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WO2014096374A1 - Procédé de synthèse de pyrrolidines et de pyrroles - Google Patents

Procédé de synthèse de pyrrolidines et de pyrroles Download PDF

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Publication number
WO2014096374A1
WO2014096374A1 PCT/EP2013/077726 EP2013077726W WO2014096374A1 WO 2014096374 A1 WO2014096374 A1 WO 2014096374A1 EP 2013077726 W EP2013077726 W EP 2013077726W WO 2014096374 A1 WO2014096374 A1 WO 2014096374A1
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compound
formula
carbon atoms
aryl
residues
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Roland Barth
Martin Langner
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members

Definitions

  • the invention relates to pyrrolidines, pyrroles and processes for the preparation of pyrrolidines and pyrroles, wherein the processes require less process steps, allow a more rapid access towards the pyrrolidines and pyrroles and/or do not require the use of advanced starting materials compared to several of the known processes.
  • Some of the pyrrolidines and the pyrroles might be suitable as intermediates for the preparation of ethyl (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1-carboxylate and/or the preparation of telaprevir or a pharmaceutically acceptable salt or solvate thereof.
  • 2,3,4-Trisubstituted pyrrolidines and pyrroles are interesting and suitable building blocks for a wide range of active agents.
  • Telaprevir (CAS Number 402957-28-2; lUPAC Name: (1S,3aR,6aS)-2-[(2Sv)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3- dimethylbutanoyl]-N-[(3S)-1-(cyc!opropylamino)-1 ,2-dioxohexan-3-yl]-3,3a,4,5,6,6a- hexahydro-1 H-cyclopenta[c] pyrrol-1-carboxamid) is a protease inhibitor that can be used as antiviral drug.
  • telaprevir inhibits the hepatitis C virus NS3-4A serine protease.
  • Ethyl (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate (CAS Number: 402958-25-2) is one of the building blocks of telaprevir.
  • WO 0218369 A2 discloses the preparation of 2,3,4-trisubstituted pyrrolidines such as ethyl (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1-carboxylate.
  • 2,3,4-trisubstituted pyrrolidines such as ethyl (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole-1-carboxylate.
  • the preparation of them is often associated with complex syntheses that either start with already advanced starting materials (WO 2007022459 A2, WO 2008090819 A1 ) or require multistep syntheses (WO 0218369 A2, WO 2008090819 A1 ).
  • Figure 1 shows a scheme of some of the processes as disclosed herein.
  • FIG. 2 shows a further scheme of some of the processes as disclosed herein.
  • Figure 3 shows a chiral HPLC analysis.
  • electron withdrawing group as used herein shall be understood as known in the art. In particular, it shall be understood as a group that draws electrons away from a reaction center. When this center is an electron rich position, the presence of the electron- withdrawing substituent has a stabilizing effect.
  • electron withdrawing groups are sulfones, nitriles (CN), carbonyls (CO), phosphonates (PO(OR) 2 ) and nitro groups (N0 2 ). Suitable electron withdrawing group are listed for example in standard text books such as J. A. Joule and K. Mills, Heterocyclic Chemistry, 4 th edition, 2000, published by Blackwell Science Ltd., ISBN: 978-0-632-05453-4, pp. 259 - 260.
  • protecting group as used herein shall be understood as known in the art. In particular, it shall be understood as a group which has been introduced into a molecule by chemical modification of a functional group of the molecule to avoid a reaction of said functional group in a subsequent reaction.
  • the "protective group” is introduced in to the molecule by a reaction of a functional group of the molecule and an "agent suitable for introducing a protective group”. Particularly, the “protective group” may be selected from t - butyloxycarbonyl, carboxybenzyl, fluorenylmethyloxycarbonyl.
  • agent suitable for removing the protective group or the PG residue shall be understood as known in the art.
  • agent which cleaves the "protective group” from the said functional group and allows the functional group to react in a subsequent reaction.
  • it may be an acid, particularly a
  • a “protective group” that is “capable of protecting an amine group” as used herein shall be understood as a protective group which avoids a reaction of said amine group under the conditions of a step b 2 ), a step e 2 ) and/or a step c) as defined herein, especially as exemplified in the examples.
  • a “protective group” that is “capable of protecting an amine group” avoids between 95 to 100 %, particularly between 98 to 100 %, more particularly 100 %, of a reaction of said amine group in the presence of lithium
  • diisopropylamide at 0 °C in THF for at least 1 hour, particularly between 1 and 2 hours, in the absence of an "agent suitable for removing the protective group or the PG residue".
  • halide or halogenide as used herein shall be understood as including at least chlorine, iodine, and bromine.
  • leaving group as used herein shall be understood as known in the art. Suitable leaving groups are listed for example in standard text books such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition; Wiley & Sons.
  • Preferred leaving groups are f-butyloxycarbonyl, halogenides, particularly chloride and bromide, alkyl sulfonates and aryl sulfonates.
  • ambient temperature and “room temperature” used herein will be understood by the person skilled in the art as referring to a temperature between about 20 °C and about 25 °C, particularly between 20 °C and 25 °C.
  • All compounds as disclosed herein may, if possible, be present in form of a salt.
  • all amines as disclosed herein may be present in form of a salt.
  • Suitable salts may include, but are not limited to the group consisting of hydrochloride, hydrobromide, sulphates or phosphates as well as organic salts such as acetate, citrate, maleate, succinate, lactate, tartrate, o-substituted tartrate, mesylate, tosylate, trifluoroacetate, benzoate and salts of mandelic acid.
  • a "dry” solvent as used herein typically contains 0.005 % (50 ppm) or less water.
  • the present invention relates to a process comprising the following steps:
  • Z is selected from carbonyl groups
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; or particularly from -CON-XY groups, wherein X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • N-QW constitutes a fragment of any natural or non-natural amino acid
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; and wherein the EWG residue is an electron withdrawing group;
  • PG residue is a protective group, which is capable of protecting an amine group
  • step b) may comprise a step b 1 ) of converting the compound of formula (III) to a compound of formula (V)
  • Step b) may, however, also comprise a step b 3 ) of converting the compound of formula (III) to a compound of formula (IV)
  • the process may start with commercially available starting material, e.g. a sulfone and an isocyanide. More specifically, isocyanides such as compound (I), particularly the compound of formula (la) defined below, and compounds such as compounds (II), particularly the compound of formula (I la) defined below, may be condensed in the presence of a suitable base to form pyrroles such as compound (III), particularly the compound of formula (Ilia) defined below. The pyrrole can be converted to pyrrolidines such as compounds (VI), particularly to the compound of formula (Via) defined below, e.g. by the steps explained above.
  • isocyanides such as compound (I), particularly the compound of formula (la) defined below
  • compounds such as compounds (II), particularly the compound of formula (I la) defined below may be condensed in the presence of a suitable base to form pyrroles such as compound (III), particularly the compound of formula (Ilia) defined below.
  • the pyrrole can be converted to
  • a base preferably a strong base such as lithium diisopropylamide (LDA)
  • LDA lithium diisopropylamide
  • VIII pyrrolidines of formula (VIII), particularly the compound of formula (Villa) defined below, which is ethyl (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1 -carboxylate.
  • the process allows the rapid preparation of a variety of 2,3,4-subsituted pyrrolidines, e.g. compounds of formulae (VI), (VII) and (VIII), by a simple pyrrole-cyclization/hydrogenation strategy.
  • the relative stereochemistry is cis after the hydrogenation but can be equilibrated to trans after treatment with a suitable base.
  • the process allows the rapid preparation of a variety of pyrroles, e.g. compounds of formulae (III) and (V).
  • the substituted pyrroles of formula (III) may be formed in ⁇ 90% yield and the hydrogenation of pyrroles of formula (III) may give yields in a range of 50-90% (depending on the reaction conditions).
  • the hydrogenation of BOC-pyrroles of formula (V) proceeds almost quantitiatively.
  • Some of the reactions pyrrole synthesis, hydrogenation
  • may give clean conversions low amounts or even no side products).
  • the route avoids critical solvents and reagents with respect to safety and should be well suited for large scale reactions.
  • some of the materials may be crystalline compounds (e.g. the compounds of formulae (I la) and (Ilia) below).
  • the present invention relates to a process comprising the following steps:
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; or particularly from -CON-XY groups, wherein X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • N-QW constitutes a fragment of any natural or non-natural amino acid
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • step e) may comprise a step e 1 ) of converting the compound of formula (III) to a compound of formula (V)
  • step e) may also comprise a step e 4 ) of converting the compound of formula (III) to the compound of formula (IV).
  • the process may start with commercially available starting material, e.g. a sulfone and an isocyanide. More specifically, isocyanides such as compound (I), particularly the compound of formula (la) defined below, and compounds such as compounds (II), particularly the compound of formula (Ma) defined below, may be condensed in the presence of a suitable base to form pyrroles such as compound (III), particularly the compound of formula (Ilia) defined below.
  • the pyrroles can e.g. be directly hydrogenated under pressure and temperature to give pyrrolidines of compounds (IV), particularly the compound of formula (IVa) defined below.
  • the pyrroles can be protected to give PG-pyrroles such as compounds (V), particularly the compound of formula (Va) defined below, which can be hydrogenated under very mild conditions to yield PG-pyrrolidine such as compounds (VI), particularly the compound of formula (Via) defined below.
  • PG-pyrrolidine such as compounds (VI), particularly the compound of formula (Via) defined below.
  • These can be easily converted into pyrrolidine such as compounds (IV), particularly the compound of formula (IVa) defined below under acidic conditions.
  • the racemic c/ ' s-products of compounds of formula (IV) particularly when the compound of formula (IVa) is obtained, may be obtained almost exclusively ("endo-products").
  • the substituted pyrroles of formula (III) may be formed in ⁇ 90% yield and the hydrogenation of pyrroles of formula (III) may give yields in a range of 50-90% (depending on the reaction conditions).
  • the hydrogenation of BOC-pyrroles of formula (V) proceeds almost quantitiatively.
  • Both reactions pyrrole synthesis, hydrogenation
  • the route avoids critical solvents and reagents with respect to safety and should be well suited for large scale reactions.
  • some of the materials may be crystalline compounds (e.g. the compounds of formulae (lla) and (Ilia) below). According to further aspects, the present invention relates to the following processes:
  • step a) compriing a compound of formula (I) wherein Z is selected from carbonyl groups,
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • N-QW constitutes a fragment of any natural or non-natural amino acid
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • Step a) may be carried out at a temperature of -10 °C to 30 °C, particularly 0 °C to room temperature, more particularly first at 0 °C and then at room temperature. Furthermore, step a) may be carried out in a solvent, particularly an aprotic solvent, more particularly a dry aprotic solvent.
  • the solvent may be selected from tetrahydrofuran (THF), acetonitrile, dimethylacetamide (DMAc), dimethylformamide (DMF), methyl tert-butyl ether, 2- methyltetrahydrofuran, /V-methyl-2-pyrrolidone (NMP), and any combination thereof, and is particularly THF, and more particularly dry THF.
  • Step a) may be carried out under an inert gas atmosphere, particularly under a nitrogen or argon gas atmosphere. Moreover, step a) may be carried out in the presence of a base.
  • the base may be selected from KOBui, NaOEt, diazabicycloundecene (DBU), lithium diisopropylamide, potassium
  • hexamethyldisilazide sodium hexamethyldisilazide, lithium hexamethyldisilazide, NaOBuf, K 2 C0 3 , Na 2 C0 3 , KOAc, NaOAc, tetramethylguanidine, diazabicyclononene, and any combination thereof, and is particularly KOBuf.
  • step a) comprises reacting a compound of formula
  • step a) is carried out in the presence of KOBuf first at 0 °C and then at room temperature in dry THF.
  • step b 1 ) or step e 1 ) as defined herein comprise converting a compound of formula (III)
  • PG residue is a protective group, which is capable of protecting an amine group.
  • Said steps may be carried out at a temperature of 15 °C to 40 °C, particularly from 20 °C to 30 °C, and more particularly at room temperature.
  • the converting is typically carried out by adding an agent suitable for introducing a protective group, particularly by adding a compound of formula (IX)
  • the PG residue is as defined herein and wherein L is a leaving group.
  • L may be selected from f-butyloxycarbonyl, halogenides, particularly chloride and bromide, and is particularly i-butyloxycarbonyl.
  • the PG residue may be selected from f - butyloxycarbonyl, carboxybenzyl, fluorenylmethyloxycarbonyl, and is particularly f- butyloxycarbonyl.
  • the compound of formula (IX) may be selected from di-f-butyl dicarbonate, carboxybenzylchlorid, fluorenylmethyloxycarbonyl chloride, and is particularly di-f-butyl dicarbonate.
  • Said steps may be carried out in a solvent, particularly an aprotic solvent.
  • the solvent may be selected from tetrahydrofuran (THF), dimethylformamide (DMF),
  • step b 1 ) or e ) may be carried out in the presence of a base.
  • the base may be selected from tertiary and secondary amines, particularly dimethylaminopyridine, diisopropylethylamine, isopropylmethylamine, butylmethylamine, and triethylamine; cyclic tertiary amines, particularly c/ ' s-2,6-dimethylpiperidine, 1 ,4-diazabicyclo[2.2.2]octane, N-methylpiperidine and N-methylmorpholine; and any combination thereof, and is particularly dimethylaminopyridine.
  • said step b 1 ) or e 1 ) comprises converting a compound of formula (Ilia)
  • a process comprising a step b 2 ) or a step e 2 ) as defined herein comprises converting a compound of (V)
  • Said step b 2 ) or e 2 ) may be carried out at a temperature of 20 °C to 100 °C, particularly from 50 °C to 70 °C, and more particularly 60 °C.
  • Said step b 2 ) or e 2 ) may be carried out with hydrogen at a pressure of 1 to 100 bar, particularly between 2 bar and 10 bar, more particularly at 2 bar or at 10 bar.
  • said step b 2 ) or e 2 ) may be carried out in the presence of a catalyst.
  • the catalyst is a solid-supported catalyst.
  • the catalyst may be selected from rhodium, palladium, platinum, platinum oxide, or nickel, and is particularly rhodium and the solid support may be selected from activated charcoal, carbon, alox, and is particularly activated charcoal.
  • the solid-supported catalyst is selected from rhodium-on-activated charcoal, palladium-on-activated charcoal, raney nickel, and is particularly rhodium-on-activated charcoal.
  • step b 2 ) or e 2 ) is typically carried out in the presence of a base and the base may be selected tertiary and secondary amines, particularly triethylamine, dimethylaminopyridine, diisopropylethylamine,
  • step b 2 ) or e 2 ) is carried out in a solvent, particularly selected from ethanol, methanol, propanol, isopropanol, butanol, and any combination thereof, and is particularly ethanol.
  • said step b 2 ) or e 2 ) comprises converting a compound of (Va)
  • step b 2 ) or e 2 ) may also be carried out with hydrogen at a pressure of 20 to 100 bar, particularly of 40 to 60 bar, and more particularly 50 bar.
  • Said step b 2 ) or e 2 ) is then typically carried out in the presence of a catalyst.
  • the catalyst is then a homogenous catalyst comprising a transition metal compound and at least one ligand.
  • the transition metal compound may be selected from Rhodium complexes, particularly Rh(lll)- chloronorbornadiene-dimer, and Ruthenium complexes, particularly [(Ru(r
  • the at least one ligand may selected from phosphine ligands, particularly diphosphine and monophosphine ligands, and any combination thereof.
  • the at least one ligand may also be selected from Josiphos ligands, Walphos-type ligands, Taniaphos-type ligands, Mandyphos- type ligands and Du-Phos-type ligands.
  • the at least one ligand is selected from diphosphine ligands, particularly from 2,2-bis(diphenylphosphino)-1 , 1 -binaphthale, 1 ,2- bis(diphenyl-phosphino)benzene, (Oxydi-2, 1 -phenylene)bis-(diphenylphosphine), (R)-2,2- bis(diphenylphosphino)-1 , 1 -binaphthalene, (S)-2,2-bis(diphenylphosphino)-1 , 1 -binaphthale, and any combination thereof.
  • diphosphine ligands particularly from 2,2-bis(diphenylphosphino)-1 , 1 -binaphthale, 1 ,2- bis(diphenyl-phosphino)benzene, (Oxydi-2, 1 -phenylene)bis-(diphenylphosphine), (R)-2,2- bis(diphenylphosphino)
  • the homogenous catalyst may also comprise [(Ru(r] 3 - methylallyl)(cod)] and a Josiphos ligand or [(Ru(r
  • Said step b 2 ) or e 2 ) may be carried out in the presence of a base and the base may selected tertiary and secondary amines, particularly triethylamine, dimethylaminopyridine, diisopropylethylamine, isopropylmethylamine, and butylmethylamine; cyclic tertiary amines, particularly c/ ' s-2,6-dimethylpiperidine, 1 ,4- diazabicyclo[2.2.2]octane, N-methylpiperidine and N-methylmorpholine; and any combination thereof, and is particularly triethylamine.
  • said step b 2 ) or e 2 ) may be carried out in a solvent, particularly selected from methanol, ethanol, propanol, isopropanol, butanol, and any combination thereof.
  • said step b 2 ) or e 2 ) may then comprise converting a compound of (Va)
  • a process comprising a step b 3 ) or a step e 4 ) as defined herein comprises converting a compound of formula (III)
  • Said step b 3 ) or e 4 ) may be carried out at a temperature of 40 °C to 80 °C, particularly from 50 °C to 70 °C, and more particularly 60 °C.
  • Said step b 3 ) or e 4 ) may be carried out with hydrogen at a pressure of 30 to 70 bar, particularly of 40 to 60 bar, more particularly 50 bar.
  • Said step b 3 ) or e 4 ) may be carried out in the presence of a catalyst.
  • the catalyst is a solid-supported catalyst, typically selected from rhodium, palladium, platinum, platinum oxide, and nickel, and is particularly rhodium.
  • the solid support may be selected from activated charcoal, carbon, and alox, and is particularly activated charcoal.
  • the solid-supported catalyst is selected from rhodium-on-activated charcoal, palladium-on- activated charcoal, raney nickel, and is more particularly rhodium-on-activated charcoal.
  • Said step b 3 ) or e 4 ) may be carried out in the presence of an acid, wherein the acid may be selected from sulfuric acid, HCI and acetic acid and any combination thereof, and is particularly sulfuric acid.
  • Said step b 3 ) or e 4 ) may be carried out in a solvent, particularly selected from ethanol, methanol, ethanol, propanol, isopropanol, butanol, and any combination thereof, and is particularly ethanol.
  • said step b 3 ) or e 4 ) comprises converting a compound of formula (Ilia)
  • a process comprising a step b 4 ) as defined herein comprises converting a compound of formula
  • Step b 4 may be carried out as step b 1 ) or e 1 ) as defined herein.
  • step b 4 comprises converting a compound of formula (IVa)
  • a process comprising a step e 3 ) as defined herein comprises converting a compound of (VI)
  • Step e 3 may be carried out at a temperature of between room temperature and 100 °C, particularly 20 °C to 30 °C, more particularly at room temperature.
  • Step e 3 ) may be carried out in a solvent, particularly selected from water, dichloromethane, ethanol, methanol, dioxane, THF, ethyl acetate, and any combination thereof.
  • Step e 3 ) is typically carried out in the presence of an agent suitable for removing the PG residue, particularly an acid, a base or hydrogen, depending on the PG residue.
  • step e 3 comprises converting a compound of formula (Via)
  • a process comprising a step c) as defined herein comprises converting a compound of formula (VI)
  • Step c) may be carried out at a temperature of -10 °C to 10 °C, particularly -5 °C to +5 °C, more particularly at 0 °C.
  • Step c) may be carried out in a solvent, particularly an aprotic solvent.
  • the solvent is selected from tetrahydrofuran (THF), dimethylacetamide (DMAc), dimethylformamide (DMF), 2-methyltetrahydrofuran, A/-methyl-2-pyrrolidone (NMP), and any combination thereof, and is particularly THF.
  • step c) may be carried out in the presence of a base, wherein the base may be selected from lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, and any combination thereof, and is particularly lithium diisopropylamide.
  • the base may be selected from lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, and any combination thereof, and is particularly lithium diisopropylamide.
  • step c) comprises converting the compound of (Via)
  • Step d) as defined herein may be carried out as a step e 3 ) as defined herein.
  • a process comprising a step f) as defined herein comprises performing chiral resolution with a mixture of compounds of formula (IV)
  • Step f) is typically carried out by performing a crystallizing step in the presence of dibenzoyl tartaric acid and acetonitrile. Particularly, a dibenzoyl tartrate salt of the compound of formula (IV), particularly the compound of formula (Iva) is obtained. Step f) may be carried out at a temperature of -25 to + 25 °C, particularly 0 to +8 °C, more particularly at 4 °.
  • the Z group as defined herein is selected from carbonyl groups, particularly from -C0 2 1 groups or -CON-QW groups as defined herein.
  • Z may be -C0 2 R 1 and R 1 may be selected from ethyl, methyl, i-propyl, n-propyl, n- t-butyl, i- t-butyl, s- t-butyl, t-butyl, pentyl, hexyl benzyl, cyclohexyl, and is particularly ethyl.
  • R 1 may be a phenyl group substituted with: N0 2 , F, CI, OPh, SPh, S0 2 -alkyl, S0 2 -aryl, alkyloxy, aryloxy, alkyl, aryl, CH(Oalkyl) 2 , or tertiary amines.
  • Z may also be a -CON-XY group, wherein X and Y may be independently selected from the R 1 groups, alkyloxy or aryioxy groups, particularly ethyl, ethyloxy, hydrogen, methyl, methyloxy, i-propyl, i-propyloxy, n-propyl, n-propyloxy, n- t-butyl, n- t-butyloxy, i- t-butyl, i- 1- butyloxy, s- t-butyl, s- t-butyloxy, t-butyl, t-butyloxy, phenyloxy, and benzolxy.
  • X is methoxy and Y is methyl.
  • Z may also be a -CON-QW group, wherein Q and W constitute a fragment of any natural or non-natural amino acid.
  • Q and W constitute a fragment of any natural or non-natural amino acid.
  • Q and W may also constitute the remaining proline fragment.
  • -CON- -N-QW may be
  • R 2 and R 3 may form a ring analogous to the compound of formula
  • R 2 and R 3 are identical or different, and are independently selected from hydrogen, alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted; cycloalkyl residues having from 3 to 12 carbon atoms, wherein the cycloalkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted, aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; aryl residues constituting a heterocycle, or a phenyl group substituted with: N0 2 , F, CI, OPh, SPh, S0 2 -alkyl, S0 2 -aryl, alkyloxy, aryloxy, alkyl, aryl, CH(O
  • the EWG residue may be selected from S0 2 R 4 groups, wherein R 4 is selected from
  • aryl residues having from 6 to 24 carbon atoms, particularly phenyl, chlorophenyl, particularly p-chlorophenyl, bromophenyl, particularly p- bromophenyl, fluorophenyl, particularly p-fluorophenyl, nitrophenyl, particularly p-nitrophenyl, and toluenyl, particularly p-toluenyl, wherein the aryl residues are optionally alkyl substituted;
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • the compound of formula (III) as disclosed herein may in all aspects be the compound of formula (Ilia)
  • the compound of formula (V) as disclosed herein may in all aspects be the compound of formula (Va)
  • the compound of formula (VI) as disclosed herein may in all aspects be the compound of formula (Via)
  • a further aspect of the present invention relates to a compound of formula (IV)
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted.
  • the compound is the compound of formula (IVa) H ( ⁇ ) (IVa).
  • a further aspect of the present invention relates to a compound of formula (V)
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at ieast one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • the compound of formul V) is the compound of formula (Va)
  • Another aspect of the present invention relates to a compound of formula (VI)
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • the PG residue is particularly selected from t -butyloxycarbonyl, carboxybenzyl,
  • the compound of formula (VI) is the compound of formula (Via)
  • Another aspect of the present invention relates to a com ound of formula ( ⁇ )
  • the formation of the compound of formula (Ilia) was done as follows: a solution of the compound of formula (la) (36.0 g, 318 mmol) in tetrahydrofuran (THF) (635 mL) was added within 15 minutes to a stirred suspension of potassium terf.-butoxide (47.5 g, 423 mmol) in dry THF (1279 mL) at 0 °C under N 2 -atmosphere and stirring was continued for 15 minutes. A solution of the compound of formula (Ma) (52.2 g, 251 mmol) in THF (1253 mL) was then added within 20 minutes and the reaction mixture was stirred at 0 °C for 10 minutes and at room temperature for 180 minutes.
  • THF tetrahydrofuran
  • Triethylamine (70.7 g, 699 mmol) and Boc 2 0 (30.75 g, 141 mmol) were added to a stirred solution (Ilia) (12.5 g, 70 mmol) and dimethylaminopyridine (0.85 g, 7 mmol) in dichloromethane (700 mL) at room temperature.
  • the reaction mixture was stirred for three hours and the reaction progress was monitored by HPLC.
  • the reaction was quenched by the addition of H 2 0 (280 mL), the organic phase was separated and washed two more times with H 2 0 (280 mL each) and brine (280 mL).
  • the reaction mixture was hydrogenated at a pressure of 50 bar and a temperature of 60 °C. In this case the conversion was approximately 50% after 24 hours as determined by GC.
  • basic work-up (NaHC0 3 ) spiking experiments and NMR experiments confirmed the formation of the compound of formula (IVa):
  • the data of the compound of formula (IVa) are in complete agreement with the data obtained in experiment #6 (deprotection of the compound of formula (Via)).
  • the hydrogen pressure was raised to 50 bar and the temperature was elevated to approximately 60 °C.
  • the reaction mixture was stirred for a period of 72h under these conditions. Reaction control by HPLC indicated complete consumption of the starting material. After releasing the overpressure, the mixture was concentrated under reduced pressure and the crude product was dried overnight under vacuum at 40 °C and ⁇ 50 mbar. The structure of the pyrrolidine product was confirmed by 1 H-NMR spectroscopy (data see above).
  • Z is selected from carbonyl groups
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted; (iii) aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; and wherein the EWG residue is an electron withdrawing group;
  • PG residue is a protective group, which is capable of protecting an amine group
  • step b) comprises a step b 1 ) of converting the compound of formula (III) to a compound of formula (V)
  • step b) comprises a step b 3 ) of converting the compound of formula (III) to a compound of formula (IV)
  • Z is selected from carbonyl groups
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or - are identical or different, and are independently selected from
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; and wherein the EWG residue is an electron withdrawing group;
  • step e) comprises a step e 1 ) of converting the compound of formula (III) to a compound of formula (V)
  • step e) comprises a step e 4 ) of converting the compound of formula (III) to the compound of formula (IV).
  • a process comprising a step a) of reacting a compound of formula (I)
  • Z is selected from carbonyl groups
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R 1 groups, alkyioxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • step a) is carried out at a temperature of -10 °C to 30 °C, particularly 0 °C to room temperature, more particularly first at 0 °C and then at room temperature.
  • step a) is carried out in a solvent, particularly an aprotic solvent, more particularly a dry aprotic solvent
  • step a) is carried out in a solvent selected from tetrahydrofuran (THF), acetonitrile, dimethylacetamide (DMAc), dimethylformamide (DMF), methyl tert-butyl ether, 2-methyltetrahydrofuran, -methyl- 2-pyrrolidone (NMP), and any combination thereof, and is particularly THF, and more particularly dry THF.
  • a solvent selected from tetrahydrofuran (THF), acetonitrile, dimethylacetamide (DMAc), dimethylformamide (DMF), methyl tert-butyl ether, 2-methyltetrahydrofuran, -methyl- 2-pyrrolidone (NMP), and any combination thereof, and is particularly THF, and more particularly dry THF.
  • step a) is carried out under an inert gas atmosphere, particularly under a nitrogen or argon gas atmosphere.
  • step a) is carried out in the presence of a base.
  • DBU diazabicycloundecene
  • hexamethyldisilazide sodium hexamethyldisilazide, lithium hexamethyldisilazide, NaOBui, K 2 C0 3 , Na 2 C0 3 , KOAc, NaOAc, tetramethylguanidine, diazabicyclononene, and any combination thereof, and is particularly KOBuf.
  • step a) comprises reacting a compound of formula (la)
  • step a) is carried out in the presence of KOBuf first at 0 °C and then at room temperature in dry THF.
  • a process comprising a step b 1 ) as defined in item 2 or a step e 1 ) as defined in item 5 of converting a compound of formula (III)
  • PG residue is a protective group, which is capable of protecting an amine group.
  • step b 1 ) or e 1 ) is carried out at a temperature of 15 °C to 40 °C, particularly from 20 °C to 30 °C, and more particularly at room temperature.
  • PG residue is as defined in item 1 and wherein L is a leaving group.
  • L is selected from i-butyloxycarbonyl, halogenides, particularly chloride and bromide, and is particularly i-butyloxycarbonyl.
  • step b 1 ) or e 1 ) is carried out in a solvent, particularly an aprotic solvent.
  • step b 1 ) or e 1 ) is carried out in a solvent selected from tetrahydrofuran (THF), dimethylformamide (DMF),
  • tertiary and secondary amines particularly dimethylaminopyridine, diisopropylethylamine, isopropylmethylamine, butylmethylamine, and triethylamine; cyclic tertiary amines, particularly c/s-2,6- dimethylpiperidine, 1 ,4-diazabicyclo[2.2.2]octane, N-methylpiperidine and N- methylmorpholine; and any combination thereof, and is particularly
  • step b 1 ) or e 1 ) comprises converting a compound of formula Ilia)
  • a process comprising a step b 2 ) as defined in item 2 or a step e 2 ) as defined in item 5 of converting a compound of (V)
  • PG residue is a protective group, which is capable of protecting an amine group; to a compound of formula (
  • step b 2 ) or e 2 ) is carried out at a temperature of 20 °C to 100 °C, particularly from 50 °C to 70 °C, and more particularly 60 °C.
  • step b 2 ) or e 2 ) is carried out with hydrogen at a pressure of 1 to 100 bar, particularly between 2 bar and 10 bar, more particularly at 2 bar or at 10 bar.
  • the catalyst is selected from rhodium, palladium, platinum, platinum oxide, or nickel, and is particularly rhodium.
  • the solid support is selected from activated charcoal, carbon, alox, and is particularly activated charcoal.
  • the solid-supported catalyst is selected from rhodium-on-activated charcoal, palladium-on-activated charcoal, raney nickel, and is particularly rhodium-on-activated charcoal.
  • step b 2 ) or e 2 ) comprises converting a compound of (Va
  • step b 2 ) or e 2 ) is carried out with hydrogen at a pressure of 20 to 100 bar, particularly of 40 to 60 bar, and more particularly 50 bar.
  • the catalyst is a homogenous catalyst comprising a transition metal compound and at least one ligand.
  • the transition metal compound is selected from Rhodium complexes, particularly Rh(lll)-chloronorbornadiene-dimer, and Ruthenium complexes, particularly [(Ru(r
  • the at least one ligand is selected from phosphine ligands, particularly diphosphine and monophosphine ligands, and any combination thereof.
  • the at least one ligand is selected from Josiphos ligands, Walphos-type ligands, Taniaphos-type ligands, Mandyphos-type ligands and Du-Phos-type ligands.
  • the at least one ligand is selected from diphosphine ligands, particularly from 2,2-bis(diphenylphosphino)-1 ,1-binaphthale, 1 ,2- bis(diphenyl-phosphino)benzene, (Oxydi-2, 1 -phenylene)bis-(diphenylphosphine), (R)- 2,2-bis(diphenylphosphino)-1 , 1 -binaphthalene, (S)-2,2-bis(diphenylphosphino)-1 ,1 - binaphthale, and any combination thereof.
  • diphosphine ligands particularly from 2,2-bis(diphenylphosphino)-1 ,1-binaphthale, 1 ,2- bis(diphenyl-phosphino)benzene, (Oxydi-2, 1 -phenylene)bis-(diphenylphosphine), (R)- 2,2-bis(diphenylphosphino)-1
  • step b 2 ) or e 2 ) is carried out in a solvent, particularly selected from methanol, ethanol, propanol, isopropanol, butanol, and any combination thereof.
  • step b 2 ) or e 2 ) comprises converting a compound of (Va
  • a process comprising a step b 3 ) as defined in item 3 or a step e 4 ) as defined in item 6 of converting a compound of formula (III)
  • step b 3 ) or e 4 is carried out at a temperature of 40 °C to 80 °C, particularly from 50 °C to 70 °C, and more particularly 60 °C.
  • step b 3 ) or e 4 is carried out with hydrogen at a pressure of 30 to 70 bar, particularly of 40 to 60 bar, more particularly 50 bar.
  • the catalyst is selected from rhodium, palladium, platinum, platinum oxide, and nickel, and is particularly rhodium.
  • any of items 55 to 56, wherein the solid support is selected from activated charcoal, carbon, and alox, and is particularly activated charcoal.
  • the solid-supported catalyst is selected from rhodium- on-activated charcoal, palladium-on-activated charcoal, raney nickel, and is particularly rhodium-on-activated charcoal.
  • step b 3 ) or e 4 is carried out in a solvent, particularly selected from ethanol, methanol, ethanol, propanol, isopropanol, butanol, and any combination thereof, and is particularly ethanol.
  • a solvent particularly selected from ethanol, methanol, ethanol, propanol, isopropanol, butanol, and any combination thereof, and is particularly ethanol.
  • step b 3 ) or e 4 comprises converting a compound of formula (Ilia) to a compound of formula (IVa
  • a process comprising a step b 4 ) as defined in item 3 of converting a compound of formula
  • step b 4 is carried out as defined in any of items 16 to 25.
  • step b 4 comprises converting a compound of formula (IVa)
  • a process comprising a step e 3 ) as defined in item 5 of converting a compound of (VI)
  • step e 3 is carried out at a temperature of between room temperature and 100 °C, particularly 20 °C to 30 °C, more particularly at room temperature.
  • step e 3 is carried out in a solvent, particularly selected from water, dichloromethane, ethanol, methanol, dioxane, THF, ethyl acetate, and any combination thereof.
  • a solvent particularly selected from water, dichloromethane, ethanol, methanol, dioxane, THF, ethyl acetate, and any combination thereof.
  • step e 3 is carried out in the presence of an agent suitable for removing the PG residue, particularly an acid, a base or hydrogen, depending on the PG residue.
  • step e 3 comprises converting a compound of formula (Via)
  • a process comprising a step c) as defined in item 1 of converting a compound of
  • step c) is carried out at a temperature of -10 °C to 10 °C, particularly -5 °C to +5 °C, more particularly at 0 °C.
  • step c) is carried out in a solvent, particularly an aprotic solvent.
  • step c) is carried out in a solvent selected from tetrahydrofuran (THF), dimethylacetamide (DMAc), dimethylformamide (DMF), 2-methyltetrahydrofuran, A/-methyl-2-pyrrolidone (NMP), and any combination thereof, and is particularly THF.
  • a solvent selected from tetrahydrofuran (THF), dimethylacetamide (DMAc), dimethylformamide (DMF), 2-methyltetrahydrofuran, A/-methyl-2-pyrrolidone (NMP), and any combination thereof, and is particularly THF.
  • step c) is carried out in the
  • step c) comprises converting the compound of (Via)
  • step d) is carried out as defined in any of items 67 to 69.
  • a process comprising a step f) as defined in item 4 of performing chiral resolution with a mixture of compounds of formula (IV)
  • step f) is carried out by performing a crystallizing step in the presence of dibenzoyl tartaric acid and acetonitrile.
  • Z is -C0 2 R 1 and R 1 selected from ethyl, methyl, i-propyl, n-propyl, n- t-butyl, i- t-butyl, s- t-butyl, t-butyl, pentyl, hexyl benzyl, cyclohexyl, and is particularly ethyl, or wherein Z is -CON-QW, wherein Q and W constitute a fragment of any natural or non-natural amino acid.
  • aryl residues having from 6 to 24 carbon atoms, particularly phenyl, chlorophenyl, particularly p-chlorophenyl, bromophenyl, particularly p- bromophenyl, fluorophenyl, particularly p-fluorophenyl, nitrophenyl, particularly p-nitrophenyl, and toluenyl, particularly p-toluenyl, wherein the aryl residues are optionally alkyl substituted;
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • Z is selected from carbonyl groups, particularly from -C0 2 R 1 groups, wherein R 1 is selected from
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted.
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R 1 groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or identical or different, and are independently selected from
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; wherein the PG residue is a protective group, which is capable of protecting an amine group.
  • Z is selected from carbonyl groups
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl substituted;
  • X and Y are independently selected from the R groups, alkyloxy or aryloxy groups, particularly wherein X is methoxy and Y is methyl;
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms; or
  • alkyl residues having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl, aryloxy, alkoxy, and/or carbonyl substituted;
  • aryl residues having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl substituted; wherein the PG residue is a protective group, which is capable of protecting an amine group.
  • n 1 , 2, 3, 4 or 5, wherein the ring is optionally substituted at at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms;
  • R 4 is selected from phenyl, chlorophenyl, particularly p- chlorophenyl, bromophenyl, particularly p-bromophenyl, fluorophenyl, particularly

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Abstract

L'invention concerne des pyrrolidines, des pyrroles et des procédés de préparation de pyrrolidines et de pyrroles.
PCT/EP2013/077726 2012-12-21 2013-12-20 Procédé de synthèse de pyrrolidines et de pyrroles Ceased WO2014096374A1 (fr)

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CN116554075B (en) * 2023-05-18 2026-02-03 西北工业大学 Catalytic asymmetric synthesis method of chiral 3-alkyl substituted pyrrolidine

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