Processes for preparing toll-like receptor modulator compounds

Patent metadata

Field	Value
Publication number	US-11286257-B2
Application number	US-202016911643-A
Country	US
Kind code	B2
Filing date	Jun 25, 2020
Priority date	Jun 28, 2019
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

The present disclosure provides methods for preparing (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol or a salt thereof and related key intermediates.

First claim

What is claimed is:

1. A method for preparing a compound of Formula I:

or a salt thereof, comprising:
a) forming a first reaction mixture comprising a compound of Formula III:

a compound having the Formula PG-NHC(═NH)NH 2 or a salt thereof, a first base, and a first solvent to form a compound of Formula II:

or a salt thereof; and
b) forming a second reaction mixture comprising the compound of Formula II or the salt thereof, a deprotecting agent, and a second solvent to provide the compound of Formula I or the salt thereof,

wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy;
R 4 is hydrogen or methyl;
R 5 is C 3-6 alkyl;
X is F, Cl, Br, I, or OTs; and
PG is an amino protecting group.

2. The method of claim 1 , comprising
a) forming the first reaction mixture comprising the compound of Formula III:

a compound having the Formula PG-NHC(═NH)NH 2 or the salt thereof, a first transition-metal catalyst, the first base, and the first solvent to form the compound of Formula II:

or the salt thereof; and

b) forming the second reaction mixture comprising the compound of Formula II or the salt thereof, the deprotecting agent, and the second solvent to provide the compound of Formula I or the salt thereof,

wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy;
R 4 is hydrogen or methyl;
R 5 is C 3-6 alkyl;
X is Cl, Br, I, or OTs; and
PG is an amino protecting group.

3. The method of claim 1 , wherein the salt of the compound having the Formula PG-NHC(═NH)NH 2 is a hemisulfate, a sulfate, a chloride, a bromide, a carbonate, a nitrate, or an acetate salt.

4. The method of claim 1 , wherein PG is 2,4-dimethoxybenzyl.

5. The method of claim 2 , wherein the first transition-metal catalyst comprises a copper metal, a copper oxide, a copper (I) salt, a copper (II) salt, or combinations thereof.

6. The method of claim 2 , wherein the first transition-metal catalyst is Cu(I) iodide, Cu(I) bromide, Cu(I) chloride, Cu(I) acetate, Cu(I) carbonate, Cu(I) nitrate, Cu(I) sulfate, Cu(I) phosphate, Cu(I) 3-methylsalicylate, Cu(I) thiophene-2-carboxylate, Cu(I) oxide, Cu(II) iodide, Cu(II) bromide, Cu(II) chloride, Cu(II) acetate, Cu(II) carbonate, Cu(II) nitrate, Cu(II) sulfate, Cu(II) pyrophosphate, Cu(II) phosphate, Cu(II) tartrate, Cu(II) oxide, or combinations thereof.

7. The method of claim 2 , wherein the first transition-metal catalyst comprises Cu(II) acetate.

8. The method of claim 1 , wherein the first base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate tribasic, potassium phosphate tribasic, potassium acetate, potassium trimethylacetate, tetrabutylphosphonium malonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-en, or combinations thereof.

9. The method of claim 2 , wherein the first base comprises potassium phosphate tribasic.

10. The method of claim 1 , wherein the first reaction mixture further comprises a first ligand.

11. The method of claim 10 , wherein the first ligand is an amino acid, a polypyridyl ligand, or a tertiary amine.

12. The method of claim 10 , wherein the first ligand is arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, α-(methylamino)isobutyric acid, (4-methyl-1-piperazinyl)acetic acid, N-acetyl-cysteine, 2,2′-bipyridine, 1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine, 6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine, 2,2′-bipyridine-4,4′-dicarboxylic acid, N,N,N′,N′-tetramethylethylenediamine, or combinations thereof.

13. The method of claim 10 , wherein the first ligand comprises cysteine.

14. The method of claim 1 , wherein the deprotecting agent is an acid.

15. The method of claim 14 , wherein the acid is trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof.

16. The method of claim 14 , wherein the acid comprises trifluoroacetic acid.

17. The method of claim 1 , wherein the deprotecting agent is a hydrogen source and the second reaction mixture further comprises a second transition-metal catalyst.

18. The method of claim 17 , wherein the hydrogen source is ammonium formate, formic acid, hydrogen gas, or combinations thereof.

19. The method of claim 17 , wherein the second transition-metal catalyst is palladium hydroxide on carbon, palladium on carbon, or platinum oxide.

20. The method of claim 1 , wherein the deprotecting agent is boron tribromide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, eerie ammonium nitrate, or a combination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

21. The method of claim 1 , further comprising prior to step a):
a1) forming a third reaction mixture comprising a compound of Formula IV:

or a salt thereof, a second base, and a third solvent to form the compound of Formula III, or the salt thereof, wherein AG 1 is Cl, Br, OSO 3 H, OSO 3 − , OMs, OTs, or OTf.

22. The method of claim 21 , further comprising prior to step a1):
a2) forming a fourth reaction mixture comprising a compound of Formula V:

or a salt thereof, a first activating agent, and a fourth solvent to form the compound of Formula IV:

or the salt thereof.

23. The method of claim 1 , further comprising prior to step a):
a1-2) forming a fifth reaction mixture comprising a compound of Formula V:

or a salt thereof, one or more cyclizing agents, and a fifth solvent to form the compound of Formula III or the salt thereof.

24. The method of claim 22 , further comprising prior to step a2) or a1-2):
a3) forming a sixth reaction mixture comprising a compound of Formula VII:

or a salt thereof, a compound of Formula VI:

or a salt thereof, a third base, and

Assignees

• Gilead Sciences Inc

Inventors

• Ambrosi Andrea
• Bachrach Florence J
• Badalov Pavel R
• Lathrop Stephen P
• Merit Jeffrey E
• Pritchett Beau P
• Regens Christopher S
• Vieira Tiago
• Weinstein Adam B
• Wenderski Todd A
• Zheng Zehua

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D213/81

  Amides; Imides · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title