Process for the preparation of a suvorexant intermediate

Abstract

The application discloses a preparation method of a suvorexant intermediate and belongs to the technical field of pharmaceutical intermediates. The 5-chloro-2-methoxybenzo[d]oxazole intermediate is synthesized from 2-amino-4-chlorophenol and tetramethoxymethane as raw materials under the catalysis of tris(pentafluorophenyl)boron, is not purified, and then is directly reacted with 5-methyl-1,4-diazepane to generate 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate. The 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate is synthesized by using a one-step method, and compared with the prior art, has the advantages of low raw material cost, simple operation, high yield and the like, and is easy to be industrially produced.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a suvorexant intermediate, and belongs to the technical field of preparation of pharmaceutical intermediates. BACKGROUND

[0002] Suvorexant, chemical name 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-benz[d]oxazole, developed by Merck Company, was approved for marketing by FDA in August 2014, and is used for treating insomnia, with trade name Suvorexant has good safety and tolerability in treating primary insomnia, can significantly improve insomnia symptoms, and can relieve the influence caused by insomnia, such as anxiety, mental debilitation and depression, etc., and its structural formula is as follows:

[0003]

[0004] 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate, as an important intermediate of suvorexant, plays a very important role in the synthesis of suvorexant, and its chemical structural formula is as follows:

[0005]

[0006] For this product, after literature retrieval of the prior art, the current synthesis methods mainly include the following methods.

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

[0008]

[0009] In the method provided in the above literatures, the raw material cost is high, the route is long, and the operation is complex. Therefore, it is necessary to further research the synthesis route of 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate, and provide a more optimal, easily available raw material, simple, safe and stable and economical process route. SUMMARY

[0010] The technical problem solved by the present application is to provide a preparation method of a suvorexant intermediate.

[0011] The present application aims to achieve the following technical solutions.

[0012] The method comprises the following steps:

[0013] The 2-amino-4-chlorophenol and the tris(pentafluorophenyl) boron catalyst are mixed in a solvent, tetramethoxymethane is added, and the reaction is carried out under a temperature condition, and then 5-methyl-1,4-diazepane and a base are added to generate 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl) benzoxazole racemate.

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

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

[0016] Preferably, in the above step, the temperature condition is 30-40 DEG C.

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

[0018] The present application has the following beneficial effects:

[0019] A、The present application develops a simple and practical synthesis route, and 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl) benzoxazole racemate is synthesized by one-step method, which provides a beneficial reference for the preparation of the compound.

[0020] B、2-amino-4-chlorophenol and tetramethoxymethane are used as raw materials, and 5-chloro-2-methoxybenzo[d]oxazole is synthesized under the action of tris(pentafluorophenyl) boron, and then 5-methyl-1,4-diazepane is directly reacted without purification, the yield is high, and the post-treatment step is reduced.

[0021] C, using 5-methyl-1,4-diazepane, the characteristic of which is that the amino group without methyl at the ortho position is easier to react, the steps of protection and deprotection of the amino group are reduced, and the complexity of the process is greatly reduced. Specific embodiments

[0022] Although the present application has been described in detail by preferred embodiments, the present application is not limited thereto. Any modification or replacement of the embodiments of the present application made by those skilled in the art without departing from the spirit and essence of the present application shall fall within the scope of the present application. Any modification or replacement made by those skilled in the art within the technical range disclosed by the present application shall fall within the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope described in the claims.

[0023] Example 1

[0024]

[0025] Under nitrogen protection, 2-amino-4-chlorophenol 14.3 g (0.1 mol) was mixed with tris(pentafluorophenyl)boron 1 g (0.002 mol) in 220 mL trifluoroethanol, tetramethoxymethane 15 g (0.11 mol) was added, and the reaction was carried out at 30-40°C for 4 hours, and then the temperature was lowered to room temperature, cesium carbonate 35.8 g (0.11 mol) and 5-methyl-1,4-diazepane 12.6 g (0.11 mol) were added, and the reaction was continued at 30-40°C for 2 hours, and then the temperature was lowered to room temperature, filtration was performed, 100 mL water was added to the filtrate, followed by extraction with 100 mL dichloromethane twice, the organic layer was concentrated, and the crude product was purified by column chromatography with ethyl acetate / n-hexane (v / v=1 / 3-10) as the eluent, to obtain 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate 22.1 g, with a yield of 83% (8% of isomer impurities were calculated by NMR external standard in the mother liquor), and HPLC 99.0%. 1 H NMR (400 MHz, 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, 2-amino-4-chlorophenol 14.3 g (0.1 mol) was mixed with tris(pentafluorophenyl)boron 1 g (0.002 mol) in 220 mL of chloroform, tetramethoxymethane 15 g (0.11 mol) was added, the temperature was raised to 60°C and the reaction was left for 8 hours, the temperature was lowered to room temperature, cesium carbonate 35.8 g (0.11 mol) and 5-methyl-1,4-diazepane 12.6 g (0.11 mol) were added, the temperature was raised to 60°C and the reaction was left for 6 hours, the temperature was lowered to room temperature, the mixture was filtered, the filtrate was added to 100 mL of water, then extracted twice with 100 mL of dichloromethane, the organic layer was concentrated, the crude product was purified by column chromatography using ethyl acetate / n-hexane (v / v = 1 / 3-10) as eluent, 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate was obtained, 14.6 g, 55% yield (32% of isomer impurities in the mother liquors by NMR external standard), HPLC 98.2%.

[0029] Example 3

[0030]

[0031] Under nitrogen, 2-amino-4-chlorophenol 14.3 g (0.1 mol) was mixed with tris(pentafluorophenyl)boron 1 g (0.002 mol) in 220 mL of chloroform, tetramethoxymethane 15 g (0.11 mol) was added, the temperature was raised to 60°C and the reaction was left for 8 hours, the temperature was lowered to room temperature, cesium carbonate 35.8 g (0.11 mol) and 5-methyl-1,4-diazepane 12.6 g (0.11 mol) were added, the temperature was raised to 60°C and the reaction was left for 6 hours, the temperature was lowered to room temperature, the mixture was filtered, the filtrate was added to 100 mL of water, then extracted twice with 100 mL of dichloromethane, the organic layer was concentrated, the crude product was purified by column chromatography using ethyl acetate / n-hexane (v / v = 1 / 3-10) as eluent, 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate was obtained, 14.6 g, 55% yield (32% of isomer impurities in the mother liquors by NMR external standard), HPLC 98.2%.

[0032] Although the present application has been described in detail by preferred embodiments, the scope of the present application is not limited to the above-mentioned embodiments, and any person skilled in the art should understand that any equivalent replacement or change within the technical scope disclosed in the present application and according to the technical solution and inventive concept of the present application should be covered within the scope of the present application.

Claims

1. A process for the preparation of a Suvorexant intermediate characterized in that, comprising the steps of mixing 2-amino-4-chlorophenol with tris(pentafluorophenyl)borane catalyst in an organic solvent, adding tetramethoxymethane, reacting under elevated temperature conditions, followed by adding 5-methyl-1,4-diazepane with a base to form 5-chloro-2-(hexahydro-5-methyl-1H-1,4-diazepin-1-yl)benzoxazole racemate; the organic solvent is trifluoroethanol; the elevated temperature conditions are 30-40 °C.

2. The process for the preparation of a Suvorexent intermediate according to claim 1, characterized by: the base is cesium carbonate.

3. The process for the preparation of Suvorexent intermediate as claimed in claim 1 wherein: the 2-amino-4-chlorophenol, tetramethoxymethane, tris(pentafluorophenyl)borane, 5-methyl-1,4-diazepane, and base are in a molar ratio of 1:1-1.2:0.01-0.05:1-1.2:1-1.1.

Images