MXPA99011409A - Method of producing tiazofurin and other c-nucleosides - Google Patents

Abstract

C-nucleosides are synthesized by a method in which a sugar is derivatized in a single step to provide a heterocycle at the C1 position, and then the heterocycle is aromatized in another single step. In one class of preferred embodiments a cyano sugar is converted into thiocarboxamide, and subsequently condensed to form an azole ring. In a second class of preferred embodiments a cyano sugar is condensed with an amino acid to provide the azole ring. In a third class of preferred embodiments a halo sugar is condensed with a preformed heterocycle to provide the azole ring.

Description

METHOD OF PRODUCTION OF TIAZOFURINE AND OTHER C-NUCLEOSIDES Background C-nucleosides are interesting compounds that have potential activity as pharmaceutical agents. One of these compounds, Thiazofurin, [6, 2 - (β-D-ribofuranosyl) thiazole-4-carboxamide)], has significant activity against both the human limfoid (F. Earle and RI Glazer, Cancer Res., 1983, -Jl 133), lung tumor cell lines (DN Carnex, GS Abluwalia, HN Jayaram, DA Cooney and DG Johns, J. Clin. Invest., 1985, 13. 175) and human ovarian cancers implanted in murine (JP Micha, PR-Kucera, CN Prevé, MA Rettenmaier, JA Stratton, PJ Disaia, Gynecol Oncol 1985, 21,351). Thiazofurine also shows efficacy in the treatment of acute myeloid leukemia (GT Tricot, H N. Jasyaram CR Nichols, K. Pennington, E. Lapis, G. Weber and R. Hoffman, Cancer Res. 1991, 4-7 4988) . In addition, recent discoveries have caused interest in thiazofurin as a possible treatment for patients with chronic myeloid leukemia (CML) in blast crisis (G. Weber, U.S. Patent 5,405,837, 1995). In the cells, Thiazofurin is converted to its active metabolite, thiazole-4-carboxamide adenine dinucleotide (DAT), which inhibits IMP dehydrogenase, and as a result voids the nucleotide pool Ref. 032016 guanosine. (E. Olah, Y. Natusmeda, T. Ikegami, Z. Kote, M. Horanyi, I Szelenye, E. Paulik, T. Kremmer, SR Hol n, J. Sugar and G. Weber, Proc. Nati Acad. Sci USA, 1988, ££, 6533).

Although thiazofurin has been known for more than 15 years, and is currently tested in humans under phase II / III, there is no appropriate synthesis for large-scale production. Thiazofurin was first independently synthesized by M. Fuertes et al. (J. Org. Chem., 1976, AX, 4076) and Srivastava et al. (J. Med. Chem., 1977, 20., 256) with a low yield. In both methods, the authors obtained byproducts (ie compound 12) and used column chromatography at each stage to purify the products. The main disadvantage of these methods is the formation of the furan derivative, as well as the utility of highly toxic hydrogen sulfide gas.

W.J. Hannon et al. (J. Org. Chem., 1985, ££, 1741) developed a different route in some way for thiazofurin with a yield of 19%. The Hannon method also suffers from low yield, the use of H2S gas and chromatographic purifications. More recently, P. Vogel et al. (Helv. Chem. Acta., 1989, 72., 1825) synthesized thiazofurine in nine steps with a yield of 25%. Still more recently, D.C. Humber et al. (J. Chem. Soc. Perkin Trans. 1, 1990, 283) carried out a synthesis for thiazofurin starting from (2, 3, 5-tri-Q-benzioyl-β-D-ribofuranosyl) penicillinate benzyl The only known method that is at all appropriate for large-scale production is by Parsons et al. (US 4,451,684). Unfortunately, the Parsons method uses both mercury cyanide and hydrogen sulfide, both of which have safety and environmental problems. The Parsons method also gives a mix of products.

The problems discussed above, which accompany a large-scale production of thiazofurin, are applicable to a large-scale production of other C-nucleosides. In the production of thiocarboxamides, for example, most known methods use gaseous hydrogen sulfide as a reagent to convert a cyano group to a corresponding ticarboxamide group. Such methods have inherent environmental problems. In the production of C-nucleosides in general, most or all known syntheses give a mixture of products during a ring closure step. Thus, there is a constant need for a new process for large-scale production of thiazofurin and other C-nucleosides.

Brief Description of the Invention The present invention relates to a novel method for synthesizing C-nucleosides, in which the C ± position of a sugar is derived in a single step to provide a heterocycle, and then the heterocycle is aromatized in a single other step.

In a class of preferred embodiments, a cyano-sugar is converted to thiocarboxamide, and subsequently condensed to form an azole ring. In a second class of preferred embodiments a cyano-sugar is condensed with an amino acid to provide the azole ring. In a third class of preferred embodiments a halo-sugar is condensed with a preformed heterocycle to provide the azole ring.

There are many advantages to the present method. An advantage is that the method eliminates the need for gaseous hydrogen sulfide, which is environmentally unsafe. Another advantage is that the performance is substantially improved over the previous methods. A third advantage is that the present method eliminates the need for chromatic process purification, which reduces the cost of production.

These and other objects, features, aspects and different advantages of the present invention will become apparent from the following detailed description of the preferred embodiments of the invention, together with the accompanying drawings, in which like numerals represent like components.

Brief Description of the Drawings Figure 1 is a series of reaction schemes showing various embodiments of the present invention.

Figure 2 is another series of reaction schemes showing various embodiments of the present invention.

Figure 3 is another series of reaction schemes showing various embodiments of the present invention.

Detailed description There are three preferred classes of methods for carrying out the present invention, each of which is exemplified with respect to the production of thiazofurin in Figures 1, 2 and 3.

In a preferred class of embodiments, a cyano-sugar is converted to thiocarboxamide, and subsequently condensed to form an azole ring. In the particular example shown in Figure 1, a blocked cyano-sugar (2.) is converted to thiocarboxamide (2.), and subsequently condensed with ethylbromopyruvate to give an intermediate of thiazofurin (4). The process shown provides Tiazofurin with a quantitative yield without any of the side products (12. or the a-anomer of 4.).

In a second class of preferred embodiments, a cyano-sugar is condensed with an amino acid to provide the azole ring. In the particular example shown in Figure 2, a known cyano (£) is condensed with cyclostene ethyl ester hydrochloride to give the finished ring product (-2.), Which is then aromatized with activated manganese dioxide to provide the intermediary of Tiazofurina (1-Q.). This key intermediary (ID.) Is conveniently transformed into Tiazofurin with good performance.

In a third class of preferred embodiments, a halo-sugar is condensed with a preformed heterocycle to provide the azole ring. In the particular example shown in Figure 1, a preformed heterocycle (2 = 2.) Is condensed with a known halo sugar (14) to provide the key intermediate (4), from which the thiazofurin can be easily.

Of course, the inventive methods described herein are not limited to the production of thiazofurin, and can be easily generalized, including especially the generalization of the second and third classes of methods to virtually all C-nucleosides. In general, a C-nucleoside according to the present invention falls within the general structure A, where A is O, S, CH2 or NR where R is H or a blocking group, -X is O, S, Se or NH; Rlf R2, R3 and R4 are independently H or lower alkyl; and Zl r Z2 and Z3 are independently H or not H, Structure A To achieve the different compounds comprised by structure A, the variability in the sugar portion of the molecule may be considerable. Among other things, sugar itself does not need to be a simple furan. For example, oxygen can be replaced with sulfur to form a thio-sugar, or nitrogen to form an amino-sugar. In addition, the sugar can be substituted at positions C2 ', C3' and C4 'with a different group of hydrogen. Still further, the sugar may have a D or L configuration, and may be an alpha or beta anomer. Still further, sugar may have blocking groups at various stages in the synthesis. All these permutations are comprised by Structure B, where A is O, S, CH2 or NR, where R is H or a blocking group; Bx, B2, and B3 are independently blocking or lower alkyl groups, and Zi, Z2 and Z3 are independently H or not H. The group L is a reactive functionality, such as CN, halogen or CHO.

Structure B Focusing again on the second class of preferred embodiments, the use of cysteine ethyl ester hydrochloride can be generalized to the use of a compound according to Structure C, where X is O, S, Se or NH; Y is H or lower alkyl; and R is H or lower alkyl.

Structure C Similarly, in the third class of preferred embodiments, the use of a preformed heterocycle can be generalized to the use of a compound according to Structure D, where R 4 is H or lower alkyl.

Structure D There are, of course, numerous blocking groups which should be appropriate. Among other things, one can use benzoyl, benzyl, silyl, or isopropylidene. In addition, it is specifically contemplated that the blocking groups at positions C2 'and C3' in the sugar may be formed in an isopropylidene group, as shown in Structure E.

Structure E This isopropylidene group can be removed by many processes, including by treatment with a reagent selected from the group consisting of trifluoroacetic acid, formic acid, acetic acid, an H + resin in an organic solvent, or iodine in methanol. Applying the present method to Structure E can then give a compound according to Structure F, where R5 is H, lower alkyl, amine or aryl.

Structure F The embodiment also includes aromatization of Structure F with activated manganese dioxide or other reagents and followed by unblocking of protecting groups to provide the referred thiazofurin or C-nucleosides.

Especially the preferred embodiments according to the inventive theme here include Reaction A or Reaction B, shown below.

Reaction to Reaction B These and other characteristics can be appreciated by the following working examples, which are interpreted as illustrative of several aspects of the claimed subject, but not limiting in terms of the scope of the claimed subject.

EXPERIMENTAL Example 1 2,3,5-Tri-Q-benzoyl-β-D-ribofuranbsyl-1-carbonitrile (2.): The carbonitrile was prepared by the procedure established by Robins et al. (PCT / US96 / 02512) Example 2 2, 5-Anhydro-3,4,6-tri-O-benzoyl-D-alontioamide (3): Method A: Hydrogen sulphide was passed through a cold (5 ° C) stirred suspension of cyanide. 2 ', 3', 5 '-tri-jQ-benzoyl-β-D-ribofuranosyl (2.50 g, 106.16 mmoles) in dry EtOH (900 ml) for 5 minutes, then added in a portion N, N- dimethylaminopyridine (1.2 g, 10 mmol). Hydrogen sulfide was passed slowly through the stirred reaction mixture for 5 hours (the outlet tube of the reaction flask was bubbled through the bleaching solution made of 5% NaOH). After 5 hours, the flask was sealed and the stirring was continued below 25 ° C for 16 hours. Argon was passed through the reaction mixture for 1 hour to remove the last traces of H2S. The suspension was stirred at 0 ° C for 2 hours and the separated solid was filtered, washed with cold dried EtOH and dried over P205 under vacuum.

Yield 52 g (97%); p.f. 133-135 ° C. X H NMR (CDC13): d 4.72 (m, 2 H), 4.74 (m, H H), 5.12 (d, H H), 5.71 (t, H H), 5.98 (t, H H), 7.30-7.60 (m, 10 H) , 7.86 (d, 2H), 8.14 (m, 4H) and 8.46 (bs, ÍH).

Method B: A 2 ', 3', 5 '-tri-Q-benzoyl-β-D-ribofuranosyl cyanide solution (2., 4.71 g, 10.00 mmol) and thioacetamide (1.50 g, 20.00 mmol) in dry DMF (50 mL) was saturated with anhydrous hydrogen chloride and heated at 70-60 ° C for 2 hours. The reaction was cooled and evaporated to dryness. The residue was dissolved in methylene chloride (150 ml), washed with a saturated NaHCO 3 solution (100 ml), water (100 ml) and brine (70 ml). The organic extract was dried over anhydrous MgSO, filtered and washed with CH2C12 (50 ml). The combined filtrate was evaporated to dryness. The residue was dissolved in a minimum amount of dry ethanol, which upon cooling gave a pure product. Yield 4.20 g (83%). The p.f. and the spectral characteristics of this product corresponded with the product prepared in Method A previous.

Example 3 2- (2 ', 3', 5'-tri-ü-benzoyl-β-D-ribofuranosyl) thiazole-4-carboxylic acid ethyl ester (4): To a stirred mixture of 2,5-anhydro-3 ', 4 ', 6' -tri-O-benzoyl-D-alontioamide (2, 10.12 g, 20.00 mmol) and solid NaHCO 3 (16.8 g, 200 mmol) in 1,2-dimethoxyethane dry (60 ml) at 0 ° C under a Argon atmosphere was added ethyl bromopyruvate (7.8 g, 40.00 mmol) over a period of 10 minutes. After the addition, the reaction mixture was stirred at 0 ° C under an argon atmosphere for 6 hours. The CLT indicated a complete conversion of the starting material into a single product (Hex: EtOAc, 7: 3). The reaction was cooled to -15 ° C in dry ice / CCl under an argon atmosphere. A solution of trifluoroacetic anhydride (12.6 g, 60.00 mmol) and 2,6-lutidine (12.84 g, 120 mmol) dissolved in dry 1,2-dimethoxyethane (20 ml) was added slowly over a period of 15 minutes. After the addition, the reaction was stirred at -15 ° C for 2 hours under an argon atmosphere. The reaction mixture was filtered, washed with dry methylene chloride (100 ml). The combined filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in CH2C12 (200 ml) and the pH was adjusted to 7 with a saturated NaHCO3 solution. The organic extract was washed with IN HCl (100 ml), saturated NaHCO 3 solution (200 ml) and brine (100 ml). The organic layer was dried over anhydrous Na 2 SO 4, filtered, washed with CH 2 C 12 (100 ml) and evaporated to dryness. The unpurified material was used as such for a subsequent reaction. A small amount was purified by flash chromatography on silica gel using hexane-ethyl acetate as eluent. XH NMR (CDC13): d 1.36 (t, 3H), 4.40 (m, 2H), 4.62 (dd, IH), 4.74 (m, 1H), 4.86 (dd, IH), 5.74 (d, IH), 5.84 (m, 2H) 7.30-7.60 (m, 9H), 7.91 (d, 2H), 7.98 (d, 2H), 8.08 (m, 2H) and 8.12 (s, IH) Example 4 2- (ß-D-ribofuranosyl) thiazole-4-carboxylic acid ethyl ester (5_): Ethyl- (2 ', 3', 5 '-tri-0_-benzoyl-β-D-ribofuranosyl) thiazole-4-carboxylate without purifying (4.15.00 g) was dissolved in dry ethanol (100 ml) and treated with sodium ethoxide powder (1.36 g, 20 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 12 hours under an argon atmosphere. The solution was neutralized with H + 50W-X8 Dowex resin, filtered and washed with methanol (100 ml). The filtrate was evaporated to dryness. The residue was partitioned between water (100 ml) and chloroform (150 ml). The aqueous layer was washed with chloroform (100 ml) and evaporated to dryness. The residue was dissolved in methanol (100 ml), silica gel (15 g) was added and evaporated to dryness. The silica gel absorbed from the dried compound was placed on top of the silica column (5 x 20 cm) packed with CH2C12. The column was eluted with CH2Cl2 / acetone (7: 3, 500 ml), followed by CH2Cl2 / methanol (95: 5, 1000 ml). The CH2Cl2 / methanol fractions were collected together and evaporated to give the pure compound 5. A small amount was crystallized with 2-propanol / ether as a colorless product. Yield 4.8 g (83%), m.p. 62-64 ° C. ? NMR (DMSO-de); d 1.36 (t, 3H), 3.52 (m, 2H), 3.84 (m, 2H), 4.06 (m, IH), 4.28 (m, 2H), 4.94 (t, IH), 4.98 (d, ÍH), 5.08 (d, IH), 5.46 (d, IH) and 8.52 (s, ÍH).

Example 5 2 - . 2-β-D-Ribofuranosylthiazole-4-carboxamide (Tiazofurine) (6J: 2- (β-ribofuranosyl) thiazole-4-carboxylic acid ethyl ester (4.6 g, 15.92 mmol) was placed in a steel pump and Mixed with freshly prepared methanolic ammonia (saturated at 0 ° C, 70 ml) The reaction mixture was stirred at room temperature for 12 hours.The steel pump was cooled, opened carefully and the contents evaporated to dryness. it was triturated with dry ethanol (60 ml) and evaporated to dryness.The residue was treated with dry ethanol (60 ml), which upon trituration gave a pale yellow solid.The solid was filtered, washed with acetate of ethyl and dried The solid was crystallized with ethanol / ethyl acetate to give a pure product Yield 3.6 g (87%), mp 142-144 ° C, X NMR (DMSO-d6); d 3.57 (m, 2H), 3.89 (bs, 2H), 4.06 (m, IH), 4.84 (t, 1H), 4.93 (d, IH), 5.06 (m, IH), 5.37 (d, 1H), 7.57 (s, IH), 7.69 (s, IH) and 8.21 (s, IH).

Example 6 -ü-Benzoyl-β-D-ribofuranosyl-1-carbonitrile (7.): A solution of 2 ', 3', 5 '-tri-Q-benzoyl-β-D-ribofuranosyl-1-carbonitrile (2, 61 g, 129.40 mmoles) in chloroform (200 ml) was added with stirring in an ice cold saturated methanolic ammonia (500 ml) under an argon atmosphere. The reaction mixture was stirred at 0 ° C for 4.5 hours. The CLT indicated a complete conversion of the starting material. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (500 ml), washed with saturated NaHCO 3 solution (100 ml), water (300 ml) and brine (150 ml). The organic extract was dried over anhydrous MgSO, filtered, washed with ethyl acetate (100 ml) and the filtrates were combined, and evaporated to dryness to give a dark brown liquid. The liquid was dissolved in benzene (100 ml), diluted with hexane (50 ml) and acetone (15 ml). The solution at rest at room temperature overnight gave crystals. The solid was filtered, washed with hexane and dried. Yield 29 g (85%); p.f. 116-117 ° C.

Example 7 -β-benzoyl-2,3-Q-isopropylidene-β-D-ribofuranosyl-1-carbonitrile (2): 5'-β-Benzoyl-β-D-ribofuranosyl-1-carbonitrile solid (7.26.3 g , 100 mmol) was added to a stirred solution of 72% perchloric acid (4 ml) in 2,2-dimethoxypropane (30 ml) and dry acetone (150 ml) under an argon atmosphere in one portion. The reaction mixture was stirred at room temperature for 3 hours. The solution was neutralized with ammonium hydroxide and evaporated to dryness. The residue was dissolved in chloroform (250 ml) and washed with water (2 x 200 ml) and brine (100 ml). The organic phase was dried over anhydrous MgSO4, filtered, washed with chloroform (50 ml) and the filtrate was evaporated to dryness. The residue with crystallization from ether-hexane gave colorless crystals.

Yield 28.5 g (95%); p.f. 62-63 ° C. ^ RMN (CDC13) d: 1.35 (s, 3H), 1.52 (s, 3H), 4.51 (m, 2H), 4.59 (m, 2H), 4.77 (d, IH), 4. 87 (d, IH), 5.10 (m, IH), 7.46 (m, 2H), 7.57 (m, ÍH) and 8.07 (m, 2H).

Example 8 2- (5'-Q-Benzoyl-2 ', 3'-£ > -isopropylidene-β-D-ribofuranosyl) thiazoline-4-ethylcarboxylate (2.): To a stirred solution of 5'-£ > -Benzoyl-2 ', 3' -Q-isopropylidene-β-D-ribofuranosyl-1-carbonitrile (2. 4.71 g, 15.55 mmol) in dry methylene chloride (150 ml) at room temperature under an argon atmosphere was added Cysteine ethyl ester hydrochloride (1.49 g, 8 mmol) and (0.81 g, 8 mmol) at 0 o'clock, second hour, fourth hour and sixth hour. The reaction mixture was stirred at room temperature under an argon atmosphere for 24 hours. The reaction was diluted with methylene chloride (100 ml), washed with water (200 ml) and brine (150 ml). The CHC12 extract was dried over anhydrous. MgSO4, filtered, washed with CH2C12 (50 ml) and the filtrate was evaporated to dryness. The residue was used as such for the next reaction. A small amount of the unpurified product was purified by flash chromatography on silica gel using hexane / ethyl acetate as eluent and characterized by proton spectroscopy. XH NMR (CDC13): d 1.24 (t, 3H), 1. 35 (s, 3H), 1.52 (s, • 3H), 3.40 (m, 2H), 4.20 (m, 2H), 4.42 (m, 3H), 4.80 (m, 2H), 5.12 (m, 2H), 7.42 (m, 2H), 7.58 (m, ÍH) and 8.08 (m, 2H).

Example 9 2- (5'-Cj-Benzoyl-2 ', 3'-O-isopropylidene-β-D-ribofuranosyl) thiazole-4-carboxylic acid ethyl ester (10) Method A: To a vigorously stirred solution of 2- (5') - £) -Benzoyl-2 ', 3' -Q-isopropylidene-β-D-ribofuranosyl) thiazoline-4-carboxylic acid ethyl ester without purification (- £, 7.0 g) in methylene chloride (300 ml) was added dioxide activated manganese (27.8 g) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, it was filtered through a layer of CELITE and washed with acetone (200 ml). The filtrates were combined and evaporated to dryness to give an oily residue. Yield 5.9 g (88% of cyano-sugar 2) • A small amount of the unpurified product was purified by flash chromatography on silica gel using CH2Cl2-ethyl acetate as eluent and characterized by proton spectroscopy. ^ "H NMR (CDC13): d 1.39 (t, 6H), 1.63 (s, 3H), 4.39 (m, 3H), 4.60 (m, 2H), 4.84 (m, IH), 5.26 (m, ÍH), 5.40 (d, 1H), 7.40 (m, 2H), 7.52 (m, ÍH), 7.89 (m, 2H) and 8.02 (s, ÍH).

Method B: A mixture of unpurified ethyl 2- (5'-Q-Benzoyl-2 ', 3'-Q-isopropylidene-β-D-ribofuranosyl) thiazoline-4-carboxylate (£ 7.0g) and dioxide Activated manganese (27.8 g) in dry benzene (150 ml) was heated at 80 ° C for 2 hours. The reaction mixture was filtered through a layer of CELITE and washed with acetone (200 ml). The filtrates were combined and evaporated to dryness to give an oily residue. Yield 6.0 g (89% of cyano-sugar 2). A small amount of the unpurified product was purified by flash chromatography on silica gel using CH2Cl2-ethyl acetate as eluent and by proton spectroscopy. The products obtained by both methods were found to be identical in all respects.

Method C: To a vigorously stirred solution of crude 2- (5'-Q-Benzoyl-2 ', 3'-Q-isopropylidene-β-D-ribofuranosyl) thiazoline-4-carboxylate without purification (¿, 2.0 g) in methylene chloride (100 ml) was added nickel peroxide (10.0 g) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, filtered through a layer of CELITE and washed with acetone (200 ml). The filtrates were combined and evaporated to dryness to give an oily residue. Yield 5.9 g (88% of cyano-sugar 8). The product obtained by this method was found to be identical with the products obtained by methods A and B in all respects.

Example 10 2- (5 '-Q-Benzoyl-β-D-ribofuranosyl) thiazole-4-carboxylic acid ethyl ester (11): A solution of 2- (5' -j-Benzoyl-2 ', 3'-Q-isopropylidene- crude ß-D-ribofuranosyl) iazole-4-carboxylic acid ethyl ester (1J2, 4.5 g, 10.39 mmol) in a mixture of trifluoroacetic acid: tetrahydrofuran: water (30: 20: 6 ml) was allowed to stir at room temperature for 1 hour. hour. The reaction mixture was evaporated to dryness. The residue was suspended in methylene chloride (100 ml), cooled and neutralized with saturated NaHCO 2 solution. The aqueous solution was extracted with CH2C12 (2 x 100 ml), washed with saturated NaHCO3 solution (100 ml), water (100 ml) and brine (100 ml). The organic extract was dried over MgSO4, filtered, washed with CH2Cl2 (100 ml) and the filtrate was evaporated to dryness. The residue was crystallized with ethanol / water (1: 1) to give colorless crystals. The solid was filtered and dried over P2O5 under vacuum. performance 4. 0 g (98%) '; p.f. 82-85 ° C. X H NMR (CDC13): d 1.33 (t, 3 H), 4.31 (m, 4 H), 4.45 (m, 3 H), 4.55 (m, H H), 4.74 (m, 1 H), 5.32 (d, H H), 7.37. (m, 2H), 7.51 (m, ÍH) and 7.99 (m, 3H).

Example 11 2-ß-D-Ribofuranosylthiazole-4-carboxamide (Thiazofurine) (£): Ethyl 2- (5'-O-Benzoyl-β-D-ribofuranosyl) thiazole-4-carboxylate (11, 3.7 g, 942 mmol) was placed in a steel pump and mixed with cold methanolic ammonia prepared recently (70 ml, saturated at 0 ° C). The mixture was protected from moisture and stirred at room temperature for 12 hours. The steel pump was cooled to 0 ° C, opened carefully and evaporated to a viscous foam. The residue was triturated with dry toluene (3 x 50 ml) and the toluene layer discharged. The residue that was obtained was treated with anhydrous ethanol (60 ml) and triturated to give a light yellow solid. The solid was filtered, washed with ethyl acetate and dried. The solid was crystallized with ethanol-ethyl acetate to provide 2.25 g (90%) of the pure product: m.p. 145-147 ° C. X H NMR (DMS0-ds): d 3.57 (M, 2 H), 3.89 (s, 2 H), 4.07 (m, H H), 4.83 (t, H H), 4.92 (d, H H), 5.05 (d, ÍH), 5.36 (d, ÍH), 7.56 (s, 1), 7.69 (s, 1) and 8.20 (s, 1).

In this way, the specific modalities and applications of the method of production of Thiazofurin and other C-Nucleosides have been discovered. It should be apparent, however, to those skilled in the art that many more modifications, in addition to those already described, are possible without departing from the inventive concepts herein. The inventive topic, therefore, is not restricted, except in the spirit of the amended claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (24)

1. A method of synthesizing a nucleoside according to Structure A, characterized in that it comprises: Structure A provide a compound according to Structure B, wherein L is a reactive group; Structure B in a single step reacting L of Structure B to form Structure D having a heterocyclic ring; Y Structure D in a single step aromatize the hetrocyclic ring; wherein A is O, S, CH2 or NR, where R is H or a blocking group; X is O, S, Se or NH; R1 R2, R3 and R4 are independently H or lower alkyl; R5 is H, lower alkyl, amine or aryl; Blr B2, and B3 are independently blocking or lower alkyl groups, and Zi, Z2 and Z3 are independently H or not H.

2. The method according to claim 1, characterized in that L is -CN or -CHO.

3. The method according to claim 2, characterized in that the step of reacting L of Structure B to form Structure D comprises reacting Structure B with Structure C, wherein Y is H or lower alkyl. Structure C

4. The method according to claim 1, characterized in that the compound according to Structure B is Structure E. Structure E

5. The method according to claim 4, characterized in that the step of reacting L to form Structure D comprises reacting Structure E with Structure C, wherein Y is H or lower alkyl. Structure C

6. The method according to claim 1, characterized in that the step of replacing L comprises Reaction A. Reaction to

7. The method according to claim 2, characterized in that L is replaced with Structure D.

8. The method according to claim 7, characterized in that it further comprises reacting the compound with a reagent selected from the group consisting of an amino acid and a substituted amino acid to produce an intermediate according to Structure F, where R5 is H, lower alkyl , amine or aryl.

9. The method according to claim 8, characterized in that the amino acid is a cysteine alkyl ester hydrochloride.

10. The method according to claim 8, characterized in that it also comprises aromatizing the compound of Structure F. Structure F

11. The method according to claim 8, characterized in that the step of aromatizing comprises treating the compound of Structure F with activated manganese dioxide. Structure F

12. The method according to claim 1, characterized in that the step of reacting L comprises Reaction B. Reaction B

13. The method according to claim 11, characterized in that the compound contains a group of isopropylidene, and the isopropylidene group is removed by treatment with a reagent selected from the group consisting of trifluoroacetic acid, formic acid, acetic acid, an H + resin in an organic solvent, and iodine in methanol.

14. The method according to any of claims 1-13, characterized in that the nucleoside is thiazofurin.

15. The method according to any of claims 1-13, characterized in that the compound of Structure B comprises an L-ribose.

16. The method according to claim 15, characterized in that at least one of Zi, Z2, and Z3 is not H.

17. The method according to any of claims 1-13, characterized in that the compound of Structure B is an alpha isomer.

18. The method according to any of claims 1-13, characterized in that the compound of Structure B is a beta isomer.

19. The method of conformance to any of claims 1-13, characterized in that A is NR, R is C0CH3, and X is not S.

20. A compound produced "by the methods according to any of claims 1-13, CRQ has a structure according to Structure A.

21. A compound produced by the methods according to any of claims 1-13, and having a structure according to Structure A, characterized in that the sugar portion is an alpha isomer.

22. A compound produced by the methods according to any of claims 1-13, and having a structure according to Structure A, characterized in that the sugar portion has an L configuration.

23. A compound produced by the methods according to any of claims 1-13, and having a structure according to Structure A, characterized in that the sugar portion is an alpha isomer.

24. A compound produced by the methods according to any of claims 1-13, and having a structure according to Structure A, characterized in that at least one of Zl r _Z2, and Z3 is not H.