The method of obtaining phosphoric esters thiamine

 

(57) Abstract:

Usage: obtain phosphoric esters of thiamine. The inventive product fosfotiamina, exit 42 Reagent 1: thiamine-Mononitrate. Reagent 2: P2O5H3PO4Reaction conditions: in the presence of RCONH2where R is H, NH2C4H24+1when n=1-4 and at elevated temperatures.

The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs.

A method of obtaining phosphoric esters thiamine phosphorylation of thiamine-chloride-sodium pyrophosphate in the presence of an excess of phosphoric acid. Phosphorylation occurs indiscriminately, which formed as a result of the mixture of phosphate esters of thiamine, consisting of thiamine-0-monophosphate (phosphatemia), thiamine-0-diphosphate (acarboxy - LAZ) and thiamine-0-triphosphate. The mixture of phosphate esters of thiamine share chromatographytandem on ionoobmennoi resin. Fractions of the eluate containing, respectively, thiamine-0-monophosphate, thiamine-0-diphosphate and thiamine-0-triphosphate, evaporated and the residue Mine [1]

The disadvantage of this method is the use of sodium pyrophosphate, because pyrophosphoryl acid and its salts are easily available on an industrial scale.

Also known is a method of obtaining phosphoric esters thiamine phosphorylation of thiamine-chloride phosphorus oxychloride in the presence of phosphoric acid. As with the previous method it is neselektivno phosphorylation process. The mixture of phosphate esters of thiamine can be separated into individual components by chromatographytandem on ion-exchange resin, as described above [2]

The disadvantage of this method is the use of significant quantities of phosphorus oxychloride as its interaction with phosphoric acid produces large volumes of gaseous hydrogen chloride.

The closest to the technical nature of the claimed is a method of obtaining phosphoric esters thiamine phosphorylation of teminology fosforiliruyusciye mixture prepared from phosphoric anhydride and phosphoric acid. This phosphorylation process, as described above, also provides selectivity and leads to the formation of a mixture of phosphate esters of thiamine. The resulting mixture chromatograph is phat [3]

The disadvantage of this method is the use as feedstock thiamine-chloride, which refers to hard-to-reach products.

The proposed solution allows to obtain a phosphoric ester of thiamine thiamine-Mononitrate phosphorylation mixture of phosphoric anhydride and phosphoric acid.

This is achieved by the fact that the phosphorylation of thiamine-Mononitrate carried out in the presence of amides of carboxylic acids of General formula RCONH2where R is H, NH2CnH2n+1when n=1-4, when the molar ratio of amide carboxylic acid and thiamine-Mononitrate from 0.5:1 to 2:1.

The use of thiamine-Mononitrate enables industrial production of phosphoric esters of thiamine (phosphatemia, cocarboxylase) more affordable raw materials than thiamine chloride. It is known that thiamine-Mononitrate used in industry as an intermediate for the production of thiamine-chloride.

Amides of carboxylic acids prevent the oxidation of thiamine-Mononitrate and phosphoric esters of thiamine in the process of phosphorylation. It was established experimentally that the phosphorylation of thiamine-Mononitrate accompanied by the formation of oxides of nitrogen is ion environment. Thus the decomposition of nitric acid takes place at a high speed in the process of phosphorylation under the influence of increased temperature. The resulting nitrogen oxides easily react deamination of amides of carboxylic acids, during which they are associated and thus removed from the reaction medium. In the absence of amides of carboxylic acids under the influence of accumulating in the reaction medium of oxides of nitrogen flow in the deep oxidation of thiamine-Mononitrate and phosphoric esters of thiamin.

Reduction of amide carboxylic acid in the reaction mixture below the lower limit leads to the phosphorylation process cannot be fully bind the formed nitrogen oxides and to prevent the oxidative degradation of thiamine-Mononitrate and phosphoric esters of thiamine. The use of quantities of carboxylic acid amide, exceeding the upper limit, it is impractical, because with smaller amounts result in almost complete suppression side of the oxidation process.

The essence of the proposed method is that the mixture of phosphoric anhydride and phosphoric acid when heated add amide carboxylic acid and then gradual the mixture of phosphate esters of thiamine dissolved in distilled water and chromatographytandem on the ion exchange column is divided into separate components thiamine-0-monophosphate (fosfotiamina), thiamine-0-diphosphate (kokarboksilazu) and thiamine-0-triphosphate. When a sufficiently high degree of purity, the yield of the target products from diaminomaleonitrile not lower than thiamine-chloride, which is currently used as the initial product in the production of phosphatemia and cocarboxylase.

P R I m e R 1. To 99 g of 85% orthophosphoric acid slowly with stirring was added 132 g of phosphoric anhydride, preventing temperature increase above the 100aboutWith, and maintained at a temperature of 100aboutC for 1 h To thus prepared fosforiliruyusciye mixture at the same temperature was added 9 g of urea is stirred until complete dissolution and then gradually add 38 g of thiamine-Mononitrate (36.5 g of 100% substance), incubated at 100aboutC for 1 h While experiencing the allocation colorless gas. Reaction mass takes a light-brown color. After exposure it is cooled in a bath of ice. When cooled it becomes viscous and difficult to stir. The cooled reaction mass is dissolved in 550 ml of cold distilled water, keeping the temperature when dissolved at 0aboutC.

The resulting solution, containing a mixture of phosphoric epimeno cation exchanger KU-23 to N+-form. Flowing the solution through the column, put the phosphoric esters of thiamine on the cation exchanger. Chromatographic separation of the phosphoric esters of thiamine carried out, sequentially passing through the column of 0.05 N. acetate buffer solutions with a pH of 2.5 and 4.3. The first buffer solution aluinum column with thiamine-0-trisphosphate, a second thiamine-0-diphosphate. On the cation remains thiamine-0-monophosphate.

The first fraction of the eluate evaporated in vacuum at a temperature not exceeding 20aboutWith, one stripped off the solution, add 10 times by volume the amount of absolute ethanol and incubated at a temperature of about 0aboutC. Precipitated precipitate was separated by filtration and dried in vacuum. Get 7,1 g thiamine-0-triphosphate (6 g 100% substance). The output of 10.7% of theoretical, counting on thiamine-Mononitrate.

The second fraction of the eluate also evaporated in vacuum at a temperature not exceeding 20aboutWith one stripped off the solution acidified with concentrated hydrochloric acid, add 10 times by volume the amount of absolute ethanol and incubated at a temperature of about 0aboutC. Precipitated precipitate was separated by filtration and dried in vacuum. Obtain 13.8 g of thiamine hydrochloride-0-diphosphate (cocarboxylase hydrochloride) and m m e R 2. To 99 g of 85% orthophosphoric acid slowly with stirring was added 132 g of phosphoric anhydride, preventing temperature increase above the 100aboutS, and incubated at 100aboutC for 1 h To thus prepared fosforiliruyusciye mixture at the same temperature was added 7 g of formamide and then gradually add 38 g of thiamine-Mononitrate (36.5 g of 100% substance), maintained at a temperature of 100aboutC for 1 h While experiencing the allocation colorless gas. Reaction mass takes a light-brown color. After exposure it is cooled to 60aboutWith and dissolved in 550 ml of distilled water. The obtained acidic solution containing a mixture of phosphate esters of thiamine and phosphoric acid, is heated at a temperature of 90aboutC for 6 h to hydrolysis of thiamine-0-diphosphate and thiamine-0-triphosphate to thiamine-0-monophosphate. The hot solution lighten activated carbon, cooled to a temperature of 25aboutWith and add to 7-fold by volume quantity of acetone. After holding at a temperature of about 0aboutSkipped the precipitate was separated by filtration and dried in vacuum. The product is crystallized twice from 50% ethanol, using a 5-fold volume of colio thiamine-0-monophosphate (phosphatemia) or 20.7 g in terms of 100% substance. Exit 42% of theoretical, counting on thiamine-Mononitrate.

P R I m e R 3. The process is conducted as described in example 2, with the same quantities of reagents and with the only difference that instead of 7 g of formamide using 15 g of amide valerianic acid. Obtain 17.3 g thiamine phosphate-0-monophosphate (phosphatemia) or 15.4 g in terms of 100% substance. Exit 31.2% of theoretical, counting on thiamine-Mononitrate.

The METHOD of OBTAINING PHOSPHORIC ESTERS THIAMINE phosphorylation salt of thiamine mixture of phosphoric anhydride and phosphoric acid, characterized in that as the salt of thiamine is used thiamin-Mononitrate and phosphorylation is carried out in the presence of amides of carboxylic acids of General formula RCONH2where R is H, NH2CnH2n+1when n is 1-4, with a molar ratio of amide carboxylic acid and thiamine-Mononitrate from 0.5:1 to 2:1.

 

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FIELD: organic chemistry, medicine, pharmacy.

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15 cl, 8 tbl, 1 dwg

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

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EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: medicine; pharmacology.

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46 cl, 1 tbl, 233 ex

FIELD: chemistry.

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EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine, pharmaceutics.

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25 cl, 126 ex, 5 tbl

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EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.

EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

18 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.

EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.

20 cl, 42 ex, 8 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidate of general formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, having properties of nucleoside inihibitors of RNA polymerase NS5B of the hepatitis C virus. The invention also relates to a method of producing compounds, pharmaceutical compositions and a medicinal agent based on said compounds. In general formula 1 , R1 is hydrogen, (CH3)2[(CH3)3C]Si, C2-C6acyl, optionally substituted with a benzyloxy group, NR5R6 group, wherein R5 and R6 are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl; R2 and R3 are F or R2 is F or OH and R3 is CH3; R4 is hydrogen or methyl; Ar is phenyl, pyridyl or naphthyl, where the phenyl, pyridyl or naphthyl is optionally substituted with at least one of C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2; Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4-(4-amino-2-oxo-2H-pyrimidin-1-yl), wherein the amino group is optionally substituted with 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C(O)R8 radical, where R8 is C1-C4alkyl, optionally substituted with a NR6R7 group, where R6 and R7 are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted with a phenyl; X is O or N-R9, where R9 is C1-C4alkyl, optionally substituted with OH or OCH3; n=1, 2 or 3.

EFFECT: compounds can be used to prevent and treat viral infections, including hepatitis C.

12 cl, 1 tbl, 11 ex

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