Method for producing benzazepine compound

Abstract

To provide a method for producing a benzazepine compound capable of easily removing impurities which are difficult to remove by purification by crystallization.SOLUTION: There is provided a method for producing a high-purity benzazepine compound by bringing a benzazepine compound into contact with activated carbon in a first solvent. The volume of pores having a diameter of 1.5 nm or more and 3.0 nm or less by a nitrogen gas adsorption method using activated carbon is preferably 0.1 mL / g or more and 0.5 mL / g or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a process for preparing a benzazepine compound. [Background technology]

[0002] [ka]

[0003] Tolvaptan (chemical name: (7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine)) represented by the above formula (4) is a compound useful as a vasopressin V2-receptor antagonist with aquaretic activity.

[0004] Many methods for producing benzazepine compounds represented by formula (1), including tolvaptan, have been reported. For example, Patent Document 1 describes a method for synthesizing a benzazepine compound and a method for obtaining crystals of the benzazepine compound by crystallization using ethyl acetate, as shown in Scheme A below. Scheme A

[0005] [ka]

[0006] Furthermore, Patent Document 2 describes a method for synthesizing a benzazepine compound and a method for obtaining crystals of the benzazepine compound by crystallization using methanol / water (4:1), as shown in the following formula scheme B. Scheme B

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 2020-015686 [Patent Document 2] Patent No. 5583172 Summary of the Invention [Problem to be solved by the invention]

[0009] Generally, when a compound is used as a drug substance, it is desirable to use one with extremely high purity. However, when the present inventors produced tolvaptan by the synthesis and subsequent crystallization methods described in Patent Documents 1 and 2, they found that several impurities were by-produced during the amidation reaction and remained in tolvaptan.

[0010] These by-products are difficult to remove, and repeated purification procedures are required to obtain highly pure tolvaptan. Furthermore, the amount of these by-products remaining is strongly dependent on the purity of the compound of formula (3) used in the synthesis of tolvaptan. Therefore, to obtain highly pure tolvaptan, it is necessary to maintain the purity of the raw materials, for example, the compounds represented by formulas (2) and (3), at extremely high levels, which poses significant problems in terms of cost and operability.

[0011] Therefore, an object of the present invention is to provide a method for producing a benzazepine compound, which can easily remove these impurities. [Means for solving the problem]

[0012] The present inventors have conducted extensive research into the above-mentioned problems. Specifically, they carried out purification of a benzazepine compound using an adsorbent as a purification procedure. Therefore, they decided to introduce a purification step using an adsorbent after separating the crude benzazepine compound after the amidation reaction. As a result, they found that when the benzazepine compound was purified by contacting it with activated carbon, the remaining impurities could be efficiently removed.

[0013] That is, the present invention provides a method for producing a benzazepine compound, which comprises washing a crude benzazepine compound after an amidation reaction by separation and then contacting the crude benzazepine compound with activated carbon.

[0014] Furthermore, in a first pore size distribution obtained by a nitrogen gas adsorption method, in which the horizontal axis represents pore diameter and the vertical axis represents differential pore volume, the maximum peak of the activated carbon is preferably located in the range of 1.5 nm to 3.0 nm, and the volume of pores with a diameter of 1.5 nm to 3.0 nm is preferably 0.1 mL / g to 0.5 mL / g. [Effects of the Invention]

[0015] The benzazepine compound obtained by the method of the present invention is a highly purified product with reduced content of impurities that are difficult to remove by purification by crystallization, and therefore can be optimally used as a highly pure drug substance in pharmaceutical preparations. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention is a method for producing a benzazepine compound, which comprises contacting a crude benzazepine compound with a first solvent and activated carbon. (Target benzazepine compounds) The benzazepine compound is represented by the following formula (1):

[0017] [ka]

[0018] The crude benzazepine compound is not particularly limited, and can be produced by a known method, for example, by contacting an acid chloride represented by the following formula (2) with an aniline compound represented by the following formula (3).

[0019] [ka]

[0020] [ka]

[0021] The synthetic route for tolvaptan, a benzazepine compound, is shown in Scheme C below. Scheme C

[0022] [ka]

[0023] Specifically, 2-methyl-4-[(2-methylbenzoyl)amino]benzoic acid and thionyl chloride are stirred in N,N-dimethylformamide solvent at room temperature for 1 hour, and then this N,N-dimethylformamide reaction solution is added to an N,N-dimethylformamide solution of 8-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol and 2,6-lutidine, followed by stirring at 0°C for 2 hours, thereby producing crude tolvaptan.

[0024] The crude benzazepine compound before contact with activated carbon may be in a state dissolved in the first organic solvent, or in the form of a powder, a lump, or a mixture thereof, or in the form of an anhydrate, a solvate, or a mixture thereof.

[0025] The purity of the benzazepine compound used is not particularly limited, and the compound obtained by the above-mentioned production method can be used as is. However, in order to further improve the purity of the benzazepine compound obtained after final purification, it is also possible to use a compound that has been subjected to separation as a general washing operation or crystallization as a purification operation. Specifically, it is preferable to use a benzazepine compound whose peak area ratio exceeds 90% when measured under the high performance chromatography (HPLC) conditions described in the Examples below. (First solvent) The first solvent is typically a solvent capable of dissolving or dispersing the benzazepine compound represented by formula (1).

[0026] The first solvent to be used is not limited, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate; ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, and xylene; aqueous solutions containing water and salts; and mixed solvents thereof. Among these, organic solvents that dissolve benzazepine compounds and their salts, and polar solvents such as alcohols and water are preferred, and at least one organic solvent selected from the group consisting of methanol, ethanol, propanol, ethyl acetate, and acetonitrile may be used.

[0027] The first solvent may be the organic solvent used in the liquid separation and extraction of the crude benzazepine compound. (activated carbon) In the first pore distribution obtained by nitrogen gas adsorption, in which the horizontal axis represents pore diameter and the vertical axis represents differential pore volume, the activated carbon preferably has a maximum peak in the range of 1.5 nm to 3.0 nm. The use of activated carbon with a relatively small pore diameter having such a maximum peak tends to further reduce impurities. The maximum peak is more preferably in the range of 1.5 nm to 2.5 nm, and even more preferably in the range of 1.6 nm to 2.0 nm.

[0028] The activated carbon to be used has a first pore size distribution in which the volume of pores of 1.5 nm or more and 3.0 nm or less is 0.1 mL / g or more and 1.0 mL / g or less, and preferably 0.1 mL / g or more and 0.5 mL / g or less.

[0029] The shape of the activated carbon used in the present invention is not limited as long as it allows contact between the solvate of the benzazepine compound and the activated carbon, and for example, powdered carbon or granular carbon can be used. (Method of contact with activated carbon) Unlike existing purification methods using crystallization, the step of contacting a benzazepine compound with activated carbon has the advantage of being versatile. Therefore, purification can be performed at any step in the production process of a benzazepine compound, preferably after a separation washing step, or before or after a crystallization operation. The time for contacting the benzazepine compound with activated carbon is not limited, but can be, for example, 5 minutes or more, preferably 15 minutes or more, and more preferably 30 minutes or more. The amount of solvent used for contacting the benzazepine compound with activated carbon is not particularly limited, but can be, for example, 1 v / w to 5000 v / w relative to the crude benzazepine compound, preferably 2 v / w to 2000 v / w, and more preferably 2 v / w to 1000 v / w. Thus, purification can be performed using a wide range of solvent amounts. The amount of activated carbon used is not particularly limited, but is preferably adjusted depending on the purity of the crude benzazepine compound. A concentration of 1 w / w% to 200 w / w% of the benzazepine compound can generally be used. Of these, 5 w / w% to 100 w / w% is preferred, and 10 w / w% to 50 w / w% is particularly preferred. The solution temperature when contacting the benzazepine compound with activated carbon is not particularly limited, but can be, for example, -30°C to 120°C, preferably 0°C to 100°C, and more preferably 40°C to 80°C. [Example]

[0030] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0031] The purity and impurity contents of tolvaptan obtained in the Production Examples, Examples, and Comparative Examples were measured by the following methods. <Measurement of tolvaptan purity and impurity content> The purity of tolvaptan and the contents of other impurities in the tolvaptan obtained in Examples 1, 2, 3, and Comparative Example 1 were measured by HPLC (high performance liquid chromatography). The apparatus and conditions used for the measurement are as follows: Equipment: High performance liquid chromatography (HPLC) Model: Alliance e2695 (Waters) Detector: Ultraviolet absorption altimeter (λ=254nm) Column: YMC-Pack ODS-A (particle size: 5 μm, inner diameter: 4.6 mm, column length: 150 mm) (manufactured by YMC) Column temperature: 25℃ Injection volume: 5μL Mobile phase A: Dissolve 4.08 g of potassium dihydrogen phosphate in 3.00 L of distilled water, and add phosphoric acid to adjust the pH to 3.1. Mobile phase B: acetonitrile Flow rate: 1.0mL / min Measurement time: 50 minutes Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 1 below to control the concentration gradient.

[0032] [Table 1]

[0033] Under the above HPLC conditions, tolvaptan is detected at approximately 14.8 minutes. In the following examples and comparative examples, the purity of tolvaptan and the content of impurities are both values of peak area % measured under the above conditions.

[0034] In the following examples and comparative examples, the removal rate is a value calculated by the following formula.

[0035]

number

[0036] <Production Example 1> (Production of crude tolvaptan) 500 mg of 2-methyl-4-[(2-methylbenzoyl)amino]benzoic acid was dissolved in 2.50 mL of N,N-dimethylformamide and stirred for 5 minutes at 0°C under a nitrogen atmosphere. 0.148 mL of thionyl chloride was slowly added to this solution and stirred for 1 hour. The temperature was then raised to room temperature and the mixture was stirred for 1 hour to obtain an N,N-dimethylformamide solution of 2-methyl-4-[(2-methylbenzoyl)amino]benzoyl chloride.

[0037] 550 mg of 8-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol and 590 mg of potassium carbonate were dissolved in 8.20 mL of N,N-dimethylformamide and stirred at 0°C for 5 minutes under a nitrogen atmosphere. The prepared N,N-dimethylformamide solution of 2-methyl-4-[(2-methylbenzoyl)amino]benzoyl chloride was added dropwise to this solution and stirred for 2 hours. The reaction was then quenched by adding 1.15 mL of water to the reaction solution. 10.7 mL of tetrahydrofuran, 10.7 mL of ethyl acetate, and 10.7 mL of 15% aqueous sodium chloride were added, and the organic layer was separated. The organic layer was washed twice with 3.55 mL of 5% aqueous hydrochloric acid and once with 3.55 mL of 10% aqueous potassium carbonate / 10% aqueous sodium chloride to obtain an ethyl acetate solution of tolvaptan. The HPLC purity of tolvaptan in this ethyl acetate solution was 93.00%. Example 1 To the ethyl acetate solution of tolvaptan obtained in Production Example 1, 250 mg of Shirasagi WP-H (registered trademark) (Osaka Gas Chemicals Co., Ltd.) activated carbon (in the first pore size distribution, the maximum peak was 1.8 nm, and the volume of pores ranging from 1.5 nm to 3.0 nm was 0.2 mL / g) was added. The mixture was stirred at room temperature for 4 hours. After stirring, the solution was filtered, and the filtrate was concentrated to 3.60 mL by vacuum distillation, followed by the addition of 7.30 mL of ethyl acetate. This procedure was repeated twice. The mixture was again concentrated to 3.60 mL, and 3.60 mL of ethyl acetate was added to adjust the total solvent volume to 7.20 mL. The mixture was stirred overnight at 0°C, and the precipitated solid was collected by filtration. The resulting solid was washed with 2.20 mL of ethyl acetate. The wet tolvaptan was vacuum dried at 40°C for 3 hours, yielding 481 mg of crude tolvaptan in an isolation yield of 58%. The HPLC purity of this tolvaptan was 99.76%. <Example 2> 481 mg of crude tolvaptan obtained in Example 1 was suspended in 5.77 mL (12 v / w) of methanol and dissolved by heating to 65°C. 240 mg of the same activated carbon as in Example 1 was added to the suspension, followed by stirring at 65°C for 2 hours. After filtration, 1.44 mL (3 v / w) of water was added, and the mixture was stirred at room temperature for 2 hours with natural heat dissipation, followed by stirring at 0°C overnight. The precipitated solid was collected by filtration and vacuum dried at 40°C overnight to obtain 328 mg of the target tolvaptan in an isolation yield of 68%. The HPLC purity of this tolvaptan was 99.91%. Example 3 10.0 mg of crude tolvaptan, obtained by vacuum distillation of the ethyl acetate solution of tolvaptan in Production Example 1, was dissolved in 10.0 mL of methanol. This methanol solution was subjected to HPLC analysis. 10.0 mg of Shirasagi WP-H (registered trademark) activated carbon (manufactured by Osaka Gas Chemicals Co., Ltd.) (in the first pore size distribution, the maximum peak was 1.8 nm, and the volume of pores between 1.5 nm and 3.0 nm was 0.2 mL / g) was added to the solution, which was then stirred at room temperature. After 4 hours, HPLC analysis was performed to calculate the HPLC purity and impurity removal rate. The results are shown in Table 2 below. Table 2 shows the removal rates for each impurity observed at each retention time (RT) on HPLC.

[0038] [Table 2]

[0039] These results confirmed that when activated carbon Shirasagi WP-H (registered trademark) (manufactured by Osaka Gas Chemicals Co., Ltd.) (in the first pore size distribution, the maximum peak is 1.8 nm, and the volume of pores between 1.5 nm and 3.0 nm is 0.2 mL / g) is used as an adsorbent, it is possible to remove many impurities at a removal rate of 90% or more. In particular, it was found that an impurity with a retention time of 9.14 minutes, which is difficult to remove by recrystallization, can be removed at a removal rate of 40% or more. <Examples 4 to 9> 10.0 mg of crude tolvaptan, obtained by vacuum distillation of the ethyl acetate solution of tolvaptan in Production Example 1, was dissolved in 10.0 mL of methanol. This methanol solution was subjected to HPLC measurement. 10.0 mg of Adsorbent 1 (see below) was added to the solution, and the mixture was stirred at room temperature. HPLC measurement was performed after 4 hours, and the HPLC purity and impurity removal rate were calculated. The results are shown in Table 3 below. Table 3 shows the removal rate for each impurity observed at each retention time (RT) on HPLC. ("Shirasagi" and "ANOX" are registered trademarks of Osaka Gas Chemicals Co., Ltd.) HPLC measurements were carried out in the same manner as above, except that adsorbent 1 was changed to adsorbents 2 to 6 below. Example 4 Adsorbent 1: Activated carbon Shirasagi WP-Z (registered trademark) (Osaka Gas Chemicals Co., Ltd.) Example 5 Adsorbent 2: Activated carbon, Purified Shirasagi (registered trademark) (Osaka Gas Chemicals Co., Ltd.) Example 6 Adsorbent 3: Activated carbon Special Shirasagi (registered trademark) (Osaka Gas Chemicals Co., Ltd.) Example 7 Adsorbent 4: Activated carbon Shirasagi P (registered trademark) (Osaka Gas Chemicals Co., Ltd.) Example 8 Adsorbent 5: Activated carbon Shirasagi ANOX-1 (registered trademark) (Osaka Gas Chemicals Co., Ltd.) Example 9 Adsorbent 6: Activated carbon Yuki A (manufactured by Serachem Co., Ltd.)

[0040] [Table 3]

[0041] <Comparative Examples 1 and 2> 10.0 mg of crude tolvaptan, obtained by vacuum distillation of the ethyl acetate solution of tolvaptan in Preparation Example 1, was dissolved in 10.0 mL of methanol. This methanol solution was subjected to HPLC measurement. 10.0 mg of Adsorbent 7 (see below) was added to the solution and stirred at room temperature. After 4 hours, HPLC measurement was performed to calculate the HPLC purity and impurity removal rate. The results are shown in Table 4 below. Table 4 shows the removal rate for each impurity observed at each retention time (RT) on HPLC.

[0042] HPLC measurement was carried out in the same manner as above, except that adsorbent 7 was changed to adsorbent 8 below. Adsorbent 7: Acidic alumina, SuperI (MP Biomedicals) Adsorbent 8: Basic alumina, Super I (MP Biomedicals)

[0043] [Table 4]

[0044] Preferred embodiments are listed below. [1] A method for producing a benzazepine compound, comprising contacting a crude benzazepine compound represented by the following formula (1) with a first solvent and activated carbon:

[0045] [ka]

[0046] [2] The manufacturing method according to [1], wherein in a first pore distribution of the activated carbon obtained by a nitrogen gas adsorption method, the horizontal axis represents pore diameter and the vertical axis represents differential pore volume, the maximum peak is located within a range of 1.5 nm or more and 3.0 nm or less. [3] The method according to [2], wherein the volume of pores of the activated carbon having a diameter of 1.5 nm or more and 3.0 nm or less, measured by a nitrogen gas adsorption method, is 0.1 mL / g or more and 0.5 mL / g or less. [4] The crude benzazepine compound represented by the formula (1) can be obtained by contacting an acid chloride represented by the following formula (2) with an aniline compound represented by the following formula (3), in accordance with any one of the production methods of [1] to [3]:

[0047] [ka]

[0048] [ka]

[0049] [5] The method for producing a benzazepine compound represented by the formula (1) according to any one of [1] to [4], comprising washing the crude benzazepine compound by separation and then contacting the crude benzazepine compound with the activated carbon.

Claims

1. A method for producing a benzazepine compound, comprising contacting a crude benzazepine compound represented by the following formula (1) with a first solvent and activated carbon: 【Chemical 1】

2. 2. The method according to claim 1, wherein a first pore size distribution of the activated carbon obtained by a nitrogen gas adsorption method, the horizontal axis representing pore diameter and the vertical axis representing differential pore volume, has a maximum peak located in a range of 1.5 nm or more and 3.0 nm or less.

3. 3. The method according to claim 2, wherein the activated carbon has a pore volume of 1.5 nm or more and 3.0 nm or less, measured by a nitrogen gas adsorption method, of 0.1 mL / g or more and 0.5 mL / g or less.

4. The method according to claim 1, wherein the crude benzazepine compound represented by formula (1) is obtained by contacting an acid chloride represented by the following formula (2) with an aniline compound represented by the following formula (3): 【Chemistry 2】 【Chemistry 3】

5. 2. The method according to claim 1, comprising washing the crude benzazepine compound represented by formula (1) by liquid separation and then contacting the washed crude benzazepine compound with the activated carbon.

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