Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-02-17
2001-10-30
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S554000, C562S575000
Reexamination Certificate
active
06310242
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns improvement in a process for preparing D-alloisoleucine, which is useful for preparing medicines, particularly, drugs for cardiovascular disease (typically, WO94/28,901), and a novel complex which occurs as the intermediate in the process of preparation thereof. The invention also concerns an improved process for epimerizing L-isoleucine for the purpose of producing D-alloisoleucine from L-isoleucine.
The present invention makes it possible to produce D-alloisoleucine, which has not been available in a large quantity, from L-isoleucine which is commercially mass-produced, by a simple process at a high yield.
In this specification RS-indication is used in relation to the configuration of tartaric acid and derivatives thereof. This is because the conventional DL(or dl)-indication may cause confusion, in fact, in the past there was a case where one researcher regarded an isomer as D-form while another indicated the same compound as L-form. As far as amino acids are concerned there is no such problem and thus conventional DL-indication is used. The term “isomerization” is used to encompass both racemization and epimerization. In some cases these are represented by the term “racemization”.
PRIOR ART
D-alloisoleucine, or (2R,3S)-2-amino-3-methylpentanoic acid of formula II below
is a stereoisomer of L-isoleucine which is one of essential amino acids. To date, it has been difficult to obtain D-alloisoleucine in a large quantity, because there has been established so far no process for preparation which can be carried out in an industrial scale.
Of the known processes for preparing this compound the following two are important. One is resolution of racemate of alloisoleucine, and the other is to separate D-allo form from mixture of epimers obtainable by epimerizing L-isoleucine of formula III below:
[See, for example, T. Kaneko ed. “Amino Acid Industry, Synthesis and Utilization”, Kodansha Scientific, 1973, p.133].
The above mentioned optical resolution of racemic alloisoleucine can be carried out by resolving N-acetyl derivative thereof using quinine as the resolving agent [W. A. Huffmann, A. W. Ingersoll, J. Am. Chem. Soc., 73, 3366 (1951)]. This process is, however, not practical, because, in addition to the fact that it requires transformation of alloisoleucine to an N-acetyl derivative thereof, the racemate itself is not easily available.
On the other hand, epimerization of commercially produced L-isoleucine can be relatively easily practiced.[By, for example, U.S. Pat. No. 4,401,820 to Chibata et al.]
However, in all the known processes for resolution of epimer mixture, the epimers are resolved after being derived to derivatives, and it has been established no process which resolves the epimer mixture as it is. Reported processes are: recrystalization of N-formyl derivative from MEK [Dow Chemical, British Patent 704983 (1954)]; Cbz-protection or Boc-protection of the epimer mixture followed by separation relying on the difference in solubilities of optically active &agr;-phenylethyl-amine salts [G. Flouret, S. H. Nagasawa, J. Org. Chem., 40, 2635 (1975)]; removal of L-isoleucine resulted from N-acetyl derivative by asymmetric hydrolysis using an enzyme and recovery of the remaining N-acetyl-D-isoleucine [P. Lloyd-Williams et al., J. Chem., Soc., Perkin Trans. I, vol. 1994, 1969]. Anyway in these processes, the resolved products are given as the derivatives, and therefore, further steps such as removal of substituents are necessary until the desired optically active compounds are recovered. These processes are troublesome and cannot be said to be practical.
Generally speaking, extensive research has been done on the resolution of amino acids. Most amino acids are usually resolved in the form of N-acyl derivatives or esters, and successful reports of resolution of non-derivatized amino acids are relatively few. Strong acidic resolving agents such as sulfonic acids, tartaric acid or mandelic acid are useful to resolve some non-dervatized amino acids, for example phenylglycine, phenylalanine, while no successful resolution of neutral aliphatic amino acids such as leucine and isoleucine is reported.
There has been known some cases where neutral amino acids, or amino acids having no functional group other than amino and carboxylic groups are derived to esters thereof, and the esters are resolved with dibenzoyl tartaric acid or its substituted derivative as the resolving agent. For example, benzyl ester of alanine is resolved by using (2R,3R)-dibenzoyl-tartaric acid, and in the process the salt of D-alanine ester with the tartaric acid derivative precipitates as the less soluble salt [W. Langenbeck, O. Herbst, Chem. Ber., 86, 1524 (1953)]. In case of ethyl ester of leucine, analogous to this, a salt of L-ester and (2R,3R)-dibenzoyl tartaric acid precipitates [W. Langenbeck, G. Zimmermann, Chem. Ber., 84, 524 (1951); G. Losse, H. Jeschkeit, Chem. Ber., 90, 1275, (1957)]. As examples of resolution of amino acids having no protecting group by using dibenzoyl tartaric acid as the resolving agent, only the resolution of lysine [F. J. Kearley, A. W. Ingersoll, J. Am. Chem. Soc., 73, 5783 (1951)] and resolution of asparagine [E. Fogassy, M. Acs, J. Gressay, Periodica Polytechnica, 20, 179 (1976)] are reported. No trial has been made, however, on direct optical resolution of neutral aliphatic amino acids such as alanine, valine, leucine, isoleucine without deriving them to esters and using dibenzoyl tartaric acid or substituted derivative thereof.
In production of optically active amino acids from racemates thereof it is desirable to recover the unnecessary enantiomer separated from the desired enantiomer and to subject to racemization or epimerization for recycling it to the optical resolution step and reusing. Particularly, for industrial practice of optical resolution this kind of isomerization is almost essential.
For the purpose of isomerization various methods have been proposed and practiced from the old days. The methods are summarized in regard to amino acids as follows [I. Chibata et al., “Kagaku Sosetsu” No. 4. Chemistry of Asymmetric Reactions, p.233-262, 1974]:
1) chemical methods,
2) thermal methods,
3) catalytic methods, and
4) enzymatic or biotechnological methods.
Of these methods usually those of 3, catalytic methods are the most suitable. A concrete example (above mentioned U.S. Pat. No. 4,401,820) comprises dissolving various amino acids in glacial acetic acid, adding salicylaldehyde to the solution in a molar ratio of 0.2 based on the amino acid, and heating to 100° C. for 1 hour. Then, racemization, the extent of which is as low as 3-35% if no aldehyde is added, proceeds to such a high level as 90-100%.
After racemization in this way, it is not necessarily easy to recover the target amino acids from the reaction mixture. In case where the amino acids are readily soluble in acetic acid it is necessary to concentrate the reaction solution under reduced pressure nearly to dryness, to dissolve the dried substance in a solvent such as alcohol or acetone, and to crystallize out the amino acids from the solution. In the cases of some specific amino acids, for example, phenylglycine, p-hydroxy-phenylglycine and serine, racemates of the amino acids crystallize out by simple cooling of the reaction solution using acetic acid as the reaction medium and the crystal can be separated by filtration. However, this procedure can be applied only to a limited number of amino acids. The higher the solubility of the Amino acid in acetic acid is, the larger the quantity of acetic acid to remove by concentration is. Due to the facts that energy consumption increases to an unbearable extent and that recovery of the aldehyde added as the catalyst is difficult, racemization of amino acids in acetic acid solvent is in many cases not suitable for industrial practice.
SUMMARY OF THE INVENTION
An object of the present invention is t
Murakami Hisamichi
Noda Hirofumi
Ohsaka Koji
Sakai Ken'ichi
Kubovcik & Kubovcik
Richter Johann
Witherspoon Sikarl A.
Yamakawa Chemical Industry Co., Ltd.
LandOfFree
Process for preparing D-alloisoleucine and intermediates for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for preparing D-alloisoleucine and intermediates for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing D-alloisoleucine and intermediates for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2604712