Processes to produce elagolix

Abstract

The present invention relates to a scalable process for the making of elagolix, its salts and the process of intermediate compounds.

Claims

1. A process of making the compound elagolix or elagolix sodium comprising: converting a compound of formula VIII to a compound of formula IX in an organic solvent ##STR00037## and converting the compound of formula IX to the elagolix or elagolix sodium.

2. The process of claim 1 wherein the organic solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, acetonitrile, n-butanol, tert-butanol, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, and mixtures thereof.

3. The process of claim 1, wherein the organic solvent is dimethylformamide or N-methylpyrrolidone.

4. The process of claim 1 wherein the step of converting the compound of formula IX to the elagolix or elagolix sodium comprises: reacting the compound of formula IX with N-iodosuccinimide in the presence of acetic acid to obtain a compound of formula XIV, and reacting the compound of formula XIV with a compound of formula XV in the presence of methanesulfonato[tri (tert-butyl) phosphine (2′-amino-1,1′-biphenyl-2-yl)] palladium (II) as a catalyst to obtain the compound of formula X: ##STR00038##

5. The process of claim 4 wherein the step of converting the compound of formula IX to the elagolix or elagolix sodium further comprises: reacting the compound of formula X with a compound of formula XI in a solvent to make a compound of formula XII: ##STR00039##

6. The process of claim 5, wherein the solvent is selected from the group consisting of dichloromethane, toluene, 1, 4-dioxane, tetrahydrofuran, methyltetrahydrofuran, and mixtures thereof.

7. The process of claim 5, wherein the solvent is tetrahydrofuran.

8. The process of claim 5 wherein the step of converting the compound of formula IX to the elagolix or elagolix sodium further comprises: reacting the compound of formula XII with an acid to make a compound of formula XIII: ##STR00040##

9. The process of claim 8, wherein the acid is hydrochloric acid.

10. The process of claim 4 wherein the step of converting the compound of formula IX to the elagolix or elagolix sodium further comprises a one-pot process comprising: conducting a Mitsunobu reaction of the compound of formula X and a compound of formula XI to produce a compound of formula XII, and an acidic Boc group deprotection of the compound of formula XII to produce a compound of formula XIII: ##STR00041##

11. The process of claim 10 wherein the acidic deprotection is conducted in the presence of hydrochloric acid.

12. A compound of formula VIII having Z- or E-configuration or mixture of them: ##STR00042##

13. A process for the preparation of the compound of formula VIII of claim 12 comprising reacting a compound of formula VII with a compound of formula V or a salt thereof in a solvent: ##STR00043##

14. The process of claim 13, wherein the solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, isopropanol, n-butanol, tert-butanol, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane and mixtures thereof.

15. The process of claim 13, wherein the solvent is isopropanol.

16. The process of claim 13 comprising reacting a compound of formula IV with an acid to make the compound of formula V or a salt thereof: ##STR00044##

17. The process of claim 16 comprising hydrogenating a compound of formula III in presence of a transition-metal catalyst and di-tert-butyl dicarbonate under H.sub.2 atmosphere to produce the compound of formula IV: ##STR00045##

18. The process of claim 17, wherein the transition-metal catalyst is Pd/C or Raney nickel.

19. The process of claim 17 comprising: conducting formylation of a compound of formula I in the presence of one or more amines and an organolithium reagent to produce a compound of formula II, and reacting the compound of formula II with hydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine, a salt of hydroxylamine, a salt of O-methylhydroxylamine, or a salt of O-ethylhydroxylamine, to produce the compound of formula III: ##STR00046##

20. The process of claim 19 wherein the amines are selected from the group consisting of tetramethylethylenediamine, diisopropylamine, diethylamine, di-sec-butylamine, pentamethyldiethylenetriamine, and combinations thereof.

Description

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

Example

Example 1: Synthesis of Compound II

(1) ##STR00022##

(2) To a round-bottom flask were added compound I (20 g), tetramethylethylenediamine (15.6 g), diisopropylamine (0.6 g) and THF (200 mL). The mixture was cooled to −60˜78° C. n-BuLi solution in hexanes (53.5 mL, 2.5 M) was added at −60˜78° C. The reaction mixture was stirred at −60˜78° C. for 1 h. DMF (13.4 g) was added at −60˜78° C. After completion of the reaction, the reaction mixture was quenched with saturated NH.sub.4Cl solution (100 mL). The layers were separated. The organic phase was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with hexane to get compound II as yellow oil (1.1 g, 4.5% yield, 99.0% purity).

(3) .sup.1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H) 7.71 (m, 1H), 7.64 (d, J=7.6 Hz, H), 7.44 (t, J=9.2 Hz, 1H).

Example 2: Synthesis of Compound III

(4) ##STR00023##

(5) To a 100 L reactor were added THF (25 L), compound I (2.5 Kg), tetramethylethylenediamine (1.95 Kg) and diisopropylamine (77.5 g). The mixture was cooled to −60˜−78° C. n-BuLi solution in hexanes (4.55 Kg, 2.5 M) was added at −60˜−78° C. After the reaction mixture was stirred at −60˜−78° C. for 1 h, DMF (1.68 Kg) was added at −60˜−78° C. After completion of the reaction, the reaction mixture was warmed to −40˜−20° C. The reaction mixture was poured into 20% AcOH aqueous solution. The layers were separated. The organic layer was added hydroxylamine hydrochloride (1.27 Kg) and sodium bicarbonate (1.02 Kg). The reaction mixture was stirred at 15˜25° C. for 1 h. After the completion of the reaction, the reaction mixture was added HCl solution. The layers were separated. The product was crystallized with EtOH/H.sub.2O to give the product as off-white solid (2.27 Kg, 72% yield, 99.3% purity).

(6) .sup.1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.22 (dd, .sup.1J=4.0 Hz, .sup.2J=2.0 Hz, 1H), 7.68-7.63 (m, 3H).

(7) Mass: [M+H]+: 208.1;

Example 3: Synthesis of Compound IV

(8) ##STR00024##

(9) To a 20 L reactor were added MeOH (7.1 Kg), Raney Ni (100 g), di-tert-butyl dicarbonate (1.06 Kg) and compound III (500 g), the reactor was degassed three times and refilled with H.sub.2 (0.3 MPa). The mixture was stirred at 2040° C. under H.sub.2 (0.1-0.3) MPa. After completion of the reaction, the reaction mixture was filtered to remove Raney Ni. 1/25 of the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with heptane/EA to give the product as a white solid (19.01 g, 95.05% yield).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.47 (d, J=8.0 Hz, 1H), 7.43-7.38 (m, 1H), 7.32-7.29 (m, 1H), 4.56 (d, J=6.8 Hz, 1H), 1.45 (s, 9H).

(11) Mass: [M-.sup.tBu+H].sup.+: 238.1;

Example 4: Synthesis of Compound VI

(12) ##STR00025##

(13) To a 20 L reactor were added MeOH (7.1 Kg), Raney Ni (100 g), di-tert-butyl dicarbonate (1.06 kg) and compound III (500 g). The reactor was degassed three times and refilled with H.sub.2 (0.3 MPa). The mixture was stirred at 20˜40° C. under H.sub.2 (0.1˜0.3 MPa). After completion of the reaction, the reaction mixture was filtered to remove Raney Ni. The filtrate was concentrated to 1.5 L, and then added 30% HCl in EtOH (535 g). The mixture was stirred at 30˜40° C. for 3 h. After the completion of the reaction, the solvent was exchanged to IPAC. The resulting suspension was filtered to give the product as a white solid (482 g, 87% yield). HPLC showed the ratio of compound VI, impurity A and impurity B was 99.9:0.1:0.

(14) Mass: [M+H].sup.+: 194.1;

Example 5: Synthesis of Compound V

(15) ##STR00026##

(16) To a mixture of H.sub.2O (2 L), MTBE (1.5 L) and compound VI (475 gin a 5 L reactor was added 25% NaOH (331 g) dropwise. After the reaction complete, the layers were separated. The aqueous layer was extracted with MTBE (1.5 L). The combined organic phase was washed with H.sub.2O and concentrated to dryness. The product was obtained by vacuum distillation as colorless oil (367.9 g, 92.1% yield).

(17) Mass: [M+H].sup.+: 194.1;

Example 6: Synthesis of Compound V

(18) ##STR00027##

(19) To a 2 L reactor was added MeOH (1 L), Raney Ni (40 g) and compound III (200 g). The reactor was degassed three times and refilled with H.sub.2 (3.0˜4.0 MPa). The mixture was stirred at 60˜70° C. under H.sub.2 (2.0-3.5 MPa). After completion of the reaction, the reaction mixture was filtered to remove Raney Ni. HPLC showed the ratio of compound V, impurity A and impurity B was 90.2:0.9:8.9.

Example 7: Synthesis of Compound V

(20) ##STR00028##

(21) To a 250 mL reactor was added MeOH (100 mL), Pd/C (1 g), HCl (8 mL) and compound III (10 g). The reactor was degassed three times and refilled with H.sub.2. The mixture was stirred at 60˜70° C. under H.sub.2 (2.0˜3.0 MPa). After completion of the reaction, HPLC showed the ratio of compound V, impurity A and impurity B was 97.7:0.1:2.2.

Example 8: Synthesis of Compound VIII

(22) ##STR00029##

(23) To a 100 mL round bottom flask was added isopropanol (50 mL), compound V (5 g) and compound VII (5.33 g), the reaction mixture was heated to 80˜90° C. for 3 h. After completion of the reaction, H.sub.2O (100 mL) was added to the reaction mixture. The mixture was extract with DCM. The organic phase was concentrated. The crude product was purified by silica gel column chromatography to give the product as a yellow solid (9.2 g, 98% yield, 98.0% purity).

(24) 1H NMR (400 MHz, DMSO) δ 12.91 (s, 1H), 11.66 (s, 1H), 7.73 (dd, J=7.4, 4.5 Hz, 3H), 4.94 (d, J=5.0 Hz, 2H), 2.69 (s, 3H).

Example 9: Synthesis of Compound VIII

(25) ##STR00030##

(26) To a 5 L reactor was added IPA (3.2 L), NaOH (70 g), compound VI (400 g) and compound VII (358.7 g). The reaction mixture was heated to 80˜90° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to 15˜25° C. The resulting suspension was filtered to give the product as a light yellow solid (650 g, 104.5% yield, 98.9% purity).

Example 10: Synthesis of Compound IX

(27) ##STR00031##

(28) To a 100 mL round-bottom flask was added DMF (25 mL) and compound VIII (5 g). The reaction mixture was heated to 120˜130° C. for 8 h. After completion of the reaction, H.sub.2O (50 mL) was added to the reaction mixture. The resulting suspension was filtered to give the product as a light yellow solid (3.44 g, 82.5% yield, 98.0% purity).

(29) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.03 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.46-7.41 (m, 1H), 7.30-7.25 (m, 1H), 5.61 (s, 1H), 5.38 (s, 2H), 2.17 (s, 3H).

(30) Mass: [M+H].sup.+: 303.1;

Example 11: Synthesis of Compound IX

(31) ##STR00032##

(32) To a 50 mL round bottom flask was added DMF (5 mL), compound V (1 g) and compound VII (1.07 g). The reaction mixture was heated to 140° C. for 0.5 h. After completion of the reaction, H.sub.2O (15 mL) was added to the reaction mixture at 50˜60° C. The resulting suspension was filtered. The cake was washed with EtOH (1 mL) to give the product as a white solid (1.05 g, 67% yield, 98.6% purity).

Example 12: Synthesis of Compound X

(33) ##STR00033##

(34) To a 50 mL round bottom flask was added AcOH (20 mL), compound IX (2 g) and N-Iodosuccinimide (1.5 g). The reaction mixture was heated to 50° C. for 1 h. After completion of the reaction, H.sub.2O (10 mL) was added to the reaction mixture. The resulting suspension was filtered. The cake was washed with MeOH (4 mL). The solid was slurried with MeOH (20 mL) to give the product as a white solid (2.3 g, 82% yield, 96.1% purity).

(35) .sup.1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 77.67-7.61 (m, 1H), 7.59-7.50 (m, 2H), 5.39 (s, 1H), 2.56 (s, 3H).

(36) To a 1.0 L reactor was added compound XIV (30 g), compound XV (13.1 g), acetone (90 mL) and 14.4% KOH solution (113 g). The reaction mixture was degassed with N.sub.2 for 1 h. Methanesulfonato tri(tert-butyl)phosphine (2′-amino-1,1′-biphenyl-2-yl) palladium (II) (200 mg) was added. The reaction mixture was stirred at 50° C. After completion of the reaction, AcOH (8.4 g) was added. The resulting suspension was filtered. The cake was washed with H.sub.2O (60 mL) and MeOH (120 mL) to give the product as an off-white solid (21.6 g, 72.3% yield, 98% purity).

(37) .sup.1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 2H), 7.17-7.13 (m, 2H), 6.76-6.72 (m, 1H), 5.34 (s, 2H), 3.85 (s, 3H), 2.05 (s, 3H).

Example 13: Synthesis of Compound XII

(38) ##STR00034##

(39) To a 50 mL round bottom flask was added DMF (9 mL), compound X (1.5 g), potassium carbonate (1.22 g) and compound XXV (1.44 g). The reaction mixture was stirred at 55° C. for 16 h. After completion of the reaction, H.sub.2O was added to the reaction mixture. The mixture was extracted with IPAC. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with IPAC/heptane to give the product (1.65 g, 86% yield, 92% purity).

(40) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.58 (d, J=7.9 Hz, 1H), 7.43 (m, 3H), 7.34 (t, J=7.4 Hz, 2H), 7.31-7.23 (m, 2H), 7.16 (t, J=8.0 Hz, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.86 (t, J=6.9 Hz, 1H), 5.78 (t, J=8.4 Hz, 1H), 5.62 (m, 1H), 5.45 (m, 1H), 5.13 (m, 1H), 4.37 (m, 1H), 4.13 (m, 1H), 3.92 (s, 3H), 2.10 (s, 3H), 1.37-1.17 (m, 9H).

(41) Mass: [M+H-Boc].sup.+546.1

Example 14: Synthesis of Compound XII

(42) ##STR00035##

(43) To a mixture of THF (150 mL), compound X (10.0 g), compound XI (6.97 g), and PPh.sub.3 (9.23 g) in a 250 mL round-bottom flask, diisopropyl azodicarboxylate (7.12 g) was added dropwise at 20˜30° C. After completion of the reaction, HPLC showed the desired product XII formed.

Example 15: Synthesis of Compound XIII

(44) ##STR00036##

(45) To a mixture of THF (3.0 L), compound X (200.0 g), compound XI (139.1 g), and PPh.sub.3 (184 g) in a 5 L reactor was added diisopropyl azodicarboxylate (142 g) dropwise at 20˜30° C. After 1 h, conc. HCl (187.6 g) was added. The reaction mixture was heated and stirred at 50˜60° C. After completion of the reaction, the mixture was concentrated to 1 L. IPAC and potassium carbonate aqueous solution was added. The layers were separated. The organic layer was added H.sub.3PO.sub.4 solution. The layers were separated. The aqueous phase was washed with IPAC for 3 times. The pH of the aqueous phase was adjusted to 8˜9 with potassium carbonate aqueous solution. The mixture was extracted with IPAC. The organic phase was concentrated. The crude product was recrystallized with IPAC/heptane to give the product as a white solid (210 g, 82.1% yield, 99.8% purity)

(46) .sup.1H NMR (400 MHz, DMSO-d6) δ 7.67-7.65 (m, 1H), 7.59-7.53 (m, 2H), 7.29-7.25 (m, 4H), 7.20-7.14 (m, 3H), 6.76-6.61 (m, 1H), 5.35-5.33 (m, 2H), 4.12-4.10 (m, 1H), 3.96-3.89 (m, 2H), 3.86 (s, 3H), 2.10 (s, 3H).

(47) Mass: [M+H].sup.+546.2.