CH424782A - Process for the preparation of tetrahydroisoquinoline derivatives - Google Patents

Description

  

  Process for the preparation of tetrahydroisoquinoline derivatives It has been found that compounds of the formula
EMI0001.0002
    (in which the meaning of A is a 3,4-diethoxybenzal group, while R is hydrogen, an alkyl, aralkyl or aryl group) have valuable properties that differ from the properties known for similar compounds in meh differ in other respects, and that these compounds can be used in pharmacy.

    This is because it is known that compounds which contain an isoquinoline ring generally have spasmolytic properties. The compounds prepared according to the invention (tetrahydroperparin derivatives) sometimes have a significantly stronger spasmolytic effect or they can be used because of their analgesic, vasodilatory or blood pressure-lowering effect.



       According to the invention, the compounds of the formula 1 are prepared by adding a compound of the formula
EMI0001.0021
    subjected to a ring-closing condensation in the presence of a water-binding condensation means at a temperature below 100 C in an acidic medium.



  When carrying out the method according to the invention, for. B. phosphorus oxychloride or phosphorus pentoxide can be used. The reaction is conveniently carried out in an organic solvent, e.g. B. in benzene or chloroform carried out. After condensation has taken place, the reaction mixture can then be acidified, whereupon the excess condensation agent (e.g. phosphorus oxychloride) is decomposed by adding water and the solvent is driven off.

        In this case, the compound is obtained in the form of the hydrochloric acid salt, from which it can optionally be converted into further salts.



  The products of the process according to the invention can be converted into pharmaceutical preparations by process steps known per se, optionally after mixing with additives.

   The products are particularly suitable for use in combined pharmaceutical preparations, where compounds with analgesic or tranquillising effects, compounds similar to atropine or anti-inflammatory, spasmolytic, choleretic and vasodilatory agents can be added as further active ingredients.

      <I> Example 1 </I> 104 g of 3,4-diethoxyphenyl-acetyl-3,4-diethoxyphenylethylamide (F: 108-109 C) are dissolved in 250 ml of benzene for 2 hours in the presence of 50 g of phosphorus oxychloride heated to the boil. Then who expelled about 200-220 ml of benzene.

   300 ml of 96 percent alcohol and 30 ml of concentrated hydrochloric acid are added to the light yellow, viscous residue. The reaction mixture warms up and is brought to light by further heating. Part of the benzene-alcohol solution is driven off, whereupon the hot solution is cooled while stirring.

   The product separates out in the form of glittering, light yellow crystals, which are filtered off, washed with alcohol and dried at 70 to 80 C. 104-105 g of 6,7,3 ', 4'-tetraethoxy-benzal-1,2,3,4-tetrahydroiso-quinoline-4HCl are obtained. F. 206-208 C.

   The product can be recrystallized from a 2 to 3 times the volume of alcohol, whereupon 96 g of a product melting at 210 to 212 ° C. are obtained.



       The hydrobromide (F <B> - </B> 200-202'C) can also be produced in a similar manner. The hydroiodide, obtainable from the hydrochloride or from the hydrobromide in aqueous solution by adding potassium iodide, melts at 2l2-214 C.



  By reacting the base with the corresponding acid or an alkali salt thereof can, for. B. the following other salts are produced:
EMI0002.0067
  
    <U> Salts </U> <SEP> Melting point <SEP> C
<tb> hydrogen fluoride <SEP> 55-69
<tb> nitrate <SEP> 98-100
<tb> Sulphate <SEP> 173-174.
<tb> Phosphate <SEP> 165-168
<tb> Rhodanide <SEP> 115-160
<tb> acetate <SEP> 114-116
<tb> Oxalate <SEP> 160-161
<tb> Tartarate <SEP> 130-133
<tb> p-nitrophenyl lactate <SEP> 91-99
<tb> o-Phenoxy-benzoate <SEP> 112-116
<tb> Xanthene carbonate <SEP> 116-119
EMI0002.0068
  
    Dimethoxyphenyl acetate <SEP> 106-110
<tb> Diethoxy-phenyl acetate <SEP> 73-78-85
<tb> p-chloro-phenyl-propionate <SEP> 83-86
<tb> tropanate <SEP> 100-103
<tb> Mandelat <SEP> 80-84-85
<tb> phenoxyacetate <SEP> 113
<tb> Dimethoxybenzoate <SEP> 108-110
<tb> malonate

  <SEP> 140-141
<tb> Ethylbenzoquinolisyl acetate <SEP> 117-119
<tb> Yatrenat <SEP> 182-184 The salts can be recrystallized from alcohol.



  The pharmacological investigation of the acidic salt gave the following results: Toxicity DL50 = <B> 19.0 </B> mg / kg i. v. 95.0 mg / kg s. c. and over 1000 mg / kg p. o. (in mice).

   In anesthetized cats, a 25 mg / k, -, - dose administered duodenally showed a severe depression of blood pressure (in the same experiment, Perparin showed no effect even at 400 mg / kg doses;

   this means that duodenal absorption is much better than in the case of Perparin). In a Tyrode solution on the intestines of mice, it was observed that the spasmolytic effect of the substance is ED50 = 0.056 mg (with Perparin the same value is 0.108 mg). In the presence of blood serum, the same value is ED5o = 0.250 mg (with Perparin 0.756 mg).

    <I> Example 2 </I> 104 g of 3,4-diethoxyphenyl-acetyl-3,4-diethoxyphenyl-ethyl-amide (F: 108-109 'C) are in 250 ml of benzene for 2 hours in The presence of 50 g of phosphorus oxychloride is heated to boiling.



  300 ml of water and 30 ml of concentrated hydrochloric acid are then added to the reaction mixture, whereupon the benzene is driven off with stirring. The residue is filtered warm and cooled. The product precipitates in the form of pale yellow crystals, which are filtered, washed and dried at 80-90C. There are 110 g of 6,7,3 ', 4'-tetra-ethoxy-benzal-1,2,3,4-tetrahydro-isoquinoline-HCl he keeps. F: 202-206 C.

   Recrystallized from a 2.5-fold volume of water, 103 g of light yellow crystals are obtained. F: 211-212 C.

 

Claims (1)

PATENT CLAIM Process for the preparation of isoquinoline derivatives of the formula EMI0002.0122 wherein A is the 3,4-diethoxybenzal group and R hydrogen, an alkyl, aralkyl or aryl group, characterized in that one is a compound of the formula EMI0003.0006 in the presence of a water-binding condensation agent at a temperature below 100 C in an acidic medium, ring-closing condensation. SUBClaims 1. Method according to claim, characterized in that phosphorus oxychloride is used as the condensing agent. 2. The method according to claim or sub-claim 1, characterized in that salts of the products with mineral acids or organic acids are prepared. 3. Process according to dependent claim 2, characterized in that the halides, nitrates, sulphates, phosphates, rhodanides, acetates, oxalates, tartrates, lactates, benzoates, xanthene carbonates, dialkoxyphenyl acetates, propionates, tropanates, mandrels are delate , Phenoxy acetates, dialkoxy benzoates, Malonate or Yatrenate of the products.