Amides of 4-oxoazetidin-2-sulphonic acids and their salts, method of production thereof

 

(57) Abstract:

The inventive compounds of the formula I, where R1is hydrogen or halogen; R2is hydrogen, halogen, NH2, phenyl-CH2CONH, phenyl-OCH2CONH, phthalimide, O-MeNHCOC6H4CONH, 3-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl; R3is hydrogen, Me2C= C-COOMe, H2C= C(Me)-CH-COOMe, Me2C= C-COOCH2-phenyl, H2C=C(Me)-CHCOOCH2C6H4NO2-p, Me2C=CCOOCH2C6H4NO2-p, Me2C=CCOOCH2C6H4Me-m,

H2C=C(Me)-CH-COOCH2C6H4Me-m, Me2C=C-COOH; R4is hydrogen or sodium; R5- alkyl, benzyl, 5-methylisoxazol, 3,4-dimethylisoxazole and 2-phenylpyrazole and their salts, possess antibacterial activity. Compound I is produced by oxidation of amides Sultanovich acids of the formula II. 2 C. and 37 C.p. f-crystals, 1 PL.

< / BR>

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to the way they are received. These compounds can be used for the manufacture of medicines.

In a number of publications have already described some 4 - oxoazetidin-sulfonic acids [(Chemistry in Britain (1983) 302]. The most famous among them 4-oxoazetidin-1-sodalia some 4-oxoazetidin-2 - sulfonic acids, which is produced by cleavage of bicyclic molecules [Angew. Chem. 95 (1983) 912] or by oxidation of the corresponding derivatives of 4-oxoazetidin-2-Sultanovich acids [patent Yugoslavia P-240/91; patent application Yugoslavia P-1390/91 and patent application EU 92 10 23 35.4/92].

Known also some derivatives of 4-oxoazetidin-2-sulphonic acids, such as chlorides of these acids [application Germany 2556071/76], ethers [Croat. Chem. Acta 62 (1989) 521 - 527] and thioethers [Journ. Chem. Soc. Chem. Commun. 23 (1972) 1304 - 1305].

According to the private information of the applicant regarding the prior art amides of 4-oxoazetidin-2-sulphonic acids and their salts to date is not yet known.

The subject invention are new amides of 4-oxoazetidin - 2-sulphonic acids and their salts of General formula 1

< / BR>
where

R1denotes hydrogen, halogen;

R2denotes hydrogen, halogen, NH2, phenyl-CH2CONH, phenyl-OCH2CONH, phthalimide, o-MeNHCOC6H4CONH, 3-o-chlorophenyl-5-methylisoxazol-4 - ylcarbonyl;

R3denotes hydrogen, Me2C= C-COOMe, H2C=C(Me)-CH-COOMe, Me2C=C-COOCH2-phenyl, H2C=C(Me)-CH-COOCH2C6H4NO2-p, Me2C=C-COOCH2C6H4NO2-p,

Me2C=C-COOCH2C6H
R5denotes alkyl, benzyl, 5-methylisoxazole, 3,4-dimethylisoxazole and 2-phenylpyrazole.

The preferred compounds are the following:

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C= C-COOCH2-phenyl, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C-COOCH2-phenyl, R4denotes sodium and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3denotes hydrogen, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes bromine, R2denotes hydrogen, R3refers to Me2C=C-COOCH2-phenyl, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes bromine, R3refers to Me2C=C-COOCH2-phenyl, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes bromine, R2denotes bromine, R3refers to Me1denotes bromine, R2denotes bromine, R3refers to Me2C=C-COOCH2-phenyl, R4denotes sodium and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C-COOCH2-phenyl, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C - COOCH2-phenyl, R4denotes sodium and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes bromine, R2denotes bromine, R3refers to Me2C= C-COOCH2-phenyl, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C-COOCH2-phenyl, R4denotes hydrogen and R5denotes 3,4-dimethylisoxazol-5-yl;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C-COOCH2-phenyl, R4denotes sodium and R5denotes 3,4-dimethylisoxazol-5-yl;

the connection is phenyl, R4denotes hydrogen and R5denotes 2-phenylpyrazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C-COOCH2-phenyl, R4denotes sodium and R5denotes 2-phenylpyrazol-3-yl;

the compound in which R1denotes hydrogen, R2denotes phenyl-OCH2CONH, R3refers to Me2C=C-COOMe, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes phenyl-OCH2CONH, R3denotes H2C= C(Me)-CH-COOMe, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes phenyl-OCH2CONH, R3refers to Me2C=C-COOMe, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2indicates phthalimido, R3denotes H2C=C(Me)-CH-COOCH2C6H4NO2-p, R4denotes hydrogen, R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2indicates phthalimido, R3aromatisation-C-Il;

the compound in which R1denotes hydrogen, R2denotes phenyl-CH2CONH, R3denotes hydrogen, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes phenyl-CH2CONH, R3refers to Me2C=C-COOCH2C6H4NO2-n, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes phenyl-CH2CONH, R3refers to Me2C=C-COOH, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C=C - COOH, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2indicates C-o-chlorophenyl - 5-methylisoxazol-4-ylcarbonyl, R3denotes H2C= C(Me)-CH-COOCH2C6H4Me-m, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2indicates C-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl, R3aboneaza-C-Il;

the compound in which R1denotes hydrogen, R2indicates phthalimido, R3refers to Me2C= C-COOH, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes the amino group, R3refers to Me2C=C-COOCH2C6H4NO2-p, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes hydrogen, R2denotes o-MeNHCO-C6H4CONH, R3refers to Me2C-COOCH2C6H4NO2-p, R4denotes hydrogen and R5denotes methyl;

the compound in which R1denotes hydrogen, R2denotes o-MeNHCO - C6H4CONH, R3denotes H2C=C(Me)-CH-COOCH2C6H4NO-p, R4denotes hydrogen and R5denotes methyl;

the compound in which R1denotes hydrogen, R2denotes o-MeNHCO - C6H4CONH, R3refers to Me2C=C-COOH, R4denotes hydrogen and R5denotes methyl;

the compound in which R1denotes hydrogen, R2denotes phenyl-CH2CONH, R3refers to Me2C=C-COOH, Rthe, R2denotes phenyl-CH2CONH, R3refers to Me2C=C-COOCH2C6H4NO2-p, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes phenyl - CH2CONH, R3refers to Me2C=C-COOCH2C6H4NO2-p, R4denotes hydrogen and R5denotes methyl;

the compound in which R1denotes hydrogen, R2denotes phenyl-CH2CONH, R3refers to Me2C=C-COOH, R4denotes hydrogen and R5denotes methyl;

the compound in which R1denotes hydrogen, R2denotes hydrogen, R3refers to Me2C= C-COOH, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il;

the compound in which R1denotes bromine, R2denotes bromine, R3refers to Me2C=C-COOH, R4denotes hydrogen and R5denotes benzyl;

the compound in which R1denotes hydrogen, R2denotes phenyl - OCH2CONH, R3refers to Me2C=C-COOH, R4denotes hydrogen and R5denotes 5-methylisoxazol-C-Il.

Another object of the present invention is the radicals have the above significance, by oxidation of amides 4-oxoazetidin-2-Sultanovich acids of General formula II

< / BR>
where

R1denotes hydrogen or halogen;

R2denotes hydrogen, halogen, phenyl-CH2CONH, phenyl-OCH2CONH, phthalimide, o-MeNHCOC6H4CONH, 3-o-chlorophenyl-2 - methylisoxazol-4-ylcarbonyl;

R3refers to Me2C= C-COOMe, H2C=C(Me)-CH-COOMe, Me2C=C-COOCH2-phenyl, H2C= C(Me)-CH - COOCH2C6H4NO2-p, Me2C = C-COOCH2C6H4NO2-p, Me2C = C-COOCH2C6H4Me-m H2C = C(Me) -CH-COOCH2C6H4Me-m;

R4denotes hydrogen;

R5denotes alkyl, benzyl, 5-methylisoxazol, 3,4-dimethylisoxazole and 2-phenylpyrazole.

The oxidation is carried out using known means commonly used in organic chemistry at carrying out oxidative reactions, such as hydrogen peroxide, percetakan acid, m-chloroperbenzoic acid and potassium permanganate in acidic or neutral aqueous or aqueous-organic medium and in the temperature range from 0 to 100oC. All reactions carried out in normal conditions and at normal molar ratios. Processing of the reaction mixture and isolation of the URS response receive various derivatives of amides of 4-oxoazetidin-2-sulphonic acids, described in the following examples. Depending on the type of processing and separation of amides of 4-oxoazetidin-2-sulphonic acids can be obtained as free of amides or their inorganic salts. Amino - and carboxyamide group if necessary otscheplaut by the usual known methods.

Sulfinamide General formula II is produced by interaction of the respective sulphonylchloride with amines is similar to that described in U.S. patent N 4052387 (1977). Sulphonylchloride receive in situ, based on penicillinallergic [see U.S. patent N 4081440 (1978)] or on the basis of sulfinol acid [see Croat. Chem. Acta 62 (1989) 521].

The new compounds according to the invention can find use as intermediates in obtaining various analogues of beta-lactams, especially new bicyclic systems.

Compounds according to the invention can also be used as active substances in the manufacture of drugs antimicrobial action.

Example 1.

(2R, 3R) 1-(1'-methoxycarbonyl-2'-methylprop - 1'-enyl)-2 - benzylaminocarbonyl-3-phenoxyacetamide-4-oxoazetidin.

A solution of methyl ester (5R,6R) 6 - phenoxyacetophenone-sulfoxide (1.9 grams, 5 is b) and the reaction mixture was stirred in a stream of nitrogen at boiling temperature for 1.5 hours The mixture is then cooled to 0oC, treated with benzylamine (of 2.26 g, 21 mmol) and continue stirring for another 2 hours After that the reaction mixture is filtered, the mother liquor is washed with water (290 ml), dried (Na2SO4), filtered and concentrated in vacuo. The remainder elute at silicagel column using a solvent mixture of methylene chloride/methanol (20:1). The resulting mixture (1.8 g, 74.4 per cent) of epimeric (2R,3R) 1-(1'-methoxycarbonyl-2'-methylprop-1'-enyl)-2-benzylaminocarbonyl - 3-phenoxyacetamide-4-oxoazetidin [isomer in excess of1H-NMR (CDCl3) : to 2.13 and 2.26 (6H, 2s, CMe in), 3.75 (3H, s, OMe), 4,13 - 4,50 (5H, m, CH2N, CH2O SNH), of 4.95 (1H, d, J 5.0 Hz, C2H), by 5.87 (1H, dd, J 5.0, and 10.0 Hz, C3H), 6.75 in - 7,37 (5H, m, C6H5O) of 8.47 (1H, d, J 10.0 Hz, CONH) ppm million] dissolved in methylene chloride (35 ml) and formic acid (7 ml), treated with 30% aqueous solution of H2O2(28 ml) and stirred the reaction mixture for 6 h at room temperature. The organic extract was separated, washed with water, dried (Na2SO4), filtered and concentrated. The rest is a foamy product (1.98 g, 95%):

RfO,55 (CH2Cl2:MeOH=20:1)

IR (KBr): 3420 - 3230 m, 1785s, 1735m, 1690s, 1605m, 1530s, 1495m, 1440m, 1370m, 1335m, 1225s, 1162s, 1065s, 995w cm-1>
H) of 5.83 (1H, dd, J and 10.8 Hz, C3H), 6.87 in - 7,44 (5H, m, C6H5O) to 7.77 (1H, d, J and 10.8 Hz, CONH) ppm million

Example 2.

(2R, 3R) 1-(1'-methoxycarbonyl-2'-methylprop-2'-enyl)-2-[(5'- methylisoxazole-3'-yl)aminosulfonyl]-3-phenoxyacetamide-4 - oxoazetidin/

Methyl ester of (5R,6R) 6 - phenoxyacetophenone-sulfoxide (1.9 g, 5 mmol) is subjected to interaction with N-chlorosuccinimide, as described in example 1, and then instead of benzylamine treated with 3-amino-5 - methylisoxazole from 2.06 g, 21 mmol). After mixing and processing of the reaction mixture allocate epimeno a mixture of (2R,3R) 1-(1'- methoxycarbonyl-2'-methylprop-2'-enyl)-2-[(5'-methylisoxazole-3'- yl)-aminosulfonyl] -3-phenoxyacetamide-4-oxoazetidin. After concentrating the toluene solution crystallizes the epimer with so pl. 185 - 190oC. [1H-NMR (CDCl3) : 1,99 (3H, s, Me), of 2.15 (3H, s, Me-isoxazol), 3,85 (3H, s, OMe), 4,43 (2H, bs, OCH2), of 5.05 (1H, s, NCHCO), 5,09 and at 5.27 (2H, 2bs, =CH2), lower than the 5.37 (1H, d, J 4.5 Hz, C2H), 5,79 (1H, s, CH-isoxazol), of 5.84 (1H, dd, J 4.5 and 9.5 Hz, C3H), 6,95 - 7,34 (5H, m, C6H5O), of 7.70 (1H, d, J 9.5 Hz, CONH) 8,29 (1H, s, SNH) frequent. /million; analysis of C21H23O8N4S; fact. : C, 52,42; H, of 5.82; N, 12,02; S 6,34%; Rasch. : C, 52,93; H, TO 5.08; N, 11,76; S, 6.73 X%]. After suction, the crystals are dissolved in methylene chloride and at what get foamy product:

Rf0,20 (CH2Cl2:MeOH = 20:1);

IR (KBr): 3400 - 3000 m, 1795vs, 1690m, 1620m, 1605m, 1535 - 1494s, 1465m, 1440m, 1245s, 1165s cm-1;

1H-NMR (CDCl3: 1,91 (3H, s, Me), to 2.18 (3H, s, Me-isoxazol), with 3.79 (3H, s, OMe), of 4.44 (2H, bs, OCH2), the 4.90 (1H, s, NCHCO), 5,00 and 5.17 (2H, 2bs, = CH2), 5,46 (1H, d, J 5.0 Hz, C2H), 6,01 (1H, dd, J 5.0 and 10,3 Hz, C3H), 6,82 - 7,41 (5H, m, C6H5O) of 7.75 (1H, d, J 10.3 Hz, CONH) ppm million

Example 3.

(2R, 3R)-1-(1'- methoxycarbonyl-2'-methylprop-1'-enyl)-2-[ (5'-methylisoxazole-3'-yl)aminosulfonyl]-3-phenoxyacetamide-4-oxoazetidin.

Obtained according to example 2 sulfinamide (so pl. 185 - 190oC) is dissolved in methylene chloride and then stirred with triethylamine for 2 h at room temperature. After treatment of the reaction mixture by chromatography on silicagel get column (2R,3R) 1-(1'-methoxycarbonyl-2'-methylprop-1'-enyl)-2-[(5'- methylisoxazole-3'-yl)-aminosulfonyl]-3-phenoxyacetamide-4 - oxoazetidin with 80% output:

1H-NMR (CDCl3: to 2.06 and are 2.19 (6H, 2s, CMe2in ), 2.25 (3H, s, Me-isoxazol), 3,76 (3H, s, OMe), 4: 31 and and 4.40 (2H, ABq, J 15,0 Hz, OCH2), of 5.34 (1H, d, J 5.0 Hz, C2H) 5,80 (1H, s, CH-isoxazol), the ceiling of 5.60 (1H, dd, J 5.0 and an 8.8 Hz, C3H), 6,84 - to 7.32 (5H, m, C6H5O-), a 7.92 (1H, d, J 8,8 Hz, CONH), 8,43 (1H, s, SNH-), frequent. /million], which is then oxidized with POM is m:

Rf0,24 (CH2Cl2: MeOH= 20:1);

IR (KBr): 1790s, 1735m, 1700s, 1620m, 1540 - 1495s, 1465m, 1440m, 1380m, 1230s, 1165 cm-1;

1H-NMR (CDCl3) : 2,09 and 2,22 (6H, 2s, CMe2), and 2.26 (3H, s, Me-isoxazol), 3,71 (3H, s, OMe), 4,46 and 4.57 (2H, ABq, J 15,0 Hz, OCH2), of 4.57 (1H, s, SNH), 5,54 (1H, d, J 5.2 Hz, C2H), 6,07 (1H, s, CH-isoxazol), the 6.06 (1H, dd, J of 5.2 and 10.4 Hz, C3H), 6,95 - 7,37 (5H, m, C6H5O) 7,76 (1H, d, J 10.4 Hz, CONH), part./million

Example 4.

(2R, 3R) 1-(1'-p-nitrobenzenesulfonyl-2'- methylprop-2'-enyl)-2-[(5'-methylisoxazole-3'-yl)-aminosulfonyl] -3-phthalimido-4-oxoazetidin/

p-Nitrobenzyloxy ether (5R,6R) 6-phthalimidomethyl-sulfoxide (1.5 g, 3 mmol) is subjected to interaction with N-chlorosuccinimide (0.4 g, 3 mmol) as described in example 1 and then treated with 3 - amino-5-methyl-isoxazol (1.18 g, 12 mmol) and the reaction mixture stirred for 4 h at 10oC. the Toluene solution is decanted, washed with water, dried, filtered and concentrated in vacuo. By chromatography on silicagel column in the solvent system methylene chloride/ethyl acetate (4:1) obtain 0.88 g of (2R, 3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-2'-enyl)-2- [(5'-methylisoxazole-3'-yl)aminosulfonyl]-3-phthalimido-4 - oxoazetidin [1H-NMR (CDCl3) : 1,90 (3H, s, Me), and 2.27 (3H, s, Me-isoxa the 1H, bs, CH-isoxazol), 7,52, and to 8.20 (4H, 2d, J 9,04 Hz, C6H4NO2), 7,71 - of 7.95 (4H, m, phthalimide), and with 8.05 (1H, bs, SNH) frequent. /million] . Interaction with hydrogen peroxide (12 ml, 30% aqueous solution) in methylene chloride (15 ml) and formic acid (2 ml) as described in example 1, get 0,63 g sulfonamida:

Rf0,58 (CH2Cl2:MeOH = 9:1);

IR (KBr): 1805s, 1790s, 1735vs, 1615m, 1525m, 1475m, 1390s, 1350s, 1270w, 1170w, 1110w, 720m cm-1;

1H-NMR (CDCl3) : 2,02 (3H, s, Me), 2,22 (3H, s, Me-isoxazol), to 4.98 (1H, s, NCHCO), 5,09 to 5.35 (4H, m, =CH2, OCH2), to 5.57 (1H, d, J 4.5 Hz, C2H), USD 5.76 (1H, d, J 4.5 Hz, C3H), 5,97 (1H, s, CH-isoxazol), 7,51 and of 8.15 (4H, 2d, J 8,4 Hz, C6H4NO2), 7,69 - with 8.05 (4H, m, phthalimide) part./million

Example 5.

(2R,3R) 2-benzylaminocarbonyl-3-phenylacetamido-4-oxoazetidin.

p-Nitrobenzyloxy ether (5R,6R) 6 - phenylacetonitrile - sulfoxide (2.10 g, 4.3 mmol) is subjected to interaction with N-chlorosuccinimide (0,72 g, 5.4 mmol) as described in example 1, and then using benzylamine (1.5 ml) receive epimeno a mixture of (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-1'-enyl) -2-benzylaminocarbonyl-3-phenylacetamido-4-oxoazetidin (1.78 g, 69.4 per cent); [epimer in excess of1H-NMR (DMSO-d6) :2,11 and 2.25 (6H, 2s, CMe2), 3,53 (2H, s, CH2CO), 3,81 is 4.36 (3H, m, Sm, 2C6H5), 7,44 and 8,17 (4H, 2d, J 9.0 Hz, C6H4NO2) part./million]. The product is dissolved in ethyl acetate (25 ml) and 80% acetic acid (25 ml), then for 1 h at a temperature of 0oC is added dropwise aqueous 4% solution of potassium permanganate (50 ml). Then added dropwise 30% hydrogen peroxide solution to the disappearance of permanganate color. The organic extract was separated, washed with aqueous solution of NaHCO3and water, dried (Na2SO4) and concentrated in vacuo. By chromatography on silicagel column and elution in the solvent system methylene chloride/ethyl acetate (4:1) allocate 0.3 g (23.5%) sulfonamida with so pl. 135 - 137oC:

Rf0,92 (n-BuOH:HOAc:H20=4:1:1);

IR (KBr): 3360m, 3290m, 1770vs, 1655s, 1515m, 1320s, 1135s, 720s cm-1;

1H-NMR (DMSO-d6) : of 3.56 (2H, bs, CH2CO), 4,15 - 4,20 (2H, m, NCH2), is 4.85 (1H, d, J 4,7 Hz, C2H) to 5.57 (1H, dd, J 4.7 and 9.5 Hz, C3H), 7.25 and 7,38 (10H, 2bs, 2C6H5), 7,87 - to 7.93 (1H, m, SNH), 8,49 (1H, d, J 9.5 Hz, CONH), 9,24 (1H, bs, N1H) part./million;

analysis of C18H19N3O4S

fact.: C 57,70, H 5,90, N 11,74, S OF 8.47%

Rasch.: C 57,89, H 5,13. N 11,25, S 8,59%.

Example 6.

(2R, 3R) 1-(1'-carboxy-2'-methylprop-1'-enyl)-2-[(5'- methylisoxazole-3'-yl)aminosulfonyl]-3-Hairdryer (3.0 g, 6.2 mmol) is subjected to interaction with N-chlorosuccinimide (1.0 g, 7.5 mmol) as described in example 1 and then treated with Z-amino-5-methylisoxazole (2.4 g, 25 mmol) and the reaction mixture stirred for 3 h at 5oC. the Toluene solution is decanted, washed with water, dried and concentrated in vacuo. The result of 1.43 g of (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-2'-enyl)-2- [(5'-methylisoxazole-3'-yl)-aminosulfonyl] -3 - phenylacetamido-4-oxoazetidin [so pl. 157 - 160oC;1H-NMR (CDCl3) : of 1.93 (3H, s, Me), to 2.35 (3H, s, Me-isoxazol), 3,61 (2H, s, CH2CO), 4,94 (1H, bs, NCHCO), 5,07 and 5,19 (2H, 2bs, =CH2, 5,13 (1H, d, J 4.8 Hz, C2H), 5,28 (2H, bs, OCH2), to 5.57 (1H, bs, CH-isoxazol), 5,77 (1H, dd, J 4.8 and 9.0 Hz, C3H), 7,22 (5H, bs, C6H5), 7,44 (1H, d, J 9.0 Hz, CONH), 7,49 and 8,21 (4H, 2d, J 8,8 Hz, C6H4NO2) part./million], which under stirring in triethylamine and methylene chloride is transformed into (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-1'-enyl)-2- [(5'-methylisoxazole-3'-yl)aminosulfonyl] -3 - phenylacetamido-4-oxoazetidin [1H-NMR (CDCl3) : 2,18 and 2,22 (6H, 2s, CMe2), was 2.34 (3H, s, Me-isoxazol), 3,61 (2H, s, CH2CO), 5,11 (1H, d, J 4.9 Hz, C2H) a 5.25 (2H, s, OCH2), 5,64 (1H, dd, J 5.0 and an 8.4 Hz, C3H), 5,63 (1H, s, CH-isoxazol), from 7.24 (5H, s, C6H5), 7,26 (1H, d, J 8,4 Hz, CON, the AK outlined in example 1, to oxidize (2R,3R) 1-(1'-p - nitrobenzenesulfonyl-2'-methylprop-1'-enyl)-2-(5'- methylisoxazole-3'-yl)aminosulfonyl-3-phenylacetamido-4 - oxoazetidin.

[Rf0,57 (CH2Cl2: MeOH=8:1) IR (KBr) 3680 - 2500m, 1785s, 1730m, 1665s, 1615m, 1520s, 1350s, 1215m, 1160m cm-1;1H-NMR (CDCl3) : 1,99 and 2.15 (6H, 2s, CMe2, of 2.28 (3H, s, Me-isoxazol) and 3.59 (2H, s, CH2CO), 5,19 (2H, s, OCH2), 5,44 (1H, d, J 5.3 Hz, C2H) of 5.81 (1H, s, CH-isoxazol), of 5.84 (1H, dd, J 5.3 and 9.9 Hz, C3H), at 6.84 (1H, d, J 9.9 Hz, CONH), 7,28 (5H, s, C6H5), 7,45 and 8,17 (4H, 2d, J a 8.9 Hz, C6H4NO2) part./million]. Then the resulting sulfonamide (0.35 g, 0.6 mmol) dissolved in methanol (25 ml) and hydronaut for 2 h at a pressure of 2.4 bar using 10% palladium on coal (50 ml). After that the reaction mixture is filtered and the mother liquor was concentrated in vacuo. The residue is dissolved in methylene chloride (20 ml) and water (20 ml) and addition of sodium bicarbonate is set at a value of pH 8.5. Then the aqueous extract is separated, isolated by shaking with fresh methylene chloride, add a new portion of methylene chloride (15 ml) and additives hydrochloric acid to establish a pH value of 2.2. The organic extract was separated, dried (Na2SO4), filtered and concentrated in vacuo. As a result, 680bs, 1620s, 1465m, 1270m, 1165m, 930w cm-1;

1H-NMR (CDCl3) : 1,93 and 2.07 (6H, 2s, CMe2), to 2.35 (3H, s, Me-isoxazol), to 3.67 (2H, s, CH2CO), of 5.68 (1H, d, J 5.2 Hz, C2H) 6,0 (1H, dd, J of 5.2 and 9.3 Hz, C3H), 6,12 (1H, s, CH-isoxazol), 6,63 (1H, d, J 9.3 Hz, CONH), 7,27-7,31 (5H, m, C6H5) part./million

Example 7.

(2R, 3R) 1-(1'-m - methylbenzyloxycarbonyl-2'-methylprop-2'-enyl)-2-[ (5'-methylisoxazole - 3'-yl)aminosulfonyl] -3-[(3'-o-chlorophenyl-5'-methylisoxazole-4'- yl)carboxamido]-4-oxoazetidin.

m-Methylbenzylamine ether (5R,6R) 6-(3'-o-chlorophenyl-5'-methylisoxazole-4'-yl)- carboxymethycellulose (2.0 g, 3.6 mmol) is subjected to interaction with N-chlorosuccinimide as described in example 1, and then add 3-amino-5-methylisoxazole (1.1 g, 11 mmol) and the reaction mixture stirred for 3 h at room temperature. The mixture is then filtered, the mother liquor is extracted with water (360 ml), dried (Na2SO4), filtered and concentrated in vacuo. The result epimeno compound (1.92 g) of (2R, 3R) 1-(1'-m - methylbenzyloxycarbonyl-2'-methylprop-2'-enyl)-2-[(5'- methylisoxazole-3'-yl)aminosulfonyl]-3-[(3'-o-chlorophenyl-5'- methylisoxazole-4'-yl)carboxamido] -4-oxoazetidin [Rfof 0.40 and 0.26 in methylene chloride/ethyl acetate (4: 1)] . The product dissolve chromatographic on silicagel column and by elution with a solvent mixture of methylene chloride/ethyl acetate. The result of 0.62 g (44%) sulfonamida:

Rf0,55 (CH2Cl2:MeOH=10:1);

IR (KBr): 3405w, 1795vs, 1745s, 1680vs, 1620s, 1520s, 1465s, 1385m, 1340m, 1265m, 1160m, 770m cm-1;

1H-NMR (CDCl3:to 1.79 (3H, s, Me), 2,31 (3H, s, phenyl-Me), 2.35 and of 2.72 (6H, 2s, 2Me-isoxazol), is 4.85 (1H, s, NCHCO), 4,90, and 5,10 (2H, 2s, =CH2), 5,08 and to 5.13 (2H, ABq, J 12.0 Hz, OCH2), 5,44 (1H, d, J 5.0 Hz, C2H) 5,95 (1H, dd, J 5.0 and 9.6 Hz, C3H), 6,04 (1H, s, CH-isoxazol), 6,37 (1H, d, J 9.6 Hz, CONH), 7,01 - 7, 26 and 7,41 - of 7.55 (8H, 2m, 2C6H4) part./million

Example 8.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-benzylamino - sulfonyl-3,3-dibromo-4-oxoazetidin/

Benzyl ether of (5R) 6,6-dibromobenzene-sulfoxide (7.0 g, 15 mmol) is subjected to interaction with N-chlorosuccinimide as described in example 1, after which the reaction continues to perform with benzylamine (4 ml, 37.5 mmol). Then the reaction mixture is sucked off, the mother liquor is washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude product chromatografic on silicagel column by elution with solvents methylene chloride/ethyl acetate (6: 1), resulting in a gain is 3.08 g (36%) of (2R) 1-(1'- benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-benzylaminocarbonyl-3,3 - dibromo-4-oxoazetidin [1H-A - 7,30 (10H, m, 2C6H5) part./million], which oxidizes in chloroform m-chloroperbenzoic acid (1.2 g, 6 mmol). Next, the reaction mixture is stirred first for 20 min at -10oC and then for 1 h at room temperature. After this process a 1 M solution of sodium bisulfite (36 ml, 6 mmol), the organic layer was separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue is dissolved in methylene chloride and passed through silicagel column, resulting in a gain of 2.1 g (59%) of white crystalline product with so pl. 120 - 122oC:

Rf0,88 (CH2Cl2/EtOAc=4:l);

IR (KBr): 3250vs, 1780vs, 1730vs, 1640s, 1444vs, 1370b, 1255s, 1200s, 1165vs, 1055vs, 755vs, 700vs cm-1;

1H-NMR (CDCl3) : 2,09 and of 2.28 (6H, 2s, CMe2), 4.09 to (2H, d, J 5.8 Hz, NCH2phenyl), 4,63 (1H, t, J 5.8 Hz, SNH), 5,08 and of 5.34 (2H, ABq, J 11.7 Hz, OCH2), 5,32 (1H, s, C2H), 7,29 - to 7.35 (10H, m, 2C6H5), part./million

Example 9.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-2- [(5'-methylisoxazole-3'-yl)aminosulfonyl]-3,3-dibromo-4-oxoazetidin.

a) Benzyl ether (5R) 6,6-dibromobenzene-sulfoxide (7.0 g, 15 mmol) is subjected to interaction with N-chlorosuccinimide as described in example 1 and then processed is sucked off, dried, dissolved in methylene chloride (30 ml) and stirred with triethylamine (1.5 ml) for 1 h at 20oC. Then the reaction mixture is washed with 0.1 H hydrochloric acid (pH 1-2) and water, the organic extract is dried (Na2SO4), filtered and concentrated in vacuo. The remainder represents 1.85 g (2R) 1-(1'-benzyloxycarbonyl-2'-methylprop - 1'-enyl)-2-[(5'-methylisoxazole-3'- yl)aminosulfonyl] -3,3-dibromo-4 - oxoazetidin [so pl. 58 - 60oC; Rf0,51 (CH2Cl2: EtOAc=4:l);1H-NMR (CDCl3) : 1,88 and 2.13 (6H, 2s, CMe2), 2,31 (3H, s, Me-isoxazol), to 5.13 (2H, s, OCH2), to 5.56 (1H, s, C2H), 5,67 (1H, s, CH - isoxazol), to 7.35 (5H, s, C6H5and 8,32 (1H, s, SNH) frequent. /million] , which is oxidized with m-chloroperbenzoic acid as described in example 8. The crude product chromatografic on silicagel column by elution with a solvent mixture of methylene chloride/ethyl acetate (4:1), resulting in getting a white crystalline product (52,6%) with T. pl. 168 - 170oC:

RfO,25 (CH2Cl2:EtOAc=4:1);

IR (KBr): 3160m, 1780vs, 1765vs, 1625s, 1500s, 1395vs, 1383s, - 1220s, 1175vs cm-1;

1H-NMR (CDCl3) :to 2.06 and 2.15 (6H, 2s, CMe2), is 2.37 (3H, s, Me-isoxazol), of 5.05 (2H, s, OCH2), 5,70 (1H, s, C2H), 6,07 (1H, s, CH-isoxazol), 7,31 (5H, s, C6H5) chloride (5 ml) and formic acid (5 ml) and oxidized with hydrogen peroxide (0,56 ml) for 1 h at boiling temperature. The cooled reaction mixture is treated with water, the organic layer is separated, shaken with a 5% solution of NaHCO3and water, dried (Na2SO4), filtered and concentrated. The result is a product that is identical to the get method).

Example 10.

(2R) 1-(1'-carboxyl-2'-methylprop-1'-enyl)-2 - benzylaminocarbonyl-3,3-dibromo-4-oxoazetidin.

Ice slurry from trichloride aluminum (0.4 g, 3 mmol) in methylene chloride (15 ml) is treated in a stream of nitrogen with a solution of (2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-2 - benzylaminocarbonyl-3,3-dibromo-4-oxoazetidin (0,59 g, 1 mmol) and anisole (0.65 g, 6 mmol) in methylene chloride (15 ml) and stirred for 30 min at room temperature. Then the reaction solution is treated with ethyl acetate (15 ml) and 0.1 H hydrochloric acid (5 ml). Then the layers are separated and an ethyl acetate layer is extracted with 5% aqueous sodium hydrogen carbonate solution (220 ml). Then the layers re-share. Water extract using a 0.1 H hydrochloric acid set at pH 1, treated with fresh ethyl acetate (20 ml) and sodium chloride and produce by careful shaking. An ethyl acetate layer is separated, re-ol(98%) of the desired product with so pl. 47 - 50oC:

RfO,66 (EtOAc:MeOH=3:l);

IR (film): 3300m, 2960-2930m, 1805vs, 1700s, 1625m, 1425m, 1350s, 1160s cm-1;

1H-NMR (DMSO-d6) :1,98 and of 2.23 (6H, 2s, CMe2), and 4.09 to 4,20 (2H, ABX, J 5,7, 6,0 and 15.2 Hz, CH2phenyl), the 5.51 (1H, s, C2H), 7,29 - 7,39 (5H, m, C6H5), 8,49 (1H, dd, J 5.7 and 6.0 Hz, NH), and 13.5 (1H, b, COOH) ppm million

Example 11.

(2R) 1-(1'- carboxyl-2'-methylprop-1'-enyl)-2-benzylaminocarbonyl-4 - oxoazetidin.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-4 - oxoazetidin - 2-sulinowo acid (3,23 g, 10 mmol) is dissolved in thionyl chloride (20 ml) and the solution stirred for 1 h at 25oC. the Excess thionyl chloride concentrated under reduced pressure to education oily residue, after which it is dissolved in methylene chloride (50 ml), the solution is cooled to 10oC and under stirring and cooling process 5% solution of benzylamine in methylene chloride to obtain pH 7 and at this temperature, continue to mix for another 30 minutes Besieged hydrochloric acid salt of benzylamine sucked off and washed with methylene chloride. The mother liquor is treated with water (50 ml), the mixture is acidified with 10% hydrochloric acid to pH 1.3 and layers dissolve, then the organic layer is repeatedly washed with the dimensional (2R) 1-(1'-benzyloxycarbonyl-2'- methylprop-1'-enyl)-2 - benzylaminocarbonyl-4-oxoazetidin with Rf-value of 0.64 and 0.72 (CH2Cl2/EtOAc= 2: 1), which is shared by chromatography on silicagel column. [Substance with Rf-value of 0.64: IR (CH2Cl2): 3020vs, 2980s, 1760vs, 1700m, 1415m, 1260vs, 1210s, 1070m, 900s, cm-1;

1H-NMR (CDCl3) : 1,95 2.24 (6H, 2s, CMe2), the 3.11 (1H, dd, J 5.0 and 15.3 Hz, C3H), 3,39 (1H, dd, J 2.6 and 15.3 Hz, C3H) 4,0 - 4,3 (3H, m, SNHCH2), of 4.77 (1H, 2d, J 2.6 and 5.0 Hz, C2H), 5.08 to and from 5.29 (2H, ABq, J 12.0 Hz, CH2phenyl), to 7.32 (10H, s, 2C6H5) part./million; [substance with Rf-value 0,72:

IR (CH2Cl2): 3025vs, 2980s, 1755vs, 1700m, 1420m, 1260vs, 1210s, 1075m, 900s cm-1;

1H-NMR (CDCl3) : 2,08, and of 2.21 (6H, 2s, CMe2), 2,94 and to 3.16 (2H, 2d, J of 3.2 and 4.7 Hz, C3H and C3H) 4,19 (3H, b, NHCH2), of 4.77 (1H, dd, J 3.2 and a 4.7 Hz, C2H) of 5.06 and 5,28 (2H, ABq, J 12.3 Hz, CH2phenyl), to 7.32 (10H, s, 2C6H5) frequent. /million] . Sulfinamide (1.65 g, 4 mmol) is subjected to interaction with 10 potassium permanganate, as described in example 5. After a brief presence of the coloring caused by the use of potassium permanganate, the reaction ends. The result of 1.32 g (77%) of (2R) 1-(1 - benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-benzylaminocarbonyl - 4-oxoazetidin, which purify by chromatography on silicagel column by er>C;

IR (KBr): 3300vs, 1775vs, 1650vs, 1430m, 1350s, 1335s, 1290vs, 1200m, 1150s, 1070w cm-1;

1H-NMR (CDCl3) : 2.05 and of 2.23 (6H, 2s, CMe2), and 3.16 (2H, d, J 3.8 Hz, C3H and C3H) 4,08 (2H, d, J 5,9 Hz, NCH2), 4,50 (1H, t, J 5.0 Hz, NH), 4,89 (1H, t, J 3.8 Hz, C2H) 5,09 and is 5.18 (2H, ABq, J 12.0 Hz, CH2phenyl), 7.25 and 7,34 (10H, 2s, 2C6H5)part./million].

The resulting sulfonamide (0.4 g, of 1.16 mmol) analogously to that described in example 6, hydronaut and process, resulting in a gain of 0.36 g acid:

Rf0,88 (n-BuOH:HAc:H20=4:1:1);

IR (KBr): 3260s, 1760vs, 1700s, 1630m, 1430m, 1330s, 1170s, 1070m cm-1;

1H-NMR (CDCl3) : 2,09 and 2.26 (6H, 2s, CMe2), 3,17 (2H, d, J 4,1 Hz, C3H), 4.26 deaths (2H, s, NCH2), to 4.98 (1H, t, J 4,1 Hz, C2H), 7,30 (5H, s, C2H) part./million

Example 12.

(2R) 2-benzylaminocarbonyl-4-oxoazetidin.

a) (2R) 1-(1'-methoxycarbonyl-2'-methylprop-1'-enyl)-4 - oxoazetidin-2-sulinowo acid (5.0 g, 20 mmol) is dissolved in thionyl chloride (20 ml) and treated as described in example 11. The result is a mixture of 5.4 g, 80,4%) of epimeric (2R) 1-(1'- methoxycarbonyl-2'-methylprop-1'-enyl)-2-benzylaminocarbonyl-4 - oxoazetidin with Rf-values of 0.20 and 0.27 (CH2Cl2/EtOAc= 2:1), which is shared by chromatography on silicagel /SUP>H-NMR (CDCl3) : 1,99, and of 2.23 (6H, 2s, CMe2), 3,17 (1H, dd, J 5.0 and 15.2 Hz, C3H), of 3.46 (1H, dd, J 2.6 and 15.2 Hz, C3H in), 3.75 (3H, s, OCH3), 4,15 - 4,30 (1H, b, NH), to 4.23 (2H, s, CH2phenyl), to 4.92 (1H, 2d, C2H, J 2.6 and 5.0 Hz), 7,31 (5H, s, C6H5) part./million; substance with Rf-value of 0.27: IR (CH2Cl2): 3300m, 2950m, 1775vs, 1720s, 1360s, - 1220s, 1080s cm-1;1H-NMR (CDCl3) : 2,07 and of 2.20 (6H, 2s, CMe2), of 2.97 (1H, dd, J 3.1 and 15,5 Hz, C3H) at 3.25 (1H, dd, J 5.0 and 15,5 Hz, C3H) to 3.73 (3H, s, OCH3), 4,15 - to 4.33 (1H, b, NH), 4.26 deaths (2H, s, CH2phenyl), a 4.83 (1H, 2d, J 3.1 and 5.0 Hz, C2H) to 7.32 (5H, s, C6H5) part./million]. Sulfinamide (3,36 g, 10 mmol) is subjected to interaction with potassium permanganate, as described in example 5. The oily product (2.5 g) is treated with simple ether (30 ml) and the resulting gelatinousness mass was stirred at room temperature for 8 hours the Precipitated crystalline product is sucked off and washed with simple ether. so pl. 111 - 130oC, Rf0,10 (benzene/tOA= 3:1); IR (KBr): 3300vs, 1790vs, 1740vs, 1430s, 1330s, 1300s, 1120s, 1070s cm-1;1H-NMR (DMSO-d6) : 2,96 (3H, dd, J 2.1 and 15.2 Hz, C3H) 3,29 (1H, dd, J 4.7 and 15.2 Hz, C3H) to 4.23 (2H, d, J 5,9 Hz, NCH2), 4,71 (1H, dd, J 2.1 and a 4.7 Hz, C2H), 7,33 (5H, s, C6H5), of 7.96 (1H, t, J 5,9 Hz, SNH), of 8.92 (1H, s, N2H) part./million

b) (2R) 1-(1'- benzyloxy the method (a) is subjected to interaction with potassium permanganate, in the result, get the identical product.

Example 13.

(2R) 1-(1'- carboxyl-2'-methylprop-1'-enyl)-2-[(5'-methylisoxazole-3'- yl)aminosulfonyl]-4-oxoazetidin.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl) -4 - oxoazetidin-2-sulinowo acid (3,23 g, 10 mmol) is dissolved in thionyl chloride (10 ml). The solution is stirred for 1 h at 25oC. the Excess thionyl chloride concentrated under reduced pressure to education oily residue. Then the residue is dissolved in methylene chloride (50 ml), treated with Z-amino-5-methylisoxazole (2,94 g, 30 mmol) and stirred for 3 h at room temperature. Next, the reaction mixture is treated with water (50 ml) and with 10% hydrochloric acid install on the pH value of 1.5. Then the layers separated. The organic layer is repeatedly washed with water (50 ml). After that, the organic layer is repeatedly treated with water (50 ml) and with saturated sodium hydrogen carbonate solution set to the value of pH 8.0. The layers separated, the organic layer is repeatedly washed with water, dried over sodium sulfate and evaporated until dry. The result is a mixture of 3.80 g, 92.6 per cent) epimeric (2R) 1-(1'- benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-[(5'-methylisoxazole-3T by chromatography on silicagel column.

[Substance with Rf-value of 0.29: IR (CH2Cl2): 1780vs, 1720m, 1620s, 1465s, 1360s, 1290m, 1215s, 1100s, 1080m cm-1;

1H-NMR (CDCl3) : 1,98 and of 2.20 (6H, 2s, CMe2), was 2.34 (3H, s, Me-isoxazol), or 3.28 (1H, dd, J 4.7 and 15,5 Hz, C3H), of 3.54 (1H, dd, J 2.6 and 15,5 Hz, C3H) of 5.06 (1H, dd, J 2.6 and a 4.7 Hz, C2H), 5,19 (2H, s, CH2phenyl), of 5.82 (1H, s, CH-isoxazol), 7,33 (5H, s, C6H5), to 8.40 (1H, s, NH) ppm million;

substance with Rf-value of 0.35; IR (CH2Cl2): 1780vs, 1725m, 1630s, 1470s, 1360m, 1290m, - 1220s, 1100s cm-1;

1H-NMR (CDCl3) : 2,09 2.24 (6H, 2s, CMe2), a 2.36 (3H, s, Me-isoxazol), totaling 3.04 (1H, dd, J 2.9 and 15,5 Hz, C3H), 3,30 (1H, dd, J 5.0 and 15,5 Hz, / C3H), 5,11 (1H, dd, J 2.9 and J 5.0 Hz, C2H) to 5.21 (2H, s, CH2phenyl), 5,80 (1H, s, CH-isoxazol), 7,26 (5H, s) ppm million].

Solution sulfinamide (a 4.03 g, 10 mmol), m-chloroperbenzoic acid (4,30 g, 25 mmol) and ethyl acetate (50 ml) is stirred for 24 h at room temperature. After the reaction are added dropwise aqueous sodium thiosulfate solution (15 mmol) and continue to mix for another 30 minutes Then the reaction mixture with 5% aqueous sodium hydrogen carbonate solution set at pH 8.5 and the layers separated. The water component is saturated with sodium chloride and extracted with ethyl acetate (330 ml). about status. The result is 3.5 g (79%) of crude product in the form of sodium salt. After dissolving the crude product in water and acidification of 10% hydrochloric acid solution until a pH value of 2.0 to obtain (2R) 1-(1'- benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-[(5'-methylisoxazole-3'- yl)aminosulfonyl]-4-oxoazetidin [so pl. 141 - 143oC (crystallization of simple ether); Rf0,40 (CH2Cl2:EtOAc = 2:1); IR (KBr): 3200s, 1790vs, 1720vs, 1620s, 1465s, 1395s, 1300s, 1175s cm-1;1H-NMR (CDCl3) : 2,02 and 2.14 (6H, 2s, CMe2), is 2.37 (3H, s, Me-isoxazol), 3,32 (2H, d, J 3.5 Hz, C3H and C3H) to 5.10 (2H, s, CH2phenyl), 5,28 (1H, t, J 3.5 Hz, C2H), 6,10 (1H, s, CH-isoxazol), to 7.25 (5H, s, C6H5) part./million

Analysis: C19H21N3O6S; fact.: C, 54,21; H, OF 5.34; N, 9,96, S, 8,23%;

Rasch.: C, 54,41, H, OF 5.05, N, 10,02, S, OF 7.64%].

The resulting sulfonamide (419 mg, 1 mmol) hydronaut and treated as described in example 6. The result 227 mg (69%):

Rfof 0.91 (n-BuOH:HAc:H20=4:1:1);

IR (KBr): 3600 - 3000b, 3175s, 1795s, 1760s, 1680vs, 1620vs, 1520m, 1470vs, 1400vs, 1310s, 1270m, 1180vs, 1080m, 1045m cm-1;

1H-NMR (DMSO-d6) : 1,89 and 2.13 (6H, 2s, CMe2), to 2.35 (3H, s, Me-isoxazol), 3,21 (1H, dd, J 1.8 and 15.3 Hz, C3H), 3,55 (1H, dd, J 4.5 and 15.3 Hz, C3H) of 5.34 (1H, dd, J 1.8 and 4.5 Hz, C2H), 6,07 (1H, s, CH-isoxazol), made 11.32 (1H, bs, NH), 13 is isoxazol - 5'-yl)aminosulfonyl]-4-oxoazetidin.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-4 - oxoazetidin-2-sulinowo acid (3,23 g, 10 mmol) is dissolved in thionyl chloride (10 ml). The solution is stirred for 1 h at 25oC. Excess thionyl chloride concentrated under reduced pressure to education oily residue. Then obtained after concentration the residue is dissolved in methylene chloride (50 ml), treated with 5-amino-3,4-dimethylisoxazole (of 3.78 g, 30 mmol) and carry out further processing, as described in example 13. The result is a mixture of (3,20 g, 76.7 percent) of epimeric (2R) 1-(1'- benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-[(3', 4'- dimethylisoxazol-5'-yl)aminosulfonyl]-4-oxoazetidin with Rf- values at 0.31 and 0.38 (CH2Cl2/EtOAc= 2:1), which is shared by chromatography on silicagel column [substance with Rfthe value of 0,31: IR (KBr): 1790vs, 1730m, 1710s, 1650s, 1370m, 1300m, 1225vs, 1100m cm-1;1H-NMR (CDCl3) : 1,82, 1,97, 2,16, 2,20 (12H, 4s, 4Me), 3,17 (1H, d, J 4,1 Hz, C3H) to 3.45 (1H, d, J 3.2 Hz, C3H) 5,04 (1H, dd, J of 3.2 and 4.1 Hz, C2H), of 5.24 (2H, s, CH2phenyl), to 7.35 (5H, s, C6H5), 7,87 (1H, s, NH) ppm million; substance with Rf-value of 0.38; IR (KBr): 1785vs, 1730s, the 1700s, 1650s, 1370m, 1300m, 1230s, 1100s cm-1;1H-NMR (CDCl3) : 1,81, 2,10, 2,17, 2,24 (12H, 4s, 4Me), to 3.09 (1H, d, J 2.9 Hz, C3H), 3,3 is./million].

Solution sulfinamide (4,17 g, 10 mmol), meta-chlorbenzoyl acid (4.3 g, 25 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 24 h and treated further as described in example 13. The result is 3.2 g (70%) of product in the form of sodium salts with so pl. 160oC:

Rfof 0.44 (EtOAc);

IR (CH2Cl2): 1790vs, 1730m, 1365s, - 1220s, 1170s, 1070m cm-1;

1H-NMR (CDCl3) : 1,90, 2,03, 2,21, 2,23 (12H, 4s, 4Me), 3,29 (2H, d, J 4.0 Hz, C3H and C3H) to 5.17 (1H, t, J 4.0 Hz, C2H), of 5.24 (2H, s, CH2phenyl), to 7.35 (5H, s, C6H5) part./million

Example 15.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-2- [(2'-phenylpyrazol-3'-yl)aminosulfonyl]-4-oxoazetidin.

(2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-4-oxoazetidin-2 - sulinowo acid (10 mmol) is dissolved in thionyl chloride (3,23 g, 10 ml) and treated as described in example 13, and instead of Z-amino-5-methylisoxazole add 2-phenyl-C-aminopyrazole (4.77 g, 30 mmol). The result is a mixture of 4.04 g, 86%) of epimeric (2R) 1-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-2-[(2'- phenylpyrazol-3'-yl)aminosulfonyl]-4-oxoazetidin with Rf-values of 0.44 and 0.50 (CH2Cl2/EtOAc= 2:1), which is shared by chromatography on the>1H-NMR (CDCl3) : 1,93 and 2.16 (6H, 2s, CMe2), 2,96 (1H, dd, J 4.9 and 15.3 Hz, C3H), of 3.07 (1H, dd, J 2.5 and 15.3 Hz, C3H), 4,79 (1H, dd, J 2.5 and 4.9 Hz, C2H) 5,14 (2H, s, CH2phenyl), 6,22 and EUR 7.57 (2H, 2d, J 1.9 Hz, =CH-CH=), 7,26 was 7.45 (10H, m, 2C6H5) part./million; substance with Rf-value of 0.50:IR (KBr): 1780vs, 1720s, 1600m, 1500s, 1455m, 1385m, 1360m, 1290m, - 1220s, 1100s, 1070m cm-1;1H-NMR (CDCl3) : 2,01 and 2.13 (6H, 2s, CMe2), 2,80 (1H, dd, J 2.3 and 15,5 Hz, C3H) of 2.92 (1H, dd, J 5.3 and 15,5 Hz, C3H) 4,80 (2H, b, C2H) 5,09 and is 5.18 (2H, ABq, J and 12.4 Hz, CH2phenyl), 6,21 and 7,58 (2H, 2d, J 1.6 Hz, =CH-CH=), 7,20 - 7,40 (10H, m, 2C6H5) frequent. /million Solution sulfinamide (with 4.64 g, 10 mmol), m-chloroperbenzoic acid (4.3 g, 25 mmol) and ethyl acetate (50 ml) is stirred for 24 h at room temperature and processed as described in example 13. The result is 3.4 g (67%) of product in the form of sodium salt:

Rfto 0.47 (EtOAc);

IR (CH2Cl2): 3340w, 1785s, 1725m, 1700m, 1500s, 1390s, 1360s, 1290m, 1215s, 1170s, 1075m cm-1;

1H-NMR (CDCl3) : 1,96 and 2.16 (6H, 2s, CMe2), is 2.88 (1H, dd, J 5,2 and 15.5 Hz, C3H) to 3.00 (1H, dd, J 2.3 and 15,5 Hz, C3H) to 4.92 (1H, dd, J 2.3 and 5.2 Hz, C2H) 5,07 and is 5.18 (2H, ABq, J 12.1 Hz, CH2phenyl), 6,20 and 7,56 (2H, 2d, J 1.7 Hz, =CH-CH=), 7,20-7,40 (10H, m, 2C6H5) part./million

Example 16.

(2R, 3R) 1-(1'-m - methylbenzoic is oxamide]-4-oxoazetidin.

Epimeno mixture of sulfinamides (2.24 g) obtained by the method described in example 7, is dissolved in methylene chloride (10 ml) and stirred with triethylamine (0,48 ml) for 2 h at room temperature. Then extracted first with the help of 0.1 H hydrochloric acid (5 ml) and then with water (10 ml), after which the organic extract is dried (Na2SO4), filtered and concentrated in vacuo. The result of 2.23 g (99,5%) of crude product, from which by chromatography on silicagel column and elution with a solvent mixture of CH2Cl2/EtOAc get (2R,3R) 1-(1'-m-methylbenzyloxycarbonyl-2'-methylprop-1'-enyl)-2- [(5'-methylisoxazole-3'-yl)aminosulfonyl] -3-[(3'-o-chlorophenyl-5'- methylisoxazole-4'-yl)carboxamido]-4-oxoazetidin.

[Rf0,21 (CH2Cl2/EtOAc= 4: 1); so pl. 94-96oC;1H-NMR (CDCl3) : 1,95 and 2,22 (6H, 2s, CMe2, and 2,35 2,33 (6H, 2s, 2Me-isoxazol), 2,77 (3H, s, Me-phenyl), 4,96 (1H, d, J 4.5 Hz, C2H) to 5.13 (2H, bs, OCH2), 5,61 (1H, dd, J 4.5 and 8.5 Hz, C3H) 5,72 (1H, s, CH-isoxazol), 6,69 (1H, d, J 8.5 Hz, CONH),? 7.04 baby mortality - AT 7.55 (8H, m, 2C6H5) part./million], which is then oxidized with hydrogen peroxide as described in example 1. The result is a sulfonamide with 85,8% output:

Rf0,55 (CH2Cl;

1H-NMR (CDCl3) :1,94 and 2,11 (6H, 2s, CMe2), and 2.26 and of 2.33 (6H, 2s, 2Me-isoxazol), of 2.72 (3H, s, Me-phenyl), free 5.01 (2H, bs, OCH2), are 5.36 (1H, d, J 5.0 Hz, C2H), 5,71 - of 5.92 (2H, m, C3H and CH-isoxazol), 6,41 (1H, d, J 10 Hz, CONH), 7,01 TO 7.62 (8H, m, 2C6H4) part./million

Example 17.

(2R, 3R) 1-(1'-carboxyl-2'-methylprop-1'-enyl)-2-[(5'-methylisoxazole - 3'-yl)aminosulfonyl]-C-phthalimido-4-oxoazetidin.

(a) Obtained according to example 4 (2R,3R) 1-(1'-p - nitrobenzyl-oxycarbonyl-2'-methylprop-2'-enyl)-2-[(5'-methylisoxazole - 3'-yl)aminosulfonyl] -3-phthalimido-4-oxoazetidin dissolved in methylene chloride and stirred with triethylamine, resulting in getting (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-1'- enyl)-2-[(5'-methylisoxazole-3'-yl) aminosulfonyl]-3-phthalimido - 4 - oxoazetidin [1H-NMR (CDCl3) : and 2.14 (6H, bs, CMe2), 2,31 (3H, s, Me-isoxazol), 5,08 and 5,23 (2H, ABq, J 13.5 Hz, OCH2), to 5.58 (1H, d, J 5.4 Hz, C2H), 5,71 (1H, bs, CH-isoxazol), 6,0 (1H, d, J 5.4 Hz, C3H), 7,45 and 8.16 (4H, 2d, J 9.0 Hz, C6H4NO2), 7,70-7,94 (4H, m, phthalimide) frequent. /million] , which by oxidation with hydrogen peroxide, as described in example 1, to obtain (2R,3R) 1-(1'-p - nitrobenzenesulfonyl-2'-methylprop-1'-enyl)-2-[(5'-methylisoxazole - 3'- yl)aminosulfonyl]-C-phthalimido-4-oxoazetidin [Rf2), 2,32 (3H, s, Me-isoxazol), to 5.21 (2H, bs, OCH2), 5,73 (1H, d, J 5.4 Hz, C2H) of 5.83 (1H, d, J 5.4 Hz, C3H), equal to 6.05 (1H, bs, CH-isoxazol), 7,50 and 8,18 (4H, 2d, J 9.0 Hz, C6H4NO2), 7,60 - 7,86 (4H, m, phthalimide) part./million]. The sulfonamide (840 mg, 1.38 mmol) was dissolved in methanol (25 ml), hydronaut and treated as described in example 6. Mixing organic extract at room temperature emit acid (490 mg, 75%) so pl. 160 - 165oC:

IR (KBr): 3515m, 3200m, 1795s, 1780s, 1735vs, 1685m, 1625m, 1525w, 1475m, 1415m, 1390vs, 1310w, 1180m cm-1;

1H-NMR (DMSO-d6) : 2,17 (6H, s, CMe2), and 2.27 (3H, s, Me-isoxazol), and 3.31 (2H, bs, SNH, COOH, HOH), of 5.68 (1H, d, J 4.9 Hz, C2H), of 5.82 (1H, d, J 4.9 Hz, C3H) of 5.89 (1H, s, CH-isoxazol), 7,92 (4H, s, phthalimido) part./million

b) Obtained according to example 4 of the sulfonamide (0,63 g) dissolved in methylene chloride (10 ml) and 10oC for 5 h and stirred with triethylamine (0.1 g). By chromatography on silicagel column from the concentrated residue receive 0,57 g sulfonamida, which are identical to those described in a) and from which by hydrogenolysis get acid.

Example 18.

(2R, 3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-1' -enyl)-2-[(5'-methylisoxazole-3'-yl)aminosulfonyl]-3-amino-4 - oxoazetidin.

Example 19.

(2R, 3R) 1-(1'-carbonyl-2'-methylprop-1'-enyl)-2-methylaminomethyl-3-o - methylaminoanthraquinone-4-oxoazetidin.

p-Nitrobenzyloxy ether (5R,6R) 6-phthalimidomethyl-sulfoxide (1.5 g, 3 mmol) is subjected to interaction with N-chlorosuccinimide (0.4 g, 3 mmol) as described in example 1, after which the reaction solution is cooled to 5oC and treated with methylamine (1 ml) in toluene (4 ml). Then the reaction mixture was stirred for 3 h at 5oC and concentrated in vacuo. The residue is suspended in methylene chloride (15 ml), insoluble components are sucked off and the mother liquor was concentrated in vacuo. The result epimeno the mixture of 1.53 g of (2R,3R) 1-(1 '-p-nitrobenzyl the [IR (film): 3250bm, 3065w, 2950w, 1780s, 1730sh, 1715vs, 1650m, 1605w, 1525s, 1350s, 1295m, 1220m, 1185s, 1060m, 855w, 820w, 740m cm-1], which oxidizes hydrogen peroxide as described in example 1. The result of 1.23 g of (2R,3R) 1-(1'- p-nitrobenzenesulfonyl-2'-methylprop-1'-enyl)-2 - methylaminomethyl-3-o-methylaminoanthraquinone-4 - oxoazetidin [Rf0,81 (CH2Cl2:MeOH = 9:1);1H-NMR (CDCl3) : 2,15 and 2,31 (6H, 2s, CMe2), of 2.86 (3H, d, J 4.5 Hz, CONMe), 2,98 (3H, d, J 4.9 Hz, SO2NMe), 5,16 (1H, d, J 4.9 Hz, C2H), 5,31 and 5.38 (2H, ABq, J 13,2 Hz, OCH2), 5,94 (1H, dd, J 4.9 and 10.4 Hz, C3H) 6,38 (1H, m, SO2NH), 6,97 (1H, d, J 10.4 Hz, CONH), 7,18 (1H, q, J 4.9 Hz, CONH), 7,44 - 7,52 (4H, m, OCC6H4CO), 7,54 and of 8.25 (4H, 2d, J 8.7 Hz, C6H4NO2) part./million], of which by hydrogenolysis as described in example 17, are acid (0.68 g) so pl. 142oC (decomposition).

IR (KBr): 3410m, 3370m, 3170m, 2960m, 1785vs, 1720s, 1680s, 1615s, 1600w, 1560w, 1515m, 1440w, 1415w, 1375w, 1330s, 1315s, 1285s, 1210s, 1185w, 1155w, 1080m, 735m, 700m cm-1;

1H-NMR (DMSO-d6) : 2,01 and are 2.19 (6H, 2s, CMe2), of 2.64 (3H, d, J 4.5 Hz, CONMe), a 2.75 (3H, d, J 4,7 Hz, SO2NMe), of 5.24 (1H, d, J 5.0 Hz, C2H), the 5.65 (1H, dd, J 5.0 and 8.7 Hz, C3H), 7,17 (1H, q, J 4,7 Hz, SO2NH), of 7.48 - 7,56 (4H, m, C6H4), scored 8.38 (1H, q, J 4.5 Hz, CONH), 9,07 (1H, d, J 8.7 Hz, CONH) ppm million

Example 20.

(2R,3R) 1-(1'- carboxyl-2'-methylprop-1'-enyl)-2-penicillanic-sulfoxide (3.0 g, 6.2 mmol) is subjected to interaction with N-chlorosuccinimide (1.0 g, 7.5 mmol), as described in example 1 and then treated with benzylamine (1.3 ml, 12.4 mmol) and the reaction mixture stirred for 2 h at 5oC. the Toluene solution is decanted, washed with water, dried and concentrated in vacuo. Due to the addition of ethyl acetate to obtain (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-2'-enyl)-2 - benzylaminocarbonyl-3-phenylacetamido-4-oxoazetidin, which is sucked off (1,82 g) [1H-NMR (CDCl3) : 1,91 (3H, s, Me), of 3.48 (2H, s, CH2CO), 3.95 to 4,32 (3H, m, SNHCH2), 4,80 - 5,14 (4H, m, NCHCO=CH2C2H), of 5.26 (2H, bs, OCH2), by 5.87 (1H, dd, J 5.0 and 9.8 Hz, C3H) of 6.52 (1H, d, J 9.8 Hz, CONH), 7,12-7,37 (10H, m, 2C6H5), 7,47 and by 8.22 (4H, 2d, J 8,8 Hz, C6H4NO2) part./million], using triethylamine in methylene chloride will isomerized in (2R, 3R) 1-(1'-p-nitrobenzenesulfonyl - 2'-methylprop-1'-enyl)-2-benzylaminocarbonyl - 3-phenylacetamido-4-oxoazetidin (1.66 g) and oxidized by hydrogen peroxide, as described in example 1. The result is (2R, 3R) 1-(1'-p-nitrobenzenesulfonyl - 2'- methylprop-1'-enyl)-2-benzylaminocarbonyl-3-phenylacetamido - 4-oxoazetidin (1,57 g):

Rf0,60 (CH2Cl2/EtOAc=4:1);1H-NMR (CDCl3: to 2.06 2.24 (6H, 2s, CMe2), 3,59 - 3,98 (5H, m, CH00 - of 7.36 (10H, m, 2C6H5), 7,42 and 8,19 (4H, 2d, J 8,8 Hz, C6H4NO2frequent. /million] , which is then, as indicated in example 6, hydronaut. As a result, there 0,91 g of the product:

Rf0,38 (CH2Cl/MeOH=4:1);

IR (film): 3500 - 2300bm, 1785s, 1740 - 1600bs, 1525m, 1340s, 1270m, 1210m, 1160s, 1070m, 740m, 705s cm-1;

1H-NMR (CDCl3) : 2,07 and 2.25 (6H, 2s, CMe2), 3,56, and to 3.64 (2H, ABq, J 14,8 Hz, CH2CO), 3,98 - was 4.02 (3H, m, SNHCH2), 4,94 (1H, d, J 5.2 Hz, C2H), of 5.84 (1H, dd, J of 5.2 and 10.3 Hz, C3H) 6,77 (1H, d, J 10.3 Hz, CONH), 7,11-7,37 (10H, m, 2C6H5) part./million

Example 21.

(2R, 3R) 1-(1'-carboxyl-2'-methylprop-1'-enyl)-2-methylaminomethyl-3-phenylacetamido-4-oxoazetidin.

p-Nitrobenzyloxy ether (5R,6R) 6-phenylacetonitrile-sulfoxide (3.0 g, 6.2 mmol) is subjected to interaction with N - chlorosuccinimide (1.0 g, 7.5 mmol), as described in example 1 and then treated with methylamine (1 ml) and the reaction mixture stirred for 2 h at 5oC. Then the precipitate is sucked off, the mother liquor is washed with water, dried and concentrated in vacuo. After chromatography on silicagel get column (2R,3R) 1-(1'- p-nitrobenzenesulfonyl-2'-methylprop-1'-enyl)-2 - methylaminomethyl-3-phenylacetamido-4-oxoazetidin (1.63 g).

1H-NMR (CDCl2), 5,80 (1H, dd, J 5.0 and 9.9 Hz, C3H), 7,19 (1H, d, J 9.9 Hz, CONH), 7,26 - 7,38 (5H, m, C6H5), 7,50 and 8,24 (4H, 2d, J 8.7 Hz, C6H4NO2) part./million], which is then oxidized with hydrogen peroxide as described in example 1. The result is (2R, 3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-1-enyl) -2-methylaminomethyl-3-phenylacetamido-4-oxoazetidin (0,98 g)

[IR (KBr): 3460 - 3140bw, 1785s, 1730m, 1700 - 1675bm, 1610w, 1525s, 1350s, 1220m, 1155m, 1070m, 850w cm-1;

1H-NMR (CDCl3) : 2,09 and 2.26 (6H, 2s, CMe2), the 2.46 (3H, d, J 5.0 Hz, NMe), 3,17 (1H, q, 5.0 Hz, SNH), 3,55, and of 3.69 (2H, ABq, J 14,5 Hz, CH2CO), equal to 4.97 (1H, d, J 5.0 Hz, C2H), 5,27 and 5,33 (2H, ABq, J 13,2 Hz, OCH2), 5,80 (1H, dd, J of 5.2 and 10.3 Hz, C3H) to 6.58 (1H, d, J 10.3 Hz, CONH), 7,32-7,51 (5H, m, C6H5), 7,50 and 8,23 (4H, 2d, J 8.7 Hz, C6H4NO2) part./million]. The resulting sulfonamide hydronaut, as described in example 6, and the resultant hydrogenolysis acid (0,43 g) are:

IR (KBr): 3660 - 2440bm, 1785s, 1740 - 1620bm, 1335m, 1160m, 1075w, 740w, 705w cm-1;

1H - NMR (CDCl3) :2,07 and 2.25 (6H, 2s, CMe2), 2,53 (3H, d, J 4.5 Hz, NMe), 3,63 (2H, ABq, J 15.1 Hz, CH2CO) to 4.16 (1H, m, SNH), of 5.24 (1H, d, J 5.2 Hz, C2H), 5,88 (1H, dd, J of 5.2 and 10.3 Hz, C3H), at 6.84 (1H, d, J 10.3 Hz, CONH), 7,26 - 7,40 (5H, m, C6H5) part./million

Example 22.

(2R, 3R) 1-(1'-carboxyl-2'-methylprop-1'-enyl)-2-[(5'-m - proxyauthenticationrequired (5.0 g, 10 mmol) is subjected to interaction with N-chlorosuccinimide (1.7 g, 13 mmol) as described in example 1 and then treated with 3 - amino-5-methylisoxazole (4.1 g, 40 mmol) and the reaction mixture stirred for 2 h at 0oC. the Toluene solution is decanted, washed with water, dried and concentrated in vacuo. The result epimeno mixture (5.0 g, 83.6 percent), consisting of (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-2'-enyl) -2-[(5-methylisoxazol-3'-yl)-aminosulfonyl] -3-phenoxyacetamide-4-oxoazetidin; [dominant epimer with so pl. 196 - 198oC; IR (KBr): 3310w, 1775s, 1755m, 1665m, 1625m, 1520s, 1350s, 1240m, 1170m, 1100s, 915w, 855w, 755wc with-1;1H-NMR (CDCl3) : 2,02 (3H, s, Me in), 2.25 (3H, s, Me-isoxazol), 4,45, and of 4.54 (2H, ABq, J 15.1 Hz, OCH2CO), 5,07 (1H, bs, NCHCO), 5,07 and 5,19 (2H, 2bs, =CH2), of 5.39 (1H, d, J 5.1 Hz, C2H) to 5.35 (2H, bs, OCH2), USD 5.76 (1H, bs, CH-isoxazol), to 5.85 (1H, dd, J 5.0 and 9.0 Hz, C3H) 6,91 and 7.36 (5H, m, C6H5), 7,49 (1H, d, CONH), 7,49 and 8,21 (4H, 2d, J 8,8 Hz, C6H4NO2part./million] .

Received epimeno mixture of oxidised as described in example 1, hydrogen peroxide and subjected to isomerization by using triethylamine in methylene chloride, resulting in a gain of 3.5 g (68.2%) of (2R,3R) 1-(1'-p-nitrobenzenesulfonyl-2'-methylprop-1'-enyl) -2-(5'-methylisoxazole-3'-yl)-aminosol the 1795s, 1735m, 1700s, 1620m, 1525s, 1500m, 1465m, 1400m, 1355s, 1300m, - 1220s, 1165m, 1065 - 1110m cm-1;

1H-NMR (CDCl3) :2,11 and of 2.20 (6H, 2s, CMe2), 2,24 (3H, s, Me-isoxazol), of 4.35 and 4.50 (2H, ABq, J 15.1 Hz, OCH2CO), of 5.26 (2H, s, OCH2), 5,59 (1H, d, J 5.2 Hz, C2H) to 6.00 (1H, s, CH-isoxazol), 6,03 (1H, dd, J of 5.2 and 10.5 Hz, C3H), 6.90 to - to 7.35 (5H, s, OC6H5), 7,52, and by 8.22 (4H, 2d, J 8,8 Hz, C6H4NO2) part./million].

Then the resulting sulfonamide (0.56 g of 0.91 mmol) is subjected to hydrogenolysis as described in example 6, and release of 0.23 g (52.5 per cent) of the target product:

Rf-value of 0.35 (CH2Cl2/MeOH = 1,5:1,0);

IR (KBr): 3600 - 2400bm, 1795s, 1700bs, 1620m, 1500 - 1550s, 1235s, 1170s, 1065 - 1090m, 940m cm-1;

1H-NMR (CDCl3) : 2.05 and are 2.19 (6H, 2s, CMe2), and 2.27 (3H, s, Me-isoxazol), 4,50 and 4.59 (2H, ABq, J 15,0 Hz, OCH2CO), 5,78 (1H, d, J 4.8 Hz, C2H) 6,09 (1H, dd, J 4.8 and 10.5 Hz, C3H), 6,23 (1H, s, CH-isoxazol), 6,91 - 7,40 (5H, m, OC6H5), 7,78 (1H, d, J 10.5 Hz, CONH) ppm million

The compound of formula (1) obtained in accordance with example 13 (R1=H, R2= H, R3= Me2C= C-COOH, R4=H, R5- 5-methylisoxazole-3-yl), in combination with amoxicillin in mass ratio of 1: 2 was tested for inhibitory activity against S. aureus Pliva 7667R. Similar tests were carried out with Augmentin (clavulanic cyclidium, that the claimed compounds exhibit antibacterial activity similar to clavulanic acid.

All covered by the formula (1) compounds, regardless of the stated values radicals possess antibacterial activity of approximately the same level.

Indicator of acute toxicity LD50(tests were carried out on mice) is in the range 3700 - 4600 mg/kg

1. Amides of 4-oxoazetidin-2-sulphonic acids of the General formula I

< / BR>
where - R1hydrogen, halogen;

R2is hydrogen, halogen, NH2, phenyl - CH2CONH, phenyl - OCH2CONH, phthalimide, o-MeNHCOC6H4CONH, 3-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl;

R3is hydrogen, Me2C=C-COOMe, H2C=C(Me)-CH-COOMe, Me2C=C-COOCH2- phenyl, H2C=C(Me)-CH-COOCH2C6H4NO2-p, Me2C=C-COOCH2C6H4NO2-p, Me2C=C-COOCH2C6H4Me-m,

H2C=C(Me)-CH-COOCH2C6H4Me-m, Me2C=C-COOH;

R4is hydrogen or sodium;

R5- alkyl, benzyl, 5-methylisoxazole, 3,4-dimethylisoxazole and 2-phenylpyrazole

and their salts.

2. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R31denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is sodium and R5- benzyl.

4. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3is hydrogen, R4is hydrogen and R5- benzyl.

5. Connection on p. 1, in which R1denotes bromine, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R5- benzyl.

6. Connection on p. 1, in which R1denotes hydrogen, R2is bromine, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R5- benzyl.

7. Connection on p. 1, in which R1denotes bromine, R2is bromine, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R5- benzyl.

8. Connection on p. 1, in which R1denotes bromine, R2is bromine, R3- Me2C=C-COOCH2- phenyl, R4is sodium and R5- benzyl.

9. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

10. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2denotes bromine, R2is bromine, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

12. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R53,4 - dimethylisoxazol-5-yl.

13. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is sodium and R53,4 - dimethylisoxazol-5-yl.

14. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is hydrogen and R5- 2-phenylpyrazol-3-yl.

15. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOCH2- phenyl, R4is sodium and R5- 2-phenylpyrazol-3-yl.

16. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - OCH2CONH, R3- Me2C=C-COOMe, R4is hydrogen and R5- benzyl.

17. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - OCH2CONH, R3- H2C=C(Me)-CH-COOMe, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

18. Connection on p. 1, in which the 5
- 5-methylisoxazol-3-yl.

19. Connection on p. 1, in which R1denotes hydrogen, R2- phthalimido, R3- H2=C(Me)-CH-COOCH2C6H4NO2-n, R4is hydrogen and R5- 5-methylisoxazol-3-yl. 20. Connection on p. 1, in which R1denotes hydrogen, R2- phthalimido, R3- Me2C=C-COOCH2C6H4NO2-p, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

21. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - CH2CONH, R3is hydrogen, R4is hydrogen and R5- benzyl.

22. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - CH2CONH, R3- Me2C= C-COOCH2C6H4NO2-p, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

23. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - CH2CONH, R3- Me2C=C-COOH, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

24. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOH, R4is hydrogen and R5- benzyl.

25. Connection on p. 1, in which R1denotes hydrogen, R2- 3-o-chlorophenyl-5-m is B>5- 5-methylisoxazol-3-yl.

26. Connection on p. 1, in which R1denotes hydrogen, R2- 3-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl, R3- Me2C= C-COOCH2C6H4Me-m, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

27. Connection on p. 1, in which R1denotes hydrogen, R2- phthalimido, R3- Me2C=C-COOCH, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

28. Connection on p. 1, in which R1denotes hydrogen, R2the amino group, R3- Me2C=C-COOCH2C6H4NO2-p, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

29. Connection on p. 1, in which R1denotes hydrogen, R2- o-MeNHCOC6H4CONH, R3- Me2C=C-COOCH2C6H4NO2-p, R4is hydrogen and R5is methyl.

30. Connection on p. 1, in which R1denotes hydrogen, R2- o-MeNHCOC6H4CONH, R3- H2C=C(Me)-CH-COOCH2C6H4NO2-p, R4is hydrogen and R5is methyl. 31. Connection on p. 1, in which R1denotes hydrogen, R2- o-MeNHCOC6H4CONH, R3- Me2C=C-COOH, R4is hydrogen and R5is methyl.

32. UB>4is hydrogen and R5- benzyl.

33. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - CH2CONH, R3- Me2C=C-COOCH2C6H4NO2-p, R4is hydrogen and R5- benzyl.

34. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - CH2CONH, R3- Me2C=C-COOCH2C6H4NO2-p, R4is hydrogen and R5is methyl.

35. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - CH2CONH, R3- Me2C=C-COOH, R4is hydrogen and R5is methyl.

36. Connection on p. 1, in which R1denotes hydrogen, R2is hydrogen, R3- Me2C=C-COOH, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

37. Connection on p. 1, in which R1denotes bromine, R2is bromine, R3- Me2C=C-COOH, R4is hydrogen and R5- benzyl.

38. Connection on p. 1, in which R1denotes hydrogen, R2- phenyl - OCH2CONH, R3- Me2C=C-COOH, R4is hydrogen and R5- 5-methylisoxazol-3-yl.

39. The method of obtaining the amides of 4-oxoazetidin-2-sulphonic acids and their salts of General formula I, characterized in p. 1, wherein the
R2is hydrogen, halogen, phenyl - CH2CONH, phenyl - OCH2CONH, phthalimide, o-MeNHCOC6H4CONH, 3-o-chlorophenyl-2-methylisoxazol-4-ylcarbonyl;

R3- Me2C= C-COOMe, H2C= C(Me)-CH-COOMe, Me2C=C-COOCH2- phenyl, H2C= C(Me)-CH-COOCH2C6H4NO2-p, Me2C= C-COOCH2C6H4NO2-p, Me2C=C-COOCH2C6H4Me-m,

H2C=C(Me)-CH-COOCH2C6H4Me-m;

R4- hydrogen and

R5- alkyl, benzyl, 5-methylisoxazole, 3,4-dimethylisoxazole and 2-phenylpyrazole,

oxidized using known means commonly used in organic chemistry at carrying out oxidative reactions, such as hydrogen peroxide, percetakan acid, m-chloroperbenzoic acid and potassium permanganate in acidic or neutral aqueous or aqueous-organic medium and in the temperature range from 0 to 100oC and then, if necessary, carry out the removal of the protective groups, the treatment of the reaction mixture and isolation of the product by conventional methods.

 

Same patents:

The invention relates to a method for 3-{ 2-[4-(6-toranzo[d]isoxazol-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine-4-it (I) interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (II) isoxazol derivative of the formula (III)where Y and Z represent the deleted group, such as halogen or alkyl - or arylsulfonate, in the presence of a suitable solvent and base

The invention relates to a derivative of pyrazine, which has antagonistic activity relative to the glutamate receptor, represented by the formula:

< / BR>
in which Z represents C or N, provided that two Z are nitrogen atoms; R1is:

< / BR>
in whichisor, R6represents H or alkyl, and R7and R8are each H, alkyl, nitro or phenyl, or alternatively, R7and R8taken together, represent butadiene or 1,4-butylene; R2and R3are each H, F, cyano, acyl, nitro, alkyl, morpholino or one of the above definitions for R1; R4and R5are each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents a hydroxyl, acyloxy, F - substituted methyl, cycloalkyl, tetrahydrofuranyl, carboxyl, alkoxycarbonyl or

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new, therapeutically valuable derivative tetrazole, method of their production and their use

The invention relates to a new alkylenediamine derivative, a method for obtaining and drug treatment for dysuria containing the specified new alkylenediamine derivative or its pharmaceutically acceptable salt as an active ingredient

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to a method for producing derivatives taxane General formula (I) by esterification of protected baccatin III or protected 10-desacetyl-baccatin III using the acid of General formula (II)

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties

The invention relates to endothelin antagonists, used inter alia for the treatment of hypertension

The invention relates to novel 1,2,4-oxalatotetraaminecobalt, to the way they are received, to the containing compositions and methods for their use as antiviral agents

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts
Up!