SI9300003A - 4-oxo-azetidine-2-sulphonic acid amides and their salts, process for their production and their use - Google Patents

Abstract

4-Oxo-azetidine-2-sulfonic acids amides and their salts of the formula: in which the radicals are: R 1 is hydrogen, halogen; R2 is hydrogen, halogen, NH2l phenyl-CH2CONH, phenyl-OCH2CONH, phthalimido, o-MeNHCOCehUCONH, thoxoxazolylcarbonylamino; R3 is hydrogen, Me2C = C-COOMe, H2C = C (Me) -CHCOOMe, Me2C = C-COOCH2-phenyl, H2C = C (Me) -CHCOOCH2C6H4NO 2.p, Me2C = C-COOCH2C6H4NO 2-p, Me2C = COOCH2C6H4Me-rn, H2C = C (Me) -CHOCCH2- C6H4Me-m, Me2C = C-COOH; R4. hydrogen or sodium and R5 hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole, etc., processes for their preparation and theirs use as intermediates for beta-lactam synthesis analogues or as active ingredients in antimicrobial preparations therapy.

Description

(57) 4-Oxo-azetidine-2-sulfonic acids amides and their salts of the formula:

in which the radicals are: R ^{1 is} hydrogen, halogen; R ^{2 is} hydrogen, halogen, NH ² I phenyl-CH 2 CONH, phenyl-OCH 2 CONH, phthalimido, o-MeNHCOCehUCONH, thoxazolylcarbonylamino; R ^{3 is} hydrogen, Me ₂ C = C-COOMe, H ₂ C = C (Me) -CHCOOMe, Me ₂ C = C-COOCH ₂ -phenyl, H ₂ C = C (Me) -CHCOOCH ₂ C ₆ H ₄ NO ₂ . _p , Me ₂ C = C-COOCH ₂ C6H ₄ NO ₂ - _p , Me ₂ C = COOCH ₂ C ₆ H ₄ Me-rn, H ₂ C = C (Me) -CHOCCH ₂ C6H ₄ Me-m, Me ₂ C = C-COOH; R ⁴ . hydrogen or sodium and R ^{5 is} hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole, etc., processes for their preparation and their use as intermediates for the synthesis of beta-lactam analogues or as active ingredients in antimicrobial therapy preparations.

PLIVA ZAGREB t

4-Oxo-azetidine-2-sulfonic acids amides and their salts, processes for their preparation and use

Technical field of the invention

IPK: C 07D 205/08

A61 / K 31/395

The present invention relates to novel amides of 4-oxo-azetidine-2-sulfonic acids and their salts, to processes for their preparation and to their use as active ingredients for the preparation of antimicrobials.

The state of the art

Some 4-oxo-azetidine-sulfonic acids have been described, the most well-known being 4-oxo-azetidine-1-sulfonic acids [Chemistry and Britan (1983) 302]; these include the beta-lactam antibiotic Aztreonam [Drugs of the Future 8 (1983) 295].

Some of the 4-oxo-azetidine-2-sulfonic acids obtained by degradation of bicyclic molecules are also known [Angew. Chem. 95 (1983) 912] or by oxidation of the corresponding 4-oxo-azetidine-2-sulfinic acid derivatives [YU patent application P-240/91; YU patent application P-1390/91 and EP patent application 92 10 23 35.4 / 92] .

Also known are some 4-oxo-azetidine-2-sulfonic acid derivatives, such as e.g.

acid chlorides [DE patent application 2556071/76], esters [Croat. Chem. Acta 62 (1989) 521-527] and thioesters [J. Chem. Soc. Chem. Commun. 23 (1972) 1304-1305].

According to the applicant's own knowledge of the prior art, the 4-oxo-azetidine-2-sulfonic acid amides and their salts are unknown.

'35

Description of solution to a technical problem with implementation examples

The present invention provides novel amides of 4-oxo-azetidine-2-sulfonic acids and their salts of the general formula I

I in which the remains have the following meanings:

R1 is hydrogen, halogen;

R ^{2 is} hydrogen, halogen, NH 2, phenyl-C 1-4 CONH, phenyl-OCH ^ CONH, phthalimido, o-MeNHCOCgHztCONH, isoxazolylcarbonylamino;

R ^{3 is} hydrogen, Me ₂ C = C-COOMe, H ₂ C = C (Me) -CH-COOMe,

Me ₂ C = C-COOCH ₂ -phenyl, H ₂ C = C (Me) -CH-COOCH2C ₆ H ₄ NO ₂ -p, Me ₂ C = C-COOCH2C ₆ H ₄ NO2-A

Me ₂ C = C-COOCH2C ₆ H ₄ Me-m, H ₂ C = C (Me) -CHCOOCH2C ₆ H ₄ Me-zn, Me ₂ C = C-COOH;

hydrogen or sodium and

R ^{3 is} hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole, etc.

It is a further object of the present invention to provide a process for the preparation of 4-oxoazetidine-2-sulfonic acids amides of general formula I in which residues have the upper meaning which is derived by the oxidation of 4-oxo-azetidine-2-sulfonic acids amides of general formula II

Kateri in which the remains have the following meanings:

R1 is hydrogen or halogen;

R ^{2 is} hydrogen, halogen, phenyl-CH 2 CONH, phenyl-OCH 2 CONH, phthalimido, o-MeNHCOC ^ H ^ ONH, isoxazolylcarbonylamino; >

R3 Me ₂ C = C-COOMe, H ₂ C = C (Me) -CH-COOMe,

Me ₂ C = C-COOCH ₂ -phenyl, H ₂ C = C (Me) -CH-COOCH ₂ C ₆ H ₄ NO ₂ -p,

Me ₂ C = C-COOCH ₂ C ₆ H4NO ₂ -p,

Me ₂ C = C-COOCH ₂ C ₆ H ₄ Me-m, H ₂ C = C (Me) -CHCOOCH ₂ C ₆ H ₄ Me-m;

R ^ hydrogen and

Is hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole, etc.

The oxidation is carried out in conventional oxidizing agents known in organic chemistry, such as e.g. hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or potassium permanganate, in acidic or neutral, aqueous or aqueous-organic medium, at a temperature of 0 to 100 ° C. All reactions take place under normal reaction conditions and molecular ratios and using the standard isolation method. Depending on the type of oxidizing agent, molar ratios and reaction temperature, different derivatives of 4-oxo-azetidine-2-sulfonic acids amides are obtained, as indicated in the individual cases. Depending on the treatment and isolation method, 4-oxoazetidine-2-sulfonic acids amides may be obtained in the form of free amides or in the form of their inorganic salts. The protecting amino and carboxyl groups are removed by conventional known methods.

Sulfinamides of general formula II are prepared by reaction of the corresponding sulfinyl chlorides with amines, as described in U.S. Patent 4 052 387/77. Sulfinyl chlorides can be prepared in situ from penicillin sulfoxides as described in US patent 4 081 440/78, or from sulfinic acid as described in Croat. Chem. Acta 62 (1989) 521.

Another object of the present invention is to use the present compounds as intermediates for the preparation of various beta-lactam analogues, in particular novel bicyclic systems.

Another object of the invention is the use of the present compounds as active ingredients in antimicrobial agents.

Another object of the invention is the use of the present compounds as active ingredients for the preparation of antimicrobial agents.

The invention is illustrated by the following examples.

EXAMPLE 1 (2R, 3R) 1- (r-Methyloxycarbonyl-2'-methyl-prop-2'-enyl) -2-benzylaminosulfonyl] 3-phenoxyacetamido-4-oxo-azetidine _t

To a solution of methyl ester (5R, 6R) of 6-phenoxyacetamidopenicilanate sulfoxide (1.9 g, 5 mmol) in dry toluene (215 ml) was added calcium oxide (1.65 g, 28.4 mmol) and N-chlorosuccinimide (0.85 g, 6.4 mmol) and the reaction mixture stirred under nitrogen for 1.5 hours at boiling point. The contents were cooled to 0 ° C, benzylamine (2.26 g, 21 mmol) was added and stirring was continued for 2 hours. The reaction mixture was filtered, the mother liquor was washed with water (2 x 90 ml), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with a solvent of methylene chloride-methanol (20: 1). The resulting mixture (1.8 g, 74.4%) of epimemic (2R, 3R) 1- (r-methyloxycarbonyl-2'-methyl-prop-r-enyl) -2-benzylaminosulfinyl-3-phenoxyacetoamido-4-oxo-azetidine [isomer in NMR excess (CDCI3) δ: 2.13 and 2.26 (6H 2s, CMe ₂ ), 3.75 (3H, s, OMe), 4.13-4.50 (5H, m, CH ₂ N, CH ₂ O, SNH), 4.95 (1H. d, J 5.0 Hz, C ₂ H), 5.87 (1H, dd, J 5.0 and 10.0 Hz, C ₃ H), 6.75-7.37 (5H, m, C ₆ H ₅ O),

8.47 (1H, d, J 10.0 Hz CONH) ppm] was dissolved in methylene chloride (35 ml) and formic acid (7 ml), 30% aqueous H ₂ O ₂ (28 ml) was added and the reaction mixture was stirred at room temperature for 6 hours . The organic extract was removed, washed with water, dried (Na ₂ SO ₄ ), filtered and evaporated. Residual foam product (1.98 g, 95%): R _f 0.55 (CH ₂ Cl ₂ : MeOH = 20: 1);

IR (KBr) 3420-3230m, 1785s, 1735m, 1690s, 1605m, 1530s, 1495m, 1440m, 1370m, 1335m, 1225s, 1162s, 1065s, 995w cm ^-1 ;

1 h NMR (CDCl 3) δ: 2.09 and 2.25 (6H, 2s, CMe ₂ ), 3.69 (3H, s, OMe), 4.09-4.41 (5H, m, CH ₂ N, CH ₂ O, SNH), 4.8O (1H, d, J 5.3 Hz, C ₂ H), 5.83 (1H, dd, J

5.3 and 10.8 Hz, C ₃ H), 6.87-7.44 (5H, m, C ₆ H ₅ O), 7.77 (1H, d, J 10.8 Hz, CONH) ppm.

EXAMPLE 2 (2R, 3R) 1- (1'-Methyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) aminosulfonyl] -3-phenoxyacetamido -4-Oxo-azetidine

(5R, 6R) 6-phenoxyacetamidopenicilanate sulfoxide (1.9g, 5 mmol) measuring ester was reacted with N-chlorosuccinimide as in Example 1, and then 3-amino-5-methylisoxazole (2.06 g, 21 mmol) was added instead of benzylamine. . After stirring and treating the reaction mixture, the epimemic mixture of (2R, 3R) 1- (Γmethyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) -aminosulfinyl is isolated ] -3phenoxyacetamido-4-oxo-azetidines. When the toluene solution is evaporated, the epimer crystallizes from the ground. 185-190 ° C [1H NMR (CDCl ₃ ) 5: 1.99 (3H, s, Me),> 2.15 (3H, s, Meisoxazole), 3.85 (3H, s, OMe), 4.43 (2H, bs, OCH ₂ ), 5.05 (1H, s, NCHCO), 5.09 and 5.27 (2H, 2bs, = CH ₂ ), 5.37 (1H, d, J 4.5 Hz, C ₂ H), 5.79 (1H, s, CH-isoxazole). 5.84 (1H, dd, J 4.5 and 9.5 Hz, C ₃ H), 6.95-7.34 (5H, m, C ₆ H ₅ O), 7.7O (1H, d, J 9.5 Hz, CONH), 8.29 (1H. s, SNH) ppm; Anal. C ₂₁ H ₂₃ O ₈ N ₄ S; found: C, 52.42; H, 5.82; N, 12.02; S, 6.34%; Calc'd: C, 52.93; H, 5.08; N, 11.76; S, 6.73%]. The aspirated crystals were dissolved in methylene chloride and formic acid and oxidized with hydrogen peroxide as in Example 1 to give a foam product: Rf 0.20 (CH ₂ Cl ₂ : MeOH = 20: l);

IR (KBr) 3400-3000m, 1795vs, 1750s, 1690m, 1620m, 1605m, 1535-1494s, 1465m, 1440m, 1245s, 1165s, cm'l;

1 H NMR (CDCl ₃ ) δ: 1.91 (3H, s, Me), 2.18 (3H, s, Me-isoxazole), 3.79 (3H, s, OMe), 4.44 (2H, bs, OCH ₂ ), 4.90 (1H , s, NCHCO), 5.00 and 5.17 (2H, 2bs, = CH ₂ ),

5.46 (1H, d, J 5.0 Hz, C ₂ H),

6.01 (1H, dd, J 5.0 and 10.3 Hz, C ₃ H), 6.82-7.41 (5H, m, C ₆ H ₅ O), 7.75 (1H, d, J

10.3 Hz, CONH) ppm.

EXAMPLE 3 (2R, 3R) 1- (r-Methyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) aminosulfonyl] -3-phenoxyacetoamido-4 -oxo-azetidine

Sulfinamide (mp 185-190 ° C), prepared as indicated in Example 2, was dissolved in methylene chloride and stirred with triethylamine for 2 hours at room temperature. After treatment of the reaction mixture by chromatography on a silica gel column, (2R, 3R) 1- (Γmethyloxycarbonyl-2'-methyl-prop-r-enyl) -2- [5'-methyl-isoxazol-3'-yl) -amino- sulfinyl] -3-phenoxyacetamido-4-oxo-azetidine in 80% yield; 1 H NMR (CDCl ₃ ) δ: 2.06 and 2.19 (6H, 2s, CMe ₂ ), 2.25 (3H, s, Me-isoxazole), 3.76 (3H, s, OMe), 4.31 and 4.40 (2H, ABq, J 15.0 Hz, OCH ₂ ), 5.34 (1H, d, J 5.0 Hz, C ₂ H), 5.80 (1H, s, CH-isoxazole), 5.60 (1H, dd, J 5.0 and 8.8 Hz, C ₃ H), 6.84-7.32 (5H, m, C ₆ H ₅ O), 7.92 (1H, d, J 8.8 Hz,

CONH), 8.43 (1H, s, SNH) ppm], which is then oxidized with hydrogen peroxide as indicated in Example 1.

A foam product is obtained in 85% yield:

R f 0.24 (CH ₂ Cl ₂ : MeOH = 20: 1);

IR (KBr) 1790s, 1735m, 1700s, 1620m, 1540-1495s, 1465m, 1440m, 1380m, 1230s, 1165s cm -1; t lH NMR (CDCl ₃ ) δ: 2.09 and 2.22 (6H, 2s, CMe ₂ ), 2.26 (3H, s, Me-isoxazole), 3.7l (3H, s, OMe), 4.46 and 4.57 (2H, ABq J 15.0 Hz, OCH ₂ ), 4.57 (1H, s, SNH) 5.54 (1H, d, J 5.2 Hz, C ₂ H), 6.07 (1H, s, CH-isoxazole), 6.06 (1H, dd, J 5.2 and 10.4 Hz, C3H), 6.95-7.37 (5H, m, C ^ O), 7.76 (1H, d, J 10.4 Hz, CONH), ppm.

EXAMPLE 4 (2R, 3R) 1- (1'-p-Nitrobenzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methylisoxazol-3'-yl) aminosulfonyl] -3-phthalimido -4-Oxo-azetidine p-Nitrobenzyl ester (5R, 6R) of 6-phthalimidopenicilanate sulfoxide (1.5 g, 3 mmol) was reacted with N-chlorosuccinimide (0.4g, 3 mmol) as indicated in Example 1, then added 3-amino-5-methyl-isoxazole (1.18 g, 12 mmol) and the reaction mixture was stirred for 4 hours at 10 ° C. The toluene solution was decanted, washed with water, dried, filtered and evaporated in vacuo. Chromatography on a silica gel column in a solvent methylene chloride-ethyl acetate system (4: 1) gave 0.88 g (2R, 3R) 1- (p-nitrobenzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2- [5'- Methyl-iso-xazol-3'-yl) aminosulfinyl] -3-phthalimido-4-oxo-azetidine [1 H NMR (CDCl 3) δ: 1.90 (3H, s, Me), 2.27 (3H, s, Me-isoxazole) ), 4.76 (1H, bs, NCHCO), 4.92 and 5.06 (2H, 2bs, = CH ₂ ), 5.25 (2H, bs, OCH ₂ ), 5.67 (1H, d, J 5.4 Hz, C ₂ H), 6.09 (1H, d, J 5.4, Hz, C3H), 7.20 (1H, bs, CH-isoxazole), 7.52 and 8.20 (4H, 2d, J 9.04 Hz, 0 ₆ Η ₄ Ν0 ₂ ), 7.71-7.95 (4H. m, phthalimido), and 8.05 (1H, bs, SNH) ppm]. Reaction with hydrogen peroxide (12 ml, 30% aqueous solution) in methylene chloride (15 ml) and formic acid (2 ml) as in Example 1 gave 0.63 g of sulfonamide:

R _f 0.58 (CH ₂ Cl ₂ : MeOH = 9: 1);

IR (KBr) 1805s, 1790s, 1735vs, 1615m, 1525m, 1475m, 1390s, 1350s, 1270w, 1170w,

1110w, 720m cm < 1 > H NMR (CDCI3) δ: 2.02 (3H, s, Me), 2.22 (3H, s, Me-isoxazole),

4.98 (1H, s, NCHCO), 5.09-5.35 (4H, m, = CH ₂ , OCH ₂ ),

5.57 (1H, d, J 4.5 Hz, C ₂ H), 5.76 (1H, d, J 4.5 Hz, C 3 H),

5.97 (1H, s, CH-isoxazole), 7.51 and 8.15 (4H, 2d, J 8.4 Hz, C6H ₄ NO ₂ ), 7.69-8.05 (4H, m, phthalimido) ppm].

EXAMPLE 5 (2R, 3R) 2-Benzylaminosulfonyl-3-phenylacetamido-4-oxo-azetidine k

p-Nitrobenzyl ester (5R, 6R) of 6-phenylacetamidopenicilanate sulfoxide (2.10 g, 4.3 mmol) was reacted with N-chlorosuccinimide (0.72 g, 5.4 mmol) as indicated in Example 1, and then benzylamine (1.5 ml) was prepared. epimer mixture of (2R, 3R) 1- (p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl) -2-benzylaminosulfinyl3-phenylacetamido-4-oxo-azetidine (1.78 g, 69.4%) [epimer in excess NMR (DMSO-d ₆ ) 5: 2.11 and 2.25 (6H, 2s, CMe ₂ ), 3.53 (2H, s, CH ₂ CO), 3.81-4.36 (3H, m, SNHCH ₂ ), 4.78 (1H, d, J 5.4 Hz, C ₂ H), 5.24 (2H, bs, OCH ₂ ), 5.70 (1H, dd, J 5.4 and 9.0 Hz, C 3 H), 6.65 (1H, d, J 9.0 Hz, CONH), 7.07-7.35 ( 10H, m, 2C6H5), 7.44 and 8.17 (4H, 2d, J 9.0 Hz, CgH4NO ₂₎ ppm]. The product was dissolved in ethyl acetate (25 ml) and 80% acetic acid (25 ml) and a 4% aqueous potassium permanganate solution (50 ml) was added dropwise over 1 hour at 0 ° C. 30% hydrogen peroxide solution was added to the permanganate discoloration. The organic extract was decided, washed with aqueous NaHCO3 solution and water, dried (Na ₂ SO4) and evaporated in vacuo. Chromatography on a column of silica gel in a solvent system of methylene chloride: ethyl acetate (4: 1) afforded 0.3 g (23.5%) of sulfonamide from the soil. 135-137 ° C:

R _f 0.92 (n-BuOH: HOAc: H ₂ O = 4: 1: 1);

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

1 h NMR (DMSO-d 6) δ; 3.56 (2H, bs, CH ₂ CO), 4.15-4.20 (2H, m, NCH ₂ ), 4.85 (1H, d, J 4.7 Hz, C ₂ H), 5.57 (1H, dd, J 4.7 and 9.5 Hz, respectively). C3H), 7.25 and 7.38 (10H, 2 bs, 2C ₆ H5), 7.87-7.93 (1H, m, SNH), 8.49 (1H, d, J 9.5 Hz,

CONH) 9.24 (1H, bs, NiH) ppm;

Anal. C18H19N3O4S Found: C 57.70, H 5.90, N 11.74, S 8.47% Calc .: C 57.89, H 5.13, N 11.25, S 8.59%.

EXAMPLE 6 (2R, 3R) 1- (r-Carboxyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) aminosulfonyl] -3-phenylacetamido-4 -oxo-azetidine p-Nitrobenzyl ester (5R, 6R) of 6-phenylacetamidopenicilanate sulfoxide (3.0 g, 6.2 mmol) was reacted with N-chlorosuccinimide (1.0 g, 7.5 mmol) as indicated in Example 1, after which 3-amino was added. -5-methyl-isoxazole (2.4 g, 25 mmol) and the reaction mixture was stirred for 3 hours at 5 ° C. The toluene solution was decanted, washed with water, dried and evaporated in vacuo. 1.43 g of (2R, 3R) 1- (1'-pnitrobenzyl-oxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methyl-iso-xazol-3'-yl) is obtained. aminosulfinyl] -3-phenylacetamido-4-oxo-azetidine [m.p. Mp 157-160 ° C; NMR (CDCl3) δ: 1.93 (3H, s, Me), 2.35 (3H, s, Me-isoxazole), 3.61 (2H, s, CH ₂ CO), 4.94 (1H, bs, NCHCO), 5.07 and 5.19 ( 2H, 2bs, = CH ₂ ), 5.13 (1H, d, J 4.8 Hz, C ₂ H), 5.28 (2H, bs, OCH ₂ ), 5.57 (1H, bs, CH-isoxazole), 5.77 (1H, dd , J 4.8 and 9.0 Hz, C3H), 7.22 (5H, bs, CgHs), 7.44 (1H, d, J 9.0 Hz, CONH), 7.49 and 8.21 (4H, 2d, J 8.8 Hz, C ^ NO ^ ppm] which, when mixed with triethylamine in methylene chloride, is converted to (2R, 3R) 1- (1'-pnitrobenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3'- yl) aminosulfinyl] -3-phenylacetamido-4-oxo-azetidine [1 H NMR (CDCl 3) δ: 2.18 and 2.22 (6H, 2s, CMe ₂ ), 2.34 (3H, s, Me-isoxazole), 3.61 (2H. s, CH ₂ CO), 5.11 (1H, d, J 4.9 Hz, C ₂ H), 5.25 (2H, s, OCH ₂ ), 5.64 (1H, dd, J 5.0 and 8.4 Hz, C 3 H), 5.63 (1H , s, CH-isoxazole), 7.24 (5H, s, C ₆ H ₅ ), 7.26 (1H, d, J 8.4 Hz, CONH), 7.47 and 8.18 (4H, 2d, J 8.5 Hz, CgH ₄ NO ₂ ) The sulfinamide obtained is oxidized with hydrogen peroxide as indicated in Example 1 in (2R, 3R) 1- (p-nitrobenzyloxycarbonyl-2'-methyl-propenyl) -2- (5'-methyl-isoxazol-3'-yl) -aminosulfonyl-3-phenylacetamido-4-oxo-azetidine [Rf 0.57 (CH ₂ Cl ₂ : MeOH = 8: 1) IR (KBr) 3680-2500m , 1785s, 1730m, 1665s, 1615m, 1520s, 1350s, 1215m, 1160m cm '¹; 1 H NMR (CDCl 3) δ: 1.99 and 2.15 (6H, 2s, CMe ₂ ), 2.28 (3H, s, Me-isoxazole), 3.59 (2H, s, CH ₂ CO), 5.19 (2H, s, OCH ₂ ), 5.44 (1H, d, J 5.3 Hz, C ₂ H), 5.81 (1H, s, CH-isoxazole), 5.84 (1H, dd, J 5.3 and 9.9 Hz, C 3 H), 6.84 (1H, d, J) 9.9 Hz, CONH), 7.28 (5H, s, C ^), 7.45 and 8.17 (4H, 2d, J 8.9 Hz _y C ₆ H ₄ NO ₂ ) ppm].

The sulfonamide (0.35 g, 0.6 mmol) obtained was then dissolved in methanol (25 ml) and hydrated for 2 hours at a pressure of 2.4 bar with 10% Pd on charcoal (50 mg). The reaction mixture was filtered and the mother liquor was evaporated in vacuo. The residue was dissolved in methylene chloride (20 ml) and water (20 ml) and the pH adjusted to 8.5 with the addition of sodium hydrogen carbonate. The aqueous extract was decided, shaken with fresh methylene chloride, a new amount of methylene chloride (15 ml) was added and the pH was adjusted to 2.2 with the addition of hydrochloric acid. The organic extract was removed, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. 0.14 g (52.4%) of the product are obtained.

Rf 0.48 (CH ₂ Cl ₂ : MeOH = 3: 2)

IR (KBr) 3660-2300bm, 2910m, 1790s, 1680bs, 1620s, 1465m, 1270m, 1165m, 930w cml;

1 H NMR (CDCl 3) δ: 1.93 and 2.07 (6H, 2s, CMe ₂ ), 2.35 (3H, s, Me-isoxazole),

3.67 (2H, s, CH ₂ CO), 5.68 (1H, d, J 5.2 Hz, C ₂ H),

6.0 (1H, dd, J 5.2 and 9.3 Hz, C3H), 6.12 (1H, s, CH-isoxazole),

6.63 (1H, d, J 9.3 Hz, CONH), 7.27-7.31 (5H, m, C ₆ H ₅ ) ppm.

EXAMPLE 7 (2R, 3R) 1- (1'-m-Methylbenzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) aminosulfonyl] -3 - [(3'-o-chlorophenyl-5'-methyl-isoxazol-4'-yl) carboxy-amido] 4-oxo-azetidine m-Methylbenzyl ester (5R, 6R) 6- (3'-o-chlorophenyl- 5'-methyl-isoxazol-4'-yl) carboxamido-penicillanate sulfoxide (2.0 g, 3.6 mmol) was reacted with N-chlorosuccimide as indicated in Example 1, then 3-amino-5-methylisoxazole (1.1 g was added). 11 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered, the mother liquor was extracted with water (3 x 60 ml), dried (Na 2 SO 4), filtered and evaporated in vacuo. An epimeric mixture of (1.92 g) (2R, 3R) 1- (1'-methyl-benzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) is obtained ) aminosulfinyl] -3 - [(3'-o-chlorophenyl-5'-methyl-isoxazol-4'-yl) -carboxamido] -4-oxo-azetidine [R ^ 0.40 and 0.26 in methylene chloride: ethyl acetate (4: 1) )]. The product was dissolved in methylene chloride and formic acid and oxidized with hydrogen peroxide as in Example 1. The crude product was chromatographed on a silica gel column, eluting with a solvent of methylene chloride: ethyl acetate. 0.62 g (44%) of sulfonamide are obtained:

R _f 0.55 (CH ₂ Cl ₂ : MeOH = 10: 1);

IR (KBr) 3405w, 1795vs, 1745s, 1680vs, 1620s, 1520s, 1465s, 1385m, 1340m, 1265m,

1160m, 770m cm'l;

₁ H NMR (CDCl ₃ ) δ: 1.79 (3H, s, Me), 2.31 (3H, s, phenyl-Me), 2.35 'and 2.72 (6H, 2s, 2Me-isoxazole) 4.85 (1H, s, NCHCO). 4.90 and 5.10 (2H, 2s, = CH ₂ ), 5.08 and 5.13 (2H, ABq, J 12 0 Hz, OCH ₂ ), 5.44 (1H, d, J 5.0 Hz, C ₂ H), 5.95 (1H, dd ,

J 5.0 and 9.6Hz, C ₃ H), 6.04 (1H, s, CH-isoxazole), 6.37 (1H, d, J 9.6 Hz,

CONH), 7.01-7.26 and 7.41-7.55 (8H, 2m, 2 (^ 4) ppm.

EXAMPLE 8 (2R) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-r-enyl) -2-benzylaminosulfonyl-3,3dibromo-4-oxo-azetidine

The (5R) benzyl ester of 6,6-dibromopenicilanate sulfoxide (7.0 g, 15 mmol) was reacted with N-chlorosuccinimide as indicated in Example 1, followed by the reaction with benzylamine (4 ml, 37.5 mmol). The reaction mixture was filtered off with suction, the mother liquor was washed with water, dried (Na ₂ SO 4), filtered and evaporated in vacuo. The crude product was chromatographed on a silica gel column eluting with a solvent of methylene chloride: ethyl acetate (6: 1) to give 3.08 g (36%) (2R) 1- (Γbenzyloxycarbonyl-2'-methyl-prop-1'-enyl) - 2-Benzylamino-sulfinyl-3,3-dibromo-4-oxoazetidine. [1 H NMR (CDCl 3) 5: 1.84 and 2.26 (6H, 2s, CMe ₂ ), 3ώ8-4.40 (3H, m, SNHCH ₂ ), 5.07 and 5.24 (2H, ABq, J 12 Hz, OCH ₂ ), 5.09 ( 1H, s, C ₂ H), 7.10-7.30 (10H, m, 2C6H5) ppm], which is oxidized in chloroform with m-chloroperbenzoic acid (1.2 g, 6 mmol). The reaction mixture was stirred for 20 minutes at -10 ° C and then at room temperature for 1 hour. IM solution of sodium bisulphite (36ml, 6mmol) was added, the organic layer was removed, washed with water, dried (Na ₂ SO4), filtered and evaporated in vacuo. The residue was dissolved in methylene chloride and passed through a column of silica gel to give 2.Ig (59%) of a white crystalline product from the ground. 120-122 ° C:

R f 0.88 (CH ₂ Cl ₂ / EtOAc = 4: 1);

IR (KBr): 3250vs, 1780vs, 1730vs, 1640s, 1440vs, 1370b, 1255s, 1200s, 1165vs,

1055vs, 755vs, 700vs cmI;

^X H NMR (CDCl 3) δ: 2.09 and 2.28 (6H, 2s, CMe ₂ ), 4.09 (2H, d, J 5.8 Hz,

NCH ₂ -phenyl), 4.63 (1H, t, J 5.8 Hz, SNH), 5.08 and 5.34 (2H, ABq, J 11.7 Hz, OCH ₂ ), 5.32 (1H, s, C ₂ H), 7.29-7.35 ( 10H, m, 2C ₆ H ₅ ), ppm.

EXAMPLE 9 (2R) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) amino-sulfonyl] -3,3-dibromo -4-oxo-azetidine ^a )

(5R) 6,6-Dibrompenicilanate sulfoxide benzyl ester (7.0g, 15 mmol) was reacted with N-chlorosuccinimide as indicated in Example 1, then 3-amino5-methyl-isoxazole (4.47g, 45 mmol) was added and the reaction was the mixture was stirred at 20 ° C for 3 hours. The precipitate was filtered off with suction, dried, dissolved in methylene chloride (30 ml) and stirred with triethylamine (1.5 ml) for 1 hour at 20 ° C. The reaction mixture was washed with 0.1 N hydrochloric acid (pH 1-2) and water, the organic extract was dried (Na ₂ SO4), filtered and evaporated in vacuo. 1.85 g of (2R) 1- (1'-benzyloxycarbonyl-2'methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) -amino-sulfinyl] -3.3 is remaining -dibromo-4-oxoazetidine; [tal. 58-60 ° C; R f 0.51 (CH ₂ Cl ₂ : EtOAc = 4: 1); 1 H NMR (CDa ₃ ) δ: 1.88 and 2.13 (6H, 2s, CMe ₂ ), 2.31 (3H, s, Me-isoxazole), 5.13 (2H, s, OCH ₂ ), 5.56 (1H, s, C ₂ H) ), 5.67 (1H, s, CH-isoxazole), 7.35 (5H, s, C6H5) and 8.32 (1H, s, SNH) ppm], which is oxidized with m-chloroperbenzoic acid as described in Example 8. The crude product was chromatographed on a silica gel column eluting with a solvent of methylene chloride: ethyl acetate (4: 1) to give a white crystalline product (52.6%), m.p.

168-170 ° C:

R _f 0.25 (CH ₂ Cl ₂ : EtOAc = 4: 1);

IR (KBr): 3160m, 1780vs, 1765vs, 1625s, 1500s, 1395vs, 1383s, 1220s> 1175vs cm '¹; 1 H NMR (CDCl ₃ ) δ: 2.06 and 2.15 (6H, 2s, CMe ₂ ), 2.37 (3H, s, Me-isoxazole), 5.05 (2H, s, OCH ₂ ), 5.70 (1H, s, C ₂ H) ), 6.07 (1H, s, CH-isoxazole), 7.31 (5H, s, C ₆ H ₅ ) ppm.

b)

The sulfinamide (0.85 g, 1.5 mmol) prepared by the above procedure was dissolved in methylene chloride (5 ml) and formic acid (5 ml) and oxidized with hydrogen peroxide (0.56 ml) for 1 hour at boiling point. Water was added to the cooled reaction mixture, the organic layer was decomposed, shaken with a 5% NaHCO ₂ solution, water, dried (Na ₂ SO 4), filtered and evaporated. An identical product is obtained as in procedure a).

EXAMPLE 10 (2R) 1- (r-Carboxyl-2'-methyl-prop-r-enyl) -2-benzylaminosulfonyl-3,3-dibromo-4-oxo-azetidine

To a ice-cooled suspension of aluminum trichloride (0.4 g, 3 mmol) in methylene chloride (15 ml) in a stream of nitrogen was added a solution of (2R) 1- (r-benzyloxycarbonyl-2'methyl-prop-r-enyl) -2-benzylaminosulfonyl- 3,3-dibromo-4-oxo-azetidine (0.59 g, mmol) and anisole (0.65 g, 6 mmol) in methylene chloride (15 ml) and stirred at room temperature for 30 minutes. Ethyl acetate (15 ml) and 0.1 N hydrochloric acid (5 ml) were added to the reaction solution. The layers were separated and the ethyl acetate layer was extracted with 5% sodium hydrogen carbonate solution (2 x 20 ml). The layers are separated again. The aqueous extract was acidified to pH 1 with 0.1 N hydrochloric acid, fresh ethyl acetate (20 ml) and sodium chloride were added and shaken well. The ethyl acetate layer was separated and then washed with saturated brine, then dried and evaporated in vacuo. Yield: 0.49 g (98%) m.p. 47-50 ° C:

R f 0.66 (EtOAc: MeOH = 3: 1);

IR (film): 3300m, 2960-2930m, 1805vs, 1700s, 1625m, 1425m, 1350s, 1160s cm-1; 1 H NMR (DMSO-d ₆ ) δ: 1.98 and 2.23 (6H, 2s, CMe ₂ ), 4.09 and 4.20 (2H, ΑΒΧ, J 5.7, 6.0 and 15.2 Hz, CH ₂ -phenyl), 5.51 (1H, s. C ₂ H), 7.29-7.39 (5H, m, C ₆ H ₅ ), 8.49 (1H, dd, J 5.7 and 6.0 Hz, NH), 13.5 (1H, b, COOH) ppm.

EXAMPLE 11 (2R) 1- (r-Carboxy-2'-methyl-prop-r-enyl) -2-benzylaminosulfonyl] -4-oxo-azetidine (2R) 1- {E-Benzyloxycarbonyl} -methyl-prop-r- Enil-A-oxo-azetidine N-sulfonic acid (3.23 g, 10 mmol) was dissolved in thionyl chloride (20 ml) and the solution was stirred for 1 hour at 25 ° C. The excess thionyl chloride was evaporated under reduced pressure to an oily residue, which was then dissolved in methylene chloride (50 ml), the solution cooled (

at 10 ° C, while stirring and cooling, a 5% solution of benzylamine in methylene chloride was added dropwise to pH 7.0 and continued stirring at the same temperature for 30 minutes. The extracted benzylamine hydrochloride salt was filtered off and washed with methylene chloride. Water (50 ml) was added to the mother liquor, acidified with 10% hydrochloric acid at pH 1.3, and the layers were separated, the organic layer was again washed with water, dried over sodium sulfate and evaporated to dryness. A mixture of (3.85 g, 93%) epimeric (2R) 1- (Γbenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2-benzylaminosulfinyl-4-oxo-azetidines was obtained with Rf values of 0.64 and 0.72 (CH ₂ Cl ₂ : EtOAc = 2: l) which are separated by chromatography on a silica gel column. [Substance having an Rf value of 0.64: IR (CH ₂ C1 ₂ ): 3020vs, 2980s, 1760vs, 1700m, 1415m, 1260vs, 1210s, 1070m, 900s, cnr ¹ ; 1 h NMR (CDCl 3) δ: 1.95 and 2.24 (6H, 2s, CMe2), 3.11 (1H, dd, J 5.0 and 15.3 Hz, a C3H), 3.39 (1H, dd, J 2.6 and 15.3 Hz, β C3H) , 4.0-4.3 (3H, m, NHCH2), 4.77 (1H, 2d, J 2.6 and 5.0 Hz, C2H), 5.08 and 5.29 (2H, ABq, J 12.0 Hz, CH2-phenyl), 7.32 (10 H, s , 2C5H5) ppm; substance with an Rf value of 0.72: IR (CH2Cl2): 3025vs, 2980s, 1755vs, 1700m, 1420m, 1260vs, 1210s, 1075m, 900s cm ¹ ; 1 H NMR (CDCl 3) δ: 2.08 and 2.21 (6H, 2s, CMe ₂ ), 2.94 and 3.16 (2H, 2d, J 3.2 and

4.7 Hz, β C ₃ H and a C ₃ H), 4.19 (3H, b, NHCH ₂ ), 4.77 (1H, dd, J 3.2 and 4.7 Hz, C ₂ H) 5.06 and 5.28 (2H, ABq, J 12.3 Hz, CH ₂ -phenyl), 7.32 (10H, s, 2C 4 H 5) ppm]. The sulfinamide (1.65 g, 4 mmol) was reacted with potassium permanganate as indicated in Example 5. After a short retention of the potassium permanganate color, the reaction was complete. 1.32 g (77%) of (2R) 1- (1'-benzyloxycarbonyl-2'-methyl-prop-1'enyl) -2-benzylaminosulfonyl-4-oxo-azetidine are obtained, which is purified by chromatography on a silica gel column, eluting with a solvent mixture. CH ₂ C1 ₂ : EtOAc = 2: l [Rf 0.62 (benzene: EtOAc = 2: l); mp: 92 - 94 ° C; IR (KBr): 3300vs, 1775vs, 1650vs, 1430m,

1350s, 1335s, 1290vs, 1200m, 1150s, 1070w cm '¹;

1 H NMR (CDCl ₃ ) δ: 2.05 and 2.23 (6H, 2s, CMe ₂ ), 3.16 (2H, d, J 3.8 Hz, α C ₃ H and β

C ₃ H), 4.08 (2H, d, J 5.9 Hz, NCH ₂ ), 4.50 (1H, t, J 5.9 Hz, NH), 4.89 (IH, t, J 3.8 Hz.

C ₂ H), 5.09 and 5.18 (2H, ABq, J 12.0 Hz, CH ₂ -phenyl), 7.25 and 7.34 (10H, 2s, 2 ^ 5) ppm].

The resulting sulfonamide (0.4 g, 1.16 mol) was hydrated and treated as in Example 6 to give 0.36 g of acid:

R _f 0.88 (n-BuOH: HAc: H ₂ O = 4: 1: 1);

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

^X H NMR (CDCl ₃ ) δ: 2.09 and 2.26 (6H, 2s, CMe ₂ ), 3.17 (2H, d, J 4.1 Hz, C 3 H),

4.26 (2H, s, NCH ₂ ), 4.98 (1H, t, J 4.1 Hz, C ₂ H), 7.30 (5H, s, C ₆ H ₅ ) ppm.

EXAMPLE 12 (2R) 2-Benzylaminosulfonyl-4-oxo-azetidine

a) (2R) 1- (r-Methyloxycarbonyl-2'-methyl-prop-1'-enyl) -4-oxo-azetidine-2-sulfinic acid (5.0 g, 20 mmol) was dissolved in thionyl chloride (20 ml) and was treated as described in Example 11. A mixture of (5.4 g, 80.4%) epimer (2R) 1- (Γmethyloxycarbonyl-2'-methyl-prop-r-enyl) -2-benzylaminosulfinyl-4-oxo-azetidine was obtained with Rf values 0.20 and 0.27 (CH ₂ Cl ₂ : EtOAc = 2: l) separated by chromatography on a silica gel column [substance having Rf value 0.20: IR (CH ₂ Cl ₂ ): 3200-3300m, 2930m, 1760vs, 1715s, 1220s, 1080s cm '¹; ^X H NMR (CDCl 3) δ: 1.99 and 2.23 (6H, 2s, CMe ₂ ),

3.17 (1H, dd, J 5.0 and 15.2 Hz, a C3H), 3.46 (1H, dd, J 2.6 and 15.2 Hz, 0 C3H), 3.75 (3H, s, OCH3), 4.15-4.30 (1H, b, NH ), 4.23 (2H, s, CH ₂ -phenyl, 4.92 (1H, 2d, C ₂ HJ 2.6 and 5.0 Hz), 7.31 (5H, s, CgHs) ppm, substance with an Rf value of 0.27: IR (CH ₂ C1 ₂ ): 3300m, 2950m, 1775vs, 1720s, 1360s, 1220s, 1080s cm- ¹ ; ^X H NMR (CDCI3) δ: 2.07 and 2.20 (6H, 2s, CMe ₂ ), 2.97 (1H, dd, J 3.1 and 15.5 Hz) , β C ₃ H), 3.25 (1H, dd, J 5.0 and 15.5 Hz, a C ₃ H), 3.73 (3H, s, OCH3), 4.15-4.33 (1H, b, NH), 4.26 (2H, s, CH _2- phenyl), 4.83 (1H, 2d, J 3.1 and 5.0 Hz, C ₂ H), 7.32 (5H, s, C ₆ H ₅ ) ppm] .Sulfinamide (3.36 g, 10 mmol) was reacted with potassium permanganate. as indicated in Example 5. Ether (30 ml) was added to the oily product (2.5 g) and the resulting gelatinous mass was stirred at room temperature for 8 hours. The separated crystals were sucked off and washed with ether: mp 111-130 ° C; Rf 0.10 (benzene) : EtOAc = 3: 1);

IR (KBr): 3300vs, 1790vs, 1740vs, 1430s, 1330s, 1300s, 1120s, 1070s cm- ¹ ;

^X H NMR (DMSO-dg) δ: 2.96 (3H, dd, J 2.1 and 15.2 Hz, β C ₃ H), 3.29 (1H, dd, J

4.7 and 15.2 Hz, a C3H), 4.23 (2H, d, J 5.9 Hz, NCH ₂ ), 4.71 (1H, dd, J 2.1 and

4.7 Hz, C ₂ H), 7.33 (5H, s, C ₆ H 5), 7.96 (1H, t, J 5.9 Hz, SNH), 8.92 (1H, s, N] H) ppm.

b) (2R) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-r-enyl) -2-benzylamosulfonyl-4-oxoazetidine prepared in Example 11 is reacted with potassium permanganate, analogous to process a), wherein we get an identical product. ,

EXAMPLE 13 (2R) 1- (r-Carboxyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) aminosulfonyl] -4-oxo-azetidine (2R ) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-1'-enyl) -4-oxo-azetidine-2-sulfinic acid (3.23 g, 10 mmol) was dissolved in thionyl chloride (10 ml). The solution was stirred for 1 hour at 25 ° C. The excess thionyl chloride was evaporated under reduced pressure to an oily residue. The evaporated residue was dissolved in methylene chloride (50 ml), 3 amino-5-methyl-isoxazoa (2.94 g, 30 mmol) was added and stirred at room temperature for 3 hours. Water (50 ml) was added to the reaction mixture and acidified with 10% hydrochloric acid to a pH of 1.5. The layers are separated. The organic was washed again with water (50 ml). Water (50 ml) was added to the organic layer and basified with saturated sodium bicarbonate solution to a pH of 8.0. The layers were separated, the organic layer was again washed with water, dried over sodium sulfate and evaporated to dryness. A mixture of (3.80 g, 92.6%) epimer (2R) 1- (1'-benzyloxycarbonyl-2'-methyl-propenyl) -2 - [(5'-methyl-isoxazol-3'yl) amino-sulfinyl is obtained -4-oxo-azetidines having Rf values of 0.29 and 0.35 (CH ₂ Cl ₂ : EtOAc = 2: 1), separated by chromatography on a silica gel column.

[Substance having an Rf value of 0.29: IR (CH2Cl2) 1780vs, 1720m, 1620s, 1465s, 1360s, 1290m, 1215s, IlOOs, 1080m cm * ¹ ; Ή NMR (CDCl3) δ: 1.98 and 2.20 (6H, 2s, CMe ₂ ), 2.34 (3H, s, Me-isoxazole), 3.28 (1H, dd, J 4.7 and 15.5 Hz, a C3H), 3.54 (1H. dd, J 2.6 in

15.5 Hz, β C ₃ H), 5.06 (1H, dd, J 2.6 and 4.7 Hz, C ₂ H) 5.19 (2H, s, CH ₂ -phenyl), 5.82 (1H, s, CH-isoxazole), 7.33 ( 5H, s, CgH5), 8.40 (1H, s, NH) ppm; substance with an Rf value of 0.35; IR (CH ₂ C1 ₂ ) 1780vs, 1725m, 1630s, 1470s, 1360m, 1290m, 1220s, IlOOs cm-1; 1 H NMR (CDCl 3) δ: 2.09 and 2.24 (6H, 2s, CMe ₂ ), 2.36 (3H, s, Meisoxazole), 3.04 (1H, dd, J 2.9 and 15.5 Hz, β C3H), 3.30 (1H, dd, 1H). J 5.0 and 15.5 Hz, a C 3 H), 5.11 (1H, dd, J 2.9 and J 5.0 Hz, C ₂ H), 5.21 (2H, s, CH ₂ -phenyl), 5.80 (1H, s, CHisoxazole), 7.26 (5H, s) ppm]. A solution of sulfinamide (4.03 g, 10 mmol), mchloroperbenzoic acid (4.30 g, 25 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 24 hours. After completion of the reaction, an aqueous solution of sodium thiosulphate (15 mmol) was added dropwise and stirred for a further 30 minutes. The reaction mixture was basified with 5% aqueous sodium hydrogen carbonate solution to a pH of 8.5 and the layers were separated. The aqueous portion was saturated with sodium chloride and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. 3.5g (79%) of the crude product is obtained as the sodium salt. By dissolving the crude product in water and acidifying it with a 10% hydrochloric acid solution to a pH of 2.0, (2R) 1- (enzbenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2- [5'-methyl-isoxazole-3 is obtained '-yl) aminosulfonyl] -4 ~ oxo-azetidine. [Tal. 141-143 ° C (ether crystalline); R f 0.40 (CH 2 Cl 2: EtOAc = 2: 1); IR (KBr): 3200S, 1790vs, 1720vs, 1620s, 1465s, 1395s, 1300s, 1175s ^cm-1; 1 H NMR (CDCl 3) δ: 2.02 and 2.14 (6H, 2s, CMe ₂ ), 2.37 (3H, s, Me-isoxazole), 3.32 (2H, d, J 3.5 Hz, a C ₃ H and β C ₃ H ), 5.10 (2H, s, CH ₂ -phenyl), 5.28 (1H, t, J 3.5 Hz, C ₂ H), 6.10 (1H, s, CH-isoxazole), 7.25 (5H, s, CgHs) ppm. Anal: Cf9H2iN ₃ O (5S; Found: C, 54.21; H, 5:34; N, 9.96, S, 8.23%; calculated: C, 54.41, H; 5.05, N 10.02, S, 7.64%]. The obtained sulfonamide ( 419 mg, 1 mmol) was hydrated and treated as in Example 6. 227 mg (69%) was obtained:

R f 0.91 (n-BuOH: HAc: H ₂ O = 4: 1: 1);

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

1 H NMR (DMSO-d ₆ ) δ: 1.89 and 2.13 (6H, 2s, CMe ₂ ), 2.35 (3H, s, Me-isoxazole),

3.21 (IH, dd, J 1.8 and 15.3 Hz, β C ₃ H), 3.55 (IH, dd, J 4.5 and 15.3 Hz, a C ₃ H),

5.34 (1H, dd, J 1.8 and 4.5 Hz, C ₂ H), 6.07 (1H, s, CH-isoxazole), 11.32 (1H, bs, NH), 13.05 (1H, b, COOH) ppm.

EXAMPLE 14 (2R) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(3 ', 4'-dimethyl-isoxazol-5'yl) aminosulfonyl] -4-oxo-azetidine (2R) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-r-enyl) -4-oxoazetidine-2-sulfinic acid (3.23 g, 10 mmol) was dissolved in thionyl chloride (10 ml). The solution was stirred for 1 hour at 25 ° C. The excess thionyl chloride was evaporated under reduced pressure to an oily residue. The absorbent residue was dissolved in methylene chloride (50 ml), 5 amino-3,4-dimethyl-isoxazole (3.78 g, 30 mmol) was added and treated as indicated in Example 13. A mixture (3.20 g, 76.7%) of epimemes (2R) was obtained. 1- (1'-Benzyloxycarbonyl2'-methyl-prop-r-enyl) -2 - [(3 ', 4'-dimethyl-isoxazol-5'-yl) amino-sulfinyl] -4-oxoazetidine having Rf values of 0.31 and 0.38 (CH2Cl2: EtOAc = 2: 1), separated by chromatography on a silica gel column [substance having an Rf value of 0.31: IR (KBr): 1790vs,

1730m, 1710s, 1650s, 1370m, 1300m, 1225vs, IlOOm cm '¹; 1 H NMR (CDCl 3) δ: 1.82, 1.97, 2.16, 2.20 (12H, 4s, 4Me), 3.17 (1H, d, J 4.1 Hz, a C 3 H), 3.45 (1 H, d, J 3.2 Hz, β C 3 H) , 5.04 (1H, dd, J 3.2 and 4.1 Hz, C2H), 5.24 (2H, s, CH2-phenyl), 7.35 (5H, s, C5H5), 7.87 (1H, s, NH) ppm; substance with an Rf value of 0.38; IR (KBr): 1785vs, 1730s, 1700s, 1650s, 1370m, 1300m, 1230s, IlOOs cm ⁴ ; 1 H NMR (CDCl 3) δ: 1.81,2.10,2.17,

2.24 (12H, 4s, 4Me), 3.09 (1H, d, J 2.9 Hz, β C ₃ H), 3.34 (1H, d, J 5.0 Hz, a C ₃ H), 5.05 (1H, dd, J 2.9 in 5.0 Hz, C ₂ H), 5.20-5.30 (3H, m, CH ₂ Phenyl and NH), 7.35 (5H, s, C6 ^h 5), Ppm] ·

A solution of sulfinamide (4.17 g, 10 mmol), meta-chloroperbenzoic acid (4.3 g, 25 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 24 hours and treated as described in Example 13. 3.2 g (70%) was obtained Product in the form of sodium salt with a melting point of 160 ° C:

Rf0.44 (EtOAc);

IR (CH ₂ C1 ₂ ): 1790vs, 1730m, 1365s, 1220s, 1170s, 1070m cm ⁴ ; Ή NMR (CDCl ₃ ) δ: 1.90, 2.03, 2.21, 2.23 (12H, 4s, 4Me), 3.29 (2H, d, J 4.0 Hz, a C ₃ H and β C ₃ H), 5.17 (1H, t. J 4.0 Hz, C ₂ H), 5.24 (2H, s, CH ₂ -phenyl), 7.35 (5H, s, CgH 5) ppm.

EXAMPLE 15 (2R) 1- (r-Benzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(2'-phenyl-pyrazol-3'yl) aminosulfonyl] -4-oxo-azetidine (2R) 1- (1'-Benzyloxycarbonyl-2'-methyl-prop-1'-enyl) -4-oxo-azetidine-2-sulfinic acid (10 mmol) was dissolved in thionyl chloride (3.23 g, 10 ml) and treated as in the example 13, 2-phenyl-3-aminopyrazole (4.77 g, 30 mmol) was added instead of 3-amino-5-methyl-isoxazole. A mixture of (4.04 g, 86%) epimemic (2R) 1- (1'-benzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(2'-phenyl-pyrazol-3'-yl) amino- sulfmyl] -4oxo-azetidines with Rf values of 0.44 and 0.50 (CH ₂ Cl ₂ : EtOAc = 2: 1), separated by chromatography on a silica gel column; [substance having an Rf value of 0.44: IR (KBr): 1780vs, 1720s, 1600m, 1500s, 1455m, 1360m, 1290m, 1215vs, 1080m cm ⁴ ; 1 H NMR (CDCl ₃ ) δ: 1.93 and 2.16 (6H, 2s, CMe ₂ ), 2.96 (1H, dd, J 4.9 and 15.3 Hz, a C ₃ H), 3.07 (1H, dd, J

2.5 and 15.3 Hz, β C ₃ H), 4.79 (1H, dd, J 2.5 and 4.9 Hz, C ₂ H), 5.14 (2H, s, CH ₂ -phenyl), 6.22 and 7.57 (2H, 2d, J 1.9 Hz, = CH-CH =), 7.26-7.45 (10H, m, 2C0H5) ppm; substance with an Rf value of 0.50: IR (KBr): 1780vs, 1720s, 1600m, 1500s, 1455m, 1385m, 1360m, 1290m, 1220s, IlOOs, 1070m cm ⁴ ; 1 H NMR (CDCl ₃ ) δ: 2.01 and 2.13 (6H, 2s, CMe ₂ ),

2.80 (1H, dd, J 2.3 and 15.5 Hz, β C ₃ H), 2.92 (1H, dd, J 5.3 and 15.5 Hz, α C ₃ H), 4.80 (2H, b, C ₂ H), 5.09 and 5.18 (2H, ABq, J 12.4 Hz, CH ₂ -phenyl), 6.21 and 7.58 (2H, 2d, J 1.6 Hz = CH-CH =), 7.20-7.40 (10H, m, 2C5H5) ppm. A solution of sulfinamide (4.64 g, 10 mmol), m-chloroperbenzoic acid (4.3 g, 25 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 24 hours and treated as in Example 13. 3.4 g (67%) of the product are obtained as sodium salts:

R _f 0.47 (EtOAc);

IR (CH ₂ Cl ₂ ); 3340w, 1785s, 1725m, 1700m, 1500s, 1390s, 1360s, 1290m, 1215s,

1170s, 1075m cm -1;

₁ H NMR (CDCl ₃ ) δ: 1.96 and 2.16 (6H, 2s, CMe ₂ ), 2.88 (1H, dd, J 5.2 and 15.5 Hz, α C ₃ H), 3.00 (1H, dd, J 2.3 and 15.5 Hz, β C ₃ H), 4.92 (1H, dd, J 2.3 and 5.2,

C ₂ H), 5.07 and 5.18 (2H, ABq, J 12.1 Hz, CH ₂ -phenyl), 6.20 and 7.56 (2H, 2d, J

1.7 Hz, = CH-CH =), 7.20-7.40 (10H, m, 2C ₆ H ₅ ) ppm.

EXAMPLE 16 (2R, 3R) 1- (rm-Methylbenzyloxycarbonyl-2'-methyl-prop-r-enyl-2 - [(5'-methylisoxazol-3'-yl) aminosulfonyl] -3 - [(3'-o -chlorophenyl-5'-methyl-isoxazol-4'-yl) carboxamido] -4-oxoazetidine

An epimeric mixture of sulfinamides (2.24 g) prepared according to the procedure described in Example 7 was dissolved in methylene chloride (10 ml) and stirred with triethylamide (0.48 ml) for 2 hours at room temperature. It was extracted with 0.1 N hydrochloric acid (5 ml) then water (10 ml) and the organic extract was dried (Na ₂ SC> 4), filtered and evaporated in vacuo. 2.23 g (99.5%) of the crude product are obtained from which, by chromatography on a silica gel column and eluting with a solvent mixture of CH ₂ CL ₂ , the (2R, 3R) 1- (1'-methylbenzyloxycarbonyl-2'-methyl-prop) is selected -r-enyl) -2 - [(5'-methyl-isoxazol-3'-yl) aminosulfinyl] -3 - [(3'-o-chlorophenyl-5'-methyl-isoxazol-4'-yl) -carbox -amido] -4-oxo-azetidine [Rf 0.21 (CH ₂ Cl ₂ : EtOAc = 4: 1); m.p. 94-96 ° C; ³ H NMR (CDCl ₃ ) δ: 1.95 and 2.22 (6H, 2s, CMe ₂ ), 2.33 and 2.35 (6H, 2s, 2Me-isoxazole), 2.77 (3H, s, Me-phenyl), 4.96 (1H, d , J 4.5 Hz, C ₂ H), 5.13 (2H, bs, OCH ₂ ), 5.61 (1H, dd, J 4.5 and 8.5 Hz, C ₃ H), 5.72 (1H, s, CHisoxazole), 6.69 (1H. d, J 8.5 Hz, CONH), 7.04-7.55 (8H, m, 2C5H4) ppm], which is then oxidized with hydrogen peroxide as in Example 1. Sulfonamide is obtained in 85.8% yield:

R _f 0.55 (CH ₂ Cl ₂ : MeOH = 10: 1);

IR (movie) 3410w, 3160vw, 3070vw, 1795vs, 1735w, 1685bs, 1620s, 1640m, 1580bs, 1420w, 1300m, 1270m, 1220m, 1170m, 1120m, 1060m, 770m, 740m cml;

NMR (CDCl ₃ ) 5: 1.84 and 2.11 (6H, 2s, CMe ₂ ), 2.26 and 2.33 (6H, 2s, 2Misoxazole), 2.72 (3H, s, Me-phenyl), 5.01 (2H, bs, OCH ₂ ), 5.36 (1H, d,

J 5.0 Hz, C ₂ H), 5.71-5.92 (2H, m, C ₃ H and CH-isoxazole), 6.41 (1H, d, J 10 Hz, CONH), 7.01-7.62 (8H, m, 2 ^ 4) ppm .

k

EXAMPLE 17 (2R, 3R) 1- (1 '-Carboxyl-2'-methyl-prop-1'-enyl) -2 - [(5'-methylisoxazol-3'-yl) aminosulfonyl] -3-phthalimido-4 -oxo-azetidine

a) (2R, 3R) 1- (p-Nitrobenzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methylisoxazol-3'-yl) aminosulfinyl] -3-phthalimido-4- The oxo-azetidine prepared according to Example 4 was dissolved in methylene chloride and mixed with triethylamine to give (2R, 3R) 1 (p-nitrobenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(5'- methyl-isoxazol-3'-yl) aminosulfinyl] -3-phthalimido-4-oxo-azetidine [1 H NMR (CDCl 3) δ: 2.14 (6H, bs, CMe ₂ ), 2.31 (3H, s, Me-isoxazole) , 5.08 and 5.23 (2H, ABq, J 13.5 Hz, OCH ₂ ), 5.58 (1H, d, J 5.4 Hz, C ₂ H), 5.71 (1H, bs, CH-isoxazole), 6.0 (1H, d, J 5.4 Hz, C3H), 7.45 and 8.16 (4H, 2d, J 9.0 Hz, C6H4NO ₂ ), 7.70-7.94 (4H, m, phthalimido) ppm] which, upon oxidation with hydrogen peroxide, as indicated in Example 1, gives (2R, 3R) 1- (1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-iso-xazol-3'-yl) aminosulfonyl] -3-phthalimido- 4-oxo-azetidine [Rf 0.60 (CH ₂ Cl ₂ : MeOH = 9: 1); IR (KBr): 1790bs, 1730vs, 1615m, 1520m, 1465m, 1385s, 1350m, 1290w cm ^-1 ; 1 H NMR (CDCl 3) δ: 2.12 and 2.26 (6H, 2s _r CMe ₂ ), 2.32 (3H, s, Me-isoxazole), 5.21 (2H, bs, OCH ₂ ), 5.73 (1H, d, J 5.4 Hz) , C ₂ H), 5.83 (1H, d, J 5.4 Hz, C 3 H), 6.05 (1 H, bs, CH-isoxazole), 7.50 and 8.18 (4H, 2d, J 9.0 Hz, C ₆ H ₄ NO ₂ ), 7.60-7.86 ( 4H, m, phthalimido) ppm]. The sulfonamide (840 mg, 1.38 mmol) was dissolved in methanol (25 ml) and hydrated and treated as in Example 6. By stirring the organic extract at room temperature, acid (490 mg, 75%) was precipitated from the melt. 160-165 ° C:

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

1 H NMR (DMSO-d 6) δ: 2.17 (6H, s, CMe ₂ ), 2.27 (3H, s, Me-isoxazole), 3.31 (2H, bs, SNH, COOH, HOH), 5.68 (1H, d. J 4.9 Hz, C ₂ H), 5.82 (1H, d, J 4.9 Hz,

C3H), 5.89 (1H, s, CH-isoxazole), 7.92 (4H, s, phthalimido) ppm.

b)

Sulfonamide (0.63 g) prepared according to Example 4 was dissolved in methylene chloride (10 ml) and stirred with triethylamine (0.1 g) at 10 ° C for 5 hours. Chromatography on a silica gel column isolated from the absorbent residue 0.57 g of sulfonamide identical to that described in a), by hydrogenolysis, which gave the acid.

EXAMPLE 18 (2R, 3R) 1- (p-Nitrobenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2 - [(5'-methylisoxazol-3'-yl) aminosulfonyl] -3-amino-4-oxo -azetidine

The sulfonamide prepared in Example 17 is reacted with sodium sulfide, then with dicyclohexylcarbodiimide and finally with methylhydrazine as described in Croat. Chem. Acta 49 (1977) 779. A foam product is obtained which gives a positive reaction with ninhydrin:

R _f 0.48 (CH ₂ Cl ₂ : MeOH = 9: l)

IR (KBr) 1785s, 1735m, 1710m, 1620m, 1525s, 1465w, 1400w, 1150s, 1300w, 1275w, 1220m, 1165m cm * I;

1 H NMR (CDCl ₃ ) δ: 2.13 and 2.25 (6H, 2s, CMe ₂ ), 2.39 (3H, s, Me-isoxazole),

4.66 (1H, d, J 5.2 Hz, C ₂ H), 5.21 (1 H, d, J 5.2 Hz, C ₃ H), 5.22 and 5.29 (2H,

ABq, J 12.8 Hz, OCH ₂ ), 6.12 (1H, s, CH-isoxazole), 7.49 and 8.22 (4H, 2d,

J 8.5 Hz, CgH ₄ NO ₂ ) ppm.

EXAMPLE 19 (2R, 3R) 1- (r-Carboxyl-2'-methyl-prop-r-enyl) -2-methylaminosulfonyl-3-o-methylaminocarbonylphenylcarboxamido-4-oxo-azetidine p-Nitrobenzyl ester (5R, 6R) The 6-phthalimidopenicilanate sulfoxide (1.5 g, 3 mmol) was reacted with N-chlorosuccinimide (0.4 g, 3 mmol) as indicated in Example 1, after which the reaction solution was cooled to 5 ° C and methylamine (1 ml) in toluene was added. (4 ml). The reaction mixture was stirred for 3 hours at 5 ° C and evaporated in vacuo; the residue was suspended in methylene chloride (15 ml); The insoluble part is sucked off and the mother liquor is evaporated in vacuo. An epimeric mixture of (1.53 g) (2R, 3R) 1- (N-nitrobenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2-methylaminosulfinyl-3-o-methylaminocarbonylphenylcarboxamido-4-oxo-azetidine [IR (film ): 3250bm, 3065w, 2950w, 1780s, 1730sh, 1715vs, 1650m, 1605w, 1525s, 1350s, 1295m, 1220m, 1185s, 1060m, 855w, 820w, 740m cm-ί], which is oxidized with hydrogen peroxide as indicated in case 1.

1.23 g of (2R, 3R) 1- (1'-p-nitrobenzyloxycarbonyl-2'-methyl-p-prop-p-yl) -2methylaminosulfonyl-3-o-methylaminocarbonylphenylcarboxamido-4-oxo-azetidine are obtained [R _f 0.81 ( CH ₂ Cl ₂ : MeOH = 9: 1); ³ H NMR (CDCl ₃ ) δ: 2.15 and 2.31 (6H, 2s, CMe ₂ ),

2.86 (3H, d, J 4.5 Hz, CONMe), 2.98 (3H, d, J 4.9 Hz, SO ₂ NMe), 5.16 (1H, d, J 4.9 Hz, C ₂ H), 5.31.in 5.38 ( 2H, ABq, J 13.2 Hz, OCH ₂ ), 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 (IH, q, J 4.9 Hz, CONH), 7.44-7.52 (4H, m, OCC6H4CO), 7.54 and 8.25 (4H, 2d, J 8.7 Hz, C ₆ H4NO ₂ ) ppm] provided by hydrogenolysis as indicated in Example 17, it provided an acid (0.68 g) from the melt. 142 ° C on 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 ³ ;

1 H NMR (DMSO-d ₆ ) δ: 2.01 and 2.19 (6H, 2s, CMe ₂ ), 2.64 (3H, d, J 4.5 Hz,

CONMe), 2.75 (3H, d, J 4.7 Hz, SO ₂ NMe), 5.24 (1H, d, J 5.0 Hz, C ₂ H),

5.65 (1H, dd, J 5.0 and 8.7 Hz, C3H), 7.17 (1H, q, J 4.7 Hz, SO ₂ NH), 7.487.56 (4H, m, C ₆ H ₄ ), 8.38 (1H, q, J 4.5 Hz, CONH), 9.07 (1H, d, J, 8.7 Hz, CONH) ppm.

EXAMPLE 20 (2R, 3R) 1- (r-Carboxyl-2'-methyl-prop-1'-enyl) -2-benzylaminosulfonyl-3-phenylacetamido-4-oxo-azetidine p-Nitrobenzyl ester (5R, 6R) 6 -phenylacetamidopenicilanate sulfoxide (3.0 g, 6.2 mmol) was reacted with N-chlorosuccinimide (1.0 g, 7.5 mmol) as in Example 1, then benzylamine (1.3 ml, 12.4 mmol) was added and the reaction mixture was stirred for 2 hours at 5 ° C. The toluene solution was decanted, washed with water, dried and evaporated in vacuo. Addition of ethyl acetate precipitates (2R, 3R) 1- (1'-pnitrobenzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2-benzylaminosulfinyl-3-phenylacetamido-4-oxo-azetidine, which is aspirated (1.82 g ) [ ² H NMR (CDCl 3) δ: 1.91 (3H, s, Me), 3.48 (2H, s, CH ₂ CO), 3.95-4.32 (3H, m, SNHCH ₂ ), 4.80-5.14 (4H, m. NCHCO = CH2, C ₂ H), 5.26 (2H, bs, OCH ₂ ), 5.87 (1H, dd, J 5.0 and 9.8 Hz, C3H), 6.52 (1H, d, J 9.8 Hz, CONH), 7.12-7.37 (10H, m, 2ΟΗ _5), 7.47 and 8.22 (4H, 2d, J 8.8 Hz, C6H4.NO2) ppm], is isomerized with triethylamine in methylene chloride to (2R, 3R) 1- (Γp-nitrobenzyloxycarbonyl-2'-methyl -prop-r-enyl) -2-benzylaminosulfinyl-3-phenylacetamido-4-oxo-azetidine (1.66 g) and oxidized with hydrogen peroxide as indicated in Example 1. (2R, 3R) 1- (1'- p-Nitrobenzyloxycarbonyl-2'-methyl21 prop-1'-enyl) -2-benzylaminosulfonyl-3-phenyl-acetamido-4-oxo-azetidine (1.57 g) [Rf 0.60 (CH ₂ Cl ₂ : EtOAc = 4: 1) ; [≪ 1 > H NMR (CDCI3) δ: 2.06 and 2.24 (6H, 2s, CMe ₂ ), 3.593.98 (5H, m, CH ₂ CO, SNHCH ₂ ), 4.67 (1H, d, J 5.0 Hz, C ₂ H) ), 5.21 (2H, bs, OCH ₂ ),

5.73 (1H, dd, J 5.0 and 10.3 Hz, C3H), 6.68 (1H, d, J 10.3 Hz, CONH), 7.00-7.36 (10H, m, 2C5H5), 7.42 and 8.19 (4H, 2d, J 8.8 Hz) , C5H4NO2) ppm] which is subsequently hydrated as indicated in Example 6. Isolate 0.91 g of product:

R f 0.38 (CH ₂ Cl ₂ : MeOH = 4: 1);

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

1 H NMR (CDCl 3) δ: 2.07 and 2.25 (6H, 2s, CMe ₂ ), 3.56 and 3.64 (2H, ABq, J 14.8 Hz, CH ₂ CO), 3.98-4.02 (3H, m, SNHCH ₂ ), 4.94 ( 1H, d, J 5.2 Hz, C ₂ H),

5.84 (1H, dd, J 5.2 and 10.3 Hz, C3H) 6.77 (1H, d, J 10.3 Hz, CONH), 7.117.37 (10H m, 2CgH5) ppm.

EXAMPLE 21 (2R, 3R) 1- (1'-Carboxyl-2'-methyl-prop-r-enyl) -2-methylaminosulfonyl-3-phenylacetamido-4-oxo-azetidine p-Nitrobenzyl ester (5R, 6R) 6 -phenylacetamidopenicilanate sulfoxide (3.0 g, 6.2 mmol) was reacted with N-chlorosuccinimide (1.0 g, 7.5 mmol) as in Example 1, then methylamine (1 ml) was added and the reaction mixture was stirred for 2 hours at 5 ° C. The precipitate was aspirated, the mother liquor was washed with water, dried and evaporated in vacuo. Chromatography on a silica gel column gave (2R, 3R) 1- (1'-pnitrobenzyloxycarbonyl-2'-methyl-prop-r-enyl) -2-methyl-anino-sulfinyl-3-phenylacetamido-4-oxo-azetidine (1.63 g) [1 H NMR (CDCl 3) δ: 2.12 and 2.26 (6H, 2s, CMe ₂ ), 2.47 (3H, d, J 5.4 Hz, NMe), 3.63 (2H, ABq, J 14.9 Hz, CH ₂ CO) , 4.68 (1H, d, J 5.0 Hz, C ₂ H), 5.28 (2H, s, OCH ₂ ), 5.80 (1H, dd, J, 5.0 and 9.9 Hz, C 3 H), 7.19 (1H, d, J 9.9 Hz, CONH), 7.26-7.38 (5H, m, C ₆ H ₅ ), 7.50 and 8.24 (4H, 2d, J 8.7 Hz, C5H4NO2) ppm], which was then oxidized with hydrogen peroxide as indicated in Example 1. Isolated (2R, 3R) 1- (p-nitrobenzyloxycarbonyl-2'-methylprop-r-enyl) -2-methylaminosulfonyl-3-phenyl-acetamido-4-oxo-azetidine (0.98 g) [IR (KBr): 3460- 3140bw, 1785s, 1730m, 1700-1675bm, 1610w, 1525s, 1350s, 1220m, 1155m, 1070m, 850w cnr ¹ ; Ή NMR (CDCI3) δ: 2.09 and 2.26 (6H, 2s, CMe ₂ ), 2.46 (3H, d, J 5.0 Hz, NMe), 3.17 (1H, q, J 5 Hz, SNH), 3.55 and 3.69 (2H , ABq, J 14.5 Hz, CH ₂ CO), 4.97 (1H, d, J 5.0 Hz, C ₂ H) 5.27 and 5.33 (2H, ABq, J 13.2 Hz, OCH ₂ ), 5.80 (1H, dd, J. 5.2 and 10.3 Hz, C ₃ H), 6.58 (1H, d, J 10.3 Hz, CONH), 7.32-7.51 (5H, m, C5H5), 7.50 and 8.23 (4H, 2d, J 8.7 Hz, C ₆ H ₄ NO ₂ ) ppm].

The sulfonamide obtained was hydrated as in Example 6 and the resulting acid (0.43 g) was isolated by hydrogenolysis:>

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

1 H NMR (CDCl 3) δ: 2.07 and 2.25 (6H, 2s, CMe ₂ ), 2.53 (3H, d, J 4.5 Hz, NMe),

3.63 (2H, ABq, J 15.1 Hz, CH ₂ CO), 4.16 (1H, m, SNH), 5.24 (1H, d, J 5.2 Hz, C ₂ H), 5.88 (1H, dd, J 5.2 and 10.3 Hz , C3H), 6.84 (1H, d, J = 10.3 Hz,

CONH), 7.26-7.40 (5H, m, C ^) ppm.

EXAMPLE 22 (2R, 3R) 1- (r-Carboxyl-2'-methyl-prop-r-enyl) -2 - [(5'-methyl-isoxazol-3-yl) aminosulfonyl] -3-phenoxyacetamido-4- Oxo-azetidine p-Nitrobenzyl ester (5R, 6R) of 6-phenoxyacetamidopenicilanate sulfoxide (5.0 g, 10 mmol) was reacted with N-chlorosuccinimide (1.7 g, 13 mmol) as indicated in Example 1, then 3-amino- 5-methyl-isoxazole (4.1 g, 40 mmol) and the reaction mixture was stirred for 2 hours at 0 ° C. The toluene solution was decanted, washed with water, dried and evaporated in vacuo. An epimeric mixture was obtained (5.0 g, 83.6%) (2R, 3R) 1- (p-nitrobenzyloxycarbonyl-2'-methyl-prop-2'-enyl) -2 - [(5'-methylisoxazol-3'-yl) - aminosulfinyl)] - 3-phenoxyacetamido-4-oxo-azetidines; [dominant epimer from soil. Mp 196-198 ° C; IR (KBr): 3310w, 1775s, 1755m, 1665m, 1625m, 1520s, 1350s, 1240m, 1170m, IlOOs, 915w, 855w, 755w cm ^-1 ; 1 H NMR (CDCl 3) δ: 2.02 (3H, s, Me), 2.25 (3H, s, Me-isoxazole), 4.45 and 4.54 (2H, ABq, J 15.1, OCH ₂ CO), 5.07 (1H, bs. NCHCO), 5.07 and 5.19 (2H, 2bs, = CH ₂ ), 5.39 (1H, d, J 5.1 Hz, C ₂ H) 5.35 (2H, bs, OCH ₂ ), 5.76 (1H, bs, CH-isoxazole) , 5.85 (1H, dd, j 5.0 and 9.0 Hz, C3H), 6.91-7.36 (5H, m, C6H5), 7.49 (1H, d, CONH), 7.49 and 8.21 (4H, 2d, J 8.8 Hz, C < 5H4NO ₂ ) ppm].

The resulting epimer mixture was oxidized with hydrogen peroxide as in Example 1 and subjected to isomerization with triethylamine in methylene chloride, after which (3.5 g, 68.2%) (2R, 3R) 1- (1'-p-nitrobenzyloxycarbonyl-2 'was isolated -methyl-prop-phenyl) -2- (5'-methyl-isoxazol-3'-yl) -aminosulfonyl-3-phenoxyacetamido-4-oxo-azetidine. [Rf 0.67 CH ₂ Cl ₂ : MeOH = 9: 1); IR (KBr): 3410-2700m, 1795s, 1735m, 1700s, 1620m,

1525s, 1500m, 1465m, 1400m, 1355s, 1300m, 1220s, 1165m, 1065-1110m cm '¹; * Η NMR (CDCI3) δ: 2.11 and 2.20 (6H, 2s, CMe ₂ ), 2.24 (3H, s, Me-isoxazole), 4.35 and 4.50 (2Η, ABq, J 15.1 Hz, OCH ₂ CO), 5.26 ( 2H, s, OCH ₂ ), 5.59 (1H, d, J 5.2 Hz, C ₂ H), 6.00 (1H, s, CH-isoxazole), 6.03 (1H, dd, J 5.2 and 10.5 Hz, C ₃ H) , 6.90-7.35 (5H, s, OC6H5), 7.52 and 8.22 (4H, 2d, J 8.8 Hz, C ^ NC ^) ppm].

The resulting sulfonamide (0.56 g, 0.91 mmol) was then subjected to hydogenolysis as described in Example 6, after which 0.23 g (52.5%) of the product was isolated:

Rf value 0.35 (CH ₂ Cl ₂ : MeOH = 1.5: 1.0)

IR (KBr) 3600-2400bm, 1795s, 1700bs, 1620m, 1500-1550s, 1235s, 1170s, 10651090m, 940m cm * I;

1 H NMR (CDCl 3) d: 2.05 and 2.19 (6H, 2s, CMe ₂ ), 2.27 (3H, s, Me-isoxazole), 4.50 10 and 4.59 (2H, ABq, J 15.0 Hz, OCH ₂ CO), 5.78 (1H, d, J 4.8 Hz, C ₂ H), 6.09 (1H, dd, J 4.8 and 10.5 Hz, C ₃ H), 6.23 (1H, s, CH-isoxazole), 6.91-7.40 (5H, m. OC ₆ H ₅ ), 7.78 (1H, d, J 10.5 Hz, CONH) ppm.

Claims (40)

1. Amides of 4-oxo-azetidine-2-sulfonic acids and their salts of general formula I I in which the remains have the following meanings: R ^{2 is} hydrogen, halogen; R ^{7 is} hydrogen, halogen, NH ₂ , phenyl-CH ₂ CONH, phenyl-OCH ₂ CONH, phthalimido, o-MeNHCOCfpr ^ CONH, isoxazolylcarbonylamino; R ^{3 is} hydrogen, Me ₂ C = C-COOMe, H ₂ C = C (Me) -CH-COOMe, Me ₂ C = C-COOCH ₂ -phenyl, H ₂ C = C (Me) -CH-COOCH ₂ C ₆ H ₄ NO ₂ -p, Me ₂ C = C-COOCH ₂ C6H ₄ NO ₂ -p. Me ₂ C = C-COOCH ₂ C6H ₄ Me-zn, H ₂ C = C (Me) -CHCO-OCH ₂ C ₆ H ₄ Me-m, Me ₂ C = C-COOH; R ^ hydrogen or sodium and R ^{3 is} hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole. A compound according to claim 1, wherein R ^{3 6 is} hydrogen, R ^{7 is} hydrogen, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R # is hydrogen and R ^{3 is} phenyl-CH 2. A compound according to claim 1, wherein R ^{3 is} hydrogen, R is hydrogen, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R # is sodium and R ^{3 is} phenyl-CH 2. A compound according to claim 1, wherein R ³ is hydrogen, R ⁴ is hydrogen, R ^{3 is} hydrogen, R # is hydrogen, and R ^{3 is} phenyl-CH ₂ . A compound according to claim 1, wherein R ³ bromine, R ² hydrogen, R ³ Me 2 C = C-COOCH 2 -phenyl, R # hydrogen and R ³ phenyl-CH 2. A compound according to claim 1, wherein R ^{3 is} hydrogen, R ^{2 is} bromine, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R 4 is hydrogen and R ^{3 is} phenyl-CH 2. A compound according to claim 1, characterized in that R 1 is bromine, R ^{2 is} bromine, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R ^{4 is} hydrogen and R ⁴ is phenyl-CH 28. A compound according to claim 1, wherein Ri bromine, R ² bromine, R ³ Me ₂ Ci = C-COOCH2-phenyl, R ⁴ sodium and R ³ phenyl-CH2 · A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} hydrogen, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R ^{4 is} hydrogen and R ^{4 is} hydrogen. 5-Methyl-isoxazol-3-yl. A compound according to claim 1, wherein R is hydrogen, R ² is hydrogen, R ³ Me2C = C-COOCH2-phenyl, R ⁴ is sodium and R 5-Methyl-isoxazol-3-yl. Compound according to claim 1, characterized in that Rl bromine, R ² bromine, R ³ Me ₂ C = C-COOCH2-phenyl, R ⁴ hydrogen and R ³ 5-Methyl-isoxazol-3-yl. A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} hydrogen, R ^{3 is} Me ₂ C = C-COOCH 2 -phenyl, R ^{4 is} hydrogen and R is 3,4-dimethyl-isoxazol-5-yl. A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} hydrogen, R ^{3 is} Me ₂ C = C-COOCH ₂ -phenyl, R ^{4 is} sodium and R ³ 3,4-Dimethyl-isoxazol-5-yl. A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} hydrogen, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R ^{4 is} hydrogen and R is 2-phenyl-pyrazol-3-yl. A compound according to claim 1, characterized in that R 1 is hydrogen, R ^{2 is} hydrogen, R ^{3 is} Me 2 C = C-COOCH 2 -phenyl, R ^{4 is} sodium and R ^{3 is} 2-phenyl-pyrazol-3-yl. A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} phenyl-OCH ² CONH, R ^{3 is} Me 2 C = C-COOMe, R ^{4 is} hydrogen and R ^{5 is} phenyl-CH 2. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} phenyl-OCH ² CONH, R ^{3 is} H2C = C (Me) CH-COOMe, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A compound according to claim 1, characterized in that it is R ¹ hydrogen, R ² phenyl-OCH2CONH, R ³ Me2C = C-COOMe, R ⁴ hydrogen and R ⁵ 5-Methyl-isoxazol-3-yl. A compound according to claim 1, characterized in that it is Rl is hydrogen, R ^{2 is} phthalimido, R ^{3 is} H2C = C (Me) -CH-COOCH ₂ C ₆ H ₄ NO2-p, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A compound according to claim 1, characterized in that it is R ^{1 is} hydrogen, R ^{2 is} ptaimido, R ^{3 is} Me 2 C = C-COOCH 2 C 6 H ⁴ NO 2 -p> R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. i A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} phenyl-CE ^ CONH, R ^{3 is} hydrogen, R ^{4 is} hydrogen and R ^{3 is} phenyl-CH 2 · A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} phenyl-CH ₂ CONH, R ² Me ² C = C-COOCH ² C 6 H 4 NO 2 -p, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} phenyl-CH ₂ CONH, R ² Me ² C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} hydrogen, R ³ Me 2 C = C-COOH, R ⁴ hydrogen and R ⁵ phenyl-CH 2. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} 3-o-chlorophenyl-5-methyl-isoxazol-4-yl, R ³ H2C = C (Me) -CH-COOCH2C ₆ H ₄ Me-m, R ⁴ hydrogen and R ³ 5-methyl-isoxazol-3-yl. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} 3-o-chlorophenyl-5-methyl-isoxazol-4-yl, R ³ Me ₂ C = C-COOCH ₂ C ₆ H ₄ Me-m, R 4 hydrogen and R ³ 5-Methyl-isoxazol-3-yl. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} phthalimido, R ^{3 is} Me ₂ C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A compound according to claim 1, wherein R ¹ hydrogen, R ² phthalimido, R ³ Me 2 C = C-COOCH ² C 6 H ⁴ NO 2 - / 7, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} o-MeNHCOC6H ₄ CONH, R ³ Me 2 C = C-COOCH ₂ C ₆ H ₄ NO 2 P, R ⁴ hydrogen and R ³ methyl. A compound according to claim 1, wherein R ¹ hydrogen, R ² o-MeNHCOC ₆ H ₄ CONH, R ³ H2C = C (Me) -CH-COOCH ₂ C ⁶ H ⁴ NO ₂ -p, R ⁴ hydrogen and R ³ methyl. A compound according to claim 1, characterized in that Rl is hydrogen, R ^{2 is} o-MeNHCOC ₆ H ₄ CONH, R ³ Me ₂ C = C-COOH ₂ , R ⁴ hydrogen and R ⁵ methyl. A compound according to claim 1, wherein R ^{1 is} hydrogen, R ^{2 is} phenyl-CH ² CONH, R ³ Me 2 C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} phenyl-CH ₂ . A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} phenyl-CH ₂ CONH, R ³ Me ₂ C = C-COOCH ₂ C6H ₄ NO ₂ - / ?, R ^{4 is} hydrogen and R ^{3 is} phenyl-CH? A compound according to claim 1, wherein R 1 is hydrogen, R ^{2 is} phenyl-CH ₂ CONH, R ³ Me ₂ C = C-COOCH ₂ C ₆ H ₄ NO ₂ -p, R ^{4 is} hydrogen and R ^{3 is} methyl. A compound according to claim 1, characterized in that R is hydrogen, R ² is phenyl-CH2CONH, R ³ Me2C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} methyl. A compound according to claim 1, characterized in that R 1 is hydrogen, R ^{2 is} hydrogen, R ^{3 is} Me ₂ C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. The compound of claim 1, wherein Rl bromine, R ² bromine, R ³ Me ₂ C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} phenyl-CH ₂ . A compound according to claim 1, characterized in that R 1 is hydrogen, R ^{2 is} phenyl-OCH ² CONH, R ^{3 is} Me 2 C = C-COOH, R ^{4 is} hydrogen and R ^{3 is} 5-methyl-isoxazol-3-yl. A process for the preparation of 4-oxo-azetidine-2-sulfonic acids amides and their salts of the general formula I, wherein the radicals have the meanings as claimed in claim 1, characterized in that the 4-oxo-azetidine-2- amides sulfinic acids of general formula II II in which the remains have the following meanings: R1 is hydrogen or halogen; R ^{2 is} hydrogen, halogen, phenyl-CH ₂ CONH, phenyl-OCH ₂ CONH, phthalimido, o-MeNHCOCglH ^ CONH, isoxazolylcarbonylamino; R ³ Me ₂ C = C-COOMe, H ₂ C = C (Me) -CH-COOMe, Me ₂ C = C-COOCH ₂ CH ₂ -phenyl, H ₂ C = C (Me) -CH-COOCH ₂ C ₆ H ₄ NO ₂ -p, Me ₂ C = C-COOCH ₂ C ₆ H ₄ NO ₂ ~ p, Me ₂ C = C-COOCH ₂ C6H4Me-w, H ₂ C = C (Me) -CHCOOCH ₂ C ₆ H ₄ Me-m; R ^ hydrogen and R5 is hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole, oxidized in conventional oxidizing agents such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or potassium permanganate, in acidic or neutral, aqueous or aqueous-organic medium, at a temperature of 0 to 100 ° C, and isolated the product according to the standard insulation method. Use of the compound of claim 1 as an intermediate in the synthesis of beta-lactam analogues, in particular bicyclic systems. Use of the compound of claim 1 for the preparation of active ingredients in antimicrobial therapy preparations. 557-P / AG ABSTRACT 4-Oxo-azetidine-2-sulfonic acids amides and their salts of formula I in which the residues are: R1 is hydrogen, halogen; r 2 hydrogen, halogen, NH ₂ , phenyl-CH ₂ CONH, phenyl-OCH ₂ CONH, phthalimido, o-MeNHCOCgHzjCONH, isoxazolylcarbonylamino; R ^{3 is} hydrogen, Me ₂ C = C-COOMe, H ₂ C = C (Me) -CH-COOMe, Me ₂ C = C-COOCH ₂ -phenyl, H ₂ C = C (Me) -CH-COOCH ₂ C ₆ H ₄ NO ₂ -p, Me ₂ C = C-COOCH ₂ C ₆ H ₄ NO ₂ -p. Me ₂ C = C-COOCH ₂ C6H ₄ Me-m, H ₂ C = C (Me) -CHCOOCH ₂ C ₆ H ₄ Me-w, Me ₂ C = C-COOH; R4 is hydrogen or sodium and R ^{3 is} hydrogen, alkyl, benzyl or heterocycle, e.g. isoxazole, pyrazole, etc., processes for their preparation and their use as intermediates for the synthesis of betacactam analogues or as active ingredients in antimicrobial therapy preparations.