Maleate, tosylate, fumarate and oxalate salts of 5-(1-(S)-amino-2-hydroxyethyl)-N-[(2,4-difluorophenyl)-methy]-2-[8-methoxy-2-(triflouromethy)-5-quinoline]-4-oxazolecarboxamide and preparation process therefore

1. An isolated amount of a crystalline salt form of compound I selected from a crystalline maleate monohydrate salt form I, crystalline tosylate hydrate salt form I, a crystalline fumarate salt form having the X-ray powder diffraction pattern characteristic of FIG. 12 , and a crystalline oxalate salt form having the X-ray powder diffraction pattern characteristic of FIG. 24

2. The crystalline salt form of claim 1 wherein the salt form is crystalline maleate monohydrate salt form I.

3. A process for making a crystalline maleate monohydrate salt form of the compound of Formula I:

the process comprising:

(a) suspending an aliquot of the free base compound of Formula I in a mixed isopropanol/water solvent comprising at least 50 vol % i-propanol, wherein the ratio of suspended material to solvent is at least about 1:8 weight in g/vol in ml;

(b) heating the suspension prepared in step “a” to at least 50° C.;

(c) admixing over a 10 minute period with the heated suspension prepared in Step “b” a solution made by dissolving at least one equivalent of maleic acid in sufficient amount of a mixed solvent to dissolve it, the mixed solvent comprising 50% by volume i-propanol and 50% by volume water;

(d) filtering the admixture from Step “c” to provide a solution while maintaining the temperature of the solution at a temperature of at least about 50° C.;

(e) adding over a 10 minute period to the filtrate from Step “d” additionally about 1.25 volumes of water based on the volume of water used in Step “a” while maintaining the mixture at a temperature of at least about 50° C.;

(f) cooling the solution from Step “e” to about 40° C. over 30 minutes, thereby forming a precipitate slurry;

(g) stirring the slurry from Step “f” for a first period of time at a temperature of about 40° C., followed by cooling the slurry to 5° C. over a 2 hour period;

(h) optionally collecting the solids precipitated in Step “g” and washing them in a mixed isopropanol/water solvent containing at least 66% isopropanol by volume;

(i) optionally drying the solids obtained in step “h” in a vacuum oven for 5 hours at 55 ° C.

4. The crystalline maleate monohydrate salt form I of the maleate salt of 5-(1(S)-amino-2-hydroxyethyl)-N-[(2,4-difluorophenyl)-methyl]-2-[8-methoxy-2-(trifluoromethyl)-5-quinoline]-4-oxazolecarboxamide in isolated amount, characterized by the infrared spectrum of FIG. 10 , and further characterized by the X-ray powder diffraction pattern shown in Table I expressed in terms of diffraction angle (in 2θ, all values reflect an accuracy of ±0.2) lattice “d” spacing (in angstroms) and relative peak intensities(“RI”):

TABLE I

Diffraction angle

Lattice Spacing

(2θ, ±0.2

RI

(Å ± 0.04)

6.5

Strong

13.59

7.5

Very Strong

11.78

21.2

Very Strong

4.19

27.2

Very Strong

3.28.

5. A process for making crystalline tosylate hydrate salt form I of the compound of Formula I

the process comprising:

(a) preparing a crystalline tosylate anhydride salt by:

(1) suspending an aliquot of the free base compound of Formula I in at least 10 ml of acetonitrile/ g of the compound of Formula I suspended;

(2) heating the suspension prepared in Step “a” to a temperature of at least about 60° C.;

(3) mixing at least one equivalent of toluenesulfonic acid into the suspension;

(4) heating the mixture prepared in Step “c” to at least about 70° C. yielding a solution;

(5) mixing t-butylmethyl ether into the hot solution prepared in Step “d” over a period of at least about 20 minutes in an amount that provides a ratio of 13:8 acetonitrile:t-butylmethylether in the mixture; and

(6) cooling the mixture to ambient temperature over a period of at least about 2 hours precipitating the crystalline anhydrous tolysulfonate salt of the compound of Formula I;

(b) collecting an aliquot of the precipitate salt prepared in Step “a(6)” and combining it with an amount of water to give a ratio of 6 ml of water/g of salt for a period of time necessary to produce a first solid scum;

(c) slurrying first solid scum produced in Step “b” with an amount of water equal to 1.66× the amount of water used in Step “b”;

(d) agitating the slurry prepared in Step “c” for a period of time necessary to produce a wet cake;

(e) adding an additional 3× the amount of water added in Step “c” to form a second slurry with the wet cake produced in Step “d” and agitating the slurry for 5 days;

(f) drying the solids from the slurry produced in Step “e” under vacuum at ambient temperature, thereby producing the tosylate hydrate Form I salt form of the compound of Formula I.

6. The crystalline tosylate hydrate salt Form I of 5-(1(S) -amino-2-hydroxyethyl)-N-[(2,4-difluorophenyl)-methyl]-2-[8-methoxy-2-(trifluoromethyl)-5-quinoline]-4-oxazolecarboxamide compound of Formula IV isolated from the process of claim 5 ,

said crystalline tosylate hydrate salt form I being characterized by the Infrared Spectrum schematically illustrated in FIG. 11 and by the X-ray powder diffraction pattern shown in Table II expressed in terms of diffraction angle (in 2θ, all values reflect an accuracy of ±0.2) lattice “d” spacing (in angstroms) and relative peak intensities(“RI”):

TABLE II

Diffraction angle

Lattice Spacing

(2θ, ±0.2

RI

(Å ± 0.04)

5.2

Weak

16.98

12.5

Medium

7.08

20.0

Weak

4.44

26.3

Strong

3.39.

7. A process for making a crystalline fumarate salt form of 5-(1(S)-amino-2-hydroxyethyl)-N-[(2,4-difluorophenyl)-methyl]-2-[8-methoxy-2-(trifluoromethyl)-5-quinoline]-4-oxazolecarboxamide fumarate salt compound having the structure of Formula V),

the process comprising:

(a) suspending an aliquot of the free base compound having the structure of Formula I in 50 ml of acetonitrile;

(b) heating the suspension formed in Step “a” to about 60° C.;

(c) mixing with the heated suspension at least one equivalent of fumaric acid;

(d) heating the mixture prepared in Step “c” to a temperature at which the suspended materials are dissolved;

(e) cooling the solution prepared in Step “d” to ambient temperature over a period of about 2 hours to provide a precipitate; and

(f) collecting the precipitate and drying it in a vacuum oven at a temperature of about 50° C.;

said crystalline fumarate salt form thus produced having an X-ray powder diffraction pattern yielding the following values, expressed in terms of diffraction angle (in 2θ, all values reflect an accuracy of ±0.2) lattice “d” spacing (in angstroms) and relative peak intensities(“RI”):

Diffraction angle

Lattice Spacing

(2θ, ±0.2

RI

(Å ± 0.04)

8.0

Strong

11.04

19.9

Medium

4.46

22.5

Medium

3.95

25.6

Medium

3.48.

8. The process of claim 7 wherein in said heating Step “d” the mixture is heated to temperature of at least about 80° C. and in cooling Step “e” ambient temperature is about 25° C.

9. Crystalline fumarate salt isolated from the process of claim 7 .

10. The crystalline maleate monohydrate salt form I of claim 4 wherein the salt form is made from the maleate salt compound of Formula II produced by the process of claim 3