KR100368896B1 - A process for preparing 6-aminomethyl-5H-dibenz[b,e]azepine - Google Patents

Abstract

The present invention relates to a method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine, and more particularly, using a compound represented by the following Chemical Formula 2 as a starting material and a hydrogenation reaction with a hydrogen gas. Instead of the conventional manufacturing method of performing a multi-step process of reduction using hydrazine, the compound represented by the following Chemical Formula 2 is reacted with sodium borohydride, followed by a simple process of acid hydrolysis and base treatment. (one-pot reaction), it can be inconvenient to handle, such as hydrogen gas and hydrazine used in the conventional method, and can eliminate the use of dangerous and harmful substances, and it can eliminate the cumbersome process of intermediate separation or purification The present invention relates to a method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by the following general formula (1).

Description

Process for preparing 6-aminomethyl-5H-dibenz [b, e] azepine}

The present invention relates to a method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine, and more particularly, using a compound represented by the following Chemical Formula 2 as a starting material and a hydrogenation reaction with a hydrogen gas. Instead of the conventional manufacturing method of performing a multi-step process of reduction using hydrazine, the compound represented by the following Chemical Formula 2 is reacted with sodium borohydride, followed by a simple process of acid hydrolysis and base treatment. (one-pot reaction), it can be inconvenient to handle, such as hydrogen gas and hydrazine used in the conventional method, and can eliminate the use of dangerous and harmful substances, and it can eliminate the cumbersome process of intermediate separation or purification The present invention relates to a method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by the following general formula (1).

6-aminomethyl-5H-dibenz [b, e] azepine represented by Chemical Formula 1 is 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5- a] is useful as an intermediate for the synthesis of various pharmaceuticals, including azepine hydrochloride. Thus, a multifaceted study has been conducted on the method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by Chemical Formula 1.

As a general method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by Chemical Formula 1, a multistage reaction as shown below is described in European Patent No. 496,306 and Japanese Patent Application Laid-Open No. 4-346988. Known in

According to the general manufacturing method described above, first, the imino group of the compound represented by Chemical Formula 2 is heated and hydrogenated under hydrogen gas under a palladium metal catalyst, and hydrogenated to produce an amine compound represented by the following Chemical Formula 4 and then purified. In addition, the phthalimide group of the compound represented by Chemical Formula 4 is reduced with hydrazine and decomposed by sodium hydroxide to prepare a compound represented by Chemical Formula 1.

However, the general manufacturing method described above is composed of a multi-stage process of a hydrogenation step using a hydrogen gas under heating and pressurization and a reduction step using hydrazine. And there is a problem that the use of a large amount of harmful substances, and also the hassle of separation and purification of the compound represented by the formula (4) obtained as a result of the hydrogenation reaction.

Therefore, there is a limit to applying the above general manufacturing method to industrial mass production.

The inventors have found the problem of the use of a large amount of dangerous and harmful substances and the separation and purification of intermediates, which is a problem in the general manufacturing method of 6-aminomethyl-5H-dibenz [b, e] azepine represented by Chemical Formula 1 above. I tried to solve it. As a result, the starting material represented by the formula (2) was reacted with sodium borohydride to generate a new azepine intermediate, and the acid hydrolysis and base treatment were performed immediately without separation and purification of the resulting intermediate. The present invention has been completed by developing a new manufacturing method that can solve all the same problems.

Accordingly, the present invention provides a method for economically preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by Chemical Formula 1, which is useful as an intermediate of a pharmaceutical product by a simpler and shorter synthetic process. The purpose is.

The present invention provides a method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by the following Chemical Formula 1 using a compound represented by the following Chemical Formula 2 as a starting material,

After reacting the compound represented by Chemical Formula 2 with sodium borohydride (NaBH ₄ ), the reaction solution was sequentially treated with acid and base without separation of the intermediate to produce 6-aminomethyl-5H represented by the following Chemical Formula 1. -A method for producing dibenz [b, e] azepine.

Referring to the present invention in more detail as follows.

The present invention is a general manufacturing method for synthesizing 6-aminomethyl-5H-dibenz [b, e] azepine represented by Chemical Formula 1 using the compound represented by Chemical Formula 2 as a starting material, wherein Chemical Formula 2 Sodium tetraborate tetrahydrochloride (NaBH ₄ ) is selected as a reactant with the compound represented by the present invention, and thus, it is characterized by the method of preparation in that it produces an azepine intermediate having a structure completely different from the known methods. The azepine intermediate thus obtained is immediately converted to a compound represented by Chemical Formula 1 in high purity and high yield by a simple process of treating with an acid and then sequentially with a base without separation and purification.

The following Reaction Scheme 1 shows the difference in reaction mechanism between the general known method and the preparation method according to the present invention in preparing the compound represented by Formula 1 from the compound represented by Formula 2.

That is, in the present invention, the selective use of sodium borohydride (NaBH ₄ ) as a reactant with the compound represented by the formula (2) to generate an azepine intermediate represented by the formula (3) of a structure completely different from the known method, and The resulting azepine intermediate is subjected to a simple process of sequentially treating with acid and base without separate separation and purification to obtain a compound represented by Chemical Formula 1 above. Therefore, as in the conventional manufacturing method, the handling is inconvenient, and the use of dangerous and harmful reactants is excluded, and the yield and purity are excellent, and it must be an advanced manufacturing method without any difficulty in industrial application.

The reaction of the compound represented by Formula 2 according to the present invention with sodium boron tetrahydride is carried out under a mixed solvent of water, such as methanol, ethanol, propanol, isopropanol, butanol and the like, and an organic solvent selected from tetrahydrofuran (THF) and the like. In this case, when the mixing ratio of the solvent was maintained in the range of 1: 10 to 10: 1 volume ratio, it was confirmed that the production rate of the azepine intermediate was remarkably high. In the case of the reaction temperature, the reaction proceeds sufficiently even at room temperature, and heating to the reflux temperature of the solvent is possible, and the heating temperature is particularly preferably about 50 ° C.

In addition, it is preferable to use acetic acid as an acid used to hydrolyze the azepine intermediate, and in addition to acetic acid, an aqueous solution of an acid such as hydrochloric acid or sulfuric acid may be used, and the hydrolysis temperature is from room temperature to reflux temperature of the solvent. Can be up to about 82 ℃.

In the basicization process, an aqueous solution of an alkali metal or alkaline earth metal salt may be used, and preferably, an aqueous sodium hydroxide solution is used, and is performed at room temperature.

On the other hand, the following scheme 2 is prepared from the compound represented by the formula (2) 6-aminomethyl-5H-dibenz [b, e] azepine represented by the formula (1) by the method of the present invention as described above Then, 3-amino-9,13b-dihydro represented by the following Chemical Formula 7 by a series of preparation methods in which the compound represented by Chemical Formula 1 is reacted with cyanogen bromide, and subsequently subjected to basicization and acid treatment. -1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride is an example of a method for producing hydrochloride.

When the compound represented by Chemical Formula 1 prepared by the above-described preparation method of the present invention is reacted with a brominated cyanogen, the compound is converted into bromate of the imidazo compound represented by Chemical Formula 5, and is basicized with an aqueous sodium hydroxide solution. After obtaining the free base compound represented by, and then treated with an aqueous hydrochloric acid solution it can be easily obtained the compound represented by the formula (7).

On the other hand, the compound represented by the formula (2) used as a starting material in the production method according to the invention is a known synthesis method already known as a known compound [ J. Med. Chem., 35 (1970) , J. Am. Chem. Soc. , 2786 (1950)].

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example: Synthesis of 6-aminomethyl-5H-dibenz [b, e] azepine (Formula 1)

To 6-phthalimidomethyl-5H-dibenz [b, e] azepine (Formula 2; 6.4 g), add a mixed solution of isopropanol (32 mL) and purified water (5.3 mL), and add sodium tetraborate (3.4 g). Stir at room temperature for 48 hours. At this time, a part of the reaction solution was taken to determine whether an azepine intermediate (Formula 3) was produced.

¹ H-NMR (CDCl ₃ ) δ 1.60 (1H, brs), 3.98 to 4.03 (3H, m), 4.15 (1H, brs), 4.30 (1H, d, J = 14.8 Hz), 4.63 (2H, s ), 5.02 (1 H, m), 6.82 (1 H, brs), 6.63-7.75 (12 H, m).

Direct acetic acid (32 mL) was added slowly to the reaction solution without azepine intermediate separation and refluxed for 3 hours. Distilled water (50 mL) was added, the reaction solvent was distilled under reduced pressure, distilled water (100 mL) was added, washed twice with ethyl acetate (50 mL), and the aqueous layer was basified with 2N aqueous sodium hydroxide solution (100 mL). The organic layer was extracted twice with dichloromethane (35 mL) and the organic layer was dried over anhydrous sodium sulfate (2 g), and the solvent was removed by distillation under reduced pressure to obtain 3.92 g (yield 84%) of a pale brown oily title compound.

Melting point 109 to 110 ° C; ¹ H-NMR (CDCl ₃ ) δ 1.64 (3H, brs), 3.11 to 3.31 (2H, m), 3.95 (1H, d, J = 14.8 Hz), 4.37 (1H, d, J = 14.8 Hz), 4.74 (1H, m), 6.64-7.62 (8H, m).

Comparative Example 1: Synthesis of 6- (phthalimidomethyl) -6,11-dihydro-5H-dibenz [b, e] azepine (Formula 4)

Dimethylformamide (911.4 L) was added to 6-phthalimidomethyl-5H-dibenz [b, e] azepine (Formula 2; 110 kg), and formic acid (28.7 kg) and 10% palladium carbon (12.5 kg) were suspended. Dimethylformamide (25 L) was added. The temperature of the reaction solution was warmed to 70 ° C. and stirred while adding hydrogen at 7 atm. The filtrate was washed with dimethylformamide (80 L) and the filtrate was evaporated under reduced pressure at 70 to 80 ° C. After cooling to 50 ° C., 150 L of acetone was added thereto, cooled to 15 ° C., and the precipitated crystals were filtered and dried to obtain 99.5 kg (yield 90%) of the title compound.

Comparative Example 2: 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [via 6-aminomethyl-5H-dibenz [b, e] azepine (Formula 1) Synthesis of 1,5-a] azepine (Formula 6)

Ethylene glycol (176 L) was added to 6- (phthalimidomethyl) -6,11-dihydro-5H-dibenz [b, e] azepine (Formula 4; 62.3 kg), and hydrazine monohydrate (9 kg) and 45% aqueous sodium hydroxide solution (10.8 L) was added sequentially and stirred at 110 ° C. for 2 hours. The reaction solution was cooled to 15 ° C., water (315 L) was added, extracted with dichloromethane (140.8 L), and the aqueous layer was reextracted with dichloromethane (95 L and 10 L) to give Solution 1 (solution 1). .

Bromine (29.6 kg) was added to an aqueous solution (88 L) in which sodium bromide (19.9 kg) was dissolved at 10-15 ° C., followed by 26.5% aqueous sodium cyanide solution (34.0 kg) and water (35.2 L) to add solution 2 Anogen solution).

Solution 1 (solution of Formula 1) was cooled to 15 ° C. and mixed with Solution 2. The temperature was raised to 20-25 ° C. and stirred. After distilling the solvent under reduced pressure, an oily liquid was obtained. Toluene (88 L) was added thereto, heated to 80 ° C., a 45% aqueous sodium carbonate solution was added thereto, and the mixture was stirred at this temperature for 30 minutes. The reaction solution was cooled to 5 ° C, washed and dried to obtain the title compound (33.3 kg) (yield 76%).

Reference Example 1 Synthesis of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrobromide (Formula 5)

To a solution of 6-aminomethyl-5H-dibenz [b, e] azepine (Formula 1; 2.0 g) in tetrahydrofuran (10.5 mL) of cyanogen bromide (1.9 g) was added 1 Dropwise added for time. After stirring for 14 hours at room temperature, the solvent was distilled off under reduced pressure to obtain a solid. A mixed solvent of dichloromethane-diethyl ether (2: 1) (50 mL) was added, followed by filtration and recrystallization with a mixed solvent (50 mL) of methanol-ethyl acetate (1: 7) to give 2.5 g of the title compound (yield 85%). )

Melting point 283-284 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 3.53 (1H, dd, J = 10, 10 Hz), 3.72 (1H, d, J = 14 Hz), 4.30 (1H, dd, J = 10, 10 Hz) , 4.50 (1H, d, J = 14 Hz), 5.37 (1H, m), 7.18-7.51 (8H, m), 8.15 (3H, brs).

Reference Example 2 Synthesis of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrobromide (Formula 5)

To 6-phthalimidomethyl-5H-dibenz [b, e] azepine (Formula 2: 6.4 g), a mixed solution of isopropanol (16 mL) and purified water (2.65 mL) was added thereto, and sodium tetraborate (1.7 g) was added thereto. . After stirring for 48 hours at room temperature, acetic acid (16 mL) was added slowly and refluxed for 3 hours. Distilled water (30 mL) was added thereto, the organic solvent was distilled under reduced pressure, distilled water (50 mL) was added thereto, washed twice with ethyl acetate (30 mL), and the aqueous layer was basified with 2N aqueous sodium hydroxide solution (50 mL). The mixture was extracted twice with dichloromethane (15 mL) and the organic layer was dried over anhydrous sodium sulfate (1 g), and the solution was added dropwise to a dichloromethane (10 mL) solution of cyanobromide (1.9 g) for 1 hour. After stirring for 20 hours at room temperature, diethyl ether (20 mL) was added, and the obtained solid was filtered and recrystallized with a mixed solvent of methanol-ethyl acetate (1: 7) (50 mL) to give 2.45 g (72% yield) of the title compound. )

Reference Example 3: Synthesis of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine (Formula 6)

3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrobromide (Formula 5; 2.5 g) was purified water (10 mL) and dichloromethane ( 20 mL) and added 2N aqueous sodium hydroxide solution (4.5 mL) and stirred for 30 minutes. The organic layer was separated and the aqueous layer was reextracted with dichloromethane (10 mL). The organic layer was collected, dried over anhydrous sodium sulfate (1 g), and the solvent was removed by evaporation under reduced pressure to obtain 1.81 g (yield 97%) of the title compound.

Melting point 205 to 208 ° C; ¹ H-NMR (CDCl ₃ ) δ 3.40 (1H, d, J = 12 Hz), 3.46 (1H, dd, J = 9, 9 Hz), 4.01 (1H, dd, J = 9, 9 Hz), 4.56 (1H, d, J = 12 Hz), 4.94 (3H, m), 6.91-7.31 (8H, m).

Reference Example 4: Synthesis of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride (Formula 7)

3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine (Formula 6; 1.81 g) was dissolved in isopropanol (5 mL) and then in an ice bath. A solution of concentrated hydrochloric acid (0.72 mL) in isopropanol (5 mL) was added. The temperature was raised and stirred at room temperature for 30 minutes. Then, diethyl ether (10 mL) and acetone (30 mL) were added slowly to obtain a solid. The obtained solid was recrystallized from a mixed solvent of methanol (7 mL) and ethyl acetate (42 mL) to obtain 1.73 g (yield 83%) of the title compound.

Melting point 273 to 274 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 3.48 (1H, dd, J = 10, 10 Hz), 3.66 (1H, d, J = 14 Hz), 4.26 (1H, dd, J = 10, 10 Hz) 4.45 (1H, d, J = 14 Hz), 5.32 (1H, m), 7.12-7.46 (8H, m), 8.31 (3H, brs).

As described above, in the preparation method according to the present invention, by using sodium tetraborate which is easy to handle as a reactant of the compound represented by Chemical Formula 2, it is dangerous to synthesize an intermediate having a completely different structure from that of the conventional preparation method. It is economical and easy to work with since it can eliminate the use of harmful substances and proceed the reaction continuously without separating intermediates.

Claims (5)

In the method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine represented by the following Chemical Formula 1 using the compound represented by the following Chemical Formula 2, After reacting the compound represented by Chemical Formula 2 with sodium borohydride (NaBH ₄ ), the reaction solution is sequentially represented by the following formula (1), characterized in that the reaction solution is subjected to acid treatment and base treatment without the intermediate separation process. Method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine. Formula 2 Formula 1 The method of claim 1, wherein the reaction of the compound represented by Formula 2 with sodium borohydride (NaBH ₄ ) is carried out at room temperature to the reflux temperature of the solvent 6-aminomethyl-5H-dibenz [b, e] method of preparing azepine. The reaction of the compound represented by the formula (2) with sodium borohydride (NaBH ₄ ) is selected from methanol, ethanol, propanol, isopropanol, butanol and tetrahydrofuran (THF). Process for the preparation of 6-aminomethyl-5H-dibenz [b, e] azepine, characterized in that carried out under. The 6-aminomethyl-5H-dibenz [b, wherein the acid treatment is performed at room temperature to solvent reflux temperature using an aqueous acid solution selected from acetic acid, hydrochloric acid and sulfuric acid. e] method of preparing azepine. The method for preparing 6-aminomethyl-5H-dibenz [b, e] azepine according to claim 1, wherein the base treatment is performed at room temperature using an aqueous solution of an alkali metal or alkaline earth metal salt.