# US 11,078,158 B2 · (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine or pharmaceutically acceptable salts thereof, a process for preparation thereof and uses thereof

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- Number: US 11,078,158 B2
- Document ID: US11078158B2
- Status: Granted
- Kind: B2
- Application number: 16/338,055
- Filed: 2018-05-18
- Published: 2020-01-23
- Granted: 2021-08-03
- Earliest claimed: 2017-05-19
- Assignees: Integrative Research Laboratories Sweden AB
- Applicants: Integrative Research Laboratories Sweden AB
- Inventors: Clas Sonesson; Maija Buksa; Inese Reine
- Web page: https://patentgrep.com/patent/US11078158B2

## CPC

- C07D 207/12: Oxygen or sulfur atoms
- A61P 25/00: Drugs for disorders of the nervous system
- C07C 57/15: Fumaric acid
- C07B 2200/11: Compounds covalently bound to a solid support
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The disclosure provides a process for manufacturing thereof a salt of Formula IIb:

## Claims

### Claim 1

A process for manufacturing the salt of Formula IIb
said process comprising:
resolution of a compound of Formula I:
by combining said compound of Formula I with (−)-dibenzoyl-L-tartaric acid in the presence of at least one solvent thereby providing a salt of Formula IIa:
optionally isolating and drying the salt of Formula IIa,
removing the (−)-dibenzoyl-L-tartaric acid from the salt of Formula IIa thereby providing a compound of Formula II,
and
combining the compound of Formula II with fumaric acid thereby providing the salt of Formula IIb.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the (−)-dibenzoyl-L-tartaric acid is removed from the salt of Formula IIa by treating the salt of Formula IIa with a base thereby providing the compound of Formula II.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the resolution comprises:
a) dissolving the (−)-dibenzoyl-L-tartaric acid in the at least one solvent, optionally by heating, to provide a first solution,
b) adding a solution comprising the compound of Formula I and at least one further solvent to said first solution thereby providing a second solution, and
c) precipitating the salt of Formula IIa, optionally by cooling, from said second solution.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the at least one solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, or 2-butanol, and any combination thereof.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the at least one solvent comprises ethanol.

### Claim 6 (depends on 2)

The process according to claim 2, wherein said treatment with the base comprises the steps of:
mixing the salt of Formula IIa with a mixture of a first water-insoluble solvent and an aqueous solution comprising a base, thereby forming:
(i) a solvent phase comprising the first water-insoluble solvent, and
(ii) an aqueous phase comprising the aqueous solution comprising the base,
extracting (ii) with a second water-insoluble solvent to provide:
(iii) at least one phase comprising the second water-insoluble solvent,
combining the phases (i) and (iii),
evaporating the first and second water-insoluble solvents from the combined phases (i) and (iii) thereby providing the compound of Formula II.

### Claim 7 (depends on 6)

The process according to claim 6, wherein:
the base comprises potassium carbonate, and/or
the first water-insoluble solvent and/or the second water-insoluble solvent comprise(s) dichloromethane.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the molar ratio between the compound of Formula I and the (−)-dibenzoyl-L-tartaric acid is within the range of from about 1.9:1 to about 2.1:1.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the salt of Formula IIb is precipitated from an ethanol solution comprising the compound of Formula II and fumaric acid in a 1:1 ratio.

### Claim 10 (depends on 1)

The process according to claim 1, wherein the compound of Formula I is prepared using a method comprising the steps of:
reacting a compound of Formula IV with a compound of Formula V to provide a compound of Formula VI:
wherein:
“M” represents an alkali metal or an alkaline earth metal halide,
PG represents a protecting group,
subjecting the compound of Formula VI to recrystallization from at least one solvent comprising cyclohexane,
converting the compound of Formula VI into the compound of Formula VII:
and
removing the protecting group from the compound of Formula VII thereby providing the compound of Formula I:

### Claim 11

A salt of Formula IIa:

### Claim 12 (depends on 10)

The process according to claim 10, wherein the protecting group is tert-butoxycarbonyl.

### Claim 13 (depends on 3)

The process according to claim 3, wherein the at least one further solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, or 2-butanol, and any combination thereof.

### Claim 14 (depends on 13)

The process according to claim 13, wherein the at least one further solvent comprises ethanol.