Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1996-03-11
1998-03-17
Kumar, Shailendra
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
435131, 435195, 435196, 435280, 546247, C07C23102, C07C23116
Patent
active
057288763
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 94/03102, filed Sep. 19, 1994.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel process for resolving the racemates of primary and secondary amines by reacting with an ester in the presence of a hydrolase and subsequently separating one amine which has been enantioselectively acylated from the other, unreacted, enantiomer of the amine.
2. Description of Related Art
Resolution of the racemates of amines by enzyme-catalyzed reaction with esters is known. Kitaguchi et al. (J. Amer. Chem. Soc. 111 (1989) 3094-3095) describe the resolution of racemates of amines with trifluoroethyl butyrate with catalysis by subtilisin. The enantioselectivity of this reaction is, however, greatly dependent on the solvent. Even with the most suitable of the solvents described (3-methyl-3-pentanol) only moderate selectivity is achieved.
WO 91/19002 describes a process for the chiral enrichment of asymmetric primary amines, in which the amines are reacted with ethyl acetate or ethyl butyrate with catalysis by subtilisin. The enantiomeric excesses achieved thereby are, however, unsatisfactory; in addition, long reaction times of up to several weeks are required.
Gotor et al. (J. Chem. Soc. Chem. Commun. (1988) 957-958) describe the enantioselective acylation of 2-amino-1-butanol with ethyl acetate with catalysis by pig pancreatic lipase (PPL). In this case, the ester used (ethyl acetate) is also employed as a solvent. No satisfactory results are obtained on use of other solvents or other enzymes.
Brieva et al. (J. Chem. Soc. Chem. Commun. (1990) 1386-1387) describe the enantioselective synthesis of amides from racemic primary amines by reaction with 2-chloropropionate with catalysis by subtilisin in hexane or Candida cylindracea lipase in 3-methyl-3-pentanol.
Quiros et al. (Tetrahedron: Asymmetry 4 (1993) 1105-1112) describe the lipase-catalyzed synthesis of optically active amides from racemic .alpha.-halo-substituted ethyl propionates and primary amines. However, the enantioselectivity achieved with this reaction is unsatisfactory.
Asensio et al. (Tetrahedron Letters 32 (1991) 4197-4198) describe the lipase-catalyzed enantioselective acylation of secondary amines. However, this reaction takes place enantioselectively only with one amine and even there only with moderate success. Other amines show absolutely no enantioselectively.
The processes hitherto disclosed for enzyme-catalyzed racemate resolution either have too little enantioselectivity or can be carried out only under very specific conditions (solvent, enzyme). In addition, they require long reaction times and enormous amounts of enzyme for the catalysis so that a process based thereon is uneconomic.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process for the enzyme-catalyzed resolution of racemates of primary and secondary amines which ensures high enantioselectivity, can be employed in a wide range of reaction conditions and moreover makes do with minimal amounts of catalyst.
We have found that this object is achieved by a process for resolving the racemates of primary and secondary amines by reacting with an ester with specific catalysis by a hydrolase and subsequently separating one amine which has been enantioselectively acylated from the other, unreacted, enantiomer of the amine, which process functions particularly well when the acid component of the ester has an electron-rich heteroatom selected from the group comprising fluorine, nitrogen, oxygen and sulfur atoms in the vicinity of the carbonyl carbon atom.
We have also found a process for preparing acylated primary and secondary amines by reacting the amines with an ester with specific catalysis by a hydrolase, wherein the acid component of the ester has a fluorine, nitrogen, oxygen or sulfur atom in the vicinity of the carbonyl carbon atom.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Esters suitable for the process according to the invention are those which have an electron-rich heteroatom
REFERENCES:
patent: 5057607 (1991-10-01), Zmijewski, Jr. et al.
Enzymatic Aminolysis . . . Gotor et al., Tetrahedron, vol. 47, No. 44, pp. 927-2914, 1991.
Chem Abst. 115:278181j, Fermentations, vol. 115, 1991, p. 847.
Enzymatic Synthesis of Amides . . . Brieva et al., J. Chem So., 1990, pp. 1386-1387.
Lipase-Catalyzed Synthesis . . . , Tetrahedron, vol. 4, No. 6, pp. 1105-1112, 1993, Quiros et al.
Balkenhohl Friedhelm
Hauer Bernhard
Ladner Wolfgang
Nubling Christoph
Pressler Uwe
BASF - Aktiengesellschaft
Kumar Shailendra
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