WO2006064340A2 - Elaboration de n-acyl beta-aminoaldehydes - Google Patents

Elaboration de n-acyl beta-aminoaldehydes Download PDF

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WO2006064340A2
WO2006064340A2 PCT/IB2005/003759 IB2005003759W WO2006064340A2 WO 2006064340 A2 WO2006064340 A2 WO 2006064340A2 IB 2005003759 W IB2005003759 W IB 2005003759W WO 2006064340 A2 WO2006064340 A2 WO 2006064340A2
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formula
compound
alkyl
phenyl
substituted
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PCT/IB2005/003759
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WO2006064340A3 (fr
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Jens Bertil Ahman
Lee Terence Boulton
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Pfizer Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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

  • This invention relates to a process for the preparation of enantiomerically enriched N- acyl ⁇ -aminoaldehydes. In particular it relates to asymmetric hydrogenation of N-acyl enamides.
  • Enantiomerically enriched N-acyl ⁇ -aminoaldehydes are useful intermediates, in particular, for the preparation of pharmaceuticals. More particularly N-[(1S)-1-(3-fluorophenyl)- 3-oxopropyl]acetamide and (1 S)-4,4-difluoro-N-(3-oxo-1- phenylpropyl)cyclohexanecarboxamide are key intermediates for the preparation of methyl 1- eA)c/o- ⁇ 8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propylJ-8-azabicyclo[3.2.1]oct-3-yl ⁇ -2-methyl- 4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine-5-carboxylate, methyl 3-endo- ⁇ 8-[(3S)-3- (acetylamino)-3-(3-fluorophenyl)prop
  • a particular advantage of the present invention is effective asymmetric hydrogenation of both E and Z-enamides, which may be present in isolation or as an isomeric mixture, to yield N-acyl ⁇ -aminoaldehydes which are enriched in the same enantiomer, irrespective of the geometry of the parent enamide.
  • a process for the preparation of an enantiomerically enriched compound of formula (I) comprising asymmetric hydrogenation of a compound of formula (V) or a protected derivative thereof, wherein the hydrogenation is catalysed by a cationic group 8 or 9 transition metal complex comprising a chiral phosphine ligand; followed by deprotection as required;
  • R 1 is OR 1a ; Cv 6 alkyl; C 2 . 6 alkenyl; C 2 . 6 alkynyl; C 3 . 7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF 3 , OR 4 , CN, NR 3 R 4 , COR 4 , CO 2 R 4 or CONR 3 R 4 ; wherein said heterocycles contain one to three heteroatoms selected from N, O or S; and wherein said heterocycles are substituted by 0 to 3 atoms or groups selected from C 1 ⁇ alkyl, C 1 ⁇ alkylcarbonyl, C,. 6 alkoxy, C,. 6 alkoxycarbonyl, halogen, CF 3 , OH, CN,
  • R 1a is Cv 6 alkyl substituted by O to 3 atoms or groups selected from phenyl, a 5 or 6- membered aromatic heterocycle, halogen, C 2 . 6 alkenyl, fluorenyl, adamantyl, or trimethylsilyl; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said phenyl and heterocycle are substituted by O to 3 atoms or groups selected from d. 6 alkyl, C 1 ⁇ alkylcarbonyl, Ci.
  • R 2 is Ci- 6 alkyl; phenyl; or a 5 or 6-membered aromatic heterocycle; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said phenyl and heterocycle are substituted by O to 3 atoms or groups selected from C 1 ⁇ alkyl, Ci. 6 alkylcarbonyl, Ci.
  • R 3 is H, C, . 6 alkyl; C 2 . ⁇ alkenyl; C 2 . 6 alkynyl; C 3 .
  • R 4 is H or C,. 6 alkyl; or, when R 3 and R 4 are both attached to the same N atom, NR 3 R 4 may also represent a 5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from O to 2 additional heteroatoms selected from O, N or S; and
  • alkyl as a group or part of a group includes straight chain and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • C 3 . 7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • halogen means fluoro, chloro, bromo or iodo.
  • enantiomerically enriched means that one enantiomer is present in an amount in excess of the opposite enantiomer. Enantiomeric excess is defined as the excess of one enantiomer over the other, expressed as a percentage of the whole.
  • a chiral phosphine ligand is a chiral ligand which contains one or more chiral centres and one or more phosphorous atoms suitable for coordinating to a transition metal ion to form an organometallic complex.
  • a protected derivative of a compound of formulae (I) or (V) is a compound of formulae (I) or (V) wherein the carbonyl group of the aldehyde is protected.
  • groups are suitable for protecting the carbonyl group of an aldehyde. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 4, pages 293-368 ("Protection for the Carbonyl Group"), incorporated herein by reference, which also describes methods for the removal of such groups.
  • Suitable protected derivatives include, but are not limited to, acyclic acetals (including but not limited to dimethyl and diisopropyl) ibid pp297-306, cyclic acetals (including but not limited to 1 ,3-dioxanes and 1 ,3 dioxolanes) ibid pp307-325 and acyclic and cyclic thioacetals At ⁇ dpp329-347.
  • the asymmetric hydrogenation is effected in the presence of a solvent system.
  • the chiral phosphine ligand and the group 8 or 9 transition metal ion form part of a precatalyst.
  • precatalysf refers to isolated precatalyst which is added to the reaction vessel to effect catalysis of the hydrogenation process and which typically undergoes a change in composition in situ to generate one or more catalytically active species.
  • equivalent catalysis may be achieved by generation of catalytically active species from the chiral phosphine ligand and an achiral group 8 or 9 transition metal ion containing precursor.
  • the group 8 or 9 transitional metal is preferably Rh, Ir or Ru, more preferably Rh or Ru, most preferably Rh.
  • the precatalyst is of formula [M(Ligand)(diene)]A, wherein M is a group 8 or 9 transition metal ion;
  • Ligand is the chiral phosphine ligand; diene is either cyclooctadiene (COD) or norbornadiene (NBD); and
  • A is an anion selected from BF 4 " , PF 6 " , trifluoromethylsulfonate (TfO ), SbF 6 " and tetra[3,5- bis(trifluoromethyl)phenyl]borate.
  • the diene is COD and A is BF 4 ' .
  • the process for the preparation of an enantiomerically enriched compound of formula (I) comprises asymmetric hydrogenation of a protected derivative of a compound of formula (V).
  • R 1 is C 1 ⁇ alkyl substituted by 0 to 3 fluorine atoms, C 3 . 7 cycloalkyl substituted by 0 to 3 fluorine atoms, C-,. 6 alkoxy substituted by 0 to 3 fluorine atoms, or a 4 to 7-membered saturated heterocycle containing 1 to 3 heteroatoms selected from N, O or S.
  • R 1 is C 1 ⁇ alkyl substituted by 0 to 3 fluorine atoms, C 3 - 6 cycloalkyl substituted by 0 to 3 fluorine atoms, C,. 4 alkoxy substituted by 0 to 3 fluorine atoms , or a 5 or 6-membered, N, O or S containing, saturated heterocycle.
  • R 1 is C 1 ⁇ alkyl substituted by 0 or 3 fluorine atoms, C 3 . 6 cycloalkyl substituted by 0 to 2 fluorine atoms, C 1 . 3 alkoxy substituted by 0 to 3 fluorine atoms, or a 5 or 6-membered, O-containing, saturated heterocycle.
  • R 1 is C 1 ⁇ alkyl or Ci- 2 alkoxy.
  • R 1 is 4,4-difluorocyclohexyl. In yet a further embodiment, R 1 is benzyloxy or t-butyloxy.
  • R 2 is phenyl substituted by 0 to 3 fluorine atoms.
  • R 2 is phenyl substituted by 0 or 1 fluorine atoms. In yet a further embodiment of the invention R 2 is unsubstituted phenyl.
  • R 2 is mono-fluoro-substituted (e.g. meta substituted) phenyl. It is to be understood that the invention covers all combinations of particular embodiments of the invention as described herein.
  • the enriched enantiomer of a compound of formula (I) is a compound of formula (IA)
  • R 1 and R 2 are as previously defined for a compound of formula (I).
  • the enriched enantiomer of a compound of formula (I) is a compound of formula (IB)
  • R 1 and R 2 are as previously defined for a compound of formula (I).
  • the chiral phosphine ligand is of formula (A) or the opposite enantiomer thereof
  • R 11 is Ci- 6 alkyl or phenyl
  • L is ferrocene; C 2 . 4 alkylene, C 2 . 4 alkenylene, phenyl, naphthyl, or a 5 to 10-membered aromatic heterocycle; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said phenyl, naphthyl or heterocycle is optionally substituted by 0 to 3 atoms or groups selected from C 1 ⁇ alkyl, Ci_ 6 alkylcarbonyl, C 1 . 6 alkoxy, C 1 ⁇ alkoxycarbonyl, halogen, CF 3 , OH, CN; n is 0,1 or 2.
  • the chiral phosphine ligand is of formula (B) or the opposite enantiomer thereof
  • R 11 is as defined above.
  • chiral phosphine ligand is of formula (C) or the opposite enantiomer thereof
  • R 11 is as defined above.
  • the chiral phosphine ligand is of formula (D) or the opposite enantiomer thereof
  • R 11 is as defined above.
  • the chiral phosphine ligand is of formula (E) or the opposite enantiomer thereof
  • the chiral phosphine ligand is of formula (F) or the opposite enantiomer thereof
  • R 11 is as defined above.
  • R 11 is C 1 -C 6 alkyl.
  • R 11 is C 1 -C 4 alkyl.
  • R 11 is methyl, ethyl or isopropyl.
  • R 11 is phenyl
  • the chiral phosphine ligand is of formula (G) or the opposite enantiomer thereof
  • R 12 , R 13 , R 14 and R 15 are each independently selected from cyclohexyl, t-butyl or phenyl, wherein said phenyl is optionally substituted by -CF 3 , methyl, or methoxy ,
  • R 16 is methyl, methoxy or NMe 2 .
  • the chiral phosphine ligand is of formula (H) or the opposite enantiomer thereof
  • R 12 , R 13 , R 14 ' R 15 and R 16 are as defined above.
  • the chiral phosphine ligand is of formula (J) or the opposite enantiomer thereof
  • R 17 , R 18 and R 19 are independently Ci- 6 alkyl or phenyl wherein said phenyl is optionally substituted by -CF 3 , methyl, or methoxy; and R 17 and R 18 are different from each other ; n is 0,1 or 2.
  • the chiral phosphine ligand is of formula (K) or the
  • R 17 and R 18 are independently C 1 ⁇ alkyl or phenyl wherein said phenyl is optionally substituted by -CF 3 , methyl, or methoxy; and R 17 and R 18 are different from each other ; n is 0,1 or 2. In yet a further embodiment, R 17 is t-butyl.
  • R 18 is methyl
  • R 19 is t-butyl.
  • n 0.
  • asymmetric hydrogenation according to the present process yields a compound of formula (IA) in a range between 70% and 100% enantiomeric excess.
  • asymmetric hydrogenation according to the present process yields a compound of formula (IA) in a range between 90% and 100% enantiomeric excess.
  • asymmetric hydrogenation according to the present process yields a compound of formula (IB) in a range between 70% and 100% enantiomeric excess.
  • asymmetric hydrogenation according to the present process yields a compound of formula (IB) in a range between 90% and 100% enantiomeric excess.
  • the solvent system comprises an alcohol having between 1 and 10 carbon atoms.
  • the protected derivative of the compound of formula (V) is an acetal derivative.
  • the acetal derivative of the compound of formula (V) is a compound of formula (III). wherein R 1 and R 2 are as previously defined for a compound of formula (I) and R 5 is C,. 6 alkyl.
  • the solvent present during asymmetric hydrogenation according to the present process is R 5 OH (IV) wherein R 5 is as previously defined for a compound of formula (III).
  • R 5 is methyl
  • the acetal derivative of the compound of formula (V) is a compound of formula (IIIA).
  • R 1 and R 2 are as previously defined for a compound of formula (I).
  • the preparation of the acetal of formula (III) comprises reaction of a compound of formula (V)
  • the preparation of a compound of formula (V) comprises formylation of a compound of formula (Vl)
  • the preparation of a compound of formula (Vl) comprises reaction of a compound of formula (VII)
  • R 1 , R 2 and R 5 are as defined hereinabove.
  • the preparation of a compound of formula (V), wherein R 1 is methyl comprises reaction of a compound of formula (IX)
  • a compound of formula (V), wherein R 1 is methyl can be prepared according to Scheme 1 a.
  • the invention provides processes for the preparation of a compound of formula (Xl)
  • R 1 and R 2 are as previously defined for a compound of formula (I); X and Y are selected from CH 2 and NR 24 such that one of X and Y is CH 2 and the other is NR 24 ;
  • R 24 is R 25 ; COR 25 ; CO 2 R 25 ; CONR 26 R 27 ; SO 2 R 25 ; or (C 1 - G alkylene)phenyl, wherein phenyl is substituted by 0 to 3 atoms or groups selected from Ci- 6 alkyl, d- ⁇ alkylcarbonyl, C 1 . 6 alkoxy, C,. 6 alkoxycarbonyl, halogen, CF 3 , OH, CN, NR 26 R 27 , COR 27 , CO 2 R 27 or CONR 26 R 27 ;
  • R 23 is C 1 - I alkyl substituted by O to 3 fluorine atoms
  • R 25 is Ci- 6 alkyl; C 2 . 6 alkenyl; C 2 . 6 alkynyl; C 3 . 7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by O to 3 atoms or groups selected from oxo, halogen, CF 3 , OR 27 , CN, NR 26 R 27 , COR 27 , CO 2 R 27 or CONR 26 R 27 ; wherein said heterocycles contain one to three heteroatoms selected from N, O or S; and wherein said heterocycles are substituted by O to 3 atoms or groups selected from Ci- 6 alkyl, d- 6 alkylcarbonyl, Ci- 6 alkoxy, C 1 ⁇ alkoxycarbonyl
  • R 26 is H; d- 6 alkyl; C 2 . 6 alkenyl; C 2 . 6 alkynyl; C 3 . 7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by O to 3 atoms or groups selected from oxo, halogen, CF 3 , OR 27 , CN, COR 27 or CO 2 R 27 ; wherein said heterocycles contain one to three heteroatoms selected from N, O or S; and wherein said heterocycles are substituted by O to 3 atoms or groups selected from C,. 6 alkyl, Ci. 6 alkylcarbonyl, Ci. 6 alkoxy, Ci. 6 alkoxycarbonyl, halogen, CF 3 , OH 1 CN, COR 27 or CO 2 R 27 ;
  • R 27 is H or d. 6 alkyl; or, when R 26 and R 27 are both attached to the same N atom, NR 26 R 27 may also represent a 5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from O to 2 additional heteroatoms selected from O, N or S.
  • the invention provides processes for the preparation of a compound of formula (XIII)
  • compounds of formula (Xl) may be prepared by reductive amination of a compound of formula (IA), prepared according to the asymmetric hydrogenation process of the invention as described hereinabove, with an amine of formula
  • Reductive amination may conveniently be effected according to the conditions described in WO 03/084954 (p14, step (g)).
  • compounds of formula (XIII) may be prepared by reductive amination of a compound of formula (IA) 1 prepared according to the asymmetric hydrogenation process of the invention described hereinabove, with an amine of formula (XIV)
  • Reductive amination may conveniently be effected according to the conditions described in WO 01/90106 (p13, lines 11 to 22).
  • compounds of formula (Xl) may be prepared by a) preparation of a carbamate of formula (Xl), wherein R 1 is OR 1a , prepared by reductive amination of a compound of formula (IA), prepared according to the asymmetric hydrogenation process of the invention described hereinabove, with an amine of formula (XII); followed by b) cleavage of the carbamate of formula (Xl), to yield an amine of formula (XV) wherein R 2 , R 23 , X and Y are as defined for a compound of formula (Xl); followed by c) acid amine coupling of an amine of formula (XV) with an acid of formula (XVI) R 1 COZ (XVI) wherein Z is OH, or a carboxylic acid activating group such as chloro or 1 H- imidazol-1 -yl; under conventional conditions.
  • Acid amine coupling may conveniently be effected according to the conditions described in WO 03/084954 (p14 line 29 to p15 line 7).
  • compounds of formula (XIII) may be prepared by a) preparation of a carbamate of formula (XIII), wherein R 1 is OR 1a , prepared by reductive amination of a compound of formula (IA), prepared according to the asymmetric hydrogenation process of the invention described hereinabove, with an amine of formula (XIV); followed by b) cleavage of the carbamate of formula (XIII), to yield an amine of formula
  • R 2 is as defined for a compound of formula (XIII); followed by c) acid amine coupling of an amine of formula (XV) with an acid of formula (XVI)
  • Acid amine coupling may conveniently be effected according to the conditions described in WO 01/90106 (p5 line 11 to 18 and p7 line 21 to p8 line 23 ).
  • compounds of formula (Xl) wherein Y is NR 24 may be prepared by a) reductive amination of a compound of formula (IA), prepared according to the asymmetric hydrogenation process of the invention as described hereinabove, with an amine of formula (XVIII)
  • Conversion of an amine of formula (XIX) to a compound of formula (Xl) may be conveniently carried out according to methods described in WO 03/084954 (in particular method M described therein at p 10 line 15).
  • TBME tertiary butyl methyl ether
  • Example 1 Asymmetric hydroqenation of ⁇ /-Acetyl-3-amino-3-(3-fluoro-phenyl)-1 ,1- dimethoxy-2-propene a) (3S)- ⁇ /Acetyl-3-amino-3-(3-fluoro-phenyl)-1.1-dimethoxy-propane
  • the aqueous phase was saturated with sodium chloride and then extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were then washed with brine (200 ml), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (150 ml) and concentrated in vacuo. This was repeated once and the residue was then dissolved in a mixture of dichloromethane (100 ml) and methyl fert-butyl ether (100 ml) and concentrated in vacuo. The residue was finally dissolved in methyl tert- butyl ether (100 ml) and concentrated in vacuo.
  • Example 2 Asymmetric hvdro ⁇ enation of 3-(4,4-Difluoro-cvclohexanecarbonylamino)-3- phenyl-1 ,1-dimethoxy-2-propene
  • Example 3 Asymmetric hvdroqenation of 3-(4.4-Difluoro-cvclohexanecarbonylamino)-3- phenyl-1.1-dimethoxy-2-propene (3fl)- ⁇ / -(4.4-Difluoro-cvclohexanecarbonylamino)-3-amino-3-(3-phenyl)-1.1 -dimethoxy-
  • Example 4 Asymmetric hydro ⁇ enation of N-r2-(5.5-Dimethyl-f1.31dioxan-2-yl)-1 -phenyl-vinv ⁇ - ace tarn ide
  • Example 6 Asymmetric hvdroqenation of N-(1 -tert-Butyl-3.3-dimethoxy-propenyl)-acetamide Asymmetric hydrogenation of N-(1 -tert-Butyl-3,3-dimethoxy-propenyl)-acetamide utilizing various precatalysts is illustrated in Table 5.
  • Example 7 Asymmetric hvdro ⁇ enation of ⁇ /-Acetyl-3-amino-3-phenyl -2-propenal ⁇ /-Acetyl-3-amino-3-phenyl-2-Dropenal
  • the mixture was then transferred to the tube containing the precatalyst solution.
  • the tube was then placed in an autoclave that had been placed under argon.
  • the autoclave was then closed and set to the prescribed pressure of hydrogen and prescribed temperature. After 18 h the reaction was stopped and the crude reaction mixture was filtered over silica and analysed by HPLC.
  • Methylmagnesium bromide (2.4 I of a 3M solution in ether, 7.20 mol) was added to a stirred suspension of 3-fluorobenzonitrile (793 g, 6.55 mol) and copper(l) bromide (37.6 g, 131 mmol) in THF (5.7 I) over 140 minutes. An exotherm of 24 0 C was noted and the mixture was at a gentle reflux. Once the addition was complete, the mixture was heated at reflux (internal temperature: 52 0 C) for 135 minutes.
  • Oxalyl chloride (394 ml, 4.59 mol) was added over one hour to a stirred solution of DMF (370 ml, 4.80 mol) in acetonitrile (2.45 I) whilst maintaining the temperature below 10 0 C (internal). Once the addition was complete, the mixture was stirred for one hour during which the temperature rose to 12 0 C.
  • the aqueous phase was extracted with ethyl acetate (3.4 I) and the combined organic extracts were washed with brine (3.4 I), dried (MgSO 4 ), filtered and concentrated in vacuo.
  • the residue was slurried for 17 hours in a mixture of methyl fert-butyl ether (2.52 I) and DCM (840 ml). Filtration was followed by washing the residue with two portions of methyl fert-butyl ether /dichloromethane (3:1 v/v) (670 ml then 400 ml). The filtrate was then dried In vacuo to provide the crude product (298 g).
  • Methylmagnesium bromide (16.1 ml of a 3M solution in diethyl ether, 48.3 mmol) was added dropwise to a stirred suspension of copper(l) bromide (252 mg, 0.88 mmol) and benzonitrile (4.53 g, 43.9 mmol) in tetrahydrofuran (30 ml). The mixture was then heated at reflux for 2 hours and was then cooled to room temperature before placing in an ice-water bath. A solution of 4,4-difluorocyclohexanecarbonyl chloride (8.82 g, 48.3 mmol) in tetrahydrofuran (20 ml) was then added dropwise.
  • the addition funnel was washed through with further tetrahydrofuran (10 ml) and the mixture was warmed to room temperature. After stirring for 72 hours the mixture was diluted with methyl fert-butyl ether (100 ml) and then sequentially washed with saturated ammonium chloride (2 x 100 ml) and saturated sodium bicarbonate (100 ml). The aqueous washes were extracted with methyl ferf-butyl ether (100 ml) and the combined organic extracts were then washed with brine (100 ml), dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Potassium carbonate (68 mg, 0.49 mmol) was added to a solution of the fraction enriched in the diacylated derivative (2.02 g, 1.47 mmol based on -30% purity as determined by integration of the 1 H NMR spectrum of the mixture) in methanol (8 ml). After stirring at room temperature for 2 hours the mixture was concentrated in vacuo. The residue was partitioned between water (20 ml) and dichloromethane (20 ml). The organic extract was washed with brine (20 ml), dried (MgSO 4 ), filtered and concentrated in vacuo to provide the title compound as a light yellow solid (1.80 g, quantitative).
  • Methylmagnesium bromide 160 ml of a 1.4 M solution in Toluene:THF (3:1 ), 224 mmol was charged to a dry inert reaction vessel under N 2 .
  • Benzonitrile 23 ml, 225 mmol was added dropwise over 25 min (-10 0 C exotherm observed) and the reaction mixture stirred for 18 h.
  • the solution was then added dropwise over 140 min to a stirred solution of 4,4- difluorocyclohexanecarbonyl chloride (41 g, 225 mmol) in toluene (4.5 ml/g, -150 ml) ( ⁇ 5 0 C exotherm observed).
  • reaction mixture was stirred for 1 h and quenched with aqueous ammonium chloride (10%, 100 ml) over 5 min.
  • the organic phase was washed with water (50 ml), concentrated in vacuo to 140 ml and granulated over 12 h.
  • the resulting slurry was cooled to 0 0 C for 4 h, filtered, washed with toluene (2 x 20 ml) and dried under vacuum at 35 "C/50 mbar for 18 h to provide the title compound as a pure white solid (24 g, 40%).
  • the reaction mixture was then cooled with an ice-water bath and sodium acetate (37.0 g, 450 mmol) in water (80 ml) was added dropwise over 20 min. Once the addition was complete, the ice- water bath was removed and the mixture was granulated for 16 h. The slurry was filtered and washed with water (50 ml). The filtrate was stirred for 10 min and the resulting precipitate was filtered and washed with further water (50 ml).
  • reaction completion was confirmed by TLC (1:1 ethylacetate/heptane, visualised under uv) confirmed complete consumption of starting material.
  • Sodium acetate (122g, 1.49mol) in water (400ml) was added and stirred for 1 h. The phases were separated. The organic phase was concentrated in vacuo and the residue was partitioned between water (640ml) and ethylacetate (640ml). The phases were separated. The combined aqueous phases were re-extracted with ethyl acetate (2x640ml).
  • Oxalyl chloride (14.9 ml, 174 mmoi) was added to a stirred solution of DMF (14.0 ml, 182 mmol) in acetonitrile (130 ml) at such a rate so as to maintain the temperature between O 9 C and 5 S C (internal). The reaction was stirred at 10 3 C (internal) for 15 minutes before being recooled to 2 S C (internal). A solution of ⁇ /-(1-ferf-butyl-vinyl)-acetamide (22.338 g, 158 mmol) in acetonitrile (35ml + 15 ml) was added over 15 minutes.
  • the reaction was stirred for 1 hour at 2 S C (internal) before a solution of sodium acetate (65 g, 791 mmol) in water (180 ml) was added.
  • the reaction was allowed to warm slowly to room temperature over 3 hours before the two layers were separated and then the aqueous layer was extracted with ethyl acetate (180 ml).
  • the combined organics were washed with brine (100 ml + 50 ml), dried (MgSO 4 ), filtered and concentrated under reduced pressure.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un traitement destiné à l'élaboration de N-acyl ß-aminoaldéhydes énantiomériquement enrichis. L'invention concerne plus particulièrement l'hydrogénation asymétrique de N-acyl énamides.
PCT/IB2005/003759 2004-12-13 2005-12-06 Elaboration de n-acyl beta-aminoaldehydes WO2006064340A2 (fr)

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GB0427293A GB0427293D0 (en) 2004-12-13 2004-12-13 A process
GB0427293.6 2004-12-13
US64565805P 2005-01-20 2005-01-20
US60/645,658 2005-01-20

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WO2006064340A2 true WO2006064340A2 (fr) 2006-06-22
WO2006064340A3 WO2006064340A3 (fr) 2006-09-08

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010025663A1 (de) * 2010-06-30 2012-01-05 Karl-Heinz Glüsenkamp Neue beta-Aminoaldehyd-Derivate, Verfahren zu ihrer Herstellung und ihre chemische Verwendung als reaktive Intermediate
CN105330550A (zh) * 2015-10-13 2016-02-17 凯瑞斯德生化(苏州)有限公司 一种光学活性的1-环己基乙胺的制备方法
CN108610267A (zh) * 2018-06-15 2018-10-02 中触媒新材料股份有限公司 一种频呐酮肟合成方法
CN111217809A (zh) * 2018-11-27 2020-06-02 江苏奥赛康药业有限公司 一类手性含氮双烯配体及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4073795A (en) * 1976-06-22 1978-02-14 Hoffmann-La Roche Inc. Synthesis of tryptophans
US6214763B1 (en) * 1997-05-20 2001-04-10 Firmenich Sa Ruthenium catalysts and their use in the asymmetric hydrogenation of weakly coordinating substrates
WO2001090106A2 (fr) * 2000-05-26 2001-11-29 Pfizer Limited Derives du tropane utiles en therapie
EP1199301A1 (fr) * 2000-10-16 2002-04-24 Pfizer Limited Formation d'oléfines pour la préparation de dérivés d'acide itaconique et succinique
WO2003084954A1 (fr) * 2002-04-08 2003-10-16 Pfizer Limited Derives de tropane utilises comme modulateur as de ccr5

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4073795A (en) * 1976-06-22 1978-02-14 Hoffmann-La Roche Inc. Synthesis of tryptophans
US6214763B1 (en) * 1997-05-20 2001-04-10 Firmenich Sa Ruthenium catalysts and their use in the asymmetric hydrogenation of weakly coordinating substrates
WO2001090106A2 (fr) * 2000-05-26 2001-11-29 Pfizer Limited Derives du tropane utiles en therapie
EP1199301A1 (fr) * 2000-10-16 2002-04-24 Pfizer Limited Formation d'oléfines pour la préparation de dérivés d'acide itaconique et succinique
WO2003084954A1 (fr) * 2002-04-08 2003-10-16 Pfizer Limited Derives de tropane utilises comme modulateur as de ccr5

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A.H.COOK AND I.M.HEILBRON: "Thiazolidines derived from cysteine" CHEM.PENICILLIN PRINCETON, 1949, page 968, XP001247057 *
HELLER D ET AL: "PRESSURE DEPENDENT HIGHLY ENANTIOSELECTIVE HYDROGENATION OF UNSATURATED BETA-AMINO ACID PRECURSORS" JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 66, no. 20, 5 October 2001 (2001-10-05), pages 6816-6817, XP002198463 ISSN: 0022-3263 cited in the application *
NW.ALCOCK ET AL: "degradation of cobaloximes to derivatives of imidazo(1,2-a)pyridine" J.CHEM.SOC. PERKIN TRANS., vol. 1, 1975, pages 386-394, XP009066725 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010025663A1 (de) * 2010-06-30 2012-01-05 Karl-Heinz Glüsenkamp Neue beta-Aminoaldehyd-Derivate, Verfahren zu ihrer Herstellung und ihre chemische Verwendung als reaktive Intermediate
CN105330550A (zh) * 2015-10-13 2016-02-17 凯瑞斯德生化(苏州)有限公司 一种光学活性的1-环己基乙胺的制备方法
CN105330550B (zh) * 2015-10-13 2018-01-30 凯瑞斯德生化(苏州)有限公司 一种光学活性的1‑环己基乙胺的制备方法
CN108610267A (zh) * 2018-06-15 2018-10-02 中触媒新材料股份有限公司 一种频呐酮肟合成方法
CN111217809A (zh) * 2018-11-27 2020-06-02 江苏奥赛康药业有限公司 一类手性含氮双烯配体及其制备方法和应用

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