Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1991-04-08
1993-09-28
Marx, Irene
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
435222, 435220, 435196, 435197, 435126, C12P 762, C12P 1704, C12N 956
Patent
active
052486095
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The invention relates to a process for the stereospecific acylate hydrolysis of racemic 7.alpha.-acyloxy-6.beta.-hydroxymethyl-2-oxabicyclo[3.3.0]octan-3-ones to the corresponding optically active alcohols with the aid of enzymes.
The process is especially suitable for the production of optically active (-)-oxabicyclo[3.3.0]octanolones of Formula (-)-I, ##STR2## wherein R means hydrogen or the residue ##STR3## wherein R.sub.1 is a hydrogen atom, alkyl of 1-7 carbon atoms, or phenyl.
The process is characterized by enzymatically subjecting racemic oxabicyclo[3.3.0]octanolone acylates of Formula (.+-.)-II ##STR4## wherein R.sub.1 has the meanings set forth above, to a stereospecific acylate hydrolysis and separating the (-)-I (R= ##STR5## from the saponified (+)-I (R=H) or separating the saponified (-)-I (R=H) from the unsaponified (+)-II.
If R.sub.1 represents an alkyl residue of 1-7 carbon atoms, this means the residues methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, etc.
The compounds of Formula (-)-I are valuable intermediates in the synthesis of pharmacologically valuable prostaglandin and prostacyclin analogs (overviews, for example, by J. Bindra, R. Bindra, "Prostaglandin Synthesis", Academic Press, New York 1977 and by C. Szantay, L. Novak, "Synthesis of Prostaglandins", Akademiai Kiado, Budapest, 1978).
For the synthesis of the structures analogous to the natural products, the esters of this series of enantiomers are required.
Although asymmetric syntheses are known, the preferred route in industrial production is the introduction of the optical activity by way of a racemic separation at intermediate stage (.+-.)-3. In this connection, the following process steps are necessary:
1. Saponification of the lactone to the hydroxy acid.
2. Conversion into a mixture of diastereomeric salts, e.g., with d-.alpha.-phenylethylamine.
3. Crystallization to obtain the diastereomeric pure salt.
4. Conversion of the salt into the optically active lactone (-)-3.
5. Further reaction to the optically active precursor (-)-I.
On account of the tendency displayed by the hydroxy acid of reforming the lactone before optical purification can take place, as well as due to losses in yield during crystallization, the process set out below has not proven satisfactory. ##STR6##
In the present invention, the separation at the stage of the racemic 7.alpha.-acyloxy-6.beta.-hydroxymethyl-2-oxabicycl[3.3.0]octan-3-ones of Formula (.+-.)-II is carried out by enzymatic saponification, leading to a product mixture from which the desired compounds of Formula (-)-I can be obtained either by extraction or from the aqueous phase.
The starting compounds can be produced in accordance with British Patent 1,579,464.
The use of the optically active esters of Formula (-)-I (R= ##STR7## obtained according to the process of this invention as intermediates for the production of pharmacologically valuable prostaglandin and prostacyclin analogs can be derived from the aforementioned overview articles.
The likewise obtainable, optically active diol of Formula (-)-I (R=H) can be utilized, in particular, if, in the subsequent synthesis, the primary hydroxy group must initially be blocked, and the secondary hydroxy group can remain unprotected. This is the case, for example, in the synthesis of carbacyclin intermediates, as described in EP 41 661.
Preferably suited as enzymes for the process of this invention are
The enzymes can be utilized in dissolved, suspended or immobilized form (for example on BrCN-activated "SEPHAROSE.RTM." or on oxirane-acrylic beads, or in some other immobilized form).
The optically active oxabicyclo-octanolone derivatives of Formula (-)-I producible in accordance with the process of this invention are valuable intermediates for the synthesis of pharmacologically effective prostaglandins and prostacyclins. It has been found that the major portion of the stereospecifically hydrolyzing enzymes
REFERENCES:
patent: 3963573 (1976-06-01), Stauffer
Schutt et al., "Preparation of Optically Active . . . , " Biotech. and Bioeng. vol. 27, Apr. 1985 pp. 420-433.
Dahl Helmut
Petzoldt Karl
Marx Irene
Schering Aktiengesellschaft
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