Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-12-01
2000-12-26
McKane, Joseph K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548406, 548539, 548565, C07D20718, C07D20724
Patent
active
061662224
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP98/03284 filed Jun. 2, 1998.
The present invention relates to a process for preparing chiral 3,4-dehydroprolines.
Chiral 3,4-dehydroprolines are prepared starting from 4-hydroxyproline by a Chugaev reaction (P. Grogg, Angew. Chem. 92 (1980) 761). Besides yields which are comparatively poor (64%), this method requires the use of highly toxic compounds such as carbon disulfide, methyl iodide and methyl mercaptan. The pyrolytic decomposition at 180-190.degree. C. and 12 Torr requires great industrial expenditure.
It is also possible in place of the xanthates to convert the corresponding iodides, sulfoxides or selenoxides by thermolysis (J.-R. Dormoy, Synthesis (1982) 752). However, this does not solve the fundamental problems of toxicity and industrial expenditure.
Achiral syntheses normally start from pyrrolecarboxylic acid, which is reduced with phosphonium iodide/hydrogen iodide (J. W. Scott, Synth. Commun. 10 (1980) 529). The racemate is then resolved by crystallization with chiral amines (S. S. Kerwar, J. Biol. Chem. 251 (1976) 503; U.S. Pat. No. 4,066,658) or tartaric acid (A. Corbella, Chem. Ind. (1969) 583). The disadvantage of this synthesis is the use of the highly toxic phosphine and a maximum yield of 50% in the racemate resolution.
German Patent Application 19630082.7, which is not a prior publication, describes the elimination of sulfonic esters of hydroxyproline ester and subsequent enzymatic racemate resolution. The elimination is associated with racemization of the center of asymmetry of the proline. The maximum yield possible in principle in both the classical and the enzymatic raceinate resolutions is 50%. This can be improved by recycling the unresolved enantiomer only with considerable expenditure.
Alkylating asymmetric Birch reductions are described by A. G. Schultz (J. Am. Chem. Soc. 110 (1988) 7828) on benzoic acid derivatives and by T. Kinoshita (J. Heterocycl. Chem. 33 (1996) 1313) on furancarboxylic acid derivatives.
Birch reduction of pyrrole derivatives was unknown until recently. T. J. Donohoe was the first to describe, in J. Org. Chem. 61 (1996) 7664, the achiral Birch reduction of pyrrole-2-carboxylic acid derivatives. To date, it has been possible to resolve these into the enantiomers only by classical or enzymatic racemate resolution.
We have now found that chiral 3,4-dehydroprolines can be obtained by diastereoselective Birch reduction.
The invention relates to a process for preparing chiral 3,4-dehydroprolines of the formula I ##STR1## where R is a chiral group, -arylalkyl or tri-C.sub.1-4 -alkylsilyl radical and II ##STR2## in ammonia with an alkali metal or alkaline earth metal and then with an aqueous salt solution or a compound of the formula III
Particularly suitable sources of the chiral groups R are nonaromatic chiral secondary amines and nonaromatic chiral alcohols of the formula RH. Specific mention may be made of the following ##STR3## Of these, compound D is particularly preferred.
R' is preferably hydrogen, C.sub.1-3 -alkyl, allyl or benzyl. A tri-C.sub.1-4 -alkylsilyl radical which should be particularly mentioned is the trimethylsilyl radical.
Protective groups which should be mentioned for R" are Boc, C.sub.1-6 -acyl, mesyl, benzenesulfonyl and tosyl, and preferably Boc.
Preferred leaving groups for X are Cl, Br, I, MesO, TosO or triflate.
Alkali metals and alkaline earth metals which should be mentioned for the reaction are magnesium and, especially, lithium, sodium and potassium. The reaction takes place in liquid or supercritical ammonia, to which an inert solvent may also be added. Preferred solvents are THF and C.sub.1-6 -alcohols.
The reaction is generally carried out at a temperature in the range from -100 to +100.degree. C. and under a pressure in the range from 1 to 200 bar. The boiling point of the reaction mixture and 1 bar are preferred. A reaction under autogenous pressure is very particularly preferred.
The reaction is complete when pyrrole derivatives are no longer detectable in the reaction mixture (eg. by GC
REFERENCES:
Donohoe et al., J. Org. Chem., 1996, 61, 7664-7665.
Donohoe et al., J. Chem. Soc. Perkin Trans., 1998, 667-676.
Jones et al., Tetrahedron Letters, 36(37), 1995, 6743-44.
BASF - Aktiengesellschaft
McKane Joseph K.
Oswecki Jane C.
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