Process for making arylomycin ring analogs

Patent metadata

Field	Value
Publication number	US-11702452-B2
Application number	US-202117517103-A
Country	US
Kind code	B2
Filing date	Nov 2, 2021
Priority date	Mar 27, 2017
Publication date	Jul 18, 2023
Grant date	Jul 18, 2023

Abstract

Methods for making an arylomycin ring of formula tor salts or solvates thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R5, R10 and Pg1 are as defined herein.

First claim

What is claimed is:

1. A method of making an arylomycin ring of formula o:

or a salt or solvate thereof,
wherein:
R is: hydrogen; or C 1-4 alkyl;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; cyano-C 1-6 alkyl; or nitro, wherein the amino and hydroxyl moieties may each optionally include a protecting group;
R 7 is: hydrogen; or C 1-4 alkyl;
R 8 is: hydrogen; C 1-4 alkyl; halo-C 1-4 alkyl; halo; amino; amino-C 1-4 alkyl; hydroxy; hydroxy-C 1-6 alkyl; cyano; or cyano-C 1-6 alkyl, wherein the amino and hydroxyl moieties may each optionally include a protecting group;
Pg 1 is an optional amine protecting group; and
Pg 2 is an optional hydroxyl protecting group;

the method comprising:
reacting a phenyl boronate compound of formula l:

or a salt or solvate thereof,
wherein:
R a is: hydrogen; or C 1-4 alkyl; and may be the same or different on each occurrence, or two R a groups may form a C 2-6 alkylene that, together with the atoms to which they are attached, may form a five- or six-membered ring; and
R, R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 and Pg 2 are as defined in the arylomycin ring of formula o;

with a phenyl halide compound of formula e:

or a salt or solvate thereof,
wherein:
Y is halogen; and
R 1 , R 2 , R 3 , and Pg 1 are as defined in the arylomycin ring of formula o;

in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II), and after said reacting removing one amine protecting group Pg 1 , to form a compound of formula y:

or a salt or solvate thereof,
wherein:
R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 , and Pg 2 are as defined in the arylomycin ring of formula o; and

cyclizing the compound of formula y, or a salt or solvate thereof, by forming an amide bond to make the arylomycin ring of formula o, or a salt or solvate thereof.

2. The method of claim 1 , further comprising reacting a compound of formula k:

or a salt or solvate thereof,
wherein:
Y, R, R 4 , R 5 , R 6 , R 7 , R 8 , Pg 1 , and Pg 2 are as defined in claim 1 ;

with a boronating agent to form the compound of formula l, or a salt or solvate thereof.

3. The method of claim 2 , further comprising:
reacting a compound of formula h:

or a salt or solvate thereof,
wherein:
Y, R, R 4 , R 5 , R 6 , and R 7 are as defined in claim 1 ;

with an amino acid of formula i:

or a salt or solvate thereof,
wherein:
R 8 and Pg 1 are as defined in claim 1 ;

to form a compound of formula j:

or a salt or solvate thereof,
wherein:
Y, R, R 4 , R 5 , R 6 , R 7 , R 8 , and Pg 1 are as defined in claim 1 ; and

introducing a hydroxyl protecting group Pg 2 to the compound of formula j, or a salt or solvate thereof, to form the compound of formula k, or a salt or solvate thereof.

4. The method of claim 3 , further comprising:
esterifying a compound of formula g:

or a salt or solvate thereof,
wherein:
Y, R 4 , R 5 , R 6 , and R 7 are as defined in claim 1 ;

to form the compound of formula h, or a salt or solvate thereof.

5. The method of claim 4 , further comprising:
halogenating a compound of formula f:

or a salt or solvate thereof,
wherein:
R 4 , R 5 , R 6 , and R 7 are as defined in claim 1 ;

to form the compound of formula g, or a salt or solvate thereof.

6. The method of claim 1 , further comprising:
reducing a compound of formula d:

or a salt or solvate thereof,
wherein:
Y, R 1 , R 2 , R 3 , and Pg 1 are as defined in claim 1 ;

to form the compound of formula e, or a salt or solvate thereof.

7. The method of claim 6 , further comprising:
reacting a compound of formula c:

or a salt or solvate thereof,
wherein:
Y, R 1 , R 2 , R 3 , and Pg 1 are as defined in claim 1 ;

with trioxane to form the compound of formula d, or a salt or solvate thereof.

8. The method of claim 7 , further comprising:
halogenating a compound of formula a:

or a salt or solvate thereof,
wherein:
R 1 , R 2 , and R 3 are as defined in claim 1 ;

to form a compound of formula b:

or a salt or solvate thereof,
wherein:
Y, R 1 , R 2 , and R 3 are as defined in claim 1 ; and

introducing an amine protecting group Pg 1 to the compound of formula b, or a salt or solvate thereof, to form the compound of formula c, or a salt or solvate thereof.

Assignees

• Genentech Inc

Inventors

• Petronijevic Filip
• Lim Ngiap-Kie
• Wong Nicholas
• Hong Allen
• Hou Haiyun
• Linghu Xin
• Gosselin Francis

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K1/061

  using protecting groups · CPC title

• C07D245/02 Primary

  not condensed with other rings · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/395

  having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins · CPC title