# US 11,306,093 B2 · Process for preparation of 2-(6-nitropyridin-3-yl)-9H-dipyrido[2,3-b;3′,4′-d]pyrrole

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- Number: US 11,306,093 B2
- Document ID: US11306093B2
- Status: Granted
- Kind: B2
- Application number: 16/294,627
- Filed: 2019-03-06
- Published: 2019-10-03
- Granted: 2022-04-19
- Earliest claimed: 2016-09-09
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Bjoern Bartels; Philipp Cueni; Matthias Koerner; Dieter Muri
- Web page: https://patentgrep.com/patent/US11306093B2

## CPC

- C07D 471/14: Ortho-condensed systems
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A process for preparing the compound of formula I comprising: a) coupling a compound of formula 2 wherein a leaving group O—SO2—R is selected from the triflate group, the tosylate group, the mesylate group, the besylate group, the nosylate group or the brosylate group, with a suitable boronic acid, a trifluoroborate or a boronic acid ester under argon condition and in the presence of a catalyst and a base in a suitable solvent and then isolating the product as an acid addition salt to afford the compound of formula Ia and b) converting the acid addition salt of formula Ia wherein the acid HX comprises suitable organic or inorganic acids into the compound of formula I by treatment with at least a stoichiometric equivalent of a suitable base.

## Claims

### Claim 1

A process for preparing a compound of formula I, wherein the process comprises:
a) coupling a compound of formula 2
with a boron reagent selected from
under argon condition in the presence of a catalytic amount of a transition metal complex and a first base in a polar solvent, wherein the group O—SO2—R is selected from triflate, tosylate, mesylate, besylate, nosylate, and brosylate;
isolating the product of the coupling as an acid addition salt by treatment with an acid HX to afford a compound of formula Ia, wherein HX is an organic or inorganic acid,
and
b) converting the acid addition salt of formula Ia, into the compound of formula I by treatment with at least a stoichiometric equivalent of a second base.

### Claim 2 (depends on 1)

The process of claim 1, wherein the compound of formula 2 is 9H-pyrrolo[2,3-b:4,5-c′]dipyridin-2-yl trifluoromethanesulfonate.

### Claim 3 (depends on 1)

The process of claim 1, wherein the boron reagent is 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

### Claim 4 (depends on 1)

The process of claim 1, wherein the transition metal complex is dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II).

### Claim 5 (depends on 1)

The process of claim 1, wherein the first base is potassium fluoride.

### Claim 6 (depends on 1)

The process of claim 1, wherein the polar solvent is selected from THF, 2-Me-THF and dioxane.

### Claim 7 (depends on 1)

The process of claim 1, wherein the organic or inorganic acid is acetic acid, trifluoroacetic acid, cinnamic acid, oxalic acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

### Claim 8 (depends on 1)

The process of claim 1, wherein the second base is sodium hydroxide, potassium hydroxide, trimethylamine, triethylamine, potassium carbonate, sodium bicarbonate or ammonia.

### Claim 9 (depends on 1)

The process of claim 1 wherein the transition metal complex is tris(dibenzylideneacetone)dipalladium(0).

### Claim 10 (depends on 1)

A process for synthesizing [18F]-2-(6-fluoro-pyridin-3-yl)-9H-dipyrido [2,3-b;3′,4′-d]pyrrole, the process comprising:
synthesizing a compound of formula I, according to the process of claim 1; and
dissolving the compound of formula I in dimethylsulfoxide and treating it with [18F]fluoride.

### Claim 11 (depends on 1)

The process of claim 1, wherein the compound of formula 2 is synthesized by a process comprising:
cross-coupling 2-halo-methoxy pyridine 4, wherein X is Cl or Br, with 3-halo-pyridin-4-amine 5 using a catalyst and a third base in a polar solvent, to produce bipyridylamine 6;
wherein the catalyst is
dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II),
the third base is cesium carbonate, and
the polar solvent is 1,4-dioxane;
cyclizing the compound of formula 6 to form 1,6-diazacarbazole 7;
cleaving the methoxy group from the compound of formula 7 using strong acid to give an acid addition salt of a compound having formula 8;
and
converting the compound of formula 8 into the compound of formula 2 wherein R is CF3, with an activating agent in presence of a fourth base at a temperature between 0 and 50 C,
wherein the activating agent is N,N-bis(trifluoromethyl-sulfonyl)aniline, and the fourth base is N,N-diisopropylethylamine.

### Claim 12 (depends on 11)

The process of claim 11, wherein X is chloro.

### Claim 13 (depends on 1)

The process of claim 1, wherein the polar solvent is a mixture of 1,4-dioxane and water.

### Claim 14 (depends on 7)

The process of claim 7, wherein the organic or inorganic acid is acetic acid.

### Claim 15 (depends on 8)

The process of claim 8, wherein the second base is triethylamine.