DE1919307A1 - Pyrimidine nucleosides - Google Patents

Abstract

Pyrimidine nucleosides. In a process for title compds. useful, as medicaments, a 1-0-acyl, 1-0-alkyl or 1-halo-OH-protected sugar is reacted with a O-silyl, -N-silyl or alkyl pyrimidine in a Lewis acid sol. in organic solvents esp. SnCl4, TiCl4, TiCl4, ZnCl2 or BF3 etherate to give an OH-protected product.

Description

Process for the preparation of nucleosides The invention relates to a process for the preparation of compounds of the general formula where R is a hydrogen atom, an alkyl group with 1-4 C atoms, a halogen atom, a nitro or nitrile group, W is an oxygen or sulfur atom, X is an oxygen atom or the group NB (with 3 meaning a hydrogen atom or an alkyl group with 1-4 carbon atoms), Y is a nitrogen atom or the group CH and Z are a protected sugar residue, characterized in that the l-acyl or l-0-alkyl derivative of the protected sugar is made with compounds of the general formula wherein R and Y are as defined above, D is a silylated 0 or NB radical, where 3 is the same as above, or a lower alkoxy group and 3 is a silylated 0 or S radical or a lower alkoxy group, in the presence of a Friedel-Crafts catalyst converts sugar residues are especially those from ribose, deoxyribose, arabinose and glucose.

Appropriately, all free hydroxyl groups of the sugars are protected. Sugar is used as sugar protection groups for the 1- / acyl- or 1-O-alkyl derivatives preferably the benzoyl, p-chlorobenzoyl, cetyl, p-nitrobenzoyl, p-toluyl and Benzyl group i question.

Among the silyl radicals suitable for the reaction are the Trialkylsilyl radicals - especially the trimethylsilyl radical - to highlight.

All known Lewis acids are suitable as Friedel-Crafts catalysts, especially tin tetrachloride and zinc chloride and mixtures thereof.

The reaction can be carried out in most common solvents e.g. in hydrocarbons, halogenated hydrocarbons (such as diethylene chloride, Chloroform, carbon tetrachloride, chlorobenzene), carbon disulfide or dimethylformamide.

Dichloroethane and acetonitrile are very particularly suitable. The implementation can be used at room temperature or higher temperatures, preferably at 0 - 1500 C, be performed. The reactants will generally be approximately Equimolecular narrower is used in the reaction, but the silyl compound is often used in small excess. The reaction is generally at temperatures of 200 ° C. after 12 hours.

It is known (Y. Furukawa, M. Honjo, Chem. Pharm. Bull. 16, 1076 (1968)), that you can purines with the above sugar derivatives with the help of Priedel-Crafts catalysts can convert to the corresponding N-glycosides. However, this reaction fails with uracils and cytosines and the sugar derivatives mentioned completely.

It t caher surprising that the connections are general Formula II with the above sugar derivatives in smooth reaction and very good yields in the presence of Friedel-Crafts.

Catalysts, such as SnCl4 or ZnCl2, to the corresponding N1-Glyko.

let siden implement.

It is further very noteworthy that the glycosides formed almost only have the ß configuration. This is therefore very beneficial, because only the ß-glycosides have a biological effect. According to the invention The glycosides obtained do not need to be used in a complicated manner Anomers to be separated.

Exploit the dic obtained by carrying out the new process, are generally higher than in the previously known processes. On average the yields are twice as high.

In addition, the compounds of general formula I according to aci new process is much easier to produce, since this synthetic route the stable protected sugars are not converted into their sensitive halogen derivatives Need to become.

The compounds produced by the new process have cytotoxic, antiviral and enzyme inhibiting properties. Example 1 2 ', 3', 5'-Tri-O-benzoyl-6-aza-uridine 0 2.5 - (5 mmol) 2,3,5-tri-O-benzoyl-1 / acetylribose were in 100 ml of absolute dichloroethane dissolved and with 6.25 mmol of the bis-silyl compound of 6-azauracil in 5.54 ml of absolute Benzene added.

After adding 0.4 ml of SnCl4 (3.6 mmol), oil was room temperature for 4 hours touched. Then 50 ml of saturated NaHCO3 solution were poured with 50 ml of dichloroethane diluted and sucked through kieselguhr. Instead of dichloroethane, CH2Cl2, CHCl3 or ethyl acetate can be used. The clear organic phase was separated off, dried over Na2SO4 and the solvent removed in vacuo. It 2.7 g of an almost white crystalline residue remained. After recrystallization 2.6 g of white needles (92% of theory) of melting point were obtained from ethanol 192-194 ° C.

Example 2 2 ', 3', 5'-tri-O-benzoyl-5-ethyl-uridine 4.27 g of 1-acetyl-tribenzoylribose (8.4 mmol) 3.0 g of bis-silyl compound of 5-ethyluracil (10.5 mmol) 0.71 ml of SnCl4 (6mMol) in dichloroethane (150 ml) were stirred for 2 days at room temperature and how indicated in Example 1 worked up. Obtained after recrystallization from ethanol 4.7 g (95% of theory) of white prisms @ melting point 159 - 1600 C.

Example 3 2'-Deoxy-3 ', 5'-di-O-toluyl-6-aza-uridine 1.91 g (5 mmol) 1-O-methyl-2-deoxy-3,5-di-toluyl-ribose was dissolved in 4c ml of absolute dichloroethane and with 6.25 mmol of the bis-silyl compound of 6-azauracil in 5.54 ml of absolute benzene offset.

After adding 0.42 ml of SnCl4 in 30 ml of absolute dichloroethane Stirred at 500 ° C. for j hours. After cooling, the procedure was as described in Example 1 worked up.

The residue (2.5 g oil) was dissolved in a little chloroform and the Nucleoside precipitated with pentane. The treatment was repeated with the nucleoside. The nucleoside was dissolved in ethanol, clarified with activated charcoal and allowed to ionize scheduled. 0.5 g of white needles (20.5 of theory) from the melting point crystallized 178 - 1790 C.

Example 4 2-Thio-2 ', 3', 5'-tri-O-benzoyl-uridine 2.6 g (5.16 mmol) 1-pcetyl-2,3,4-tri-0-benzoyl-ribose in 70 ml of absolute dichloroethane 6.25 mmol of bis-silyl compound des 2-thiouracil were dissolved in 5.3 ml of absolute benzene and with 0.42 ml of SnCl4 (6.25 mmol) in 20 ml of absolute dichloroethane for 24 hours at room temperature (or 5 hours at 50 ° C.).

The work-up was carried out as in Example 1. After crystallization of the crude product from ethanol were 1.21 g of white needles (41% of theory) from Melting point 104-1060 C obtained.

Example 5 2-Thio-5-cyano-2 ', 3', 5'-tri-O -benzoyl-cytidine 2.6 g of 1-O- / acetyl-2,3,5-tri-O -benzoyl-ribose (5.16 mmol) were dissolved in 60 ml of absolute dichloroethane and mixed with 6.25 mmol of bis-silyl compound of 2-thio-5-cyano-cytosine in 10.8 ml of absolute benzene. After adding 0.84 ml of SnC14 (7.2 mmol) was stirred at room temperature for 24 hours.

The work-up was carried out according to Example 1.

The residue was dissolved in CHCl3 and the nucleoside was precipitated with pentane. After repeated reprecipitation, it was dissolved in acetone -t activated charcoal and clarified after Addition of cyclohexane crystallizes.

After recrystallization from benzene, 1.1 g of finely crystalline material were obtained (36.4 ffi of theory) with a melting point of 130-135 ° C.

Example 6 1 - (@ '- Deoxy-3', 5'-di-O-p -nitrobenzoyl-ribofuranosyl) -5- @ od @ -u 6.1 g of bis-silyl compound of 5-iodouracil (16 mmol) were dissolved in 5o ml of absolute dichloroethane dissolved and with 7.12 g of 1-O-methyl-2-deoxy-3,5-di-p-nitrobenzoylribose (16 mmol) added to 100 ml of absolute dichloroethane. After adding 1.87 ml of SnC14 (16 mmol) in 15 ml of absolute dichloroethane was stirred overnight. siac; relocating again with 0.94 ml of SnCl4 (8 mmol) in 10 ml of absolute ethylene chloride was a further 6 hours touched. It was then diluted with 0.5 l of CH2C12 and shaken with 200 ml of iXaHC03 solution and sucked off through kieselguhr. The diatomaceous earth was washed out well.

The combined organic phases were dried over Na2S04 and concentrated in vacuo, the reaction product beginning to crystallize out. To Evaporation of the solvent, the sugar was boiled out with toluene. The nucleoside was recrystallized from dioxane / alcohol.

Yield 4.73 g (45.3% of theory) with a melting point of 247-249C C.

@ -Thi-5-cyano-cytidine-2'-deoxy-3 ', 5'-ditoluylate 1.9 g of 1-O-methyl-2-deoxy-3,5-di-toluylribose (5 mmol) were dissolved in 70 to absolute dichloroethane and with 6.25 mmol of the dissilyl compound of the 2-thio-5-cyano-cytosine in 5.8 ml of absolute benzene. After adding 0.42 ml of SnCl4 (3.6 mmol) was stirred for 3 hours at room temperature. Then became Worked up as described in Example 1.

The residue was dissolved in ethyl acetate and colored with activated charcoal. The Nuclecsid was freed from sugar by reprecipitation with ethyl acetate / pentane and recrystallized from benzene / cyclohexane.

Yield: 505 mg of white needles (21% of theory) from the melting point 138-140 ° C.

Example 8 5-nitro-uridine tribenzoate 2.5 g of 1-acetyl-tribenzoylribofuranose (5 mmol) were dissolved in 100 ml of absolute dichloroethane and 6.25 mmol of the bis-silyl compound of the 5-nitrouracil in 3.6 ml of absolute benzene.

After adding 0.42 ml of SnCl4 (3.6 mmol), the mixture was 2 hours at room temperature touched. It was worked up as in Example 1. After removing the solvent 2.85 g of a white foam remained.

Crystallization from methylene chloride / hexane yielded 1.85 g of white needles (6i, 5% of theory) with a melting point of 1400 C.

Example 9 2-Thio - @ - aza-thymidine-tribenzoate 2, @ g 1-acetyl-tribenzoyl-ribose (4.96 mmol), 6.25 mmol of bis-silyl compound of 2-thio-6-aza-thymine in 7.9 ml of absolute Benzene and 0.42 ml of SnCl4 (3.6 mmol) were in 100 ml of absolute dichloroethane for 3 hours touched. It was expanded as described in Example 1. The crude product was crystallized from ethanol. Plan received 2.41 g of colorless flakes (82.6% of theory) from the melting point - 1570 0.

Example 10 1 - (@ '- Deoxy-3', 5'-di-O-p-t @ luyl-ribofuranosyl) -5-iodo-uracil 3.84 g of 1-0-methyl-2-deoxy-3,5-di-toluyl ribose (10 mmoles), 3.7 g of bis-silyl compound des 5-iodouracil and 1.18 ml of SnCl4 (10 mmol) were dissolved in 75 ml of absolute CH2Cl2 solved. It was refluxed for 1.5 hours. Then it was cooled down and how Worked up described in Example 1.

The residue was dissolved in ethyl acetate and clarified with activated charcoal.

The sugar was extracted from pentane and the nucleoside from methanol crystallized.

Yield: 1.6 g (27.4 / o of theory) with a melting point of 193-1940 C.

Example 11 6-azauridine triacetate 1.39 g of tetraacetyl ribose (5 mmol), 6.25 mmol of bissilyl compound of 6-azauracil in 5.54 ml of absolute benzene and 0.42 ml of SnCl4 (3, c mmol) were in 100 ml of absolute dichloroethane overnight at Room temperature stirred. It was worked up as described in Example 1.

The crude product - 1.4 g of an almost colorless oil - was made from ethanol crystallized after the addition of a seed crystal.

Yield: 968 mg of colorless needles (52.2% of theory) from the melting point 1G2 - 1030 C.

Example 12 6-aza-thymidine tribenzoate 2.5 g of 1-acetyl-2,3,5-tribenzoylribose (4.96 mmol), 6.25 mmol of bis-silyl compound of 6-azathymine in 3.36 ml of absolute Benzene and 0.42 ml of SnC14 (3.6 mmol) were dissolved in 100 ml of absolute dichloroethane and stirred for 24 hours at room temperature. Then as in Example 1 was described worked up. After evaporation of the solvent, 2.4 g of a white viscous remained Mass back, which after recrystallization from ether / ethanol has a melting point of 132 - 133 ° C. Yield: 2.2 g (77% of theory).

Example 13 1- (2 ', 3', 4 ', 5'-Tetra-acetyl-glucopyranosyl) -6-aza-uracil 1.95 g of pentaacetylglucose (5 mmoles), 6.25 mmoles of bis-silyl compound of 6-azauracil in 3.95 ml of absolute benzene and 0.42 ml of SnCl4 (3.6 mmol) were in 100 ml of absolute Dichloroethane was stirred at 600 ° C. for 5 hours. After cooling it was as in example 1 described worked up.

After the solvent had been stripped off, 1.59 g of a yellowish color remained Oil back. Crystallization from ethanol gave 1.26 g (56.8 o / o of theory) colorless needles with a melting point of 206-2070C were obtained.

Example 14 1 - (@ ', 3', 5'-Tri-benzyl-arabinofuranosyl) -6-aza-uracil 2.31 g of 1-acetyl-2,3,5-tri-benzyl-arabinofuranose (5 mmoles), 6.25 mmoles of bis-silyl compound des o-azauracil in 3.5 ml of absolute benzene and 0.42 ml of SnCl4 (3.6 mmol) dissolved in 100 ml of absolute dichloroethane and stirred for 5 hours at room temperature. It was worked up as described in Example 1.

The oily residue (2.43 g) was crystallized from methylene chloride / pentane. 0.7 g of silk-gloss long needles (27.2 ° C., 3 of theory) with a melting point were obtained 123 - 124 ° C.

Example 15 o @ -O-methyl-5-iodine / uridine tribenzoate 2.5 g of 1-acetyl-tribenzoylribose (5 mmol) and 1.66 g of 2,4-dimethoxy-5-iodo-pyrimidine (6.25 mmol) and 0.84 ml of SnCl4 (7.2 mmol) were stirred in 100 ml of absolute dichloroethane for 4 hours. IT became like Worked up described in Example 1.

after the solvent had been stripped off, 3.3 g of a yellow-colored product remained Oil back.

Crystallization from ethanol yielded 2.31 g (66.5% of theory) of white Needles from melting point 183 - 1840 C.

Example 16 The reaction according to Example 1 was carried out in various solvents and with several catalysts. The table below gives an overview of the reaction yields under different reaction conditions. Reaction conditions Time temperature yield in% Solvent catalyst (S @@@@@@@) (° C) raw @@@@@@ llin Cl-CH2-CH2-Cl SnCl4 3.6 mmol 4 20 97 92 CH3CN SnCl4 3.6 mmol 4 20 97 82.5 Dioxane SnCl4 3.6 mmol 4 101 77 57 Tetrahydrofuran SnCl4 3.6 mmol 3 65 98 75 Dimethylformamide SnCl4 3.6 mmol 4 153 77.5 68.5 Benzene SnCl4 3.6 mmol 6 80 80.5 66 Toluene SnCl4 3.6 mmol 6 111 86 66 CS2 SnCl4 3.6 mmol 4 46 87 67 CCl4 SnCl4 3.6 mmol 4 77 93 73 Cl-CH2-CH2-Cl ZnCl2 980 mg 5 84 100 83 Cl-CH2-CH2-Cl TiCl4 0.4 ml 30 20 65 40 Chlorobenzene AlCl3 9 @@ mg 6 132 63 40 Tetrachloroethane FeCl3 1.18 g 5 146 44 25 CS2 BF3-Et2O 0.88 ml 6 46 70 60

Claims (1)

P atentan sp r. uch process for the preparation of compounds of the general formula where R is a hydrogen atom, an alkyl group with 1-4 C atoms, a halogen atom, a nitro or nitrile group, W is an oxygen or sulfur atom, X is an oxygen atom or the group NB (with B meaning a hydrogen atom or an alkyl group with 1 -4 carbon atoms), Y is a nitrogen atom or the group CH and Z is a protected sugar residue, characterized in that the l-acyl or l-0-alkyl derivative of the protected sugar with compounds of the general formula in which R and Y are as defined above, D is a silylated 0 or NB radical, in which B is the same as above, or a lower alkoxy group and E is a silylated 0 or S radical or a lower alkoxy group, in the presence of a Friedel-Crafts catalyst.