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WO2012000608A2 - Nouveaux dérivés bêta-aminoaldéhyde, procédé de préparation de ces dérivés et leur utilisation en chimie comme intermédiaires réactifs - Google Patents

Nouveaux dérivés bêta-aminoaldéhyde, procédé de préparation de ces dérivés et leur utilisation en chimie comme intermédiaires réactifs Download PDF

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WO2012000608A2
WO2012000608A2 PCT/EP2011/002923 EP2011002923W WO2012000608A2 WO 2012000608 A2 WO2012000608 A2 WO 2012000608A2 EP 2011002923 W EP2011002923 W EP 2011002923W WO 2012000608 A2 WO2012000608 A2 WO 2012000608A2
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group
branched
straight
chain
halogen
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WO2012000608A3 (fr
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Karl-Heinz GLÜSENKAMP
Christian Mengede
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Gluesenkamp Karl-Heinz
Christian Mengede
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Definitions

  • the present invention describes novel beta-aminoaldehyde derivatives of the formulas (I), (II) and (III),
  • Beta-aminoaldehyde derivatives are a class of compounds with a wide range of applications in modern chemistry. These reactive compounds can serve as versatile synthons or reactive intermediates for the preparation of potentially biologically active molecules, eg, novel peptidomimetics, coupling reagents, etc.
  • a particular advantage of these beta-aminoaldehyde derivatives is mainly due to their carbonyl and amino functionality, which give them bifunctional properties and a valuable dual reactivity. Due to this dual reactivity, the substance class of the beta-aminoaldehyde derivatives is predestined for a large number of synthetic transformations on carrier resins or in the liquid phase. Furthermore, these can beta-aminoaldehyde derivatives confer valuable properties via further functional reactive groups.
  • Beta-aminoaldehyde derivatives are derived formally from beta-amino acids in which the carboxyl group is transformed into an aldehyde group and the amino functionality carries a protective group.
  • Known methods for the preparation of such amino aldehydes in general are, for. Example, the reduction of the corresponding methyl ester with diisobutylaluminum hydride (Ito et al, Chem. Pharm. Bull. 1975, 23, 3081).
  • Another known method uses the reduction of Weinrebamides with LiAlH 4 (Fehrentz et al, Synthesis 1983, 676).
  • beta-aminoaldehyde derivatives include the electrochemical reduction of N 2 -Boc-amino acids (Maeda et al, Tetrahedron Letters, 1992, 33, 1347) and the reductive cleavage of Fmoc-Aminoklarenbenzylthioester with the system triethylsilanes / Pd (Pak et al, Journal of Org. Chem. 1993, 58, 2313).
  • beta-aminoaldehyde derivatives which preferably have improved variability with respect to compounds, in particular beta-aminoaldehyde derivatives, from the prior art.
  • a further object of the present invention was to provide novel processes for preparing such novel beta-aminoaldehyde derivatives which enable a good or preferably better yield than previous processes
  • A is C 3 -C 24 cycloalkyl, optionally containing at least one or more
  • Carbon atoms e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., are substituted by nitrogen, oxygen and / or sulfur atoms; or
  • an adamantyl is; are the same or different and R and R 2 are each independently hydrogen,
  • a C 3 -C 6 -cycloalkyl which is optionally substituted by at least one halogen, at least one straight-chain or branched C 1 -C 6 -alkoxy group or at least one hydroxyl group,
  • R 6 and R 7 are the same or different and each independently represents a hydrogen or a straight or branched C, -C 6 - alkyl, or
  • R, and R 2 together or independently with any atom or any two atoms of the ring A is a saturated, unsaturated or aromatic fused homo- or heterocyclic ring having 4 to 100, 4 to 50, 4 to 30, or 4 to 20 carbon atoms and 3 to 1 form 5, 3 to 10 or 3 to 5 members, wherein the heterocyclic ring optionally contains at least one or more heteroatom (s), eg 2, 3, 4, 5, 6, 7, 8, 9, 10, etc ., from the group N, S or O and / or the homo- or heterocyclic rings are optionally substituted by straight-chain or branched C, -C 8 -alkyl; is a protective group for amines, preferably selected from (conventional) protecting groups for amines, including, but not limited to, eg allyloxycarbonyl (aloe), benzyl (Bn), benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), tert-butoxycarbonyl (Boc )
  • ⁇ is a hydrogen, a C 3 -C 6 -cycloalkyl which is optionally substituted by at least one halogen, at least one straight-chain or branched C 1 -C 6 -alkoxy group or at least one hydroxyl group,
  • Q is alkoxy group or at least one hydroxy group, is a straight-chain or branched [C 2 -C 8 -] alkenyl
  • phenyl or benzyl which is optionally in each case by at least one halogen, at least one nitro group, at least one cyano group, at least one boronyl group, at least one carboxy group, or at least one straight-chain or branched QQ-alkyl, C, -C 6 -alkoxy, C, -Q-acyl or C, -C 6 alkoxycarbonyl group are substituted,
  • heteroaryl radical which may contain one or more heteroatoms from the N, S or O series
  • R 4 and R 5 may together form a saturated, unsaturated or aromatic homo- or heterocyclic ring having 4 to 100, 4 to 50, 4 to 30, or 4 to 20 carbon atoms and 3 to 15, 3 to 10 or 3 to 5 members in which the heterocyclic ring contains at least one or more heteroatoms (e), for example 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., from the group consisting of N, S or O, or a C 2 C 9 alkenyl radical optionally substituted with C 1 -C 5 alkyl groups and containing at least one double bond.
  • the object underlying the present invention is achieved by novel beta-aminoaldehyde derivatives of the formula (II):
  • C 3 -C 24 cycloalkyl is C 3 -C 24 cycloalkyl, optionally substituted by at least one or more carbon atoms, eg 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., by nitrogen, oxygen and / or sulfur atoms are; or
  • R and R 2 are the same or different and R and R 2 are each independently hydrogen
  • a C 3 -C 6 -cycloalkyl which is optionally substituted by at least one halogen, at least one straight-chain or branched C 1 -C 6 -alkoxy group or at least one hydroxyl group,
  • Q-alkoxy group and / or at least one hydroxy group is substituted is a halogen, is a hydroxy group
  • R 6 and R 7 are the same or different and each independently Is hydrogen or a straight or branched C, -Q-alkyl, or
  • R, and R 2 together or independently with any atom or any two atoms of the ring A is a saturated, unsaturated or aromatic fused homo- or heterocyclic ring having 4 to 100, 4 to 50, 4 to 30, or 4 to 20 carbon atoms and 3 to 15, 3 to 10 or 3 to 5 members, said heterocyclic ring optionally having at least one or more heteroatoms (e), eg 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. , from the group N, S or O and / or the homo- or heterocyclic rings are optionally substituted by straight-chain or branched C, -C 8 -alkyl; is a protective group for amines, preferably selected from (common)
  • Amines protecting groups include, but are not limited to, for example, allyloxycarbonyl (aloe), benzyl (Bn), benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), tert -butoxycarbonyl (Boc), tert -butyldimethylsilyl (TBS), tert -butyldiphenylsilyl (TBDPS), p-methoxybenzyl (PMB), metho-methyl (MOM), p-methoxyphenyl (PMP), tosyl (Ts), 2-tosylethoxycarbonyl (Tsoc), 2- (trimethylsilyl) ethoxycarbonyl (Teoc), triisopropylsilyl (TIPS), and Trityl (Tr), etc.
  • the object underlying the present invention is achieved by novel beta-aminoaldehyde derivatives of the formula (III):
  • R and R 2 are the same or different and R and R 2 are each independently hydrogen
  • a C 3 -C 6 -cycloalkyl which is optionally substituted by at least one halogen, at least one straight-chain or branched C 1 -C 6 -alkoxy group or at least one hydroxyl group,
  • linkage is directly or via the bridging members -CH 2 - or - CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - can be carried out is a phenyl or benzyl, each being optionally substituted by at least one halogen, at least one nitro group, at least one cyano group, at least one boronic acid group, at least one carboxy group, at least one straight-chain or branched C, -C 6 alkyl, C, -C 6 Alkoxy, C, -C 6 acyl or C, -Q-alkoxycarbonyl group, is a heteroaryl radical, where the heteroaryl radical optionally contains at least one or more heteroatoms (e), for example 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., from the group N, S or O, and wherein the linkage is direct or via the bridge members -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2
  • heterocyclic ring having 4 to 100, 4 to 50, 4 to 30, or 4 to 20 carbon atoms and 3 to 15, 3 to 10 or 3 to 5 members, wherein the heterocyclic ring is optional at least one or more heteroatom (s), eg 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., from the group N, S or O, is a protective group for amines, optionally selected from (conventional) protecting groups for amines, comprising, without to be limited to, for example Allyloxycarbonyl (aloe), benzyl (Bn), benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), tert -butoxycarbonyl (Boc), tert -butyldimethylsilyl (TBS), tert -butyldiphenylsilyl (TBDPS), p -methoxybenzyl (PMB), metho-methyl ( MOM), p
  • ⁇ is a straight-chain or branched C 1 -C 40 -alkyl which is optionally substituted by at least one halogen, at least one straight-chain or branched C 1 -C 6 -alkoxy group or at least one hydroxyl group, is a straight-chain or branched [C 2 -C 8 ] -alkenyl,
  • aryl which is optionally substituted by at least one halogen, at least one nitro group, at least one cyano group, at least one boronyl group, at least one carboxy group, and / or at least one straight or branched C, -C 6 alkyl, C, -C 6 - Alkoxy, C 1 -C 6 -acyl or C 1 -C 6 -alkoxycarbonyl group is substituted,
  • heteroaryl radical is a heteroaryl radical, wherein the heteroaryl radical optionally contains at least one or more heteroatoms (e), e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., from the
  • Group N, S or O contains, wherein the linkage of the heteroaryl radical directly or via the bridge members -CH 2 -, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - can be carried out
  • CH 2 - can be done
  • a C 1 -C 40 alkyl typically comprises linear or branched C, -C 40 , C, -C 30 , C, -C 20 , CC 10 , C, -C 6 -, C 10 -C 40 -, C 20 -C 40 -, C 30 -C 40 -, Ci _ C 10 -, C 5 -C 15 -, C 10 -C 20 -, C 1S -C 2 5- , C 20 -C 30 , C 25 -C 35 , C 30 -C 40 , C 35 -C 45 , or C 40 -C 50 -alkyl groups or any combination of these ranges or any single integer value of these ranges.
  • Similarly typically comprises a QQ-alkyl, linear or branched C, -C 8 -, C, to C 7 -, C, -C 6 -, C, to C 5 -, QQ, C, -C 3 -, C, -C 2 -, or C 1 -, alkyl groups or any combination of these ranges or any integer value of these ranges, a C 1 -C 6 -alkyl typically linear or branched C, -C 6 -, C, -C 5 -, C , -C 4 , C 1 -C 3 , C 1 -C 2 , or C 1 -C 6 alkyl groups or any combination of these ranges and a C 1 -C 5 -alkyl, typically linear or branched C, -C 3 , QQ, C, -C 3 , C, -C 2 , or C, alkyl groups or any combination of these ranges or any single integer value of these ranges.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, s and t-butyl, neopentyl, isoamyl, isobutyl, pentyl, hexyl, Heptyl, octyl, decyl, etc., with.
  • alkenyls and alkynyls are preferably defined as hereinbefore defined alkyl groups from 2 carbon atoms, alkenyls typically having at least one double bond and alkynyls typically having at least one triple bond.
  • alkenyls or alkynyls of the present invention preferably comprise C 2 -C 40 -alkenyls having at least one double bond or C 2 -C 40 -alkyls having at least one triple bond, typically linear or branched C 2 -C 40 -, C 2 - C 30 -, C 2 -C 20 -, C 2 -C 10 -, C 10 -C 40 -, C 20 -C 40 -, C 30 -C 40 -, C J -C I Q- / C 5 - C 15 -, C 10 - Q ⁇ r, C 15 -C 25 -, Q 0 -C 30 -, C 25 -C 35 -, C 30 -C 40 -, C 35 -C 45 -, or C 40 - C 50 alkenyl groups or alkynyl groups or any combination of these ranges or any single integer value of these ranges.
  • a C 2 -C 8 alkenyl or C 2 -C 8 alkynyl typically includes linear or branched C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , C 2 -C 5 -, C 2 -C 4 , C 2 -C 3 or C 2 alkenyl groups or alkynyl groups or any combination of these ranges or any single integer value of these ranges, a C 2 -C 6 alkyl typically linear or branched C 2 - C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , or C 2 alkenyl groups or alkynyl groups or any combination of these ranges or any single integer value of these ranges and a C 2 C 5 alkyl typically linear or branched C, -C 5 , C, -C 4 , C, -C 3 , C, -C 2 , or C, alkyl groups or any combination of these ranges or any
  • alkenyl groups include, but are not limited to, methenyl, ethenyl, propenyl, isopropenyl, butenyl, s and t-butenyl, pentenyl, hexenyl, octenyl, and decenyl groups, etc. with a.
  • An alkyl, alkenyl or alkynyl group further comprises also a heteroalkyl, a heteroalkenyl, a heteroalkynyl, or having a C, -C 40 alkyl as defined above, C 2 -C 40 - alkenyl or C 2 -C 40 - Alkynyl group in which at least one carbon atom, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., are replaced by a heteroatom such as oxygen, nitrogen or sulfur.
  • An alkyl, alkenyl or alkynyl group preferably also includes an arylalkyl, an arylalkenyl or an arylalkynyl.
  • An arylalkyl, an arylalkenyl or an arylalkynyl is preferably a defined Q-Qo-alkyl, C 2 -C 40 -alkenyl or a C 2 -C 40 -alkynyl group as defined above, to which an aryl or heteroaryl as defined herein is bound.
  • arylalkyl radicals include, but are not limited to, benzyl, Phenethyl, pyridinylmethyl, pyrimidinylethyl, pyridazinyl, indolyl, imidazolyl, quinolyl, pyrrolyl, thienyl, furanyl, pyranyl, oxepanyl, naphthyridinyl, isoxazoyl, etc., with.
  • a C 3 -C 2 4-cycloalkyl is preferably a sub-group of the alkyls defined herein and includes cyclic hydrocarbon groups of 3 to 24 carbon atoms, for example C 3 -C 5 -, C 5 -C 15 - , C 10 - C 15 -C 2o 2 4- C 20 -C 4 -, C3-C20 / C 3 -C 10 -, C3-C9, C 3 -C 8 -, C 3 -C 7 - , C 3 -C 6 -, C 3 -C 5 -, C 3 -C 4 -, C 3 , C 4 , 5, C 6 , C 7 , C 8 , Cg, C 10 , C 11, C 12 / C 13 , C 14 , C 15 , C 16 , C) 7 , C 18 , C 19 , C 20 , C 2 i, C 22 , C 23 , or C 24 -
  • C 3 -C 24 -cycloalkyls also include tetra-, penta-, hexa- or even heptacyclic ring systems or ring systems having even more cycles.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, cyclohexyl, cycloheptyl, etc.
  • C 3 -C 24 -cycloalkyls as defined above also include C 3 -C 24 -cycloalkenyls and C 3 -C 24 -cycloalkynyls, ie C 3 -C 24 -cycloalkyls as previously defined having at least one double or triple bond.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl groups, etc.
  • C 3 -C 24 cycloalkyls as defined above also include heterocycles, preferably C 3 -C 24 cycloalkyls as defined above in which at least one carbon atom is replaced by a heteroatom such as oxygen, nitrogen or sulfur.
  • Heterocycles include, but are not limited to, pyrrolidine, tetrahydrofuran, dioxane, tetrahydrothiophene, etc.
  • alkoxy groups according to the present invention refer to groups of typically 1 to 8, preferably 1 to 6, hydrocarbon atoms of unbranched, branched or cyclic configuration and combinations thereof linked via an oxygen atom (to the main compound). Examples include, for example, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, etc.
  • alkoxy or alkoxyl groups according to the present invention also include alkenoxy or alkenoxyl groups preferably of 1 to 8 carbon atoms of an unbranched, a branched or a cyclic unsaturated configuration and combinations thereof linking to the main compound through an oxygen atom are.
  • alkoxycarbonyl groups refer to alkoxy groups as defined herein, which preferably contain a carbonyl group.
  • Aryls and heteroaryls according to the present invention relate, for example, to a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic or heteroaromatic ring containing, for example, 0-5 heteroatoms, for example 0, 1, 2, 3 , 4 or 5, selected from O, N, or S; to a bicyclic 8, 9, 10, 11, 12 or 12 membered aromatic or heteroaromatic ring system containing, for example, 0-6 heteroatoms, for example 0, 1, 2, 3, 4, 5 or 6, selected from O , N, or S; or a tricyclic 12-, 13-, 14-, 15- or 16-membered aromatic or heteroaromatic ring system containing, for example, 0-7 heteroatoms, for example 0, 1, 2, 3, 4, 5, 6 or 7, selected from O, N, or S, but also tetra-, penta-, hexa- or even heptacyclic ring systems or ring systems with even more cycles, for example 0-7 heteroatoms, for example 0, 1, 2, 3,
  • Aryls and heteroaryls include, for example, 5- or 6- to 14-membered aromatic ring systems, for example, but not limited to, benzene, naphthalene, indane, tetralin, and fluorene, and to 10-membered aromatic heterocyclic rings, for example, but not limited to, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • heteroaryls falling within the scope of this invention include, but are not limited to, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxole (commonly referred to as methylenedioxyphenyl when it occurs as a substituent ), Tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, and the like.
  • Acyls according to the present invention preferably refer to groups of 1 to 6 hydrocarbon atoms of the form RCO, but R may be any of the above mentioned QG ⁇ alkyl, C 2 -C 40 alkenyl or C 2 -C 40 alkynyl groups, but also any of the above-mentioned C 3 -C 24 -cycloalkyls, C 3 -C 24 -cycloalkenyls or C 3 -C 24 -cycloalkynyls.
  • Exemplary acyl groups of the present invention include, but are not limited to, methanoyl, acetyl, ethanoyl, propanoyl, butanoyl, malonyl, benzoyl groups, etc.
  • All the beta-aminoaldehyde derivatives of the formulas (I), (II) and (III) according to the present invention and the intermediates for the preparation of these compounds e.g. Compounds of formulas (IV), (V) and (VI) and compounds of formulas (VII), (VIII) and (IX) may contain one or more asymmetric centers and therefore enantiomers which behave as image and mirror image, diastereomers, which do not behave like image and mirror image, and form other stereoisomeric forms designated (R) -or (S) - according to the terms of absolute stereochemistry.
  • the present invention includes such possible isomers as well as their pure and racemic forms, the antipodes of such compounds as well as diastereomeric or enantiomeric mixtures.
  • Optically active (R) or (S) isomers can be prepared using stereoselective methods or resolved using standard techniques.
  • the racemate forms as well as the diastereomers can be separated in a known manner into the stereoisomerically uniform constituents (cf., E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).
  • E.L. Eliel Stereochemistry of Carbon Compounds, McGraw Hill, 1962.
  • geometric E and Z isomers are also included.
  • all tautomeric forms are included according to the invention.
  • beta-aminoaldehyde derivatives of the formulas (I), (II) and (III) according to the invention preferably have the following specific structures: Table 1: Examples of beta-aminoaldehyde derivatives of the formula of the invention
  • beta-aminoaldehyde derivatives of the general formula (III) according to the invention examples of beta-aminoaldehyde derivatives of the general formula (III) according to the invention (specific formulas (61) to (III))
  • the underlying object is achieved by a novel synthetic route which, via the selective reductive ring opening of beta-lactams, enables the preparation of novel beta-aminoaldehyde derivatives of the general formulas (I), (II) and (III) With a very large variety of structures and with surprisingly high yields and sometimes even quantitatively possible.
  • the presentation of the compounds according to the invention differs fundamentally from methods known from the literature.
  • the compounds according to the invention are preferably prepared by the process according to the invention for the synthesis of the inventive beta-aminoaldehyde derivatives of the general formulas (I), (II) or (III) shown below.
  • This process according to the invention for the synthesis of the beta-aminoaldehyde derivatives of the general formulas (I), (II) or (III) according to the invention preferably comprises the following process steps a) to d):
  • step b) reductive ring opening of the protected beta-lactam obtained in step b) by reacting the protected beta-lactam with a reducing agent, preferably a (complex hydride), preferably in a temperature range from -90 ° C to -10 ° C, to give a protected beta-aminoaldehyde derivative of the general formulas (I), (II) or (III);
  • a reducing agent preferably a (complex hydride), preferably in a temperature range from -90 ° C to -10 ° C
  • step a) optional isolation and / or purification of the protected beta-aminoaldehyde derivative of the general formulas (I), (II) or (III) obtained from step c).
  • the process according to the invention for the synthesis of the beta-aminoaldehyde derivatives of the general formulas (I), (II) or (III) according to the invention preferably comprises in a first step a) the preparation of beta-lactams of the general formulas (VII), (VIII) or (IX);
  • step a) may be effected by addition of chlorosulfonyl isocyanate (CSI) to a linear or cyclic olefin, preferably of the general formulas (X), (XI) or (XII) and conversion to a beta-lactam of the general formulas (VII), (VIII) or (IX).
  • CSI chlorosulfonyl isocyanate
  • step a) is carried out as described in Barrett et al., Graf et al., Erasmuset et al. or Nativi et al. Chem. 1985, 50, 169-1 75, R. Graf, Angew Chem. 1968, 1 79-189, Wilsonet et al, J. Med. Chem. 1999, 42 , 2358-2363, Nativi et al., Tetrahedron Lett., 1991, 32, 2265-2268).
  • the reactant used is preferably a linear or cyclic olefin of the general formulas (X), (XI) or (XII):
  • radicals of the general formula (XI) preferably have the meanings given in the description of the radicals of the general formula (II) of the invention.
  • radicals of the general formula (XII) preferably have the meanings mentioned in the description of the radicals of the general formula (III) of the same name.
  • radicals of the general formula (VIII) preferably have the meanings mentioned in the description of the radicals of the general formula (II) of the invention.
  • radicals of the general formula (IX) preferably have the meanings mentioned in the description of the radicals of the general formula (III) of the same name.
  • the reaction of the starting material of the general formula (X) in step a) with CSI leads to a beta-lactam of the general formula (VII). Furthermore, the reaction of the starting material of the general formula (XI) in step a) with CSI leads to a beta-lactam of the general formula (VIII). Finally, the reaction of the starting material of the general formula (XII) in step a) with CSI leads to a beta-lactam of the general formula (IX).
  • the beta-lactams of the general formula (X), (XI) and (XII) thus represent intermediates of the reaction according to the invention, which are also included within the scope of the present invention.
  • step a) may be accomplished by the cyclization of ketenes or zwitterionic enolates with imines.
  • Such cyclization of ketenes or zwitterionic enolates with imines is preferably carried out as described in France et al. or in Hart et al. Res. 2004, 37, 592-500, Hart et al., Chem. Rev. 1989, 89, 1447-1465, Tetrahedron Lett., 1991, 32, 5187-5190).
  • the second alternative also leads to the formation of a beta-lactam of the general formulas (VII), (VIII) or (IX), as described above.
  • step a) can alternatively be carried out by a radical cyclization.
  • a radical cyclization is preferably carried out as in Alcaide et al. (see Alcaide et al., Synthesis 2005, 2335-2340).
  • the third alternative also results in the formation of a beta-lactam of general formulas (VII), (VIII) or (IX) as previously described.
  • the -NH group of the beta-lactams obtained from step a) is obtained by reaction of these beta-lactams with an amino-protecting group -R 3 to form a beta-lactam of the general formulas (IV), (V ) or (VI).
  • the amino-protecting group -R 3 is preferably a (customary) protecting group for amines known to a person skilled in the art, more preferably selected from (customary) protective groups for amines, including, but not limited to, for example allyloxycarbonyl (aloe), benzyl (Bn) , Benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), tert-butoxycarbonyl (Boc), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), p-methoxybenzyl (PMB), metho-methyl (MOM), p-methoxyphenyl (PMP) , Tosyl (Ts), 2-tosylethoxycarbonyl (Tsoc), 2- (trimethylsilyl) ethoxycarbonyl (Teoc), triisopropylsilyl (TIPS), and
  • step b) of the synthesis process according to the invention leads to a protected beta-lactam of the general formulas (IV), (V) or (VI), which preferably have the following structures:
  • radicals of the general formula (V) preferably have the meanings mentioned in the description of the radicals of the general formula (II) of the invention.
  • radicals of the general formula (VI) preferably have the meanings given in the description of the radicals of the general formula (III) of the same name.
  • the reaction of the beta-lactam of the general formula (VII) in step b) of the process according to the invention leads to a protected beta-lactam of the general formula (IV).
  • the reaction of the beta-lactam of the general formula (VIII) in step b) of the process according to the invention leads to a protected beta-lactam of the general formula (V).
  • the reaction of the beta-lactam of the general formula (IX) in step b) of the process according to the invention leads to a protected beta-lactam of the general formula (VI).
  • the beta-lactams of the general formulas (IV), (V) and (VI) thus represent intermediates of the reaction according to the invention, which are also included within the scope of the present invention.
  • step c) of the process according to the invention the protected beta-lactam of the general formulas (IV), (V) or (VI) obtained in step b) is subjected to a reductive ring opening by reacting the protected beta-lactam with a reducing agent which to give a protected beta-aminoaldehyde derivative of the general formulas (I), (II) or (III).
  • a (complex) hydride is preferably used as the reducing agent, more preferably a hydride which is known to a person skilled in the art for the reductive ring opening or hydrogenation is.
  • hydrides include, but are not limited to, diisobutylaluminum hydride (DIBAL), lithium aluminum hydride (LiAlH 4 ), sodium borohydride (NaBH 4 ), etc. DIBAL is most preferably used.
  • the reducing agent in particular the (complex) hydride preferably used as the reducing agent in step c) of the process according to the invention, is generally used in an amount of from 1 mol to 10 mol, preferably from 2 mol to 4 mol, relative to 1 mol of the compounds of the general formula (IV), (V) or (VI) used.
  • the solvent used is typically also an inert solvent or a combination of inert solvents.
  • inert solvents are typically suitable and customary organic solvents which do not change under the reaction conditions, in particular the reaction conditions of the synthesis reaction according to the invention.
  • such inert solvents in step c) of the process according to the invention typically comprise ethers, such as, for example, diethyl ether, butyl methyl ether, dioxane or tetrahydrofuran, or (aromatic) hydrocarbons, for example benzene, toluene or xylene, or mixtures of the abovementioned solvents , preferably mixtures of two or three of the aforementioned solvents.
  • ethers such as, for example, diethyl ether, butyl methyl ether, dioxane or tetrahydrofuran, or (aromatic) hydrocarbons, for example benzene, toluene or xylene, or mixtures of the abovementioned solvents , preferably mixtures of two or three of the aforementioned solvents.
  • tetrahydrofuran as the inert solvent.
  • Such inert solvents can also be used in other steps of the process.
  • the reaction according to step c) of the process according to the invention is typically carried out in a temperature range from -90 ° C to -10 ° C, preferably from -80 ° C to -30 ° C, even more preferably from -75 ° C to -60 ° C. , eg about -70 ° C.
  • This low temperature choice allows a nearly quantitative conversion not achieved by the prior art and thus outstanding yield with a high purity of the products obtained.
  • the reaction is also typically carried out at atmospheric pressure. However, it is also possible to carry out the reaction at elevated or reduced pressure, for example in a range of e.g. 0.5 to 5 bar, or in a range of 0.5 bar to 1 bar or in a range of 1 bar to about 5 bar.
  • the reaction in step c) of the process according to the invention is preferably carried out under protective gas, such as nitrogen or argon.
  • the reaction is preferably allowed to continue for a further 10 minutes to 5 hours, more preferably 10 minutes to 1.5 hours, in order to complete the reaction.
  • the reaction mixture is preferably added dropwise with an amount of 10 to 30 mol of water based on one mole of the compounds of general formulas (IV), (V) or (VI). Thereafter, the reaction mixture is preferably allowed to warm to room temperature.
  • step d) of the process according to the invention the protected beta-aminoaldehyde derivative of the general formulas (I), (II) or (III) obtained in step c) is preferably isolated and / or purified.
  • the beta-aminoaldehyde derivatives of the general formulas (I), (II) or (III) prepared by the process according to the invention can be isolated by literature methods, for example crystallization, extraction or by chromatographic methods.
  • the crude product from step c) of the process according to the invention after removal of the solvent is of very high purity and can be used for further reactions, e.g. for olefination reactions and other reactions.
  • the beta-aminoaldehyde derivatives of the general formulas (I), (II) or (III) prepared by the process according to the invention may additionally or alternatively still be purified, e.g. by recrystallization, etc.
  • the process according to the invention for preparing a beta-aminoaldehyde derivative of the general formula (I) according to the invention can be carried out by way of example.
  • the olefin (1 12) prepared by standard methods (Organikum, 22nd edition, Wiley-VCH Verlag GmbH & C. KGaA, page 539) is preferably prepared according to Graf (R. Graf, Angew. Chem -189) with CSI for Lactam (1 13) and then transformed with Boc 2 0 to the protected lactam (1 14) (PJ Kocienski, Protecting Groups, Georg Thieme Verlag Stuttgart, 1994 (pp 192-195)).
  • the compound (6) of the present invention is quantitatively obtained by reduction with diisobutylaluminum hydride (DIBALH).
  • DIBALH diisobutylaluminum hydride
  • the compound (6) of the present invention is a specific compound of the beta-aminoaldehyde derivative of the general formula (I), s. Table.
  • the process according to the invention for preparing a beta-aminoaldehyde derivative of the general formula (II) according to the invention can be carried out by way of example.
  • the enantiomerically pure terpene ( ⁇ -pinene) (1 15) is preferably transformed into the beta-lactam (1 16) and then to the protected compound (1 1 7). Reduction with DIBALH gives the enantiomerically pure beta-aminoaldehyde (38) in high yields.
  • the compound (38) of the present invention is a specific compound of the beta-aminoaldehyde derivative of the general formula (II), s. Table 2.
  • the process according to the invention for preparing a beta-aminoaldehyde derivative of the general formula (III) according to the invention can be carried out.
  • the natural product isoprene ((1 18)) is transformed to the lactam (1 19) and then to the Boc-protected compound (120). Reduction with DIBALH quantitatively provides the highly functionalized, protected aldehyde (77).
  • the compound (77) of the present invention is a specific compound of the beta-aminoaldehyde derivative of the general formula (III) (see Table 3).
  • the process according to the invention for the synthesis of the beta-aminoaldehyde derivatives of the general formulas (I), (II) or (III) according to the invention can also be carried out exclusively on the basis of process steps c) and d) (ie a) and b ) are optional), wherein for step c) only the end products described in step b) must be provided.
  • the object underlying the present invention is achieved by novel uses of the compounds according to the invention, in particular the inventive beta-aminoaldehyde derivatives of the general formulas (I), (II) and (III), as well as the inventive beta-lactams general formulas (IV), (V) and (VI) or the inventive beta-lactams of the general formulas (VII), (VIII) and (IX) and their specific compounds of the formulas (1) - (1 1 1) (s Tables 1, 2 and 3).
  • the compounds of the formulas (X), (XI) or (XII), the inventive beta-lactams of the general formulas (VII), (VIII) or (IX), and / or the compounds according to the invention Beta-lactams of the general formulas (IV), (V) or (VI), and their specific compounds of the formulas (1) - (11) (see Table 1, 2 and 3) for the preparation of the beta- aminoaldehyde according to the invention Derivatives of general formulas (I), (II) and (III).
  • the beta-aminoaldehyde derivatives of the general formulas (I), (II) and (III) according to the invention the inventive beta-lactams of the general formulas (IV), (V) and (VI) and /or the inventive beta-lactams of the general formulas (VII), (VIII) and (IX), and their specific compounds of the formulas (1) - (11) (see Table 1, 2 and 3) for the preparation of reactive intermediates or used as reactive intermediates themselves.
  • Such reactive intermediates can be used, for example, as a peptidomimetic, eg for diagnostic purposes in vivo or in vitro, as a coupling agent, for example for chemical synthesis, as a synthon, for example as a synthon in chemical synthesis, etc.
  • Such peptidomimetics can be used, for example, in medicine, for example in prophylaxis, diagnostics or therapy, preferably in the prophylaxis, diagnosis or therapy of specific diseases, for example in tumor therapy, or in infectious diseases, e.g. in viral and / or bacterial infectious diseases or in infectious diseases caused by pathogenic agents, etc.
  • a medicament in the form of a peptidomimetic for example, used for the prophylaxis, diagnosis or therapy of specific diseases such as, for example, cancer or infectious diseases, e.g. in viral and / or bacterial infectious diseases or in infectious diseases caused by pathogenic agents, etc.
  • the inventive beta-aminoaldehyde derivatives of the general formulas (I), (II) and (III) and their specific compounds of the formulas (1) - (1 1 1) see Table 1, 2 and 3
  • the compounds of the formulas (X), (XI) or (XII) the beta- Lactams of the general formulas (VII), (VIII) or (IX)
  • the inventive beta-lactams of the general formulas (IV), (V) or (VI) used for the preparation of coupling agents or as coupling agents themselves.
  • Such coupling agents can be used, for example, in medicine, for example in prophylaxis, diagnostics or therapy, preferably in the prophylaxis, diagnosis or therapy of specific diseases as described above.
  • the process conditions mentioned in the description were used, especially the process conditions mentioned using CSI in process step a).
  • the olefin (1 12) prepared by standard methods (Organikum, 22nd edition, Wiley-VCH Verlag GmbH & C. KGaA, page 539) by Graf (R. Graf, Angew Chem, 1968, 1 79-189) with CSI to lactam (1 1 3) and then transformed with Boc 2 O to the protected lactam (1 14) (PJ Kocienski Protecting Groups, Georg Thieme Verlag Stuttgart, 1994 (pp 192-195)).
  • the compound (6) of the present invention was quantitatively obtained by reduction with diisobutylaluminum hydride (DIBALH).
  • the aqueous phase is extracted 2 x diethyl ether and then the organic phases are combined and then extracted by shaking 1 x with water, 1 x with sodium bicarbonate, 1 x with water and finally 2 x with brine. After drying over sodium sulfate, the organic phase i.vak. concentrated and the residue was purified on silica gel (petroleum ether / diethyl ether 3: 1). This gives 18.2 g of (6) as a colorless oil. Yield: 76%.

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Abstract

L'invention concerne de nouveaux dérivés bêta-aminoaldéhyde représentés par les formules (I), (II) et (III) dans lesquelles les substituants R1 à R5 et A ont les significations données dans le descriptif, un nouveau procédé de préparation de ces dérivés, leurs produits intermédiaires et des utilisations de ces nouveaux dérivés bêta-aminoaldéhyde par exemple pour l'utilisation (en chimie) comme intermédiaires réactifs, et pour l'utilisation en médecine, par exemple comme peptidomimétiques, comme agents de couplage etc.
PCT/EP2011/002923 2010-06-30 2011-06-14 Nouveaux dérivés bêta-aminoaldéhyde, procédé de préparation de ces dérivés et leur utilisation en chimie comme intermédiaires réactifs WO2012000608A2 (fr)

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DE102010025663A DE102010025663A1 (de) 2010-06-30 2010-06-30 Neue beta-Aminoaldehyd-Derivate, Verfahren zu ihrer Herstellung und ihre chemische Verwendung als reaktive Intermediate
DE102010025663.3 2010-06-30

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