# US 12,594,274 B2 · Method for preparing a crystalline form of rabeximod

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- Number: US 12,594,274 B2
- Document ID: US12594274B2
- Status: Granted
- Kind: B2
- Application number: 18/000,943
- Filed: 2021-06-10
- Published: 2023-07-20
- Granted: 2026-04-07
- Earliest claimed: 2020-06-10
- Assignees: Gulch Pharma AB
- Applicants: Cyxone AB
- Inventors: Ulf Björklund
- Web page: https://patentgrep.com/patent/US12594274B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 37/02: Immunomodulators
- C07D 487/04: Ortho-condensed systems
- A61K 9/485: {Inorganic compounds}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a process for preparing 9-Chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline, wherein said process is suitable for large scale synthesis.

## Claims

### Claim 1

A process for preparing 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo-[2,3-b]quinoxaline (rabeximod) or a salt thereof, wherein the process comprises the step of:
reacting a solution or suspension of 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline in the presence of an aqueous base sufficiently strong to deprotonize the indole N—H, with 2-chloro-N-(2-dimethylaminoethyl) acetamide or a salt thereof to obtain rabeximod or a salt thereof.

### Claim 2 (depends on 1)

The process of claim 1, wherein a catalyst is present in the solution or suspension.

### Claim 3 (depends on 1)

The process of claim 1, wherein 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline or a salt thereof is dissolved in an organic solvent and wherein 2-chloro-N-(2-dimethylaminoethyl) acetamide or a salt thereof is dissolved in an organic solvent.

### Claim 4 (depends on 1)

The process of claim 1, wherein the aqueous base is NaOH.

### Claim 5 (depends on 1)

The process of claim 1, wherein 1 molar equivalent 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline is deprotonized with at least 2 volumes of the aqueous base and wherein 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline and the aqueous base are mixed at a suitable temperature until a clear solution is formed.

### Claim 6 (depends on 2)

The process of claim 2, wherein the catalyst in a suitable amount is added under vigorous stirring and mixed for 10 to 60 minutes at a suitable temperature.

### Claim 7 (depends on 1)

The process of claim 1, wherein 2-chloro-N-(2-dimethylaminoethyl) acetamide or a salt thereof is added to the solution of 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline in the aqueous base and mixed for at least 1 hour at a suitable temperature.

### Claim 8 (depends on 1)

The process of claim 1, wherein rabeximod is purified and isolated as a crystalline free base.

### Claim 9 (depends on 1)

The process of claim 1, wherein the process comprises the preceding step of:
reacting a solution or suspension of 4,5-dimethyl-1,2-phenylenediamine with 5-chloroisatin under acidic conditions at elevated temperatures up to reflux to obtain the 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline or a salt thereof.

### Claim 10 (depends on 1)

The process of claim 1, wherein the process comprises the preceding step of:
reacting a solution or suspension of chloroacetyl chloride with N,N-dimethylethylene diamine to obtain the 2-chloro-N-(2-dimethylaminoethyl) acetamide or a salt thereof.

### Claim 11 (depends on 1)

The process of claim 1, wherein the process comprises the preceding steps of
reacting a solution or suspension of 4,5-dimethyl-1,2-phenylenediamine with 5-chloroisatin under acidic conditions at elevated temperatures up to reflux to obtain 9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxaline or a salt thereof; and
reacting a solution or suspension of chloroacetyl chloride with N,N-dimethylethylene diamine to obtain 2-chloro-N-(2-dimethylaminoethyl) acetamide or a salt thereof.

### Claim 12 (depends on 9)

The process of claim 9, wherein the acidic condition is an organic acid.

### Claim 13 (depends on 9)

The process of claim 9, wherein 4,5-dimethyl-1,2-phenylenediamine and 5-chloroisatin are both dissolved in the acid before the reaction.

### Claim 14 (depends on 9)

The process of claim 9, wherein the elevated temperature is reflux temperature.

### Claim 15 (depends on 11)

The process of claim 11, wherein the acidic condition is an organic acid.

### Claim 16 (depends on 11)

The process of claim 11, wherein 4,5-dimethyl-1,2-phenylenediamine and 5-chloroisatin are both dissolved in the acid before the reaction.

### Claim 17 (depends on 11)

The process of claim 11, wherein the elevated temperature is reflux temperature.