The method of obtaining 1,4 : 3,6-dianhydro-d-sorbitol
(57) Abstract: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. Describes how to obtain carbide, which consists in boiling when 130-150oWith food sorbitol in the medium of xylene with water separator until the cessation of water separation in the presence as catalyst p-toluenesulfonic acid, taken in an amount of 5.0% by weight of sorbitol. The technical result consists in simplifying the process and increasing the yield of the target product, while maintaining its high quality. table 2. 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 are used as a vasodilator prolonged action in hypertension, angina and other cardiovascular SV acid type scheme
< / BR>There are several ways to get isosorbide, however they mostly have only laboratory value, their implementation in an industrial environment is difficult due to the high cost and complexity of the process.The most noteworthy ways dehydration of sorbitol in toluene or xylene in the presence of acid catalysts nature [1-3]. According to these works, the output isosorbide ranges from 8 to 67%. Methods for isolation and purification of isosorbide complex, long and multi-stage.Currently isosorbide get improved method proposed by P. M. Kochergin with employees [4, 5]. This method is implemented in Krasnouralsk copper smelting plant in Krasnouralsk the Ekaterinburg region) and adopted us for the prototype.In this way isosorbide is obtained by boiling at 130-150oC food sorbitol in the medium of xylene with water separator until the complete termination of water (about 8 h) in the presence as catalyst p-toluenesulfonic acid, taken in an amount of 5.0% by weight of sorbitol.So, 2.0 kg of the crushed food sorbitol take 7.5 l technical xylene and 100 g of p-toluenesulfonic acid. The reaction water is collected in the water separator. On iconastas dark residue is dissolved in 10 l of water and boil 1,0 h with 0.5 kg of activated carbon, then the solution is cooled to 50-60oC and filtered from coal. The filtered coal boiled for 1 h with 2.0 l of water for a more complete extraction of isosorbide and filtered. From United almost colorless filtrate water is distilled off in a vacuum at a temperature not higher than 75,0oC. a Thick residue (about 1.5 kg) of isosorbide raw cleanse by deep-vacuum distillation (pressure of 1.0 to 4.0 kPa, the temperature in pairs 160-175oC).Isosorbide is obtained as a pale yellow oil that crystallized upon standing or making seed yield 68-70% of theoretical.The advantage of this process is that sorbed get high quality and for further processing there is no need for additional recrystallization him from flammable solvents.The disadvantages of the method are:
- a multi-stage process;
- use GZH as the reaction medium, which makes the process of fire;
high labour and energy cost;
- the use of a large number of scarce catalyst and activated carbon (in 5.0 and 25.0 wt.% respectively);
- poor performance.According to the authors [4, 5] and patent  decrease if the littelest reaction of dehydration.The aim of the present invention is
- creation of a single-stage, high-performance, fire-get isosorbide;
- eliminate labor intensive and energy-intensive stages;
- reduce consumption of raw materials;
- increase the yield of the target product, while maintaining its high quality.This goal is achieved by combining the processes of dehydration food carbide and purification of the resulting isosorbide.Distinctive features of the method is that the process of dehydration is carried out with simultaneous separation from the reaction zone of the target product and the reaction water. The reaction is carried out in the presence of catalytic amounts of water (3-10 wt.%) and acid catalyst (0.2 to 0.6 wt.% p-toluenesulfonic acid or sulfuric ortho-phosphoric acid).The process is performed at a pressure of 1.0 to 4.0 kPa, which corresponds to the boiling temperature of the reaction mass 165-195oC, but not above 205oC because at this temperature already has a partial resinification of the reaction mass, resulting in a loss of yield of the target product. For the criterion of the process is the vacuum (or residual pressure), which determines the boiling point (othonna, equipped with a thermometer, was loaded 75,0 g food sorbed (in terms of 100%), of 0.15-0.45 g of catalyst and 2.25-7,50 ml of water. The flask through the nozzle vyurts connected with receiver isosorbide connected through a cooler-condenser with a collection of water that connects to a vacuum pump. The reaction mass was heated on a sand bath under vacuum. Thus the boiling temperature of the reaction mass was 170-195oC. When this temperature was held for selection of isosorbide in the form of a light yellow oil that crystallized upon standing or when making seed. The reaction water passing through the collector isosorbide, was condensed in the cooler-condenser and collected in the water collection.On the technological regime in the laboratory were developed samples of isosorbide, of which, after nitration was obtained 2,5-dinitrate treatment-1,4:3,6-dianhydro-D-sorbitol with a good solution that meets the requirements of the Federal Assembly of 42-422-86.The results of the experiments are presented in table.2, which shows that the isosorbide is obtained from the output 70,6-78,1%. The quality of isosorbide was evaluated by gas chromatography. Found that the quality of isosorbide received by existing and proposed technology, islanova catalyst at elevated temperature, characterized in that, to simplify and enhance the security of the process and increase the yield of the target product as the acid catalyst used p-toluensulfonate, phosphoric or sulphuric acid taken in the quantity of 0.2 - 0.6 wt.%, and the process is carried out in the presence of 3.0 - 10.0 wt.% water at a temperature of 165 to 195oC and a pressure of 1.0 to 4.0 kPa (-0,96oC -0,99 kgf/cm2with simultaneous distillation of the water and the desired product from the reaction zone.
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
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
SUBSTANCE: developed method of sucralose production using acyl-sucralose implies (a) adjustment of pH factor of specified supplied mixture to value ranged from 8.0 to 12.0 by alkali metal hydroxide addition; (b) buffer addition to specified base mixture in amount enough for specified pH factor stabilization within stated range over holding stage (c); (c) holding of specified base mixture at appropriate temperature over time period enough for effective transformation of specified acyl-sucralose compound into free sucralose; (d) reduction of specified pH factor of specified base mixture up to value from 4 to 8; (e) sucralose release from product of step (d) resulted thereby in released sucralose.
EFFECT: improved method of water deacylation procedure stabilization.
22 cl, 1 tbl, 1 ex
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.
EFFECT: efficient removal of admixtures from compositions.
34 cl, 4 tbl, 2 dwg, 2 ex
SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.
EFFECT: method improvement.
11 cl, 3 ex
SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.
EFFECT: efficient method of obtaining derivatives of the abovementioned agent.
11 cl, 6 ex
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
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
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
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