Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Patent
1991-11-06
1994-01-04
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
435109, 435232, 435280, 560155, C07C22900, C12P 1300, C12P 1304
Patent
active
052759415
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of N-protected dialkyl (2S,3S)-3-ethylaspartates or their salts, from unpurified (2S,3S)-3-ethylaspartic acid obtainable by enzymatic amination of ethylfumaric acid.
N-protected dialkyl (2S, 3S) -3-ethylaspartates are useful intermediates for the preparation of a .gamma.-lactambridged 2S,3R,2'S-isoleucine-alanine dipeptide (for example J. P. Wolf, H. Rapoport, J. Org. Chem. 1989, 54, 3164-3173.).
Above and below, the abbreviations have the meaning:
The-dimethyl ester I can be prepared by enantioselective alkylation of dimethyl N-9-phenylfluorenylaspartate according to J. P. Wolf and H. Rapoport (loc. cit.) as in Scheme 1. ##STR1## KHMDS=potassium hexamethyldisilacide
This process, however, has several disadvantages which make introduction of this synthetic route into large-scale production impossible. On the one hand, the bulky amino protective group 9-phenylfluorenyl, which is essential for the success of the enantioselective alkylation, is accessible with difficulty and hard to introduce, and on the other hand the base potassium hexamethyldisilazane, which is prepared by reaction of potassium hydride with di(trimethylsilyl)amine, can only be handled with particular safety measures. Moreover, the alkylation takes place only with an enantioselectivity of 3.5:1, i.e. about 25% of the (2S,3R) enantismer is formed.
The use of the expensive ethyl trifluoromethanesulfonate as the required alkylating agent also stands in the way of an economically worthwhile use.
According to D. Seebach et al., Angew. Chemie 93 (1981) No. 11, pp. 1007-1008, the di-tert-butyl ester of .beta.-ethylaspartic acid can also be obtained by reaction of di-tert-butyl N-formyl aspartate with lithium diethylamide and ethyl iodide. However, in this case the product alkylated in the .alpha.-position is also formed.
According to M. Akhtar et al., Tetrahedron 43, 5899-5908 (1987), (2S,3S)-3-ethylaspartic acid can be prepared from 2-ethylfumaric acid by reaction with ammonia in the presence of 3-methylaspartase from Clostridium tetanomorphum according to Scheme 2. ##STR2##
The object of the present invention was then to make available a process for the preparation of N-protected dialkyl (2S,3S)-3-ethylaspartates which does not have the disadvantages of the known processes or only has these to a small extent.
Surprisingly, it has been found that the reaction of (2S,3S)-ethylaspartic acid (sic) obtainable by enzymatic amination, as in Scheme 3, with a halogenating agent in the presence of an alkanol leads to dialkyl (2S,3S)-3-ethylaspartates. ##STR3## PG is a suitable amino protective group X is a leaving group
The invention thus relates to a process for the preparation of N-protected dialkyl (2S,3S)-3-ethylaspartates from unpurified (2S,3S)-3-ethylaspartic acid obtainable by enzymatic amination of ethylfumaric acid, in which the product mixture from the enzymatic amination is treated with a halogenating agent in the presence of an alkanol, the dialkyl 2-ethylfumarate obtained is separated off, and the free amino group is provided with a protective group, in particular a process in which the product mixture is treated with thionyl chloride in the presence of methanol or ethanol.
The invention furthermore relates to the use of the N-protected dialkyl (2S,3S)-3-ethylaspartates thus prepared for the preparation of a .gamma.-lactam-bridged 2S,3R,2'S-isoleucine-alanine dipeptide.
The process according to the invention is simple to carry out. The unpurified product mixture obtained by the enzymatic amination of the 3-ethylfumaric acid is taken up in the alkanol and treated with the halogenating agent. Unbranched or branched alcohols having 1 to 6 C atoms, such as, for example, methanol, ethanol, n-propanol, isopropanol or n-butanol, in particular methanol or ethanol, are preferably used as the alkanol. Preferred halogenating agents are thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, antimony trichloride, antimony pentachloride or t
REFERENCES:
patent: 4552846 (1985-11-01), Tsuda
patent: 4569911 (1986-02-01), Tsuda
J. P. Wolf et al. "Jour. Org. Chem" Band 54 No. 13 (1989) pp. 3164-3173.
M. Akhtar "Tetrahedron" Band 43 No. 21 (1987) pp. 5899-5908.
Casutt Michael
Heywang Ulrich
Schwartz Harry
Lilling Herbert J.
Merck Patent Gesellschaft mit beschrankter Haftung
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