Claims for Patent: 12,325,714

Summary for Patent: 12,325,714

Title:	Compositions of thienopyrimidine derivatives
Abstract:	The present invention provides a production method of a thienopyrimidine derivative or a salt thereof which has a gonadotropin releasing hormone (GnRH) antagonistic action with high quality in high yield. The present invention provides a method of producing a thienopyrimidine derivative, which comprises reacting 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or salt thereof, 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof, and the like.
Inventor(s):	Kazuhiro Miwa
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US18/927,346
Patent Claims:	1. A solid mixture comprising 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, or a salt or solvate thereof, and 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea. 2. The solid mixture of claim 1, wherein the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of about 0.1% or less of the mixture, as determined by high performance liquid chromatography (HPLC). 3. The solid mixture of claim 1, wherein the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of from about 0.1% to about 0.02% of the mixture, as determined by HPLC. 4. The solid mixture of claim 1, wherein the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of about 0.04% or less of the mixture, as determined by HPLC. 5. The solid mixture of claim 2, wherein the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl) -1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture using an ultraviolet absorptiometer. 6. The solid mixture of claim 5, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume, wherein the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl -2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm, and wherein the reverse phase chromatography column is a C18 column. 7. The mixture of claim 3, wherein the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture using an ultraviolet absorptiometer. 8. The mixture of claim 4, wherein the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture using an ultraviolet absorptiometer. 9. The solid mixture of claim 1 comprising 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea and 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea. 10. The solid mixture of claim 1, wherein the solid mixture comprises crystals. 11. A solid mixture comprising 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, or a salt or solvate thereof, and N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide. 12. The solid mixture of claim 11, wherein the N-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of about 0.08% or less of the mixture, as determined by HPLC. 13. The solid mixture of claim 11, wherein the N-{b 4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of about 0.08% to about 0.02% of the mixture, as determined by HPLC. 14. The mixture of claim 12 wherein the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture using an ultraviolet absorptiometer. 15. The solid mixture of claim 14, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume, wherein the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl -3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm, and wherein the reverse phase chromatography column is a C18 column. 16. The mixture of claim 13, wherein the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture using an ultraviolet absorptiometer. 17. The solid mixture of claim 11 comprising 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, and N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide. 18. The solid mixture of claim 11, wherein the solid mixture comprises crystals. 19. A solid mixture comprising 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, or a salt or solvate thereof, 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, and N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide. 20. The solid mixture of claim 19, wherein the 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of about 0.10% or less of the mixture, as determined by high performance liquid chromatography (HPLC). 21. The solid mixture of claim 19, wherein the 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of from about 0.10% to about 0.02% of the mixture, as determined by HPLC. 22. The solid mixture of claim 19, wherein the 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of about 0.04% or less of the mixture, as determined by HPLC. 23. The solid mixture of claim 20, wherein the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the 1-{4-[1-(2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the mixture using an ultraviolet absorptiometer. 24. The solid mixture of claim 23, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume, wherein the percentage amount of 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl -2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl56 -3-methoxyurea in the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm, and wherein the reverse phase chromatography column is a C18 column. 25. The solid mixture of claim 19, wherein the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of about 0.08% or less of the mixture, as determined by HPLC. 26. The solid mixture of claim 19, wherein the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of about 0.08% to about 0.02% of the mixture, as determined by HPLC. 27. The solid mixture of claim 25, wherein the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo -1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture is determined by an HPLC method comprising: a) contacting a stationary phase of a reverse phase chromatography column with the mixture; b) eluting the mixture with a mobile phase such that the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide traverses the column with a retention time that is different than the remainder of the mixture; wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and c) measuring the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture using an ultraviolet absorptiometer. 28. The solid mixture of claim 27, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume, wherein the percentage amount of N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl -3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide in the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm, and wherein the reverse phase chromatography column is a C18 column. 29. The solid mixture of claim 19 comprising 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, and N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridzin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide. 30. The solid mixture of claim 19, wherein the solid mixture comprises crystals.