# US 11,111,263 B2 · 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 > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,111,263 B2 - Document ID: US11111263B2 - Status: Granted - Kind: B2 - Application number: 16/876,878 - Filed: 2020-05-18 - Published: 2020-11-26 - Granted: 2021-09-07 - Earliest claimed: 2019-05-20 - Assignees: H. Lundbeck A/S - Applicants: H. Lundbeck A/S - Inventors: Martin Juhl; Frans Dennis Therkelsen; Tobias Gylling Frihed - Web page: https://patentgrep.com/patent/US11111263B2 ## CPC - C07D 405/12: linked by a chain containing hetero atoms as chain links - C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings - A61P 25/00: Drugs for disorders of the nervous system - C07D 455/06: containing benzo [a] quinolizine ring systems - C07H 1/00: Processes for the preparation of sugar derivatives - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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 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 new intermediates of said process. ## Claims ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 A compound of formula (A2) below: or a salt thereof. ### Claim 4 (depends on 1) 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 ### Claim 5 A compound of formula (A3) below: or a salt thereof. ### Claim 6 (depends on 4) 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). ### Claim 7 (depends on 6) 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. ### Claim 8 (depends on 4) The process according to claim 4, wherein compound (A3) is obtained in the form of a hydroiodide salt with the formula (A3-HI) below ### Claim 9 (depends on 5) The compound according to claim 5, which is in the form of a hydroiodide salt with the formula (A3-HI) below ### Claim 10 (depends on 1) 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 ### Claim 11 (depends on 10) The process according to claim 10, wherein compound (A3) is in the form of the hydroiodide salt (A3-HI) with the formula below: ### Claim 12 A compound of formula (A4) below: or a salt thereof. ### Claim 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. ### Claim 14 (depends on 13) 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. ### Claim 15 A compound of formula (A5) below: or a salt thereof. ### Claim 16 (depends on 15) 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. ### Claim 17 (depends on 1) 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. ### Claim 18 (depends on 1) 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.