CH485752A - Process for the preparation of basic substituted heterocycles - Google Patents

Description

  

  Process for the Production of Basically Substituted Heterocycles The invention relates to a process for the production of 11-base substituted dibenz [b, f] -1,4-oxazepines, dibenzo [b, f] -1,4-thiazepines and dibenzo [- b, el-1,4-diazepines of the formula:
EMI0001.0008
    as well as acid addition salts thereof. In formula <B> 1 </B>, Z represents an oxygen atom, a sulfur atom or an imino group.

   R 1 is hydrogen, lower alkyl, lower hydroxyalkyl, which can be acyl-tertiary, or alkoxyalkylene with a maximum of 5 carbon atoms.



  Lower alkyl, etc. is understood as meaning those with <B> 1 </B> to <B> 3 </B> carbon atoms. The desired products are obtained when a compound of the formula:
EMI0001.0021
    where Z has the meaning mentioned and X is a radical which can be split off from amines with the hydrogen with C, with piperazine or a piperazine derivative of the formula:
EMI0001.0026
    wherein R, has the meaning given above, reacts.

    A halogen atom, the sulfhydryl group, an optionally activated alkoxy or alkyl mercapto group, can be used as a radical which can be split off from amines with the hydrogen and which can be covalently or optionally also ionically bonded to the carbon atom. for example the methoxy, thiomethyl or p-nitrobenzylthio group, or a tosyl radical.



       Starting materials of the formula II are obtained, for example, by converting lactams of the formula:
EMI0001.0043
    where Z has the meaning mentioned, into the thiolactams, if desired with subsequent alkification of the latter, or by reacting the lactams with a halogenating agent,

      such as phosphorus oxychloride or phosphorus pentachloride, preferably in the presence of catalytic compounds of dimethyl aniline or 9 dimethyl formamide. Lactams of the formula IV are in turn formed by ring closure of compounds of the formulas:

      
EMI0002.0001
    wherein Z has the meaning mentioned and R., hydrogen or lower alkyl is, or
EMI0002.0004
    in which Z has the meaning mentioned and Hal stands for a lialo2enatom.



       Oils obtained in the manner described are in most cases crystallizable, otherwise they can be distilled without decomposition in a high vacuum, and form with inorganic, anic and or, anic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid.

   Phosphoric acid. Acetic acid, oxalic acid, maleic acid, tartaric acid, toluenesilfonic acid and the like Like., addition salts which are stable in water. in which form the products can also be used.



  The bases obtained in the manner described and their acid addition salts are new compounds. which are used as active ingredients in pharmaceuticals. They exert a -, ünsti-, e effect -, on the central nerve - #, - system and fall as neuroleptics. Sedatives and especially as antiemetics into consideration.



  The antiemetic effect manifests itself pharmacologically in dogs and rats in an antagonism over the effect of apomorphine. The Z - '\, fethvlsulfonyl-1 1- (4-methyl- <B> 1 </B>) obtained according to Example <B> 1 </B> has proven to be particularly effective. B> -piperazinyl) -dibenz- [b, f] -1,

  # -oxa-zepin e # proven.
EMI0002.0046
  
    <I> table </I>
<tb> example
<tb> <B> Z <SEP> iz, </B> <SEP> physical <SEP> constants
<tb> <B><U>1)</U> </B> <SEP> H <SEP> Base: <SEP> <B> Smp. <SEP> 189-191 <SEP> ## <SEP> C </B>
<tb> <B> 0 </B> <SEP> (from <SEP> Ac / Ae / Pe)
<tb> <B> 3 <SEP> -CH, </B> <SEP> Base: <SEP> Smp. <SEP> <B> 219-223 '<SEP> C </B>
<tb> <B> s </B> <SEP> (from <SEP> Ac / Pe)
<tb> H <SEP> Base: <SEP> Smp. <SEP> <B> 180-1833 <SEP> C </B>
<tb> <B> S </B> <SEP> (from <SEP> <B> ChTe) </B>
<tb> <B> <I> 5 </I> <SEP> -CH, </B> <SEP> Dihydrobrorrtid: <SEP> Smp. <SEP> <B> 225-230 '<SEP> C </ B>
<tb> <B> NH </B> <SEP> (dec .; <SEP> from <SEP> Me,; vinegar window)
<tb> <B> 6 </B> <SEP> H <SEP> Dihydrobron- # d:

   <SEP> Smp. <SEP> <B> 233-248- <SEP> C </B>
<tb> <B> NH </B> <SEP> (from <SEP> MelEssiaester)
<tb> <B> C </B>
<tb> <B> 7 <SEP> -CH., - CH :, </B> <SEP> Base: <SEP> Smp. <SEP> <B> 190-1911 <SEP> C </B>
<tb> <B> 0 </B> <SEP> (from <SEP> Ac! Pe)
<tb> <B> 8 <SEP> -CH. # - CH., OH </B> <SEP> Base: <SEP> Smp. <SEP> <B> 175-177- <SEP> C </ B >
<tb> <B> 0 </B> <SEP> (from <SEP> Ac / Pe)
<tb> <B> 9 <SEP> -CH., - CH., OCH :, </B> <SEP> Base:

   <SEP> Smp. <SEP> 146-149 ## <SEP> <B> C </B>
<tb> <B> 0 </B> <SEP> (from <SEP> Ac / Pe) <I> Example<B>1</B> </I> <B> 5 g </B> 2- Methytsulfonyt-1,1 1-dihydro # -1 1 - oxo-dibenz [b, 2-1,4-o # xazepine (mp. 242-244-- <B> Q </B> are n-ü < B> 1.8 ml of N, N-dimethylmuine and 50 ral Phosphorox chloride heated under reflux for 5 hours, whereupon the reaction mixture was concentrated to dryness in vacuo becomes.

   The residue is mixed with xylene and evaporated again. The residue is then dissolved in xylene and poured onto ice, whereupon it is extracted three times with xyloi. The xylene solution is washed with dilute hydrochloric acid, water and aqueous sodium chloride solution and dried with sodium sulfate. treated with activated charcoal and filtered through little aluminum oxide.

   The filtrate is heated under reflux for <B> 6 </B> hours (then with 12 m] N-, Ivieth # rlpiperazine.

   The reaction mixture is mixed with water and concentrated caustic soda and poured out twice with ether. The extracts are washed several times with water and then extracted with ml of dilute hydrochloric acid. The acid extracts are made alkaline, and extracted twice with ethers.

   The ether phases are washed with water and aqueous sodium chloride solution, dried with sodium sulfate, treated with activated charcoal and filtered through a little aluminum oxide. The filtrate is strongly evaporated and petroleum ether is added.

   The separated crystals are dissolved in acetone oil and after vigorous evaporation of the solution. recrystallized on addition from ether / petroleum ether. This gives <B> 5.8 </B> <U> L </U> 2-methylsulfonyl-1 <B> 1 </B> - (4-methyl-1 -piperazinyl) -dibenz- [b, f] - 1,4-oxazepine in the form of pale yellowish needles with a melting point of 178-179 '<B> C. </B>



  If you proceed in the same way as in the previous example, you still get the products mentioned in the following table according to formula <B> 1. In the table, R and Z have the meanings given earlier. In the column on the right, acetone means acetone. Ae ether, Ch chloroform. Ni1c methanol and Pe petroleum ether.

 

Claims (1)

<B> PATENT CLAIM </B> Process for the preparation of 11-basic substituted C dibenz [b, f1-1,4-oxazepines, dibenzo [b, f] -1,4-thiazepines and dibenzo [b, ej-1,4 -diazepines of the formula: EMI0003.0005 where Z represents an oxygen atom or a sulfur atom or an imino group, R represents hydrogen, lower alkyl, lower hydroxyalkyl, which can be acylated, or alkoxyalkyl with at most 5 carbon atoms, and acid -Addition salts thereof; characterized in that a compound of the formula: EMI0003.0015 wherein Z has the meaning mentioned and X represents a radical which can be split off from amines with the hydrogen, with piperazine or a piperazine derivative of the formula: EMI0003.0020 in which R, which has the meaning given above, reacts, whereupon the reaction products obtained are used as a free base or in the form of their acid addition salts with ae-C suitable inorganic or organic acids isolated. <I> Note from the </I> Federal <I> Office </I> for <I> intellectual property: </I> If parts of the description are inconsistent with the definition of the invention given in the claim, so be aware reminds that according to Art. <B> 51 </B> of the Patent Act, the patent claim is authoritative for the material scope of the patent.