Preparation method of suvorexant

Abstract

The invention relates to a preparation method of suvorexant, which comprises the following steps: (1) dissolving a compound VIII (R)-4-(5-chlorobenzo [d] oxazole-2-yl)-7-methyl-1, 4-diazacycloheptane-1-carboxylic acid tert-butyl ester in a reaction solvent, adding an acidic reagent at the temperature of 5-15 DEG C, and reacting at the temperature of 25-35 DEG C to prepare a compound IX (R)-5-chloro-2-(5-methyl-1, 4-diazacycloheptane-1-carboxylic acid tert-butyl ester; 2, 4-diazacycloheptane-1-yl) benzo [d] oxazole is used as a raw material; and (2) in an alkaline environment and an aprotic solvent, carrying out acylation nucleophilic reaction on the compound IX and 5-methyl-2-(2H-1, 2, 3-triazole-2-yl) benzoic acid to obtain the suvorexant. According to the preparation method, the obtained product is high in yield, the purity reaches 99.9% or above, and the intermediate product is good in character, few in impurity and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a method for preparing suvorexin. Background Technology

[0002] Orexin is a neuropeptide involved in the regulation of the sleep-wake cycle and plays an important role in maintaining wakefulness. Belsomra is an orexin receptor antagonist that improves sleep by blocking orexin's signaling. On August 13, 2014, the U.S. Food and Drug Administration (FDA) approved Merck's new sleep drug Belsomra.

[0003] The following literature reports the synthetic route of Suvoresen:

[0004] The synthetic route (Route 1) reported in US2008 / 132490 is as follows:

[0005]

[0006] The synthetic route (route two) reported in WO2012148553 and J.Am.Chem.Soc.2011,133,8362-8371 is as follows:

[0007]

[0008] The two routes mentioned above have the following drawbacks: both use highly toxic methyl vinyl ketone as a starting material. Methyl vinyl ketone is a strong irritant to the eyes, skin, mucous membranes, and upper respiratory tract, making it difficult to handle and expensive. In addition, Route 1 requires chiral column separation during the preparation process, which requires a large amount of expensive chromatographically pure solvents, making it unsuitable for large-scale industrial production, and the overall yield of the route is low. Route 2 uses ruthenium-catalyzed asymmetric reduction amination to obtain a chiral intermediate with a purity ee value of only 94%, requiring further chiral separation. At the same time, this route is costly and environmentally unfriendly.

[0009] The synthetic route (Route 3) reported in WO2016020406 is as follows:

[0010]

[0011] This route uses N-benzylethylenediamine as a raw material to prepare svorex. The preparation process uses reagents such as DBU, ketene, cyanuric acid, and Cu(OAc)₂, and also uses (+)₂,3-dibenzoyl-D-tartaric acid for resolution, but the ee value is not disclosed. The entire process is lengthy and the reaction operation is cumbersome. Furthermore, the resolution using general resolving agents is not kinetic, and the atom utilization rate is not high, leading to increased costs and hindering commercial production.

[0012] In summary, there is an urgent need to develop new synthetic methods for suvoresen and its intermediate compounds to solve the problems of low yield, high cost and environmental unfriendliness in existing technologies. Summary of the Invention

[0013] The purpose of this invention is to provide a method for preparing suvorexin, comprising the following steps:

[0014] (1) Compound VIII(R)-4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester was dissolved in a reaction solvent, and an acidic reagent was added at 5-15℃. The reaction was carried out at 25-35℃ to prepare compound IX(R)-5-chloro-2-(5-methyl-1,4-diazacycloheptane-1-yl)benzo[d]oxazol;

[0015] (2) In an alkaline environment and an aprotic solvent, compound IX was reacted with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid by an acylation nucleophilic reaction to obtain suvoresen.

[0016] In a preferred embodiment of the present invention, in step (1), the acidic reagent is selected from an acid or a solvation of an acid, wherein the acid is selected from HCl, HBr, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid or any one or a combination thereof, and the solvation of the acid is selected from a solvation of HCl, preferably selected from any one or a combination of HCl / ethyl acetate, HCl / methanol or HCl / 1,4-dioxane.

[0017] In a preferred embodiment of the present invention, in step (1), the amount of acid used is 1-20 eq of compound VIII, preferably 1-15 eq.

[0018] In the preferred embodiment of the present invention, in step (1), an acidic reagent is added at 10-15°C and the reaction is carried out at 30-35°C.

[0019] In a preferred embodiment of the present invention, in step (1), the reaction solvent is selected from any one or a combination of ethyl acetate, dichloromethane, N,N-dimethylformamide, acetonitrile, toluene, methanol, and ethanol.

[0020] In the preferred embodiment of the present invention, in step (1), the volume-to-mass ratio of the reaction solvent to compound VIII is 1-20:1, preferably 1-10:1.

[0021] In a preferred embodiment of the present invention, the concentration of ethyl hydrochloride is 1N-6N, preferably 3N-4N.

[0022] In the preferred embodiment of the present invention, step (1) further includes a purification step of compound IX, wherein the purification step includes: dissolving in methanol, refluxing, adding isopropyl acetate, stirring slowly at 15-30°C, precipitating a white solid, filtering the solution, adding dichloromethane, and adjusting the pH to 10-14 with alkali, preferably to 11-13.

[0023] In a preferred embodiment of the present invention, step (2) includes:

[0024] (S-1) Dissolve 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in an aprotic solvent, and add acyl chloride dropwise to prepare an acyl chloride intermediate compound. Preferably, the acyl chloride is selected from any one or a combination of oxalyl chloride, sulfonyl chloride, and phosphorus oxychloride.

[0025] (S-2) Compound IX was dissolved in an aprotic solvent, and the acyl chloride intermediate compound from (S-1) was added dropwise. A base was added, and the reaction was carried out to obtain svorexin.

[0026] In the preferred embodiment of the present invention, in steps (S-1) and (S-2), the aprotic solvent is selected from any one or a combination of isopropyl acetate, acetonitrile, tetrahydrofuran, toluene, dichloromethane, and N,N-dimethylformamide solvent.

[0027] In the preferred embodiment of the present invention, in step (S-1), after adding acyl chloride dropwise and stirring to evaporate to dryness, the mixture is then dissolved in an aprotic solvent to prepare an acyl chloride intermediate compound.

[0028] In the preferred embodiment of the present invention, in step (S-2), the volume-to-mass ratio of the aprotic solvent to compound IX is 1-15:1, preferably 1-8:1.

[0029] In a preferred embodiment of the present invention, in step (S-2), the base is selected from any one or a combination of triethylamine, 1,8-diaminobicyclo(5.4.0)undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), N-methylmorpholine, N-methylpiperazine, or piperidine.

[0030] In the preferred embodiment of the present invention, in step (S-2), the amount of alkali used is 1-10 eq of compound IX, preferably 1-3 eq.

[0031] In a preferred embodiment of the present invention, the purification step of the suvoresen includes: recrystallization using isopropyl acetate and n-heptane, and optionally the addition of suvoresen seed crystals.

[0032] In the preferred embodiment of the present invention, the volume ratio of isopropyl acetate to n-heptane is 1:2-10, preferably 1:3-7.5.

[0033] In the preferred embodiment of the present invention, the volume-to-mass ratio of isopropyl acetate to suvaisen is 1:1-2, preferably 1:1.2-1.5.

[0034] In a preferred embodiment of the present invention, compound VIII is prepared by reacting tert-butyl ester of compound VII(R)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid in a reaction solvent with 2,5-dichlorobenzoxazole under alkaline conditions.

[0035] In a preferred embodiment of the present invention, in the preparation of compound VIII, the base is selected from any one or a combination of triethylamine, pyridine, N-methylmorpholine, piperidine, N-methylpiperazine, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium hydride, and diisopropylethylamine.

[0036] In a preferred embodiment of the present invention, in the preparation of compound VIII, the amount of alkali used is 1-10 eq of compound VII, preferably 1-3 eq.

[0037] In a preferred embodiment of the present invention, the reaction solvent in the preparation of compound VIII is selected from one or a combination of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, methanol, acetonitrile, ethyl acetate, etc.

[0038] In a preferred embodiment of the present invention, in the preparation of compound VIII, the volume-to-mass ratio of the reaction solvent to compound VII is 1-20:1, preferably 1-15:1.

[0039] In a preferred embodiment of the present invention, the preparation of compound VIII further includes a purification step of compound VIII, the purification step comprising: dichloromethane extraction, collection of the organic phase, washing and extraction with an acid solution, wherein the acid is selected from any one or a combination of citric acid, fumaric acid, and dilute hydrochloric acid.

[0040] In a preferred embodiment of the present invention, compound VII is prepared by dissolving compound VI(R)-4-benzyl-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester in a reaction solvent and reacting it under reducing catalyst conditions.

[0041] In a preferred embodiment of the present invention, in the preparation of compound VII, the reduction catalyst is selected from any one of Pd / C, Pt / C, and Ru / C, and undergoes a catalytic reduction reaction together with hydrogen.

[0042] In a preferred embodiment of the present invention, the reaction solvent in the preparation of compound VII is selected from any one or a combination of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran (THF), and dioxane.

[0043] In a preferred embodiment of the present invention, in the preparation of compound VII, the volume-to-mass ratio of the reaction solvent to compound VI is 1-15:1, preferably 1-10:1.

[0044] In a preferred embodiment of the present invention, compound VI is prepared by dissolving compound V(R)-1-benzyl-5-methyl-1,4-diazacycloheptane in a reaction solvent and reacting it with a BOC protecting group at 5-15°C in the presence of a base.

[0045] In a preferred embodiment of the present invention, in the preparation of compound VI, the base is selected from any one or a combination of triethylamine, N-methylmorpholine, piperidine, N-methylpiperazine, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium hydride, and diisopropylethylamine.

[0046] In a preferred embodiment of the present invention, in the preparation of compound VI, the amount of alkali used is 1-10 eq of compound V, preferably 1-5 eq.

[0047] In a preferred embodiment of the present invention, the BOC protecting group is selected from either BOC anhydride (di-tert-butyl dicarbonate) or BOC-Cl (tert-butyloxycarbonyl chloride).

[0048] In a preferred embodiment of the present invention, the amount of the BOC protecting group is 1-10 eq of compound V, preferably 1-5 eq.

[0049] In a preferred embodiment of the present invention, in the preparation of compound VI, the reaction solvent is selected from C1-C4 lower alcohols or haloalkanes, preferably from any one or a combination of methanol, ethanol, and 1,2-dichloroethane.

[0050] In a preferred embodiment of the present invention, in the preparation of compound VI, after obtaining compound VI, the reaction solution is evaporated to dryness, citric acid or citric acid monohydrate is added, and the mixture is extracted with an organic solvent. The aqueous phase is taken, and the pH is adjusted to 7-10 with alkali. The mixture is then extracted with an organic solvent, washed, and dried to obtain the final product. The preferred pH is 8-9.

[0051] In a preferred embodiment of the present invention, compound V is prepared by dissolving compound IV(R)-4-benzyl-7-methyl-1,4-diazacycloheptane-2,5-dione in a reaction solvent and undergoing a reduction reaction at 5-25°C under a reducing catalyst.

[0052] In a preferred embodiment of the present invention, the reduction catalyst is selected from any one or a combination of borane-tetrahydrofuran, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride sodium hydride, and lithium tritert-butoxyborohydride.

[0053] In a preferred embodiment of the present invention, the amount of the reduction catalyst is 1 to 10 eq of compound IV, preferably 1 to 5 eq.

[0054] In a preferred embodiment of the present invention, the reaction solvent in the preparation of compound V is selected from any one or a combination of dichloromethane, tetrahydrofuran, methyltetrahydrofuran, methanol, and ethanol.

[0055] In a preferred embodiment of the present invention, in the preparation of compound V, the volume-to-mass ratio of the reaction solvent to compound IV is 1 to 60:1, preferably 1 to 20:1.

[0056] In a preferred embodiment of the present invention, the preparation of compound V further includes a post-processing step, which specifically includes: quenching the reaction with an aqueous solution of alkali, adding a desiccant, filtering, and concentrating to obtain compound IV.

[0057] In a preferred embodiment of the present invention, in the post-processing step, the alkali is selected from any one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and lithium hydroxide.

[0058] In a preferred embodiment of the present invention, in the post-processing step, the desiccant is selected from any one or a combination of anhydrous magnesium sulfate (MgSO4), anhydrous sodium sulfate (Na2SO4), anhydrous calcium chloride (CaCl2), and phosphorus pentoxide (P2O5).

[0059] In a preferred embodiment of the present invention, compound IV is prepared by dissolving compound III(R)-N-(3-aminobutyryl)-N-benzylglycine ethyl ester in a reaction solvent and reacting it in the presence of a base.

[0060] In a preferred embodiment of the present invention, in the preparation of compound IV, the base is selected from any one or a combination of sodium methoxide, sodium ethoxide, sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium tert-butoxide, and triethylamine.

[0061] In a preferred embodiment of the present invention, in the preparation of compound IV, the amount of base used is 0.5-10 eq of compound III, preferably 1-5 eq.

[0062] In a preferred embodiment of the present invention, in the preparation of compound IV, the reaction solvent is selected from any one or a combination of ethyl acetate, dichloromethane, N,N-dimethylformamide, acetonitrile, toluene, methanol, and ethanol.

[0063] In a preferred embodiment of the present invention, in the preparation of compound IV, the volume-to-mass ratio of the reaction solvent to compound III is 1 to 20:1, preferably 1 to 10:1.

[0064] In a preferred embodiment of the present invention, the preparation of compound IV further includes a purification step, which includes: first extraction, and then purification by slurry mixing of ethyl acetate and n-heptane to obtain the compound.

[0065] In a preferred embodiment of the present invention, the purification step includes: first adding a saturated ammonium chloride solution to quench the reaction, then evaporating to dryness, then adding an alkaline solution, then extracting with an organic solvent, drying, filtering, and concentrating the organic solvent.

[0066] In a preferred embodiment of the present invention, in the extraction step, the alkali is selected from any one or a combination of sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

[0067] In a preferred embodiment of the present invention, in the pulping and purification step, the ratio of ethyl acetate to n-heptane (v:v) is 1:2-3.5, preferably 1:2.5-3.

[0068] In a preferred embodiment of the present invention, in the purification step, the volume-to-mass ratio of ethyl acetate to compound III is 0.4 to 2:1, preferably 0.6 to 1:1.

[0069] In a preferred embodiment of the present invention, compound III is prepared by dissolving compound II(R)-N-benzyl-N-[3-(tert-butoxycarbonylamino)butyryl]glycine ethyl ester in an organic solvent, adding ethyl hydrochloride, and reacting at 40-60°C.

[0070] In a preferred embodiment of the present invention, ethyl hydrochloride is added at 5-15°C.

[0071] In a preferred embodiment of the present invention, the concentration of ethyl hydrochloride is 1N-6N, preferably 3N-4N.

[0072] In a preferred embodiment of the present invention, the organic solvent used in the preparation of compound III is selected from any one or a combination of ethyl acetate, dichloromethane, N,N-dimethylformamide, acetonitrile, toluene, methanol, ethanol, and 1,4-dioxane.

[0073] In a preferred embodiment of the present invention, in the preparation of compound III, the volume-to-mass ratio of the organic solvent to compound II is 1 to 5:1, preferably 1 to 1.15:1.

[0074] In a preferred embodiment of the present invention, compound II is prepared by reacting compound I(R)-3-(BOC-amino)butyric acid and N-benzylglycine ethyl ester with a condensing agent in batches in the presence of a reaction solvent, an activator and a base at 25-35°C.

[0075] In a preferred embodiment of the present invention, in the preparation of compound II, the activator is selected from any one or a combination of 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole (HOAt), and N-hydroxyphthalimide (NHPI).

[0076] In a preferred embodiment of the present invention, in the preparation of compound II, the condensing agent is selected from any one or a combination of carbodiimides or urea salts.

[0077] In a preferred embodiment of the present invention, the carbodiimide is selected from any one or a combination of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI).

[0078] In a preferred embodiment of the present invention, the urea salt is selected from any one or a combination of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazol-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), and N,N,N',N'-tetramethyl-O-(N-succinimide)urea tetrafluoroborate (TSTU).

[0079] In a preferred embodiment of the present invention, the amount of the condensing agent is 1 to 5 eq of compound I.

[0080] In a preferred embodiment of the present invention, the condensing agent is added in 2-5 batches.

[0081] In a preferred embodiment of the present invention, the condensing agent is added in batches at 15-20°C.

[0082] In a preferred embodiment of the present invention, in the preparation of compound II, the base is selected from any one or a combination of triethylamine ((C2H5)3N), pyridine (C5H5N), morpholine (C4H9NO), sodium methoxide (CH3ONa), and sodium ethoxide (C2H5ONa).

[0083] In a preferred embodiment of the present invention, the reaction solvent in the preparation of compound II is selected from any one or a combination of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and ethyl acetate.

[0084] In a preferred embodiment of the present invention, the volume-to-mass ratio of the reaction solvent to compound I is 1 to 20:1, preferably 1 to 10:1.

[0085] Compared with the prior art, the present invention has the following beneficial technical effects:

[0086] (1) The preparation method of the present invention avoids the use of flammable and highly toxic compound methyl vinyl ketone to construct the skeleton of diazacycloheptane and avoids the use of explosive reagents such as AlMe3. The reagents and solvents used in the preparation method of the present invention have low toxicity, ensuring the safety of drug use.

[0087] (2) The reagents used in the preparation method of the present invention are relatively mild, and the starting materials are selected as chiral raw materials with low cost, avoiding chiral separation and the use of chiral catalysts, which further reduces costs.

[0088] (3) Through condition exploration, the present invention has developed a process route suitable for mass production. Using the preparation method of the present invention, the product yield is high and the purity is as high as 99.9% or more. Moreover, the intermediate product has good properties and few impurities, which is suitable for industrial production.

[0089] (4) The preparation method of the present invention has mild reaction conditions, which not only has good safety, but also low energy consumption, bringing economic benefits; the post-processing operation is simple, easy to purify, has high yield, low cost, high ee value, low environmental pollution, and is easy to industrialize. Detailed Implementation

[0090] The present invention will be further illustrated by the following embodiments, but the invention is not limited to the scope of the embodiments described herein.

[0091] Example 1:

[0092] Synthesis of (R)-N-benzyl-N-[3-(tert-butoxycarbonylamino)butyryl]glycine ethyl ester (compound II)

[0093] (R)-3-(BOC-amino)butyric acid (1000 g, 4.92 mol) and N,N-dimethylformamide were dissolved by stirring (4 L). Then, N-benzylglycine ethyl ester (950 g, 4.92 mol), 1-hydroxybenzotriazole (831 g, 6.15 mol), and triethylamine (747 g, 7.38 mol) were added and stirred at 10 °C for 30 min. 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1131 g, 5.9 mol) was added in three portions. The reaction was stirred at 20 °C for 4 h, then the temperature was increased to 30 °C and stirring continued for 2 h. The mixture was cooled to room temperature and quenched with 10% citric acid, then extracted with ethyl acetate. The organic phase was washed with 5% K₂CO₃, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 2.5 L of liquid (100% yield). This liquid was directly added to the next reaction without further purification.

[0094] 1 H NMR (600MHz, DMSO) δ7.40–7.18(m,5H),6.71(t,J=9.1Hz,1H),4.79–4.54(m,2H),4.33(dd,J =90.0,16.8Hz,1H),4.07(p,J=7.1Hz,2H),3.98(dd,J=39.1,16.9Hz,1H),3.90–3.78(m,1H) ,2.56(ddd,J=20.6,15.3,4.9Hz,1H),2.28(ddd,J=58.3,15.2,8.3Hz,1H),1.36(d,J=7.8Hz ,9H),1.16(td,J=7.1,5.0Hz,3H),1.05(dd,J=12.8,6.6Hz,3H).MS(ESI)m / z279.1705([M+H] + ).

[0095] Example 2:

[0096] Synthesis of (R)-N-(3-aminobutyryl)-N-benzylglycine ethyl ester (compound III)

[0097] The (R)-N-benzyl-N-[3-(tert-butoxycarbonylamino)butyryl]glycine ethyl ester (2.5 L, 2230 g) prepared in Example 1 was dissolved in ethyl acetate (300 ml), cooled to 10 °C, and 4N ethyl hydrochloride (2.5 L) was added. After reacting for 1 h, the temperature was raised to 50 °C and stirred for 2 h.

[0098] Extraction was performed with water, and the pH of the aqueous phase was adjusted to 9-10 with a 25% potassium carbonate solution. Extraction was performed again with ethyl acetate, followed by washing with purified water and then with saturated brine. The mixture was dried over MgSO4, filtered, and evaporated to dryness to obtain 1360g of oil (yield 99.2%). No further purification was required before it was added to the next reaction.

[0099] Example 3:

[0100] Synthesis of (R)-4-benzyl-7-methyl-1,4-diazacycloheptane-2,5-dione (compound IV)

[0101] The (R)-N-(3-aminobutyryl)-N-benzylglycine ethyl ester (1360 g, 4.88 mol) prepared in Example 2 was dissolved in anhydrous methanol (4.8 L) and stirred until dissolved. Sodium methoxide (288 g, 5.33 mol) was added at room temperature and stirred for 4 hours.

[0102] Add 1.8 L of saturated ammonium chloride solution and evaporate to dryness. Concentrate under reduced pressure to remove methanol. Add 20% potassium carbonate solution (2 L) and extract with dichloromethane. Wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and evaporate to dryness to obtain a crude white solid product. Take 11 g of the product for subsequent process research.

[0103] Ethyl acetate (900 ml) was added to the remaining white solid and stirred for 3 h. Then, n-heptane (2.7 L) was added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of ethyl acetate and n-heptane (volume ratio of ethyl acetate to n-heptane 1:3). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain 953.9 g of white solid (yield 86.4%, HPLC purity 98.5%).

[0104] 1 H NMR (600MHz, DMSO) δ7.70 (s, 1H), 7.37–7.18 (m, 5H), 4.60–4.48 (m, 2H), 4.04 (q, J = 17.2Hz, 2H), 3.67– 3.57(m,1H),2.81(ddd,J=22.8,14.3,5.9Hz,2H),1.12(d,J=6.4Hz,3H).MS(ESI)m / z233.1286([M+H] + ).

[0105] Experimental Example 1: Purification Process Study

[0106] 1 g of the crude white solid prepared in Example 3 was mixed with 1.8 ml of ethyl acetate and stirred for 3 h. Then, 1.8 ml of n-heptane was added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of ethyl acetate and n-heptane (volume ratio of ethyl acetate to n-heptane 1:1). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain the white solid, with a yield of 72.46% and a purity of 83.57%.

[0107] 1 g of the crude white solid prepared in Example 3 was mixed with 1.2 ml of ethyl acetate and stirred for 3 h. Then, 2.4 ml of n-heptane was added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of ethyl acetate and n-heptane (volume ratio of ethyl acetate to n-heptane 1:2). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain the white solid. The yield was 76.39% and the purity was 81.86%.

[0108] 1 g of the crude white solid prepared in Example 3 was mixed with 1.0 ml of ethyl acetate and stirred for 3 h. 2.5 ml of n-heptane was then added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of ethyl acetate and n-heptane (volume ratio of ethyl acetate to n-heptane 1:2.5). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain the white solid, with a yield of 80.36% and a purity of 89.89%.

[0109] 1 g of the crude white solid prepared in Example 3 was mixed with 0.9 ml of ethyl acetate and stirred for 3 h. 2.7 ml of n-heptane was then added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of ethyl acetate and n-heptane (volume ratio of ethyl acetate to n-heptane 1:3). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain the white solid, with a yield of 86.38% and a purity of 98.34%.

[0110] 1 g of the crude white solid prepared in Example 3 was mixed with 0.8 ml of ethyl acetate and stirred for 3 h. Then, 2.8 ml of n-heptane was added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of ethyl acetate and n-heptane (volume ratio of ethyl acetate to n-heptane 1:3.5). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain the white solid, with a yield of 86.39% and a purity of 98.31%.

[0111] 1 g of the crude white solid prepared in Example 3 was mixed with 0.9 ml of isopropyl acetate and stirred for 3 h. Then, 2.7 ml of n-hexane was added and stirred for 2 h. The mixture was filtered, and the white solid filter cake was washed with a mixed solution of isopropyl acetate and n-hexane (volume ratio of isopropyl acetate to n-hexane 1:3). The mixture was then dried in a vacuum oven at 50 °C for 10 h to obtain the white solid with a yield of 81.98% and a purity of 92.20%.

[0112] Example 4:

[0113] Synthesis of (R)-1-benzyl-5-methyl-1,4-diazacycloheptane (compound V)

[0114] (R)-4-benzyl-7-methyl-1,4-diazacycloheptane-2,5-dione (942.9 g, 4.05 mol) prepared in Example 3 was dissolved in tetrahydrofuran (16 L). The air in the flask was replaced with nitrogen gas, and the nitrogen flow rate was maintained. The temperature inside the flask was kept at 10 °C. Lithium aluminum hydride (288 g, 7.59 mol) was added, and the mixture was stirred for 4 h. The temperature was raised to 30 °C, and the mixture was stirred for 2 h while maintaining nitrogen purging. The temperature inside the flask was lowered to 10 °C, and purified water (288 ml) was added. Then, 15% sodium hydroxide solution (288 ml) was added dropwise, followed by 148 ml of water and magnesium sulfate (430 g, 3.57 mol). The mixture was stirred for 3 h, filtered, dried over MgSO4, and evaporated to dryness to obtain 787.0 g of yellow liquid (yield 95.1%, HPLC purity 98.7%).

[0115] 1 H NMR (600MHz, DMSO) δ7.39–7.14(m,2H),3.70–3.35(m,1H),3.11–2.73(m,1H),2.67– 2.39(m,2H),1.80–1.58(m,1H),0.97(d,J=6.4Hz,1H).MS(ESI)m / z205.1701([M+H] + ).

[0116] Comparative Example 1

[0117] The crude white solid (2.4 g, 0.0103 mol) of (R)-4-benzyl-7-methyl-1,4-diazacycloheptane-2,5-dione, prepared in Example 3, was dissolved in tetrahydrofuran (6.3 ml). The air in the flask was replaced with nitrogen gas, and the nitrogen flow rate was maintained. The temperature in the flask was kept at 10°C. Lithium aluminum hydride (1.2 g) was added, and the mixture was stirred for 4 h. The temperature was raised to 30°C, and the mixture was stirred for 2 h while maintaining nitrogen purging. The temperature in the flask was lowered to 10°C, and purified water (1.2 ml) was added. Then, 15% sodium hydroxide solution (1.2 ml) was added dropwise, followed by 1.4 ml of water and magnesium sulfate (2 g). The mixture was stirred for 3 h, filtered, dried over MgSO4, filtered, and evaporated to dryness to obtain 1.85 g of yellow liquid (yield 90%, HPLC purity 83.7%, containing a large amount of (R)-N-(3-aminobutyryl)-glycine ethyl ester impurity).

[0118] Example 5

[0119] Synthesis of (R)-4-benzyl-7-methyl-1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester (compound VI)

[0120] (R)-1-benzyl-5-methyl-1,4-diazacycloheptane (780.0 g, 3.82 mol) prepared in Example 4 was dissolved in methanol (2.7 L), and the mixture was stirred at 10 °C with di-tert-butyl dicarbonate (881 g, 4.04 mol) and triethylamine (409 g, 4.04 mol) for 3 h. The reaction mixture was evaporated to dryness, and 10% citric acid monohydrate (7 L) was added. The mixture was extracted with ethyl acetate, and the lower aqueous phase was collected. The pH was adjusted to 8-9 with 30% sodium hydroxide (6 L), and then extracted again with ethyl acetate. The mixture was washed with saturated sodium chloride solution, dried over MgSO4, filtered, and evaporated to dryness to obtain 1035 g of a light brown liquid (yield 89%, HPLC purity 97%).

[0121] 1 H NMR (600MHz, DMSO) δ7.40–7.18(m,5H),6.71(t,J=9.1Hz,1H),4.79–4.54(m,2H),4.33(dd,J =90.0,16.8Hz,1H),4.07(p,J=7.1Hz,2H),3.98(dd,J=39.1,16.9Hz,1H),3.90–3.78(m,1H) ,2.56(ddd,J=20.6,15.3,4.9Hz,1H),2.28(ddd,J=58.3,15.2,8.3Hz,1H),1.36(d,J=7.8Hz ,9H),1.16(td,J=7.1,5.0Hz,3H),1.05(dd,J=12.8,6.6Hz,3H).MS(ESI)m / z305.2231([M+H] + ).

[0122] Comparative Example 2

[0123] (R)-1-benzyl-5-methyl-1,4-diazacycloheptane (7.0 g, 0.034 mol) prepared in Example 4 was dissolved in methanol (27 ml), and then at 10 °C, di-tert-butyl dicarbonate (8.2 g) and triethylamine (13.2 g) were added, followed by stirring for 3 h. The reaction mixture was concentrated under reduced pressure and diluted with water (25 ml); it was extracted with DCM (2 × 15 ml), and the organic layer was collected, washed with 5% citric acid solution (25 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 8.6 g of a light brown liquid, with a yield of 83.07%.

[0124] Example 6

[0125] Synthesis of (R)-7-methyl-1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester (compound VII)

[0126] The (R)-4-benzyl-7-methyl-1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester (1035 g, 3.4 mol) prepared in Example 5 was dissolved in methanol (5 L), and 10% Pd / C (90 g, 0.0846 mol) was added. The air in the flask was replaced with hydrogen, and the reaction temperature was controlled at 30-35 °C. The mixture was stirred for 4 h. The mixture was filtered, the filter cake was washed with methanol, dried with MgSO4, filtered, and evaporated to dryness to obtain 699 g of an oily substance (yield 96%, HPLC purity 99%).

[0127] 1 H NMR (600MHz, DMSO) δ4.03–3.85(m,1H),3.74–3.43(m,1H),3.29–3.03(m,1H),2.97–2.63(m,1H) ),2.59–2.20(m,1H),1.98(qd,J=14.2,6.7Hz,1H),1.51–1.27(m,1H),1.01(dd,J=23.6,6.3Hz,

[0128] 1H).MS(ESI)m / z159.1127([M+H] + ).

[0129] Comparative Example 3

[0130] (R)-4-benzyl-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (7.9 g, 0.0259 mol) prepared in Comparative Example 2 was dissolved in methanol (35 ml), and 10% Pd / C (3 g) was added. The air in the flask was replaced with hydrogen, and the reaction temperature was controlled at 30-35 °C. The mixture was stirred for 4 h. The mixture was filtered, the filter cake was washed with methanol, dried with MgSO4, filtered and evaporated to dryness to obtain 5.12 g of oil (0.0238 mol, yield 92%, HPLC purity 78%, containing a large amount of (R)-7-methyl-1,4-diazacycloheptane-1,4-dicarboxylic acid tert-butyl ester).

[0131] Example 7

[0132] Synthesis of (R)-4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (compound VIII)

[0133] The (R)-7-methyl-1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester (699 g, 3.26 mol) prepared in Example 6 was dissolved in dichloromethane (5.9 L) at 10 °C. 2,5-dichlorobenzoxazole (517.7 g, 2.77 mol) was added, followed by the addition of triethylamine (308 g, 3.05 mol). The temperature was then raised to room temperature, and the mixture was stirred for 4 h. Dichloromethane (2 L) was added, followed by washing and extraction with water. The organic phase was then washed and extracted with 10% citric acid monohydrate solution (1.5 L). Finally, the mixture was washed and extracted with saturated sodium chloride (900 ml), dried over MgSO4, filtered, and evaporated to dryness to obtain 1180.8 g of an oily compound (99% yield, 97% HPLC purity).

[0134] 1 H NMR (600MHz, DMSO) δ7.40(d,J=8.4Hz,1H),7.31(d,J=1.7Hz,1H),7.01(dd,J=8.4,1.6Hz,1H),4 .22–3.19(m,1H),2.24–1.86(m,1H),1.64(d,J=5.7Hz,1H),1.37(s,1H),1.09(d,J=6.3Hz,1H). MS(ESI)m / z366.1580([M+H] + ).

[0135] Example 8

[0136] Synthesis of (R)-5-chloro-2-(5-methyl-1,4-diazacycloheptane-1-yl)benzo[d]oxazole (compound IX)

[0137] The (R)-4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (1180.8 g, 3.23 mol) prepared in Example 7 was dissolved in ethyl acetate (200 ml), cooled to 10 °C, and 4N hydrochloric acid-ethyl acetate (3.5 L) was added and stirred. The mixture was kept at 30 °C and stirred for 2.5 h. The reaction system was light white. The sample was filtered, washed with ethyl acetate, and heated to 75°C with methanol (2.4 L). The mixture was then refluxed until clear and stirred for 30 min. Isopropyl acetate (6.6 L) was added, the stirring speed was reduced, and the temperature was lowered to room temperature. The mixture was stirred for 2 h, and a white solid precipitated. The solution was filtered off, and then dichloromethane (3 L) and 12% sodium hydroxide solution (2 L) were added to adjust the pH to 11-13. The mixture was stirred for 10 min, extracted with dichloromethane, dried over MgSO4, filtered, and evaporated to dryness to obtain 823.8 g of a light yellow oil (yield 96%, HPLC purity 98%).

[0138] 1H NMR(600MHz,DMSO)δ7.38(d,J=8.4Hz,1H),7.29(d,J=2.1Hz,1H),6.98(dd,J=8.4,2.2Hz,1H), 3.85(ddd,J=14.3,5.6,3.9Hz,1H),3.67(dt,J=13.3,3.5Hz,1H),3.59–3.17(m,1H),3.11(ddd1 ,J=14.2,4.2,3.4Hz,1H),2.79(ddd,J=14.3,10.7,3.8Hz,1H),2.72–2.55(m,1H),2.22(s,1H), 1.85(ddt,J=14.0,6.1,3.1Hz,1H), 1.42(dtd,J=13.9,10.0,3.7Hz,1H), 1.01(d,J=6.4Hz,1H). MS(ESI)m / z266.1057([M+H] + ).

[0139] Comparative Example 4

[0140] The (R)-4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (5 g, 0.0136 mol) prepared in Example 7 was dissolved in ethyl acetate (2.5 ml). At 25 °C, 4N hydrochloric acid-ethyl acetate (30 ml) was added and stirred. The solution became slightly turbid. The reaction temperature was naturally raised to 50 °C and stirred for 2.5 h. The color of the system gradually deepened to light brown. The sample was filtered, washed with ethyl acetate, and heated to 75°C with methanol (7 ml). The mixture was then refluxed until clear and stirred for 30 min. Isopropyl acetate (10 ml) was added, the stirring speed was reduced, and the temperature was lowered to room temperature. The mixture was stirred for 2 h, and a white solid precipitated. The solution was filtered off, and then dichloromethane (10 ml) and 12% sodium hydroxide solution were added to adjust the pH to 11-13. The mixture was stirred for 10 min, extracted with dichloromethane, dried over MgSO4, filtered, and evaporated to dryness to obtain 3.01 g of a light yellow oily substance (0.0113 mol, yield 83.3%, HPLC purity 92.4%). Two new impurity peaks were detected, presumably tert-butyl derivatives and amino oxide impurities.

[0141] Comparative Example 5

[0142] The (R)-4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (5 g, 0.0136 mol) prepared in Example 7 was dissolved in ethyl acetate (2.5 ml). At -5 °C, 4N hydrochloric acid-ethyl acetate (30 ml) was added and stirred. A small amount of white flocculent precipitate appeared in the solution. The solution was kept at 15 °C and stirred for 2.5 h. The sample was filtered, washed with ethyl acetate, and heated to 75°C with methanol (7 ml). The mixture was then refluxed until clear and stirred for 30 min. Isopropyl acetate (10 ml) was added, the stirring speed was reduced, and the temperature was lowered to room temperature. The mixture was stirred for 2 h, and a white solid precipitated. The solution was filtered off, and then dichloromethane (10 ml) and 12% sodium hydroxide solution were added to adjust the pH to 11-13. The mixture was stirred for 10 min, extracted with dichloromethane, dried over MgSO4, filtered, and evaporated to dryness to obtain 2.8 g of a light yellow oily substance (yield 76.7%, HPLC purity 94.5%).

[0143] Example 9: Synthesis of Suvoresin

[0144] (1) 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (552.4 g, 2.72 mol) was dissolved in isopropyl acetate (3.3 L) and N,N-dimethylformamide (55 ml) at 25 °C. Oxaloyl chloride (394.7 g, 3.11 mol) was added dropwise and stirred for 1 h. After evaporation to dryness, isopropyl acetate (3.3 L) was added to dissolve the acyl chloride intermediate compound, which was then set aside.

[0145] (2) Dissolve (R)-5-chloro-2-(5-methyl-1,4-diazacycloheptane-1-yl)benzo[d]oxazole (813.8 g, 3.06 mol) prepared in Example 8 in isopropyl acetate (10.3 L). At a temperature below 20 °C, slowly add the acyl chloride intermediate compound prepared in step (1) using a constant pressure dropping funnel. Finally, add triethylamine (524.2 g, 5.18 mol) and stir for 3 h. Add purified water (4.5 L) and stir. Raise the temperature to 40-45 °C and stir until clear. Extract, collect the upper organic phase, wash with saturated sodium chloride solution, dry with MgSO4, filter, and evaporate to dryness. The solid was dissolved in isopropyl acetate (1.2 L), and the temperature was raised to 80 °C to dissolve it completely. The temperature was then lowered to 65 °C, and 500 mg of Suvoresin seed crystals were added. The mixture was stirred rapidly for 1 h, then cooled to 50 °C, and 9 L of n-heptane was added dropwise. The mixture was stirred at 45 °C for 5 h. The mixture was filtered, and the filter cake was washed with n-heptane. The cake was then dried in a vacuum drying oven at 70 °C for 10 h to obtain 1198 g of Suvoresin (yield 87%, HPLC purity 99.92%).

[0146] 1NMR(600MHz,DMSO-d6)8ppm8.05-7.88(m,2H),7.82-7.78(m,1H),7.42-7.25(m,2H),7.06-7.00(m,1H),4.29-4.06(m,1H) ,4.01-3.72(m,2H),3.66-3.49(m,2H),2.10(s,3H),2.06-2.01(m,1H),1.50(m,1H),1.78-1.50(m,1H),1.14-1.13(d,3H); 13 C NMR (151MHz, DMSO) δ168.87(s), 168.51(s), 168.07(s), 163.33(d, J=19.2Hz ),147.78(d,J=10.3Hz),145.64–145.25(m),138.60(d,J=22.1Hz),136.84–1 36.29(m),134.09(s),133.68(d,J=11.2Hz),130.91(s),130.75(d,J=4.8Hz ),130.57(s),129.85(s),129.67(s),128.81(d,J=13.2Hz),128.59(s),128. 37(s),123.01(s),122.82(s),122.57(s),120.19(d,J=11.8Hz),115.69(d, J=9.1Hz),110.32(s),52.38(s),51.80(s),48.27(d,J=11.8Hz),47.04(s),4 5.08(s),44.15(s),43.68(d,J=15.3Hz),35.58(s),33.51(s),20.88(s),20 .74(s),19.70(s),18.04(s),17.89(s),16.76(s).MS(ESI)m / z451.17([M+H] + ).

[0147] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing suvorexin, comprising the following steps: (1) Compound VIII(R)-4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester was dissolved in a reaction solvent, and an acidic reagent was added at 5-15℃. The reaction was carried out at 25-35℃ to prepare compound IX(R)-5-chloro-2-(5-methyl-1,4-diazacycloheptane-1-yl)benzo[d]oxazol; (2) In an alkaline environment and an aprotic solvent, compound IX was reacted with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid by an acylation nucleophilic reaction to obtain suvoresen.

2. The method according to claim 1, wherein in step (1), the acidic reagent is selected from an acid or a solvation of an acid, wherein the acid is selected from HCl, HBr, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid or any one or a combination thereof, and the solvation of the acid is selected from a solvation of HCl, preferably selected from any one or a combination thereof of HCl / ethyl acetate, HCl / methanol or HCl / 1,4-dioxane.

3. The method as described in any one of claims 1-2, wherein step (2) comprises: (S-1) Dissolve 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in an aprotic solvent, add acyl chloride dropwise, and dissolve in an aprotic solvent to prepare an acyl chloride intermediate compound. Preferably, the acyl chloride is selected from any one or a combination of oxalyl chloride, sulfonyl chloride, and phosphorus oxychloride. (S-2) Compound IX was dissolved in an aprotic solvent, and the acyl chloride intermediate compound from (S-1) was added dropwise. A base was added, and the reaction was carried out to obtain svorexin.

4. The method according to any one of claims 1-3, wherein the compound VIII is prepared by reacting tert-butyl ester of compound VII(R)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid in a reaction solvent with 2,5-dichlorobenzoxazole under alkaline conditions.

5. The method according to any one of claims 1-4, wherein the compound VII is prepared by reacting compound VI(R)-4-benzyl-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester in a reaction solvent under reducing catalyst conditions.

6. The method according to any one of claims 1-5, wherein the compound VI is prepared by dissolving compound V(R)-1-benzyl-5-methyl-1,4-diazacycloheptane in a reaction solvent and reacting it with a BOC protecting group at 5-15°C in the presence of a base.

7. The method according to any one of claims 1-6, wherein the compound V is prepared by dissolving compound IV(R)-4-benzyl-7-methyl-1,4-diazacycloheptane-2,5-dione in a reaction solvent and subjecting it to a reduction reaction at 5-25°C under a reduction catalyst.

8. The method according to any one of claims 1-7, wherein the preparation of compound IV is by compound III(R)- N-(3-aminobutyryl)-N-benzylglycine ethyl ester was prepared by reacting it with the solvent in the presence of a base.

9. The method according to any one of claims 1-8, wherein compound III is prepared by dissolving compound II(R)-N-benzyl-N-[3-(tert-butoxycarbonylamino)butyryl]glycine ethyl ester in an organic solvent, adding ethyl acetate hydrochloride, and reacting at 40-60°C.

10. The method according to any one of claims 1-9, wherein compound II is prepared by reacting compound I(R)-3-(BOC-amino)butyric acid and N-benzylglycine ethyl ester with a condensing agent added in batches in the presence of a reaction solvent, an activator and a base at 25-35°C.

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