WO2007104357A1

WO2007104357A1 - Synthesis of amines with catalytic amounts of mild lewis acids

Info

Publication number: WO2007104357A1
Application number: PCT/EP2006/060713
Authority: WO
Inventors: Thomas Christopher Nugent; Vijay Narayan Wakchaure; Mohamed Mahmoud El-Shazly
Original assignee: Jacobs University Bremen Ggmbh
Priority date: 2006-03-14
Filing date: 2006-03-14
Publication date: 2007-09-20

Abstract

The invention relates to methods for producing primary, secondary and tertiary amines and corresponding enantiopure or enantioenriched primary or secondary amine products, comprising the steps of reductively aminating a ketone, with a nitrogen auxiliary in the presence of a hydrogenating catalyst and a hydrogenating agent, wherein the reductive animation is performed under the influence of a mild Lewis acid, the mild Lewis acid being present at the onset of the reductive amination in at most 25 mol% of the ketone or the nitrogen auxiliary.

Description

Synthesis of amines with catalytic amounts of mild Lewis acids

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. In the unique case when 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.

Within the present invention, the term "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.

Similarly, a reference to an "aliphatic amine" product denotes an amine product obtained from an aliphatic ketone educt according to the invention; whereas the term "aromatic amine" product 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. The term "prochiral ketone" denotes a ketone educt wherein the carbon atom of the carboxy group is not directly covalently connected to a chiral centre.

Accordingly, 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. Preferably, the prochiral ketone is devoid of any chiral centre(s).

Within the present invention, all references to stereoisomers (diastereomers and enantiomers) relate exclusively to a) the newly generated chiral centre at 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. For example, 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.

Within the present invention, 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 their corresponding primary or secondary amine enantiomeric products. The chiral nitrogen auxiliary is preferably of ≥ 80% enantiomeric or diastereomeric excess. However, 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. Additionally a chiral centre (in racemic or enantioenriched form) could be present but not directly linked to the nitrogen atom of the nitrogen auxiliary, or comprise a chiral center directly linked to the nitrogen atom but in racemic form. However, when non-chiral amines are employed, the corresponding reaction products may still exhibit a diastereomeric excess, but will be racemates. Accordingly, no enantiomeric excess after hydrolysis or dealkylation of the non-nitrogen portion of the nitrogen auxilary is possible in view of the newly introduced nitrogen atom of the nitrogen auxiliary. According to the present invention, the nitrogen-conferring reaction partner during reductive amination of the ketone educt is generally termed a "nitrogen auxiliary". This is solely to designate that the 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. However, 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. In the specific case of using ammonia during the reductive amination, the second step, auxiliary removal, is not necessary.

Clifton et al. (J. Med. Chem., 1982, 670-679) disclose a method for producing [R- (R*, R*)]-α-methyl-N-(1-phenylethyl)benzenepropanamine by reacting (R)-(+)-α- methylbenzylamine and excess benzylacetone under hydrogenating conditions in the presence of Raney nickel. They achieved a crude yield (before purification) of 91% with a diastereomeric ratio of 90:10 (RR/SR). After recrystallisation the highly enriched RR diastereoisomer was obtained in 37% yield. Furthermore, they disclose a method for producing the corresponding primary amine R-α- methylbenzenepropanamine by hydrogenolysis of the highly enriched RR diastereomer [R-(R*, R*)]-α-Methyl-N-(1-phenylethyl)benzenepropanamine over 10% PdO/C. The primary amine is produced in 70% yield and in >99% enantiomeric purity.

R-4-Phenyl-2-aminobutane R,R -diastereomer, ₃7 % yield

However, the reaction of (R)-(+)-α-methylbenzylamine and benzylacetone (4- phenyl-2-butanone) is very slow and requires 5 days (120 h) to yield sufficient quantities of the secondary amine and requires 1.67 molar equivalents of benzylacetone as compared to (R)-(+)-α-methylbenzylamine.

Ellman et al., Tetrahedron Letters 1999, 40, 6709-6712 describe a process in which several aliphatic ketones are reacted with (R)- or (S)-2-methyl-2- propanesulfinamide [H₂NS(O)t-Bu] and NaBH₄ in the presence of Ti(OzPr)₄ for selective synthesis of the corresponding amine diastereomers. However, the reaction depends on maintaining very low reaction temperatures of -48°C and necessitates use of expensive reactants.

Alexakis et al. (Tetrahedron Letters, 2004, 1449-1451) disclose a method for producing C₂-symmetrical aromatic secondary amines by reacting an aromatic ketone and different enantiopure aromatic primary amines with an effective amount of Ti(OiPr)₄/H₂/Pd-C. However, 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 (Organic Process Research and Development 2006, 10, 142-148) 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/H₂ or aluminium isoproxide and special ketone educts for effecting the reductive amination. Further aspects of the usefulness of titanium ispropoxide 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. Also, the costs for performing such reductive aminations is considered to be high.

It was therefore a problem of the present invention to provide a method for producing a secondary or tertiary amine diastereomer, wherein the method should allow for the production of secondary or tertiary amine diastereomers with a diastereomeric excess (de) of ≥70 %. 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 ⁰C, and should preferably not rely on reaction temperatures higher than 50°C and/or lower than -10°C. It was also a problem of the present invention to provide a method for generally producing primary, secondary or tertiary amines that should be fast, should not rely on reaction pressures higher than 60 bar and reaction temperatures higher than 100 °C. Also, the method should allow the ketone educt to be present in the reaction product mixture in < 15 yield % (isolated yield) and/or formation of alcohol by-product should be of < 15 yield % (isolated yield) relative to the amount of limiting reagent (ketone educt or nitrogen auxiliary) at the initiation of reductive amination.

A further object of the invention was to provide a method for producing enantiomerically pure or enantiomerically enriched primary or secondary amine products. The method should also be useful for producing enantiopure or enantioenriched aliphatic primary or secondary amine products. The object of the invention is accomplished by a method for producing a primary, secondary or tertiary amine, preferably a corresponding diastereomer, comprising or consisting of the step of reductively aminating an aromatic or aliphatic, 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, the mild Lewis acid being present at the onset of the reductive amination in at most 25 mol % of the limiting reagent (ketone educt or nitrogen auxiliary).

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 Lewis acid, with a high yield and under reaction pressures of less than 60 bar and reaction temperatures of less than 80 °C, and preferably less than 50 ⁰C and further preferably higher than -10⁰C, and also allows the production of respective non-chiral primary, secondary or tertiary amines by using respective non-chiral nitrogen auxiliaries.

The reaction parameters, in particular the meaning of the term "mild Lewis acid", will be described hereinafter.

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:

wherein 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, heteroalkenylarγl, heteroalkynylaryl, 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 form a ring. Preferred ketones and nitrogen auxiliaries are described in greater detail below. By using a chiral primary or secondary amine as the nitrogen auxiliary, prochiral ketones can be reductively aminated to become secondary or tertiary amine diastereomeres. Clearly, 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.

It is particularly preferred that either R1 or R2 is methyl, with the other substituent further preferably being aliphatic instead of aromatic. High diastereoselectivities and excellent reaction rates could generally be achieved with ketones comprising a methyl group directly covalently attached to the ketone's carbonyl group.

When compared to the prior art, 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. Compared to previous methods employing titanium isopropoxide, 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 (S)-i-methylbenzylamine, a preferred chiral nitrogen auxiliary) without significant (>15%) accumulation of the alcohol by-product, and preferably with <10% alcohol formation.

Within the present invention, a "good diastereoselectivity" is one with a diastereomeric excess of ≥ 70 %. The present invention generally allows a diastereomeric excess of ≥ 70 % to be achieved.

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 preferably is directly covalently connected or not more than one atom removed from 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. When a diastereomeric excess or enantiomeric excess of the product of the respective reaction of the invention is not a consideration, 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

MgSO₄. When hydratable mild Lewis acids are used in the reductive amination according to the invention, 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 MgSO₄ a reduction of the reaction time can be expected.

The mild Lewis acid is preferably not a proton source. Preferably, the mild Lewis acid is selected from the group consisting of

a) a metal alkoxide, in particular

a metal isopropoxide,

- a metal methoxide or metal ethoxide,

b) a composite of a metal and a ligand with at least one carboxylic acid group, preferably a metal 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, (R)- or (S)-mandelic acid, D- or L-amino acids, D- or L- glyceric acid, D- or L-gluconic acid,

c) a metal acetyl acetonate, a metal hexafluoroacetylacetonate,

d) a metal halogenide,

e) a metal 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,

or a mixture of two or more members of the group. Preferred mild Lewis acids have scandium, iron, nickel, copper, zinc, gallium, arsenic and/or a metal of the 5^th and 6^th period of the periodic table, in particular rubidium, strontium, yttrium, silver, indium, tin, antimony, cesium, barium, cerium, praseodymium, neodymium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, scandium, lutetium, hafnium, tantalum, tungsten, mercury, thallium, lead and bismuth. Preferred metals in the respective oxidation state are indium (III), bismuth (III), scandium (III), dysprosium (III), ytterbium (III), yttrium (III), cerium (III), copper (I), erbium (III), neodymium (III), gadolinium (III), lead (II), lead (IV), nickel (II), iron (II), iron (III), zinc (II), arsenic (III), cesium (I), barium (II), tin (II), tin (IV), rubidium (I), strontium (II), antimony (III), praseodymium (III), europium (III), terbium (III), holmium (III), thulium (III), lutetium, (III), hafnium (IV), tantalum (Vl), tungsten (IV and Vl), mercury (II), thallium (I and III), gallium (III), and silver (I)-

A particularly preferred Lewis acid is a metal acetate hydrate in fully hydrated, partly hydrated or non-hydrated form. These Lewis acid forms allow particularly high diastereomeric excess 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.

Of the mild Lewis acids, when examining a metal with a series of different ligands, those with acetate ligands, particularly preferably in partly or non- hydrated form, are preferred over halogenides and acetylacetonates, which in turn are preferred over triflates and alkoxides for higher product yield and/or diastereoselectivity achieved.

Preferably, the mild Lewis acid is free of titanium, aluminium, zirconium, boron and lanthanum. Most preferably, the mild Lewis acid is not titanium (IV) isopropoxide, aluminium (III) isopropoxide, zirconium (IV) isopropoxide, titanium (IV) methoxide, trimethylborate, triisopropylborate or borontrifluoride.

Preferred mild Lewis acids in the methods according to the invention comprise, as metal components, indium, particularly indium (III), bismuth, particularly bismuth (III), antimony, particularly antimony (III), ytterbium, particularly ytterbium (III), yttrium, particularly yttrium (III), zinc, particularly zinc (II), silver, particularly silver (I), copper, particularly copper (I), erbium, particularly erbium (III), lead, particularly lead (Il and IV), gadolinium, particularly gadolinium (III), and/or scandium, particularly scandium (III). Most preferred are non-hydrated or partly hydrated forms of antimony (III) acetate, indium (III) acetate, lead (IV) acetate, bismuth (III) acetate, scandium (III) acetate, and ytterbium (III) acetate. Most particularly preferred are bismuth (III) acetate and ytterbium (III) acetate for the examples shown herein for their overall effectiveness regarding high yield, reaction rate, and diastereomeric excess. Each ketone should be examined with the preferred mild Lewis acids list above, to achieve the best overall yield, reaction rate, and diastereomeric excess for a particular ketone. These mild Lewis acids allow one to achieve a particularly high ketone turnover to be achieved combined with a particularly low formation of alcohol by-product and a high diastereomeric excess. Also preferred are dysprosium (III) acetate, cerium (III) acetate, nickel (II) acetate, tin (II) acetate, neodymium (III) acetate, gallium (III) chloride, hafnium (IV) chloride, and scandium (III) chloride. These mild Lewis acids frequently offer a good compromise between ketone turnover and alcohol formation with maintaining good to high diastereomeric excess.

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), Rh/C, Ru/C and/or a copper metal catalyst, and preferably in a Raney metal catalyst form. High product yields and good diastereomeric excess values have been achieved by using a 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. These catalysts have so far resulted in the highest product yields and diastereomeric excesses in a method according to the invention (see examples). 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 %.

When a catalyst comprising platinum is employed, e.g. Pt or Pt/C, it is advisable to add fresh catalyst during the reductive amination reaction and not only at or before the onset of hydrogenation. It is particularly preferred to add fresh platinum catalyst after 3 and 6 hours after start of the reductive amination reaction by onset of hydrogenation. Typically, 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. Less than 2.0 mole % of Pt should be used and preferably more than 0.05 mol % in total during the course of the reaction. Regarding Pd, delivered as Pd/C, similar mol % as Pt should be used, but need not necessarily be added in several steps over the course of the reaction, but is preferably added at the onset of hydrogentation.

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. pinacalone in Table 11. Pd-C is preferred for benzocyclic (cyclic aromatic-aliphatic) ketones, of which α-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. Additionally, the particular mixture of Rh₂O₃/PtO₂ in a three to two molar ratio can be advantageously used to reduce dehalogenation during reductive amination. Furthermore, 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:

(1 ) solvent (if applicable),

(2) ketone, preferably a prochiral ketone,

(3) mild Lewis acid,

(4) chiral nitrogen auxiliary.

Then, after formation of the pre-reaction mixture, the metal catalyst is added and hydrogenation is initiated. 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. For poorly performing reductive aminations, particularly for reductive aminations with a high percentage of unwanted alcohol by-product or insufficient reaction rate, it is frequently advisable to form a pre-reaction mixture of the aforementioned type and allow it to stand, stirred or unstirred, for at least 1 h, preferably for 2-6 h. Also, it is preferred for poorly performing reductive aminations to let the pre-reaction mixture sit at temperatures higher than room temperatures, preferably at ≥ 30 °C and less than 100 °C, most preferably at 30-60 ⁰C. These pre-reaction conditions have frequently been found to be beneficial for the reaction rate/yield of a subsequent reductive amination reaction and for supression of alcohol by-product formation. When prereaction mixtures are heated, it is generally helpful to continue heating the reaction at the initiation of hydrogenation. 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.

According to the invention, at the initiation of hydrogenation, 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 are particularly preferred in an equimolar amount. 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.

The mild Lewis acid is preferably present, at the onset of the reductive amination in a minimum amount of 0.5 mol %, and even more preferably in a minimum amount of 5 mol %, relative to the limiting reagent (ketone educt or nitrogen auxiliary). Preferred amounts of the mild Lewis acid are 1 to 25 mol %, further preferably 3 to 15 mol %, and most preferably 8 to 12 mol%, relative to when the limiting reagent is preferably the ketone educt over the nitrogen auxiliary. These ratios between mild Lewis acid and limiting reagent are particularly suitable for preventing or reducing the formation of unwanted alcohol by-product, reducing the Lewis acid waste by-product, while maintaining a good turnover number for the Lewis acid and high diastereoselectivity. 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. In some instances as given above, diastereomeric excesses (des) 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 6 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.

If the nitrogen auxiliary is a chiral primary amine, then it is used in the reductive amination reaction as enantiopure (with respect to the chiral centre adjacent to or not more than one atom removed from the nitrogen atom) or is present in the reaction in an enantiomeric excess (ee) of ≥70%, preferably ≥90% and most preferred ≥ 95%. In general, the greater the enantiomeric excess of the chiral primary amine, the greater the enantiomeric excess of the desired primary or secondary amine enantiomer produced after hydrogenolysis.

The chiral nitrogen auxiliary preferably is one of the formula

R³ _X R⁴ N

H

(I)

wherein

R3 and R4 are, independent from one another, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylaryl, heteroalkenylaryl, heteroalkynylaryl, 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

at least one of R3 and R4 comprises a chiral centre. Preferably, 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.

Particularly preferred is a method according to the present invention wherein the 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). Also, 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.

Further useful 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)-H₂NS(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.

It is furthermore particularly preferred if the ketone is a ketone of the form

O R¹^R²

(Formula II), wherein moieties R1 and R2 are, independent from one another, a) alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroarγl, 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.

Preferably, each moiety R1 and R2 comprises at most 30 carbon atoms, whether united by a ring or not.

Furthermore, it is preferred that 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 24 h, at a temperature below 100 °C, typically at or below 80 °C and a pressure of less than 60 bar. For many commercially valuable primary or secondary amine product enantiomers, the corresponding reductive amination reactions, required for their synthesis, even proceed in less than 20 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. These advantages particularly apply to those methods according to the invention that use aliphatic prochiral ketones. Particularly preferred generic and specific examples of ketones are:

O O O O O O O

R. X R R R R R

J n X R

and

O O

O O O

OtBu N Ph

OH

O O H

where 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, heteroarγl, 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 O onwards, and where X is equal to R, or in the instance in which X is indicated as having only on single covalent bond, can also be a halogen Particularly preferred ketones are those that comprise a methyl group directly covalently attached to the ketone's carbonyl group:

O

R¹

with R1 having any of the meanings given in the previous paragraph. These ketones allow particularly speedy, mostly complete reductive amination reactions with few unwanted by-product and high diastereoselectivity.

Furthermore, 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. Of these, methanol, alone or in combination with tetrahydrofuran and/or ethyl acetate, is particularly preferred as the solvent used in the reductive amination step. These 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.

The method according to the present invention is preferably performed at a temperature from -10 ⁰C to 100 ⁰C, particularly -10⁰C to 80⁰C, more preferably at a temperature from 5 °C to 50 ⁰C. 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. Particularly, the method according to the present invention can be performed at a temperature of 15 °C to 60 °C (in many economically important reactions even at a temperature of 15 ⁰C to 30 ⁰C) with a pressure of 2 bar to 60 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. Generally, 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. Preferred reaction times after the initiation of hydrogenation are 6 h to 24 h, particularly preferred is a reaction time of 8 h to 16 h at a reaction temperature of -10 ⁰C to 60 ⁰C, preferably 5 ⁰C to 40 ⁰C, and a reaction pressure of 0.5 bar to 30 bar, particularly 2 to 10 bar. The reaction time is defined herein as the time necessary to consume 85 % of the limiting reagent (ketone educt or nitrogen auxiliary) after initiation of the (pressurized) hydrogenation.

The reductive amination of the invention can thus preferably be performed by:

using a solvent, particularly one comprising methanol,

using a prochiral ketone educt, preferably a methylketone, and preferably an aliphatic methylketone,

- using a mild Lewis acid, preferably an indium, ytterbium, bismuth or scandium Lewis acid,

using a chiral nitrogen auxiliary, forming a pre-reaction mixture of the above components and stirring or letting the pre-reaction mixture sit at 40°C for at least 1 h,

adding a metal catalyst as described above and

pressurizing the reaction mixture with hydrogen.

According to the invention, there is also provided a method for producing a primary or secondary amine product, comprising the steps of

a) performing a method according to the invention as described above to form a secondary or tertiary amine (preferably a secondary or tertiary amine diastereomer), and then

b) cleaving the remainder of the (preferably chiral) auxiliary from the amine of step a) to yield the preferably enantioenriched primary or secondary amine product.

Advantageously, 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:

O R³ _X R⁴ R³x R⁴ N N R^{1 /}^R² H X

R¹ R²

_□3 p4 p3 I i ^κ _N ^κ hydrogenolysis ^κ _N ^M

R¹^ R² R¹ ^ R² wherein all moieties R1 , R2, R3 and R4 have the respective meaning as described above with reference to formula I and II, with R2 being preferably methyl.

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 readily available materials, can generally be performed at a temperature of at most 60 °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.

It is particularly preferred to cleave the remainder of the chiral auxiliary from the respective secondary or tertiary amine diastereomer by hydrogenolysis, e.g. when using (R)- or (S)-i-methylbenzylamine as a chiral nitrogen auxiliary, or by hydrolysis, e.g. when using (R)- or (S)-H₂NS(O)R with R being t-Bu or aromatic moiety as a chiral nitrogen auxiliary. 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. Sometimes it is advantageous to also add an acid, examples of which are HCI, CH₃SO₃H, and HOAc, in stoichiometric or greater quantities.

The methods according to the present invention are hereinafter further described by way of examples. It is to be understood that the scope of the invention is defined exclusively by the claims, the examples are not intended to limit the scope of invention. Example 1 : Examination of particularly useful Lewis acids for reductive amination

9 α-MBA, Lewis acid ^ HN^Ph ₊ HN^Ph ₊ °^H

Ph^^{^}^^ Raney NI, H₂ (^β.3 bar)* _ph/\^\ ⁺ _Ph/\/\ ⁺ Ph^^^ benzylacetone ^solvent _{major minor a|coho|} diastereomer diastereomer byproduct

Benzylacetone (2.5 mmol), methanol (0.5 M, anhydrous), (S)- or (R)-α- methylbenzylamine (1.1 equiv), and 10 mol % (relative to the ketone educt) of the Lewis acid (all acetate mild Lewis acids are added in partly hydrated form) indicated in table 1 were mixed and stirred for 2 h at room temperature. After addition of 100 wt % Raney Nickel (relative to the ketone educt), the mixture was pressurized with 8.3 bar (120 psi) of H₂ and further stirred. All reactions provided the secondary amine diastereomers in a diastereomeric excess of 76-80%. The Lewis acids consistently provided the same diastereomeric excess measurements, but some Lewis acids, examples of which are Yb(OAc)₃ and Bi(OAc)₃, provided higher diastereomeric excesses than other Lewis acids. All data was collected by gas chromatography analysis at 8 h from the onset of pressurising with hydrogen. In table 1 and all further tables below, starting material is defined as the total amount of detected ketone and imine. Additionally for all tables, the catalog # refers to the Sigma-aldrich catalog number, and % refers to gas chromatography area percent data, unless otherwise indicated as isolated yield data after column chromatography. Table 1 shows that bismuth (III) acetate, indium (III) acetate, scandium (III) acetate, antimony (III) acetate, and ytterbium (III) acetate are particularly good mild Lewis acids in that most of the ketone educt has been converted and very few unwanted alcohol by-product has been formed. Table 1 Starting material and alcohol present in the reaction mixture after 8 h reaction time

Lewis acid Starting material (GC area %) Alcohol (GC area %)

Bi(OAc)₃ <3 <3 bismuth (III) acetate catalog # 401587

In(OAc)₃ <3 <7

Indium (III) acetate catalog # 510270

Sc(OAc)₃ <3 <5

Scandium (III) acetate catalog # 325899

Yb(OAc)₃ <3 <7

Ytterbium (III) acetate catalog #: 544973

Sb(OAc)₃ <5 <5

Antimony (III) acetate catalog # 483265 No Lewis acid added <3 >35

Example 2: Useful catalytic Lewis acids for asymmetric reductive amination of benzylacetone

Reactions were performed as given in example 1 above, with the mild Lewis acid as given in table 2 below. Table 2 shows that the mild Lewis acids enumerated therein are also well suited for the reductive amination of benzylacetone in that they consume most of the ketone educt and lead to low alcohol by-product formation. Table 2

Starting material and alcohol present in the reaction mixture after 8 h reaction time

Lewis acid Starting material (% Alcohol = X%

Dy(OAc)₃ <3 10<X<15 dysprosium (III) acetate

Ce(OAc)₃ <3 11 <X<16 cerium (III) acetate

Nd(OAc)₃ <3 11 <X<16 neodynium (III) acetate

Y(OAc)₃ <5 5<X<10 yttrium (III) acetate catalog # 326046

Gd(OAc)₃ <3 9<X<14 gadolinium (III) acetate

Er(OAc)₃ <5 6<X<11

Erbium (III) acetate

Catalog # 325570

CuOAc <3 7<X<12 copper (I) acetate catalog # 403342

AgOAc <3 7<X<12 silver (I) acetate catalog # 204374

Example 3: Comparison of Yb Lewis acids

Reactions were performed as given in example 1 above, with the mild Lewis acid as given in table 3 below. Table 3 shows that ytterbium (III) acetate in partly hydrated form was far better suited to reductively aminate benzylacetone, leading to consistently higher ketone educt consumption and lower formation of alcohol by-product.

table 3 Starting material and alcohol present in the reaction mixture after 8 h reaction time

Lewis acid Starting material (%) Alcohol (%)

Yb(OAc)₃ <5 <5 catalog # 544973

Yb(OiPr)₃ <3 >40 catalog # 514063

Yb(OTf)₃ >8 >20 catalog # 430595

Example 4: Comparison of triflate and acetate mild Lewis acids for benzylacetone

Reactions were performed as given in example 1 above, with the mild Lewis acid as given in table 4 below. All GC data in table 4 represents data after 24 h of hydrogenation time, except for the Lanthanum (La) entries which represent GC data at 8 h. Table 4 shows that the respective acetate mild Lewis acid consistently performed better than the corresponding triflate mild Lewis acids in terms of high consumption of ketone educt and low formation of alcohol byproduct.

table 4

Starting material and alcohol present in the reaction mixture after 8 h reaction time Lewis acid Starting material (%) Alcohol (%)

Ce(OAc)₃ <3 11 < X < 16

Ce(OTf)₃ >15 >12

La(OAc)₃ <5 >18 La(OTf)₃ <5 >30

Bi(OAc)₃ <3 <5

Bi(OTf)₃ >15 <3

In(OAc)₃ <5 <5

In(OTf)₃ >15 >15

Example 5: Comparison of chloride and acetate mild Lewis acids

Reactions were performed as given in example 1 above, with the mild Lewis acid as given in table 5 below. Table 5 shows that the respective acetate mild Lewis acid consistently performed better than the corresponding chloride mild Lewis acids in terms of reduced alcohol by-product formation.

table 5 Starting material and alcohol present in the reaction mixture after 8 h reaction time

Lewis acid Starting material (%) Alcohol (%)

Ce(OAc)₃ <3 11 < X < 16

CeCI₃ <2 >15

AgOAc <3 7 < X < 12

AgCI <2 >15

Sc(OAc)₃ <3 <5

ScCI₃ <2 >15

Example 6: Comparison of ligands for Yb and Sc mild Lewis acids

Reactions were performed as given in example 1 above, with the mild Lewis acid as given in table 6 below. Table 6 shows that the influence of the ligand was far greater for ytterbium mild Lewis acids compared to scandium mild Lewis acids with regards to the formation of alcohol by-product. Scandium (III) mild Lewis acids produced few alcohol by-product, regardless of the ligand being acetate, triflate or chloride, while the presence of triflates and chlorides of ytterbium in the reaction mixture led to high formation of alcohol by-product.

table 6 Starting material and alcohol present in the reaction mixture after 8 h reaction time

Lewis acid Starting material (%) Alcohol (%)

Yb(OAc)₃ <5 <5

Yb(OiPr)₃ <3 >40

Yb(OTf)₃ >8 >20

Sc(OAc)₃ <3 <5

Sc (III) <5 <5 hexafluoroacetylacetonate (24 h instead of 8 h reaction time)

ScCI₃ (24 h instead of 8 h <2 <8 reaction time)

Example 7: Effect of using 50 wt % Raney Ni for benzylacetone

Reactions were performed as given in example 1 above, with the mild Lewis acid Yb(OAc)₃ (10 mol %, catalog # 544973). The solvent for all reactions was THF/MeOH (1 :1 volume ratio, overall molarity 0.5 M, both solvents were anhydrous). All data is GC area % data. Table 7 shows that 50 wt % of Raney Ni (instead of 100 wt % Raney Ni), relative to the ketone, can be used. Consumption of the ketone educt is slowed, but consistently low levels of alcohol by-product formation are maintained while also providing high diastereomeric excess for the secondary amine products formed.

Example 8: titanium, zirconium, aluminium and boron mild Lewis acids perform poorly at substoichiometric quantities.

Reactions were performed as given in example 1 above, with the indicated mild Lewis acid (10 mol %) and reaction times (time after initiation of hydrogenation) as given in table 8 below. Table 8 shows that the respective mild Lewis acids either lead to poor ketone educt (benzylacetone) consumption or to high formation of the alcohol by-product.

table 8 compounds present in the reaction mixture after 8 h reaction time

Lewis acid Reaction time (h) Starting material (%) Alcohol (%)

Ti(OiPr)₄ 24 90 <5

Ti(OCH₃)₄ 8 <2 >20

Zr(OiPr)₄ 14 <2 >20

AI(OiPr)₃ 24 <2 >25

B(OiPr)₃ 8 <2 >25

B(OCH₃J₃ 8 <2 Example 9: Isolated yield data for the reductive amination of benzylacetone

α-MBA, Lewis acid HN ^Ph HN Ph OH

Ph ^ ^ Raney NI, H₂ (^β.3 bar)* _ph/\^\ ⁺ _Phr Ph" benzylacetone solvent major minor alcohol diastereomer diastereomer byproduct

Methanol (5.0 ml), benzylacetone (2.5 mmol), Bi(OAc)₃ (catalogue number # 401587), 10 mol%, relative to the ketone educt) and (S)-α-methylbenzylamine (1.1 equiv, relative to the ketone educt) were stirred for 2 h at room temperature. Raney Ni (100 wt % relative to the ketone educt) was added and the reaction pressurised with H₂ (8.3 bar/120 psi) for 10 h and then worked-up. Ketone and alcohol content of the reaction mixture were determined by gas chromatography before work-up. Purification by column chromatography provided at isolated yield of 87% of the secondary amine diastereomers in 80% de. All spectroscopic and chromatographic data matched that of the known enantiomeric compounds, see: Nugent et al. Organic Letters 2005 (7), 22, 4967-4970.

Example 10: Isolated yield data for the reductive amination of 2-octanone

Ph HN Ph OH ύ minor alcohol

er diastereomer byproduct

In a solvent mixture of tetrahydrofuran and methanol (1 :1, 5.0 ml total volume, anhydrous solvents used), 2-octanone (2.5 mmol), Yb(OAc)₃ (10 mol % relative to the ketone educt, catalog # 544973), and (S)-α-methylbenzylamine (1.1 equiv relative to the ketone educt) were stirred for 2 h at room temperature. Raney Ni (100 wt % relative to the ketone educt) was added and the reaction pressurized with H₂ (8.3 bar/120 psi). Table 10 shows that, after 18 h of hydrogenation, most of the ketone educt has been consumed and turned into (2R)- and (2S)-N-((S)-1- phenylethyl)octan-2-amine with high diastereomeric excess (de), high yield and low formation of the corresponding alcohol. Ketone and alcohol content of the reaction mixture were determined by gas chromatography before work-up. All spectroscopic and chromatographic data matched that of the known enantiomeric compounds, see: Nugent et al. Organic Letters 2005 (7), 22, 4967-4970.

Example 11 : Pinacolone with Pt/C

o α-MBA, Bi(OAc)₃ HN Ph HN Ph OH t-Bu X ^ Pt/C, H₂ (8.3 bar) I t-Bu t-Bu ^^" t-Bu I ^ pinacolone THF/MeOH, 30 h major minor alcohol diastereomer diastereomer byproduct Following the general procedure outlined for Table 1 using Bi(OAc)₃ (catalogue # 401587), with the noted exceptions of using anhydrous MeOH in higher concentration (0.8 M), prestirring the ketone, amine, solvent and Bi(OAc)₃ for 4 h at 50 ⁰C, then adding Pt/C (instead of Raney Ni) in four equal portions at t= 0, 6, 12, 2O h (total added Pt equals 1.0 mol %), with a total hydrogenation time of 30 h at 8.3 bar (120 psi) and at 50 ⁰C. Note all data was obtained from GC area % data. The product has been fully characterized .

Example 12: Production of selected amines

Table 12 shows a number of amines that can be produced in a method according to the invention. Table 12 further indicates corresponding ketone educts and nitrogen auxiliaries employed. The mild Lewis acid is preferably, indium (III), bismuth (III), antimony (III), ytterbium (III), yttrium (III), zinc (II), silver (I), copper (I), erbium (III), lead (Il or IV), gadolinium (III), and/or scandium (III), where the following Lewis acids have been particularly useful for the examples shown: indium (III) acetate, bismuth (III) acetate, ytterbium (III) acetate and scandium (III) acetate, each in partly hydrated or non-hydrated form. Diagram 1 shows interesting drug targets

Rivastigmine 13

Mexitil 18

Substance P antagonists 20

Repaglinide 19

Claims

1. Method for producing a primary, secondary or tertiary amine, comprising or consisting of the step of reductively aminating a ketone, preferably a methylketone, with a nitrogen auxiliary to produce the respective primary, secondary or tertiary amine, 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, the mild Lewis acid being present at the onset of the reductive amination in at most 25 mol% of the limiting reagent, preferably the ketone.

2. Method according to claim 1, wherein

the hydrogenating catalyst is a metal catalyst 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 metal catalysts or mixtures thereof.

3. Method according to any of claims 1 to 2, wherein the mild Lewis acid is

a) a metal alkoxide, in particular

a metal isopropoxide,

a metal methoxide or metal ethoxide,

c) a metal acetyl acetonate, a metal hexafluoroacetylacetonate,

d) a metal halogenide,

or a mixture of two or more members of the group.

4. Method according to any of claims 1 to 3, wherein the mild Lewis acid comprises as metal component, indium (III), bismuth (III), scandium (III), ytterbium (III), yttrium (III), copper (I), erbium (III), antimony (III), gadolinium (III), lead (IV), Zn(II), and silver (I).

5. Method according to any of claims 1 to 4, wherein the metal catalyst is (a) a Raney catalyst, in particular a Raney nickel metal catalyst, or (b) a Pt catalyst, or (c) a Pd/C catalyst.

6. Method according to any of claims 1 to 5, wherein the nitrogen auxiliary is a chiral nitrogen auxiliary, and preferably is present in the reaction in an enantiomeric excess (ee) of ≥ 70 %.

7. Method according to any of claims 1 to 6, wherein the nitrogen auxiliary is (R)-1 -methylbenzylamine or (S)-1 -methylbenzylamine.

8. Method according to any of claims 1 to 5, wherein the nitrogen auxiliary is (a) a nitrogen auxiliary without a chiral centre directly or less than one atom removed from being directly covalently attached to the nitrogen atom or (b) a nitrogen auxiliary that is racemic with respect to any chiral centre directly covalently attached to or no more than one atom removed from the nitrogen atom or (c) a nitrogen auxiliary which only has hydrogen covalently directly attached to the nitrogen atom, i.e. ammonia.

9. Method according to any of claims 1 to 8, wherein the ketone is of the form

O

R¹ R^

wherein moieties R1 and R2 are, independent from one another, a) alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylaryl, heteroalkenylarγl, heteroalkynylarγl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, and wherein b) moieties R1 and R2 may together form a ring, and wherein moieties Ri and R₂ are selected such that any aromatic group is separated from the reactive carboxy group by a bridge of at least one atom in length, with the proviso that the ketone is an aliphatic ketone.

10. Method according to any of claims 1 to 9, wherein the reaction is performed in a solvent, preferably a protic solvent other than water, and 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, ionic solvents or a mixture of two or more thereof.

11. Method according to any of claims 1 to 10, wherein the reaction is performed at a temperature from -10 °C to 100 °C and a pressure from 0.5 bar to 60 bar and a reaction time of up to 48 h.

12. Method for producing a primary or secondary, preferably chiral, amine product, comprising the steps of

a) performing a method according to any of claims 1 to 11 to form a respective primary, secondary or tertiary amine, and then

b) cleaving the remainder of the auxiliary, in the case of secondary and tertiary amines, from the amine of step a) to yield the primary or secondary amine product.