CH367831A - Process for the production of new basic substituted azepine derivatives - Google Patents

Description

  

  



  Process for the production of new basic substituted azepine derivatives
The present invention relates to a process for the preparation of new basic substituted azepine derivatives with valuable pharmacological properties.



   It has been found that N-substituted azepine derivatives of the formula
EMI1.1
 where X is the ethylene or vinylene group, -CH2-CH2 or -CH = CH-, Y is the direct bond or an alkylene radical with 1-3 carbon atoms, Z, and Z2 is hydrogen, halogen atoms or low molecular weight alkyl radicals, and Am is an N-alkyl Pyrrolidyl or N-alkyl-piperidyl radicals have valuable pharmacological properties, in particular antiallergic and sedative activity. Quaternary ammonium salts derived from the tertiary bases defined above act as ganglioplegics.



   The process according to the invention for preparing the new compounds of the formula I is characterized in that an azepine derivative of the formula
EMI1.2
 that is, an optionally substituted 5-dibenzo (b, f) azepine or 10, ll-dihydro-5-dibenzo (b, f) azepine, which is hereinafter referred to as optionally substituted iminostilbene or iminodibenzyl, in the presence of an acid-binding agent a reactive ester of a basic alcohol of the formula HO-Y-Am III.



   Sodium amide, sodium hydride, lithium amide, potassium amide, sodium, lithium or potassium are particularly suitable as acid-binding agents. The halides are particularly suitable as reactive esters of basic alcohols of the formula III. The following may be mentioned in detail: 1-methyl-3-chloropiperidine,
1-methyl-4-chloropiperidine,
1-methyl-pyrrolidyl- (2) -methyl chloride,
1-methyl-piperidyl- (2) -methylchloride,
1-methyl-piperidyl- (3) -methylchloride,
1-methyl-piperidyl- (4) -methylchloride, [l-methyl-piperidyl- (2)] -ethyl chloride and the corresponding bromides.



   Suitable starting materials of the formula II are, for example, iminodibenzyl and imino stilbene and mono- and disubstitution products thereof, such as
3-ethyl-iminodibenzyl,
3-ethyl-iminostilbene,
3, 7-dimethyl-iminodibenzyl,
2, 8-dimethyl-iminodibenzyl,
3, 7-dichloro-iminodibenzyl and
3, 7-dichloro-iminostilbene.



   By addition of halides or sulfates of aliphatic or araliphatic alcohols, e.g. B. of methyl iodide, dimethyl sulfate, ethyl bromide, ethyl iodide or benzyl chloride, arise from the tertiary amines of the formula I in the usual way monoquateric ammonium compounds, the tertiary amino group in the remainder Am reacting.



   With inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, sithanesulphonic acid, ethane disulphonic acid, acetic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid and phthalic acid form the tertiary bases, some of which are water-soluble are.



   In the examples below, parts mean parts by weight; these relate to parts by volume as g to cm3. The temperatures are given in degrees Celsius.



   example 1
19.5 parts of iminodibenzyl are dissolved in 125 parts by volume of o-xylene and mixed with 3.9 parts of finely powdered sodium amide. The resulting suspension is heated to 100 while stirring and passing in nitrogen until no more ammonia escapes. The contents of the flask are then cooled to 50 and a solution of 13.4 parts of 1-methyl-3-chloropiperidine in 60 parts by volume of o-xylene is added dropwise at this temperature. The suspension is then stirred for two hours at 100 and then refluxed for 14 hours. The reaction mixture, cooled to 0, is treated dropwise with water and stirred well for 2 hours. The two phases are now separated and the organic phase is extracted with 1N hydrochloric acid.

   The acidic aqueous extract is made alkaline and extracted with ether, the ether is evaporated and the remaining oil is fractionated in a high vacuum. 5- [1'-Methyl-piperidyl- (3 ')] - iminodibenzyl of boiling point 165-167 is obtained at 0.02 mm pressure.



   In an analogous manner one obtains: 5- [1'-methyl-piperidyl- (4)] - iminodibenzyl of bp 002 151-1546; 5- [1'-methyl-piperidyl- (3 ') -methyl] -iminodibenzyl of bp ool 157-160;
5- [ss- {1'-methyl-piperidyl- (2 ')} - ethyl] -inino-dibenzyl of bp 0003 178-181 and 5- [1'-methyl-pyrrolidyl- (2') - methyl] - iminodibenzyl from Kp. o, ol 145-147.



   Example 2
19.5 parts of iminodibenzyl are dissolved in 100 parts by volume of benzene. Nitrogen is passed into the solution and 3.9 parts of sodium amide are introduced. The contents of the flask are then heated to 80 until no more ammonia escapes, and then cooled to 45. A solution of 14.8 parts of 1-methyl-piperidyl- (2) -methylchloride in 200 parts by volume of benzene is added dropwise to the resulting suspension in one and a half hours. The reaction mixture is then stirred for 12 hours at 45 and finally for a further two hours Boiled under reflux. The mixture, cooled rapidly to 5, is mixed with water, stirred for two hours and the two phases are separated. The benzene part is extracted with 1N hydrochloric acid.

   The acidic aqueous extract is made mimosa-alkaline with sodium hydroxide solution and extracted with ether. After the ethereal solution has been dried with potassium carbonate, the ether is evaporated off and the residue is fractionated in a high vacuum, the 5- [1'-methyl-piperidyl- (2 ') -methyl] -imino-dibenzyl under 0.02 mm pressure at 165 -167 passes over. 5- [1'-methyl piperidyl- (4R) -methyl] -iminodibenzyl of boiling point 0.02172 to 174 is obtained in an analogous manner.



   Example 3
19.3 parts of iminostilbene are dissolved in 500 parts by volume of benzene at 50-60. A solution of 14.8 parts of N-methylpiperidyl-4-methyl chloride in 400 parts by volume of benzene and a suspension of 4.0 parts of sodium amide in 12 parts by volume of toluene are added dropwise to this solution, while stirring in nitrogen. The suspension obtained is heated to 45 for a further 7 hours and then refluxed for 14 hours. After cooling with ice, 400 parts of water are added to the reaction mixture at 0-5.



  The two phases are separated and the alkaline aqueous part is shaken well with ether. The ether solution is combined with the benzene phase and both extracted with 1 n hydrochloric acid. The hydrochloric acid extract is then made alkaline with sodium hydroxide solution and extracted with ether. The ether solution is dried with sodium carbonate and the ether is then evaporated. The crude oil that remains is distilled in a high vacuum, giving 5- [1'-methyl-piperidyl- (4 ') -methyl] -iminostilbene with a bp.



   5- [1'-methyl-piperidyl- (2 ') -methyl] -iminostilbene with a boiling point of 0.05 169 to 172 is obtained in an analogous manner.



   Example 4
19.3 parts of iminostilbene are dissolved in 600 parts by volume of xylene at 50-60. 16.2 parts of cJ- [1-methyl-piperidyl- (2)] ethyl chloride, dissolved in 400 parts by volume of xylene, are added dropwise to this solution. A suspension of 4.0 parts of sodium amide in 12 parts by volume of toluene is then added to the reaction mixture, the whole is stirred for 7 hours at 55 and finally refluxed for 14 hours. It is then cooled to 0 with ice and worked up analogously to the preceding examples, with the 5- [ss-w 1'-methyl-piperidyl- (2 ')} -ethyl] -iminostilbene of bp 170-172} under Receives 0.004mm print.

 

Claims (1)

PATENT CLAIM Process for the preparation of new basic substituted azepine derivatives of the formula EMI2.1 where X is the ethylene or vinylene group, -CH2-CH2- or -CH = CH-, Y is the direct bond or an alkylene radical having 1-3 carbon atoms, ZA and Z2 are hydrogen, halogen atoms or low molecular weight alkyl radicals, and Am is an N-alkyl -pyrrolidyl or N-alkyl-piperidyl radical, characterized in that an azepine derivative of the formula EMI3.1 in the presence of an acid-binding agent with a reactive ester of a basic alcohol of the formula HO-Y-Am III implemented. SUBCLAIMS 1. Process according to claim, characterized in that the compounds of the formula I are converted into their salts with inorganic or organic acids. 2. Process according to claim, characterized in that halides are used as reactive esters of basic alcohols of the formula III.