Classifications

• • 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

Definitions

• the invention relates to an asymmetric hydrogenation process and, more particularly, to the use of a chiral-diphosphine rhodium homogeneous hydrogenation catalyst to achieve improved catalyst loadings and shorter reaction times in such an asymmetric hydrogenation process.
• Unnatural ⁇ -amino acids form an important class of building blocks for the synthesis of active pharmaceutical ingredients (APIs). For example, the metabolic stability of peptide and peptide-like APIs, and hence bioavailability, may be improved by incorporating one or more such amino acids.
• Unnatural ⁇ -amino acids can be further categorized into several structural sub-types including 3,3-diarylalanines (I), in which the two aryl substituents are typically the same. Several applications of these compounds have been reported. For example, a 3,3-diphenylalanine residue has been incorporated into thrombin inhibitors (Cody et al., Bioorg. Med. Chem. Lett, 1999, 9, 2497-2502), factor Ha antagonists (WO 2004073747) and HIV aspartyl protease inhibitors (WO 2004056764).
• enamide (II) As a tetrasubstituted olefin, enamide (II) has much lower activity as a hydrogenation substrate compared with standard trisubsituted enamides of formula (HI).
• Asymmetric hydrogenation of the latter class of compounds, catalyzed by rhodium complexes of DuPhos and other chiral diphosphine ligands, is well known as a preferred method to make a wide range of 3-arylalanine derivatives (for representative references, see Burk et al., J Am. Chem. Soc, 1993, 115, 10125-10138; Pye et al., J. Am. Chem. Soc, 1997, 119, 6207-6208).
• ⁇ -Methylphenylalanine derivatives have also been prepared using asymmetric hydrogenation of enamides of formula (IV) with rhodium-DuPhos and rhodium- BPE based catalysts, by the groups of Burk (J. Am. Chem. Soc, 1995, 117, 9375-76) and Turner (J. Am. Chem. Soc, 2004, 126, 4098-4099). While useful, these processes rely on the use of high catalyst loadings, high reaction pressure and lengthy reaction times.
• the inventors have discovered a process for asymmetric hydrogenation of the bulky 3,3-diaryl enamides of formula II that achieves both high enantioselectivity and improved activity over processes using catalysts derived from DuPhos and BPE ligands. This due to the high activity and selectivity, there will be lower catalyst loadings required and shorter processing time, both of which can provide substantial cost savings.
• the invention comprises a process for the preparation of an enantiomerically enriched 3,3-diarylalanine derivative of formula (1), or the opposite enantiomer thereof, which comprises asymmetric hydrogenation of the corresponding enamide of formula (2), in the presence of a chiral-diphosphine rhodium homogeneous hydrogenation catalyst in which the diphosphine is a PhanePhos ligand (Pye et al, J. Am. Chem. Soc, 1997, 119, 6207-6208) having the structure shown in formula (3).
• the language "having the structure shown in the formula” means the structure in the formula is present but additional substitutions may also be present.
• each of Ar 1 and Ar 2 is independently a C 6-3 o aryl group or a C 4-3O heteroaryl group and may be unsubstituted or substituted
• R 1 is H, alkyl (preferably having 1 to 10, more preferably 1-3, more preferably still 1 or 2 carbon atoms), alkoxy (preferably having 1 to 10, more preferably 1-3, more preferably still 1 or 2 carbon atoms) or aryl (preferably having 6-10, more preferably 6 carbon atoms)
• R 2 is H or alkyl (preferably having 1 to 10, more preferably 1-3, more preferably still 1 or 2 carbon atoms)
• Ar is either phenyl or a substituted phenyl group bearing one or more alkyl or alkoxy groups (preferably these alkyl or alkoxy groups have 1-10, more preferably 1-3, more preferably still 1-2, most preferably 1 carbon atom).
• the substitution is preferably on the [2.2]paracyclophane backbone.
• the substitution preferably is an substituted or unsubstitued aryl or aryloxy or arylalkyl or alkylaryl or ofarylalkyloxy or alkylaryloxy or alkyl or alkoxy having 1 to 36 carbon atoms.
• a trityloxymethyl group in a para position relative to one of the PAr 2 groups (see Hems et al., WO 2004111065).
• the resulting diarylalanine derivatives (1) are suitable for use as pharmaceutical intermediates in various applications, particularly to prepare synthetic peptides with enhanced metabolic stability. Such derivatives may also find utility in other industrial sectors that require chiral fine chemicals, such as the agrochemicals and fragrance chemicals sectors.
• Asymmetric hydrogenation according to the invention comprises the steps of providing a hydrogenation substrate according to formula (2), and reacting with hydrogen gas in the presence of a PhanePhos ligand according to formula (3) complexed to rhodium.
• Ar 1 Ar 2 and more preferably each is phenyl or substituted phenyl, R 1 is alkyl and is more preferably methyl, R 2 is methyl or ethyl.
• substrate (2) is dissolved in a suitable solvent, preferably an alcohol solvent selected from the group comprising methanol, ethanol, isopropanol and trifluoroethanol or mixtures thereof. More preferably, the solvent is methanol.
• a suitable solvent preferably an alcohol solvent selected from the group comprising methanol, ethanol, isopropanol and trifluoroethanol or mixtures thereof. More preferably, the solvent is methanol.
• the reaction may be run at hydrogen pressures in the range of 2-30 bar, or higher, and is preferably run at a hydrogen pressure in the range of 5-15 bar.
• the reaction may be run at temperatures in the range of 10-100 0 C, or higher, and is preferably run at a temperature in the range of 20-60 0 C.
• the resultant 3,3-diarylalanine derivative (1) is formed with an enantiomeric excess of at least 80%, more preferably of around 90% ee, or higher. If required for a specific application, the enantiomeric excess of the resultant 3,3-diarylalanine derivative (1) may be enhanced to from about 80-90% e.e to 95% ee or higher, by the addition of a further step selected from the group consisting of crystallization, crystallization of a salt derivative or by selective hydrolysis in the presence of an enantioselective biocatalyst.
• the preferred catalysts demonstrated both high selectivity and activity in comparison to prior art catalysts based on alternative ligands such as bis(phosphacycles), as evidenced by the results summarized in Table 1 of Example 1, for the asymmetric hydrogenation of methyl 2-acetylamino-3,3-diphenylacrylate.
• the invention is further illustrated by the following examples.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Catalysts (AREA)

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• 2006
  • 2006-05-09 EP EP06770147A patent/EP1885688B1/en not_active Not-in-force
  • 2006-05-09 AT AT06770147T patent/ATE482182T1/de not_active IP Right Cessation
  • 2006-05-09 WO PCT/US2006/017978 patent/WO2006127273A2/en not_active Ceased
  • 2006-05-09 DE DE602006017064T patent/DE602006017064D1/de active Active
  • 2006-05-09 CN CN2006800170720A patent/CN101175715B/zh not_active Expired - Fee Related
  • 2006-05-09 JP JP2008512351A patent/JP5001263B2/ja not_active Expired - Fee Related

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