KR100486320B1 - Preparation method of 5,11-dihydro-6H-dibenz[b,e]azepin-6-one - Google Patents

Abstract

In the present invention, 5,11-dihydro-6H-dibenz of the following formula (I) consisting of the reaction of the compound of the formula (VI) using a iodic acid and red phosphorus as a reaction catalyst, and the acetic acid as a reaction solvent Provided are methods for preparing [b, e] azin-6-one.

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

Description

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

The present invention provides 5,11-dihydro-6H-dibenz [b, e] azin-6-one (or 5,6-dihydro-6) which is a compound of formula (I) -Oxomopantridine).

[Formula 1]

The compound of formula (I) is used for the synthesis of various pharmaceuticals, including the antihistamine 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride. Useful as an intermediate. Accordingly, various studies on the preparation method of the compound of formula (I) have been conducted.

A general method for preparing the compound of formula (I) is Indian J. Chem. 23B, 165 (1984), German Patent No. 2431409, US Patent No. 3367930, German Patent No. 2505714, US Patent No. 3910890, and the like. Representative production methods of formula (I) described in these known production methods can be divided into three types as follows.

First, the method of preparing the compound of the target compound (I) by Beckman potential reaction of the compound of the formula (II) and

Scheme 1

Secondly, to prepare the desired compound (I) by reacting the compound of formula (III) with phosgene to produce formula (IV) and then using aluminum chloride as a catalyst;

Scheme 2

Third, a method for preparing the desired compound (I) by reacting the compound of formula (V) with hydrofluoric acid or aluminum chloride in a benzene solvent is known.

Scheme 3

However, the synthesis of the target compound (I) from the compound of formula (II) using the Beckman potential reaction, which is the first of these methods, hardly occurs. In addition, the second method of preparing the formula (IV) from the compound of the formula (III) is a very dangerous process because it requires the use of phosgene, a compound with strong toxicity. In addition, compound (III), which is used as a starting material, has to be prepared through a multi-step process. Third, the method of preparing the compound of formula (I) from the compound of formula (V) should also be prepared using the toxic phosgene, which is also a starting material, and the highly toxic benzene in the reaction. It has various disadvantages such as using as a solvent and using highly corrosive hydrofluoric acid.

In addition, 11-hydroxy-5,11 dihydro-dibenz [b, e] azepin-6-one was converted into the desired 5,11-dihydro-6H-dibenz [b, e using iodic acid and acetic acid. ] Methods for preparing azepin-6-one are known (Can. J. Chem. 1994, 72 (2), 334). However, the starting material, 11-hydroxy-5,11dihydro-dibenz [b, e] azepin-6-one, was used as the starting material by the present inventors, 5H-dibenz [b, e] azepine-6. Since, 11-dione is prepared by reduction using sodium borohydride, it is uneconomical because the process is long and the yield is low because the reaction is performed twice. In addition, sodium borohydride, a reducing agent, is difficult to handle because it generates dangerous hydrogen gas during the reaction.

In general, the reduction of the diaryl ketone uses a Wolf-Kishner reduction reaction, a clemencene reduction reaction, and a reduction reaction using a strong reducing reagent such as Lyni-nickel or lithium aluminum hydride, but the inventors used 5H as a starting material. Dibenz [b, e] azepine-6,11-dione compounds and the above reaction methods did not yield satisfactory yields and effects.

Reduction of aryl ketones using iodic acid and red phosphorus has been reported to be used for the synthesis of anthracene structures, but there have been no reports applied to the synthesis of azepine structures with such amide functional groups.

The present invention solves various problems such as long reaction process, low yield and use of highly toxic and corrosive compounds, which are disadvantages of known methods in synthesizing the target compound, and high yield under simple reaction process and mild and easy reaction conditions. Its purpose is to provide a method for preparing the target compound with high purity.

The present invention is characterized in that the target compound (I) is prepared through a reduction reaction using 5H-dibenz [b, e] azepine-6,11-dione compound (VI) as a starting material.

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

The present invention relates to the preparation of 5,11-dihydro-6H-dibenz [b, e] azepin-6-one as shown in Scheme 4 as shown in Scheme 4 The target compound (I) can be obtained through reduction reaction using acetic acid solvent, iodic acid and red phosphorus using, 11-dione as starting material.

Wherein 5H-dibenz [b, e] azepine-6,11-dione is a known substance and known synthetic methods [J. Med. Chem. 1965, 8, 74., etc.].

In the present reaction, iodic acid and red phosphorus were used as catalysts for the reduction reaction, and an equivalent amount of iodic acid was used in an amount of 1.0 to 20.0 equivalents based on the compound of formula (VI), and preferably around 2.0 equivalents. In addition, the equivalent amount of red phosphorus was 1.0 to 20.0 equivalents based on the compound of the formula (VI), preferably about 1.1 equivalents. Acetic acid is used as the reaction solvent. The reaction temperature is from room temperature to reflux temperature, preferably from 100 ° C to 120 ° C. The reaction time is about 1 hour to 48 hours, preferably about 12 hours to 20 hours.

Scheme 4

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

Reference Example 1

Synthesis of 5H-dibenz [b, e] azepine-6,11-dione

20.0 g (96 mmol) of anthraquinone was dissolved in 120 ml of sulfuric acid and 30 ml of chloroform and the reaction mixture was cooled to 0 ° C. 8.8 g (0.135 mol) of sodium azide were added in portions to the reaction mixture while maintaining the temperature below 10 ° C, and reacted with stirring at room temperature for 12 hours. The reaction solution was added to 1 L of ice water to form crystals. After further stirring at room temperature for 1 hour, the resulting crystalline compound was filtered and washed several times with water to obtain a white target compound. The desired compound was obtained in a yield of 21.1 g (98% of theory).

Melting Point: 246 ~ 248 ℃

IR cm ^-1 (KBr): 3190, 3030, 2980, 2910, 1660, 1650, 1580, 1560, 1480, 1430, 1390, 1300, 1233, 1160

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.22 (t, 1H, J = 7.9 Hz), 7.34 (d, 1H, J = 8.0 Hz), 7.58 (t, 1H, J = 7.7 Hz) , 7.71 (d, 1H, J = 1.9 Hz), 7.69-7.85 (m, 3H), 8.17 (m, 1H), 11.1 (s, 1H)

Example 1

Synthesis of 5,11-dihydro-6H-dibenz [b, e] azin-6-one

Dissolve 10.0 g (44.8 mmol) of 5H-dibenz [b, e] azepine-6,11-dione in 50 ml of acetic acid, add 1.5 g (48.4 mmol) of red phosphorus, and 15 ml of 57% iodic acid for 18 hours. Stirred at reflux. After cooling to room temperature, 300 ml of ice water in which 7 g of sodium hydrogen sulfite was dissolved was poured into the reaction mixture, stirred, 300 ml of chloroform was added thereto, and then vigorously stirred. The organic layer was separated, washed with an aqueous solution of saturated sodium hydrogen carbonate, It dried with anhydrous magnesium sulfate, the insoluble red phosphorus was filtered out, the organic layer was concentrated under reduced pressure, and the target compound was obtained as white crystal | crystallization. The desired compound was obtained in a yield of 9.05 g (96.5% of theory).

Melting Point: 200 ~ 201 ℃

IR cm ^-1 (KBr): 3190, 3030, 2980, 2910, 1650, 1590, 1570, 1490, 1450, 1440, 1380

¹ H-NMR (CDCl ₃ ): δ 3.87 (s, 2H), 7.00 ~ 7.27 (m, 6H), 7.37 (t, 1H, J = 7.5Hz), 7.86 (d, 1H, J = 7.7Hz) 8.64 (s, 1H)

MASS m / z: 209 (M +), 180 (M ⁺ -29)

Example 2

0.6 g (2.7 mmol) of 5H-dibenz [b, e] azepine-6,11-dione was dissolved in 6.7 ml of acetic acid, followed by 0.33 g (10.7 mmol) of red phosphorus and 4.0 ml of 47% iodine It was stirred at reflux for 19 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of ice water in which 1 g of sodium bisulfite was dissolved and stirred, and the resulting crystals were filtered. The obtained crystals were dissolved in 200 ml of methylene chloride, and the undissolved red phosphorus was filtered and concentrated. To obtain the desired compound as white crystals. The desired compound was obtained in a yield of 0.5 g (89.0% of theory).

In the production method according to the present invention, using acetic acid as a reaction solvent, using iodic acid and red phosphorus as a catalyst, the reaction is carried out under mild reaction conditions, and a target compound and a similar compound are prepared in high yield and purity through an easy post-treatment process. Provide a method.

Claims (3)

A method for preparing 5,11-dihydro-6H-dibenz [b, e] azin-6-one represented by Chemical Formula 1 by reducing the compound represented by Chemical Formula 2 using iodic acid and red phosphorus as a reducing agent. [Formula 1] [Formula 2] (delete) The method of claim 1, wherein acetic acid is used as a reaction solvent.