Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-09-11
2004-07-06
Desai, R. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06759551
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a chiral &agr;-amino acid in the crystalline form, to its process of preparation and to the use of the said chiral &agr;-amino acid as intermediate in the synthesis of chiral organic compounds.
STATE OF THE ART
Amino acids are compounds which are very widely used in a very large number of fields. In particular, they are becoming increasingly important in the syntheses of compounds for pharmaceutical, veterinary and phytopharmaceutical use. In these fields of human, animal and plant health, there is a constant search for products which are highly active at a low dose. One means of combining these two aspects is to use, in the case of compounds having at least one asymmetric centre, only the optical isomer possessing the desired activity.
It is then necessary to find a simple, economical and efficient means of synthesizing this active optical isomer. This compound generally has a relatively complex chemical structure, so much so that the centre of chirality is introduced during the synthesis, that is to say that it is contributed by a compound with a simpler chemical structure, for example a synthetic intermediate.
Among chiral intermediates which are entirely favoured, chiral amino acids occupy a dominant position in these fields of human, animal and plant health. The problem which is posed is thus to find processes for the synthesis of chiral amino acids which are inexpensive, are readily accessible from an industrial viewpoint and give high yields.
Processes for the preparation of amino acids from hydantoins are known, for example in Patents JP 60224661 and JP 62103049. However, these processes result in racemic amino acids.
Processes for the preparation of chiral amino acids are already known in the literature. They are mainly based on processes for the resolution of racemic mixture by liquid chromatography, resolution by means of alkaloids or resolution by an enzymatic process, such as, for example, in the not yet published French Patent Application No. 98 06339. These various processes for the resolution or for the preparation of chiral compounds exhibit the problem of resulting in products as a mixture in the reaction medium, without it being possible to easily isolate the desired product.
An additional problem is that the chiral amino acids have a degree of purity which is not very satisfactory. This is because the synthesis of chemical compounds developed for uses in human, animal and/or plant health requires synthetic intermediates of very high purity.
Furthermore, it is well known that the purity of such chiral intermediates is difficult to control; in particular, it is relatively difficult to obtain acceptable purities for such syntheses, that is to say purities of greater than 99%.
In point of fact, it is well known that one means for obtaining a high purity consists, for example, in purifying the product which exists in the crystal form. Mention may be made, among these techniques, for example, of recrystallization, which makes it possible, by dissolution of the crystal and then slow recrystallization, to obtain a purity in the region of 100%.
A problem is thus to be able to separate the desired product from the reaction medium, the product having to have a high chemical and enantiomeric purity. In order to obtain this high purity, it is advantageous, for example, to be able to have available the product in the crystalline form. In point of fact, it is well known to a person skilled in the art that to obtain amino acids in the form of crystals from a reaction medium is an operation which is difficult and not described, for example, for the amino acid known as 2-methyl-2-phenylglycine.
General Definition of the Invention
A first object of the invention consists in providing a chiral &agr;-amino acid in the crystalline form, more particularly (S)-(+)-methylphenylglycine (or (S)-(+)-2-phenylalanine) or (R)-(−)-methylphenylglycine (or (R)-(−)-2-phenylalanine) in the crystalline form. A second object of the invention is to provide a process for the preparation of (S)-(+)-methylphenylglycine or of (R)-(−)-methylphenylglycine in the crystalline form from chiral hydantoins. A third object of the present invention is to synthesize chiral organic compounds prepared from (S)-(+)-methylphenylglycine or from (R)-(−)-methylphenylglycine in the crystalline form.
Detailed Definition of the Invention
Thus, a first object of the present invention relates to the (S)-(+)-2-methyl-2-phenylglycine crystal and the (R)-(−)-2-methyl-2-phenylglycine crystal (subsequently named (S)-(+)-methylphenylglycine and (R)-(−)-methylphenylglycine respectively), characterized in that the single crystal is an orthorhombic crystal system, the unit cell parameters of which are a=5.778 Å, =6.692 Å and c=22.127 Å, with a P2
1
2
1
2
1
space group and possessing four molecules per unit cell.
More particularly, the present invention relates to the (S)-(+)-methylphenylglycine crystal and the (R)-(−)-methylphenylglycine crystal, characterized by the following crystallographic parameters of the single crystal:
Crystal system:
orthorhombic;
Unit cell parameters:
a = 5.778 Å
&agr;= 90°;
b = 6.692 Å
&bgr;= 90°;
c = 22.127 Å
&ggr; 90°;
Asymmetric unit:
1 molecule;
Space group:
P2
1
2
1
2
1
;
Number of molecules
4;
per unit cell:
Volume of the unit cell:
855.6 Å
3
;
Calculated density:
1.282 g/cm
3
;
Absorption coefficient &mgr;:
0.91 cm
−1
(CuK&agr;).
The above parameters are obtained by milling the product and then analysed, in order to obtain an experimental reference diagram with respect to the resolution of the structure: from this powder, a single crystal is synthesized in a suitable solvent or a suitable mixture of solvents, for example water, by very slow evaporation; by means of an X-ray diffraction device specially designed for single crystals, all the diffraction lines are analysed (position, intensity); the crystal parameters are finally obtained using calculating computer programs.
The crystal defined above has in addition the following characteristics of not being a solvate, that is to say that the (S)-(+)-methylphenylglycine or (R)-(−)-methylphenylglycine molecule is not bonded (chemically and/or physically) to a solvent molecule, and of not comprising solvent in the crystal unit cell.
The possibility has thus been discovered of obtaining (S)-(+)-methylphenylglycine (pure enantiomer) or (R)-(−)-methylphenylglycine (pure enantiomer) in the crystalline form, which has in particular the advantage of conferring on this product high chemical and physical stability over time. In particular, (S)-(+)-methylphenylglycine or (R)(−)-methylphenylglycine in the crystalline form exhibits the advantage of not being hygroscopic, which makes possible easy handling, storage and manipulation and which is consequently a major asset when this product is used as starting material in the synthesis of organic compounds.
Thus, another object of the present invention relates to the process for the preparation of (S)-(+)-methylphenylglycine (or of (R)-(−)-methylphenylglycine) in the crystalline form, characterized in that:
(S)-(+)-methylphenylglycine (respectively (R)-(−)-methylphenylglycine) is dissolved, in the free amino acid form or in the salified form, in a pH region of less than approximately 4.5 or greater than approximately 9, then
the value of the pH is gradually brought, by addition of a base or of an acid respectively, into a region of greater than approximately 4.5 and less than approximately 9.
The value of the pH of the reaction medium, measured at the beginning of the crystallization reaction, will advantageously be either very much less than 4.5 or very much greater than 9, highly advantageously either less than 2 or greater than 12.
In the process described above, the addition of base or of acid has to be carried out to a
Maret Jean-Claude
Pelta Isabelle
Bayer Cropscience S.A.
Desai R.
Ostrolenk Faber Gerb & Soffen, LLP
Wright Sonya
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