~™ mil mum nun minim (19) J European Patent Office Office europeen des brevets (1 1 ) EP 0 505 573 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publicationation and mention (51) Int. CI.6: C07H 3/02, C07H 19/01 of the grant of the patent: 27.03.1996 Bulletinulletin 1996/13 (86) International application number: PCT/JP91/01376 (21) Application number: 91917514.1 (87) International publication number: WO 92/06986 (30.04.1992 Gazette 1992/10) (22) Date of filing : 09.1 0.1 991 (54) PROCESS FOR PRODUCING D-ALTROSE VERFAHREN ZUR HERSTELLUNG VON D-ALTROSE PROCEDE DE PRODUCTION DE D-ALTROSE (84) Designated Contracting States: (74) Representative: Reinhard - Skuhra - Weise & DE FR GB Partner Postfach 44 01 51 (30) Priority: 12.10.1990 JP 272186/90 D-80750 Munchen (DE) (43) Date of publication of application: (56) References cited: 30.09.1992 Bulletin 1992/40 • CARB. RES. vol. 60 , 1978 pages C11 - C12 J.S. BRIMACOMBE ET AL. 'The stereochemistry of Tobacco Inc. (73) Proprietor: Japan the reduction of 1,6-an hydro-3,4-dideoxy-beta- Shinagawa-ku, Tokyo 140 (JP) D-glycero-hex-3-eno pyranos-2-ulose (levoglucosenone) with lithium aluminium (72) Inventors: hydride' * • MATSUMOTO, Katsuya, • CAN. J. CHEM. vol. 49 1971 pages 1179-1186 Japan Tobacco Inc. , U.P. SINGH ET AL. 'Total Synthesis of alpha,beta- Yokohama-shi, Kanagawa-ken 227 (JP) DL-Allose and alpha, beta-DL-Galactose. • EBATA, Takashi, Stereoselective cis-Hydroxylation by Osmium Tobacco Inc. Japan Tetroxide' * Yokohama-shi, Kanagawa-ken 227 (JP) • ACTA CHEM. SCAND. vol. B34 1 980 page 389 K. • MATSUSHITA, Hajime, , BOCK ET AL. 'A Simplified Synthesis of Penta-O- Japan Tobacco Inc. acetyl-alpha-D-altropyranose' * Yokohama-shi, Kanagawa-ken 227 (JP) • Bulletin of the Chemical Society of Japan Vol. 64, No. 7, pages 2309 to 2310 (July 1991) K. MATUMOTO et al. "Synthesis of D-Altrose via D- Altrosan from Levoglucosenone. CO CO LO LO o Note: Within nine months from the publication of the mention of the grant of the European patent, give LO any person may notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in o a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. Q_ 99(1) European Patent Convention). LU Printed by Rank Xerox (UK) Business Services 2.9.13/3.4 EP 0 505 573 B1 Description The present invention relates to a method of preparing D-altrose, which is a rare sugar, more particularly, to a method of preparing D-altrose from levoglucosenone. 5 D-altrose is a kind of pyranose type aldohexose represented by structural formula (4) given below. The D-altropyran- ose (4) is in equilibrium with D-altrofuranose (6) via a ring-opened aldohexose (5) as an intermediate. It should also be noted that each of pyranose (4) and furanose (6) has a- and p-anomers. In other words, D-altrose is present as an equilibrium mixture of these plurality of anomers. 15 20 D-altrose is a rare sugar, which is present in the nature in an extremely small amount. Altrose presently available 25 on the market is a synthetic substance produced by, for example, Aldrich Inc. Naturally, altrose available on the market is markedly costly, compared with sugars present in the nature in large amounts such as glucose. For example, the prices of altrose available on the market at present as a reagent are given below: $62.40 (100 mg) for altrose produced by Aldrich Inc. ¥21 ,400 (100 mg) for altrose produced by Junsei Kagaku Inc. 30 Recently, sugar chains such as oligosaccharides and polysaccharides, which perform functions useful as a pyhys- iologically active substance, attract attentions in the field of fine chemicals such as medicines and agricultural chemicals. Presently, the objects of researches on the sugar chain are restricted to that consisting of monosaccharides present in the nature in large amounts and readily available to the researchers such as D-glucose, D-mannose and D-galactose. However, it is expected that various monosaccharides other than those present in the nature will be required in the future 35 in the research on the synthesis of sugar chains performing more useful functions. Under the circumstances, it is highly significant and necessary to develop a method which permits preparing D-altrose, which is a rare sugar and is difficult to obtain, with a high yield while diminishing the number of treating steps. Various methods were proposed in the past in an attempt to synthesize D-altrose. For example, a method of syn- thesizing D-altrose based on Kiliani-Fischer method, in which D-ribose is converted into D-altronic acid and, then, into 40 D-altrose, is described in "PA. Leven and W.A. Jacobs, Ber., 43, 3141 (1910)". In this method, however, involved is a reaction in which 1 -position of D-ribose is converted to cyanohydrin. Since this reaction is not stereoselective, D-allonic acid, which is C-2 epimer of D-altronic acid, is also generated as a by-product, in addition to D-altronic acid which is an intermediate product generated in the synthesis of D-altrose. Thus, it is necessary to employ fractional crystallization in order to isolate D-altronic acid, with the result that the product yield is as low as only 3%. 45 Another method is described in, for example, "N.K. Richtmyer, C.S. Hudson, J, Am. Chem. Soc, 57, 1716 (1935)". In this method, 2- and 3-positions of D-glucose portion included in lactose are subjected to Walden inversion so as to obtain neolactose consisting of D-altrose and D-galactose, followed by hydrolyzing neolactose so as to obtain the desired product of D-altrose. The D-galactose contained in the mixture obtained after the hydrolysis is consumed by allowing yeast to act thereon and, thus, is removed. The remaining D-altrose is refined as a benzyl mercaptal derivative and, so then, returned to D-altrose. It should be noted that this method necessitates a step of protecting the hydroxyl group which is irrelevant to the reaction and another step of releasing the protective group after the reaction. It follows that as many as eight steps are involved in this method starting with the Walden inversion of lactose. Naturally, troublesome operations are required for synthesizing the product D-altrose. In addition, the product yield is as low as only 8%. Still another method of synthesizing D-altrose is described in, for example, "Methods in Carbohydrate Chemistry" 55 Vol. I, Academic Press, New York and London, p. 107 (1962). In this method, D-glucose, which is used as the starting material, is converted first into its 2,3-epoxy derivative and, then, the steric configuration of the hydroxyl groups in the 2- and 3-positions is inverted. In this method, it is also necessary to employ the steps of protecting the hydroxyl group, releasing the protective group, and the refining step. It follows that this method also comprises as many as eight steps starting with the treatment of the starting material glucose. In addition, the product yield is as low as only 9 %. 2 EP 0 505 573 B1 D1 - Can. J. Chem., 1971, vol. 49, p. 1 1 79-86 discloses the reaction of osmic acid with 1 ,6-anhydro-3,4-dideoxy-p- DL-erythro-hex-3-enopyranose and its 2-0-methyl and 2-0-acetyl derivatives in either pyridine or dioxane solution to produce 1 ,6-anhydro-p-DL-allopyranose and 1 ,6-anhydro-p-DL-galactopyranose and the corresponding 2-0-methyl and 2-0-acetyl derivatives. These or the fully acetylated derivatives could be hydrolyzed to a,p-DL-allose and a,p-DL-galac- tose and the 2-0-methyl derivatives. In compound 1 of this document, however, the OH group in the 2-position faces the a side, with the result that the steric hindrance on the p side is smaller than that in compound 2 of the present invention. D2 - Carb. Res., 1978, vol. 60, p. C11-C12, discloses the stereochemistry of the reduction of 1 ,6-anhydro-3,4- dideoxy-p-D-glycero-hex-3-enopyranos-2-ulose(levoglucosenone) with lithium aluminium hydride. D3 - Acta Chem. Scand., 1989, vo.B34, p. 389 discloses the synthesis of Penta-O-acetyl-a-D-altropyranose. [Disclosure of the Invention] The present invention is intended to overcome the above-noted difficulties inherent in the prior art, and provides a method of preparing D-altrose, which permits to produced D-altrose with a high yield and also permits to diminish the number of treating steps. The present invention is described as a method of manufacturing D-altropyranose represented by structural formula (4) referred to previously. As described previously, D-altropyranose (4) is an equilibrium mixture with the ring-opened D- aldohexose (5) and D-altrofuranose (6), each of isomers (4) and (6) having a- and p-anomers. Naturally, it is reasonable to interpret the present invention to include the method of preparing these isomers and anomers, too. As a result of an extensive research made in an attempt to achieve the object described above, the present inventors have arrived at an effective method of preparing D-altrose, which permits preparing D-altrose with a high yield by using levoglucosenone as a starting material. In the method reached by the present inventors, it is unnecessary to employ troublesome operations such as introduction of a protective group and fractional crystallization, making it possible to prepare the desired product of D-altrose by only three steps.