Synthesis process of estetrol

Abstract

The present invention provides an estetrol synthesis process, and relates to the technical field of steroid compound synthesis processes, and the method comprises the following steps: taking estrone as an initial raw material, firstly carrying out 3-site hydroxyl protection, and then carrying out an oxidative dehydrogenation reaction in the presence of a metal catalyst and in an oxygen atmosphere to prepare a key intermediate ketene, then 17-site carbonyl reduction, 17-site hydroxyl protection, 15, 16-site double bond dihydroxylation, 3-site protecting group removal and hydrolysis reaction are sequentially carried out, and finally the target product estetrol is obtained. The method adopts metal catalysis to directly oxidize to construct cycloenone, effectively avoids the problem of poor stability of partial intermediates in the prior art, has the advantages of simple process, short reaction steps, greenness, environmental protection and the like, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of synthetic process technology for active pharmaceutical ingredients, and specifically relates to a synthetic process for estradiol. Background Technology

[0002] Estetrol (chemical name: est-1,3,5(10)-triene-3,15α,16α,17β-tetraol) is a compound with weak estrogenic activity that is endogenously produced by the fetal liver during human pregnancy. It is effective in hormone replacement therapy (HRT), treatment of vaginal dryness, treatment of perimenopausal symptoms (such as hot flashes and night sweats), contraception, libido enhancement, treatment of skin and wound healing, treatment or prevention of autoimmune diseases, breast tumors, prostate cancer and colorectal cancer, and neuroprotection (such as neonatal encephalopathy).

[0003] The following are the currently reported synthetic routes for estradiol: 1. WO2004041839 (CN100343269C): This route uses estrone as a raw material and involves hydroxyl protection, ketalization, bromination, elimination, and hydrolysis to obtain a key intermediate. Then, the target product is obtained through carbonyl reduction, hydroxyl protection, osmium tetroxide dihydroxylation, debenzylation, and hydrolysis. This route is lengthy, has low yield, and is complex to operate.

[0004] 2. WO2004 / 041839A2: This route uses estradiol as a raw material and proceeds through a one-step reaction to the key intermediate 6. However, the operation described is difficult to reproduce, and it is difficult to obtain compound 6 solely through benzyl bromide.

[0005] 3. EP2383279 (CN103781795B): In 2012, Dornes Biosciences Inc. published "A Method for Preparing Estradiol," which also uses estrone as a raw material, but differs in the protection group of the carbonyl group.

[0006] 4. WO2015040051: This patent also uses estrone as a starting material, but the difference lies in the different protecting groups. Benzoyl is used instead of benzyl to protect the 3-position hydroxyl group, which facilitates its removal.

[0007] In summary, the existing technologies for synthesizing estradiol from estradiol using estradiol as a raw material usually require the preparation of the key intermediate 3-hydroxyestradiol-1,3,5(10),15-tetraen-17-one. These routes generally suffer from problems such as long reaction steps, low overall yield, and poor stability of some intermediates. Therefore, developing a simple, high-yield, green and energy-saving synthetic method has important application value. Summary of the Invention

[0008] To overcome the problems in the prior art, the present invention provides a new process for synthesizing estradiol, which overcomes the defects of long synthetic routes, low yields and unstable intermediates in the prior art.

[0009] To achieve the above objectives, the present invention is implemented through the following technical solution: A synthetic process for estradiol, using compound A (estradiol ketone) as a starting material, yields estradiol via the following reaction route: Includes the following steps: (1) Compound A reacts with a hydroxyl protecting agent under alkaline conditions to generate compound B; (2) Compound B is subjected to an aerobic dehydrogenation reaction in the presence of palladium catalyst and oxygen to generate compound C; (3) The 17-carbonyl group of compound C was selectively reduced in the presence of a reducing agent and cerium salt to obtain compound D; (4) The compound D was reacted with an acylation reagent to protect the hydroxyl group at position 17, yielding compound E; (5) Compound E was subjected to cis-dihydroxylation of the double bond at positions 15 and 16 under the action of an oxidizing agent and a co-oxidizing agent to obtain compound F; (6) The 3-position protecting group of the compound F was removed under a catalyst and hydrogen atmosphere to obtain compound G; (7) The ester group at position 17 of compound G was removed by hydrolysis in an alkaline solution, and the purified compound was estradiol.

[0010] Further, the solvent in step (1) is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, and tetrahydrofuran; the base is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and sodium methoxide; the hydroxyl protecting agent is selected from one of benzyl bromide, benzyl chloride, benzyltrichlorosilane, p-methoxybenzyl chloride, p-methoxybenzyl bromide, 2,4-dimethoxybenzyl chloride, and 2,4-dimethoxybenzyl bromide; the amount of the hydroxyl protecting agent is 1.1-2.0 times the molar amount of estradiol.

[0011] Further, in step (1), the hydroxyl protecting agent is benzyl bromide, the base is potassium carbonate, and the solvent is a mixture of dichloromethane and methanol in a volume ratio of 1:1.

[0012] Further, in step (2), the solvent is selected from methanol, ethanol, ethyl acetate, DMSO, and acetonitrile; the catalyst is selected from palladium hydroxide, palladium acetate, and palladium trifluoroacetate coordinated with DMSO; the amount of the catalyst is 0.01-0.1 wt% of the substrate weight; and the oxygen pressure range is 0.03-0.15 MPa.

[0013] Furthermore, the catalyst is palladium acetate, the solvent is ethyl acetate, and the reaction temperature is 80°C.

[0014] Furthermore, in step (3), the metal reducing agent is NaBH4 / CeCl3·7H2O, and the amount used is 1.0-1.5 times the molar amount of the substrate. The reaction solvent is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 4:1.

[0015] Further, in step (4), the acetylation reagent is acetic anhydride or acetyl chloride, preferably acetic anhydride; the amount of acylation reagent is 1.5-3.0 times the molar amount of the substrate; the base is an organic base selected from at least one of triethylamine, N,N-diisopropylethylamine and DBU; 4-dimethylaminopyridine is further added as a catalyst in the reaction, and the amount is 0.03 equivalents of the substrate.

[0016] Further, in step (5), the solvent is selected from acetone, tetrahydrofuran, and 2-methyltetrahydrofuran, with tetrahydrofuran being preferred as the solvent; the oxidant is selected from potassium permanganate, sodium periodate, osmium tetroxide, potassium osmium tetroxide, N-methylmorpholine, and the complex of iodine and cerium ammonium nitrate, and the amount used is 1.1-2.0 times the molar amount of the substrate; the amount of KOsO4·2H2O used is the catalytic amount, preferably 0.05 equivalents.

[0017] Further, in step (6), the hydrogenation catalyst is selected from at least one of palladium on carbon and palladium hydroxide; the reaction solvent is at least one of methanol, ethanol, ethyl acetate, dimethyl sulfoxide or acetonitrile; and the reaction hydrogen pressure is 0.1-1.0 MPa.

[0018] Further, the base mentioned in step (7) is at least one of alkali metal carbonate, alkali metal bicarbonate, alkali metal alkoxide or alkali metal hydroxide, and the amount used is 2.5-5.0 times the molar amount of the substrate; the reaction solvent is at least one of methanol, ethanol, tetrahydrofuran or acetonitrile.

[0019] The beneficial effects of this invention are: The technical solution provided by this invention uses a metal-catalyzed synthesis method for cycloenones, which successfully avoids the problem of intermediate instability. This process route is simple, has few steps, and has the advantages of being green and energy-saving. Detailed Implementation

[0020] To make the objectives, technical solutions, and beneficial effects of the present invention clearer, the preferred embodiments of the present invention will be described in detail below to facilitate understanding by those skilled in the art.

[0021] A process for synthesizing estradiol: Reaction 1: Estradiol ketone was dissolved in a solvent at room temperature. A base was added to the system and stirred for 30 min. A protecting group reagent was then slowly added dropwise. The mixture was heated to reflux and reacted for 16 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and filtered to remove the solid. The filtrate was concentrated under reduced pressure to 2-3°C. A displacement solvent was added to the system twice for solvent displacement. Concentration was stopped when the system reached 2-3°C. The mixture was cooled to 0-10°C, stirred for 30 min, and then filtered. The filter cake was washed with pre-cooled displacement solvent to obtain a white solid product B. Among them, estradiol (compound A) 1.0 eq; The solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, and tetrahydrofuran, preferably a 1:1 mixture of dichloromethane and methanol. The protecting group reagents selected are benzyl bromide, benzyl chloride, benzyltrichlorosilane, p-methoxybenzyl chloride, p-methoxybenzyl bromide, 2,4-dimethoxybenzyl chloride, and 2,4-dimethoxybenzyl bromide, with benzyl bromide being the preferred choice; The alkali selected is an inorganic alkali such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and sodium methoxide, with potassium carbonate being the preferred choice. The proportion of the protective base is 1.1-2.0 eq, preferably 1.2-1.5 eq.

[0022] The displacement solvent can be petroleum ether, n-heptane, methyl ether, or n-hexane, with n-heptane being the preferred choice.

[0023] Reaction 2 Intermediate B and solvent were added to a reaction vessel at room temperature and stirred for 0.5 h. The catalyst was then added and the mixture was purged with nitrogen three times. Oxygen was introduced into the reaction vessel, and the temperature was raised to 80 °C and maintained for 6 h. If the pressure was less than 0.08 MPa during the reaction, oxygen was added to bring the pressure up to 0.1 MPa. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with solvent. The resulting organic phase was concentrated to obtain the target product C. Among them, intermediate B 1.0eq The solvent is selected from methanol, ethanol, ethyl acetate, DMSO, and acetonitrile, with ethyl acetate being preferred; The catalyst is selected from palladium hydroxide, palladium acetate, and palladium trifluoroacetate coordinated with DMSO, with palladium acetate being preferred.

[0024] The catalyst dosage ratio is 0.01-0.1 wt, preferably 0.03-0.06 wt.

[0025] The oxygen pressure range is 0.03-0.15 MPa, preferably 0.1 MPa.

[0026] Reaction 3 Compound C was dissolved in a solvent and a metal reducing agent was added. Sodium borohydride was added in batches under ice bath conditions. After 1 hour, water was added to the reaction solution, and the mixture was distilled under reduced pressure. Water was added again, and the mixture was stirred under ice bath conditions for 1 hour. The product D was then obtained by filtration. Among them, intermediate C is 1.0 eq; The solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, and tetrahydrofuran, preferably a methanol / tetrahydrofuran mixed solvent of 4 / 1; The metal reducing agent is selected from LiAlH4, AlH3, NaBH4, NaBH(OAc)3, ZnBH4 and NaBH4 / CeCl3, with NaBH4 / CeCl3·7H2O being preferred; The catalyst dosage ratio is 1.0-1.5 eq, preferably 1.2 eq.

[0027] Reaction 4 Compound D was dissolved in a solvent and added to a reaction flask. A base was added, followed by an acetylation reagent, and finally DMAP was added. The mixture was stirred at room temperature for 2 hours. Most of the solvent was removed by vacuum distillation. Water was added and the mixture was stirred for 3 hours. The mixture was filtered and dried to obtain product E.

[0028] Among them, intermediate D is 1.0 eq; The solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, and tetrahydrofuran, with dichloromethane being preferred.

[0029] The base is selected from organic bases such as triethylamine, DIEA, and DBU, with triethylamine being preferred. The acetylation agent is selected from acetic anhydride or acetyl chloride, preferably acetic anhydride to protect the 17-hydroxyl group; The amount of acetylation reagent used is 1.5-3.0 eq, preferably 2.0 eq.

[0030] Reaction 5 Compound E was dissolved in a solvent and added to a reaction flask. An oxidant was added, and the reaction progress was monitored by TLC. After stirring overnight at room temperature, the reaction was completed. A saturated sodium thiosulfate solution was added, and the mixture was stirred for 30 min. A solvent was added, and the mixture was washed three times with an equal volume of saturated sodium thiosulfate solution. The organic phase was distilled off under reduced pressure to remove the solvent, filtered, and the crude product was dried. Methanol was added and the mixture was stirred for 5 h. The mixture was filtered, dried, and ethyl acetate and petroleum ether were added and stirred overnight to obtain product F. Among them, intermediate E 1.0eq The solvent is selected from acetone, tetrahydrofuran, and 2-methyltetrahydrofuran, with tetrahydrofuran being preferred. The oxidizing agents are selected from potassium permanganate, sodium periodate, osmium tetroxide, potassium osmium tetroxide and N-methylmorpholine, and iodine and cerium ammonium nitrate complex, with potassium osmium tetroxide and N-methylmorpholine being preferred; The amount of oxidant used is 1.1-2.0 eq, preferably 1.3 eq; The amount of KOsO4·2H2O used is the catalytic amount, preferably 0.05 eq.

[0031] Reaction 6 Compound F was dissolved in a solvent and a catalyst was added. After purging with nitrogen three times, hydrogen was introduced. The mixture was stirred at room temperature for 24 hours and then controlled. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain product G.

[0032] Among them, intermediate F is 1.0 eq; The solvent is selected from methanol, ethanol, ethyl acetate, DMSO, and acetonitrile, with methanol being preferred; The catalyst is selected from palladium on carbon and palladium hydroxide, preferably 10% palladium on carbon; Pressure range 0.1-1.0MPa, preferably 0.5MPa.

[0033] Reaction 7 Compound G was added to the solvent in a reaction flask, alkali was added, the reaction was monitored by TLC, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by vacuum distillation, water was added, the mixture was stirred for 30 minutes, filtered, and the filtrate was collected. The pH was adjusted to 7-8 with glacial acetic acid, and a white solid was formed. The solid was filtered (if little or no precipitate was formed, the filtrate could be concentrated), and dried to obtain the product estradiol.

[0034] Among them, intermediate G1.0eq; The solvent is selected from methanol, ethanol, tetrahydrofuran, and acetonitrile, with methanol being preferred; Alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, or alkali metal hydroxides are preferred, with potassium carbonate being the preferred choice. The amount of alkali used is 2.5-5.0 eq, preferably 4.0 eq.

[0035] Example 1 At room temperature, 100 g (0.37 mol) of estrone was dissolved in a mixed solvent of dichloromethane (500 ml) and methanol (500 ml). Potassium carbonate (76.7 g, 0.55 mol) was added to the system and stirred for 30 min. Then, benzyl bromide (94.07 g, 0.55 mol) was slowly added dropwise. The mixture was heated to reflux and reacted for 16 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature and filtered to remove the solid potassium carbonate. The filtrate was concentrated under reduced pressure to 2-3 V. The system was then replaced twice with n-heptane (500 ml, 5 V). Concentration was stopped when the system reached 2-3 V. The mixture was cooled to 0-10 °C, stirred for 30 min, and then filtered. The filter cake was washed with pre-cooled n-heptane to obtain a white solid product. After drying in an oven at 40-50 °C, 130 g of product B (white solid) was obtained, with a yield of 97.5% and a purity of 98.3%.

[0036] Example 2 Intermediate B (100g) and ethyl acetate (500ml) were added to a reaction vessel at room temperature and stirred for 0.5h. Palladium acetate (5g) was then added, and the mixture was purged with nitrogen three times. Oxygen was introduced into the reaction vessel to 0.1MPa, and the temperature was raised to 80℃ and maintained for 6h. If the pressure was less than 0.08MPa during the reaction, oxygen was added to 0.1MPa. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The obtained organic phase was concentrated to obtain 93g of the target product C solid, with a yield of 93.5% and a purity of 97.6%.

[0037] Example 3 Compound C (100g) was dissolved in a mixture of methanol and tetrahydrofuran (methanol / tetrahydrofuran = 4 / 1), and CeCl3·7H2O (124g) was added. Sodium borohydride (13.7g) was added in portions under ice bath conditions. After 1 hour, 300mL of water was added to the reaction solution, and the solution was distilled under reduced pressure to 300mL. Then, 1000mL of water was added, and the mixture was stirred under ice bath conditions for 1 hour. The product D solid was filtered to obtain 99g of product D, with a yield of 98.4% and a purity of 96.6%.

[0038] Example 4 Compound D (100 g) was dissolved in 1500 mL of dichloromethane and added to a reaction flask. Triethylamine (112 g, 3 eq) was added, followed by acetic anhydride (54 g, 2 eq), and finally DMAP (0.03 eq). The mixture was stirred at room temperature for 2 h, and most of the dichloromethane was removed by vacuum distillation. 5 mL of water was added and the mixture was stirred for 3 h. The mixture was filtered and dried to obtain 102 g of solid product E, with a yield of 91.3% and a purity of 97.7%.

[0039] Example 5 Compound E (100 g) was dissolved in 1000 mL of tetrahydrofuran and added to a reaction flask. NMO (37 g, 1.3 eq) was added, and KOsO4·2H2O (0.05 eq) was added under stirring. The reaction progress was monitored by TLC. After stirring at room temperature overnight, the reaction was completed. 200 mL of saturated sodium thiosulfate solution was added, and the mixture was stirred for 30 min. 300 mL of tetrahydrofuran was added, and the mixture was washed three times with an equal volume of saturated sodium thiosulfate solution. The tetrahydrofuran was removed by vacuum distillation of the organic phase, and the mixture was filtered. The crude product was dried, and 100 mL of methanol was added and stirred for 5 h. The mixture was filtered, dried, and 1000 mL of ethyl acetate and 1000 mL of petroleum ether were added and stirred overnight to obtain 68 g of product F solid, with a yield of 62.7% and a purity of 98.4%.

[0040] Example 6 Compound F (100g) was dissolved in 1000ml of methanol and 10g of palladium on carbon (10%) was added. After purging with nitrogen three times, hydrogen was introduced to 0.5Mpa and stirred at room temperature for 24h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain 77g of product G solid, with a yield of 97% and a purity of 98.2%.

[0041] Example 7 Compound G (100g) was added to 1000mL of methanol and then added to a reaction flask. K2CO3 (117g, 4eq) was added, and the reaction was monitored by TLC. The mixture was stirred at room temperature for 2h. After the reaction was completed, half of the methanol was removed by vacuum distillation. 800mL of water was added, and the mixture was stirred for 30min. The mixture was filtered, and the filtrate was collected. The pH was adjusted to 7-8 with glacial acetic acid, and a white solid was formed. The solid was filtered, dried, and 79g of estradiol was obtained, with a yield of 89.9% and a purity of 99%.

[0042] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. A process for synthesizing estradiol, characterized in that, Using compound A, estradiol, as a starting material, estradiol was obtained via the following reaction route: ; Includes the following steps: Compound A reacts with a hydroxyl protecting agent under alkaline conditions to generate compound B; Compound B was subjected to an aerobic dehydrogenation reaction in the presence of a palladium catalyst and oxygen to produce compound C. The 17-carbonyl group of compound C was selectively reduced in the presence of a reducing agent and a cerium salt to obtain compound D; The compound D was reacted with an acylation reagent to protect the hydroxyl group at position 17, yielding compound E; Compound E was subjected to cis-dihydroxylation of the double bond at positions 15 and 16 under the action of an oxidizing agent and a co-oxidizing agent to obtain compound F; Compound F was deprotected at the 3-position under a catalyst and hydrogen atmosphere to obtain compound G; The ester group at position 17 of compound G was removed by hydrolysis in an alkaline solution, and the purified compound yielded estradiol.

2. The synthesis process of estradiol according to claim 1, characterized in that: In step (1), the hydroxyl protecting agent is benzyl bromide, and the amount used is 1.2-1.5 times the molar amount of estradiol; the base is potassium carbonate; and the solvent is a mixture of dichloromethane and methanol in a volume ratio of 1:

1.

3. The synthesis process of estradiol according to claim 1, characterized in that: In step (2), the solvent is ethyl acetate; the catalyst is palladium acetate, and the amount used is 0.03-0.06 wt% of the substrate; the oxygen pressure is 0.03-0.15 MPa, and the reaction temperature is 80℃.

4. The synthesis process of estradiol according to claim 1, characterized in that: In step (3), the metal reducing agent is NaBH4 / CeCl3·7H2O, and the amount used is 1.0-1.5 times the molar amount of the substrate. The reaction solvent is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 4:

1.

5. The synthesis process of estradiol according to claim 1, characterized in that: In step (4), the acetylation reagent is acetic anhydride, and the amount used is twice the molar amount of the substrate; the base is triethylamine, an organic base; 4-dimethylaminopyridine is further added as a catalyst in the reaction, and the amount used is 0.03 equivalents of the substrate.

6. The synthesis process of estradiol according to claim 1, characterized in that: In step (5), the solvent is tetrahydrofuran; the oxidant is potassium osmate and N-methylmorpholine, and the amount used is 1.3 times the molar amount of the substrate; the amount of KOsO4·2H2O used is the catalytic amount, preferably 0.05 equivalents.

7. The synthesis process of estradiol according to claim 1, characterized in that: In step (6), the hydrogenation catalyst is 10wt% palladium on carbon, the reaction solvent is methanol, and the reaction hydrogen pressure is 0.5MPa.

8. The synthesis process of estradiol according to claim 1, characterized in that: The base mentioned in step (7) is potassium carbonate, and the amount used is 4 times the molar amount of the substrate; the reaction solvent is methanol.

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