Thienopyrimidine derivatives and production methods thereof
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.
1. A compound represented by the formula (I)
or a salt thereof, wherein R 1 is a C1-6 alkoxy group.
2. The compound of claim 1 or salt thereof, wherein R 1 is a methoxy group.
3. The compound of claim 1 or salt thereof, wherein R 1 is an ethoxy group.
4. The compound of claim 1 or salt thereof, wherein R 1 is a C3 alkoxy group.
5. The compound of claim 1 or salt thereof, wherein R 1 is a C4 alkoxy group.
6. The compound of claim 1 or salt thereof, wherein R 1 is a C5 alkoxy group.
7. The compound of claim 1 or salt thereof, wherein R 1 is a C6 alkoxy group.
8. A method of producing the compound of claim 3 , or a salt thereof, which comprises reacting ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate, or a salt thereof, with N-bromosuccinimide and a radical initiator, and reacting the obtained ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate, or salt thereof, with dimethylamine or a salt thereof.
9. The method of claim 8 , wherein the N-bromosuccinimide is used in an amount in the range of 1.0 to 1.5 molar equivalents per molar equivalent of the ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.
10. The method of claim 8 , wherein the reaction of ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with N-bromosuccinimide and the radical initiator is performed in the presence of trifluoromethylbenzene.
11. The method of claim 10 , wherein the trifluoromethylbenzene is used in an amount in the range of 0.1 mL to 1.0 mL per 1 mmol of the ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.
12. The method of claim 8 , wherein the radical initiator is 2,2′-azobis (2,4-dimethylvaleronitrile).
13. The method of claim 12 , wherein the 2,2′-azobis(2,4-dimethylvaleronitrile) is used in an amount in the range of 0.01 to 0.2 molar equivalents per molar equivalent of the ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.
14. The method of claim 8 , wherein the radical initiator is 2,2′-azobisisobutyronitrile.
15. The method of claim 8 , wherein the reaction of ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with N-bromosuccinimide and the radical initiator is performed in a solvent.
16. The method of claim 15 , wherein the solvent comprises ethyl acetate, carbon tetrachloride, dichloromethane, dichloroethane, chlorobenzene, or acetonitrile.
17. The method of claim 8 , wherein the dimethylamine is used in an amount in the range of 1.0 to 3.0 molar equivalents per molar equivalent of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.
18. The method of claim 8 , wherein the dimethylamine is used in an amount in the range of 1.2 to 1.8 molar equivalents per molar equivalent of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.
19. The method of claim 8 , wherein the reaction of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with dimethylamine or salt thereof is performed in the presence of a solvent.
20. The method of claim 19 , wherein the solvent comprises dimethylformamide, dimethylacetamide, or tetrahydrofuran.
21. The method of claim 8 , wherein the reaction of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with dimethylamine or salt thereof is performed in the presence of a base.
22. The method of claim 21 , wherein the base is triethylamine or diisopropylethylamine.