Sonstiges: |
- Nachgewiesen in: USPTO Patent Grants
- Sprachen: English
- Patent Number: 11858,901
- Publication Date: January 02, 2024
- Appl. No: 17/755412
- Application Filed: March 10, 2020
- Assignees: MOEHS IBERICA, S.L. (Barcelona, ES)
- Claim: 1. A compound of formula (I) or a salt thereof [chemical expression included]
- Claim: 2. The compound according to claim 1 , which is 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) [chemical expression included]
- Claim: 3. 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) according to claim 2 in a solid form.
- Claim: 4. 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) according to claim 3 , characterized in that it has an X-ray powder diffractogram measured with CuKα radiation comprising peaks at 8.5, 9.9, 14.7, 16.9, 19.5, 21.0, and 22.9° 2θ±0.2° θ.
- Claim: 5. 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) according to claim 3 , characterized in that it has an X-ray powder diffractogram measured with radiation Cu Kα essentially as that of FIG. 2 .
- Claim: 6. 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) according to claim 3 , any of claim 3 , characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having an onset temperature of about 240.7° C.±2° C. and an exothermic peak having an onset temperature of about 248.6° C.±2° C.
- Claim: 7. 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) according to claim 3 , characterized in that it has a differential scanning calorimetry (DSC) diagram essentially as that of FIG. 1 .
- Claim: 8. A process for preparing a compound of formula (I) or a salt thereof according to claim 1 , wherein the process comprises: a) reacting 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (II) with iodine monochloride in the presence of an organic solvent to give 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) [chemical expression included] b) optionally treating the 3-((R)-2-(amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (Ia) with a base to give the compound of formula (I) [chemical expression included] and c) optionally treating the compound of formula (I) with an acid to give a salt of the compound of formula (I).
- Claim: 9. The process according to claim 8 , wherein the organic solvent of said a) is selected from the group consisting of a C 1 -C 4 alkanol, dichloromethane or a mixture thereof.
- Claim: 10. The process according to claim 9 , wherein the C 1 -C 4 alkanol is methanol.
- Claim: 11. The process according to claim 8 , wherein in said a) 4 to 8 mL of organic solvent are used with respect to each gram of 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (II).
- Claim: 12. The process according to claim 8 , wherein said a) is performed at a temperature of 45° C. to 60° C.
- Claim: 13. The process according to claim 8 , wherein in said a) 2 to 4 mol of iodine monochloride are used with respect to each mol of 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (II).
- Claim: 14. The process according to claim 8 , wherein said a) comprises the addition of a solution of 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (II) in the organic solvent to a solution of iodine monochloride in the organic solvent.
- Claim: 15. The process according to claim 8 , wherein said b) and c) are not performed.
- Claim: 16. The process according to claim 8 , wherein said b) is performed or wherein said b) and c) are performed.
- Claim: 17. The process according to claim 8 , wherein 3-((R)-2-(tert-butoxycarbonyl)amino-2-phenylethyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (II) is obtained by reaction of 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (III) with a compound of formula (IV), wherein LG is a leaving group, in an organic solvent and in the presence of a base [chemical expression included]
- Claim: 18. The process according to claim 17 , wherein LG in the compound of formula (IV) is a mesylate group.
- Claim: 19. The process according to claim 17 , wherein a phase-transfer catalyst is also used.
- Claim: 20. The process according to claim 19 , wherein the phase-transfer catalyst is tetrabutylammonium iodide.
- Claim: 21. The process according to claim 17 , wherein the base is K 2 CO 3 .
- Claim: 22. The process according to claim 17 , wherein the organic solvent is acetone.
- Claim: 23. A process for preparing elagolix sodium (V) comprising: a) reacting the compound of formula (I) or a salt thereof according to claim 1 with 2-fluoro-3-methoxyphenylboronic acid (VI) in the presence of a palladium catalyst, a phosphine-type ligand, and a base to give 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (VII) [chemical expression included] optionally performing b1) to b3): b1) treating the 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (VII) with HCl to give 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (VIIa) [chemical expression included] b2) isolating the 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (VIIa); and b3) treating the 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione hydrochloride (VIIa) with a base to give 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (VII); c) reacting the 3-((R)-2-(amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione (VII) obtained in said a) or in said b3) with a C 1-4 alkyl 4-halobutyrate to obtain a compound of formula (VIII) [chemical expression included] wherein R represents a C 1-4 alkyl group; and d) hydrolyzing the ester group of the compound of formula (VIII) by treatment with NaOH to obtain elagolix sodium (V) [chemical expression included]
- Claim: 24. The process according to claim 23 , wherein the palladium catalyst used in said a) is palladium(II) acetate, the phosphine-type ligand used in said a) is tri-tert-butyltetraphosphonium tetrafluoroborate, and/or the base used in said a) is potassium phosphate or a hydrate thereof.
- Claim: 25. The process according to claim 23 , wherein the of C 1-4 alkyl 4-halobutyrate used in said c) is ethyl 4-bromobutyrate, so that the product obtained in said c) is 4-((R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino)-butyric acid ethyl ester (VIIIa) [chemical expression included]
- Claim: 26. The process according to claim 23 , wherein said b1) to b3) are not performed.
- Claim: 27. The process according to claim 23 , wherein the compound of formula (I) or a salt thereof used in said a) is prepared by the process according to claim 8 .
- Patent References Cited: 112125855 December 2020 ; WO 2005/007164 January 2005 ; WO 2005/007165 January 2005 ; WO 2009/062087 May 2009 ; WO 2019/115019 June 2019
- Other References: International Search Report issued in International Application No. PCT/EP2020/056368, dated Sep. 6, 2020. cited by applicant ; Klyubin et al., “Dependence of the Electronic Absorption Spectra of Aqueous Solutions of Iodine Monochloride on the Conditions of Dilution and Storage Time”, Russian Journal of Physical Chemistry A., 91(4): 645-649 (2017). cited by applicant ; Zope et al., “The Kinetics Studies on the Rapid Iodination of Anthranilic Acid by Iodine Monochloride in Aqueous Solution”, Research Journal Of Chemistry And Environment, 11(2):43-48 (2007). cited by applicant
- Primary Examiner: Rao, Deepak R
- Attorney, Agent or Firm: Knobbe, Martens, Olson & Bear, LLP
|