Methods of preparing toll-like receptor modulators

Patent metadata

Field	Value
Publication number	US-9573952-B2
Application number	US-201514853883-A
Country	US
Kind code	B2
Filing date	Sep 14, 2015
Priority date	Sep 16, 2014
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

The present invention provides methods of preparing 4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one and related compounds.

First claim

What is claimed is:

1. A method of making a compound of Formula Ia:

comprising:
(a) forming a first reaction mixture comprising a compound of Formula IIa:

a non nucleophilic base, a first solvent, and a compound of Formula IIIa:

under conditions suitable to form a compound of Formula IVa:

 and

(b) forming a second reaction mixture comprising the compound of Formula IVa, a second solvent and a reducing agent under conditions suitable to prepare the compound of Formula I,

wherein
R 1 and R 11 are each independently C 1 -C 6 alkyl; and
LG is selected from the group consisting of halogen, —OH, and —OSO 2 R 13 , wherein R 13 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and aryl, wherein the aryl group is substituted with 1 to 3 R 13a groups each independently selected from the group consisting of C 1 -C 6 alkyl, halogen, and NO 2 .

2. The method of claim 1 , wherein the non-nueleophilic base is selected from the group consisting of triethylamine, diisopropylethyl amine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine.

3. The method of claim 1 , wherein the non-nucleophilic base is triethylamine.

4. The method of claim 1 , wherein the non-nucleophilic base is 2,4,6-collidine.

5. The method of claim 1 , wherein the first solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile, and combinations thereof.

6. The method of claim 1 , wherein the first solvent comprises ethyl acetate.

7. The method of claim 1 , wherein the first solvent comprises isopropyl acetate.

8. The method of claim 1 , wherein the first solvent comprises acetonitrile.

9. The method of claim 1 , wherein the compound of Formula IIIa is the bis-oxalate salt of Formula IIIa.

10. The method of claim 1 , further comprising prior to step (b):
(a1) forming a reaction mixture comprising the compound of Formula IVa and hydrochloric acid to form a monohydrochloride form of the compound of Formula IVa.

11. The method of claim 1 , wherein the reducing agent is selected from the group consisting of zinc, iron, Raney nickel, sodium sulfide, sodium dithionite, ammonium sulfide, palladium on carbon, lithium aluminum hydride, and sodium borohydride.

12. The method of claim 1 , wherein the reducing agent is zinc.

13. The method of claim 1 , wherein the reducing agent is Raney nickel.

14. The method of claim 1 , wherein the second solvent is selected from the group consisting of acetic acid, water, methanol, ethanol, isopropanol, tetrahydrofitran, and combinations thereof.

15. The method of claim 1 , wherein the second solvent comprises acetic acid and water.

16. The method of claim 1 , wherein the second reaction mixture is maintained at a temperature of from about 10° C. to about 30° C.

17. The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, tert-pentyl, neopentyl, iso-pentyl, sec-pentyl, 3-pentyl, hexyl, and 2-ethyl-butyl.

18. The method of claim 1 , wherein the leaving group LG is selected from the group consisting of chloro, —OH, and —O—tosyl.

19. The method of claim 1 , wherein the compound of Formula Ia has the structure:

and the method comprises:
(a) forming the first reaction mixture comprising the compound of Formula IIa having the structure:

triethylamine, ethyl acetate, and the bisoxalate salt of the compound of Formula IIIa having the structure:

under conditions suitable to form the compound of Formula IVa having the structure:

(a1) forming a reaction mixture comprising the compound of Formula IVa and hydrochloric acid to form a monohydrochloride form of the compound of Formula IVa; and
(b) forming the second reaction mixture comprising the monohydrochloride firm of the compound of Formula IVa, zinc, and acetic acid, under conditions suitable to prepare the compound of Formula Ia.

20. The method of claim 1 , wherein the compound of Formula Ia has the structure:

and the method comprises:
(a) forming the first reaction mixture comprising the compound of Formula IIa having the structure:

triethylamine, isopropyl acetate, and the bisoxalate salt of the compound of Formula IIIa having the structure:

under conditions suitable to form the compound of Formula IVa having the structure:

(a1) forming a reaction mixture comprising the compound of Formula IVa and hydrochloric acid to form a monohydrochloride form of the compound of Formula IVa; and
(b) forming the second reaction mixture comprising the monohydrochloride form of the compound of Formula IVa, zinc, and acetic acid, under conditions suitable to prepare the compound of Formula Ia.

21. The method of claim 1 , wherein the compound of Formula Ia has the structure:

and the method comprises:
(a) forming the first reaction mixture comprising the compound of Formula IIa having the structure:

2,4,6-collidine, acetonitrile, and tosyl-Cl, under conditions suitable to form the compound of Formula IIa having the structure:

and adding to the reaction mixture the bisoxalate salt of the compound of Formula IIIa having the structure:

under conditions suitable to form the compound of Formula IVa having the structure:

 and

(b) forming the second reaction mixture comprising the compound of Fo

Assignees

• Gilead Sciences Inc

Inventors

• Allen Darin
• Brown Brandon Heath
• Chao Jessica Jade
• Halcomb Randall L
• Hrvatin Paul
• Mcfadden Ryan
• Roethle Paul
• Rudio Erwina
• Yang Hong
• Yu Richard Hung Chiu

Classifications

• C07D207/06

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title

• C07D239/545

  with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms · CPC title

• C07D207/09

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D475/06 Primary

  with a nitrogen atom directly attached in position 4 · CPC title