Indian Patents. 223289:PROCESS FOR THE RACEMISATION OF ENANTIOMERICALLY ENRICHED ALPHA-AMINO NITRILES

Title of Invention	PROCESS FOR THE RACEMISATION OF ENANTIOMERICALLY ENRICHED ALPHA-AMINO NITRILES
Abstract	The present invention relates to Process for the racemisation of an enantiomerically enriched a-amino nitrile characterized in that the enantiomerically enriched a-amino nitrile is contacted with a Lewis acid catalyst at a temperature in the range between 20 to 120°C and the concentrate of amino nitrile is in the range of 0.1 and 2M.

Full Text	PROCESS FOR THE RACEMISATION OF ENANTIOMERICALLY ENRICHED g-AMlNO NITRILES The invention relates to a process for the racemisation of enantiomerically enriched a-amino nitriies. Many enantiomerically enriched active ingredients like pharmaceuticals and agrochemicals can be prepared using enantiomerically enriched a-amino nitriies, which are commonly used as a precursor for a-amino acids or derivatives thereof. The preparation of pharmaceuticals or agrochemicals generally involves a process with many consecutive steps. a-Amino nitriies can be converted into a wide variety of compounds, for example a-amino acids, a-amino acid amides, p-amino alcohols, vicinal diamines and protected a-amino aldehydes, and therefore are broadly applicable in the preparation of enantiomerically enriched active ingredients. The preparation of enantiomerically enriched compounds commonly includes a resolution step wherein the undesired enantiomer is left as a byproduct. In such resolutions the theoretical maximum yield with regard to the starting material is 50%. The yield can increase significantly by racemisation and recycling of the undesired enantiomer. Preferably the resolution process is combined with racemisation in situ. Therefore, there exists a need for a racemisation process of a-amino nitriies that is compatible with a large variety of resolution processes. A process wherein an in situ racemisation of an enantiomerically enriched a-amino nitrile occurs is described in US-A-4683324. A disadvantage of the process of US-A-4683324 is that a protic solvent has to be used. It is known that a-amino nitriies partly decompose in protic solvents. Therefore, in the process of US-A-4683324 HCN is added in order to suppress decomposition. From EP-A-1050529 it is further known that non polar, (but actually meaning aprotic) solvents stabilize a-amino nitriies with respect to decomposition and prevent racemisation. It is the object of the invention to provide a process for the racemisation of a-amino nitriies wherein a racemisation with less decomposition is achieved, and that can be used in combination with resolutions in the preparation of enantiomerically enriched compounds in high yield and high enantiomeric excess. This object is achieved according to the invention by using a Lewis acid catalyst. Lewis acids by definition are able to accept an electron pair from compounds that have a free available electron pair. Suitable Lewis acid catalysts according to the invention comprise a metal ion M , which is complexed according to the genaral structure MnXpSqLr in which n represents an integer larger than or equal to 1, for instance is equal to 1, 2, 3, 4, 5, 6, 7 and p, q and r each independently represent an integer larger than or equal to 0, for instance 0, 1, 2, 3, 4, 5, 6, 7 and in which n and p are chosen such that MnXp is neutral. The metal M may be in the ionic form (Mk+) with suitable counter ions X, wherein k represents the valence of the metal ion, or in the zero valent form (M°) with p = 0. Suitable metals are for instance metals chosen from main group elements IA-IVA of the Periodic Table (CAS version), the transition metals and the lanthanides, preferably Al, Ti, Zr, or a lanthanide, for example Sm or La, or combinations thereof. X represents an anionic counter ion or covalently bound anionic ligand for non zero valent metals. Suitable examples are halides, in particular CI" or Br' ; alkyl groups with e.g. 1-12 C-atoms, for example methyl, ethyl, n-propyl (nPr) or i-butyl (Bu) groups, alkoxy groups with e.g. 1-12 C-atoms, for example n-pentoxy, i-propoxy, t-butoxy groups preferably the alkoxy groups derived from a secondary alcohol; anions derived from amides, aminoalcohols or amines; CN" groups; anionic aromatic ligands, in particular cyclopentadienyl (Cp), pentamethyl cyclopentadienyl (Cp) or indenyl. S represents a so-called spectator ligand, a neutral ligand which is difficult to exchange by other ligands, for example aromatic compounds or olefines. Examples of aromatic compounds are aromatic hydrocarbons, for instance benzene, toluene, cumene, cymene or mesitylene. Suitable olefines are for instance dienes, in particular 1,5-cyclooctadiene or 1,5-hexadiene. L represents a neutral ligand, which can be relatively easy exchanged by other ligands, for example phosphines in particular PPh3 or PCy3, nitriles or coordinating solvent molecules, especially tetrahydrofuran (THF), acetonitrile, dimethylfomamide, alcohols, amines, in particular tertiary amines, for example Et3N. Catalyst represented by the general structure MnXpSqLr as described above are generally known in the art. As will be understood by the person skilled in the art the distinction between spectator ligand S and neutral ligands L is gradual and amenable to discussion; besides that it may depent on the reaction conditions. Examples of suitable catalyst are: LiBr, AKO'Prfe, AICI3i Al(alkyl)3, with each alkyl is a C1-C12 alkyl group, AI(Et2)CN, AI(iBu)2H,i AI(CH3)-0-) n. Zr(OtBu)4, Zirconocene, Sm(0'Pr)3(Sm(Cp)3, La(Cp)3. Particularly preferred catalyst are aluminum alkoxides, aluminum alkyls, lanthanide alkoxides, for instance samarium alkoxides, and lanthanocenes, for instance lanthanide tris-cyclopentadienyl compounds. The racemisation can be carried out in the presence of a solvent. Preferably aprotic solvents are used in the racemisation according to the invention, for instance aliphatic hydrocarbons, for example hexane, heptane; aromatic hydrocarbons, for example toluene and xylene; ethers, for example methyl t-butyl ether (MTBE); esters, for example ethyl acetate; or mixtures thereof. The concentration of the amino nitrile in the reaction mixture preferably is between 0.1 and 2 M. The temperature for the racemisation preferably will be chosen as high as possible and such that still a sufficiently low level of decomposition is maintained under the reaction conditions. The optimal temperature can be determined by the skilled person and lies for instance between -20 and 120 °C, preferably between 30 and 100 °C. The racemisation according to the invention can be combined with a separate resolution processes or with an in situ resolution process so that in principle the product can be obtained in 100% yield and 100% ee. In a particularly preferred embodiment of the invention, racemisation is applied in combination with an in situ resolution process. Examples of resolution processes that can be combined with the racemisation according to the invention are for instance, crystallization induced resolutions (classical resolutions), for instance resolutions via diastereoisomeric salt formation or entrapment, enzymatic resolutions, or resolutions achieved by physical separation methods. Examples of resolution process in combination with an insitu racemisation are, for instance, crystallization induced asymmetric transformations or dynamic kinetic resolutions (DKR). A clear advantage of the racemisation according to the invention is that an aprotic solvent can be chosen. In order to achieve a "100% yield, 100° ee" result as a rule it is better to use aprotic solvents in resolution processes. For instance, aprotic organic solvents show less deactivation of enzymes in enzymatic processes than protic organic solvents. Thus, in combination with an enzymatic resolution (DKR) aprotic solvents are particularly suitable solvents to be used in stereoselective reactions e.g. stereoselective acylation reactions or stereoselective nitrile converting reactions. For asymmetric transformations low solubilities of diastereomeric salts are preferred and can be achieved by aprotic solvents. In such "100% yield and 100% ee" concepts the racemisation system is chosen such that the racemisation system is compatible with the stereo differentiating process, for instance with the resolving agents or the enzyme used in the resolution. The choice of the optimum reaction conditions will as a rule be a compromise between the optimum resolving or stereo differentiating process conditions and the optimum racemisation conditions. The person skilled in the art will be able to find the optimal conditions for his situation. The temperature range, for instance, mostly will be chosen between 0 and 120 °C, preferably 20 and 110 °C. The concentration of the amino nitrile in the reaction mixture preferably is between 0.1 and 2M. Examples of amino nitriles that can be racemised according to the invention are for instance amino nitriles with formula (1) wherein denotes a chiral C-atom, R\ R2, R3 and R4 each independently represent H, an optionally substituted alkyl, aryl, alkaryl or aralkyl group with, for instance 1-20 C-atoms, or R1 and R2 or R1 and R3 or R 3and R4 together with the atom(s) to which they are attached form an optionally substituted 4-8 membered (hetero)cyclic group with for instance 3-20 C-atoms. The invention will be elucidated by the following examples, without however being limited thereby. Example I Racemisation using diethvlaluminum cyanide In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 1 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. A 1 M solution of diethylaluminum cyanide in toluene was added by syringe and the reaction mixture was stirred under nitrogen at 80°C for 18 h. The results are given in Table 1. Example II Racemisations at room temperature using aluminum complexes Fresh stock solutions (0.1 m in toluene) were prepared from a) diethylaiuminum cyanide ((C2H5)2AICN)), b) triethylaluminum ((C2H5)3AI), c) tri-i-butylaluminum [(CH3)2CHCH2]3AI and d) MAO (methylaluminoxane). each stock solution was used as catalyst solution in following racemisation procedure for 2-amino-3-phenylpropionitrile. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, 0.1 ml of catalyst solution was added by syringe and the reaction mixture was stirred under nitrogen at room temperature. The results are given in Table 2, below. Example 111 Racemisation at room temperature using DIBAL A 0.1 M stock solution of DIBAL (diisobutylaluminum hydride) in hexane was prepared by dilution from a 1 M solution in hexane. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, 0.1 ml of the 0.1 M stock solution in hexane was added by syringe and the reaction mixture was stirred under nitrogen at room temperature. After 1.25 h, 2-amino-3-phenylpropionitrile was racemised to 59 % e.e.. Example IV Racemisation of (R)-2-amino-3-phenvlpropionitrile using heterogeneous racemisation catalyst Catalyst and solid (R)-2-amino-3-phenylpropionitrile (0.1 mmol, e.e. > 99 %) were weight under a dry atmosphere in a glovebox in a pre-dried 5 ml vial, equipped with magnetic stirrer bar. The vial was sealed with a teflon-lined cap and taken out of the glovebox. To the heterogeneous mixture, 1 ml dry solvent was added by syringe, and the reaction mixture was stirred under nitrogen at temperature given in Table 3 below. Example V Racemisation of (R)-2-amino-3-phenvlpropionitrile using aluminum isopropoxide A) Catalysis with solid aluminum isopropoxide Solid aluminum isopropoxide (AI(0'Pr)3) and solid (R)-2-amino-3-phenylpropionitrile (0.1 mmol, e.e. > 99 %) were placed in a vial of 5 ml and dissolved in 1 ml solvent. The vial was sealed with a teflon-lined cap, the solution degassed by nitrogen and the racemisation was carried out at temperatures given in Table 4 below. B) Aluminum isopropoxide prepared from other aluminum derivatives Catalyst solution 1: Aluminum isopropoxide derived from diethylaluminum cyanide (C2H5)2AICN) Into a 25-ml vial was added isopropanol (3 mmol) and toluene (9 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 1 ml of a 1 M solution of (C2H5)2AICN in toluene was added under nitrogen atmosphere. Catalyst solution 2: Aluminum isopropoxide derived from diethylaluminum cyanide (C2H5)2AICN) Similar procedure as for catalyst solution 1 followed by heating at 80°C for 1 h. Catalyst solution 3: Aluminum isopropoxide derived from triethylaluminum ((C2H5)3AI). Into a 25-ml vial was added isopropanol (4 mmol) and toluene (9 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 1 ml of a 1 M solution of (C2H5)3AI in toluene was added under nitrogen atmosphere. The obtained catalyst solution was allowed to stand for 1 night at room temperature. Catalyst solutions 1, 2 and 3 were used in standard racemisation protocol for (R)-2- amino-3-phenylpropionitrile: In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, catalyst solution was added by syringe and the reaction mixture was heated at temperature given in Table 5 below. C) Aluminum isoproooxide prepared from other aluminum derivatives, catalytic racemisation in the presence of triethvlamine Catalyst solution: Aluminum isopropoxide derived from trimethylaluminum ((Ch^A!). Into a 25-ml vial was added isopropanol (3 mmol) and toluene (9.5 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 0.5 ml of a 2 M solution of (CH3)3AI in toluene is added under nitrogen atmosphere. The obtained catalyst solution was allowed to stand for 15 minutes at room temperature and for 15 minutes at 80°C respectively. Stock solution triethylamine: Into a 50-ml vial was added triethylamine (2,54 mmol) and toluene (25 ml). The vial was sealed with a teflon-lined cap and stored at room temperature. Catalyst solution was used in standard racemisation protocol for (R)-2-amino-3- phenylpropionitrile in presence of triethylamine: In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in toluene and stock solution of triethylamine was added. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, catalyst solution was added by syringe and the reaction mixture was heated at 60°C for 19 h. D) Racemisation of (R)-2-amino-3-phenvlpropionitrile using AMO'Prtg prepared from trimethvlaluminum ((CHa)aAI) v.s. solid AlfO'Prta Catalyst solution was derived from trimethylaluminum ((CH3)3AI). Into a 25-mt vial was added isopropanol (3 mmol) and toluene (9.5 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 0.5 ml of a 2 M solution of (CH3)3AI in toluene is added under nitrogen atmosphere. The obtained catalyst solution was allowed to stand for 15 minutes at room temperature and for 15 minutes at 80°C, respectively. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) and solid AI(OjPr)3 was dissolved in toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, catalyst solution was added by syringe and the reaction mixture was heated at 60°C for 2 h. The results are given in Table 7. Example VI Racemisation of (R)-2-amino-3-phenvlpropionitrile using AKO'Prk in the presence of trimethvlsilvl cyanide (TMS-CN) In a 5 ml vial, toluene (1 ml) was added to 0.1 mmol (R)-2-amino-3-phenyIpropionitrile (e.e. > 99 %), AI(0'Pr)3 (0.01 mmol) and TMS-CN. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. The temperature of the reaction mixture was increased to 80°C for 3 h. The results are given in Table 8. Example VII Racemisation of (R)-2-amino-3-phenvlpropionitrile using diethvlaluminum cyanide (CgHsWMCN) in combination with isopropanol Catalyst solution: Into a 50-ml vial was added toluene (10 ml). The vial was sealed with a teflon-lined cap and the toluene was degassed by nitrogen. To the toluene is added under nitrogen atmosphere respectively, 0.4 ml of a 1 M solution of (C2H5)2AICN in toluene and isopropanol (8.5 mmol). The obtained catalyst solution was allowed to stand for 1 night at room temperature and used in catalytic racemisation of (R)-2-amino-3-phenylpropionitrile: In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 1 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, catalyst solution was added by syringe and the temperature was increased to 80°C. The results are given in Table 9. ExampleVIII Racemisation of (R)-2-amino-3-phenylpropionitrile using aluminum/amine catalyst Catalyst solution 1: Into a 50-ml vial was added benzylamine (2 mmol) and toluene (9 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 1 ml of a 1 M solution of (C2H5)2AICN in toluene was added under nitrogen atmosphere. Catalyst solution 2, 3 and 4: Into a 25-ml vial was added amine (3 mmol) and toluene (9 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 0.5 ml of a 2 M solution of (CH3)3AI in toluene was added under nitrogen atmosphere. Temperature was increased to 80°C for 1 night. Catalyst solutions were used in the catalytic racemisation of (R)-2-amino-3-phenylpropionitrile: In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, 0.1 ml catalyst solution was added by syringe and the temperature was increased to 60°C for 1 hour. The results are given in Table 10. Example IX Racemisation of (R)-2-amino-3-phenvlpropionitrile using diethvlaluminum cyanide (C2H5)2AICN in presence of isopropyl acetate Catalyst solution: Into a 50-ml vial was added toluene (9 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 1 ml of a 1 M solution of (C2H5)2AICN in toluene was added under nitrogen atmosphere. Catalyst solution was used in standard racemisation protocol for (R)-2-amino-3- phenylpropionitrile in presence of isopropyl acetate: In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) and isopropyl acetate (0.11 mmol) were dissolved in 0,9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the degassed solution, 0.1 ml catalyst solution was added by syringe and the reaction mixture was allowed to stand at ambient temperature for 1 h, after which 2-amino-3- phenylpropionitrile was racemised to 23 % e.e.. Example X Racemisation of (R)-2-amino-3-phenylpropionitrile using lithium salts LiBr was dried under vacuum at 300°C prior to use. New LiPF6 was used as such in glovebox. Stock lithium salts In a glovebox, lithium salt was added to a 25 ml-vial. The vial was sealed with a teflon-lined cap and taken out of the glovebox. Dry THF was added and the lithium salt was dissolved. Racemisation of (R)-2-amino-3-phenylpropionitrile using lithium salts To a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was added. The vial was sealed with a teflon-lined cap and degassed by nitrogen. To the (R)-2-amino-3-phenylpropionitrile-containing vial was added catalyst solution (1 ml) and the 2-amino-3-phenylpropionitrile was dissolved. The racemisation was performed under nitrogen at given temperature. The results are summarized in Table 11. Example XI Racemisation of (R)-2-amino-3-phenvlpropionitrile nitrile using early transition metal catalysts Racemisation using Zr(OBu')4 Preparation catalyst solution, a general procedure: Zr(OBu')4 was placed in a 5 ml vial under an atmosphere of dry nitrogen and toluene, freshly distilled from sodium metal, was introduced and the vial was sealed with a teflon-lined cap. Racemisation of (R)-2-amino-3-phenylpropionitrile In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenyIpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added a toluene solution of Zr(OBu')4 (0.1 ml) by syringe and the reaction mixture was stirred for 24 h at 80°C. The results are given in Table 12. Catalyst solution The complex (0.1 mmol) was placed in a 5 ml vial under an atmosphere of dry nitrogen and toluene (1 ml) freshly distilled from sodium metal was introduced. The vial was sealed with a teflon-lined cap and the mixture was stirred until the complex was completely dissolved. Racemisation of (R)-2-amino-3-phenylpropionitrile. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the reaction mixture was stirred for 24 h at 50°C. The results are given in Table 13. Example XII Racemisation of (R)-2-amino-3-phenvlpropionitrile using aluminum alkoxides Aluminum alkoxide catalysts prepared from Me3AI. Preparation catalyst solution, a general procedure: Alcohol (3 mmol) was placed in a 25 ml-vial and toluene (9.5 ml) freshly distilled from sodium metal was introduced. The vial was sealed with a teflon-lined cap and degassed by nitrogen. To this solution was added a 2 M toluene solution of Me3AI (0.5 ml, 1 mmol) and a stream of dry nitrogen removed the generated methane. After standing for 15 minutes at room temperature, the temperature is increased to 80°C for a period of time given in Table. Racemisation of (R)-2-amino-3-phenylpropionitrile In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the temperature of the reaction mixture was increased to 60°C. Degrees of racemisation during a period of time are given in Table 14. Aluminum alkoxide catalyst prepared from Bu3AI Isopropanol (3 mmol) was placed in a 25 ml-vial and toluene (9 ml) freshly distilled from sodium metal was introduced. The vial was sealed with a teflon-lined cap and degassed by nitrogen. To this solution was added a 1 M toluene solution of Bu3AI (1 ml, 1 mmol) and a stream of dry nitrogen removed the generated butane. After standing for 15 minutes at room temperature, the temperature is increased to 80°C for a period of time given in Table. Racemisation of (R)-2-amino-3-phenylpropionitrile. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the temperature of the reaction mixture was increased to 60°C. Degree of racemisation is given in Table 15. Example XIII Racemisation of (R)-2-amino-3-phenvlpropionitrile catalysed by bis(1.5- cvclooctadiene)rhodium (I) tetrafluoroborate (R)-2-Amino-3-phenylpropionitrile (e.e. > 99 %) (146 mg, 0.1 mmol) and bis(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (4.5 mg, 0.011 mmol) were placed in a dry 5 ml vial. The vial was sealed with a teflon-lined cap, freshly distilled toluene (0.9 ml) was introduced and the reaction mixture was degassed by nitrogen. The temperature of the reaction mixture was increased to 60°C for 18 h, after which time (R)-2-Amino-3-phenylpropionitrile was racemised to 62 % e.e.. Example XIV Racemisation of (R)-2-amino-3-phenvlpropionitrile using metal isopropoxides Catalyst solution Into a previously dried 25-ml vial was added metal isopropoxide (1 mmol) under an atmosphere of dry nitrogen. To the metal isopropoxide was added freshly from sodium distilled toluene (10 ml) and the vial was sealed with a teflon-lined cap. Racemisation of (R)-2-amino-3-phenylpropionitrile A 5 ml vial was charged with 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) and dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the homogeneous solution was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the temperature of the reaction mixture was increased to 60°C. Degrees of racemisation during a period of time using different metal catalysts are given in Table 16. Example XV Racemisation of (R)-2-amino-2.3-dimethylbutyronitrile using Al(O'Pr)a In two 5 ml vial, 0.1 mmol (R)-2-amino-2,3-dimethylbutyronitrile (e.e. 86 %) was weighed. To these vails 0.9 ml of toluene was added. The vials were sealed with teflon-lined caps and the solutions were degassed by nitrogen. To one of the degassed solution, 0.2 ml of a 0.1 M AI(0'Pr)3 catalyst solution in toluene was added by syringe. The temperature of the reaction mixture and blank reaction was increased to 60°C. After Vz hour a sample of the reaction mixture and blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 17. Example XVI Racemisation of (R)-2-amino-2,3-dimethvlbutvronitrile using AlEt3 In two 5 ml vial, 0.1 mmol (R)-2-amino-2,3-dimethylbutyronitrile (e.e. 86 %) was weighed. To these vails 0.9 ml of toluene was added. The vials were sealed with teflon-lined caps and the reaction mixture and blank were degassed by nitrogen. To one of the degassed solutions, 0.2 ml of a 0.1 M AIEt, catalyst solution in toluene was added by syringe. The reaction mixture and blank reaction were allowed to stand at room temperature. After 5 minutes a sample of the reaction mixture and blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 18. Example XVII Racemisation of (R)-2-amino-2.3-dimethvlbutvronitrile using Zr(BuO)4. In two 5 ml vials, 0.1 mmol (R)-2-amino-2,3-dimethylbutyronitrile (e.e. 86 %) was weighed. To these vails 0.4 ml of toluene was added. The vials were sealed with teflon-lined caps and the reaction mixtures were degassed by nitrogen. To one of the degassed solutions, 0.6 ml of a 1M Zr(tBuO)4 catalyst solution in toluene was added by syringe. The temperature of the reaction mixture and blank reaction was increased to 80 °C. After 1 day a sample of the reaction mixture and blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 19. Example XVIII Racemisation of (R)-2-amino-3-methvlbutvronitrile using AI(0'Pr)s in two 5 ml vial, 0.1 mmol (R)-2-amino-3-methylbutyronitrile (e.e. 74 %) was weighed. To both 0.9 ml toluene was added. The vials were sealed with a teflon-lined cap and the reaction mixtures were degassed by nitrogen. To one of the degassed solution, 0.1 ml of a 0.1 M AI(O'Pr)3 catalyst solution in toluene was added by syringe. The temperature of the reaction mixtures was increased to 60°C. After 55 minutes a sample of the reaction mixture and the blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 20. Example XIX Dynamic Kinetic Resolution of (R)-2-amino-3-phenylpropionitrile by racemisation with AKO'Pria and enzymatic acvlation catalyzed by Novozvme 435® To a solution of 75 mg (0.51 mmol) (R)-2-amino-3-phenylpropionitrile and 104 mg (0.59 mmol) i-propyl phenylacetate in 4.2 g o-xylene was added 201 mg of Novozyme 435®. After stirring the reaction mixture for 20 minutes at ambient temperature, under reduced pressure (-100 mbar), 0.44 g (0.05 mmol) of a 0.1 M AI(0'Pr)3 solution in toluene was added. The reaction mixture was stirred at 70°C, under reduced pressure (-100 mbar) for 43 hours. After -20 hours another 185 mg Novozyme 435® and 0.42 g AI(OjPr)3 solution in toluene was added. The reaction was analysed by HPLC. After 43 hours N-phenylacetyl-(S)-2-amino-3-phenylpropionitrile was formed 64% e.e.(S). The starting material was partially racemised. Example XX Asymmetric transformation of 2-amino-3-phenvlpropionitrile using AKO'Prta as racemisation catalyst The 1:1 diastereomeric salt of racemic 2-amino-3-phenylpropionitrile and N-(4- chlorobenzoyl)-L-glutamic acid was made by dissolving an 2.5 g (17 mmol) of 2-amino- 3-phenylpropionitrile and 4.8 g (17 mmol) of N-(4-chlorobenzoyl)-L-glutamic acid in 68 ml of methanol. The mixture was stirred at room temperature till everything was dissolved. The methanol was evaporated under reduced pressure to yield 7.2 g of the 1:1 diastereomeric salt (HPLC analysis: 2-amino-3-phenylpropionitrile Example XXI Asymmetric transformation of 2-amino-3-phenvlpropionitrile in toluene using SmgOfO'PrV^ as racemisation catalyst In 4.0 ml of methanol is dissolved 250 mg (1.7 mmol) of 2-amino-3-phenylpropionitrile, 480 mg (1.7 mmol) of N-(4-chlorobenzoyl)-L-glutamic acid and 100 mg of samarium iso-propoxide (Sm5O(OPr)13). The methanol was removed under reduced pressure, the residue was suspended in 2 ml of toluene. The toluene was evaporated to remove the last traces of methanol and to the residue was added 4 ml of toluene. The reaction mixture was stirred for 21.5 h at 80°C. After cooling the diastereomeric salt and the Sm5O(OiPr)13 was filtered off. This residue was suspended in CH2CI2 and washed with saturated NaHC03 solution. The CH2CI2 solution was dried and evaporated. The remaining (R)-2-amino-3-phenylpropionitrile (200 mg) was analysed by HPLC. The results are given in Table 22. Example XXII Asymmetric transformation of 2-amino-3-phenvlpropionitrile in heptane using Sm5O(O'Pr)13 as racemisation catalyst In 4.0 ml of methanol is dissolved 250 mg (1.7 mmol) of 2-amino-3-phenylpropionitrile, 480 mg (1.7 mmol) of N-(4-chlorobenzoyl)-L-glutamic acid and 100 mg of samarium iso-propoxide ( Sm5O(O'Pr)13 ). The methanol was removed under reduced pressure, the residue was suspended in 2 ml of heptane. The heptane was evaporated to remove the last traces of methanol and to the residue was added 4 ml of heptane. The reaction mixture was stirred for 21.5 h at 80°C. After cooling the diastereomeric salt and the Sm5O(O'Pr)i3 was filtered off. This residue was suspended in CH2CI2 and washed with saturated NaHC03 solution. The CH2CI2 solution was dried and evaporated. The remaining (R)-2-amino-3-phenylpropionitrile (205 mg) was analysed by HPLC. The results are given in Table 23. 1. Process for the racemisation of an enantiomerically enriched α -amino nitrite characterized in that the enantiomerically enriched α-amino nitrile is contacted with a Lewis acid catalyst in an aprotic solvent. 2. Process according to claim 1, wherein the Lewis acid catalyst comprises a metal chosen from main group elements IA-IVA of the Periodic Table (CAS version), the transition metals and the lanthanides, 3. Process according to claim 2 wherein the metal is chosen from the group consisting of Al, Ti, Zr, or lanthanides. 4. Process according to any one of claims 1-3, wherein a catalyst with the general structure MnXpSqLr is used, wherein M represents the metal, X represents an anionic counterion or covalently bound anionic ligand for non zero valent metals, S represents a spectator ligand, L represents a neutral ligand, n represents an integer larger than or equal to 1 and p, q and r each independently represent an integer larger than or equal to 0, and in which n and p are chosen such that MnXp is neutral. 5. Process according to claim 4, wherein the catalyst is chosen from the group of aluminum alkoxides, aluminum alkyls, lanthanide alkoxydes and lanthanocenes. 6. Process according to any one of claims 1-5, wherein the racemisation is performed in combination with a resolution process. 7. Process according to claim 6, wherein the racemisation is performed in combination with an enzymatic resolution process. 8. Process according to claim 6, wherein the racemisation is performed in combination with a crystallization induced resolution. 9. Process according to any one of claims 6-8, wherein the resolution process is combined with racemisation in situ. 10. Process according to claim 9, wherein the racemisation is performed in situ in a crystallization induced asymmetric transformation process.

Full Text

PROCESS FOR THE RACEMISATION OF ENANTIOMERICALLY ENRICHED
g-AMlNO NITRILES
The invention relates to a process for the racemisation of enantiomerically enriched a-amino nitriies.
Many enantiomerically enriched active ingredients like pharmaceuticals and agrochemicals can be prepared using enantiomerically enriched a-amino nitriies, which are commonly used as a precursor for a-amino acids or derivatives thereof. The preparation of pharmaceuticals or agrochemicals generally involves a process with many consecutive steps. a-Amino nitriies can be converted into a wide variety of compounds, for example a-amino acids, a-amino acid amides, p-amino alcohols, vicinal diamines and protected a-amino aldehydes, and therefore are broadly applicable in the preparation of enantiomerically enriched active ingredients. The preparation of enantiomerically enriched compounds commonly includes a resolution step wherein the undesired enantiomer is left as a byproduct. In such resolutions the theoretical maximum yield with regard to the starting material is 50%. The yield can increase significantly by racemisation and recycling of the undesired enantiomer. Preferably the resolution process is combined with racemisation in situ. Therefore, there exists a need for a racemisation process of a-amino nitriies that is compatible with a large variety of resolution processes.
A process wherein an in situ racemisation of an enantiomerically enriched a-amino nitrile occurs is described in US-A-4683324.
A disadvantage of the process of US-A-4683324 is that a protic solvent has to be used. It is known that a-amino nitriies partly decompose in protic solvents. Therefore, in the process of US-A-4683324 HCN is added in order to suppress decomposition. From EP-A-1050529 it is further known that non polar, (but actually meaning aprotic) solvents stabilize a-amino nitriies with respect to decomposition and prevent racemisation.
It is the object of the invention to provide a process for the racemisation of a-amino nitriies wherein a racemisation with less decomposition is achieved, and that can be used in combination with resolutions in the preparation of enantiomerically enriched compounds in high yield and high enantiomeric excess.
This object is achieved according to the invention by using a Lewis

acid catalyst. Lewis acids by definition are able to accept an electron pair from compounds that have a free available electron pair.
Suitable Lewis acid catalysts according to the invention comprise a metal ion M , which is complexed according to the genaral structure
MnXpSqLr
in which n represents an integer larger than or equal to 1, for instance is equal to 1, 2,
3, 4, 5, 6, 7 and p, q and r each independently represent an integer larger than or
equal to 0, for instance 0, 1, 2, 3, 4, 5, 6, 7 and in which n and p are chosen such
that MnXp is neutral.
The metal M may be in the ionic form (Mk+) with suitable counter ions X, wherein k represents the valence of the metal ion, or in the zero valent form (M°) with p = 0.
Suitable metals are for instance metals chosen from main group elements IA-IVA of the Periodic Table (CAS version), the transition metals and the lanthanides, preferably Al, Ti, Zr, or a lanthanide, for example Sm or La, or combinations thereof.
X represents an anionic counter ion or covalently bound anionic ligand for non zero valent metals. Suitable examples are halides, in particular CI" or Br' ; alkyl groups with e.g. 1-12 C-atoms, for example methyl, ethyl, n-propyl (nPr) or i-butyl (Bu) groups, alkoxy groups with e.g. 1-12 C-atoms, for example n-pentoxy, i-propoxy, t-butoxy groups preferably the alkoxy groups derived from a secondary alcohol; anions derived from amides, aminoalcohols or amines; CN" groups; anionic aromatic ligands, in particular cyclopentadienyl (Cp), pentamethyl cyclopentadienyl (Cp*) or indenyl.
S represents a so-called spectator ligand, a neutral ligand which is difficult to exchange by other ligands, for example aromatic compounds or olefines. Examples of aromatic compounds are aromatic hydrocarbons, for instance benzene, toluene, cumene, cymene or mesitylene. Suitable olefines are for instance dienes, in particular 1,5-cyclooctadiene or 1,5-hexadiene.
L represents a neutral ligand, which can be relatively easy exchanged by other ligands, for example phosphines in particular PPh3 or PCy3, nitriles or coordinating solvent molecules, especially tetrahydrofuran (THF), acetonitrile, dimethylfomamide, alcohols, amines, in particular tertiary amines, for example Et3N.
Catalyst represented by the general structure MnXpSqLr as described above are generally known in the art. As will be understood by the person skilled in the art the distinction between spectator ligand S and neutral ligands L is gradual and

amenable to discussion; besides that it may depent on the reaction conditions.
Examples of suitable catalyst are: LiBr, AKO'Prfe, AICI3i Al(alkyl)3, with each alkyl is a C1-C12 alkyl group, AI(Et2)CN, AI(iBu)2H,i AI(CH3)-0-) n. Zr(OtBu)4, Zirconocene, Sm(0'Pr)3(Sm(Cp)3, La(Cp)3. Particularly preferred catalyst are aluminum alkoxides, aluminum alkyls, lanthanide alkoxides, for instance samarium alkoxides, and lanthanocenes, for instance lanthanide tris-cyclopentadienyl compounds.
The racemisation can be carried out in the presence of a solvent. Preferably aprotic solvents are used in the racemisation according to the invention, for instance aliphatic hydrocarbons, for example hexane, heptane; aromatic hydrocarbons, for example toluene and xylene; ethers, for example methyl t-butyl ether (MTBE); esters, for example ethyl acetate; or mixtures thereof. The concentration of the amino nitrile in the reaction mixture preferably is between 0.1 and 2 M.
The temperature for the racemisation preferably will be chosen as high as possible and such that still a sufficiently low level of decomposition is maintained under the reaction conditions. The optimal temperature can be determined by the skilled person and lies for instance between -20 and 120 °C, preferably between 30 and 100 °C.
The racemisation according to the invention can be combined with a separate resolution processes or with an in situ resolution process so that in principle the product can be obtained in 100% yield and 100% ee. In a particularly preferred embodiment of the invention, racemisation is applied in combination with an in situ resolution process.
Examples of resolution processes that can be combined with the racemisation according to the invention are for instance, crystallization induced resolutions (classical resolutions), for instance resolutions via diastereoisomeric salt formation or entrapment, enzymatic resolutions, or resolutions achieved by physical separation methods. Examples of resolution process in combination with an insitu racemisation are, for instance, crystallization induced asymmetric transformations or dynamic kinetic resolutions (DKR). A clear advantage of the racemisation according to the invention is that an aprotic solvent can be chosen. In order to achieve a "100% yield, 100° ee" result as a rule it is better to use aprotic solvents in resolution processes. For instance, aprotic organic solvents show less deactivation of enzymes in enzymatic processes than protic organic solvents. Thus, in combination with an enzymatic resolution (DKR) aprotic solvents are particularly suitable solvents to be

used in stereoselective reactions e.g. stereoselective acylation reactions or stereoselective nitrile converting reactions. For asymmetric transformations low solubilities of diastereomeric salts are preferred and can be achieved by aprotic solvents.
In such "100% yield and 100% ee" concepts the racemisation system is chosen such that the racemisation system is compatible with the stereo differentiating process, for instance with the resolving agents or the enzyme used in the resolution. The choice of the optimum reaction conditions will as a rule be a compromise between the optimum resolving or stereo differentiating process conditions and the optimum racemisation conditions. The person skilled in the art will be able to find the optimal conditions for his situation. The temperature range, for instance, mostly will be chosen between 0 and 120 °C, preferably 20 and 110 °C. The concentration of the amino nitrile in the reaction mixture preferably is between 0.1 and 2M.
Examples of amino nitriles that can be racemised according to the invention are for instance amino nitriles with formula (1)

wherein * denotes a chiral C-atom, R\ R2, R3 and R4 each independently represent H, an optionally substituted alkyl, aryl, alkaryl or aralkyl group with, for instance 1-20 C-atoms, or R1 and R2 or R1 and R3 or R 3and R4 together with the atom(s) to which they are attached form an optionally substituted 4-8 membered (hetero)cyclic group with for instance 3-20 C-atoms.
The invention will be elucidated by the following examples, without however being limited thereby.
Example I
Racemisation using diethvlaluminum cyanide
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 1 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. A 1 M solution of diethylaluminum cyanide

in toluene was added by syringe and the reaction mixture was stirred under nitrogen at 80°C for 18 h. The results are given in Table 1.

Example II
Racemisations at room temperature using aluminum complexes
Fresh stock solutions (0.1 m in toluene) were prepared from a) diethylaiuminum cyanide ((C2H5)2AICN)), b) triethylaluminum ((C2H5)3AI), c) tri-i-butylaluminum [(CH3)2CHCH2]3AI and d) MAO (methylaluminoxane). each stock solution was used as catalyst solution in following racemisation procedure for 2-amino-3-phenylpropionitrile.
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, 0.1 ml of catalyst solution was added by syringe and the reaction mixture was stirred under nitrogen at room temperature. The results are given in Table 2, below.

Example 111
Racemisation at room temperature using DIBAL
A 0.1 M stock solution of DIBAL (diisobutylaluminum hydride) in hexane was prepared by dilution from a 1 M solution in hexane. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, 0.1 ml of the 0.1 M stock solution in hexane was added by syringe and the reaction mixture was stirred under nitrogen at room temperature. After 1.25 h, 2-amino-3-phenylpropionitrile was racemised to 59 % e.e..
Example IV
Racemisation of (R)-2-amino-3-phenvlpropionitrile using heterogeneous racemisation
catalyst
Catalyst and solid (R)-2-amino-3-phenylpropionitrile (0.1 mmol, e.e. > 99 %) were weight under a dry atmosphere in a glovebox in a pre-dried 5 ml vial, equipped with magnetic stirrer bar. The vial was sealed with a teflon-lined cap and taken out of the glovebox. To the heterogeneous mixture, 1 ml dry solvent was added by syringe, and the reaction mixture was stirred under nitrogen at temperature given in Table 3 below.

Example V
Racemisation of (R)-2-amino-3-phenvlpropionitrile using aluminum isopropoxide
A) Catalysis with solid aluminum isopropoxide
Solid aluminum isopropoxide (AI(0'Pr)3) and solid (R)-2-amino-3-phenylpropionitrile (0.1 mmol, e.e. > 99 %) were placed in a vial of 5 ml and dissolved in 1 ml solvent. The vial was sealed with a teflon-lined cap, the solution degassed by nitrogen and the racemisation was carried out at temperatures given in Table 4 below.

B) Aluminum isopropoxide prepared from other aluminum derivatives
Catalyst solution 1:
Aluminum isopropoxide derived from diethylaluminum cyanide (C2H5)2AICN) Into a 25-ml vial was added isopropanol (3 mmol) and toluene (9 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 1 ml of a 1 M solution of (C2H5)2AICN in toluene was added under nitrogen atmosphere.
Catalyst solution 2:
Aluminum isopropoxide derived from diethylaluminum cyanide (C2H5)2AICN)
Similar procedure as for catalyst solution 1 followed by heating at 80°C for 1 h.
Catalyst solution 3:
Aluminum isopropoxide derived from triethylaluminum ((C2H5)3AI).
Into a 25-ml vial was added isopropanol (4 mmol) and toluene (9 ml). The vial was

sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the
solution, 1 ml of a 1 M solution of (C2H5)3AI in toluene was added under nitrogen
atmosphere.
The obtained catalyst solution was allowed to stand for 1 night at room temperature.
Catalyst solutions 1, 2 and 3 were used in standard racemisation protocol for (R)-2-
amino-3-phenylpropionitrile:
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved
in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture
was degassed by nitrogen. To the solution, catalyst solution was added by syringe and
the reaction mixture was heated at temperature given in Table 5 below.

C) Aluminum isoproooxide prepared from other aluminum derivatives, catalytic racemisation in the presence of triethvlamine
Catalyst solution:
Aluminum isopropoxide derived from trimethylaluminum ((Ch^A!).
Into a 25-ml vial was added isopropanol (3 mmol) and toluene (9.5 ml). The vial was
sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the
solution, 0.5 ml of a 2 M solution of (CH3)3AI in toluene is added under nitrogen
atmosphere.
The obtained catalyst solution was allowed to stand for 15 minutes at room
temperature and for 15 minutes at 80°C respectively.
Stock solution triethylamine:
Into a 50-ml vial was added triethylamine (2,54 mmol) and toluene (25 ml). The vial

was sealed with a teflon-lined cap and stored at room temperature.
Catalyst solution was used in standard racemisation protocol for (R)-2-amino-3-
phenylpropionitrile in presence of triethylamine:
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved
in toluene and stock solution of triethylamine was added. The vial was sealed with a
teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution,
catalyst solution was added by syringe and the reaction mixture was heated at 60°C for
19 h.

D) Racemisation of (R)-2-amino-3-phenvlpropionitrile using AMO'Prtg prepared from trimethvlaluminum ((CHa)aAI) v.s. solid AlfO'Prta
Catalyst solution was derived from trimethylaluminum ((CH3)3AI). Into a 25-mt vial was added isopropanol (3 mmol) and toluene (9.5 ml). The vial was sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 0.5 ml of a 2 M solution of (CH3)3AI in toluene is added under nitrogen atmosphere.
The obtained catalyst solution was allowed to stand for 15 minutes at room temperature and for 15 minutes at 80°C, respectively. In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) and solid AI(OjPr)3 was dissolved in toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, catalyst solution was added by syringe and the reaction mixture was heated at 60°C for 2 h. The results are given in Table 7.

Example VI
Racemisation of (R)-2-amino-3-phenvlpropionitrile using AKO'Prk in the presence of trimethvlsilvl cyanide (TMS-CN)
In a 5 ml vial, toluene (1 ml) was added to 0.1 mmol (R)-2-amino-3-phenyIpropionitrile (e.e. > 99 %), AI(0'Pr)3 (0.01 mmol) and TMS-CN. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. The temperature of the reaction mixture was increased to 80°C for 3 h. The results are given in Table 8.

Example VII
Racemisation of (R)-2-amino-3-phenvlpropionitrile using diethvlaluminum cyanide
(CgHsWMCN) in combination with isopropanol
Catalyst solution:
Into a 50-ml vial was added toluene (10 ml). The vial was sealed with a teflon-lined cap
and the toluene was degassed by nitrogen. To the toluene is added under nitrogen
atmosphere respectively, 0.4 ml of a 1 M solution of (C2H5)2AICN in toluene and
isopropanol (8.5 mmol).
The obtained catalyst solution was allowed to stand for 1 night at room temperature
and used in catalytic racemisation of (R)-2-amino-3-phenylpropionitrile:
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved
in 1 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture

was degassed by nitrogen. To the solution, catalyst solution was added by syringe and the temperature was increased to 80°C. The results are given in Table 9.

ExampleVIII
Racemisation of (R)-2-amino-3-phenylpropionitrile using aluminum/amine catalyst
Catalyst solution 1:
Into a 50-ml vial was added benzylamine (2 mmol) and toluene (9 ml). The vial was
sealed with a teflon-lined cap and the solution was degassed by nitrogen. To the
solution, 1 ml of a 1 M solution of (C2H5)2AICN in toluene was added under nitrogen
atmosphere.
Catalyst solution 2, 3 and 4:
Into a 25-ml vial was added amine (3 mmol) and toluene (9 ml). The vial was sealed
with a teflon-lined cap and the solution was degassed by nitrogen. To the solution, 0.5
ml of a 2 M solution of (CH3)3AI in toluene was added under nitrogen atmosphere. Temperature was increased to 80°C for 1 night.

Catalyst solutions were used in the catalytic racemisation of (R)-2-amino-3-phenylpropionitrile:

In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To the solution, 0.1 ml catalyst solution was added by syringe and the temperature was increased to 60°C for 1 hour. The results are given in Table 10.

Example IX
Racemisation of (R)-2-amino-3-phenvlpropionitrile using diethvlaluminum cyanide
(C2H5)2AICN in presence of isopropyl acetate
Catalyst solution:
Into a 50-ml vial was added toluene (9 ml). The vial was sealed with a teflon-lined cap
and the solution was degassed by nitrogen. To the solution, 1 ml of a 1 M solution of
(C2H5)2AICN in toluene was added under nitrogen atmosphere.
Catalyst solution was used in standard racemisation protocol for (R)-2-amino-3-
phenylpropionitrile in presence of isopropyl acetate:
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) and isopropyl
acetate (0.11 mmol) were dissolved in 0,9 ml toluene. The vial was sealed with a
teflon-lined cap and the reaction mixture was degassed by nitrogen. To the degassed
solution, 0.1 ml catalyst solution was added by syringe and the reaction mixture was
allowed to stand at ambient temperature for 1 h, after which 2-amino-3-
phenylpropionitrile was racemised to 23 % e.e..

Example X
Racemisation of (R)-2-amino-3-phenylpropionitrile using lithium salts
LiBr was dried under vacuum at 300°C prior to use. New LiPF6 was used as such in glovebox.
Stock lithium salts
In a glovebox, lithium salt was added to a 25 ml-vial. The vial was sealed with a teflon-lined cap and taken out of the glovebox. Dry THF was added and the lithium salt was dissolved.

Racemisation of (R)-2-amino-3-phenylpropionitrile using lithium salts To a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was added. The vial was sealed with a teflon-lined cap and degassed by nitrogen. To the (R)-2-amino-3-phenylpropionitrile-containing vial was added catalyst solution (1 ml) and the 2-amino-3-phenylpropionitrile was dissolved. The racemisation was performed under nitrogen at given temperature. The results are summarized in Table 11.

Example XI
Racemisation of (R)-2-amino-3-phenvlpropionitrile nitrile using early transition metal
catalysts
Racemisation using Zr(OBu')4

Preparation catalyst solution, a general procedure:
Zr(OBu')4 was placed in a 5 ml vial under an atmosphere of dry nitrogen and toluene, freshly distilled from sodium metal, was introduced and the vial was sealed with a teflon-lined cap.

Racemisation of (R)-2-amino-3-phenylpropionitrile
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenyIpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added a toluene solution of Zr(OBu')4 (0.1 ml) by syringe and the reaction mixture was stirred for 24 h at 80°C. The results are given in Table 12.

Catalyst solution
The complex (0.1 mmol) was placed in a 5 ml vial under an atmosphere of dry nitrogen and toluene (1 ml) freshly distilled from sodium metal was introduced. The vial was sealed with a teflon-lined cap and the mixture was stirred until the complex was completely dissolved.
Racemisation of (R)-2-amino-3-phenylpropionitrile.
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the reaction mixture was stirred for 24 h at 50°C. The results are given in Table 13.

Example XII
Racemisation of (R)-2-amino-3-phenvlpropionitrile using aluminum alkoxides
Aluminum alkoxide catalysts prepared from Me3AI. Preparation catalyst solution, a general procedure:
Alcohol (3 mmol) was placed in a 25 ml-vial and toluene (9.5 ml) freshly distilled from sodium metal was introduced. The vial was sealed with a teflon-lined cap and degassed by nitrogen. To this solution was added a 2 M toluene solution of Me3AI (0.5 ml, 1 mmol) and a stream of dry nitrogen removed the generated methane. After standing for 15 minutes at room temperature, the temperature is increased to 80°C for a period of time given in Table.
Racemisation of (R)-2-amino-3-phenylpropionitrile

In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the temperature of the reaction mixture was increased to 60°C. Degrees of racemisation during a period of time are given in Table 14.

Aluminum alkoxide catalyst prepared from Bu3AI
Isopropanol (3 mmol) was placed in a 25 ml-vial and toluene (9 ml) freshly distilled from sodium metal was introduced. The vial was sealed with a teflon-lined cap and degassed by nitrogen. To this solution was added a 1 M toluene solution of Bu3AI (1 ml, 1 mmol) and a stream of dry nitrogen removed the generated butane. After standing for 15 minutes at room temperature, the temperature is increased to 80°C for a period of time given in Table.
Racemisation of (R)-2-amino-3-phenylpropionitrile.
In a 5 ml vial, 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) was dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the reaction mixture was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml)

by syringe and the temperature of the reaction mixture was increased to 60°C. Degree of racemisation is given in Table 15.

Example XIII
Racemisation of (R)-2-amino-3-phenvlpropionitrile catalysed by bis(1.5-
cvclooctadiene)rhodium (I) tetrafluoroborate
(R)-2-Amino-3-phenylpropionitrile (e.e. > 99 %) (146 mg, 0.1 mmol) and bis(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (4.5 mg, 0.011 mmol) were placed in a dry 5 ml vial. The vial was sealed with a teflon-lined cap, freshly distilled toluene (0.9 ml) was introduced and the reaction mixture was degassed by nitrogen. The temperature of the reaction mixture was increased to 60°C for 18 h, after which time (R)-2-Amino-3-phenylpropionitrile was racemised to 62 % e.e..
Example XIV
Racemisation of (R)-2-amino-3-phenvlpropionitrile using metal isopropoxides
Catalyst solution
Into a previously dried 25-ml vial was added metal isopropoxide (1 mmol) under an atmosphere of dry nitrogen. To the metal isopropoxide was added freshly from sodium distilled toluene (10 ml) and the vial was sealed with a teflon-lined cap.
Racemisation of (R)-2-amino-3-phenylpropionitrile
A 5 ml vial was charged with 0.1 mmol (R)-2-amino-3-phenylpropionitrile (e.e. > 99 %) and dissolved in 0.9 ml dry toluene. The vial was sealed with a teflon-lined cap and the homogeneous solution was degassed by nitrogen. To this solution was added catalyst solution (0.1 ml) by syringe and the temperature of the reaction mixture was increased

to 60°C. Degrees of racemisation during a period of time using different metal catalysts are given in Table 16.

Example XV
Racemisation of (R)-2-amino-2.3-dimethylbutyronitrile using Al(O'Pr)a
In two 5 ml vial, 0.1 mmol (R)-2-amino-2,3-dimethylbutyronitrile (e.e. 86 %) was weighed. To these vails 0.9 ml of toluene was added. The vials were sealed with teflon-lined caps and the solutions were degassed by nitrogen. To one of the degassed solution, 0.2 ml of a 0.1 M AI(0'Pr)3 catalyst solution in toluene was added by syringe. The temperature of the reaction mixture and blank reaction was increased to 60°C. After Vz hour a sample of the reaction mixture and blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 17.

Example XVI
Racemisation of (R)-2-amino-2,3-dimethvlbutvronitrile using AlEt3
In two 5 ml vial, 0.1 mmol (R)-2-amino-2,3-dimethylbutyronitrile (e.e. 86 %) was

weighed. To these vails 0.9 ml of toluene was added. The vials were sealed with teflon-lined caps and the reaction mixture and blank were degassed by nitrogen. To one of the degassed solutions, 0.2 ml of a 0.1 M AIEt, catalyst solution in toluene was added by syringe. The reaction mixture and blank reaction were allowed to stand at room temperature. After 5 minutes a sample of the reaction mixture and blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 18.

Example XVII
Racemisation of (R)-2-amino-2.3-dimethvlbutvronitrile using Zr(BuO)4.
In two 5 ml vials, 0.1 mmol (R)-2-amino-2,3-dimethylbutyronitrile (e.e. 86 %) was weighed. To these vails 0.4 ml of toluene was added. The vials were sealed with teflon-lined caps and the reaction mixtures were degassed by nitrogen. To one of the degassed solutions, 0.6 ml of a 1M Zr(tBuO)4 catalyst solution in toluene was added by syringe. The temperature of the reaction mixture and blank reaction was increased to 80 °C. After 1 day a sample of the reaction mixture and blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 19.

Example XVIII
Racemisation of (R)-2-amino-3-methvlbutvronitrile using AI(0'Pr)s
in two 5 ml vial, 0.1 mmol (R)-2-amino-3-methylbutyronitrile (e.e. 74 %) was weighed.

To both 0.9 ml toluene was added. The vials were sealed with a teflon-lined cap and the reaction mixtures were degassed by nitrogen. To one of the degassed solution, 0.1 ml of a 0.1 M AI(O'Pr)3 catalyst solution in toluene was added by syringe. The temperature of the reaction mixtures was increased to 60°C. After 55 minutes a sample of the reaction mixture and the blank was taken and analysed by HPLC. At this point the reaction mixture was racemic. The results are given in Table 20.

Example XIX
Dynamic Kinetic Resolution of (R)-2-amino-3-phenylpropionitrile by racemisation with
AKO'Pria and enzymatic acvlation catalyzed by Novozvme 435®
To a solution of 75 mg (0.51 mmol) (R)-2-amino-3-phenylpropionitrile and 104 mg (0.59 mmol) i-propyl phenylacetate in 4.2 g o-xylene was added 201 mg of Novozyme 435®. After stirring the reaction mixture for 20 minutes at ambient temperature, under reduced pressure (-100 mbar), 0.44 g (0.05 mmol) of a 0.1 M AI(0'Pr)3 solution in toluene was added. The reaction mixture was stirred at 70°C, under reduced pressure (-100 mbar) for 43 hours. After -20 hours another 185 mg Novozyme 435® and 0.42 g AI(OjPr)3 solution in toluene was added. The reaction was analysed by HPLC. After 43 hours N-phenylacetyl-(S)-2-amino-3-phenylpropionitrile was formed 64% e.e.(S). The starting material was partially racemised.
Example XX
Asymmetric transformation of 2-amino-3-phenvlpropionitrile using AKO'Prta as
racemisation catalyst
The 1:1 diastereomeric salt of racemic 2-amino-3-phenylpropionitrile and N-(4-
chlorobenzoyl)-L-glutamic acid was made by dissolving an 2.5 g (17 mmol) of 2-amino-
3-phenylpropionitrile and 4.8 g (17 mmol) of N-(4-chlorobenzoyl)-L-glutamic acid in 68
ml of methanol. The mixture was stirred at room temperature till everything was

dissolved. The methanol was evaporated under reduced pressure to yield 7.2 g of the 1:1 diastereomeric salt (HPLC analysis: 2-amino-3-phenylpropionitrile
Example XXI
Asymmetric transformation of 2-amino-3-phenvlpropionitrile in toluene using
SmgOfO'PrV^ as racemisation catalyst
In 4.0 ml of methanol is dissolved 250 mg (1.7 mmol) of 2-amino-3-phenylpropionitrile, 480 mg (1.7 mmol) of N-(4-chlorobenzoyl)-L-glutamic acid and 100 mg of samarium iso-propoxide (Sm5O(OPr)13). The methanol was removed under reduced pressure, the residue was suspended in 2 ml of toluene. The toluene was evaporated to remove the last traces of methanol and to the residue was added 4 ml of toluene. The reaction mixture was stirred for 21.5 h at 80°C. After cooling the diastereomeric salt and the Sm5O(OiPr)13 was filtered off. This residue was suspended in CH2CI2 and washed with saturated NaHC03 solution. The CH2CI2 solution was dried and evaporated. The remaining (R)-2-amino-3-phenylpropionitrile (200 mg) was analysed by HPLC. The results are given in Table 22.

Example XXII
Asymmetric transformation of 2-amino-3-phenvlpropionitrile in heptane using
Sm5O(O'Pr)13 as racemisation catalyst
In 4.0 ml of methanol is dissolved 250 mg (1.7 mmol) of 2-amino-3-phenylpropionitrile, 480 mg (1.7 mmol) of N-(4-chlorobenzoyl)-L-glutamic acid and 100 mg of samarium iso-propoxide ( Sm5O(O'Pr)13 ). The methanol was removed under reduced pressure, the residue was suspended in 2 ml of heptane. The heptane was evaporated to remove the last traces of methanol and to the residue was added 4 ml of heptane. The reaction mixture was stirred for 21.5 h at 80°C. After cooling the diastereomeric salt and the Sm5O(O'Pr)i3 was filtered off. This residue was suspended in CH2CI2 and washed with saturated NaHC03 solution. The CH2CI2 solution was dried and evaporated. The remaining (R)-2-amino-3-phenylpropionitrile (205 mg) was analysed by HPLC. The results are given in Table 23.

1. Process for the racemisation of an enantiomerically enriched α -amino nitrite
characterized in that the enantiomerically enriched α-amino nitrile is contacted
with a Lewis acid catalyst in an aprotic solvent.
2. Process according to claim 1, wherein the Lewis acid catalyst comprises a
metal chosen from main group elements IA-IVA of the Periodic Table (CAS
version), the transition metals and the lanthanides,
3. Process according to claim 2 wherein the metal is chosen from the group
consisting of Al, Ti, Zr, or lanthanides.
4. Process according to any one of claims 1-3, wherein a catalyst with the
general structure MnXpSqLr is used, wherein M represents the metal, X
represents an anionic counterion or covalently bound anionic ligand for non
zero valent metals, S represents a spectator ligand, L represents a neutral
ligand, n represents an integer larger than or equal to 1 and p, q and r each
independently represent an integer larger than or equal to 0, and in which n
and p are chosen such that MnXp is neutral.
5. Process according to claim 4, wherein the catalyst is chosen from the group of
aluminum alkoxides, aluminum alkyls, lanthanide alkoxydes and
lanthanocenes.
6. Process according to any one of claims 1-5, wherein the racemisation is
performed in combination with a resolution process.
7. Process according to claim 6, wherein the racemisation is performed in
combination with an enzymatic resolution process.
8. Process according to claim 6, wherein the racemisation is performed in
combination with a crystallization induced resolution.
9. Process according to any one of claims 6-8, wherein the resolution process is
combined with racemisation in situ.
10. Process according to claim 9, wherein the racemisation is performed in situ in
a crystallization induced asymmetric transformation process.

Documents:

« Previous Patent

Next Patent »

Patent Number

223289

Indian Patent Application Number

966/CHENP/2005

PG Journal Number

47/2008

Publication Date

21-Nov-2008

Grant Date

09-Sep-2008

Date of Filing

18-May-2005

Name of Patentee

DSM IP Assets B.V

Applicant Address

HET OVERLOON 1, 6411 TE HEELEN,

Inventors:

#	Inventor's Name	Inventor's Address
1	VERZIJL, GERARDUS, KAREL, MARIA	NICOLAASSTRAAT 12, NL-5855 AR WELL,
2	BROTERMAN, QUIRINUS, BERNARDUS	GELRESTRAAT 11, NL-6151 JA MUNSTERGELEEN,
3	KAPTEIN, BERNARDUS	IRENELAAN 33, NL-6133 BE SITTARD,

PCT International Classification Number

C07C 253/30

PCT International Application Number

PCT/EP03/12412

PCT International Filing date

2003-11-03

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	02102614.1	2002-11-21	EUROPEAN UNION