Manufacturing process for triazine, pyrimidine and pyridine derivatives

Patent metadata

Field	Value
Publication number	US-10766874-B2
Application number	US-201816045427-A
Country	US
Kind code	B2
Filing date	Jul 25, 2018
Priority date	Apr 22, 2014
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The invention relates to a method of manufacturing triazine, pyrimidine and pyridine derivatives of formula (I)

wherein U, V, W and Z are nitrogen or carbon atoms, whereby at least one of U, V and W is nitrogen, and the other substituents are defined as in the specification, by condensing a corresponding halo-triazine, pyrimidine or pyridine in a type of Suzuki coupling with a pyridyl- or pyrimidinyl-borane, wherein the amino function is protected as a formamidine. The invention further relates to suitable intermediates and methods of manufacturing of such intermediates. Furthermore the invention relates to pure 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine in solid form.

First claim

The invention claimed is:

1. A method of manufacturing a compound of formula (I)

or a stereomer, tautomer or a salt thereof, wherein,
U is CR U or N, wherein R U is hydrogen;
V is CR V or N, wherein R V is hydrogen;
W is CR W or N, wherein R W is hydrogen;
provided that at least one of U, V and W is N;
Z is CR Z or N, wherein R Z is hydrogen;
R 1 is selected from the group consisting of hydrogen, halogen and —N(R T )R S , wherein R T and R S are hydrogen or C 1 -C 7 -alkyl, or wherein R T and R S together with the nitrogen to which they are attached form a C 4 -C 6 heterocyclic ring selected from the group consisting of

R 2 is selected from the group consisting of hydrogen, cyano, halogen, methyl and trifluoromethyl; and
R 3 is hydrogen or halogen,
comprising reacting a compound of formula (II)

wherein
Y 2 B represents a residue of an acyclic boronic acid, an acyclic boronic ester, or a cyclic boronic ester, and R 2 and R 3 are defined as for the compound of formula (I);
R 4 is hydrogen, C 1 -C 7 -alkyl or C 5 -C 7 -cycloalkyl;
R 5 and R 6 are C 1 -C 7 -alkyl, or R 5 and R 6 together represent C 4 -C 6 -cycloalkyl:
and the crossed double bond between N and C(R 4 )N indicates a cis and/or trans double bond;
with a compound of formula (III)

in which the groups U, V, W and R 1 are defined as above; and
R 7 is halogen;
in an aqueous organic solvent or an immiscible organic solvent-water mixture at temperatures from 0° C. to the boiling point of the solvent or solvent mixture in the presence of a Pd(0) or Pd(II) phosphine catalyst and a base;
and the resulting formamidine of formula (IV)

wherein the substituents have the meanings as defined above,
is hydrolyzed, in situ or after isolation, in aqueous acid or basic solution.

2. The method of claim 1 , wherein in the compound of formula (I)
R 2 is trifluoromethyl;
and R 3 is hydrogen.

3. The method of claim 1 , wherein in the compound of formula (II)
Y 2 B represents a cyclic boronic ester;
R 4 is hydrogen; and
R 5 and R 6 are methyl.

4. The method of claim 1 , wherein the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane and toluene.

5. The method of claim 1 , wherein the Pd phosphine catalyst is a mixture of triphenylphosphine and palladium(II) acetate or palladium dichloride.

6. A method of manufacturing a compound of formula (II)

wherein
Y 2 B represents a residue of a boronic acid, an acyclic boronic ester, or a cyclic boronic ester;
Z is CR Z or N, wherein R Z is hydrogen;
R 2 is selected from the group consisting of hydrogen, cyano, halogen, methyl and trifluoromethyl;
R 3 is hydrogen or halogen;
R 4 is hydrogen, C 1 -C 7 -alkyl or C 5 -C 7 -cycloalkyl;
R 5 and R 6 are C 1 -C 7 -alkyl, or R 5 and R 6 together represent C 4 -C 6 -cycloalkyl;
and the crossed double bond between N and C(R 4 )N indicates a cis and/or trans double bond;
comprising treating a compound of formula (V)

with an organometallic compound in an organic solvent at temperatures between −80° C. to the boiling point of the solvent and, after completion of the bromine-metal exchange reaction, is further reacted with an organoboron reagent of formula (VI)
R 8 —BY 2   (VI)

wherein R 8 is a leaving group.

7. A method of manufacture of an acid addition salt of formula (Ia)

or a stereomer or tautomer, wherein,
U is CR U or N, wherein R U is hydrogen;
V is CR V or N, wherein R V is hydrogen;
W is CR W or N, wherein R W is hydrogen;
provided that at least one of U, V and W is N;
Z is CR Z or N, wherein R Z is hydrogen;
R 1 is selected from the group consisting of hydrogen, halogen and —N(R T )R S , wherein R T and R S are hydrogen or C 1 -C 7 -alkyl, or wherein R T and R S together with the nitrogen to which they are attached form a C 4 -C 6 heterocyclic ring selected from the group consisting of

R 2 is selected from the group consisting of hydrogen, cyano, halogen, methyl and trifluoromethyl; and
R 3 is hydrogen or halogen; and
HX is a protonic acid;
comprising treating a free base of formula (I)

wherein said free base of formula (I) is manufactured according to the method of claim 1 ; and
wherein the substituents are defined as indicated for formula (Ia),
with protonic acid HX, optionally in a suitable solvent, and the resulting acid addition salt is purified by precipitation from a solvent or recrystallization.

8. The method of claim 1 , wherein
R 1 is selected from the group consisting of halogen and —N(R T )R S , wherein R T and R S are, independently of each other, hydrogen, methyl or ethyl, or wherein R T and R S together with the nitrogen to which they are attached form a C 4 -C 6 -heterocyclic ring selected from the group consisting of

R 2 is trifluoromethyl; and
R 3 is hydrogen;
and wherein further said resulting formamidine of formula (IV) is reacted with morpholine prior to said its hydrolyzation.

9. The method of claim 1 , wherein
R 1 is selected from the group consisting of chlorine and —N(R T )R S , wherein R T and R S are, independently of each other, hydrogen, methyl or ethyl, or wherein R T and R S together with the nitrogen to which they are attached form a C 4 -C 6 -heterocyclic ring selected from the group consisting of

R 2 is trifluoromethyl; and
R 3 is hydrogen;
and wherein further said resulting formamidine of formula (IV) is reacted with morpholine prior to said its hydrolyzation.

10. The method of claim 1 , wherein
U is N; V is N; W is N; Z is CR Z , wherein R Z is hydrogen;
R 1 is selected from the group consisting of halogen and —N(R T )R S , wherein R T and R S are, independently of each other, hydrogen, methyl or ethyl, or wherein R T and R S together with the nitrogen to which they are attached form a C 4 -C 6 -heterocyclic ring selected from the group consisting of

R 2 is trifluoromethyl; and
R 3 is hydrogen.

Assignees

• Univ Basel
• Piqur Therapeutics Ag

Inventors

• Hebeisen Paul
• Beaufils Florent
• Langlois Jean-Baptiste

Classifications

• C07D213/53

  Nitrogen atoms · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D213/127 Primary

  Preparation from compounds containing pyridine rings · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• C07D401/04 Primary

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