Improved sucralose-containing composition and method for its preparing

FIELD: pharmaceutical technology.

SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.

EFFECT: improved preparing method, improved properties of composition.

24 cl, 4 tbl, 4 ex

 

This application has priority application U.S. Ser. No. 60/249782, filed November 17, 2000, the contents of which are incorporated here by reference.

The present invention relates to an improved form of Sucralose and to the way it was received.

Sucralose (4,1',6'-trichloro-4,1',6'-tridyakisicosahedron), is a strong sweetener made from sucrose, which can be used in a variety of foods and beverages. Unlike many artificial sweeteners Sucralose can be used in cooking and baking without losing its sweetening ability.

Usually Sucralose receive, using the methods described in U.S. patents№№ 4362869, 4380476, 4801700, 4950746, 5470969 and 5498709. All of these methods one of the final stages of the synthesis is diallylamine with subsequent crystallization of Sucralose. Laboratory methods of crystallization of Sucralose described in U.S. patents№№ 4343934, 5141860, 4977254, 4783526, 4380476, 5298611, 4362869, 4801700 and 4980463. As described in many of these patents, the predecessor of Sucralose decelerat in methanol with catalytic amount of sodium methylate. After diallylamine, the resulting solution Sucralose enter into contact with ion exchange resin to convert residual sodium methylate in methanol. Then the ion exchange resin and remove volatile solvents and by-products of interaction between the Oia is removed by distillation with water, that facilitates transfer of the solvent into the water. The mixture discolor, subjecting it to contact with activated carbon. The coal is removed, getting discolored solution Sucralose, suitable for crystallization. A solution of Sucralose concentrate to approximately 55 wt.% Sucralose (at a temperature of about 50°). The crystallization is carried out, reducing the temperature to approximately 22°and adding about 2% of the seed crystals Sucralose. The formed crystals are separated from mother liquor by centrifugation, and then dried. The mother liquor separated from the crystals add to the next batch immediately before bleaching.

Unfortunately, this method has several disadvantages. The mother liquor after some time may become acidic. In addition, the accumulation of impurities can affect the crystallization of Sucralose, causing the need to periodically purge or drain the mother liquor. In the crystalline Sucralose obtained as described above, contains trace amounts of hydrochloric acid, which, however, reduce the retention period Sucralose.

The purpose of this invention is to provide an improved method for more sustainable forms of crystalline Sucralose.

Another objective of the invention is to provide improved compositions which ristalliceski Sucralose, with increased stabilizatorami found that the addition of a buffer to the solution of Sucralose to its crystallization significantly increases the stability kristallisoituu Sucralose, and also improves the stability of the fallopian solutions during processing.

It was also found that maintaining pH skrelosdamage crystallization solution in the range of from about 5.5 to about 8.5 allows you to increase the final stability of crystalline Sucralose.

Another object of the invention relates to a stable product of crystalline Sucralose, which after storage does not occur smell of acetic acid.

Another object of the invention relates to a method of making a stable product of crystalline Sucralose, which after storage does not occur smell of acetic acid.

In accordance with the invention it was also unexpectedly discovered that crystalline Sucralose with residual moisture from about 0.5 to about 10 wt.% has increased stability.

Another object of the present invention concerns a product comprising crystalline Sucralose in a container that supports its humidity. This container preferably has a rate of water vapor permeability (MVTR) of no higher than 0.25 g of water per 100 square inches of surface area per 24 hours, determined at 38°and concerning the second humidity of 92%.

These and other features will be understood specialists in this field after reading the following description (including the examples and claims). Figure 1 shows a process diagram of one of these methods of crystallization. As shown in figure 1, water Sucralose containing the reaction mixture, is introduced into contact with the uterine fluid, and then served in the tank for bleaching. The mixture is then filtered and concentrated. The concentrated solution containing Sucralose, served in the mold, tatrallyay, cool, and Sucralose crystals separated from the mother liquor by centrifugation. Then the Sucralose crystals are dried and packaged. The mother liquor recycle to the beginning of this process.

Sucralose and the means of its production are described in numerous patents, such as U.S. patent No. 4801700, 4950746, 5470969 and 5498709 included in this description by reference. During the synthesis of Sucralose after diallylamine protected alcohol groups of the reaction mixture containing Sucralose, must be subjected to neutralization, stabilization, discoloration and destruction of Sucralose from the mixture by crystallization.

The reaction mixture containing Sucralose, can be neutralized processing, converting any existing residual methylate in methanol. Typically, this conversion is carried out, EXT is vlaa [H+] ion-exchange resin. Suitable ion exchange resins are known in this area and include AMBERLITE® IRC50 [H+] company Rohm and Haas.

To facilitate concentration and further processing of the neutralized reaction mixture all residual volatile solvents or reaction products are removed by distillation. This distillation is preferably carried out under reduced pressure. In order to concentrate neutralized reaction mixture, water is added, obtaining an aqueous solution containing from about 30 to about 70 wt.% Sucralose, preferably, from about 45 to about 65 wt.% Sucralose. The reaction mixture is support at a temperature sufficient to maintain the Sucralose dissolved. Typically, this temperature is from about 45 to about 50°C.

Before or after neutralization of the solution containing Sucralose, it can be put into contact with a decolorizing agent. Most often, the decolorizing agent is an activated carbon, however, can also be applied to other decolorizing agents. Coal may be a powder or Packed in a column. However, the coal must be removed from the solution prior to crystallization. The number of coal depends on the amount of dye in the reaction mixture and type of coal. Specialists in this field can easily determine the minimum appropriate if estvo coal, want to add to discoloration of the mixture. Adding coal in a free form, it can be removed by conventional methods (e.g., filtering).

At this point, add a small amount of buffer to stabilize concentrated solution of Sucralose. Also provide further adjustment of the pH to obtain a neutral solution. The buffer can be any acceptable salt food of weak acids, such as acetate, citrate, ascorbate, benzoate, kaprilat, diacetate, fumarate, gluconate, lactate, phosphate, sorbate, sodium tartrate, or potassium, and mixtures thereof. A preferred buffer comprises sodium acetate and sodium citrate. In practice, as a by-product may be a small amount of sodium acetate, is insufficient to provide a buffer effect on the crystallization. Neutralization can be carried out using any acidic or basic compounds for pH control, compatible with food use Sucralose or make acceptable taste of the final product of Sucralose. As a rule, can be used the following compounds regulating pH: sodium, potassium, or other acceptable salt hydroxide, carbonate, bicarbonate, acetate, citrate, ascorbate, benzoate, kaprilat, diacetate, fumarata, gluconate, lactate, phosphate, sorbate, Arteta and mixtures thereof. The preferred connection, regulating pH is sodium hydroxide.

The authors, however, found that it is preferable to use a small amount of sodium acetate to the amount of sodium acetate in the crystallization mother solution was less than 100 ppm (ppm), preferably less than 50 ppm, most preferably from about 35 to about 50 ppm, to prevent odor of acetic acid in solid Sucralose products.

During the crystallization pH containing Sucralose solution must be maintained in the range of from about 5.5 to about 8.5, preferably from about 6.5 to about 7.8, and most preferably from about 7 to about 7.8. Maintaining the pH in these intervals significantly improves long-term stability of the product from Sucralose and recycled mother solutions.

Sucralose can be crystallized from containing Sucralose solution using traditional equipment for crystallization. An aqueous solution of Sucralose concentrate to the content of Sucralose about 55 wt.% and cooled to a temperature of from about 10 to about 30°preferably from about 20 to about 25°C. to cause crystallization, an aqueous solution of Sucralose tatrallyay crystals Sucralose. As a General guide, the seed crystals containing about 2 wt.%Sucralose in the crystallization mixture, ensure the desired crystallization.

The crystals are separated from mother liquor by centrifuge or filter and the mother liquor recycle at an earlier point in the process after neutralization and crystallization. The mother liquor, preferably, recycled and added to the reaction mixture after neutralization and to the stage of bleaching.

The crystals can be washed to remove residual mother liquor and dried using conventional equipment for drying, such as a shelf or a chamber dryer, vertical shelf turbomachine with mixing, drum dryer periodic action with stirring, dryer, fluidized bed or pneumatic conveying dryer. The dryer can operate at atmospheric or reduced pressure periodically or continuously. As a result of experiments, it was unexpectedly found that the stability of Sucralose increases when the content of residual moisture in Sucralose is from about 0.5 to about 10 wt.%, preferably, from about 0.5 to about 5 wt.%, most preferably, from about 0.5 to about 2 wt.%. Such Sucralose is anhydrous, i.e. does not contain a significant quantity of hydrates Sucralose (for example, pentahydrate Sucralose). When drying Sucralose before the lower authorities and it really becomes less stable. The temperature in the dryer should be below 60°preferably from about 35 to about 45°C.

The optimal moisture content in the final Sucralose the product during loading and transportation should be from about 0.5 to about 10 wt.% using packaging that supports this moisture content. The lower the permeability of the material, the more moisture will be retained and the more stable product. Typically, this package is a container that supports the moisture content in Sucralose. It is desirable that the rate of water vapor permeability (MVTR) of such container was not more than 0.25 grams of water per 100 square inches of surface area per 24 hours as measured at 38°C and 92% relative humidity. Preferably, the MVTR of the container is not more than 0.2 grams per 100 square inches per 24 hours. More preferably, the MVTR of the container is not more than 1 gram per 100 square inches per 24 hours. Packaging can be flexible or rigid. Suitable materials for the manufacture of packaging for Sucralose include, but are not limited to, not leaky packaging materials, such as metallic or laminated aluminum foil substrates, such as polymer film or Kraft paper. Suitable polymers include, but are not limited to, polyolefins (such as polyethylene of high density improvement and (linear), polypropylene, etc.), polyesters (such as polyalkylacrylate, for example, polyethylene terephthalate, politological-1,4-dimethylterephthalate, polybutylene terephthalate, etc.), polyvinyl chloride, polivinilhlorid and copolymers of polyvinyl chloride and polyvinyl. In addition, the applicable packaging materials include, but are not limited to, multilayer paper bags with a suitable barrier to moisture, the cylinder of fibrous material coated with a polymeric film or aluminum foil constituting one whole side of the cylinder or in the form of a free insert. Can also be used in rigid containers, such as obtained by blowing cylinders and bucket, made of polymers with vegeburgers. Preferred are flexible packaging, such as packaging bags made of polymeric substrate. Most preferred are the bags, aluminum foil, laminated to a polymer film of polymers commonly used for moisture-proof packaging (for example, laminates of aluminum foil and the above-mentioned polyolefins or polyesters).

EXAMPLES

GENERAL METHOD:

Sample preparation for rapid test for stability:

Seven 6-unsieved and seven 18-unsieved plastic bags from WHIRLPAK® permanent marker nano is it the name of each party, subjected to the test for stability. Measure 25±0.1 g Sucralose in each of the 6-unsieved plastic bags from WHIRLPAK®which seal by heating or pulsed welding, ensuring airtightness. Cut off the excess polyethylene in the upper part of the bag over the weld seam. Sealed 6-Unseelie bags placed in 18-Unseelie bags that hermosabeach, ensuring airtightness. Twist the top part 18-unsieved bags over the weld seam and bend metal strip for the formation of the hooks.

An accelerated test for stability.

Prepared bags are placed in an oven stabilized at 50±0,5°, hanging them on the shelves for the hooks. Bags should hang freely and do not touch it. Record the time the bags were placed in the oven.

The stability of the pH.

Sucralose put to the test on the stability of pH, the starting point from the moment of placement of samples (time "0") in the oven before exposure to Sucralose elevated temperature every 24 hours until the stability of the pH of the investigated party.

The preparation of water with the right pH.

Pour approximately 100 ml of deionized water in a 150 ml beaker. Using 0.1 G. of hydrochloric acid and/or 0.1 n sodium hydroxide to bring the pH of the water to 5.8 to 6.0. Record the pH value.

Preparation of sample solution Sucralose is.

Measure 5±0.001 g of the investigated product and transfer it into a 50 ml volumetric flask. Dissolve the product and bring its volume up to the mark, adding water with adjusted pH. If the test sample is subjected to a heat treatment, get one bag of the investigated party from the oven and allow it to cool to room temperature before opening it and taking a sample.

The measurement of pH.

Pour the solution into a 100 ml beaker equipped with a blade for mixing, and slowly stir the solution with a magnetic stirrer. Immerse the pH electrode in the sample, allow the pH to stabilize and record the pH level in the sample.

If after examination of all the bags is not observed drop in pH, the experiment failed and must be repeated with a higher number of bags.

Color stability.

For this test requires only one sample. Prepare a double bag, which is subjected to heating by following the above technique. Every 24 hours visually check the contents of the bag on color stability. Record the number of days prior to the first color change.

CALCULATIONS AND INTERPRETATION.

The stability of the pH.

Record (with one decimal) pH as prepared with water, and the sample solution is Sucralose. Subtract the pH of the sample solution from the pH value of the prepared water. Record the result sonacom (-) at lower pH and with the sign (+) at higher pH, for example:

the pH of the prepared water 6,0

the pH of the sample to 5.7

the result -0,3

The sample passes the test if the decrease in pH is 1.0 pH units or more. The pH stability of the party defined as the number of days up until the pH decreases between the sample solution and prepared water will not be ≥and 1.0.

Color stability.

Color stability of the party defined as the number of days prior to the first color change.

EXAMPLE 1

The EFFECT of BUFFER CONCENTRATION IN the CRYSTALLIZATION mother SOLUTION ON the STABILITY of the PRODUCT

Get a number of parties Sucralose with different amounts of sodium acetate in the mother solution, and examine them in accordance with the above description.

The RESULTS:

Sample numberThe content of sodium acetate (ppm) in the mother solutionThe initial pHThe initial difference in pHDays prior to the violation of pH
1>3005,72-0,206
2>3005,73-0,196
3>3005,44-0,486
4>3005,64-0,286
5>300 5,64-0,286
6>300of 5.530.39 per4
7>3005,70-0,225
8>3005,19-0,735
9>300to 6.19+0,237
10>3005,90to-0.055
11>3006,05+0,106
12>3005,85-0,106
13>3005,85-0,105
1435-505,95+0,026
1535-50the 6.06+0,135
1635-506,20+0,276
1735-506,03+0,106
1835-506,00+0,076
1935-50the 6.06+0,136
2035-50+0,086
2135-506,05+0,106
2235-50between 6.08+0,096
2335-506,12+0,135
2435-506,02+0,035
2535-506,03+0,056
2635-50the 6.06+0,106
2735-505,99+0,036
2835-506,00+0,026
2935-506,09+0,126
3035-505,95-0,025
3135-506,03+0,065

From the table it follows that the average pH stability (in the days before her loss products crystallized from a solution containing >300 ppm (ppm) - ppm sodium acetate, is 5.6 days. The average initial pH of the sample solution is 5.7, and the average difference in pH between the sample solution and the wearable is prepared with water in zero time is -0,21 (decrease in pH). Some parties arises moderate or strong smell of acetic acid.

The parties crystallized from a solution containing only 30 to 50 ppm of sodium acetate, the number of days before the violation was the same (on average 5.7 days). The average initial pH is 6.0 at that time, as the average difference in pH during the "0" is +0,08. None of these parties do not have any odor of acetic acid.

CONCLUSIONS.

The optimal level of sodium acetate in solution during the crystallization of Sucralose is 35-50 ppm, Such content is sufficient to maintain the pH during crystallization at an acceptable level. The stability of the final product is high and the smell of acetic acid in it is missing.

EXAMPLE 2

The EFFECT of pH ON the STABILITY of the PRODUCT DURING CRYSTALLIZATION

Regardless of the number of acetate or other buffering agents present during crystallization, the pH of the mother liquor with time tends to decrease. Typically, the pH ranges from about 3 to about 4. It was found that if the pH is almost neutral during crystallization, the stability of the final product is significantly increased. The following table shows the stability of some parties, in which the pH during crystallization ranges.

Sample number
the pH in the crystallizerThe initial pH differenceDays prior to the violation of pH
322,75-0,903
332,97-0,944
342,97-1,033
356,28+0,105
365,99+0,045
375,99-0,065
386,07+0,176
396,07-0,027
407,01+0,407
416,13+0,405
426,34+0,175
436,13+0,295
447,11-0,186
457,17+0,177
468,05+0,437

From the above data it follows that the pH close to neutral (from about 6 to about 8), significantly increases the average stability andforming rapid test for stability.

EXAMPLE 3

The INFLUENCE of RESIDUAL MOISTURE ON the STABILITY of SUCRALOSE

Samples of several parties Sucralose for the accelerated test on the selected stability during drying at intermediate values of humidity and the test subject is partially dried product, and the final dried product. The moisture level is determined by applying the method of determining the moisture loss during drying (LOD). The results are presented in the table below.

0,05
Sample numberThe initial moisture content (%)Days prior to the violation of pHThe moisture content in the final product (%)Days prior to the violation of pH
352,0470,055
361,8770,025
378,71210,025
388,07230,836
394,55132,007
404,01131,597
413,43120,085
423,1695
435,0080,025

The results clearly show that the stability of the dry product is proportional to the residual moisture. This result was unexpected, since most of the crystalline products are much more stable in the dry form.

SUMMARY

Despite the fact that the level of residual moisture has the greatest effect on the stability of the product, it in no way is not the only important variable. For example, it may not exceed the action control pH during crystallization. This is confirmed by the fact that the experimental samples 32, 33 and 34, crystallized without pH control, the creature appeared to be less stable at intermediate values of moisture content (3 to 5%)than when the target moisture level of 0.05, of 0.11 and 0.21%, respectively).

EXAMPLE 4

The USE of moisture-proof CONTAINERS TO STORE SUCRALOSE

Samples Sucralose is examined for stability using the methods described above, but using bags with different moisture permeability. All other experimental conditions are the same. Bags, TYVEK®/polyethylene are permeable, while the WHIRLPAK bags® less permeable. Bags of A include aluminum foil, Lam is nerosannow to low density polyethylene, giving them a high moisture resistance. The results are shown below.

Sample numberPacking materialMaterial propertiesThe initial humidityStability pH
24FF 91 TYVEK®/ polyethyleneVery permeable0,05%4 days
24Polyethylene WHIRLPAK®Moderately permeable0,05%5 days
24AImpermeable0,05%8 days
47FF 91 TYVEK®/ polyethyleneVery permeable0,24%4 days
47AImpermeable0,24%33 days

CONCLUSIONS

The application of impermeable packaging is capable of retaining moisture in the bag, in an accelerated test for stability was possible to increase the stability of Sucralose from 4 to 33 days. There is a direct relationship between the moisture resistance of the bag and the stability of the product. Obviously, for packing Sucralose and ensure that this increased stability can be used and other waterproof materials.

1. The method of crystallization of Sucralose from an aqueous solution, providing control of specified pH of an aqueous solution so as to maintain the pH in the range of from about 5.5 to about 8.5 during the formation of crystals Sucralose.

2. The method according to claim 1, in which the aqueous solution containing Sucralose add the buffer.

3. The method according to claim 2, in which the buffer is a food acceptable salt of a weak acid.

4. The method according to claim 3, in which the specified cation salt selected from the group comprising sodium, potassium and mixtures thereof.

5. The method according to claim 4, in which the anion of the salt is selected from the group comprising acetate, citrate, ascorbate, benzoate, kaprilat, diacetate, fumarate, gluconate, lactate, phosphate, sorbate, tartrate, and mixtures thereof.

6. The method according to claim 3, in which the buffer is a sodium acetate.

7. The method according to claim 2, in which the aqueous solution contains less than 100 ppm of the buffer.

8. The method according to claim 2, in which the aqueous solution contains less than 50 ppm sodium acetate.

9. The method according to claim 1, wherein the aqueous solution contains from about 35 to about 50 ppm of sodium acetate.

10. The method according to claim 1, in which during the recrystallization solution of Sucralose tatrallyay crystalline Sucralose.

11. The method according to claim 1, wherein the pH of the solution is from about 6.5 to about 7.8.

12. The method according to claim 1, wherein the pH of the solution is from about 7 to about 7.8.

13. The way pop, in which carry out: a) the regulation of the pH of the solution containing Sucralose, to a pH in the range of from about 5.5 to about 8.5, (b) crystallization of Sucralose crystals of containing Sucralose solution at the specified pH, while receiving the Sucralose crystals and mother liquor, (C) the Department of Sucralose crystals from the mother liquor, and (d) drying the crystals Sucralose.

14. The method according to item 13, in which Sucralose dried to a moisture content of from about 0.5 to about 10 wt.%.

15. The method according to item 13, which contains Sucralose solution tatrallyay crystalline Sucralose before crystallization.

16. The method according to item 13, in which pH containing Sucralose solution adjusted to a pH from about 6.5 to about 7.8.

17. Anhydrous crystalline Sucralose obtained by the method according to claim 1 or 13, which has a residual moisture content of from about 0.5 to about 10 wt.%.

18. Sucralose at 17, having a residual moisture content of from about 0.5 to about 5 wt.%.

19. Sucralose on p, which has a residual moisture content of from about 0.5 to about 2 wt.%.

20. Product comprising crystalline Sucralose on any of PP-19 in the container, with the rate of water vapor permeability not greater than 0.25 grams of water per 100 square inches of surface area per 24 h, determined at a temperature of 38°C and relative humidity of 92%.

21. The product according to claim 20, in which Sucralose has the moisture content of from about 0.5 to about 10 wt.%.

22. The product according to claim 20, in which the container is a sealed polymer bag.

ABC according to claim 20, wherein said bag is metallized.

24. The product according to claim 20, wherein said bag is made of aluminium foil laminated to the polyolefin or a film of a complex of the polyester.

Priority items:

17.11.2000 - claims 1 to 19;

16.11.2001 - PP-24. (see the HOUSE from 03.10.2005)



 

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FIELD: pharmaceutical technology.

SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.

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24 cl, 4 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

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and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

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22 cl, 1 tbl, 1 ex

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SUBSTANCE: invention concerns a variant of admixture extraction from composition containing extraneous matter and sucralose, which is used as a sweetener. One of the variants includes following stages: (a) first solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of another solvent, at least partially immiscible, in order to remove admixtures to the said second solvent; (b) second solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of the third solvent, at least partially immiscible, in order to transfer sucralose to the said third solvent; where stage (a) removes at least a part of admixtures to the second solvent; and stage (b) transports most of sucralose to the third solvent and detains most of admixtures in the first solvent.

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34 cl, 4 tbl, 2 dwg, 2 ex

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EFFECT: method improvement.

11 cl, 3 ex

FIELD: chemistry.

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EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a protected fluorinated glucose derivative, involving reaction of a tetraacetylmannose derivative with a fluoride, distinguished by that the reaction is carried out in a solvent which contains water in amount of more than 1000 parts per million and less than 50000 parts per million. Preferably, the protected fluorinated glucose derivative is 2-fluoro-1,3,4,6-tetra-O-acetyl-D-glucose (tetraacetylfluroglucose or pFDG), the tetraacetylmannose derivative is 1,3,4,6-tetra-0-acetyl-2-0-trifluoromethanesulphonyl-β-D- mannopyranose (tetraacetylmannose triflate), the solvent is acetonitrile, the fluoride is a fluoride ion with a potassium counter-ion, and a phase-transfer catalyst, such as 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]-hexacosa, is added to the fluoride.

EFFECT: improved method.

14 cl, 2 tbl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 and R5 independently denote H, benzoyl, pivaloyl or methoxymethyl. The invention also

relates to a method of producing one of the said compounds

(formula 45), involving the following steps: (a) reaction of compound

with alkyl-2-bromopropionate in the presence of activated zinc in a suitable solvent to obtain a compound of formula

; (b) adding an oxidising agent to obtain a ketone of formula

; (c) fluorination of the product from step (b) to obtain a fluorinated ketone of formula

; (d) reduction of the fluorinated ketone from step (c) to obtain a compound of formula

; (e) benzylation of the product from step (d) to obtain a compound of formula

, where Bz denotes benzoyl; (f) cyclisation of the product from step (e) to obtain lactone of formula 45 as the end product.

EFFECT: lactones can be used in synthesis of nucleosides with high anti-HIV activity.

8 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: method enables to obtain 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one of formula (IV), which is a strong inhibitor of NS5B polymerase of hepatitis C virus (HCV).

EFFECT: high yield.

2 cl, 4 ex

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