NUCLEOSIDE PHOSPHORAMIDATES
Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.
1 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.
2 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate having:
(1) XRPD 2θ-reflections (°) at about: 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2;
(2) XRPD 2θ-reflections (°) at about: 5.0, 7.3, 9.4, and 18.1;
(3) XRPD 2θ-reflections (°) at about: 4.9, 6.9, 9.8, 19.8, 20.6, 24.7, and 26.1;
(4) XRPD 2θ-reflections (°) at about: 6.9, 9.8, 19.7, 20.6, and 24.6;
(5) XRPD 2θ-reflections (°) at about: 5.0, 6.8, 19.9, 20.6, 20.9, and 24.9;
(6) XRPD 2θ-reflections (°) at about: 5.2, 6.6, 7.1, 15.7, 19.1, and 25.0; or
(7) XRPD 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3.
3 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 2 having:
(1) XRPD 2θ-reflections (°) at about: 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2;
(2) XRPD 2θ-reflections (°) at about: 5.0, 7.3, 9.4, and 18.1; or
(7) XRPD 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3.
4 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 2 having:
(1) XRPD 2θ-reflections (°) at about: 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2;
(2) XRPD 2θ-reflections (°) at about: 5.0, 7.3, 9.4, and 18.1; or
(7) XRPD 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3.
5 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 2 having XRPD 2θ-reflections (°) at about: 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2.
6 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 2 having XRPD 2θ-reflections (°) at about: 5.0, 7.3, 9.4, and 18.1.
7 . Crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 2 having XRPD 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3.
8 . A composition comprising crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 1 .
9 . A pharmaceutical composition comprising crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 1 and a pharmaceutically acceptable medium.
10 . A method of treating a hepatitis C virus infection in a subject in need thereof, which comprises:
administering to the subject an effective amount of crystalline (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate of claim 1 .
11 . A compound represented by the structural formula
where LG′ is a leaving group.
12 . The compound of claim 11 , wherein LG′ is tosylate, camphorsulfonate, a benzo[d]thiazolide-2(3H)-thione, an aryloxide, or an aryloxide substituted with at least one electron withdrawing group.
13 . The compound of claim 11 , wherein LG′ is 2,4-dinitrophenoxide, 4-nitrophenoxide, 2-nitrophenoxide, 2-chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, or pentafluorophenoxide.
14 . (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino) propanoate.
15 . Crystalline (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy) phosphoryl)amino)propanoate.
16 . A process for preparing the compound of claim 11 , which comprises:
crystallizing the compound from a composition, comprising
a) a first composition;
b) a second leaving group precursor;
c) a non-nucleophilic base; and
d) a liquid composition;
wherein the first composition comprises the compound and its corresponding P-based diastereomer.
17 . The process of claim 16 , wherein the mole amount of the compound and the mole amount of its P-based diastereomer are the same or different.
18 . The process claim 17 , wherein the mole amount of the compound is greater than the mole amount of its corresponding P-based diastereomer.
19 . The process of claim 16 , wherein the second leaving group precursor is 2,4-dinitrophenol, 4-nitrophenol, 2-nitrophenol, 2-chloro-4-nitrophenol, 2,4-dichlorophenol, or pentafluorophenol.
20 . The process of claim 19 , wherein LG′ is pentafluorophenoxide.
21 . The process of claim 20 , wherein the second leaving group precursor is pentafluorophenol.
22 . The process of claim 21 , wherein the amount of pentafluorophenol ranges from about 0.01 mole equivalents to about 10 mole equivalents relative to the mole amount of the compound and its P-based diastereomer.
23 . The process of claim 21 , wherein the amount of pentafluorophenol ranges from about 0.1 mole equivalents to about 1 mole equivalents relative to the mole amount of the compound and its P-based diastereomer.
24 . The process of claim 16 , wherein the crystallizing occurs at a temperature that ranges from about −10° C. to about +40° C.
25 . The process of claim 16 , wherein the crystallizing occurs at about room temperature.
26 . The process of claim 16 , wherein the non-nucleophilic base is selected from among potassium carbonate, cesium carbonate, di-isopropylamine, di-isopropylethylamine, triethylamine, quinuclidine, naphthalene-1,8-diamine, 2,2,6,6-tetramethylpiperidine, 1,8-diazabicycloundec-7-ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-C 1-6 -alkyl-pyridine, a 2,4,6-tri-C 1-6 -alkyl-pyridine, and mixtures thereof.
27 . The process of claim 16 , wherein the non-nucleophilic base is triethylamine.
28 . The process of claim 16 , wherein the non-nucleophilic base is present in an amount that ranges from about 0.01 equivalents mol to about 10 mol equivalents relative to the total mole amount of the compound and its P-based diastereomer.
29 . The process of claim 16 , wherein the non-nucleophilic base is present in an amount that ranges from about 0.1 mol equivalents to about 1 mol equivalents relative to the total mole amount of the compound and its P-based diastereomer.
30 . The process of claim 16 , wherein the solubility of the compound is less than the solubility of its corresponding P-based diastereomer in the liquid composition.
31 . The process of claim 16 , wherein the liquid composition comprises at least one of a solvent and an anti-solvent.
32 . The process of claim 16 , wherein the liquid composition comprises at least one of a C 1 to C 8 alcohol, a C 2 to C 8 ether, a C 3 to C 7 ketone, a C 3 to C 7 ester, a C 1 to C 2 chlorocarbon, a C 2 to C 7 nitrile, a C 5 to C 12 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
33 . The process of claim 16 , wherein the liquid composition comprises at least one of a C 2 to C 8 ether, a C 3 to C 7 ester, a C 5 to C 12 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
34 . The process of claim 16 , wherein the liquid composition comprises at least one of a C 2 to C 8 ether, a C 3 to C 7 ester, and a C 5 to C 12 saturated hydrocarbon.
35 . The process of claim 34 , wherein the liquid composition comprises at least one of ethyl acetate, t-butyl-methylether, and hexane.
36 . The process of claim 34 , wherein the liquid composition comprises ethyl acetate and hexane.
37 . The process of claim 34 , wherein the liquid composition comprises t-butyl-methylether and hexane.
38 . The process of claim 16 , wherein the amount of liquid composition ranges from about 1 mL to about 10 mL for every gram of the first composition.
39 . The process of claim 16 , which further comprises adding crystalline compound to the composition.
40 . The process of claim 16 , which further comprises adding about 0.1 to about 1 wt. % of crystalline compound to the first composition.
41 . The process of claim 16 , which further comprises
a) reacting PhOP(O)(LG) 2 and i Pr-Ala-NH 2 HCl in the presence of a first base to obtain (PhO)P(O)(LG)(NHAla- i Pr);
b) reacting (PhO)P(O)(LG)(NHAla- i Pr) with a first leaving group precursor (LG′H) in the presence of a second base to obtain the composition comprising the compound and its P-based diastereomer;
wherein LG and LG′, independent of each other, are leaving groups;
wherein the first leaving group precursor and the second leaving group precursor are the same or different; and
wherein the first base and the second base are the same or different.
42 . A process for preparing crystalline (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate, which comprises:
crystallizing (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl) amino)propanoate from a second composition comprising
a) a first composition;
b) pentafluorophenol;
c) a non-nucleophilic base; and
d) a liquid composition;
wherein the second composition comprises (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate and (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy)phosphoryl)amino) propanoate.
43 . The process of claim 42 , wherein the mole amount of the (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate and the mole amount of (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy)phosphoryl)amino) propanoate are the same or different.
44 . The process of claim 42 , wherein the mole amount of the (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate is greater than the mole amount of (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy)phosphoryl) amino)propanoate.
45 . The process of claim 43 , wherein the amount of pentafluorophenol ranges from about 0.01 mole equivalents to about 10 mole equivalents relative to the mole amount of (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl) amino)propanoate and (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy) phosphoryl)amino)propanoate.
46 . The process of claim 42 , wherein the crystallizing occurs at a temperature that ranges from about −10° C. to about +40° C.
47 . The process of claim 42 , wherein the crystallizing occurs at about room temperature.
48 . The process of claim 42 , wherein the non-nucleophilic base is selected from among potassium carbonate, cesium carbonate, di-isopropylamine, di-isopropylethylamine, triethylamine, quinuclidine, naphthalene-1,8-diamine, 2,2,6,6-tetramethylpiperidine, 1,8-diazabicycloundec-7-ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-C 1-6 -alkyl-pyridine, a 2,4,6-tri-C 1-6 -alkyl-pyridine, and mixtures thereof.
49 . The process of claim 42 , wherein the non-nucleophilic base is triethylamine.
50 . The process of claim 42 , wherein the non-nucleophilic base is present in an amount that ranges from about 0.1 to about 1 mol equivalents relative to the total mole amount of (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl) amino)propanoate and (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy) phosphoryl)amino)propanoate.
51 . The process of claim 42 , wherein the solubility of (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate is less than the solubility of (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy)phosphoryl)amino) propanoate in the liquid composition.
52 . The process of claim 42 , wherein the liquid composition comprises at least one of a solvent and an anti-solvent.
53 . The process of claim 42 , wherein the liquid composition comprises at least one of a C 1 to C 8 alcohol, a C 2 to C 8 ether, a C 3 to C 7 ketone, a C 3 to C 7 ester, a C 1 to C 2 chlorocarbon, a C 2 to C 7 nitrile, a C 5 to C 12 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
54 . The process of claim 42 , wherein the liquid composition comprises at least one of a C 2 to C 8 ether, a C 3 to C 7 ester, a C 5 to C 12 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
55 . The process of claim 42 , wherein the liquid composition comprises at least one of a C 2 to C 8 ether, a C 3 to C 7 ester, and a C 5 to C 12 saturated hydrocarbon.
56 . The process of claim 55 , wherein the liquid composition comprises at least one of ethyl acetate, t-butyl-methylether, and hexane.
57 . The process of claim 55 , wherein the liquid composition comprises ethyl acetate and hexane.
58 . The process of claim 55 , wherein the liquid composition comprises t-butyl-methylether and hexane.
59 . The process of claim 42 , wherein the amount of liquid composition ranges from about 1 to about 10 mL for every gram of the first composition.
60 . The process of claim 42 , which further comprises adding crystalline (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate to the second composition.
61 . The process of claim 42 , which further comprises adding about 0.1 to about 1 wt. % of crystalline (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy) phosphoryl)amino)propanoate based on the total weight of (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate in the first composition.
62 . Crystalline (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy) phosphoryl)amino)propanoate obtained by the process of claim 42 .
63 . A process for preparing (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, which comprises:
crystallizing (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl) amino)propanoate from a second composition comprising
a) a first composition;
b) pentafluorophenol;
c) a non-nucleophilic base; and
d) a liquid composition;
wherein the first composition comprises (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate and (S)-isopropyl 2-(((R)-(perfluorophenoxy)(phenoxy)phosphoryl)amino) propanoate.
64 . A process for preparing (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, which comprises:
contacting (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl) amino)propanoate with a product obtained by reacting a t-butylmagnesium halide with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione with a t-butylmagnesium halide.
65 . The process of claim 64 , wherein the contacting occurs in a medium having a temperature that ranges from about 0° C. to about 40° C.
66 . The process of claim 64 , wherein the contacting occurs in a medium having a temperature that ranges from about 0° C. to about 30° C.
67 . The process of claim 64 , wherein the mole ratio of t-butylmagnesium halide to 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione ranges from about 2 to about 2.2.
68 . The process of claim 64 , wherein the mole ratio of t-butylmagnesium halide to 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione is about 2.1.
69 . The process of claim 64 , wherein the t-butylmagnesium halide is t-butylmagnesium chloride.
70 . A process for preparing substantially pure (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, which comprises:
obtaining (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate according to the process of claim 35 and
crystallizing the so-formed (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.