The way to obtain [2-18f]-2-deoxyglucose

 

(57) Abstract:

The invention relates to medicine, more specifically to radiopharmaceuticals for diagnostic purposes, and may find application in positron emission tomography. To acetic anhydride type D-mannose in the presence of a 70% aqueous solution of chloric acid. Stand at room temperature until a 1,2,3,4,6-pentaacetate D-mannose. Then the temperature is not above 25°C add trichromacy phosphorus and cooling water. The mixture was kept at room temperature until a alpha acetobromo-D-mannose. To it was added a solution of sodium acetate at a temperature not exceeding 5°C and maintained at room temperature to obtain a mixture of 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose. The reaction was poured on ice and extracted several times with an organic solvent. The extract is dried, evaporated and the residue is crystallized from diethyl ether. Received 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose dissolved in dry methylene chloride with the addition of anhydrous pyridine and at a temperature of 20°C To give the anhydride of triftoratsetata. The reaction mass is maintained at room temperature, the solvent is removed. Received 1,3,4,6-face and at a temperature of 85°C for 5 min add fluoride-18 and interphase catalysts. The solvent is distilled off. To the residue add 1 -2 M solution of hydrochloric acid and incubated the mixture for 6-10 minutes at a temperature of 120-130°C., or 0.2-0.5 M sodium hydroxide solution and incubated for 1-2 min at a temperature of 20-30°C. water is Added and the resulting mass is purified by anyone-, cation-exchange and obrashennih resins to obtain the desired product. When receiving 1,2,3,4,6-pentaacetate D-mannose the temperature of the reaction mass is maintained within the range of 35-40°C and left overnight at a temperature of 0-4°C. Trichromacy phosphorus and water is added at a molar ratio of 1,2,3,4,6-pentaacetate D-mannose : PBr3: H2O - 1 : 2.5:13.6. When you add water, the temperature of the reaction mass support does not exceed 10°C. as the organic solvent for extraction of a mixture of 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose use methylene chloride. The extract is evaporated to a volume of 125 ml Before crystallization from diethyl ether put on a chromatographic column filled with neutral alumina. Elute with a mixture of hexane - methylene chloride gradient last from 10 to 50%. Select a second fraction containing 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose. The solvents are evaporated in vacuum. Siropoobraznaja ether. After receiving 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D-mannopyranose, the reaction mixture was subjected to flash chromatography on silica gel. Then the solvent is removed. The residue is crystallized from diethyl ether. The first fraction after column chromatography and the mother liquor after crystallization of tetraacetate D-mannopyranose is evaporated, consolidate, dissolve them in methylene chloride. The last is removed. With the remainder carried out a full cycle of the above-described chemical reactions. Repeat the procedure at least three times. Received three cycles of 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose unite and purify by crystallization from absolute ethanol. When cleaning the target product through anion-exchange resin using the resin AV-17. The invention improves the quality and yield of product. 1 Il.

The invention relates to medicine, more specifically to radiopharmaceuticals for diagnostic purposes, and may find application in positron emission tomography.

in [218F] -2-deoxyglucose (FDG) is the most widely used radiodiagnostic drug in PET studies. It is intended for in vivo assessment of local metabolic rate of glucose glodow. Moreover, short-lived radionuclide fluorine-18 (half-life of 109.77 min) on its nuclear-physical characteristics is only suitable isotope of fluorine for the purposes of radionuclide diagnostics by means of positron emission tomography (PET). Its distinguishing feature is the relatively low radiation load on the blood and the body in General. FDG is widely used for the diagnosis of different pathologies: primary tumors and metastases, differential diagnosis of tumor recurrence and tumor necrosis localization of epileptic foci, degenerative-dystrophic diseases and other Receiving FDG is carried out in day of the study and introduce it into the body by simultaneous intravenous injection. The preparation is described in the U.S. Pharmacopoeia and the European Union.

Synthesis of FDG is based on the nucleophilic radiotolerance 1,3,4,6-Tetra-O-acetyl-2-O - trifloromethyl-beta-D-mannose (TATM). This method, proposed by Amahara al. [1], is the most common and currently the only promising method of obtaining FDG. This method is taken as a prototype.

Since it is known that TATM - unstable product, and the quality of D-mannose. According to various authors, the radiochemical yield FDG in terms of radioactive decay of fluorine-18 in the course of the synthesis is the maximum 69% [1], 58-73% [2]. Radiochemical yield FDG when we receive using TTM production UKE-Zyclotron (Germany) by the method of Hamacher was 46-71% in terms of the decay of fluorine-18.

Getting FDG in the prototype method [2] is carried out, starting with 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D-mannopyranose (TATM), which Hamacher [3] synthesized from 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose, and it is from D-mannose [4].

The full scheme of synthesis FDG shown in the drawing.

Getting 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose [4].

A few milligrams of D-mannose is added to acetic anhydride (25 ml), then add 2 drops of 70% solution of chloric acid and portions 6.6 g of D-mannose, stirred for 20 min, the internal temperature of the reaction mixture is maintained within the range of 40-45oC. the Mixture was kept at room temperature for 60 min, then cooled to 15oC and added dropwise 4.3 ml trichromate phosphorus, maintaining an internal temperature of 20-25oC. Then add 2.3 ml of water and the mixture was incubated for 90 min while maintaining the internal temperature of 35-40oC. the Resulting yellow solution was kept at this temperature for 25 min, after which it was poured on ice and extracted with chloroform (CH ml). The chloroform extracts are combined, washed with cold water, a cold solution of sodium bicarbonate and again with water and dried with magnesium sulfate. The solution is evaporated to dryness, the residue is crystallized from anhydrous diethyl ether. Obtained 2.3 g after crystallization of 1.8 g (29%) with MP. 164-165oC.

Getting 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta - D-mannopyranose (TATM) [3].

To a solution of 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose (3.14 g, 9 mmol) in dry dichloromethane (80 ml) with addition of pyridine (1.7 ml) was added anhydride of triftoratsetata (3.4 ml, 2.1 mmol) dropwise at -20oC. Yellow-green suspension was kept at room temperature for 1 h, washed with cold water, a solution of sodium bicarbonate and again with water, dried with sodium sulfate, filtered and concentrated to dryness. The residue crystallized twice from ethanol. Obtain 2.6 g (60%) with MP. 120oC.

Getting FDG [2,6].

1,3,4,6-Tetra-O-acetyl-2-O-triptorelin-beta-D-mannopyranose dissolved in acetonitrile and at a temperature of 85oC for 5 min debaty [2], maintaining the mixture within 6-10 minutes at a temperature of 120-130oC, or 0.2-0.5 M sodium hydroxide solution [6], soaking for 1-2 min at a temperature of 20-30oC, water is added and the resulting mass is purified by anyone-, cation-exchange and obrashennih resins to obtain the desired product with a yield 58-73% (using tar 900-PS-HCO3). Radiochemical purity characterized by fluoride-18 in the preparation ranges from 0.16-1.39%, on average, 0.42+0.44%.

As for the quality of FDG, it is known that fluoride-18 is the primary radiochemical impurity. Its content in the crude target product can reach 50%. It is known that fluoride-18 when entering the body accumulates in the bones of the skeleton and unlike FDG is not excreted from the body. Therefore, the presence of fluoride-18 in a final product leads to an increase in dose loads on the body of the patient and complicates the interpretation of medical diagnostic tests. This, in turn, dictates the need for a thorough cleaning and fluoride-18. For this purpose use microcolony filled with strong anionoobmyennymi resins, Dowex IX-10, TIN-100 or 900-PS-HCO3 (Nuclear Interface), Germany, containing tetraalkylammonium group. When using the manufacturers module for the synthesis of FDG (Nuclear Interface") for the removal of fluoride-18 proposed third resin (900-PS-HCO3). Using the fluoride-18 in the target product (for our records) ranges from 0.16% to 1.39%, on average, 0.42+0.44%.

This prompted us to look for opportunities to improve the quality of FDG.

The technical result of the present invention is to improve the quality and output of FDG by improved modes of synthesis TATM and purification of the intermediate and target products.

This result is achieved by the fact that in the known method of obtaining FDG, consisting in the fact that acetic anhydride type D-mannose in the presence of a 70% solution of chloric acid, incubated at room temperature to obtain 1,2,3,4,6-pentaacetate D-mannose, then the temperature is not above 25oC add trichromacy phosphorus and cooling water, the mixture was kept at room temperature until a alpha acetobromo-D-mannose, and to it was added a solution of sodium acetate at a temperature of not higher than 5oC and incubated at room temperature to obtain a mixture of 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose, the reaction was poured on ice and extracted several times with an organic solvent, the extract is dried, evaporated and the residue is crystallized from diethyl ether, obtained 1,3,4,6-Tetra-OI at -20oC add the anhydride of triftoratsetata, the reaction mass is maintained at room temperature, the solvent is removed, the obtained 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D-mannopyranose crystallized, then it is dissolved in acetonitrile and at a temperature of 85oC for 5 min add fluoride-18 and interphase catalysts, the solvent is distilled off, to the residue add 1-2 M solution of hydrochloric acid, keeping the mixture for 6-10 minutes at a temperature of 120-130oC, or 0.2-0.5 M sodium hydroxide solution, soaking for 1-2 min at a temperature of 20-30oC, water is added and the resulting mass is purified by anyone-, cation-exchange and obrashennih resins to obtain the desired product according to the invention, upon receipt 1,2,3,4,6-pentaacetate D-mannose temperature of the reaction mass support within 35-40oC and left overnight at a temperature of 0-4oC, trichromacy phosphorus and water is added thereto at a molar ratio of 1,2,3,4,6-pentaacetate D-mannose: PBr3: H2O - 1 : 2.5 : 13.6, and adding water temperature of the reaction mass does not support above 10oC, as the organic solvent for extraction of a mixture of 2,3,4,6 - 1,3,4,6-tetraacetate D-kanalizacija from diethyl ether put on a chromatographic column filled with neutral alumina elwira a mixture of hexane - methylene chloride gradient last from 10 to 50%, select the second fraction, containing mainly 1,3,4,6-Tetra-O-acetyl-beta-D - mannopyranose, the solvents evaporated in vacuum, the syrupy residue is maintained at 5-10 mm RT.article and the temperature of 35-40oC for 1.5-2 h, and then crystallized from diethyl ether, after receipt of 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D - mannopyranose, the reaction mixture was subjected to flash chromatography on silica gel, after which the solvent is removed, the residue is crystallized from diethyl ether, and the completeness of the conversion of D-mannose in 1,2,3,4,6-pentaacetate D-mannose, its subsequent conversion into alpha acetobromo-D-mannose, last - 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose, the separation of these isomers, the completeness of the transition 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose in 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D-mannopyranose and completeness of the selection 1,3,4,6-tetraacetyl-beta-D-mannopyranose with elution on a chromatographic column is controlled by means of thin-layer chromatography in the system hexane:acetone 2:1, to improve the yield of the target product of the first fraction after column chromatography and the mother liquor after crini removed and residue containing mainly 2,3,4,6-leads to compounds, which D-mannopyranose, and products of incomplete acetylation of D-mannose, again carry out a full cycle of the above chemical reactions, repeating this procedure at least three times, resulting in three cycles of 1,3,4,6-Tetra-O-acetyl-beta-D - mannopyranose unite and purify by crystallization from absolute ethanol, and the purification of the target product through anion-exchange resin using the resin AB-17.

The increase in the yield of FDG is achieved by the authors of the present invention based on the optimization of regimes (temperature, time) for each step of the cycle the FDG.

Thus, the temperature of the reaction mass during the acetylation of D-mannose within 35-40oC with defending her over night at a temperature of 0-4oC contributes to a more complete conversion of D-mannose in 1,2,3,4,6-pentaacetate D-mannose, which is controlled by thin-layer chromatography (Rf 0.61 in the system hexane:acetone 2:1).

The molar ratio of 1,2,3,4,6-pentaacetate D-mannose : PBr3: H2O 1 : 2.5 : 13.6, we found empirically, and subsequent maintenance of the temperature in the reaction mixture during the addition of water does not exceed 10oC o is annosa (Rf 0.72).

Extraction of the mixture of 2,3,4,6-(Rf 0.41) and 1,3,4,6-(Rf 0.29) tetraacetate D-mannopyranose methylene chloride allows, as we have shown, most fully remove them from the reaction mixture, and subsequent chromatographic separation of the isomers is to highlight searched 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose with 30% yield and at the same time to remove resinous by-products, which in turn allows to use it in the future and the other factions.

Two additional cycles of receipt of 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose of "waste" the first cycle provides additional number and bring the output up to 52.3% in the calculation of D-mannose versus 29% in the prototype. However, in the method prototype made a mistake when calculating the output - it is not 29% and 14%, based on the above output, in grams. Thus, we were able to increase output 1,3,4,6-Tetra-O-acetyl - beta-D-mannopyranose 3.5 times in comparison with the prototype.

Perform flash chromatography on silica gel for separation of 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D-mannopyranose (TATM) from the reaction mixture, followed by its crystallization from diethyl ether provides the output TATM 94% (vs. 60% in the prototype) to obtain the modes offered by us provides the output of the target product (FDG) within 65-94%, on average 7612%, against 46-71%, on average, 619% in the prototype. The reliability of differences in solid samples (7 and 7 synthesis) > 95%.

Use for the purification of the target product from the fluoride-18 domestic anion exchange resin AB-17 in the bicarbonate form with a particle size of 100-150 mesh and exchange capacity 2.1 mgecw/g provides high radiochemical purity, namely the contents in the preparation of fluoride-18 ranges from 0.06 to 0.21%, on average 0.120.06%, whereas in the prototype it is 0.16-1.39%, on average 0.420.44%.

As can be seen from the above data, the achievement of the technical result improved quality and yield of the target product in the proposed method of obtaining FDG provided.

The method is as follows.

Getting 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose.

To 200 ml of fresh acetic anhydride was added 0.3 ml of 70% solution of chloric acid and then with stirring in small portions sprinkled 54 g (0.1 mol) of dry D-mannose for 1 h, maintaining the temperature of the reaction mass within 35-40oC. the Mixture is stirred for 1.5-2 h at 20-25oC and left overnight at 0-4oC. complete conversion of D-mannose in 1,2,3,4,6-pentaacetate Dr. Mann is assured acetylation to the reaction mass while cooling with ice water was added dropwise with stirring 45.9 ml (0.25 mol) of fresh trichromate phosphorus in a molar ratio of 1,2,3,4,6-pentaacetate D-mannose: PBr3:H2O - 1 : 2.5 : 13.6 and the temperature not exceeding 25oC. the Mass is then cooled with ice and salt with vigorous stirring slowly added dropwise 25 ml of water, preventing the rise of temperature of the reaction mass above 10oC and can withstand the resulting solution for 2-2.5 h until complete conversion of pentaacetate D-mannose, alpha acetobromo-D-mannose (Rf 0.72). Then slowly added dropwise a cooled solution of sodium acetate (98.7 g, 0.59 mol) in 220 ml of water, the temperature of the reaction mixture should not exceed 5-10oC. Remove the cooling and the solution was stirred at room temperature for 0.5-1.0 h, locking TLC full conversion of alpha-acetobromo-D-mannose mainly 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose (Rf respectively 0.41 and 0.29). The mass is then poured into 600 g of ice and stirred until complete decomposition of acetic anhydride. The product is thoroughly extracted with methylene chloride (4 x 200 ml), the organic layer was washed with a cold solution of sodium bicarbonate, ice water, the extract is dried with magnesium sulfate. After separating the drying agent, the solution is treated with activated charcoal, filtered, methylene chloride is evaporated on a rotary evaporator to a volume of about 125 ml of a Concentrated solution of the product nanocollege from 10 to 50% to complete leaching of substances under control TLC. Selected 2 fractions: the first contains mainly 2,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose with small admixtures of other products dezazetilirovanie of pentaacetate D-mannopyranose; the second is mostly targeted product 1,3,4,6-tetraacetyl-beta-D-mannopyranose. The second fraction is evaporated on a rotary evaporator under vacuum, the syrupy residue is maintained at 5-10 mm RT.article and the temperature of 35-40oC for 1-1.5 hours Then the product is poured 200 ml of absolute diethyl ether, heated to boiling, and after complete dissolution of the slowly cooled to the onset of crystallization. After holding overnight at 0-4oC colorless precipitate is filtered off, washed with a small amount of dry ether. Receive 31.3 g (0.09 mol, 30%) of white crystalline substance - 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose with a melting point 162-163oC.

To better use the original D-mannose first fraction after column chromatography and the mother liquor from crystallization of tetraacetate D-mannose is evaporated, then combine by dissolving in a minimum amount of methylene chloride, evaporated in vacuum until constant weight. The rest of raw, containing mainly 2,3,4,6-Tetra-O-acetyl-bet is ranose in compliance with the above-described reaction conditions: under acetylation raw treated with 140 ml of acetic anhydride in the presence of 0.2 ml of perchloric acid; when receiving alpha-acetobromo-D-mannose use 30.8 ml trichromate phosphorus and 16.4 ml of water, and the hydrolysis it is a solution of 66 g of sodium acetate in 150 ml of water. The product is isolated and subjected to chromatographic separation on the same column with alumina. After crystallization from ether to obtain 14.6 g (0.042 mol) 1,3,4,6-Tetra-O-acetyl-beta-D - mannopyranose. At the end of the remnants of raw tetraacetate mannose from chromatographic and uterine fluids (about 14 mol) obtain 8.7 g (0.025 mol), subject to the same reaction conditions and product selection. The total output 1,3,4,6-Tetra-O-acetyl-beta - mannopyranose is 52.3% (54.6 g, 0.16 mol) in the calculation of the original D-mannose. After crystallization from absolute ethanol and drying in vacuo get 52.4 g (0.15 mol, 50%) 1,3,4,6-Tetra-O - acetyl-beta-D-mannopyranose in the form of colorless crystals with a melting point of 166-167oC.

Getting 1,3,4,6-Tetra-O-acetyl-2-O - tittermatorter-D-mannopyranose (TATM).

To a solution of 52.4 g (0.15 mol) 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose in 1200 ml of dry methylene chloride is poured 31.7 ml of anhydrous pyridine. The solution is cooled to -20oC for 1-1.5 h was added dropwise a solution of 87.7 g (0.31 mol, d 1.677) anhydride of triftoratsetata absorb and the reaction mass was stirred at room temperature for 1.5-2 hours until complete disappearance in the chromatogram of the source leads to compounds, which D-mannose. The reaction mixture is washed with ice water, cold solution of sodium bicarbonate and again with ice water. Water layers additionally extracted with methylene chloride, the combined organic extract is dried with sodium sulfate. After separating the drying agent, the filtrate is treated with bleaching with activated carbon, is subjected to flash chromatography on silica gel and then evaporated on a rotary solvent under reduced pressure. The product is maintained at 30-35oC and 10-15 mm RT.article to complete crystallization and recrystallized from absolute diethyl ether (1 g/15 mg). After drying in vacuo get 69.17 g (0.144 mol) 1,3,4,6-Tetra-O-acetyl-2-O - triptorelin-beta-D-mannopyranose (output per 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose 96% on the original mannose - 48%). It is a white crystalline substance with MP.122-123oC. Spectral and chromatographic analyses show that the product is stable during prolonged storage (up to 1 year) in the fridge with protection from moisture in the air.

Getting FDG

Synthesis of [2-18F] FDG is based on the nucleophilic radiotolerance 1,3,4,6-Tetra-O-acetyl-2-O - trifloromethyl-beta-D-mannopyranose

(TATM) in acetonitrile at catalytic part between the SHL.

Radioactive raw material is fluoride, fluorine-18, which is produced by nuclear reactions18O(p, n)18F in the target cyclotron by irradiation of protons with energies up to 15 MeV. The resulting radionuclide is stabilized in the chemical form of fluoride, fluorine-18. As the irradiated substance use water enriched with oxygen-18 (H2O-18), as the target material is titanium, the radiochemical yield of the nuclear reaction is 120 MkI/ A h

The preliminary stage of the synthesis of the drug - extract target radionuclides from irradiated material combined with technologically enriched regeneration of water and separation of the anion fluoride, fluorine-18 from compounds containing radionuclide impurity nitrogen-13.

Followed by dehydration of the reaction mass. It is achieved by azeotropic distillation of water with acetonitrile (20% acetonitrile : 80% water). The distillation of acetonitrile conduct a current of inert gas (helium) while evacuating the reaction vessel to the almost complete dehydration reaction medium.

The main chemical stage of the synthesis is the nucleophilic substitution triflate group of TATM on fluorine-18. The reaction is carried out in a solution of acetonitrile at temperature is the mechanism, i.e., address configuration, so its radioactive product is a derivative of D-glucose - 1,3,4,6-Tetra-O-acetyl-2-18F-beta-D - glucopyranose. After the fluorination reaction is conducted complete distillation of the solvent in a stream of helium.

Hydrolysis of the reaction mixture containing 1,3,4,6-Tetra-O-acetyl-2-18F-beta-D - glucopyranose, and unreacted TATM, leads to the formation of the target product - [2-18F] FDG and glucose. The hydrolysis is carried out under acidic or alkaline catalysis. Acid hydrolysis carried out by the action of a 2 M solution of hydrochloric acid at a temperature of 125oC for 6-10 min, and alkaline - 0.3 M sodium hydroxide solution at 25oC for 1-2 minutes

After completion of the hydrolysis reaction vessel add water for complete rinsing of the reaction mass from the walls of the reaction vessel, after which the reaction mass is passed to a purification column, as fillers for using cation exchange resin of the strong type in the H+ form - KU-2, anion exchange resin of the strong type in the bicarbonate form AB-17, neutral aluminum oxide Alox-N and brasindiana resin HR-P type C18. The yield of purified target product is 65-94%, on average 7612% (in the prototype 58-73%, polur CLASS="ptx2">

The proposed method is compared with the known has a number of significant advantages:

1. Provides the output of the target product (FDG) on average 76+12%, whereas the prototype is equal to 619%.

2. Provides high radiochemical purity of the target product - fluoride-18 average 0.120.06%, whereas in the prototype - 0.420.44%.

3. The method is highly economical when you consider the cost of 1 dose of FDG, which on the international market is 500-1000 $, then increase its output per cycle allows for considerable savings.

4. The method is suitable for large-scale production of TATM, as it provides high yield (96% instead of 60% on prototype) shelf-stable product, continuing without change of properties during the year.

5. The method also provides high output 1,3,4,6-Tetra-O-acetyl - beta-D-mannopyranose (50% vs. 29%, as reported by the authors of the prototype, in fact he is only 14%, and according to reports by other authors, from 6 to 9%).

All of the above advantages of the proposed method to obtain FDG distinguish it from presently known, is able to replace any of them.

The method developed in the Department of cyclotron cnrri and is used for p the LASS="ptx2">

[2] K.-Run Bed And Breakfast, G. Blessing, Nebeling, B. Appl. Radiat. Isot. 1990. V. 41. P. 49/

[3] K-Run Bed And Breakfast, Carbohydrate Res. Vol. 128, p. 291-295, 1984.

[4] Deferrari, Carbohydr. Res. 1967, Vol. 4, p. 432-434.

[5] Bovin N. In. and other math. An SSSR, Ser. Chem. 1981, S. 1638-1641.

[6] Fuechtner P., Steinbach J., Maeding P., Johannsen B. 1996. Appl. Radiat. Isot. 47. P. 61-66.

The way to obtain [2 -18F]-2-deoxy-glucose, consisting in the fact that acetic anhydride type D-mannose in the presence of a 70% aqueous solution of chloric acid, can withstand up to get 1,2,3,4,6-pentaacetate D-mannose, then the temperature is not above 25oTo add trichromacy phosphorus and cooling water, the mixture was kept at room temperature until a alpha acetobromo-D-mannose, and to it was added a solution of sodium acetate at a temperature of not higher than 5oC and maintained at room temperature to obtain a mixture of 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose, the reaction was poured on ice and extracted with an organic solvent, the extract is dried, evaporated and the residue is crystallized from diethyl ether, obtained 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose dissolved in dry methylene chloride with the addition of anhydrous pyridine and at a temperature of -20oWith the added anhydride triftormetilfullerenov the Teal-2-O-trifloromethyl-beta-D-mannopyranose crystallized, then it is dissolved in acetonitrile and at a temperature of 85oC for 5 min add fluoride-18 and interphase catalysts, the solvent is distilled off, to the residue add 1 - 2 M hydrochloric acid, keeping the mixture for 6 to 10 minutes at a temperature of 120 - 130oWith, or 0.2 - 0.5 M sodium hydroxide solution, soaking for 1 to 2 minutes at a temperature of 20 - 30oSince, water is added and the resulting mass is purified by anyone-, cation-exchange and obrashennih resins to obtain the desired product, characterized in that when receiving 1,2,3,4,6-pentaacetate D-mannose the temperature of the reaction mass is maintained within the range of 35 - 40oC and left overnight at a temperature of 0 to 4oWith, trichromacy phosphorus and water is added thereto at a molar ratio of 1,2,3,4,6-pentaacetate D-mannose : PBr3: H2O 1 : 2.5 : 13.6, and adding water temperature of the reaction mass does not support above 10oWith, as the organic solvent for extraction of a mixture of 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose use methylene chloride, the extract is evaporated to a volume of about 125 ml before and crystallization from diethyl ether put on a chromatographic column filled with neutral alumina Alyona 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose, the solvents are evaporated in vacuum, the syrupy residue is maintained at 5 to 10 mm RT. Art. and a temperature of 35 - 40oC for 1.5 - 2 h, and then crystallized from diethyl ether, after receipt of 1,3,4,6-Tetra-O-acetyl-2-O-trifloromethyl-beta-D-mannopyranose, the reaction mixture was subjected to flash chromatography on silica gel, after which the solvent is removed, the residue is crystallized from diethyl ether, and the completeness of the conversion of D-mannose in 1,2,3,4,6-pentaacetate mannose, its subsequent conversion into alpha acetobromo, last - 2,3,4,6 - 1,3,4,6-tetraacetate D-mannopyranose, the separation of these isomers, the completeness of the transition 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose in 1,3,4,6-Tetra-O-acetyl-2-O-Cryptor-methanesulfonyl-beta-D-mannopyranose and completeness of the selection 1,3,4,6-tetraacetyl-beta-D-mannopyranose with elution on a chromatographic column is controlled by means of thin-layer chromatography in the system hexane : acetone 2 : 1, the first fraction after column chromatography and the mother liquor after crystallization of tetraacetate mannopyranose is evaporated, unite, dissolving them in methylene chloride, the latter is removed, and the residue containing mainly 2,3,4,6-leads to compounds, which D-mannopyranose, and Vtoraya this procedure at least three times, received three cycles of 1,3,4,6-Tetra-O-acetyl-beta-D-mannopyranose unite and purify by crystallization from absolute ethanol, and the purification of the target product through anion-exchange resin using the resin AV-17.

 

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The invention relates to pharmaceutical industry and relates to a method of production of a medicinal product antiarthrosis action of chitin

The invention relates to medicine, namely to synthetic biologically active compounds derived class 1 detoxi-1-N - methylaminoethanol and N-greenexpo acid

The invention relates to the technology of 1,4 : 3,6-dianhydro-D-sorbitol (sorbed, isosorbide), which is an intermediate in the production of medicines on the basis of its mono - and dinitropropane, which is used as a vasodilator prolonged action in hypertension, angina and other cardiovascular diseases

The invention relates to the field of organic chemistry and relates to the process of obtaining intermediate for the synthesis of vitamin B2

The invention relates to the field of organic chemistry and relates to the process of obtaining intermediate for the synthesis of vitamin B2

The invention relates to compounds that are used as medicines, which have antiendotoxin activity, in particular analogs of lipid A

The invention relates to compounds that are used as medicines, which have antiendotoxin activity, in particular analogs of lipid A

The invention relates to medicine, namely to radiopharmaceutical drugs containing a radionuclide samarium-153, and may be used for the treatment of metastases of malignant tumors in the bones and rheumatoid arthritis

The invention relates to pharmaceutical industry and relates to a pharmaceutical composition for radiation therapy

The invention relates to a method for producing synthetic hydrochloride of 5-aminolevulinic (5-amino-4 - oxopentanoate) acid formula HCLH2NCH2COCH2CH2COOH

The invention relates to radioactive immunoreagent directional, which is a conjugate complexing agent and the immunoreactive group, labeled ion of a radioactive metal

The invention relates to biologically active compounds labeled with radionuclides

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

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.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: medicine, radionuclide diagnostics.

SUBSTANCE: 199Т1 chloride intravenous injection is followed by early planar scintigraphy in 20 min, visual determination of increased marker accumulation area, quantitative estimation of early accumulation in lesion (ER), additionally, delayed imaging is taken in 180 min following 199Т1 chloride injection, at that, area of increased marker accumulation is determined repeatedly, accumulation intensity is determined quantitatively (DR), retention index (RI) is calculated as DR/ER and nonspecific inflammatory process is diagnosed if at least 2 of 3 following signs are found: RI<-0.047ER+0.979 in early and delayed imaging, borders of early marker hyperfixation area in early imaging are more distinct than in delayed phase of test, homogeneity of hyperfixation area in delayed imaging, while malignant tumour process is diagnosed if at least 2 of 3 following signs are found: RI>-0.047ER+0.979 in early and delayed imaging, less distinct borders of marker hyperfixation area in early imaging as compared to delayed imaging or without significant changes depending on imaging phase, heterogeneity of hyperfixation area in delayed imaging.

EFFECT: precision and informative value of differential diagnosis of nonspecific inflammatory and malignant processes of musculoskeletal system is increased as a result of enhanced qualitative and quantitative evaluation of scintigraphy image.

4 dwg, 1 tbl, 2 ex

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