Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonate esters
Reexamination Certificate
2001-12-07
2002-12-10
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonate esters
Reexamination Certificate
active
06492541
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority from German Application No. 198 22 912.7, filed on May 22, 1998, the subject matter of which is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the preparation of compounds of the general formula I and their salts
wherein
R
1
may represent H, (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
2
-C
8
)-alkoxyalkyl, (C
1
-C
8
)-acyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C
3
-C
7
)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, N-bonded amino acid or peptide residue,
R
2
may represent H, (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
2
-C
8
)-alkoxyalkyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C
3
-C
7
)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms,
R
3
may represent H, ClCO, (C3-C
8
)-acyl, which may optionally be linear or branched, a C-bonded amino acid or peptide residue or a conventional peptide-protecting group such as, for example, formyl, carbamoyl, benzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl.
The invention relates also to novel intermediates of the general formulae V, IV and II and their salts
wherein R
1
, R
2
, R
3
are as defined above and R
4
represents (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkoxy, (C
2
-C
8
) alkenyloxy, which are optionally linear or branched and are optionally substituted by one or more halogen atoms, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, arylalkyloxy, such as benzyloxy, and R
5
represents H, or R
5
and R
3
are bonded together via a C═O group to form a ring, wherein in formula V, when R
2
is H, R
3
may not be H, and to the uses of those intermediates.
2. Background Information
The compounds that can be prepared by the process according to the invention and the novel intermediates are valuable intermediates for the production of biologically active substances. For example, 3-amino-2-oxo-pyrrolidines are preferably used as a structural unit for peptide mimetics, which are used as pharmaceuticals. In WO 94/22820, 3-amino-1-phenyl-2-oxo-pyrrolidines substituted at the phenyl ring, for example, are described as intermediates for thrombocyte aggregation inhibitors. Other biologically active compounds containing those &ggr;-lactams have been studied by Kottirsch et al. (Bioorg. Med. Chem. Lett. 1993, 3, 1675). In other examples, they are used in highly potent neurokinin NK-2 receptor antagonists according to Deal et al. (J. Med. Chem. 1992, 35, 4195).
The majority of the processes used hitherto for the preparation of substituted 3-amino-2-oxo-pyrrolidines consist in first converting the corresponding open-chained methionine compounds into their sulfonium salts and cyclising the latter with strong bases in a suitable solvent. Friedinger et al. (J. Org. Chem. 1982, 47, 104-109) use for that purpose methyl iodide and sodium hydride, which is difficult to handle in a large-scale process. In U.S. Pat. No. 5,484,946, trimethylsulfonium or trimethylsulfoxonium salts are used for the alkylation instead of methyl iodide, which is readily volatile. The cyclisation is then carried out using potassium carbonate.
However, the main problem of those procedures, namely the unavoidable release from the methionine precursor of dimethyl sulfide, which is extremely strong-smelling, cannot be avoided in the process just mentioned either. Moreover, the necessary use of expensive aprotic polar solvents such as, for example, DMSO in the cyclisation with potassium carbonate appears to be a further disadvantage.
WO 94/22820 mentions a process in which racemic homoserine derivatives, which have been prepared starting from butyrolactone, are cyclised to pyrrolidones by means of triphenylphosphine and azodicarboxylic acid diesters. However, those reagents are not very suitable for use in an industrial process since they are relatively expensive. Moreover, the cyclisation in that variant yields a number of secondary products which are difficult and hence time-consuming and expensive to separate from the desired derivative (K. Nakajima et al. Peptide Chemistry 1983, 77-80).
Although L-homoserine is a naturally occurring amino acid, as yet there are known only a relatively small number of syntheses of homoserineamides, for example peptides, that start from homoserine. The reasons therefor are that homoserine and the corresponding N-acyl compounds very readily form the corresponding lactones under acid conditions (J. P. Greenstein, M. Winitz, “Chemistry of the Amino Acids”, Wiley, N.Y. 1961, Vol. 3, p. 2612). The same also occurs when the carboxy group is activated, as is necessary for the preparation of homoserineamides.
Although it is possible to react also N-acylhomoserine-lactones with alkylamines and amino acid esters or amino acid salts to form the corresponding amides (Sheradsky et al., J. Org. Chem. 1961, 26, 2710), the reaction requires either very long reaction times or relatively high temperatures. For that reason, this method has not been used for the preparation of complex, optionally optically active compounds.
For the preparation of homoserineamides there are used homoserine derivatives in which the hydroxy function is protected by a suitable group. Hitherto, that was achieved either by a trityl group (Barlos et al., J. Chem. Soc., Chem. Commun. 1986, 1259), by mono- or di-methoxytrityl groups (Beltran et al., Lett. Pept. Sci. 1997, 4, 147), tert.-butyldimethylsilyl group (WO 97/46248) or benzyl groups (Cornille et al., J. Am. Chem. Soc. 1995, 117, 909). The disadvantage of those protecting groups is that they either require expensive chemicals or can be introduced only in a complicated manner.
O-Acyl compounds could be simple and inexpensive protecting groups. However, the problem with those compounds is that they very rapidly undergo an O->N-acyl shift under basic conditions, with formation of the corresponding N-acylhomoserines. Furthermore, for the preparation of O-acetylhomoserine there has hitherto been described only the reaction of homoserine with acyl anhydrides in perchloric acid which, on account of the explosive tendency of perchlorates, appears to be very disadvantageous and unsuitable for larger batches. The yields are onl
Drauz Karlheinz
Knaup Günter
Schwarm Michael
Degussa-Huls Aktiengesellschaft
Pillsbury & Winthrop LLP
Rotman Alan L.
Shameem Golam M M
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