Preparation method of suvorexant intermediate

Abstract

The invention discloses a preparation method of a suvorexant intermediate, and belongs to the technical field of medical intermediates. According to the method, 2-amino-4-chlorophenol and tetramethoxymethane are taken as raw materials, a 5-chloro-2-methoxybenzo [d] oxazole intermediate is synthesized under the catalysis of tris (pentafluorophenyl) boron, and the 5-chloro-2-methoxybenzo [d] oxazole intermediate is directly reacted with 5-methyl-1, 4-diazacycloheptane without being purified to generate the 5-chloro-2-(hexahydro-5-methyl-1H-1, 4-diazacycloheptane). The invention relates to a 2, 4-diazepine-1-yl) benzoxazole racemate. The 5-chloro-2-(hexahydro-5-methyl-1H-1, 4-diazepine-1-yl) benzoxazole racemate is synthesized by adopting a one-step method, and compared with the prior art, the 5-chloro-2-(hexahydro-5-methyl-1H-1, 4-diazepine-1-yl) benzoxazole racemate has the advantages of low raw material cost, simplicity and convenience in operation, high yield and the like, and is easy for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing a suvorexant intermediate, belonging to the technical field of pharmaceutical intermediate preparation. Background Art

[0002] Suvorexant, chemically named 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-benzo[d]oxazole, was developed by Merck and approved by the U.S. FDA in August 2014 for the treatment of insomnia. Its trade name is Suvorexant has good safety and tolerability in the treatment of primary insomnia, can significantly improve insomnia symptoms, and can alleviate the effects of insomnia, such as anxiety, mental fatigue and depression. Its structural formula is as follows:

[0003]

[0004] 5-Chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate is an important intermediate of suovolexin and plays a very important role in the synthesis of suovolexin. Its chemical structure is as follows:

[0005]

[0006] For this product, after literature search of existing technologies, the current synthesis methods mainly include the following methods.

[0007] Literature and patents [Organic Process Research and Development, 2011, 15, 367; WO2012148553A; Synthetic Communications, 2021, 51, 2225] report that the synthesis method is as follows:

[0008]

[0009] The methods provided in the above literature have high raw material costs, long routes and complicated operations. Therefore, it is necessary to conduct in-depth research on the synthetic route of 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepine-1-yl)benzoxazole racemate to provide a better, easy-to-obtain raw material, simple, safe, stable and economical process route. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for preparing a suvorexan intermediate. The method provided by the present invention uses 2-amino-4-chlorophenol and tetramethoxymethane as raw materials, synthesizes a 5-chloro-2-methoxybenzo[d]oxazole intermediate under the catalysis of tri(pentafluorophenyl)boron, and then directly reacts with 5-methyl-1,4-diazepine without purification to generate a 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepine-1-yl)benzoxazole racemate.

[0011] The objective of the present invention is achieved through the following technical solutions, and the reaction equation is expressed as follows:

[0012] The steps include:

[0013] 2-Amino-4-chlorophenol and tris(pentafluorophenyl)borane catalyst are mixed in a solvent, tetramethoxymethane is added, and the mixture is reacted under elevated temperature conditions, and then 5-methyl-1,4-diazepane and a base are added to generate a 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate.

[0014] Preferably, in the above steps, the solvent is trifluoroethanol.

[0015] Preferably, in the above steps, the base is cesium carbonate.

[0016] Preferably, in the above steps, the temperature is raised to 30-40°C.

[0017] Preferably, in the above steps, the molar ratio of 2-amino-4-chlorophenol, tetramethoxymethane, tris(pentafluorophenyl)boron, 5-methyl-1,4-diazacycloheptane and base is 1:1-1.2:0.01-0.05:1-1.2:1-1.1.

[0018] Beneficial effects of the present invention:

[0019] A. The present invention develops a simple and practical synthetic route, and synthesizes the racemic form of 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepine-1-yl)benzoxazole in one step, which provides a useful reference for the preparation of this type of compound.

[0020] B. Using 2-amino-4-chlorophenol and tetramethoxymethane as raw materials, 5-chloro-2-methoxybenzo[d]oxazole is synthesized under the action of tri(pentafluorophenyl)boron, and directly reacted with 5-methyl-1,4-diazacycloheptane without purification, with high yield and reduced post-processing steps.

[0021] C. Use 5-methyl-1,4-diazepane and take advantage of the steric hindrance of the methyl group ortho to the amino group, so that the amino group without methyl group ortho to the amino group is more likely to react, thus reducing the steps of protection and deprotection on the amino group and greatly reducing the complexity of the process. Specific embodiments

[0022] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

[0023] Example 1

[0024]

[0025] Under nitrogen protection, 14.3 g (0.1 mol) of 2-amino-4-chlorophenol and 1 g (0.002 mol) of tri(pentafluorophenyl)boron were mixed in 220 mL of trifluoroethanol, 15 g (0.11 mol) of tetramethoxymethane was added, the temperature was raised to 30-40 ° C, the reaction was carried out for 4 hours, the temperature was lowered to room temperature, 35.8 g (0.11 mol) of cesium carbonate and 12.6 g (0.11 mol) of 5-methyl-1,4-diazacycloheptane were added, and the temperature was continued to rise to 50 ° C. The reaction was carried out at 30-40°C for 2 hours, cooled to room temperature, filtered, 100 mL of water was added to the filtrate, and then extracted twice with 100 mL of dichloromethane. The organic layer was concentrated, and the crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v=1 / 3-10) to generate 22.1 g of 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate with a yield of 83% (isomer impurities 8% calculated by NMR external standard of the mother liquor), HPLC 99.0%. 1 H NMR(400MHz, CDCl3):7.26(d,1H),7.16(d,1H),6.98(d,1H),3.88(m,2H),3. 72(m,2H),3.35(m,1H),3.05(m,2H),2.06(m,1H),1.82(m,1H),1.25(d,3H).

[0026] Example 2

[0027]

[0028] Under nitrogen protection, 14.3 g (0.1 mol) of 2-amino-4-chlorophenol and 1 g (0.002 mol) of tri(pentafluorophenyl)boron were mixed in 220 mL of chloroform, 15 g (0.11 mol) of tetramethoxymethane was added, the temperature was raised to 60 ° C, the reaction was carried out for 8 hours, the temperature was lowered to room temperature, 35.8 g (0.11 mol) of cesium carbonate and 12.6 g (0.11 mol) of 5-methyl-1,4-diazacycloheptane were added, and the temperature was further raised to 60 ° C. The mixture was reacted for 6 hours, cooled to room temperature, filtered, 100 mL of water was added to the filtrate, and then extracted twice with 100 mL of dichloromethane. The organic layer was concentrated, and the crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v=1 / 3-10) to generate 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate, 14.6 g, with a yield of 55% (32% isomeric impurities calculated based on NMR external standard of the mother liquor), HPLC 98.2%.

[0029] Example 3

[0030]

[0031] Under nitrogen protection, 14.3 g (0.1 mol) of 2-amino-4-chlorophenol was mixed in 220 mL of trifluoroethanol, 15 g (0.11 mol) of tetramethoxymethane was added, and the temperature was raised to 60 ° C. The reaction was carried out for 12 hours. The liquid phase yield of 5-chloro-2-methoxybenzo[d]oxazole was 35% (reaction liquid HPLC external standard conversion).

[0032] Although the present invention has been described in detail by way of preferred embodiments, the protection scope of the present invention is not limited thereto, and any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent substitutions or changes according to the technical scheme and inventive concept of the present invention, should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a suvorexant intermediate, characterized in that: The method comprises the following steps: mixing 2-amino-4-chlorophenol and tris(pentafluorophenyl)boron catalyst in an organic solvent, adding tetramethoxymethane, reacting under elevated temperature conditions, and subsequently adding 5-methyl-1,4-diazepine and a base to generate a 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepine-1-yl)benzoxazole racemate.

2. The method for preparing the suvorexant intermediate according to claim 1, characterized in that: In the above steps, the organic solvent is trifluoroethanol.

3. The method for preparing the suvorexant intermediate according to claim 1, characterized in that: In the above steps, the base is cesium carbonate.

4. The method for preparing the suvorexant intermediate according to claim 1, characterized in that: In the above steps, the temperature is raised to 30-40°C.

5. The method for preparing the suvorexant intermediate according to claim 1, characterized in that: In the above steps, the molar ratio of 2-amino-4-chlorophenol, tetramethoxymethane, tris(pentafluorophenyl)boron, 5-methyl-1,4-diazacycloheptane and base is 1:1-1.2:0.01-0.05:1-1.2:1-1.1.

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