UA61987C2 - Aromatic amides, a method for preparing the same and application thereof as medicaments - Google Patents

Abstract

balanTarasThe invention concerns compounds of formula (I), in which X is oxygen, N-Nalc1 or NOalc2; X represents hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, CONOR or NRcRd, Rc and Rd being hydrogen or alkyl; Z represents hydrogen, halogen orfree, etherified or esterified OH; R2 hydrogen or halogen; R3 hydrogen, alkyl or halogen; R hydrogen or alkyl; R1 hydrogen, alkyl, alkenyl or alkynyl; R5 hydrogen or O-alkyl; R2 alkyl or CH2-O-alkyl and R7 hydrogen or alkyl; or R6 and R7 form with the carbon atom which bears them a cyclic radical containing up to 8 carbon atoms. The compounds of formula (I) have antibiotic properties. (I)

Description

Description of the invention

This invention relates to new aromatic amides, the method of their production and their use as medicinal products.

The object of this invention are compounds of formula (1): () 70 E 2 bu o FI 15 . in o o

Kk and d. ! "with

Me u ach -

Di 0 which in/o MY in which: He - M means an oxygen atom or a radical M-Malki or MOalk»o in which alk/; and alko mean an alkyl radical containing up to 12 carbon atoms, optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, optionally substituted by one or several halogen atoms, an aryl radical (optionally substituted by one or several halogen atoms), heterocyclic a radical, one or several radicals -

Ka so t F b i "- (Se) in which Ka and KB are the same or different mean a hydrogen atom, an alkyl radical containing up to 8 carbon atoms is substituted, if necessary, or Ka and KO are formed together with a nitrogen atom with which they conjugated, a heterocycle, which may also contain another heteroatom selected from oxygen, sulfur or nitrogen, « - X means a hydrogen atom, a hydroxyl radical, an alkyl, alkenyl or alkynyl radical, if necessary 470 interrupted by one or more oxygen, sulfur or nitrogen atoms. Linear, branched or cyclic containing up to 12 carbon atoms, if necessary substituted by one or more halogen atoms, "with a heterocyclic radical, one or more OH radicals, free or etherified by the C-M group, "MO" group

Ф m - Tv in which Ka and KB, the same or different, mean a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, (ee) or Ka and KB together with the nitrogen atom to which they are connected will form a heterocycle, containing, if necessary, another heteroatom selected from nitrogen, sulfur or oxygen, or X means an alkoxy radical or a radical: d) in which Ke means an alkyl radical containing up to 8 carbon atoms, optionally substituted by

GF! -C-MOKe, replaced by one or more of the above-mentioned substituents, or X means the radical MKskKa, in which Ke and Ka are the same or different, means a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, optionally substituted by one or more of the specified above 60 deputies; or Ke and Ka together with the nitrogen atom combined with them will form a heterocycle containing, if necessary, another heteroatom selected from nitrogen, sulfur or oxygen, - 7 means a hydrogen or halogen atom or an OH group, free or transformed into a simple or complex ether, - K" means a hydrogen or halogen atom, - Kz means a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom, because - K means a hydrogen atom or an alkyl radical containing up to 4 carbon atoms,

- Ku means a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, a radical

С- M; an aryl radical containing up to 14 carbon atoms, - K5 means a hydrogen atom, an O-alkyl radical containing up to 4 carbon atoms, - or K5 means an alkyl radical or CH»-O-alkyl, in which alkyl means an alkyl radical that contains up to 8 carbon atoms, - K7 means a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, - or P; and K7, together with the carbon atom to which they are connected, will form a ring containing up to 8 carbon atoms, 70 as well as salts of the compound of formula (I), when the compound of formula (I) has a basic function.

Examples of salts include salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, paratoluenesulfonic, hydrochloric, hydrogen bromide, hydrogen iodide, sulfuric, phosphoric acid, as well as with stearic, ethylsuccinic or laurylsulfonic acid.

In the definition of substituents: - an alkyl, alkenyl or alkynyl radical preferably means a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical, - halogen preferably means a fluorine or chlorine or bromine atom, - an aryl radical preferably means a phenyl radical, - a heterocyclic radical preferably means a pyrroryl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl radical , benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl.

More specifically, the object of the invention is compounds of the formula (I), in which M is an oxygen atom, compounds in which U is a MO-alkyl radical, in which the alkyl radical contains up to 4 carbon atoms, for example, compounds in which U is He ! means the radical МОС»оНб. at

Among the preferred compounds of the invention, it is possible to name the compounds of the formula (I), in which X is an alkyl radical containing up to 4 carbon atoms, in particular, the CH3 radical, or compounds in which X is the MH radical, or compounds in which Х means the radical ча и ге г) - МН(СНою M и Ф

And -

Among the preferred compounds according to the invention, compounds of the formula (I) can be named, in which Ku means a radical: (Ce) ns c-cH, - compounds in which K means a hydrogen atom, or compounds in which Kz means a methyl radical, or compounds in which « 7 means a hydrogen atom, or compounds in which Ko means a hydrogen atom, or compounds in which K5 means a radical

Osn", or compounds in which K 5 means the methyl radical, or compounds in which K; means the methyl radical, - with compounds in which K is 7; means ethyl radical, compounds in which Ki KK; together with the carbon atom with which they are combined will form a cyclopentyl radical. ," Among the preferred compounds can be named the compounds, the preparation of which is described below in

Compounds of the general formula (I) have high antibiotic activity against gram bacteria, such as staphylococci, streptococci, pneumococci, enterococci, listeria, anaerobic bacteria. (o) The compounds according to the invention can be used as drugs in the treatment of drug-sensitive infections, and in particular in the treatment of staphylococcal infections, such as staphylococcal sepsis, malignant staphylococcal diseases of the face and skin, pyoderma, septic or purulent ulcers, boils, carbuncles , (Se) phlegmons, erysipelas and acne, in the treatment of staphylococcal infections such as acute simple tonsillitis or post-influenza tonsillitis, bronchopneumonia, lung suppurations, in the treatment of streptococcal infections such as acute tonsillitis, otitis, sinusitis, scarlet fever, pneumococcal inflammations, such as pneumonia, bronchitis and diphtheria. that the compounds of this invention are also active against infections caused by Naethorpiyiasis ipichepae.

Thus, the object of this invention is compounds of formula (I) as medicinal products.

More specifically, the compounds listed above as preferred can be used as drugs.

The object of this invention is also Pharmaceutical compositions containing as an active basis at least one of the aforementioned medicinal products. o These compositions can be administered orally, rectally, parenterally, or topically applied to the skin and mucous membranes, but the preferred route of administration is through the mouth or by injection. 60 They can be solid or liquid and represent the usual pharmaceutical forms used in medicine, for example, simple or coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; these pharmaceutical forms are prepared according to conventional preparation methods. The active base can be introduced into these pharmaceutical compositions together with one or more excipients traditionally used in pharmaceutical compositions. Excipients can be 65 talc. gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fatty substances of vegetable or animal origin, paraffin derivatives, glycols, various wetting agents, dispersants,

emulsifiers, preservatives.

These compositions can also be in the form of a powder intended for dissolution before use in a suitable carrier, for example, in pyrogen-free sterile water.

The administered dose varies depending on the specific disease, the patient, the method of administration and the medicinal product itself. It can be, for example, from 500mg to 300mg of the preferred compounds per day for oral administration or as an injection for an adult.

The object of this invention is also a method of obtaining compounds of formula (I), which consists in the fact that compounds of formula (II) 70 (1) 7 on c) with 2 h-x di

И и 7 b To, о х / З no Оу in which the radicals K», Kz, 7, Kb, Ke and Ku have the above value, OMU means a blocked hydroxyl group, and M/ means an alkyl or O-alkyl radical, containing up to 4 carbon atoms, is subjected - to the influence of an agent capable of introducing the radical o 0- M-OK, (ee) or a number of operations capable of introducing the radical (o) o into -

І І ов (Се) and K and Ку have the above value, - the effect of an agent capable of liberating a hydroxyl radical from an OMU radical, " 20 - a possible effect of an agent capable of replacing Mu with a X radical, which differs from alkyl or O-alkyl, ш-в с - the possible effect of an agent capable of introducing the radical В, which is different from oxygen, - the possible effect of a salt-forming agent. The compounds of formula (I) used as starting materials in the method according to the invention are new compounds, the preparation of some compounds of formula (II) is described below in the experimental part.

Other compounds of formula (III) can be synthesized similarly to the methods described in the experimental part b.

More specifically, the invention relates to compounds of formula (II), the preparation of which is described in the experimental part. со The preferred version of the invention consists in the fact that the introduction of the radical о Кк (ее) е и. І and ов b- 4 are carried out in several stages, first they act with phenyl chloroformate, substituted or substituted, then 25 are affected by a compound of the formula K.:ОНК, in which K. and К have the above value, the OH group is blocked in the form

HF) of tetrahydrofuran, the release of the hydroxyl group is carried out by acid hydrolysis, for example, by exposure to paratoluenesulfonic acid, the possible conversion of the MU radical into the X radical and the conversion of the Y radical is carried out according to classical methods. The transformation of the В radical is carried out, in particular, under the influence of an amine. 60 The object of this invention is also a method, which consists in the fact that the compounds of the formula (II) are obtained by exposure to the compound of the formula (II): b5

(PP) in which K5, Kz and Ku have the above value, to the compound of the formula (IM): and

Sq

Nv, oh! он с нн он мМ 2: он "7 тв В ХУ no о о; still yk! in which Ko, Kz and 7 have the above value, then by exposure to an agent that blocks the free hydroxyl radical.

The following compounds of formula (II) are new compounds and are themselves the object of this invention, namely: o

Meo tn MeO N y x t- it-'

BUT y" o BUT te o so that E F . eat 7 now, - chi: no he i he no Ge) yu MeO v z s o N i M 4 sh 7 no o he Tsya vi a" i,

F b, t E no on - - no on

The following non-limiting examples illustrate the present invention. ik Preparation 1:

Go! 20 ethyl-7-((b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-i-lyxo-hexopyranosyl|oxy)- 4-hydro oxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylate "m STAGE: A ethyl-7-(b-deoxy-5-C-methyl-4-O-methyl-alpha- and -lixo-hexopyranosyl)oxy|-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyran-3Z-carboxylate 59 Stir in an argon atmosphere the solution containing 80g

HF) ethyl 7-hydroxy-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyran-3-carboxylate in 1200 ml of methylene chloride. At a temperature of 0"C, add 52.07g of 5-deoxy-5-C-methyl-4-O-methyl-i-lixo-hexopyranose and 71.22g of triphenylphosphine. At a temperature of 0"C, add 54.7.8ml of diisopropylazocarboxylate. An hour after the start of the reaction at room temperature, 34 g of triphenylphosphine and 25.6 ml of diisopropylazocarboxylate are again added. Stir for 16 hours at room temperature. Half is evaporated, the suspension is filtered, eluting with a mixture of toluene/isopropyl alcohol (95-5). When the product begins to pass, continue elution with a mixture containing isopropyl alcohol. After thickening in 70 Oml of the hexane/ethyl acetate mixture (4-1), 64.4 g of the target product is obtained, which is used in the next stage.

STAGE B: because ethyl-(b-deoxy-5-C-methyl-4-O-methyl-3-O-(triethylsilyl)-alpha-!-lixo-hexopyranosyl)oxy|-8-methyl-2-oxo- 4-(

phenylmethoxy)-2H-1-benzopyran-3-carboxylate

Stir in an argon atmosphere at room temperature 50g of a solution of the product obtained at stage A in 50Oml of methylene chloride. Add 42 ml of diisopropylethylamine and 9.66 mg of imidazole. The solution is stirred for 15

MINUTES or cooled to 0"C, and then 20.6b4ml of triethylchlorosilane are added dropwise over 30 minutes and stirred for 2 hours at 0"C. The reaction mixture is poured into a molar solution of primary sodium phosphate. Extract methylene chloride. Dry and evaporate to dryness.

66.27 g of the product is obtained, which is purified on silicon dioxide, eluting with a mixture of methylene chloride and 0.7590 acetone. When the product is practically isolated, elute with a methylene chloride solution containing 195 g of acetone. After /o thickening in a mixture of hexane/ethyl acetate (9-1), 41.04 g of the target product are obtained.

NMR 1H (300 MHz, SOSI", ppm) 0.73 (k, 6H), 1.04 (t, 9H), 1.04 (s, ЗН) 1.30 (s, ЗН), 1, 40 (t, ZN), 2.24 (s, ZN), 2.74 (d, 9-1 Hz, 1IN movement), 3.28 (d, 1H, 9-9), 3.53 (s ) d, 1H, 9-2 Hz), 7.12 (d, 1H, 1-9 Gu), 7.43 (m, 5H), 7.63 (d, 1H, 9-9 Hz).

STAGE C: ethyl-7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-3-O-(triethylsilyl)-alpha- !-lyxo-hexopyranosyl|oxy|-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyran-3-carboxylate

A solution containing 40.9 g of the product obtained at the previous stage in 400 ml of methylene chloride is stirred in an argon atmosphere at room temperature. Add a few drops of paratoluenesulfonic acid, then 11.54 ml of dihydrofuran.

Stir for 2 hours at room temperature. Add BG of sodium bicarbonate. The suspension is stirred for 15 minutes. It is diluted in 1000 ml of a mixture of hexane/ethyl acetate (2-1) and poured into water.

Decant, dry the organic phase over sodium sulfate and evaporate to dryness. 54.67 g of the product is obtained, which is purified by eluting with a mixture of hexane/ethyl acetate (4-1). In this way, 36.83 g of product are obtained. high school

STAGE 0: ethyl-7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-3-O-(triethylsilyl)-alpha- l-lyxo-hexopyr i) anosyl|oxy)|-4-hydroxy-8-methyl-2-oxo-2H-1-enzopyran-3-carboxylate

Hydrogenate 18 g of the product obtained at the previous stage, dissolved in ZbOml of tetrahydrofuran, in the presence of 0.240 g of palladium on charcoal. They filter. The catalyst is washed with a small amount of tetrahydrofuran. Evaporate 100 ml of the solvent and obtain a solution that is used in the next stage. co

STAGE E: b ethyl-7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-Y-lixo-hexopyranosyloxy |- 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylate --

A solution containing 15.31 g of the product obtained at the previous stage in 250 ml of tetrahydrofuran is cooled in an argon atmosphere at 0 °C. Add 1 ml of tetrabutylammonium fluoride (1 M in THF) dropwise. The reaction medium is diluted with 400 ml of a mixture of hexane/ (ethyl acetate (1-2). Add ZbOml of a 1095-th solution of secondary sodium sulfate and decant. Dry and evaporate to dryness. Dissolve the crude product obtained in 2Oml of ethyl ether, cool to -10"C and add with stirring 800ml of pentane. « Stir the obtained suspension at -207 C, filtered at -167 C. The product obtained is washed with pentanom splu) and dried. 9.4 g of the target product are obtained.

Preparation 2: ; » 3-Acetyl-7-(b-deoxy-5-C-methyl-4-O-methid-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-!-lyxo-hexopyranosyl|oxy | -4- hydroxy-8-methyl-2H-1-benzopyran-2-one

Stage A: 4-(diphenylmethoxy)-8-methyl-7-(tetrahydro-2H-pyran-2-yl)-2H-1-benzopyran-2-one

Add 55 g of 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yl)-2H-1-benzopyran-2-one to 25 Oml of anhydrous dimethylformamide heated to 407°C and add the solution dropwise from 58.3 g of diphenyldiazomethane in 25 Oml of dimethylformamide. The addition is carried out over 3 hours at a temperature of 40"C.

Ge) Add several portions of 3g of diphenyldiazomethane again and stir for an hour at 40"C.

The reaction medium is poured into 2 liters of ethyl ether. The organic solution is washed with an aqueous solution of sodium bicarbonate, a solution of caustic soda (0.1 M), water and brine. Evaporate to dryness. The residue is mixed with "M" in a mixture of isopropyl ether/hexane (1-2). The undissolved product is squeezed and dried. 20.5 g of the target product is obtained.

Thin-layer chromatography SNCI»-AsOBi (95-5). K, - 0.44.

STAGE B: 4-(diphenylmethoxy)-7-hydroxy-8-methyl-2H-1-benzopyran-2-one

Add 35 ml of a 0.9 molar solution of hydrochloric acid in methanol to a solution containing a mixture of 20 g of the product,

F) obtained in stage A, 100 ml of dichloromethane and 100 ml of methanol. Stir for 2 hours at room temperature and evaporate the solvents. The residue is processed in absolute ethanol cooled to 0"C.

The undissolved product is squeezed out, washed with ice-cold alcohol, then with ethyl ether. It is dried and 15.53 g of the product is obtained, which is treated with simple ether, squeezed and dried. 14.54 g of the target product are obtained.

NMR 1H (300 MHz, SOSI»z, ppm) 2.31 (s, ЗН), 5.62 (s, 1H), 6.35 (s, 1H), 6.78 (d, 1H, u - Hz), 7.75 (d, 1H, 9U- Hz), 6.99-7.10 (m, H), 7.30-7.42 (m, H).

STAGE C: 65 7-(6b-deoxy-5-C-methyl-4-O-methyl-alpha-Y-lixo-hexopyranosyl|oxy|-4-(diphenylmethoxy)-8-methyl-2H-1-benzopyran -2-on

Cool the mixture to C! 91.13g of the product obtained in stage B, 58.6g of b-deoxy-5-C-methyl-4-O-methyl-1-lyxo-hexopyranosyl and 80g of triphenylphosphine in 90O0ml of dichloromethane. Add bOml of diisopropylazodicarboxylate drop by drop. Stir for an hour at room temperature.

Add 34g of triphenylphosphine and 25ml of diisopropylazodicarboxylate. Stir for 1 hour at room temperature. Add 34g of triphenylphosphine and 25ml of diisopropylazodicarboxylate and stir for 12 hours at room temperature. Concentrate under reduced pressure. Chromatograph by elution with a mixture of toluene/isopropyl alcohol (95-5). After combining the fractions and evaporating the solvents, after recrystallization in isopropyl ether, 86.83 g of the target product are obtained. 70 NMR 1H (300 MHz, SOSI», ppm) 1.13 (s, ZN), 1.37 (s, ZN), 2.24 (s, ZN), 2.69 (s, 1H), 2.79 (s, 1H), 3.38 (d, 1H, 9-10 Hz), 3.60 (s,

ЗН), 4.24 (m, 1Н), 4.28 (m, 71Н), 5.56 (s, 1Н), 5.64 (d, 1Н, 9-1.5 Hz), 6.35 ( s, 1H), 7.18 (d, 71H), 7.81 (d, 1H), 7.39 (m, TON).

STAGE 0: 75. 7-Ib-deoxy-5-C-methyl-4-O-methyl-3-O-(triethylsilyl)-alpha-i -lyxo-hexopyranosyl|oxy)-4-(diphenylmethoxy)-8- methyl-2H-1-benzopyran-2-one.

Add 26.6 g of imidazole and 70.15 ml of diisopropylethylamine to a solution cooled to 0"C containing 80 g of the product obtained at the previous stage and 100 ml of dichloromethane. Add 33.5 ml of triethylsilyl chloride dropwise. Stir for 1 hour at room temperature. Wash with 1M aqueous 2. With primary sodium phosphate, water and brine. Dry over magnesium sulfate, filter and concentrate. Obtain 97.58 g of product, which is purified by chromatography on silicon dioxide, eluting with a mixture of dichloromethane/acetone (from 0.8 to 195). Obtain 46.5 g product

NMR 1H (300 MHz, SOSIz-dv ppm) 5 0.60 (k, 9-8 Hz, 2H), 0.74 (k, 9-8 Hz, 4H), 0.98 (t, 9U- 8 Hz, ЗН), 1.05 (t, 9-8 Hz, 6Н), 1.10 (s, ЗН), s 285 1.32 (s, ЗН), 2.24 (s, 2Н), 2 ... ; 32 HC, 1), 4.28 (dd, IN, 2-9.55 Z Gu, 1), 5.64 (d, 3-2 HC, 1H), 5.56 (s, 1H), 6 .35 (s, 1H), 7.19 (d, 1H, i) 3-9 Hu), 7.82 (d, 9-9 Hz, 1H), 7.29-7.42 (m, 1OH) .

STAGE E: 7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-3-O-(triethylselyl)-alpha-!- Lixo-hexopyranose M zo-lioxy|-4--diphenylmethoxy)-8-methyl-2H-1-benzopyran-2-one.

Add 19Uml of dihydropyran and 400mg of paratoluenesulfonic acid (ART5) to a solution containing 7g of the product obtained at the previous stage and 1 liter of dichloromethane. Stir for 40 minutes at Ge! room temperature and add 30 mg of paratoluenesulfonic acid. After 30 minutes of stirring, add 100 mg of paratoluenesulfonic acid, then another 100 mg of the same acid. Stir again 20.7

Wait for MINUTES, then inject crushed secondary sodium carbonate. Stir for 10 minutes, dilute the reaction mixture with a mixture of hexane/ethyl acetate (1-2), wash with water and brine. Drying Filter and evaporate the solvents. The obtained product is chromatographed, eluting with a mixture of heptane/ethyl acetate (4-1).

77.9 g of the target product are obtained.

NMR 1H (300 MHz, OM50O-dv, ppm) Mixture of 65/35 isomers « 5 0.64 (u) and 0.73 (u (9-8 Hu, 6H), 0.98 (t) and 1 .05(t)-(9-8 Hu, 9H); 2.25 (s) and 2.27 (s) (ZH); 3.30 (d, 9-7.5 Hz), and 3.41 in s (d, U -10 HZ), (1); 3.53 (s, width) and 3.54 (s width, ZN); 3.88 (m) 3.92 (m) 3.96 (m) 3.99 (m) (1H); 3.59 (m, and 1H); 4.92 (m) and 4.96 (m) (1H); 5.56 (with width, 1H); 5.55 (shielded) and 5.66 (d, 9-2 Hz) (1); 4.07 (dd, 9-2 Hz "» and 3 Hz) and 4.14 (dd, 9-3 Hz and 7.5 Hz) (18); 6.36 (s wide, 1H); 7.15 (d) and 7.19 (d) (9-9 Hu, 11H); 7.80 (d, split 4-9 Hz, 1H), 1.48 -1.97 (m, 8H); 1H (s) and 1.17 (s) 1.32 (s) and 1.43 (s) (6H); 7.30-7, 44 (m, 1OH).

STAGE B:

Gee! 7-(ob-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-3-O-(trimethylselyl)-alpha-!-lyxo-hexopyranose ilyoxy1|-4-hydroxy-8-methyl-2H-1-benzopyran-2-one - Hydrogenate in the presence of palladium on charcoal (2g, 1095), 15g of the product obtained in the previous stage, in

Te) 150 ml of absolute ethanol. Remove the catalyst by filtration and evaporate the solvents to dryness.

14.4 g of product is obtained. so STAGE C: "I 3-acetyl-7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-3-O-( triethylsylyl)-alpha-Yi-lixo-hexopyranosyl|oxy)|-4-hydroxy-8-methyl-2H-1-benzopyran-2-one.

Add 150ml of dichloromethane, 5B 6.52g of dimethylaminopyridine to the solution containing 14.37g of the product obtained at the previous stage. Inject 2.72 ml of acetic anhydride drop by drop. Stir at room temperature in an argon atmosphere for 1 hour. Dilute in 200 ml of dichloromethane, wash with an aqueous solution of primary sodium phosphate. dry over magnesium sulfate, filter and concentrate. They receive 14.9 target products.

STAGE H: in 3-acetyl-7-((b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-!-lyxo- hexopyranosyl|oxy|-4-hydroxy-8-methyl-2H.-1-benzopyran-2-one

27 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran is introduced dropwise at 07"C into a solution containing 15.2 ml of the product obtained at the previous stage in 250 ml of tetrahydrofuran. Stir in an argon atmosphere for 48 hours at room temperature. Dilute the reaction medium with a mixture of 65% ethyl acetate/hexane, washed with water and brine. Dried, filtered and concentrated to dryness. 13 g of the product is obtained, which is ground to a powdery state with pentane, the part that has floated is removed and the process is repeated several times. washed and dried. They get 6.99g of the target product.

NMR 1H (300 MHz, SOSIz-dv, ppm) 1.09 (s, ZN), 1.11 (s, ZN), 1.35 (s, ZN), 1.36 (s, 1H), 1.50 to 1.90 (m, 8), 2.23 (s, ЗН), 2.24 (s, ЗН), 2.16 (s, ЗН), 3.28 (d, 1Н, 9- Hzsh), 3.33 (d, 1H, 9U- Hz), 3.63 (s, ЗН), 3.64 (s, ЗН), 3.54 (m), 3.97 (m), 4, 07 (m), 4.20-4.30 ( , 2H), 4.59 (m, H), 4.82 (m, H), 5.63 (s width, H), 5.85 (s width, H), 7.20 (d, 1H, - Gu), 7.88 (m, H).

EXAMPLE 1: 7-(b-deoxy-5-C-methyl-4-O-methyl-alpha-i-lyxo-hexopyranosyl|oxy|-4-hyproxy-8-methyl-2-oxo-2H-1-benzopyra 70 n-3-carboxamide, 3'-ester (2-propynyloxy)-carbamic acid

STAGE A: 3-(4-nitrophenylcarbonate) ethyl-7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-

Y -lixo-hexopyranosyl|oxy |-4-hydroxy-8. -methyl-2-oxo-2H-1-benzopyran-3-carboxylate

In an argon atmosphere, dissolve 4 g of the product obtained in 1 in 80 mL of methylene chloride. Add 2.15 g/5 dimethylamine pyridine and 2 g of 4-nitrophenyl chloroformate at 07C. Stir for 71 hours at 0"7C.

Methylene chloride is evaporated and the target product is obtained.

STAGE B: ethyl-7-(b-deoxy-5-C-methyl-4-O-methyl-3-O-|(2-propynyloxy)amino|carbonyl|-2-O-(tetrahydro-2H-pyran- 2-yl)-alpha α-I-lyxo-hexopyranosyl|oxy|-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylate

Dissolve 1.215 g of O-propargylhydroxylamine chlorhydrate in 40 ml of dimethylformamide. At 0"C, add 0.392g of sodium hydrate (5095th oil) and stir for an hour at this temperature. At 0"C, inject 4ml of a solution of the product obtained at the previous stage in dimethylformamide and 940mg of dimethylaminopyridine into this suspension. Stir for 1 hour at 0"C. Dilute with a mixture of hexane/ethyl acetate (1-2).

The organic solution is washed with 400 ml of a 1095 solution of secondary sodium sulfate, dried over sodium sulfate and evaporated to dryness. 7.87m of crude target product is obtained.

STAGE C: o 7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-!-lyxo-hexopyranosyl|oxy |- 4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide?73'-ester (2-propynyloxy)-carboxylic acid.

Dissolve 2g of the product obtained at the previous stage in 5Oml of tetrahydrofuran. The resulting Mzo solution is saturated with ammonium hydroxide at 0"C for 10 minutes and stirred for 48 hours at room temperature.

Dilute with 100 ml of a mixture of hexane/ethyl acetate (1-1). The organic solution is washed with 100 ml of 1 M sodium phosphate solution, then dried over magnesium sulfate and evaporated to dryness. They receive 2 g.YSHH (KdU of the target product.

STAGE 0: -- 7-(b-deoxy-5-C-methyl-4-O-methyl-alpha-i-lyxo-hexopyranosyl|oxy1-4-hydroxy-8-methyl-2-oxo-2H-1- benzopyran o -3-carboxamide, 3'-ester (2-propynyloxy)-carbamic acid.

Dissolve 2 g of the product obtained at the previous stage and 200 mg of paratoluenesulfonic acid in 20 ml of methanol. Stir for one hour. Dilute in 100 ml of a mixture of hexane/ethyl acetate (1-1).

Wash with a saturated solution of primary sodium phosphate, dry. 1.6 g of the product is obtained, which is purified by eluting with a mixture of methylene chloride/methanol 890. It is thickened with a mixture of ethyl ether/pentane. pt) with 0.574 g of the target product are obtained.

1H NMR (300 MHz, OM5O-dv, ppm). and? 1.04 (с, ЗН), 1.26 (с, ЗН), 2.20 (с, ЗН), 3.45, (с, ЗН), 3.52 (d, 1Н), 3.56 ( m, 1H), 4.14 (m, 1H), 4.46 (m, 2H), 5.20 (m, 1H), 5.59 (with width, 1H), 5.77 (d, 1H movement), 7.22 (d, 1Hz), 7.83 (d, 1H), 8.71 (m), 8.96 (m) (2H movement).

EXAMPLE 2:

Ge» 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-! -lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-M-2-(4-morpholinyl)ethyl -2-oxo-2H-1-benzopyran-3-carboxamide, 3'-ester (2-propynyloxy- carbamic acid - STAGE A:

Ge) 7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-!-lyxo-hexopyranosyl|oxy |-4- Hydroxy-8-methyl-M-(2-(4-morpholinyl)ethyl/|-2-oxo-2H-1-benzopyran-3-carboxamide 3-ester of (2-propynyloxy)-carbamic acid. "M Enter 7 .5 ml of 2-(4-morpholino)ethylamine in a solution containing 1 g of the product obtained in stage B of example 1 in 4 ml of tetrahydrofuran. Stir for 24 hours at room temperature. Dilute in 100 ml of hexane/ethyl acetate/tetrahydrofuran (1-4-14) Wash with a saturated solution of primary sodium phosphate, shake over magnesium sulfate and evaporate to dryness. 1 g of the target product is obtained.

STAGE B: 7-IK6-

F) deoxy-5-C-methyl-4-O-methyl-alpha-Y! -lixo-hexopyranosyl)oxy1|-4-hydroxy-8-methyl-N-(2-(4-morpholinyl)ethyl-2-oxa-2H-1-benzopyran-3-carboxamide, 3'-ester (2 -propynyloxy)-carbamic acid

Dissolve 0.97 mol of the product obtained at the previous stage in 1 mL of methanol. Add 10 mg of paratoluenesulfonic acid. Stir for 1 hour at room temperature. Add 80 g of paratoluenesulfonic acid again. Stir for three hours. Dilute in 50 ml of a mixture of hexane/ethyl acetate (1-3). Wash with 75 ml of 1 M solution of primary sodium phosphate, dry over magnesium sulfate and evaporate to dryness. The product is purified by chromatography on silicon dioxide, eluting with a mixture of methylene chloride/methanol (91-93). The obtained product is concentrated with a mixture of ethyl ether/pentane. 65 0.150 g of the target product are obtained.

NMR 1H (300 MHz, OM5O-dv, ppm)

1.03 (s, ZN), 127 (s, ZN), 2.21 (s, ZN), 2.50 (shielded 4H), 2.57 (t, 24), 3.45 (s, ZN) , 3.40-3.69 (m, 4H), 4.13 (m, 1H), 4.47 (d, 2H, 9-2.5 Gsh), 5.20 (dd, 1H, 9-3 And 10 Hz), 5.60 (d, 1H, 9-2 Hz), 5.77 (d, 1H, 9-5 Gu), 7.21 (d, 1H, 9-9 Hz), 7.84 (d, 1H, 9-9 Hz), 9.45 (t, 1H movement), 10.72 (m, 1H movement).

EXAMPLE 3: 7(b-deoxy-5-C-methyl-4-C-methyl-alpha-!-lyxo-hexopyranosyl|oxy|-4-hydroxy-3-11-(methoxymino)ethyl/|-8-methyl l-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)-carbamic acid

STAGE A: 7-Cob-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl-alpha-Y-lyxo-hexopyranosyloxy|-4-hydroxy-3 70 -P-(methoxyimino)dethyl|-8-methyl-2H-1-benzopyran-2-one.

Heat at 40"C in the presence of 0.597g of potassium acetate and 0.407mg of O-methylhydroxylamine chlorhydrate, a solution containing 1.2g of the product obtained in preparation example 2. Stir the reaction mixture for one hour and 30 minutes at 407"C, then dilute it with a mixture of ethyl acetate/hexane (4-1), washed with 150 ml of secondary sodium phosphate solution. Wash with water, dry, filter and evaporate /5 to dryness.

STAGE B: 3-(4-nitrophenylcarbonate)7-(o-deoxy-5-C-methyl-4-O-methyl-2-O-(tetrahydro-2H-pyran-2-yl)-alpha-i-lyxo -hexopyr anosyl|oxy)|-4-hydroxy-3-(1-(methoxyimino)ethyl|-8-methyl-2H-benzopyran-2-one

In a solution containing 1.28 mol of the product of the previous stage and 12 ml of dichloromethane, add 0.390 g of 2o dimethylaminopyridine. Add 0.319 g of 4-nitrophenyl chloroformate. Stir for 30 minutes at

Methyl chloride is evaporated and the resulting product is dried. Thus, 1.218 mol of the target product are obtained.

STAGE C: 7-(b-deoxy-5-C-methyl-4-O-methyl-2-O-(tetra-hydro-2H-pyran-2-yl)alpha-!-lyxo-hexopyranosyl|oxy |- 4-Hyroxy-3-P-(methoxyimino)dethyl|-8-methyl-2H-1-benzpyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid

0.240 g of sodium hydride (in the form of 5595th mineral oil) is added to a solution cooled to 0"C of 0.655 g of O-propargylhydroxylamine chlorhydrate in 1 ml of dimethylformamide. Stir for 30 minutes at 07C and pour into a solution containing 1.218 mol of the product obtained in the previous stage and bml of DMF in the presence of 0.150 g of dimethylaminopyridine. After an hour at 0"C, the reaction mixture is poured into a mixture of ethyl acetate/hexane (2096), washed with a 1075% solution of secondary sodium sulfate, water and brine. Dry and evaporate the solvents to dryness. 0.865 g of the target product is obtained.

STAGE 0: so 7-Cob-deoxy-5-C-methyl-4-O-methyl-alpha-Y! -lixo-hexopyranosilyoxy|-4-hydroxy-3-(1-(methoxyimino)ethyl)|-8-methyl Ge! l-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)-carbamic acid

To a solution containing 1.218 mol of the product obtained in the previous stage and 12 ml of methanol, add 150 mg (87) of paratoluenesulfonic acid. Stir for an hour at room temperature. Dilute with a mixture of ethyl acetate/hexane (1-14) and wash with a 1M aqueous solution of the primary sodium phosphate, then brine. The organic phase is dried over magnesium sulfate. The solvents are evaporated to dryness. The product obtained is chromatographed, eluting with a mixture of dichloromethane/acetone, (85-15) and 0.394 g of product is obtained; which is again dissolved in ether and precipitated with pentane. The product, which has not dissolved is isolated by filtration and stirred under reduced pressure. Thus, 0.380 g of the target product is obtained. from c EXAMPLE 4: 7-Cob-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo -hexopyranosilyoxy |-3-(1-(ethoxyimino)ethyl|-4-hydroxy-8-methyl y»-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid

Work as described above and get the target product.

NMR SOSI", h/mln

Ge» 1.17 (s) -1.38 (s): 2 SNu Set; 1.38 (t): СНЗСнННХО; 1.61 (s): 4rukhl., 2.25 (s) - 2.53 (s): 2СНаЗ-0-; 2.57(t): 9U-2.5 -С С-; 2.64 (with width) ОН -СН ; 3.54 (s): OSNU 3.61 - (d): 9U-9.5 NA geh; 4.23 (ku) SNU-SNO-O small deficit; 4.43 (with width: No eq.; 4.57 (d); 2H OSN-C CH; 5.46

Ge) (dd): U-2.5 19.5 N» oh; 5.61 (d): 9U-2.5 NO ead; 7,12. (d): NO; 7.77 (d): H'5; Nrukhl. 7.78: 14.151 15.11

Absorption along the spectrum. so 2.05 (acetone) 4.13,4.75-4.60-15.67.

I EXAMPLE 5: Hyc-(7 alpha, 8 beta, 9 beta, 10 alpha))|-(2-propynyl-oxy)-carbamate 8-hydroxy-7-14-hydroxy-3-(1-(methoxy-iminoethyl) |-8-methid-2-oxo-2H-1-benzopyran-7-yl|-10-methoxy-6b-oxaspire 9|I4.5)|decan-9-yl 5B Obtaining this compound, as well as obtaining initial compounds used can be schematized as follows:

F) name) 60 b5 vyty iy i

That about leading and Ma in pinna ask ton tlo wife nodrvyut lk and NOT Z r:I am

Руу.5О, with omo

AND

But divan OS

Toshepe

TNE nt, pt cheno Zfrot s y u -5e 6 (5) no, m no so te

R, , F. shk and (se) koi. VA sdya "- s sche ," nya, KRONA RY, sn, h 45. and: there is

Ge) o ionna i o t pz ' oi so no on BYU On bo nn Z y. , ARTZ

And her sleep, and (F) ko 60 65

Ros No. h M, -x x TNE in! and U o (in; 70 ia oto t

BYU OO OTNR vtsvyu! OTne

LOBSTER where

Sn.s,

And

N N o v: vim a h TNE and she: ts oto

And a --- . EE

EBBYUE 0 OtNR en o0OtnR sch . (8) t RMO, S, NOSOsi sno, Z in EYUN so

Mn, No (o)

M

! with a needle - y: Man' uh - OMAR N "Ya (Se) / OM ts

NN 4 id - te ts. Preparation 3: (VK-(8 alpha, 9 alpha, 10 beta)|-10-methoxy-6b-oxa-spiro|4.5|)decane -7,8,9-triol

STAGE A: (45-14 alpha, 5 alpha (571 -2,2-dimethyl-5-(1-hydroxycyclopentyl)methoxymethyl/)|-1,3-dioxolane-4-methanol y y y b Inject 20 ml of dibromobutane solution ( 10 bml of dibromobutane in 200 ml of tetrahydrofuran), into a mixture containing 43 g of magnesium, 100 ml of tetrahydrofuran and one crystal of iodine. The reaction mixture is treated with ultrasound. Add - 1.7 liters of tetrahydrofuran. Add the rest of the dibrominated solution. Stir for 2 hours 30 minutes. Add at 1776 a solution containing 80.37 g of delta-lastone 2-O-methyl-3,4-0-(1-methylethylidene)-I-arabinonic acid and 1 liter of tetrahydrofuran. Stir for about 5 (ee) 50 hours at room temperature. Cool to 0"C, add a saturated solution of ammonium chloride. Decant, filter the organic phase, extract with a solution of ethyl acetate from 2090 heptane. Wash, dry and evaporate to dryness. 111.85 g of the target product are obtained.

STAGE B: IZ'az-(Za alpha, t alpha, and beta)|-?-methoxy-dihydro-spiroYcyclopentane-1,6'-ene-1,3-dioxolo|4,5-c|pyran|-4 (Zan)-on

Add 221 g of sulfur pyridine trioxide (RuzO»z) to a solution containing 111 g of the product obtained in stage A and

GF) a mixture of one liter of methylene chloride, 1 liter of DMSO, 0.607 l of triethylamine (TEA). Stir for 2 hours at 7 room temperature. Pour into an aqueous solution of acid sodium phosphate, extract with a mixture of ethyl acetate/heptane (1-1). Dry, filter and evaporate to dryness. 57.7 g of the target product are obtained. in STAGE C: |VK-(8 alpha, 9 alpha, 10 beta)|-10-methoxy-6b-oxaspiro|4.5|decane-7,8,9-triol

Add at -57C 157ml of a 1.5M solution of diisobutylaluminum hydride (OIVAN) in toluene to a solution containing 56bg of the product obtained at the previous stage and ZO0ml of THF. Stir at -3"C for one hour.

Add 1 liter of 1M solution of double sodium and potassium tartrate. Stir for 15 minutes at room temperature. The reaction medium is extracted with a mixture of ethyl acetate-heptane 1-1. Wash with water, brine, dry and evaporate to dryness. The precipitate obtained in the presence of 1500 ml of sulfuric acid solution and 150 ml of water is stirred at 707°C for 2.5 hours. Cool to room temperature, add barium carbonate, and stir for an hour at room temperature. Filter and evaporate to dryness.

49g of target product is obtained.

EXAMPLE 5: |7K-(7 alpha, 8 beta, 9 beta, 10 alpha)|-(2-propynyloxy)-carbamate 8-hydroxy-7-14-hydroxy-3-P-methoxy-imino)dethyl|-8 -methyl-2-oxo-2H-1-benzopyran-7-yl|-10-methoxy-6-oxaspiro|4.5)|decan-9-yl

STAGE A: (7K-(7 alpha, 8 beta, 9 beta, 10 alpha) 1-7-M(8,9-dihydroxy-10-methoxy-b-oxaspiro C4.5)decan-7-yl). oxy|-4-diphenylmethoxy)-8-methyl-2H-1-benzopyran-2-one

Add 45.30 g of diisopropylazodicarboxylate (OIAS) dropwise at 0"C to a mixture of 49 g of the product. Preparation

C, 73 g of the product of stage B of Preparation 2, namely 4-(diphenylmethoxy)-7-hydroxy-8-methyl-2H-1-benzopyran-2-one and 7/0 59 g of triphenylphosphine. Stir for 1.5 hours at room temperature. Add 1 equivalent of triphenylphosphine and OIAO at 0"C. Evaporate the solvents, treat with ether and obtain the target product.

STAGE in: Hyc-(7 alpha, 8 beta, 9 beta, 10 alpha)|-4-(diphenylmethoxy)-7-|(8-hydroxy-10-methoxy-9-(triethylsilyl)oxy1|-6-oxaspiro| 4.5|decan-7-yl)oxy|-8-methyl-2H-1-benzopyran-2-one

15.21 g of imidazole, 40.1 ml of diisopropylamine and 18.75 g of triethylsilane chloride are added at 0 "C to a solution containing 48 g of the product obtained at the previous stage and 40 ml of methylene chloride. Stir for 1 hour at 0 "C, wash with 1 M acid phosphate solution sodium and rinse with water. The obtained product is dried, chromatographed on silicon dioxide, eluting with a mixture of methylene chloride/acetone 99-1, then with a mixture of toluene/tert-butyl methyl ether. 28.37 g of the target product are obtained.

STAGE p. Hyc-(7 alpha, 8 beta, 9 beta, 10 alpha)|-4-(diphenylmethoxy)-7-C1O-methoxy-8-((tetrahydro-2H-pyran-2-yl)oxy1-9-Ctriethylsilyl)oxy |-6-oxaspiro(|4.5|decan-7-yl)oxy|-8-methyl-2H-1-benzopyran-2-one

Add 7.5/ml of 3,4-dihydropyran and 400 mg of paratoluenesulfonic acid to a solution containing 28.1 g of the product obtained at the previous stage and 250 ml of dichloromethane. Stir for 1 hour at room temperature. Add sodium bicarbonate and stir for 20 minutes at room temperature.

Wash with water, dry the organic phases over sodium sulfate. The obtained product is chromatographed on i) silicon dioxide, eluting with a mixture of heptane/ethyl acetate 4/1. 16.81 g of the target product are obtained.

STAGE p: Hyc-(7 alpha, 8 beta, 9 beta, 10 alpha)|-4-hydroxy-7-((10-methoxy-8-(tetrahydro-2H-pyran-2-yl)oxy|-9- (triethylsilyl/oxy|-6-oxaspiro|4.5|)de M zocan-7-yl)oxy|-8-methyl-2H-1-benzopyran-2-one

A hydrogen solution of 16.19 g of the product obtained at the previous stage, 15 Oml of THF, in the presence of 81 Omg of palladium on charcoal is stirred in the atmosphere. Filter and obtain 15.1 g of the target product. Gee!

STAGE E: Hyc-(7 alpha, 8 beta, 9 beta, 10 alpha)|-3-acetyl-4-hydroxy-7-((10-methoxy-8-(tetrahydro-2H-pyran-2-yl)oxy |-9-Triethylsilyl)oxy|-6-oxaspy -- zv BO I4.5)|decan-7-yl)oxy|-8-methyl-2H-1-benzopyran-2-one

Add 2.28 ml of acetic anhydride to a mixture containing 13.8 g of the product obtained at the previous stage, 150 ml of methylene chloride, and 5.94 g of dimethylaminopyridine (OMAR). Stir for 1 hour at room temperature. They are treated with a molar solution of acid sodium phosphate, extracted with methylene chloride, washed with water and dried. 16.21 g of the target product is obtained, which is used in the next step. "

STAGE E: Hyc-(7 alpha, 8 beta, 9 beta, 10 C c alpha)|-3-acetyl-4-hydroxy-7-(N-hydroxy-10-methoxy-8-((tetrahydro-2H-pyran -2-yl)oxy)|-6-oxaspiro|4.5)decane. -7-yl)oxy|-8-methyl-2H-1-benzopyran-2-one and? Add at 0"C 1.5 equivalents of a 1M solution of tetrabutylammonium fluoride in THF to a solution containing the product obtained in the previous step and 200 ml of THF. The reaction mixture is constantly stirred at room temperature for 15 hours. The reaction mixture is poured into a heptane-ethyl acetate mixture , (30-70). Washed with b water, filtered and dried. Get the product that is used in the next step.

STAGE o: Hyc-(7 alpha, 8 beta, 9 beta, 10 - alpha)|-4-hydroxy-7-(OH-hydroxy-10-methoxy-8-|tetrahydro-2H-pyran-2-yl)oxy |-6-oxaspiro|4.5|decane-7-yl)oxy

Ge) 1-3-/1(methoxyimino)dethyl|-8-methyl-2H-1-benzopyran-2-one

Add 4.bg of potassium acetate and 3.12g of O-methylhydroxylamine chlorhydrate to a solution containing 18.69 mol of the product obtained at the previous stage and 10Oml of ethanol. "M Stir for 1.5 hours at room temperature. Pour into a 1M solution of acid sodium phosphate, extract with a mixture of heptane/ethyl acetate 30-70. Wash with water, dry and evaporate to dryness. The resulting product is chromatographed, eluting with a mixture of heptane/ethyl acetate (1:1 ). 6.54 g of the target product are obtained. 5B STAGE H: Hyc-(7 alpha, 8 beta, 9 beta, 10 alpha))|-(2-propynyloxy)-carbamate 8-hydroxy-7-14-hydroxy-3- (1-(Methoxyimino)ethyl)|-8-methyl-2-oxo-2H-1-benzopyran-7-yl|-10-methoxy-6b-oxaspiro

F) I4.5|decan-9-yl. ka 1) At 07C, 3.70 g of OMAR and 3.05 g of para-nitrobenzene chloroformate are introduced into a solution containing 6.37 g of the product obtained at the previous stage and 7 Oml of dichloromethane. Stir for 1 hour at 07C. 2) Add 2.3g of sodium hydride at 0"C to a solution containing 6.26bg of propargylhydroxylamine chlorhydrate and

B5Oml DMF. Stir for 1 hour at 0"C. Solution (1) is concentrated to dryness. The resulting precipitate is dissolved in 500 ml

DMF. Add 1.42 LOBSTERS. Add solution (2) at 0"C to the solution thus obtained. Stir for 1 hour at 0"C. Treated with acid sodium phosphate, washed with water, dried and concentrated to dryness. The obtained precipitate is dissolved in 100 ml of methanol. Add 2.1 g of para-toluenesulfonic acid (ART) and stir at 65 room temperature. The obtained product is chromatographed, eluting with tolusol, and then with a mixture of toluene-isopropyl ether (92-8)3. The product is dispersed by ultrasound in a mixture of isopropyl ether and pentane.

Get the target product.

NMR spectrum: SOSI, ppm and i

Preparation 4: STAGE A:

Me. ON me In the village

Eyes (c) -6--ja- o on o tu ne on cha

Dissolve 20.4 g of 2-O-methyl-3,4-0-(1-methylethylidene) in an argon atmosphere! -arabinose in 200 ml of tetrahydrofuran. Add 200 ml of a 2M solution of allylmagnesium bromide in SO tetrahydrofuran at 0"C in an argon atmosphere. The solution is stirred for 1 hour at 0"C. The reaction medium is cooled to -15C and diluted with 100 ml of heptane. To neutralize excess magnesium, add ZOOml 10 drop by drop

Background aqueous solution of secondary sodium sulfate. The organic phase is separated, and the aqueous phase is extracted with a heptane(1)/ethyl acetate(2) mixture. The organic phases are combined, dried over magnesium sulfate and evaporated to dryness. 22.96 g of the target product are obtained.

Product output: 9495.

STAGE B: iiy ih mo GU me 3. as s on | х хз» , 0 у ее он шк он Шо ше с 5 /Lч (е)) ;: Gu - Dissolve 22.96 g of the product obtained at the previous stage in 17 bml of dimethylformamide in an argon atmosphere. Add 14.88 g of imidazole, then, at 0"C in an argon atmosphere, add 23.31 g of diphenyltertbutylsilyl chloride dropwise for 30 minutes. The solution is stirred for 30 minutes at 0"C. The reaction medium oo 20 is diluted with 400 ml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with two volumes of 200 ml of 1 M aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. 45 g of a resinous product is obtained, which is purified by chromatography on silicon dioxide, eluting with a heptane(4)/ethyl acetate(1) mixture. 39.5 g of the target product is obtained. Product output: 8590

STAGE C:

SHO, (F) and MeO in - in 60 b h.. --y o z ke che They

КК " Ра вБ вн. Рв 65 Suspend 25.1 g of pyridinium chlorochromate in 200 ml of methylene chloride. Add 53.8 g of molecular sieve 4A. 39.5 g of the product obtained at the previous stage, dissolved in 10 Oml, are introduced into this suspension at once.

methylene chloride. Stir for three hours. The suspension is filtered. Vomit with a mixture of methylene chloride with

Methanol Zoo. The filtrate is evaporated to dryness. The resulting precipitate (35 g) is filtered on silicon dioxide, eluting with a mixture of heptane (4) and ethyl acetate (1). 32.9 g of the target product are obtained.

Product output: 8790

STAGE 0:

M Her x iv) a: Me U ma o . that he 7 d o se o ke or shly te x. and not dk d-k

Р РЬ Р/yr

Dissolve 32.5 g of the product obtained at the previous stage in 250 ml of tetrahydrofuran. In an atmosphere of argon, at -56"C, add bbml of a solution of methylmagnesium bromide in ether (M) drop by drop. Stir for 1 hour at room temperature. At 0"C, neutralize excess magnesium with a 10956 aqueous solution of secondary sodium sulfate. Add 2000 ml of a mixture of heptane (1) ethyl acetate (2). The organic phase is washed with 200 ml of a 1 M aqueous solution of primary sodium phosphate, dried over 20 magnesium sulfate and evaporated to dryness. The resulting product is thickened in 200 ml of a mixture of pentane/simple ether. 16.9 g of the target product are obtained.

Product output: 6490

STAGE E:

Her high school

Megeo i i, x Me0 -i o

Oz. . he - ---6.6---ie from (8) Op. ON

Ma; -

A sn on (6) (ge)

SSR

. , (22)

Dissolve 16.9 g of the product obtained at the previous stage in 150 ml of tetrahydrofuran. In an atmosphere of argon, at 0"С, bdml molar solution of tetrabutylammonium fluoride in tetrahydrofuran is added drop by drop. --

Stir for 30 minutes at room temperature. Add 200 ml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 200 ml of a molar aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by chromatography on silicon dioxide, eluting with a mixture of methylene chloride 95/methanol 5. 10.1 g of the target product are obtained.

STAGE B: "- s o 2-K. But 2. "in Y "and what god- well it and it and /y 7

Me. Dissolve 10.15 g of the product obtained at the previous stage in 10 mL of methylene chloride. In an atmosphere of argon, at room temperature, add 55 ml of triethylamine and 103 ml of dimethyl sulfoxide, which is on a molecular sieve. The solution is cooled to approximately 5°C using an ice-water bath and fractional, 19.77 g of sulfur pyridine trioxide is added so that the temperature does not exceed 157°C. Stir throughout

Go! 20 one hour. The reaction medium is poured into 1 liter of a molar aqueous solution of primary sodium phosphate, the aqueous phase is extracted twice with a heptane(1)/ethyl acetate(2) mixture. The organic phase "m" is washed with water, dried over magnesium sulfate and evaporated to dryness. The crude product is crystallized and concentrated with pentane. 6.8 g of the target product are obtained.

Product output: 6895.

STAGE 0:

GF) M - Meo yini

Po) How Shya-k ZH: Sho ZU b. o -- in be. at; 60 no 9) -- about ON

Dissolve 5.3 g of the product obtained at the previous stage in 30 ml of tetrahydrofuran. In an atmosphere of argon, at -6"C, add 13.85 ml of OIVAN. After 1 hour and 30 minutes of stirring at 0"C, the reaction is finished.

The reaction medium is poured into 17O0O0ml of a 1M solution of double sodium and potassium tartrate; the aqueous phase is extracted using a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 150 ml

1095 aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness.

5.5 g of the target product is obtained. Product output: Quantitative.

STAGE N: Jap. ул и у, е как

MeO g , MeO lin

V. about -8KMM-» - - No. I; i on Z 70 o no ON

Emulsify 5.5 g of the product obtained at the previous stage in 32 ml of a 0.05 N sulfuric acid solution. After 1 hour and 30 minutes of heating at 70"C, the reaction is completed. The emulsion is brought to room temperature, the reaction medium is neutralized with 0.00 mg of barium carbonate. The suspension is stirred for an hour at room temperature (pH-7), then filtered and evaporated to dryness. For drying product 19 is distilled twice with toluene, dried and 4.4 g of the target product is obtained.

Product output: 96905.

EXAMPLE 6: 7-(b-deoxy-4-O-methyl-5-3-(2-propenyl)-3-0O-|(2-propynyloxy)amino|carbonyl|-beta-O-gulopyranosyl|oxy |- 4-hydroxy-8-methyl-3-(1-(2-propynyloxy)imino|dethyl|-2H-1-benzopyran-2-one and 7-(b-deoxy-4-O-methyl-5-3- (2-propenyl)-3-0O-|(2-propynyloxy)amino|carbonyl|-beta-O-gulopyranosyl|oxy |-4 - hydroxy-3-(1-(methoxyimino)ethyl|-8-methyl-2H -1-benzopyran-2-one

STAGE A:

Ж Vy o o mo MOMe : t Mmome i u i. 5 Z --- In Yugi - 7 o u: o v i U so on (22)

Dissolve 4.4 g of the product obtained in Preparation 4 in 700 ml of methylene chloride. At room temperature, in an argon atmosphere, add 7.3 g of coumarin (7-hydroxy-3-(methoxyimino)methyl/|-8-methyl-4-(2-propenyloxy)-2H-1-benzopyran-2-one ), (obtained as indicated (Ce) in Preparation 8 of the international patent application UUO 9747634) and 6.29 g of triphenylphosphine. The suspension is cooled to 0"C. Add 3.0 ml of diethyl azodicarboxylate (EOEAU) drop by drop. The suspension is stirred for 1 hour at room temperature. 6.0 mg of triphenylphosphine is added again and at 0"C 3.11 ml of OEAUO. After stirring for 1 hour at room temperature, add 50 ml of pentane so that the reduced OEAUO precipitates. The suspension is filtered, the filtrate is evaporated to dryness and purified on silicon dioxide with an eluent mixture of 100 ml of toluene and 200 ml of isopropyl alcohol. 7.1 g of product is obtained. The product is filtered on 60% silicon dioxide, eluting first with a mixture of simple ether and heptane, then with simple ether. 6.13 g of the target product are obtained. STAGE B: dk

FO xx io; MmOme - Me s- -

FI, with | h/o 5 -- s-- 2 mu re

Mo o what -/ about o nn SN y

Gee! Dissolve BG of the product obtained at the previous stage in 7/bml of tetrahydrofuran. Add 3.86 g of carbonyldiimidazole and the reaction is carried out for an hour under reflux. The reaction mixture is diluted with 700 ml of heptane (1)/ethyl acetate (2) mixture. The organic phase is washed with a 1095% aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness for 60 minutes. 4.94 g of the target product are obtained.

STAGE C: b5

X z o nome ok 0 kmome uya- ) 7 5 ' t

Ha pon tru a meo "tuya, med "y" ch - oi 5 b j o (e)

Dissolve 4.94 g of the product obtained at the previous stage in 120 ml of tetrahydrofuran. Add 8.44 ml of diisopropylamine at 0"C, 1.05 g of palladium tetrakistriphenylphosphine. Stir for 20 minutes at 0"7C. 72 The reaction medium is diluted with BOml of a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with a 10905 aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. 5.5 g of crude product is obtained, which is purified on silicon dioxide by eluting with a mixture of methylene chloride and 295 g of acetone. 3.1 g of the target product is obtained.

STAGE R: p.

ON o Mmome on oOm- - ih! with

And with ) t/o 2 t o o o

Meo oo mo o okho yah u Io) : o o z -, u | neo On m 30 . o so ich | F

With -

Dissolve 0.65 g of the product obtained at the previous stage in b.5 ml of pyridine dried over 32 potassium hydroxide. At room temperature, add 1.5 g of propargylhydroxylamine chlorhydrate and 0.14 g of lithium perchlorate. ise)

Stir at room temperature for 48 hours. The organic phase is diluted with a mixture of heptane(1)/ethyl acetate(2), washed with a 1095% solution of secondary sodium sulfate, and dried over magnesium sulfate.

1.8 g of the product is obtained, which is purified by chromatography on silicon dioxide, with an elution mixture of methylene chloride 80/tert-butyl methyl ether 20. 200 mg of the target product are obtained in the form of an isomer in the position

Z,i5BOo0g of the product in the form of an isomer in position 2. From c STAGE E: from to g. go: SHY sho on them (22) I - - / - Kv! in s oo MO I o poto so 2000 MO o oto yuyu b 0- still cito on

Another BUT oh- what oh what

NO and | x o x 10 yu . . X e 60 y y y

Dissolve in an argon atmosphere, 0.5 g of the isomer in position 2, obtained at the previous stage, in 1 Oml of methylene chloride. Add 100 μl of OVO. Stir for 24 hours at room temperature. It is diluted in 500 ml of a heptane(1)/ethyl acetate(3) mixture, and the organic phase is washed with a 1M solution of primary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. The product obtained above is dissolved in 5 ml of ethanol. At room temperature, add 0.72g of methylhydroxylamine hydrochloride and 0.94g of sodium acetate. The reaction medium is stirred for 5 hours at room temperature. It is diluted in B5Oml of a mixture of heptane (1)/ethyl acetate/(3), and the organic phase is washed with a 1M solution of primary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. 0.45 g of crude product is obtained, which is purified by chromatography on silicon dioxide with an eluent mixture methylene chloride (80)/tert-butyl methyl ether (20) to give 100 mg of the target product.

Preparation 5

STAGE A: but o o and X g Me "y

But o pe-- - 01 2 000 more shSh- i no i

Dissolve 204g of 2-O-methyl-3,4-0(1-methylethylidene) in an argon atmosphere! -arabinose in 25 Oml of tetrahydrofuran. Add 1700ml of a 1M solution of vinylmagnesium bromide in tetrahydrofuran at 0"C in the atmosphere, argon, then 2O00ml of a 1.7M solution of magnesium chloride in tetrahydrofuran; (0.34 mol). The solution is stirred for 1 hour at room temperature. The reaction medium is cooled to -157С and diluted with 100 ml of heptane. To neutralize the excess, magnesium is added dropwise to a mixture of tetrahydrofuran with 2096 molar aqueous solution of primary sodium phosphate. Magnesium salts are precipitated.

Add 20Oml of a mixture of heptane (1)/ethyl acetate//2) and 15O0ml of a 10956 solution of secondary sodium sulfate.

The organic solution is dried over magnesium sulfate and evaporated to dryness. 19.3 g of the target product are obtained. high school

Product output: 83905. o

STAGE B: meo yY-va | As g 0. ok zo 0. he yan ke Z o - er. Ko Son and -k so c)

Rv vv (o)

Dissolve 19.3 g of the product obtained at the previous stage in 150 ml of dimethylformamide. Add 10.8 g of imidazole, then add 234 mL of diphenyltertbutylsilyl chloride dropwise at 0"C in an argon atmosphere for 30 minutes. The solution is stirred for 30 minutes at 0"C. The reaction medium is diluted using 40 Oml of the heptane (1)/ethyl acetate (2) mixture. The organic phase is washed with a 1 M aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. 30.2 g of a resinous product is obtained, which is purified by chromatography on silicon dioxide, eluting with a mixture of "heptane(4)/ethyl acetate(1). 30.2 g of the target product are obtained.

Product output: 7795. From c STAGE C: p. --- g» MO - meb, o

Ge") I: vk S o; t M- Ge) and; -th |! their PP (Te) TR: bo 50 Dissolve 19.1 g of pyridinium chlorochromate in 250 ml of methylene chloride. Then add 40g of molecular sieve 4A.

28.19 g of the product obtained at the previous stage, dissolved in 100 ml of methylene chloride, are introduced into this suspension at one time. After 4 hours of stirring at room temperature, the reaction is terminated.

They filter. The filtrate is evaporated to dryness. The obtained product is chromatographed on silicon dioxide, eluting with a mixture of heptane/ethyl acetate (6-1). 10.5 g of the target product are obtained.

Product output: 36905.

STAGE 0: o meo sh- Me shSh- ko t:

In pet toininchttonnnyatya- Ku PO. он 60 и- о - о о че 4 9 "vi / | / ве У РЕ У 65 Dissolve 10 g of the product obtained at the previous stage in 100 ml of tetrahydrofuran. In an atmosphere of argon, at -56 "C, add 14 ml of the ZM solution drop by drop methylmagnesium bromide in ether. Stir for 30 minutes at 0"C, neutralize excess magnesium with a 10956 aqueous solution of secondary sodium sulfate.

Add 200 ml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 200 ml of a molar aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. The crude product is purified on silicon dioxide eluting with a mixture of heptane (4) ethyl acetate (1). The resulting product is thickened with pentane. They receive 2.76 bg of the target product.

Product yield: 27905.

STAGE E: 70 Me d-

Ov. he z" -- - o o I on b h i- - on t ry Ri . and tetrahydrofuran. In an argon atmosphere, at 0"C, add dropwise 11.vml of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran. Stir for 1 hour at room temperature. Add 200ml of a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 200ml of a molar solution of primary of sodium phosphate, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by chromatography on silica, eluting with a mixture of methylene chloride and 595 methanol. 1.2 g of the target product was obtained.

Product output: 86905.

STAGE B: p

AND

MeO sht- meo sh- o -- 5 vch lsh-y

N. "on Ov. o on o t zo -o -o so

Dissolve 1.2 g of the product obtained at the previous stage in 12.5 ml of methylene chloride. In an atmosphere of (o) argon, at room temperature, add 6.67 ml of triethylamine and 12.5 ml of dimethyl sulfoxide, which is "- on a molecular sieve." The solution is cooled to approximately 5"C using an ice-water bath and 2.39 g of sulfur pyridine trioxide is added in fractions so that the temperature does not exceed 15"C. After 1 hour (Ce) of stirring at room temperature, the reaction is terminated. Stir for 1 hour at room temperature.

The reaction medium is poured into 100 ml of a molar aqueous solution of primary sodium sulfate, the aqueous phase is extracted twice with a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting product is thickened with pentane. 0.75 g of the target product is obtained. t s Product output: 5995.

STAGE 0: ;z" it

MeO d- MeO Ut- I to her about t-t non I shk . si on Ku ON

F Shk sn

Go! 20 Dissolve 0.73 g of the product obtained at the previous stage in 3 ml of tetrahydrofuran. In an argon atmosphere, at -6"C, add 2.5 ml of a 1.5M solution of SIVAN in toluene. Stir for 1 hour and 30 minutes at -67C. "M The reaction medium is poured into a solution of double sodium and potassium tartrate; the aqueous phase is extracted using a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 1095% aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. The resulting product is thickened with pentane. 29 0.95 g of the target product is obtained.

GF) Product yield: quantitative.

STAGE N: o i 6bo MeOo sh ry Me XX , o ge o tt, o 7 ma; b5 t

Emulsify 0.9 g of the product obtained at the previous stage in 5 ml of О,О5n sulfuric acid solution. After one hour of heating at 70"C, the reaction ends. The emulsion is brought to room temperature, the reaction mixture is extracted with pentane, and the aqueous phase is neutralized with the help of 0.1 g of barium carbonate. The suspension is stirred for one hour at room temperature (pH-7), then filtered and evaporate to dryness. To dry the product, make two distillations of toluene, then dissolve in methylene chloride, dry the solution over magnesium sulfate and evaporate to dryness. 0.5 g of the target product is obtained.

Product output: 86905.

EXAMPLE 7: 7-(b-deoxy-5-C-ethenyl-4-O-methyl-3-O-((2-propynyloxy)amino|carbonyl|-beta-O-gulopyranosylthoxy|-4-hydroxy-3 70 -P-(methoxyimino)dethyl|-8-methyl-2H-1-benzopyran-2-one

STAGE A:

I | LI Ah! OMme about MOoMe

Me day - well 7 7

On. mashe oh oh

Zno WHO 070 0 st MO o oo na - nn,

In bno:

Dissolve 0.5 g of the product obtained in Preparation 5 in 17 ml of methylene chloride. At room temperature in an argon atmosphere, 0.89 g of curamine (obtained as indicated in the international patent application UUO 9747634) and 0.76 g of triphenylphosphine are added. The suspension is cooled to 0"C, 045ml of diethyl azodicarboxylate CM (BEAB) is added dropwise. The suspension is stirred for 1 hour at room temperature. 0.63g of triphenylphosphine is added again and, at 0"C, 0.37ml (OEAB). A yellow solution is obtained. After one hour of stirring at room temperature, 70 mL of pentane is added to precipitate the reduced HYDSO. The suspension is filtered, the filtrate is evaporated to dryness and purified by chromatography on silicon dioxide, eluting with a mixture of toluene (97)/isopropyl alcohol (3) (elution ends at 695). The obtained product in the form of a mixture is then filtered on silicon dioxide 60, eluting with a mixture of heptane (1)/simple ether (2), then with simple ether. co

0.55 g of white crystals are obtained. Product output: 47965.

STAGE B: (22) ! "-

I r Ge) (uk) I na on o o o Om o o o gu 07. 4 h 075 h i . "7 Y and 2 s zom o hom o ;" I am A

Dissolve 0.55 g of the product obtained at the previous stage in 7 ml of tetrahydrofuran. Add 0.364 g of carbonyldiimidazole and heat the reaction mixture for 71 hours at reflux.

The reaction medium is diluted with 40 Oml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 50 ml of a 1095 aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. 0.5 g of the target product is obtained.

Product yield: 8895. bo STAGE C: "I g 07 mome ono Mome

F! /Й - / ke yu that -- 6 - in o

MeO o oho Mo o oho bo 7 -shi, in | from 0 0 65 Dissolve 0.5 g of the product obtained at the previous stage in 12 ml of tetrahydrofuran. Add 0.82g of diisopropylamine and, at 0"C, 0.11g of palladium tetrakistriphenylphosphine (0.1 equivalent). Stir for 20 minutes at 0"C. The reaction medium is diluted with 5 Oml of heptane(1)/ethyl acetate(2) mixture.

The organic phase is washed with 50 ml of a 1095 aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. 0.58 g of crude product is obtained, which is purified by chromatography on silicon dioxide, eluting with a heptane(3)/ethyl acetate(2) mixture. 0.257 g of the target product is obtained.

Product yield: 57905.

STAGE 0: - A on o MoOMe on ii / a // . - o --u o o o c) Iv) o (o; 9. Mt. and meO

U- -y4 0 , - t Su i o u shield? on 20 o ( 25 Dissolve 0.257 g of the product obtained in the previous stage, 2.5 ml of pyridine, dried over potassium carbonate. At room temperature, add 0.58 g of propargylhydroxylamine chlorhydrate and 0.057 g of lithium perchlorate. (3

The reaction medium is stirred for 48 hours at room temperature. Dilute with a mixture of heptane(1)/ethyl acetate(2), and the organic phase is washed with a 10956 solution of secondary sodium sulfate, dried over magnesium sulfate. 0.28 g of the target product is obtained. The obtained crude product is dissolved in 5 ml of ethanol, 0.45 g of methylhydroxylamine hydrochloride and 0.58 g of sodium acetate are added. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2), and the organic phase is washed with (1M) primary sodium sulfate solution, dried over magnesium sulfate and evaporated to dryness. b"

0.3 g of crude product is obtained, which is purified by chromatography on silicon dioxide, eluting with a mixture of methylene chloride (80)/ethyl acetate (19) and acetic acid (1). 0.090 g of the target product is obtained. --

Output p 3190. 35 d of product about so

Preparation 6

STAGE A:

MeO

MO -- h what "that S" And same (o; ; not . In o) х и"? Zo chad. - (o) bi 0 Ma: / r her

RN OSRV r

F RE RE

- Dissolve 10.5 g in 110 ml of tetrahydrofuran. In an atmosphere of argon, at -6"C, add 329 ml of a 0.135M solution

Ge) of zinc tetraborohydride in ether. They are left with stirring for 30 minutes without an ice bath, the 5p reaction ends. TM is added to the primary sodium phosphate solution. The aqueous phase is extracted with a mixture of heptane (1)/ethyl acetate/(2). "M The organic phase is dried over magnesium sulfate and evaporated to dryness. 10.5 g of the target product is obtained, which is purified by chromatography, eluting with a heptane(4)/ethyl acetate(1) mixture. 8.75 g of the target product is obtained.

Product output: 83905. 5B STAGE C:

Me - shh

F) Y

Meo Ya z Ot on E 60 KU o Op on (o) x

P --YMB- - - i

ХК и он / 0

Ra RE b5

Dissolve 8.75 g of the product obtained at the previous stage in 100 ml of tetrahydrofuran. In an atmosphere of argon, at 0"C, add 37ml of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran. After 30 minutes of stirring at 07"C, add 200ml of a mixture of heptane(1)/ethyl acetate(2). The organic phase is washed with 200 ml of a molar aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. The crude product (10.5 g) is purified by chromatography on silicon dioxide, eluting with a mixture of methylene chloride and 2095 acetone. They receive 3.bg of the target product.

Product yield: 7890

STAGE C: -0 70 o x no -0 int v NI o po no. in about the neck she- O2y

3.57 g of the product obtained at the previous stage is placed in 1 ml of methylene chloride. In an atmosphere of argon, at room temperature, add 20.5 ml of triethylamine and 1 ml of dimethyl sulfoxide. The solution is cooled to approximately 5"7C and 7.bg sulfur pyridine trioxide is added so that the temperature does not exceed 157"C. Stir for 2 hours. The reaction medium is poured into 5X00 ml of a molar aqueous solution of primary sodium phosphate, the aqueous phase is extracted twice with a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed twice with 500 ml of water, dried over magnesium sulfate and evaporated to dryness.

The crude product is crystallized and thickened with pentane. 1.92 g of the target product is obtained.

Product yield: 56905.

STAGE R: p

MeO sh- MegOo sh-- o o GI (8 Go) I ch (9)

Dissolve 1.9 g of the product obtained at the previous stage in 1 Oml of tetrahydrofuran. In an argon atmosphere, at 0"C, add 6.6 bml of a 1.5M solution of OBIVAN in toluene. Stir for 1 hour and 30 minutes. The reaction medium is poured into 100ml of a 1M solution of double sodium and potassium tartrate; the aqueous phase is extracted using a mixture heptane(1)/ethyl acetate(2). The organic phase is washed with 150 ml of a 1095 aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. (Ce)

Product output: Quantitative.

STAGE E: no ON o ch gu no x : - s (v; on Te! . pe zhi o a 6, dz n t sia- SY

Emulsify 1.95 g of the product obtained at the previous stage in 11.5 ml of 0.05 N sulfuric acid solution.

Me. Heat for 1 hour ЗОхв. to 70"C. Leave to cool to room temperature, and the reaction medium is neutralized with 0.3 g of barium carbonate. The suspension is stirred for 1 hour at room temperature (pH-7), then filtered and evaporated to dryness. To dry the product, 2 distillations are made and, toluene. After drying (for one night at 407C in the presence of P»2Ob) 1.2 g of the target product are obtained. 295 bo o Product yield: Quantitative

EXAMPLE 8: "M 7-(b-deoxy-6-C-methyl-4-O-methyl-3-O-|(2-propynyloxy)-amino|carbonyl|-alpha-I-mannopyranosyloxy |-4-hydro xy-8-methyl 3-(1-(2-propynyloxy)imino|ethyl|-2H-1-benzopyran-3-yl|-2-one 7-Kb-deoxy-6-C-methyl-4-O- methyl-3-O-((2-propynyloxy)-amino|carbonyl|-alpha-I!-maniopyranosyl)oxy1-4-hydr 59 oxy-3-I1--"methoxyimiso)ethylI-8-methyl-2H. 1 -benzopyran-3-yl|-2-one

F! STAGE A: name) 60 b5 a nOome o mOome me sht u h / i a

BUT pi o - What 7 a nb on - cho

Z: but he is

Dissolve 1.16 g of the product obtained in preparation 6 in 25 ml of methylene chloride. At room temperature in an argon atmosphere, add 2.19 g of coumarin and 7-hydroxy-3(methoxyimino)methyl/|-8-methyl-4-(2-propenyloxy)-21-1-benzopyran-2-one (obtained as indicated in the international patent application U/09747634) and 1.89 g of triphenylphosphine. The suspension is cooled to 0"C, 1.12ml of EOEAUO is added dropwise. The suspension is stirred for 1 hour at room temperature. 1.58g of triphenylphosphine and, at 0"C, 0.9ml of EOEAU are added again. After an hour of stirring at room temperature, add

B5Oml of pentane to precipitate the reduced OEAU. The suspension is filtered, the filtrate is evaporated to dryness and purified by chromatography on silicon dioxide, eluting with a mixture of toluene and 3095 isopropyl alcohol.

0.870 g of white crystals and 0.850 g of a mixture containing traces of reduced OEAU are obtained. The product is quickly filtered through 100 g of silicon dioxide 60, eluting with ether. 0.4 g of the target product is obtained.

Total weight: 1.27 m. Product output: 44905. swarm STAGE V cm ' (8) уй ГТ о чОМе 6) MOМе / | i- / a t o in 0 so my o-o -Ж---- me oho (22) x - ;, h

NU on Fo r y (se)

Dissolve 1.27 g of the product obtained at the previous stage in 10 ml of tetrahydrofuran. Add 0.85 g of carbonyldiimidazole and heat for 1 hour under reflux. The reaction medium is diluted with 50 ml of a mixture of heptane (1 uethyl acetate (2). The organic phase is washed twice with volumes of 50 ml each) with a 1095 aqueous solution of secondary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. . 1.41 g of the target product is obtained. and?" Product output: Quantitative

STAGE C:

F ' s on - / | MOMe ono Mm-

She

E - iy 50 uk g (c) t o o 5 "and Ga o and now on o

I pay him in; - , ich about U:

Dissolve 0.6 ml of the product obtained at the previous stage in 5 ml of pyridine dried over potassium hydroxide. At room temperature, add 1.5 g of propargylhydroxylamine chlorhydrate and 0.14 g of lithium perchlorate.

Stir for 48 hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 1096% solution of secondary sodium sulfate, dried over magnesium sulfate. 1.8 g of the product is obtained, which is chromatographed on silicon dioxide, eluting with a mixture of methylene chloride (80)/ethyl acetate ( 19uacetic acid (1). 186bmg of the target compound is obtained by isomerism in the position

With and 40Omg compounds isomerism in position 2. 65 ! used background; ! ! !

Product yield: 7495. Opening of the cycle to form a carbonate in which 3095 is an isomer with isomerism in position

STAGE 0:

IF) 7 ok HER o i 70 ra s on h o 4 Z Z -Meo ge) sha! I o Z same 18 Cl Meo o she; he o-Y -- b

М- 0 у о ОН

N | NM. -- klzh o

Dissolve 0.4g of the product obtained at the previous stage (isomer in position 2) in 1Oml of methylene chloride. Add 1O0O0μl of OVO. Stir for 24 hours at room temperature.

It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 1M solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. 0.4 g of the mixture obtained above is dissolved in 1 O ml of ethanol in a 100 ml flask. At room temperature, add 0.59 g of methylhydroxylamine chlorhydrate and 0.7 g of sodium acetate. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 1M solution of primary sodium sulfate, dried over magnesium sulfate and evaporated to dryness. 0.45 g of the crude product is obtained, which is purified on silicon dioxide eluting with a mixture of methylene chloride (80)/ethyl acetate (19-acetic acid (1). Only compounds with isomerism in position 3 are isolated. 0.140 g of the target product is obtained.

Product output; 3795. (about)

Preparation 7. -

STAGE A: , (Se)

Mmeo, ON Meb057U ) pn p i - and eat at 5 si 7 o) o on -- ze» . "» Dissolve 26.8 g of the product in an argon atmosphere in 250 ml of tetrahydrofuran. Add 400 or 1 M solution of ethylmagnesium bromide in tetrahydrofuran drop by drop at 0"C in an argon atmosphere. The solution is stirred for 2 hours at room temperature. The reaction medium is cooled to 0"C and diluted with 100 ml of heptane. (o) To neutralize excess magnesium, add drop by drop 300 ml of a molar aqueous solution of primary sodium phosphate. Magnesium salts are precipitated. Add 200 ml of a mixture of heptane (1)/ethyl acetate (2 ) and 150 ml of a 1095 solution of secondary sodium sulfate. The organic solution is dried over magnesium sulfate and evaporated to dryness. (Ce) 29 g of product is obtained, which is chromatographed on silicon dioxide eluting with a heptane(1)/ethyl acetate(4) mixture.

17 g of the target product are obtained. so:

Product output: 5295. that STAGE B: mg pcs

MeOoo4-5ZeiIRya»3O. g -

Sa on iF) Se on now shi ge io; dc With 0 ch

He has; in o, Their 1. Rv Rv

Dissolve 16/g of the product obtained at the previous stage in an argon atmosphere in 15 Oml of dimethylformamide. Add 10.07 g of imidazole, then add 19.23 ml of diphenyltertbutylsilyl chloride dropwise over 30 minutes at 0"C in an argon atmosphere. The solution is stirred for 1 hour and 30 minutes at room temperature. The reaction medium is diluted with 400 ml of a mixture of heptane(1)/ ethyl acetate (2). The organic phase is washed with a molar aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. 38 g of product is obtained, which is purified by chromatography on silicon dioxide, eluting with a mixture of methylene chloride and 1095 acetone. 33.23 g of the target product are obtained.

Product output: Quantitative

STAGE C: meO g meO -I5eK x - . a tyu be shchi i vk - o as 87 o x i o x 5i "-Yi them

KhM Ra Rv. Rvolv

Suspend 22.57 g of chlorochromate pyridinium (0.104 mol) in ZOO ml of methylene chloride. Add 110g of molecular sieve 4A. ZZg of the product obtained at the previous stage, dissolved in 100 ml of methylene chloride, is introduced into this suspension. After three hours of stirring at room temperature, the suspension is filtered. The filtrate is evaporated to dryness. The resulting precipitate (357) is purified on silicon dioxide, eluting with a heptane(4)/ethyl acetate(1) mixture. Get 27g of target product,

Product output: 83905.

STAGE 0:

Meo state Meo her oo . dis tone sch

From ----lbyu»y» x

From o. ) Zo o o

You are

RE TV Dissolve 16.5 g of the product obtained at the previous stage in 1500 ml of tetrahydrofuran. In an atmosphere of argon, at -5"C, add 17.52 g of a 3M solution of methylmagnesium bromide in ether. Stir for 1 hour at room temperature. At 0"C, neutralize the excess magnesium TM with an aqueous solution of primary He! sodium phosphate. Add 200 ml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with 200 ml of a molar aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated --

From Ddosukha. The resulting product is thickened with pentane. 14.85 g of the target product are obtained. "at

Product output: 87905.

STAGE E:

MeO t «

Ov on Me -- n- s vk U o che chi | I drink i" b chi a on ryu rv Zo on

Dissolve 14.85 g of the product obtained at the previous stage in 150 ml of tetrahydrofuran. In an argon atmosphere, at 0"C, 33 ml of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran are added drop by drop. After 30 minutes of stirring at room temperature, the reaction is terminated. 200 ml of a mixture of heptane (1)/ethyl acetate (2) is added. The organic phase is washed with 200 ml of a molar aqueous solution (ee) of 50 primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. The crude product -h is purified on silicon dioxide, eluting with a mixture of methylene chloride with 1595 acetone and then with 3095 acetone.

7.85 g of the target product are obtained.

Product output: Quantitative. rya STAGE B: o Me tt Me OO ko o Ek / . he --- nya yang go) GI . 9) because Zv on ov (o;

Dissolve 7.85 g of the product obtained at the previous stage in 82.5 ml of methylene chloride. In an atmosphere of argon, at room temperature, add 44.5 ml of triethylamine and 82.5 ml of dimethyl sulfoxide, which is on a molecular sieve. The solution is cooled to approximately 5"C in a water-ice bath and 65 15.8g of sulfur pyridine trioxide are added in fractions so that the temperature does not exceed 157"C. Stir for 1 hour.

The reaction medium is poured into 1 liter of a molar aqueous solution of primary sodium phosphate, the aqueous phase is extracted with a heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting product is thickened with pentane. 5.77 g of the target product are obtained.

Product yield: 80905.

STAGE 0:

Mei shsh-OIU- Me -t-OO- d)! "I; (8) set uyu about her GO) - ! z -o o - y

Dissolve 5.46 g of the product obtained at the previous stage in 25 ml of tetrahydrofuran. In an atmosphere of argon, at 0"C, add 16.7 ml of a 1.5M solution of RIVAN in toluene. Stir for 1 hour 30 minutes at 75 0"C. The reaction medium is poured into 250 ml of a 1 M solution of double sodium and potassium tartrate; the aqueous phase is extracted with a mixture of heptane (1)/ethyl acetate (2). The organic phase is washed with 150 ml of a 1095 aqueous solution of sodium sulfate, dried over magnesium sulfate and evaporated to dryness. 5.5 g of the target product is obtained.

Product output: Quantitative.

STAGE N:

Me El. I am 57

Oh " go and Na "tp. Ge) p

In i i o o on no on

Emulsify 5.5 g of the product obtained at the previous stage in 32 ml of 0.05 N sulfuric acid solution. After 1 hour and 30 minutes of heating at 70°C, the reaction is terminated. The reaction medium is brought to room temperature and neutralized with 0.6 g of barium carbonate; the suspension is stirred for one hour at room temperature (pH-7). Then it is filtered on tiiroge filter paper and evaporate to dryness. F)

To dry the product, make two distillations with toluene. Dried at 40"C in the presence of RoOv, 4.8 g of a white resinous precipitate are obtained. --

Product output: quantitative. (Se)

EXAMPLE 9 7-(6b-deoxy-5-C-ethyl-4-O-methyl-beta-O-gulopyranosyl)oxy1|-4-hydroxy-8-methyl-3-11-(2-propynyloxy)imino)ethyl |-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)-carbamic acid « 7-(6b-deoxy-5-C-ethyl-4-O-methyl-beta-O-gulopyranosyl) oxy1|-4-hydroxy-3-(/1-methoxyimino|ethyl|-8-methyl-2H-1-benzopyran-2-one, 3'-ester(2-propynyloxy)-carbamic acid - c 7-(6b) -deoxy-5-C-ethyl-4-O-methyl-beta-O-gulopyranosyl)oxy1-3-(1-(ethoxyimino)ethyl|-4-hydroxy-8-methyl-2H a -1-benzopyran-2 -on, 3'-ester (2-propynyloxy)-carbamic acid, STAGE A: ot ol

Me, MeO pcs - ; - day tr / w

Noe o - -/ o i-o 2 no o c) meo o o o bo 70 no OH . | Mk "mch neo on

Dissolve 4.8 g of the product obtained in Preparation 7 in 700 ml of methylene chloride. At room temperature, in an argon atmosphere, add 9.98 g of curamine and 7.23 g of triphenylphosphine. The suspension is cooled to 0"C, and 4.34 ml of REAU is added dropwise. The light yellow suspension is stirred for 1 hour at room temperature.

Again add BG triphenylphosphine and, at 07C, 33.57 ml of REAR. A yellow solution is obtained. After 1 hour of stirring at room temperature, 50ml of pentane was added to precipitate the reconstituted REAR. ime) The suspension is filtered, the filtrate is evaporated to dryness and purified on 1.75O0 kg of silicon dioxide 60 with an eluting mixture of toluene with 3905 isopropyl alcohol, and then with bob isopropyl alcohol. 10 g of white 60 crystals containing traces of reconstituted REAR are obtained. The product is rapidly filtered over silica 60 with heptane(1)/ethyl acetate/(2) as eluant to remove reduced REAR, then methylene chloride(95)/methanol(b5) to give 7.3 g of the target product.

Product output: 5895. b5

STAGE B: nev, i o A SNeV, - chn: sho - x 70 o I v'p'so M -0 i ego oto b he i-sk o

Introduce 7.2 g of the product obtained at the previous stage in 1000 ml of THF. Add 4.41 g of diimidazole carbonate and heat under reflux for 1 hour. Pour into 150 ml of 10956 solution of secondary phosphate and extract with a mixture of hexane/ethyl acetate. Dry and obtain 7.1 g of the target product. 70 STAGE C:

See, 9 on / their 4 - s t, 88-x» ,, - o meo uz : cm y» : o 7 " 1 bu y o Y s

Dissolve 7.1 g of the product in 100 ml of tetrahydrofuran. Add O0./g of palladium on charcoal and place in a hydrogen atmosphere. After three hours of stirring, the reaction is completed. The reaction medium is filtered and the filtrate is evaporated to dryness. The product is recrystallized in an ether/pentane mixture. They get 4.75 g of the target product.

Product output: 9595. and

STAGE 0: on ono / - s / « и - "z 2 pnia a i Megeo (c) o Me o

Ше У (е)) о У (в; най се) Dissolve 1.5 g of the product obtained at the previous stage in 25 ml of methylene chloride. Add 0.99g

Go! 20 dimethylaminopyridine and, in an atmosphere of argon, at ОС, dropwise, O0.3 ml of acetic anhydride. After 30 minutes of stirring at 0"C, add 9U5μl of acetic anhydride and 0.225g of dimethylaminopyridine. Stir for 45"M minutes. The reaction medium is diluted with 100 ml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed twice with 150 ml of 1 M aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. Select the target product. 1.56 g of the target product is obtained. 59 Product output: 93965.

F! STAGE E: ime) 60 b5 t on Ge) ? / to her t y - 7 Й - «о тын; m th at 6 Ach

In he what

I .

Dissolve 1.5 g of the product obtained at the previous stage in 15 ml of pyridine dried over potassium hydroxide. At room temperature, add 3.bg of propargylhydroxylamine chlorhydrate and 0.36bg of lithium perchlorate.

The reaction medium is stirred for 48 hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 10956 solution of secondary sodium sulfate, dried over magnesium sulfate. 1.8 g of the target product is obtained. 200 mg of this crude product is purified on silicon dioxide, eluting with a methylene chloride (80)/tert-butyl methyl ether (20) mixture. 9Omg of the target product with isomerism at position C and 75mg of product with isomerism at position 2 are obtained.

Yield: 7790 55/45 with 3-position isomerism.

STAGE B: s t o nom on «y / t / -i GA - 7 o g g! (uh)

MO o oho Mo o oho F o - iy i o z - l o o n tsilo on tynu (Se)

Dissolve 0.5 g of the product obtained at the previous stage in 5 ml of ethanol. At room temperature. add 0.85 g of methylhydroxylamine chlorhydrate and 0.94 g of potassium acetate. The reaction medium is stirred for 5 minutes. hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 1 M solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. The crude product is obtained, which is purified on silicon dioxide with an eluent mixture of methylene chloride with 2095

Ge" of tert-butyl methyl ether. 0.095 g of the target product is obtained.

STAGE 0: - d te t o so on Y . he

B / Z her Z "Ho -0

Mezhi ono to Me oh oho oh oh

F. U-o he o he what nm -- vo I I

They act in the same way as at the ER stage, using 0.85 g of ethylhydroxylamine chlorhydrate. 0.103 g of the target product with isomerism in position 3 is obtained. b5 EXAMPLE 10

7-(6b-deoxy-5-C-ethyl-4-0-methyl-beta-O-gulopyranosyl)oxy|-3-(/1-methoxyimino)propyl1-4-hydroxy-8-methyl-2

H-1-benzopyran-2-one. Marshmallow of G2-propynyloxy)-carbamic acid

STAGE A: ' on on o / x / Z - Ge) 7 o yu MO o o-o MeO o oko pn Z u z

Dissolve 0.6 mg of the product obtained as described in step C of example 9 in 15 ml of methylene chloride. They add

0.3bg of dimethylaminopyridine and, in an argon atmosphere, at 00"C, dropwise, 0.20g of propionic anhydride.

Stir for 30 minutes at room temperature, then for 1 hour at room temperature. The reaction medium is diluted with 100 ml of heptane(1)/ethyl acetate(2) mixture. The organic phase is washed with an aqueous solution of primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. They receive 0.bg of the target product.

Product output: 6895.

STAGE B: ono 4 sch » cher aly CHI; / -

Mmeo about the same

M- me or soho - zo oo -j- o. so in U-o on o nm (is) o , En -

Zo Dissolve 0.bg of the product obtained at the previous stage in bml of pyridine dried over potassium hydroxide. At room temperature, add 1.39g of propargylhydroxylamine chlorhydrate and 0.13g of lithium perchlorate.

The reaction medium is stirred for 48 hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 10956 solution of secondary sodium sulfate, dried over magnesium sulfate. 0.56 g of the product is obtained, which is dissolved in 1 ml of ethanol, 1.07 g of methylhydroxylamine chlorhydrate and 1.39 g of sodium acetate are added. The reaction medium is stirred for 5 hours at room temperature. It is diluted with a mixture of heptane (1)/ethyl acetate (2) and the organic phase is washed with a 1 M solution of "" primary sodium phosphate, dried over magnesium sulfate and evaporated to dryness. 0.45 g of crude " product is obtained, which is purified by chromatography on silicon dioxide, eluting with a mixture of methylene chloride with 2095 tert-butyl methyl ether. 0.170 g of the target product is obtained. o 45 When performing the above-described actions, products corresponding to the formula were also obtained: - se) o 50 what

F) name) 60 b5

Kk ono s sn sn us Kk) 3 and o; o o eh o 70 us sn i z

M de - neshshSNIO TU a on 8;

Kk: | -

О(СН,),Вк . with 7 d o usn,

Y y t ' s osn ХУ F «- z " Ge) osn. Zh

As a result of the actions described above, the following products corresponding to formula (1) were obtained:

F osUM o - Kk s. so Oo(SnIvM ); that zhk

O(SNIH M Z IM tributes to M yu o 60 b5

E E

. E E o. M 70 / o(0Н2»I-s ZK

N

7 he in in . 2

With td Kh

Not about o o) o at 5 Az se

V - I o r: o on wo y Sche sh o ' so

Ge) - (Se) « - s z (e)) shk (se) bo i (F) ko bo 65 сСн3 | in OSNZ | sez SNZ no 1 sn i Go) | осСзн5 70 сСзн5 but ТОосСнНзЗ and sya siz | N | snz n o OosSzNo son | but fosnz|snz|snu| but snz| no) at 6 sten |osyuosv st || but learn it

Sveten|nfte(vv tv is, koe n"Geeteyu|«|evi|sv|

And with o

СН, but fОосСиз|снЗ) СНЗ | but) SN B about MN

A. cha sn m "a - (ee)

But IosNnzIsnz| SNZ | but osnz n o | осС2н5 Ф сн, - |se) n ИоСы3з|сСНЗ| SNZ | but | SKZ n MN sn i « -en- " « y y - s SNU . ;z" i a osSsnz sНnz | СНЗ no 1 sya Н МН2

F -Sn- "Z -y - so 4 nn oTOsSNz and se | SNZ no| cSNZ | BASIC plural -Sn; And: so - whatever. SU no fosnzisnz| snz | but snz no | about | SnNosez

F); ; kyu osnz|syz| snz | nn nn basics: o MN no

BO b5 about | и ШИ ШО 0 -сСНИ-Sasn их |osnz Si siz | N skz n o! | sno -СНаз-СеСН | n KG osnz3 sleep | snz | K |snz N o OSzne 18 -snz-SSE - OSY snZziIsnI| nose B | about EM(sSnz1zMka

SN ra nosnzZ snZISNZI| but |sSNzZ o Sian -- sch si, Ge) thing In Osn | сНз сн сСНз| but osn OosSzne ro . Z and i- 30.

SN, niosnzisnzisnz| but isnz) In o oszna so

F

SN (Se)

With nifosnz|snzisnz| vn |cSya3| in o MN r « , shi sn : s 13 niosnzisnz|snI! nosVz| ts o o (in :» ' ra ' y mesni" " 27 Nevetyuov tyu sv|ee| i feya in shk oo retttn vree|terv| koso "mch " (F) o bo b5 i Ge 1h15951: 11

ZheEsno IoosSnzisnziI sSYaz ni snzi| oh that ms. :

The following compounds were obtained during the above-mentioned operations: 3-(11-K(5-chloro-1,2,3-thiadiazol-4-yl)methoxy|imino|ethylI-7-Kb-deoxy-5-C-methyl- 4-O-methyl-alpha-i-lyxo-hexopyranosyl)oxy-1|-4-hydroxy-8-methyl-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)-carbamic acid; 3-P1-Cyanomethoxy)imino|ethyl-7-((b-deoxy-5-C-methyl-4-O-methyl-alpha-Y!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl -2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)-carbamic acid; 3-1-(2-aminoethoxy)imino)cethyl-7-Kb-deoxy-5-C-methyl- 4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy1-4-hydroxy-8-methyl-2H-1-benzopyran-d) 2-one, 3Z'-ester of (2-propynyloxy)-carbamic acid; 7-Kbv-deoxy-5-C-methyl-4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-K(2-hydroxyethoxy)imino|)ethyl|-2H-1-benzopyran-2-one, 3'-ester (2 -propynyloxy)-carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-KZ-psheridinyl-oxyimino|ethyl|-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)- carbamic acid (isomer B); co 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1- (Z-piperidine l)oxyimino|)ethyl|-2H-1-benzopyran-2-one, (2-propynyloxy)-carbamic acid (isomer A); 7-Kb-deoxy-5-C -methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-K1-methylethoxy)-imino|ethyl|-2H-1-benzopyran -2-one, 3'-ester of (2-propynyloxy)-carbamic acid;

Zo 3-11-Kcyclobutyloxy)imino)ise)ethyl-7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-i -lyxo-hexopyranosyl)oxy1|-4-hydroxy-8-methyl- 2H-1-benzopyran-2-one, 3Z'-ester of (2-propynyloxy)-carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-! -lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-|(1-(propoxyimino « )ethyl|-2H-1-benzopyran-2-one 3'-ester of (2-propynyloxy)-carbamic acid 7-Kbv-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-1-(2,2,2-trifluoro With c toxy)imino|ethyl|-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid; "» 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy)|-4-hydroxy-8-methyl-3-(1-((pentafluorophenyl) )methoxy|imino|)ethyl|-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)-carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl- alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-I((3-I4-(3-pyridinyl)-1H-imidazol-1-yl|)propoxy)! imino) ethyl I-2H-1-benzopyran-2-one, 3-ester of (2-propynyloxy)-carbamic acid; - 7-Kbv-deoxy-5-C-methyl-4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-(2-(1-dileridinyl)ethoxy)imino|ethyl|-2H-1-benzopyran-2-one, 3'- (2-Hyphopinyloxy)-carbamic acid ester; (1-(2-(4-morphol

Go! 20 nyl)ethoxy)imino)ethyl|-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-|(1-(methoxyimino)"M propyl|-2H-1-benzopyran-2-one, 3'-ester (2-propynyloxy)- carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-(2,2, 2-Triftorethoxy)imino)propyl|-2H-1-benzopyran-2-one, (2-propynyloxy)-carbamic acid 3'-ester; 59 7-Kb-deoxy-5-C-methyl-4-O- methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-|(1-(propoxyimino

HF) )propyl|-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-! -lyxo-hexopyranosyl)oxy|-3-(1-ethoxyimino)propyl)-4-hydroxy-8-demethyl-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid; 7-(b-deoxy-5-C-methyl-4-O-methyl-3-O-|(2-propynyloxy)amino|carbonyl|-alpha-i-lixo-hexopyranosyl)oxy |- 60 3-1- -ethoxymethoxy)imino| ethyl/1-4-hydroxy-8-methyl-2H-1-benzopyran-2-one; 7-(b-deoxy-5-C-methyl-4-O-methyl-3-O-|(2-propynyloxy)propynyloxy)amino|carbonyl|-alpha-i-lyxo-hexopyranosyl)oxy1-4-hydroxy -8-methyl-3-(1-I((2-methyl-4-thiazolyl)methoxy|imino|ethylI|-2H-1-benzopyran-2-one; 7-Kb-deoxy-5-C-methyl- 4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-((2-thiazolyl)methoxyimino)ethyl|-2H-1-benzopyran-2-one , "Z"-ester of (2-propynyloxy)-carbamic acid; bo 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8 -methyl-3-(1-((3-furanyl)methoxyimino)ethyl|-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid; 7-Kb-deoxy-5 -C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-(1-((3-thienyl)umethoxy)imino|ethyl|-2H -1-benzopyran-2-one, (2-propynyloxy)-carbamic acid 3'-ester;7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxo-hexopyranosyl)oxy| -4-hydroxy-3-11-(|(2-furanylmethoxy)imino|ethyl|-8-methyl-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamic acid; 7 -Kbv- deoxy-5-C-methyl-4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy|-4-hydroxy-3-11-|I(3,5-dimethylisoxazol-4-yl)|methoxy|imino|ethyl|-8-methyl-2H-1-benzopyran-2- hen, 3'-ester of (2-propynyloxy)-carbamic acid; 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-! -lixo-hexopyranosyl)oxy|-4-hydroxy-8-methyl-3-|(1-(phenoxyimino) 70 ethyl|-2H-1-benzopyran-2-one, 3'-ester of (2-propynyloxy)-carbamino acids; methyl((1-(7-C(b-deoxy-5-C-methyl-4-O-methyl-3-O-|(2-propynyloxy)amino|carbonyl|-alpha-!i -lyxo- hexopyranosyl)oxy|-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-ylethylideneamino|oxy|acetate.

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

Tablets containing:

Compounds of example 1 150 mg

Excipient up to 1 year

Excipient: starch, talc or magnesium stearate

Compounds of example 5 150 mg

Excipient up to 1 year

Excipient: starch, talc or magnesium stearate

Solutions for injections were obtained on the basis of compounds in salt form.

PHARMACOLOGICAL TESTING OF COMPOUNDS ACCORDING TO THE INVENTION

A. Method of dilutions in a liquid medium

A number of test tubes were prepared, in which the same amount of sterile nutrient medium was placed. Each test tube is placed in increasing amounts of the product being studied, then each tube is inoculated with a bacterial strain. After 24-hour incubation in a drying cabinet (thermostat) at 37"C, growth retardation i) is evaluated by transillumination, which allows to determine the minimum inhibitory concentrations (MIC) expressed in micrograms/cm.

Activity of ip mygo M zo MIC in μg/ml

On the following strains: so (22)

App.1 App. 2 App.Z3 App.A

Ziarp. ashgeivO11NTIV 0.04 0.04 004 004 --

Zvarp Eridegtides 0126042 004 0.04 0.4 015 s

Salary soad Medaime 012NT15 03 0.04 0150 015 grains. ruodepe 0О2АТИСИ1 0.6 03 06 0.6 zgeryu. rpestopiae 030812 0.04 0.08 Shshch008 10.15

Epiego GaesiptO20O31R2 o, 08 0.6 1.2 1.2 "

Epiego Gaesaev 0202005 0.3 1.2 1.2 1.2 shsh s B. Inhibition of gyrase B :z» Compounds according to the invention are inhibitors of gyrase B; the dose of the compound that causes the 5095th superspiralization

DNA lower than bmg/pc.

Me,

Claims (1)

The formula of the invention - I. Aromatic amide of formula (I) and 2 ono m o 50 h Kk and in 2 x x 7 Kot bo (in o (F) and I in 7 Kk R zhi Z b o. "on zer o where - Ж means atom of oxygen or the radical MM-M-alky or MO-alk»o, in which alk/y and alko mean an alkyl radical that 65 Contains up to 12 carbon atoms, if necessary interrupted by one or more atoms of oxygen, sulfur or nitrogen, if necessary substituted by one or more halogen atoms, an aryl radical (if necessary substituted by one or more halogen atoms), a heterocyclic radical, one or more radicals K a r M o b where K a and K b are the same or different mean a hydrogen atom, an alkyl radical containing up to 8 atoms carbon, if necessary substituted, or Ka and Co form, together with the nitrogen atom with which they are combined, a heterocycle, which may also contain another heteroatom selected from oxygen, sulfur or nitrogen, - X means a hydrogen atom, a hydroxyl radical, an alkyl radical, alkenyl or alkynyl, optionally interrupted by one or more atoms of oxygen, sulfur or a zotu, linear, branched or cyclic containing up to 12 carbon atoms, if necessary substituted by one or more halogen atoms, 19 heterocyclic radical, one or more OH radicals, free or etherified by the SEM X MO group; , Ka rai M o b where Ka and KB, the same or different, mean a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, or Ka and Kb together with the nitrogen atom to which they are connected will form a heterocycle containing if necessary, another c heteroatom selected from nitrogen, sulfur or oxygen, or X means an alkoxy radical or a radical o 1) I cha -C-MOKe, (ee) where Ke means an alkyl radical containing up to 8 carbon atoms, optionally substituted by one or more substituents specified above, o or X means the radical MKskKa, where Ks and Ka are the same or different, mean a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, optionally substituted by one or more substituents specified above ; or All ka form, together with the nitrogen atom to which they are bound, a heterocycle containing, if necessary, another heteroatom selected from nitrogen, sulfur or oxygen, - 7 means a hydrogen or halogen atom or an OH group, free or transformed into simple or complex ether, - K" means a hydrogen or halogen atom, " - Kz means a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom, Z - K means a hydrogen atom or an alkyl radical containing up to 4 carbon atoms, c - Ku means a hydrogen atom, an alkyl radical, alkenyl or alkynyl , linear, branched or cyclic, containing up to 8 carbon atoms, if necessary substituted by one or more halogen atoms, the Sem radical. an aryl radical containing up to 14 carbon atoms, - K5 means a hydrogen atom, an O-alkyl radical containing up to 4 carbon atoms, - or K; means alkyl radicals, propenyl, ethenyl or СНо-О-alkyl, in which alkyl means an alkyl radical containing up to 8 carbon atoms, - - K7 means a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, - or Ke and K7, together with the carbon atom to which they are connected, form a ring containing up to 8 carbon atoms, as well as salts of compounds of formula (I), when compounds of formula (I) have the main function. Ge | 20 2. Compounds of formula (I), according to claim 1, where U means an oxygen atom. . C. Compounds of formula (I), where ХУ means the MO-alkyl radical, in which the alkyl contains up to 4 carbon atoms. in 4. Compounds of formula (I), according to item C, where U means the radical МОС»оНбББ. 5. Compounds of formula (I), according to any of claims 1-4, where X means an alkyl radical containing up to 4 carbon atoms, and in particular the SNU radical. 6. Compounds of formula (I), according to any of claims 1-4, where X means the MH radical." GF) 7. Compounds of formula (I), according to any of claims 1-4, where X means the radical o re ' 600 - МН (СНУ). - 8. Compounds of formula (I), according to any of claims 1-7, where K. means the radical nsiao-СН bo 9. Compounds of formula (I), according to any of claims 1-8, where K means a hydrogen atom . 10. Compounds of formula (I), according to any of claims 1-9, where Kz means the methyl radical. 11. Compounds of formula (I), according to any of claims 1-10, where 7 means a hydrogen atom. 12. Compounds of formula (I), according to any of claims 1-11, where Co" means a hydrogen atom. 13. Compounds of formula (I), according to any of claims 1-12, where K5 means the radical OSN". 14. Compounds of formula (I), according to any one of claims 1-13, where Ke means a methyl radical. 15. Compounds of formula (I), according to any of claims 1-14, where K7 means the methyl radical. 16. Compounds of formula (I), according to any of claims 1-14, where K7 means the ethyl radical. 17. Compounds of formula (I), according to any of claims 1-13, where Kb; and K7 together with the carbon atom to which they are connected, 7/0 will form a cyclopentyl radical. 18. Compounds of formula (I), according to claim 1, which are 7-(b-deoxy-5-C-methyl-4-O-methyl-alpha-i-lyxohexopyranosyl|oxy)|-4-hydroxy-8-methyl -2-oxo-2H-1-benzopyran-3-carboxamide, (2-propynyloxy)carbamic acid 3'-ester, 7-(b-deoxy-5-C-methyl-4-O-methyl-alpha-! -lixohexopyranosyloxy|-4-hydroxy-8-methyl-M-(2-(4-morpholinyl)ethyl|-2-oxo-2H-1-benzopyran-3-carboxamide, 3'-ester of (2-propynyloxy)carbamine acid, 7-(ob-deoxy-5-C-methyl-4-O-methyl-alpha-Y!-lyxohexopyranosyl|oxy|-4-hydroxy-3-(1-(methoxyimino)ethyl|-8-m ethyl -2H-1-benzopyran-2-one, (2-propynyloxy)carbamic acid 3'-ester, 7-Kb-deoxy-5-C-methyl-4-O-methyl-alpha-!-lyxohexopyranosyl)oxy1-3 -11-(ethoxyimino)ethyl/|-4-hydroxy-8-m ethyl-2H-1-benzopyran-2-one, (2-propynyloxy)carbamic acid 3'-ester. 19. Compounds of formula (I) according to claim 1, which are 7-(6-deoxy-5-C-ethyl-4-O-methyl-beta-O-gulopyranosyl)oxy|-4-hydroxy-3-|1- (Methoxyimino) ethyl-8-methyl-2H-1-benzopyran-2-one, (2-propynyloxy)carbamic acid 3'-ester, (/k-(7-alpha, 8-beta, 9-beta, 10- alpha)|-(2-propynyloxy)|-carbamate 8-hydroxy-7-I4-hydroxy-3-(1-(methoxyimino)dethyl)|-8-methyl-2-oxo-2H-1-benzopyran-7- Ilu|-10-methoxy-6-oxaspiro ch dv 4.5 |decan-9-ilu. 20. Compounds of formula (I), according to any of claims 1-18, as well as their pharmaceutically acceptable salts as medicinal products i) 21. Compounds of formula (I), according to claim 19, as well as their pharmaceutically acceptable salts as medicinal products. 22. Pharmaceutical composition containing as an active basis at least one compound defined in claims 20 or 21. 23. The method of obtaining compounds of the formula (I), defined according to any of claims 1-19, which consists in the fact that the compounds of the formula (II) | Gee! ; (1) . 7 on c) -- And! in the village (Se) in. eh Mu Kw Inv, " ". ге) о о о З с и щ . д. з" - Z 15 no OM Ge") where the radicals K", Kz, 2, Kb, Kv and Ku have the above values, OMU means a protective hydroxyl group, and МІ with means an alkyl radical or O-alkyl containing up to 4 carbon atoms, exposed - to the influence of an agent capable of introducing a radical and 50 o V "m s- M-ov, or a number of operations capable of introducing a radical (Ф) Кк! about || 1. where K and Ku have the above values, 60 - the effect of an agent capable of liberating a hydroxyl radical from an OMU radical, - the possible effect of an agent capable of replacing Mu with a radical X, which differs from alkyl or O-alkyl, - the possible effect of an agent, capable of introducing the radical B, which is different from oxygen, to the possible influence of a salt-forming agent. 24. Compounds of formula (II) b5 sho ; (1) . 2 he c) in ! 2 , В х Me Кв Inv, о (в, о (в, yuyu Kk no Shche, where the radicals K", Kz, 2, Kb, Kv and Ku have the above values, OMU means a protective hydroxyl group, and MY means a radical alkyl or O-alkyl containing up to 4 carbon atoms. 25. The method according to claim 23, which differs in that the compound of the formula (II) is obtained by the interaction of the compound of the formula (1); (II c, (t) in bu, . ". Ge) he Kv c 2 sya i z o no "on where Kb, Kv and K7 have the values indicated above, with the compound of the formula (IM): ; (M) M. c Yv- 2 --k Me "- (Se) no o o With "de Ko", Kz and 7 have the above values, under the influence of an agent that blocks the free hydroxyl radical. ; : - 26. Compounds of formula (II), described in claim 25, such as with "from shen RYM; " Meo E Meo dan I YN E ; x (22) no Tse Ge) no Shin. Ge) - because no he NO. he: "- (CHI and ta and MeO E 55 . In h) i) M o NO pe. o name) he x bo she mu ne no y he he 65 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 12, 15.12.2003. State Department of Intellectual Property of the Ministry of Education and