A method for the synthesis of norgestimate

Abstract

The application belongs to the field of medicine preparation and relates to a synthesis method of norgestimate. The synthesis method of norgestimate takes estr-4,9-diene-3,17-dione as a starting material, and norgestimate is prepared through eight steps of ketal protection, epoxidation, copper-catalyzed selective addition of methyl Grignard reagent, catalytic hydrogenation, acid deprotection and dehydration, trimethylsilyl cyanide addition, methyl Grignard reagent addition / acid hydrolysis and acetylation. The method replaces traditional primary Grignard reduction with catalytic hydrogenation and replaces toxic inorganic cyanide with trimethylsilyl cyanide, and has the advantages of mild reaction conditions, high operation safety, easy purification of intermediates, good yield and product purity and suitability for industrial production.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparation and relates to a method for synthesizing phenoxylate. Background Technology

[0002] Norgestomet is a synthetic progestin derivative. Acetylation of the 17α-hydroxyl group in its structure enhances its oral activity. This drug allows for artificial intervention in the reproductive health of mammals. It synchronizes ovulation in female mammals, increases pregnancy rates, and shortens calving time. Currently, large-scale industrial production is not feasible. Although literature and patents report different synthetic routes, these remain at the laboratory research stage and cannot be scaled up for mass production. Therefore, there is an urgent need to develop a process suitable for industrial production, which would solve the problem of drug sourcing and create considerable economic value.

[0003] The literature reports roughly four synthetic methods for phenoxymethyl, or simple adjustments or reagent optimizations based on these routes.

[0004] like Figure 1 As shown, Route 1: Patent US3527778 reports a 17-step reaction using 11-methylen-5a-androstan-3,17-dione as a starting material. This route is too long and has a low yield, making it suitable only for route research.

[0005] like Figure 2 As shown, Route 2: Patent No. US3381003 discloses a route using 1,3,5-trienasteride as raw material, but similar to Route 1, the route is also cumbersome and not easy to scale up for production.

[0006] like Figure 3 As shown, Route 3: Bioorganic & Medicinal Chemistry 49(2021)116425 cites the synthetic method disclosed in patent publication number WO2015 / 075693A1, which uses 3-ketal as raw material. Its disadvantages are that it uses inorganic cyanide, Burch reduction uses liquid ammonia and lithium, and the overall yield is 3.4%.

[0007] like Figure 4 As shown, Route 4: Patent CN201910049848.6 discloses a method for synthesizing nystatin, but the product purity is only 90%. Its disadvantages are that the raw materials are not commercially available and are not easy to prepare, which limits the practical application value of this route; in addition, it also uses liquid ammonia and lithium metal for reduction, which is risky; if industrial production is to be carried out, high safety and environmental protection requirements are required.

[0008] However, the existing synthesis methods described above have the following drawbacks: The routes are all very long, with low yields, and there are problems such as difficulty in controlling isomer impurities; or the starting materials themselves are difficult to obtain or require multiple reaction steps to obtain; or the reaction conditions are harsh, high-risk reagents are used, and the operation is not safe. Summary of the Invention

[0009] The purpose of this application is to overcome the shortcomings of the prior art and provide a method for synthesizing nystatin, the technical solution of which is as follows: The method for synthesizing von nifedipine provided in this application includes the following steps: S1: Using estradiol-4,9-diene-3,17-dione (4,9-dione) as the starting material, the carbonyl group of the starting material is ketalized with an alcohol in an organic solvent in the presence of an acid catalyst to obtain compound one; S2: Compound 1 is subjected to an epoxidation reaction in an oxidation system to obtain compound 2; S3: In the presence of a copper salt catalyst, compound II is selectively added to magnesium methyl halide to obtain compound III; S4: Compound III was subjected to catalytic hydrogenation in a hydrogen atmosphere to reduce the double bonds in the molecule, yielding compound IV; S5: Compound four is subjected to a deketalizing and dehydrating reaction in an acid and an organic solvent to obtain compound five; S6: Compound five is reacted with trimethylsilyl cyanide (TMSCN) in the presence of a catalyst to give compound six; S7: Compound VI is subjected to an addition reaction with a methyl Grignard reagent, followed by acid hydrolysis to obtain compound VII; S8: In the presence of an acid-binding agent, the compound VII is subjected to an acetylation reaction with an acetylation reagent to obtain von gestrin.

[0010] The structural formula of compound one is: The structural formula of compound two is: ; The structural formula of compound three is: The structural formula of compound four is: ; The structural formula of compound five is: The structural formula of compound six is: ; The structural formula of compound seven is: .

[0011] 2. The synthesis method according to claim 1, characterized in that, in step S1, the reaction is carried out by reflux and water separation in an organic solvent, benzene or toluene; Wherein, the alcohol is selected from monohydric alcohols or dihydric alcohols; the monohydric alcohol is at least one of methanol and ethanol, and the dihydric alcohol is at least one of ethylene glycol and 2,2-dimethyl-1,3-propanediol; The acid catalyst is p-toluenesulfonic acid (PTSA) or p-toluenesulfonic acid pyridinium salt (PPTSA). In some embodiments, in step S1, the reaction is carried out under reflux in the organic solvent toluene for water separation; wherein the alcohol is selected from diols; the acid catalyst is pyridinium p-toluenesulfonate (PPTSA); the molar ratio of estradiol-4,9-diene-3,17-dione to the diol is 1:(2.2–5.0); the amount of acid catalyst used is 1%–10% of the molar amount of estradiol-4,9-diene-3,17-dione; and the reaction time is 5–18 hours. In step S1, the mass ratio of estradiol-4,9-diene-3,17-dione to the organic solvent is 1:(5–20).

[0012] In some embodiments, in step S2, dichloromethane is used as a solvent in an oxidation system to selectively oxidize the conjugated double bonds of compound one to generate an epoxy compound, thus obtaining compound two; the oxidation system is a perhaloacetone, hydrogen peroxide, and pyridine system; or the oxidation system is a perhaloacetone, hydrogen peroxide, and phosphate buffer system; wherein, the perhaloacetone is hexachloroacetone or hexafluoroacetone; the reaction temperature is controlled between -10°C and 25°C; the molar ratio of hydrogen peroxide to compound one is approximately (3-12):1, the molar ratio of hexachloroacetone to compound one is (0.1-0.8):1, and the molar ratio of pyridine to compound one is (0.1-0.8):1.

[0013] In some embodiments, in S2, the volume of dichloromethane is 5 to 10 times the mass of compound one.

[0014] In some embodiments, in step S3, the copper salt catalyst is cuprous chloride or cuprous iodide, and its molar amount is 0.05 to 0.3 times the number of moles of compound 2; the methyl magnesium halide is methyl magnesium chloride or methyl magnesium bromide; the solvent used is an aprotic solvent; and the reaction temperature is controlled between -20°C and 30°C.

[0015] In some embodiments, in step S3, the aprotic solvent is tetrahydrofuran, methyl tert-butyl ether, diethyl ether, or crown ether. The solvent is 5 to 10 times w / v of compound two.

[0016] In some embodiments, in step S4, in the presence of a palladium-on-carbon or platinum-on-carbon catalyst and an organic base, compound three is subjected to a catalytic hydrogenation reaction in a hydrogen atmosphere to reduce the double bonds in the molecule, yielding compound four; wherein the organic base is selected from at least one of triethylamine, diisopropylethylamine, and pyridine, and its amount is 2% to 10% of the molar amount of compound three; the amount of palladium-on-carbon or platinum-on-carbon is 2% to 10% of the weight of compound three; the solvent for the catalytic hydrogenation reaction is selected from at least one of ethyl acetate, methanol, ethanol, and tetrahydrofuran, the reaction pressure is 0.1 MPa to 1 MPa, and the reaction temperature is 10°C to 50°C.

[0017] In some embodiments, in step S5, the acid is at least one of hydrochloric acid, sulfuric acid, and trifluoroacetic acid; the concentration of the acid in the reaction system is 0.3% to 3%; the reaction is carried out in a mixture of one or more organic solvents, such as methanol, ethanol, or isopropanol, and water, and the reaction temperature is from room temperature to reflux temperature.

[0018] In some embodiments, in step S6, the catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium carbonate, and its amount is 1% to 5% of the five moles of the compound; the reaction solvent is dichloromethane, tetrahydrofuran, methyl tert-butyl ether or acetonitrile; and the reaction temperature is 25°C to 70°C.

[0019] In some embodiments, in step S7, without the protection of the six-hydroxyl group of the compound, a methyl Grignard reagent is added to the cyano group of the compound six to generate a hydroxyl group at position 17, followed by acid hydrolysis to obtain compound seven; wherein the methyl Grignard reagent is methyl magnesium chloride or methyl magnesium bromide, and its amount is 1.5 to 5 times the molar amount of compound six; the acid used in the acid hydrolysis is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or trifluoroacetic acid, and the mass concentration of the acid in the reaction solution is 5% to 20%; the solvent is toluene, and its amount is 4 to 20 times the weight of compound six.

[0020] In some embodiments, in step S8, in the presence of an acid-binding agent, compound seven is subjected to an acetylation reaction with an acetylation reagent to acetylate the hydroxyl group at position 17 of compound seven, thereby obtaining novogestrol; wherein the acetylation reagent is acetyl chloride or acetic anhydride, and its amount is 1.2 to 3 times the molar amount of compound seven; the acid-binding agent is selected from organic bases, and its amount is 1.2 to 3 times the molar amount of the acetylation reagent; the reaction solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide or acetonitrile, the reaction concentration is 0.1 to 1 mol / L, and the reaction temperature is -10°C to room temperature.

[0021] In some embodiments, in step S8, the organic base is at least one of triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, and DMAP.

[0022] Compared with the prior art, the solution of this application has the following advantages: (1) Using catalytic hydrogenation (Pd / C-H2) instead of the traditional high-risk Birch reduction (liquid ammonia / alkali metal) avoids the safety hazards of ultra-low temperature operation and alkali metal, simplifies equipment requirements, and makes the reaction process mild and controllable; (2) Using trimethylsilyl cyanide (TMSCN) as a cyanide source as a precursor for the construction of the 17-position side chain fundamentally eliminates the use of highly toxic sodium cyanide or potassium cyanide, significantly improving the environmental protection and safety of the process. (3) Using inexpensive and readily available estradiol-4,9-diene-3,17-dione as the starting material, and combining it with steps such as ketal protection, epoxidation, copper-catalyzed Grignard addition, and one-pot deprotection / dehydration, a complete and efficient eight-step synthetic route is formed. Each intermediate has strong crystallinity, and high-purity products can be obtained, which is suitable for industrial scale-up.

[0023] In summary, the synthetic method of phenoxymethyl provided in this application uses 49 compounds as starting materials and utilizes their inherent chiral configuration to achieve chiral control at each step through modification and alteration of functional groups. The reactions all use common synthetic methods, are simple to operate, and have low equipment requirements. The intermediates have high chiral selectivity, are easy to purify, have few isomer impurities, and have high purity of the target product. Attached Figure Description

[0024] The accompanying drawings, which are provided to further illustrate this application and form part of this application, illustrate exemplary embodiments of this application and are used to explain this application, but do not constitute an undue limitation of this application.

[0025] Figure 1 This is a synthetic route diagram for existing technology route one (US3527778); Figure 2 This is a synthetic route diagram for existing technology route two (US3381003); Figure 3 This is a synthetic route diagram for existing technology route three (WO2015 / 075693A1); Figure 4 This is a synthetic route diagram for existing technology route four (CN109575098A); Figure 5 This is a process route diagram for the synthesis of NovoMed in this application; Figure 6 This is an HPLC detection result of the novogestrol product synthesized in Example 1 of this application. Detailed Implementation

[0026] The present application will now be described in further detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it. Furthermore, it should be noted that, for ease of description, only the parts relevant to the invention are shown in the accompanying drawings.

[0027] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. This application will now be described in detail with reference to the accompanying drawings and embodiments.

[0028] To verify the effectiveness of this application, the following embodiments are provided: Example 1: Protection of carbonyl groups using ethylene glycol like Figure 5 The synthetic process route diagram of phenoxymethyl in this application is shown, and includes the following preparation steps: Preparation of compound one In a 5L four-necked flask equipped with an oil-water separator, thermometer, and mechanical stirrer, 270g (1.0mol) of compound 49, 9.5g (0.05mol) of p-toluenesulfonic acid, 248g (4.0mol) of ethylene glycol, and 2.7L of toluene were added. The mixture was heated under reflux for 4 hours, and the water produced in the reaction was separated. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, washed with 1L of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow oil. Then, 1L of petroleum ether and 200mL of MTBE were added, and the mixture was stirred at 0℃ for 4 hours to induce crystallization. After filtration, washing, and vacuum drying at 50℃, compound 1 was obtained, a white solid of 322g, with a yield of 90%.

[0029] Preparation of compound II In a 5L reaction flask, compound 1 (358g, 1.0mol), 1.5L of dichloromethane, hexachloroacetone (79g, 0.3mol), and pyridine (24g, 0.3mol) were added. The system was cooled to -10°C, and then 500mL of 30% hydrogen peroxide was added dropwise, controlling the reaction temperature to not exceed 5°C. After the addition was complete, the reaction was kept at a constant temperature for 18 hours. The reaction was monitored by TLC until it ended. The phases were separated, and the organic phase was washed once with 300mL of saturated sodium thiosulfate solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid. The solid was then slurried with 600mL of isopropyl ether, filtered, and washed to obtain compound 2 (261g, 70% yield).

[0030] Preparation of compound three In a 5L four-necked flask equipped with a dropping funnel, thermometer, and mechanical stirrer, 1M magnesium methyl chloride (2L, 2mol) and cuprous chloride (20g, 0.2mol) were added. Under nitrogen protection, the system was cooled to -10℃. Compound II (374g, 1.0mol), dissolved in 1000mL tetrahydrofuran, was slowly added to the reaction system, controlling the dropping rate to keep the reaction temperature ≤-5℃. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 5 hours. The reaction was monitored by TLC until completion. Then, 2L of saturated ammonium chloride solution was added dropwise to the above reaction system, and the mixture was stirred at room temperature for 30 minutes. After separation, the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily compound III (324g, 83% yield). The crude product was directly used in the next reaction.

[0031] Preparation of compound four In a 3L hydrogenation reactor, compound III (390g, 1.0mol), ethyl acetate (2.4L, 0.7v / w), triethylamine (10g, 0.1mol), and 10% Pd / C (39g, 10% w / w) were added. The mixture was purged three times each with nitrogen and hydrogen. The hydrogen pressure was then adjusted to 0.3MPa, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the mixture was purged again with nitrogen, and Pd / C was removed by filtration. The filtrate was concentrated and then purified by silica gel column chromatography to obtain compound IV (313g, 80% yield).

[0032] Preparation of compound five Compound IV (392 g, 1.0 mol), methanol (2350 mL, 6 v / w), and concentrated hydrochloric acid (20 mL) were added to a 3 L four-necked flask and reacted at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was neutralized with saturated sodium bicarbonate, concentrated under reduced pressure to remove methanol. The crude product was then dissolved in 2 L of dichloromethane, washed with saturated sodium chloride, saturated sodium bicarbonate, and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and then 100 mL of ethyl acetate and 1 L of petroleum ether were added. Crystallization was carried out at 0 °C for 4 hours, filtered, washed, and dried under vacuum at 50 °C to obtain compound V (172 g, yield 60%).

[0033] Preparation of compound six In a 3L four-necked flask, compound five (330g, 1.0mol), 1650mL of dichloromethane, and DBU (7.6g, 0.05mol) were added. Stirring was started, and the mixture was cooled to 0°C. Then, TMSCN (150g, 1.5mol) was added dropwise to the reaction system, maintaining the reaction temperature below 10°C. After the addition was complete, the reaction mixture was allowed to react at room temperature for 12 hours. After the reaction was complete, the reaction solution was poured into a 10% sodium carbonate solution. The organic phase was then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization from petroleum ether and ethyl acetate yielded compound six (236g, 55% yield).

[0034] Preparation of compound seven In a 10L four-necked flask, compound six (429g, 1.0mol) and 2500mL of toluene were added. Stirring was started, and the mixture was cooled to 0℃. Then, 1M methyl magnesium bromide (1.5L, 1.5mol) was added dropwise to the reaction system, maintaining the reaction temperature below 10℃. After the addition was complete, the reaction mixture was reacted at 70℃ for 12 hours. After the reaction was complete, the reaction solution was poured into 2L of saturated ammonium chloride solution, and then 300mL of concentrated hydrochloric acid was added dropwise with stirring for 1 hour (the acid concentration in the reaction solution was 1.6%). The aqueous phase was extracted once again with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was obtained. 200mL of ethyl acetate and 1L of petroleum ether were added, and the mixture was crystallized at 10℃, filtered, and dried. 218g of compound seven was obtained, representing a two-step yield of 66% from compound five to compound seven. The 13C NMR and 1H NMR spectra of compound seven are as follows: 1HNMR (500MHz, CDCl3): δ (ppm): 5.84 (s, 1H), 2.73-2.88 (br, 1H), 2.64–2.70 (m, 1H), 2.35–2.50 (m, 2H), 2.11-2.33 (m ,8H),2.00-2.06(m,1H),1.68-1.85(m,2H),1.48-1.62(m,2H),1.07–1.18(m,2H),1.05(d,J=10Hｽ3H),0.83(s,3H),; 13CNMR (125MHz, CDCl3) δ211.3, 200.0, 167.5, 124.5, 89.8, 52.5, 51.0, 48.2 ,38.5,37.6,36.4,35.4,34.6,33.4,31.5,28.7,27.8,26.1,23.5,18.5,17.3 Preparation of Nogest In a 3L four-necked flask, add compound seven (330g, 1.0mol), pyridine (150g, 2.0mol), DMAP (5.6g, 0.05mol), and 1780mL of dichloromethane. Start stirring and cool to 0°C. Then, add acetyl chloride (118g, 1.5mol) dropwise to the reaction system, maintaining the reaction temperature below 10°C. After the addition is complete, react at room temperature for 6 hours. After the reaction is complete, pour the reaction solution into 1L of ice water and stir for 15 minutes. After separation, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and concentrate. The crude product is obtained. Add 330mL of ethyl acetate and 1650mL of petroleum ether, crystallize at 10°C, filter, and dry. 320g of phenoxymethyl is obtained, with a yield of 86%.

[0035] The 13C NMR and 1H NMR spectra of the target product, phenoxymethyl, are as follows: 1HNMR (500MHz, CDCl3): δ (ppm): 5.86 (s, 1H), 2.90-2.95 (m, 1H), 2.36-2.50 (m, 2H), 2.14-2.23 (m, 6H) ,2.09(s,3H),2.03(s,3H),1.88–1.96(m,1H),1.45–1.80(m,6H),1.23-1.34(m,1H),1.19-1.20(m,2H ),1.06(d,J=10.0Hz,3H),0.74(s,3H),;13CNMR(125MHz,CDCl3)δ203.8,199.8,170.6,167.2,124.5, 96.4, 52.3, 52.1, 46.8, 38.5, 36.3, 35.3, 34.6, 31.5, 30.1, 28.8, 26.3, 26.1, 23.5, 21.3, 17.5, 17.3.

[0036] like Figure 6 As shown, HPLC analysis results indicate that the purity of the target product, novogestrol, in this embodiment is 99.26%. The impurities, accounting for 0.74%, are primarily compound seven.

[0037] Example 2 Preparation of Compound 1 (using 2,2-dimethyl-1,3-propanediol to protect the carbonyl group) In a 5L four-necked flask equipped with an oil-water separator, thermometer, and mechanical stirrer, 270 g (1.0 mol) of compound 49, 12.5 g (0.05 mol) of p-toluenesulfonic acid pyridinium salt, 416 g (4.0 mol) of 2,2-dimethyl-1,3-propanediol, and 2.7 L of benzene were added. The mixture was heated under reflux for 12 hours, and the water produced in the reaction was separated. After the reaction was completed under TLC monitoring, the mixture was cooled to room temperature, washed with 1 L of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow oil. Finally, 1 L of petroleum ether and 200 mL of MTBE were added, and the mixture was stirred at 0°C for 4 hours to induce crystallization. After filtration, washing, and drying under vacuum at 50°C, compound 1 was obtained, a white solid of 349 g, with a yield of 79%.

[0038] Preparation of compound two (by increasing the reaction temperature) In a 5L reaction flask, compound 1 (442g, 1.0mol), 1.5L of dichloromethane, hexachloroacetone (79g, 0.3mol), and pyridine (24g, 0.3mol) were added. The system was cooled to -10°C, and then 1.2L of 30% hydrogen peroxide was added dropwise, controlling the reaction temperature to not exceed 25°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 8 hours. The reaction was monitored by TLC until it ended. The phases were separated, and the organic phase was washed once with 300mL of saturated sodium thiosulfate solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid. The solid was then slurried with 600mL of isopropyl ether, filtered, and washed to obtain compound 2 (242g, 65% yield).

[0039] Preparation of compound three (using magnesium methyl bromide) In a 5L four-necked flask equipped with a dropping funnel, thermometer, and mechanical stirrer, 3M methylmagnesium bromide (667mL, 2mol) and cuprous chloride (20g, 0.2mol) were added. Under nitrogen protection, the system was cooled to -10℃. Compound II (459g, 1.0mol), dissolved in 1000mL tetrahydrofuran, was slowly added to the reaction system, controlling the dropping rate to keep the reaction temperature ≤-5℃. After the addition was completed, the mixture was allowed to return to room temperature and reacted for 5 hours. The reaction was monitored by TLC until completion. Then, 2L of saturated ammonium chloride solution was added dropwise to the above reaction system, and the mixture was stirred at room temperature for 30 minutes. After separation, the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily compound III (380g, 75% yield).

[0040] Preparation of Compound 4 (increasing the hydrogenation reaction pressure) In a 3L hydrogenation reactor, compound III (474g, 1.0mol), ethyl acetate (2.4L, 0.7v / w), triethylamine (10g, 0.1mol), and 10% Pd / C (39g, 10%w / w) were added. The mixture was purged three times each with nitrogen and hydrogen. The hydrogen pressure was then adjusted to 0.8MPa, and the reaction was carried out at room temperature for 6 hours. After the reaction was complete, the mixture was purged again with nitrogen, and Pd / C was removed by filtration. The filtrate was concentrated and then purified by silica gel column chromatography to obtain compound IV (355g, 75% yield).

[0041] Preparation of Compound 5 (by increasing the concentration of hydrochloric acid) Compound IV (476 g, 1.0 mol), methanol (2350 mL, 6 v / w), and concentrated hydrochloric acid (60 mL) were added to a 3 L four-necked flask and reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to remove methanol. The crude product was then dissolved in 2 L of dichloromethane, washed with saturated sodium chloride, saturated sodium bicarbonate, and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and then 100 mL of ethyl acetate and 1 L of petroleum ether were added. Crystallization was carried out at 0 °C for 4 hours, filtered, washed, and dried under vacuum at 50 °C to obtain compound V (143 g, 50% yield).

[0042] Preparation of Compound Six (Potassium Carbonate Catalysis) In a 3L four-necked flask, add compound five (330g, 1.0mol), 1650mL of dichloromethane, and potassium carbonate (6.9g, 0.05mol). Start stirring and cool to 0°C. Then, add TMSCN (150g, 1.5mol) dropwise to the reaction system, maintaining the reaction temperature below 10°C. After the addition is complete, react at room temperature for 18 hours. After the reaction is complete, pour the reaction solution into a 10% sodium carbonate solution. The organic phase is then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is directly used for the next reaction step.

[0043] Preparation of compound seven (3M methyl magnesium chloride addition) In a 10L four-necked flask, compound six (357g, 1.0mol) and 1780mL of toluene were added. Stirring was started, and the mixture was cooled to 0°C. Then, 3M methylmagnesium chloride (0.5L, 1.5mol) was added dropwise to the reaction system, maintaining the reaction temperature below 10°C. After the addition was complete, the reaction mixture was allowed to react at room temperature for 12 hours. After the reaction was complete, the reaction solution was poured into 2L of saturated ammonium chloride solution and stirred for 1 hour to allow complete hydrolysis of the imine. The aqueous phase was extracted once again with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to crystallization at 10°C with 200mL of ethyl acetate and 1L of petroleum ether, filtered, and dried. 250g of compound seven was obtained, representing a 76% yield from the two-step reaction from compound five to compound seven.

[0044] Preparation of Nogestrol (using acetic anhydride) In a 3L four-necked flask, add compound seven (330g, 1.0mol), pyridine (150g, 2.0mol), DMAP (5.6g, 0.05mol), and 1780mL of dichloromethane. Start stirring and cool to 0°C. Then, add acetic anhydride (162g, 1.5mol) dropwise to the reaction system, maintaining the reaction temperature below 10°C. After the addition is complete, react at room temperature for 6 hours. After the reaction is complete, pour the reaction solution into 1L of ice water and stir for 15 minutes. After separation, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and concentrate. The crude product is then added to 330mL of ethyl acetate and 1650mL of petroleum ether, crystallized at 10°C, filtered, and dried. 320g of phenoxymethyl was obtained, with a yield of 86%.

[0045] The 13C NMR and 1H NMR spectra of the target product, phenoxymethyl, are the same as those in Example 1.

[0046] HPLC analysis results showed that the purity of the target product, novogestrol, in this embodiment was 99%.

[0047] Comparative Example 1: An example of the synthesis method disclosed in patent publication number WO2015 / 075693A1 uses 3-ketal as a starting material to synthesize the target product novogestrol.

[0048] This route uses 3-ketal as a starting material and employs inorganic cyanide (such as sodium cyanide) in the construction of the 17α-hydroxy-20-one side chain. Furthermore, it requires subsequent Birch reduction via a lithium metal / liquid ammonia system. The overall yield of this route, according to literature, is only about 3.4%. This process not only has extremely low yields but also introduces two major safety hazards: highly toxic inorganic cyanide and the highly dangerous Birch reduction. Intermediate purification also relies on column chromatography, making it unsuitable for large-scale production.

[0049] The method described in this application uses low-toxicity trimethylsilyl cyanide (TMSCN) to replace highly toxic inorganic cyanide, eliminating the use of cyanide-containing highly toxic materials at the source. Furthermore, this application uses catalytic hydrogenation instead of Birch reduction, and all intermediates are purified by pulping or crystallization, demonstrating advantages in safety, environmental friendliness, and economy.

[0050] Comparative Example 2: The synthesis method disclosed in patent CN201910049848.6 uses liquid ammonia and metallic lithium for Birch reduction, requiring operation under cryogenic conditions of -70℃ to -60℃. This results in demanding equipment requirements, significant safety risks, and is unsuitable for large-scale industrial production. Furthermore, the product purity is only 90%. Its disadvantages include the requirement that the starting materials be self-produced and not commercially available, increasing the overall cost and complexity of the preparation process.

[0051] The proposed solution does not use any high-risk reagents, operates under mild conditions, and produces a high-purity final product, making it more suitable for industrial production.

[0052] In comparison, the method described in this application completely abandons Birch reduction, employing palladium-catalyzed hydrogenation at mild conditions of 10°C–50°C and 0.1 MPa–1 MPa to reduce the double bonds in the molecule. This fundamentally improves operational safety, and the entire process can obtain a high-purity final product without column chromatography. Furthermore, this application uses readily available and inexpensive estradiol-4,9-diene-3,17-dione as a starting material, resulting in limited route extension while significantly improving safety and scalability.

[0053] Summarize the design concept and beneficial effects of this application. (1) Fundamental improvement in process safety: Step S4 is replaced by catalytic hydrogenation (Pd / C, H2) to reduce double bonds, completely eliminating the Birch reduction (liquid ammonia, metallic lithium or sodium) that is essential in the traditional synthesis of nystatin. Catalytic hydrogenation can be carried out at room temperature or with mild heating and at low to medium pressure, which not only eliminates the strong corrosion, high activity and safety risks brought by liquid ammonia and alkali metals, but also reduces equipment investment and operation difficulty, clearing away the core obstacles to large-scale production.

[0054] (2) Practice of green chemistry concept: Step S6 uses trimethylsilyl cyanide (TMSCN) as a precursor for 17-position side chain extension, replacing highly toxic inorganic cyanides such as sodium cyanide and potassium cyanide used in known routes. TMSCN is stable and controllable at the reaction temperature, and avoids the problem of treating cyanide-containing compounds in wastewater, greatly reducing environmental hazards and occupational exposure risks.

[0055] (3) Economy of raw materials and steps: Starting with the inexpensive commercial raw material estradiol-4,9-diene-3,17-dione, the entire route consists of only eight steps and does not require cumbersome group protection and deprotection sequences. The reaction types of each step are classic, the reagents are readily available, and the intermediates are mostly crystalline solids that can be purified by recrystallization or pulping. Column chromatography was never used, saving time and solvents and significantly reducing production costs.

[0056] (4) Excellent yield and purity: In Example 1, the single-step yield of the final product, novogestrol, reached 86%, and its structure was confirmed to be correct and its purity to be high by NMR. The overall yield of the entire route was ideal, with good reproducibility, and the product quality met the requirements for further pharmaceutical research, demonstrating good prospects for industrial application.

[0057] (5) Overall synergistic effect: The synthetic design of this invention is not a simple replacement of individual steps, but a recombination of unit reactions such as ketal protection, epoxidation, copper-catalyzed Grignard addition, catalytic hydrogenation, TMSCN addition and Grignard addition / acid hydrolysis, forming a complete new pathway of "non-Birch reduction and non-toxic cyanide". The conditions of each step are mild and synergistically connected.

[0058] It should be noted that: (1) Definition: In this article, “~” is used to represent the range of values, and the range of values ​​represented by this expression includes two endpoint values.

[0059] (2) Raw materials used in implementation: The reagents or raw materials used in the above embodiments are all commercially available products that can be purchased and obtained by those skilled in the art.

[0060] In summary, the specific parameters or some commonly used reagents or raw materials in the above embodiments are specific or preferred embodiments under the concept of this application, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of this application.

[0061] In addition, unless otherwise specified, the raw materials used may be commercially available products in the field or prepared by conventional methods in the field; that is, the reagents and instruments used in this embodiment do not specify the manufacturer or other information, and are all conventional products that can be purchased from the market.

[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

[0063] The specific embodiments of this application have been described above, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A method for synthesizing phenoxylate, characterized in that, Includes the following steps: S1: Starting from estradiol-4,9-diene-3,17-dione, the carbonyl group of the starting material is ketalized with an alcohol in an organic solvent in the presence of an acid catalyst to obtain compound one; S2: Compound 1 is subjected to an epoxidation reaction in an oxidation system to obtain compound 2; S3: In the presence of a copper salt catalyst, compound II is selectively added to magnesium methyl halide to obtain compound III; S4: Compound III was subjected to catalytic hydrogenation in a hydrogen atmosphere to reduce the double bonds in the molecule, yielding compound IV; S5: Compound four is subjected to a deketalizing and dehydrating reaction in an acid and an organic solvent to obtain compound five; S6: Compound 5 is reacted with trimethylsilyl cyanide in the presence of a catalyst to give compound 6; S7: Compound VI is subjected to an addition reaction with a methyl Grignard reagent, followed by acid hydrolysis to obtain compound VII; S8: In the presence of an acid-binding agent, the compound VII is subjected to an acetylation reaction with an acetylation reagent to obtain von gestrin. The structural formula of compound one is: The structural formula of compound two is: ; The structural formula of compound three is: The structural formula of compound four is: ; The structural formula of compound five is: The structural formula of compound six is: ; The structural formula of compound seven is: .

2. The synthesis method according to claim 1, characterized in that, In step S1, the reaction is carried out by reflux and water separation in an organic solvent, benzene or toluene. Wherein, the alcohol is selected from monohydric alcohols or dihydric alcohols; the monohydric alcohol is at least one of methanol and ethanol, and the dihydric alcohol is at least one of ethylene glycol and 2,2-dimethyl-1,3-propanediol; The acid catalyst is p-toluenesulfonic acid or p-toluenesulfonic acid pyridine salt.

3. The synthesis method according to claim 2, characterized in that, In step S1, the reaction is carried out by reflux and water separation in the organic solvent toluene. Wherein, the alcohol is selected from diols; the acid catalyst is pyridinium p-toluenesulfonate; The molar ratio of the estradiol-4,9-diene-3,17-dione to the diol is 1:(2.2-5.0); the amount of the acid catalyst is 1%-10% of the molar amount of estradiol-4,9-diene-3,17-dione; and the reaction time is 5-18 hours.

4. The synthesis method according to claim 1, characterized in that, In S2, dichloromethane is used as a solvent to selectively oxidize the conjugated double bonds of compound one in an oxidation system to generate an epoxy compound, which is compound two. The oxidation system is a perhalogenated acetone, hydrogen peroxide, and pyridine system; or the oxidation system is a perhalogenated acetone, hydrogen peroxide, and phosphate buffer system; wherein the perhalogenated acetone is hexachloroacetone or hexafluoroacetone. The reaction temperature is controlled between -10℃ and 25℃; the molar ratio of hydrogen peroxide to compound one is approximately (3-12):1, the molar ratio of hexachloroacetone to compound one is (0.1-0.8):1, and the molar ratio of pyridine to compound one is (0.1-0.8):

1.

5. The synthesis method according to claim 1, characterized in that, In S3, the copper salt catalyst is cuprous chloride or cuprous iodide, and its molar amount is 0.05 to 0.3 times the number of moles of compound two; The methyl magnesium halide is methyl magnesium chloride or methyl magnesium bromide; the solvent used is an aprotic solvent; the reaction temperature is controlled between -20°C and 30°C.

6. The synthesis method according to claim 1, characterized in that, In step S4, in the presence of a palladium-carbon or platinum-carbon catalyst and an organic base, compound three is subjected to a catalytic hydrogenation reaction in a hydrogen atmosphere to reduce the double bonds in the molecule and obtain compound four. The organic base is selected from at least one of triethylamine, diisopropylethylamine, and pyridine, and its amount is 2% to 10% of the three moles of the compound. The amount of palladium on carbon or platinum on carbon is 2% to 10% of the weight of the compound; the solvent for catalytic hydrogenation is selected from at least one of ethyl acetate, methanol, ethanol, and tetrahydrofuran; the reaction pressure is 0.1 MPa to 1 MPa; and the reaction temperature is 10°C to 50°C.

7. The synthesis method according to claim 1, characterized in that, In step S5, the acid is at least one of hydrochloric acid, sulfuric acid, and trifluoroacetic acid; the concentration of the acid in the reaction system is 0.3% to 3%; the reaction is carried out in a mixed system of one or more organic solvents, such as methanol, ethanol, or isopropanol, and water, and the reaction temperature is from room temperature to reflux temperature.

8. The synthesis method according to claim 1, characterized in that, In step S6, the catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium carbonate, and its amount is 1% to 5% of the five moles of the compound; The reaction solvent is dichloromethane, tetrahydrofuran, methyl tert-butyl ether, or acetonitrile; the reaction temperature is 25℃~70℃.

9. The synthesis method according to claim 1, characterized in that, In S7, without the protection of the six-hydroxyl group of the compound, the methyl Grignard reagent is added to the cyano group of the compound six to generate a hydroxyl group at position 17, which is then subjected to acid hydrolysis to obtain compound seven; The methyl Grignard reagent is methyl magnesium chloride or methyl magnesium bromide, and its amount is 1.5 to 5 times the number of six moles of the compound. The acid used in the acid hydrolysis treatment is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or trifluoroacetic acid, and the mass concentration of the acid in the reaction solution is 5% to 20%; the solvent is toluene, and its amount is 4 to 20 times the weight of compound six.

10. The synthesis method according to claim 1, characterized in that, In step S8, in the presence of an acid-binding agent, compound seven is subjected to an acetylation reaction with an acetylation reagent to acetylate the hydroxyl group at position 17 of compound seven, thereby obtaining von nifedipine. The acetylation agent is acetyl chloride or acetic anhydride, and its amount is 1.2 to 3 times the number of moles of the compound. The acid-binding agent is selected from organic bases, and its amount is 1.2 to 3 times the molar amount of the acetylation reagent; the reaction solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide or acetonitrile, the reaction concentration is 0.1 to 1 mol / L, and the reaction temperature is -10℃ to room temperature.

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