WO2014083150A1 - Preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors - Google Patents

Preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors Download PDF

Info

Publication number
WO2014083150A1
WO2014083150A1 PCT/EP2013/075072 EP2013075072W WO2014083150A1 WO 2014083150 A1 WO2014083150 A1 WO 2014083150A1 EP 2013075072 W EP2013075072 W EP 2013075072W WO 2014083150 A1 WO2014083150 A1 WO 2014083150A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
compound
unsubstituted
formula
alkyl
Prior art date
Application number
PCT/EP2013/075072
Other languages
French (fr)
Inventor
Gaj STAVBER
Jerome Cluzeau
Original Assignee
Lek Pharmaceuticals D.D.
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 Lek Pharmaceuticals D.D. filed Critical Lek Pharmaceuticals D.D.
Priority to CN201380071692.2A priority Critical patent/CN104955803B/en
Publication of WO2014083150A1 publication Critical patent/WO2014083150A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • 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
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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 pharmaceutically active agents such as tofacitinib or derivatives thereof.
  • 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.
  • Scheme 3 Preparation of 3-amino-piperidine building block using Rh-catalyzed direct total reduction of pyridine ring.
  • 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- piperidine compounds representing valuable key intermediates for the preparation of pharmaceutically active agents such as tofacitinib or derivatives thereof.
  • R-i is selected from -CH2-R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl, which process comprises treating a compound of formula II wherein R- ⁇ and R 2 are defined as above,
  • alkyl as used herein means straight or branched 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.
  • cycloalkyl as used herein means 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-i , R 3 and R 4 are unsubstituted.
  • base means a proton acceptor, preferably a water soluble proton acceptor and/or sterically hindered organic proton acceptor, more preferably the water soluble proton acceptor is selected from the group consisting of carbonate salts, ie f-butanolate salts and hydroxides of alkaline or earth alkaline metals.
  • R-i is selected from -CH2-R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4 wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyi, which process comprises treating a compound of formula II
  • R-i and R 2 are defined as above,
  • catalytic base means a catalytic amount of organic proton acceptor, preferably said catalytic base is trialkylamine in a catalytic amount of from 0.1 mol% to 0.5 mol %.
  • catalytic base is selected from the group consisting of Et 3 N, Bu 3 N, quinidine, quinine, 4-dimethylaminopyridine (DMAP), 1 ,4-diaza- bicyclo[2.2.2]octane (DABCO) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • organic alcohol as employed herein means C1 -C8-organic alcohol, preferably C1 -C5-alcohol, more preferably C1 -C3-alcohol. Particularly preferred is iPrOH.
  • R is selected from -CH 2 -R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 4 , -CO-OR 4 and -S0 2 -R 4 wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents alkyl or cycloalkyi, and R 2 ' derives from R 2 representing alkyl or cycloalkyi in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R 2 ' is formed, by treating compound of formula IV
  • R-i is selected from -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4 wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyi, with a dehydrating agent, optionally in a presence of a base.
  • compound of formula IV is prepared by a process according to any one of items (1 ) to (10).
  • the dehydrating agent is selected from the group consisting of MsCI, (TFA) 2 0, TsCI, l 2 , Al 2 0 3 , Ac 2 0, AcCI, SOCI 2 , preferably the dehydrating agent is MsCI or (TFA) 2 0.
  • R-i is selected from -CH 2 -R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S0 2 -R 4 , wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl, by reducing compounds of formulae Va, Vb and Vc
  • R-i is selected from -CH2-R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R 4 , -CO-OR 4 and -S0 2 -R 4 , wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 2 represents alkyl or cycloalkyl, and R 2 ' derives from R 2 representing alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R 2 ' is formed, with a hydride source and/or by hydrogenation in the presence of a transition-metal catalyst.
  • compounds of formulae Va, Vb and Vc are prepared by a process according to any one of items (1 1 ) to (13).
  • hydride source is selected from the group consisting of LiAIH 4 , BH 3 , BH 3 ⁇ Et 2 0, NaBH 4 , LiBH 4 , RED-AL and DIBAL-H.
  • the transition metal catalyst comprises a transition metal selected from the group consisting of highly activated nickel catalyst (Raney® nickel), Zn, Fe and Ir.
  • an additive is present in the reaction mixture, preferably 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.
  • R-i is selected from -CH2-R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl.
  • R-i is selected from -CH2-R 3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S0 2 -R 4 , wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl,
  • 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 the nitrogen of the piperidine ring of the compound of formula IV is in protonated form.
  • Any organic or inorganic proton donor can be used as acid for acid addition salt formation.
  • Preferred inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid and sulfuric acid.
  • Preferred organic acid is selected from the group consisting of benzoic, formic, acetic, oxalic, glycolic, glutaric, succinic, mandelic, citric, tartatic, p- toluenesulfonic and benzenesulfonic acid.
  • the most preferred organic acid is benzoic acid.
  • R-i is selected from -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl, R 2 ' represents alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen, preferably R 2 ' represents C1 -C4-alkylidene, more preferably R 2 ' is methylene,
  • R-i is -CH 2 -R 3 wherein R 3 represents substituted or unsubstituted aryl, preferably Ri is benzyl (-CH 2 -Ph).
  • the pharmaceutically active agent is a Janus kinase inhibitor, preferably a Janus kinase 3 inhibitor, more preferably the
  • composition having the structural formula
  • 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 tofacitinib is in a 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.
  • novel compounds of formulae III, IV, Va, Vb and Vc represent particularly suitable intermediate compounds for preparing 3-aminopiperidine compounds.
  • Compounds of formulae III and IV 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 compounds of formulae IV, Va, Vb and/or Vc can subsequently be conveniently converted to a pharmaceutically active agent such as tofacitinib or derivatives thereof.
  • acid addition salts of the compounds of formulae IV, Va, Vb and Vc provide for a simple and cost-beneficial purification of these intermediates.
  • 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 tofacitinib or derivatives thereof.
  • 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 contacting an amine compound of formula I with methyl alkyl ketone, for example acetone, in the presence of formaldehyde as described for example in WO2009/037220.
  • the compound of formula II can be converted directly to a compound of formula IV by reaction with nitromethane in the presence of a proton acceptor, for example NaHC0 3 , in a suitable solvent, for example toluene.
  • the compound of formula II is first converted to a compound of formula III, which is subsequently in situ converted to the compound of formula IV in the presence of a catalytic base, for example Et 3 N.
  • a catalytic base for example Et 3 N.
  • the compound of formula III can be or cannot be isolated.
  • the 3-nitropiperidine-4-ol (compound of formula IV) is then contacted with a dehydrating agent, for example with MsCI or (TFA) 2 0, yielding alkene compounds of formula Va, Vb or Vc or a mixture thereof.
  • a dehydrating agent for example with MsCI or (TFA) 2
  • a compound of formula VI can be obtained by reducing the alkene compounds Va, Vb or Vc with a hydride source, for example LiAIH 4 , and/or by hydrogenating said alkene compounds in the presence of a transition metal catalyst, for example highly activated nickel catalyst (Raney® nickel), optionally a modifier for hydrogenation or a mixture thereof can be present as well (e.g. Lewis acid).
  • a transition metal catalyst for example highly activated nickel catalyst (Raney® nickel)
  • a modifier for hydrogenation or a mixture thereof e.g. Lewis acid
  • R-i is -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl, preferably Ri is benzyl, and R 2 is methyl
  • R-i is -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl, preferably Ri is benzyl, and R 2 is methyl
  • R-i is -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl, preferably Ri is benzyl, and R 2 is methyl
  • a proton acceptor preferably NaHC0 3
  • a suitable solvent for example aqueous solution of toluene or iPrOH, preferably at a reaction temperature of 0 to 50 °C.
  • a catalytic base preferably Et 3 N or quinidine
  • a catalytic base preferably Et 3 N or quinidine
  • a dehydrating agent preferably with MsCI or (TFA) 2
  • a base preferably Et 3 N or l 2
  • a compound of formula VI' is obtained by reducing the alkene compounds Va', Vb' or Vc' with a hydride source, for example LiAIH 4 or NaBH 4 , and/or by hydrogenating said alkene compounds in the presence of a transition metal catalyst, preferably highly activated nickel catalyst, such as Raney® nickel.
  • a transition metal catalyst preferably highly activated nickel catalyst, such as Raney® nickel.
  • the compound of formula VII' can be obtained by subjecting the compound of formula VI' to a formylation/reduction reaction using alkyl formate / hydride source tandem reagent, for example methyl formate / sodium borohydride tandem reagent, in the presence of a acid, for example sulfuric acid, in a suitable solvent, preferably THF.
  • the reduction of the compound Va' or Vb' provides for a selective formation of 3- amino-piperidine product VI', with diastereomeric ratio shifted towards the preferred c/ ' s- configuration of the substituents in 3 and 4 position of the piperidine ring. Moreover, if reduction is performed in this manner no oxime or hydroxylamine side products are detected in the obtained product.
  • compound of formula IV is prepared by treating the compound of formula II' with a proton acceptor, preferably a water soluble proton acceptor and/or sterically hindered organic proton acceptor, more preferably the water soluble proton acceptor is selected from the group consisting of carbonate salts, tert- butanolate salts and hydroxides of alkaline or earth alkaline metals, more preferably, the water soluble proton acceptor is selected from the group consisting of NaHC0 3 , Na 2 C0 3 , K 2 C0 3 , NaOiBu, KOiBu KOH, NaOH, in particular, the water soluble proton acceptor is NaHC0 3 , for example 1 M aqueous solution of NaHC0 3 .
  • a proton acceptor preferably a water soluble proton acceptor and/or sterically hindered organic proton acceptor
  • the water soluble proton acceptor is selected from the group consisting of carbonate salts, tert- butanolate salts and
  • the amount of the water soluble proton acceptor applied it is preferred to apply a hyperstoichiometric amount relative to compound of formula II' preferably at least 2 mol equivalent relative to compound of formula II', preferably excess.
  • the preferred organic proton acceptor is trialkylamine in a catalytic amount of from 0.1 mol% to 0.5 mol %.
  • reaction time for converting compound of II' to compound of formula IV is 4 to 24 hours.
  • conversion of a compound of formula II' to the compound of formula IV is carried out in water/toluene biphasic solution.
  • Toluene in concentrations from 0.1 to 1 M, preferably from 0.1 to 0.5 M is particularly preferred as it provides for higher reaction selectivity, increased yield and less side-products.
  • compound of formula IV is converted to a compound of formula Va ⁇ Vb' or Vc' respectively, by treating the compound of formula IV with a dehydrating agent.
  • the dehydrating agent is selected from the group consisting of MsCI, (TFA) 2 0, TsCI, l 2 , Al 2 0 3 , Ac 2 0, AcCI, SOCI 2 , preferably the dehydrating agent is MsCI or (TFA) 2 0.
  • Compounds of formulae Va', Vb' or Vc' may be further converted to a compound of formula VI', as illustrated in Scheme 8, by reducing the alkene compounds Va', Vb' or Vc' with a hydride source and/or by hydrogenating said alkene compounds in the presence of a transition metal catalyst, optionally in the presence of an additive.
  • the hydride source is selected from the group consisting of LiAIH 4 , BH 3 , BH 3 ⁇ Et 2 0, NaBH 4 , LiBH 4 , DIBAL-H, RED-AI
  • the hydride source is applied in an amount of 0.5 to 8 equivalents, preferably 1 to 6 equivalents, most preferably the amount of the hydride source is from 2 to 4 equivalents.
  • the transition metal catalyst comprises a transition metal selected from the group consisting of highly activated nickel catalyst (Raney® nickel), Zn, Fe and Ir, preferably highly activated nickel catalyst (Raney® nickel).
  • the transition metal e.g. highly activated nickel catalyst (Raney® nickel) is used as the sole agent for hydrogenation of the compound of formulae Va, Vb and Vc, or a mixture of transition metal with the hydride source is used, e.g. NaBH 4 with Zn
  • the diastereomeric ratio between the c/ ' s and irans-configu ration of the substituents in 3 and 4 position of the piperidine ring is shifted towards the irans-configu ration.
  • the intermediate VI can be obtained in the stereo-chemical configuration preferred in view of the final product, which is of crucial importance in view of the yield and reaction costs.
  • an 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.
  • Broensted acids 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.
  • compounds of formulae IV, Va, Vb and Vc can be converted to their acid addition salts.
  • Scheme 9 illustrates for example conversion of compounds of formula IV and Va' into IV -s and Va'-s, respectively.
  • the benzoate salt is formed in a mixture of one or more solvents selected from the group consisting of MeOH, iPrOH, EtOH, THF, 2-MeTHF, in combination with n-hexane or heptane.
  • the preferred reaction temperature is from -20°C to 30°C.
  • 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 the nitrogen of the piperidine ring of the compound of formula IV is in protonated form.
  • Any organic or inorganic proton donor can be used as acid for acid addition salt formation.
  • Preferred inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid and sulfuric acid.
  • Preferred organic acid is selected from the group consisting of benzoic, formic, acetic, oxalic, glycolic, glutaric, succinic, mandelic, citric, tartatic, p-toluenesulfonic and benzenesulfonic acid. The most preferred acid is benzoic acid.
  • Ri is selected from -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl.
  • Ri is selected from -CH2-R3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl,
  • compound of formula IV may be in its free amine form or in form of its acid addition salt.
  • Ri is selected from -CH 2 -R3 wherein R 3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO 2 -R4, wherein R 4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R 2 represents alkyl or cycloalkyl, R 2 ' represents alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen, preferably R 2 ' represents C1 -C4-alkylidene, more preferably R 2 ' is methylene,
  • compound of formulae Va, Vb and Vc may be in the free amine form or in form of the acid addition salt.
  • Acid addition salts of compounds of formulae IV and Va, Vb and Vc are preferably benzoic acid addition salts.
  • Ri is -CH 2 -R3 wherein R 3 represents substituted or unsubstituted aryl, preferably Ri is benzyl (-CH 2 -Ph).
  • R 2 is alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, most preferably R 2 is methyl (-CH 3 ).
  • a compound selected from the group of compounds defined by formulae III, IV, Va, Vb and Vc is used in a process for preparing a pharmaceutically active agent.
  • 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 from the compound of formula VII to tofacitinib may be carried out as described in WO 2002/096909, WO 2004/0461 12 or WO 2007/012953.
  • Isomers were separated by MPLC on silica gel using MCH/EtOAc (80/20) as eluent.
  • Toluene phase was dried and concentrated to give a yellow liquid which was analyzed/confirmed using 1 H NMR spectroscopy (28.9 g, molar ratio 1 .5/1 compound IV vs. toluene and d.r. 5/1 ).
  • Example 6 Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from IV via dehydration reaction using methanesulfonyl chloride and triethyl amine in toluene:
  • liquid starting material (IV) (1 .5 mmol) and during intensive stirring (900 rpm) catalytic amount of iodine (fine powder) was added in two portions (0.075 mmol; 5 mol% according to IV). Reaction mixture was vigorously stirred overnight at 60 °C. To this solution aqueous solution of Na 2 S 2 0 3 was added and reaction mixture was then extracted with EtOAc (2 x 60 mL). The combined organic phases were finally washed with aqueous solution of Na 2 S0 3 and dried over anhydrous Na 2 S0 4 .
  • Example 12 Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from 1 - benzyl-4-methyl-3-nitropiperidin-4-ol benzoate salt (IV -s) via dehydration reaction using methanesulfonyl chloride and triethylamine in toluene:
  • Example 13 Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via reduction reaction using lithium aluminum hydride in THF:
  • Example 14 Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine Va' via reduction reaction using Raney ® Nickel and hydrogen in methanol:
  • Example 15 Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via reduction reaction using borane and catalytic amount of sodium borohydride in THF:
  • Example 16 Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via one-pot reduction process using sodium borohydride and fine zinc powder:
  • Aqueous phase was basified to 1 1 .5 using 20% aq. solution of NaOH and extracted with hot ethyl acetate. Combined organic phases were dried over Na 2 S0 4 and concentrated under reduced pressure to obtain crude VI' which was purified with flash column chromatography (Si0 2 ; CH 2 CI 2 ) to afford 235 mg of final product (cis/trans mixture).
  • Example 17 Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via one-pot reduction process using sodium borohydride and fine iron powder:
  • Aqueous phase was basified to 1 1 .5 using 20% aq. solution of NaOH and extracted with hot ethyl acetate. Combined organic phases were dried over Na 2 S0 4 and concentrated under reduced pressure to obtain crude VI' which was purified with flash column chromatography (Si0 2 ; CH 2 CI 2 ) to afford 70 mg of final product (cis/trans mixture).
  • Example 18 Preparation of 1 -benzyl-N,4-dimethylpiperidin-3-amine (VII') from 1 -benzyl-4- methylpiperidin-3-amine (VI') via formylation / reduction reaction using methyl formate / sodium borohydride tandem reagent in the presence of sulfuric acid in

Landscapes

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

Abstract

The present invention relates to the preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors and salts thereof. These compounds can be used as intermediates in the synthesis of pharmaceutically active agents such as tofacitinib or derivatives thereof.

Description

PREPARATION OF 3-AMINO-PIPERIDINE COMPOUNDS VIA
NITRO-TETRAHYDROPYRIDINE PRECURSORS
Field of the Invention
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 pharmaceutically active agents such as tofacitinib or derivatives thereof.
Background of the Invention
3-amino-piperidine compounds represent valuable intermediates for the preparation of pharmaceutically active agents. For example, the Janus kinase 3 (JAK3) inhibitor tofacitinib having the structural formula
Figure imgf000002_0001
comprises a 3-4-methyl-3-(methylamino)piperidin-1 -yl moiety (indicated in the above illustrated structure by oval framing) as 3-amino-piperidine moiety.
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.
D. H. Brown, et. al, Org. Proc. Res. Dev. 2003, 7, pages 1 15 to 120 discloses the preparation of 3-amino-piperidine building block D via reductive amination of ketone C using methylamine as reagent. Ketone C was prepared by a combined hydroboration/oxidation process of
tetrahydropyridine A as disclosed in M. A. lorio, et. al., Tetrahedron 1970, 26, page 5519 and D. H. Brown Ripin, et. al., Tetrahedron Lett. 2000, 41, page 5817. The resulting compound B was subjected to oxidation of the toluenesulfonate salt of the piperidine alcohol by an excess of costly S03 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 NaBH4 or BH3 complexes and strong oxidants such as hydrogen peroxide, bleach or Oxone®. These hazardous reagents bear a safety risk for large scale production.
Figure imgf000003_0001
Scheme 1 : Preparation of 3-amino-piperidine building block via reductive amination.
W. Cai., Org. Proc. Res. Dev. 2005, 9, pages 51 to 56 and WO 2004/0461 12 A2 disclose a method as depicted in Scheme 2, in which method 4-methylpiperidine-1 -carboxylate E is converted to compound F by means of electrochemical oxidation in the presence of acetic acid. Subsequent acetylation, elimination, acetyl cleavage and amination via boration provides for compound H. However, deprotection of carbamate H is critical and requires the costly reagent trimethylsilyl iodide (TMSI).
Figure imgf000003_0002
E F G H
Scheme 2: Preparation of 3-amino-piperidine building block via reductive amination of carbamates.
Furthermore, W. Cai.; Org. Proc. Res. Dev. 2005, 9, pages 51 to 56 and WO2007/012953 A2 disclose an alternative procedure as depicted in Scheme 3, wherein a protected 3-amino-4- picoline is converted to 3-amino-piperidine by means of total reduction of the pyridine ring. However, in this synthetic pathway, the rare and costly 3-amino-4-picoline is required as starting material, and the hydrogenation requires costly Rh-catalysts. Besides, hydrogenation has to be carried out at high hydrogen pressure in order to achieve total reduction of the pyridine moiety to piperidine.
Figure imgf000003_0003
PG = protecting group
Scheme 3: Preparation of 3-amino-piperidine building block using Rh-catalyzed direct total reduction of pyridine ring. WO 2007/012953 discloses a further synthetic pathway in which 3-amino-4-picoline is used as starting material. As can be gathered from Scheme 4, the pathway contains the steps of benzyl activation of pyridine ring and partial reduction using sodium borohydride. In the final step, 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.
Figure imgf000004_0001
Scheme 4: Preparation of 3-amino-piperidine building block using Rh -catalyzed asymmetric hydrogenation approach.
X. E. Hu, et. al., Org. Lett. 2002, 4, pages 4499 to 4502 discloses a synthetic route for preparation of (3S)-amino-piperidine intermediates as depicted in Scheme 5. In this synthetic route, predominantly products having trans-configuration of the substituents in 3 and 4 position of the piperidine ring are obtained. However, trans-configuration is not desired for intermediate compounds for preparing pharmaceutical active agents such as tofacitinib. Rather, c/'s- configuration is desired. Besides, this synthetic route requires high amounts of costly Grubbs catal sts.
Figure imgf000004_0002
Scheme 5: Preparation of 3-amino-piperidine building blocks using ring-closing metathesis reaction.
B.-J . Hao, et. al., Synthesis 201 1 , 8, pages 1208 to 1212 discloses a synthetic route as depicted in Scheme 6 which starts from ethyl 1 -benzyl-3-oxopiperidine-4-carboxylate hydrochloride. It is noteworthy to mention that the process is long in terms of the amount of procedural steps required. Furthermore, the process requires hazardous and expensive reagents such as DCM, LiAIH4, PPh3 and starts from an advance intermediate. Asymmetric reduction of olefin in the presence of cobalt catalysts affords modest diastereomeric excess of 71 %. Reductive amination to incorporate methyl group on amine part of molecule represents the key step, however, accomplishing this reductive amination is problematic. Besides, stereoselective transformation of ester group to methyl requires costly and hazardous reagents. Ph3
Figure imgf000005_0001
100%
Scheme 6: Preparation of 3-amino-piperidine building block via cobalt catalyzed asymmetric hydrogenation.
The object of the present invention is to provide an improved process for preparing 3- piperidine compounds representing valuable key intermediates for the preparation of pharmaceutically active agents such as tofacitinib or derivatives thereof.
Summary of the Invention
Various aspects, advantageous features and preferred embodiments of the present invention as summarized in the following items, respectively alone or in combination, contribute to solving the object of the invention.
(1 ) A process for preparing a compound of formula IV
Figure imgf000005_0002
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl, which process comprises treating a compound of formula II
Figure imgf000005_0003
wherein R-ι and R2 are defined as above,
with nitromethane and formaldehyde in the presence of a base.
The term "alkyl" as used herein means straight or branched 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.
The term "cycloalkyl" as used herein means 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.
The term "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.
The term "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.
The term "substituted" as employed herein 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. Typical 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. It will be understood that the 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. For example, substituents which may be unstable or may affect reactions disclosed herein may be omitted. Preferably, R-i , R3 and R4 are unsubstituted.
The term "base" as employed herein means a proton acceptor, preferably a water soluble proton acceptor and/or sterically hindered organic proton acceptor, more preferably the water soluble proton acceptor is selected from the group consisting of carbonate salts, ie f-butanolate salts and hydroxides of alkaline or earth alkaline metals. A process for preparing a compound of formula IV
Figure imgf000007_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4 wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyi, which process comprises treating a compound of formula II
Θ
Figure imgf000007_0002
wherein R-i and R2 are defined as above,
with nitromethane and formaldehyde in the presence of a base to obtain a compound of formula III
Figure imgf000007_0003
which is further converted to the compound of formula IV in the presence of a catalytic base.
The term "catalytic base" as employed herein means a catalytic amount of organic proton acceptor, preferably said catalytic base is trialkylamine in a catalytic amount of from 0.1 mol% to 0.5 mol %.
As regards the meaning of the terms "alkyl", "cycloalkyi", "aryl", "heteroaryl", "substituted or unsubstituted", "base" reference is made to the explanations under item (1 ) above.
The process according to item (1 ) or (2), wherein R-i is -CH2-R3 wherein R3 represents substituted or unsubstituted aryl, preferably Ri is benzyl (-CH2-Ph). The process according to any one of items (1 ) to (3), wherein R2 is alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, most preferably R2 is methyl (-CH3).
The process according to to item (1 ) or (2), wherein the base is selected from the group consisting of NaHC03, Na2C03, K2C03, KOBu-i, NaOBu-i, KOH and NaOH, preferably the base is NaHC03.
The process according to item (2), wherein the catalytic base is selected from the group consisting of Et3N, Bu3N, quinidine, quinine, 4-dimethylaminopyridine (DMAP), 1 ,4-diaza- bicyclo[2.2.2]octane (DABCO) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The process according to item (1 ) or (2), wherein the reaction is carried out in a solvent selected from the group consisting of water, organic alcohols, MeTHF, THF, toluene and mixtures thereof.
The term "organic alcohol" as employed herein means C1 -C8-organic alcohol, preferably C1 -C5-alcohol, more preferably C1 -C3-alcohol. Particularly preferred is iPrOH.
The process according to item (7), wherein the reaction is carried out in a water/toluene biphasic solution as the solvent.
The process according to item (8), wherein the concentration of toluene is from 0.1 to 1 M.
The process according to item (8) or (9), wherein the reaction is carried out at a reaction temperature of 0 to 50 °C. A process for preparing a compound of formula Va or Vb or Vc, or a mixture thereof
Figure imgf000008_0001
in which R is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S02-R4 wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R2 represents alkyl or cycloalkyi, and R2' derives from R2 representing alkyl or cycloalkyi in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R2' is formed, by treating compound of formula IV
Figure imgf000009_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4 wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyi, with a dehydrating agent, optionally in a presence of a base.
Preferably, compound of formula IV is prepared by a process according to any one of items (1 ) to (10).
The process according to item (1 1 ), wherein the dehydrating agent is selected from the group consisting of MsCI, (TFA)20, TsCI, l2, Al203, Ac20, AcCI, SOCI2, preferably the dehydrating agent is MsCI or (TFA)20.
The process according to item (1 1 ), wherein the base is selected from the group consisting of Et3N, pyridine, Ν,Ν-diisopropylethylamine (DIEA), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably Et3N.
A process for preparing a compound of formula VI
Figure imgf000009_0002
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S02-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl, by reducing compounds of formulae Va, Vb and Vc
Figure imgf000010_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S02-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R2 represents alkyl or cycloalkyl, and R2' derives from R2 representing alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R2' is formed, with a hydride source and/or by hydrogenation in the presence of a transition-metal catalyst.
Preferably, compounds of formulae Va, Vb and Vc are prepared by a process according to any one of items (1 1 ) to (13).
The process according to item (14), wherein the hydride source is selected from the group consisting of LiAIH4, BH3, BH3 · Et20, NaBH4, LiBH4, RED-AL and DIBAL-H.
When the hydride source is used as the sole agent for reduction of the compound of formulae Va, Vb and Vc, and by carefully selecting the reaction conditions, the diastereomeric ratio between the cis and irans-configu ration of the substituents in 3 and 4 position of the piperidine ring is shifted towards the c/s-configu ration, which is the preferred configuration in the synthesis of tofacitinib.
The process according to item (14) or item (15), wherein the transition metal catalyst comprises a transition metal selected from the group consisting of highly activated nickel catalyst (Raney® nickel), Zn, Fe and Ir. The process according to items (14) to (16), wherein an additive is present in the reaction mixture, preferably 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, BF3 dietherate, copper salts, magnesium salts, iron salts, D- glucosamine, 1 ,4-diazoniabicyclo[2.2.2]octane (DABCO), amino acids.
The term "additive" as used herein means a compound which improves conversion rate and/or yield of the hydrogenation reaction. A compound of formula
Figure imgf000011_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl.
As regards the meaning of the terms "alkyl", "cycloalkyl", "aryl", "heteroaryl", "substituted or unsubstituted", reference is made to the explanations under item (1 ) above.
A compound of formula IV
Figure imgf000011_0002
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S02-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl,
or an acid addition salt thereof.
As regards the meaning of the terms "alkyl", "cycloalkyl", "aryl", "heteroaryl", "substituted or unsubstituted", reference is made to the explanations under item (1 ) above. The term "acid addition salt" as used herein means a salt formed of compound of formula IV and an acid in the form of a proton donor, in which salt the nitrogen of the piperidine ring of the compound of formula IV is in protonated form. Any organic or inorganic proton donor can be used as acid for acid addition salt formation. Preferred inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid and sulfuric acid. Preferred organic acid is selected from the group consisting of benzoic, formic, acetic, oxalic, glycolic, glutaric, succinic, mandelic, citric, tartatic, p- toluenesulfonic and benzenesulfonic acid. The most preferred organic acid is benzoic acid.
A compound of formula Va, Vb and Vc or a mixture thereof
Figure imgf000012_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl, R2' represents alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen, preferably R2' represents C1 -C4-alkylidene, more preferably R2' is methylene,
or acid addition salt(s) thereof.
As regards the meaning of the terms "alkyl", "cycloalkyl", "aryl", "heteroaryl", "substituted or unsubstituted", reference is made to the explanations under item (1 ) above.
As regards the meaning of the terms "acid addition salt", reference is made to the explanation under item (19) above.
The compounds of formulae III, IV, Va, Vb and Vc according to any one of items (18) to
(20) , wherein R-i is -CH2-R3 wherein R3 represents substituted or unsubstituted aryl, preferably Ri is benzyl (-CH2-Ph).
The compounds of formulae III, IV, Va, Vb and Vc according to any one of items (18) to
(21 ) , wherein R2 is alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, most preferably R2 is methyl (-CH3). (23) The compound of formulae III, IV, Va, Vb and Vc according to any one of items (18) to (22), wherein any one of these compounds are selected from the group consisting of
Figure imgf000013_0001
Va'-s
Use of a compound selected from the group of compounds defined by formulae III, IV, Va, Vb and Vc in a process for preparing a pharmaceutically active agent.
The use according to item (24), wherein 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
Figure imgf000013_0002
or an acid addition salt thereof.
The term "acid addition salt" as used herein 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 tofacitinib is in a protonated form. Any organic or inorganic proton donor can be used as acid for acid addition salt formation. Preferably an acid is selected which provides for a pharmaceutically acceptable acid addition salt. Detailed description of the invention
The present invention is now described in more detail by referring to further preferred and further advantageous embodiments and examples, which are however presented for illustrative purposes only and shall not be understood as limiting the scope of the present invention.
In order to find a more efficient and shorter way to prepare pharmaceutically active agents which chemical structure comprises a 3-aminopiperidine moiety, it was surprisingly found that the novel compounds of formulae III, IV, Va, Vb and Vc represent particularly suitable intermediate compounds for preparing 3-aminopiperidine compounds. Compounds of formulae III and IV 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 compounds of formulae IV, Va, Vb and/or Vc can subsequently be conveniently converted to a pharmaceutically active agent such as tofacitinib or derivatives thereof. In addition, acid addition salts of the compounds of formulae IV, Va, Vb and Vc provide for a simple and cost-beneficial purification of these intermediates.
Compared with conventional syntheses for preparing 3-aminopiperidine compounds discussed in the above "background of the invention" part, 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 tofacitinib or derivatives thereof.
According to one aspect of the invention, 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.
According to the embodiment of Scheme 7 (wherein the compounds of formulae II, III, IV, Va, Vb, Vc and VI are respectively defined as in the preceding items), a compound of formula II is prepared by contacting an amine compound of formula I with methyl alkyl ketone, for example acetone, in the presence of formaldehyde as described for example in WO2009/037220. Next, the compound of formula II can be converted directly to a compound of formula IV by reaction with nitromethane in the presence of a proton acceptor, for example NaHC03, in a suitable solvent, for example toluene. Alternatively, the compound of formula II is first converted to a compound of formula III, which is subsequently in situ converted to the compound of formula IV in the presence of a catalytic base, for example Et3N. Depending on reaction conditions (type and amount of proton acceptor, presence or absence of catalytic organic base) the compound of formula III can be or cannot be isolated. The 3-nitropiperidine-4-ol (compound of formula IV) is then contacted with a dehydrating agent, for example with MsCI or (TFA)20, yielding alkene compounds of formula Va, Vb or Vc or a mixture thereof. With careful selection of reaction conditions (solvent, the dehydrating agent, time and reaction temperature) compounds Va, Vb or Vc can be selectively obtained. Next, a compound of formula VI can be obtained by reducing the alkene compounds Va, Vb or Vc with a hydride source, for example LiAIH4, and/or by hydrogenating said alkene compounds in the presence of a transition metal catalyst, for example highly activated nickel catalyst (Raney® nickel), optionally a modifier for hydrogenation or a mixture thereof can be present as well (e.g. Lewis acid). Finally, the compound of formula VII is obtained by formylation and subsequent reduction of the compound of formula VI.
R. NH
Figure imgf000015_0001
VII VI
Scheme 7: General procedural concept of the present invention.
Compounds of formula I as well as alkyl methyl ketones are readily available, e.g. the compound of formula I in which Ri is benzyl, and acetone are commercially available.
According to a preferred embodiment illustrated in Scheme 8, a compound of formula IV
Figure imgf000015_0002
in which R-i is -CH2-R3 wherein R3 represents substituted or unsubstituted aryl, preferably Ri is benzyl, and R2 is methyl, is prepared by contacting acetone with respective aryl amine, preferably benzylamine, in the presence of formaldehyde (following the procedure disclosed in WO2009/037220) to yield the compound of formula II'. Next, the compound of formula II' is contacted with nitromethane in the presence of a proton acceptor, preferably NaHC03, in a suitable solvent, for example aqueous solution of toluene or iPrOH, preferably at a reaction temperature of 0 to 50 °C. Optionally, a catalytic base, preferably Et3N or quinidine, is added to convert nitroethene precursor (III') in situ to IV. The obtained compound of formula IV is then contacted with a dehydrating agent, preferably with MsCI or (TFA)20, in the presence of a base, preferably Et3N or l2, yielding alkene compounds of formula Va', Vb' or Vc' or a mixture thereof. With careful selection of reaction conditions (solvent, the dehydrating agent, time, stirring and reaction temperature) compounds Va', Vb' or Vc' are obtained selectively. Next, a compound of formula VI' is obtained by reducing the alkene compounds Va', Vb' or Vc' with a hydride source, for example LiAIH4 or NaBH4, and/or by hydrogenating said alkene compounds in the presence of a transition metal catalyst, preferably highly activated nickel catalyst, such as Raney® nickel. Finally, the compound of formula VII' can be obtained by subjecting the compound of formula VI' to a formylation/reduction reaction using alkyl formate / hydride source tandem reagent, for example methyl formate / sodium borohydride tandem reagent, in the presence of a acid, for example sulfuric acid, in a suitable solvent, preferably THF.
ArNH
Figure imgf000016_0001
VII" vr
Scheme 8: Specific embodiment of the present invention.
The process illustrated in Scheme 8 provides for a simple and efficient synthesis providing novel 3-nitropiperidine-4-ol compound of formula IV representing a highly valuable intermediate for the preparation of pharmaceutically active agents such as tofacitinib or derivatives thereof. In particular, it was surprisingly found that by careful selection of reaction conditions, starting from the compound of formula IV, simple dehydration protocols enable selective formation of nitro olefin with the double bond on position 3 (double bond between CH3 and N02; compound Va'), or on position 4 (double bond between CH3 and cyclic methylene; compound Vb'), which is of crucial importance in view of diastereoselectivity after reduction.
In addition, the reduction of the compound Va' or Vb', using hydrides as the sole reducing agents and with careful selection of reaction conditions, provides for a selective formation of 3- amino-piperidine product VI', with diastereomeric ratio shifted towards the preferred c/'s- configuration of the substituents in 3 and 4 position of the piperidine ring. Moreover, if reduction is performed in this manner no oxime or hydroxylamine side products are detected in the obtained product.
In a preferred embodiment of the process illustrated in Scheme 8, compound of formula IV is prepared by treating the compound of formula II' with a proton acceptor, preferably a water soluble proton acceptor and/or sterically hindered organic proton acceptor, more preferably the water soluble proton acceptor is selected from the group consisting of carbonate salts, tert- butanolate salts and hydroxides of alkaline or earth alkaline metals, more preferably, the water soluble proton acceptor is selected from the group consisting of NaHC03, Na2C03, K2C03, NaOiBu, KOiBu KOH, NaOH, in particular, the water soluble proton acceptor is NaHC03, for example 1 M aqueous solution of NaHC03. As regards the amount of the water soluble proton acceptor applied, it is preferred to apply a hyperstoichiometric amount relative to compound of formula II' preferably at least 2 mol equivalent relative to compound of formula II', preferably excess. The preferred organic proton acceptor is trialkylamine in a catalytic amount of from 0.1 mol% to 0.5 mol %.
In a further preferred embodiment of the process illustrated in Scheme 8, conversion of compound of formula II' to compound of formula IV is carried out at a reaction temperature of 0 to 50 °C. In this way, the process can be carried out at a relative low reaction temperature which is beneficial in terms of energy savings. Preferably, reaction time for converting compound of II' to compound of formula IV is 4 to 24 hours.
In a still further preferred embodiment of the process illustrated in Scheme 8, conversion of a compound of formula II' to the compound of formula IV is carried out in water/toluene biphasic solution. Toluene in concentrations from 0.1 to 1 M, preferably from 0.1 to 0.5 M is particularly preferred as it provides for higher reaction selectivity, increased yield and less side-products. In another preferred embodiment of the process illustrated in Scheme 8, compound of formula IV is converted to a compound of formula Va\ Vb' or Vc' respectively, by treating the compound of formula IV with a dehydrating agent. The dehydrating agent is selected from the group consisting of MsCI, (TFA)20, TsCI, l2, Al203, Ac20, AcCI, SOCI2, preferably the dehydrating agent is MsCI or (TFA)20.
As mentioned above, careful selection of reaction conditions enables a selective formation of nitro olefin with the double bond on position 3 (double bond between CH3 and N02; compound Va'), or on position 4 (double bond between CH3 and cyclic methylene; compound Vb'), which is of crucial importance in view of diastereoselectivity after reduction.
Compounds of formulae Va', Vb' or Vc' may be further converted to a compound of formula VI', as illustrated in Scheme 8, by reducing the alkene compounds Va', Vb' or Vc' with a hydride source and/or by hydrogenating said alkene compounds in the presence of a transition metal catalyst, optionally in the presence of an additive.
When the hydride source is used as the sole agent for reduction of the compound of formulae Va, Vb and Vc, and by carefully selecting the reaction conditions, the diastereomeric ratio between the c/'s and frans-configu ration of the substituents in 3 and 4 position of the piperidine ring is shifted towards the c/'s-configuration, which is the preferred configuration in the synthesis of tofacitinib.
According to a preferred embodiment, the hydride source is selected from the group consisting of LiAIH4, BH3, BH3 · Et20, NaBH4, LiBH4, DIBAL-H, RED-AI
Preferably, the hydride source is applied in an amount of 0.5 to 8 equivalents, preferably 1 to 6 equivalents, most preferably the amount of the hydride source is from 2 to 4 equivalents.
According to a further preferred embodiment, the transition metal catalyst comprises a transition metal selected from the group consisting of highly activated nickel catalyst (Raney® nickel), Zn, Fe and Ir, preferably highly activated nickel catalyst (Raney® nickel).
When the transition metal, e.g. highly activated nickel catalyst (Raney® nickel) is used as the sole agent for hydrogenation of the compound of formulae Va, Vb and Vc, or a mixture of transition metal with the hydride source is used, e.g. NaBH4 with Zn, the diastereomeric ratio between the c/'s and irans-configu ration of the substituents in 3 and 4 position of the piperidine ring is shifted towards the irans-configu ration. With careful selection of the reduction/hydrogenation agent(s) and conditions, the intermediate VI can be obtained in the stereo-chemical configuration preferred in view of the final product, which is of crucial importance in view of the yield and reaction costs.
According to a further preferred embodiment, an 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, BF3 dietherate, copper salts, magnesium salts, iron salts, D- glucosamine, 1 ,4-diazoniabicyclo[2.2.2]octane (DABCO), amino acids.
THF or a C1 -C3 alcohol, preferably methanol, is applied as a solvent for hydrogenation.
According to a further aspect of the invention, compounds of formulae IV, Va, Vb and Vc can be converted to their acid addition salts. Scheme 9 illustrates for example conversion of compounds of formula IV and Va' into IV -s and Va'-s, respectively.
Figure imgf000019_0001
IV Ar= preferably Ph IV'-s
Figure imgf000019_0002
Va' Va'-s
Scheme 9: Specific embodiment of the present invention.
In a preferred embodiment of the process illustrated in Scheme 9, the benzoate salt is formed in a mixture of one or more solvents selected from the group consisting of MeOH, iPrOH, EtOH, THF, 2-MeTHF, in combination with n-hexane or heptane. The preferred reaction temperature is from -20°C to 30°C.
The term "acid addition salt" as used herein means a salt formed of compound of formula IV and an acid in the form of a proton donor, in which salt the nitrogen of the piperidine ring of the compound of formula IV is in protonated form. Any organic or inorganic proton donor can be used as acid for acid addition salt formation. Preferred inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid and sulfuric acid. Preferred organic acid is selected from the group consisting of benzoic, formic, acetic, oxalic, glycolic, glutaric, succinic, mandelic, citric, tartatic, p-toluenesulfonic and benzenesulfonic acid. The most preferred acid is benzoic acid.
According to a further aspect of the invention, compounds of formulae III, IV, Va, Vb and Vc are provided which are defined as follows:
In compound of formula III
Figure imgf000020_0001
Ri is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl.
In compound of formula IV
Figure imgf000020_0002
Ri is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl,
wherein compound of formula IV may be in its free amine form or in form of its acid addition salt.
In compounds of formulae Va, Vb and Vc
Figure imgf000021_0001
Ri is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyl, R2' represents alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen, preferably R2' represents C1 -C4-alkylidene, more preferably R2' is methylene,
wherein compound of formulae Va, Vb and Vc may be in the free amine form or in form of the acid addition salt.
Acid addition salts of compounds of formulae IV and Va, Vb and Vc are preferably benzoic acid addition salts.
Preferably, in any one of compounds of formulae III, IV, Va, Vb and Vc Ri is -CH2-R3 wherein R3 represents substituted or unsubstituted aryl, preferably Ri is benzyl (-CH2-Ph).
Furthermore, in any one of compounds of formulae III, IV, Va, Vb and Vc R2 is alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, most preferably R2 is methyl (-CH3).
According to yet another aspect of the invention, a compound selected from the group of compounds defined by formulae III, IV, Va, Vb and Vc, is used in a process for preparing a pharmaceutically active agent.
According to a preferred embodiment, 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
Figure imgf000021_0002
or an acid addition salt thereof. For example, conversion from the compound of formula VII to tofacitinib may be carried out as described in WO 2002/096909, WO 2004/0461 12 or WO 2007/012953.
The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way. The examples and modifications or other equivalents thereof will become apparent to those versed in the art in the light of the present entire disclosure.
Examples
Example 1 : Synthesis of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol (IV) from II' in water/iPrOH
(3/1 ) mixture:
Figure imgf000022_0001
Into a flask equipped with magnetic stir bar were placed starting material (II'; 9.37 mmol, 2 g, II' was prepared according to reference WO 2009/037220 A1 ) and /'so-propanol (12.5 mL) and 1 M sodium bicarbonate (4.5 equiv., 42 mL). Mixture was warmed up to 50°C until clear solution has been obtained. Afterwards solution was cooled down to 40°C and nitromethane (0.51 mL, 1 eq) and formaldehyde 37% (1.4 equiv., 0.97 mL) were added successively. Reaction mixture was vigorously stirred for 5 hours. Reaction system was cooled down to r.t, diluted with water (20 mL) and dichloromethane (30 mL). Phases were separated and water was re-extracted with dichloromethane (30 mL). Combined organic phase was dried and concentrated to give an oil. Oil was dissolved in MTBE (50 mL) and solid was filtered and concentrated to obtain IV (2.2 g, 68% HPLC purity, 63% yield), as a 3/1 mixture of isomers. Product was finally confirmed using 1H and 13C NMR analysis and mass analysis.
Isomers were separated by MPLC on silica gel using MCH/EtOAc (80/20) as eluent.
For major isomer (racemic mixture of RS and SR): (confirmed by COSY and NOESY NMR experiments)
1H NMR (500 MHz, CDCI3, ppm) δ 7.30 (m, 5H, ArH), 4.58 (dd, J = 4.0 Hz, J = 10.9 Hz, 1 H), 3.63 (d, J = 13.1 Hz, 1 Ha of benzyl), 3.56 (d, J = 13.1 Hz, 1 Hb of benzyl), 3.04 (ddd, J = 1 .3 Hz, J = 3.9 Hz, J = 10.4 Hz, 1 H), 2.92 (t, J = 10.8 Hz, 1 H), 2.65 (m, 1 H), 2.54 (dt, Jd = 3.0 Hz, Jt = 1 1.7 Hz, 1 H), 1 .82 (td, Jt = 2.9 Hz, Jd = 14.0 Hz, 1 H), 1.65 (dd, J = 4.7 Hz, J = 14.0 Hz, 1 H), 1 .35 (s, 3H); 13C NMR (125 MHz, CDCI3, ppm) δ 137.5, 128.9, 128.4, 127.3, 89.7, 68.4, 62.1 , 51.9, 48.1 , 37.4, 26.9.
For minor isomer (racemic mixture of RR and SS):
1H NMR (500 MHz, CDCI3, ppm) δ 7.30 (m, 5H, ArH), 4.56 (dd, J = 4.4 Hz, J = 13.1 Hz, 1 H), 3.64 (d, J = 13.2 Hz, 1 Ha of benzyl), 3.59 (d, J = 13.2 Hz, 1 Hb of benzyl), 3.24 (m, 1 H), 2.81 (m, 1 H), 2.51 (t, J = 1 1 .2 Hz, 1 H), 2.18 (m, 1 H), 1.91 (m, 1 H), 1 .64 (m, 1 H), 1.26 (s, 3H); 13C NMR (125 MHz, CDCIs, ppm) δ 137.4, 128.9, 128.4, 127.4, 89.5, 71 .1 , 62.1 , 51.9, 50.0, 38.3, 21.0. was confirmed in HPLC-MS and in 1H NMR for some protons. Both methods gave similar ratio, (in 1H NMR, methyl singlet at 1 .45 and 1 .40 ppm were used)
Example 2: Synthesis of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol (IV) from II' in water/toluene mixture:
Figure imgf000023_0001
Into a flask equipped with magnetic stir bar were placed starting material II' (93.7 mmol, 20 g) and toluene (470 mL) and 1 M sodium bicarbonate (2.5 equiv., 234 mL) Mixture was stirred for 10 minutes at 15°C. Afterwards quinidine (0.01 equiv., 0.3 g), nitromethane (1 .4 equiv., 7.1 mL) and formaldehyde 37% (1 .4 equiv., 9.7 mL) were added successively. Reaction mixture was vigorously stirred overnight. Toluene phase was dried and concentrated to give a yellow liquid which was analyzed/confirmed using 1H NMR spectroscopy (28.9 g, molar ratio 1 .5/1 compound IV vs. toluene and d.r. 5/1 ).
Example 3: Synthesis of 4-(benzyl(2-nitroethyl)amino)butan-2-one III' from II' in water/toluene mixture:
Figure imgf000023_0002
Into a flask equipped with magnetic stir bar were placed starting material II' (9.37 mmol, 2 g) and toluene (4.7 mL) and 1 M sodium bicarbonate (2.5 equiv., 23.4 mL). Mixture was stirred for 10 minutes at 15°C. Afterwards nitromethane (1 .4 equiv., 0.71 mL) and formaldehyde 37% (0.97 mL, 1 .4 equiv.) were added successively. Reaction mixture was vigorously stirred at 15°C overnight. Toluene phase was dried and concentrated to give an oil product which was analyzed and confirmed using 1H NMR analysis (2.8 g, 7/1 ratio II7III').
1H NMR (500 MHz, CDCI3, ppm) δ 7.30 (m, 5H, ArH), 4.41 (t, J = 6.0 Hz, 2H), 3.64 (s, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2,82 (t, J = 7.0 Hz 2H), 2.57 (t, J = 7.0 Hz, 2H), 2.1 1 (s, 3H).
Example 4: Synthesis of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol IV from III':
Figure imgf000024_0001
Compound III' (4,68 g, 18,7 mmol) was dissolved in toluene (5 mL). Afterwards Et3N (0.1 equiv. 0.26 mL) was added and the reaction mixture was stirred overnight at room temperature. Solution was concentrated to give pure compound 3 which was confirmed with 1H NMR and LC- MS analysis (d.r. 63/37).
Example 5: Preparation of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol benzoate salt (IV -s):
Figure imgf000024_0002
To a solution of benzoic acid (4 mmol; 485 mg) in 1 mL of 2-methyltetrahydrofuran (2-MeTHF) was slowly added crude 1 -benzyl-4-methyl-3-nitropiperidin-4-ol dissolved in 2-MeTHF and homogenous reaction mixture was stirred for 15 min at room temperature. Afterwards the solution was concentrated under reduced pressure and to the syrupy residue n-hexane (10 mL) was added. The reaction mixture was allowed to stand than at -20 °C for few days and the syrupy product was crystallized. White crystalline powder was filtered off to afford 1.25 g of material (Yield: 84%) which was finally characterized with NMR and FT-IR spectroscopy.
1H NMR (500 MHz, DMSO, ppm) δ 7.95 (m, 2H, ArH), 7.60 (m, 1 H, ArH), 7.45 (m, 2H, ArH), 7.25-7.40 (m, 5H, ArH), 5.00 (bs, 1 H), 4.55 (m, 1 H), 3.65 (s, 2H), 2.87 (m, 1 H), 2.75 (m, 1 H), 2.50 (m, 1 H), 2.30 (m, 1 H), 1 .60 (m, 2H), 1 .27 (s, 3H); 13C NMR (125 MHz, CDCI3, ppm) δ 167.4, 137.9, 132.9, 130.9, 129.3, 128.9, 128.6, 128.3, 127.1 , 88.4, 68.3, 61.4, 50.22, 47.6, 38.1 , 27.1 ; IR (KBr): v = 3424 {broad), 1627, 1554, 1455, 1385, 718 cm"1. Example 6: Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from IV via dehydration reaction using methanesulfonyl chloride and triethyl amine in toluene:
Figure imgf000025_0001
To a stirred solution of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol (IV) (0.5 mmol, 125 mg) in toluene (3.5 mL) was added triethylamine (1 .05 mmol) and such reaction mixture was stirred under nitrogen atmosphere for 10 min at room temperature. Reaction system was cooled down to 0 °C and then methanesulfonyl chloride (1 .75 equiv. according to 3) was slowly added and stirred for 15 min. The resulting mixture was than warmed to room temperature and stirred there for 3.5 hours. The reaction mixture was diluted with aqueous solution of Na2C03 and organic phase were separated. Aqueous phase was re-extracted with toluene (2 x 20 mL), organic phases were then washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product was finally purified with flash chromatography (Si02; EtOAc/ n-hexane) to afford 104 mg (Yield: 90%) of red liquid material Va' which was confirmed using 1H, 13C NMR and LC-MS (m/z: 233 (M + H)+) analysis.
1H NMR (500 MHz, DMSO, ppm) δ 7.45-7.35 (m, 5H, ArH), 3.67 (s, 2H of benzyl), 3.47 (m, 2H), 2.57 (m, 2H), 2.42 (m, 2H), 2.18 (s, 3H); 13C NMR (125 MHz, CDCI3, ppm) δ 142.7, 137.4, 129.1 , 128.7, 128.5, 127.5, 61 .5, 52.3, 48.5, 33.9, 21 .1.
Example 7: Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from IV
via dehydration reaction using trifluoroacetic anhydride and triethylamine in toluene:
Figure imgf000025_0002
To a stirred solution of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol (IV) (1 mmol, 250 mg) in toluene (5 mL) was added triethylamine (2.25 mmol; 313 μί) and reaction mixture was stirred under nitrogen atmosphere for 10 min at room temperature. Reaction system was cooled down to 0 °C and then trifluoroacetic anhydride (1.15 equiv. according to IV) was slowly added and stirred for 30 min. The resulting mixture was then warmed up to room temperature and stirred for 12 hours. The reaction mixture was diluted with aqueous solution of Na2C03 and organic phase was separated. Aqueous phase was re-extracted with toluene (2 x 25 mL), organic phases were then washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product was finally purified with flash chromatography (Si02; EtOAc/ n-hexane) to afford 180 mg (Yield: 77%) of liquid material Va' which was confirmed with 1H NMR and LC-MS (m/z = 233 (M + H)+) analysis.
Example 8: Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from IV
via dehydration reaction using trifluoroacetic anhydride and triethylamine in 2- methytetrahydrofuran:
Figure imgf000026_0001
To a stirred solution of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol (IV) (0.5 mmol, 125 mg) in 2- MeTHF (3.5 mL) was added triethylamine (1 .1 mmol) and reaction mixture was stirred under nitrogen atmosphere for 10 min at room temperature. Reaction system was cooled down to 0 °C and then trifluoroacetic anhydride (1 .5 equiv. according to 3) was slowly added and stirred for 30 min. The resulting mixture was then warmed up to room temperature and stirred overnight. The reaction mixture was diluted with aqueous solution of Na2C03 and organic phase was separated. Aqueous phase was re-extracted with toluene (2 x 20 mL), organic phases were then washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product was finally purified with flash chromatography (Si02; EtOAc/ n-hexane) to afford 97 mg (Yield: 84%) of liquid material Va' which was confirmed with 1H NMR and LC-MS (m/z = 233 (M + H)+) analysis.
Example 9: Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from IV
via dehydration reaction using thionyl chloride and triethyl amine: N°2
Figure imgf000026_0002
Into a test tube equipped with magnetic stirrer and septum was placed starting material (IV) (0.5 mmol, 125 mg) which was dissolved in dry CH2CI2 (3.5 mL) and such solution was cooled down to 0 °C. Thionyl chloride (2.5 mmol; 182 μί) was then slowly added andreaction mixture was stirred for an hour at 0 °C. To this solution Et3N (2.5 mmol, 0.4 mL) was added and reaction mixture was intensively stirred in an ice-bath overnight. To this solution NaHC03 (aq.) was added to quench the reaction and then extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product was finally purified with flash chromatography (Si02; EtOAc/ n-hexane 1 : 10) to give 67 mg (Yield: 58%) of liquid material Va' which was confirmed with 1H NMR and LC-MS (m/z = 233 (M + H)+) analysis.
Example 10: Preparation of 1 -benzyl-4-methyl-3-nitro-1 ,2,3,6-tetrahydropyridine (Vb') from IV
via dehydration reaction using trifluoroacetic anhydride and triethylamine under solvent-free conditions
Figure imgf000027_0001
Into a test tube equipped with magnetic stirrer and septum were placed starting material (IV) (1 .5 mmol) and Et3N (4.5 mmol) and reaction mixture was vigorously stirred for 20 minutes at room temperature. Afterwards the reaction system was cooled down to 0 °C and trifluoroacetic anhydride (2.25 mmol) was slowly added. The reaction mixture was warm up to room temperature and vigorously stirred overnight. To this solution NaHC03 (aq.) was added and mixture was then extracted with EtOAc (2 x 50 ml_). The combined organic phases were finally washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product mixture was finally purified with flash chromatography (Si02; EtOAc/ n-hexane 1 : 10) to give 193 mg (Yield: 55%) of final material Vb' which was confirmed with LC-MS (m/z = 233 (M + H)+) and 1H NMR analysis.
1H NMR (500 MHz, DMSO, ppm) δ 7.35-7.20 (m, 5H, ArH), 5.87 (m, 1 H), 4.78 (m, 1 H), 3.65 (d, J = 13 Hz, 1 Ha of benzyl), 3.57 (d, J = 13 Hz, 1 Hb of benzyl), 3.38 (dd, J = 12.4 Hz, J = 3.5 Hz, 1 H), 3.27 (m, 1 H), 2.86 (m, 1 H), 2.77 {dd, J = 12.4 Hz, J = 3.8 Hz, 1 H), 1.82 (m, 3H).
Example 11 : Preparation of 1 -benzyl-4-methyl-3-nitro-1 ,2,3,6-tetrahydropyridine (Vb') from IV
via dehydration reaction in the presence of iodine
Figure imgf000027_0002
Into a test tube equipped with magnetic stirrer and septum was placed liquid starting material (IV) (1 .5 mmol) and during intensive stirring (900 rpm) catalytic amount of iodine (fine powder) was added in two portions (0.075 mmol; 5 mol% according to IV). Reaction mixture was vigorously stirred overnight at 60 °C. To this solution aqueous solution of Na2S203 was added and reaction mixture was then extracted with EtOAc (2 x 60 mL). The combined organic phases were finally washed with aqueous solution of Na2S03 and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product mixture (5-10% of Va' was also observed with NMR in the reaction mixture) was finally purified with flash chromatography (Si02; EtOAc/ n-hexane 1 : 10) to give 212 mg (Yield: 61 %) of final material Vb' which was confirmed with LC-MS (m/z = 233 (M + H)+) and 1H NMR analysis.
Example 12: Preparation of 1 -benzyl-4-methyl-5-nitro-1 ,2,3,6-tetrahydropyridine (Va') from 1 - benzyl-4-methyl-3-nitropiperidin-4-ol benzoate salt (IV -s) via dehydration reaction using methanesulfonyl chloride and triethylamine in toluene:
Figure imgf000028_0001
To a stirred solution of 1 -benzyl-4-methyl-3-nitropiperidin-4-ol benzoate salt (0.5 mmol) in toluene (3.5 mL) was added triethylamine (1.65 mmol) and reaction mixture was stirred under nitrogen atmosphere for 10 min at room temperature. Reaction system was cooled down to 0 °C and then methanesulfonyl chloride (1 .75 equiv. according to starting material; 0.875 mmol) was slowly added and stirred for an hour. The resulting mixture was then warmed up to room temperature and stirred there overnight. The reaction mixture was diluted with aqueous solution of Na2C03 and organic phase was separated. Aqueous phase was re-extracted with toluene (2 x 20 mL), organic phases then washed with brine and dried over anhydrous Na2S04. The solvent was evaporated under reduced pressure and obtained crude product was finally purified with flash chromatography (Si02; EtOAc/ n-hexane) to afford 65 mg (Yield: 56%) of liquid material Va' which was confirmed using 1H NMR analysis.
Example 13: Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via reduction reaction using lithium aluminum hydride in THF:
To a stirred suspension of LiAIH4 (1 .07 g, 4 eq) in THF (30 mL), was added slowly at room temperature a solution of compound Va' (1 ,6 g, 7 mmol) in THF (10 mL). Reaction mixture was heated at reflux overnight. Under nitrogen stream, reaction was quenched by dropwise addition of water (5 mL) followed by 3M H3P04 (2 mL). Solution was basified by addition of NaOH 1 M (30 mL). Solution was extracted three times with toluene (3 * 20 mL). Combined toluene phases were dried over Na2S04 and concentrated. Product was confirmed by GC-MS (m/z = 205 (M + H)+) ,1H NMR and GC analysis, (d.r. 63/37 with c/s-isomer being as the main product).
Example 14: Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine Va' via reduction reaction using Raney® Nickel and hydrogen in methanol:
Figure imgf000029_0001
To a stirred solution of compound Va' (0.4 g, 1 .7 mmol) in methanol (10 mL) under nitrogen atmosphere was added Raney Nickel slurry in water (1 mL). Hydrogen balloon was added and the reaction mixture was stirred overnight at room temperature. Reaction was filtered on Celite® and concentrated to give crude amine VI'. Product was confirmed by 1H NMR and GC analysis, (d.r. 34/66 with irans-isomer being as the main product).
Example 15: Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via reduction reaction using borane and catalytic amount of sodium borohydride in THF:
Figure imgf000029_0002
To a stirred solution of compound Va' (0.4 g, 1 .7 mmol) in THF (4 mL) was slowly added borane-THF complex (6.9 mL of 1 M solution in THF, 4 equiv. according to starting material) under nitrogen atmosphere at 0 °C. Afterwards NaBH4 (16 mg, 0.25 equiv.) was added and the reaction mixture was warmed up and stirred 4 days at room temperature. Solution was quenched with water (2 mL) and 1 M HCI (aq.) (4 mL). Solution was stirred than for additional 2 hours. Solution was washed with Et20 (10 mL). Water phase was basified to pH 12 using NaOH 4M. Water phase was extracted twice with DCM (2 χ 20 m,L). Organic phase was dried over Na2S04 and concentrated to give crude amine VI'. Product was confirmed by 1H NMR and GCMS analysis, (m/z 204; d.r. 70/30 with c/s-isomer being as the main product). Example 16: Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via one-pot reduction process using sodium borohydride and fine zinc powder:
Figure imgf000030_0001
To a stirred solution of compound Va' (1 mmol; 232 mg) in THF was added dry MeOH (volume ratio 10 : 1 ) and afterwards the reducing agent NaBH4 (2 mmol; 76 mg) was added in three portions at room temperature. The reaction system was vigorously stirred for 1 .5 hours at room temperature and then fine Zn dust was added in an excess. Finally glacial acetic acid (1.8 ml_; 0.9 mL/h) was slowly dropping into reaction system at 0 °C. Reaction system was than stirred for 10 hours at 40 °C. Zinc was filtered off and washed with ethyl acetate, organic phase was than washed with aqueous NaHC03. Aqueous phase was basified to 1 1 .5 using 20% aq. solution of NaOH and extracted with hot ethyl acetate. Combined organic phases were dried over Na2S04 and concentrated under reduced pressure to obtain crude VI' which was purified with flash column chromatography (Si02; CH2CI2) to afford 235 mg of final product (cis/trans mixture). Product mixture of isomers was analyzed with GC-MS (m/z = 204; in ratio 1 : 7 with irans-isomer being as the main product; 10% of m/z = 202 was also detected) and was finally confirmed by 1H NMR.
Example 17: Preparation of 1 -benzyl-4-methylpiperidin-3-amine (VI') from 1 -benzyl-4-methyl- 5-nitro-1 ,2,3,6-tetrahydropyridine (Va') via one-pot reduction process using sodium borohydride and fine iron powder:
Figure imgf000030_0002
To a stirred solution of compound Va' (0.5mmol; 1 16 mg) in THF was added dry MeOH (volume ratio 10 : 1 ) and afterwards the reducing agent NaBH4 (1 mmol; 38 mg) was added in two portions at room temperature. The reaction system was vigorously stirred for 1 .5 hours at room temperature and then fine iron powder was added in an excess. Finally glacial acetic acid (0.65 ml_; 0.65 mL/h) was slowly dropping into reaction system at 0 °C. Reaction system was than stirred overnight at 40 °C. Iron was first filtered off and washed with ethyl acetate, organic phase was than washed with aqueous NaHC03. Aqueous phase was basified to 1 1 .5 using 20% aq. solution of NaOH and extracted with hot ethyl acetate. Combined organic phases were dried over Na2S04 and concentrated under reduced pressure to obtain crude VI' which was purified with flash column chromatography (Si02; CH2CI2) to afford 70 mg of final product (cis/trans mixture). Product mixture of isomers was analyzed with GC-MS (m/z = 204; in ratio 1 : 8 with irans-isomer being as the main product; 15-20% of m/z = 234 was also detected) and was finally confirmed by 1H NMR.
Example 18: Preparation of 1 -benzyl-N,4-dimethylpiperidin-3-amine (VII') from 1 -benzyl-4- methylpiperidin-3-amine (VI') via formylation / reduction reaction using methyl formate / sodium borohydride tandem reagent in the presence of sulfuric acid in
THF
Figure imgf000031_0001
Compound Via' (0.316 g, 1 .55 mmol) was dissolved in HC02Me (15 mL) and solution was stirred overnight at room temperature. Solution was concentrated and residue was dissolved in THF (3 mL) under N2 atmosphere. Sodium borohydride (236 mg, 4eq) was added and solution was cooled down to 0°C. A solution of H2S04 (0.174 mL, 2 eq) in THF (1 .5 mL) was added dropwise in one hours. Solution was slowly warmed-up to room temperature and stirred for 48 h. Reaction was quenched with 4N NaOH (1 mL) and solution was stirred for 2 hours. Solution was diluted with water (5 mL) and DCM (10 mL). Phases were separated and DCM phase was dried over sodium sulfate and concentrated to give compound VII'.

Claims

Claims
1 . A process for preparing a compound of formula IV
Figure imgf000032_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyi, or an acid addition salt thereof, which process comprises treating a compound of formula II
Figure imgf000032_0002
wherein R-i and R2 are defined as above,
with nitromethane and formaldehyde in the presence of a base, and
optionally converting the obtained compound of formula IV into its acid addition salt.
2. The process according to claim 1 , wherein the compound of formula II is first converted to a compound of formula III
Figure imgf000032_0003
which is further converted to the compound of formula IV in the presence of a catalytic base.
3. The process according to claim 1 or claim 2, wherein R-i is -CH2-R3, wherein R3 represents substituted or unsubstituted aryl, preferably Ri is benzyl.
The process according to any of the previous claims, wherein the reaction is carried out in a solvent selected from the group consisting of water, iPrOH, MeTHF, THF and toluene, or mixtures thereof.
The process according to claim 2, wherein the catalytic base is selected from the group consisting of Et3N, Bu3N, quinidine, quinine, 4-dimethylaminopyridine (DMAP), 1 ,4-diaza- bicyclo[2.2.2]octane (DABCO) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The process according to any one of the previous claims, wherein compound of formula IV or an acid addition salt thereof is converted to a compound of formula Va, Vb and Vc respectively
Figure imgf000033_0001
in which R-i and R2 are defined as above,
and R2' derives from R2 representing alkyl or cycloalkyl in which the carbon atom adjacent to the piperidine ring is bonded with at least one hydrogen, which hydrogen is abstracted whereby R2' is formed, by treating compound of formula IV with a dehydrating agent, optionally in a presence of a base.
The process according to claim 6, wherein compounds of formulae Va, Vb and Vc are converted to a compound of formula VI
Figure imgf000033_0002
in which R-i and R2 are defined as above, by reducing the compounds of formulae Va, Vb and Vc in the presence of a hydride source and/or by hydrogenation in the presence of a transition-metal catalyst.
The process according to claim 7, characterized by either one or a combination of the following features (x) and (y): (x) the hydride source is selected from the group consisting of LiAIH4, BH3, BH3 · Et20,
NaBH4, LiBH4, RED-AL and DI BAL-H;
(y) the transition metal catalyst comprises a transition metal selected from the group consisting of highly activated nickel, Zn, Fe and Ir;
A compound of formula
Figure imgf000034_0001
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S02-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyi.
A compound of formula IV
Figure imgf000034_0002
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -S02-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyi, or an acid addition salt thereof. 1. A compoun
Figure imgf000034_0003
in which R-i is selected from -CH2-R3 wherein R3 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or from -CO-R4, -CO-OR4 and -SO2-R4, wherein R4 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2 represents alkyl or cycloalkyi, R2' represents alkyl or cycloalkyi in which the carbon atom adjacent to the piperidine ring is substituted with at least one hydrogen, preferably R2' represents C1 -C4-alkylidene and R2 represent C1 -C4-alkyl, more preferably R2' is methylene and R2 is methyl, or acid addition salt(s) thereof.
12. The compound according to claim 10 or claim 1 1 , wherein the acid addition salt is
benzoic acid salt.
13. The compounds of formulae III, IV, Va, Vb and Vc according to any one of claims 9 to 12, characterized by at least one of the following structural features (I) to (II):
(I) Ri is CH2-R3, wherein R3 is substituted or unsubstituted aryl, preferably Ri is benzyl;
(II) R2 is C1 -C4-alkyl, preferably R2 is methyl.
14. Use of a compound selected from the group of compounds defined by formulae III, IV, Va, Vb and Vc according to any one of claims 9 to 13 in a process for preparing a pharmaceutically active agent.
15. The use according to claim 14, wherein 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
Figure imgf000035_0001
or an acid addition salt thereof.
PCT/EP2013/075072 2012-11-30 2013-11-29 Preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors WO2014083150A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201380071692.2A CN104955803B (en) 2012-11-30 2013-11-29 3 aminopiperidines are prepared by nitro tetrahydropyridine precursor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12195149.5 2012-11-30
EP12195149 2012-11-30

Publications (1)

Publication Number Publication Date
WO2014083150A1 true WO2014083150A1 (en) 2014-06-05

Family

ID=47278688

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/075072 WO2014083150A1 (en) 2012-11-30 2013-11-29 Preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors

Country Status (2)

Country Link
CN (1) CN104955803B (en)
WO (1) WO2014083150A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7301023B2 (en) * 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
SI1913000T1 (en) * 2005-07-29 2012-02-29 Pfizer Prod Inc Pyrrolo [2,3-d] pyrimidine derivatives; their intermediates and synthesis

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HAO BAO-YU ET AL: "A Novel Asymmetric Synthesis of cis-(3R,4R)-N-(tert-Butoxycarbonyl)-4-methyl-3-(methylamino)piperidine", no. 8, 2011, pages 1208 - 1212, XP008153301, ISSN: 0039-7881, Retrieved from the Internet <URL:https://www.thieme-connect.com/ejournals/issue/10.1055/s-002-21843> DOI: 10.1055/S-0030-1259963 *
ROTH, HERMANN J. ET AL.: "Synthese polyfunktioneller Heterocyclen durch Aminoalkylierung von Nitroalkanen", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 311, no. 6, 1978, pages 492 - 498, XP008162606, ISSN: 0365-6233, [retrieved on 20060926], DOI: 10.1002/ARDP.19783110607 *
X. ERIC HU ET AL: "Synthesis of trans -(3 S )-Amino-(4 R )-alkyl- and -(4 S )-Aryl-piperidines via Ring-Closing Metathesis Reaction", ORGANIC LETTERS, vol. 4, no. 25, December 2002 (2002-12-01), pages 4499 - 4502, XP055049117, ISSN: 1523-7060, DOI: 10.1021/ol027019m *
YUNFENG CHEN ET AL: "One-Pot Asymmetric Synthesis of Substituted Piperidines by Exocyclic Chirality Induction", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 11, no. 11, 6 June 2009 (2009-06-06), pages 2333 - 2336, XP008161837, ISSN: 1523-7060, [retrieved on 20090513], DOI: 10.1021/OL900708D *

Also Published As

Publication number Publication date
CN104955803B (en) 2017-11-28
CN104955803A (en) 2015-09-30

Similar Documents

Publication Publication Date Title
EP3398952B1 (en) Synthesis process of ruxolitinib
KR100286874B1 (en) Method for preparing protected 4-aminomethyl-pyrrolidone-3-on
EP2914574B1 (en) New process
ZA200507141B (en) New process for preparing 4-aminomethyl-3-alkoxy- iminopyrrolidine methanesulfonate
CN104837817B (en) Synthetic route for preparation of 3-amino-piperidine compounds
KR20220156560A (en) Synthesis of capsaicin derivatives
WO2014083150A1 (en) Preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors
JP5130212B2 (en) Optically active 3-amino-2,5-dioxopyrrolidine-3-carboxylates, process for producing the same and use of the compounds
WO2020171073A1 (en) Method for producing benzazepine derivative and intermediate of same
JPH0262854A (en) Production of substituted phenoxyethylamines
KR101686087B1 (en) Process for Production of Optically Active Indoline Derivatives or Salts Thereof
CN111471041A (en) Synthetic method of oxazolidinone antibacterial drug intermediate
CN112824381B (en) Preparation method of piperidine amine
KR101299720B1 (en) A novel process for preparing 3-amino-5-fluoro-4-dialkoxypetanoic acid ester
KR100850558B1 (en) Process for preparing useful in synthesis of atorvastatin
JP2012116775A (en) Method for producing ecteinascidin
CN117886795A (en) Process for the preparation of antifungal compounds and intermediates therefor
KR100896087B1 (en) Synthetic method of optically pure 2-methylpyrrolidine and the salt thereof
KR20220011669A (en) Methods and intermediates for the preparation of BTK inhibitors
KR100566562B1 (en) Method of Preparing Sumatriptan
JP5344287B2 (en) Process for producing α-difluorohalomethylcarbonyl compound
CN115710213A (en) Preparation method of cis-chiral 3-fluoro-4-hydroxypiperidine and derivatives thereof
CN117659018A (en) Chiral C1 symmetrical imidazole-pyridine-imidazolidinone tridentate nitrogen ligand, synthesis and application thereof
CN112724077A (en) Synthetic method of Laolatinib intermediate
KR100574343B1 (en) Process for preparation of chiral 4-hydroxy-2-piperidinone

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13799025

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13799025

Country of ref document: EP

Kind code of ref document: A1