# US 9,040,716 B2 · Copper-catalysed ligation of azides and acetylenes

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- Number: US 9,040,716 B2
- Document ID: US9040716B2
- Status: Granted
- Kind: B2
- Application number: 14/508,552
- Filed: 2014-10-07
- Published: 2015-01-29
- Granted: 2015-05-26
- Earliest claimed: 2002-05-30
- Assignees: The Scripps Research Institute
- Applicants: The Scripps Research Institute
- Inventors: K. Barry Sharpless; Valery Fokin; Vsevold A. Rostovtsev; Luke Green; Fahmi Himo
- Web page: https://patentgrep.com/patent/US9040716B2

## CPC

- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- B01J 31/1805: {the ligands containing nitrogen}
- C07D 249/06: with aryl radicals directly attached to ring atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- B01J 2231/327: Dipolar cycloadditions
- B01J 2531/16: Copper
- B01J 2531/96: Water
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS

## Abstract

A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting an organic azide and a terminal alkyne with a source of reactive Cu(I) ion in human blood plasma to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole. The source of reactive Cu(I) ion can be, for example, a Cu(I) salt, Cu(II) ion in the presence of a reducing agent, or copper metal.

## Claims

### Claim 1

A copper catalyzed process for preparing a 1,4-disubstituted 1,2,3-triazole comprising:
contacting a solution of an organic azide and a terminal alkyne with a source of catalytic Cu(I) ion and a ligand for Cu(I) to form a 1,4-disubstituted 1,2,3-triazole, wherein the solution comprises at least one solvent selected from the group consisting of water, a nitrile, and an alcohol.

### Claim 2 (depends on 1)

The process of claim 1, wherein the solvent comprises one or more of acetonitrile, ethanol, and tert-butanol.

### Claim 3 (depends on 2)

The process of claim 2, wherein the solvent further comprises water.

### Claim 4 (depends on 1)

The process of claim 1, wherein the solvent comprises water and an alcohol.

### Claim 5 (depends on 1)

The process of claim 1, wherein the solvent comprises water and a nitrile.

### Claim 6 (depends on 1)

The process of claim 1, wherein the ligand comprises one or more functional groups selected from the group consisting of a nitrile, an isonitrile, a primary amine, a secondary amine, a tertiary amine, a nitrogen bearing heterocycle, a carboxylate, a halide, an alcohol, a thiol, a sulfide, a phosphine, and a phosphite.

### Claim 7 (depends on 1)

The process of claim 1, wherein the ligand is a polyvalent ligand.

### Claim 8 (depends on 1)

The process of claim 1, wherein the source of catalytic Cu(I) ion comprises a Cu(I) salt.

### Claim 9 (depends on 1)

The process of claim 1, wherein the source of catalytic Cu(I) ion comprises Cu(II) and a reducing agent for reducing Cu(II) to Cu(I).

### Claim 10 (depends on 9)

The process of claim 9, wherein the reducing agent comprises one or more material selected from ascorbate, hydroquinone, glutathione, and cysteine.

### Claim 11 (depends on 1)

The process of claim 1, wherein the source of catalytic Cu(I) comprises copper metal.

### Claim 12

A copper catalyzed process for preparing a 1,4-disubstituted 1,2,3-triazole comprising:
contacting an aqueous solution of an organic azide and a terminal alkyne with a source of catalytic Cu(I) ion to form a 1,4-disubstituted 1,2,3-triazole, wherein the source of catalytic Cu(I) ion comprises Cu(II) ion subjected to a reducing electrochemical potential sufficient to generate Cu(I) ion therefrom.

### Claim 13 (depends on 12)

The process of claim 12, wherein the aqueous solution further comprises a cosolvent selected from a nitrile and an alcohol.

### Claim 14 (depends on 12)

The process of claim 12, wherein the aqueous solution further comprises a ligand for Cu (I).

### Claim 15

A two-step process for derivatizing an amine-containing molecule with a triazole comprising the steps of:
derivatizing an amino group of an amine-containing molecule with a terminal alkyne moiety to form an amino-substituted terminal alkyne; and
contacting a solution of the amino-substituted terminal alkyne with an organic azide in the presence of a source of catalytic Cu(I) ion to form a 1,4-disubstituted 1,2,3-triazole derivative therefrom.

### Claim 16 (depends on 15)

The process of claim 15, wherein the solution comprises at least one solvent selected from the group consisting of water, a nitrile, and an alcohol.

### Claim 17 (depends on 16)

The process of claim 16, wherein the solvent comprises one or more of acetonitrile, ethanol, and tert-butanol.

### Claim 18 (depends on 15)

The process of claim 15, wherein the source of catalytic Cu(I) ion comprises a Cu(I) salt.

### Claim 19 (depends on 15)

The process of claim 15, wherein the source of catalytic Cu(I) ion comprises Cu(II) and a reducing agent for reducing Cu(II) to Cu(I).

### Claim 20 (depends on 19)

The process of claim 19, wherein the reducing agent comprises one or more material selected from ascorbate, hydroquinone, glutathione, and cysteine.