Methods and intermediates for preparing therapeutic compounds

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

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

combining a 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),

a palladium catalyst selected from the group consisting of palladium(II) chloride, palladium acetate, palladium trifluoroacetate, dichloro(1,5-cyclooctadiene)palladium(II), allylpalladium(II) chloride dimer, palladium(II) acetylacetonate, (tetrakis(triphenylphosphine)palladium(0) and bis(dibenzylideneacetone)palladium(0),

a base selected from the group consisting of potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N-methylmorpholine, and triethylamine, and

a solvent selected from the group consisting of n-butyl acetate, water, di-n-butyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and combinations thereof, to provide the compound of formula III or a co-crystal, solvate, salt, or combination thereof.

2. The process of claim 1 , wherein R 1 is B(OC(Me) 2 C(Me) 2 O).

3. The process of claim 1 , wherein the palladium catalyst is palladium(II) chloride and the process further comprises a phosphine ligand which is cyclohexyldiphenylphosphine.

4. The process of claim 1 , wherein the base is potassium bicarbonate.

5. The process of claim 1 , wherein the solvent is a mixture of 2-methyltetrahydrofuran and water.

6. The process of claim 1 , further comprising combining a 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,

a base selected from the group consisting of triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, 2,6-lutidine, and N-methylimidazole,

a solvent selected from the group consisting of acetonitrile, ethyl acetate, n-butyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylenes, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, propionitrile, butyronitrile, and combinations thereof, and

optionally a coupling reagent selected from the group consisting of n-propylphosphonic anhydride, 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-1-methylpyridinium iodide, boric acid, tetramethyl orthosilicate, trimethoxysilane, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyl diimidazole, isobutyl chloroformate, diphenylphosphinic chloride, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N′,N′-tetramethyluronium-hexafluoro-phosphate, O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphonium chloride, and (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate,

in the temperature range of from about 0° C. to about 40° C.,

to provide a compound of formula IV:

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

7. The process of claim 6 , wherein the coupling reagent is n-propylphosphonic cyclic anhydride.

8. The process of claim 6 , wherein the base is triethylamine.

9. The process of claim 6 , wherein the solvent is acetonitrile.

10. The process of claim 6 , further comprising combining a compound of formula VIII-02:

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

a compound of formula IX:

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

a base selected from the group consisting of triethylamine, diisopropylamine, ethyldiisopropylamine, pyrrolidine, 1,4-diazabicylo[2.2.2]-octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo-4.3.0]non-5-ene, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, piperidine, potassium phosphate, and tetrabutylammonium fluoride,

a solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylenes, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, water, and combinations thereof, and

a palladium catalyst selected from the group consisting of [(π-allyl)PdCl] 2 , Pd(acac) 2 , (SIPr)PdCl 2 , PdCl 2 (PPh 3 ) 2 , PdCl 2 , Pd(OAc) 2 , PdCl 2 (CH 3 CN) 2 , and Pd 2 (dba) 3 , optionally, in combination with a tertiary phosphine, selected from the group consisting of triphenylphosphine, tri-cyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, and 1,1′-bis(diphenylphosphino)ferrocene,

wherein the process is carried out in the temperature range of from about 50° C. to about 80° C., to provide a compound of formula VI:

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

11. The process of claim 10 , wherein HX is N-Boc-D-leucine or (−)-N-acetyl-D-leucine.

12. The process of claim 10 , wherein the palladium catalyst is PdCl 2 (PPh 3 ) 2 .

13. The process of claim 10 , wherein the base is triethylamine.

14. The process of claim 10 , wherein the solvent is acetonitrile.

15. The process of claim 1 , further comprising:

(a) combining the compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a second solvent and an acid to provide a compound of formula III-02:

or a co-crystal, solvate, or combination thereof, wherein HY 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, propionic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and

(b) free-basing the compound of formula III-02 or a co-crystal, solvate, or combination thereof, by combining it with a second base and a third solvent in the temperature range of from about 0° C. to about 50° C. to provide the compound of formula III or a co-crystal, or solvate, or combination thereof.

16. The process of claim 15 , wherein HY is methanesulfonic acid.

17. The process of claim 15 , wherein the second solvent is selected from the group consisting of 1-propanol, isopropanol, ethanol, methanol, tert-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl ether, methyl tert-butyl ether, toluene, and cyclopentyl methyl ether, and combinations thereof.

18. The process of claim 15 , wherein the compound of formula III-02 is produced as an ethanol solvate.

19. The process of claim 15 , wherein the second base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, ammonium hydroxide, and diethylamine.

20. The process of claim 19 , wherein the second base is sodium hydroxide.

21. The process of claim 15 , wherein the third solvent is selected from the group consisting of water, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, toluene, xylenes, ethyl acetate, isopropyl acetate, and combinations thereof.

22. The process of claim 21 , wherein the third solvent is 2-methyltetrahydrofuran and water.