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  • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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  • 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
  • B01J31/1865—Phosphonites (RP(OR)2), their isomeric phosphinates (R2(RO)P=O) and RO-substitution derivatives thereof
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  • 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
  • B01J31/1865—Phosphonites (RP(OR)2), their isomeric phosphinates (R2(RO)P=O) and RO-substitution derivatives thereof
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  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
  • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
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  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
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  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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  • C07F17/00—Metallocenes
  • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
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  • 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)
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  • 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
  • B01J2531/0263—Planar chiral ligands, e.g. derived from donor-substituted paracyclophanes and metallocenes or from substituted arenes
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  • 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"
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  • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
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  • B01J2531/821—Ruthenium
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  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to the preparation of ruthenium complexes of chiral diphosphonites and their use as catalysts in the asymmetric reduction of ketones, ⁇ -ketoesters and ketimines, which products are enantiomerically pure or enriched alcohols or amines, which are industrially valuable building blocks in the production of compounds such as pharmaceuticals, pesticides, fragrances and natural products or intermediates in their synthesis.
• transition metal-catalyzed enantioselective reduction of prochiral ketones I, ß-ketoestem III and ketimines V require enantiomerically pure or enriched chiral alcohols II, ß-hydroxyester IV or amines VI, which are valuable intermediates for the industrial production of a variety of pharmaceutical agents, pesticides, Fragrances or other products are (R. Noyori, Angew Chem, Int., Ed., 2002, 41, 2008-2022, H.U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M Studer, Adv. Synth.Catal., 2003, 345, 103-151; MJ Palmer, M.
• WiIIs Tetrahedron: Asymmetry 1999, 10, 2045-2061.
• a variety of catalyst systems have been developed for such reductions, either by H 2 hydrogenation or by transfer hydrogenation using, for example, isopropanol as the hydrogen donor.
• a few known chiral ligands give high enantioselectivities (ee> 90%) for some but not for all substrates (R. Noyori, Angew Chem, Int. Ed., 2002, 41, 2008-2022, H.-U. Blaser , C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer, Adv. Synth Catal 2003, 345, 103-151; MJ Palmer, M. WiIIs, Tetrahedron: Asymmetry 1999, 10, 2045 -2061).
• the present invention overcomes many of the disadvantages described above.
• the present invention relates to chiral ruthenium complexes which can be obtained by reaction of one or more ruthenium salts with a chiral diphosphonite.
• Another object is a process for the enantioselective reduction of prochiral ketones, ß-keto esters and ketimines using these ruthenium complexes as catalysts in the H 2 hydrogenation or transfer hydrogenation.
• the invention utilizes ruthenium complexes with inexpensive and readily available chiral diphosphonites.
• Phosphonites are compounds with a carbon-phosphorus bond and two phosphorus-oxygen bonds.
• Nitrogen analogs, ie, derivatives of phosphonites in which one or both of the oxygen moieties have been replaced by an amino group, are also encompassed by the present invention.
• the ligands of the present invention consist of an achiral or chiral backbone to which two phosphonitrile residues are attached, each residue containing a chiral ligand, such as a chiral diol (Scheme 1), diamine (Scheme 2), or an aminoalcohol (Scheme 3). contains, wherein all stereoisomeric forms are part of the invention:
• ferrocene derivatives which have a phosphorus residue each cyclopentadienyl group (IE Nifant'ev, LF Manzhukova, MY Antipin, YT Struchkov, EE Nifant'ev, Zh Obshch, Khim, 1995, 65, 756-760; MT Reetz, A. Gosberg, R. Goddard, Commun. (Cambridge, UK) 1998, 2077-2078; MT Reetz, A. Gosberg, Int. Pat. Appl. WO 00/14096, 2000).
• a particularly inexpensive chiral auxiliary at the phosphorus in the diphosphonites, among many other possibilities, is (R) - or (S) -dinaphthol (BINOL). Typical examples are shown below (VII-X):
• xanthene eg Xl or XII
• homo-xanthene eg XIII
• sexanthene eg XIV
• thixanthene eg XV
• nixanthene eg XVI
• phosxanthene eg XVII
• Benzoxanthen eg XVIII
• acridine eg XIX
• Dibenzofuran eg XXX
• the chiral auxiliary is on the phosphorus BINOL (A), the invention is not limited to this particular chiral diol.
• Octahydro-BINOL (B) can be used among many others.
• axially chiral diols may also be used, many of which have been prepared according to literature using efficient synthetic processes, e.g. substituted BINOL derivatives C, substituted diphinol derivatives D with axial chirality and diols with axial chirality containing the heterocycles according to E.
• the present invention encompasses all combinations of the radicals mentioned for R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , including all C 1 or C 2 -symmetric substitution patterns of the basic structure of binaphthol.
• one or more carbon atoms of the naphthol nucleus can also be replaced by heteroatoms, such as nitrogen.
• the dihydroxy-based block is a functionalized and configuration-stable biphenol.
• R 4 H EL Eliel, SH Wilen, LN Mander, Stereochemistry of Organic Compounds, Wiley, New York, 1994.
• R 1 to R 4 show the same range of radicals R 1 to R 6 from the compound class C.
• Chiral spiro-diols such as F (A.G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int Ed., 2002, 41, 2348-2350), paracyclophane-derived diols G, or C1- or C2-symmetric diols with central chirality, eg, 1, 3-diols or type-H diols, may also be used as components in the synthesis of diphosphonite Ligands are used.
• F A.G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int Ed., 2002, 41, 2348-2350
• paracyclophane-derived diols G or C1- or C2-symmetric diols with central chirality, eg, 1, 3-dio
• the radicals R 1 and R 2 in the diols H may be identical (C 2 symmetry) or different (Ci symmetry). They may be a saturated hydrocarbon which may optionally be functionalized, as in the case of 1,3-diol units of protected carbohydrates. Possible radicals also include aromatic or heteroaromatic groups, such as phenyl, naphthyl or pyridyl, which may themselves be functionalized, if desired or required.
• radicals have ester or amide groups, such as -CO 2 CH 3 , -CO 2 C 2 H 5 , -CO 2 -JC 3 H 7 or -CO [N (CH 3 ) 2 ], CO [N (C 2 Hs) 2 ] or - CO [N (JC 3 Hy) 2 ], where the corresponding diols H are tartaric acid derivatives.
• ester or amide groups such as -CO 2 CH 3 , -CO 2 C 2 H 5 , -CO 2 -JC 3 H 7 or -CO [N (CH 3 ) 2 ], CO [N (C 2 Hs) 2 ] or - CO [N (JC 3 Hy) 2 ], where the corresponding diols H are tartaric acid derivatives.
• chiral diamides or amino alcohols can also be used in the preparation of the chiral diphosphonites.
• the other diphosphonites must be considered when certain substrates are to be hydrogenated.
• the ligand X which is derived from diphenyl ether, is preferred.
• the invention also encompasses novel metal complexes as catalysts by reacting the above-defined chiral diphosphonites with ruthenium salts, a wide variety of which are available (Encyclopedida of Inorganic Chemistry (RB King, Ed.), Vol. 7, Wiley, New York, 1994; Comprehensive Coordination Chemistry (Wilkinson, Ed.), Chapter 45, Pergamon Press, Oxford, 1987).
• Ru (II) salts are used, but it is also possible to use Ru (II.sub.1) salts which are reduced to Ru (II) under the reaction conditions.
• the invention relates not only to complexes of the chiral diphosphonites and Ru (II) or Ru (III) salts, but also to their use as catalysts in the asymmetric hydrogenation of prochiral ketones I, ketoesters III and ketimines V.
• a reducing agent a variety of Compounds are used, in particular in the hydrogenation based on the compound of H 2 or in the transfer hydrogenation, in which the use of agents such as formic acid, alcohols, sodium dithionite or NaH 2 PO 2 .
• one of the most preferred variants is transfer hydrogenation using an alcohol both as a reducing agent and as a solvent.
• the hydrogenation or transfer hydrogenation is carried out in the presence of a base.
• Typical bases are NaOH, KOH, MgO, Na 2 CO 3 , K 2 CO 3 , NaF, KF, NaOCH (CH 3 ) 2 , KOCH (CH 3 ) 2 , NaOC (CH 3 ) 3 or KOC (CH 3 ) 3
• preferred bases are NaOH, KOH, NaOC (CH 3 ) 3 or KOC (CH 3 ) 3 .
• ketones that are readily available for enantioselective reduction using the catalysts and methods of the present invention are the ketones of Formulas Ia-m. ig Ih
• Typical ⁇ -ketoesters which are subjected to asymmetric Ru-catalyzed reduction are III a-e, but R 1 and R 2 can be varied accordingly, if necessary.
• R 1 CH 3 ;
• R 2 C 2 H 5 c
• R 1 C 2 H 5 ;
• R 2 CH 3 d
• R 1 nC 3 H 7 ;
• R 2 C 2 H 5 e
• R 1 C 6 H 5 ;
• R 2 C 2 H 5 f
• R 1 2-thiophenyl (C 4 H 3 S);
• R 2 CH 3
• Typical corresponding substrates are those ⁇ -ketoesters having a stereogenic center at the 2-position, such as XXI or XXIII, which can also be reduced.
• XXI XXII
• Typical prochiral ketimines which are subjected to reduction with the Ru catalysts in the process according to the invention are those having the formulas XXVa-b or XXVII:
• a ketone such as ⁇ -ketoester (III) (0.8 mmol) was filled in each vessel, then 3 ml each of ethanol was added. These were then transferred to a high pressure autoclave. After it had been purged three times with H 2, the autoclave with H2 at 60 bar was set pressure, the reactions were stirred magnetically at 60 0 C 20s. The autoclave was then cooled to room temperature and H 2 was carefully vented. Samples were taken from each reaction solution and passed over a small amount of silica gel prior to GC analysis to determine the conversions and ee values. The absolute configuration was determined in comparison with known compounds described in the literature.
• diastereomer ratio is 1: 1, 95% ee each; b) only one diastereomer (96: 4).

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