Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4AR,10AR)-7-hydroxy-1- propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid

Patent metadata

Field	Value
Publication number	US-11104697-B2
Application number	US-202016876843-A
Country	US
Kind code	B2
Filing date	May 18, 2020
Priority date	May 20, 2019
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

The present invention relates to a process for manufacturing (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]guinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid with the formula (Id) below and pharmaceutically acceptable salts thereof

The compound of formula (Id) is a prodrug of a catecholamine for use in treatment of neurodegenerative diseases and disorders such as Parkinson's Disease.

The invention also relates to a new intermediate of said process.

First claim

The invention claimed is:

1. A process for the preparation of compound (Id) with the formula below

or a pharmaceutically acceptable salt thereof
from compound (I), with the formula below

wherein said process comprises the following step
reacting compound (A2) with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate to obtain compound (A3) according to the reaction scheme below

wherein said reaction takes place in an aprotic solvent in the presence of a Lewis acid.

2. A process for the manufacturing of compound (A3) below comprising the following step
reacting compound (A2) with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate to obtain compound (A3) according to the reaction scheme below

wherein said reaction takes place in an aprotic solvent in the presence of a Lewis acid.

3. The process according to any of claim 1 , wherein said aprotic solvent is dichloromethane or benzotrifluoride and said Lewis acid is boron trifluoride diethyl etherate.

4. A compound of formula (A3) below

or a salt thereof.

5. A process for the preparation of compound (Id), or a pharmaceutically acceptable salt thereof with the formula below

from compound (I) with the formula below

wherein said process comprises the following step
deprotecting compound (A3) by contacting compound (A3) with a nucleophilic reagent to obtain compound (Id), or a pharmaceutically acceptable salt thereof according to the reaction scheme below

6. The process according to claim 1 , further comprising the following step
deprotecting compound (A3) by contacting compound (A3) with a nucleophilic reagent to obtain compound (Id), or a pharmaceutically acceptable salt thereof according to the reaction scheme below

7. The process according to claim 6 , wherein the nucleophilic reagent is selected from potassium hydroxide and sodium hydroxide.

8. The process according to claim 6 , wherein said deprotection takes place in a mixture of methanol and water.

9. The process according to claim 1 , wherein compound (A2) has been obtained by the following step
reacting compound (I), or a salt thereof with triisopropylsilyl chloride to obtain compound (A2) according to the reaction scheme below

wherein the reaction takes place in an aprotic solvent in the presence of a base.

10. The process according to claim 9 , wherein said aprotic solvent is dichloromethane and said base is N,N-diisopropylethylamine (DIPEA).

11. The process according to claim 10 , wherein said N,N-Diisopropylethylamine (DIPEA) is present in an amount of 4-5 equivalents relative to compound (I).

12. The process according to claim 1 , comprising an additional step of formulating compound (Id), or pharmaceutically acceptable salt thereof into a solid oral dosage form.

Assignees

• H Lundbeck As

Inventors

• Juhl Martin
• Kværnø Lisbet
• Jacobsen Mikkel Fog

Classifications

• C07H17/02 Primary

  Heterocyclic radicals containing only nitrogen as ring hetero atoms · CPC title

• C07H1/00 Primary

  Processes for the preparation of sugar derivatives · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title