Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-18
2001-04-24
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06222052
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for preparing an optically active 2 amino-&ohgr;-oxoalkanoic acid derivative represented by formula 1
wherein n equals 0, 1, 2, 3, or 4 and R
1
and R
2
each independently represent an alkyl group with 1-10 carbon atoms or jointly form an alkylene group to thereby form a ring with 3 or 4 carbon atoms together with the oxygen atoms to which they are bound and the carbon atom to which the oxygen atoms are bound. The starting materials for preparing formula 1 are readily commercially available.
BACKGROUND OF THE INVENTION
A preparation of a racemic mixture of a 2-amino-&ohgr;-oxoalkanoic acid derivative of formula 1 is described in Biorg. & Med. Chem. (1995) 1237-1240. However, the preparation method described therein proceeds via an 8-step process, starting from 3,4-dihydro-2H-pyran, with various protection and de-protection steps and is hence very laborious.
SUMMARY AND OBJECTS OF THE INVENTION
The invention provides a new, simple method for preparing 2-amino-&ohgr;-oxoalkanoic acid derivatives represented by formula 1
wherein n equals 0, 1, 2, 3, or 4 and R
1
and R
2
each independently represent an alkyl group with 1-10 carbon atoms or jointly form an alkylene group to thereby form a ring with 3 or 4 carbon atoms together with the oxygen atoms to which they are bound and the carbon atom to which the oxygen atoms are bound. The starting materials for preparing a compound of formula 1 are readily commercially available.
A process is disclosed for preparing an (S)-2-amino-&ohgr;-oxoalkanoic acid derivative in which the corresponding aldehyde is converted into the corresponding acetal-protected aldehyde, the acetal-protected aldehyde is converted into the corresponding aminonitrile, the aminonitrile is converted into the corresponding amino acid amide, the amino acid amide is subjected to an enzmatic, enantioselective hydrolysis in which the (R)-enantiomer of the amino acid amide remains and the (S)-enantiomer is converted into the (S)-amino acid, and the (S)-amino acid is isolated. Preferably, the reaction mixture obtained after the conversion of the aminonitrile into the amino acid amide is treated with a benzaldehyde, in which the Schiff base of the amino acid amide is formed, the Schiff base is separated and is converted into the free amino acid amide.
This is achieved according to the invention with a process converting the corresponding aldehyde of formula 2
wherein n is as described above into the corresponding acetal-protected aldehyde of formula 3
wherein n, R
1
and R
2
are as described above,
converting the acetal-protected aldehyde into the corresponding aminonitrile of formula 4
wherein n, R
1
and R
2
are as described above,
converting the aminonitrile into the corresponding amino acid amide of formula 5
wherein n, R
1
and R
2
are as described above,
subjecting the amino acid amide to an enzymatic, enantioselective hydrolysis in which the (R)-enantiomer of the amino acid amide remains and the (S)-enantiomer is converted into the (S)-amino acid represented by formula (1), and
isolating the (S)amino acid.
It has been discovered that, in spite of the fact that the selectivity in the first step of the process can be relatively low, an economically attractive process can nevertheless be obtained.
The optically active compounds represented of formula 1 are novel and are particularly suitable for use in the preparation of, for example, allysin, an important crosslink precursor in proteins, as described in Int. J. Pept. Protein Res. (1988), 307-20, and in the preparation of pharmaceuticals, for example as described in EP-A-629627, the complete disclosures of both are incorporated herein by reference.
Allysin can be obtained by an acid catalysed (e.g. an Amberlist -15) deacetylation of a compound of formula 1 with n=3.
Without protection such compound will be immediately converted in the cyclic compound:
For use in the peptide synthesis a compound of formula 1 with n=3 is treated with HCl and MeOH in order to obtain
An example of peptide chemistry is shown in
FIG. 1
, using the above compound (8), and is also further described in J. Pept. Protein Res. (1988), 307-20, incorporated by reference above.
The preparation of a pharmaceutical as referred to above is shown in
FIG. 2
, and is described in EP-A-629627, incorporated by reference above.
More particularly, in the process according to the invention, one of the two aldehyde functional groups in the aldehyde represented by formula 2 is first protected through conversion, in a manner known per se, into an acetal. cf. T. H. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1981). This can for example be done with the aid of an alcohol, for example an alcohol with 1-5 carbon atoms when R
1
and R
2
represent an alkyl group, or with the aid of a diol with 1 to 5 carbon atoms, in particular a 1,2-ethanediol or a 1,3-propanediol, whether or not substituted with for example an alkyl group with 1-5 carbon atoms, for example 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol or 2,3-butanediol, when R
1
and R
2
form part of a ring structure; or via re-acetalization, for example with the aid of ortho-formate esters.
The acetalization can, for example, be carried out by bringing the aldehyde represented by formula 2 into contact with an alcohol or a diol under acid conditions such as, for example, in the presence of a sulphonic acid, in particular p-toluenesulphonic acid. The acetalization is optionally carried out in the presence of a solvent. In principle, any solvent that does not interfere with the reaction can be used as a solvent such as, for example, aromatic hydrocarbons, in particular benzene, toluene and xylene; halogenated hydrocarbons, for example dichloromethane; esters, preferably hindered esters, in particular isopropyl acetate or isobutyl acetate or other esters having bulky ester groups; and ethers, in particular methyl-t-butyl ether (MTBE). The acetalization with an alcohol or diol is preferably carried out at elevated temperature, for example at a temperature of between about 50° C. and about 150° C., preferably at reflux temperature.
The acetal-protected aldehyde obtained is subsequently converted into the corresponding aminonitrile, for example via a Strecker synthesis. cf., J. March, Advanced Organic Chemistry, John Wiley & Sons, New York, pp. 855-856 (3
rd
Ed. 1981); T. W. Graham Solomons, Fundamentals of Organic Chemistry, John Wiley & Sons, New York, pp. 980-981 (4
th
Ed. 1994). The acetal-protected aldehyde can, for example, be converted into the amnonitrile in the presence of ammonia with the aid of a cyanide compound, for example HCN, NaCN or KCN.
The aminonitrile compounds represented by formula 4 intermediates are novel compounds. The invention hence also relates to these intermediates. The racemic (R,S)-amide mixture is enantioselectively hydrolysed using an enzyme, so as to give the (R)-amide and the (S)-acid. In order to obtain the (R)-acid the (R)-amide is subsequently hydrolysed into the (R)-acid.
The aminonitrile represented by formula 4 is subsequently converted into the corresponding racemic amino acid amine. One suitable method is described, for instance, in GB-A-1548032, the disclosure of which is herein incorporated by reference. The aminonitrile is converted at a pH of between 11 and 14, preferably between 12.5 and 13.5, in the presence of a base and a ketone or aldehyde, optionally followed by hydrolysis of the intermediately formed Schiff base in the presence of water. Preferably, an alkali metal hydroxide, such as KOH or NaOH, or a corresponding base is used as the base and an aliphatic ketone, for example acetone, methyl ethyl ketone or cyclohexanone, or an aromatic aldehyde, for example benzaldehyde, is used as the ketone or aldehyde.
Aminonitile obtained as formula 4 can be isolated via extraction from the aqueous phase using an organic solvent (e.g. aromatic hydrocarbons such as toluene, esters or chlorinated hydrocarbons), and separation of the two layers, if desired. Th
Boesten Wilhelmus H. J.
Broxterman Quirinus B.
Plaum Marcus J. M.
DSM N.V.
Pillsbury & Winthrop LLP
Stockton Laura L.
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