HU198949B - Process for producing 5-substituted-3'azido-2',3'-dideoxyribonucleosides - Google Patents

Abstract

For the prepn. of 5-substd.-3'-azido-2'.3'-di:-dezoxy- ribo-nucleosides of formula (VI) where R is a hydrogen or a halogen, atom, a 1-3C straight or branched gp.; in this case a subst. alkyl and particularly gp.,-cpds. (I) are tritylated to obtain cpds. (II), which are mesylated to cpds. (III). Mesyl-oxy gps. of cpds. are cleaved off cpds. (III) to yield cpds. (IV). These are de-trithylated at room temp. with acetic acid to cpds. (V). Cpds. (V) and alkali-metal anodes form cpds. (VI). The end product is purified by continuous ethyl-acetate extraction.

Description

The present invention relates to a novel process for the preparation of 5-substituted-3'-azido-2 ', 3'-dideoxyribonucleosides of formula VI wherein R is hydrogen or C 1-3 straight or branched alkyl.

Compounds of formula VI are known to exhibit significant antiviral activity against retroviruses, particularly HTLV-III / LAV / AAV (Aids) viruses (Tai-Shun Lin et al., J. Med. Chem. 30, 440/1987). /).

Several syntheses have been developed for the preparation of compounds of formula VI.

One of the known methods (J. Org. Chem. 29, 2076 (1964)) is based on 1- (2'-deoxy-3'-O-mesyl-β-D-lyxofuranosyl) thymine, which is lithium azide. responds assessment. The disadvantage of the process is that the preparation of lyxofuranosyl nucleosides is complicated and very expensive.

J. Org. Chem. 38, 4299 (1973), reacting 5'-trityl-3'-mesylthymidine with dimethylformamide with potassium phthalimide, followed by 5'-trityl-2,3'-anhydro-thymidine with sodium with azide. The desired compound is obtained in 30% yield. The disadvantage of the process, in addition to the low yield, is that the phthalimide formed during the reaction can only be removed by complex purification operations.

J. Org. Chem. 38, 4293 (1973), by the reaction of 2,3'-anhydro-thymidine, which is 40% with thymidine and 2-chloro-N- (1,1,2-trifluoroethyl) -diethylamine. (Zh. Obsh. Khim, 29, 2159 (1959); Tetrahedron Letters £ 5, 3863 (1969)) is converted to 3'-azido-3-deoxythymidine by reaction with lithium azide. The product is purified by column chromatography using ether as the eluent. The compound is obtained in a yield of 55%, which corresponds to a yield of 23% in a two-step process starting from thymidine. This process is unsuitable for large quantities of product due to its low yield, expensive reagent and chromatographic purification, and the explosive nature of the ether used for purification.

In 199,451. s. European and 3,608,606. s. According to German patents, 2,3'-anhydrothymidine is reacted with sodium azide in aqueous dimethylformamide. The 3'-azido-3-deoxythymidine thus formed can be isolated from the mixture in very poor yields (30-40%).

The common disadvantage of the known solutions is therefore the low yield and the fact that the desired product can be obtained only by a multi-step process, isolation of intermediates and, in some cases, by the use of expensive reagents or explosive materials. Therefore, known solutions are not suitable for operational implementation. The present invention seeks to overcome these drawbacks.

In our experiments, it has been found that when tritylation of compounds of formula I wherein R is as defined above and mesylation of the resulting compounds of formula II where Tr is trityl, R is as defined above, it is not in pyridine whereby various by-products (dithrityl compounds, alkylated derivatives, polymers, etc.) are formed during the reactions, but using dioxane as solvent and triethylamine as acid scavenger, it is not necessary to isolate intermediate (II) and (III). Intermediates of general formula (III) wherein Tr represents a trityl group, Ms a mesyl group and R represents a demesylating agent immediately after removal of the acid acceptor salt and optionally without purification. Thus, the compounds of formula (1) can be prepared from the compounds of formula (IV) in an in situ reaction sequence in a total yield of from 80 to 82%, wherein Tr and R are as defined above.

Detritylation of compounds of formula (IV) has been found to be carried out by boiling for 20 to 60 minutes in 80% acetic acid, as described in the literature, with the desired compound of formula (V) and its 3 '. -acetyl derivative, and the compound of formula (V) can be isolated from said by-products only in 20-25% yield. However, it has been found that when acetic acid detritilization is carried out at room temperature, no by-product is formed and 90-95% of the desired compound of formula (V) is obtained, wherein R is as defined above. A further advantage is that all triphenylcarbinol formed during the reaction crystallizes out of the mixture casing so that it can be removed by simple filtration and does not require any purification of the compound of formula (V).

The resulting compounds of formula (V) are converted to the desired end products of formula (VI) by reaction with sodium azide as described above.

The compounds of formula (VI) are isolated from the aqueous solution by extraction several times with ethyl acetate and purification, generally by column chromatography. Since the compounds of formula (VI) are significantly more soluble in water than in ethyl acetate, the product can only be lost in such a way in the? from mixture. However, it has been found that, with continuous extraction, substantially less solvents can be obtained almost quantitatively from the formation mixtures of the final products of formula (VI).

The present invention thus relates to a process for the preparation of compounds of formula VI wherein R is as described above, by tritylation of compounds of formula I wherein R is as defined above with triphenylmethyl halide to give the resulting compound of formula II. mesylation of the compounds of formula (III) wherein Tr is trityl and R is methanesulfonyl halide, to give compounds of formula (III) wherein Ms mesyl is jc-21

HU 198949 and Tr and R are as described above, the alkyloxy cleavage of the mesyloxy group, the acetic acid detritylation of the resulting compounds of formula IV wherein Tr and R are as defined above, and the resulting compounds of formula V Wherein R is as defined above by reaction of the above with an alkali metal azide and isolation of the resultant products of formula (VI) from an aqueous medium by ethyl acetate extraction.

According to the invention, the compounds of formula (I) are tritylated in dioxane medium in the presence of triethylamine, and the resulting compounds of formula (II) are reacted directly with the mesylating agent in the presence of dioxane and triethylamine in the formation mixture. After isolation, the compounds of formula (V) are detritilized with acetic acid at room temperature, the compounds of formula (V) thus formed are reacted with alkali metal azide in a known manner, and the solvent is removed and purified by continuous extraction of compounds.

According to the invention, it is preferred to proceed as follows:

The compounds of formula (I) are reacted with trityl chloride in a 1: 1.1 molar ratio in the presence of triethylamine in dioxane medium to reflux. The precipitated triethylamine hydrochloride is filtered off, the reaction mixture is cooled to 10 ° C, and mesyl chloride and triethylamine (1.5-2 times molar) are added and mesylation is carried out at room temperature. The resulting triethylamine hydrochloride was filtered off and the dioxane was evaporated under reduced pressure. The remaining syrupy mass was mixed with aqueous alcoholic sodium hydroxide solution, refluxed, the alcohol distilled and the resulting sodium mesylate dissolved in hot water. The residue is isolated by hot alcoholic crystallization to isolate the compound of formula (IV) in 80% yield. The product thus obtained is detritilized at room temperature with 80% acetic acid. The precipitated triphenylcarbinol was filtered off and the acetic acid was evaporated under reduced pressure from the filtrate. The remaining crystalline product is optionally mixed with a small amount of alcohol, refluxed, cooled and the crystalline compound of formula (V) filtered off. The compound of formula (V) is then reacted with excess sodium azide in boiling dimethylformamide, the solvent is evaporated under reduced pressure, the residue is dissolved in a little water, and the aqueous solution is isolated by continuous extraction with ethyl acetate. final product of the general formula. The ethyl acetate extract is dried, evaporated and the final product recrystallized from water or other suitable solvent.

In the process of the present invention, the compounds of formula (VI) may be prepared from the starting materials of formula (I) in a total yield of about 70%; thus, the yield of the process is significantly better than the methods known hitherto. The technology is simple, no isolation of most of the intermediates and cumbersome separation methods are required. The process does not require difficult-to-access expensive chemicals such as 2-chloro-N- (1,1,2-trifluoroethyl) diethylamine, virtually no by-products are formed, and the heat demand of the process is lower than the known methods.

The following examples illustrate the invention without limiting it.

Example 1

3'-azido-2 ^', 3'-dideoxy-uridine (compound of formula / VI / formula, R = H)

Step a) Preparation of 5'-Trityl-2,3'-anhydro-2 ', 3'-dideoxyuridine (compound of formula IV, R = H)

Into a 100 ml round-bottomed flask was added 3.5 g (15.3 mmol) of anhydrous 2'-deoxyuridine, 4.6 g (16.6 mmol) of trityl chloride and 4 ml of triethylamine, and 30 ml of anhydrous dioxane were added. . The mixture was refluxed for 2 hours. After boiling for 10 to 15 minutes, a homogeneous solution is formed, and after a short time crystalline triethylamine hydrochloride begins to precipitate. The reaction was followed by TLC (Merck Kieselgel HF254 plate, 95: 5 ethyl acetate: methanol as eluent). After refluxing for about 2 hours, when no starting material is detected in the mixture, the precipitated triethylamine hydrochloride is filtered off, washed with a little dioxane, and the washings are combined with the filtrate. The solution was cooled to below 10 ° C in ice water, mesyl chloride (2 mL, 25.6 mmol) and triethylamine (3 mL) were added and the mixture was stirred overnight at room temperature. The precipitated triethylamine hydrochloride is then filtered off, washed with a little dioxane, the dioxane solutions are combined and the solvent is evaporated under reduced pressure. To the syrupy residue was added 30 ml of ethanol and 30 ml of 1 M aqueous sodium hydroxide solution and the mixture was refluxed until the starting material disappeared. The reaction was followed by thin layer chromatography; Merck Kieselgel HF254 was used as adsorbent and chloroform: methanol (9: 1 by volume) as eluent. After 2-3 hours, when no starting material is present, the alcohol is evaporated under reduced pressure and the syrupy residue is washed three times with 50 ml of hot water. The residue was poured into ethanol (30 mL), heated to reflux and allowed to stand at room temperature for 4-5 hours. The precipitated crystalline product is filtered off and used without further purification. 5.0 g (72.4%) of 5'-trityl-2,3'-anhydro-2'-deoxy-uridine are obtained.

Step b) Preparation of 2,3'-Anhydro-2'-deoxy-uridine (R) H

To a 250 mL round bottom flask was added 5 g (11.0 mmol) of 5'-triyl-2,3'-anhydro-2'-deoxyuridine and mL of 80% acetic acid and allow to stand at room temperature for 4 days. The precipitated triphenylcarbinol was filtered through a glass filter, washed with a little 80% acetic acid, and the acetic acid solutions were combined and concentrated under reduced pressure. Water (2 x 10 mL) was added to the residue and evaporation was repeated. The crystalline product thus obtained was mixed with 20 ml of ethyl acetate and filtered through a glass filter. The product can be used without recrystallization. 2.0 g (86%) of 2,3'-anhydro-2'-deoxyuridine are obtained; mp 212-214 ° C.

Step c) Preparation of 3'-Azido-2 ', 3'-dideoxyuridine in a 1 ml round bottom flask, 0.63 g (3 mmol) of 2,3'-anbidro-2'-deoxyuridine, 0.78 g sodium azide (5 mmol) and dimethylformamide (5 ml) were added and the mixture was refluxed until the starting material was completely reacted. The reaction was followed by thin layer chromatography; Merck Kieselgel HF254 was used as the adsorbent, and ethyl acetate: methanol (8: 2) was used as eluent. After refluxing for about 3 hours, when no starting material is detected in the mixture, the mixture is cooled to room temperature, decanted from the residue of sodium azide, and the dimethylformamide is evaporated under reduced pressure. Water (2 x 10 mL) was added to the residue and evaporation was repeated. Finally, the residue is dissolved in 10 ml of water and extracted from a continuous extraction vessel with about 150 ml of ethyl acetate for 48 hours. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with 10 ml of ethyl acetate and kept overnight in a refrigerator. The precipitated crystals are filtered off. 0.34 g (44%) of 3'-azido-2 ', 3'-dideoxyuridine are obtained; mp 168-169 'C.

NMR (CDCl3 4- _DMSO-d6): 2.38 (2H, dd, J = 6.3 and 5.9Hz), 3.6-4.0 (3H, m), 4.36 (1 H , td, J = 4.4Hz, 4.83 (1H, broad t), 5.64 (1H, d, J = 8.2Hz), 6.17 (1H, t), 7.89 (1H, d), 10.76 (1H, bs) ppm.

Example 2

3'-azido-2 ^', 3'-dideoxy-thymidine (/ VI / general formula A, R = methyl) A solution of

Step a) Preparation of 5'-Trityl-2,3'-anhydro-thymidine (IV), R = methyl)

Into a 500 ml round-bottomed flask was added 20 g (82.5 mmol) of thymidine, 25 g (89.92 mmol) trithyl chloride, 20 ml triethylamine and 200 ml dioxane, previously dried under reduced pressure for 2 hours at 120 ° C. and the mixture is heated to reflux. After boiling for 5-10 minutes, a clear clear solution is formed, and after a short time crystalline triethylamine hydrochloride begins to precipitate. The reaction was monitored by TLC using Merck Kieselgel HF2S4 as the adsorbent, eluting with 95: 5 by volume ethyl acetate: methanol. After refluxing for one and a half hours, when no starting material is detected in the mixture, the precipitated crystals are filtered off on a glass filter and washed with 20 ml of dioxane. The dioxane solutions were combined, cooled in ice water to below 10 ° C, and triethylamine (16 mL) was added. Thereafter, 10 ml (128.0 mmol) of mesyl chloride are added dropwise over about 30 minutes. After stirring overnight at room temperature, the precipitated triethylamine hydrochloride was filtered through a glass filter and concentrated under reduced pressure. The residue was stirred with 20 ml of ethanol and the evaporation was repeated. To the syrup thus obtained was added ethanol (100 ml) and a 1M aqueous sodium hydroxide solution (100 ml), and the mixture was refluxed for 2 hours. The ethanol is then evaporated under reduced pressure and the syrup-like residue is washed three times with 10 ml of hot water. To the residue was added ethanol (100 mL), the mixture was refluxed for 10-20 minutes, then cooled and refrigerated overnight. The precipitated crystals are filtered off with suction and dried. 32 g of 5'-trityl-2,3'-anhydro-thymidine are obtained; Yield: 80%.

Step b: Preparation of 2,3'-Anhydro-thymidine (Compound (V), R = methyl)

Into a 500 ml round bottom flask was added 34.0 g of 5'-trityl-2,3'-anhydrothymidine and 300 ml of 80% acetic acid, and the solution was allowed to stand for 4 days at room temperature. The precipitated triphenylcarbinol was filtered through a glass filter and washed with a little 80% acetic acid. The acetic acid solutions were combined and concentrated under reduced pressure. Water (2 x 20 mL) was added to the residue and evaporation was repeated. The residue was then mixed with 50 ml of chloroform and filtered through a glass filter. 15.0 g (92%) of 2,3'-anhydrothymidine are obtained; mp 242-243'C.

Step c) Preparation of 3'-Azido-2 ', 3'-deoxy-thymidine in a 2 ml round bottom flask, 2.2 g (10 mmol) of 2,3'-anhydrothymidine, 2.8 g (40 mmol) of sodium azide and 25 ml of dimethylformamide are added and the mixture is refluxed until the starting material disappears. The reaction was followed by thin layer chromatography; Merck Kieselgel HF254 was used as the adsorbent and ethyl acetate: methanol (95: 5 by volume) as eluent. After boiling for 2 to 3 hours, when no starting material is detectable in the mixture, the dark brown liquid is decanted from the residue of sodium azide and the dimethylformamide is evaporated under reduced pressure. Water (2 x 10 mL) was added to the residue and evaporation was repeated. The resulting solid residue was dissolved in water (10 mL) and extracted from a continuous extraction vessel with ethyl acetate (250 mL) for 48 hours. The ethyl acetate solution was dried over magnesium sulfate and concentrated under reduced pressure. To the residue was added water (10 mL) and the mixture was stored overnight in a refrigerator. 1.5 g (55.63%) of crystalline white 3'-azido-2 ', 3'-dideoxy-imidine are obtained; mp 121-122 'C.

Nuclear Magnetic Resonance Spectrum (CDCl 3 + DMSO-d 6): 1.89 (3H, d, J-1.3Hz), 2.38 (2H, dd, J -6.4 and 6.0Hz), 3.6-4 , 0 (3H, m), 4.37 (1H, td,

-4HU 198949 B

J ** 4.4Hz), 4.4 (1H broad s), 6.18 (1H, t), 7.65 (1H, q), 10.0 (1H, broad s) ppm.

Example 3

3'-azido-2 ^', 3'-dideoxy-5-ethyl-uridine (/ VI / formula of compound J, R = ethyl) A solution of

Step a) Preparation of 5'-Trityl-2,3 ^, -anhydro-5-ethyl-2 ', 3'-didcoxyuridine (IV), R' ethyl)

To a 500 mL round bottom flask was added 20.0 g (78.0 mmol) of 5-elyl-2'-deoxyuridine, 24.5 g (88.0 mmol) trlylchloride idol, previously dried at 120 ° C under reduced pressure. 25 ml of triethylamine and 200 ml of anhydrous dioxane were added and the mixture was heated to reflux. A clear solution is formed and after 10-15 minutes crystalline triethylamine hydrochloride begins to precipitate. The reaction was followed by thin layer chromatography; Merck Kieselgel HF254 was used as adsorbent and chloroform: methanol (9: 1 by volume) as eluent. When starting material is no longer detectable (after about 2 hours), the precipitate formed is filtered off and washed with 20 ml of dioxane. The dioxane solutions were combined, cooled in ice water to below 10 ° C, and triethylamine (16 mL) was added. Thereafter, 10 ml (128 mmol) of mesyl chloride are added dropwise over about 30 minutes. The ice water bath was removed and the mixture was stirred overnight at room temperature. The precipitated triethylamine hydrochloride was filtered through a glass filter and washed with 20 ml of dioxane. The dioxane solutions were combined and concentrated under reduced pressure. Ethanol (50 mL) was added to the residue and evaporation was repeated. To the syrupy residue was added 100 ml of ethanol and 80 ml of 1 M aqueous sodium hydroxide solution and the mixture was refluxed for 2 hours. The mixture was cooled to room temperature and the ethanol was evaporated under reduced pressure. The residue is washed three times with 10 ml of hot water, 100 ml of ethanol are added to the crystalline syrup, the mixture is refluxed for 10 to 20 minutes, then cooled and refrigerated overnight. The precipitated crystals are filtered off with suction and dried. 30 g (79.35%) of 5'-trityl-2,3'-anhydro-5-ethyl-2 ', 3'-dideoxyuridide are obtained; m.p. 130-132 'C.

Step b) Preparation of 2,3'-Anhydro-2 ', 3'-dideoxy-5-ethyluridine (compound of formula V, R-ethyl) g 5'-Trityl-2,3'-anhydro- in 5-ethyl-2 ', ^{3-dideoxy-uridine} in 200 ml of 80% acetic acid and allowing the solution to stand at room temperature for 4 days. The precipitated triphenylcarbinol was filtered through a glass filter and washed with 20 ml of 80% acetic acid. The acetic acid solutions were combined and concentrated under reduced pressure. Water (2 x 50 mL) was added to the residue and evaporation was repeated. The crystalline residue was stirred with ethyl acetate and filtered through a glass filter. 8.5 g (85.8%) of 2,3'-anhydro-N, 4'-t-didcoxy-5-ethyl-uridine are obtained. M.p. (after recrystallization from ethanol): 242-243 ° C.

Step c) Preparation of 3'-Azido-2 ', 3'-dideoxy-5-ethyluridine in a 1 ml round bottom flask, 0.952 g (4 mmol) of 2,3'-anhydro-2', 3'-dideoxy-5-ethyl -uridine, 1.040 g (16 mmol) of sodium azide and 28 ml of dimethylformamide are added and the mixture is refluxed for 2 hours. TLC analysis showed no starting material was present in the reaction. The solution was decanted from the sodium azide residue and the dimethylformamide was evaporated under reduced pressure. Water (2 x 10 mL) was added to the residue and evaporation was repeated. The solid residue was dissolved in water (10 mL) and extracted from a continuous extraction flask with ethyl acetate (about 100 mL) for 48 hours. The ethyl acetate solution was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was dissolved in 10 ml of ethyl acetate: hexane (6: 4) and stored in a refrigerator for one day. 0.64 g (57.1%) of 3'-azido-2 ', 3'-dideoxy-5-ethyluridine is obtained; 109-111 ° C (recrystallized from 6: 4 ethyl acetate / hexane).

NMR (CDCl3 + _DMSO-d6): 1.13 (3H, t, J = 7.5Hz), 2.18 (1H, ddd, J = 15.0, 3.5, 2.2 Hz); 2.36 (2H, qd, J = 1.1Hz), 2.74 (1H, ddd, J = 7.5, 6.3Hz), 3.75-4.25 (3H, m), 4.36 (1H, ddd, J = 4.0Hz), 6.20 (1H, dd), 7.54 (1H, t), 10.1 (1H, broad s) ppm.

Example 4

Preparation of 3'-Azido-2 ', 3'-dideoxy-5-isopropyl-uridine (compound of formula VI, R = »isopropyl)

Step a) Preparation of 5'-Trityl-3'-anhydro-2 ', 3'-dideoxy-5-isopropyl-uridine (Compound VI, R = isopropyl) in a 2.5 ml round bottom flask (9.2 g) anhydrous 5-isopropyl-2'-deoxyuridine, 3.0 g (10.7 mmol) of trityl chloride, 20 ml of anhydrous dioxane and 3.0 ml of triethylamine were added. The reaction mixture is refluxed. After 5 minutes, a clear solution formed and crystalline triethylamine hydrochloride began to precipitate. The reaction was followed by thin layer chromatography; Merck Kieselgel HF254 was used as the adsorbent, and ethyl acetate: methanol (95: 5 by volume) was used as eluent. After about 2 hours, when the starting material is no longer detectable in the mixture, the mixture is cooled in an ice-water bath to below 10 ° C and 1.5 ml of triethylamine and 1 ml (12.8 mmol) of mesyl chloride are added. After stirring overnight at room temperature, the precipitated crystalline triethylamine hydrochloride was filtered through a glass filter and washed with a little dioxane. The dioxane solutions were combined and evaporated under reduced pressure. To the syrupy residue was added 15 ml of ethanol and 10 ml of 1 M aqueous sodium hydroxide solution and the mixture was refluxed for 5-10 minutes. After allowing the solution to stand at room temperature for 24 hours, the precipitated crystalline product is filtered off with suction and dried. 3.7 g (80%) of 5'-trityl-2,3'-anhydro-5-isopropyl-2'-deoxyuridine are obtained.

Step b) Preparation of 2,3'-Anhydro-5-isopropyl-2'-deoxyuridine (compound of formula V, R = isopropyl) in a 3 ml round bottom flask (3.2 g, 6.4 mmol) 5'- trityl-2,3'-anhydro-5-isopropyl-2'-deoxyuridine and 30 ml of 80% acetic acid were added. A clear solution is obtained and after about half an hour crystallization begins. The reaction was followed by thin layer chromatography; Merck Kieselgel HF254 was used as the adsorbent and chloroform: methanol (9: 1 by volume) was used as eluent. When no starting material is detected in the mixture (after about 2 days), the precipitated tritanol is filtered off, washed with a little 80% acetic acid, and the acetic acid solutions are combined and concentrated under reduced pressure. Water (2 x 10 mL) was added to the residue and evaporation was repeated. The resulting residue was crystallized from ethanol. 880 mg (59%) of 2,3'-anhydro-5-isopropyl-2'-deoxyuridine were obtained; m.p. 197-198 ° C.

Step c: Into a 25 ml round bottom flask was added 0.484 g (2 mmol) of 2,3'-anhydro-5-isopropyl-2'-deoxyuridine, 0.52 g (8 mmol) of sodium azide and 14 ml of anhydrous dimethylformamide. in. The mixture was refluxed for 1.5 hours, cooled to room temperature, water (5 mL) was added and evaporated. Water (5 mL) was added to the residue and evaporation was repeated. The syrup-like residue thus obtained is mixed with 5 ml of water and the aqueous mixture is extracted with 50 ml of ethyl acetate in a continuous extraction flask for 48 hours. The ethyl acetate solution was dried over magnesium sulfate, filtered and evaporated. The resulting syrup-like residue was stirred with a little isopropyl ether and allowed to stand at room temperature. The precipitated crystals are filtered off on a glass filter and recrystallized from ethyl acetate. 300 mg (50%) of 3'-azido-2 ', 3'-dideoxy-5-isopropyl-uridine are obtained; 135 DEG C.,

NMR (CDCl3 + _DMSO-d6): 1.15 (6H, J = 7.0Hz), 2.41 (2H, dd, J = 6.4 and 6.0Hz), 2.89 (1H, m), 3.65-4.05 (3H, m), 4.3 (1H, broad t), 4.37 (1H, td, J = 4.5Hz), 6.18 (1H,

t) 7.59 (1H, d), 9.7 (1H, broad s) ppm.

Claims (1)

Patent Claim Point A process for the preparation of 5-substituted-3'-azido-2 ', 3'-dideoxyribonucleosides of formula VI wherein R is hydrogen or C 1-3 straight or branched alkyl - Compounds of formula I wherein R is tritylation of the above with triphenylmethyl halide, mesylation of the resulting compounds of formula II wherein Tr is trityl and R is as described above with methanesulfonyl halide to give the resulting compound of formula III with alkali, cleavage of the mesyloxy group of the compounds of the formula wherein Ms represents Tr and R with alkali, the acetic acid detritylation of the resulting compound of formula IV wherein Tres R is as defined above, with the resultant compound of formula V Reaction of a compound of formula (II) wherein R is as defined above with an alkali metal azide and the resulting (VI) by separating the final products of formula (II) from an aqueous medium by ethyl acetate extraction, characterized in that the compounds of formula (I) are tritylated in dioxane medium in the presence of triethylamine, the resulting compounds of formula (II) in the presence of dioxane and triethylamine by reacting directly with the mesylating agent, the resulting compounds of formula (III) are directly treated with an alkali metal hydroxide in aqueous alcoholic solution after removal of the triethylamine salt and optionally the solvent, and the resulting compounds of formula (IV) are isolated by acrylic acid removal at room temperature. The compound of formula (V) thus formed is reacted with an alkali metal azide in a known manner, then the solvent is removed and isolated by continuous extraction of the remaining aqueous solution with ethyl acetate. compounds of formula VI.