Claims for Patent: 8,426,586

Summary for Patent: 8,426,586

Title:	Process for preparing amino crotonyl compounds
Abstract:	An improved process for preparing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline and related aminocrotonyl compounds and the preparation of a suitable salt of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline for use as a pharmaceutically active substance.
Inventor(s):	Soyka; Rainer (Biberach, DE), Rall; Werner (Mittelbiberach, DE), Schnaubelt; Juergen (Oberhoefen/Warthausen, DE), Sieger; Peter (Mittelbiberach, DE), Kulinna; Christian (Attenweiler, DE)
Assignee:	Boehringer Ingelheim International GmbH (Ingelheim am Rhein, DE)
Application Number:	11/457,622
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,426,586
Patent Claims:	1. A process for preparing a compound of the formula (VII) ##STR00013## wherein X denotes a methyne group or a nitrogen atom, R.sub.a denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group and R.sup.3 and R.sup.4 denote a straight-chain or branched C.sub.1-4-alkyl group, comprising the following synthesis steps: a) reacting a compound of the formula (V) ##STR00014## wherein X denotes a methyne group or a nitrogen atom and R.sub.a denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, in suitable solvents after corresponding activation with di-(C.sub.1-4-alkyl)-phosphonoacetic acid and b) reacting the resulting compound of the formula (VI) ##STR00015## wherein X denotes a methyne group or a nitrogen atom, R.sub.a denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group and R.sup.1 denotes a straight-chain or branched C.sub.1-4-alkyl group, with the aldehyde of formula ##STR00016## wherein R.sup.3 and R.sup.4 in each case represent a straight-chain or branched C.sub.1-C.sub.4-alkyl group, while the groups may be identical or different, or a corresponding aldehyde equivalent, using suitable organic or inorganic bases. 2. A process for preparing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7- ((S)-tetrahydrofuran-3-yloxy)-quinazoline, comprising the following synthesis steps: a) reacting N.sup.4-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline- -4,6-diamine in suitable solvents after corresponding activation with di-(C.sub.1-4-alkyl)-phos -phonoacetic acid and b) reacting the resulting dialkylester {[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quina- zolin-6-ylcarbamoyl]-methyl}-phosphonate with the aldehyde prepared in situ from the corresponding (dimethylamino)-acetaldehyde-dialkylacetal using suitable organic or inorganic bases. 3. The process according to claim 2, wherein in step a) diethylphosphonoacetic acid is used as reagent. 4. The process according to claim 1, wherein in step b) DBU (1,5-diaza-bicyclo[4.3.0]non-5-ene), sodium hydroxide or potassium hydroxide is used as base. 5. The process according to claim 4, wherein in step b) potassium hydroxide is used as base. 6. A process for preparing the dimaleates of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino }-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, comprising steps a and b according to claim 1 as well as the following step c): c) converting the resulting 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline into the dimaleate by reacting with maleic acid in a suitable solvent, with heating. 7. The process according to claim 6, wherein ethanol or isopropanol is used as solvent, optionally with the addition of water. 8. The process according to claim 6, wherein at least 2equivalents of maleic acid are used. 9. Crystalline 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7-((S))-tetrahydofuran-3-yloxy)-quinazoline dimaleate, characterized by 2 .THETA. [.degree.] values obtained by X-ray powder diffraction using CuK.sub..alpha.1 radiation, .lamda.=1.5418.ANG. in the following table: TABLE-US-00002 2-.THETA. intensity [.degree.] I/I.sub.o [%] 4.91 47 6.42 33 7.47 27 8.13 30 10.37 30 17.19 36 19.43 38 19.91 100 21.33 21 22.94 32 25.56 37. 10. Crystalline 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate, characterized by 2 .THETA. [.degree.] values obtained by X-ray powder diffraction using CuK.sub..alpha.1 radiation, .lamda.=1.5418 .ANG. in the following table: TABLE-US-00003 2-.THETA. intensity [.degree.] I/I.sub.o [%] 4.91 47 6.42 33 7.47 27 8.13 30 10.37 30 12.91 20 14.94 11 16.58 12 17.19 36 19.43 38 19.91 100 20.84 13 21.33 21 21.58 12 22.25 15 22.94 32 25.56 37. 11. Crystalline 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- n-1-yl]amino}-7-((S))-tetrahydofuran-3-yloxy)-quinazoline dimaleate, characterized by 2 .THETA. [.degree.] values obtained by X-ray powder diffraction using CuK.sub..alpha.1 radiation, .lamda.=1.5418 .ANG. in the following table: TABLE-US-00004 2-.THETA. d-value intensity [.degree.] [.ANG.] I/I.sub.o [%] 4.91 18.0 47 6.42 13.8 33 7.47 11.8 27 8.13 10.9 30 10.37 8.53 30 11.69 7.56 2 12.91 6.85 20 13.46 6.58 3 13.66 6.48 2 14.94 5.93 11 16.58 5.34 12 17.19 5.15 36 17.87 4.96 5 19.43 4.57 38 19.91 4.46 100 20.84 4.26 13 21.33 4.16 21 21.58 4.12 12 22.25 3.992 15 22.94 3.873 32 23.67 3.756 9 24.82 3.584 7 25.56 3.482 37 26.71 3.335 9 27.46 3.245 4 28.37 3.143 8 30.71 2.909 3 29.31 3.045 4 29.57 3.019 4 31.32 2.854 10 32.31 2.769 4 33.10 2.705 5 33.90 2.643 1 34.84 2.573 2 35.71 2.512 1 36.38 2.46 71 36.96 2.430 1 37.99 2.367 2 39.94 2.255 5.