EP3230265A1 - A process for the manufacture of idalopirdine - Google Patents

A process for the manufacture of idalopirdine

Info

Publication number
EP3230265A1
EP3230265A1 EP15821029.4A EP15821029A EP3230265A1 EP 3230265 A1 EP3230265 A1 EP 3230265A1 EP 15821029 A EP15821029 A EP 15821029A EP 3230265 A1 EP3230265 A1 EP 3230265A1
Authority
EP
European Patent Office
Prior art keywords
compound
mixture
fluoro
solvent
catalyst
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15821029.4A
Other languages
German (de)
English (en)
French (fr)
Inventor
Mikkel Fog JACOBSEN
Ole Nielsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by H Lundbeck AS filed Critical H Lundbeck AS
Priority claimed from PCT/EP2015/079209 external-priority patent/WO2016091997A1/en
Publication of EP3230265A1 publication Critical patent/EP3230265A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to the preparation of N-(2-(6-fluoro-lH-indol-3-yl)-ethyl)- 3-(2,2,3,3-tetrafluoropropoxy)-benzylamine, INN-name idalopirdine, and pharmaceutically acceptable salts thereof.
  • N-(2-(6-fiuoro-lH-indol-3-yl)-ethyl)-3-(2,2,3,3-tetrafluoropropoxy)-benzylamine is a potent and selective 5-HT 6 receptor antagonist which is currently in clinical development. Its chemical structure is depicted below as Com ound (I).
  • This method of manufacture comprises the steps
  • WO2011/076212 further discloses 2-(6-fluoro-lH-indol-3-yl)ethylamine hydrogen L-(+)-tartrate (the 1 :1 salt of 2-(6-fluoro-lH-indol-3-yl)ethylamine and L-(+)-tartaric acid) as well as a process for the purification of 2-(6-fluoro-lH-indol-3-yl)ethylamine comprising the steps of:
  • DMF N,N-dimethylformamide
  • MeOH is methanol.
  • THF is tetrahydrofuran.
  • TCE 2,2,2-trichloroethanol
  • i-PrOH is 2-propanol (isopropyl alcohol).
  • RaNi'VRaney nickel is an activated nickel catalyst which is optionally doped with another metal and that comes in different particle sizes and forms
  • Cyanide source is KCN, NaCN, or other agents which release the CN “ anion.
  • DI is distilled or ultra-pure.
  • M is molar
  • v/v volume per volume
  • HPLC high pressure liquid chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Pd/C is palladium on charcoal.
  • Platinum/C is platinum on charcoal.
  • Rh/C is rhodium on charcoal.
  • Pore/Alumina is rhodium on aluminium oxide.
  • Ni/Silica-alumina is nickel on a mixture of silicon oxide and aluminium oxide
  • PRICATTM is the trademark for a series of supported nickel catalysts on silica with/without added promotors, from Johnson Matthey Process Technologies.
  • NMP N-methylpyrrolidinone.
  • DMF-DMA N,N-dimethylformamide dimethyl acetal.
  • EDG is ethylene glycol
  • nickel catalyst refers to catalysts comprising nickel or nickel oxides or mixtures thereof.
  • embodiment of the invention is disclosed a process for the preparation of Compound (IV)
  • the nickel catalyst is supported on silica or alumina.
  • the supported nickel catalyst is selected from the group comprising PRICAT 55/5P and PRICAT 62/15P.
  • the alcoholic solvent is methanol, ethanol or 2-propanol.
  • the hydrogenation is run at a pressure from approx. 2 to approx. 10 bar, more particularly from approx. 2 to approx. 6 bar and most particularly from approx. 2 to approx. 4 bar.
  • the hydrogenation is run at a temperature from about 40 °C to about 70 °C, more particularly from about 50 °C to about 60 °C.
  • the hydro genation is run with a loading from about 8 % to about 31 % (w/w) supported nickel catalyst relative to (6-fluoro- lH-indol-3-yl)acetonitrile.
  • sodium borohydride is used as the reducing agent for the reduction to Compound I.
  • Compound (XIII) is reacted in DMF or NMP as solvent. In a more particular embodiment Compound (XIII) is converted to Compound (XI) using DMF- DMA.
  • Compound (XI) is reduced to Compound (X) using Raney nickel or palladium on charcoal as catalyst. In a more particular Compound (XI) is reduced to Compound (X) using hydrazine or hydrogen as reductant.
  • Compound (I) forms pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Such salts include the pharmaceutically acceptable salts listed in Berge, S. M.et al., J. Pharm. Sci. 1977, 66, 1-19 which are known to the skilled artisan. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-l ,4-dicarboxylate, hexyne-1 , 4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptarioate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate, phen
  • the mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20 °C) was added drop-wise to reactor B while keeping the temperature at 2-8 °C.
  • the reaction mixture was stirred for additional 10 min at 2-8 °C.
  • the reaction mixture was slowly warmed to approx. 40 °C over a 1 h period.
  • the reaction mixture was stirred at approx. 40 °C for an additional 1 h.
  • the reaction mixture was cooled to about 20°C.
  • a 250 L reactor was charged with approx. 40% aq. dimethylamine (35.7 kg, 317 mol) at approx. 17 °C under an inert atmosphere.
  • the mixture was cooled to approx. 4.5 °C and glacial acetic acid (43.4 kg, 723 mol) was added dropwise over 140 min while maintaining the temperature at approx. 15°C.
  • 37% aqueous formaldehyde 25.9 kg, 319 mol
  • reaction was exothermic and reached a final temperature of approx. 40 °C, and it was then cooled down to approx. 20°C.
  • the reaction solution was slowly added to a 650 L reactor previously charged with aq. NaOH (3 M) over a period of approx. 40 min.
  • the formed suspension was stirred for approx. 40 min while keeping the temperature between 5 to 20 °C.
  • the precipitate was filtered from solution, washed with water on the filter, and dried at approx. 50°C to afford Compound (II) (45.4 kg, 81%).
  • the mixture was hydrogenated at 4 bar and at the specified temperature for the specified time.
  • the reaction mixture was analysed directly by LC-MS.
  • DPPF l, -Bis(diphenylphosphino)ferrocene, cas number: 12150-46-8.
  • Tris(triphenylphosphine)ruthenium(II) dichloride cas number 15529-49-4.
  • Tris(triphenylphosprtine)rhodiutri(I) carbonyl hydride cas number 17185-29-4.
  • Example 7 Screening of rhodium, platinum and nickel catalysts
  • PRICAT type 55/5P catalyst (14.0 kg) was charged to a reactor followed by charging of a solution of Compound (III) (46.3 kg, 266 mol) in isopropanol (76.4 kg). Then isopropanol (106 L) and aq. ammonia (302 L, 25%) was charged. The mixture was transferred to a steel autoclave under nitrogen, using extra isopropanol (92 L) for washing of reactor. The autoclave was evacuated and then pressurized with hydrogen gas to 3 bar. The content was heated to 55 °C and hydrogenated at 3 bar hydrogen for 48 h. The content was cooled to 25 °C, and the autoclave was purged with nitrogen gas, and the content filtered on a pressure nutsch filter. The filter was washed with isopropanol (2 x 145 L). This yielded a solution of Compound (IV).
  • the formed suspension was stirred at 60 °C for 3 h, and cooled over a period of 3 h to 25 °C.
  • the suspension was filtered on a pressure nutsch filter, and the filter cake was washed twice with a mixture of isopropanol (170 L), ethyl acetate (78 kg) and water (17 L).
  • the filter cake was broken up and dried on trays in a vacuum oven at 60 °C for 5 days to yield Compound (V) (163 kg, 94%) as an off-white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP15821029.4A 2014-12-12 2015-12-10 A process for the manufacture of idalopirdine Withdrawn EP3230265A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA201400721 2014-12-12
PCT/EP2015/079209 WO2016091997A1 (en) 2014-12-12 2015-12-10 A process for the manufacture of idalopirdine

Publications (1)

Publication Number Publication Date
EP3230265A1 true EP3230265A1 (en) 2017-10-18

Family

ID=59011415

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15821029.4A Withdrawn EP3230265A1 (en) 2014-12-12 2015-12-10 A process for the manufacture of idalopirdine

Country Status (13)

Country Link
EP (1) EP3230265A1 (he)
JP (1) JP2017537128A (he)
KR (1) KR20170093821A (he)
CN (1) CN107001266A (he)
AU (1) AU2015359347A1 (he)
BR (1) BR112017012021A2 (he)
CA (1) CA2968770A1 (he)
CL (1) CL2017001466A1 (he)
CO (1) CO2017005357A2 (he)
IL (1) IL252471A0 (he)
MA (1) MA41148A (he)
MX (1) MX2017007510A (he)
RU (1) RU2017120216A (he)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6757565B2 (ja) 2014-12-12 2020-09-23 日本たばこ産業株式会社 ジヒドロピリミジン−２−オン化合物およびその医薬用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3042685A (en) * 1962-07-03 Process of making g-fluoro tryptamine
AR065804A1 (es) * 2007-03-23 2009-07-01 Smithkline Beecham Corp Compuesto de indol carboxamida, composicion farmaceutica que lo comprende y uso de dicho compuesto para preparar un medicamento
TW201139370A (en) * 2009-12-23 2011-11-16 Lundbeck & Co As H Processes for the manufacture of a pharmaceutically active agent

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2016091997A1 *

Also Published As

Publication number Publication date
CO2017005357A2 (es) 2017-09-20
BR112017012021A2 (pt) 2018-03-13
CA2968770A1 (en) 2016-06-16
IL252471A0 (he) 2017-07-31
JP2017537128A (ja) 2017-12-14
MX2017007510A (es) 2017-08-22
AU2015359347A1 (en) 2017-06-08
RU2017120216A (ru) 2019-01-15
CN107001266A (zh) 2017-08-01
KR20170093821A (ko) 2017-08-16
MA41148A (fr) 2017-10-17
CL2017001466A1 (es) 2018-01-05

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