Preparation method of suvorexant intermediate

Abstract

The invention relates to a preparation method of a suvorexant intermediate, and belongs to the field of medical compounds. According to the invention, 2-bromo-5-methyl benzoic acid with low price is used as a reaction raw material, and the Ullmann coupling reaction can be carried out at a lower temperature by adding amine, amino acid or oxamide ligands, so that the yield and selectivity of the product are greatly improved, and the ratio of the product to a regioisomer is remarkably increased. The route is low in cost, high in yield, simple and convenient to operate, mild in reaction condition and safe, and better meets the requirements of industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing a suvorexant intermediate, and belongs to the fields of medicine and organic chemistry. Background Art

[0002] Suvorexant (trade name: Belsomra), 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-benzoxazole, is a highly selective orexin receptor antagonist that selectively acts on neurons that mediate the transition between wakefulness and sleep by binding to the wake-promoting neuropeptides orexin A and orexin B, thereby increasing total sleep time and shortening the time it takes to fall asleep. It is the first approved orexin receptor antagonist and is clinically used to treat insomnia and other diseases.

[0003] 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (hereinafter referred to as compound IV) is a key intermediate in the synthesis of suvorexant, and its structure is shown below:

[0004]

[0005] The original patent WO2013169610A1 reported the synthesis method of compound IV, which uses 2-iodo-5-methylbenzoic acid (V) and triazole (II) as substrates, cuprous iodide as a catalyst, and potassium carbonate as a base to perform an Ullmann coupling reaction. The synthesis route is as follows:

[0006]

[0007] However, the method in the patent has complex post-processing, difficulty in separating the target product and isomers, and low conversion rate of the product, with a yield of only 60%.

[0008] The preparation method disclosed in WO2014141065A1 uses cuprous iodide as a catalyst, cesium carbonate as a base, and N,N'-dimethylformamide as a solvent to cause 2-iodo-5-methylbenzoic acid and 1,2,3-triazole to undergo an Ullmann reaction at 120°C. The reaction temperature of this route is high, and column chromatography is required to remove isomeric compounds, which is not suitable for industrial production. Chinese patent CN104557744A discloses a preparation method for compound VI, which is relatively simple to operate, but the product has poor properties (light green solid) and low purity (94% to 95%). The method disclosed in CN109810067B requires an additional recrystallization step, which is relatively cumbersome. In addition, the above prior arts all require the use of aryl iodide V as a raw material, which is expensive, resulting in high product cost, and cannot meet the dual needs of industrial production for cost control and efficiency improvement.

[0009] The document ChemMedChem (2009), 4 (7), 1069-1074 reported the route of using cheap 2-bromo-5-methylbenzoic acid to replace expensive 2-iodo-5-methylbenzoic acid. However, due to the low activity of aryl bromides, the Ullmann coupling reaction needs to be carried out under high temperature conditions of about 120 ° C; the yield of the target isomer is only 62%. Patent WO2018202689A1 also uses 2-bromo-5-methylbenzoic acid as a raw material, but the ratio of the target product to the regional isomer impurities is 78 / 22, and the post-processing purification is difficult, requiring two to three hot beatings to purify the regional isomer impurities, which is not suitable for industrial production. In order to solve the above problems, the inventors have developed a new method for preparing compound IV using 2-bromo-5-methylbenzoic acid as a raw material, which is easy to operate, mild reaction conditions, good product yield and purity, high regional selectivity, simple post-processing, suitable for industrial production, and therefore has good market value and far-reaching practical significance. Summary of the invention

[0010] In view of the above technical background, the purpose of the present invention is to provide an improved method for preparing a suvorexan intermediate compound IV, which has the characteristics of high regioselectivity, high yield, low cost, simple post-treatment, etc.

[0011] The present invention provides a method for preparing compound IV, comprising the following steps:

[0012]

[0013] Wherein, M is selected from sodium ion, potassium ion or lithium ion;

[0014] (1) Compound I and Compound II are reacted with a copper catalyst, a ligand and a base to obtain Compound III through an Ullmann coupling reaction;

[0015] (2) Compound III is reacted with an acid to obtain Compound III;

[0016] The ligand is selected from amine, amino acid or oxalamide ligands.

[0017] Furthermore, the Ullmann coupling reaction in step (1) is carried out in an organic solvent.

[0018] Furthermore, in step (1), the copper catalyst is selected from any one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cupric oxide, copper powder, or a combination thereof; preferably any one of cuprous iodide and cuprous bromide;

[0019] Furthermore, in the step (1), the molar ratio of the copper catalyst to the compound I is (0.01-0.5):1, preferably (0.05-0.3):1.

[0020] Furthermore, in step (1), the amine ligand is selected from (1S, 2S)-N1, N2-dimethylcyclohexane-1, 2-diamine; the amino acid ligand is selected from L-proline and N, N-dimethylglycine; the oxamide ligand is selected from N, N'-diphenyloxamide, N, N-bis (2, 4, 6-trimethoxyphenyl) oxamide, bis (4-hydroxy-2, 6-dimethylphenyl) oxamide; preferably, it is an amino acid ligand or an oxamide ligand, and further preferably, N, N-dimethylglycine, N, N'-diphenyloxamide, N, N-bis (2, 4, 6-trimethoxyphenyl) oxamide, bis (4-hydroxy-2, 6-dimethylphenyl) oxamide; the most preferably, it is N, N'-diphenyloxamide.

[0021] Furthermore, in step (1), the molar ratio of the ligand to the compound I is (0.01-1):1; preferably (0.05-0.2):1.

[0022] Furthermore, in the step (1), the molar feed ratio of compound II to compound I is (1.2-4.5):1; preferably (2.0-2.5):1;

[0023] Furthermore, in step (1), the base is selected from one or a combination of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, sodium bicarbonate, and potassium bicarbonate; preferably one of potassium carbonate, sodium carbonate, and lithium hydroxide.

[0024] Furthermore, in the step (1), the molar feed ratio of the base to the compound I is (1.5-5.0):1; preferably (2.0-3.0):1;

[0025] Furthermore, in the step (1), the organic solvent is selected from any one of halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, nitriles, amides, and sulfone solvents, or a combination thereof. The halogenated hydrocarbon solvents are, for example, dichloromethane, dichloroethane, and chloroform; the aromatic hydrocarbon solvents are, for example, toluene; the ester solvents are, for example, ethyl acetate and isopropyl acetate; the ether solvents are, for example, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane; the nitrile solvents are, for example, acetonitrile; the amides are, for example, N,N-dimethylformamide; the sulfone solvents are, for example, dimethyl sulfoxide and sulfolane; and the organic solvent is preferably acetonitrile.

[0026] Furthermore, in the step (1), the ratio of the volume of the organic solvent used in mL to the mass of the compound I in g is (1-20):1; preferably (5-20):1.

[0027] Furthermore, in step (1), the reaction temperature is 50 to 80°C, preferably 60 to 75°C, and more preferably 60 to 65°C.

[0028] Furthermore, the reaction time in step (1) is 1 to 24 hours.

[0029] Furthermore, the specific operation in step (2) includes: concentrating the reaction solution obtained in step (1), adding water, and adding acid to adjust the pH of the reaction solution; then adding an organic solvent for extraction and separation, and concentrating and crystallizing the obtained organic phase to obtain product IV.

[0030] Furthermore, in step (2), the acid is selected from one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or a combination thereof, preferably hydrochloric acid.

[0031] Furthermore, the organic solvent used for extraction in step (2) is selected from any one of halogenated hydrocarbons, aromatic hydrocarbons, esters, and ethers, or a combination thereof. The halogenated hydrocarbon solvents are, for example, dichloromethane, dichloroethane, and chloroform; the aromatic hydrocarbon solvents are, for example, toluene; the ester solvents are, for example, ethyl acetate and isopropyl acetate; the ether solvents are, for example, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane; and the organic solvent is preferably methyl tert-butyl ether.

[0032] Preferably, the ratio of the volume of the organic solvent in mL to the mass of the compound I in g in step (2) is selected from (1-20):1; preferably (5-20):1.

[0033] The present invention also provides a method for preparing suvorexant, comprising the above method for preparing compound IV.

[0034] The beneficial effects brought by the technical solution of the present invention include:

[0035] 1. The present invention uses cheap 2-bromo-5-methylbenzoic acid to replace expensive 2-iodo-5-methylbenzoic acid as a reaction raw material, making the overall route more economical and suitable for industrial production. However, due to the low activity of aromatic bromides, the prior art needs to carry out Ullmann coupling at a high temperature of 120° C., which is harsh. The present invention allows the reaction to be carried out at a temperature of, for example, 60 to 75° C. by adding amines, amino acids or oxamide ligands, thereby reducing the required reaction temperature, and the reaction conditions are mild and safe, which is more in line with the requirements of industrial production.

[0036] 2. Due to the low activity of aryl bromide, the yield of the reaction in the prior art is only 62%, and the ratio of isomeric impurities is as high as 22%. The present invention greatly improves the yield and selectivity of the product by adding a ligand, so that the ratio of the product to the regional isomer is significantly improved. Compared with the prior art, the present invention can make the yield of the target isomer increase to more than 90% by adding a suitable ligand, and the regional selectivity is increased to more than 95%, and the product purity can reach more than 99%. Therefore, this route can obtain a highly purified product in high yield, high atom utilization, and high selectivity while using cheap 2-bromo-5-methylbenzoic acid as a raw material, and simultaneously satisfies the requirement of being more suitable for industrial mass production.

[0037] 3. The purification process of the present invention is simple. After the reaction is completed, the regional isomers can be effectively removed by a simple filtration step. There is no need to use column chromatography to remove isomeric compounds, which greatly simplifies the purification process and is more suitable for industrial production. Specific embodiments

[0038] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under normal conditions.

[0039] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0040] The room temperature in the examples refers to 20-30° C. Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Sigma Aldrich, and used without treatment.

[0041] Example 1

[0042]

[0043] Add acetonitrile (900 mL, 9.0 V), compound I (100 g, 1.0 eq), compound II (64.24 g, 2.0 eq), cuprous iodide (6.20 g, 0.07 eq) and N, N'-diphenyloxamide (12.29 g, 0.11 eq) into a 2 L three-necked flask and stir at room temperature for 1.0 hour; then heat to 60-65 ° C for reaction, and add sodium carbonate (123.22 g, 2.5 eq) in batches; The reaction was carried out at 0-65°C for 14 h until the raw material was completely converted; the reaction solution was concentrated to remove the organic solvent, water (500 mL, 5.0 V) was added to the concentrated residue, and then 2.0 N hydrochloric acid was added to adjust the pH of the reaction solution to 1-2; then methyl tert-butyl ether (1200 mL, 12.0 V) was added for extraction and separation, and the obtained organic phase was concentrated and crystallized, and filtered to obtain the product IV (88.92 g, yield: 94.1%, purity: 99.97%).

[0044] Example 2

[0045] In a 2L three-necked flask, acetonitrile (900mL, 9.0V), compound I (100g, 1.0eq), compound II (80.30g, 2.5eq), cuprous iodide (6.20g, 0.07eq) and oxalylanilide (12.29g, 0.11eq) were added and stirred at room temperature for 1.0 hour; then the temperature was raised to 60-65°C for reaction, and sodium carbonate (123.22g, 2.5eq) was added in batches; 60-6 The reaction was kept at 5°C for 14 h until the raw material was completely converted; the reaction solution was concentrated to remove the organic solvent, water (500 mL, 5.0 V) was added to the concentrated residue, and then 2.0 N hydrochloric acid was added to adjust the pH of the reaction solution to 1-2; then methyl tert-butyl ether (1200 mL, 12.0 V) was added for extraction and separation, and the obtained organic phase was concentrated and crystallized, and filtered to obtain the product IV (89.67 g, yield: 94.9%, purity: 99.98%).

[0046] Example 3

[0047] Referring to the method in Example 1, using cuprous iodide (0.05 eq) as a catalyst precursor, sodium carbonate (2.5 eq) as a base, and acetonitrile as a solvent (9.0 V), the effect of the Ullmann coupling reaction under non-high temperature conditions and different ligands were preliminarily investigated, and the experimental results are as follows:

[0048]

[0049]

[0050] Experiments show that without adding ligands, due to the low activity of aromatic bromides, a large amount of raw material I remains under non-high temperature conditions, and the ratio of product IV / isomer VI is 79.6 / 20.4; based on this reaction condition, ligands are added to the reaction system to accelerate the reaction rate. Using (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine as a ligand, the conversion rate of raw material I is greatly improved. Using L-proline and N,N-dimethylglycine as ligands, the conversion rate and reaction regioselectivity of raw material I are improved, but there is still a lot of room for improvement; using N,N'-diphenyloxamide as a ligand, under the reaction condition of 75 degrees, the conversion rate and reaction regioselectivity of raw material I are significantly improved. Lowering the reaction temperature to 65 degrees, the reaction regioselectivity of raw material I is increased to 96.9 / 3.1.

[0051] Experiments have shown that the addition of amine, amino acid or oxamide ligands can enable compound I to obtain the target product with high yield and high selectivity under non-high temperature conditions.

[0052] Example 4

[0053] Add acetonitrile (900 mL, 9.0 V), compound I (100 g, 1.0 eq), compound II (64.24 g, 2.0 eq), cuprous iodide (4.43 g, 0.05 eq) and N, N'-diphenyloxamide (11.17 g, 0.10 eq) into a 2 L three-necked flask and stir at room temperature for 1.0 hour; then heat to 60-65 ° C for reaction, and add sodium carbonate (123.22 g, 2.5 eq) in batches; The reaction was carried out at 60-65°C for 14 h until the raw material was completely converted; the reaction solution was concentrated to remove the organic solvent, water (500 mL, 5.0 V) was added to the residue, and then 2.0 N hydrochloric acid was added to adjust the pH of the reaction solution to 1-2; then methyl tert-butyl ether (1200 mL, 12.0 V) was added for extraction and separation, and the obtained organic phase was concentrated and crystallized, and filtered to obtain the product IV (85.61 g, yield: 90.6%, purity: 99.92%).

[0054] Example 5

[0055] Add acetonitrile (900 mL, 9.0 V), compound I (100 g, 1.0 eq), compound II (64.24 g, 2.0 eq), cuprous bromide (4.67 g, 0.07 eq) and N, N'-diphenyloxamide (12.29 g, 0.11 eq) into a 2 L three-necked flask and stir at room temperature for 1.0 hour; then heat to 60-65 ° C for reaction, and add sodium carbonate (123.22 g, 2.5 eq) in batches; 6 The reaction was carried out at 0-65°C for 14 h until the raw material was completely converted; the reaction solution was concentrated to remove the organic solvent, water (500 mL, 5.0 V) was added to the concentrated residue, and then 2.0 N hydrochloric acid was added to adjust the pH of the reaction solution to 1-2; then methyl tert-butyl ether (1200 mL, 12.0 V) was added for extraction and separation, and the obtained organic phase was concentrated and crystallized, and filtered to obtain the product IV (86.08 g, yield: 91.1%, purity: 99.95%).

[0056] Example 6

[0057] In a 2L three-necked flask, acetonitrile (900mL, 9.0V), compound I (100g, 1.0eq), compound II (64.24g, 2.0eq), cuprous iodide (6.20g, 0.07eq) and N,N-bis(2,4,6-trimethoxyphenyl)oxalamide (21.50g, 0.11eq) were added and stirred at room temperature for 1.0 hour; then the temperature was raised to 60-65°C for reaction, and sodium carbonate (123.22g, 2.0eq) was added in batches. 5eq); keep the reaction at 60-65°C for 14h until the raw material is completely converted; concentrate the reaction solution to remove the organic solvent, add water (500mL, 5.0V) to the concentrated residue, and then add 2.0N hydrochloric acid to adjust the pH of the reaction solution to 1-2; then add methyl tert-butyl ether (1200mL, 12.0V) for extraction and separation, concentrate and crystallize the obtained organic phase, and filter to obtain product IV (87.31g, yield: 92.4%, purity: 99.96%).

[0058] The above description of the embodiments is to facilitate those skilled in the art to understand and use the invention. The present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A method for preparing compound IV, characterized in that: The steps include: Wherein, M is selected from sodium ion, potassium ion or lithium ion; (1) Compound I and Compound II are reacted with a copper catalyst, a ligand and a base to obtain Compound III through an Ullmann coupling reaction; (2) Compound III is reacted with an acid to obtain Compound III; The ligand is selected from amine, amino acid or oxalamide ligands.

2. The method according to claim 1, characterized in that: The copper catalyst is selected from any one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cupric oxide, copper powder or a combination thereof; preferably any one of cuprous iodide and cuprous bromide.

3. The method according to claim 2, characterized in that The molar ratio of the copper catalyst to the compound I is (0.01-0.5):1, preferably (0.05-0.3):

1.

4. The method according to any one of claims 1 to 3, characterized in that: The molar ratio of the ligand to compound I is (0.01-1):1; preferably (0.05-0.2):

1.

5. The method according to claim 4, characterized in that The amine ligand is selected from (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine; the amino acid ligand is selected from L-proline and N,N-dimethylglycine; the oxamide ligand is selected from N,N'-diphenyloxamide, N,N-bis(2,4,6-trimethoxyphenyl)oxamide, and bis(4-hydroxy-2,6-dimethylphenyl)oxamide; preferably, it is an amino acid ligand or an oxamide ligand, and further preferably, it is N,N-dimethylglycine, N,N'-diphenyloxamide, N,N-bis(2,4,6-trimethoxyphenyl)oxamide, and bis(4-hydroxy-2,6-dimethylphenyl)oxamide; the most preferred is N,N'-diphenyloxamide.

6. The method according to any one of claims 1 to 4, characterized in that: The molar feed ratio of the compound II to the compound I is (1.2-4.5):1; preferably (2.0-2.5):

1.

7. The method according to claim 1, characterized in that The molar feed ratio of the base to the compound I is (1.5-5.0):1; preferably (2.0-3.0):1; And / or, preferably, the base is selected from one or a combination of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate; preferably one of potassium carbonate, sodium carbonate and lithium hydroxide.

8. The method according to claim 1, characterized in that The step (1) satisfies one or more of the following conditions: 1) In the step (1), the reaction solvent is selected from any one of halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, nitriles, amides, and sulfone solvents or a combination thereof; the halogenated hydrocarbon solvent is selected from dichloromethane, dichloroethane, and chloroform; the aromatic hydrocarbon solvent is selected from toluene; the ester solvent is selected from ethyl acetate and isopropyl acetate; the ether solvent is selected from methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane; the nitrile solvent is selected from acetonitrile; the amide is selected from N,N-dimethylformamide; the sulfone solvent is selected from dimethyl sulfoxide and sulfolane; preferably acetonitrile; 2) In step (1), the ratio of the volume of the reaction solvent used in mL to the mass of the compound I in g is (1-20):1; preferably (5-20):1; 3) The reaction temperature of step (1) is 40-80°C, preferably 60-75°C, and more preferably 60-65°C; 4) The reaction time in step (1) is 1 to 24 hours.

9. The method according to claim 1, characterized in that: The specific operation in step (2) includes: concentrating the reaction solution obtained in step (1), adding water, and adding acid to adjust the pH of the reaction solution; then adding an organic solvent for extraction and separation, and concentrating and crystallizing the obtained organic phase to obtain product IV; The step (2) also satisfies one or more of the following conditions: 1) In step (2), the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or a combination thereof, preferably hydrochloric acid; 2) The organic solvent used for extraction in step (2) is selected from any one of halogenated hydrocarbons, aromatic hydrocarbons, esters, and ethers, or a combination thereof. The halogenated hydrocarbon solvent is, for example, dichloromethane, dichloroethane, and chloroform; the aromatic hydrocarbon solvent is selected from toluene; the ester solvent is selected from ethyl acetate and isopropyl acetate; the ether solvent is selected from methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, and 1,4-dioxane; and the organic solvent is preferably methyl tert-butyl ether; 3) In step (2), the ratio of the volume of the organic solvent used in mL to the mass of compound I in g is selected from (1-20):1; preferably (5-20):

1.

10. A method for preparing suvorexant, characterized in that: The method comprises the method for preparing compound IV as claimed in claim 1.

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