The method of obtaining 5-aryl-2-hydroxy-2- (triphenylphosphonium) -methoxycarbonylmethyl - 2,3-dihydro - 3-furanones

 

(57) Abstract:

Usage: in medicine as drugs with antimicrobial action. The inventive product 2-hydroxy-2- (triphenylphosphonio) methoxycarbonylmethyl-5-phenyl - 2,3-dihydro-3-furanone f-ly BF C31H25O5P, yield 83% , so different. 124 - 125, 2-hydroxy-2-(triphenylphosphonio) methoxycarbonylmethyl-5-n-chlorophenyl - 2,3-dihydro-3-furanone f-ly BF C31H24ClO5P, yield 91% , so pl. 163 - 164 ° C.. Reagent 1: where R is H, Cl. Reagent 2: (C6H5)3P=CHCOOCH3. Reaction conditions: inert organic solvent at room temperature.

The invention relates to organic chemistry, to the class of heterocyclic compounds - drive dihydrofuran with one carbonyl group in the cycle and the phosphorus-containing fragment in the side chain, namely to a new way to obtain previously unknown connections - 5-aryl-2-hydroxy-2-(triphenylphosphonio)methoxycarbonylmethyl-2,3-dihydr-3-formulaHBrwhich can find application in medicine as drugs with antimicrobial action.

A method of obtaining 2-hydroxy-2-phenacyl-5-phenyl-2,3-dihydro-3-furanoside decomposition of the resulting disodium derivative of compound III 5% aqueous solution of sulfuric acid [1] . The target compound is obtained with a yield of 2.5% , is very unstable and when standing, as well as at heating and recrystallization quickly becomes acyclic form III [1] .

A method of obtaining 5-aryl-2-hydroxy-2-methoxycarbonylmethyl-2,3-dihydro-3-furanones, which consists in the fact that the 5-aryl-2-methoxycarbonylmethylene-2,3-dihydro-3-furanones is subjected to heating with hydrochloric acid in the medium of acetone at a temperature of 45-50about[2] .

Also known is a method of obtaining 1-triphenylphosphorane-4-aryl-5-carbethoxy-4-cyclopenten-2,3-diones, which consists in the fact that the 5-aryl-2,3-dihydro-2,3-furandione are heated with exalenteverything in the environment of benzene [3] . This method is similar taken as a prototype.

The disadvantages of these methods-analogues, including the method of the prototype are:

inability to obtain 2-hydroxy-2(triphenylphosphorane)alkoxycarbonylmethyl-2,3-dihydro-3-wagon howtek as a source of phosphorus-containing carbonyl compounds is unknown and cannot be obtained by known methods;

the necessity of heating the reaction mixture;

not a high yield of the target compounds.

The aim of the invention is okim yield 5-aryl-2-hydroxy-2-(triphenylphosphonio)methoxycarbonylmethyl-2,3-dihydr-3-formula 1. Expected from the use of the invention, the positive effect is that underlying the invention, the method of synthesis of the target compounds is preparative and can be widely used in laboratory and industrial conditions of synthesis of biologically active substances, including drugs with the anti - OMICRON action.

This goal is achieved by the fact that 5-aryl-2,3-dihydro-2,3-furandione subjected to interaction with meloxicam - belmetrospetsstroi in an inert organic solvent at room temperature according to the following scheme + (C6H5)3P = CHCOOCH3and produce target products by the known methods.

The compounds are colorless crystalline substances, soluble in ethanol, chloroform, acetone, dimethylsulfoxide, difficultly soluble in benzene, ether and insoluble in water and hexane.

This reaction underlying the proposed method is unexpected because it is known that carbonyl compounds react with phosphorane with the formation of reaction products by Wittig - olefins and phosphine oxide [4] .

P R I m e R 1. 2-Hydroxy-2-(triveneto-2,3-furandione in 50 ml of benzene at room temperature, add with stirring a solution to 1.67 g (0,005 mol) of methoxycarbonylmethylene in 100 ml of benzene, after one hour the precipitate is filtered off and recrystallized from benzene. Get 2,10 g (83% ) of crystalline compound 1A with so different. 124-125aboutC.

Found, % : C 73,01; N 5,23; P 6,27;

WITH31H25O5P M 508,53.

Calculated, % : C 73,22; N 4,96; P 6,09.

IR spectrum , cm-1, CHCl: 1700 (C3= O), 1660, 1600 (P--C--C--O). Range AMRN, 300 MHz , M. D. , CDCl3: 3,17 with at 3.25 (3H, OCH3), 4,35 (1H, OH), 6,30 (1H, SN), of 7.35-7.85 m (H 2O, 4C6H5).

An NMR spectrum13S, 300 MHz , M. D. , J, Hz, CDCl3: 49,85 with, 49,95 (OCH3), to 49.9 d, J 4 (P= SS), 66,7 d, Jcf111, 67,9 d, Jcf111 (P= C), 123,3 d, Jcf94, 125,3 d, Jcf94 [PC(C6H5)] , 128,68, 128,84, 129,06, 129,32, 133,85, 133,97, 134,06, 134,17 (WITH6H5), 137,38, 137,44 (C6H5), 131, 5mm, 132,9 C (C= CH), 168,16, 168,43 C (C= CH), 189,69 d, Jcf4,8, 191 d, Jcf4,8 (C= O), 195,6 d, Jcf11,5, 197,2 d, Jcf11,5 (C= O).

An NMR spectrum31R, 300 MHz,p, M. D. , l3: 15,5, 16,9 C.

When carrying out the reaction with the same quantities of reagents, but:

P R I m m e R 2. When used as a solvent of toluene, the yield of the desired product 1A is 88% .

P R I m e R 3. When using as solvent chloroform - yield 1A, were(1B).

To a solution of 1.04 g (0,005 mol) 5-p-chlorophenyl-2,3-dihydro-2,3-furandione in 100 ml of benzene at room temperature, add with stirring a solution to 1.67 g (0,005 mol) of methoxycarbonylmethylene in 100 ml of benzene, after one hour the precipitate is filtered off and recrystallized from benzene. Obtain 2.15 g (79% ) of crystalline compound 1B with so different. 125-126aboutC.

Found, % : C 68,42; N 4,63; Cl 6,37; P 5,58.

WITH31H24ClO5P.M 542,98.

Calculated, % : C 68,58; N 4,46; Cl 6,53; P 5,70.

P R I m e R 5. If the reaction 0.87 g (0,005 mol) of 5-phenyl-2,3-dihydro-2,3-furandione from 1.67 g (0,005 mol) of methoxycarbonylmethylene in 100 ml of benzene at a temperature of 80aboutC for 5 minutes produces 2-methoxycarbonylmethyl-5-phenyl-2,3-dihydro-3-furanone with the release of 1.05 g (91% ), so pl. 163-164aboutC.

IR spectrum , cm-1(the crystals): 1670 (C3= O), 1550-1590 (P--C--C--O).

An NMR spectrum1H, 60 MHz , M. D. , CDCl3: 3,12, 3,20 (3H, OCH3). 4,30 s (1H, OH), 6,18 (1H, C4H), 7,25-7,70 m (19 H 3C6H5WITH6H4).

The structure of the target compounds proved by IR and NMR spectra. In NMR spectra1N has the signal of the proton of the hydroxyl group at 4,30-4,35 m is t in favor of the proposed for these compounds structure. Using NMR spectra13With shot using the technique of the ART (Attached Proton Test) found that when the carbon atom in the fragment P= C there are no protons, and this suggests that the compounds may not have the structure of betaines or phosphonium salts. All signals in NMR spectra doubled, which indicates the existence of two stable colormenu due to slow rotation around the C-C.

The practical significance of the target compounds is their protocolectomy activity. Thus, compound 1B has a strong bacteriostatic activity against reference strains of Staphylococcus aureus (gram-positive bacteria) and Escherichia coli (gramotritsatelnymi bacteria), resulting in stunted growth of these bacterial cultures with a minimum inhibitory concentration (MIC) of 500 substances and, respectively, 250 μg/ml of Compound 1A actively when MICK 500 µg/ml.

The inventive method of obtaining 5-aryl-2-hydroxy-2-(triphenyl-phosphoramidite)methoxycarbonylmethyl-2,3-dihydr-3-formula 1A, b in comparison with the prototype has the following advantages.

The inventive method is simple in implementation does not require heating of the reaction mixture; target products 1A, b on yet the possibility of obtaining a wide range of previously unknown 5-aryl-2-hydroxy-2-(triphenylphosphonio)methoxycarbonylmethyl-2,3-dihydr-3-kotorye cannot be obtained by known methods.

Thus, the method of obtaining 5-aryl-2-hydroxy-2-(triphenylphosphonio)methoxycarbonylmethyl-2,3-dihydr-3-flojet find application both in laboratory and industrial conditions of synthesis of biologically active substances. (56) Poje, M. , Balenovic K. // J. Heterocycl. Chem. 1979. Vol. 16. # 4. R. 417-420.

USSR author's certificate N 1606510, class C 07 D 307/56, 1989.

USSR author's certificate N 960185, class C 07 D 9/50, 1981.

Barton D. , Ollis U. D. General organic chemistry. M. : Chemistry, 1983. So 4. S. 173.

The METHOD of OBTAINING 5-ARYL-2-HYDROXY-2-(TRIPHENYLPHOSPHONIUM)-METHOXYCARBONYLMETHYL-2,3-DIHYD O-3-a General formula

/

where R is H or Cl,

namely, that 5-aryl-2,3-dihydro-2,3-furandione subjected to interaction with methoxycarbonylmethylene in an inert organic solvent at room temperature.

 

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FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing chlorophosphoranimines of general formula R2(Cl)P=NSiR′3 and can be used in chemical industry. Method of producing chlorophosphoranimines general formula R2(Cl)P=NSiR′3 comprises reacting chlorophosphorane of general formula R2PCl3, where R is a chloro, alkyl, aryl, alkoxy or aryloxy group, with silazane and is characterised by that starting silazane used is hexaalkyl disilazane of general formula HN(SiR′3)2, dissolved in a chlorohydrocarbon, chlorophosphorane is added in crystalline form, synthesis is carried out at a temperature of -60 to 0 °C with a gradual raise, and hexaalkyl disilazane is used in an amount of 1 to 1.33 mol per 1 mol chlorophosphorane.

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FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

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2 tbl, 1 ex

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

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. 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Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

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

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

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: 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: 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.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

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