Method of preparation of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz [e]indole and valuable intermediates related thereto

Abstract

A novel method of preparing the valuable compound 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole is described, said compound possessing antiinflammatory and analgetic activity. Also described are novel intermediates useful in the disclosed method.

I claim: .[. 
     
       1.  A method of preparing 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole which comprises reacting an enammonium salt which, in one of the possible tautomeric forms, is represented by the formula ##STR3## wherein R 1  and R 2  are the same or different and each represents alkyl of from 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino, or piperidino ring and X is bromine or chlorine with 5-aminosalicylic acid in a solvent and at a temperature of from about ambient to the boiling point of the solvent..]. .[. 
     
     
       2.  The method defined in claim 1 wherein the solvent is methanol, 2-propanol or glacial acetic acid..]. .[.3. The method defined in claim 2 wherein the solvent is methanol and the reaction is carried out under reflux..]. .[.4. The method defined in claim 3 wherein the enammonium salt is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide..]. .[.5. The method defined in claim 3 wherein the enammonium salt is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide..]. .[.6. The method defined in claim 3 wherein the enammonium salt is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide..]. .[.7. The method defined in claim 2 wherein the solvent is glacial acetic acid and the reaction is carried out at a temperature of from 70° to 80° C..]. .[.8. The method defined in claim 7 wherein the enammonium salt is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide..]. .[.9. The method defined in claim 7 wherein the enammonium salt is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide..]. .[.10. The method defined in claim 7 wherein the enammonium salt is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide..]. .[.11. The method defined in claim 2 wherein the solvent is glacial acetic acid and the reaction is carried out at reflux..]. .[.12. The method defined in claim 11 wherein the enammonium salt is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide..]. .[.13. The method defined in claim 11 wherein the enammonium salt is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide..]. .[.14. The method defined in claim 11 wherein the enammonium salt is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide..]. .Iadd. 15. A method of preparing 3-(3-carboxy-4-hydroxyphenyl-4,5-dihydro-2-phenylbenz[e]indole which comprises reacting a tautomeric compound of the formula ##STR4## wherein R 1  and R 2  are the same or different and each represents alkyl of from 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino or piperidino ring and X is bromide or chloride with 5-aminosalicylic acid in a solvent at a temperature of from about ambient to the boiling point of the solvent. 
     
     
        .Iaddend..Iadd. 16.  The method as defined in claim 15 wherein one tautomeric form is represented by the formula ##STR5## 
     
     
        .Iaddend. .Iadd. 17.  The method as defined in claim 15 wherein one tautomeric form is represented by the formula ##STR6## 
     
     
       .Iaddend. .Iadd. 18.  The method as defined in claim 15 wherein X is bromide. .Iaddend..Iadd. 19. The method as defined in claim 18 wherein R 1  and R 2  each represent alkyl of from 1 to 6 carbon atoms. .Iaddend..Iadd. 20. The method as defined in claim 18 wherein the tautomeric compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 21. The method as defined in claim 18 wherein the tautomeric compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]piperidinium bromide in equilibrium with 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend. .Iadd. 22. The method as defined in claim 19 wherein the tautomeric compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthenylidene]-N-methylmethanaminium bromide in equilibrium with 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 23. The method as defined in claim 19 wherein the tautomeric compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-butylbutanaminium bromide in equilibrium with 1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 24. The method defined in claim 19 wherein the tautomeric compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-pentyl-pentanaminium bromide in equilibrium with 1-phenacyl-2-diamylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 25. The method defined in claim 17 wherein the compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide. .Iaddend..Iadd. 26. The method defined in claim 17 wherein the compound is 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]piperidinium bromide. .Iaddend..Iadd. 27. The method defined in claim 17 wherein the compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-methyl-methanaminium bromide. .Iadd. 28. The method defined in claim 17 wherein the compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-butyl-butanaminium bromide. .Iaddend..Iadd. 29. The method defined in claim 17 wherein the compound is N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-pentyl-pentanaminium bromide. .Iaddend..Iadd. 30. The method defined in claim 16 wherein the compound is 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 31. The method defined in claim 16 wherein the compound is 1-phenacyl-2-(1-piperidino)-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 32. The method defined in claim 16 wherein the compound is 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 33. The method defined in claim 16 wherein the compound is 1-phenacyl-2-di-n-butylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 34. The method defined in claim 16 wherein the compound is 1-phenacyl-2-diamylamino-3,4-dihydronaphthalene hydrobromide. .Iaddend..Iadd. 35. The method defined in claim 15 wherein the solvent is methanol, 2-propanol or glacial acetic acid. .Iaddend..Iadd. 36. The method defined in claim 35 wherein the solvent is methanol and the reaction is carried out under reflux. .Iaddend. .Iadd. 37. The method defined in claim 35 wherein the solvent is glacial acetic acid and the reaction is carried out at a temperature of from 70° to 80° C. .Iaddend..Iadd. 38. The method defined in claim 35 wherein the solvent is glacial acetic acid and the reaction is carried out at reflux. .Iaddend.