Process for preparing 3-pyrroline-2-carboxylic acid derivatives

Details Process for preparing 3-pyrroline-2-carboxylic acid derivatives Process for preparing 3-pyrroline-2-carboxylic acid derivatives

1999-01-22

2000-09-26

McKane, Joseph

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548532, 548535, 548565, C07D20718, C07D20724

Patent

active

061244724

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a novel process for preparing pyrroline-2-carboxylic acid derivatives.
Replacement of proline by 3,4-dehydroproline in biologically active peptides or peptide mimetics rarely causes a loss of activity (A. M. Felix et al. Int. J. Pept. Prot. Res. 10, (1977) 299; C. R. Botos et al. J. Med. Chem. 22, (1979) 926; G. H. Fisher, W. Ryan, FEBS Lett. 107, (1979) 273); on the contrary, in some cases the effect is increased while there is a simultaneous reduction in toxicity (G. H. Fisher, W. Ryan FEBS Lett. 107, (1979) 273; S. Natarajan et al., in Peptide, Structure and Biological Function, E. Gross, J. Meienhofer, Eds., Pierce Chemical Company, 1979, p. 463).
Synthesis of N-protected 3,4-dehydroprolines on the industrial scale by processes disclosed in the literature is very elaborate as shown, for example, by the thermal cis elimination of the S-methylxanthate from hydroxyproline by the Tchugaeff method. The disadvantages of this process are that large amounts of methyl iodide are used, and methyl mercaptan and carbon oxysulfide are produced (J.-R. Dormay et al., Angew. Chem. 92, (1980) 761; Houben-Weil, Methoden der Organischen Chemie, Vol. 5/1b, 126 (1972)).
The reduction of pyrrole-2-carboxylic acid with phosphonium iodide in fuming hydroiodic acid is also problematic because of the use of a large excess of gaseous hydrogen iodide, and of a marked reduction in yield and onset of polymerization in large reactions (J. W. Scott et al., Synth. Commun. 10(7), (1980) 529). On the other hand, elimination of the Boc-protected 4-phenylseleninylproline methyl ester takes place under distinctly milder conditions (J.-R. Dormay, Synthesis 9, (1982) 753. The elimination takes place at room temperature and results in the .DELTA..sup.3 -olefin with high selectivity. Thermal cis eliminations afford considerable amounts of the isomeric .DELTA..sup.4 olefin. However, elimination of the selenium oxide is also disadvantageous because of the production of toxic selenium-containing residues which require costly disposal precisely in the case of reactions on the pilot-plant scale, and addition of the previously eliminated selenigenic acid to the double bond is disadvantageous especially in the case of pharmaceutical active ingredients in which even tiny amounts of selenium-containing compounds result in toxic properties.
Small amounts of 3-pyrroline have been obtained from N-substituted 3-methylsulfonyloxypyrrolidine (T. Uno et al., J. Heterocycl. Chem. 24, (1987) 1025). Elimination of sulfonates, eg. methylsulfonate, to prepare 3-pyrroline-2-carboxylic acid derivatives has not previously been described.
Said processes disclosed in the literature for preparing 3-pyrroline-2-carboxylic acid derivatives are unsuitable for industrial syntheses.
The present invention relates to a process for preparing 3-pyrroline-2-carboxylic acid derivatives of the formula I ##STR3## where R.sup.1 is H, C.sub.1 -C.sub.6 -alkyl, benzyl, benzyl substituted on the phenyl, allyloxycarbonyl, C.sub.1 -C.sub.6 -alkyloxycarbonyl, benzyloxycarbonyl where the benzyl residue can be substituted by OCH.sub.3 radicals, or C.sub.1 -C.sub.4 -alkylcarbonyl or and may be alkylated or acylated on the nitrogen, and -C.sub.4 -alkyl, benzyl, phenyl or pyridyl, it being possible for the aromatic systems in R.sup.3 and R.sup.4 to be substituted by up to three identical or different substituents selected from the group consisting of methyl, methoxy, hydroxyl, cyano or halogen, which comprises eliminating the sulfonic acid residue with the aid of a base from a sulfonate of the formula II ##STR4## where R.sup.1 and R.sup.2 have the meanings described above, and R.sup.5 is C.sub.1 -C.sub.6 -alkyl, benzyl, trifluoromethyl, naphthyl or phenyl which may be unsubstituted or substituted by radicals from the group consisting of methyl, nitro or halogen.
Preferred as R.sup.1 are C.sub.1 -C.sub.4 -alkylcarbonyl, benzyl, benzyl substituted on the phenyl, C.sub.1 -C.sub.6 -alkyloxycarbonyl and benzyloxycarbonyl. If the benzyloxycarbonyl radical is substitute

REFERENCES:
patent: 4066658 (1978-01-01), Felix
patent: 4501901 (1985-02-01), Thottathil et al.
Tet. Ltr. vol. 27, No. 2, -151-154, 1986.
Tet. Ltr. vol. 31, No. 9, 1241-1244, 1990.

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