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WO2007104359A1 - Synthèse d'amines à l'aide d'acides de lewis contenant de l'ytterbium - Google Patents

Synthèse d'amines à l'aide d'acides de lewis contenant de l'ytterbium Download PDF

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Publication number
WO2007104359A1
WO2007104359A1 PCT/EP2006/060715 EP2006060715W WO2007104359A1 WO 2007104359 A1 WO2007104359 A1 WO 2007104359A1 EP 2006060715 W EP2006060715 W EP 2006060715W WO 2007104359 A1 WO2007104359 A1 WO 2007104359A1
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acid
ytterbium
chiral
reaction
nitrogen
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Thomas Christopher Nugent
Vijay Narayan Wakchaure
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Jacobs University gGmbH
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Jacobs University gGmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to methods for conversion of aliphatic or aromatic ketones with a nitrogen auxiliary to provide primary, secondary or tertiary amines and the corresponding primary or secondary amine products arrived at by cleavage of an auxiliary moiety, e.g. by dealkylation or hydrolysis.
  • the nitrogen auxiliary is ammonia
  • the nitrogen auxiliary only has hydrogen covalently linked to the nitrogen and primary amines are directly produced from aliphatic or aromatic ketones.
  • the methods are particularly useful for conversion of aliphatic or aromatic ketones to secondary or tertiary amine diastereomers and the corresponding enantioenriched primary or secondary chiral amine products after dealkylation or hydrolysis.
  • the synthesis of amines is commonly achieved through the manipulation of ketones.
  • Two types of processes have been established: The ketone can be directly converted to an amine in a reductive amination reaction. This reaction has the advantage of being a one-step reaction, it eliminates the need to extract and purify any intermediates.
  • the frequently applied alternative process is a two- step process. In the first step, a ketone is reacted with an amine to give an imine. Said imine is isolated and further reduced in a second step to provide the desired amine.
  • All references to amine nitrogen atoms relate exclusively to the nitrogen atom that is introduced into a ketone educt to yield a respective amine, unless otherwise indicated. All substances referred to hereinafter may comprise further nitrogen atoms or further amine moieties.
  • aliphatic ketone educt denotes a ketone educt wherein the carbon atom of the carboxy group that is converted into an amine group is not directly covalently connected to an atom of an aromatic or heteroaromatic moiety.
  • Aliphatic ketones according to the invention therefore may comprise one or more aromatic moieties, provided that, for each aromatic moiety, the shortest chain of atoms covalently linking an atom of the aromatic moiety to the carbon atom of the reactive carboxy group is of at least one or more atoms in length.
  • An "aromatic ketone” educt according to the invention denotes a ketone educt wherein the carbon atom of the carboxy group is directly covalently connected to one or more aromatic or heteroaromatic moieties.
  • aliphatic amine denotes an amine product obtained from an aliphatic ketone educt according to the invention
  • aromatic amine denotes an amine product obtained from an aromatic ketone according to the invention
  • the ketone educt may contain a chiral centre. According to the invention, the maximum value of the method is generally realized when a prochiral ketone is used.
  • prochiral ketone denotes a ketone educt wherein the carbon atom of the carboxy group is not directly covalently connected to a chiral centre.
  • a prochiral ketone useful within the method of the present invention may have one or more chiral centre(s), as long as it/they is/are not directly covalently connected to the carbon atom of the carboxy group that is to be turned into an amino group.
  • the prochiral ketone is devoid of any chiral centre(s).
  • references to stereoisomers relate exclusively to a) the newly generated chiral centre of the former ketone educt carbon of the carboxy group, or b) the chiral centre(s) directly covalently attached to or no more than one atom removed from the nitrogen atom of the preferably chiral nitrogen auxiliary, unless otherwise indicated.
  • a compound will be regarded as being enantiopure for the purposes of the present invention if the chiral centre(s) adjacent to the amino nitrogen atom has/have the same stereoconfiguration for essentially all molecules of that compound, regardless of any further chiral centres comprised in said compound.
  • references to a "chiral amine” or a “chiral ketone” denote those amine and ketone preparations, respectively, that are not racemic in view of the stereoisomeric centre discussed in the previous paragraph; instead,
  • chiral amines and ketones are preparations either of (a) a pure respective stereoisomer or (b) a mixture of stereoisomers with one stereoisomers in excess, over the other stereoisomers, preferably with a diastereomeric or enantiomeric excess of ⁇ 70%, more preferably ⁇ 80%.
  • the invention is hereinafter described frequently with references to chiral nitrogen auxiliaries, respective secondary or tertiary amine diastereomers, and corresponding primary or secondary amine enantiomeric products.
  • the chiral nitrogen auxiliary is preferably of ⁇ 80% enantiomeric or diastereomeric excess.
  • the invention is not limited to the use of chiral nitrogen auxiliaries, and in fact can also be worked by using non-chiral nitrogen auxiliaries which do not comprise a chiral centre adjacent to the nitrogen atom of the nitrogen auxiliary.
  • a chiral centre in racemic or enantioenriched form
  • the nitrogen-conferring reaction partner of the ketone educt during reductive amination is generally termed a "nitrogen auxiliary".
  • reaction partner aids in the formation of the primary, secondary or tertiary amine in so far as the reaction partner provides the nitrogen atom to replace the oxygen atom of the (then former) ketone educfs carbonyl group.
  • particularly preferred nitrogen auxiliaries are those that can be removed from the secondary or tertiary amine, resulting from reductive amination, to produce the corresponding primary or secondary amine product.
  • the second step, auxiliary removal is not necessary.
  • Alexakis et al. disclose a method for producing C 2 -symmetrical aromatic secondary amines by reacting an aromatic ketone and different enantiopure aromatic primary amines with an effective amount of Ti(OiPr) 4 /H 2 /Pd-C.
  • the reported isolated yields of 51 % and 63 % are comparatively low.
  • the method is not adaptable for the production of aliphatic primary amine enantiomers.
  • Nugent and Seemayer disclose a method of synthesis of a precursor to substance P antagonists with high enantiomeric excess by reductive amination.
  • the method is limited to titanium isopropoxide/Pt-C/H 2 or aluminium isopropoxide and special ketone educts for effecting the reductive amination. Further aspects of the usefulness of titanium isopropoxide in asymmetric reductive amination reactions are disclosed in Nugent et al. (Organic Letters 2005, 7 (22), 4967-4970). However, diastereoselectivity and yield have not always been satisfactory.
  • the method should also be fast, preferably achieving a secondary amine diastereomer yield of 70 % with a diastereomeric excess of ⁇ 70 % within 48 h of reaction time and should not rely on reaction pressures higher than 60 bar and/or reaction temperatures higher than 80 °C, and should preferably not rely on reaction temperatures higher than 50 0 C and/or lower than -10 0 C.
  • a further object of the invention was to provide a method for producing enantiomerically pure or enantioenriched primary or secondary amine products.
  • the method should also be useful for producing enantiopure or enantioenriched aliphatic or aromatic primary or secondary amine products.
  • the object of the invention is accomplished by a method for producing a primary, secondary or tertiary amine, preferably the corresponding diastereomer, comprising or consisting of the step of reductively aminating an aliphatic or aromatic, preferably prochiral ketone with a preferably chiral nitrogen auxiliary to produce the respective primary, secondary or tertiary amine (diastereomer), wherein - the reductive amination is effected in the presence of a hydrogenating catalyst and a hydrogenating agent, optionally with the removal of water, and wherein the reductive amination is performed under the influence of a mild Lewis acid comprising ytterbium.
  • This method allows the production of secondary or tertiary amine diastereomers with an exceptionally high diastereomeric excess (de) in a fast reaction, with minimal consumption of the mild Lewis acid, with a high yield and under reaction pressures of less than 50 bar and reaction temperatures of less than 80 °C, and preferably less than 50 °C and further preferably higher than -10°C, and also allows the production of respective non-chiral primary, secondary or tertiary amines by using respective non-chiral nitrogen auxiliaries.
  • the hydrogenating agent is hydrogen gas or a hydrogen donor, where the hydrogen donor is described as a molecule capable of releasing hydrogen under the reaction conditions, e.g. formic acid or cyclohexadiene or derivatives thereof, for example salts of formic acid. Hydrogen gas is particularly preferred.
  • the hydrogenating catalyst for the reductive amination step is preferably a metal catalyst, and is most preferably selected from the group consisting of metal catalysts with a catalytically active amount of nickel, copper, iron, cobalt, ruthenium, rhodium, palladium, osmium, iridium and platinum or mixtures thereof, wherein catalysts with a catalytically active amount of nickel and/or platinum and/or palladium are particularly preferred .
  • This preferred method can generally be described by the following reaction scheme:
  • each moiety R1 , R2, R3 and R4 is, independent from any other moiety R1 , R2, R3 and R4, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylaryl, heteroalkenylaryl, heteroalkynylar ⁇ l, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, and wherein R3 and/or R4 can also be hydrogen, and wherein at least one of R3 and R4 comprises, in the case of a preferred chiral nitrogen auxiliary, a chiral centre adjacent to or no more than one atom removed from the nitrogen atom, and wherein R1 and R2 may together form a ring and wherein R3 and R4 may together
  • ketones and nitrogen auxiliaries are described in greater detail below.
  • prochiral ketones can be reductively aminated to become secondary or tertiary amine diastereomers.
  • R1 and R2 cannot be such that a heteroatom is directly covalently attached to the ketone carbonyl group, otherwise the respective educt is no longer a ketone
  • R1 or R2 is methyl, with the other substituent further preferably being aliphatic instead of aromatic. High diastereoselectivities and reaction rates could be achieved with ketones comprising a methyl group directly covalently attached to the ketone's carbonyl group.
  • the method according to the invention is particularly advantageous because hydrides, as employed by the prior art, have turned out to generally impart a lower de (diastereomeric excess) on the secondary or tertiary chiral amine diastereomer, generate excessive amounts of waste compared to the method of the invention, cannot be used in as many different solvents as the method of the invention and in some instances are toxic and/or are price restrictive.
  • the method according to the present invention allows a reduction in the consumption of the Lewis acid to be achieved (with enantiomers of (R)- or
  • a "good diastereoselectivity" is one with a diastereomeric excess of ⁇ 70 %.
  • the present invention generally allows a diastereomeric excess of ⁇ 70 % to be achieved.
  • a "good diastereoselectivity” is one with a diastereomeric excess of ⁇ 80%.
  • the preferably chiral nitrogen auxiliary is a primary or secondary nitrogen auxiliary in substantially enantiopure form or, preferably, with an enantiomeric excess or diastereomeric excess of ⁇ 70 %.
  • a chiral nitrogen auxiliary either comprises at least one centre of chirality covalently connected to the nitrogen atom that is to react with the carboxy group of the ketone educt by a chain of at most 3 atoms, and most preferably directly attached, and preferably is directly covalently connected thereto.
  • the chiral nitrogen auxiliary may also or alternatively comprise a chiral axis or plane which like a chiral centre is/are capable of stereo-differentiation and thus is/are capable of influencing the enantiomeric excess at the new chiral centre where the carboxy group of the ketone educt used to reside, and therefore the diastereomeric excess of the secondary or tertiary chiral amine produced when using chiral nitrogen auxiliaries.
  • a non-chiral (without chiral centre) or racemic-chiral nitrogen auxiliary can also be employed, e.g. ammonia.
  • Water is optionally removed from the reductive amination reaction, typically by entrapping it with a molecular sieve, a zeolite and/or a dehydrating agent like MgSO 4 .
  • a molecular sieve typically a molecular sieve
  • a zeolite typically a zeolite
  • a dehydrating agent like MgSO 4 .
  • water may also be entrapped by the mild Lewis acid. Water removal (or trapping) will typically enhance the reaction rate, so that a faster reaction time is common under otherwise identical reaction conditions.
  • Reaction times of 6 h to 16 h, in which ⁇ 70 mol% of the ketone educt have been consumed, can generally be achieved when the reductive amination according to the invention is performed in the absence of an effective amount of an entrapping agent, particularly a molecular sieve or zeolite; in the presence of an effective amount of a water entrapping agent like a molecular sieve, a zeolite and/or MgSO 4 a reduction of the reaction time can be expected.
  • an entrapping agent particularly a molecular sieve or zeolite
  • the mild Lewis acid is preferably not a proton source.
  • the mild Lewis acid is selected from the group consisting of
  • a ytterbium methoxide or ytterbium ethoxide b) a composite of a ytterbium and a ligand with at least one car boxy lie acid group, preferably a ytterbium acetate, be it fully hydrated, partly hydrated or not hydrated, particularly preferred a carboxylic acid selected from the group consisting of acetic acid, ethanoic acid, propanoic acid, butanoic acid, decanoic acid, oxalic acid, suberic acid, cis-4-cyclohexene-1,2- dicarboxylic acid, thioglycolic acid, thioacetic acid, thiolacetic acid, trichloroacetic acid, malonic acid, succinic acid, adipic acid, citric acid, ethylenediaminetetraacetic acid, L- or D-ascorbic acid, L- or D-tartaric acid, L- or D-malic acid
  • a ytterbium dialkoxide diamide, amide alkoxide, alkoxide phosphine (or phosphine derivative thereof), amide phosphine (or phosphine derivative thereof), amino phosphine (or phosphine derivative thereof), or multidentate ligands comprising a combination of the above described moieties, wherein any of these species can be chiral,
  • the ytterbium containing mild Lewis acid may also be used in the form of a mixture with one or more additional mild Lewis acids comprising an element in the respective oxidation state selected from the group consisting of Ti (IV), Al (III), Zr (IV), V (III, IV, V), Nb (III, IV, V), Bi (III), In (III), Ag (I), Sc (III), Y (III), Fe (III), B (III), Hf (IV), Zn (II), La(III), Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), Lu(III), Pb (Il or IV), Sb (III).
  • particularly preferred mild Lewis acids to be included in such mixtures with a ytterbium-comprising mild Lewis acid are metal alkoxides, acetates in fully, partly or not hydrated from, acetylacetonates, triflates, and halogenides, all of which can be in fully, partly, or not hydrated form, but are preferably not fully hydrated and which comprise an element in the respective oxidation state selected from the group consisting of Ti (IV), Al (III), Zr (IV) 1 V (III, IV 1 V) 1 Nb (III, IV 1 V) 1 Bi (III), In (III), Ag (I) 1 Sc (III), Y (III), Fe (III), B (III), Hf (IV) 1 Zn (II), lanthanides (III).
  • These mild Lewis acids are particularly suitable to be used in a method according to the invention.
  • a particularly preferred Lewis acid comprising ytterbium is ytterbium acetate in fully hydrated, partly hydrated or non-hydrated form. These Lewis acid forms allow particularly high diastereomeric excess and good rates of reaction to be achieved when used in combination with a chiral nitrogen auxiliary, particularly preferably on a ketone educt with a methyl group directly covalently attached to the ketone's carbonyl group.
  • ytterbium acetate hydrate allows to achieve, for a vast number of useful ketone educts, a fast reaction, few or negligible by-product formation (particularly the corresponding alcohol), compared to the corresponding ytterbium halogenides (particularly ytterbium chloride) and ytterbium triflate.
  • the metal catalyst preferably is a nickel, palladium (particularly in the form of a Pd/C catalyst), platinum (particularly in the form of a Pt/C catalyst), RhIC, Ru/C and/or a copper metal catalyst, and preferably in a Raney metal catalyst form.
  • nickel metal catalyst in a method according to the present invention. It is particularly preferred when the nickel metal catalyst is a powder with a median particle diameter of 2 mm or less. Most preferred is a method according to the invention, wherein the metal catalyst is Raney nickel, platinum or palladium.
  • Typical weight loadings relative to the ketone limiting reagent are 5-200 wt %, with preferred wt loadings of Raney-Ni in the range of 20-120 wt %.
  • a catalyst comprising platinum e.g. Pt or Pt/C
  • the amount of platinum catalyst added after 3 and 6 hours is substantially equal to the amount of platinum catalyst at the onset of hydrogenation.
  • Raney Ni is preferred for acyclic or acyclic ketones that lack a tertiary carbon, e.g. f-butyl moiety, directly covalently linked to the carbonyl carbon of the ketone educt, e.g. 2-octanone.
  • Pt-C is preferred for acyclic or cyclic ketones that contain a tertiary carbon directly covalently linked to the carbonyl carbon of the ketone educt, e.g. pinacolone in Table 3.
  • Pd-C is preferred for benzocyclic (cyclic aromatic-aliphatic) ketones, of which ⁇ -tetralone is an example.
  • General experimental protocols have been established for these different classes of ketones, and readily allow experimental starting points for yet untested but similarly functionalized and preferably prochiral ketones. Preference is based on the observation of high yield and/or high diastereomeric excess.
  • the activity of the Raney nickel catalyst can generally be increased by addition of small amounts of triethylamine hexachloroplatinate (IV) or by small amounts of aluminium resident in the catalyst.
  • the particular mixture of Rh 2 CVPtO 2 in a three to two molar ratio can be advantageously used to reduce dehalogenation during reductive amination.
  • the diastereoselectivity of the method according to the invention can generally be enhanced when the Raney catalyst, in particular Raney nickel, has attached thereto an enantiopure or enantioenriched (de or ee, respectively, ⁇ 70 %) compound, e.g. an enantiopure or enantioenriched acid or ester, e.g. chiral cinchonidine ligands.
  • the method according to the present invention preferably comprises the step of forming a pre-reaction mixture by mixing the starting materials and reagents in the following order:
  • the pre-reaction mixture is preferably allowed to stand stirred or unstirred for up to 14 h, more preferably for up to 8 h, and most preferably for up to 2 h, and preferably for at least 1 h.
  • the pre-reaction mixture is preferably allowed to stand stirred or unstirred for up to 14 h, more preferably for up to 8 h, and most preferably for up to 2 h, and preferably for at least 1 h.
  • pre-reaction mixture it is preferred for poorly performing reductive aminations to let the pre-reaction mixture stand at temperatures higher than room temperatures, preferably at ⁇ 30 0 C and less than 100 0 C, most preferably at 30-60 0 C.
  • These pre-reaction conditions have frequently been found to be beneficial for the reaction rate/yield of a subsequent reductive amination reaction.
  • the amount of Raney Ni and pressure of hydrogen used will generally have a beneficial effect when used in larger quantities and pressures respectively. Without being bound by the following theory, it is believed that maintaining a pre-reaction mixture as described above aids in the formation of an advantageous imine intermediate.
  • the preferably prochiral ketone and the preferably chiral nitrogen auxiliary are preferably present in the reaction mixture in a molar ratio of 1 :4 to 4:1 and particularly preferred in an equimolar amount.
  • the (preferably chiral) nitrogen auxiliary and/or the (preferably prochiral) ketone on the one hand and the mild ytterbium Lewis acid on the other hand are preferably present in the reaction mixture (at the initiation of hydrogenation) in a molar ratio of 1 :4 to 4:1 , preferably in an equimolar amount.
  • the (prochiral) ketone, the chiral nitrogen auxiliary and the mild Lewis acid are present in the reaction mixture in equimolar amounts. These preferred ratios aid the purification of the secondary or tertiary amine diastereomer product, reduce the cost of the process, and the waste produced, while providing good reaction yields and good diastereoselectivity for the chiral amine product. Particularly good results have been obtained when the mild Lewis acid comprising ytterbium, particularly ytterbium acetate in partly or non-hydrated form, is present at the onset of hydrogenation in an amount of ⁇ 60 mol% relative to the amount of the (preferably prochiral) ketone educt (see table 6 below).
  • the metal catalyst in particular Pd/C and/or Raney nickel and/or Raney platinum, respectively, is preferably added to said pre-reaction mixture 5 min to 6 h after formation of said pre-reaction mixture with simultaneous initiation of hydrogenation. It is particularly preferred to add the metal catalyst, particularly Raney nickel, and then initiate hydrogenation within 0-60 min after addition of the said metal catalyst.
  • diastereomeric excesses are slightly improved, alcohol by-product formation can be reduced and reaction rates increased if the reaction mixture is pre-stirred for 30 min to 2 h, sometimes with heating, before adding the metal catalyst, particularly Pd/C and/or Raney nickel and/or Pt/C, respectively, and initiating hydrogenation, sometimes with heating, by pressurising the reaction mixture with hydrogen gas.
  • the metal catalyst particularly Pd/C and/or Raney nickel and/or Pt/C, respectively
  • the nitrogen auxiliary is a chiral primary amine
  • it is used in the reductive amination reaction in enantiopure form (with respect to the chiral centre adjacent to or not more than one atom removed from the nitrogen atom) or in an enantiomeric excess (ee) of ⁇ 70%, preferably ⁇ 90% and most preferred ⁇ 95%.
  • ee enantiomeric excess of the chiral primary amine
  • the chiral nitrogen auxiliary preferably is one of the formula
  • R3 and R4 are, independent from one another, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylar ⁇ l, heteroalkenylar ⁇ l, heteroalkynylar ⁇ l, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, and wherein R3 can also be hydrogen, and wherein
  • moieties R3 and R4 may together form a ring, and wherein
  • each moiety R3 and R4 comprises a chiral centre.
  • each moiety R3 and R4 comprises at most 30 carbon atoms.
  • a heteroatom e.g. sulphur, phosphorus, nitrogen, oxygen, or a halogenide can be directly covalently attached to the nitrogen atom of formula I.
  • chiral nitrogen auxiliary is a chiral primary amine, such that R3 is H.
  • a particularly preferred chiral primary amine nitrogen auxiliary is (R)-1- methylbenzylamine.
  • Another particularly preferred chiral primary nitrogen auxiliary is (S)-i-methylbenzylamine.
  • These amines are readily obtainable in enantiopure form or with an enantiomeric excess (ee) of ⁇ 70% (technical grade quantities).
  • the part of the chiral nitrogen auxiliary that is not generally a constitutive part of the amine product can be easily cleaved by hydrogenolysis, or other preferred methods, e.g. hydrolysis, to produce a substantially enantiopure or enantioenriched primary or secondary amine product.
  • chiral auxiliaries are those with a chiral axis or chiral plane. Of these groups, particularly preferred chiral auxiliaries are 2,2'-diamino-6,6'- dimethyl-1 ,1'-biphenyl and 2, 2 l -diamino-1 ,1'-binaphthyl.
  • Another nitrogen auxiliary according to Formula I is (R)- or (S)-H 2 NS(O)R, where R is defined as having a carbon atom directly covalently attached to the sulphur atom, and of which e.g. are t-butyl or phenyl moieties.
  • the ketone is a ketone of the form
  • moieties R1 and R2 are, independent from one another, a) alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroar ⁇ l, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylaryl, heteroalkenylaryl, heteroalkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, where at no time the heteroatom of the above heteroatom defined species can be directly covalently attached to the carbonyl carbon of the ketone educt b) and wherein moieties R1 and R2 may together form a ring, and wherein moieties R1 and R2 comprise, where necessary, a bridge of at least one atom to render the ketone aliphatic in the meaning of the aforementioned definition.
  • each moiety R1 and R2 comprises at most 30 carbon atoms, whether united by a ring or not.
  • the ketone is prochiral. Synthesis of the corresponding secondary or tertiary amine diastereomers and subsequent cleavage of the chiral auxiliary produces enantiopure or enantioenriched primary or secondary amine products respectively. Previously, the production of enantiopure or enantioenriched primary or secondary amine products had been difficult.
  • the method according to the invention advantageously allows production of such secondary or tertiary amine diastereomers and the corresponding primary or secondary amine product enantiomers in a fast reaction, typically in less than 20 h, at a temperature below 100 °C, typically at or below 80 °C and a pressure of less than 60 bar.
  • a fast reaction typically in less than 20 h
  • the corresponding reductive amination reactions required for their synthesis, even proceed in less than 16 h at a reaction temperature between -10 °C and 50 °C and at a pressure (esp. the pressure of hydrogen gas) of less than 30 bar and preferably less than 10 bar.
  • ketones are:
  • any moiety (substituent) R can be connected to another or can be independent from any other moiety R hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylaryl, heteroalkenylaryl, heteroalkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl any - CH2- can be replaced with -CHR- or -CRR- (where any R is as described just before), where m may be any positive integer from O onwards, and where n may be any positive integer from O onwards and where p may be any positive integer from 0 onwards, and where X can equal R or, in the instance of a single bond, X can additionally be a
  • ketones are those that comprise a methyl group directly covalently attached to the ketone's carbonyl group:
  • ketones allow particularly speedy, providing mostly complete reductive amination reactions with few unwanted by-product and high diastereoselectivity.
  • the method of the present invention can be performed with or without using a solvent, and is preferably performed in a protic solvent other than water, and preferably comprises an alcohol.
  • the solvent is preferably selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, hexane, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, tetrahydrothiophene-1 ,1 -dioxide, 1 ,3-dioxolane, dimethylsulfoxide, dimethylformamide, diethylcarbonate, ethyl acetate, methanol, ethanol, n- propanol, n-butanol, ethylene glycol, glycerol, or an ionic liquid or a mixture of two or more thereof.
  • methanol alone or in combination with tetrahydrofuran and/or ethyl acetate, is particularly preferred as the solvent used in the reductive amination step.
  • solvents have allowed sufficiently fast reaction times coupled with particularly high yields and diastereomeric excess values of the secondary amine diastereomers.
  • the mild Lewis acid may not be completely solvable in the solvent. Yet, it is preferred if the mild Lewis acid is present in the reaction mixture in the above preferred ratios relative to the limiting reagent, e.g. 1 to 25 mol% relative to the amount of ketone educt, and particularly preferably 5-15 mol% relative to the amount of the ketone educt. Some of the mild Lewis acid can then be present in the reaction mixture in the form of a solid. For example, using acetate-containing mild Lewis acids like bismuth (III) acetate in less than 5 mol% relative to the amount of ketone educt in a methanolic solvent, e.g. methanol, methanol/tetrahydrofuran or methanol/ethylacetate, can result in a decrease in reaction rate and increase in alcohol by-product formation.
  • acetate-containing mild Lewis acids like bismuth (III) acetate in less than 5 mol% relative to the amount of ketone educt in a
  • the method according to the present invention is preferably performed at a temperature from -10 0 C to 100 0 C, particularly -10 0 C to 80 0 C, more preferably at a temperature from 5 °C to 50 0 C. Also, the method is preferably performed at a pressure from 0.5 bar to 60 bar of hydrogen gas, and furthermore preferably is performed within a reaction time of up to 48 h.
  • the method according to the present invention can be performed at a temperature of 15 °C to 40 °C (in many economically important reactions even at a temperature of 15 0 C to 30 0 C) with a pressure of 2 bar to 50 bar, more preferably 2 bar to 30 bar, and even more preferably 2 bar to 10 bar yielding the desired secondary or tertiary amine diastereomer in high yields and superior diastereomeric excess.
  • the pressure and/or temperature should be increased if the reductive amination reaction takes more than 20 h to consume 95 % of the (prochiral) ketone educt.
  • reaction times after the initiation of hydrogenation are 6 h to 20 h, particularly preferred is a reaction time of 6 h to 12 h at a reaction temperature of 5 0 C to 50 0 C and a reaction pressure of 0.5 bar to 10 bar.
  • the reaction time is defined herein as the time necessary to consume 85 % of the limiting reagent upon initiation of the (usually pressurised) hydrogenation.
  • the reductive amination of the invention can thus preferably be performed by:
  • a solvent particularly one comprising methanol
  • a prochiral ketone educt preferably a methylketone, and preferably an aliphatic methylketone
  • a ytterbium Lewis acid preferably Yb(OAc) 3 in its partly or non- hyd rated form, using a chiral nitrogen auxiliary,
  • step b) cleaving the remainder of the (preferably chiral) auxiliary from the secondary or tertiary amine of step a) to yield the preferably enantioenriched primary or secondary amine product.
  • the primary or secondary amine product of step b) can be enantiopure or at least enantioenriched.
  • This method according to the present invention can generally be described as being a second step following the aforementioned method according to the invention, as exemplified by the following reaction scheme:
  • the method for producing the primary or secondary amine product according to the invention requires fewer reaction steps than previous methods for producing an enantiopure or enantioenriched primary or secondary amine, uses inexpensive and rea dily available materials, can generally be performed at a temperature of at most 60 0 C (and frequently even at ambient temperature) and low pressure as described above and provides superior enantiomeric excess at high product yields compared to the other available methods. It exploits the advantages of the method for producing secondary or tertiary amine diastereomers according to the invention as described above.
  • a particularly preferred catalyst for use in step b) is one selected from the group consisting of Pd/C and Pd(OH) 2 /C, wherein the latter is generally preferred.
  • an acid examples of which are HCI, CH 3 SO 3 H, and HOAc, in stoichiometric or greater quantities.
  • Example 1 The effect of different ligands on Ytterbium
  • ketone is defined as the total amount of detected ketone and imine. Additionally for all tables, the catalogue # refers to the Sigma-aldrich catalog number, and % refers to gas chromatography area percent data, unless otherwise indicated as isolated yield data which is obtained only after column chromatography. Table 1 shows that the acetate ligand clearly provides a high rate of reaction with excellent de.
  • Example 6 Effect of the mol % of Yb(OAc) 3 on the diastereoselectivity of the secondary amine product
  • Table 7 shows a number of amines that can be produced in a method according to the invention. Table 7 further indicates corresponding ketone educts and nitrogen auxiliaries employed.
  • the mild Lewis acid is one of indium (III) acetate, bismuth (III) acetate, ytterbium (III) acetate and scandium (III) acetate, each in partly hydrated or non-hydrated form.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne des méthodes de production d'amines primaires, secondaires et tertiaires et de dérivés d'amines primaires ou secondaires énantiopurs ou énantioenrichis correspondants à partir de diastéréoisomères d'amines secondaires ou tertiaires.
PCT/EP2006/060715 2006-03-14 2006-03-14 Synthèse d'amines à l'aide d'acides de lewis contenant de l'ytterbium Ceased WO2007104359A1 (fr)

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US8586742B2 (en) 2008-08-10 2013-11-19 Yeda Research And Development Co. Ltd. Process for preparing amines from alcohols and ammonia
CN105384708A (zh) * 2015-10-21 2016-03-09 河南普瑞制药有限公司 一种（s）-（+）-1-（2-哌啶苯基）-3-甲基正丁胺的制备方法
WO2016189129A1 (fr) * 2015-05-28 2016-12-01 Basf Se Procédé pour l'amination réductive catalysée de façon homogène de composés carbonyle

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8586742B2 (en) 2008-08-10 2013-11-19 Yeda Research And Development Co. Ltd. Process for preparing amines from alcohols and ammonia
US8779136B2 (en) 2008-08-10 2014-07-15 Yeda Research And Development Co. Ltd. Process for preparing amines from alcohols and ammonia
US8889865B2 (en) 2008-08-10 2014-11-18 Yeda Research And Development Co. Ltd. Process for preparing amines from alcohols and ammonia
WO2016189129A1 (fr) * 2015-05-28 2016-12-01 Basf Se Procédé pour l'amination réductive catalysée de façon homogène de composés carbonyle
CN107980011A (zh) * 2015-05-28 2018-05-01 巴斯夫欧洲公司 均相催化还原胺化羰基化合物的方法
US10450261B2 (en) 2015-05-28 2019-10-22 Basf Se Method for the homogeneous catalytic reductive amination of carbonyl compounds
CN107980011B (zh) * 2015-05-28 2020-10-27 巴斯夫欧洲公司 均相催化还原胺化羰基化合物的方法
CN105384708A (zh) * 2015-10-21 2016-03-09 河南普瑞制药有限公司 一种（s）-（+）-1-（2-哌啶苯基）-3-甲基正丁胺的制备方法

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