DE1132556B - Process for the preparation of derivatives of 5- (ª † -piperazino-propyl) -dibenzo [b, f] azepine - Google Patents

Description

GERMAN

PATENT OFFICE

G 27713 IVd / 12ρ

REGISTRATION DATE: AUG U S T 12, 1959

NOTICE THE REGISTRATION ANDOUTPUTE EDITORIAL:

JULY 5, 1962

The invention relates to a process for the preparation of derivatives of 5- (γ-piperazinopropyl) -dibenzo- [b, f] azepine the general formula

(CHJ ₁ -N,

, N -CH ^ -CH ₂ -OR

where R is a hydrogen atom or a low molecular weight saturated aliphatic acyl group, and their salts. These compounds have valuable pharmacological properties, especially sedative, anticonvulsant, antiallergic, antiemetic, antiophlogistic and antipyretic Efficacy, and are used as psychotherapeutics, especially for the treatment of mood depression, usable.

To achieve the same histamine-antagonistic effect on the isolated guinea pig intestine, from the new 5- {y- (4'-Hydroxyäthylpiperazino) -propyl} -dibenzo [b, f] azepine [R = H in above formula I] only a third and to achieve the same histamine detoxifying Effect on living guinea pigs is only one sixteenth that of the well-known 5- {y- (4'-methylpiperazino) - propyl} - dibenzo [b, f] azepine required amount. The antihistamine effectiveness the new connection is therefore much more pronounced.

To prepare the compounds of general formula I, either in a manner known per se

a) a reactive ester of 5- (γ-hydroxypropyl) -dibenzo [b, f) azepine the formula

' N ^v

(CH ₂ ) ₃ -OH II

with N - (/ 3-hydroxyethyl) piperazine of the formula

HN _n N-CH ₂ -CH ₂ -OH III

around, or one brings

Method of manufacture

of derivatives of 5- (y-piperazino-propyl) -

dibenzo [b, f] azepins

Applicant: J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority: Switzerland of August 13, 1958 (No. 62 880)

Dr. Walter Schindler, Riehen (Switzerland), has been named as the inventor

b) 5- (γ-piperazinopropyl) -dibenzo [b, f)] azepine der formula

(CH ₂ J ₈ -N,

NH

with a reactive monoester of ethylene glycol for reaction and then optionally esterifies the 5- {y- (4'-Hydroxyäthylpiperazino) -propyl} -dibenzo [b, f] azepine obtained with the anhydride of a low molecular weight saturated aliphatic carboxylic acid.

Suitable reactive esters of 5- (γ-hydroxypropyl) -dibenzo (b, f) azepine of the formula II are, in particular, its hydrohalic acid and aryl sulfonic acid esters. It is advantageous to carry out the reaction in the presence of 1 mol of an alkali iodide in an inert organic solvent and heating the reaction mixture to the boil Reflux. As examples of suitable starting materials for the production of which no protection is claimed its the 5- (y-bromopropyl) -, 5- (y-chloropropyl) - and 5- (y-p-toluenesulfonyl-oxypropyl) -diben-

209 618/334

zo [b, f] called azepine. Such compounds are in turn, for example, by reacting dibenzo [b, f] azepine with reactive diesters of Propane-1,3-diols, especially those with two different ones Acid components, e.g. B. «-Bromo-y-chloropropane and aryl sulfonic acid esters of γ-chlorine or γ-bromopropanol are available.

The 5- (y-piperazinopropyi) -dibenzo [b, f] azepine serving as starting material for procedure b) Formula IV, for the production of which no protection is claimed, is z. B. by implementing the next Above-mentioned reactive ester of 5- (γ-hydroxypropyl) -dibenzo [b, f] azepine with easily cleavable N-acyl-piperazines such as N-formyl, N-acetyl or N-carbomethoxy-piperazine and subsequent hydrolytic cleavage of the acyl radical accessible.

With inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Methanesulphonic acid, ethanesulphonic acid, ethane disulphonic acid, acetic acid, succinic acid, fumaric acid, Maleic acid, malic acid, tartaric acid, citric acid, benzoic acid and phthalic acid, make up the tertiary bases of the general formula I mono- and di-acid salts, some of which are water-soluble.

The following examples are intended to explain the preparation of the new compounds in more detail. Parts mean therein parts by weight, these are related to parts by volume as grams to cubic centimeters. the Temperatures are given in degrees Celsius.

30th

example 1

19 parts of 5- (p-chloropropyl) -dibenzo [b, f] azepine become dissolved in 130 parts by volume of butanone and the solution after adding 10 parts of sodium iodide and 19 parts of N- (iS-hydroxyethyl) piperazine were stirred under reflux for 16 hours. Then distilled the solvent is removed, water is added and the whole thing is thoroughly etherified. The essential solution After thorough washing with water, the basic components are removed by pulling them out three times removed from dilute hydrochloric acid. The acidic extracts are made alkaline and the base which has separated out reabsorbed into ether. After drying and evaporation the essential solution remains 5- {y- (4'-Hydroxyäthylpiperazina) -propyl} -dibenzo- [b, f] azepine with a melting point of 100 °; Yield: 88%

The dihydrochloride prepared with alcoholic hydrochloric acid melts at 228 to 230 °.

1 part of the 5- {y- (4'-Hydroxyäthylpiperazino) -propyl} -dibenzo [b, f] azepins is mixed with 5 parts of acetic anhydride. Boiled under reflux for 4 hours. That Excess acetic anhydride is evaporated off in vacuo, the residue dissolved in cold water, the Solution filtered and made alkaline with sodium carbonate solution. The precipitate is in ether added, the ethereal solution washed with water, dried over sodium sulfate and the Solvent distilled off. The residue is dissolved in petroleum ether, the solution filtered and the filtrate evaporated. 5- {y- (4'-j5-acetoxyethylpiperazino) propyl} -dibenzo [b, f] azepine is obtained as a yellow oil; Yield: 80%.

1 part of this oil is dissolved in a little acetone, whereupon the calculated amount of absolute alcoholic hydrochloric acid is admitted. The dihydrochloride crystallizes out after some time and melts from alcohol recrystallized, at 209 to 212 °.

To prepare the 5- (p-chloropropyl) -dibenzo (b, f] azepine required as starting material, 19 parts of dibenzo [b, f] azepine and 20 parts of l-chloro-3-bromopropane are dissolved in 800 parts by volume of absolute benzene and added to the 4.4 parts of sodium amide in toluene were added dropwise to the solution at 50 ° with vigorous stirring in the course of ¹ _{1/2 hours} added and the benzene layer separated off, washed with water, dried and evaporated. The oily residue is taken up in 400 parts by volume of petroleum ether, any undissolved dibenzo [b, f] azepine is filtered off and the filtrate is evaporated, whereby the 5 - (y - chloropropyl) - Dibenzo [b, f] azepine remains, which after recrystallization from absolute ether melts at 67 °; Yield: 63%.

Example 2

16 parts of 5- (γ-piperazinopropyl) -dibenzo [b, f] azepine are mixed with 7 parts of potassium carbonate and 6.35 parts / 9-bromoethanol in 15 parts by volume of toluene for 4 hours heated to 120 °. After cooling the reaction mass, this is mixed with 50 parts by volume of chloroform and Treated 30 parts by volume of water. The aqueous part is decanted off and the chloroform solution is extracted several times with dilute hydrochloric acid. The combined acidic solutions are made with potassium carbonate made alkaline, whereupon the crude base precipitates. The excreted oil is absorbed into the ether Solution dried and concentrated to a small volume, whereupon crystallization occurs. The thus obtained 5- {y- (4'-Hydroxyäthylpiperazino) -propyl} -dibenzo [b, f] azepine melts at 100 to 101 °; yield 72%.

Claims (1)

PATENT CLAIM: Process for the preparation of derivatives of 5- (γ-piperazinopropyl) -dibenzo [b, f] azepine of the general formula N-CH ₁ -CH ₁ -OR wherein R is a hydrogen atom or a low molecular weight saturated aliphatic acyl group, and salts thereof, characterized in that either in a known manner a) a reactive ester of 5- (γ-hydroxypropyl) -dibenzo [b, f] azepine the formula . (CEy ₁ -OH with N- (jS-hydroxyethyl) piperazine of the formula HN ' N-CH ₂ -CH ₂ -OH implements, or b) 5- (γ-piperazinopropyl) -dibenzo [b, f] azepine of the formula (CH ₂ ) ₃ -N NH with a reactive monoester of ethylene glycol to react and optionally then the 5- {y- (4'-Hydroxyäthylpiperazino) -propyl} -dibenzo [b, f] azepine obtained esterified with the anhydride of a low molecular weight saturated aliphatic carboxylic acid and / or optionally the basic end products obtained are converted into their salts. Documents considered: German Patent No. 939 630; Belgian Patent No. 549 299; Ind. Chim. BeIg., 19 (1954), p. 1179. A priority document was displayed when the registration was announced.