A process for the synthesis of a zuranolone intermediate

Abstract

The application discloses a synthesis method of a zuranolone intermediate, and comprises the following steps: obtaining a 3-position epoxide isomer mixture IN2 through an epoxidation reaction of a compound IN1, then stirring the IN2 in petroleum ether or methanol, removing a non-target configuration isomer through filtration, and cooling and precipitating a solid after concentrating the filtrate to obtain an epoxide product; the structural formula of the compound IN1 and IN2 is as follows: The application avoids a dangerous and expensive aluminum reagent, removes isomer impurities through improvement of the method, the preparation method is green and safe, some steps can be directly put into a next step reaction without purification, the operation is simple, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a zuranolone intermediate. BACKGROUND

[0002] Zuranolone, the chemical name of which is 3beta-methyl-3alpha-hydroxy-5beta-hydrogen-19-nor-20-keto-21-(1H-pyrazole-4-carbonitrile)-pregnane, has the following structural formula:

[0003]

[0004] In August 2023, the FDA approved zuranolone for the treatment of adult postpartum depression (PPD). Zuranolone is a neuroactive steroid produced by the US biopharmaceutical company Sage Therapeutics (SAGE.US) and the US pharmaceutical company Biogen (BIIB.US).

[0005] The compound TM is a key intermediate for synthesizing zuranolone, and it can be synthesized into zuranolone through two-step reactions.

[0006]

[0007] The synthesis method of zuranolone is described in the document “J. Med. Chem. 2017, 60, 7810-7819”, which uses the compound SM (4-ene-3,17-diketone estrone) as a raw material and synthesizes zuranolone through 7-step reactions, and the synthesis of the key intermediate 1 (compound TM) is 5-step reactions. Overall, the yield of each step of synthesizing the intermediate 1 is acceptable, and the total yield is 42.6%, but the second step of the synthesis process, the methylation reaction, needs to use MAD, which is extremely expensive, and it is synthesized by trimethylaluminum, which is also expensive, and more importantly, it is extremely flammable, and a large amount of methane gas is generated in the reaction, which is not conducive to the safety of industrial production.

[0008] SUMMARY

[0009] The technical problem to be solved by the application is to overcome the deficiencies and defects mentioned in the above background, and to provide a preparation method of a zuranolone intermediate which is cheap in starting materials and reagents, high in safety, and suitable for industrial production.

[0010] To solve the above technical problems, the technical scheme provided by the application is:

[0011] A synthesis method of a zuranolone intermediate, comprising the following steps:

[0012] The compound IN1 is subjected to an epoxidation reaction to obtain a mixture of 3-epoxy isomers IN2, then IN2 is stirred in petroleum ether or methanol, the non-target isomer is removed by filtration, and the filtrate is concentrated and cooled to precipitate a solid, which is the epoxy product;

[0013] The structural formula of the compound IN1 and IN2 is:

[0014] .

[0015] As a further improvement, the volume of petroleum ether or methanol is 5-20 times the mass of IN2; the stirring is at 20-50°C for 2-3h.

[0016] As a further improvement, the epoxidation reaction is a reaction of compound IN1 with a base and trimethylsulfonium bromide in an organic solvent, after the reaction is complete, the reaction liquid is extracted with isopropyl ether and water, separated, and the organic phase is concentrated to dryness to obtain IN2.

[0017] As a further improvement, it further comprises the following steps:

[0018] The obtained epoxy product is subjected to a Wittig reaction to obtain intermediate IN3;

[0019] The intermediate IN3 is subjected to a reduction ring-opening reaction to obtain intermediate IN4;

[0020] The intermediate IN4 is subjected to silyl ether protection and separation to obtain intermediate IN5;

[0021] The structural formula of the intermediate IN3, intermediate IN4, and intermediate IN5 is:

[0022] .

[0023] As a further improvement, the silyl ether protection and separation comprises: under alkaline conditions, the intermediate IN4 is subjected to a silyl ether reaction with chlorosilane in an organic solvent, and then subjected to isomer separation.

[0024] As a further improvement, the organic solvent is dichloromethane.

[0025] As a further improvement, the silyl ether reaction is controlled at a reaction temperature of -30°C to -15°C.

[0026] As a further improvement, the silyl ether protection and separation further comprises: the silyl ether reaction, after quenching the reaction with water, stirring at room temperature, separating, then replacing the organic phase with a low-polarity solvent and adding silica gel, and stirring to adsorb unreacted raw materials and isomer impurities.

[0027] As a further improvement, the low polarity solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane.

[0028] As a further improvement, the silica gel is added in an amount of 0.2-2 times the weight of intermediate IN4 and stirred for 3-4h after the addition of the silica gel.

[0029] Compared with the prior art, the present application has the following advantages:

[0030] The present application uses 4-ene-3,17-diketosteroid (SM) as a raw material to prepare the key intermediate TM of the target product zuranolone through 7 steps of reaction, and the starting compound is relatively cheap and can be obtained from the market, which is convenient to source. The method for 3-methylation is improved in the present application, although the reaction steps are increased and the reaction yield is reduced, but the dangerous and expensive aluminum reagent is avoided. The present application uses the solubility difference of 3-position epoxide isomers (IN2) to remove the isomers, and further removes the isomers by using the reactivity difference of 3-position hydroxyl groups of two configurations. Moreover, the preparation method of the present application is green and safe, some steps can be directly used in the next step reaction without purification, the operation is simple, and it is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art description. Obviously, the drawings described below are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0032] Figure 1 The nuclear magnetic hydrogen spectrum of IN-1 is shown in Figure 1;

[0033] Figure 2 The nuclear magnetic carbon spectrum of IN-1 is shown in Figure 2;

[0034] Figure 3 The nuclear magnetic hydrogen spectrum of IN-2 isomer is shown in Figure 3;

[0035] Figure 4 The nuclear magnetic carbon spectrum of IN-2 isomer is shown in Figure 4;

[0036] Figure 5 The nuclear magnetic hydrogen spectrum of IN-2 target configuration is shown in Figure 5;

[0037] Figure 6 The nuclear magnetic carbon spectrum of IN-2 target configuration is shown in Figure 6;

[0038] Figure 7 The nuclear magnetic hydrogen spectrum of IN-3 is shown in Figure 7;

[0039] Figure 8NMR of IN-3;

[0040] Figure 9 NMR of IN-4;

[0041] Figure 10 NMR of IN-4;

[0042] Figure 11 NMR of IN-5;

[0043] Figure 12 NMR of IN-5;

[0044] Figure 13 NMR of TM;

[0045] Figure 14 NMR of TM;

[0046] Figure 15 NMR of IN2, a mixture of 3-epi isomers;

[0047] Figure 16 NMR of IN2, a mixture of 3-epi isomers, after slurry with petroleum ether;

[0048] Figure 17 TLC of IN5. DETAILED DESCRIPTION

[0049] For the purpose of promoting an understanding of the principles of the application, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same. It will, nevertheless, be understood that no limitation of the scope of the application is intended by the use of such specific language.

[0050] Unless otherwise defined, all terms used in connection with the present application, are to be interpreted according to their ordinary meaning to a person skilled in the art. The professional terms used in the present application are only for the purpose of describing the specific embodiments and are not intended to limit the scope of the present application.

[0051] Unless otherwise specified, the various materials, reagents, instruments and equipment used in the present application can be purchased on the market or can be prepared by the existing methods.

[0052] In some embodiments, the preparation method of the present application uses 4-ene-3, 17-diketosteroid (SM) as the raw material to prepare the intermediate 1 (compound TM) of zuranolone. The raw material SM can be obtained from the market and has a low cost. The synthetic route is as follows:

[0053]

[0054] The synthetic route includes the following steps:

[0055] (1) The raw material SM is reduced by hydrogenation to obtain the intermediate IN1;

[0056] In some embodiments, SM is dissolved in an organic solvent, and then palladium-carbon is added to react under a hydrogen atmosphere. The reaction is carried out at normal pressure and room temperature. After the hydrogenation reaction is completed, IN1 is obtained by post-treatment, and can be directly used in the next step without purification.

[0057] In some embodiments, the organic solvent is ethanol, methanol, ethyl acetate, dichloromethane, tetrahydrofuran, or a mixed solvent thereof, preferably tetrahydrofuran, and the amount of solvent used is 4 to 20 times the volume of SM.

[0058] In some 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.

[0059] An acid or a base can be added to adjust the reaction speed and stereoselectivity. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, or sulfuric acid, and the base is triethylamine or pyridine, preferably hydrobromic acid.

[0060] (2) IN1 is subjected to epoxidation to obtain a mixture of 3-epoxy isomers IN2;

[0061] In some embodiments, IN1 is dissolved in an organic solvent, a base and trimethylsulfonium bromide are added, and the reaction is carried out. After the reaction is completed, post-treatment is carried out.

[0062] In some 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, and the volume ratio of the mixed solvent of DMSO and THF is 1:3 to 3:1.

[0063] In some embodiments, the base is potassium hydroxide powder, sodium hydroxide powder, or sodium ethoxide, the amount of potassium hydroxide or sodium hydroxide added is 0.3 to 0.8 times the weight of IN1, and the amount of sodium ethoxide added is an equimolar amount of the amount of trimethylsulfonium bromide added.

[0064] In some embodiments, the amount of trimethylsulfonium bromide used is 1 to 1.1 times the molar amount of IN1. The reaction temperature is 10-30°C, and the reaction time is 6h-24h.

[0065] In some embodiments, the reaction is post-treated to obtain a mixture of 3-epoxy isomers IN2. The post-treatment process is as follows: the reaction solution is extracted with isopropyl ether and water, the organic phase is concentrated to dryness to obtain IN2. Then, petroleum ether or methanol is added to IN2, and the mixture is stirred at elevated temperature for 2-3h, cooled, filtered to remove the 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.

[0066] The isomer impurities cannot be dissolved in petroleum ether or methanol, and the petroleum ether or methanol is mainly used to dissolve the target product. Heating is beneficial to the dissolution, and filtration can remove the isomers. Preferably, the volume of petroleum ether or methanol is 5-20 times the mass of IN2. Preferably, the temperature is increased to 20-50°C.

[0067] The IN2 obtained by the reaction is a mixture of 3-position isomers, and the 3β methylene configuration of the target product accounts for about 50-60% according to the nuclear magnetic resonance spectrum, such as Figure 15 (the target configuration characteristic peak shifts to 2.57, and the isomer is 2.61). After studying a series of solvents, it is found that the two configurations have large solubility differences in petroleum ether or methanol. After beating with petroleum ether or methanol, most of the isomers can be removed, and the proportion of the target configuration is increased to about 90%, such as Figure 16 If other solvents such as dichloromethane, acetone or tetrahydrofuran are used for beating, the solubility difference between the two configurations is not large, and it is difficult to separate them.

[0068] (3) IN2 is subjected to Wittig reaction to obtain intermediate IN3;

[0069] In some specific embodiments, ethyl triphenyl phosphonium 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 triphenyl phosphine oxide are removed to obtain IN3 for the next step.

[0070] In some specific embodiments, the amount of ethyl triphenyl phosphonium bromide added is 1.2-3 times the molar amount of IN2, and the amount of potassium tert-butoxide added is 1 times the molar amount of ethyl triphenyl phosphonium bromide.

[0071] In some specific embodiments, the reaction temperature for preparing phosphorus ylide from ethyl triphenyl phosphonium bromide and potassium tert-butoxide is -10-10°C, and the reaction temperature for the reaction between the phosphorus ylide and IN2 is 40-60°C.

[0072] (4) IN3 is subjected to reduction ring opening to obtain intermediate IN4;

[0073] In some specific embodiments, IN4 is dissolved in an organic solvent, and lithium aluminum hydride is added to obtain IN4.

[0074] In some specific embodiments, the organic solvent is tetrahydrofuran or diethyl ether, preferably tetrahydrofuran, and the amount of the organic solvent added is 6-20 times the volume of IN4. The amount of lithium aluminum hydride added is 0.07 to 0.2 times the weight of IN4.

[0075] (5) IN4 is subjected to silyl ether protection and separation to obtain intermediate IN5;

[0076] Due to the incomplete removal of isomers in IN2, the 3-hydroxyl isomer is contained in IN4. By selectively silylating a certain configuration, the 3-hydroxyl isomer is removed by the difference in polarity. The hydroxyl group of the target configuration is a flat-bonded hydroxyl group, which is more prone to silylation, while the isomer is a straight-bonded hydroxyl group, which is difficult to react. In addition, after silylation of the 3-hydroxyl group, it is beneficial to avoid the reaction of the hydroxyl group with borane in the next step of borohydride oxidation, avoiding the problem of borane performing tandem on the steroid molecule to make the solution solidify and difficult to stir.

[0077] In some embodiments, the target product is silylated by dissolving IN4 in an organic solvent under basic conditions, controlling the temperature and the amount of chlorosilane added, while the isomer does not undergo silylation. Then, the chlorosilane and the generated salt are 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.

[0078] In some embodiments, the organic solvent is dichloromethane. If petroleum ether or ethyl acetate is used as the solvent, there is essentially no selectivity in the reaction of the target configuration and the isomer with trimethylchlorosilane, and the selectivity is poor when acetone is used as the solvent. TLC shows that dichloromethane has a clear advantage in the selectivity of the reaction of the target configuration.

[0079] Figure 17 The left graph shows that the ratio of the isomer and the target configuration in the starting material S of this step of silylation reaction is about 1:9, and after the reaction using dichloromethane as the solvent, the silylation conversion of the target configuration is faster, and the ratio of the target configuration that does not undergo silylation in the starting material S becomes about 1:1, indicating that the silylation speed of the target configuration is significantly faster than that of the isomer. The middle graph shows that after changing the developing agent to petroleum ether, no silylated product of the isomer is found in the reaction, and the isomer basically does not undergo silylation, and the isomer and the unreacted target configuration and other impurities are at the origin in the petroleum ether developing agent, which are easily adsorbed and removed by silica gel.

[0080] Figure 17 The right graph is the silylation reaction using petroleum ether or ethyl acetate as the reaction solvent, and both the target configuration and the isomer undergo silylation, and the silylation reaction has no selectivity.

[0081] In some embodiments, the basic condition is the addition of triethylamine or pyridine, and the amount of triethylamine or pyridine added is 1.0-1.5 times the molar amount of chlorosilane.

[0082] In some embodiments, the reaction temperature is -30°C to -15°C. If the reaction temperature is too high, the selectivity decreases, and the end point of the reaction is difficult to control; if the temperature is too low, the reaction time is too long.

[0083] In some embodiments, the chlorosilane is trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane, and the amount of chlorosilane added is 1.0-1.5 times the amount of IN4. The amount of trimethylchlorosilane is too large, and it is difficult to control the end of the reaction.

[0084] In some embodiments, the post-treatment process is: stopping the reaction by adding water, stirring at room temperature, and separating the liquid. After replacing the organic phase with a low-polarity solvent and adding silica gel, stirring for 3-4 hours, adsorbing unreacted raw materials and isomer impurities, filtering, and collecting the organic phase.

[0085] In some embodiments, the low-polarity solvent is petroleum ether, n-hexane, n-heptane, or cyclohexane, and the amount of low-polarity solvent added is 8-20 times the amount of IN4. The amount of silica gel added is 0.2-2 times the amount of IN4 by weight, and the particle size of the silica gel is 80-600 mesh, preferably 200-300 mesh.

[0086] (6) IN5 is subjected to borohydride oxidation and deprotection to obtain intermediate IN6;

[0087] In some embodiments, after IN5 is subjected to borohydride reaction with borane, it is reacted with hydrogen peroxide under alkaline conditions to introduce a hydroxyl group at position 20, and finally the reaction solution is adjusted to be acidic (pH 3-4) to remove the siloxane to obtain intermediate IN6. The product generally has two products, and the two products are isomers at position 20.

[0088] In some embodiments, the borane is a commercial borane-tetrahydrofuran solution, a borane-dimethyl sulfide-tetrahydrofuran solution, or can also be prepared by sodium borohydride. The amount of borane added is 0.5-2 times the amount of IN5 by mole. 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 amount of IN5 by mole.

[0089] (7) IN6 is subjected to oxidation reaction to obtain the target product TM;

[0090] In some embodiments, the hydroxyl group at position 20 of IN6 can be oxidized to generate 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 after post-treatment and purification.

[0091] The "room temperature" in the present application has the general meaning in the art, for example, 15-35°C.

[0092] The technical solutions of the present application are described in detail below through specific embodiments.

[0093] Example 1:

[0094] Synthesis of compound IN1

[0095] Take SM 100 g, add 600 mL tetrahydrofuran, 2 mL hydrobromic acid solution, room temperature stirring, nitrogen replacement, add 5 g palladium carbon (containing 10% palladium), hydrogen replacement, placed in normal pressure hydrogen atmosphere, room temperature reaction until raw material disappears. Add 300 mL dichloromethane, dissolve the product, remove the palladium carbon by suction filtration, concentrate the organic phase to obtain the product, the ratio of 5β configuration: 5α configuration at position 5 is 98:2, and it is directly used in the next step without purification.

[0096] 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.

[0097] Example 2

[0098] Synthesis of compound IN1

[0099] Take SM 100 g, add 500 mL tetrahydrofuran and 500 mL dichloromethane, 2 mL hydrobromic acid solution, room temperature stirring, nitrogen replacement, add 5 g palladium carbon (containing 10% palladium), hydrogen replacement, placed in normal pressure hydrogen atmosphere, room temperature reaction until raw material disappears. Remove the palladium carbon by suction filtration, 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 used in the next step without purification.

[0100] Example 3:

[0101] Synthesis of compound IN2

[0102] Take 20 ml DMSO and 20 mL tetrahydrofuran, add 5 g sodium hydroxide powder, 10-15 ℃ stirring, then add IN1 10 g obtained by the method of Example 1, finally add 5.7 g trimethylsulfonium bromide, 15-20 ℃ reaction overnight, TLC monitoring to reaction complete.

[0103] Take 40 mL isopropyl ether and 100 mL ice water, stir, slowly pour the reaction liquid into the extraction, separate, the aqueous phase is extracted with 2V isopropyl ether once, the organic phase is washed with 20 mL water twice, concentrated to dryness, IN2 is obtained, which is a mixture of two isomers of 3-position epoxide, the ratio of target configuration and isomer is about 56%:44% (calculated according to the peak area ratio of nuclear magnetic hydrogen spectrum).

[0104] Add 100 mL petroleum ether to the obtained mixture of isomers of epoxide, 30 ℃ stirring for 2 h, a large amount of solid precipitates, suction filtration, the solid is basically the isomer of epoxide, the ratio of target configuration and isomer in the solution is improved to about 90%:10%. Concentrate the petroleum ether mother liquor to about 20 mL, cool to 0-5 ℃, precipitate solid, suction filtration, about 4.5 g of IN2 of target configuration is obtained, the total yield of the first two steps is 45%.

[0105] Isomer IN2 nuclear magnetic resonance: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.

[0106] Nuclear magnetic resonance of IN2 of target configuration: 1H 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). 13 C 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.

[0107] Example 4:

[0108] Synthesis of compound IN3

[0109] Weigh 128g of ethyltriphenylphosphine bromide and add 350mL of tetrahydrofuran. Under nitrogen protection, in an ice bath, stir. Add 38.5g of potassium tert-butoxide solid. The reaction solution turns orange-red. Stir in an ice-water bath for 1 hour. Add 50g of IN2 obtained by the method in Example 3 to the reaction solution. Heat to 50°C and react for about 2 hours until complete. Cool to room temperature, filter, wash the filter cake with 150mL of petroleum ether, concentrate the organic phase, and after concentrating to dryness, add 500mL of petroleum ether. Heat to 50°C to dissolve for 2 hours. Cool to room temperature, filter, wash the filter cake with 100mL of petroleum ether, combine the organic phases, add 25g of silica gel to the organic phase, stir at room temperature for 1 hour, filter, wash the filter cake with 50mL of petroleum ether, combine the organic phases, concentrate to dryness to obtain a colorless oil, which is directly added to the next step.

[0110] IN3 NMR: 1H NMR (400 MHz, CDC13) 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). 13 C NMR (101 MHz, CDC13) 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.

[0111] Example 5:

[0112] Synthesis of compound IN4

[0113] IN3 prepared from 50 g of IN2 by the method of Example 4 was weighed out, 300 mL of tetrahydrofuran was added, and stirring was carried out in an ice bath. 5 g of lithium aluminum hydride was added, and the reaction was gradually warmed to room temperature until the starting material disappeared. The reaction was quenched in stages with ethyl acetate and water, and the reaction liquid gradually became a white turbid liquid. Filtration was carried out under suction, and the filter cake was washed with 2 V of dichloromethane. The organic phases were combined, dried, and concentrated to give 48 g of a colorless oil, which was used directly in the next reaction.

[0114] NMR of IN4: 1H 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.

[0115] Example 6:

[0116] Synthesis of compound IN5

[0117] Take 48 g IN4 obtained from the method of Example 5, dissolve in 240 mL DCM, cool to -20 °C, stir, add 18 g triethylamine, then add 18 g trimethylchlorosilane, monitor the reaction by TLC until most of the conversion, add 120 mL water to stop the reaction when there is a small amount of starting material and most of the isomer unreacted, stir at room temperature for 30 min, separate the liquid, wash twice with 120 mL water, separate the liquid, and concentrate to dryness.

[0118] Add 240 mL petroleum ether and 30 g silica gel, stir at room temperature for 3 h to adsorb unreacted starting material and isomer impurities, pad a Buchner funnel with 30 g silica gel to prepare for filtration, pour the petroleum ether solution and silica gel into the funnel, then wash the silica gel with 60 mL petroleum ether, collect the organic phase, and concentrate to obtain 52 g of colorless oil for the next step.

[0119] NMR of IN5: 1H NMR (400 MHz, CDC13) 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), 1.90 - 1.63 (m, 8H), 1.63 - 1.52 (m, 3H), 1.49 - 1.28 (m, 7H), 1.27 (s, 4H), 1.26 - 1.02 (m, 6H), 0.87 (s, 3H), 0.25 (s, 6H), 0.22 (s, 3H). 13 C NMR (101 MHz, CDC13) δ 150.72, 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.

[0120] Comparative Example 1

[0121] Take 5g IN4 obtained by the method of Example 5, dissolved in 50mL ethyl acetate, cooled to -20°C, stirred, added 1.7g triethylamine, then added 1.7g trimethylchlorosilane, TLC monitoring reaction, the starting material was not converted, and the isomer silylether product was obviously generated, which was difficult to remove.

[0122] Comparative Example 2

[0123] Take 5g IN4 obtained by the method of Example 5, dissolved in 50mL dichloromethane, cooled to 0°C, stirred, added 2.5g triethylamine, then added 2.5g trimethylchlorosilane, TLC monitoring reaction, the starting material was converted faster, and the isomer was completely converted to the silylether product, which was difficult to remove.

[0124] Example 7:

[0125] Synthesis of compound IN6

[0126] To IN5 (52 g, 0.1 mol) in 300 mL of THF was added 5.2 g of NaBH4. The mixture was stirred in an ice bath under a nitrogen atmosphere. The addition of 25.8 g of boron trifluoride etherate was started and completed in 30 min. The reaction was continued in an ice bath for 40 min. The addition of 52 g of IN5 in 400 mL of THF was started and completed in 40 min. The reaction was continued in an ice bath for 3 h. TLC monitoring showed that the starting material was consumed. The reaction was quenched by the dropwise addition of 37.5 g of NaOH (40%) in 300 mL of water. The mixture was stirred for 1 h. The reaction was monitored by TLC. The reaction was quenched by the dropwise addition of 75 g of H2O2. The mixture was stirred for 1 h. The reaction was monitored by TLC. The reaction was quenched by the dropwise addition of 300 mL of dilute H2SO4. The pH was adjusted to 3-4. The mixture was stirred for 1 h. The reaction was monitored by TLC. The reaction was quenched by the dropwise addition of 300 mL of isopropyl acetate. The mixture was stirred for 1 h. The organic phase was separated. The aqueous phase was extracted with 150 mL of isopropyl acetate. The combined organic phase was washed with 300 mL of 5% Na2S2O3 and 200 mL of water. The organic phase was concentrated to 150 mL. The mixture was added to 300 mL of MeOH. The mixture was concentrated to 150 mL. The mixture was added to 300 mL of MeOH. The mixture was concentrated to 150 mL. The mixture was added to 150 mL of MeOH. The mixture was concentrated to 150 mL. The mixture was stirred in an ice bath for 1 h. The mixture was filtered. The filter cake was washed with cold MeOH. IN6 was obtained as a white solid (21.2 g). The overall yield of IN6 from IN2 was 42.4%.

[0127] Example 8:

[0128] Synthesis of Zolano Intermediates TM

[0129] IN6 (20 g, 62.5 mmol) prepared in Example 7 was dissolved in a mixture of 100 mL of acetonitrile and 20 mL of acetic acid. The mixture was stirred in an ice bath. 80 mL of NaClO2 (7.5%) was added dropwise. The reaction was stirred for 4 h. The reaction was quenched by the addition of Na2S2O3. The mixture was concentrated. The mixture was added to 100 mL of water. The mixture was filtered. The filter cake was dried. The mixture was added to 100 mL of isopropyl ether. The mixture was filtered. The filter cake was washed with isopropyl ether. The product was obtained as a white solid (18.81 g). The yield was 94.05%.

[0130] TM NMR: 1 H 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). 13C 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.

[0131] The above is only the preferred embodiment of the present application, and does not limit the present application in any form. Therefore, any simple modification, equivalent change and modification of the above embodiment according to the technical essence of the present application, without departing from the technical scheme of the present application, shall fall within the protection scope of the technical scheme of the present application.

Claims

1. A method of synthesizing a zuranolone epoxy intermediate, characterized in that, The method comprises the following steps: The compound IN1 is subjected to an epoxidation reaction to obtain an isomer mixture of 3-epoxy IN2, then the IN2 is stirred in petroleum ether, the non-target isomer is removed by filtration, and the filtrate is concentrated and cooled to precipitate a solid, thereby obtaining the epoxy product; The compound IN1 and IN2 have the following structural formula: 。 2. The process for the synthesis of zuranolone epoxy intermediate according to claim 1, characterized by, The volume of the petroleum ether is 5-20 times the mass of the IN2; the stirring is performed at 20-50 DEG C for 2-3 h.

3. The process for the synthesis of zuranolone epoxy intermediate according to claim 1, characterized by, The epoxidation reaction is performed by reacting the compound IN1 with a base and trimethylsulfonium bromide in an organic solvent, after the reaction is completed, the reaction solution is extracted with isopropyl ether and water, the organic phase is concentrated to dryness, thereby obtaining the IN2.

4. A process for the synthesis of zanolimumab intermediate IN5, characterized by, The method for synthesizing the zuranolone epoxy intermediate according to any one of claims 1-3 further comprises the following steps: The obtained epoxy product is subjected to a wittig reaction to obtain the intermediate IN3; The intermediate IN3 is subjected to a reduction ring-opening reaction to obtain the intermediate IN4; The intermediate IN4 is subjected to a silyl etherification protection and separation to obtain the intermediate IN5; The intermediate IN3, the intermediate IN4 and the intermediate IN5 have the following structural formula: 。 5. The process for the synthesis of zuranolone intermediate IN5 according to claim 4, characterized by, The silyl etherification protection and separation comprises: under alkaline conditions, the intermediate IN4 is subjected to a silyl etherification reaction with chlorosilane in an organic solvent, and then subjected to isomer separation.

6. The process for the synthesis of zuranolone intermediate IN5 according to claim 5, characterized by, The organic solvent is dichloromethane.

7. A process for the synthesis of zuranolone intermediate IN5 according to claim 5, characterized by, The silyl etherification reaction is controlled at a temperature of-30 DEG C to-15 DEG C.

8. The process for the synthesis of zuranolone intermediate IN5 according to claim 5, characterized by, The silyl etherification protection and separation further comprises: after the silyl etherification reaction is quenched with water, the reaction is stirred at room temperature, the liquid is separated, then the organic phase is replaced with a low-polarity solvent and silica gel is added, and the stirring is performed to adsorb the unreacted raw material and isomer impurities.

9. The process for the synthesis of the zanolamide intermediate IN5 according to claim 8, characterized by, The low-polarity solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane.

10. A process for the synthesis of zanolimum intermediate IN5 according to claim 8, characterized by, The added amount of the silica gel is 0.2-2 times the weight of the intermediate IN4, and the stirring is performed for 3-4 h after the silica gel is added.

Images