DE1695082A1 - Process for the production of new azepine derivatives - Google Patents

Description

J. R, GEJGY A.G BASJBi, 2i

Dr, F, Zumifein "Dr, E, Assmann

Dr «? I. Koenigsberger Dipt. Phys. R. Hotzbawer

1895082

2212/2222 * New complete arrival documents

Munich 2, Bräuhausshafje 4 / ΙΙί

Process for the production of new azepine derivatives

The invention relates to novel azepine derivatives and methods for their preparation gk.

Azepine derivatives of the general formula I,

CD

in which

Rn a lower one. Alkyl radical,

R2 is hydrogen or the methyl radical,

R ₃ and ■

R ^ hydrogen or lower alkyl radicals or

ο KR ₃ (R ₄ ) optionally with the imirio group, a lower alkyl

^to imino, hydroxyalkylimino or alkanoyloxyalkylimino

^ l group as a ring member means a saturated heterocyclic radical, of 5-7 ring members,

and their addition with inorganic or organic acids airul not yet known »

. 1605082

As has now been found, there are such connections valuable central and peripheral pharmacological properties. When administered perorally, rectally or parenterally, they have a sedative, anticonvulsant, anesthetic effect; they inhibit monosynaptic and polysynaptic reflexes and antagonize Pharmaceuticals, such as, for example, tetrabenazine, depressive on the central Act on the nervous system, they also have spasmolytic, histamino lytic and noradrenaline-potentiating activity on = this pharmacological Properties characterize the new compounds as suitable for the treatment of states of tension and excitement, caused, for example, by neuroses or depression.

In the compounds of general formula I, for example, R ₁ , R 3 and R _4, as lower alkyl radicals, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl · and the tert »butyl group, or R ^ and R * together with the neighboring nitrogen as a heterocyclic radical form the 1-pyrrolidinyl-, piperidino-, hexahydro-1H-azepin-1-yl- ₅ 1-piperazinyl-, 4- Methyl 1-piperazinyl, 4- (2-hydroxyethyl) "1-piperazinyl, 4- (2-acetoxy-ethyl) -1" plperazinyl, 4- (2-pivaloyloxy-ethyl) -1 "piperazinyl », HexahydrQ-lH ~ l, 4-diazepin ~ i-yl--, ^ -Methyl-hexahydro-lH-l ^ -diazepin-l-yl- or 4- (2-» hydroxyethyl) -hexahydro · lH-l, 4-diazepin-l-yl-resto,

For the inventive preparation of the compounds of general formula I, a reactive ester of a hydroxyl compound of general formula II is used,

009833/1970 ',

v ^; v, w _iv BAD ORIGINAL

695082

(Π)

in which

have the meaning given under formula I , with a compound of the general formula HI ₉

Around

H-N

(III)

in which R ^ and R ^ or NRg (R ^) the given under formula I. Have meaning, or with an N-acyl derivative of piperazine or Hexahydro-1fr-1,4-diazepine, or with a metal compound 3ines N-acyl derivative of a lower alkylanine, um, subject if necessary the reaction product of hydrolysis for cleavage one possibly bound to a nitrogen atom of the side chain Acyl radicals, treated if a compound of the desired general formula I with the imino group as a ring member with a lower alkylene oxide, with a reactive monoester one lower alkanediol or with a reactive ester of a lower alkanoyloxyalkanol, if desired acylated a compound of the general formula I which is a lower hydroxyalkyl contains imino group as a ring member, su such with a lower alkanoyloxyalkyliininogruppe and leads, if desired a compound of general formula I with an arorganisehen or organic acid in an aeditic salt

009833/1970

Suitable reactive esters of hydroxy compounds of the general formula il there are the halides, especially the bromides, into consideration, '/' urther · such derivatives are in the S ¹ Jlfonsäureestern such as Toaylestern or Mesylestern before. "

Dissolutions of reactive esters of compounds of the general formula II with airins of the general formula IJl. .verden, for example, in inert solvents, in which case an excess of amine as an acid-binding agent can also be used as the sole reaction medium. Suitable inert solvents are, for example, hydrocarbons, such as benzene or toluene, lower alkanols such as methanol or ethanol-1, lower alkanones, ie acetone or methyl ethyl ketone and also water. Depending on the meaning of R ,, R ^, R ^ ^unr ^ R / ₄ ", the reaction is more or less exothermic, if necessary it is completed by heating the reaction mixture. The reactive esters of compounds of the general formula JI can, for example, with the Di methyl amine, methylethyl amine, diethylamine, dipropylamine, dirutylamine, methylamine, ethylamine, propylamine, iso-ropylamine, sec, butylamine, ammonia, pyrrolidine, piperidine, hexalylyiro- ^1- azepine, 1-methyl piperazine , Piperazine-1 ~ ethanol, 1- (2-acetoxy-ethyl) piperazine, 1 ~ (2-pivalolyloxy-ethyl) -piperazine or 1-methyl-hexahydro-1H-1,4-diazepine are reacted.

The reaction of a reactive ester of a compound of the general formula II with an N-acyl derivative of piperazine or hexahydro ^: 'lH-1,4-diazepine, such as an N-formyl-, N-acetyl-, iT-phenoxycarbonyl-, N- Phenoxythiocarbonyl or a lower R-alkoxycarbonyl or N-alkylthiocarbonyl derivative or with a metal compound of an N-acyl derivative of a lower alkylair.in,>: ie z ..- E ^ dar. Aa ^ LrUiiB ^ rbind a lower N-formyl

ORIGINAL

-j N-phenoxycarbonyl-, N-alkoxythioearbonyl or an N-phenoxythiocarbonyl-alkylamiiisj occurs e.g. in an inert organic solvent under anhydrous conditions, the said piperazines or hexahydro lH "l, 4- <diazepinderirate are in the presence of an acid-binding agent, preferably implemented in excess, basic starting material , Examples of suitable solvents for these reactions are hydrocarbons, such as benzene or toluene * Der Acyl radical: of the reaction product obtained attached to a nitrogen atom the side chain is bound, can then be split off by treating the reaction product with an alkali metal hydroxide, like potassium hydroxide, heated in an organic solvent. Suitable reaction media are, for example, those containing hydroxyl groups Solvents such as ethylene glycol or Βία ethylene glycol, their lower alkyl ethers or lower AlkaaoLe, like ethanol. The lower alkanols are preferred in the closed Vessel used »Furthermore, the hydrolysis can z.J, can also be done by boiling with aicanolic hydrochloric acid.

Lower hydroxyalkyl or alkanoyloxyalkyl radicals are introduced into the free imino group of compounds of the general formula 1 in which NR ₃ (R ₄ ) form a heterocyclic radical with an imino group as a ring member, by adding such compounds, in particular l ™ piperazinyl or hexahydro- 1H »1,4-diazepin-1-yl compounds, for example with ethylene oxide, propylene oxide, 2-bromoethanol, 2- (p» tolylsulfonyloxyethanol) or (2-bromoethy-acetate. The reaction is preferably treated in a solvent carried out, to which - if the reaction proceeds with the elimination of 1 molar equivalent of acid - an acid-binding agent is added. Examples of suitable solvents are hydrocarbons such as benzene or toluene, lower ones

009833/1970

Alkanones, such as acetone or methyl ethyl ketGn, and as acidic bins agents alkali carbonates) such as potassium carbonate,

The hydroxyl groups of compounds of general Formula I, in soft MR-j (R,) with a lower hydroxyalkyl * itnino group as a ring member form a heterocyclic radical, in particular '/ on 4 "rtydroXyaikyl 1 plperazinyl or 4 hydroxyalkylhexahydro-1H —1,4-diazepin-1 yl compounds v / earth acylated, by for example in the anhydride of a lower alkane * acids like acetic acid, propionic acid, butyric acid or piva Linic acid heated or with an appropriate acid halide treated in a tertiary nitrogen base such as pyridine. Further one can also use the sodium derivatives of such thiydroxyalkyl compounds urraetzen with the appropriate acid halide

Starting materials of the general formula II are, for example, 10-bromomethyl- or 10- (a-bromo-ethyl) -5-alkyl-5 :: dl .anz [b, f] asepine. These connections can surprisinglyv / eLse ζ h. be prepared by bromination with bromosuccinimide to 10-methyl- or 10-ethyl-5-alkyi - dibenz [b, f] azepines,

Wach a second method according to the invention one - / erbindungen of the general formula I by making compounds of the general formula IV,

(IV)

3/1970

Ψ-

in which

R ~, H- and H, which have the meaning given under Formula 1, on jnd [NR-jiR ^)] ^r, onfalls uit. ier linino group, a nit-there alkylimino or alkanoyloxyalkylinilno group as a member is a saturated ¹ .- en heterocyclic - 'is from 5-7 ring members,

preferably in the presence of solution and acid, a customization cut using a reactive ester from Alknno] er, the aligoiiiGiuen formula V ₅

R ₁ - OH ■ (Y)

in which R-, which has the meaning given under formula 1, is alkylated and, if appropriate, the now obtained compounds n; i1 anorronistic organic acids are converted into their addition salts. . ... - ^ ... -

Raw materials for the general fore. ¹ LoI I '/ are described in the literature. »Further links of this type are made analogously. As a second Reaktionskoniponente reactive esters are used of alkanols of all non gernei formula V in which the radical R, with the ansehliessend to the general Korane! I explicitly mentioned groups agrees. As reactive esters, halides, vie chlorides, bromides or iodides, sulfonic acid esters, such as kethanesulfonic acid, benzenesulfonic acid, o- and p-toluenesulfonic acid or 2j4-dinitro-lenzene sulfonic acid ester and Schv.ef el acid esters such as dimethyl or diethy1 sulfate, can be used .

The reaction can be carried out in the presence or absence of an inert organic solvent. Suitable inert solvents are, for example, hydrocarbons, such as Feni'cl j toluene, xylene, cumene or tetralin, ath-r · .: *: r-

BATH

Liquids such as dioxane. Alkanones such as acetone or methyl ethyl ketone, carboxamides such as dimethylformamide or sulfoxides such as dimethyl or diethyl sulfoxide. Suitable basic condensing agents are, for example eignen- _t alkali metals such as · sodium, potassium or lithium, alkali metal hydroxides such as potassium hydroxide or Natrium--, alkali metal carbonates such as potassium carbonate, alkali metal amides such as sodium, potassium or lithium amide, alkali metal hydrides such as sodium or lithium hydride, Alkali alkanolates, such as sodium methylate, sodium ethyla.t or sodium tert-butylate, or alkyl and aryl lithium compounds such as butyl or phenyl lithium.

The compounds of the general formula I obtained by the process according to the invention are then if desired in the usual way in their addition salts with inorganic ones and organic acids. For example, a solution of a compound of the general formula is added I in an organic solvent with the salt com component desired acid or with a solution thereof. Organic solvents are preferably chosen for the reaction, in which the resulting salt is sparingly soluble, so that it can be separated by filtration. Such solvents * are e.g. methanol, ethanol, methanol diethyl ether or Ethanol diethyl ether,

For use as pharmaceuticals, acid addition salts can be used instead of free bases, i.e. salts with those acids whose anions are pharmaceutically acceptable at the dosages in question. Furthermore, it is from Advantage if the salts to be used as medicinal substances are easy to crystallize and are not or only slightly hygroscopic! For the preparation of pharmaceutically acceptable salts of compounds of the general formula I, for example, the chlorine

· *: «- ,, ... 00 98 33/1970; ■

ORIGINAL

hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Methanesuixonic acid, ethanesulphonic acid, ß ~: iydroxyethanesulphonic acid, Acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, Maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid are used,

'The following examples explain the preparation of the new compounds of general formula I and of oisher intermediates not described in more detail, but are not intended to limit the scope of the invention in any way are given in degrees Celsius.

Q09833 / 1970 BAO

never.ui. 40

.a) 15 g of 5-methyl-1Q-bromomethyl-5H »dibenz [b, f] azepine are dissolved in 50 ml of abs. Dissolved benzene and introduced at a temperature of Q 5 ^C in a solution of 10 g of dimethylamine in 100 ml of abs «berr / ol, then the reaction vessel is stirred for 1 hour at 40-50 °. Then the organic phase is washed 'c with v / ater and extracted with 2N hydrochloric acid, the acidic extracts are made phenolphthslsin alkaline with concentrated "aqueous ammonia and with diethyl ether out Schütting" Wk telt- The ethereal solution is washed with water, dried over potassium carbonate and evaporated in vacuo a. The residue, which is distilled in a high vacuum, boils Dei 140 144t / Q 01 Torr. The free base obtained, the 5-methyl-10-dimethylaminomethyl-5H-dibenz [b, f] azepine, is converted into the hydrochloride with absolute ethereal hydrochloric acid üoerführung, mp, 225-228 ⁰ from abs = ethanol ·.

The starting material, the .5 ~ methyl-10-bromomethyl-5H ~ dibenzfb, fjazepine, is made as follows:

b) 37.5 g of 5,10-dimethyl-5H »dibenz [b, fJazepin are heated with stirring to 70 ° dissolved in 3 ⁷ 5 ml of carbon tetrachloride, and is at once with 30.5 g bromosuccinimide \ ,, -rersetzt The reaction mixture and exposed to two 200 watt lamps. The temperature is kept at 70 ° for 3-5 minutes by gentle cooling. The reaction mixture is then cooled to 20 °, the succinimide is filtered off with suction and washed with carbon tetrachloride. The filtrate is extracted with water, the organic phase is dried over sodium sulfate and evaporated in vacuo at 40 ° = 'The residue is recrystallized from cyclohexane, whereupon the compound obtained melts at 109-111 °.,

".. ■■ - ■. 0 0 9 8 3 3 / 19-70 · & AD ORIGINAL

Example fn%

On & iof example la) one prepares from b -methyl-lOr-bromo-methyl ^f , -: i diben /; b, f] az €; pin produces the following end products:

η) rit. l '. ^ thylamln das 5-Methyl -10 -methylaminomethyl- iU ciU-iM'i L,'".&:'epin, Kp. 147 l« 9 ^c / 0.05> Torr, Hydrochloric! , Srp I '5- 1 " ⁷ ^ ^; £ r abs. AeU.anol diethyl ether);

b; with piperazine 1-ethanol the 4 ~ (5 - ket.hyl ~ 5H-dibeiiz [b, fj arcpin 10 ylmethyl) -piperazine-1-ethanol, Sinp. des Dihydrochlc] iar. Π-1-21? ⁰ (a \; s absolute methanol diethyl ether);

c; with diethylaiüin the 5-Met.hyl-10 - dietliylaminoraethyl 5 !: ditcnri t, f jazepine, bp, 17-150 ° / 0, QA Torr, fumarate, mp 148-14 9 · '' ans abs ethanol); .

d) with 4 «ethyl pijerazin the ^r 3-methyl-10-i4- _rr .et, hyll-pipera ^ inylrrei hyl) -" rH-dilenzf b, f] azepi η (crude product), Li hydrochloride, Srp 224-229 - ° (with decomposition from Ethaiicl);

C-) with 1 - (? -Äcetoxy-äihyD-piperazine the l- (2 Aod oxy ätlsyl) -4 (5 · irethyl - b'il- dibenz [i, f] azepi η 10 - ylrt * f. Tiiyl) pi perazin ■ ·

Example 3

a) "Analogously to example la), the following end products are prepared from 5 ethyl-10-bror.rreihyl bli dibens [bjfJar.epin:

■ λ ¹ ) with diir.ethylamine the f - Aethy 1-10- .'di-nethyla.T.ino · methyl) 5K-dilens [b _t f] atepin, bp. 150--1S2 ^C /0.04 Torr, i-ydrc "chloride, m.p. 247-249- ° (from abs" ethanol) -;

a) with pyrrolidine 5-ethyl-10 »(l-pyrrolidiiiylmethyl) -5K direns [b, fjazepine, m.p. 92 ^{° C} (from pentane), hydrochloride, m.p. ;

009833/1970 ■ ::

b) The required 5-ethyl-10-bromomethyl-5H-dibenz [b, fjazepin ■ (crude product) is obtained analogously to the .5 "methyl-10-bromomethyl-5H-dibenz [b, fjazepine] described in Example Ib) 5-Ethyl ~ 10-methyl-5H-dibenz [b, fjazepine, m.p. 14 3-14 5 ° (from ethanol). This starting material is prepared analogously to the 5,10 ~ dimethyl ~ 5H-dibenz [ b, f] ajrepine starting from 1 0-methoxy-5H-dibenz [b, f jazepine, m.p. 124 ^r -, obtained via the following intermediates:

5-Ethyl ~ 10-methoxy-5H-dibenz [b, f Jazepin, Srap. 186-188 ^C (from ethanol),

5-ethyl-5H-dibenz [b, fJazepin-10 (IIH) -one, m.p. 126-128 ^Ü (from ethanol),

5 - Aothyl-10 ~ methyl-10,11-dihydro-5H-dibenz [b, f] azepine-10 oil (crude product),

Eeirpiel 4

To 72 g of 10-dimethylaminomethyl-5H-dibenz [b _T fjazepine in 720 ml of abs. Toluene is added dropwise with stirring over the course of 15 minutes, a suspension of 13.8 g of N-atrium amide in 30 ml of abs toluene and the reaction mixture is then boiled under reflux for one hour. It is cooled to 50 ° and 45 g are added dropwise over the course of 90 minutes Methyl iodide by maintaining a temperature of 50 52 °. The reaction mixture is then stirred for 16 hours between 50 and 52 ^{° C.} and then for 1 hour between 85 and 95 ° and cooled to 20 °. 100 ml of water are added, the organic phase is separated off and extracted with 2η hydrochloric acid. The free base is precipitated from the hydrochloric acid extract with concentrated sodium hydroxide solution and washed with di-

, ethyl ether extracted. The essential solution is washed with ^{: i} --VuS 00 9 83 3 M 97 0

BADORtOINAL-

Water ¹ , dry it over potassium carbonate and evaporate it in a vacuum. The distillation of the residue in a vacuum ranext the 5-methyl-10: -dimethylarainoiiiethyl-5H-dibenz [b _y f] azepine of bp 140-144 VO. oil torr. The free base is introduced into the hydrochloride with ethanolic hydrochloric acid via the, from, abs, recrystallized ethanol. 225 ~ 228 ³ . melts c. . .

Example 5 '. ',

Analogously to example 4 the following are obtained:. .,. - ■ _ ..

a) from 10- (l ~ pyrrolidinylmethyl) ~ 5H-dibenz _[b,; f] azepine and methyl iqdide 5-methyl-10- (l ~ py, rrolldinylmethyl) -5Ii-dibenz [b, f] azepine, bp. 160-164 ° / 0.01 torr, hydrochloride, m.p. 130-132 ° (from Isopropanol);

b) from 10-piperidinomethyl-SH-dibenzC'b, fjazepine with methyl iodide 5-methyl-10-piperidinomethyl-5H-dibenz [b, f] _: azepine, bp ₀ 172-175 ° / 0 <.01 Tqrr ^ Hydrpchlarid , -.Snip ... 171-174 ° (from isopropanol) .; . _<; . .,.,: .-. ,, -. -. ■■ -. . =,. ■ - > r ■ .--. ·

c) _r from 10- (a-Dijnethylamin.o ~ ethyl _:) -r5ii ~ dibenz. [; b ₃ f ■] ·. ... azepine jnit methyl iodide the S-methyl-r-lO ^ Ccc.-dimesthylafflino-ethyl) -SH-dibenzfbjf] azepine ,: .Kp .. 14.5 _r l43? /O..O4 .Tori - ^. Hydrpch- lOr.id, m.p.> 156-160 ° (from abs_, ethanol-diethyl ether)., and. · .-, -.-- ■ -:

d) from_ XO-Ict-XlTr-JPyr.rQliidinyl) .--, ä'thy; l]. ^. 5E-dibsn3 [.b, f] azepine with methyl j odi.d..das, 5-Me_thy | lr _; 10 --- [- iic->_; (3 _T - '. PyrrQl: i-di-nyl -) ^ · - etnyl] 5n-dlbenz. [B, ^. ^ Ζ.βρ, χη, Kp ... L6S-0.72 ⁰ / aii. & 3 ..- Tor.p.,: H ^ chloride, ümp .. 1_93-196 ^O ^. (From, s _r bs, -, _(; . ^. Etha.npl ') .- ?. _i; ->'-" ^: -,. · -.

0 0 9 833 / Ί ^ ώί. ν C C 11- :: w BAD

Example '6. ■ -

a) 15 g of crude 5-Kethyl-10- (1-piperazlny! methyl) -51-1-- '"''dibenz [b, f} azepine,.'dissolved" in 150 ml of toluene ^ are mixed with? Ö g ^; Potassium carbonate uri'd 'T2,: 5 "g"' ß-Bröm-äthattoi 4 hours 'boiled under' reflux, 1) the "cooled deaktionsgemi sch""is mixed with 100 ml of water, the organic phase is separated and r: ¹ : t? N hydrochloric acid extracted, the hydrochloric acid extract is made alkaline with an sodium hydroxide solution. The raw bane precipitates; it is taken up in ether, the ethereal solution is washed with water, dried over potassium carbonate and concentrated they a, 'The' concentrated 'solution is replaced with ethanolic acid "" to pH 4-5 X ^r , whereupon the obtained 4 - (5 -Methyl- 5H -dilenz' [b, f ^ azepih-10-yimetiiylT- pip'era ^ in-i-at'h'änbl-iilhydrochlörid 'precipitates ι it melts'at' 214-217 ° (from methanol-abs, ether) '^;'

The initial substance, 5- -Me'tnyl-Ib-'Ci - piperazinyi methyl) '5H-d'ibenz [b, f] azepih, can be analogous to' Example'la) or can be made as follows: "'" ""

b) 17.0 g piperazine-1-carboxylic acid ethy! 'ester are under Stirring in "100 ml abs, 'benzene" = added dropwise to this solution * 15 g of 5 »methyl-10-bromomethyl-5H-dibenz [b, f] azepine in 75 ml abs, 3enzol and reflux the mixture for one hour. Then it is cooled and the organic phase is washed with; iasne "r", "'" "" V " dry them over potassium carbonate and evaporate them "in a vacuum,

18 g of the residue, 4- (5'Methyl ~ 5H-dibenz [b, f] a5repiri ^: 10-ylme'thyD-piperazine-1-carboxylic acid ethyl ester, and a solution of 18 g of potassium hydroxide in 72 ml of absolute ethanol will 8 8tun.-.

the refluxed. Then you pour the cooled re-

■: ■ - ··;, - ■ ·· ' -: i \: -r. ·; ■>...'-'; - ■ --- iL.; ■ '«.- ■■?. ^ j.- "f / i" .: ': - * · ■': ^; .'- ^ 'ίί · ^! " ^f : ';' ϊ '. "* λ -.-" action mixture on water and takes it up in ether- Pie Aether -

· -. ':. ■ - ■ ν: - ', · ■ -; -..- · -'.-- ■■ "· .'-; -. ·: -'^; :: ό; i ·. ^ \« Ί ·>^; -, · ■ -.-. "---'.-: i / - '. ■>;: -ί ^ · * ·: _-: ■■ ν solution is extracted with 2η hydrochloric acid and the acidic extract with concentrated ammonia pheholphthalein-aikaliscli ^ g.esteilo Man '; Wtv ,, ^ 0 0 9 8 3 3/1 9 7 Q '''''" ^S "'"

_{OfflG | NAL}

takes up the precipitated crude base in ether, washes the ethereal solution with water, dries it over potassium carbonate and evaporates it. The crude 5-methyl-10- (l-pipera7inyl methyl) -5H-dibenz [b, f] azepine is obtained, which in acetone solution with hydrochloric acid gives the hydrochloride, which melts at 184-189 ° ^C. (from ethanol).

Example 7 .

7 g of ethylene oxide are in a solution of 5-Met.hyl LO- (l-piperazinylniethyl) -5H-dibenz [b, f jazepine in 250 ml of ethanol initiated and the mixture refluxed for 2 hours. The cooled reaction mixture is concentrated in vacuo and the residue is mixed with the calculated amount of rcethanolischer Hydrochloric acid, whereupon the 4- (5-methyl-5H-dibenz [b, f] arej.in · 10-ylmethyD-piperazin-1-ethanol-aihydrochloride precipitates. ; it melts at 214-217 ° (from methanol-abs-ether).

The starting material, the S-methyl-10-Cl-piperaziny .; ;; o: Lyl) -5H-dibenz [b, f] azepine, is produced according to Example 6t).

Example 8

33.6 g * _ (5-methyl-5H-dibenz [b, f} azepin-1.0-ylmethyl) -piperazine-1-ethanol and 101 g of acetic anhydride are refluxed for 3 hours. Thereupon the excess becomes Acetic anhydride distilled off in vacuo and the Residue with conc. Ammonia added. The precipitated base is extracted with diethyl ether, the ethereal solution with Washed with water, dried over sodium sulfate and in vacuo evaporated. The residue is dissolved in acetone and treated with a:

009833/1970

ethanolic hydrochloric acid neutralized, whereby the l - (2 - acetoxyethyl) -4 ". (5-methyl-5H ~" dibenz [b, f] azepin-10-y! Methyl) -piperazine dihydrochloride crystallized out.

009833/1970

BATH ORIGINAL

Claims (2)

-Vf- patent claims e 1. New azepine derivatives the general l'Orinel I, ϊ, CH - C = CH • R. (D in which R, a lower alkyl radical, ... R _{9 is} hydrogen or the methyl radical, R ₃ and R _{4 is} hydrogen or lower alkyl radicals or NRo (R ^) optionally with the Iraino group, a lower alkyl imino, hydroxyalkylimino --- or alkanoyl-hydroxyalkylimino group as a ring member mean a saturated heterocyclic radical of 5-7 ring members, and their addition salts with inorganic or organic Acids. 2. Process "for the production of new Äzepinde'rlYät the general Foraiel I ,. ■■■■■ R '' ■ '='^; .:.: ■■■. ■■ .-- ■ CH - U C = CH ^Λ 3 (D O
, in which R, a lower alkyl radical, Rp hydrogen or the methyl radical, imd Hydrogen or lower. Alkyl radicals or NR ₃ (R ₁ ) optionally with the imino group, a lower alkyl imino, hydroxyalkylimino or alkanoyloxyalkylimino group as ring member denote a saturated heterocyclic radical of 5-7 ring members, and their addition salts with inorganic or organic acids, characterized in that one is a reactive Ester of a compound of the general formula II, R, (II) 009833/1970 " BATH ORIGINAL in which R, and R _{n has} the meaning given under formula I en, with a compound of the general formula III, H - N- (III) in which
R ₃ and R ₄ or NR ₃ (R ₄ ) have the meaning given under formula I, or with an FI-acyl derivative of piperazine okr Ilc ^ ah ^ lro-lWj / i-aiai ^ pir: .. ca er with a metal compound ?; N-acyl derivative of a lower alkylamine converts, if necessary, the reaction product, a hydrolysis to split off a? if subjected to acyl radicals bound to a stick = to ^rr atom of the side chain, a compound of the general formula I with the Iir.ino group as a ring member with a lower alkylene oxide, with a reactive monoester of a lower alkanediol or with one Treated reactive ester of a lower Alkanqyloxyalkanols , if desired acylated a compound of the general formula I with a lower hydroxyalkylimino group as a ring member to one with a lower Alkanoyloxyalkylirr-ino group and, if desired, a compound of the general formula I with an inorganic or organic one Acid converted into an addition salt. >.) Modification of the method according to claim I _1, characterized in that one compounds. of the general formula IV, 009833/1970 • Civ) in which Rp, R ₃ and R, which have the meaning given in Claim 1 under Formula I, and [NRo (R /)] 'optionally with the imino group, a lower one Alkylimino or alkanoyloxyalkyliraino group as Ring member means a saturated heterocyclic radical of 5-7 ring members, preferably in the presence of solvents and basic condensing agents with the aid of reactive esters of alkali oils of the general formula V, R ₁ - OH (V) In which-Rj. has the meaning given in claim 1 under formula I, alkylated and optionally the compounds obtained with inorganic or organic acids in their Transferred addition salts. 009 833/1 ^ 70 SAD QBlSlNAL