WO2020212399A1 - Procédé de préparation d'un composé ester d'acide carboxylique trans-3-aminobicyclo [2.2.2] octane-2-carboxylique - Google Patents

Procédé de préparation d'un composé ester d'acide carboxylique trans-3-aminobicyclo [2.2.2] octane-2-carboxylique Download PDF

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Publication number
WO2020212399A1
WO2020212399A1 PCT/EP2020/060551 EP2020060551W WO2020212399A1 WO 2020212399 A1 WO2020212399 A1 WO 2020212399A1 EP 2020060551 W EP2020060551 W EP 2020060551W WO 2020212399 A1 WO2020212399 A1 WO 2020212399A1
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Prior art keywords
compound
formula
binap
chiral
salt
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PCT/EP2020/060551
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English (en)
Inventor
Marius MEWALD
Steffen TROLTSCH
Siebo GELLHAAR
Jozef Ludo Jan Cuypers
Walter Ferdinand Maria Filliers
Tor Wim L. MAES
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Janssen Pharmaceutica Nv
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Publication of WO2020212399A1 publication Critical patent/WO2020212399A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/44—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing eight carbon atoms

Definitions

  • the present invention relates to a method for the preparation of a chiral amine, in particular ethyl (2S,
  • Compound (A) is also known as (2S,3S)-3- ⁇ [5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)- pyrimidin-4-yl]amino ⁇ bicyclo[2.2.2]octane-2-carboxylic acid or under its INN as pimodivir.
  • solvates thereof such as the hydrochloride salt hemihydrate, inhibit the replication of influenza
  • Diastereoselective catalytic hydrogenation of the double bond was performed in the presence of hydrogen gas (H 2 ) and palladium on carbon (Pd/C).
  • This method presents several drawbacks.
  • the hydrogenation step was carried out under high pressure.
  • palladium is a hazardous reagent. Working under high pressure presents also a risk of explosion of the reactor or of the reaction vessel in the case of an over-pressurizing.
  • hydrogen is a highly flammable gas and palladium is a pyrophoric reagent.
  • WO2005/028419 describes a synthesis method for producing an amino acid derivative by reacting a keto acid derivative with ammonia or an amine or a salt thereof in the presence of a chiral catalyst and molecular hydrogen.
  • the described method uses hydrogen gas at high pressure and thus presents the same safety drawbacks mentioned above. Additionally, said method yields only moderate enantiomer selectivity, also referred to by enantiomer excess (ee), as reported in the examples section below. Consequently, there is a need for a synthesis method for chiral cyclic beta-amino esters such as Compound (I) and salts thereof that at least overcomes the above-mentioned drawbacks.
  • R 1 is C 1-6 alkyl
  • the present invention provides a method of preparing Compound (I) or a salt thereof:
  • Also described herein is a method of preparing Compound (A) or a salt or solvate thereof comprising treating a racemic compound of Formula (IIb) or Compound (II) with HCO 2 NH 4 and a chiral transfer hydrogenation catalyst to form a compound of Formula (Ib) or Compound (I), or a salt thereof, and converting the compound of Formula (Ib) or Compound (I), or a salt thereof, to Compound (A) or a salt or solvate thereof.
  • the present invention relates to a compound of Formula (III):
  • R 1 is C 1-6 alkyl.
  • the compound of Formula (III) can exist in the enamine form as shown, or in the corresponding imine tautomer form (III’), or as a mixture thereof.
  • the present invention relates to a mixture of a racemic compound of Formula (IIa) or racemic Compound (II) and HCO 2 NH 4 and optionally a chiral transfer hydrogenation catalyst.
  • the method of the present invention presents several advantages compared to the methods of the prior art.
  • the method of the invention leads to high selectivity or ee. Additionally, it is safer as it is devoid of azide reagents thereby eliminating the need for the storage and the use of sensitive reagents.
  • the method of the invention is also devoid of hydrogenation step under high pressure as hydrogen is provided from a different source, i.e. ammonium formate.
  • the method of the invention is more efficient in term of diastereo- and enantioselectivity, shorter and safer compared to the existing synthesis routes.
  • “Compound (A)” refers to the free base form of Compound (A) and“Compound (I)” refers to the free base form of Compound (I).
  • a salt of Compound (A) or Compound (I) refers to a salt composed of a 1:1 ratio of the compound and the acid component of the salt.
  • The“HCl salt of Compound (A),” the“HCl salt of Compound (I),” and“Compound (Ia)” refer to a 1:1 ratio of the HCl and the compound free base components.
  • alkyl refers to a saturated, straight or branched chain hydrocarbon group.
  • C x-y refers to a hydrocarbon group with from x to y carbon atoms in the hydrocarbon group.
  • exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • a“chiral transfer hydrogenation catalyst” is a hydrogenation catalyst comprising a metal (II) complex, wherein the metal is ruthenium, rhodium, or iridium, and preferably ruthenium.
  • the catalyst also comprises a chiral ligand chelated to the metal atom, such as a chiral bisphosphine ligand.
  • the catalyst serves to catalyze the asymmetric transfer of hydrogen from a hydrogen donor, such as formate, to an achiral imine intermediate, thereby catalyzing an asymmetric transfer hydrogenation.
  • the imine is formed by reaction of a ketone with ammonia.
  • the source of both the ammonia and the formate is ammonium formate.
  • the imine substrate for the asymmetric transfer hydrogenation with formate is formed in situ from a ketone by reaction of the ketone with ammonia or ammonium formate.
  • Suitable salts of the compounds described herein include acid addition salts of amino compounds.
  • suitable salts include hydrochloride, hydrobromide, acetate, phosphate, and other salts.
  • the compounds described herein, and salts thereof, can exist in solvated forms, such as hydrates, including hemihydrates.
  • cis and trans refer to the relative orientation of the amino and ester groups in, for example, Compound (I) or (Ib) (trans, one group axial and one equatorial) and the diastereomer thereof (cis, both groups axial or both groups equatorial).
  • R 1 is C 1-6 alkyl
  • R 1 is methyl, ethyl, propyl, or isopropyl. In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl.
  • a method of preparing Compound (A) or a salt or solvate thereof comprising treating a racemic compound of Formula (IIb) or racemic Compound (II) with HCO 2 NH 4 and a chiral transfer hydrogenation catalyst to form a compound of Formula (Ib) or Compound (I), or a salt thereof, and converting the compound of Formula (Ib) or Compound (I), or a salt thereof, to
  • the racemic compound of Formula (IIb) is Compound (II) and the compound of Formula (Ib) is Compound (I).
  • the method is used to prepare Compound (A) hydrochloride salt or Compound (A) hydrochloride salt hemihydrate.
  • the present invention relates to a compound of Formula (III), or a tautomer thereof, or a mixture of tautomers thereof: wherein R 1 is C 1-6 alkyl.
  • R 1 is methyl, ethyl, propyl, or isopropyl.
  • R 1 is methyl or ethyl.
  • R 1 is ethyl.
  • the present invention relates to composition
  • composition comprising a racemic compound of Formula (IIb) or racemic Compound (II) and HCO 2 NH 4 and optionally a chiral transfer hydrogenation catalyst.
  • the present invention relates to a method for the preparation of Compound (I)
  • the chiral transfer hydrogenation catalyst for the transfer hydrogenation serves to transfer hydrogen from a hydrogen donor, such as formate, to an imine substrate.
  • the chiral transfer hydrogenation catalyst is a chiral ruthenium, rhodium, or iridium hydrogenation catalyst.
  • the chiral transfer hydrogenation catalyst is a chiral ruthenium hydrogenation catalyst.
  • the chiral transfer hydrogenation catalyst comprises a ruthenium (II) complex chelated to a chiral bisphosphine ligand.
  • the ruthenium catalyst is a ruthenium (II) complex. In some embodiments, the ruthenium catalyst comprises a ruthenium (II) complex chelated to a chiral bisphosphine ligand. In some embodiments, the ruthenium (II) complex is Ru(OAc)2 or RuCl2. In some embodiments, the chiral bisphosphine ligand is an atropisomeric aryl bisphosphine ligand. In some embodiments, the chiral bisphosphine ligand is a chiral binaphthalene bisphosphine ligand.
  • the chiral bisphosphine ligand is (S)-BINAP, (S)-(Xyl- BINAP), or (S)-(Tol-BINAP).
  • the chiral ruthenium hydrogenation catalyst is selected from (S)-Ru(OAc) 2 (Tol-BINAP), (S)-Ru(OAc) 2 BINAP, (S)-Ru(OAc) 2 (Xyl-BINAP), (S)- RuCl[p-cymene(BINAP)]Cl, (S)-RuCl 2 (Tol-BINAP), and (R)-RuCl 2 (Tol-BINAP).
  • the chiral ruthenium hydrogenation catalyst is selected from (S)-Ru(OAc) 2 (Tol- BINAP), (S)-Ru(OAc) 2 BINAP, (S)-Ru(OAc) 2 (Xyl-BINAP), and (S)-RuCl 2 (Tol-BINAP).
  • the chiral transfer hydrogenation catalyst or ruthenium catalyst can be used as such in the reaction mixture, or the catalyst can be pre-formed in-situ from a metal complex, such as a ruthenium (II) complex, in particular a ruthenium (II) complex chelated to an aryl ligand such as p-cymene (e.g., dichloro(p- cymene)ruthenium(II) dimer) and a bisphopshine ligand such as BINAP, a derivative of a BINAP ligand, or an analogous ligand.
  • the catalyst is a homogeneous ruthenium catalyst bearing a chiral bisphosphine ligand.
  • the chiral transfer hydrogenation catalyst is a homogeneous ruthenium (II) catalyst complexed to a chiral bisphosphine ligand.
  • BINAP is 2,2 ⁇ - bis(diphenylphosphino)-1,1 ⁇ -binaphthyl.
  • the catalyst loading is comprised between 1 mol% and 6 mol%, preferably between 2 mol% and 5 mol%, more preferably, between 3 mol% and 4 mol%. In a preferred embodiment, the catalyst loading is in the range of about 1 mol% to 6 mol%, relative to the keto-ester starting material, preferably from about 2 mol% and 5 mol%, more preferably, from about 3 mol% and 4 mol%.
  • the solvent is a C 1-4 alkanol, or a C 1-4 -fluoroalkanol, or a mixture thereof.
  • the solvent is selected from trifluoroethanol, ethanol, methanol, and acetonitrile, or any combination thereof.
  • the solvent is trifluoroethanol or ethanol, or a mixture thereof.
  • the solvent is trifluoroethanol or a mixture of trifluoroethanol and ethanol.
  • the solvent is a mixture of trifluoroethanol and ethanol. More preferably, the solvent is trifluoroethanol.
  • the ratio between the solvents is comprised between 1:1 and 1:5.
  • the ratio ranges from 1:1 to 1:3. More preferably, the ratio is comprised between 1:1 and 1:2.
  • the ratio between the solvents is in the range of about 1:1 and 1:5 by volume.
  • the ratio ranges from about 1:1 to 1:3 by volume. More preferably, the ratio is in the range of about 1:1 to 1:2 by volume.
  • the solvent is a mixture in the range of about 1:1 to 1:3 by volume of trifluoroethanol and ethanol.
  • the solvent is a mixture of about 1:1 by volume of trifluoroethanol and ethanol.
  • the volume of the solvent is comprised between 3 and 15 mL per g of ketoester (II), preferably between 5 and 12 mL per g of ketoester (II), more preferably between 7 and 11 mL per g of ketoester (II), most preferably between 9 and 10 mL per g of ketoester (II).
  • the volume of the solvent is in the range of about 3 to 15 mL per g of
  • Compound (II) or the compound of Formula (IIb) preferably in the range of about 5 to 12 mL per g of Compound (II) or the compound of Formula (IIb), more preferably in the range of about 7 to 11 mL per g of Compound (II) or the compound of Formula (IIb), most preferably in the range of about 9 to 10 mL per g of Compound (II) or the compound of Formula (IIb).
  • the amount of ammonium formate is comprised between 1 and 15 equivalents. In a preferred embodiment, the amount of ammonium formate ranges from 3 to 14, preferably from 5 to 12 equivalents, more preferably from 8 to 10 equivalents. The amount of ammonium formate is in the range of about 1 to 15 equivalents relative to Compound (II) or the compound of Formula (IIb). In a preferred embodiment, the amount of ammonium formate ranges from about 3 to 14 equivalents, preferably from about 5 to 12 equivalents, more preferably from about 8 to 10 equivalents.
  • the treating is performed in the presence of one or more additional additives.
  • An additive may be added to the reaction.
  • Said additive can be organic or inorganic base or an acid.
  • the one or more additives are selected from an organic base, an inorganic base, and an acid, and mixtures thereof.
  • a base is used, in some embodiments it is selected from triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate, sodium formate, sodium acetate, and ammonia or a combination thereof.
  • the base is ammonia.
  • the additive is an organic base.
  • the organic base is ammonia, aqueous ammonia (e.g., about 15 to 40% aqueous ammonia, or about 20 to 35% aqueous ammonia), triethylamine, diisopropylethylamine, sodium formate, and sodium acetate.
  • the additive is an inorganic base.
  • the inorganic base is selected from potassium phosphate, and potassium carbonate.
  • the additive is aqueous ammonia, such as about 15 to 40% aqueous ammonia, or about 20 to 35% aqueous ammonia, or about 25% aqueous ammonia, or about 32% aqueous ammonia.
  • an acid is used, in some embodiments it is selected from formic acid, benzoic acid and salicylic acid or any combination thereof.
  • the additive is an acid.
  • the acid is a carboxylic acid.
  • the carboxylic acid is formic acid.
  • the amount of the additive is comprised between 1 and 4 equivalents, preferably between 1.5 and 3 equivalents, more preferably the amount of additive is 2 equivalents.
  • the amount of the additive is comprised in the range of about 1 to 4 equivalents relative to Compound (II) or the compound of Formula (IIb), preferably in the range of about 1.5 to 3 equivalents, more preferably the amount of additive is about 2 equivalents.
  • the additive is about 2 equivalents of about 20 to 35% aqueous ammonia, or about 25% aqueous ammonia, or about 32% aqueous ammonia.
  • the reaction is performed at a temperature comprised between 60 and 90°C, preferably between 70 and 85°C, more preferably between 75 and 80 °C.
  • the treating is performed at a temperature between about 0 °C and about 150 °C, or between about 60 °C and 90 °C, preferably between about 70 °C and 85 °C, more preferably between 75°C and 80 °C.
  • the reaction time is comprised between 10 and 20 hours (h). In an embodiment, the reaction time ranges from 5 to 20 hours. Preferably, the reaction time is between 8 and 18 hours. More preferably, the reaction time is comprised between 10 and 17 hours. Most preferably, the reaction time ranges from 12 to 16 hours. Particularly, the reaction time is 16 hours.
  • the reaction time is in the range of about 10 to 20 hours (h), or about 5 to 20 hours, or about 8 and 18 hours, or about 10 and 17 hours, or about 12 to 16 hours, or about 16 hours. Examples
  • Compound (I) was synthesized using the method described in WO2005/028419 by mixing Compound (II) with (S)-Ru(OAc)2(Tol-BINAP) (1 mol%), ammonium acetate (3 equiv.), and trifluoroethanol (9 mL/g of Compound (II)). The mixture was stirred at 80 °C under a hydrogen pressure of 10 bar for 16 h until complete conversion of the imine/enamine intermediate was observed. The reaction yielded Compound (I) with an ee of 50% and a diastereoselectivity of 22:1 trans/cis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de la préparation d'éthyl (2S, 3S)-3-aminobicyclo [2.2.2] octane-2-carboxylate à partir de l'ester β-céto (II) par l'intermédiaire d'une réaction d'hydrogénation par transfert chiral en présence de formiate d'ammonium. La réaction se déroule avec une diastéréosélectivité élevée et un excellent excès énantiomérique.
PCT/EP2020/060551 2019-04-15 2020-04-15 Procédé de préparation d'un composé ester d'acide carboxylique trans-3-aminobicyclo [2.2.2] octane-2-carboxylique WO2020212399A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112578034A (zh) * 2020-11-04 2021-03-30 广东众生睿创生物科技有限公司 一种手性胺小分子及其盐的质量控制方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028419A2 (fr) 2003-09-18 2005-03-31 Takasago International Corporation Procede de production de derives d'acides amines
WO2010148197A1 (fr) 2009-06-17 2010-12-23 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe
US20120065426A1 (en) * 2010-09-15 2012-03-15 Kanto Kagaku Kabushiki Kaisha Process for preparing amine compound
WO2015073476A1 (fr) 2013-11-13 2015-05-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028419A2 (fr) 2003-09-18 2005-03-31 Takasago International Corporation Procede de production de derives d'acides amines
WO2010148197A1 (fr) 2009-06-17 2010-12-23 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe
US20120065426A1 (en) * 2010-09-15 2012-03-15 Kanto Kagaku Kabushiki Kaisha Process for preparing amine compound
WO2015073476A1 (fr) 2013-11-13 2015-05-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112578034A (zh) * 2020-11-04 2021-03-30 广东众生睿创生物科技有限公司 一种手性胺小分子及其盐的质量控制方法

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