CH374071A - Process for the preparation of new isoindoline derivatives - Google Patents

Description

  

      Process for the preparation of new isoindofine derivatives The present invention relates to a process for the preparation of new isoindofine derivatives with valuable pharmacological properties.



  It has surprisingly been found that isoindoline derivatives of the formula
EMI0001.0006
    where R, hydrogen, a halogen atom, a low molecular weight alkyl, alkoxy group or alkanoyl amino group or a nitro group, R, and R3 hydrogen, halogen or low molecular weight alkyl or alkoxy groups, R4 hydrogen, a halogen atom, a low molecular weight alkyl,

          Alkoxy, alkanoylamino, carbalkoxy, carbalkoxyalkoxy or nitro group, an unsubstituted or substituted one by one or two low molecular weight alkyl or alkenyl radicals or a polymethylene or 3-oxapentylene (1,5) radical Carbamyl or carbamyl alkoxy group,

      R5 is hydrogen or an alkyl, alkenyl or cycloalkyl group, R6 is a saturated aliphatic or cycloaliphatic hydrocarbon radical, or a hydroxyalkyl or Al-. kenyl radical, which radicals can also be interrupted by oxygen or sulfur, and X mean oxygen or sulfur, valuable pharmacological, gical, z. B. have anticonvulsant and anesthetic properties.

   In particular, connections in which X is embodied by oxygen, behave moreover antagonistic to ge know effects of some central damping substances such. B. Rauwolfia alkaloids.



  For the inventive production of the above. A 1-oxo-3-aryl-3-hydroxy-isoindoline or a corresponding 3-chloro or 3-bromo derivative of the formula is used
EMI0001.0055
    in which Y is chlorine or bromine or a hydroxyl group, optionally in the presence of a dehydrating or acid-binding agent, with a compound of the formula Re X-H III.



       If desired, compounds of the formula I or II, in which R5 is hydrogen, can then or optionally simultaneously implement a radical R5 other than hydrogen, for example with a reactive ester, an alkanol, alkenol or cycloalkanol in the presence of an acid-binding agent.



  Compounds of the general formula II in which Y is hydroxy can easily be reacted with alcohols or mercaptans of the formula III if an excess of compound of the formula III or an inert organic solvent is used as the reaction medium.

   Hydrogen chloride has proven itself as a dehydrating agent in reactions with alcohols; its addition is particularly recommended when reaction temperatures above about 80 are maintained.



  Starting materials of the formula II, in which Y is hydroxy, can be converted into those of the formula II in which Y is chlorine or bromine, where the former z. B. most conveniently treated with the help of the easily removed thionyl chloride. But there are also other inorganic acid halides, such as. B. phosphorus pentachloride or phosphorus tribromide in question.

   Both this conversion and the inventive reaction with compounds of the formula III can be carried out at room temperature and run exothermically. A base, such as pyridine, trimethylamine or potassium carbonate, added in excess can, if desired, serve as an acid-binding agent.

   In the case of reactions with alcohols of the formula <B> 111 </B>, the presence of an acid-binding agent is very desirable; if necessary, less reactive alcohols and mercaptans can be converted into metal compounds with suitable acid-binding agents before the main reaction.



  Starting materials of the formula II are, for example, by reacting compounds of the formula
EMI0002.0017
    or of appropriately substituted 2-carboxy-benzophenones, 2-carbalkoxy-benzophenones or 2-aryl-3-alkoxy-phthalides with amines of the formula R5-NHZ V, preferably in the presence of acid-binding agents, e.g. B. excess amine available. The connec tions of formula IV can in turn, for.

   B. starting from optionally mono- or disubstituted benzene by halogen atoms, low molecular weight alkyl or alkoxy groups on the one hand and optionally substituted phthalic anhydrides or phthalic acid ester halides on the other hand who receive the.

   Condensation of such reaction components according to Friedel-Crafts gives 2-carboxybenzophenones or 2-carbalkoxy-benzophenones with corresponding ring substituents. If desired, such compounds can now also be nitrated in the 3'-position and then optionally reduced and acylated.



  Further variations with respect to the radicals R3 and R4 are obtained using starting materials of the formula 1I, which can be prepared, for example, as follows: Optionally substituted benzoic acid halides are condensed with appropriately substituted alkylbenzenes, eg. B.

         m-cresol methyl ether or ethyl ether, m-chloro toluene or p-xylene according to Friedel-Crafts to substituted 2 - methyl - benzophenones and then oxidizes the 2 alkyl group and any other alkyl group to carboxyl groups, e.g. B. with potassium permanganate solution.

   By treatment with inorganic acid halides, the substituted benzophenone-2-carboxylic acids obtained can be converted into halolactones which either fully correspond to formula IV or instead of R4 contain a halocarbonyl group which, in the subsequent reaction with an amine of formula V passes into a carbamyl or substituted carbamyl group corresponding to the definition for R4.



  With this list, the possibilities for the production of suitable starting materials of the formula 1I by methods known per se are by no means exhausted. The following compounds may be mentioned as examples of such starting materials: 1-oxo-3-phenyl-3-hydroxy-isoindoline, 1-oxo-2-methyl-3-phenyl-3-hydroxy-isoindoline, 1-oxo-2-ethyl -3-phenyl-3-hydroxy-isoindoline, 1-oxo-2-n-propyl-3-phenyl-3-hydroxy-isoindoline, 1-oxo-2-n-butyl-3-phenyl-3-hydroxy-isoindoline , 1-oxo-2-n-hexyl-3-phenyl-3-hydroxy-isoindoline, 1-oxo-3- (4'-chlorophenyl) -3-hydroxy-isoindoline,

            1-oxo-2-ethyl-3- (4'-chloro-phenyl) -3-hydroxy-isoindoline, 1-oxo-2-allyl-3- (4'-chloro-phenyl) -3-hydroxy-isoindoline, 1-oxo-2-cyclohexyl-3- (4'-chloro-phenyl) -3-hydroxy-isoindoline, 1-oxo-3- (3'-nitro-4'-chloro-phenyl) -3-hydroxy-isoindoline , 1-oxo-3- (4'-methyl-phenyl) -3-hydroxy-isoindoline, 1-oxo-3- (3'-nitro-4'-methyl-phenyl) -3-hydroxy-isoindoline, 1- Oxo-3- (4'-fluorophenyl) -3-hydroxy-isoindoline,

            1-oxo-3- (3'-nitro-4'-methoxyphenyl) -3-hydroxy-isoindoline, 1-oxo-3- (4'-isopropoxyphenyl) -3-hydroxy-isoindoline, 1-oxo -3- (3 ', 4'-dimethyl-phenyl) -3-hydroxy-isoindoline, 1-oxo-3-phenyl-3-hydroxy-6-chloro-isoindoline, 1-oxo-3-phenyl-3-hydroxy -6-methaxy-isoindoline, 1-oxo-3- (4'-chlorophenyl) -3-hydroxy-5-bromo-6-methoxy-isoindoline, 1-oxo-3- (3'-acetylamino-phenyl) -3-hydroxy-isoindoline,

            1-oxo-2-ethyl-3-phenyl-3-hydroxy-5-ethyl-carbamyl-isoindoline. As starting materials of the formula III come for example alcohols, such as. B.



  Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec. Butanol, n-amyl alcohol, isoamyl alcohol, n-hexanol, n-heptanol, n-octanol, n-decanol and n-dodecanol, ethyl alcohol and methallyl alcohol, cyclopentanol, cyclohexanol, 4-methyl-cyclohexanol, cycloheptanol,

            Cyclooctanol, cyclopropyl-methyl-carbinol,, B-methoxy-ethanol, f-ethoxy-ethanol and tetrahydrofurfuryl alcohol or mercaptans, such as methyl mercaptan, ethyl mercaptan, isopropyl mercaptan, allyl mercaptan, cyclohexyl mercaptan, methoxyethyl mercaptan.



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



  <I> Example 1 </I> 26 parts of 4'-chloro-benzophenone-2-carboxylic acid are refluxed with 35 parts by volume of thionyl chloride for 1 hour. After removing the excess thionyl chloride in vacuo, the 3- (4'-chloro-phenyl) -3-chlorophthalide thus obtained is dissolved in 50 parts of dioxane and the solution is concentrated in 200 parts. Poured aqueous ammonia solution.

   The 1-oxo-3- (4'-chloro - phenyl) -3-hydroxy-isoindoline crystallizes out after a short time. M.p. 214-216 (from dioxane).



  26 parts of the 1-oxo-3- (4'-chlorophenyl) -3-hydroxy-isoindoline obtained in this way are dissolved in 50 parts by volume of thionyl chloride in the cold and the excess is immediately evaporated off again in vacuo. The remaining crude 1-oxo-3- (4'-chloro-phenyl) -3-chloro-isoindoline is poured over 50 parts by volume of methanol, with heating occurring.

   On cooling th, the 1- oxo-3 - (4'-chlorophenyl) -3-methoxy-isoindoline crystallizes out. 157-161 (from benzene).



  The 1-oxo-2-methyl-3 - (4'-chlorophenyl) -3-hydroxy-isoindoline (melting point 199-200) is obtained in a similar manner by reacting 3- (4'-chlorophenyl) -3-chlorophthalide and with methylamine instead of ammonia, and from it by successive treatment with thionyl chloride and methanol the 1-oxo-2-methyl-3- (4'-chlorophenyl) -3-methoxy-isoindoline of mp 83-85 (from methanol);

   also 1-oxo-2-ethyl-3-phenyl-3-methoxy-isoindoline (melting point 67-69) from the known 1-oxo-2-ethyl-3-phenyl-3-hydroxy-isoindoline by treatment with thionyl - chloride and subsequent reaction with methanol. <I> Example 2 </I> 26 parts of the 1-oxo- 3- (4'-chlorophenyl) -3-hydroxy-isoindoline obtained according to Example 1 are refluxed for 1 hour in 300 parts of methanol saturated with hydrogen chloride .

   On concentration in vacuo, the 1-oxo-3- (4'-chlorophenyl) -3-methoxy-isoindoline crystallizes out. M.p. 158-16L (from benzene).



  <I> Example 3 </I> 25 parts of 1-oxo-2-ethyl-3-phenyl-3-hydroxy-isoindoline are dissolved in 40 parts by volume of cold thionyl chloride and the excess of the latter is distilled off in vacuo. The remaining, amorphous 1-oxo-2-ethyl-3-phenyl-3-chloro-isoindoline is dissolved in 100 parts of anhydrous ether and converted into a solution of 15 parts by volume of ethyl mercaptan within 20 minutes at 10-15

      15 parts by volume of anhydrous ether and 10 parts by volume of pyridine were added dropwise. The crystallized pyridine hydrochloride is filtered off and the filtrate is evaporated to dryness. The oil that remains is dissolved in 100 parts of cyclohexane and filtered. On concentration, the 1-oxo-2-ethyl-3-phenyl-3-ethyl-mercapto-isoindoline of melting point 91-92 crystallizes.

 

Claims (1)

PATENT CLAIM Process for the production of new isoindolines, characterized in that compounds of the formula EMI0003.0091 where R1 is a hydrogen atom, a halogen atom, a low molecular weight alkyl, alkoxy or alkanoyl amino group or a nitro group, R2 and R3 are hydrogen, halogen or low molecular weight alkyl or alkoxy groups, R4 is hydrogen, a halogen atom, a low molecular weight alkyl, Alkoxy, alkanoylamino, carbalkoxy, carbalkoxyalkoxy or nitro group, an unsubstituted or substituted one by one or two low molecular weight alkyl or alkenyl radicals or a polymethylene or 3-oxapentylene (1,5) radical Carbamyl or carbamyl alkoxy group, R "is hydrogen or an alkyl, alkenyl or cycloalkyl group, R6 is a saturated aliphatic or cycloaliphatic hydrocarbon radical, or a hydroxyalkyl or alkenyl radical, which radicals can also be interrupted by oxygen or sulfur, and X is oxygen or sulfur , characterized in that one is a compound of the formula EMI0003.0129 where Y is chlorine or bromine or a hydroxyl group, with a compound of the formula R6 X-H III.