Highly purified pharmaceutical grade tasimelteon

Patent metadata

Field	Value
Publication number	US-12304896-B2
Application number	US-202418741969-A
Country	US
Kind code	B2
Filing date	Jun 13, 2024
Priority date	Dec 4, 2014
Publication date	May 20, 2025
Grant date	May 20, 2025

Abstract

A process for preparing a batch of highly purified, pharmaceutical grade tasimelteon comprises analyzing a batch of tasimelteon synthesized under GMP conditions for the presence of one or more identified impurities.

First claim

What is claimed is:

1. A process for synthesizing highly purified, pharmaceutical grade tasimelteon, the process comprising:
(a) propionylating ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof to yield tasimelteon;
(b) crystallizing the tasimelteon produced in step (a);
(c) assaying the crystallized tasimelteon from step (b) for the presence of one or both of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamido)methyl) cyclopropyl)methyl)propionamide) and Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate); and
(d)(i) if the crystallized tasimelteon meets pre-set specifications for Impurity 5 or Impurity 6, or both, then collecting the highly purified, pharmaceutical grade tasimelteon or
(d)(ii) if the crystallized tasimelteon fails to meet pre-set specifications for Impurity 5 or Impurity 6, or both, then further purifying the tasimelteon and repeating steps (c) and (d), or discarding the batch.

2. The process of claim 1 , wherein the propionylating step comprises contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof with a propionyl halide, a propionyl anhydride, a propionyl ester, a propionyl amide, a propionyl imidazolide, or with propionic acid and a dehydrating agent or the product thereof.

3. The process of claim 2 , wherein the propionylating step comprises contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof with a propionyl halide, a propionyl anhydride, a propionyl ester, a propionyl amide, a propionyl imidazolide, or with propionic acid and a dehydrating agent or the product thereof in the presence of an organic solvent.

4. The process of claim 3 , wherein the propionylating step comprises contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof with propionyl chloride in the presence of an organic solvent and an aqueous base.

5. The process of claim 4 , wherein the organic solvent comprises tert-butyl methyl ether (TBME) and the aqueous base comprises NaOH.

6. The process of claim 3 , wherein the ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof is Intermediate 5 (((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanaminium chloride) and wherein after the propionylation step and before the crystallizing step, the mixture of tasimelteon is assayed for the presence of Intermediate 5 and, if the mixture does not meet pre-set specifications for Intermediate 5, then repeating step (a) or discarding the mixture.

7. The process of claim 3 , wherein after the propionylation step and before the crystallizing step, the mixture of tasimelteon is washed with aqueous base and the aqueous layer is discarded.

8. The process of claim 7 , wherein the washed mixture is distilled and the distillate is discarded.

9. The process of claim 8 , wherein the distilling step is carried out in ethanol at a pot temperature of up to about 58° C. and a pressure of less than about 100 mmHg.

10. The process of claim 1 , wherein the crystallization step comprises dissolving the tasimelteon by stirring and warming a mixture of the tasimelteon and a C1-C4 alkanol.

11. The process of claim 10 , wherein the mixture of C1-C4 alkanol and tasimelteon is warmed to about 35 to 40° C. while stirring and then cooled to about 13 to 17° C. while stirring.

12. The process of claim 1 , wherein the crystallization step optionally comprises seeding.

13. The process of claim 1 , wherein the assaying step is carried out by HPLC.

14. The process of claim 1 , wherein the pre-set specifications for the one or both of Impurity 5 and Impurity 6 are each not more than 0.15% (Area/Area).

15. The process of any claim 1 , wherein the further purifying comprises recrystallizing the tasimelteon.

16. The process of claim 1 , wherein the particle size of crystals collected in step (d) is reduced to meet particle size specifications for pharmaceutical grade tasimelteon.

17. The process of claim 16 , wherein crystals that meet particle size specifications for pharmaceutical grade tasimelteon are admixed with one or more excipients to prepare a pharmaceutical composition comprising pharmaceutical grade tasimelteon.

Assignees

• Vanda Pharmaceuticals Inc

Inventors

• Phadke Deepak
• Platt Natalie M
• Pandrapragada Ravi K

Classifications

• C07D307/79 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D307/81 Primary

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title