound of formula II-b, the compound of formula IM1-a, the compound of formula IM2-a, the compound of formula IM1-b, and the compound of formula IM2-b are as follows:
[0064] The nuclear magnetic resonance hydrogen spectrum of the compound of formula II-a is as follows: Figure 10 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (br. s, 1H), 7.26 (s, 1H), 6.62 (s, 1H), 4.63 (dd, J = 10.7 Hz, 3.5 Hz, 1H), 4.16 - 3.99 (m, 2H), 3.99 - 3.80 (m, 2H), 2.78 - 2.58 (m, 2H), 2.33 - 2.02 (m, 3H), 1.99 - 1.57 (m, 4H), 1.51 - 1.12 (m, 4H), 0.84 (s, 3H).
[0065] The nuclear magnetic hydrogen spectrum of the compound of formula II-b is Figure 11 : 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (br. s, 1H), 7.26 (s, 1H), 6.62 (s, 1H), 4.63 (dd, J = 10.7 Hz, 3.5 Hz, 1H), 4.16 - 3.99 (m, 2H), 3.99 - 3.80 (m, 2H), 2.78 - 2.58 (m, 2H), 2.33 - 2.02 (m, 3H), 1.99 - 1.57 (m, 4H), 1.51 - 1.12 (m, 4H), 0.84 (s, 3H).
[0066] The nuclear magnetic hydrogen spectrum of the compound of formula IM1-a is Figure 12 : 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (br. s, 1H), 7.26 (s, 1H), 6.62 (s, 1H), 4.63 (dd, J = 10.7 Hz, 3.5 Hz, 1H), 4.16 - 3.99 (m, 2H), 3.99 - 3.80 (m, 2H), 2.78 - 2.58 (m, 2H), 2.33 - 2.02 (m, 3H), 1.99 - 1.57 (m, 4H), 1.51 - 1.12 (m, 4H), 0.84 (s, 3H).
[0067] The nuclear magnetic hydrogen spectrum of the compound of formula IM2-a is Figure 13 : 1H NMR (300 MHz, DMSO-d6) δ 7.38 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 5.25 (t, J = 7.5 Hz, 1H), 5.06 (t, J = 9.3 Hz, 1H), 4.89 (d, J = 6.5 Hz, 1H), 2.94 - 2.78 (m, 1H), 2.78 - 2.57 (m, 1H), 2.48 - 2.25 (m, 5H), 2.05 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.97 - 1.63 (m, 4H), 1.62 - 1.30 (m, 3H), 0.89 (s, 3H).
[0068] The NMR hydrogen spectrum of the compound of formula IM1-b is Figure 14 : 1 H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.26 (s, 1H), 6.62 (s, 1H), 4.84 (d, J = 4.8 Hz, 1H), 4.59 (d, J = 5.4 Hz, 1H), 4.24 (d, J = 5.8 Hz, 1H), 3.78 - 3.59 (m, 2H), 3.24 (t, J = 5.2 Hz, 1H), 2.76 - 2.62 (m, 2H), 2.31 - 2.02 (m, 3H), 1.81 - 1.67 (m, 1H), 1.52 - 1.37 (m, 1H), 1.36 - 1.09 (m, 3H), 1.03 (t, J = 9.3 Hz, 1H), 0.66 (s, 3H).
[0069] The NMR hydrogen spectrum of the compound of formula IM2-b is Figure 15 : 1 H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.26 (s, 1H), 6.62 (s, 1H), 4.84 (d, J = 4.8 Hz, 1H), 4.59 (d, J = 5.4 Hz, 1H), 4.24 (d, J = 5.8 Hz, 1H), 3.78 - 3.59 (m, 2H), 3.24 (t, J = 5.2 Hz, 1H), 2.76 - 2.62 (m, 2H), 2.31 - 2.02 (m, 3H), 1.81 - 1.67 (m, 1H), 1.52 - 1.37 (m, 1H), 1.36 - 1.09 (m, 3H), 1.03 (t, J = 9.3 Hz, 1H), 0.66 (s, 3H).
[0070] The present invention relates to a process for removing the impurities of formula IM1 and formula IM2 from estetrol or a derivative thereof, a compound of formula IM, comprising the following steps:
[0071] The estratetraol or its derivative containing the compound of formula IM1 and / or the compound of formula IM2 is catalytically debrominated in a solvent in the presence of a metal catalyst and a hydrogen-providing compound, to produce the estratetraol or its derivative, according to the following reaction scheme:
[0072]
[0073] In the structural formulas IM1, IM2 and IM, R1, R2, R3 and R4 are each independently selected from H or a hydroxyl protecting group. In some embodiments of the present application, the hydroxyl protecting group is acetyl.
[0074] The metal catalyst includes, but is not limited to, a palladium-containing catalyst, such as palladium dichloride, palladium on carbon, and palladium hydroxide on carbon. The hydrogen-providing compound includes, but is not limited to, sodium triacetyl borohydride, sodium borohydride, sodium formate, ammonium formate, formic acid, triethylsilane, ethyl formate, and hydrogen.
[0075] To allow sufficient reaction of the impurities, the molar ratio of the estratetraol or its derivative to the hydrogen-providing compound is preferably 1:0.5-10, and the mass ratio of the estratetraol or its derivative to the metal catalyst is preferably 1:0.01-0.05.
[0076] The debromination temperature and time are related to all catalysts and hydrogen-providing compounds. In some embodiments, the catalyst is palladium dichloride, the hydrogen-providing compound is sodium borohydride, the debromination temperature is 0-10°C, and the debromination time is 5-9 hours; in some embodiments, the catalyst is Pd / C, the hydrogen-providing compound is triethylsilane, the debromination temperature is 30-50°C, and the debromination time is 7-25 hours; in some embodiments, the catalyst is Pd / C, the hydrogen-providing compound is formic acid, the debromination temperature is 30-55°C, and the debromination time is 10-11 hours; and in some embodiments, the catalyst is Pd / C, the hydrogen-providing compound is ammonium formate, the debromination temperature is 45-55°C, and the debromination time is 3-4 hours.
[0077] In the process of preparing estratetraol or its derivative from estrone by a bromination step, the method of the present application for removing the brominated impurities of the compound of formula IM1 and the compound of formula IM2 from estratetraol or its derivative can be used to purify the intermediates or final product of the route, to obtain the target product in high purity and high yield. Compared with recrystallization and column chromatography, the method of the present application for removing the brominated impurities from estratetraol or its derivative has the following advantages:
[0078] 1. The present application first reports that the bromine-containing by-products in estetrol or its derivatives are catalytically debrominated in the presence of a metal catalyst and a hydrogen-providing compound to convert into estetrol or its derivatives, or intermediates thereof, avoiding the purification by repeated recrystallization or column chromatography in a large amount of solvent, which not only wastes solvent but also pollutes the environment, and also causes the yield of the target product to be reduced.
[0079] 2. The method for removing brominated impurities from estetrol or its derivatives of the present application has a high yield and high purity of the target product obtained by purification, since the brominated impurities therein are finally converted into estetrol or its derivatives.
[0080] The present application will be further described in conjunction with the following specific examples, and the scope of protection of the present application is not limited to the following examples. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application, and are protected by the scope of the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present application are all general knowledge and common sense in the art, and the present application has no special limitations.
[0081] In the following examples, the starting material used in Examples 1-4, the compound of formula IM-a (containing impurities of the compound of formula IM1-a and the compound of formula IM2-a) was obtained by acetylation of the compound V (containing impurities of the compound of formula IM1-c and the compound of formula IM2-c) prepared according to Route 1 described above.
[0082] In the following examples, the starting material used in Examples 5-7, the compound of formula IM-b (containing impurities of the compound of formula IM1-b and the compound of formula IM2-b) was estetrol (containing impurities of the compound of formula IM1-b and the compound of formula IM2-b) prepared according to Route 1 described above.
[0083] In the following examples, the starting material used in Examples 8-9, the compound of formula IM-c (containing impurities of the compound of formula IM1-c and the compound of formula IM2-c) was the compound of formula V (containing impurities of the compound of formula IM1-c and the compound of formula IM2-c) prepared according to Route 1 described above.
[0084] Example 1
[0085] The removal of the impurities of the compound of formula IM1-a and the compound of formula IM2-a in the compound of formula IM-a (R1, R2, R3, R4 are all acetyl groups) involves the following reaction formula:
[0086]
[0087] Under nitrogen protection, 375 mg of palladium dichloride (2.12 mmol) was added into a reaction bottle, followed by the addition of tetrahydrofuran (80 mL), methanol (20 mL) and 10.0 g of the compound of formula IM-a (21.2 mmol, HPLC purity 93.28%, wherein the content of the compound of formula IM1-a is 5.21%, and the content of the compound of formula IM2-a is 0.09%, see Figure 1a ), and the temperature was lowered to 0-10°C. Then, 400 mg of sodium borohydride (10.6 mmol) was added, and the temperature was controlled at 0-10°C for 5-6 hours. HPLC monitoring showed that the conversion of the compound of formula IM1 and the compound of formula IM2 was substantially complete, and the reaction was stopped. Acetic acid aqueous solution was added into the reaction solution to quench the reaction, and then the solution was filtered and concentrated. The obtained residue was added into a mixture of methanol (50 mL) and water (250 mL), and the mixture was continuously stirred for 1 hour. Then, the mixture was filtered, and the obtained filter cake was vacuum dried to obtain 9.04 g of the compound of formula IM-a, with a yield of 90.4% and an HPLC purity of 99.46% (HPLC spectrum see Figure 1b ), wherein the content of the compound of formula IM1-a (RRT = 1.17) is N.D. (N.D. means not detected), and the content of the compound of formula IM2-a (RRT = 1.20) is N.D.
[0088] Example 2
[0089] The removal of the impurities, i.e., the compound of formula IM1-a and the compound of formula IM2-a, from the compound of formula IM-a (R1, R2, R3 and R4 are all acetyl groups), involves the reaction formula shown in Example 1.
[0090] Under nitrogen protection, 150 mg of Pd / C, ethyl acetate (50 mL), 5.0 g of the compound of formula IM-a (10.6 mmol, HPLC purity 93.28%, wherein the content of the compound of formula IM1-a is 5.21%, and the content of the compound of formula IM2-a is 0.09%, see Figure 1a ), and 12.3 g of triethylsilane (106 mmol) were sequentially added into a reaction bottle, and the temperature was raised to 40-50°C for 24-25 hours. HPLC monitoring showed that the conversion of the compound of formula IM1-a and the compound of formula IM2-a was substantially complete, and the reaction was stopped. The reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added into a mixture of methanol (25 mL) and water (125 mL), and the mixture was continuously stirred for 1 hour. Then, the mixture was filtered, and the obtained filter cake was vacuum dried to obtain 4.73 g of the compound of formula IM-a, with a yield of 94.6% and an HPLC purity of 98.99% (HPLC spectrum see Figure 2 ), wherein the content of the compound of formula IM1-a (RRT = 1.17) is N.D., and the content of the compound of formula IM2-a (RRT = 1.20) is N.D.
[0091] Example 3
[0092] The removal of the compound of formula IM1-a and the compound of formula IM2-a from the compound of formula IM-a (R1, R2, R3, R4 are all acetyl) is shown in the reaction scheme of Example 1.
[0093] Under nitrogen protection, 200 mg Pd / C, ethyl acetate (100 mL), the compound of formula IM-a 10.0 g (21.2 mmol, HPLC purity 93.28%, wherein the content of the compound of formula IM1-a is 5.21%, and the content of the compound of formula IM2-a is 0.09%, see Figure 1a ), and 1.95 g formic acid (42.3 mmol) were added into a reaction bottle in sequence, and the mixture was stirred at 45-55°C for 10-11 hours. HPLC monitoring showed that the conversion of the compound of formula IM1-a and the compound of formula IM2-a was substantially complete, the reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added into a mixture of methanol (50 mL) and water (250 mL), and the mixture was stirred for 1 hour. Filtration and vacuum drying of the obtained filter cake gave the compound of formula IM-a 9.82 g, with a yield of 98.2% and a HPLC purity of 99.25% (HPLC spectrum see Figure 3 ), the content of the compound of formula IM1-a (RRT = 1.17) was N.D., and the content of the compound of formula IM2-a (RRT = 1.20) was N.D.
[0094] Example 4
[0095] The removal of the compound of formula IM1-a and the compound of formula IM2-d from the compound of formula IM-a (R1, R2, R3, R4 are all acetyl) is shown in the reaction scheme of Example 1.
[0096] Under nitrogen protection, 200 mg Pd / C, tetrahydrofuran (100 mL), water (20 mL), the compound of formula IM-a 10.0 g (21.2 mmol, HPLC purity 93.28%, wherein the content of the compound of formula IM1-a is 5.21%, and the content of the compound of formula IM2-a is 0.09%, see Figure 1a ), and 3.34 g ammonium formate (52.9 mmol) were added into a reaction bottle in sequence, and the mixture was stirred at 45-55°C for 3-4 hours. HPLC monitoring showed that the conversion of the compound of formula IM1-a and the compound of formula IM2-a was substantially complete, the reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added into a mixture of methanol (50 mL) and water (250 mL), and the mixture was stirred for 1 hour. Filtration and vacuum drying of the obtained filter cake gave the compound of formula IM-a 9.54 g, with a yield of 95.4% and a HPLC purity of 99.90% (HPLC spectrum see Figure 4), the content of the compound of formula IM1-a (RRT = 1.17) was N.D., and the content of the compound of formula IM2-a (RRT = 1.20) was N.D.
[0097] Example 5
[0098] The removal of the compound of formula IM1-b and the compound of formula IM2-b in the compound of formula IM-b (R1, R2, R3, R4 are all hydrogen) involves the following reaction formula:
[0099]
[0100] Under nitrogen protection, 100 mg Pd / C, tetrahydrofuran (20 mL), water (25 mL) and the compound of formula IM-b 5.00 g (16.4 mmol, HPLC purity 93.69%, wherein the content of the compound of formula IM1-b and the compound of formula IM2-b is 6.07%, and the HPLC spectrum is shown in Figure 5a ), and the temperature was lowered to 0-10°C, and then 932 mg of sodium borohydride (24.6 mmol) was added, and the temperature was controlled at 0-10°C and stirred for 8-9 hours. HPLC monitoring showed that the compound of formula IM1-b and the compound of formula IM2-b in the reaction solution were basically completely converted, the reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. After concentration, the residue was added to a mixture of methanol (25 mL) and water (50 mL), and stirring was continued for 1 hour, and then filtered, and the obtained filter cake was vacuum dried to obtain the compound of formula IM-b 4.63 g, with a yield of 92.6% and a HPLC purity of 100% (the HPLC spectrum is shown in Figure 5b ), the content of the compound of formula IM1-b (RRT = 1.36) was N.D., and the content of the compound of formula IM2-b (RRT = 1.37) was N.D.
[0101] Example 6
[0102] The removal of the compound of formula IM1-b and the compound of formula IM2-b in the compound of formula IM-b (R1, R2, R3, R4 are all hydrogen) involves the reaction formula shown in Example 5.
[0103] Under nitrogen protection, 100 mg Pd / C, tetrahydrofuran (20 mL), water (25 mL) and the compound of formula IM-b 5.00 g (16.4 mmol, HPLC purity 93.69%, wherein the content of the compound of formula IM1-b and the compound of formula IM2-b is 6.07%, and the HPLC spectrum is shown in Figure 5a) and 1.51 g of formic acid (32.9 mmol), and the temperature was raised to 30-40° C. and stirred for 10-11 hours. HPLC monitoring showed that the conversion of the compound of formula IM1-b and the compound of formula IM2-b in the reaction solution was essentially complete. The reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added to a mixture of methanol (25 mL) and water (50 mL), and stirring was continued for 1 hour. The mixture was filtered and the filter cake was vacuum dried to obtain 4.86 g of the compound of formula IM-b, with a yield of 97.2% and an HPLC purity of 98.79% (see HPLC spectrum). Figure 6 ), the content of the compound of formula IM1-b (RRT=1.36) was ND, and the content of the compound of formula IM2-b (RRT=1.37) was ND.
[0104] Example 7
[0105] The removal of the compound of formula IM1-b and the compound of formula IM2-b from the compound of formula IM-b (R1, R2, R3, and R4 are all hydrogen) involves the reaction formula shown in Example 5.
[0106] Under nitrogen protection, the reaction flask was sequentially added with a mixture of 100 mg Pd / C, tetrahydrofuran (25 mL) and ethyl acetate (25 mL), and 5.00 g (16.4 mmol, HPLC purity 93.69%) of the compound of formula IM1-b and the compound of formula IM2-b, wherein the sum of the contents of the compound of formula IM1-b and the compound of formula IM2-b was 6.07%, and the HPLC spectrum was shown in FIG. Figure 5a ) and 19.1 g of triethylsilane (164 mmol), heated to 30-40° C. and stirred for 7-8 hours. HPLC monitoring of the reaction solution confirmed that the conversion of the compound of formula IM1-b and the compound of formula IM2-b was essentially complete. The reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added to a mixture of methanol (25 mL) and water (50 mL), and stirring was continued for 1 hour. The mixture was filtered and the filter cake was vacuum dried to obtain 4.54 g of the compound of formula IM-b, with a yield of 90.8% and an HPLC purity of 99.75% (see HPLC spectrum). Figure 7 ), the content of the compound of formula IM1-b (RRT=1.36) was ND, and the content of the compound of formula IM2-b (RRT=1.37) was ND.
[0107] Example 8
[0108] The removal of the compound of formula IM1-c and the compound of formula IM2-c from the compound of formula IM-c (R1 and R4 are acetyl groups, R2 and R3 are hydrogen) involves the following reaction formula:
[0109]
[0110] A mixture of 100 mg Pd / C, tetrahydrofuran (25 mL) and ethyl acetate (25 mL) was added into the reaction flask under nitrogen protection, then 5.00 g of compound of formula IM-c (12.9 mmol, HPLC purity 92.68%, wherein the content of compound of formula IM1-c was 0.41%, and the content of compound of formula IM2-c was 2.37%, see HPLC spectrum in Figure 8a ), and 15.0 g of triethylsilane (129 mmol) was added into the reaction flask under nitrogen protection, and the mixture was stirred at 30-40 °C for 9-10 hours. HPLC monitoring showed that the conversion of compound of formula IM1-c and compound of formula IM2-c was substantially complete, the reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added into a mixture of methanol (15 mL) and water (90 mL), and the mixture was stirred for 1 hour. The mixture was filtered, and the obtained filter cake was dried under vacuum to obtain 4.57 g of compound of formula IM-c, with a yield of 91.4% and a HPLC purity of 99.63% (see HPLC spectrum in Figure 8b ), the content of compound of formula IM1-c (RRT = 1.12) was N.D., and the content of compound of formula IM2-c (RRT = 1.14) was N.D.
[0111] Example 9
[0112] The removal of compound of formula IM1-c and compound of formula IM2-c from compound of formula IM-c (R1 and R4 are acetyl, and R2 and R3 are hydrogen) involved the reaction formula in Example 8.
[0113] A mixture of 100 mg Pd / C, tetrahydrofuran (25 mL) and ethyl acetate (25 mL) was added into the reaction flask under nitrogen protection, then 5.00 g of compound of formula IM-c (12.9 mmol, HPLC purity 92.68%, wherein the content of compound of formula IM1-c was 0.41%, and the content of compound of formula IM2-c was 2.37%, see HPLC spectrum in Figure 8a ), and 1.18 g of formic acid (25.7 mmol) was added into the reaction flask under nitrogen protection, and the mixture was stirred at 45-55 °C for 10-11 hours. HPLC monitoring showed that the conversion of compound of formula IM1-c and compound of formula IM2-c was substantially complete, the reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue after concentration was added into a mixture of methanol (15 mL) and water (90 mL), and the mixture was stirred for 1 hour. The mixture was filtered, and the obtained filter cake was dried under vacuum to obtain 4.78 g of compound of formula IM-c, with a yield of 95.6% and a HPLC purity of 99.35% (see HPLC spectrum in Figure 9 ). The content of compound of formula IM1-c (RRT = 1.12) was N.D., and the content of compound of formula IM2-c (RRT = 1.14) was N.D.
[0114] As can be seen from the above examples, the method of the present invention for removing the impurities of the compound of formula IM1 and / or the compound of formula IM2 from estetrol or its derivatives, the compound of formula IM, can effectively convert the impurities into estetrol or its derivatives, thereby obtaining estetrol or its derivatives with a relatively high purity.
[0115] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.
Claims
1. A method for removing impurities of the compound of formula IM1 and / or the compound of formula IM2 from estratetrol or its derivatives, the compound of formula IM, characterized in that: The method comprises the following steps: Estetrol or its derivatives containing a compound of formula IM1 and / or a compound of formula IM2 are catalytically debrominated in a solvent in the presence of a metal catalyst and a hydrogen-providing compound to produce estetrol or its derivatives, according to the following reaction formula: In the structural formulas IM1, IM2 and IM, R1, R2, R3 and R4 are each independently selected from H or a hydroxyl protecting group, The metal catalyst is selected from palladium-containing catalysts.
2. The method according to claim 1, characterized in that The hydroxy protecting group is selected from acyl, sulfonyl, alkyl, benzyl (Bn), p-oxybenzyl or silyl, More preferably, the acyl group is selected from acetyl, propionyl, pivaloyl, benzoyl or p-toluoyl, and / or More preferably, the sulfonyl group is selected from methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, and / or More preferably, the alkyl group is selected from C1 to C6 alkyl groups, and / or More preferably, the silane group is selected from trimethylsilane or dimethylsilane.
3. The method according to claim 2, characterized in that The hydroxy protecting group is selected from acetyl.
4. The method according to claim 3, characterized in that In the structural formulae IM1, IM2 and IM, R1, R2, R3 and R4 are all selected from acetyl, or R1 and R4 are selected from acetyl and R2 and R3 are selected from H, or R1, R2, R3 and R4 are all selected from H.
5. The method according to claim 1 or 2, characterized in that The weight content of the compound of formula IM1 and the compound of formula IM2 in the estetrol or its derivatives is independently 0% to 10.0%, more preferably 0.1% to 7.0%, and / or The solvent is selected from tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, toluene, acetone, or a combination thereof, or a mixture of tetrahydrofuran and water, and / or Debromination temperature is 0-70°C, and / or The debromination time is 5 to 36 hours.
6. The method according to claim 1 or 2, characterized in that The palladium catalyst is selected from palladium dichloride, palladium carbon, palladium hydroxide carbon, or a combination thereof, and / or The hydrogen-providing compound is selected from sodium triacetylborohydride, sodium borohydride, sodium formate, ammonium formate, formic acid, triethylsilane, ethyl formate, hydrogen, or a combination thereof.
7. The method according to claim 6, characterized in that The metal catalyst is selected from palladium carbon, and The hydrogen-donating compound is selected from formic acid, sodium borohydride or triethylsilane.
8. The method according to claim 1 or 2, characterized in that The molar ratio of estetrol or its derivatives to the hydrogen source compound is 1:0.1-12, more preferably 1:0.5-10, and / or The mass ratio of estetrol or its derivatives to the metal catalyst is 1:0.001-0.1, more preferably 1:0.01-0.
05.
9. The method according to claim 1 or 2, characterized in that The method further comprises filtering, concentrating and beating the reaction solution with a mixture of methanol and water after the debromination reaction is completed to obtain estratetrol or its derivatives. Preferably, the volume ratio of methanol to water in the mixture of methanol and water is 1:3-6.
10. A compound having the structural formula shown below: