Highly purified pharmaceutical grade tasimelteon

Patent metadata

Field	Value
Publication number	US-10611744-B2
Application number	US-201816123303-A
Country	US
Kind code	B2
Filing date	Sep 6, 2018
Priority date	Feb 12, 2014
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

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 we claim is:

1. A method of determining the purity of a batch of tasimelteon that comprises:
a) obtaining a high performance liquid chromatogram or ultra-high performance liquid chromatogram of a sample of the batch;
b) identifying peaks in the chromatogram corresponding to impurities;
c) taking area measurements of the peaks to determine a relative concentration thereof;
d) using one or more standard batches of substances as a reference marker to determine elution characteristics of said substance under the chromatographic conditions used to analyze the tasimelteon composition, said one or more standard batches of substances being selected from a group consisting of:
N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (Impurity 1);
N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide (Impurity 2);
1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (Impurity 3);
N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (Impurity 4);
N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide (Impurity 5);
2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate (Impurity 6); and
N-(((1R,2R)-2-(3-Oxo-2,3-dihydrobenzofuran-4-yl) cyclopropyl)methyl) propionamide (Impurity 7).

2. A method of synthesizing tasimelteon, the method comprising:
contacting and reacting (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide with a reducing agent and an acid in an organic solvent to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof; and
contacting and reacting the ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine with a propionylating reagent to prepare tasimelteon.

3. The method of claim 2 , wherein the reducing agent comprises LiAlH4.

4. The method of claim 2 , wherein the acid comprises HCl.

5. The method of claim 2 , wherein the organic solvent comprises TBME.

6. The method of claim 2 , wherein the propionylating agent comprises propionyl chloride.

7. The method of claim 2 , wherein the propionylation step further includes an organic solvent and a base.

8. The method of claim 7 , wherein the base comprises NaOH.

9. The method of claim 2 , wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof.

Assignees

• Vanda Pharmaceuticals Inc

Inventors

• Phadke Deepak
• Platt Natalie M
• Pandrapragada Ravi K

Classifications

• C07D307/79

  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

• A61P25/20

  Hypnotics; Sedatives · CPC title