JP2022140107A - Method for producing 1,4-benzodiazepine compound - Google Patents

Abstract

To provide a method for efficiently producing a 1,4-benzodiazepine compound without the need for removing a reaction solvent.SOLUTION: The present invention discloses a method for producing a 1,4-benzodiazepine compound (2) represented by the following formula (2), by reacting a benzophenone derivative (1) represented by the following formula (1) with an amination agent in the presence of 1-butanol, where X, Y independently represent a halogen atom or a hydrogen atom, and Z represents a halogen atom.SELECTED DRAWING: None

Description

The present invention relates to a method for producing 1,4-benzodiazepine compounds useful as pharmaceutical intermediates.

A 1,4-benzodiazepine compound is a compound useful as a pharmaceutical intermediate for benzodiazepine drugs used as anxiolytics, hypnotics, muscle relaxants, and the like.
As a method for producing a 1,4-benzodiazepine compound, a method is known in which 2-chloroacetamide-5-chlorobenzophenone is reacted with hexamethylenetetramine and ammonium acetate in ethanol to cyclize it ( Non-Patent Document 1).

Ivica. Cepanec et al. , Organic Process & Research & Development 2006, 10(6), 1192-1198.

However, the method described in Non-Patent Document 1 uses ethanol as a solvent for the cyclization reaction. Before the washing step of , a step of distilling off the solvent ethanol is required. In addition, a two-stage crystallization process is performed to produce the 1,4-benzodiazepine compound, and the purification process is complicated. For this reason, there is a problem in implementing it on an industrial scale in terms of energy efficiency and an increase in the number of processes.

An object of the present invention is to provide a method for efficiently producing a 1,4-benzodiazepine compound without distilling off the reaction solvent.

As a result of intensive studies, the present inventors found that by reacting a benzophenone derivative with an aminating agent to cyclize 1-butanol as a solvent, the reaction solvent does not need to be distilled off, and efficient 1,4- A method for making benzodiazepine compounds has been discovered.
That is, the present invention is as follows.

（式（１）中、Ｘ、Ｙは、それぞれ独立してハロゲン原子または水素原子を表し、Ｚはハロゲン原子を表す。）で表されるベンゾフェノン誘導体（１）と、アミノ化剤とを反応させる、
下記式（２）；

（式（２）中、Ｘ，Ｙは前記に同じ。）で表される１，４－ベンゾジアゼピン化合物（２）の製造方法。
[２］ 前記アミノ化剤がヘキサメチレンテトラアミンである［１］に記載の製造方法。
[３] 前記反応と同一系内で、前記１，４－ベンゾジアゼピン化合物（２）を晶析させる［１］または［２］に記載の製造方法。
[４] 前記１，４－ベンゾジアゼピン化合物が下記式（３）で表される[１]～[３]のいずれかに記載の製造方法。

[1] In the presence of 1-butanol, the following formula (1);

(In the formula (1), X and Y each independently represent a halogen atom or a hydrogen atom, and Z represents a halogen atom.) is reacted with an aminating agent. ,
the following formula (2);

A method for producing a 1,4-benzodiazepine compound (2) represented by (in formula (2), X and Y are the same as described above).
[2] The production method according to [1], wherein the aminating agent is hexamethylenetetramine.
[3] The production method according to [1] or [2], wherein the 1,4-benzodiazepine compound (2) is crystallized in the same system as the reaction.
[4] The production method according to any one of [1] to [3], wherein the 1,4-benzodiazepine compound is represented by the following formula (3).

According to the present invention, a 1,4-benzodiazepine compound useful as a pharmaceutical intermediate for benzodiazepine drugs can be produced without distilling off the reaction solvent after the cyclization reaction. Further, according to the present invention, a 1,4-benzodiazepine compound can be produced by purification by a simple method.

One embodiment of the present invention will be described below, but the present invention is not limited thereto.

Benzophenone derivative (1) (hereinafter sometimes referred to as compound (1)), which is a raw material of the present invention, is represented by the following formula (1).

（式中、Ｘ、Ｙは、それぞれ独立してハロゲン原子、又は水素原子を表し、Ｚはハロゲン原子を表す。）

(Wherein, X and Y each independently represent a halogen atom or a hydrogen atom, and Z represents a halogen atom.)

X and Y are not particularly limited as long as they are each independently a halogen atom or a hydrogen atom, and the halogen atoms represented by X and Y include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, respectively. mentioned. X is preferably a chlorine atom, and Y is preferably a fluorine atom.
Further, the halogen atom represented by Z is not particularly limited as long as it is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like, and from the viewpoint of the reactivity of the cyclization reaction, it is preferably a chlorine atom or a bromine atom, A chlorine atom is more preferable.

The compound (1) can be obtained, for example, from Ivica. Cepanec et al. , Organic Process & Research & Development 2006, 10(6), 1192-1198 (Non-Patent Document 1). Specifically, it can be obtained by reacting 2-aminobenzophenone having a suitable hydrogen atom or halogen atom corresponding to X and Y with chloroacetyl chloride.

The 1,4-benzodiazepine compound (2) (hereinafter sometimes referred to as compound (2)), which is the product of the present invention, is represented by the following formula (2).

（式中、Ｘ、Ｙは前記に同じである。）

(In the formula, X and Y are the same as above.)

<Method for producing compound (2)>
The 1,4-benzodiazepine compound (2) represented by the above formula (2) is obtained by contacting the benzophenone derivative (1) with an aminating agent in a 1-butanol solvent to obtain an amino group and a benzophenone carbonyl group. It can be produced by reacting with and cyclizing.

In this reaction, 1-butanol is used as a reaction solvent. By using 1-butanol as a solvent, the desired product, compound (2), can be obtained from the reaction solution without distilling off the reaction solvent after the reaction.

The amount of the reaction solvent used is not more than 50 times the weight of the compound (1), more preferably not more than 15 times the weight of the compound (1), because too much is not preferable in terms of cost and post-treatment. The lower limit is preferably 1-fold weight or more, more preferably 10-fold weight or more, relative to the compound (1).

Examples of the aminating agent used in this reaction include hexamethylenetetramine (hereinafter sometimes referred to as HMTA), ammonia, and the like, preferably HMTA. When the reaction is performed using HMTA as an aminating agent, ammonium acetate may be added to the reaction system.

The upper limit of the amount of the aminating agent to be used is preferably 10-fold molar equivalent or less, more preferably 5-fold molar equivalent or less, relative to the compound (1), from the viewpoint of the reaction rate and removal after the reaction. . The lower limit is preferably 1-fold molar equivalent or more, more preferably 2-fold molar equivalent or more, relative to the compound (1). Within such a range, the reaction rate is sufficiently high, and it is also preferable from the viewpoint of removal after the reaction.

The reaction temperature in this reaction is not particularly limited and may be set appropriately, but the upper limit is preferably 110°C or less, more preferably 100°C or less. The lower limit is preferably 70°C or higher, more preferably 80°C or higher.

The upper limit of the reaction time for this reaction is preferably 10 hours or less, more preferably 5 hours or less, from the viewpoint of yield and formation of by-products. The lower limit is preferably 1 hour or longer, more preferably 3 hours or longer.

In this reaction, the mixing order and mixing method of the compound (1), 1-butanol and aminating agent are not particularly limited.

As the treatment after completion of the reaction, a general treatment for obtaining a product from the reaction solution may be performed. For example, water may be added to the reaction solution after completion of the reaction for washing, or an aqueous solution such as hydrochloric acid or an aqueous sodium hydrogencarbonate solution may be added for washing, if necessary.

Since 1-butanol is sparingly soluble in water and separates into an aqueous layer and an organic layer, extraction and liquid separation operations can be performed after the reaction. For this reason, it is not necessary to distill off 1-butanol prior to washing with water or an aqueous solution. The unreacted aminating agent remaining in the reaction solution after completion of the reaction and the reaction by-product derived from the aminating agent are incorporated into the aqueous layer by washing with the water or aqueous solution. On the other hand, since the desired product, compound (2), exists in the organic layer, compound (2) can be separated from these. The target compound (2) is obtained by distilling off the organic solvent from the obtained organic layer containing the compound (2) by operations such as pressure reduction and heating. The target product thus obtained may be further enriched by general purification techniques such as crystallization and column chromatography.

Next, a method for crystallizing the target compound (2) will be described. Crystallization may be carried out by completely distilling off the solvent in the organic layer containing the compound (2) and adding the solvent used for crystallization, or by removing part of the organic solvent in the organic layer and removing the compound (2). A solvent used for crystallization may be added as a concentrate.

Therefore, according to the present method, the reaction process, the washing process, and the crystallization process can be performed in the same system (one pot), so that the operation is simple and efficient even when performed on an industrial scale. can be done.

When the concentrated solution is used, the amount of the liquid is not particularly limited and may be set appropriately, but the upper limit is preferably 30 times or less by weight, more preferably 20 times or less by weight, relative to the compound (2). and particularly preferably 10 times the weight or less. The lower limit is preferably 1-fold weight or more, more preferably 3-fold weight or more, relative to the compound (2).

Solvents used for the crystallization are preferably ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol and dimethyl ether; hydrocarbons such as benzene, toluene, xylene, n-hexane and n-heptane. and alcohol solvents having 4 or more carbon atoms such as 1-butanol. These solvents may be used alone or in combination of two or more. When two or more kinds are used in combination, the ratio is not particularly limited. Combination of 1-butanol and n-hexane or n-heptane is preferred. Crystallization can also be carried out by adding n-hexane or n-heptane to the concentrate obtained by removing part of the 1-butanol used as the reaction solvent.

Seed crystals may be added during crystallization.

From the viewpoint of cost, the upper limit of the amount of the solvent used for crystallization is preferably 30 times the weight or less, more preferably 20 times the weight or less, and particularly preferably 10 times the weight of the compound (2). It is below. The lower limit is preferably at least 0.1 times the weight of compound (2), more preferably at least 0.5 times the weight.

The temperature at which crystallization is performed is not particularly limited, but may be appropriately selected depending on the type of solvent used for crystallization. Preferably, the target precipitation is carried out at a temperature below the temperature at which the compound (2) is dissolved in the solvent used for crystallization. It can be set according to the amount and quality of crystals (chemical purity/content).

The crystals of compound (2) precipitated by the above crystallization method can be separated and obtained by a method such as filtration under reduced pressure, filtration under pressure, or centrifugation. Further, if necessary, the quality can be improved by further washing with an organic solvent.

The obtained crystals are preferably dried under reduced pressure at 40° C. or less to avoid thermal decomposition or melting.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited by the following examples, and can be modified appropriately within the scope that can conform to the gist of the above and later descriptions. It is of course possible to implement them, and all of them are included in the technical scope of the present invention.

The HPLC analysis conditions used are as follows. In addition, the yield, chemical purity, and content were determined based on these conditions in the experimental examples described later, unless otherwise specified.

Column: XBridge C18 (4.6 mmφ × 250 mm, manufactured by Waters)
Eluent:
Liquid A: distilled water/acetonitrile = 750/150 (volume ratio)
Liquid B: Acetonitrile Liquid C: Methanol Flow rate: 0-30 minutes: 0.8 mL/minute: 30-55 minutes: 0.1 mL/minute Column temperature: 30°C
Measurement wavelength: 210 nm
Gradient system:
0-12 minutes: A liquid 50%, B liquid 50%, C liquid 0%
12-20 minutes: A liquid 30%, B liquid 50%, C liquid 20%
20-20.5 minutes: A liquid 50%, B liquid 50%, C liquid 0%
20.5-55 minutes: A liquid 50%, B liquid 50%, C liquid 0%

(Reference Example 1) Preparation of 2-chloroacetamido-5-fluorobenzophenone (1) To 2-amino-5-fluorobenzophenone (20.0 g, 88.1 mmol) and potassium carbonate (12.0 g, 96.9 mmol) was added tetrahydrofuran. (120.0 g) was added, and after stirring, the mixture was cooled to 0°C. Chloroacetyl chloride (10.1 g, 96.9 mmol) was added to the cooled solution and stirred for 1 hour. Subsequently, after confirming the completion of the reaction by HPLC, ethyl acetate and water were added and the aqueous layer was separated. Water was added to the obtained organic layer for washing, and the aqueous layer was separated to give an ethyl acetate solution of the title compound (1) (281.36 g, pure content: 26.1 g, yield: 100 mol%, chemical purity: 98 .6%) was obtained.
HPLC retention time: 10.9 minutes

(Comparative Example 1) Preparation of 7-chloro 1,3-dihydro-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (2) 2-chloroacetamide-5 obtained in Reference Example 1 HMTA (12.6 g, 89.7 mol) and ammonium acetate (6.9 g, 89.7 mol) were added to the fluorobenzophenone solution (130.9 g, pure content 13.3 g, 40.8 mmol) and ethanol (133.3 g, 89.7 mol) was added. 0 g). After stirring at 90° C. for 5 hours and confirming the completion of the reaction by HPLC, ethanol was distilled off by concentration. Tetrahydrofuran and ethyl acetate were added to the residue to dissolve it, then water was added and washed twice to give a solution of the title compound (2) (216.13 g, pure content 10.2 g, 35.2 mol, yield 86.4 mol%) was obtained.

(Comparative Example 2) Crystallization of 7-chloro 1,3-dihydro-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (2) 7-chloro 1, obtained in Comparative Example 1, 127.1 g of a solution of 3-dihydro-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (pure content: 6.0 g) was solvent-substituted with tetrahydrofuran to a concentration of 20.4% by mass. It was adjusted. The preparation was temperature adjusted to 40° C. and n-heptane (35.5 g) was added. The solution was then cooled to 0°C and stirred for 16 hours. The precipitated crystals were separated by filtration, washed with 11 mL of heptane, and dried to obtain white crystals (3.9 g, 13.6 mmol) of the title compound (2) (yield: 65.5 mol %). The chemical purity by HPLC analysis was 99.5% and the content was 90.2%. At this time, HMTA remained in the crystal at a content of 7.5%.

(Comparative Example 3) Crystallization of 7-chloro 1,3-dihydro-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (2) 7 obtained in the same manner as in Comparative Example 1 A solution of -chloro 1,3-dihydro-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one was solvent-substituted with 2-methyltetrahydrofuran, and the concentration was adjusted to 20.3% by mass (pure content: 3 .5 g). The preparation was temperature adjusted to 40° C. and n-heptane (28.5 g) was added. The solution was then cooled to 0°C and stirred for 16 hours. The precipitated crystals were separated by filtration, washed with 10 mL of water, and then washed with 5 mL of a mixed solvent of 2-methyltetrahydrofuran/heptane=1/3. After drying, white crystals (3.3 g, 11.4 mol) of the title compound (2) were obtained (yield 82.0 mol %). The chemical purity by HPLC analysis was 98.2% and the content was 91.2%.

(Example 1) Preparation of 7-chloro 1,3-dihydro-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2- one 2-chloroacetamido-5-fluorobenzophenone obtained in Reference Example 1 HMTA (12.3 g, 88.1 mol) and ammonium acetate (6.8 g, 88.1 mol) were added to (12.9 g, pure content 13.1 g, 40.1 mmol), and 1-butanol (130.0 g) was added. Dissolved. After stirring at 90° C. for 5 hours and confirming the completion of the reaction by HPLC, water was added and the aqueous layer was separated. Further, water was added and washed twice to obtain a 1-butanol solution of the title compound (167.3 g, pure content 9.5 g, 32.9 mol, yield 82.1 mol%).
HPLC retention time: 5.2 minutes.
When 1-butanol was used as the reaction solvent, there was no need to distill off the solvent, and compound (2) could be produced in a yield equivalent to that obtained when ethanol was used as the solvent.

Example 2 Crystallization of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2- one 7-chloro-1, obtained in Example 1, A solution of 3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 1-butanol (166.0 g, pure content 9.9 g, 34.3 mmol) was concentrated to A 20.1% by mass solution was prepared. The temperature of the prepared solution was adjusted to 80° C., n-heptane (40.0 g) was added, and the mixture was stirred for 1 hour. The solution was then cooled to 0°C and stirred for 6 hours. The precipitated crystals were separated by filtration, washed with 10 mL of water, and then washed with 10 mL of a mixed solvent of butanol/heptane=1/2. After drying, white crystals of the title compound (8.5 g, 34.2 mol) were obtained (86.3 mol % yield). The chemical purity by HPLC analysis was 99.8% and the content was 98.0%. HPLC retention time: 5.2 minutes At this time, HMTA in the crystal was not detected. By using 1-butanol, which is immiscible with water, as a solvent, HMTA, which is easily soluble in water, was incorporated into the aqueous layer by washing with water, and was efficiently separated from the target title compound, which is thought to have increased the content.
¹ H NMR (500 MHz, DMSO-d6): δ 4.21 (s, 2H), 7.10 (d, 1H), 7.24-7.28 (m, 2H), 7.32-7.36 ( dt, 1H) 7.56-7.60 (m, 2H), 7.61-7.63 (dd, 1H), 10.76 (s, 1H) ppm.

In the present invention, it was possible to easily separate and purify the 1,4-diazobenzene compound, which is the title compound of interest, in a high content without the need for crystallization by repeating washing and filtration multiple times.

Claims (4)

In the presence of 1-butanol, the following formula (1);

(In the formula (1), X and Y each independently represent a halogen atom or a hydrogen atom, and Z represents a halogen atom.) is reacted with an aminating agent. ,
the following formula (2);

A method for producing a 1,4-benzodiazepine compound (2) represented by (in formula (2), X and Y are the same as described above). 2. The method according to claim 1, wherein said aminating agent is hexamethylenetetramine. 3. The production method according to claim 1, wherein the 1,4-benzodiazepine compound (2) is crystallized in the same system as the reaction. The production method according to any one of claims 1 to 3, wherein the 1,4-benzodiazepine compound is represented by the following formula (3).