WO2014016338A1 - Nouvelle voie de synthèse pour la préparation de composés 3-amino-pipéridine - Google Patents

Nouvelle voie de synthèse pour la préparation de composés 3-amino-pipéridine Download PDF

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WO2014016338A1
WO2014016338A1 PCT/EP2013/065622 EP2013065622W WO2014016338A1 WO 2014016338 A1 WO2014016338 A1 WO 2014016338A1 EP 2013065622 W EP2013065622 W EP 2013065622W WO 2014016338 A1 WO2014016338 A1 WO 2014016338A1
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substituted
unsubstituted
compound
formula
alkyl
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PCT/EP2013/065622
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Gaj STAVBER
Jerome Cluzeau
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Lek Pharmaceuticals D.D.
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Priority to CN201380049535.1A priority Critical patent/CN104837817B/zh
Publication of WO2014016338A1 publication Critical patent/WO2014016338A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates in general to the field of organic chemistry and in particular to the preparation of 3-amino-piperidine compounds. These compounds are useful intermediates in the synthesis of various pharmaceutically active agents, such as the preferred example tofacitinib or derivatives thereof, as well as other pharmaceutically active agents comprising as a structure a 3-aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • various pharmaceutically active agents such as the preferred example tofacitinib or derivatives thereof
  • other pharmaceutically active agents comprising as a structure a 3-aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • 3-amino-piperidine compounds represent valuable intermediates for the preparation of pharmaceutically active agents.
  • the Janus kinase 3 (JAK3) inhibitor tofacitinib having the structural formula
  • Janus kinase 3 (JAK3) inhibitors are a group of compounds that are classified to interfere with the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway transmitting extracellular information into the cell nucleus and influencing DNA transcription.
  • Tofacitinib as one JAK3 inhibitor was found to be effective for many applications and can be used against e.g. rheumatoid arthritis, psoriasis inflammatory bowel disease and other immunological diseases, as well as for prevention of organ transplant rejection.
  • the resulting compound B was subjected to oxidation of the toluenesulfonate salt of the piperidine alcohol by an excess of costly S0 3 pyridine complex as disclosed in D. H. Brown, et. al, Org. Proc. Res. Dev. 2003, 7, pages 1 15 to 120.
  • the whole process is illustrated in Scheme 1 and involves application of hazardous reagents in the form hydroborating agents such as NaBH 4 or BH 3 complexes and strong oxidants such as hydrogen peroxide, bleach or Oxone ® . These hazardous reagents bear a safety risk for large scale production.
  • WO 2007/012953 discloses a further synthetic pathway in which 3-amino-4-picoline is used as starting material.
  • the pathway contains the steps of benzyl activation of pyridine ring and partial reduction using sodium borohydride.
  • asymmetric hydrogenation is carried out to finally obtain a benzyl protected 3-amino-piperidine precursor in modest enantioselectivity of at best 68 % ee.
  • This synthetic pathway requires rare and very costly chiral ligands and metal catalysts for asymmetric reduction.
  • the object of the present invention is to provide an improved process for preparing 3-amino- piperidine compounds representing valuable key intermediates for the preparation of pharmaceutically active agents, such as preferably tofacitinib or derivatives thereof, or other compounds containing a 3-amino-piperidine structural moiety.
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 2 represents hydrogen or nitrogen protecting group
  • R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • -CO-R 7 or - CO-ORy wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 4 represents alkyl, which process comprises treating nd of formula II
  • R 4 are defined as above and X is selected from CI, Br and I, with an amine NHR 2 R 3 in which R 2 and R 3 are defined as above.
  • alkyl as used herein means straight, branched or cyclic hydrocarbons having a typical meaning, preferably of 1 to 12 carbon atoms, more preferably of 1 to 8 carbon atoms, even more preferably of 1 to 6 carbon atoms and in particular of 1 to 3 carbon atoms.
  • aryl as used herein means aromatic hydrocarbons having a typical meaning, preferably of 6 to 12 carbon atoms, preferably single or condensed six-membered rings, more preferably phenyl.
  • heteroaryl as used herein means aromatic hydrocarbons incorporating at least one heteroatom such as nitrogen into the aromatic ring structure, preferably of 6 to 12 atoms comprising both carbon and heteroatoms, preferably single or condensed six- membered rings, more preferably pyridine.
  • substituted means that one or more, preferably 1 -3 hydrogen atoms of a structural moiety are replaced independently from each other by the corresponding number of substituents.
  • substituents include, without being limited thereto, for example halogen, trifluoromethyl, cyano, nitro, -NR', -OR', -N(R')R" and R'", wherein each of R', R" and R'" are selected from the group consisting of linear or branched C1 - C6 alkyl.
  • substituent(s) are at positions where their introduction is/are chemically possible, that is positions being known or evident to the person skilled in the art to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • substituents which may be unstable or may affect reactions disclosed herein may be omitted.
  • R 3 and R 4 are unsubstituted.
  • nitrogen protecting group means any group that is used for protection of amines.
  • group is selected from the group consisting of fert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), unsubstituted or substituted benzyl, or benzenesulfonyl (Bs), p-toluenesulfonyl (Ts), 2- naphthylsulfonyl, trifluoroacetyl (TFA), trityl (Tr), trichloroacetyl (TCA), formyl (CHO), acetyl (Ac), benzoyl (Bz), C 4 -C 5 -feri-alkyl, preferably fert-butyl (f-Bu).
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 2 represents hydrogen or nitrogen protecting group
  • R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • -CO-R 7 or - CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 4 represents alkyl, which process comprises treating a compound of formula III
  • R 4 are defined as above, with an amine NHR 2 R 3 in which R 2 and R 3 are defined as above.
  • NHR 2 R 3 is selected from the group consisting of N-benzylmethylamine, N-a-dimethylbenzylamine, methyl carbamate and methyl amine, preferably NHR 2 R 3 is methyl amine.
  • hyperstoichiometric amount relative to compound of formula III preferably in at least 2 mol equivalent.
  • R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or from -CO-R 6 or -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and X is selected from CI, Br and I, and R 4 represents alkyl, by reacting a compound of formula I
  • proton donor means any compound which is capable to donate a proton to another compound.
  • halogenating agent means any compound which is capable to introduce a halogen substituent to another compound.
  • halogenating agent is selected from the group consisting of N-chlorosuccinimide, N-iodosuccinimide, N-bromosuccinimide, 5,5- dimethyl-1 ,3-dibromohidantoin (DBDMH), preferably N-bromosuccinimide and DBDMH, more preferably N-bromosuccinimide.
  • F is -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, with an acid chloride CI-CO-R 6 , a chloro carboxylic ester CI-CO-OR 6 or a sulfonic acid chloride Cl-S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R/ is -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, more preferably R is benzyl (-CH 2 -Ph).
  • compound of formula III is reacted with an acid chloride CI-CO-R 6 or a chloro carboxylic ester CI-CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or from -CO-R 6 and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 is alkyl, which process comprises the steps of :
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , -CO-OR 6 and -S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or - CO-ORy wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, which process comprises the steps of : a) converting a compound of formu I
  • R 4 ' derives from R 4 representing alkyl in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R 4 ' is formed, by treating compound of formula IV
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , -CO-OR 6 and -S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, with an acidic activator.
  • compound of formula IV is prepared by a process according to any one of items (1 ) to (1 1 ) and (23) to (25).
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , -CO-OR 6 and -S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO- R7 or -CO-OR7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, by hydrogenating a compound of formula V 1 and/or V 2
  • R 4 ' derives from R 4 representing alkyl in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R 4 ' is formed, in the presence of a transition-metal catalyst.
  • compounds of formulae V 1 and V 2 are prepared by a process according to any one of items (26) to (28).
  • the transition metal catalyst comprises a transition metal selected from the group consisting of Pt, Rh, Ru, Pd and Pd-Cu which catalyst is optionally attached to a supporter selected from the group consisting of charcoal, carbon, graphite or alumina (Al 2 0 3 ); preferably the catalyst comprises Pt or Rh optionally attached to a supporter selected from the group consisting of charcoal, carbon, graphite or alumina (Al 2 0 3 ); in particular, the catalyst is Rh on activated carbon paste, Pt0 2 hydrate or Pt on charcoal.
  • the additive is selected from the group consisting of Broensted acids, Lewis acids and organic ligands, more preferably AcOH, TFA, oxalic acid, citric acid, tartaric, BF 3 dietherate, copper salts, magnesium salts, iron salts, D-glucosamine, 1 ,4- diazoniabicyclo[2.2.2]octane (DABCO), amino acids.
  • the additive is selected from the group consisting of Broensted acids, Lewis acids and organic ligands, more preferably AcOH, TFA, oxalic acid, citric acid, tartaric, BF 3 dietherate, copper salts, magnesium salts, iron salts, D-glucosamine, 1 ,4- diazoniabicyclo[2.2.2]octane (DABCO), amino acids.
  • additive means a compound which improves conversion rate and/or yield of the hydrogenation reaction.
  • the unit “bar” for pressure as used herein is a generally accepted term for exactly 100 kPa according to SI.
  • the unit “atm” is an old pressure unit for external (ambient) air pressure, defined on sea level, which is equal to 1.013 bar (101 ,3 kPa). Considering an instrumental error of pressure measuring, which is more than 2% and sea level/weather variations of air pressure, the pressure expressed by "bar” or “atm” describes herein the same reaction conditions.
  • an additional additive in the form of an organic acid is present, preferably the additional additive is selected from the group consisting of AcOH, TFA, oxalic acid, citric acid, tartaric, in particular the additional additive is AcOH.
  • P is selected from -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or from -CO-R 6 and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and X is CI, Br or I, and R 4 is alkyl, preferably C1 -C4-alkyl, more preferably R 4 is methyl, or an acid addition salt thereof.
  • R 4 is alkyl, preferably C1 -C4-alkyl, more preferably R 4 is methyl, or an acid addition salt thereof.
  • acid addition salt means a salt formed of compound of formula II and an acid in the form of a proton donor, in which salt the nitrogen of compound of formula II is in protonated form.
  • Any organic or inorganic proton donor can be used as acid for acid addition salt formation.
  • the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid and phosphoric acid, more preferably hydrochloric acid.
  • Ri is selected from -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, preferably C1 -C4-alkyl, in particular R 4 is methyl, or an acid addition
  • acid addition salt means a salt formed of compound of formula IV and an acid in the form of a proton donor, in which salt at least one nitrogen of compound of formula IV is in protonated form.
  • Any organic or inorganic proton donor can be used as acid for acid addition salt formation.
  • the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid,
  • benzenesulfonic acid toluenesulfonic acid, methanesulfonic acid and phosphoric acid, more preferably hydrochloric acid.
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 4 ' represents alkyl in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen and R 4 represents hydrogen or al
  • R ⁇ is -CH 2 -R 5 in which R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, preferably is -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, more preferably, R ⁇ is benzyl (-CH 2 -Ph).
  • R ⁇ is selected from the group consisting of -CH 2 -Ph, -CO-CH 3 , -CO-OEt, - CO-OCH 2 Ph, -CO-OCH 2 CCI 3 , -CO-OCH 2 C(CH 3 ) 3 , preferably R, is selected from the group consisting of -CH 2 -Ph, -CO-CH 3 and -CO-OEt.
  • R 2 is H; and R 3 is selected from the group consisting of H, CH 3 , -CH 2 -Ph, - CH(CH 3 )-Ph, -CO-OCH 3 and -CO-OEt.
  • acid addition salt means a salt formed of compound of tofacitinib and an acid in the form of a proton donor, in which salt the nitrogen of compound of formula II is in protonated form.
  • Any organic or inorganic proton donor can be used as acid for acid addition salt formation.
  • an acid is selected which provides for a pharmaceutically acceptable acid addition salt. More preferably, the acid is hydrochloric acid.
  • novel compounds of formulae V, IV, II and/or V 1 and V 2 represent particularly suitable intermediate compounds for preparing 3-aminopiperidine compounds.
  • Compounds of formulae IV and II can be easily prepared from simple and readily available starting materials by means of (relatively) harmless reactants providing for safer working conditions under ecologically beneficial reaction conditions.
  • Said 3-aminopiperidine compounds of formulae IV and/or II can subsequently be conveniently converted to various pharmaceutically active agents, such as preferably tofacitinib or derivatives thereof.
  • 3-aminopiperidine compounds to further pharmaceutically active agents comprising 3- aminopiperidine as a structural moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • the present invention surprisingly satisfies a hitherto unmet need for an improvement of processes for preparing a compound that is suitable for industrial production of a pharmaceutically active agent comprising a 3-aminopiperidine moiety such as preferably tofacitinib or derivatives thereof, but also other pharmaceutically active agents comprising as a structure a 3- aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • a pharmaceutically active agent comprising a 3-aminopiperidine moiety such as preferably tofacitinib or derivatives thereof, but also other pharmaceutically active agents comprising as a structure a 3- aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • a general synthetic concept is provided which is particularly suitable for preparing 3-aminopiperidine compounds.
  • a preferred embodiment and representative example of the general synthetic concept of the present invention is illustrated in Scheme 7:
  • a compound of formula II is prepared by halogenation of a compound of formula I using a halogenating agent.
  • compound of formula II can be converted into epoxide compound of formula III by applying a proton acceptor.
  • Epoxide compound of formula III can be further converted to compound of formula IV by reacting it with amine NHR 2 R 3 .
  • compound of formula II can be directly converted to compound of formula IV.
  • compound of formula IV can be converted to a mixture of alkene compounds of formulae V 1 and V 2 by means of an acidic activator.
  • a compound of formula VI can be obtained by hydrogenating alkene compounds V 1 and V 2 in the presence of a transition metal catalyst.
  • compound of formula I is converted to compound of formula III in a one-pot process, preferably without isolation of intermediate compounds.
  • compound of formula I is converted to compound of formula IV in a one- pot process, preferably without isolation of intermediate compounds.
  • an amination step for preparing compound of formula IV can be carried out by means of two alternative process variants A and/or B, which alone or in combination provide for smooth conversion to compound of formula IV.
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , -CO-OR 6 and -S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, is prepared by a process comprising treatment of a compound of formula II
  • R 4 are defined as above and X is selected from CI, Br and I, with an amine NHR 2 R 3 in which R 2 and R 3 are defined as above.
  • R 4 are defined as above, with an amine NHR 2 R 3 in which R 2 and R 3 are defined as above.
  • Process variants A and B respectively represent alternative processes for preparing a compound of formula IV which processes provide for a simple and efficient carrying out of an amination reaction providing novel amine compound of formula IV representing a highly valuable intermediate for the preparation of pharmaceutically active agents such as preferably tofacitinib or derivatives thereof, or other pharmaceutically active agents comprising as a structure a 3- aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • pharmaceutically active agents such as preferably tofacitinib or derivatives thereof, or other pharmaceutically active agents comprising as a structure a 3- aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • compound of formula II is converted to compound of formula IV without formati and/or isolation of a compound of formula III.
  • process variants A and B is CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, preferably is CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, more preferably Ri is benzyl (-CH 2 -Ph).
  • conversion rate and/or yield of the process may be efficiently increased by suitably selecting
  • amine NHR 2 R 3 is selected from the group consisting of N-benzylmethylamine, N-a-dimethylbenzylamine, methyl carbamate and methyl amine, preferably NHR 2 R 3 is methyl amine.
  • the amination reaction is carried out in water as the solvent. In this way, it can be dispensed with harmful or even toxic organic solvents, which in turn also significantly improves working conditions for carrying out the process.
  • amine NHR 2 R 3 is preferably added to compound of formula II portionwise within a predetermined time interval.
  • compound of formula II is provided neat or diluted or dissolved in a solvent as defined in item (7) of the summary of invention, and amine NHR 2 R 3 is provided neat or diluted or dissolved in a solvent as defined in item (7), more preferably, compound of formula II is provided neat and amine NHR 2 R 3 is diluted or dissolved in a solvent as defined in item (7).
  • compound of formula III is prepared by treating the compound of formula II with a proton acceptor, preferably an inorganic or sterically hindered organic proton acceptor, more preferably the proton acceptor is selected from the group consisting of carbonate salts, ferf-butanolate salts and hydroxides of alkaline or earth alkaline metals, more preferably, the proton acceptor is selected from the group consisting of Na 2 C0 3 , K 2 C0 3 , KOf-Bu, NaOf-Bu, KOH, NaOH, in particular, the proton acceptor is NaOH.
  • a proton acceptor preferably an inorganic or sterically hindered organic proton acceptor
  • the proton acceptor is selected from the group consisting of carbonate salts, ferf-butanolate salts and hydroxides of alkaline or earth alkaline metals, more preferably, the proton acceptor is selected from the group consisting of Na 2 C0 3 , K 2 C0 3 , KOf
  • reaction time for converting compound of formula II to compound of formula III is 6 to 14 hours, more preferably 8 to 12 hours.
  • conversion of compound of formula II to compound of formula III is carried out in water as the solvent.
  • an hydroxyhalogenation step (cf. STEP 1 in Scheme 7) for preparing a compound I
  • R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or from -CO-R 6 or -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and X is selected from CI, Br and I, and R 4 represents alkyl, is carried out by reacting a compound of formula I
  • R 4 are defined as above, with a proton donor and a halogenating agent in the presence of water, wherein the proton donor is added prior to the halogenating agent.
  • This aspect provides for a simple and efficient carrying out of an hydroxyamination reaction providing novel hydroxyhalogen compounds of formula II representing highly valuable intermediates for the preparation of pharmaceutically active agents such as preferably tofacitinib or derivatives thereof. Moreover, a person skilled in the art is able to convert said
  • 3-aminopiperidine compounds to further pharmaceutically active agents comprising as a structure a 3-aminopiperidine moiety, such as for example quinolone antibacterial agents or 3-aminopiperidine-based peptide analogues as inhibitors of the bacterial cystein protease IdeS.
  • compounds of formula II represent particularly suitable starting materials for the above described process variant A, and compounds of formula II also represent particularly suitable starting materials for preparing epoxide compounds of formula III applied in process variant B.
  • the addition of the proton donor prior to the halogenation agent provides for formation of an acid addition salt of compound of formula I, wherein the salt formation protects the nitrogen of the pyridine from being halogenated or reacting otherwise.
  • the halogenating agent is selected from the group consisting of N-chlorosuccinimide, N-iodosuccinimide, N-bromosuccinimide, 5,5-dimethyl-1 ,3- dibromohidantoin (DBDMH), preferably N-bromosuccinimide and DBDMH, more preferably N- bromosuccinimide.
  • the halogenating agent is preferably applied in an amount of at least 0.5 to 1 .5 mol equivalent relative to compound of formula la depending on halogenating agent used, preferably 0.75 to 1 .25 mol equivalent.
  • the amount of halogenating agent depends on the number of active halogen comprised in the halogenating reagent.
  • the succinimide-type halogenating agents are preferably applied in hyperstoichiometric amounts within the value ranges defined above, while DBDMH is preferably applied in substoichiometric amounts which lower limits are defined above.
  • the halogenating agent is added portionwise within a predetermined time interval.
  • the halogenating agent is N- chlorosuccinimide, N-iodosuccinimide or N-bromosuccinimide
  • water or a mixture of water and alcohol is applied as the solvent, preferably a mixture of water and C1 -C4-alcohol, more preferably a mixture of water and isopropyl alcohol.
  • the mixture of water and alcohol has a proportion of at least 66 vol% of water. It was surprisingly found that by applying an amount of water exceeding 66 vol%, the formation of impurities by means of reaction of an alcohol co-solvent such as isopropanol with compound of formula I can be efficiently suppressed.
  • the halogenating agent is DBDMH
  • water is applied as the solvent. In this way, it can be dispensed with harmful or even toxic organic solvents, which in turn also significantly improves working conditions for carrying out the process.
  • the proton donor applied in the hydroxyhalogenation step 1 is an inorganic or organic acid, more preferably H 2 S0 4 , H 3 P0 4 , acetic acid, TfOH, para-toluenesulfonic acid (PTSA), trifluoroacetic acid (TFA), in particular the proton donor is TFA.
  • the proton donor is preferably applied in an amount of at least 0.5 to 1 .5 mol proton equivalent relative to compound of formula I, preferably 1 .0 mol proton equivalent.
  • compound of formula I is prepared by reacting a compound of formula la
  • R is -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, with an acid chloride CI-CO-R 6 , a chloro carboxylic ester CI-CO-OR 6 or a sulfonic acid chloride Cl-S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, aryl, heteroaryl, alkylaryl or arylalkyl.
  • the N-benzyl group is substituted by -CO-R 6 , -CO-OR 6 or -S0 2 - R 6 .
  • -CO-R 6 , -CO-OR 6 or -S0 2 -R 6 improve the reactivity of the double bound in the piperidine ring moiety of compound of formula I compared to a compound of formula la in which R is -CH 2 -R 5 .
  • substitution of the N-benzyl group is carried out in toluene or acetonitrile as the solvent.
  • Substitution of the N-benzyl group is preferably accomplished by adding an acid chloride CI-CO- R 6 , a chloro carboxylic ester CI-CO-OR 6 or a sulfonic acid chloride Cl-S0 2 -R 6 in a portionwise manner within a predetermined time intervall. Furthermore, addition of the acid chloride CI-CO- R 6 , the chloro carboxylic ester CI-CO-OR 6 or the sulfonic acid chloride Cl-S0 2 -R 6 is preferably carried out at a temperature of -30 to +30 °C, preferably at a temperature of +10 to + 20 °C.
  • the reaction mixture is preferably refluxed.
  • the time for refluxing is preferably 12 to 36 hours, more preferably 20 to 28 hours.
  • reactants for substitution of the N-benzyl group are selected from the group consisting of CI-COOEt, CI-COOCH 2 Ph, CI-COOCH 2 CCI 3 , Cl- COOC(CH 3 ) 3 , CI-COCH 3 , CI-COEt, more preferably CI-COOEt is applied.
  • R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or from -CO-R 6 , -CO-OR 6 and -S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 is alkyl, is prepared by a process comprising the steps of :
  • compound of formula III can be obtained from the starting material of formula I in a highly advantageous "one pot process". That is, it can be dispensed with isolation and purification of compound of formula II.
  • reaction conditions for carrying out step ii) are as defined in any one of items (9) to (1 1 ) of the summary of invention.
  • steps i) and ii) are carried out in the same solvent.
  • no solvent exchange is necessary between process steps i) and ii) which is beneficial in terms of process efficiency, since no energy consuming removal of solvent(s) is necessary between steps i) and ii), and furthermore, it can be dispensed with laborious recycling of removed solvent(s).
  • the reaction mixture is cooled to a temperature of -30 to +30 °C, preferably at a temperature of +10 to + 20 °C.
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , -CO-OR 6 and -S0 2 -R 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, is prepared by a process comprising the steps of : a) converting a
  • compound of formula IV can be obtained from the starting material of formula I in a highly advantageous "one pot process". That is, it can be dispensed with isolation and purification of compounds of formulae II and III.
  • reaction conditions for carrying out step b) are as defined in any one of items (4) to (8).
  • steps a-1 ) or a-2) and b) are carried out in the same solvent.
  • no solvent exchange is necessary between process steps a-1 )/a-2) and b) which is beneficial in terms of process efficiency, since no energy consuming removal of solvent(s) is necessary between steps a-1 )/a-2) and b), and furthermore, it can be dispensed with laborious recycling of removed solvent(s).
  • compound of formula IV prepared by any one of the aforementioned processes is converted to a compound of formula V 1 and V 2 respectively
  • R ⁇ R 2 , R 3 and R 4 are defined as above, and R 4 ' derives from R 4 representing alkyl in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R 4 ' is formed, by treating compound of formula IV with an acidic activator.
  • the acidic activator is added portionwise within a predetermined time interval.
  • R ⁇ R 2 , R 3 and R 4 are defined as above, by hydrogenating compounds of formulae V 1 and V 2 in the presence of a transition-metal catalyst.
  • the transition metal catalyst comprises a transition metal selected from the group consisting of Pt, Rh, Ru, Pd and Pd-Cu which catalyst is optionally attached to a supporter selected from the group consisting of charcoal, carbon, graphite or alumina (Al 2 0 3 ); preferably the catalyst comprises Pt or Rh optionally attached to a supporter selected from the group consisting of charcoal, carbon, graphite or alumina (Al 2 0 3 ); in particular, the catalyst is Rh on activated carbon paste, Pt0 2 hydrate or Pt on charcoal.
  • the transition metal catalysts is applied in an amount of up to 30 mol% relative to compounds of formulae V 1 and V 2 , preferably 0.5 to 20 mol%, more preferably 1 to 10 mol% and in particular 1.5 to 5 mol%.
  • a additive is added in order to improve conversion rate and yield of the hydrogenation reaction, which additive is selected from the group consisting of Broensted acids, Lewis acids and organic ligands, preferably AcOH, TFA, oxalic acid, citric acid, tartaric, BF 3 dietherate, copper salts, magnesium salts, iron salts, D- glucosamine, 1 ,4-diazoniabicyclo[2.2.2]octane (DABCO), amino acids.
  • a C1 -C6 alcohol is applied as solvent, preferably a C1 -C3 alcohol, in particular methanol.
  • hydrogenation is carried out at a hydrogen pressure of at least 1 bar (1 atm), preferably 1 to 50 bar (1 to 50 atm), more preferably 1 to 30 bar ( 1 to 30 atm); and in case a Pt transition metal catalyst is applied, hydrogenation is carried out at a hydrogen pressure of at least 1 bar (1 atm), preferably 1 to 10 bar ( 1 to 10 atm), more preferably 1 to 5 bar (1 to 5 atm), even more preferably 1 to 2 bar (1 to 2 atm), in particular 1 to 1 5 bar (1 to 1 .5 atm).
  • hydrogenation is carried out at a reaction temperature of 10 to 70 °C.
  • the process can be carried out at a relative low reaction temperature which is beneficial in terms of energy savings.
  • Pt0 2 or Pt0 2 hydrate is used as transition metal catalyst and DABCO is used as additive.
  • RT is selected from -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -CO-R 6 and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and X is CI, Br or I, and R 4 is alkyl, preferably C1 -C4-alkyl, in particular R 4 is methyl, wherein compound of formula II may be in its free amine form or in form of its acid addition salt.
  • R 5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 4 represents alkyl, preferably C1 -C4-alkyl, in particular R 4 is methyl,
  • compound of formula IV may be in its free amine form or in form of its acid addition salt.
  • R ⁇ is selected from -CH 2 -R 5 wherein R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 6 , and -CO-OR 6 wherein R 6 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents hydrogen or nitrogen protecting group, R 3 represents hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO-R 7 or -CO-OR 7 wherein R 7 represents substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, R 4 ' represents alkyl in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen and R 4 represents alkyl, preferably R 4 ' represents C1
  • Acid addition salts of compounds of formulae II, IV, V 1 and V 2 are preferably hydrochloride addition salts.
  • R ⁇ is selected from the group consisting of -CH 2 -Ph, -CO-CH 3 , -CO-OEt, -CO-OCH 2 Ph, -CO-OCH 2 CCI 3 , -CO-OCH 2 C(CH 3 ) 3 , more preferably R ⁇ is selected from the group consisting of -CH 2 -Ph, -CO-CH 3 and -CO-OEt.
  • R 2 is H; and R 3 is selected from the group consisting of H, CH 3 , -CH 2 -Ph, -CH(CH 3 )-Ph, -CO-OCH 3 and -CO-OEt.
  • R 4 is preferably C1 -C4-alkyl, in particular R 4 is methyl.
  • a compound selected from the group of compounds defined by formulae II, III, IV , V 1 and V 2 is used in a process for preparing a pharmaceutically active agent.
  • compounds of formulae II, IV, V 1 and V 2 are selected, more preferably compounds of formulae II and IV.
  • the pharmaceutically active agent is a Janus kinase inhibitor, preferably a Janus kinase 3 inhibitor, more preferably the pharmaceutically active agent is tofacitinib having the structural formula
  • conversion tofacitinib may be carried out as described in WO 2002/096909, WO 2004/0461 12 or WO 2007/012953.
  • a person skilled in the art may carry out a conversion for example to quinolone antibacterial agents as described in Eric Hu X et al:
  • Example 2 Direct one-pot synthesis of compounds of formula IVa starting from compounds of formula Ila a) Preparation in water
  • reaction system Into a test tube equipped with magnetic stirrer and septum was placed starting material (Ila) (1 mmol, 284 mg) and afterwards an excess of 40% aqueous solution of methylamine (0.4 mL) was slowly added into reaction system. Reaction mixture was then intensively stirred at 80 °C for 20 hours. After completion of the reaction, reaction system was diluted with water, pH was measured and adjusted to 10.6 using aqueous NaOH and finally extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 S0 4 and organic solvent was evaporated under reduced pressure.
  • starting material Ila
  • Example 4 Preparation of compounds of formula II starting from compounds of formula I a) Preparation of 1 -benzyl-3-bromo-4-methylpiperidin-4-ol (Ila) in a mixture of water/alcohol
  • starting material (la') (53.4 mmol, 10 g) which was dissolved in mixture of deionized water and isopropyl alcohol in volume ratio 2 : 1. (107 mL : 54 mL). Trifluoroacetic acid (1 equiv. according to starting material) was added and such reaction system was stirred for 10 min at ambient temperature. Afterwards N- bromosuccinimide was added (64 mmol, 1 1 .4 g) in three portions over 30 minutes and reaction system was stirred at 50 °C for 20 hours. Reaction system was cooled to room temperature and then 20% aqueous solution of NaOH was slowly added. Such reaction mixture was stirred for additional 8-10 hours at 30 °C.
  • Example 7 One-pot synthesis of 1-benzyl-4-methyl-3-(methylamino)-piperidin-4-ol (IVa) starting from 1-benzyl-4-methyl-1 ,2,3,6-tetrahydropyridine (la ) in aqueous medium
  • starting material (la') (5 mmol, 935 mg) which was dissolved in mixture of deionized water and isopropyl alcohol in volume ratio 2 : 1. (10 mL : 5 mL). Trifluoroacetic acid (1 equiv. according to starting material; 383 ⁇ ) was added and such reaction system was stirred for 10 min at ambient temperature. Afterwards N- bromosuccinimide was added (6 mmol, 1 .07 g) in three portions (1 portion/ 30 min) and reaction system was stirred at 50 °C for 20 hours. Reaction system was cooled to room temperature and then aqueous solution of NaOH was slowly added.
  • the starting material was quantitatively converted to the mixture of products (endo product V 1 a) and (exo-product V 2 a) in 1 : 1.2 ratio as determined with GC-FID analysis (column: Agilent DB-23, 60m x 0.25 mm x 0.25 ⁇ ; gas: He). Obtained product (81 mg, 75% yield) was finally confirmed using 1 H NMR analysis and 2D NMR experiments (COSY, HMBC, HSQC).
  • the starting material was quantitatively converted to final product (Via; 81 % yield) as confirmed and analyzed with GC-FID (column: Agilent DB-23, 60m x 0.25 mm x 0.25 ⁇ ; gas: He) which proved the formation of c/s-VIa and frans-VIa in 1 .9 : 1 ratio. Products were confirmed also with 1 H NMR analysis which was consistent with previous reported data from the literature (D. H. Brown Ripin, et. al., Org. Process. Res. Dev. 2003, 7, 1 15-120.)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne généralement le domaine de la chimie organique et en particulier la préparation de composés 3-amino-pipéridine. Ces composés peuvent être utilisés en tant qu'intermédiaires dans la synthèse d'agents pharmaceutiquement actifs tels que de préférence le tofacitinib ou ses dérivés, ou d'autres agents pharmaceutiquement actifs comportant comme structure un groupe caractéristique de 3-amino-pipéridine.
PCT/EP2013/065622 2012-07-25 2013-07-24 Nouvelle voie de synthèse pour la préparation de composés 3-amino-pipéridine WO2014016338A1 (fr)

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CN108976164A (zh) * 2018-06-20 2018-12-11 南通常佑药业科技有限公司 手性哌啶胺化合物的制备方法及手性拆分剂的回收套用方法
CN108822112B (zh) * 2018-08-13 2019-12-20 山东罗欣药业集团恒欣药业有限公司 一种托法替尼化合物的制备方法

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CN104437557A (zh) * 2014-11-06 2015-03-25 中南大学 一种磺化石墨烯-Pd/硅铝氧化物催化剂、其制备方法及应用

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