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-11111263-B2
Application number	US-202016876878-A
Country	US
Kind code	B2
Filing date	May 18, 2020
Priority date	May 20, 2019
Publication date	Sep 7, 2021
Grant date	Sep 7, 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]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid with the formula (Id) below and salts thereofThe 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 new intermediates of said process.

First claim

The invention claimed is:

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

from compound (I) with the formula below

comprising the following step
reacting compound (I), or a salt thereof, with benzyl halogenide to obtain compound (A2) according to the reaction scheme below

wherein Ph is phenyl and X is selected from the group consisting of Cl, Br and I.

2. The process according to claim 1 , wherein:
a) said benzyl halogenide is benzyl chloride and X is Cl; or
b) said benzyl halogenide is benzyl bromide and X is Br.

3. A compound of formula (A2) below:

or a salt thereof.

4. The process according to claim 1 for the preparation of compound (Id) with the formula below

from compound (I) with the formula below

comprising the following step
subjecting compound (A2) to a debenzylation reaction to obtain compound (A3), or a salt thereof according to the reaction scheme below

5. A compound of formula (A3) below:

or a salt thereof.

6. The process according to claim 4 , wherein the debenzylation reaction comprises the steps of:
I) reacting trimethylsilyl iodide with compound (A2) to form a mixture; and
II) adding an alcohol to said mixture from step I) to obtain compound (A3) or a salt thereof; and
III) optionally isolating compound (A3), or a salt thereof as obtained in step (II).

7. The process according to claim 6 , wherein the alcohol added to said mixture in step II) is selected from the group consisting of MeOH, n-heptyl alcohol, and ethanol.

8. The process according to claim 4 , wherein compound (A3) is obtained in the form of a hydroiodide salt with the formula (A3-HI) below

9. The compound according to claim 5 , which is in the form of a hydroiodide salt with the formula (A3-HI) below

10. The process according to claim 1 for the preparation of compound (Id) with the formula below

from compound (I) with the formula below

comprising the following step
reacting compound (A3), or salt thereof, 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 (A4) according to the reaction scheme below

11. The process according to claim 10 , wherein compound (A3) is in the form of the hydroiodide salt (A3-HI) with the formula below:

12. A compound of formula (A4) below:

or a salt thereof.

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

from compound (I) with the formula below

comprising the following step
reacting compound (A4) with alkali-hydroxide to obtain (A5-Y) according to the reaction scheme below

wherein Y is selected from Li, Na and K.

14. The process according to claim 13 , wherein:
a) said alkali hydroxide is lithium hydroxide and Y is Li; or
b) said alkali hydroxide is sodium hydroxide and Y is Na; or
c) said alkali hydroxide is potassium hydroxide and Y is K.

15. A compound of formula (A5) below:

or a salt thereof.

16. The compound according to claim 15 which is in the form of an alkali salt depicted below

wherein Y is selected from the group consisting of Li, Na and K.

17. The process according to claim 1 for the preparation of compound (Id) with the formula below

from compound (I) with the formula below

comprising the following step
debenzylating compound (A5-Y) to obtain compound (Id) according to the reaction scheme below

wherein Y is selected from the group consisting of Li, Na, and K.

18. The process according to claim 1 for the preparation of compound (Id) from compound (I) comprising
a step reacting compound (I), or a salt thereof, with benzyl halogenide to obtain compound (A2) according to the reaction scheme below

wherein Ph is phenyl and X is selected from the group consisting of Cl, Br and I; followed by
a step subjecting compound (A2) to a debenzylation reaction to obtain compound (A3), or a salt thereof according to the reaction scheme below

followed by
a step reacting compound (A3), or salt thereof, 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 (A4) according to the reaction scheme below

followed by
a step reacting compound (A4) with alkali-hydroxide to obtain (A5-Y) according to the reaction scheme below

wherein Y is selected from Li, Na and K; followed by
a step debenzylating compound (A5-Y) to obtain compound (Id) according to the reaction scheme below

wherein Y is selected from the group consisting of Li, Na and K.

Assignees

• H Lundbeck As

Inventors

• Juhl Martin
• Therkelsen Frans Dennis
• Frihed Tobias Gylling

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H17/02 Primary

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

• C07D221/08 Primary

  Aza-anthracenes · CPC title

• C07D221/06

  Ring systems of three rings · CPC title