HRP990365A2 - Method of producing thiazofurin and other c-nucleosides - Google Patents

Description

Field of invention

The invention is from the field of synthetic organic chemistry.

State of the art

C-nucleosides are interesting compounds that are potentially active as pharmaceutical agents. One of these compounds, tiazofurin, [6,2-(β-D-ribofuranosyl)thiazole-4-carboxamide), possesses significant activity against human lymphoid. F. Earle and R.I. Glazer, Cancer Res., 1983, 43, 133), lung tumor cell lines (D.N. Carnex, G.S. Abluwalia, H.N. Jayaram, D.A. Cooney and D.G. Johns, J. Clin. Invest., 1985, 75, 175) mouse-implanted carcinoma. of the human ovary (J.P. Micha, P.R. Kucera, C.N. Preve, M.A. Rettenmaier, J.A. Stratton, P.J. DiSaia, Gynecol. Oncol. 1985, 21, 351). Tiazofurin has also shown efficacy in the treatment of acute mycloid leukemia (G.T. Tricot, H.N. Jasyaram, C.R. Nichols, K. Pennington, E. Lapis, G. Weber, and R. Hoffman, Cancer Res. 1997, 47 4988). Furthermore, recent findings have increased interest in tiazofurin as a possible treatment for patients with chronic myeloid leukemia (CML) in blast crisis (G. Weber, US Patent 5,405,837; 1995). In cells, tiazofurin is translated into its active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), which inhibits IMP dehydrogenase, and as a result depletes guanosine nucleotide reserves. (E. Olah, Z. Natusmeda, T. Ikegami, Z. Kote, M. Horanyi, I. Szelenye, E. Paulik, T. Kremmer, S. R. Hollan, J. Sugar and G. Weber, Proc. Natl. Acad. Sci. USA, 1988, 85, 6533).

Although tiazofurin has been known for over 15 years, and is currently in phase II/III trials in humans, there is no suitable synthesis for large-scale production. Thiazofurin was first synthesized independently by M. Fuertes et al. (J. Org. Chem., 1976, 41, 4076) and Srivastava et al. (J. Med. Chem., 1977, 20, 256) in low yield. In both procedures, the authors obtained by-products (ie, compound 12) and used column chromatography in each step to purify the product. The main disadvantage of these procedures is the formation of a furan derivative as well as the use of highly toxic hydrogen sulfide gas.

W. J. Hannon and co-workers (J. Org. Chem., 1985, 50, 1741) developed a slightly different route for tiazofurin with a yield of 19%. The Hannon process also has a low yield, using H2S gas and chromatographic purification. Subsequently, P. Vogel and co-workers (Helv. Chem. Acta., 1989, 72, 1825) synthesized tiazofurin in nine steps with a yield of 25%. Later, D.C. Humber and co-workers (J. Chem. Soc. Perkin Trans. 1, 1990, 293) synthesized tiazofurin starting from benzyl (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) penicillinate.

The only known process that is at all suitable for obtaining is that of Parsons et al. (US 4,451,684). Unfortunately, the Parsons process uses mercuric cyanide and hydrogen sulfide, both of which have safety and environmental issues. The Parsons process also gives a mixture of products.

The difficulties mentioned above and related to the mass production of tiazofurin are also related to the mass production of other C-nucleosides. In the production of thiocarboxamides, for example, most known processes use hydrogen sulfide gas as a reagent to convert the cyanide group into the corresponding thiocarboxamide group. These procedures are associated with inherent environmental problems. In general, when preparing C-nucleosides, most or all known syntheses give a mixture of products during the ring-closing step. Therefore, there is a constant need for a new process for the bulk production of tiazofurin and other C-nucleosides.

Summary of the invention

This invention relates to a new process for the synthesis of C-nucleosides, in which the C1 position of the carbohydrate is derivatized in one step to give a heterocyclic compound, and then the heterocyclic compound is aromatized in the next step.

In one group of preferred embodiments, the cyanide carbohydrate is converted to a thiocarboxamide, and then condensed to form an azole ring. In another group of preferred embodiments, the cyanide carbohydrate is condensed with an amino acid to form an azole ring. In a third group of preferred embodiments, the halide carbohydrate is condensed with the reformed heterocyclic compound to form an azole ring.

There are numerous advantages of this procedure. One advantage is that the process eliminates the need for hydrogen sulfide gas, which is hazardous to the environment. The next advantage is that the yield is significantly increased compared to previous procedures. A third advantage is that this process eliminates the need for chromatographic purification procedures, thereby reducing the cost of production.

These and various other objects, features, aspects and advantages of the present invention will become more apparent after the detailed description of the preferred embodiments of the invention, taken together with the accompanying drawings where like numbers indicate like components.

Brief description of the drawing

Figure 1 is a series of reaction schemes illustrating various embodiments of the present invention.

Figure 2 is the following series of reaction schemes illustrating various embodiments of the present invention.

Figure 3 is the following series of reaction schemes illustrating various embodiments of the present invention.

Description of the invention with examples of implementation

There are three preferred classes of processes for carrying out the present invention, each illustrated with respect to the preparation of tiazofurin in Figures 1, 2 and 3.

In one preferred class of embodiments, the cyanide carbohydrate is converted to a thiocarboxamide, and then condensed to form an azole ring. In the particular example shown in Figure 1, the blocked cyanide carbohydrate (2) is converted to the thiocarboxamide (3), and then condensed with ethyl bromopyruvate to give the thiazofurin intermediate (4). The presented procedure gives tiazofurin in quantitative yield without by-products (12 or the α-isomer of 4).

In another class of preferred embodiments, the cyanide carbohydrate is condensed with an amino acid to form an azole ring. In the specific example shown in Figure 2, the known cyano compound (8) is condensed with cysteine ethyl ester hydrochloride to give the ring-closed product (9), which is then aromatized with activated manganese dioxide to give the thiazofurin intermediate (10). This key intermediate (10) is converted to tiazofurin in the usual manner, in good yield.

In a third class of preferred embodiments, the halide carbohydrate is condensed with the previously formed heterocyclic compound to form an azole ring. In the specific example shown in Figure 1, the previously obtained heterocyclic compound (13) is condensed with a known halide carbohydrate (14) to obtain the key intermediate (4) from which tiazofurin is easily derived.

Of course, the methods of the invention described here are not limited to obtaining tiazofurin, and can be easily generalized, especially regarding the generalization of the second and third class of methods to practically all C-nucleosides. In general, the C-nucleoside according to the present invention belongs to the general structural formula A, where A is equal to O, S, CH 2 or NR where R is equal to H or a blocking group; X is equal to O, S, Se or NH; R 1 , R 2 , R 3 and R 4 are independently H or lower alkyl; while Z1, Z2 and Z3 are independently H or non-H.

[image]

To obtain the various compounds represented by the structural formula A, there is considerable variability in the carbohydrate portion of the molecule. Among other things, the carbohydrate itself need not be a simple furan. For example, oxygen can be replaced by sulfur to give a thio-carbohydrate, or nitrogen to give an amino-carbohydrate. Furthermore, the carbohydrate can be substituted at the C2', C3' and C4' positions with a group other than hydrogen. Furthermore, the carbohydrate can have a D- or L-configuration, and can be an alpha- or beta-anomer. Furthermore, the carbohydrate can have blocking groups in different degrees of synthesis. All of these permutations are encompassed by structural formula B, where A is O, S, CH 2 or NR where R is H or a blocking group; B 1 , B 2 and B 3 are independently blocking groups or lower alkyl, and Z 1 , Z 2 and Z 3 are independently H or non-H. Group L is a reactive functional group such as CN, halogen or CHO.

[image]

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 the structural formula C, where X is equal to O, S, Se or NH; Y is H or lower alkyl; and R 4 is H or lower alkyl.

[image]

Similarly, in a third class of preferred embodiments, the use of the previously formed heterocyclic compound can be generalized by the use of a compound according to the structural formula D, where R 4 is equal to H or lower alkyl.

[image]

There are, of course, numerous blocking groups that are suitable. Among others, benzoyl, benzyl, silyl or isopropylidene can be used. Furthermore, it is specifically assumed that the blocking groups at the C2' and C3' positions on the carbohydrate can be converted into an isopropylidene group, as shown in structural formula E.

[image]

This isopropylidene group can be removed by many methods, including treatment with a reagent selected from the group consisting of trifluoroacetic acid, formic acid, acetic acid, and H+ resin in an organic solvent or iodine in methanol. Application of this procedure to structure E can then give a compound according to structural formula F, where R5 is H, lower alkyl, amine or aryl.

[image]

This embodiment also involves aromatization of structure F with activated manganese dioxide or other reagents followed by deblocking of the protecting groups to give the tiazofurin or related C-nucleosides.

A particularly preferred embodiment according to the facts presented here is reaction A or reaction B, which are shown below.

[image]

[image]

These and other properties can be demonstrated by the following working examples, which should be considered illustrative of various aspects of the facts stated in the patent claims, which are not limiting in terms of the facts stated in the patent claims.

Experimental part

Example 1

2,3,5-tri-O-benzoyl-β-D-ribofuranosyl-1-carbonitrile (2): The carbonitrile was prepared by the procedure established by Robins and co-workers (PCT/US96/02512).

Example 2

2,5-anhydro-3,4,6-tri-O-benzoyl-D-alonthioamide (3): Procedure A: Hydrogen sulfide was passed through a cold (5°C) suspension of 2',3',5'- tri-O-benzoyl-β-D-ribofuranosyl cyanide (2.50 g, 106.16 mmol) in dry EtOH (900 ml) for 5 min, and then N,N-dimethylaminopyridine (1.2 g, 10 mmol). Hydrogen sulfide was then passed through the reaction mixture slowly, with stirring, for 5 h (the outlet tube from the reaction vessel passed bubbles through a solution of chlorinated lime in 5% NaOH). After 5 hours, the flask was sealed and stirring was continued below 25°C for 16 hours. Pass argon through the reaction mixture for 1 h 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 and dry EtOH and dried over P2O5 in vacuo.

Yield: 52 g (97%); d.p. 133-135°C.

1H NMR (CDCl3): δ 4.72 (m, 2H), 4.74 (m, 1H), 5.12 (d, 1H), 5.71 (t, 1H), 5.98 (t, 1H), 7.30-7.60 (m, 10H) , 7.86 (d, 2H), 8.14 (m, 4H) and 8.46 (bs, 1H).

Procedure B: A solution of 2',3',5'-tri-O-β-D-ribofuranosyl cyanide (2, 4.71 g, 10.00 mmol) and thioacetamide (1.50 g, 20.00 mmol) in of dry DMF (50 ml) was saturated with anhydrous hydrogen chloride and heated to 70-60°C for 2 hours. The reaction mixture was cooled and evaporated to dryness. The residues were dissolved in methylene chloride (150 ml), washed with saturated NaHCO3 solution (100 ml), water (100 ml) and brine (70 ml). The organic extract was dried over anhydrous MgSO4, filtered and washed with CH2Cl2 (50 mL). The combined filtrate was evaporated to dryness. The residues were dissolved in a minimal amount of dry ethanol, which gave a pure product after cooling. Yield: 4.20 g (83%). The melting point and spectral properties of this product match the product prepared in the previous procedure A.

Example 3

Ethyl 2-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)thiazole-4-carboxylate (4): With stirring, a mixture of 2,5-anhydro-3',4', of 6'-tri-O-benzoyl-D-alonthioamide (3, 10.12 g, 20.00 mmol) and solid NaHCO3 (16.8 g, 200 mmol) in dry 1,2-dimethoxyethane (60 ml) at 0 °C under argon atmosphere, ethyl bromopyruvate (7.8 g, 40.00 mmol) was added over 10 minutes. After the addition, the reaction mixture was stirred at 0°C under argon for 6 h. TLC showed complete conversion of the starting material to one product (hexane:EtOAc, 7:3). The reaction mixture was cooled to -15°C in dry ice/CCl4 under argon. 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) were added slowly over 15 min. After the addition, the reaction mixture 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 CH2Cl2 (200 ml) and the pH was adjusted to 7 with saturated NaHCO3 solution. The organic extract was washed with 1N HCl (100 ml), saturated NaHCO3 solution (200 ml) and brine (100 ml). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, washed with CH 2 Cl 2 (100 ml) and evaporated to dryness. The raw material as such was used for further reactions. A small amount was purified by "flash" chromatography on silica gel using hexane-ethyl acetate as eluent.

1H NMR (CDCl3): δ 1.36 (t, 3H), 4.40 (m, 2H), 4.62 (dd, 1H), 4.74 (m, 1H), 4.86 (dd, 1H), 5.74 (d, 1H), 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 (d, 1H).

Example 4

Ethyl 2-(β-D-ribofuranosyl)thiazole-4-carboxylate (5): Crude ethyl 2-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)thiazole-4-carboxylate (4, 15.00 g) was dissolved in dry ethanol (100 ml) and treated with powdered sodium ethoxide (1.36 g, 20 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 12 hours under argon. The solution was neutralized with Dowex 50W-X8 H+ 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 residues were dissolved in methanol (100 ml), silica gel was added and evaporated to dryness. The dried compound adsorbed by silica gel was placed on top of a silica gel column (5x20 cm) filled with CH2Cl2. The column was eluted with CH2Cl2/acetone (7:3, 500 ml) and then with CH2Cl2/methanol (95:5, 1000 ml). The CH2Cl2/methanol fractions were pooled and evaporated to dryness to give pure compound 5. A small amount was crystallized from 2-propanol/ether as a colorless product. Yield: 4.8 g (83%); d.p. 62-64°C.

1H NMR (DMSO-d6): δ 1.36 (t, 3H), 3.52 (m, 2H), 3.84 (m, 2H), 4.06 (m, 1H), 4.28 (m, 2H), 4.94 (t, 1H) , 4.98 (d, 1H), 5.08 (d, 1H), 5.46 (d, 1H) and 8.52 (s, 1H).

Example 5

2-β-D-ribofuranosylthiazole-4-carboxamide (thiazofurin) (6): Crude ethyl 2-(β-D-ribofuranosyl)thiazole-4-carboxylate (5, 4.6 g, 15.92 mmol) was placed in steel bomb 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 bomb is cooled, carefully opened and the contents evaporated to dryness.

The residues were slurried with dry ethanol (60 ml) and evaporated to dryness. The residue was treated with dry ethanol (60 ml) which after trituration gave a light yellow solid. The solid was filtered, washed with ethyl acetate and dried. The solid was crystallized from ethanol/ethyl acetate to give the dry product. Yield: 3.6 g (87%); d.p. 142-144°C.

1H NMR (DMSO-d6): δ 3.57 (m, 2H), 3.89 (bs, 2H), 4.06 (m, 1H), 4.84 (t, 1H), 4.93 (d, 1H), 5.06 (m, 1H) , 5.37 (d, 1H), 7.57 (s, 1H), 7.69 (d, 1H), 8.21 (s, 1H).

Example 6

5-O-benzoyl-β-D-ribofuranosyl-1-carbonitrile (7): A solution of 2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl-1-carbonitrile (2, 61 g, 129.40 mmol) in chloroform (200 ml) was added with stirring to ice-cold saturated dry methanolic ammonia (500 ml) under an argon atmosphere. The reaction mixture was stirred at 0°C for 4.5 hours. TLS showed complete translation of the starting material. The reaction mixture was evaporated to dryness. The residues were dissolved in ethyl acetate (500 ml), washed with saturated aqueous NaHCO3 solution (100 ml), water (300 ml) and brine (150 ml). The organic extract was dried over anhydrous MgSO4, 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 gave crystals after standing at room temperature overnight. The solid was filtered, washed with hexane and dried. Yield: 29 g (85%); d.p. 116-117°C.

Example 7

5-O-benzoyl-2,3-isopropylidene-β-D-ribofuranosyl-1-carbonitrile (8): Solid 5'-O-benzoyl-β-D-ribofuranosyl-1-carbonitrile (7, 26.3 g, 100 mmol) was added with stirring to a 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 residues were dissolved in chloroform (250 ml) and washed with water (2x200 ml) and saline (100 ml).

The organic phase was dried over anhydrous MgSO4, filtered, washed with chloroform (50 ml) and the filtrate was evaporated to dryness. The residues gave colorless crystals after crystallization from ether-hexane. Yield: 28.5 g (95%); d.p. 62-62°C.

1H NMR (CDCl3): δ 1.35 (d, 2H), 1.52 (s, 3H), 4.51 (m, 2H), 4.59 (m, 2H), 4.77 (d, 1H), 4.87 (d, 1H), 5.10 (m, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 8.07 (m, 2H).

Example 8

Ethyl 2-(5'-O-benzoyl-2',3'-O-isopropylidene-β-D-ribofuranosyl)thiazoline-4-carboxylate (9): With stirring, solutions of 5'-O-benzoyl-2', To 3'-isopropylidene-β-D-ribofuranosyl-1-carbonitrile (8, 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 h, after 2 h, 4 h and after 6 h. The reaction mixture was stirred at room temperature under an argon atmosphere for 24 hours. The reaction mixture was diluted with methylene chloride (100 ml), washed with water (200 ml) and brine (150 ml). The CH 2 Cl 2 extract was dried over anhydrous MgSO 4 , filtered, washed with CH 2 Cl 2 (50 ml) and the filtrate was evaporated to dryness. The residues were used as such for the next reaction. A small amount of the crude product was purified by "flash" chromatography on silica gel using a mixture of hexane/ethyl acetate as eluent and identified by proton spectroscopy.

1H NMR (CDCl3): δ 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, 1H), 8.08 (m, 2H).

Example 9

Ethyl 2-(5'-O-benzoyl-2',3'-O-isopropylidene-β-D-ribofuranosyl) thiazole-4-carboxylate (10):

Procedure A: With vigorous stirring, a solution of crude ethyl 2-(5'-O-benzoyl-2',3'-O-isopropylidene-β-D-ribofuranosyl)thiazoline-4-carboxylate (9, 7.0 g) in activated manganese dioxide (27.8 g) was added to methylene chloride (300 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, filtered through 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% from cyanide carbohydrate 8). A small amount of the crude product was purified by flash chromatography over silica gel using CH2Cl2-ethyl acetate as eluent and identified by proton spectroscopy.

1H NMR (CDCl3): δ 1.39 (t, 6H), 1.63 (s, 2H), 4.39 (m, 3H), 4.60 (m, 2H), 4.84 (m, 1H), 5.26 (m, 1H), 5.40 (d, 1H), 7.40 (m, 2H), 7.52 (m, 1H), 7.89 (m, 2H), 8.02 (s, 1H).

Procedure B: A mixture of crude ethyl 2-(5'-O-benzoyl-2',3'-O-isopropylidene-β-D-ribofuranosyl)thiazoline-4-carboxylate (9, 7.0 g) and activated manganese dioxide ( 27.8 g) in dry benzene (150 ml) was heated to 80°C for 2 hours. The reaction mixture was filtered through 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% from cyanide carbohydrate 8). A small amount of the crude product was purified by flash chromatography over silica gel using CH2Cl2-ethyl acetate as eluent and identified by proton spectroscopy. The products obtained from both procedures are identical in every respect.

Procedure C: With vigorous stirring, a solution of crude ethyl 2-(5'-O-benzoyl-2',3'-O-isopropylidene-β-D-ribofuranosyl)thiazoline-4-carboxylate (9, 2.0 g) in nickel peroxide (10.0 g) was added to methylene chloride (100 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, filtered through 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% from cyanide carbohydrate 8). The product obtained by this procedure was identical to the products obtained by procedures A and B, in all respects.

Example 10

Ethyl 2-(5'-O-benzoyl-β-D-ribofuranosyl)thiazole-4-carboxylate (11): A solution of crude ethyl 2-(5'-O-benzoyl-2',3'-O-isopropylidene-β -D-ribofuranosyl)thiazole-4-carboxylate (10, 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 . The reaction mixture was evaporated to dryness. The residues were suspended in methylene chloride (100 ml), cooled and neutralized with saturated NaHCO3 solution. The aqueous solution was extracted with CH2Cl2 (2x100 ml), washed with saturated NaHCO3 solution (100 ml), water (100 ml) and brine (100 ml). The organic extract was dried over MgSO 4 , filtered, washed with CH 2 Cl 2 (100 ml) and the filtrate was evaporated to dryness. The residue was crystallized from ethanol:water (1:1) to give colorless crystals. The solid was filtered and dried over P2O5 in vacuo. Yield: 4.0 g (98%); d.p. 82-85°C.

1H NMR (CDCl3): δ 1.33 (t, 3H), 4.31 (m, 4H), 4.45 (m, 3H), 4.55 (m, 1H), 4.74 (m, 1H), 5.32 (d, 1H), 7.37 (m, 2H), 7.51 (m, 1H), 7.99 (m, 3H).

Example 11

2-β-D-ribofuranosylthiazole-4-carboxamide (thiazofurin) (6): Ethyl 2-(5'-O-benzoyl-β-D-ribofuranosyl)thiazole-4-carboxylate (11, 3.7 g, 942 mmol ) was placed in a steel bomb and mixed with freshly prepared cold methanolic ammonia (70 ml, saturated at 0°C). The mixture was protected from moisture and stirred at room temperature for 12 hours. The steel bomb was cooled to 0°C, carefully opened and evaporated to dryness to produce a sticky foam. The residues were triturated with dry toluene (3x50 ml) and the toluene layer was discarded. The resulting residue 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 from ethanol-ethyl acetate to give 2.25 g (90%) of pure product: m.p. 145-147°C.

1H NMR (DMSO-d6): δ 3.57 (m, 2H), 3.89 (s, 2H), 4.07 (m, 1H), 4.83 (t, 1H), 4.92 (d, 1H), 5.05 (d, 1H) , 5.36 (d, 1H), 7.56 (s, 1H), 8.20 (s, 1H).

Therefore, specific realizations and applications of the procedures for obtaining tiazofurin and other C-nucleosides are described. It is understood, however, by those skilled in the art that many other modifications are possible in addition to those described without departing from the terms of the invention set forth herein, the scope of the invention, therefore, not being limited except in the spirit of the patent claims.

Claims (24)

1. The procedure for the synthesis of nucleosides according to the structural formula A, characterized by the fact that it includes: [image] obtaining a compound according to the structural formula B where L is a reactive group; [image] wherein in one step the L structures of B are reacted to give structure D having a heterocyclic ring; and [image] in one step, the heterocyclic ring is aromatized; wherein A is O, S, CH 2 or NR wherein R is H or a divalent group; X is equal to O, S, Se or NH; R 1 , R 2 , R 3 and R 4 are independently H or lower alkyl; B1, B2 and B3 are independently blocking groups or lower alkyl, while Z1, Z2 and Z3 are independently H or non-H. 2. Process according to claim 1, characterized in that L is equal to -CN or -CHO. 3. The method according to claim 2, characterized in that the reaction step L of structure B to form structure D includes the reaction of structure B with structure C. [image] 4. The method according to claim 1, characterized in that the compound of structural formula B is a compound of structural formula E. [image] 5. The method according to claim 4, characterized in that the stage of reaction L to form structure D includes the reaction of structure E with structure C. [image] 6. The process according to claim 1, characterized in that the substitution step L includes the reaction A: [image] 7. The method according to claim 2, characterized in that L is replaced by structure D. 8. The method according to claim 7, characterized in that it additionally includes the reaction of the compound with a reagent selected from the group consisting of an amino acid and a substituted amino acid to obtain an intermediate according to structure F, where R5 is equal to H, lower alkyl, amine or aryl. 9. The method according to claim 8, characterized in that the amino acid contains cysteine alkyl ester hydrochloride. 10. The method according to claim 8, characterized in that it additionally includes aromatization of the compound of structure F. [image] 11. The method according to claim 8, characterized in that the step of aromatizing the compound includes treating the compound of structural formula F with activated manganese dioxide. [image] 12. The method according to claim 1, characterized in that the stage of reaction L includes reaction B. [image] 13. The method according to claim 11, characterized in that the compound contains an isopropylidene group, and the isopropylidene group is removed by treatment with a reagent selected from the group consisting of trifluoroacetic acid, formic acid, acetic acid and H+ resin in an organic solvent or iodine in methanol. 14. The method according to any one of claims 1-13, characterized in that the nucleoside is tiazofurin. 15. The method according to any one of claims 1-13, characterized in that the compound of structural formula B contains L-ribose. 16. The method according to claim 15, characterized in that at least one of Z1, Z2 and Z3 is not H. 17. The method according to any one of claims 1-13, characterized in that the compound of structural formula B is an alpha isomer. 18. The method according to any one of claims 1-13, characterized in that the compound of structural formula B is a beta isomer. 19. The process of any one of claims 1-13, wherein A is NR, R is COCH 3 , and X is not S. 20. A compound obtained by the methods of any of claims 1-13, which has a structure according to the structural formula A, which is not tiazofurin. 21. A compound obtained by the methods of any one of claims 1-13, having a structure according to the structural formula A, where the carbohydrate part is an alpha isomer other than tiazofurin. 22. A compound obtained by the processes of any one of claims 1-13, having a structure according to the structural formula A, where the carbohydrate part is of the L configuration. 23. A compound obtained by the methods of any one of claims 1-13, having a structure according to the structural formula A, where the carbohydrate part is the alpha isomer. 24. A compound, characterized in that it is obtained by the methods of any of claims 1-13, which has a structure according to the structural formula A, where at least one of Z1, Z2 and Z3 is not H.