WO2015178847A1 - Process for the preparation of chiral amines by asymmetric hydrogenation of prochiral oximes - Google Patents

Process for the preparation of chiral amines by asymmetric hydrogenation of prochiral oximes Download PDF

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WO2015178847A1
WO2015178847A1 PCT/SE2015/050582 SE2015050582W WO2015178847A1 WO 2015178847 A1 WO2015178847 A1 WO 2015178847A1 SE 2015050582 W SE2015050582 W SE 2015050582W WO 2015178847 A1 WO2015178847 A1 WO 2015178847A1
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bis
ruci
cymene
previous
diphenylphosphino
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Per Ryberg
Robert Berg
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Sp Process Development Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/04—Formation or introduction of functional groups containing nitrogen of amino groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/40—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of hydroxylamino or oxyimino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/001—General concepts, e.g. reviews, relating to catalyst systems and methods of making them, the concept being defined by a common material or method/theory
    • B01J2531/002—Materials
    • B01J2531/007—Promoter-type Additives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/822—Rhodium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/827—Iridium

Definitions

  • the present invention relates to a process for the preparation of enantiomerically enriched chiral amines by asymmetric hydrogenation of prochiral oximes and oxime derivatives using a transition metal catalyst comprising an enantiomerically enriched chiral ligand, in a suitable solvent in presence of an additive.
  • the present invention relates to a method for the production of enantiomerically enriched chiral amines represented by the general formula (I)
  • 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)
  • 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 and S)-a-(dimethylamino)benzyl]ferrocene, ferrocenyl methyl, ferrocene, benzene and ethyl.
  • the method of the invention is carried out in the presence of a suitable additive and a suitable solvent using hydrogen gas as the reducing agent.
  • 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.
  • ligand is meant a group capable of binding with a transition metal.
  • Suitable oximes to be used in the method according to the invention are compounds according to the formula (III)
  • Rl and R2 are not the same and represent each independently an alkyi group which may be a straight chain alkyi group or which may be branched, and which alkyi 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, alkyi 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.
  • the additive is characterized by a compound or combination of compounds that has the effect of improving the enantioselectivity in the oxime reduction compared to when the reduction is carried out in the absence of the additive.
  • the additive can be either a neutral additive or an acid additive.
  • Examples of additives are represented by but not limited to: HCI, HBr, HI, ammonium chloride, ammonium bromide, ammonium iodide.
  • Preferred additives are HCI, HBr, ammonium chloride, ammonium bromide.
  • the amount of additive may be from 0.001-50 equivalents relative to the amount of oxime. Preferably 0.1 - 5 equivalents is used. Most preferred is 1-3 equivalents.
  • Suitable ligands L are represented by but not limited to atropisomeric biaryl- type ligands such as:
  • 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.
  • catalyst precursors examples include RuCI 3 , RuCI 3 .nH 2 0, [RuCI 2 (n ,6 -benzene)] 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,
  • the amount of catalyst may be in the range of 0.0001-0.1 mole equivalents relative to the amount of oxime. Preferable 0.001-0.03 equivalents is used.
  • 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 40 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.
  • solvent use can be made of: alcohols, esters, amides, ethers, hydrocarbons, halogenated hydrocarbons or mixtures thereof.
  • solvent use is made of methanol, ethanol and iso- propanol.
  • the amount of solvent may be in the range of 1-100 volumes relative to the amount of oxime. Preferably 3-30 volumes is used.
  • enantiomerically enriched amines may be obtained with an e.e. of of 75% or higher, in particular >80%, more in particular 85%.
  • an e.e. of >90% is obtained.
  • 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.
  • oximes which were used as substrates in the asymmetric hydrogenations were prepared from the corresponding commercially available ketones by reaction with hydroxylamine according to the procedure:
  • the reactions were carried out in small autoclaves that can be pressurized to 50 bar.
  • a 20mL glass vial is added lmmol of the oxime, 0,0125mmol of preformed catalyst, 3mmol NH 4 Br and 2mL Methanol.
  • the glass vial is put into the parallel autoclave 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.
  • Example 14-17 (example 17 was carried out in order to demonstrate the outcome when no additive is included)

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Abstract

There is provided a method for the preparation of an enantiomerically enriched amine by asymmetric hydrogenation of a prochiral oxime.

Description

Process for the preparation of chiral amines by asymmetric hydrogenation of prochiral oximes
The present invention relates to a process for the preparation of enantiomerically enriched chiral amines by asymmetric hydrogenation of prochiral oximes and oxime derivatives using a transition metal catalyst comprising an enantiomerically enriched chiral ligand, in a suitable solvent in presence of an additive.
Asymmetric hydrogenation of prochiral oximes have been described H. Alper and P. Krasik in Tetrahedron Asymmetry 1992, 1283-1288 who obtained up to 29% enantiomeric excess by using a Ru/Binap catalyst, and by A. S. C. Chan et al in J. Chem. Soc. Chem Commun, 1995, 1767-1768 who obtained up to 66% enantiomeric excess by using a Rh/Binap catalyst.
In addition Y. Jiang has described the asymmetric hydrogenation of prochiral a-ketoxime esters using Ir complexes with enantiomerically enriched diphosphine providing the corresponding a-amino ester in up to 93% enantiomeric excess albeit in low conversion (19%), Synthetic Communications, 2001, 2767-2771.
These examples represent the prior art and there is a need for improvement in order to make asymmetric oxime hydrogenation practically useful for the production of
enantiomerically enriched chiral amines in high yield and enantiomeric excess.
It has now been found as described in the present invention that the addition of certain additives to the reaction mixture can have a dramatic influence on the enantioselectivity in the reaction such that high enantioselectivities in the range of 80-98% can be obtained. Thus the present invention relates to a method for the production of enantiomerically enriched chiral amines represented by the general formula (I)
Figure imgf000002_0001
Formula (I) by asymmetric hydrogenation of prochiral oximes and oxime derivatives in presence of an additive 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)
R1v :, \, ,^3
R2 R4
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 and S)-a-(dimethylamino)benzyl]ferrocene, ferrocenyl methyl, ferrocene, benzene and ethyl.
The method of the invention is carried out in the presence of a suitable additive and 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 oximes to be used in the method according to the invention are compounds according to the formula (III)
Figure imgf000003_0001
In which formula (III) Rl and R2 are not the same and represent each independently an alkyi group which may be a straight chain alkyi group or which may be branched, and which alkyi 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, alkyi 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.
The additive is characterized by a compound or combination of compounds that has the effect of improving the enantioselectivity in the oxime reduction compared to when the reduction is carried out in the absence of the additive. The additive can be either a neutral additive or an acid additive. Examples of additives are represented by but not limited to: HCI, HBr, HI, ammonium chloride, ammonium bromide, ammonium iodide. Preferred additives are HCI, HBr, ammonium chloride, ammonium bromide. The amount of additive may be from 0.001-50 equivalents relative to the amount of oxime. Preferably 0.1 - 5 equivalents is used. Most preferred is 1-3 equivalents.
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-benzodioxole,
(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'-biphenyl,
(S)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-l,l'-biphenyl,
(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'-bi-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 RuCI3, RuCI3.nH20, [RuCI2(n,6-benzene)]2,
[RuCI2(n,6-cymene)]2, [RuCI2(n,6-mesitylene)]2, [RuCI2(n,6-hexamethylbenzene)]2, [RuBr2(r|6- benzene)]2, [Rul2(n.6-benzene)]2, trans-RuCI2(DMSO)4, RuCI2(PPh3)3,RuCI2(COD), (in which COD=l,5-cyclooctadiene), Ru(COD)(methylallyl)2, Ru(COD)(trifluoroacetat)2, [lr(COD)CI]2, Rh(COD)CI, Rh(COD)2BF4, Rh(COD)2(OTf)2. Preferred catalyst precursors are represented by but not limited to [RuCI2(n,6-benzene)]2, [RuCI2(n,6-cymene)]2, RuCI2(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)CI2,
Ru(L)CI2.DMFn.
The amount of catalyst may be in the range of 0.0001-0.1 mole equivalents relative to the amount of oxime. Preferable 0.001-0.03 equivalents is used.
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 40 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. The amount of solvent may be in the range of 1-100 volumes relative to the amount of oxime. Preferably 3-30 volumes is used. Using the process of the invention enantiomerically enriched amines may be obtained with an e.e. of 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.
The oximes which were used as substrates in the asymmetric hydrogenations were prepared from the corresponding commercially available ketones by reaction with hydroxylamine according to the procedure:
A mixture of the ketone (1 equivalent), hydroxylamine hydrochloride (1,1 equivalents) and sodium acetate (1,1 equivalents) in methanol (5-7.5 rel. volumes) is heated at reflux until the reaction was complete (as monitored by TLC) usually after 2-5h. The reaction mixture is cooled to room temperature and poured into ice/water (25 rel volumes). The solid thus formed is isolated by filtration, washed with water and dried under reduced pressure at 30 °C. The identity of the oximes were confirmed by 1H NMR and they were used without any further purification.
Example 1-13
General procedure for the asymmetric hydrogenation of oximes using ammonium bromide as the additive. All manipulations were done under an atmosphere of nitrogen. The methanol was 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, 0,0125mmol of preformed catalyst, 3mmol NH4Br and 2mL Methanol. The glass vial is put into the parallel autoclave 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 MgS04, filtered and concentrated under vacuum to afford the amine product in 83-97% yield. The products were analyzed by chiral HPLC and 1H and 13C NMR spectroscopy and were in accordance with authentic samples.
Figure imgf000007_0001
roxylamine
(a.k.a. 3',4'-di-fluoro- acetophenone oxime)
8 N-[l-(naphthalen-2- RuCI(Cymene)(S-Binap)CI 96 83 yl)ethylidene]hydroxylamine
(a.k.a. 2-acetonaphtone
oxime)
9 N- RuCI(Cymene)(S-Binap)CI 92 97
[cyclohexyl(phenyl)methyliden
e]hydroxylamine
(a.k.a. Phenylcyclohexylketone
oxime)
10 N-(l- RuCI(Cymene)(S-Binap)CI 94 98 phenylpropylidene)hydroxyla
mine
(a.k.a. Propiophenone oxime)
11 N-(l- RuCI(Cymene)(S-Xyl- Not 95 phenylpropylidene)hydroxyla Segphos)CI determined mine
12 N-[l-(4- RuCI(Cymene)(S-Binap)CI 97 96 chlorophenyl)propylidene]hydr
oxylamine
(a.k.a. 4'CI-propiophenone
oxime)
13 N-{l-[4- RuCI(Cymene)(S-Binap)CI 96 96
(benzyloxy)phenyl]propylidene
}hydroxylamine
(a.k.a. 4Benzyloxy- propiophenone oxime)
Example 14-17 (example 17 was carried out in order to demonstrate the outcome when no additive is included)
1 equivalent of N-[l-(3-bromophenyl)ethylidene]hydroxylamine, 5mol% RuCI(Cymene)(S-tol- Binap)CI, 5 equivalents additive and 70 volumes of methanol (relative to the amount of oxime) were added in glass vials which were inserted into a parallel autoclave. The autoclave was pressurized to 30 bar with hydrogen and heated to 90°C for 24 hours and then cooled to 20°C. The reaction mixtures were diluted with iso-propanol and analyzed by chiral HPLC. example additive Ee (%) Conversion(%)
14 NH4CI 80 100
15 NH4Br 80 100
16 HCI 95 100
17 (reference No additive 3 95
experiment to
demonstrate the
effect of not adding
any additive)

Claims

Claims
1. A method for the preparation of an enantiomerically enriched amine of general formula (I)
Figure imgf000010_0001
Formula (I) by asymmetric hydrogenation of a prochiral oxime of the general formula (III)
Figure imgf000010_0002
Formula (III) in which formulas (I) and (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 or
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,
wherein said method is performed in the presence of:
a) an additive (AD) comprising at least one acid and/or ammonium salt of an acid;
b) a solvent; and
c) a transition metal catalyst comprising a transition metal selected from Ru, Rh, Ir and Pd and a ligand comprising an enantiomerically enriched chiral bidentate phosphor containing ligand of the general formula (II)
Figure imgf000010_0003
R2 R4
Formula (II) in which formula (II) A is a linking group and Rl, R2, R3 and R4 may be the same or different.
2. Method according to claim 2 wherein the transition metal catalyst is comprising Ru, Rh or Ir, preferably Ru.
3. Method according to claim 2 wherein the catalyst is a Ru complex of an
enantiomerically enriched atropisomeric biaryl-type ligand.
4. Method according to any one of claims 1-3 wherein the ligand is selected from
(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-benzodioxole,
(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'-biphenyl,
(S)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-l,l'-biphenyl,
(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'-bi-l,3-benzodioxole, and (S)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-l,3-benzodioxole.
5. Method according to any of the previous claims wherein the transition metal catalyst is formed in-situ by adding a catalyst precursor and ligand directly to the reaction vessel.
6. Method according to any of the previous claims wherein the solvent is selected from alcohols, ethers, esters, amides, hydrocarbons, halogenated hydrocarbons and mixtures thereof and which solvent preferably is an alcohol or a mixture of an alcohol and an ether, ester, amide, hydrocarbon or halogenated hydrocarbon where the alcohol content is in the range of 10-100%.
7. Method according to any of the previous claims wherein the solvent is methanol or a mixture of methanol and an ether, ester, amide, hydrocarbon or halogenated hydrocarbon where the methanol content is in the range of 10-100%.
8. Method according to any of the previous claims wherein the additive is HCI, HBr, HI, NH4CI, NH4Br or NH4I .
9. Method according to any of the previous claims wherein the additive is HCI, NH4CI or NH4Br.
10. Method according to any of previous claims wherein the amount of the additive is in the range of 0.01-30 mole equivalents relative to the oxime.
11. Method according to any of the previous claims wherein the amount of the additive is in the range of 0.1-5 equivalents.
12. Method according to any of the previous claims wherein the amount of solvent is in the range of 1-100 volumes relative to the amount of oxime.
13. Method according to any of the previous claims wherein the amount of solvent is in the range of 5-20 volumes relative to the amount of oxime.
14. Method according to any of the previous claims wherein the hydrogen pressure is between 1 and 500 bar, such as between 1 and 400 bar, such as between 1 and 200 bar.
15. Method according to any of the previous claims wherein the hydrogen pressure is in the range of 3-50 bar.
16. A Method according to any of the previous claims wherein the reaction temperature is between 20°C and 150°C.
17. Method according to any of the previous claims wherein the temperature is between 50°C and 120°C.
18. Method according to any of the previous claims wherein the temperature is between 70°C and 110°C.
19. Method according to any of the previous claims wherein the amount of the catalyst is in the range of 0.0001-0.1 mole equivalents relative to the amount of oxime.
20. Method according to any of the previous claims wherein the amount of catalyst is in the range of 0.001-0.03 mole equivalents relative to the amount of oxime.
21. A method according to any one of the previous claims, wherein the linking group is (R or S)- Ι,Ι'-binaphtyl, (R or S)- 4,4'-bi-l,3-benzodioxole, (R or S)- 2,2',6,6'- tetramethoxy-3,3'-bipyridine, (R or S)- 6,6'-dimethoxy-l,l'-biphenyl, (R or S)- 4,4',6,6'-tetramethoxy-l,l'-biphenyl, 2,2'-bis-[(R or S)-a-
(dimethylamino)benzyl]ferrocene, ferrocenyl methyl, ferrocene, benzene or ethyl.
22. A method according to any one of the previous claims, wherein the transition metal catalyst is selected from the group consisting of RuCI(Cymene)(R-Tunephos)CI, RuCI(Cymene)(S-Binap)CI, RuCI(Cymene)(S-tol-Binap)CI, RuCI(Cymene)(S-H8-Binap)CI, RuCI(Cymene)(S-DTBM-Segphos)CI, RuCI(Cymene)(S-Xyl-Segphos)CI, RuCI(Cymene)(S- Tunephos)CI, RuCI(Cymene)(R-Binap)CI, RuCI(Cymene)(R-tol-Binap)CI, RuCI(Cymene)(R-H8-Binap)CI, RuCI(Cymene)(R-DTBM-Segphos)CI and RuCI(Cymene)(R-Xyl-Segphos)CI.
23. A method according to any one of the previous claims, wherein the transition metal catalyst is selected from the group consisting of RuCI(Cymene)(R-Tunephos)CI, RuCI(Cymene)(S-Binap)CI, RuCI(Cymene)(S-tol-Binap)CI, RuCI(Cymene)(S-H8-Binap)CI, RuCI(Cymene)(S-DTBM-Segphos)CI and RuCI(Cymene)(S-Xyl-Segphos)CI.
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Cited By (1)

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CN109400493A (en) * 2017-08-15 2019-03-01 成都博腾药业有限公司 Sha Ku is than bent and its intermediate preparation method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KRASIK, P. ET AL.: "The ruthenium catalyzed asymmetric hydrogenation of oximes using binap as the chiral ligand", TETRAHEDRON : ASYMMETRY, vol. 3, no. 10, pages 1283 - 1288, XP002476739, ISSN: 0957-4166 *
NUGENT, T. C. ET AL.: "Chiral Amine Synthesis - Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction", ADV. SYNTH. CATAL., vol. 352, 2010, pages 753, XP055238027, ISSN: 1615-4169 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109400493A (en) * 2017-08-15 2019-03-01 成都博腾药业有限公司 Sha Ku is than bent and its intermediate preparation method
CN109400493B (en) * 2017-08-15 2021-07-09 成都博腾药业有限公司 Preparation method of Sacubitril and intermediate thereof

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