KR100599028B1 - Preparation method of 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepin - Google Patents

Abstract

 In the present invention, 6-aminomethyl-6,11- of the following structural formula (I) is composed of a compound of the following formula (II), wherein a noble metal catalyst is used as a reaction catalyst and an inorganic acid is used as an additive to perform a hydrogenation reaction in an alcohol solvent. Provided is a method for preparing dihydro-5H-dibenz [b, e] azepine.

           (Ⅱ) (Ⅰ)

The 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepines prepared according to the present invention are useful intermediate compounds for the manufacture of pharmaceuticals, including antihistamines.

Palladium carbon, hydrochloric acid, hydrogenation reaction, dibenz [b, e] azepine

Description

Preparation method of 6-aminomethyl-6,11-dihydro-5H-dibenz [B, I] azepine {Preparation method of 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepin }

The present invention relates to 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine (or 6-amino), a compound of formula (I) which is a major intermediate that can be used in the synthesis of pharmaceuticals, etc. Methyl-5,6-dihydromopantridine).

          (Ⅰ)

The compound of formula (I) is used for the synthesis of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azine hydrochloride (Epineastine hydrochloride). Useful as an intermediate.

Methods for preparing compounds of formula (I) are described in US Pat. No. 4,339,331 and US Pat. No. 5,339,316. The manufacturing method of Structural Formula (I) described in these manufacturing methods is as follows.

First, there is a method of preparing compound (I) by reducing the compound of formula (II) using aluminum hydride obtained through the reaction of lithium aluminum hydride and 100% sulfuric acid in tetrahydrofuran [Scheme 1]. However, this synthesis method is difficult in terms of reaction conditions, there is a risk of explosion during the operation, it is economically expensive, requires a tetrahydrofuran solvent, and involves a lot of manipulation such as extraction after the reaction, filtration of a large amount of inorganic matters Difficult to use industrially

Secondly, a method of obtaining compound (I) through hydrogenation of a compound of formula (III) using formic acid and palladium followed by hydrazine decomposition is known [Scheme 2]. Although this method offers a more convenient and safer method than the first, several steps of reaction from 2-benzylaniline, which are known to be difficult to prepare in synthesizing Compound (III), which is proposed as the starting material of the patent. Compound (III) has to be prepared, and there is a problem in safety in industrial production because hydrazine, a carcinogenic substance, is used.

On the other hand, in the reduction of the nitrile functional group through the hydrogenation reaction, since secondary and tertiary amines are simultaneously generated through side reactions in addition to the primary amines, which are usually target compounds, liquids are obtained in such a manner that only the primary amines can be obtained by suppressing side reactions. A method of adding ammonia (US Pat. No. 3,520,932) or using an acylating solvent such as acetic acid or acetic anhydride is known. However, when using liquid ammonia, there are many problems in handling such as recovery and treatment, and when using an organic acid such as acetic acid or acetic anhydride, there is a problem that it is not easy to remove the organic acid after the reaction.

The present invention solves various problems such as explosion risk and difficult reaction conditions due to the use of dangerous compounds, which are disadvantages of known methods in synthesizing the target compound, excludes the use of harmful compounds, and synthesizes from inexpensive starting materials. It is an object of the present invention to provide a method for preparing a target compound in high yield under mild and easy reaction conditions.

Reaction conditions when synthesizing 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine through reduction of 6-cyano-11H-dibenz [b, e] azepine As a result, side reactions occur, such as the CN bond of the azepine moiety of the target compound or the nitrile functional group is released. Therefore, in order to obtain 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine in high yield, it is necessary to select a suitable reaction catalyst and reaction conditions. The inventors have studied to solve this problem, and surprisingly, when the hydrogenation reaction using a noble metal catalyst is carried out in the presence of an inorganic acid in an alcoholic solvent, the production of secondary and tertiary amines is suppressed, and the production of decomposed substances, etc. The present invention was completed by discovering that no side reaction substance was produced and the target compound could be prepared in high yield and high purity.

The present invention provides 6-aminomethyl of the target compound (I) through the hydrogenation reaction of 6-cyano-11H-dibenz [b, e] azepine of formula (II) with a noble metal catalyst in the presence of an inorganic acid in an alcoholic solvent. -6,11-dihydro-5H-dibenz [b, e] azepine is prepared.

The present invention will be described in more detail as follows.

The present invention relates to the preparation of 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine as shown in [Scheme 3]. e] Azepine is prepared by adding an inorganic acid and a noble metal catalyst in an alcoholic solvent followed by hydrogenation to prepare a target substance of formula (I) in high purity and high yield.

The 6-cyano-11H-dibenz [b, e] azepine used as a starting material here is a known compound 5,11-dihydro-6H-dibenz [b, e] azepine-6-one. It can be easily obtained through a two-step reaction from [Scheme 4] (US Patent No. 3389139, US Patent No. 4313931), 5,11-dihydro-6H-dibenz [b, e] azepine-6- On can be easily obtained by using the methods of the present inventors invented domestic patent applications No. 2002-0039110 and 2002-0039111.

In the reaction, a lower alcoholic solvent having a carbon number of 1 to 4, such as methanol, ethanol, propanol, or 2-propanol, may be used, and an inorganic acid such as hydrochloric acid or sulfuric acid may be used as an additive, or an alcohol in which hydrochloric acid gas is dissolved. Can be used as the reaction solvent. Among them, methanol which is preferably added with concentrated hydrochloric acid to the methanol solvent or which collects the hydrochloric acid gas is preferable. The hydrochloric acid used as the additive was 1.0 to 10.0 equivalents of a concentrated hydrochloric acid solution based on the compound of formula (II), preferably 2.0 to 6.0 equivalents, more preferably around 4.0 equivalents. When used as a hydrochloric acid gas, it is a 2% to saturated solution of methanol, preferably 2 to 5% concentration. When the amount of the inorganic acid used is small, side reactions occur and the yield tends to decrease.

Reaction temperature is a suitable reflux temperature at 0 ℃ and preferably the reaction can proceed at room temperature.

The hydrogen pressure proceeds at a pressure above atmospheric pressure, preferably 0.5 to 2 atmospheres. Suitable reaction catalysts are palladium, platinum, rhodium, ruthenium, rhenium, kappadium carbon, palladium black, platinum carbon, platinum oxide, ruthenium carbon, and more preferably palladium adsorbed on activated carbon. The amount of the catalyst used is about 0.001 to 1.0 equivalent, preferably 0.03 to 0.05 equivalent, based on the compound of formula (II). Low usage leads to longer reaction times, while high usage is not economically beneficial. The reaction time may vary depending on reaction conditions such as the type and amount of the solvent and catalyst used, the reaction temperature, and the hydrogen pressure, and is usually 1 hour to 48 hours, preferably about 12 to 24 hours.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1

10.0 g (45.8 mmol) of 6-cyano-11H-dibenz [b, e] azepine, 8.0 g of 5% palladium carbon (wet, ˜50% water), 200 ml of methanol, and 16 ml of concentrated hydrochloric acid were added to a 500 ml reaction vessel. After replacing the internal air with hydrogen, it is reacted at 2 atmospheres of hydrogen pressure and room temperature. After about 24 hours, the reaction was terminated, filtered to remove the catalyst, neutralized by addition of aqueous sodium hydroxide solution, and the reaction solution was concentrated to remove the organic solvent. Dichloromethane was added thereto, followed by extraction. The extract was washed with saturated brine and concentrated to give 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azine as light brown oil. After dissolving the oily substance in methanol, 5.32 g of fumaric acid was added and stirred to form a crystal, filtered and dried to give pale yellow 6-aminomethyl-6,11-dihydro-5H-dibenz [b. , e] Azepine fumaric acid salt was obtained in 12.94 g yield (83% of theory).

Melting Point: 192 ~ 193 ℃ (Decomposition)

IR cm ^-1 (KBr): 3390, 1700, 1650, 1600, 1560, 1500, 1355, 1310, 1285, 1250, 1170, 975, 785, 745, 640, 460

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.24 to 3.41 (2H, m), 3.8 (1H, d, J = 14.8), 4.3 (1H, d, J = 14.8), 5.03 to 5.07 (1H, m), 6.18 (bs), 6.47 (2H, s), 6.46 ~ 6.55 (2H, m), 6.8 ~ 7.3 (6H, m)

Example 2

10.0 g (45.8 mmol) of 6-cyano-11H-dibenz [b, e] azepine, 8.0 g of 5% palladium carbon (wet, ˜50% water), 200 ml of ethanol and 16 ml of concentrated hydrochloric acid were added to a 500 ml reaction vessel. After replacing the internal air with hydrogen, it is reacted at 2 atmospheres of hydrogen pressure and room temperature. After about 24 hours, the reaction was terminated, filtered to remove the catalyst, neutralized by addition of aqueous sodium hydroxide solution, and the reaction solution was concentrated to remove the organic solvent. Dichloromethane was added thereto, and the extract was washed with saturated brine and concentrated to give 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azine as light brown oil. After dissolving the oil compound obtained in methanol, 5.32 g of fumaric acid was added and stirred to form a crystal, filtered and dried to give pale yellow 6-aminomethyl-6,11-dihydro-5H-dibenz [b. , e] Azepine fumaric acid salt was obtained in 5.88 g yield (38% of theory).

Example 3

Dissolve 5.0g (22.9mmol) of 6-cyano-11H-dibenz [b, e] azepine, 4.0g of 5% palladium carbon (wet, ~ 50% water) and 4% hydrochloric acid in a 250ml reaction vessel. 100 ml of methanol is added, and the internal air is replaced with hydrogen, followed by reaction at 2 atmospheres of hydrogen and room temperature. After about 24 hours, the reaction was terminated, filtered to remove the catalyst, neutralized by addition of aqueous sodium hydroxide solution, and the reaction solution was concentrated to remove the organic solvent. Dichloromethane was added thereto, followed by extraction. The extract was washed with saturated brine and concentrated to give 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azine as light brown oil. After dissolving the oil compound obtained in methanol, 2.66 g of fumaric acid was added and stirred to form a crystal, filtered and dried to give pale yellow 6-aminomethyl-6,11-dihydro-5H-dibenz [b. , e] Azepine fumaric acid salt was obtained in 6.16 g yield (79% of theory).

Example 4

In Example V1, palladium was used instead of palladium to react to obtain a target compound.

Example 5

In Example V1, palladium black was used instead of palladium carbon to react to obtain a target compound.

Example 6

In Example V1, platinum compound was used instead of palladium to react with carbon to obtain a target compound.

Example 7

In Example V1, platinum compound was used instead of palladium carbon to react with each other to obtain a target compound.

Example 8

In Example V1, platinum compound was used instead of palladium to react with carbon to obtain a target compound.

Example 9

In Example 2, a target compound was obtained by reacting with palladium instead of palladium and using rhodium.

Example 10

In Example V2, ruthenium was used instead of palladium carbon to react to obtain a target compound.

In the production method according to the present invention, 6-cyano-11H-dibenz [b, e] azepine, which is a starting material, is used as an additive using an inorganic acid such as hydrochloric acid in an alcohol solvent, and is economical through a hydrogenation reaction using a noble metal catalyst. Provided is a method for producing a desired compound in high yield and high purity, which is a useful intermediate for the synthesis of pharmaceuticals by carrying out the reaction under mild reaction conditions in a safe manner.

Claims (4)

In the preparation of 6-amino-methyl-6,11-dihydro-5H-dibenz [b, e] azepine represented by Chemical Formula 1 by the hydrogenation reaction of the compound represented by the following Chemical Formula 2 using a noble metal catalyst And hydrogenation in the presence of 2 to 4 equivalents of an inorganic acid selected from hydrochloric acid and sulfuric acid as a reaction additive in a methanol solvent. [Formula 1]

[Formula 2]

The method according to claim 1, wherein the reaction product is hydrogenated in the presence of 0.02 to 0.05 equivalents of a noble metal catalyst selected from palladium carbon, palladium black, palladium, platinum, platinum carbon, platinum oxide, rhodium, ruthenium or ruthenium carbon as a reaction catalyst. . The method according to claim 1 or 2, wherein the target product is produced by reacting under hydrogen pressure of 1 to 2 atmospheres. The reaction product according to claim 1 or 2 is reacted under hydrogen pressure of 1 to 2 atmospheres using 2 to 4 equivalents of hydrochloric acid gas or 10 to 37% aqueous hydrochloric acid solution or 10 to 98% sulfuric acid as an inorganic acid. How to.