Methods of synthesis of heteroaryl derivatives of triazolyl acrylamides and crystalline forms

1 . A crystalline form of the compound represented by the following Structural Formula (VII):

wherein

the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°.

2 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 20.0°, 22.8°, 23.2°, and 24.4°.

3 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 19.0°, 20.0°, 22.8°, 23.2°, 23.7°, 24.4°, and 27.9°.

4 . The crystalline form of claim 1 , wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 20 .

5 . The crystalline form of claim 1 , wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 226° C.

6 . The crystalline form of claim 1 , wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG.

7 . A method of preparing a compound represented by structural formula (VII),

comprising:

reacting a compound represented by structural formula (II),

with a compound represented by structural formula (III),

in a first solvent, in the presence of a Pd catalyst and one or more inorganic bases under conditions suitable to prepare a compound represented by structural formula (VII), wherein:

each R is hydrogen, a C 1 -C 4 alkyl, or two groups R, taken together with the oxygen atoms to which they are attached, form a 5-7 member cyclic acetal moiety,

and thereby obtaining the compound represented by structural formula (VII), wherein the Pd catalyst is selected from chloro {[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2′-amino-1,1′-biphenyl-2-yl)palladium(II) or chloro(crotyl) [di-tert-butyl (4-dimethylaminophenyl)phosphine]palladium (II).

8 . The method of claim 7 , wherein the one or more inorganic base is selected from a quaternary ammonium, sodium, potassium, or cesium carbonate, bicarbonate, acetate, or hydroxide.

9 . The method of claim 7 , wherein the compound represented by structural formula (III) is a compound represented by structural formula (IIIB):

10 . The method of claim 7 , wherein the inorganic base is Cs 2 CO 3 or CsOH.

11 . The method of claim 7 , wherein the Pd catalyst is chloro {[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2′-amino-1,1′-biphenyl-2-yl)palladium(II).

12 . The method of claim 7 , wherein a Pd catalyst load is from 0.5% to mol % to 10 mol %.

13 . The method of claim 7 , wherein an amount of the inorganic base is from 0.5 to 2 molar equivalents of base with respect to the compound represented by structural formula (II).

14 . The method of claim 7 , wherein the conditions suitable to prepare the compound represented by structural formula (VII) comprise:

a Pd catalyst load from 0.5 mol % to 3 mol %;

an amount of the compound represented by structural formula (III) of from 1.0 to 2.2 molar equivalents with respect to the compound represented by structural formula (II);

an amount of the inorganic base of 0.8-1.2 total molar equivalents of base with respect to the compound represented by structural formula (II);

the first solvent comprises from 16 parts to 21 parts of dioxane and from 2 parts to 3 parts of water;

a reaction temperature from about 55° C. to about 60° C.; and

a reaction time of about 7-8 hours.

15 . The method of claim 7 , further comprising a step of preparing the compound represented by structural formula (II),

by dehydrobrominating a compound represented by structural formula (IV),

in a second solvent, in the presence of an organic base, under conditions suitable for producing the compound represented by structural formula (II).

16 . The method of claim 15 , further comprising a step of preparing the compound represented by structural formula (IV),

by reacting a compound represented by structural formula (V),

with bromine (Br 2 ) in a third solvent, in the presence of a bromide salt, under conditions suitable to prepare the compound represented by structural formula (IV).

17 . The method of claim 15 , wherein the second solvent comprises about 11 parts of ACN and about 4 parts of H 2 O with respect to the compound represented by structural formula (IV), the organic base is DIPEA, and wherein the conditions suitable for preparing the compound represented by structural formula (II) comprise:

an amount of DIPEA of about 1 molar equivalent with respect to the compound represented by structural formula (IV);

a reaction temperature of from 20° C. to 25° C.; and

a reaction time from 2 to 3 hours.

18 . The method of claim 16 , wherein the third solvent comprises acetic acid.

19 . The method of claim 16 , further comprising a step of preparing a compound represented by structural formula (V),

by amidating a compound represented by structural formula (VI),

in a fourth solvent, with an amidating agent, in the presence of a tertiary amine organic base and a chloroformate, under conditions suitable for producing the compound represented by structural formula (V).

20 . A compound represented by structural formula (V)

or a salt thereof.

21 . A method of preparing crystalline form of the compound represented by Structural Formula (VII), wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°

the method comprising:

(a) contacting crystalline form of the compound represented by Structural Formula (VII) characterized by x-ray diffraction peaks at 2θ angles 9.9°, 19.2°, 22.4°,and 24.4° with about 18 volumes of 4-methyl-2-pentanone (MIBK) to form a mixture;

(b) heating the mixture of step (a) to about 80-85° C. to form a heated mixture;

(c) optionally adding to the heated mixture of step (b) SiDMT;

(d) maintaining the heated mixture at a temperature of about 80-85° C. for about 4.5 hours;

(e) filtering the heated mixture to obtain a filtrate;

(f) adding MIBK at a temperature of about 80-85° C. to the filtrate;

(g) inducing nucleation of the crystalline form of the compound represented by Structural Formula (VII), wherein the crystalline form is characterized by x-ray power diffraction peaks at 2θ angles of 4.6°, 22.8°, 24.4° in the filtrate by cooling the filtrate to about 20-25° C.;

(h) crystallizing the crystalline form of the compound represented by Structural Formula (VII), wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4° by a controlled cooling crystallization of the filtrate with a final temperature of 0-5° C.; and

(i) isolating the crystalline form of the compound represented by Structural Formula (VII), wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4° from the filtrate.