SU382283A1 - METHOD FOR PRODUCING DERIVATIVES OF AZEPIN - Google Patents

Description

The invention relates to the field of production of new azepine derivatives, which can be used as intermediates for the production of physiologically active substances.

Of these compounds, only 10,11-dimethyl-5I-dibenz- (L, D) -azepine is known, which is prepared as follows.

5-Acetyl-5I-dibenz- (b, 1) -azepine is brominated with bromine to obtain 5-acetyl-10,11-dibromo-10, 11 -D11hydro-5H-dibenz- (b, f) -azepin.

Bromide iroduction "and gives sodium methoxide 10-methoxy-5H-dibenz- (b, f) -azepine, which is benzylated with benzyl chloride, to give 5-benzyl-10-methoxy-5H-dibenz (b, d) azenin. The resulting benzyl compound is converted with dilute hydrochloric acid to 5-benzyl-5,11-dihydro-10Nbiben- (L, 1) -azepin-10-on1, which is methylated with sodium amide and methyl iodide to 5-benzyl-11 -methyl-5,11 -dihydro-1 OI-dibenz (b, 1) -azepin-10-one.

According to Grignru, by acting on the resulting ketone with methyl magnesium iodide, 5-benzyl-10, 11 - dimethyl-10,11 - dihydro-5H - dibenz (b, {) -azepin-10-ol, which passes in the presence of dilute hydrochloric acid, are obtained. in 5-benzyl-10,11 - dimethyl-5H - dibenz- (b, f) -azepine during the cleavage of water. Debenzylation using hydrogen bromide gives &

finally Finally From the compound obtained, 10,11 dimethyl-5H-dibenz- (b, f) -azepin.

This method is not suitable for the production of 10,11-dimethyl-5I-dibenz- (b, f) -azepine derivatives, which are substituted in the benzene core, since the interaction of the corresponding 5-acetyl - 10,11-Dibrom-10,11 - By digidro-5H-dibenz- (L, G) -azepins with sodium methoxide, the corresponding isomeric 5-acetyl10-methoxy- and 5-acetyl-1 l-methoxy-5H-dibenz (b,) -azepines are obtained, which are difficult to separate.

10,11-Dimethyl- and 5,10,11-trimethyl-5H-dibenz- (L, {) -azepine, as well as derivatives of such compounds that are substituted in the benzene core, can be obtained in three stages.

The proposed method for the preparation of azepine derivatives of the general formula I

NCS CHS

Xi

where R is hydrogen or methyl group;

X is hydrogen, chlorine or trifluoromethyl;

Xs is hydrogen or, if Xi is hydrogen, also means chlorine; is that compounds of general II-,

X

wherein Xi and X-2 are as defined above, or the corresponding compounds of 10-methyacridinium, are reacted with acetaldehyde, and the resulting compounds of the general formula III

n, s;

in which R, Xi and X-2 have the highest value, are reduced to compounds of the general formula IV

THEY

 - SNE

 /

x

in which R, Xi and X-2 are as defined above, and the resulting compounds of general formula IV are treated with 70-90% sulfuric acid.

By reacting compounds of general formula II with acetaldehyde, compounds of general formula III are obtained with good yields. The reaction is preferably carried out in an acidic solution in the presence of peroxides and heavy metal ions. Diluted, non-oxidizable mineral acids, for example sulfuric acid, are used as acids, hydrogen peroxide or gret-butyl hydroperoxide as a peroxide as a peroxide, and iron ions, for example, as heavy metal ions. Temperature reaction of O-20 ° C.

The reduction of ketones of general formula III to the corresponding hydroxycouples can be carried out, for example, by means of complex metal hydrides. As complex metal hydrides, which are preferably used in a solvent, are used, for example, lithium aluminum hydride, and in particular, and sodium borohydride. Especially suitable solvents for lithium aluminum hydride are ether-like liquids (ether or tetrahydrofuran), and for sodium borohydride lower alkanols, for example

methanol or ethanol, mixtures of lower alkanols or mixtures of lower alkanols with water. If lithium aluminum hydride is used as a com plex metal hydride, the reaction temperature is preferably O-60.

and, if sodium borohydride is used, O-30 ° C. According to the second variant of the process, compounds of the general formula III can be reduced with an alcoholic metal in the corresponding alcohol or in a hydrocarbon, for example in toluene

or xylene, as appropriate under nitrogen. A particularly suitable reducing agent is aluminum isopropyl. The reaction is preferably carried out at 20-85 ° C.

Further, compounds of general formula III can be reduced with hydrogen in a solvent in the presence of a catalyst. Noble metals, for example, platinum dioxide, are suitable as catalysts.

or palladium on a carrier, for example, palladium on carbon, and also metal alloys (for example, Rene nickel). Platinum dioxide is preferably used in glacial acetic acid or lower alkanol, for example

ethanol, and palladium on coal and Rene nickel in an alkanol, for example, methanol or ethanol.

The preferred reaction temperature is about 85 ° C.

The compounds of general formula IV are converted into the desired product with 70-90% sulfuric acid at -50 ° C. Example 1. A. 19.3 g of 9-methyl acridine are dissolved in

120 ml 2 III. sulfuric acid when heated. Cool the solution, dilute it with 120 ml of ice water, put it in a bath of ice-sodium chloride and add 29 ml (0.512 mol) cooled to a temperature of 9 ° C to it.

ice acetaldehyde. The temperature of the mixture rises to 15 ° C. It is cooled, with stirring, to 8 ° C and a solution of 144 g (0.520 mol) of heptahydrate ferrosulfate in the mixture is added dropwise at the same time cooled to 4 ° C.

480 ml of water, as well as 60 lgl (0.450 mol) cooled to 2 ° C with 75% g / er-butyl hydroperoxide. At the same time, the reaction solution is stirred vigorously and the rate of addition is added dropwise in such a way that the temperature in the reaction vessel is 10-13 ° C. After the addition of half of both reagents, a crust forms on the vessel wall, which is separated. After completion of the dropwise addition, the mixture is moved for

15 minutes, the temperature inside the reaction vessel being lowered to 3 ° C. The resulting brown suspension was extracted with methylene chloride, the extract was washed with water, dried over sodium sulfate and evaporated in vacuo. Dissolve the residue in 72 ml of warm

absolute benzene, the solution is cooled, filtered through a column filled with 52 g of silica gel (grain size 0.05-0.2 mm, washed with an additional 320 ml of absolute benzene and the benzene eluate is concentrated to a small volume. With petroleum ether, the reaction product is precipitated from the benzene solution The resulting pure methyl- (9 methylacridan-9-yl) -ketone has a t.nl 165-168 ° C, yield 16.1 g, 68% of the theoretical.

B. 2.0 g (0.010 mol of 9-methylacridine is dissolved in 12.5 ml of 2N sulfuric acid and 20 ml of water when heated. The solution is cooled in an ice bath to 9 ° C, and 3.0 ml is added (0.053 mole of acetaldehyde, cooled again to 9 ° C and 6.0 ml (0.060 mol of 30% hydrogen peroxide and a solution of 15.0 g (0.054 mol of ferrosulfate gentahydrate) added dropwise over 10 minutes at 7-8 ° C 50 ml of water. Stir for an additional 5 minutes in an ice bath and extract the suspension with ether. The ether extract is washed with water until the washing water does not give a negative reaction to iodine The potassium is starch, then the extract is dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on a column filled with 30 g of silica gel (grain size 0.05-0.2 mm) using benzene hexane (3: 1) eluant. evaporated in vacuo and the residue was recrystallized from hexane, after which a pure methyl (9-methyl acridan-9-yl) ketone was obtained with a melting point of 157-161 ° C, yield 1.2 g, 49% of theory.

B. 23.7 g (0.100 mol of the obtained (in Example A of Example 1) ketoa is dissolved in 300 ml of methanol. The solution is cooled to 10 ° C and added to it with stirring in an ice bath for 10 minutes in portions 3.5 g (0.091 mol of sodium borohydride). The mixture is stirred for 1 hour at 5 ° C, then the reaction solution is concentrated in vacuum to a weight of 70 g. Addition of 6.6 ml of water and several seed crystals after cooling in an ice bath cause the onset of crystallization Next, the suspension is cooled with ice, slowly added with 100 ml of water and left to stand for 1 hour at 0 ° C. Thereafter, the resulting crude product is filtered off with suction, washed with water until neutral, and dried in vacuo over potassium hydroxide. Dry crystals are not recrystallized from methylene chloride-hexane. The resulting pure 9-dimethyl-9-acridanmethanol melts at 151 - 155 ° With decomposition; yield 23 g, 96% of theoretical.

D. In a mixture of 20 g of ice and 200 ml of concentrated sulfuric acid, cooled to room temperature, is introduced for 15 minutes with vigorous stirring 23.9 g (Q.QQ mole of the hydroxy compound obtained (but in Example 1)). The hydroxy compound slowly dissolves forming a red solution, the solution is heated to 30 ° C. 90 minutes after the start of addition,

transparent solution, which is stirring from another 45 min. After this, pour the solution into a mixture of 800 g of ice, 1 l of water and 500 ml of meth. The organic phase and the extrapure from the aqueous phase were separated with methylene chloride. The combined solutions of methylene chloride are washed with water, they are dried with sodium sulfate and evaporated in vacuo. Dissolve the residue in 200 ml of absolute benzene, np i, add the benzene solution to 100 g with a 1L1 gel (the grain size is 0.05-0.2 mm. The adsorbent is sucked off by suction, rinsing in portions from 100 ml of benzene and the filtrate from the in vacuo. The residue is introduced into hexane, the solution is to 1 nt t, then cooled to 0 ° C, after

IN 1 CRISTAL CALL BELIEVING H 1STY 10.1 1-DIMET L5H-dibenz- (b,) -azep n with m. Pl. 130-I31T .; yield 20.7 g, 94% of theoretical. Example 2.

A. 10.0 g (0.038 mol of 3-trifluoromethyl-9-methylacridine is dissolved in 200 ml of glacial acetic acid and 150 ml of 0.05 N sulfuric acid to the slots. The solution is cooled to 10 ° C, added from II ml (0.195 mol of acetaldehyde and again cooled to give up to 10 ° C in ice-chlorous sodium. After this, a solution of 55 g (0.198 mol of heptahydrate ferrosulfate in 180 ml of water and 23 ml) are added simultaneously for 20 min.

75% -1 of the tertiary butyl hydroperoxide from a separate 1 of x dropping funnels. Moving the reaction O from 1 npi to room temperature for 1 hour, diluted with 1 l of water i extract from. The ether extract was washed with water, 10% sodium carbonate solution and water to neutrality, dried over magnesium sulphate and evaporated in vacuo. The residue is introduced into absolute beisol. The solution is filtered from the column, filled with 140 g with gel gel (crucible) with a grain of 0.05-0.2 mm and washed additionally with absolute benzene. The filtrate is evaporated on a vacuum and the residue is recrystallized from hexane. Get the same ltovaty methyl- (3-trifluoromethyl-9-methyl acridan-9-yl) -keton with t. Pl. 125- 126 ° C; yield 7.0 g, 51% of theoretical.

B. 5.0 g (0.016 mol of the obtained (according to Clause A of Example 2) keto-o is dissolved in 50 ml of methanol. To the solution, add 0.760 g

(0.020 mol of sodium 1-borohydride and, once euJ, are heated for 1 hour at room temperature. The reaction mixture is carefully evaporated in vacuo and the residue is taken up in 100 ml of ethereal chloride. A small amount of anhydrous magnesium sulfate is added to the methylene chloride solution, filtered and the filtrate evaporated in vacuo to give 5.12 g of crude 3-tr 1-fluoromethyl-a, 9-dimethyl-9-acridane-methanol, and then it is processed as a crude product.

5.00 g (0.016 mol of the obtained hydr6x compound is added to 50 ml of a cooled mixture consisting of tritulfuric sulphate and water taken in a volume 01 ratio 10: 1. The resulting cycne i3 i O is stirred for 30 minutes Received 1NY solution

the red color is stirred for another 30 minutes and poured into a mixture consisting of 130 ml of 50% potassium hydroxide and 800 g of ice. The resulting suspension is diluted to dissolve the precipitated potassium sulfate. The solution is extracted with ether, the ether extract is washed with water, dissolved with magnesium sulfate and evaporated in vacuo. The residue is dissolved in hot hexane, the hot solution is purified with active charcoal, and the suspension is filtered. The filtrate is concentrated, 3-trifluoromethyl-10, 1-dimethyl-5H-dibenz- (b,) -azepine crystallizes out with mp. 153-155 ° C; yield 3.07 g, 65% of the theoretical. Example 3

A.20 g (0.088 mol of finely ground 3-chloro-5P-dibenz- (L, D) -azepine) is boiled in 600 ml of 48% hydrobromic acid for 90 minutes in a reflux vessel. After that, the reaction mixture cooled with ice, and a part of the obtained 3-chloro-9-methyl acridine hydrobromide is precipitated. While cooling with ice, 450 ml of concentrated ammonia solution are added in portions to the suspension in portions and the mixture is extracted with ether. The ether solution is washed with water and extracted with 300 ml of 1N sulfuric acid. If the crude product precipitates as sulphate, then th is again dissolved by addition of water.

The ether solution is washed three times with water, the wash water is combined with the acidic extract. The aqueous acidic solution is treated with active charcoal, filtered, and the light yellow filtrate is made alkaline with concentrated ammonia. The precipitated base is introduced into the ether. The ether solution was dissolved over magnesium sulfate, filtered and evaporated in vacuo. The residue is introduced into hot hexane, the hexane solution is purified with active carbon, filtered, and the solution is concentrated. 3-Chloro-9-methylacridine crystallizes with m.p. 117-118 ° C; yield 17.33 g, 86% of theoretical.

B. From 22.7 g (0.100 mol of the acridine derivative obtained (according to claim A of Example 1), 16.03 g (61% of theoretical) of methyl- (H-chloro-9-methyl acridan-9-yl) - ketone with mp 116-118 ° C (from ether-hexane).

27.4 g (0.100 mol) of this ketone obtained (in Example 1), 19.1 g (0.500 mol) of sodium borohydride in 550 ml of methanol are reduced to obtain 27.5 g of crude 3-chloro, 9-dimethyl 9-acridanemethanol.

B.2.74 g (0.100 mol) of the hydroxy compound obtained (in accordance with Clause B of Example 3) is subjected to a reaction (as in Example 1, paragraph D) with 200 ml of concentrated sulfuric acid mixed with water in a volume ratio of 10: 1. Obtained in an amount 29.0 g of the crude product is dissolved in absolute benzene and added to 55 g of silica gel for purification, washed with a mixture of absolute benzene and ethyl acetate, taken in a ratio of 10: 1. The filtrate is evaporated in vacuo, the residue is crystallized from ether-hexane, then get to 22.8 g of pure 3-chloro-1 0.11-dimethyl-5H-dibenz- (b, f) azepine with mp. 137-139 ° C; yield 89% of theoretical. Example 4

A.22.8 g (0.100 mol) of 2-chloro-9-methyl acridine are reacted (as in Example 1 in item A) in 35 ml of 2N. sulfuric acid

and 65 ml of ice water with 7.2 ml (0.128 mol) of acetaldehyde, 15 ml (0.114 mol) of 75% tertiary butyl hydroperoxide and 36 g (0.130 mol) of heptahydrate ferrosulfate dissolved in 120 ml of water to give 13.20 g

methyl- (2-chloro-9-methylacridan-9-yl) -ketone with t. pl. 134-135 ° C (from ether-hexane), yield 51% of theoretical, calculated on 21.8 g of the reacted starting product.

B. 3.11 g (0.114 mol) of the product obtained (under item A

of example 4) the ketone is reduced (as in example 2 of paragraph B) with 0.50 g (0.013 mol) of sodium borohydride in 40 ml of methanol under ice cooling. 3.18 g of crude 2-chloro-cc, 9-dimethyl-9-acridanmethanol are obtained, which, if not immediately consumed further, should be stored at 0 ° C.

B.15.1 g (0.055 mol} of the hydroxy compound obtained is stirred in 300 ml of concentrated sulfuric acid solution mixed with water in a 10: 3 volume ratio at room temperature until solution is obtained. The reaction mixture is then stirred for another 30 minutes with the same temperature. Then stirring it

700 ml of a 50% potassium hydroxide solution are added to a mixture of 2 kg of ice. The resulting suspension is diluted with water to dissolve the precipitated potassium sulfate, and the solution is extracted with ether. The ether solution is washed

water, dried over magnesium sulphate and evaporated in vacuo. The residue is recrystallized from ether-hexane and 11.47 g of 2-chloro-10.11-dimethyl-5H-dibenz- (b, 1) -azepine are obtained with a melting point of mp. 137-138 ° C, yield 81% of theoretical.

Example 5

A. 4.70 g (0.019 mol) of 9,10-dimethylacridine chloride is dissolved in 110 ml of water. While cooling with ice and stirring, 32.0 g (0.115 mol) of heptahydrate ferrosulfate, 6.0 mol (0.106 mol) of acetaldehyde and 12.0 ml (0.100 mol) of 75% tertiary butyl hydroperoxide were added to the solution. Thereafter, the reaction mixture is stirred for 20 minutes in an ice bath and extracted with ether. The ether solution is washed with water, dissolved over sodium sulfate and evaporated. The residue, dissolved in a mixture of hexane and benzene (3: 1), is introduced into a colum filled with 120 g of silica gel (grain size 0.05-0.2 mm) and chromatographed by elution. Hexane-benzene (3: 1) and hexane-benzene (1: 1) fractions are obtained after evaporation and recrystallization

from a small amount of hexane, 2.22 g of methyl- (9,10-dimethyl-lacridan-9-yl) -ketoi with 99 ° C; yield 46% of theoretical. B. 2.01 g (0.008 mol) of obtained keto (according to Example 5) is reduced (as in Example 2, paragraph B) in 30 ml of ethanol and 1 ml of methanol using 630 lg (0.016 jol) sodium borohydrnd at 15 ° C . The product obtained is completely crystallized by infusion with hexane, sucked off with suction and recrystallized from hexane. 1.94 g of a, 9,10-trimethyl-9-acridanemethanol with a melting point are obtained. 108 ° C (from hexane); yield 96% of theoretical. 530 mg (0.002 mol of the obtained (according to B of Example 5)) hydroxy compounds are added with stirring to a mixture cooled at room temperature from 0.50 ml of water and 5.0 ml of 96% sulfuric acid, the resulting suspension is transferred further for 1 hour at room temperature. At the end of the reaction the suspension turns into a clear solution. This solution is poured into a mixture of 20 g of ice and 50 ml of methylene chloride. The mixture is diluted with water, shaken and the organic phase is separated. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated Siege 10 ml of absolute benzene was added, the benzene solution was mixed with 1 g of silica gel. The silica gel was filtered, washed with absolute benzene, the filtrate was evaporated in vacuo. The residue was recrystallized from a small amount of hexane to give 5,10,11-trimethyl-5P-dibenz- ,) -azepine with mp 113 ° C; yield 314 mg, 61% of theoretical. Subject and issue: HI and Method for producing derivatives of the azepna of general formula I NeC CH3 (TTt where R is hydrogen or ctgroup; Xi is hydrogen, chlorine or trifluoromethyl; X2 is hydrogen, or, if Xi is hydrogen, is also chlorine, characterized in that the compounds of the general formula II where Xi and X2 have the above meaning, or the corresponding 10-metlacridini compounds, are reacted with acetaldehyde, the compounds obtained by the general formula III where R, Xi and X-2 are as defined above, reduced to compounds of the general formula IV in which R, X | and 2 have the meaning indicated under formula I, and the resulting compounds of general formula IV are rearranged using 70-90% sulfuric acid, followed by isolation of the desired product by known techniques.