Methods and intermediates for preparing therapeutic compounds

1. A process for preparing a compound of formula I:

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof with a mesylating reagent selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride; a base selected from the group consisting of N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide; and a solvent selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof, to provide a compound of formula II:

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isoropoxide, sodium t-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine; in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, 1-propanol, n-butanol, s-butanol, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and combinations thereof; to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

2. The process of claim 1 , wherein the mesylating reagent is methanesulfonyl chloride.

3. The process of claim 1 , wherein the base is triethylamine.

4. The process of claim 1 , wherein the solvent for the mesylating step is 2-methyltetrahydrofuran.

5. The process of claim 1 , wherein the mesylating step is carried out in the temperature range of from about −10° C. to about 20° C.

6. The process of claim 1 , wherein the nucleophilic reagent is sodium hydroxide.

7. The process of claim 1 , wherein the solvent for the hydrolyzing step is water and 2-methyltetrahydrofuran.

8. The process of claim 1 , wherein the hydrolyzing step is carried out in the temperature range of from about 10° C. to about 60° C.

9. A process for preparing a compound of formula I:

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:

or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula VI or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof;

(c) combining the compound of formula IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V:

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 , B(OCH(Me)CH 2 C(Me) 2 O), B((1,2-di-O)C 6 H 4 ), B(OCH 2 C(Me) 2 CH 2 O), BF 3 K, B(O 2 CCH 2 N(Me)CH 2 CO 2 ), or B(OC(Me) 2 C(Me) 2 O), under palladium-catalyzed cross-coupling conditions to provide a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof; and

(d) combining the compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

10. The process of claim 9 , further comprising:

(e) forming the sodium salt of the compound of formula I to provide a compound of formula 1-02:

by combining the compound of formula I with a sodium source and a solvent.

11. The process of claim 10 , wherein the sodium source is selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium t-butoxide, sodium hexamethyldisilazide, and sodium metal and an alcohol selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, n-butanol, and sec-butanol.

12. The process of claim 11 , wherein the sodium source is sodium hydroxide.

13. The process of claim 10 , wherein the solvent for the salt forming step is selected from the group consisting of water, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, n-heptane, toluene, xylenes, ethyl acetate, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, acetone, methyl ethyl ketone, methyl isobutylketone, methanol, ethanol, isopropanol, 1-propanol, n-butanol, sec-butanol, and combinations thereof.

14. The process of claim 13 , wherein the solvent for the salt forming step is water and 2-methyltetrahydrofuran.

15. The process of claim 9 , wherein the compound of formula VIII is a compound of formula VIII-02:

or a co-crystal, solvate, or combination thereof, wherein HX is a chiral or achiral acid.

16. The process of claim 15 , wherein HX is a chiral acid.

17. The process of claim 15 , wherein HX is selected from the group consisting of L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(−)-malic acid, D-glucuronic acid, (1R, 3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+)-menthyloxyacetic acid, (−)-pyroglutamic acid, (−)-n-acetyl-L-leucine, (−)-N-acetyl-D-leucine, N-Boc-D-leucine, N-(+)-BOC-phenylalanine, (−)-quinic acid, (+)-n-acetyl-L-phenylalanine, (+)-N-BOC-isoleucine, L-(−)-acetyl glutamic acid, (−)-acetyl mandelic acid, (R)-(−)-citramalic acid, (−)-camphanic acid, and (R)-mandelic acid.

18. The process of claim 15 , wherein HX is N-Boc-D-leucine or (−)-N-acetyl-D-leucine-.

19. The process of claim 10 , further comprising

(f) neutralizing the compound of formula 1-02 with an acid and a solvent in the temperature range of from about 0° C. to about 50° C. to provide the compound of formula I.

20. The process of claim 19 , wherein the acid for the neutralizing step is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, and propionic acid.

21. The process of claim 19 , wherein the acid for the neutralizing step is acetic acid.