WO2015178846A1 - Process for the preparation of chiral amines from prochiral ketones - Google Patents

Process for the preparation of chiral amines from prochiral ketones Download PDF

Info

Publication number
WO2015178846A1
WO2015178846A1 PCT/SE2015/050581 SE2015050581W WO2015178846A1 WO 2015178846 A1 WO2015178846 A1 WO 2015178846A1 SE 2015050581 W SE2015050581 W SE 2015050581W WO 2015178846 A1 WO2015178846 A1 WO 2015178846A1
Authority
WO
WIPO (PCT)
Prior art keywords
bis
ruci
cymene
diphenylphosphino
previous
Prior art date
Application number
PCT/SE2015/050581
Other languages
French (fr)
Inventor
Per Ryberg
Robert Berg
Original Assignee
Sp Process Development Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sp Process Development Ab filed Critical Sp Process Development Ab
Publication of WO2015178846A1 publication Critical patent/WO2015178846A1/en

Links

Classifications

    • 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
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
    • B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
    • 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
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • B01J2531/80—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
    • B01J2531/824—Palladium
    • 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
    • B01J2531/828—Platinum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • 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.
  • 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)-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.
  • 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 ketones 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 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.
  • the ketone is chiral in the a-position according to formula (IV).
  • 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.
  • 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.
  • 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.
  • a suitable 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%.
  • 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 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.
  • 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.
  • 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.
  • 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 reactions were carried out in small autoclaves that can be pressurized to 50 bar.
  • a 20mL glass vial is added lmmol of the oxime, 0,025mmol of preformed catalyst, lOmmol N H4CI and 2mL degassed methanol, lmmol NH 3 (added as a 7M solution in methanol) and 20 ⁇ _ 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.
  • 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.

Abstract

There is provided a method for the preparation of an enantiomerically enriched amine from a prochiral ketone.

Description

Process for the preparation of chiral amines from prochiral ketones
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)
Figure imgf000002_0001
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)
Figure imgf000002_0002
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)
Figure imgf000003_0001
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).
Figure imgf000003_0002
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.
Figure imgf000004_0001
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-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 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 NH3 (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 MgS04, filtered and concentrated under vacuum to afford the amine product. The products were analyzed by chiral HPLC and 1H and 13C NMR spectroscopy and were in accordance with authentic samples.
Figure imgf000007_0001
Examples 13-22
Small scale reactions using various ligands.
The reactions were carried out according to the procedure described above but at smaller scale.
Figure imgf000007_0002
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)TFA2 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 NH3 in methanol.
Figure imgf000008_0002
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 1H NMR spectroscopy.
Figure imgf000008_0001

Claims

Claims
1. A method for the preparation of an enantiomerically enriched amine of general formula (I)
Figure imgf000009_0001
Formula (I) from a prochiral ketone of the general formula (III)
Figure imgf000009_0002
Formula (III) in which formulas (I) and (II) 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 by reacting, in the presence of hydrogen gas, said prochiral ketone with a mixture of
a) an ammonium salt,
b) ammonia in a solvent (S), said mixture further containing a small amount of water in the range of 0.001-0.1 volumes relative to the amount of 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 imgf000009_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. A method according to claim 1 where the transition metal of the catalyst is Ru, Rh or Ir, preferably Ru.
3. A method according to claims 1-2 where the catalyst is a Ru complex with an
enantiomerically enriched atropisomeric biaryl-type ligand.
4. A method according to any of claims 1-3 in which 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. A method for the asymmetric hydrogenation of prochiral ketone according to any of the previous claims where the transition metal catalyst is formed in-situ by adding a catalyst precursor and ligand directly to the reaction vessel.
6. A method according to any of claims 1-5 where the amount of catalyst is in the range of 0.0001-0.1 mole equivalents relative to the ketone.
7. A method according to any of claims 1-5 where the amount of catalyst is in the range of 0.005-0.05 mole equivalents relative to the ketone.
8. A method according to any of claims 1-7 where the solvent is selected from the group consisting of alcohols, esters, amides, ethers, hydrocarbons, halogenated hydrocarbons or mixtures thereof and which solvent preferably is an alcohol or a mixture of an alcohol and an ether, ester, amide, hydrocarbon or halogenated hydrocarbon.
9. A method according to any of the previous claims where the solvent is methanol.
10. A method according to any of claims 1-9 where the ammonium salt is NH4CI, NH4Br or NH4I.
11. A method according to claim 10 where the ammonium salt is NH4CI or NH4Br.
12. A method according to any of the previous claims where the amount of the
ammonium salt is in the range of 1-50 mole equivalents relative to the ketone.
13. A method according to claim 12 where the amount of the ammonium salt is in the range of 3-15 mole equivalents relative to the ketone.
14. A method according to any of the previous claims where the ammonium salt is
generated in-situ from ammonia and HCI or HBr.
15. A method according to any of the previous claims where the amount of ammonia is in the range of 0.01-20 mole equivalents.
16. A method according to claim 15 where the amount of ammonia is in the range of 0.5- 5 mole equivalents.
17. A method according to any of the previous claims where the ammonia is generated in-situ from the ammonium salt by addition of a base.
18. A method according to any of the previous claims where the hydrogen pressure is between 1 and 500 bar, such as between 1 and 400 bar, such as between 1 and 200 bar.
19. A method according to any of the previous claims where the hydrogen pressure is in the range of 3-50 bar.
20. A method according to any of the previous claims where the reaction temperature is between 20°C and 150°C.
21. A method according to any of the previous claims where the temperature is between 50°C and 120°C.
22. A method according to any of the previous claims where the ketone is chiral in the xposition and the amine has the formula (V)
Figure imgf000011_0001
wherein R' and R" are not the same.
23. A method according to any one of the previous claims, wherein the linking group is 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.
24. A method according to any one of the previous claims, wherein the transition metal catalyst is selected from the group consisting of RuCI(Cymene)(S-tol-Binap)CI, RuCI(Cymene)(S-Binap)CI, RuCI(Cymene)(R-Segphos)CI, RuCI(Cymene)(R-Tunephos)CI, RuCI(Cymene)(S-Xyl-Segphos)CI, RuCI(Cymene)(S-H8-Binap)CI, RuCI(Cymene)(R-tol- Binap)CI, RuCI(Cymene)(R-Binap)CI, RuCI(Cymene)(S-Segphos)CI, RuCI(Cymene)(S- Tunephos)CI, RuCI(Cymene)(R-Xyl-Segphos)CI and RuCI(Cymene)(R-H8-Binap)CI.
25. A method according to any one of the previous claims, wherein the transition metal catalyst is selected from the group consisting of RuCI(Cymene)(S-tol-Binap)CI, RuCI(Cymene)(S-Binap)CI, RuCI(Cymene)(R-Segphos)CI, RuCI(Cymene)(R-Tunephos)CI, RuCI(Cymene)(S-Xyl-Segphos)CI and RuCI(Cymene)(S-H8-Binap)CI.
PCT/SE2015/050581 2014-05-20 2015-05-20 Process for the preparation of chiral amines from prochiral ketones WO2015178846A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE1450595 2014-05-20
SE1450595-2 2014-05-20

Publications (1)

Publication Number Publication Date
WO2015178846A1 true WO2015178846A1 (en) 2015-11-26

Family

ID=54554387

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2015/050581 WO2015178846A1 (en) 2014-05-20 2015-05-20 Process for the preparation of chiral amines from prochiral ketones

Country Status (1)

Country Link
WO (1) WO2015178846A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106397217A (en) * 2016-09-04 2017-02-15 王际菊 Method for synthesizing dextral alpha-cyclohexylbenzylamine
EP3301087A1 (en) * 2016-09-30 2018-04-04 DPx Fine Chemicals Austria GmbH & Co KG Process for preparing chiral amines
WO2019096860A1 (en) * 2017-11-16 2019-05-23 Syngenta Participations Ag Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1078915A1 (en) * 1999-08-27 2001-02-28 Johnson Matthey Public Limited Company Reductive amination process using a homogeneous iridium catalyst
US6884887B1 (en) * 1999-07-17 2005-04-26 Degussa Ag Method for producing amines by homogeneously catalyzed reductive amination of carbonyl compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6884887B1 (en) * 1999-07-17 2005-04-26 Degussa Ag Method for producing amines by homogeneously catalyzed reductive amination of carbonyl compounds
EP1078915A1 (en) * 1999-08-27 2001-02-28 Johnson Matthey Public Limited Company Reductive amination process using a homogeneous iridium catalyst

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BUNLAKSANANUSORN, T. ET AL.: "A Facile One-Pot Synthesis of Chiral b-Amino Esters", SYNLETT, 2005, pages 2682 - 268417, XP055238516, ISSN: 1437-2096 *
STEINHUEBEL, D. ET AL.: "Direct Asymmetric Reductive Amination", J AM CHEM SOC, vol. 131, 2009, pages 11316 - 11317, XP002645235, ISSN: 1520-5126 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106397217A (en) * 2016-09-04 2017-02-15 王际菊 Method for synthesizing dextral alpha-cyclohexylbenzylamine
EP3301087A1 (en) * 2016-09-30 2018-04-04 DPx Fine Chemicals Austria GmbH & Co KG Process for preparing chiral amines
WO2018060512A1 (en) * 2016-09-30 2018-04-05 Patheon Austria Gmbh & Co Kg Process for preparing chiral amines
WO2019096860A1 (en) * 2017-11-16 2019-05-23 Syngenta Participations Ag Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides
CN111417618A (en) * 2017-11-16 2020-07-14 先正达参股股份有限公司 Process for preparing enantiomerically and diastereomerically enriched cyclobutaneamines and cyclobutaneamides
JP2021503470A (en) * 2017-11-16 2021-02-12 シンジェンタ パーティシペーションズ アーゲー Method for preparing cyclobutaneamines and amides enriched enantiomerically and diastereomerically
US11053188B2 (en) 2017-11-16 2021-07-06 Syngenta Participations Ag Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides
TWI787391B (en) * 2017-11-16 2022-12-21 瑞士商先正達合夥公司 Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides
AU2018367119B2 (en) * 2017-11-16 2023-05-11 Syngenta Participations Ag Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides
IL274654B1 (en) * 2017-11-16 2023-07-01 Syngenta Participations Ag Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides
JP7337797B2 (en) 2017-11-16 2023-09-04 シンジェンタ パーティシペーションズ アーゲー Process for the preparation of enantiomerically and diastereomerically enriched cyclobutanamines and amides

Similar Documents

Publication Publication Date Title
Xie et al. Transition metal-catalyzed enantioselective hydrogenation of enamines and imines
Mantilli et al. Platinum metals in the catalytic asymmetric isomerization of allylic alcohols
EP2294075B1 (en) Novel ruthenium complexes having hybrid amine ligands, their preparation and use
JP5685071B2 (en) Novel ruthenium complex and method for producing optically active alcohol compound using the same as catalyst
EP1451133B1 (en) P-chiral phospholanes and phosphocyclic compounds and their use in asymmetric catalytic reactions
KR100384411B1 (en) Chiral ligand in heteroaromatic diphosphine
KR101245065B1 (en) Hydrogenation of imines
US6451727B2 (en) Catalysts for use in asymmetric synthesis comprising transition metals and chiral amine oxazolinyl ligands
WO2018060512A1 (en) Process for preparing chiral amines
CA2414049A1 (en) Ruthenium-diphosphine complexes and their use as catalysts
Wada et al. Optically Pure 1, 2‐Bis [(o‐alkylphenyl) phenylphosphino] ethanes and Their Use in Rhodium‐Catalyzed Asymmetric Hydrogenations of α‐(Acylamino) acrylic Derivatives
WO2015178846A1 (en) Process for the preparation of chiral amines from prochiral ketones
MXPA04006207A (en) Process for the preparation of nonracemic syn.
Zhou et al. Transition metal-catalyzed enantioselective hydrogenation of enamides and enamines
EP2264000B1 (en) Method for producing optically active aminoalcohol compound using ruthenium compound
WO2012137460A1 (en) Novel ruthenium complex and process for producing optically active alcohol compound using same as catalyst
CN102076634A (en) Synthesis of chiral amines
JP4286486B2 (en) Ruthenium compound, diamine ligand and method for producing optically active alcohol
JP6065259B2 (en) Method for producing optically active amines
US5919962A (en) Process for preparing ruthenium-phosphine complex
WO2015178847A1 (en) Process for the preparation of chiral amines by asymmetric hydrogenation of prochiral oximes
JP2004091488A (en) Method for production of phosphite and transition metal complex
EP2186812A1 (en) Production process of optically active 3-quinuclidinol derivative
Xie et al. New chiral phosphorus ligands with spirobiindane backbone for asymmetric hydrogenations
US20030119664A1 (en) Chiral monophosphorus compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15795517

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15795517

Country of ref document: EP

Kind code of ref document: A1