Method of preparing optically active .alpha.-amino acids and .al

Details Method of preparing optically active .alpha.-amino acids and .al Method of preparing optically active .alpha.-amino acids and .al

1998-04-30

2000-01-25

Geist, Gary

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

5483017, 560312, 562444, 562449, 562553, 562567, 562574, C07D26120, C07C23900, C07C22908

Patent

active

060180501

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates to a new process for the preparation of optically active amino acid and amino acid derivatives of the general formula I ##STR2## wherein
*=centre of asymmetry
X=O or NH
R.sup.1 =H, (C.sub.1 -C.sub.6) alkyl, benzyl or C.sub.1 -C.sub.4) alkoxycarbonylmethyl and -C.sub.6) alkyl, which can be interrupted or substituted by heteroatoms, such as N. P, O, S or Si, it being possible for the heteroatoms themselves to be substituted by (C.sub.1 -.sub.3) alkyl once or several times, (C.sub.2 -.sub.6) alkenyl, (C.sub.1 -C.sub.6) haloalkyl, halogen, aryl, such as naphthyl or phenyl, which can be substituted by (C.sub.1 -C.sub.3) alkyl, hydroxyl, halogen or (C.sub.1 -.sub.3) alkoxy once or several times, aralkyl, such as 2-naphthylmethyl or benzyl, which in its turn can be substitutes by (C.sub.1 -C.sub.3) alkyl, hydroxyl, halogen or (C.sub.1 -.sub.3) alkoxy once or several times, heteroaralkyl, such as N-protected 3-indolylmethyl, and
R.sup.4 =H,
Proteinogenic amino acids are known as the building blocks of life. These .alpha.-amino acids can be incorporated into peptides or used in amino acid or peptide mixtures, such as infusion solutions. However, non-proteinogenic .alpha.-amino acids are also increasingly being incorporated into peptides, not to compensate naturally occurring deficits but to be able to have a targeted action on reaction sequences in the mechanism of the body.
The branched amino acids in particular are also important starting substances in the field of asymmetric synthesis. For the fields of use mentioned, it is decisive that the amino acids mentioned are obtainable in the highest possible chemical and optical purity.


DISCUSSION OF THE PRIOR ART

Tetrahedron 44 (1988) 5277 thus describes a process which uses R- or S-tert.butyl-methyl-imidazolidinone (R- or S-BMI) in protected form as a glycine .alpha.-anion equivalent. The process for the preparation of the enantiomerically pure building block mentioned is initially based on the racemic three-stage synthesis. After aminolysis of glycine methyl ester hydrochloride with monomethylamine in methanol, the glycine methylamide formed is subjected to a condensation reaction with pivaldehyde in methyl tert-butyl ether to give the Schiff's base, which is then cyclized in ethanol with an ethanolic HCl solution to give rac-BMI hydrochloride. Finally, the enantiomers are separated with (R)-mandelic acid (EP 0 542 099 A2). The R- or S-BMI thus obtained can then be alkylated and cleaved to give the amino acid.
Aldrichimica Acta 25 (1992) 11 describes another process which is based on a chiral oxazinone and which can function both as a glycine .alpha.-anion equivalent (in the form of its BOC-protected derivative) and as a glycine .alpha.-cation equivalent (after NBS bromination in CCl.sub.4). erythro-1,2-Diphenylethanolamine serves as a chiral auxiliary function, and is obtained by racemate splitting with L-glutamic acid or by asymmetric Sharpless dehydroxylation. The enantiomerically pure amino acids are obtained oxidatively or reductively. The alkylation of the glycine enolate is typically carried out in THF by addition of a strong base to the mixture of the oxazinone and the electrophile at -80 .degree. C. If the reaction conditions are not carefully adhered to, undesirable dialkylation product is observed, in addition to unreacted starting material. A targeted second alkylation to give a,cac-substituted derivatives can be realized with reactive alkyl halides (allyl, benzyl) exclusively at very low temperatures (e. g. -80 .degree. C.). The complementary glycine .alpha.-cation route makes use of an .alpha.-bromo derivative, which is obtained by NBS bromination in CCl.sub.4. The unstable substance is used directly as the crude product for the alkylation. In the presence of zinc chloride, a range of organometallic reagents can be employed (organotin, -silicon, -copper, -zinc compounds). The cation route (.alpha.-halo derivative) gives alkyl and aryl derivatives in yields of between 39 and 82%, from which .alpha.-amino

REFERENCES:
Tetrahedron, vol. 44, No. 17 (1988), p5277-92, Fitzi et al, `Resolution and use in alpha amino acid synthesis of imidazolidinone glycine derivatives`.

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