Claims for Patent: 11,795,178

Summary for Patent: 11,795,178

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 thienopyrirnidine 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):	Koichiro Fukuoka, Kazuhiro Miwa, Tsuyoshi Sasaki, Fumiya Komura
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US17/694,635
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 11,795,178
Patent Claims:	1. A mixture comprising 1-{441-(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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. 2. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 4.45% or less of the mixture, as determined by high performance liquid chromatography (HPLC). 3. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.25% or less of the mixture, as determined by HPLC. 4. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.23% or less of the mixture, as determined by HPLC. 5. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.22% or less of the mixture, as determined by HPLC. 6. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.20% or less of the mixture, as determined by HPLC. 7. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 4.45% to about 0.20% of the mixture, as determined by HPLC. 8. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.20% of the mixture, as determined by HPLC. 9. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.16% or less of the mixture, as determined by HPLC. 10. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.07% or less of the mixture, as determined by HPLC. 11. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.05% of the mixture, as determined by HPLC. 12. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.16% to about 0.05% of the mixture, as determined by HPLC. 13. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.07% to about 0.05% of the mixture, as determined by HPLC. 14. The mixture of claim 1, further comprising 1444142,6-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. 15. The mixture of claim 14, 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 HPLC. 16. The mixture of claim 14, 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. 17. The mixture of claim 14, further comprising N-{441-(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}-dimethoxydicarbonimidic diamide. 18. The mixture of claim 1, further comprising N-{441-(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}-N,N′-dimethoxydicarbonimidic diamide. 19. The mixture of claim 18, wherein the N-{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}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of about 0.08% or less of the mixture, as determined by HPLC. 20. The mixture of claim 18, wherein the N-{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}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of from about 0.08% to about 0.02% of the mixture. 21. The mixture of claim 1, further comprising 1-(2,6-Difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. 22. The mixture of claim 1, further comprising ethyl (2,6-difluorobenzyl)- [4-dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-nitrophenyl)thiophen-2-yl]carbamate. 23. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.05% of the mixture, as determined by HPLC. 24. The mixture of claim 1, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.07% of the mixture, as determined by HPLC. 25. The mixture of claim 1 comprising 1-{441-(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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. 26. The mixture of claim 1, wherein the mixture is in solid form. 27. The mixture of claim 1, wherein the mixture comprises crystals. 28. The mixture of claim 1 comprising 1-{441-(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 in the form of crystals. 29. The mixture of claim 25, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.05% or less of the mixture, as determined by HPLC. 30. The mixture of claim 25, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 4.45% to about 0.05% of the mixture, as determined by HPLC. 31. The mixture of claim 25, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 4.45% to about 0.25% of the mixture, as determined by HPLC. 32. The mixture of claim 25, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.16% of the mixture, as determined by HPLC. 33. The mixture of claim 25, wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.20% to about 0.05% of the mixture, as determined by HPLC. 34. The mixture of claim 2, wherein the percentage composition of 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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 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 composition of the mixture using an ultraviolet absorptiometer. 35. The mixture of claim 34, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume. 36. The mixture of claim 35, wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume. 37. The mixture of claim 34, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 38. The mixture of claim 36, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 39. The mixture of claim 34, wherein the reverse phase chromatography column is a C18 column. 40. The mixture of claim 38, wherein the reverse phase chromatography column is a C18 column. 41. The mixture of claim 40, wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm. 42. The mixture of claim 41, wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm. 43. The mixture of claim 8 wherein the percentage composition of 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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 composition of the mixture using an ultraviolet absorptiometer. 44. The mixture of claim 43, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume. 45. The mixture of claim 44, wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume. 46. The mixture of claim 43, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 47. The mixture of claim 45, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 48. The mixture of claim 43, wherein the reverse phase chromatography column is a C18 column. 49. The mixture of claim 47, wherein the reverse phase chromatography column is a C18 column. 50. The mixture of claim 49, wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm. 51. The mixture of claim 50, wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm. 52. The mixture of claim 23, wherein the percentage composition of 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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 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 composition of the mixture using an ultraviolet absorptiometer. 53. The mixture of claim 52, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume. 54. The mixture of claim 53, wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume. 55. The mixture of claim 52, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 56. The mixture of claim 54, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 57. The mixture of claim 52, wherein the reverse phase chromatography column is a C18 column. 58. The mixture of claim 56, wherein the reverse phase chromatography column is a C18 column. 59. The mixture of claim 58, wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm. 60. The mixture of claim 59, wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm. 61. The mixture of claim 30, wherein the percentage composition of 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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 composition of the mixture using an ultraviolet absorptiometer. 62. The mixture of claim 61, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume. 63. The mixture of claim 62, wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume. 64. The mixture of claim 61, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 65. The mixture of claim 63, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 66. The mixture of claim 61, wherein the reverse phase chromatography column is a C18 column. 67. The mixture of claim 65, wherein the reverse phase chromatography column is a C18 column. 68. The mixture of claim 67, wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm. 69. The mixture of claim 68, wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm. 70. The mixture of claim 32, wherein the percentage composition of 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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 composition of the mixture using an ultraviolet absorptiometer. 71. The mixture of claim 70, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume. 72. The mixture of claim 71, wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume. 73. The mixture of claim 70, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 74. The mixture of claim 72, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 75. The mixture of claim 70, wherein the reverse phase chromatography column is a C18 column. 76. The mixture of claim 74, wherein the reverse phase chromatography column is a C18 column. 77. The mixture of claim 76, wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm. 78. The mixture of claim 77, wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm. 79. The mixture of claim 33, wherein the percentage composition of 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 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 composition of the mixture using an ultraviolet absorptiometer. 80. The mixture of claim 79, wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume. 81. The mixture of claim 80, wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume. 82. The mixture of claim 79, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 83. The mixture of claim 81, wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm. 84. The mixture of claim 79, wherein the reverse phase chromatography column is a C18 column. 85. The mixture of claim 83, wherein the reverse phase chromatography column is a C18 column. 86. The mixture of claim 85, wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm. 87. The mixture of claim 86, wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.