Preparation method of suvorexant intermediate

Abstract

The invention provides a preparation method of a suvorexant key intermediate as shown in a formula (I), which comprises the following steps: S5, carrying out Mitsunobu reaction ring closure on a compound 5 to obtain a compound 6; s6, the compound 6 is subjected to a deprotection reaction in the presence of alkali; then, salifying with acid to obtain a compound 7; and S7, dissociating the compound 7 in a salt form in the presence of alkali to obtain the compound as shown in the formula (I). The method has the remarkable advantages that the used raw materials are low in price, wide in source and easy to obtain; meanwhile, the reaction conditions of each step are mild, the process operation is simple and convenient, and the production cost is effectively reduced. In addition, the use of expensive and high-toxicity reaction reagents in the original process route is avoided, so that the safety and environmental protection property of production are improved. Therefore, the method is more suitable for large-scale industrial production and has very high application value and market prospect.

Description

Technical Field

[0001] The present invention relates to the preparation of a pharmaceutical intermediate, and in particular to a method for preparing a suvorexant intermediate. Background Art

[0002] Suvorexant, also known as Belsomra, was developed by Merck in the United States. In 2014, the drug was approved by the FDA for the treatment of insomnia, becoming the first oral orexin receptor 1 and receptor 2 dual-active antagonist hypnotic drug targeting orexin receptors. Suvorexant affects the sleep-wake system in the brain by blocking orexin receptors, and achieves the purpose of improving sleep quality and treating insomnia through the spontaneous effects of this system. Its chemical name is 5-chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole, and its molecular formula is C 23 H 23 ClN6O2, its structural formula is as follows:

[0003]

[0004] Patent US7951797B2 discloses a method for preparing suvorexant, and its synthetic route is as follows:

[0005]

[0006] The raw materials used in this synthetic route are readily available, and the reactions are all classic organic reactions. However, this route has the following significant disadvantages: it requires separation using high-performance liquid chromatography (HPLC), a method that is costly, inefficient, and difficult to apply on a large scale; and the starting material, butenone, is a highly toxic chemical, posing a high safety risk and making it unsuitable for large-scale industrial production.

[0007] Therefore, there is an urgent need to provide a synthesis method that is simple in process, low in cost, high in safety, environmentally friendly, and suitable for large-scale industrial production. Summary of the Invention

[0008] In order to solve the above problems existing in the prior art, a method for preparing a suvorexant intermediate is provided. The preparation method has simple process, low cost, high safety, and is environmentally friendly, and is suitable for large-scale industrial production.

[0009] In one aspect, the present invention provides a compound 5, the structure of which is shown below:

[0010]

[0011] On the other hand, the present invention provides a method for preparing compound 5, comprising the following steps:

[0012]

[0013] S4: Compound 4 is reacted with benzyl chloroformate in the presence of a base to undergo an amino protection reaction to obtain compound 5.

[0014] Preferably, in step S4, the base is selected from an organic base or an inorganic base.

[0015] Preferably, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

[0016] The present invention provides a method for preparing a suvorexant intermediate represented by formula (I), comprising the following steps:

[0017]

[0018] S5: Compound 5 undergoes Mitsunobu reaction to give compound 6;

[0019] S6: Compound 6 is subjected to a deprotection reaction in the presence of a base; then, it is salified with an acid to obtain compound 7;

[0020] S7: Compound 7 is cleaved in the presence of a base in the form of a salt to obtain a compound of formula (I).

[0021] Preferably, in step S5, the Mitsunobu reaction further comprises adding an activation reagent.

[0022] Preferably, the activation reagent is selected from triphenylphosphine and an azo reagent, and the azo reagent includes one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate and di-tert-butyl azodicarboxylate.

[0023] More preferably, the activating agent is selected from triphenylphosphine and diisopropyl azodicarboxylate.

[0024] Preferably, in step S6, the base is selected from an organic base or an inorganic base.

[0025] More preferably, the inorganic base is selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals.

[0026] More preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

[0027] Preferably, in step S6, the acid is selected from one or more of dibenzoyltartaric acid, tartaric acid, malic acid, mandelic acid and camphorsulfonic acid.

[0028] Preferably, in step S6, the deprotection reagent for the deprotection reaction is selected from one or more of thiophenol, methylthiophenol, 4-bromothiophenol, 4-ethylthiophenol, 4-tert-butylthiophenol, mercaptoethanol, thioglycolic acid, n-dodecyl mercaptan, methyl thioglycolate and ethyl thioglycolate.

[0029] Preferably, in step S7, the base is selected from an organic base or an inorganic base.

[0030] Preferably, the inorganic base is selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals.

[0031] More preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

[0032] Preferably, the preparation method further comprises the following steps:

[0033]

[0034] S4: Compound 4 is reacted with benzyl chloroformate in the presence of a base to undergo an amino protection reaction to obtain compound 5.

[0035] Preferably, in step S4, the base is selected from an organic base or an inorganic base.

[0036] Preferably, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

[0037] Preferably, the preparation method further comprises the following steps:

[0038]

[0039] S3: Compound 3 undergoes a nucleophilic substitution reaction with ethanolamine; then, it forms a salt with an acid to obtain compound 4.

[0040] Preferably, the acid is selected from one or more of hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfuric acid, maleic acid and butanedisulfonic acid.

[0041] Preferably, the preparation method further comprises the following steps:

[0042]

[0043] S2: Compound 2 undergoes O-sulfonylation reaction with a sulfonylating agent in the presence of a base to obtain compound 3.

[0044] Preferably, in step S2, the base is selected from an organic base or an inorganic base.

[0045] Preferably, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

[0046] Preferably, in step S2, the sulfonylating agent is selected from one or more of methylsulfonyl chloride and methylsulfonic anhydride.

[0047] Preferably, the preparation method further comprises the following steps:

[0048]

[0049] S1: Compound 1 is subjected to an amino protection reaction in the presence of a base to obtain compound 2.

[0050] Preferably, in step S1, the base is selected from an organic base or an inorganic base.

[0051] Preferably, the inorganic base is selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals.

[0052] More preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

[0053] Preferably, in step S1, the amine protection reagent of the amine protection reaction is selected from 2-nitrobenzenesulfonyl chloride.

[0054] The present invention offers significant advantages: the raw materials used are inexpensive, widely available, and readily available; mild reaction conditions in each step and simple process operation effectively reduce production costs. Furthermore, the present invention avoids the use of expensive and highly toxic reagents in conventional processes, thereby improving production safety and environmental friendliness. Therefore, the present invention is more suitable for large-scale industrial production and has high application value and market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 The compound 5 obtained in Example 4 1 H-NMR spectrum.

[0056] Figure 2 The compound of formula (I) obtained in Example 6 1 H-NMR spectrum. DETAILED DESCRIPTION

[0057] To make the technical solutions and beneficial effects of the present disclosure more clearly understood, the following detailed description is provided by way of specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly illustrate the details of the local features. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0058] In one aspect, the present invention provides a compound 5, the structure of which is shown below:

[0059]

[0060] On the other hand, the present invention provides a method for preparing compound 5, comprising the following steps:

[0061]

[0062] S4: Compound 4 is reacted with benzyl chloroformate in the presence of a base to undergo an amino protection reaction to obtain compound 5.

[0063] In certain embodiments, in step S4, the base is selected from an organic base or an inorganic base.

[0064] In certain embodiments, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

[0065] On the other hand, the present invention provides a method for preparing a suvorexant intermediate represented by formula (I), comprising the following steps:

[0066]

[0067] S5: Compound 5 undergoes Mitsunobu reaction to give compound 6;

[0068] S6: Compound 6 is subjected to a deprotection reaction in the presence of a base; then, it is salified with an acid to obtain compound 7;

[0069] S7: Compound 7 is cleaved in the presence of a base in the form of a salt to obtain a compound of formula (I).

[0070] In certain embodiments, in step S5, the Mitsunobu reaction further comprises adding an activation reagent.

[0071] In certain embodiments, the activating reagent is selected from triphenylphosphine and an azo reagent, and the azo reagent includes one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate, and di-tert-butyl azodicarboxylate.

[0072] In certain embodiments, the activating reagent is selected from triphenylphosphine and diisopropyl azodicarboxylate.

[0073] In certain embodiments, the mass ratio of the triphenylphosphine to the azo reagent is 1:(0.5-1.0).

[0074] In certain embodiments, in step S5, the temperature of the Mitsunobu reaction is 0-10°C.

[0075] In certain embodiments, in step S5, the temperature of the Mitsunobu reaction is 0-5°C.

[0076] In certain embodiments, in step S5, the Mitsunobu reaction is carried out for 1-4 hours.

[0077] In certain embodiments, in step S5, the Mitsunobu reaction time is 1-2 h.

[0078] In certain embodiments, the step S5 further includes a post-processing step.

[0079] In certain embodiments, step S5 further includes specific post-processing steps: filtration, water washing, and concentration.

[0080] In certain embodiments, in step S6, the base is selected from an organic base or an inorganic base.

[0081] In certain embodiments, in step S6, the base is selected from an inorganic base.

[0082] In certain embodiments, the inorganic base is selected from an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate.

[0083] In certain embodiments, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0084] In certain embodiments, the inorganic base is selected from potassium carbonate.

[0085] In certain embodiments, in step S6, the acid is selected from one or more of dibenzoyltartaric acid, tartaric acid, malic acid, mandelic acid, and camphorsulfonic acid.

[0086] In certain embodiments, in step S6, the deprotection reagent of the deprotection reaction is selected from one or more of thiophenol, methylthiophenol, 4-bromothiophenol, 4-ethylthiophenol, 4-tert-butylthiophenol, mercaptoethanol, thioglycolic acid, n-dodecyl mercaptan, methyl thioglycolate and ethyl thioglycolate.

[0087] In certain embodiments, the step S6 further includes a post-processing step.

[0088] In certain embodiments, step S6 further includes specific post-processing steps: slurrying, filtering and drying.

[0089] In certain embodiments, in step S7, the base is selected from an organic base or an inorganic base.

[0090] In certain embodiments, in step S7, the base is selected from an inorganic base.

[0091] In certain embodiments, the inorganic base is selected from an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate.

[0092] In certain embodiments, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0093] In certain embodiments, the inorganic base is selected from sodium hydroxide.

[0094] In certain embodiments, the step S7 further includes a post-processing step.

[0095] In certain embodiments, step S7 further includes specific post-processing steps: extracting the aqueous phase, combining, washing with water, and concentrating.

[0096] In certain embodiments, the preparation method further comprises the following steps:

[0097]

[0098] S4: Compound 4 is reacted with benzyl chloroformate in the presence of a base to undergo an amino protection reaction to obtain compound 5.

[0099] In certain embodiments, in step S4, the base is selected from an organic base or an inorganic base.

[0100] In certain embodiments, in step S4, the base is selected from an organic base.

[0101] In certain embodiments, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

[0102] In certain embodiments, the organic base is selected from triethylamine.

[0103] In certain embodiments, in step S4, the mass ratio of compound 4 to benzyl chloroformate is 1:(0.45-0.75).

[0104] In certain embodiments, the step S4 further includes a post-processing step.

[0105] In certain embodiments, step S4 further includes a specific post-processing step: adding water, stirring, separating the liquids, combining the organic phases after extraction, and concentrating and drying.

[0106] In certain embodiments, the preparation method further comprises the following steps:

[0107]

[0108] S3: Compound 3 undergoes a nucleophilic substitution reaction with ethanolamine; then, it forms a salt with an acid to obtain compound 4.

[0109] In certain embodiments, the acid is selected from one or more of hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfuric acid, maleic acid, and butanedisulfonic acid.

[0110] In certain embodiments, the acid is selected from hydrochloric acid.

[0111] In certain embodiments, the step S3 further includes a post-processing step.

[0112] In certain embodiments, step S3 further includes a specific post-processing step: adding dichloromethane and water, performing separation extraction, combining the organic phases, and concentrating; adding hydrochloric acid and ethyl acetate solution, stirring and filtering.

[0113] In certain embodiments, the preparation method further comprises the following steps:

[0114]

[0115] S2: Compound 2 undergoes O-sulfonylation reaction with a sulfonylating agent in the presence of a base to obtain compound 3.

[0116] In certain embodiments, in step S2, the base is selected from an organic base or an inorganic base.

[0117] In certain embodiments, in step S2, the base is selected from an organic base.

[0118] In certain embodiments, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

[0119] In certain embodiments, the organic base is selected from triethylamine.

[0120] In certain embodiments, in step S2, the sulfonylating agent is selected from one or more of methanesulfonyl chloride and methanesulfonic anhydride.

[0121] In certain embodiments, in step S2, the sulfonylating agent is selected from methanesulfonyl chloride.

[0122] In certain embodiments, in step S2, the temperature of the O-sulfonylation reaction is 0-20°C.

[0123] In certain embodiments, in step S2, the temperature of the O-sulfonylation reaction is 0-10°C.

[0124] In certain embodiments, in step S2, the O-sulfonylation reaction time is 1-4 hours.

[0125] In certain embodiments, in step S2, the O-sulfonylation reaction time is 1-2 hours.

[0126] In certain embodiments, the step S2 further includes a post-processing step.

[0127] In certain embodiments, step S2 further includes a specific post-processing step: adding water, stirring, separating the liquids, adding dichloromethane for extraction, and combining and concentrating.

[0128] In certain embodiments, the preparation method further comprises the following steps:

[0129]

[0130] S1: Compound 1 is subjected to an amino protection reaction in the presence of a base to obtain compound 2.

[0131] In certain embodiments, in step S1, the base is selected from an organic base or an inorganic base.

[0132] In certain embodiments, in step S1, the base is selected from an inorganic base.

[0133] In certain embodiments, the inorganic base is selected from an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate.

[0134] In certain embodiments, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0135] In certain embodiments, the inorganic base is selected from sodium bicarbonate.

[0136] In certain embodiments, in step S1, the amine protection reagent of the amine protection reaction is selected from 2-nitrobenzenesulfonyl chloride.

[0137] In certain embodiments, in step S1, the mass ratio of compound 1 to the sulfonylating agent is 1:(2.0-3.0).

[0138] In certain embodiments, in step S1, the mass ratio of compound 1 to the sulfonylating agent is 1:(2.5-3.0).

[0139] In certain embodiments, the step S1 further includes a post-processing step.

[0140] In certain embodiments, the step S1 further comprises a specific post-processing step: concentration under reduced pressure, adding dichloromethane and water, stirring to separate the liquids, extracting and combining, drying and filtering.

[0141] In certain embodiments, the preparation method is carried out in an organic solvent.

[0142] In certain embodiments, the organic solvent is selected from one or more of acetonitrile, dichloromethane, 2-methyltetrahydrofuran, acetone, methanol, toluene, ethylene glycol, tetrahydrofuran, anhydrous ethanol, 1,4-dioxane, ethyl acetate, isopropyl acetate, ethylene glycol dimethyl ether, isopropanol, n-hexane and methyl tert-butyl ether.

[0143] The method of the present invention is described below by means of specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following examples. The implementation conditions adopted in the examples can be further adjusted according to specific requirements. The implementation conditions not specified are generally the conditions in routine experiments.

[0144] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents were commercially available or synthesized according to known methods, and commercially available materials and reagents were used directly without further purification.

[0145] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0146] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0147] The following examples are provided for a better understanding of the present invention and are not intended to limit the best mode of implementation. They do not limit the content and scope of protection of the present invention. Any product identical or similar to the present invention obtained by anyone under the guidance of the present invention or by combining the features of the present invention with other prior arts shall fall within the scope of protection of the present invention.

[0148] Example 1: Synthesis of Compound 2

[0149]

[0150] To a 20 L reactor, add 1.0 kg of R-3-aminobutanol, 4.0 kg of process water, 1.4 kg of sodium bicarbonate, and 3.0 kg of tetrahydrofuran; add 2.5 kg of 2-nitrobenzenesulfonyl chloride in batches at room temperature; stir at room temperature for 2 to 4 hours, and monitor the reaction completion by TLC; after the reaction is completed, concentrate under reduced pressure until no obvious fraction remains; add dichloromethane and process water to the reactor; stir, allow to stand, and then separate the liquids; extract the aqueous phase twice with dichloromethane, combine the organic phases, dry them, and filter them. The resulting solution is directly used in the next reaction.

[0151] Example 2: Synthesis of Compound 3

[0152]

[0153] The reaction mixture from Example 1 was added to a 50 L reactor. 1.7 kg of triethylamine was then added to the reactor. The temperature in the reactor was controlled at 0-10°C, and 1.5 kg of methylsulfonyl chloride was added dropwise. After the addition, the temperature was controlled at 0-10°C and stirred for 1-2 hours. TLC confirmed the reaction was complete. 4 kg of process water was added to the reactor, stirred, and separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and concentrated.

[0154] Example 3: Synthesis of Compound 4

[0155]

[0156] The temperature in the reactor was controlled at 20-30°C, and 5.5 kg of ethanolamine was added to the concentrated solution of Example 2; the reaction was carried out at 20-30°C for 5-6 hours; after the reaction was completed by TLC, 15 kg of dichloromethane and 10 kg of process water were added, the mixture was stirred and allowed to stand for separation; the aqueous phase was extracted once with dichloromethane; the combined organic phases were concentrated until no obvious fractions were found; 10 kg of ethyl acetate was added to the concentrated solution, and 2.9 kg of a hydrochloric acid-ethyl acetate solution was added dropwise at room temperature; the solution was stirred at room temperature for 3-4 hours; the filter was filtered, and the filter cake was washed with ethyl acetate; and after drying, 3.2 kg of compound 4 was obtained with a yield of 80.5% and a purity of 92.3%.

[0157] Example 4: Synthesis of Compound 5

[0158]

[0159] To a 50 L reactor, 3.0 kg of compound 4, 15 kg of dichloromethane, and 2.2 kg of triethylamine were added; the temperature in the reactor was controlled at 20-30°C, and 1.7 kg of benzyl chloroformate was added dropwise; the mixture was stirred at room temperature for 2-3 hours; 9.0 kg of process water was added, stirred, and allowed to stand for separation; the aqueous phase was extracted with dichloromethane; the organic phases were combined, concentrated under reduced pressure until no obvious fractions remained, and used directly in the next reaction without purification.

[0160] 1 H NMR(400MHz, DMSO-d6)δ8.01(t,J=6.6Hz,2H),7.97–7.89(m,1H),m7.88–7.76(m,2H),7.40–7.20(m,5H),5 .03(s,2H),4.75–4.59(m,1H),3.46–3.36(m,2H),3.30–3.03(m,4H),1.73–1.49(m,2H),1.07–0.80(m,3H).

[0161] Example 5: Synthesis of Compound 6

[0162]

[0163] To the product of Example 4, 8.0 kg of toluene was added, stirred and dissolved, and then 2.7 kg of triphenylphosphine was added to control the temperature in the reactor to 0-5°C, and 2.1 kg of diisopropyl azodicarboxylate was added dropwise; the temperature in the reactor was controlled at 0-5°C and stirred for 1-2 hours; filtered, the filtrate was returned to the reactor, and 9 kg of process water was added for washing; the organic phase was concentrated until no obvious fraction was found, and the obtained intermediate compound 6 was directly used in the next reaction.

[0164] Example 6: Synthesis of compound of formula (I)

[0165]

[0166] 9.4 kg of acetonitrile was added to a reactor to dissolve the intermediate compound 6 from Example 5. 2.1 kg of n-dodecanethiol and 2.4 kg of potassium carbonate were added. The mixture was stirred at reflux for 12 to 16 hours and concentrated under reduced pressure until no significant fraction remained. 4.5 kg of methyl tert-butyl ether and 9 kg of process water were added, stirred, allowed to stand, and then separated. The aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were transferred to a reactor and 0.6 kg of ethyl acetate was added. 1.2 kg of dibenzoyltartaric acid (DBTA) was dissolved in 2.2 kg of methyl tert-butyl ether and 0.6 kg of ethyl acetate. The DBTA solution was slowly added dropwise to the reactor at room temperature. The mixture was stirred for 5 to 6 hours and filtered to obtain crude compound 7. The crude compound 7 was slurried with 6.0 kg of anhydrous ethanol for 2 to 3 hours, filtered, and dried to obtain 2.2 kg of DBTA salt (compound 7). The DBTA salt and 20 kg of dichloromethane were added to a reactor, stirred and dissolved, and then a solution of 0.6 kg of NaOH dissolved in 7.5 kg of water was added; the aqueous phase was extracted with dichloromethane; the organic phases were combined and washed once with water; and concentrated under reduced pressure to obtain 1.5 kg of the compound of formula (I) with a purity of 99.5% and a yield of 55.5%.

[0167] 1 H NMR (400MHz, DMSO-d6) δ7.57–7.00(m,5H),5.24–4.91(m,2H),3.56(m,1H),3.44(m,1H),3.37–3.21( m,2H),3.03–2.89(m,1H),2.68–2.47(m,2H),1.72(m,1H),1.26(m,1H),0.99(dd,J=6.4,3.0Hz,3H).

[0168] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations of the claims. Various modifications and variations may be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments merely illustrate several implementations of the present invention and do not limit the scope of protection of the patent of this invention.

Claims

1. A compound 5, the structure of which is shown below:

2. A method for preparing compound 5 according to claim 1, characterized in that: The steps include: S4: Compound 4 is reacted with benzyl chloroformate in the presence of a base to undergo an amino protection reaction to obtain compound 5.

3. The preparation method according to claim 2, characterized in that In the step S4, the base is selected from an organic base or an inorganic base; Preferably, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

4. A method for preparing a suvorexant intermediate represented by formula (I), characterized in that: The steps include: S5: Compound 5 undergoes Mitsunobu reaction to give compound 6; S6: Compound 6 is subjected to a deprotection reaction in the presence of a base; then, it is salified with an acid to obtain compound 7; S7: Compound 7 is cleaved in the presence of a base in the form of a salt to obtain a compound of formula (I).

5. The preparation method according to claim 4, characterized in that In step S5, the Mitsunobu reaction further comprises adding an activation reagent; Preferably, the activation reagent is selected from triphenylphosphine and an azo reagent, and the azo reagent includes one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate and di-tert-butyl azodicarboxylate; More preferably, the activating agent is selected from triphenylphosphine and diisopropyl azodicarboxylate. Preferably, in step S6, the base is selected from an organic base or an inorganic base; More preferably, the inorganic base is selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals; More preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; Preferably, in step S6, the acid is selected from one or more of dibenzoyltartaric acid, tartaric acid, malic acid, mandelic acid and camphorsulfonic acid; Preferably, in step S6, the deprotection reagent for the deprotection reaction is selected from one or more of thiophenol, methylthiophenol, 4-bromothiophenol, 4-ethylthiophenol, 4-tert-butylthiophenol, mercaptoethanol, thioglycolic acid, n-dodecyl mercaptan, methyl thioglycolate and ethyl thioglycolate.

6. The preparation method according to claim 4, characterized in that In the step S7, the base is selected from an organic base or an inorganic base; Preferably, the inorganic base is selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals; More preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

7. The preparation method according to claim 4, characterized in that The preparation method further comprises the following steps: S4: Compound 4 is reacted with benzyl chloroformate in the presence of a base to undergo an amino protection reaction to obtain compound 5. Preferably, in step S4, the base is selected from an organic base or an inorganic base; Preferably, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine.

8. The preparation method according to claim 7, characterized in that The preparation method further comprises the following steps: S3: Compound 3 reacts with ethanolamine to undergo nucleophilic substitution reaction; then, it forms a salt with an acid to obtain compound 4; Preferably, in step S3, the acid is selected from one or more of hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfuric acid, maleic acid and butanedisulfonic acid.

9. The preparation method according to claim 8, characterized in that The preparation method further comprises the following steps: S2: Compound 2 undergoes O-sulfonylation reaction with a sulfonylating agent in the presence of a base to obtain compound 3. Preferably, in step S2, the base is selected from an organic base or an inorganic base; Preferably, the organic base is selected from one or more of triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, piperidine, tri-n-butylamine, trimethylamine, triisopropylamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine and N-ethylmorpholine; Preferably, in step S2, the sulfonylating agent is selected from one or more of methylsulfonyl chloride and methylsulfonic anhydride.

10. The preparation method according to claim 9, characterized in that The preparation method further comprises the following steps: S1: Compound 1 is subjected to an amine protection reaction in the presence of a base to obtain compound 2; Preferably, in step S1, the base is selected from an organic base or an inorganic base; Preferably, the inorganic base is selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals; More preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; Preferably, in step S1, the amine protection reagent of the amine protection reaction is selected from 2-nitrobenzenesulfonyl chloride.

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