Synthesis method of anradrolone intermediate

Abstract

The synthesis method comprises the following steps: performing epoxidation reaction on a compound IN1 to obtain a 3-position epoxy isomer mixture IN2, then adding the IN2 into petroleum ether or methanol, stirring, filtering to remove non-target configurational isomers, concentrating filtrate, cooling, and separating out solids to obtain an epoxy product; the structural formulas of the compounds IN1 and IN2 are as follows: # imgabs0 # imgabs1 #. According to the preparation method, a dangerous and expensive aluminum reagent is avoided, isomer impurities are removed through improvement of the method, the preparation method is green and safe, part of steps can be directly put into the next reaction step without purification, the operation is simple, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a zulanosolone intermediate. Background Art

[0002] Zuranolone, chemical name is 3β-methyl-3α-hydroxy-5β-hydrogen-19-nor-20-keto-21-(1H-pyrazole-4-carbonitrile)-pregnantol, the structural formula is as follows:

[0003] In August 2023, the FDA approved Zuranolone for the treatment of postpartum depression (PPD) in adults. Zuranolone is jointly produced by the US biopharmaceutical company Sage Therapeutics (SAGE.US) and the US pharmaceutical company Biogen (BIIB.US) and is a neuroactive steroid.

[0004] Compound TM is a key intermediate in the synthesis of Zuranosolone, which can be synthesized into Zuranosolone through a two-step reaction.

[0005]

[0006] The literature "J. Med. Chem. 2017, 60, 7810-7819" describes the synthesis method of Zuranosone, which uses compound SM (4-ene-3,17-diketoestradiol) as a raw material and synthesizes Zuranosone through 7 steps of reaction, and the synthesis of its key intermediate 1 (compound TM) is a 5-step reaction. In general, the yield of each step of the synthesis of intermediate 1 is acceptable, and the total yield is 42.6%. However, the second step of the synthesis process requires the use of MAD, which is extremely expensive. It is synthesized through trimethylaluminum, which is also expensive. More importantly, it is very easy to spontaneously combust, and the reaction produces a large amount of methane gas, which is not conducive to the safety of industrial production.

[0007] Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the above background technology and provide a method for preparing a zuranolone intermediate with low starting materials and reagents, high safety and suitable for industrial production.

[0009] In order to solve the above technical problems, the technical solution proposed by the present invention is: A method for synthesizing a zuranolone intermediate comprises the following steps: Compound IN1 is subjected to epoxidation reaction to obtain a 3-epoxy isomer mixture IN2, and then IN2 is added to petroleum ether or methanol and stirred, and non-target configuration isomers are removed by filtration, and the filtrate is concentrated and cooled to precipitate a solid, thereby obtaining an epoxidation product; The structural formulas of the compounds IN1 and IN2 are: .

[0010] As a further improvement, the volume of the petroleum ether or methanol is 5 to 20 times the mass of IN2; and the stirring is carried out at 20 to 50° C. for 2 to 3 hours.

[0011] As a further improvement, the epoxidation reaction is to react compound IN1 with a base and trimethylsulfonium bromide in an organic solvent. After the reaction is completed, the reaction solution is extracted and separated with isopropyl ether and water, and the organic phase is concentrated to dryness to obtain IN2.

[0012] As a further improvement, the following steps are also included: The obtained epoxy product was subjected to a wittig reaction to obtain the intermediate IN3; The intermediate IN3 is subjected to ring opening reduction to obtain the intermediate IN4; The intermediate IN4 is protected by silane etherification and split to obtain the intermediate IN5; The structural formulas of the intermediates IN3, IN4 and IN5 are: .

[0013] As a further improvement, the silane protection and resolution comprises: subjecting the intermediate IN4 to a silane reaction with chlorosilane in an organic solvent under alkaline conditions, and then performing isomer resolution.

[0014] As a further improvement, the organic solvent is dichloromethane.

[0015] As a further improvement, the reaction temperature of the silane reaction is controlled at -30°C to -15°C.

[0016] As a further improvement, the silane protection and separation further includes: after the silane reaction is quenched with water, the temperature is raised to room temperature, stirred, and separated, and then the organic phase is replaced with a low-polarity solvent and silica gel is added, and stirred to adsorb unreacted raw materials and isomer impurities.

[0017] As a further improvement, the low polarity solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane.

[0018] As a further improvement, the amount of silica gel added is 0.2-2 times the weight of the intermediate IN4, and stirring is carried out for 3-4 hours after adding the silica gel.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The present invention uses 4-ene-3,17-diketoestradiol (SM) as a raw material and prepares the target product, the key intermediate TM of zuranolone, through 7 steps of reaction. The starting compound is relatively cheap and can be obtained commercially, and the source is convenient. The present invention improves the method of methylation at the 3rd position. Although the reaction steps are increased and the reaction yield is reduced, the dangerous and expensive aluminum reagent is avoided. The present invention removes the isomer by utilizing the solubility difference of the 3-position epoxy isomer (IN2), and further removes the isomer by utilizing the reactivity difference of the two configurations of hydroxyl groups at the 3rd position. The preparation method of the present invention is green and safe, and some steps can be directly put into the next step reaction without purification. The operation is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 is the H NMR spectrum of IN-1; Figure 2 is the C NMR spectrum of IN-1; Figure 3 This is the H NMR spectrum of IN-2 isomer; Figure 4 This is the NMR carbon spectrum of IN-2 isomer; Figure 5 This is the H-NMR spectrum of the IN-2 target configuration; Figure 6 This is the C NMR spectrum of the IN-2 target configuration; Figure 7 is the H NMR spectrum of IN-3; Figure 8 is the C NMR spectrum of IN-3; Fig. 9 is the H NMR spectrum of IN-4; Fig.10 is the C NMR spectrum of IN-4; Fig.11 is the H NMR spectrum of IN-5; Fig.12 is the C NMR spectrum of IN-5; Fig.13is the H NMR spectrum of TM; Fig.14 is the C NMR spectrum of TM; Fig.15 This is the NMR image of the 3-epoxy isomer mixture IN2; Fig.16 This is the NMR image of the 3-epoxy isomer mixture IN2 after being slurried with petroleum ether; Fig.17 This is the TLC photograph of preparation IN5. DETAILED DESCRIPTION

[0022] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively and meticulously below in conjunction with the accompanying drawings and preferred embodiments of the present invention, but the protection scope of the present invention is not limited to the following specific embodiments.

[0023] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0024] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0025] In some specific embodiments, the preparation method of the present invention uses 4-ene-3,17-diketoestradiol (SM) as a raw material to prepare the zuranolone intermediate 1 (compound TM). The raw material SM can be obtained commercially at a low cost. The synthesis route is as follows:

[0026] The synthetic route comprises the following steps: (1) The raw material SM is subjected to hydrogenation reduction to obtain the intermediate IN1; In some specific embodiments, SM is dissolved in an organic solvent, palladium carbon is added, and the reaction is carried out under a hydrogen atmosphere at normal pressure and room temperature. After the hydrogenation reaction is completed, a crude product of IN1 is obtained by post-treatment, which can be directly used in the next step without purification.

[0027] In some specific embodiments, the organic solvent is ethanol, methanol, ethyl acetate, dichloromethane, tetrahydrofuran, or a mixed solvent thereof, preferably tetrahydrofuran, and the amount of the solvent used is 4 to 20 times the volume of SM.

[0028] In some specific embodiments, the palladium carbon is 10% or 5% palladium carbon, and the amount of palladium carbon added is 0.05 to 0.2 times the weight of SM.

[0029] Acid or base can be added to the reaction to adjust the reaction rate and stereoselectivity. In some specific embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, and the base is triethylamine, pyridine, preferably hydrobromic acid.

[0030] (2) IN1 is subjected to epoxidation reaction to obtain a mixture of 3-epoxy isomers IN2; In some specific embodiments, IN1 is dissolved in an organic solvent, and a base and trimethylsulfonium bromide are added to react. After the reaction is completed, post-treatment is performed.

[0031] In some specific embodiments, the organic solvent is DMSO, or a mixed solvent of DMSO and THF, the amount of the organic solvent added is 2 to 10 times the volume of IN1 added, and the volume ratio of DMSO and THF mixed solvent is 1:3 to 3:1.

[0032] In some specific embodiments, the base is potassium hydroxide powder, sodium hydroxide powder, or sodium ethoxide, and the amount of potassium hydroxide or sodium hydroxide added is 0.3-0.8 times the weight of the amount of IN1 added, and the amount of sodium ethoxide added is an equimolar amount of trimethylsulfonium bromide added.

[0033] In some specific embodiments, the amount of trimethylsulfur bromide used is 1 to 1.1 times the molar amount of IN1 added. The reaction temperature is 10-30°C, and the reaction time is 6h-24h.

[0034] In some specific embodiments, the reaction is post-treated to obtain a mixture of 3-epoxy isomers IN2. The post-treatment process is: the reaction solution is extracted with isopropyl ether and water, separated, and the organic phase is concentrated to dryness to obtain IN2. Then petroleum ether or methanol is added to IN2, heated and stirred for 2 to 3 hours, cooled, filtered to remove isomers, and the filtrate is concentrated to a small volume, cooled to precipitate solids, and filtered to obtain a high proportion of the target configuration.

[0035] Isomer impurities cannot be dissolved in petroleum ether or methanol. Adding petroleum ether or methanol mainly dissolves the target configuration product. Heating is conducive to dissolution, and filtering can remove isomers. Preferably, the volume of petroleum ether or methanol is 5 to 20 times the mass of IN2. Preferably, the temperature is raised to 20-50°C.

[0036] IN2 obtained by the reaction is a mixture of 3-epoxy isomers. NMR shows that the 3β-methylene configuration of the target product accounts for about 50-60%. Fig.15 (The characteristic peak shift of the target configuration is 2.57, and that of the isomer is 2.61). After studying and testing a series of solvents, the two configurations have a large solubility difference in petroleum ether or methanol. After slurrying with petroleum ether or methanol, most of the isomers can be removed, and the proportion of the target configuration can be increased to about 90%, such as Fig.16If other solvents are used for slurrying, such as dichloromethane, acetone or tetrahydrofuran, the solubility difference between the two configurations is not large, making it difficult to separate.

[0037] (3) IN2 undergoes a wittig reaction to obtain the intermediate IN3; In some specific embodiments, ethyl triphenylphosphonium bromide and potassium tert-butoxide are used to prepare phosphorus ylide in tetrahydrofuran, and then reacted with IN2 to obtain IN3. After the reaction, the by-products such as salt and triphenylphosphine oxide are removed by treatment, and the obtained IN3 is directly used for the next step reaction.

[0038] In some specific embodiments, the added amount of ethyltriphenylphosphonium bromide is 1.2-3 times the molar amount of IN2, and the added amount of potassium tert-butoxide is 1 times the molar amount of ethyltriphenylphosphonium bromide.

[0039] In some specific embodiments, the reaction temperature of preparing phosphorus ylide from ethyltriphenylphosphonium bromide and potassium tert-butoxide is -10-10°C, and the reaction temperature of phosphorus ylide with IN2 is 40-60°C.

[0040] (4) IN3 undergoes reduction ring opening to obtain the intermediate IN4; In some specific embodiments, IN4 is dissolved in an organic solvent, lithium aluminum tetrahydride is added, and IN4 is reacted.

[0041] In some specific embodiments, the organic solvent is tetrahydrofuran or ether, preferably tetrahydrofuran, and the amount of the organic solvent added is 6-20 times the volume of IN4 added. The amount of lithium aluminum tetrahydride added is 0.07 to 0.2 times the weight of IN4 added.

[0042] (5) IN4 was protected by silane etherification and split to obtain intermediate IN5; Since the isomers in IN2 were not completely removed, IN4 contained the 3-hydroxyl isomer. By selectively silane-etherifying a certain configuration, the 3-hydroxyl isomer was removed by polarity difference. The hydroxyl group of the target configuration is a flat-bonded hydroxyl group, which is more prone to silane-etherification reaction, while the isomer is an upright-bonded hydroxyl group, which is difficult to react. In addition, the silane-etherification of the 3-hydroxyl group helps to avoid the hydroxyl group from reacting with borane in the next step of hydroboration and oxidation, and avoids the problem of borane connecting the steroid molecules in series, making the solution solidified and difficult to stir.

[0043] In some specific embodiments, IN4 is dissolved in an organic solvent, and the temperature and the amount of chlorosilane added are controlled under alkaline conditions to cause the target product to undergo silylation, and the isomer does not undergo silylation reaction. The chlorosilane and the generated salt are then removed by post-treatment, and the solvent is replaced with a low-polarity solvent, and the isomer is adsorbed by adding silica gel, thereby removing the non-target configuration isomer.

[0044] In some specific embodiments, the organic solvent is dichloromethane. If petroleum ether or ethyl acetate is used as the solvent, the target configuration and isomers react with trimethylsilyl chloride with substantially no selectivity, and the selectivity is poor when acetone is used as the solvent. TLC shows that dichloromethane has a significant advantage in the reaction selectivity of the target configuration.

[0045] Fig.17 The left figure shows that the ratio of isomers and target configurations in the starting material S of the silylation reaction in this step is about 1:9. After using dichloromethane as the solvent for the reaction, the silylation conversion of the target configuration is faster. The ratio of the target configuration and the isomer that have not undergone silylation in the starting material S becomes about 1:1, indicating that the silylation rate of the target configuration is significantly faster than that of the isomer. The middle figure shows that after the developing solvent is replaced with petroleum ether, no isomer silylation products are found in the reaction, and the isomers are basically not silylated. In addition, the isomers and unreacted target configurations and other impurities are at the origin in developing solvents such as petroleum ether and are easily removed by silica gel adsorption.

[0046] Fig.17 The right figure shows the silane reaction using petroleum ether or ethyl acetate as the reaction solvent. Both the target configuration and isomers are obviously silane-etherified, and the silane reaction is not selective.

[0047] In some specific embodiments, the alkaline condition is to add triethylamine or pyridine, and the amount of triethylamine or pyridine added is 1.0-1.5 times the molar amount of the amount of chlorosilane added.

[0048] In some specific embodiments, the reaction temperature is -30°C to -15°C. If the reaction temperature is too high, the selectivity is reduced and the reaction endpoint is difficult to control; if the temperature is too low, the reaction time is too long.

[0049] In some specific embodiments, the chlorosilane is trimethylchlorosilane, triethylchlorosilane, or tert-butyldimethylchlorosilane, and the amount of chlorosilane added is 1.0-1.5 times the molar amount of IN4. If the amount of trimethylchlorosilane is too large, the reaction end point is difficult to control.

[0050] In some specific embodiments, the post-treatment process is: adding water to stop the reaction, warming to room temperature and stirring, separating the liquids, replacing the organic phase with a low-polarity solvent and adding silica gel, stirring for 3 to 4 hours, adsorbing unreacted raw materials and isomer impurities, filtering, and collecting the organic phase.

[0051] In some specific embodiments, the low polarity solvent is petroleum ether, n-hexane, n-heptane, cyclohexane, and the amount of the low polarity solvent added is 8-20 times the volume of IN4 added. The amount of silica gel added is 0.2-2 times the weight of IN4 added, and the particle size of silica gel is 80-600 mesh, preferably 200-300 mesh.

[0052] (6) IN5 was subjected to hydroboration oxidation and deprotection to obtain intermediate IN6; In some specific embodiments, IN5 reacts with borane for hydroboration, and then reacts with hydrogen peroxide under alkaline conditions to introduce the 20-hydroxyl group, and finally the reaction solution is adjusted to acidic (pH 3-4) to remove the silyl ether to obtain the intermediate IN6. The product generally has two products, and the two products are isomers at the 20-position.

[0053] In some specific embodiments, the borane is a commercial borane tetrahydrofuran solution, a borane-dimethyl sulfide tetrahydrofuran solution, or can be prepared by itself using sodium borohydride. The amount of borane added is 0.5-2 times the molar amount of IN5. The alkaline condition is the addition of sodium hydroxide aqueous solution or potassium hydroxide aqueous solution. The amount of hydrogen peroxide added is 3-10 times the molar amount of IN5.

[0054] (7) IN6 is oxidized to obtain the target product TM; In some specific embodiments, the hydroxyl group at position 20 of IN6 can be oxidized to form a carbonyl group to obtain the target product TM. The oxidation methods include Jones oxidation, PCC oxidation, Anelli oxidation, Swern oxidation, IBX oxidation, Dess-Martin oxidation, Oppenauer oxidation, etc. After the oxidation reaction, TM is obtained by post-treatment and purification.

[0055] The "room temperature" mentioned in the present invention has the common meaning in the art, for example, 15-35°C.

[0056] The technical solution of the present invention is described in detail below through specific embodiments.

[0057] Embodiment 1: Synthesis of compound IN1 Weigh 100g of SM, add 600mL of tetrahydrofuran, 2mL of hydrobromic acid solution, stir at room temperature, replace with nitrogen, add 5g of palladium carbon (containing 10% palladium), replace with hydrogen, and react at room temperature in a normal pressure hydrogen atmosphere until the raw material disappears. Add 300mL of dichloromethane to dissolve the product, filter to remove palladium carbon, and concentrate the organic phase to obtain the product. The ratio of 5β configuration: 5α configuration at position 5 is 98:2. It is directly put into the next step without purification.

[0058] IN1 NMR: 1H NMR (400 MHz, CDCl3) δ 2.59 (t, J = 14.1 Hz, 1H), 2.47 (dd, J = 19.2, 8.7 Hz, 1H), 2.30–2.14 (m, 4H), 2.14–2.04 (m, 2H), 1.98 (ddd,J = 13.9, 8.8, 5.2 Hz, 1H), 1.86 (m, 2H), 1.76 (m, 1H), 1.65 (m, 3H), 1.59–1.50 (m, 2H), 1.39 (m, 4H), 1.22 (m, 2H), 0.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 220.94, 212.46, 50.48, 47.95, 42.85, 40.96, 39.75, 38.57, 38.22,36.36, 35.86, 31.57, 30.42, 27.67, 25.18, 24.38, 21.67, 13.85. Example 2 Synthesis of compound IN1 Weigh 100g of SM, add 500mL of tetrahydrofuran and 500mL of dichloromethane, 2mL of hydrobromic acid solution, stir at room temperature, replace with nitrogen, add 5g of palladium carbon (containing 10% palladium), replace with hydrogen, and react at room temperature in a normal pressure hydrogen atmosphere until the raw material disappears. Remove the palladium carbon by suction filtration, and concentrate the organic phase to obtain the product. The ratio of 5β configuration: 5α configuration at position 5 is 97.5:2.5, and it is directly put into the next step without purification.

[0059] Embodiment 3: Synthesis of compound IN2 Measure 20 ml of DMSO and 20 mL of tetrahydrofuran, add 5 g of sodium hydroxide powder, stir at 10-15° C., then add 10 g of IN1 obtained by the method of Example 1, and finally add 5.7 g of trimethylsulfonium bromide, react at 15-20° C. overnight, and monitor by TLC until the reaction is complete.

[0060] 40 mL of isopropyl ether and 100 mL of ice water were weighed and stirred, and the reaction solution was slowly poured in for extraction and separation. The aqueous phase was extracted once with 2V of isopropyl ether, and the organic phases were combined. The organic phases were washed twice with 20 mL of water and concentrated to dryness to obtain IN2, which was a mixture of two epoxy isomers at the 3-position. The ratio of the target configuration and the isomer was about 56%:44% (calculated according to the peak area ratio based on the H NMR spectrum).

[0061] 100 mL of petroleum ether was added to the obtained epoxy isomer mixture, and the mixture was stirred at 30°C for 2 h. A large amount of solid was precipitated. After filtration, the solid was basically epoxy isomer, and the ratio of the target configuration to isomer in the solution increased to about 90%:10%. The petroleum ether mother liquor was concentrated to about 20 mL, cooled to 0-5°C, solid was precipitated, and filtered to obtain about 4.5 g of IN2 of the target configuration. The total yield of the first two steps was 45%.

[0062] Isomer IN2 NMR: 1H NMR (400 MHz, Chloroform-d) δ 2.62 (q, J = 4.6 Hz,2H), 2.46 (dd, J = 19.2, 8.8 Hz, 1H), 2.30 – 2.14 (m, 2H), 2.14 – 2.02 (m,1H), 2.00 – 1.74 (m, 5H), 1.68 (m, 3H), 1.54 (m, 4H), 1.44 – 1.35 (m, 1H),1.28 (m, 3H), 1.16 (m, 2H), 1.02 – 0.92 (m, 1H), 0.89 (s, 3H). 13C NMR (101MHz, CDCl3) δ 221.34, 58.91, 53.67, 50.62, 47.98, 41.19, 39.95, 38.26, 35.88,34.44, 33.53, 31.66, 30.87, 27.26, 25.29, 25.22, 24.88, 21.69, 13.84. IN2 NMR of target configuration: 1 H NMR (400 MHz, CDCl3) δ 2.64–2.56 (m, 2H), 2.45 (ddd, J = 19.2, 8.6, 1.0 Hz, 1H), 2.29–2.18 (m, 1H), 2.17–2.09 (m, 1H), 2.09–2.05 (m, 1H), 2.02 (m, 1H), 2.01–1.90 (m, 2H), 1.89–1.76 (m, 3H), 1.74–1.63 (m, 2H), 1.61–1.47 (m, 5H), 1.47–1.07 (m, 8H), 1.02 (m, 1H), 0.94–0.90 (m,1H), 0.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 221.34, 59.96, 55.50, 50.51,47.96, 41.25, 40.01, 38.39, 36.79, 35.92, 34.32, 31.61, 31.00, 27.94, 26.93,25.04, 24.93, 21.72, 13.85. Embodiment 4: Synthesis of compound IN3 Weigh 128g of ethyl triphenylphosphonium bromide, add 350mL of tetrahydrofuran, nitrogen protection, ice bath, stirring, add 38.5g of potassium tert-butoxide solid, the reaction solution turns orange-red, and stir under ice-water bath for 1h. Add 50g IN2 obtained by the method of Example 3 to the reaction solution, warm to 50°C, and react for about 2h. Cool to room temperature, filter with suction, wash the filter cake with 150mL of petroleum ether, concentrate the organic phase, add 500mL of petroleum ether after concentration, heat to 50°C and dissolve for 2h, cool to room temperature, filter with suction, wash the filter cake with 100mL of petroleum ether, merge the organic phases, add 25g of silica gel to the organic phase, stir at room temperature for 1h, filter with suction, wash the filter cake with 50mL of petroleum ether, merge the organic phases, concentrate to obtain a colorless oil, and directly put it into the next step.

[0063] IN3 NMR: 1 H NMR (400 MHz, CDCl3) δ 5.12 (qt, J = 7.1, 2.1 Hz, 1H), 2.58(s, 2H), 2.37 (m, 1H), 2.30–2.16 (m, 3H), 2.05 (dq, J = 13.8, 3.1 Hz, 1H),2.00–1.91 (m, 1H), 1.86 (m, 1H), 1.74 (m, 2H), 1.66 (dt, J = 7.2, 2.1 Hz,4H), 1.59 (d, J = 4.5 Hz, 1H), 1.50 (m, 4H), 1.40 (m, 1H), 1.36–1.08 (m, 7H),1.05–0.96 (m, 1H), 0.89 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 150.48, 113.28,60.20, 55.56, 55.26, 44.52, 41.33, 40.12, 38.17, 37.28, 36.82, 34.37, 31.45,31.26, 28.02, 26.91, 26.08, 25.88, 24.28, 16.93, 13.12. Embodiment 5: Synthesis of compound IN4 Weigh IN3 prepared by the method of Example 4 (prepared from 50g IN2), add 300mL tetrahydrofuran, stir in an ice bath, add 5g lithium aluminum tetrahydride, gradually warm to room temperature and react until the raw material disappears. Quench the reaction with ethyl acetate and water step by step, the reaction solution gradually turns into a white turbid liquid, filter, wash the filter cake with 2V dichloromethane, combine the organic phases, dry, and concentrate to obtain 48g of colorless oil, which is directly used in the next step.

[0064] IN4 NMR: 1 H NMR (400 MHz, CDCl3) δ 5.11 (qt, J = 7.1, 2.1 Hz, 1H), 2.43–2.30 (m, 1H), 2.28–2.12 (m, 2H), 1.91–1.82 (m, 1H), 1.81 (d, J = 7.1 Hz,2H), 1.71 (m, 2H), 1.65 (dt, J = 7.2, 2.0 Hz, 4H), 1.63–1.56 (m, 2H), 1.56–1.35 (m, 8H), 1.35–1.27 (m, 3H), 1.26 (s, 4H), 1.24–1.19 (m, 2H), 1.18–1.02(m, 4H), 0.87 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 150.58, 113.20, 77.36, 77.05,76.73, 72.11, 55.31, 44.51, 41.27, 40.49, 37.81, 37.29, 34.78, 34.59, 31.48,26.41, 26.05, 25.94, 25.43, 24.28, 16.91, 13.12. Embodiment 6: Synthesis of compound IN5 Weigh 48 g of IN4 obtained by the method of Example 5, dissolve it in 240 mL of DCM, cool to -20°C, stir, add 18 g of triethylamine, and then add 18 g of trimethylsilyl chloride. Monitor the reaction by TLC until most of the conversion is achieved. If a small amount of raw materials and most of the isomers remain unreacted, add 120 mL of water to stop the reaction, warm to room temperature and stir for 30 min, separate the liquids, wash twice with 120 mL of water again, separate the liquids, and concentrate to dryness.

[0065] Add 240 mL of petroleum ether and 30 g of silica gel, stir at room temperature for 3 h to adsorb unreacted raw materials and isomeric impurities, pad the Buchner funnel with 30 g of silica gel for filtration, pour the petroleum ether solution and silica gel, wash the silica gel with 60 mL of petroleum ether, collect the organic phase, and concentrate to obtain 52 g of colorless oil for the next reaction.

[0066] IN5 NMR: 1 H NMR (400 MHz, CDCl3) δ 5.18–5.05 (m, 1H), 2.77 (s, 2H), 2.74 (s, 1H), 2.36 (ddq, J = 16.7, 8.8, 1.8 Hz, 1H), 2.30–2.10 (m, 2H), 0.22 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ150.72, 113.33, 76.37, 55.45, 44.65, 41.94, 41.37, 40.51, 38.13, 37.46,35.21, 34.83, 31.80, 31.63, 31.60, 26.94, 26.20, 26.10, 25.52, 24.39, 17.06,13.26, -0.22, -1.17. Comparative Example 1 5 g of IN4 obtained by the method of Example 5 was weighed and dissolved in 50 mL of ethyl acetate, cooled to -20°C, stirred, 1.7 g of triethylamine was added, and then 1.7 g of trimethylsilyl chloride was added. The reaction was monitored by TLC. When the raw materials were not completely converted, the isomeric silane products were obviously generated and difficult to remove.

[0067] Comparative Example 2 5 g of IN4 obtained by the method of Example 5 was weighed and dissolved in 50 mL of dichloromethane, cooled to 0° C., stirred, 2.5 g of triethylamine was added, and then 2.5 g of trimethylsilyl chloride was added. The reaction was monitored by TLC. The raw material was converted quickly, and the isomer was completely converted into a silane product, which was difficult to remove.

[0068] Embodiment 7: Synthesis of compound IN6 Measure 300mL of tetrahydrofuran, add 5.2g of sodium borohydride, stir in an ice bath, replace with nitrogen, start to drop 25.8g of boron trifluoride ether, drop in 30min, and continue to react in an ice bath for 40min. Start to drop 52gIN5 of 4V tetrahydrofuran solution obtained by the method of Example 6, drop in 40min, continue to stir in an ice bath for 3h, monitor the remaining raw materials by TLC, drop an aqueous solution containing 37.5g of sodium hydroxide (40% concentration) in an ice bath after the reaction, drop carefully and slowly, and hydrogen is generated. After the drop, add 75g of hydrogen peroxide, stir for 1h, monitor the reaction by TLC, drop dilute sulfuric acid after the reaction, adjust the pH value to about 3-4 to hydrolyze the silane, add 300mL of isopropyl acetate after the reaction, stir and extract the liquid, extract the aqueous phase with 150mL of isopropyl acetate, merge the organic phase, wash the organic phase with 300mL of 5% sodium thiosulfate aqueous solution, and then wash with 200mL of water. The organic phase was concentrated to about 150 mL, 300 mL of methanol was added, concentrated again to 150 mL, 300 mL of methanol was added, concentrated to 150 mL, 150 mL of methanol was added, slurried, stirred in an ice bath for 1 h, filtered, and washed with cold methanol to obtain 21.2 g of IN6. The total yield of the four-step reaction of IN2 to IN6 was 42.4%.

[0069] Embodiment 8: Synthesis of Zulanolone Intermediate TM 20 g (62.5 mmol) of IN6 prepared in Example 7 was dissolved in a mixed solvent of 100 ml of acetonitrile and 20 ml of acetic acid, and after dissolution, it was placed in an ice bath, and 80 ml of sodium hypochlorite aqueous solution (7.5% concentration, about 80.5 mmol) was slowly added dropwise. After reacting for 4 hours, the conversion was basically complete. Sodium thiosulfate was added to quench the reaction, and most of the acetonitrile was removed by concentration. 100 ml of water was added for precipitation, and the mixture was filtered off with suction. After drying, the mixture was slurried twice with 100 ml of isopropyl ether to obtain 18.81 g of the product with a yield of 94.05%.

[0070] TM NMR: 1H NMR (400 MHz, CDCl3) δ 2.50 (t, J = 8.8 Hz, 1H), 2.16–2.09(m, 1H), 2.08 (s, 3H), 2.01–1.93 (m, 1H), 1.87–1.74 (m, 4H), 1.64 (m, 5H),1.40 (m, 7H), 1.30–1.24 (m, 2H), 1.23 (s, 4H), 1.18 (m, 2H), 1.14–0.99 (m,4H), 0.57 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 209.74, 71.96, 63.98, 55.76,44.39, 41.66, 41.12, 40.31, 39.08, 37.62, 34.69, 34.47, 31.54, 31.37, 26.47,26.05, 25.70, 25.41, 24.25, 22.81, 13.42. The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for synthesizing a zuranolone intermediate, characterized in that: The steps include: Compound IN1 is subjected to epoxidation reaction to obtain a 3-epoxy isomer mixture IN2, and then IN2 is added to petroleum ether or methanol and stirred, and non-target configuration isomers are removed by filtration, and the filtrate is concentrated and cooled to precipitate a solid, thereby obtaining an epoxidation product; The structural formulas of the compounds IN1 and IN2 are: 。 2. The method for synthesizing a zuranolone intermediate according to claim 1, characterized in that: The volume of the petroleum ether or methanol is 5 to 20 times the mass of IN2; and the stirring is carried out at 20 to 50° C. for 2 to 3 hours.

3. The method for synthesizing a zuranolone intermediate according to claim 1, characterized in that: The epoxidation reaction is to react compound IN1 with a base and trimethylsulfonium bromide in an organic solvent. After the reaction is completed, the reaction solution is extracted and separated with isopropyl ether and water, and the organic phase is concentrated to dryness to obtain IN2.

4. The method for synthesizing the zuranolone intermediate according to any one of claims 1 to 3, characterized in that: The following steps are also included: The obtained epoxy product was subjected to a wittig reaction to obtain the intermediate IN3; The intermediate IN3 is subjected to ring opening reduction to obtain the intermediate IN4; The intermediate IN4 is protected by silane etherification and split to obtain the intermediate IN5; The structural formulas of the intermediates IN3, IN4 and IN5 are: 。 5. The method for synthesizing a zuranolone intermediate according to claim 4, characterized in that: The silane protection and splitting comprises: subjecting the intermediate IN4 to a silane reaction with chlorosilane in an organic solvent under alkaline conditions, and then performing isomer splitting.

6. The method for synthesizing a zuranolone intermediate according to claim 5, characterized in that: The organic solvent is dichloromethane.

7. The method for synthesizing a zuranolone intermediate according to claim 5, characterized in that: The reaction temperature of the silane etherification reaction is controlled at -30°C to -15°C.

8. The method for synthesizing a zuranolone intermediate according to claim 5, characterized in that: The silane protection and separation also includes: after quenching the reaction with water, the silane reaction is heated to room temperature, stirred, and separated, and then the organic phase is replaced with a low-polarity solvent and silica gel is added, and stirred to absorb unreacted raw materials and isomer impurities.

9. The method for synthesizing a zuranolone intermediate according to claim 8, characterized in that: The low polarity solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane.

10. The method for synthesizing a zuranolone intermediate according to claim 8, characterized in that: The amount of silica gel added is 0.2-2 times the weight of the intermediate IN4, and stirring is performed for 3-4 hours after adding silica gel.

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