# US 10,766,874 B2 · Manufacturing process for triazine, pyrimidine and pyridine derivatives

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- Number: US 10,766,874 B2
- Document ID: US10766874B2
- Status: Granted
- Kind: B2
- Application number: 16/045,427
- Filed: 2018-07-25
- Published: 2019-01-17
- Granted: 2020-09-08
- Earliest claimed: 2014-04-22
- Assignees: Universitaet Basel; Piqur Therapeutics AG
- Applicants: Universitaet Basel; Piqur Therapeutics AG
- Inventors: Paul Hebeisen; Florent Beaufils; Jean-Baptiste Langlois
- Web page: https://patentgrep.com/patent/US10766874B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/127: Preparation from compounds containing pyridine rings
- C07D 213/53: Nitrogen atoms
- C07F 5/025: {Boronic and borinic acid compounds}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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.

## Claims

### Claim 1

A method of manufacturing a compound of formula (I)
or a stereomer, tautomer or a salt thereof, wherein,
U is CRU or N, wherein RU is hydrogen;
V is CRV or N, wherein RV is hydrogen;
W is CRW or N, wherein RW is hydrogen;
provided that at least one of U, V and W is N;
Z is CRZ or N, wherein RZ is hydrogen;
R1 is selected from the group consisting of hydrogen, halogen and —N(RT)RS, wherein RT and RS are hydrogen or C1-C7-alkyl, or wherein RT and RS together with the nitrogen to which they are attached form a C4-C6 heterocyclic ring selected from the group consisting of
R2 is selected from the group consisting of hydrogen, cyano, halogen, methyl and trifluoromethyl; and
R3 is hydrogen or halogen,
comprising reacting a compound of formula (II)
wherein
Y2B represents a residue of an acyclic boronic acid, an acyclic boronic ester, or a cyclic boronic ester, and R2 and R3 are defined as for the compound of formula (I);
R4 is hydrogen, C1-C7-alkyl or C5-C7-cycloalkyl;
R5 and R6 are C1-C7-alkyl, or R5 and R6 together represent C4-C6-cycloalkyl:
and the crossed double bond between N and C(R4)N indicates a cis and/or trans double bond;
with a compound of formula (III)
in which the groups U, V, W and R1 are defined as above; and
R7 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein in the compound of formula (I)
R2 is trifluoromethyl;
and R3 is hydrogen.

### Claim 3 (depends on 1)

The method of claim 1, wherein in the compound of formula (II)
Y2B represents a cyclic boronic ester;
R4 is hydrogen; and
R5 and R6 are methyl.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6

A method of manufacturing a compound of formula (II)
wherein
Y2B represents a residue of a boronic acid, an acyclic boronic ester, or a cyclic boronic ester;
Z is CRZ or N, wherein RZ is hydrogen;
R2 is selected from the group consisting of hydrogen, cyano, halogen, methyl and trifluoromethyl;
R3 is hydrogen or halogen;
R4 is hydrogen, C1-C7-alkyl or C5-C7-cycloalkyl;
R5 and R6 are C1-C7-alkyl, or R5 and R6 together represent C4-C6-cycloalkyl;
and the crossed double bond between N and C(R4)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)
R8—BY2 (VI)
wherein R8 is a leaving group.

### Claim 7 (depends on 1)

A method of manufacture of an acid addition salt of formula (Ia)
or a stereomer or tautomer, wherein,
U is CRU or N, wherein RU is hydrogen;
V is CRV or N, wherein RV is hydrogen;
W is CRW or N, wherein RW is hydrogen;
provided that at least one of U, V and W is N;
Z is CRZ or N, wherein RZ is hydrogen;
R1 is selected from the group consisting of hydrogen, halogen and —N(RT)RS, wherein RT and RS are hydrogen or C1-C7-alkyl, or wherein RT and RS together with the nitrogen to which they are attached form a C4-C6 heterocyclic ring selected from the group consisting of
R2 is selected from the group consisting of hydrogen, cyano, halogen, methyl and trifluoromethyl; and
R3 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.

### Claim 8 (depends on 1)

The method of claim 1, wherein
R1 is selected from the group consisting of halogen and —N(RT)RS, wherein RT and RS are, independently of each other, hydrogen, methyl or ethyl, or wherein RT and RS together with the nitrogen to which they are attached form a C4-C6-heterocyclic ring selected from the group consisting of
R2 is trifluoromethyl; and
R3 is hydrogen;
and wherein further said resulting formamidine of formula (IV) is reacted with morpholine prior to said its hydrolyzation.

### Claim 9 (depends on 1)

The method of claim 1, wherein
R1 is selected from the group consisting of chlorine and —N(RT)RS, wherein RT and RS are, independently of each other, hydrogen, methyl or ethyl, or wherein RT and RS together with the nitrogen to which they are attached form a C4-C6-heterocyclic ring selected from the group consisting of
R2 is trifluoromethyl; and
R3 is hydrogen;
and wherein further said resulting formamidine of formula (IV) is reacted with morpholine prior to said its hydrolyzation.

### Claim 10 (depends on 1)

The method of claim 1, wherein
U is N; V is N; W is N; Z is CRZ, wherein RZ is hydrogen;
R1 is selected from the group consisting of halogen and —N(RT)RS, wherein RT and RS are, independently of each other, hydrogen, methyl or ethyl, or wherein RT and RS together with the nitrogen to which they are attached form a C4-C6-heterocyclic ring selected from the group consisting of
R2 is trifluoromethyl; and
R3 is hydrogen.

### Claim 11 (depends on 1)

The method of claim 1, wherein
U is N; V is N; W is N; Z is CRZ, wherein RZ is hydrogen;
R1 is selected from the group consisting of chlorine and —N(RT)RS, wherein RT and RS are, independently of each other, hydrogen, methyl or ethyl, or wherein RT and RS together with the nitrogen to which they are attached form a C4-C6-heterocyclic ring selected from the group consisting of
R2 is trifluoromethyl; and
R3 is hydrogen.

### Claim 12 (depends on 1)

The method of claim 1, wherein
U is N; V is N; W is N; Z is CRZ, wherein RZ is hydrogen;
R1 is —N(RT)RS, wherein RT and RS together with the nitrogen to which they are attached form a C4-C6-heterocyclic ring selected from the group consisting of
R2 is trifluoromethyl; and
R3 is hydrogen.

### Claim 13 (depends on 12)

The method of claim 12, wherein in said compound of formula (II)
Y2B represents a cyclic boronic ester;
R4 is hydrogen; and
R5 and R6 are methyl.

### Claim 14 (depends on 12)

The method of claim 12, wherein said compound of formula (II)
Y2B represents a pinacolato boronate;
R4 is hydrogen; and
R5 and R6 are methyl.

### Claim 15 (depends on 12)

The method of claim 12, wherein in said compound of formula (II)
Y2B represents a pinacolato boronate;
R4 is hydrogen;
R5 and R6 are methyl; and
R7 is chlorine.

### Claim 16 (depends on 7)

The method of manufacture of an acid addition salt of formula (Ia) according to claim 7, wherein
U is N; V is N; W is N; Z is CRZ, wherein RZ is hydrogen;
R1 is morpholino;
R2 is trifluoromethyl;
R3 is hydrogen; and
the protonic acid HX is selected from hydrochloric acid and methanesulfonic acid.

### Claim 17 (depends on 4)

The method of claim 4, wherein
U is N; V is N; W is N; Z is CRZ, wherein RZ is hydrogen;
R1 is
R2 is trifluoromethyl; and
R3 is hydrogen.

### Claim 18 (depends on 17)

The method of claim 17, wherein said compound of formula (II)
Y2B represents a pinacolato boronate;
R4 is hydrogen; and
R5 and R6 are methyl.

### Claim 19 (depends on 5)

The method of claim 5, wherein
U is N; V is N; W is N; Z is CRZ, wherein RZ is hydrogen;
R1 is
R2 is trifluoromethyl; and
R3 is hydrogen.

### Claim 20 (depends on 19)

The method of claim 19, wherein said compound of formula (II)
Y2B represents a pinacolato boronate;
R4 is hydrogen; and
R5 and R6 are methyl.