Process for the manufacture of quinoline derivatives

• US 6,875,869 B2
• Filed: 06/12/2003
• Issued: 04/05/2005
• Est. Priority Date: 06/12/2002
• Status: Active Grant

• Current Assignee: Active Biotech AB
• Original Assignee: Active Biotech AB
• Inventors: Jansson, Karl
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/459,718
• Publication Number:
  US 20040034227A1
• Time in Patent Office: 663 Days
• Field of Search: 546/90, 546/155
• US Class Current: 546/90
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4

Abstract

A process for the preparation of the compounds of general formula (I)
wherein R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl; R₅ is selected from the methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, methylthio, ethylthio, n-propylthio, methylsulphinyl, ethylsulphinyl, fluoro, chloro, bromo, trifluoromethyl, and OCH_xF_y; wherein x=0-2, y=1-3 with the proviso that x+y=3; R₆ is hydrogen; or R₅ and R₆ taken together are methylenedioxy; R′ is selected from methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and OCH_xF_y, wherein x=0-2, y=1-3 with the proviso that x+y=3; R″ is selected form hydrogen, fluoro and chloro, with the proviso that R″ is selected from fluoro and chloro only when R′ is selected from fluoro and chloro; by reacting a quinoline-3-carboxylic acid ester derivative of formula A with an aniline derivative of formula B
in a solvent selected from straight or branched alkanes and cycloalkanes or mixtures thereof with a boiling point between 80 and 200° C.

Claims

1. A process for the preparation of the compounds of general formula (I)

wherein

R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl;

R₅ is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, methylthio, ethylthio, n-propylthio, methylsulphinyl, ethylsulphinyl, fluoro, chloro, bromo, trifluoromethyl, and OCH_xF_y;

wherein

x=0-2,

y=1-3 with the proviso that

x+y=3;

R₆ is hydrogen;

or

R₅ and R₆ taken together are methylenedioxy;

R′

is selected from methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, and OCH_xF_y,

wherein

x=0-2,

y=1-3 with the proviso that

x+y=3;

R″

is selected from hydrogen,fluoro and chloro, with the proviso that R″

is selected from flouro and chloro only when R′

is selected from flouro and chloro;

by reacting a quinoline-3-carboxylic acid ester derivative of formula A with an aniline derivative of formula B according to the following reaction diagram, to give the compound of general formula (I), designated “

C”

, and methanol, designated “

D”

;

in a solvent selected from straight or branched alkanes and cycloalkanes or mixtures thereof with a boiling point between 80 and 200°

C.

2. The process according to claim 1 wherein the solvent is n-heptane, n-octane or mixtures thereof.

3. The process according to claim 1 wherein the solvent is cis,trans-decahydronaphthalene.

4. The process according to claim 1 for the preparation of N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide using n-heptane as a solvent.

5. The process according to claim 1 for the preparation of N-methyl-N-(4-trifluoromethyl-phenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide using a mixture of n-heptane and n-octane as a solvent.

6. The process according to claim 1 for the preparation of N-ethyl-N-phenyl-1,2-dihydro-5-ethyl-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide using cis,trans-decahydro-naphthalene as a solvent.