CN119569803A - Method for preparing high-purity estetrol - Google Patents
Method for preparing high-purity estetrol Download PDFInfo
- Publication number
- CN119569803A CN119569803A CN202311137408.9A CN202311137408A CN119569803A CN 119569803 A CN119569803 A CN 119569803A CN 202311137408 A CN202311137408 A CN 202311137408A CN 119569803 A CN119569803 A CN 119569803A
- Authority
- CN
- China
- Prior art keywords
- reaction
- formula
- compound
- estetrol
- purity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention discloses a method for preparing high-purity estra-1, 3,5 (10) -triene-3, 15 alpha, 16 alpha, 17 beta-tetraol (called as estetrol for short), which takes 3-hydroxy-17 beta-hydroxy estra-1, 3,5 (10), 15-tetraene as raw materials and prepares the estetrol through three steps of phenolic hydroxyl protection, asymmetric dihydroxylation and hydrolysis. In the preparation method, 3-hydroxy-17 beta-hydroxyestra-1, 3,5 (10), 15-tetraene is used as a raw material, 3-hydroxy is protected by alkoxy substituted benzoyl, asymmetric dihydroxyl reaction is carried out by catalytic oxidation of potassium osmium, double alpha-hydroxy is introduced at 15, 16-positions, chemical reagents and catalysts with high cost are not needed in the preparation method, the dihydroxylation has high stereoselectivity, the purification and separation are easy, the reaction condition is mild, the operation is simple and convenient, and the high-efficiency preparation of high-purity estetrol (more than or equal to 99.5%) can be realized.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, and relates to a method for preparing high-purity estetrol.
Background
Estetrol is produced as an estrogen by the liver of infants only during gestation. Clinical studies have shown that estetrol can be used in hormone replacement therapy and in female oral contraceptives, and that, in addition, estetrol has important applications in the treatment of autoimmune diseases, the prevention and treatment of breast and colon tumors, osteoporosis, skin care and wound healing (WO 02/094276, WO02/094279, WO02/094278, WO02/094275, WO 03/04718 and WO 03/018026).
The chemical name of the estetrol is estra-1, 3,5 (10) -triene-3, 15 alpha, 16 alpha, 17 beta-tetraol, the structure is shown in formula 1, and the main characteristic structural parts are 15 alpha, 16 alpha, 17 beta-triol.
Early estetrol synthesis was achieved by asymmetric dihydroxylation of 15-tetraene-3, 17 beta-diol using 3, 17-diacetyl protected estra-1, 3,5 (10) by osmium tetroxide (J.org.chem. 1968,33,3133-3135; steroids,1976,27,111-121; steroids,1995,60, 277-284). The total yield of the preparation of the estetrol is 7-8%, the one-step yield of the asymmetric dihydroxylation reaction is 46-47%, the dihydroxylated product/isomer ratio is 74/26, namely, the 15 alpha, 16 alpha-/15 beta, and the 16 beta-ratio is 74/26, and unfortunately, the purity of the product estetrol is not reported. The reaction Scheme is shown in Scheme 1.
When acetyl is used as the protecting group for 3-phenolic hydroxyl, not only is the protecting group unstable in the reaction, but also the production of by-products is increased when a protic solvent such as methanol is used once the intermediate product is purified by crystallization.
In 2004, patent WO 2004/041839 synthesizes estetrol by using benzyl to protect 3-hydroxy and acetyl to protect 17-hydroxy, and using estrone as initial raw material, the total yield is 10.8%, the one-step reaction of carbonyl reduction adopts NaBH 4/CeCl3 system, and in the key asymmetric dihydroxyl reaction step, osmium tetroxide oxidant is also adopted, starting from compound K, dihydroxylation is carried out to obtain compound L, the crude product yield is 84%, after three times of recrystallization, the purity of compound L is 98.7%, the refining yield is 43%, and the purity of the final product estetrol is not reported, as shown in Scheme 2.
The same scheme is repeated in patent WO 2013/012328, osmium tetroxide is changed into PVP-osmium tetroxide, the data of double hydroxylation are matched, and after deprotection through catalytic hydrogenation (92% yield) and alkaline hydrolysis (92.5% yield), the purity of the obtained estetrol is 99.5%, and the total impurity content of the estetrol process reported in the patent is not more than 1%, but the content information of single impurity is not provided.
Patent WO 2013/01328 also reports a method for preparing estetrol by asymmetric dihydroxylation reaction with different protecting groups for protecting 3-hydroxy and 17-hydroxy, wherein the 3-hydroxy is protected as benzyl ether, benzoyloxy, alkyl ether, silyl ether and the like. Asymmetric dihydroxylation was performed using PVP-osmium tetroxide with 15 alpha, 16 alpha-/and 15 beta, 16 beta-ratios of 90/10, but no refining yield of asymmetric dihydroxylation was reported. As a control experiment, the patent reports that the 3-hydroxy is not protected and directly performs asymmetric dihydroxylation reaction, the yield is low (62%), the generated estetrol wraps impurities, the solid form is poor, and the purification is difficult.
Patent WO 2013/034780 in 2013 reports the definition of 3-phenolic hydroxyl protecting groups, as shown in formula 2, the definition of R ranges from benzoyl, acetyl, benzyl.
Patent CN 103890001 in 2014 (associated patent number WO 2013050553) also reports the definition of a 3-phenolic hydroxyl protecting group, wherein P 1 is reported to be a protecting group selected from R 1 CO-, R 1 is a group selected from C1-C6 alkyl or C3-C6 cycloalkyl, as shown in formula 3.
3-Hydroxy-17β -hydroxyestra-1, 3,5 (10), 15-tetraenes as starting materials can be synthesized by the literature [ J.org.chem.1968,33,3133-3135; steroids,1976,27,111-121; steroids,1995,60,277-284 ].
In all the above patents which report asymmetric dihydroxylation, the 3-phenolic hydroxyl group is mainly protected by ester group or ether bond, and the main problem is that after dihydroxylation, purification is difficult due to the existence of isomers and impurities, and repeated refining is needed to obtain a dihydroxylation product with high purity, so that the yield is low.
For how to purify dihydroxylated products efficiently, 2022 patent CN 114514237 and patent CN 114302889 (related patent WO 2021044302) report that three hydroxyl groups at the 15,16, 17-position are first formed into ester derivatives, which are then purified and isolated as shown in Scheme 3. After the compound III is prepared, the compound III is recrystallized by methanol, the refining yield is 69.8%, and the compound III with the purity of 99.2% can be obtained, but the material loss is larger. After purification, the purity of the final estetrol can reach 99.67 percent of purity, the isomer is less than 0.04 percent, and all impurities are less than 0.10 percent through two steps of hydrogenation debenzylation and hydrolysis, but the route of the derivatization method is longer, the refining yield is low, and the loss is larger.
In conclusion, how to directly purify after asymmetric dihydroxylation can obtain a high-purity asymmetric dihydroxylation product without derivatization or repeated refining, ensures that the purity of the hydrolyzed estetrol is more than or equal to 99.5 percent, ensures that single impurity is less than 0.04 percent and the total impurity is less than 0.1 percent, and is a very challenging work.
Disclosure of Invention
The invention aims to provide a method for preparing high-purity estetrol. According to the invention, through optimized screening of 3-hydroxyl protecting functional groups, the 3-phenolic hydroxyl is protected by utilizing alkoxy substituted benzoyl, the proportion of dihydroxylation can be improved (from 93:7 to 95:5), more importantly, the physical properties (melting point, solubility, solid crystal form and the like) of products after dihydroxylation are changed, the dominant product structure (15 alpha, 16 alpha, 17 beta-) is easier to separate from impurities and isomers (15 beta, 16 beta, 17 beta-) effectively, and the dihydroxylation products with purity (more than or equal to 98.5%) can be obtained through one-time refining of a simple solvent, and then the preparation of high-purity estetrol (more than or equal to 99.5%) can be realized through post-hydrolysis deprotection.
The invention takes 3-hydroxy-17 beta-hydroxyestra-1, 3,5 (10), 15-tetraene as raw materials, and uses alkoxy substituted benzoyl to protect 3-phenolic hydroxyl, so that the subsequent dihydroxylation yield, stereoselectivity and purification of the product are effectively solved. The benzoyl containing the alkoxy provides larger steric hindrance, so that the dihydroxylation has higher stereoselectivity, and the solubility of the product after the dihydroxylation is increased, thereby having larger advantages for the subsequent purification treatment of materials. Compared with benzoyl or ether protecting groups introduced without substituent reported in the prior art, the method has the advantages of better separation and purification effects and higher dihydroxylation proportion, avoids complicated post-treatment and yield reduction, and improves the preparation yield of high-purity estetrol.
In the preparation method, 3-hydroxy-17 beta-hydroxyestra-1, 3,5 (10), 15-tetraene is used as a raw material, and the estetrol is prepared through three steps of phenolic hydroxyl protection, dihydroxylation and hydrolysis.
The reaction process of the preparation method is shown as a reaction formula (I):
wherein R is alkoxy, and the position of R is ortho, meta or para to the aromatic ring.
Wherein the R group is located at one or more of ortho, meta or para positions of the benzene ring, preferably para.
Wherein the R group on the benzene ring is an alkoxy group containing C1-C6 alkane, and is one or more of methoxy, ethoxy, isopropoxy, tert-butoxy and the like, and preferably methoxy.
The method comprises the following steps:
Step one, 3-phenolic hydroxyl protection, namely, in a first solvent, carrying out hydroxyl protection reaction on a compound of a formula (1) and an aryl reagent for protecting hydroxyl in the presence of alkali to obtain a compound of a formula (2), wherein the reaction process is shown as a reaction formula (A):
Dissolving the compound of the formula (2) obtained in the step one in a second solvent, and performing temperature control reaction in the presence of a catalyst and an oxidant to obtain a compound of the formula (3), wherein the reaction process is shown as a reaction formula (B):
Step three, hydrolysis reaction, namely dissolving the compound of the formula (3) obtained in the step two in a third solvent, and deprotecting under the condition of alkali to obtain a target product estetrol, wherein the reaction process is shown as a reaction formula (C):
In the first step of the invention, the 3-phenolic hydroxyl protection reaction is specifically that the compound of the formula (1) reacts with an aryl reagent for protecting hydroxyl in the first solvent under the action of alkali to obtain the compound of the formula (2).
Wherein the aryl reagent for protecting the hydroxyl is one or more selected from p-methoxybenzoyl chloride, o-methoxybenzoyl chloride, p-ethoxybenzoyl chloride, p-isopropoxybenzoyl chloride, p-tert-butoxybenzoyl chloride and the like, and preferably p-methoxybenzoyl chloride.
Wherein the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, DMAP and the like, and preferably is pyridine.
Wherein the first solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, DMF, toluene, tetrahydrofuran, 2-methyltetrahydrofuran and the like, and is preferably dichloromethane.
Wherein the molar ratio of the compound of formula (1), the aryl reagent for protecting the hydroxyl and the alkali is 1 (1-4): 0.05-5, and preferably 1:1.1:1.1.
Wherein the temperature of the reaction is 0-50 ℃, preferably 25 ℃.
Wherein the reaction time is 2-24 h, preferably 3h.
In the second step, the second solvent is one or more selected from dichloromethane, chloroform, acetone, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran and the like, and preferably is acetone.
In the second step, the oxidant is selected from one or more of N-methylmorpholine oxide (NMO), trimethylamine N-oxide and the like, and is preferably N-methylmorpholine oxide (NMO).
In the second step, the catalyst is selected from one or more of osmium tetroxide, potassium osmium oxide and the like, and preferably potassium osmium oxide.
In the second step, the mass ratio of the compound of the formula (3), the oxidant and the catalyst is 1 (1-2) (0.001-0.01), and preferably 1:1.2:0.005.
In the second step, the temperature of the oxidation reaction is 0-50 ℃, preferably 50 ℃.
In the second step, the time of the oxidation reaction is 6-12h, preferably 6h.
In the third step, the hydrolysis reaction is specifically that the compound of the formula (2) undergoes hydrolysis reaction in the third solvent under the action of alkali to obtain estetrol.
Wherein the alkali is selected from one or more of LiOH, KOH, naOH, t-BuOK, K 2CO3 and the like, and is preferably NaOH.
Wherein the molar ratio of the compound of formula (3) to the alkali is 1 (0.5-2), and preferably 1:2.
Wherein the third solvent is selected from one or two of water, methanol, ethanol and the like, and preferably methanol.
The temperature of the hydrolysis reaction is 10-75 ℃, preferably 65 ℃.
The hydrolysis reaction time is 0.5-12 h, preferably 6h.
In the invention, the 3-position phenolic hydroxyl group is protected by the benzoyl containing alkoxy, the steric hindrance is large, the physical property of the product after double hydroxylation is changed, the product has good fat solubility, the double hydroxylation product with high purity (the purity is more than or equal to 98.5%) can be obtained through one-step refining, and then the high-purity estetrol (the purity is more than or equal to 99.5%) is efficiently prepared through hydrolysis deprotection. In the reaction process, no matter the reaction conditions of 3 alpha-hydroxyl protection, dihydroxylation and hydrolysis reaction are safe and mild, a system of strong alkali or strong acid is not involved, the configuration of 15 alpha, 16 alpha-hydroxyl and 17 beta-hydroxyl is not influenced, the specific three-dimensional configuration is maintained, and the separation and high efficiency advantages are realized.
The preparation method has the advantages that 3-hydroxy-17 beta-hydroxyestra-1, 3,5 (10), 15-tetraene is used as a raw material, 3-hydroxy is protected by benzoyl containing alkoxy, dihydroxyl reaction is carried out by catalytic oxidation of potassium osmium, and double alpha hydroxy is introduced at 15, 16-positions, chemical reagents and catalysts with higher cost are not needed in the preparation method, and the dihydroxylation reaction has the characteristics of high stereoselectivity, easiness in purification and separation, mild reaction conditions and simplicity and convenience in operation, and can realize the efficient preparation of high-purity estetrol.
Drawings
FIG. 1 is an HPLC chart of high purity estetrol in example 12 of the present invention.
FIG. 2 is a 1 HNMR spectrum of high purity estetrol in example 12 of the present invention.
Detailed Description
The invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for the following specific references, and the present invention is not particularly limited. (the results obtained under the optimized experimental conditions are shown in the examples, and the method has potential application value).
Example 1 (protection of Parmethoxybenzoyl)
In a 1L dry three-port bottle, 54.0g (0.2 mol) of the compound shown in the formula (1), 540ml of dichloromethane and 17.5g (0.22 mol) of pyridine are added, stirring and temperature adjustment are carried out to 25 ℃, 37.4g (0.22 mol) of p-methoxybenzoyl chloride is dropwise added at 25 ℃ to control the internal temperature of a reaction system to be not higher than 25 ℃, the mixture is stirred for 3 hours at 25 ℃, 100ml of 1mol/L sodium carbonate solution is added after the reaction is finished, the mixture is stirred for 30 minutes, then standing and water phase separation are carried out, 100ml of water is used for an organic phase, the mixture is stirred for 15 minutes and then is kept standing and water phase separation, anhydrous sodium sulfide of the organic phase is dried for 2 hours, filtered and concentrated to obtain 80.0g of the compound shown in the formula (2), the purity is 99.5%, and the molar yield is 99.0 percent.
Example 2 (protection of Parmethoxybenzoyl)
80.0G (0.198 mol) of the compound of formula (2), 400ml of acetone and 32g (0.236 mol) of NMO monohydrate are added into a 1L three-port bottle, the mixture is stirred uniformly, 362mg (1 mmol) of potassium osmium carbonate dihydrate is added, the mixture is stirred for 6 hours at 50 ℃, after the reaction is finished, 300ml of NaHSO 3 (15%) is added dropwise at an internal temperature of 10 ℃, the internal temperature is controlled to be 25 ℃ when the dropwise, the mixture is stirred for 1 hour after the dropwise is finished, 400ml of dichloromethane is added and stirred again for 0.5 hour, the mixture is stood for layering, the water phase is separated, the organic phase is washed with 300ml of water, the mixture is stood for layering, after the organic phase is concentrated, 300ml of methanol is added, the mixture is stirred for 2 hours at 25 ℃, the mixture is filtered, and a filter cake is dried, so that 63.5g of the compound of formula (3) is obtained. Purity 98.5% and molar yield 73.2%.
Example 3 (protection of p-methoxybenzoyl, THF as solvent)
80.0G (0.198 mol) of the compound of formula (2), 400ml of tetrahydrofuran and 32g (0.236 mol) of NMO monohydrate are added into a 1L three-port bottle, the mixture is stirred uniformly, 362mg (1 mmol) of potassium osmium sulfate dihydrate is added, the mixture is stirred for 6 hours at 50 ℃, after the reaction is finished, 300ml of NaHSO3 (15%) is added dropwise at 10 ℃ under the internal temperature, the internal temperature is controlled to 25 ℃ under the exothermic control when the dropwise adding is finished, the mixture is stirred for 1 hour after the dropwise adding is finished, 400ml of dichloromethane is added, the mixture is stirred again for 0.5 hour, the mixture is stood for layering, the water phase is separated, the organic phase is washed with 300ml of water, the mixture is stood for layering, after the organic phase is concentrated, 300ml of methanol is stirred for 2 hours at 25 ℃, the mixture is filtered, and a filter cake is dried, so that 62.4g of the compound of formula (3) is obtained. Purity 98.3% and molar yield 71.9%.
Example 4 (protection of p-methoxybenzoyl, trimethylamine N-oxide as oxidant)
80.0G (0.198 mol) of the compound of formula (2), 400ml of acetone and 17.7g (0.236 mol) of trimethylamine N-oxide are added into a 1L three-port bottle, the mixture is stirred uniformly, 362mg (1 mmol) of potassium osmium sulfate dihydrate is added, the mixture is stirred for 6 hours at 50 ℃, after the reaction is finished, the mixture is cooled to 10 ℃ and 300ml of NaHSO3 (15%) is added dropwise, the internal temperature is controlled to 25 ℃ when the dropwise adding is carried out, the mixture is stirred for 1 hour after the dropwise adding is finished, 400ml of dichloromethane is added and stirred again for 0.5 hour, the mixture is subjected to standing delamination, water phase is separated, the organic phase is washed with 300ml of water, the mixture is subjected to standing delamination, the organic phase is concentrated, 300ml of methanol is added, the mixture is stirred for 2 hours at 25 ℃, the filtration is carried out, and a filter cake is dried, so that 61.8g of the compound of formula (3) is obtained. Purity 98.1% and molar yield 71.2%.
Example 5 (protection of Parmethoxybenzoyl)
63.5G (0.145 mol) of the compound of formula (3), 600ml of methanol and 25 ℃ are added into a 1L three-port bottle and stirred uniformly, 11.6g (0.29 mol) of sodium hydroxide is added in batches, the mixture is stirred at 65 ℃ under reflux for 6 hours, after the reaction is finished, the pH is neutralized to be neutral by acetic acid, most of the methanol is removed by concentration, 300ml of purified water is added, the mixture is stirred at room temperature for 2 hours, filtered and washed by the purified water, and 33.1g of estetrol is obtained by drying filter cakes. The purity is more than or equal to 99.5 percent, and the molar yield is 75.0 percent.
Example 6 (protection of p-methoxybenzoyl, base lithium hydroxide)
63.5G (0.145 mol) of the compound of formula (3), 600ml of methanol and 25 ℃ are added into a 1L three-port bottle and stirred uniformly, 12.2g (0.29 mol) of lithium hydroxide-water is added in batches, reflux stirring is carried out for 6 hours at 65 ℃, after the reaction is finished, the pH is neutralized to be neutral by acetic acid, the mixture is concentrated to remove most of methanol, 300ml of purified water is added, stirring is carried out for 2 hours at room temperature, the filtered purified water is used for washing, and a filter cake is dried to obtain 32.9g of estetrol. The purity is more than or equal to 99.5 percent, and the molar yield is 74.5 percent.
Example 7 (O-methoxybenzoyl protection)
In a 1L dry three-port bottle, 54.0g (0.2 mol) of the compound shown in the formula (1), 540ml of dichloromethane and 17.5g (0.22 mol) of pyridine are added, stirring and temperature adjustment are carried out to 25 ℃, 37.4g (0.22 mol) of o-methoxy benzoyl chloride is dropwise added at 25 ℃ to control the internal temperature of a reaction system to be not higher than 25 ℃, the mixture is stirred for 3 hours at 25 ℃, 100ml of 1mol/L sodium carbonate solution is added after the reaction is finished, the mixture is stirred for 30 minutes, then standing and water phase is separated, 100ml of water is used for an organic phase, the mixture is stirred for 15 minutes and then is kept standing and water phase is separated, anhydrous sodium sulfur sulfide in the organic phase is dried for 2 hours, filtered and concentrated to obtain 78.4g of the compound shown in the formula (2), 150g of methanol is added, stirring is carried out for 2 hours at 10 ℃, pumping filtration is carried out, and drying is carried out to obtain the compound shown in the formula (2), and the purity is 99.2% and the molar yield is 97.0%.
Example 8 (O-methoxybenzoyl protection)
80.0G (0.198 mol) of the compound of formula (2), 400ml of acetone and 32g (0.236 mol) of NMO monohydrate are added into a 1L three-port bottle, the mixture is stirred uniformly, 362mg (1 mmol) of potassium osmium carbonate dihydrate is added, the mixture is stirred for 6 hours at 50 ℃, after the reaction is finished, 300ml of NaHSO 3 (15%) is added dropwise at an internal temperature of 10 ℃, the internal temperature is controlled to be 25 ℃ when the dropwise, the mixture is stirred for 1 hour after the dropwise is finished, 400ml of dichloromethane is added and stirred again for 0.5 hour, the mixture is stood for layering, the water phase is separated, the organic phase is washed with 300ml of water, the mixture is stood for layering, after the organic phase is concentrated, 300ml of methanol is added, the mixture is stirred for 2 hours at 25 ℃, the mixture is filtered, and a filter cake is dried, so that 62.9g of the compound of formula (3) is obtained. Purity 98.3% and molar yield 72.5%.
Example 9 (O-methoxybenzoyl protection)
63.5G (0.145 mol) of the compound of formula (3), 600ml of methanol and 25 ℃ are added into a 1L three-port bottle and stirred uniformly, 11.6g (0.29 mol) of sodium hydroxide is added in batches, the mixture is stirred at 65 ℃ under reflux for 6 hours, after the reaction is finished, the pH is neutralized to be neutral by acetic acid, most of the methanol is removed by concentration, 300ml of purified water is added, the mixture is stirred at room temperature for 2 hours, filtered and washed by the purified water, and a filter cake is dried to obtain 32.5g of estetrol. The purity is more than or equal to 99.4 percent, and the molar yield is 73.3 percent.
Example 10 (protection against Isopropoxybenzoyl)
In a 1L dry three-port bottle, 54.0g (0.2 mol) of the compound shown in the formula (1), 540ml of dichloromethane and 17.5g (0.22 mol) of pyridine are added, stirring and temperature adjustment are carried out to 25 ℃, 43.6g (0.22 mol) of p-isopropoxybenzoyl chloride is dropwise added at 25 ℃ and the temperature in a reaction system is controlled to be not higher than 25 ℃, the mixture is stirred for 3 hours at 25 ℃,100 ml of 1mol/L sodium carbonate solution is added after the completion of the reaction, the mixture is stirred for 30 minutes, then the mixture is left stand, the aqueous phase is separated, 100ml of water is used for the organic phase, the mixture is stirred for 15 minutes and then the aqueous phase is separated, the organic phase anhydrous sodium thiosulfide is dried for 2 hours, filtered and concentrated to obtain the dry dichloromethane, 150g of methanol is added, stirring is carried out for 2 hours at 10 ℃, and the suction filtration and drying is carried out to obtain 84.6g of the compound shown in the formula (2), wherein the purity is 99.2% and the molar yield is 98.0%.
Example 11 (protection against isopropoxybenzoyl)
85.5G (0.198 mol) of the compound of formula (2), 400ml of acetone and 32g (0.236 mol) of NMO monohydrate are added into a 1L three-port bottle, the mixture is stirred uniformly, 362mg (1 mmol) of potassium osmium carbonate dihydrate is added, the mixture is stirred for 6 hours at 50 ℃, after the reaction is finished, 300ml of NaHSO 3 (15%) is added dropwise at an internal temperature of 10 ℃, the internal temperature is controlled to be 25 ℃ when the dropwise, the mixture is stirred for 1 hour after the dropwise is finished, 400ml of dichloromethane is added and stirred again for 0.5 hour, the mixture is stood for layering, the water phase is separated, the organic phase is washed with 300ml of water, the mixture is stood for layering, after the organic phase is concentrated, 300ml of methanol is added, the mixture is stirred for 2 hours at 25 ℃, the mixture is filtered, and a filter cake is dried, so that 65.7g of the compound of formula (3) is obtained. Purity 98.7% and molar yield 71.2%.
Example 12 (protection against Isopropoxybenzoyl)
67.6G (0.145 mol) of the compound of formula (3), 600ml of methanol and 25 ℃ are added into a 1L three-port bottle and stirred uniformly, 11.6g (0.29 mol) of sodium hydroxide is added in batches, the mixture is stirred at 65 ℃ under reflux for 6 hours, after the reaction is finished, the pH is neutralized to be neutral by acetic acid, most of the methanol is removed by concentration, 300ml of purified water is added, the mixture is stirred at room temperature for 2 hours, filtered and washed by the purified water, and a filter cake is dried to obtain 32.6g of estetrol. The purity is more than or equal to 99.5 percent, and the molar yield is 74 percent.
1H NMR(400MHz,CD3OD)δ7.09(d,J＝8.0Hz,1H),6.50-6.57(m,2H),3.86-3.93(m,1H),3.44(d,J＝4.0Hz,2H),2.75-2.89(m,2H),2.17-2.34(m,3H),1.90-1.93(m,1H),1.18-1.65(m,5H),0.81(s,3H).
Example 13 (control experiment, benzoyl protection)
74.1G (0.198 mol) of the compound of formula (2), 400ml of acetone and 32g (0.236 mol) of NMO monohydrate are added into a 1L three-port bottle, the mixture is stirred uniformly, 362mg (1 mmol) of potassium osmium carbonate dihydrate is added, the mixture is stirred for 6 hours at 50 ℃, after the reaction is finished, 300ml of NaHSO3 (15%) is added dropwise at 10 ℃ and the internal temperature is controlled to 25 ℃ when the reaction is finished, the mixture is stirred for 1 hour after the dropwise addition, 400ml of dichloromethane is added and stirred again for 0.5 hour, the mixture is stood for layering, the water phase is separated, the organic phase is washed with 300ml of water, the mixture is stood for layering, 300ml of methanol is added after the organic phase is concentrated, the mixture is stirred for 2 hours at 25 ℃, the mixture is filtered, and a filter cake is dried to obtain 58.1g of the compound of formula (3).
Purity 96.7% and molar yield 72%.
59.2G (0.145 mol) of the compound of formula (3), 600ml of methanol and 25 ℃ are added into a 1L three-port bottle and stirred uniformly, 11.6g (0.29 mol) of sodium hydroxide is added in batches, the mixture is stirred at 65 ℃ under reflux for 6 hours, after the reaction is finished, the pH is neutralized to be neutral by acetic acid, most of the methanol is removed by concentration, 300ml of purified water is added, the mixture is stirred at room temperature for 2 hours, filtered and washed by the purified water, and a filter cake is dried to obtain 32.2g of estetrol. Purity 97.6%, molar yield 73%.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.
Claims (10)
1. A method for preparing high-purity estetrol, which is characterized in that the reaction process of the method is shown as a reaction formula (I):
The reaction formula (I),
Wherein R is alkoxy, and the position of R is ortho, meta or para to the aromatic ring;
The method comprises the following steps:
Step one, 3-phenolic hydroxyl protection, namely, in a first solvent, reacting a compound of a formula (1) with an aryl reagent for protecting hydroxyl in the presence of alkali to obtain a compound of a formula (2), wherein the reaction process is shown as a reaction formula (A):
the reaction type (A),
Dissolving the compound of the formula (2) obtained in the step one in a second solvent, and performing temperature control reaction in the presence of a catalyst and an oxidant to obtain a compound of the formula (3), wherein the reaction process is shown as a reaction formula (B):
Reaction (B),
Step three, hydrolysis reaction, namely dissolving the compound of the formula (3) obtained in the step two in a third solvent, and deprotecting under alkaline conditions to obtain a target product estetrol, wherein the reaction process is shown as a reaction formula (C):
Formula (C).
2. The method of claim 1, wherein the R groups on the benzene ring are located in one or more of the ortho, meta, or para positions of the benzene ring.
3. The method of claim 1, wherein the R group on the benzene ring is an alkoxy group having a chain length of C1-C6 selected from one or more of methoxy, ethoxy, isopropoxy, tert-butoxy.
4. A process according to claim 1, wherein in step one, the aryl reagent protecting the hydroxyl group is selected from one or more of p-methoxybenzoyl chloride, o-methoxybenzoyl chloride, p-ethoxybenzoyl chloride, p-isopropoxybenzoyl chloride, p-tert-butoxybenzoyl chloride, and/or the first solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, DMF, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and/or the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, DMAP.
5. The method according to claim 1, wherein in the first step, the molar ratio of the compound of formula (1), the hydroxy-protecting aryl reagent and the base is 1 (1-4): 0.05-5), and/or the reaction temperature is 0-50 ℃, and/or the reaction time is 2-24 hours.
6. The method according to claim 1, wherein in the second step, the second solvent is selected from one or more of dichloromethane, chloroform, acetone, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran, and 2-methyltetrahydrofuran, and/or the oxidizing agent is selected from one or two of N-methylmorpholine oxide NMO and trimethylamine N-oxide, and/or the catalyst is selected from one or two of osmium tetroxide and potassium osmium.
7. The method according to claim 1, wherein in the second step, the mass ratio of the compound of formula (2), the oxidizing agent and the catalyst is 1 (1-2) (0.001-0.01), and/or the temperature of the oxidation reaction is 0-50 ℃, and/or the time of the oxidation reaction is 6-12h.
8. The method according to claim 1, wherein in the third step, the hydrolysis reaction is specifically performed by hydrolyzing the compound of formula (3) in the third solvent under the action of a base to obtain estetrol.
9. The method of claim 8, wherein the base is one or more selected from LiOH, KOH, naOH, t-BuOK and K 2CO3, and/or the molar ratio of the compound of formula (3) to the base is 1 (0.5-2), and/or the third solvent is one or two selected from water, methanol and ethanol.
10. The method of claim 8, wherein the hydrolysis reaction is carried out at a temperature of 10 to 75 ℃ and/or the hydrolysis reaction is carried out for a time of 0.5 to 12 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311137408.9A CN119569803A (en) | 2023-09-05 | 2023-09-05 | Method for preparing high-purity estetrol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311137408.9A CN119569803A (en) | 2023-09-05 | 2023-09-05 | Method for preparing high-purity estetrol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN119569803A true CN119569803A (en) | 2025-03-07 |
Family
ID=94811362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311137408.9A Pending CN119569803A (en) | 2023-09-05 | 2023-09-05 | Method for preparing high-purity estetrol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN119569803A (en) |
-
2023
- 2023-09-05 CN CN202311137408.9A patent/CN119569803A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2012264601B2 (en) | Process for the production of estetrol intermediates | |
| RU2624007C2 (en) | Production method for ulipristal acetate and its intermediates | |
| JP7500102B2 (en) | Intermediate for synthesizing camptothecin derivatives, production method thereof and use thereof | |
| US20180265540A1 (en) | Synthesis of estetrol via estrone derived steroids | |
| CN110330500B (en) | Stereoselective synthesis method of 6 beta-hydroxy-7, 8-dihydro-morphine derivative | |
| JP2025502499A (en) | Method for synthesizing high-purity cholesterol | |
| CN113651866A (en) | Novel method for synthesizing cholesterol by taking 21-hydroxy-20-methyl pregn-4-ene-3-one as raw material | |
| AU775831B2 (en) | Process for preparing 17alpha-acetoxy-11beta-(4-N,N-(dimethylamino)phenyl)-21- methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates | |
| CN119569803A (en) | Method for preparing high-purity estetrol | |
| CN102993257A (en) | New fulvestrant preparation method | |
| CN112062669A (en) | Process for preparing aromatic compounds | |
| TWI334781B (en) | Stereospecific synthesis of sapogenins | |
| CN115215916B (en) | A method for preparing alfaxalone key intermediate | |
| CN117486960A (en) | Preparation method of cholesterol and intermediate thereof | |
| CN114644678B (en) | Glucuronide compound, preparation method and application thereof | |
| CN115286676B (en) | Synthesis method for preparing cholesterol methyl ether from diosgenin | |
| CN114644679B (en) | Glucuronide compound, preparation method and application thereof | |
| JPH023798B2 (en) | ||
| CN118598950B (en) | Fusarium (Fu) and its preparation method Process for the preparation of a vegetable | |
| CN114478672B (en) | Synthesis method of HE3286 | |
| CN119529013A (en) | Synthesis method of Zu Lanuo dragon intermediate | |
| CN102229635B (en) | Process for the preparation of estrone and/or estradiol-derivates | |
| CN118878609A (en) | A green synthesis method of dydrogesterone and its intermediates | |
| CN119462808A (en) | A preparation method of 1α-hydroxydihydroquinone | |
| CN118084740A (en) | Preparation method of acetoguanidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |