Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Reexamination Certificate
2002-02-12
2004-11-16
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
C435S072000, C435S074000, C435S148000, C435S155000, C435S105000
Reexamination Certificate
active
06818430
ABSTRACT:
TECHNICAL FIELD
This invention relates to a one-step process for the production of L-epi-2-inosose which has biological activities in itself and which is also of high value as a starting material for use in the synthesis of medicines and others, wherein a starting compound of inexpensive myo-inositol is used in the process and is converted into L-epi-2-inosose under the action of a microorganism, without involving any chemical synthetic method. This invention further relates to a process for the efficient production of epi-inositol which has biological activities in itself and is useful as a medicine, wherein L-epi-2-inosose is chemically reduced in the process.
BACKGROUND ART
Myo-inositol is a known substance of natural occurrence, which is represented by the following planar structural formula (A)
or by the following steric structural formula (A′)
L-Epi-2-inosose is a known substance represented by the following planar structural formula (B)
or by the following steric structural formula (B′)
Further, epi-inositol is a chemically synthesized substance already known, which is represented by the following planar structural formula (C)
or by the following steric structural formula (C′)
Epi-inositol is one of the stereo-isomers of myo-inositol.
Inososes (called also as penta-hydroxycyclohexanones or alicyclic ketohexoses) are generally known to have been synthesized by a biological oxidation of inositol [A. J. Kluyver and A. Boezaardt: “Rec. Trav. Chim.” 58, p.956 (1939)], by an enzymatic oxidation of inositol [L. Anderson et al.: “Arch. Biochem. Biophys.” 78, p.518 (1958)], by oxidation of inositol with air in the presence of a platinum catalyst [K. Heyns and H. Paulsen: “Chem. Ber.” 86, p.833 (1953)], or by oxidation of inositol with an oxidizing reagent such as nitric acid [T. Posternak: “Helv. Chim. Acta” 19, p.1333 (1936)].
As such inososes which may be produced by the biological oxidation or enzymatic oxidation of myo-inositol, one of the inositols, there has been known only one inosose, namely scyllo-inosose (called also as myo-inosose-2) [A. J. Kluyver and A. Boezaardt: “Rec. Trav. Chim.” 58, p.956 (1939); L. Anderson, et al.,: “Arch. Biochem. Biophys.” 78, p.518 (1958)]. There has not been reported any micro-organism which is capable of oxidizing myo-inositol into L-epi-2-inosose. L-epi-2-Inosose is useful as the starting material for the synthesis of D-chiro-inositol (abbreviated as DCI) [see U.S. Pat. No. 5,406,005]. DCI is useful as a medicine for the therapy of insulin-resistant diabetes (Published specification of WO90/10439) and is expected to be utilizable as a medicine for ameliorating polycystic ovary syndrome [J. A. Nestler et al.: “NEW Engl. J. Med.” 340, p.1314 (1999)]. As a known process for the preparation of L-epi-2-inosose, there is reported (1) a method wherein L-epi-2-inosose is synthesized by oxidizing myo-inositol with nitric acid to form a racemic mixture of DL-epi-2-inosose (that is, (±)-epi-2-inosose), then reducing the resultant racemic mixture with hydrogen in the presence of a platinum oxide catalyst to form epi-inositol, and microbiologically oxidizing the epi-inositol with a microorganism,
Acetobacter suboxydans
, to produce L-epi-2-inosose [T. Posternak: “Helv. Chim. Acta” 29, p.1991 (1946)]. There is also reported (2) a method wherein L-epi-2-inosose is synthesized as one of such compounds which can be produced by means of an acyloin-condensation of glucodialdose after said glucodialdose had chemically been synthesized from D-glucuronic acid (U.S. Pat. No. 5,406,005).
Inositol is a general name of hexa-hydric alcohols as derived from cyclohexane, and inositol includes nine stereo-isomers thereof. There have been found the naturally-occurring inositols which include, five inositols, namely myo-inositol, D-chiro-inositol, L-chiro-inositol, muco-inositol and scyllo-inositol. The other inositols include epi-inositol, allo-inositol, neo-inositol and cis-inositol. These latter four inositols are the non-naturally-occurring inositols, which have been produced by chemical syntheses. Of the non-naturally-occurring inositols, epi-inositol is expected to be utilizable as a medicine for ameliorating mental depression and anxiety syndrome [R. H. Belmaker et al., International Published Specification WO99/22727 of PCT Patent Application, PCT/IL/00523; and R. H. Belmaker et al, “Int. J. Neuro-psychopharmacol.” Vol.1, p.31 (1998)].
As the known processes of producing epi-inositol, there are reported (1) a process for synthesis of epi-inositol which comprises oxidizing myo-inositol with nitric acid to form a racemic mixture of D,L-epi-2-inososes, followed by reducing the latter with hydrogen in the presence of a platinum oxide catalyst [T. Posternak: “Helv. Chim. Acta” 29. p.1991 (1946)]; (2) a process for synthesis of epi-inositol which comprises oxidizing a di-hydric alcohol of cyclohexadiene with osmic acid [T. Tschamber et al, “Helv. Chim. Acta” 75, p.1052 (1992)]; (3) a process for synthesis of epi-inositol which comprises hydrogenating tetrahydrobenzoquinone [L. Odier: EP Application published Specification No. 524082]; and (4) a process for synthesis of epi-inositol which comprises protecting muco-inositol appropriately and then subjecting the protected derivative thereof to oxidation and reduction reactions in combination [K. E. Espelia et al, “Carbohydrate Res.” 46, p.53 (1976)]. Also, there is known a process for synthesis of epi-inositol which comprises subjecting glucose or galactose to a combination of Ferrier's cyclization reaction with a reducing reaction with a suitable reducing agent [Takahashi et al, “J. Org. Syn. Chem. Soc., Japan” 58, p.120 (2000)].
However, these known processes for the syntheses of L-epi-2-inosose and of epi-inositol are not necessarily satisfactory as such process which may be suited for large-scale production of epi-inositol, because the known processes have such problems that they are complexed to operate, involve environmental pollution and/or are too much expensive. Therefore, there exists keen demands for seeking such a novel process which can produce L-epi-2-inosose in a commercial scale and can operate in a facile way with a high efficiency, as well as such a novel process which can produce epi-inositol in a facile way with a high efficiency. An object of this invention is to provide such a novel process for the production of L-epi-2-inosose and such a process for the production of epi-inositol, which can satisfy the above demands and show many advantages and which can produce either L-epi-2-inosose or epi-inositol efficiently.
DISCLOSURE OF THE INVENTION
We, the present inventors, have eagerly made extensive studies to attain the above-mentioned object of this invention. As a result, we have now found that, when a new microbial strain, Xanthomonas sp. AB10119 strain, which has been isolated from a soil sample by us, is reacted in an aqueous reaction medium with myo-inositol which is available cheaply and has the formula (A) or (A′) shown in the above, the 4-hydroxyl group, of myo-inositol can be oxidized (or dehydrogenated) preferentially or substantially preferentially, thereby to produce L-epi-2-inosose of the above formula (B) or (B′). When L-epi-2-inosose so produced is isolated and examined by instrumental analyses such as nuclear magnetic resonance spectroscopic apparatus, mass spectrometric apparatus, polarimetric apparatus and so on, it is confirmed that the L-epi-2-inosose product so obtained is L-epi-2-inosose which has a high optical purity.
Further, we have searched if the microorganisms having an activity or ability to convert myo-inositol into L-epi-2-inosose are present in the natural field extensively. As a result, we have now found and confirmed that some microbial strains having a high activity or ability to oxidize and convert myo-inositol into L-epi-2-inosose exist among taxonomically many varieties of gr
Kanbe Kenji
Kita Yuichi
Mori Tetsuya
Takahashi Atsushi
Takeuchi Tomio
Hokko Chemical Industry Co. Ltd.
Marx Irene
Schulman B. Aaron
Stites & Harbison PLLC
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