The present invention relates to a process for the preparation of enantiomerically enriched chiral amines by reacting a prochiral ketone with an ammonium salt and hydrogen in presence of a transition metal catalyst comprising an enantiomerically enriched chiral ligand, and ammonia in a solvent with a small amount of water present.

The present invention relates to a method for the production of enantiomerically enriched chiral amines represented by the general formula (I)

Formula (I) by reacting a mixture of a prochiral ketone, an ammonium salt, ammonia and hydrogen using a transition metal catalyst comprising a transition metal selected from the group Ru, Rh, Ir and Pd and a chiral ligand. In one embodiment, the transition metal is Ru, Rh or Ir. Ru is a preferred transition metal. The ligand is an enantiomerically enriched chiral bidentate phosphor containing ligand of the general formula (II)

Formula (II)

In which formula (II) A is a linking group and Rl, R2, R3 and R4 can be the same or different. Rl, R2, R3 and R4 can represent each independently an alkyi group which alkyi group can be branched or cyclic, or an aryl group which aryl group can be substituted.

The linking group may for example be selected from the group consisting of (R and S)- 1,1'- binaphtyl, (R and S)- 4,4'-bi-l,3-benzodioxole, (R and S)- 2,2',6,6'-tetramethoxy-3,3'- bipyridine, (R and S)- 6,6'-dimethoxy-l,l'-biphenyl, (R and S)- 4,4',6,6'-tetramethoxy-l,l'- biphenyl, 2,2'-bis-[(R)-a-(dimethylamino)benzyl]ferrocene, ferrocenyl methyl, ferrocene, benzene and ethyl.

The method of the invention is carried out in a suitable solvent using hydrogen gas as the reducing agent. The term enantiomerically enriched means that one of the enantiomers of the compound is present in excess in comparison to the other enantiomer. This excess will hereafter be referred to as enantiomeric excess or e.e. The e.e. may be determined by chiral GC or HPLC analysis. The e.e. is equal to the difference between amounts of enantiomers divided by the sum of the amounts of the enantiomers, which quotient can be expressed as a percentage after multiplication with 100.

With the term ligand is meant a group capable of binding with a transition metal.

Suitable ketones to be used in the method according to the invention are compounds according to the formula (III)

In which formula (III) Rl and R2 are not the same and represent each independently an alkyl group which may be a straight chain alkyl group or which may be branched, and which alkyl group optionally comprises one or more heteroatoms and which heteroatom optionally is substituted, an aryl group which aryl group optionally comprises one or more heteroatoms and which aryl group is optionally substituted, an alkenyl group or alkynyl group which may be a straight chain alkenyl or alkynyl group or which may be branched, and which alkenyl or alkynyl group comprises one or more heteroatoms, or Rl and R2 can together represent a ring structure, which ring structure may optionally contain one or more hetero atoms and which ring structure may also be substituted.

Suitable substituents are for example halides, alkoxy, aryloxy, esters, amines, aromatic groups, alkyl groups. It will be clear to a person skilled in the art that the substituents may themselves be substituted and may comprise heteroatoms. Typical heteroatoms that may be present are N, O, S and P. The number of atoms in Rl and R2 may vary. Typically Rl and r2 each comprise not more than 40 carbon atoms. Usually they comprise between 1 and 30 carbon atoms.

In one embodiment, the ketone is chiral in the a-position according to formula (IV).

In such an embodiment, the ketone according to formula (IV) undergoes continuous racemization under the reaction conditions whereas one of the ketone enantiomers is converted to the amine product according to formula (V) at a higher rate than the other such that both enantiomers of the ketone starting material are converted to the amine product according to formula (V) with high enantiomeric and diastereomeric excess.

Examples of suitable ammonium salts are represented by but not limited to: ammonium chloride, ammonium bromide, ammonium iodide. The amount of the ammonium salt may be from 1-50 equivalents relative to the amount of ketone. Preferably 3 - 15 equivalents is used.

In another aspect of the invention the ammonium salt is generated in situ by adding ammonia and the appropriate acid to the reaction vessel.

The amount of ammonia may be from 0.01-10 mole equivalents in relation to the ketone. Preferably 0.1-5 mole equivalents are used.

Yet another aspect of the invention involves a procedure where the ammonia is generated in-situ from the ammonium salt by addition of a suitable base. Such a base may be represented by but not limited to sodium hydroxide and triethylamine.

The amount of water in the reaction may be from 0.1-10% relative to the amount of solvent used. Preferred is 0.2-2% or 0.5-2%.

Examples of suitable ligands L are represented by but not limited to atropisomeric biaryl- type ligands such as:

(R)-2,2'-bis(diphenylphosphino)-l,l'-binaphtyl,

(S)-2,2'-bis(diphenylphosphino)-l,l'-binaphtyl,

(R)-2,2'-bis(di-p-tolylphosphino)-l,l'-binaphtyl,

(S)-2,2'-bis(di-p-tolylphosphino)-l,l'-binaphtyl,

(R)-2,2'-bis[di(3,5-xylyl)phosphino]-l,l'-binaphtyl,

(S)-2,2'-bis[di(3,5-xylyl)phosphino]-l,l'-binaphtyl,

(R)-5,5'-bis(diphenylphosphino)-4,4'-bi-l,3-benzodioxole,

(S)-5,5'-bis(diphenylphosphino)-4,4'-bi-l,3-benzodioxole,

(S)-5,5'-bis(di[3,5-xylyl]phosphino)-4,4'-bi-l,3-benzodioxol e,

(R)-5,5'-bis(di[3,5-di-t-butyl-4methoxyphenyl]phosphino)-4,4 '-bi-l,3-benzodioxole,

(S)-5,5'-bis(di[3,5-di-t-butyl-4methoxyphenyl]phosphino)- 4,4'-bi-l,3-benzodioxole,

(R)-l,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f, h] [l,5]dioxin,

(S)-l,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][ l,5]dioxin,

(R)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'- bipyridine,

(S)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'- bipyridine,

(R)-2,2',6,6'-tetramethoxy-4,4'-bis(di[3,5-xylyl]phosphino)- 3,3'-bipyridine, (S)-2,2^6,6'-tetramethoxy-4,4'-bis(di[3,5-xylyl]phosphino)-3 ,3'-bipyridine,

(R)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-l,l'-biphenyl ,

(S)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-l,l'-biphenyl ,

(R)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-l,l'-biphe nyl,

(S)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-l,l'-biphe nyl,

(R)-6,6'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-5,5'-bi -l,4-benzodioxin,

(S)-6,6'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-5,5'-bi -l,4-benzodioxin,

(R)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-b i-l,3-benzodioxole,

(S)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4 '-bi-l,3-benzodioxole. or ligands from classes represented by the trivial names: Josiphos, walphos, mandyphos, taniaphos, Duphos, BDPP, duanphos type ligands.

Most preferred ligands are atropisomeric biaryl-type ligands.

The catalyst suitable for use in the invention may consist of a preformed complex. These complexes may be formed by reacting the ligand with a suitable catalyst precursor. The complex thus obtained may be used as the catalyst of the invention. The catalyst precursor contains at least the metal M. The precursor may contain ligands that are easily displaced by the ligand L or it may contain a ligand that is easily removed by hydrogenation.

Another aspect of the invention involves a process where the catalyst is formed in-situ by adding the ligand and catalyst precursor to the reaction vessel.

Examples of suitable catalyst precursors are RuCI ₃ , RuCI ₃ .nH ₂ 0, [RuCI ₂ (n _,6 -benzene)] ₂ ,

[RuCI ₂ (n _,6 -cymene)] ₂ , [RuCI ₂ (n _,6 -mesitylene)] ₂ , [RuCI ₂ (n _,6 -hexamethylbenzene)] ₂ , [RuBr ₂ (r| ₆ - benzene)] ₂ , [Rul ₂ (n. ₆ -benzene)] ₂ , trans-RuCI ₂ (DMSO) ₄ , RuCI ₂ (PPh ₃ ) ₃ ,RuCI ₂ (COD), (in which COD=l,5-cyclooctadiene), Ru(COD)(methylallyl) ₂ , Ru(COD)(trifluoroacetat) ₂ , [lr(COD)CI] ₂ , Rh(COD)CI, Rh(COD) ₂ BF ₄ , Rh(COD) ₂ (OTf) ₂ . Preferred catalyst precursors are represented by but not limited to [RuCI ₂ (n _,6 -benzene)] ₂ , [RuCI ₂ (n _,6 -cymene)] ₂ , RuCI ₂ (COD), (in which COD=l,5- cyclooctadiene), Ru(COD)(methylallyl) ₂ , Ru(COD)(trifluoroacetat) ₂ .

Examples of fully prepared pre-catalysts/ligand complexes of the invention are represented by but not limited to RuCI(benzene)(L)CI, RuCI(cymene)(L)CI, RuCI(mesitylene)(L)CI,

RuCI(hexamthylbenzene)(L)CI, Ru(L)(acetate) ₂ , Ru(L)(trifluoroacetate)2, Ru(L)CI ₂ ,

Ru(L)CI ₂ .DMFn.

The amount of catalyst may be in the range of 0.0001-0.1 mole equivalents relative to the ketone. Preferred is 0.005-0.05 mole equivalents.

The method of the invention takes place in the presence of hydrogen gas. The hydrogen pressure may be between 1 bar and 500 bar, such as between 1 bar and 400 bar, such as between 1 bar and 200 bar, but preferably between 3 bar and 50 bar. The temperature at which the asymmetric hydrogenation is carried out is generally a compromise between reaction velocity and enantioselectivity, and preferably lies between 0°C and 150°C, more preferably between 50°C and 120°C.

As solvent use can be made of: alcohols, esters, amides, ethers, hydrocarbons, halogenated hydrocarbons or mixtures thereof. Preferably use is made of methanol, ethanol and iso- propanol.

Using the process of the invention enantiomerically enriched amines may be obtained with an e.e. of 75% or higher, in particular >80%, more in particular 85%. Preferably an e.e. of >90% is obtained.

In this text, for aspects of the method according to the invention preferred ranges, compositions or embodiments have been described. The invention explicitly covers the combination of each preferred feature or each embodiment individually with the method according to claim 1, and also by possible combination of preferred features. The invention will be elucidated with reference to the following examples, without however being restricted by these:

Examples: General.

Reaction yields in % were determined as: yield (%) = 100* (weight of product/molecular mass of product)/(weight of starting material/molecular mass of starting material)

Enantiomeric purity of the amine products were determined by chiral HPLC analysis on a Chiralpack OD-H 4.6x250mm column using iso-hexane/iso-propanol/diethylamine in 90:10:0.1 ratio.

The catalysts complexes used in the asymmetric hydrogenation experiments were all commercially available and purchased from suppliers.

Examples 1-12

General procedure for the asymmetric reductive amination using ammonium chloride as the ammonium salt.

All manipulations were done under an atmosphere of nitrogen. The methanol and water were deoxygenated by 5 vacuum/nitrogen cycles prior to use.

The reactions were carried out in small autoclaves that can be pressurized to 50 bar. To a 20mL glass vial is added lmmol of the oxime, 0,025mmol of preformed catalyst, lOmmol N H4CI and 2mL degassed methanol, lmmol NH ₃ (added as a 7M solution in methanol) and 20μΙ_ water. The glass vial is put into the parallel autoclave under an atmosphere of nitrogen gas and 40 bar of hydrogen is applied and the autoclave is heated to 90°C and agitated. After 48 hours the autoclave is cooled to 20°C and then the hydrogen pressure is released. The methanol is evaporated off and NaOH(aq) is added to the residue to pH>ll. The mixture is extracted with diethylether. The combined ether fractions are dried over MgS0 ₄ , filtered and concentrated under vacuum to afford the amine product. The products were analyzed by chiral HPLC and ¹ H and ¹³ C NMR spectroscopy and were in accordance with authentic samples.

Examples 13-22

Small scale reactions using various ligands.

The reactions were carried out according to the procedure described above but at smaller scale.

19 Propiophenone RuCI(Cymene)(R-Segphos)CI 96

20 Propiophenone RuCI(Cymene)(R-Tunephos)CI 95

21 Propiophenone RuCI(Cymene)(S-Xyl-Segphos)CI 97

22 Propiophenone RuCI(Cymene)(S-H8-Binap)CI 93

Examples 23-24

Small scale reactions using a Josiphos and a Mandyphos ligand and ammonium acetate as ammonium source.

The reactions were carried out according to the procedure described for examples 1-12 above but with the difference that the catalyst was formed by adding a solution of the desired amount of Ru(cod)TFA ₂ in methanol to the ligand in 1:1 ratio and heating to 50°C until a clear solution was obtained. The solution was then added to a vial containing the ketone, ammonium acetate, water and NH ₃ in methanol.

Example 25

Enantio- and diastereoselective reductive amination of a-chiral ketones via dynamic kinetic resolution.

The racemic ketone (IV) was reacted under conditions described for example 1-12 above but using RuCI(Cymene)(S-Xyl-Binap)CI as catalyst to give conversion of both enantiomers of the ketone (VI) to the product (VII) with 97% enantiomeric excess and 15:1 diastereomer ratio as determined by ¹ H NMR spectroscopy.