Details for Patent: 8,748,622

Title:	Process for the preparation of 4-{4[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluor- ophenoxy}-N-methylpyridine-2-carboxamide, its salts and monohydrate
Abstract:	The present invention relates to a process for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluo- rophenoxy}-N-methylpyridine-2-carboxamide, its salts and monohydrate.
Inventor(s):	Stiehl; Juergen (Sprockhovel, DE), Heilmann; Werner (Wuppertal, DE), Logers; Michael (Wuppertal, DE), Rehse; Joachim (Leichlingen, DE), Gottfried; Michael (Wuppertal, DE), Wichmann; Saskia (Berlin, DE)
Assignee:	Bayer Intellectual Property GmbH (Monheim, DE)
Filing Date:	Apr 08, 2011
Application Number:	13/640,959
Claims:	1. A process for preparing the compound of the formula (I) ##STR00010## or its monohydrate by treating the compound of the formula (IV) ##STR00011## with the compound of formula (V) ##STR00012## in a reaction mixture and thereafter the dissolved compound of the formula (I) in solution is treated with an acid to form a salt of the compound of the formula (I) which precipitates from the solution containing the dissolved compound of the formula (I), and said salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the monohydrate of the compound of the formula (I), optionally said monohydrate is dried under reduced pressure until the compound of the formula (I) is formed. 2. The process of claim 1 wherein the monohydrate of the compound of the formula (I) precipitates at a temperature of from 35.degree. C. to 45.degree. C. 3. The process of claim 1 for preparing of the compound of the formula (I) wherein the monohydrate is dried under reduced pressure until the compound of the formula (I) is formed. 4. The process of claim 1 wherein the acid is generated in situ in the reaction mixture after the compound of the formula (I) is formed by adding to the reaction mixture a protic substance and an acid precursor. 5. The process of claim 4 wherein the acid is generated in situ in the reaction mixture after the compound of the formula (I) is formed by adding to the reaction mixture an alcohol and an acylchloride. 6. The process of claim 5 wherein the alcohol is ethanol and the acylchloride is acetylchloride. 7. The process of claim 1 wherein the compound of the formula (IV) is prepared by reacting the compound of the formula (III) ##STR00013## wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl, or R.sup.1 and R.sup.2 are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring, with the compound of the formula (II) ##STR00014## in the presence of a base, followed by adding an acid to deliver the compound of the formula (IV). 8. The process of claim 7 wherein the compound of the formula (III) is used in a solution of a suitable organic solvent and is formed by reacting 4-amino-3-fluorophenol with the compound of the formula (VI) ##STR00015## wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl, or R.sup.1 and R.sup.2 are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring. 9. The process of claim 7 wherein the compound of the formula (II) is used in a solution of a suitable organic solvent which solution is prepared by neutralization the hydrochloric acid salt of the compound of the formula (II) with a base. 10. The process of claim 7 wherein the compound of the formula (II) is dissolved in a suitable organic solvent, treated with an acid which is generated in situ by adding a protic substance and an acid precursor, precipitated as a salt of the compound of the formula (II), and neutralized by adding an aqueous solution of a base. 11. The process of claim 10 wherein the protic substance is an alcohol and the acid precursor is an acylchloride.