CH433302A - Process for the preparation of new heterocyclic compounds - Google Patents

Description

  

  <B> Process </B> for the <B> production of new </B> heter cyclic <B> compounds </B> The present invention relates to a process for the production of new heterocyclic compounds. of the formula I, in which R1 is an alkyl group with 2-4 carbon atoms, an aryl or aralkyl radical, R2 is hydrogen or a lower alkyl group, and their acid addition salts with organic or inorganic acids.



  According to the invention, the new compounds of the formula I are obtained by reacting compounds of the formula II in which Hal is chlorine or bromine in a suitable organic solvent and in the presence of a basic condensing agent with 4 hydroxypip, eridine.



  The compounds of the formula I obtained can then be converted into their acid addition salts by reaction with suitable organic or inorganic acids.



  A preferred embodiment of the fiction, according to the method consists, for. B. in the fact that a compound of formula III with sodium amide in xylene is refluxed for 1 hour at 180 °. After cooling to 4.0 internal temperature.

   a solution of 1-bromo-3-chloro-propane in abs. Xylene was added dropwise. Then it is heated in an oil bath to 180 bath temperature and left to boil for 1 hour. The cold reaction mixture is washed out with 250 ccm of water and completely freed from the solvent in vacuo. The residue, i.e. H. a compound of the formula II is then treated with 4-hydroxypiperidine in the presence of an alkaline substance, eg.

   B. potassium carbonate, and an organic solvent, z. B. xylene, refluxed at about 180 for 20 hours with stirring. After cooling, the precipitate is filtered off and the filtrate is extracted with 15% aqueous tartaric acid. The tartaric acid extract is washed out with benzene, made phenol-phthalein-alkaline with sodium hydroxide solution and the base which has separated out is taken up in benzene.

   After the benzene solution has been washed out with water, it is dried over potash, filtered and concentrated, and the residue is purified by distillation under reduced pressure or crystallization and the compounds of the formula I thus obtained are converted in a known manner by reaction with organic or inorganic acids their acid a: dditions, alze converted.



  The novel phenothiazine derivatives of the formula I prepared according to the process are basic, oily or crystalline compounds at room temperature, which form salts which are stable in organic or organic acids and which crystallize at room temperature. The following seams, among others, can be used for salt formation:

       Hydrochloric acid, citric acid, tartaric acid, succinic acid, maleic acid, malic acid, acetic acid, benzoic acid, fumaric acid, gallic acid, hexahydrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene-1,5-disulfonic acid: e and phosphoric acid.



  The compounds prepared according to the invention and their salts with therapeutically acceptable organic or inorganic acids are distinguished by a particularly strong cataleptic effect and should therefore be used primarily for the treatment of neurotic and psychotic disorders.



  The compounds can be used as medicaments alone or in corresponding medicament forms for enteral or parenteral administration. In order to produce suitable dosage forms, these are processed with inorganic or organic, pharmacologically independent auxiliary substances. As auxiliary materials who used the z.

   B. for tablets and dragees: lactose, starch, talc, stearic acid, etc .; for injection preparations: water, alcohols, glycerol, vegetable oils and the like; for suppositories .: natural or hydrogenated oils and waxes, etc. a. m.



  In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorings, flavorings, etc.



  In the following examples, which explain the execution of the process but are not intended to restrict the scope of the invention in any way, all temperatures are given in degrees Celsius. The melting points are corrected.

    
EMI0002.0004
  
EMI0002.0005
    <I> Example 1: </I> 3-Ä.thylmarcapto-10- [2-methyl-3- (4 hydroxypiperidyl-1) -propyl-1] -phenothiazine A mixture of 70.0 g of 3-ethylmercapto -10- (2-methyl-3-chloropropyl-1) -phenothiazine, 25.3 g of 4-hydroxypiperidine, 41.7 g of finely powdered calcium carbonate and 350 ccm of xylene are added for 20 hours.

   Boiled at reflux at 180 oil bath temperature with stirring. After cooling, the precipitate is filtered off and the filtrate with 400 ccm 15 percent. aqueous tartaric acid extracted. The vesic acid extract is washed out with 125 ccm benzene,

       with 100 ccm conc. Sodium hydroxide solution was made alkaline with phenolphthalein and the base which had precipitated was taken up in 500 cc of benzene. After washing off the benzene solution with 150 ccm of water, it is dried over potash, filtered and concentrated.

   The evaporation residue will. distilled in a high vacuum and the main fraction passing over at 0.03 mm Hg of 242J246 collected.

   After the distillate has crystallized twice from 150 cc of acetone, pure 3-ethylmercapto-10- [2-methyl-3- (4-hydroxypiperidyl-1) propyl-1] phenothiazine with a melting point of 128-130 is obtained.



  The 3-ethyl mercapto -10 - (2-methyl-3-chloropropyl-1) - phenothiazine used as the starting compound can be prepared as follows:

   121 g of 3-ethyl-mercapto-phenotbsazine (melting point 95-97 '), 21.8 g of finely powdered sodium amide and 700 ccm of abs. Xylene is refluxed for 1 hour at an oil bath temperature of 180 ° while stirring.

   After cooling to 40 'internal temperature, a solution of 100 g of 2-methyl-1-bromo-3-chloro-propane in 100 ccm of abs. Xylene was added dropwise. Then it is heated in an oil bath to 180 bath temperature and left to boil for 1 hour.

       The cold reaction mixture is washed out with 250 ccm of water and completely freed from the solvent in vacuo. The crude evaporation residue is used directly for the reaction.

      <I> Example 2: </I> 3-Isopropylmercapto-10- [3- (4-hydroxy piperidyl- 1) -propyl-1] -phenothiazine The reaction is carried out as in Example 1, with 55.0 g of 3-isopropylmercapto -10- (3-chloropropyl-1) - phenothiazine, 19.85 g of 4-hydroxypip.ersdn, 32.6 g of fine powdered potassium carbonate and 250 ccm of xylene are made up.

   After a similar work-up, the residue is distilled in a high vacuum and the main fraction passing over at 0.02 mg Hg of 245-248 is collected. After the distillate has crystallized twice from 120 cc of acetone each time, pure 3-isopropylmercapto-10- [3- (4-hydroxypiperidyl-1) propyl-1] phenothiazine of melting point 102-104 'is obtained.



  The 3-Isopropyhnercapto-10- (3-chloropropyl-1) -phenothiazine used as the starting compound can be prepared in the same way as 3-EthylmerCapto-10- (2-methyl-3-chloropropyl-1) -phenothiazine (Example 1) can be produced.



  <I> Example 3: </I> 3-Benzylmercapto-10- [3- (4-hydroxy piperidyl-1) -propyl "1] -ph @enothiazine The reaction is carried out as in Example 1, with 114.0 g 3 Benzyhneroapto-10- (3-chloropropyl-1) phenothiazine, 36.15 g 4-hydroxypiperidine, 59.4 g calcium carbonate fine pule.

   and 500 ccm of xylene are made up. After a similar work-up, the evaporation residue is purified by chromatography: 34 g of this residue are dissolved in 50 cc of benzene / chloroform 1:

  1 dissolved and adsorbed on 1 kg of aluminum oxide. The first 1200 cc. Benzene / chloroform 1: 1 eluate and the subsequent 3200 ccm chloroform eluate are discarded. The subsequent 1600 ccm chloroform solution are concentrated separately.

   The tartrate is made from part of the evaporation residue. For this purpose, 7.9 g of the free base are dissolved in 80 cc of ethyl acetate and poured at 0 with good shaking to an ice-cold solution of 2.56 g of tartaric acid in 390 cc of ethyl acetate. After the precipitated, amorphous tartrate has been filtered off, it is concentrated in a vacuum desiccator. Sulfuric acid dried.

   The 3-Benzyhnercapto-10- [3- (4 hydroxy-piperidyl-1) -propyl-1] -phenothiaa.zine tartrate; other- dertha.1bhydrat has the melting point 90-93 according to Sint. from <B> 70 '. </B>



  The 3-benzyl mercapto-10- (3-chloro-propyl-1) -phenothiazine used as the starting compound can be prepared in the same way as 3-Ethyhnercapto-10- (2-methyl-3-chloropropyl-1) -phenothiazine (Example 1 ) getting produced.



  <I> Example 4: </I> 3-Ethylmercapto-10- [3 -. (4-hydroxypiperidyl-1) - propyl-1] phenothiazinine The reaction is carried out as in Example 1, with 52.2 g of 3 -, ethyl mercapto-1-0- (3-chloropropyl-1) phenothnazine, 19.7 g of 4-hydroxypiperidine, 32.2 g of fine powdered potassium carbonate and 250 ccm of xylene.

   After a similar work-up, the evaporation residue is distilled in a high vacuum and the

  03 mm Hg of 245-247 'C passing main fraction collected. After the distillate has crystallized twice, from 250 cc of acetone each time, the pure 3 Ethyhnercapto-10- [3- (4-hydroxypiperidyl-1)] phenothiazine of melting point 127-129 ° C. is obtained.

 

Claims (1)

PATENT CLAIM Process for the preparation of new basic substituted phenothiazines, characterized in that compounds of the formula I in which R1 is an alkyl group with 2-4 carbon atoms, an aryl .Or aralkyl group and R2 is hydrogen or a lower alkyl group, by compounds of the formula II, in which Hal is chlorine or bromine, in a suitable organic solvent and in the presence of a basic condensing agent with 4-hydroxy piperidine converts. SUBSTANTIAL CLAIM Process according to patent claim, characterized in that the compounds of the formula I obtained are converted into their acid addition salts by reaction with suitable organic or inorganic acids.