HRP960061A2 - Novel 3-bromo- and 3,3-dibromo-4-okso-1-azetidine derivatives, process for the preparation and use thereof - Google Patents

Description

New derivatives of 3-bromo- and 3,3-dibromo-4-oxo-1-azetidine, preparation procedures and use

Technical field to which the invention belongs:

Int. class: C07D 205/08

A61K 31/395

The invention relates to 3-bromo- and 3,3-dibromo-4-oxo-azetidine derivatives, methods for their preparation and use.

Some 2-chloro-derivatives-3-phthalimido-alpha-(1-methylethylidene)-4-oxo-1-azetidine of acetic acid are known, and they are prepared by reacting methyl 6-phthalimido penicillinate with chlorine or sulfuryl chloride (S. Kukolja. J. Am. Chem. Soc. 93. (1971), 6267. 2-Haloazetidinones are also prepared by reacting penicillin with halogenating agents, such as molecular chlorine or N-halosuccinimide (US Pat. No. 4,159,984). acids, derived from penicillin sulfoxide, with halogenating agents, to 2-haloazetidinones (Spitzer, W. A., Kukolja S., Goodson T., Lammert J. P., Steven R., Lilly Eli Co., EP appl. EP 60, 120 15. Sept . 1982, US Appl. 241872, 9 Mar. 1981; and Spitzer W. A., Goodson T., Lammert S. R. and Kukolja S. J. Org. Chem. 46, (1981) 3569). Narisada et al. described the synthesis of 2-chloroazetidinone from methylthioazetidinones derived from penicillin (US Pat. No. 4,138,486).S. Kukolja and S.R. Lammert further describe the preparation of the above-mentioned 2-chloro-derivatives, but now starting and from the trichloroethyl ester of 6-phenylacetamido-penicilanate (Croat. Chem. Acta 44, (1972) 299-301.). Eli Lilly patented the preparation of 2-haloazetidinone starting from 3-exomethylene cephalosporin sulfone with an acylamide group in position 7, and by reacting the same with activated zinc or magnesium and ammonium chloride, whereby sulfinic acids are formed, which with halogenating agents give sulfinyl chlorides, which then subjected to hydrolysis (EP appl. 0132395 A, 22.7.1983). 3-Bromo- and 3,3-dibromo-2-chloroazetidinones were also prepared by reacting pivaloyloxymethyl 6-bromo- or 6,6-dibromopenicillanates with chlorine or tert. with butyl hypochlorite (C. Somoza and O.A. Oreste: Tetrahedron 44, (1988) 7007-12.). The same authors described the 2-terc in the work mentioned above. butoxy derivatives of 3-bromo- and 3,3-dibromo-azetidinone.

2-Chloro-alpha-(1-bromomethylethylidene)-4-oxo-1-azetidine acetic acid methyl ester with a phthalimido-, trichloroethoxycarbonylamino or phenoxycarbonylamino group at the C-3 position are described by Saul Wolte et al. (Can. J. Chem. 50. (1972) 2898 and Can. J. Chem. 60, (1982) 144).

According to our European patent application EP 0633247 Al 11.01. 1995 (Croatian Pat. application P 931047 A dated July 9, 1993) 2-bromo- and 2-nitroxy derivatives of 3-bromo- and 3,3-dibromo-4-oxo-azetidine can be prepared by reaction 1,1-dioxide derivatives of protected penicillonic acids by treatment with DBN reagent and thionyl chloride, and by passing the obtained product through a silica gel column or by treatment with tetrabutylammonium bromide, when the 2-bromo-, 3-bromo-, or 2-bromo-3 derivatives are isolated, 3-dibromo-4-oxo azetidine, which can then be subjected to a reaction with silver nitrate in 2-propanol, and after treatment of the reaction mixture, the 2-nitroxy-, 3-bromo-, or 2-nitroxy-3,3- derivatives are isolated dibromo-4-oxo-azetidine. According to our knowledge of the state of the art, some derivatives of 3-bromo- and 3,3-di-bromo-4-oxo-azetidine are not known.

The subject of this invention relates to 3-bromo- and 3,3-dibromo-4-oxo-1-azetidine derivatives of the general formula I in which

[image]

R 1 is hydrogen or bromine

R 2 is hydrogen or bromine

[image]

where is it?

R4 is hydrogen, methyl, benzyl or some other protecting group

R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring

Y is a halogen atom

X is a halogen atom, an alkoxy group, a nitroxy group

A further subject of this invention is a process for the preparation of 3-bromo- and 3,3-dibromo-4-oxo-1-azetidine derivatives of the general formula I in which the radicals have the above meaning and which can be prepared starting from sulfinic acid derivatives of the general formula II in which the radicals have meaning

[image]

R 1 is hydrogen or bromine

R 2 is hydrogen or bromine

[image]

where is it

R4 is hydrogen, methyl, benzyl or some other protecting group

R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring

Y is a halogen atom

and R6 is halogen, -OR7, or -NH-R8, in which R7 is hydrogen, alkyl or alkylaryl, or an alkali metal or DBN group, while R8 is hydrogen, alkyl, alkylaryl or a substituted heterocyclic ring, by reaction with tetrabutylammonium halide , e.g. bromide, halogen e.g. bromine or bromine on a polymer support [J. Johar, M.Zupan and B.Šket: J.Chem. Soc. Perkin Trans. I, 2509, (1982)] or some halogenating agent in which the halogen is positively charged, e.g. with N-chlorosuccinimide or N-bromo-succinimide in an organic solvent, e.g. chloroform, tetrahydrofuran, methylene chloride or a mixture of methylene chloride and dioxane, by stirring the reaction solution at room temperature for one to twelve hours, and after treatment, 2-halo derivatives of the general formula I in which X is halogen, and the radicals have the above are isolated meaning. The obtained 2-halo derivatives of the general formula I in which X is a halogen are subjected to a reaction with silver tetrafluoroborate and alcohols, e.g. with methanol, whereby a derivative of the general formula I is formed, in which X is an alkoxy group or methoxy group, a

R 1 is hydrogen or bromine

[image]

R 2 is hydrogen or bromine

where is it?

R4 is hydrogen, methyl, benzyl or some other protecting group,

R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring

Y is a halogen atom

or 2-halo derivatives of the general formula I in which X is halogen and the radicals have the above meaning are subjected to a reaction with silver nitrate in 2-propanol, whereby a derivative of the general formula I is formed in which X is a nitroxy group, and

R 1 is hydrogen or bromine

R 2 is hydrogen or bromine

[image]

R4 is hydrogen, methyl, benzyl or some other protecting group,

R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring

Y is a halogen atom

or the derivatives of the general formula I in which

R 1 is hydrogen or bromine

R 2 is hydrogen or bromine

[image]

where is it?

R4 benzyl or some other protecting group,

Y is a halogen atom, a

X is a halogen atom, an alkoxy group, a nitroxy group

undergo a reaction to remove the protective group, for example, benzyl with aluminum trichloride, resulting in product I in which

R 1 is hydrogen or bromine

R 2 is hydrogen or bromine

[image]

R4 is hydrogen

Y is a halogen atom, a

X is a halogen atom, an alkoxy group, a nitroxy group

6,6-Dibromopenicillanic acid derivatives were prepared from 6-aminopenicillanic acid according to known procedures (R. A. Volkmann, R. D. Carroll, R. B. Drolet, M. L. Elliott, and B. S. Moore. J. Org. Chem. 47, (1982) 3344-5; and Wayne E. Barth, US Pat. 4,234,579, Nov. 18, 1980).

The starting derivatives of sulfinic acids were prepared according to DE pat. application P 42 300 53.3 from September 8, 1992; PCT/EP pat. application number 93/02428 00 08.09. 1993).

The subject of this invention is a series of newly synthesized substances that are prepared starting from azetidinone sulfinic acid derivatives, preferably 2-sulfinamide azetidinone with various substituents on the azetidinone nitrogen. The subject of this invention is also a new process, which is simple and easy to implement, by which new substances are obtained in high yield.

A further subject of this invention relates to the use of these compounds as useful intermediates in the preparation of various beta lactam analogues such as e.g. 1-oxapenem (Masyuki Murakami; Tsutomu Auki; Munenuri Matasura and Wataru Nagata: J. Antibiot. 43(1990) 1441-49: and H.R. Pfaendler, T. Neumann; and R. Bartsch: Synthesis (1992) 1179) or penem. (V.M. Girijavallabhan, A.K. Ganguly, S.W. Mc.Combie, P.Pinto, R. Rizvi: Tetrahedron Lett. 22, (1981)3485-88.; and C.M.D. Beels, M.S. Abu Rabie: J. Chem. Soc. Chem. Commun. . 1979, 665) or 1-oxacephalosporin (US Pat. 4,013,653; US Pat. 4, 234, 724; US Pat. 4, 159, 984) or provides great possibilities for transformations into other beta lactam analogues, monobactams or cyclic compounds.

A further subject of this invention relates to the use of these compounds as components in pharmaceutical preparations with antibacterial, synergistic, anti-tumor or antagonistic action.

The invention is illustrated by the following examples, which in no way limit the scope of the invention.

Example 1

Benzyl ester 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid

a) Benzyl ester of 3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-1-azetidine-acetic acid (5.61 g; 0.01 mol) is dissolved in chloroform (120 mL) and bromine is added on a polymer support (12.5 g; content of bromine bound to the polymer matrix with polyvinylpyrrolidone 26%, 0.02 mol; [prepared according to the literature: J. Johar, M. Zupan and B. Šket , J. Chem. Soc. Perkin Trans. I, 2059 (1982)]) and stirred for 12 hours at room temperature. The polymer is sucked off, and the lye is evaporated to dryness. The resulting alkali was passed through a Merck 60 silk gel column with methylene chloride, after which 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine-acetic acid benzyl ester was isolated (2.36 g, 47 .6%), T.p. 68-70°C,

Rf 0.72 (methylene chloride);

IR(KBr)v:1795(vs),1730(s)1635(m),1395(m),1375(m),1270(m),1225(vs) 1125-1070(m), 815(m) , 700(m) cm-1.

1H NMR (CDCl3) δ: 2.00(3H, s, Me), 2.34 (3H, s, Me), 5.16 and 5.25 (each 1H d, J 12 Hz, CH2Ph), 6.30 (1H, s, C2-H) , 7.36(5H, s, Ar) ppm.

13C (CDCl3) APT: 22.35 and 23.87(2 Me), 55.67 (C3-Br2), 67.44 (CH2Ph), 74.08(C2-H), 117.03(N-C=), 128.78 (Ph), 135.11(C-Ph) , 158.07(COO), 159.95(=C(Me)2), 162.28(C=O).

Anal. C15H14Br3NO3; Ráč.: C 36.32; H 2.84; N 2.82. %

Found.: C 36.61; H.15; N 2.76. %

Mole. mass: 496,018; m/e 477(-H2O), 416 (-Br), 398(-H2O), 4O4(-CH2Ph).

Silver tetrafluoroborate (0.78 g; 1 mmol) was added to a solution of 2,3,3-tribromo-1-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (0.50 g; 1 mmol) in methanol (50 ml). 4 mmol) and stirred at room temperature for one hour. The reaction mixture is filtered, and the lye is evaporated to an oily residue (0.40 g, 89.5 %)

Rf 0.54 (methylene chloride)

IR (film) v: 3520 (s), 1760-1700 (vs), 1630 (s), 1395 (s), 1370 (s), 1210 (vs), 1150-1030 (vs) 765 (m) cm- 1

1 HNMR (CDCl 3 , 300 MHz) δ: 1.99 (3H, s, Me); 2.30 (3H, s, Me); 3.46 (

3H, s, OCH3); 5.12 (1H, s, C2-H); 5.14 and 5.28 (2H, 2d, J= 11Hz, CH2Ph);

7.38(5H, m, Ar) ppm.

b) Benzyl ester of 3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-azetidine-acetic acid (5.61 g; 0.01 mol ) is dissolved in chloroform (120 mL), N-bromosuccinimide (7.12 g; 0.04 mol) is added to the reaction mixture and stirred at room temperature for two hours. The reaction mixture is evaporated, methylene chloride and n-hexane are added to the dry residue, the precipitate is filtered off with suction, and the alkali is evaporated to a dry residue. The obtained product was purified by "flash" chromatography with the solvent system petroleum ether-methylene chloride (1:1). 3.05g, 61.5% of benzyl ester 2,3,3-tribromo-alpha-(1-methylethylidene)- was obtained. of 4-oxo-1-azetidine-acetic acid which is subjected to a reaction with silver tetrafluoroborate in methanol analogously to that described under 1a). After isolation, 33-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with identical spectroscopic characteristics to those described under 1a) was obtained.

c) Benzyl ester of 3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-1-azetidine-acetic acid (5.61 g; 0.01 mol) is dissolved in chloroform (120 mL) and bromine (4.1 mL, 12.78 g, 0.08 mol) is added to the reaction mixture and stirred at room temperature for 45 minutes. The reaction mixture was evaporated to dryness, treated with isopropanol (30 mL) at -5°C, the precipitate was filtered off with suction (1,287 g), and the lye was evaporated to dryness (4,180 g). The evaporated lye was passed through a Merck 60 silica gel column with methylene chloride as eluent, whereby another 2.20 g of product was obtained. A total of 3.48 g (70.5%) of 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine-acetic acid benzyl ester was obtained, which was subjected to a reaction with silver tetrafluoroborate in methanol analogously to that described under 1a). After isolation, 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with identical spectroscopic characteristics to that described under 1a) was obtained.

d) Benzyl ester of 3,3-dibromo-alpha-(1-methylethylidene)-2-[benzylaminosulfinyl]-4-oxo-1-azetidine-acetic acid (5.7 g; 0.01 mol) is dissolved in chloroform (120 mL), add bromine on the polymer support (18.75g; content of bromine bound to the polymer matrix with polyvinylpyrrolidone 26%, 0.03 mol) and mix at room temperature for 48 hours. Then the polymer is sucked off, and the lye is evaporated to dryness. The evaporated residue was passed through a column of silica gel with methylene chloride, whereby 2,33-tribromo-alpha-(1-methyl-ethylidene)-4-oxo-1-azetidine-acetic acid benzyl ester was isolated (2.73 g; 55.0%) , which undergoes a reaction with silver tetrafluoroborate in methanol analogous to that described under 1a). After isolation, 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with identical spectroscopic characteristics to those described under 1a) was obtained.

e) Benzyl ester of 3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-1-azetidine-acetic acid (5.61 g; 0.01 mol) is suspended in chloroform (110 mL), N-chlorosuccinimide (5.34 g; 0.04 mol) is added and stirred at room temperature for 8 hours. The reaction mixture is evaporated, methylene chloride and n-hexane are added to the dry residue, the precipitate is filtered off with suction, and the alkali is evaporated to a dry residue (4.88 g). . After evaporation of the solution and drying at 0.01 mmHg, 3,3-dibromo-2-chloro-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester crystallizes (3.41g; 75.6%), T.p. 64-66°C

Rf 0.70 (methylene chloride)

IR (KBr) v: 1795 (vs), 1730(s), 1635 (m), 1395(m), 1375(m), 1270 (m), 1220 (s), 1125-1070(b, m), 820(m),700(m),cm-1.

1H NMR( CDC13,300 MHz) δ: 2.00 and 2.35 (2s, 6H, 2Me), 5.16 and 5.25 (each 1H, d, J 12 Hz, CH2Ph), 6.06 (s, 1H, C2-H), 7.37 ( s, 5H, Ar) ppm.

13C (CDCl3) APT: 22.28 and 23.81 (2 Me); 56.55 (C3-Br2); 67.43 (CH2Ph); 81.30 (C2-H), 116.75 (N-C=); 128.94 (Ph); 135.13 (C-Ph); 158.51 (COO); 160.27 (=C(Me)2).

Mole. mass: 451,558; m/e 433 (-H2O); 416 (-C1); 360 (-CH2Ph).

To a solution of the obtained 2-chloro-3,3-dibromo-1-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (0.045 g; 0.1 mmol) in methanol (5 ml) was added silver tetrafluoroborate ( 0.078 g; 0.4 mmol) and the reaction mixture was refluxed for 15 hours. After processing the reaction mixture described in procedure 1a), 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with identical spectroscopic characteristics to those described under 1a) was obtained.

f) Benzyl ester of 3,3-dibromo-alpha-(1-methylethylidene)-2-[benzylaminosulfinyl]-4-oxo-1-azetidine-acetic acid (5.7 g; 0.01 mol) is subjected to the reactions described in example 1e) and after isolation, 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with identical spectroscopic characteristics to those described under 1a) is obtained.

Example 2

3,3-Dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetate

a) A solution of benzyl ester 3,3-dibromo-2-chloro-alpha-(1-methylethylidene)-4- oxo-1-azetidine of acetic acid (1.5 g; 0.003 mol) and anisole (2.79 g; 2.7 ml, 0.024 mol) in methylene chloride (55 mL) and then stirred at room temperature for half an hour. Ethyl acetate (60 mL) and 0.1 N hydrochloric acid (60 mL) were added to the reaction mixture and the layers were separated. The ethyl acetate layer was extracted with 5% sodium hydrogen carbonate solution (2 x 50 mL) and the layers were separated. The aqueous layer was acidified with 0.1 N hydrochloric acid to pH 1, after which fresh ethyl acetate (60 mL) and sodium chloride were added and the layers were separated again. The ethyl acetate layer is washed with saturated salt solution, dried and evaporated to a dry whitish powdery residue, i.e. 3,3-dibromo-2-chloro-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid (0.9 g ; 75.0%)T t. 106-110°C

Rf = 0.50 (ethyl acetate-methanol /3:1/)

IR (KBr) v: 1800(vs), 1700(s), 1630(m), 1430(m), 1370(m), 1285(m), 1245(m)cm-1

1 H NMR (CDCl 3 , 300 MHz) δ: 2.06 (3H, s, Me), 2.39 (3H, s, Me), and 6.28 (1H, s, C2-H) and 9.57 (1H, b, COOH)ppm.

13C NMR (CDC13, 300 MHz, APT) δ: 22.51 and 24.11 (2 Me), 56.25 (C-3), 80.87 (C-2), 116.06 [(=C(COOH)], 158.21, 163.36 and 168.24 ( =C(Me)2, C=O, and COOH) ppm.

Silver tetrafluoroborate (0.780 g; 1 mmol) was added to a solution of 2-chloro-3,3-dibromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid (0.361 g; 1 mmol) in methanol (50 mL). 4.0 mmol) and stirred at room temperature for 24 hours. The precipitate is sucked off, and the lye is evaporated to a dry residue. Methylene chloride and sodium hydrogencarbonate solutions are added to the evaporated residue, the layers are thoroughly mixed and separated, the aqueous layer is acidified with 0.1 N hydrochloric acid to pH 1 and extracted again with methylene chloride, dried (Na2SO4) and evaporated to an oily residue (0.080 g 22% ).

Rf 0.40, ethyl acetate - methanol (3:1)

Rf 0.65, n-butanol-ethanol-water (7:1:2)

IR(film) v : 1795(vs), 1700(s), 1375(m), 1265(vs), 910(m),735(vs) cm-1.

1H NMR (CDCl 3 , 300 MHz) δ: 2.05 and 2.34 (6H, 2s, 2 Me), 3.61 (3H, s, OCH 3 ), 5.35 (1H, s, C 2-H) ppm.

b) A solution of benzyl ester 2,33-tribromo-alpha-(1-methylethylidene)-4-oxo-1- acetic acid azetidine (0.496 g; 0.001 mol) and anisole (0.648 g; 0.65 ml, 0.006 mol) in methylene chloride (15 mL) and then stirred at room temperature for half an hour. Ethyl acetate (15 mL) and 0.1 N hydrochloric acid (5 mL) were added to the reaction mixture and the layers were separated. The ethyl acetate layer is extracted with 5% sodium hydrogen carbonate solution (2 x 20 mL) and the layers are separated. The aqueous layer was acidified with 0.1 N hydrochloric acid to pH 1, after which fresh ethyl acetate (20 mL) and sodium chloride were added and the layers were separated again. The ethyl acetate layer is washed with saturated salt solution, dried and evaporated to a dry residue and dried again at 0.1 mmHg, whereby 2,3,3-tribromo-alpha-(1-methyl-ethylidene)-4-oxo-1- azetidine acetic acid (0.219g, 54.0%). T t. 124-6 °C;

Rf = 0.50 (ethyl acetate-methanol /3:1/)

IR (KBr) v: 1800(vs), 1700(s), 1630(m), 1430(m), 1370(m), 1285(m), 1245(m) cm-1.

1H NMR (DMSO-d6, 90 MHz) δ: 1.89 (3H, s, Me), 2.25 (3H, s, Me), and 6.73 (1H, s, C2-H)ppm.

13C NMR (DMSO-d6,300 MHz) δ: 2.17 (Me), 23.00(Me), 35.32 (C3-Br2), 74.37 (c2-H), 118.04(=C(COOH), 156.10,158.01,164.00 ( =C(Me)2, C=O, and COOH) ppm.

Silver tetrafluoroborate (0.780 g; 4.0 mmol) was added to a solution of 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid (0.45 g; 1 mmol) in methanol (20 mL). ) and stir at room temperature for 24 hours.

After the isolation described in example 2a), 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid with identical spectroscopic characteristics to those described under 2a) was obtained.

c) A solution of benzyl ester 2-methoxy-3,3-dibromo-alpha-(1-methylethylidene)-4- oxo-1-azetidine of acetic acid (0.447 g; 0.001 mol) and anisole ((0.648 g; 0.65 ml, 0.006 mol) in methylene chloride (15 mL) and then stirred at room temperature for half an hour. To the reaction mixture was added ethyl acetate ( 15 mL), and 0.1 N hydrochloric acid (5 mL) and the layers were separated. The ethyl acetate layer was extracted with 5% sodium hydrogen carbonate solution (2 x 20 mL) and the layers were separated. The aqueous layer was acidified with 0.1 N hydrochloric acid to pH 1, after which fresh ethyl acetate (20 mL) and sodium chloride were added and the layers were separated again.The ethyl acetate layer was washed with brine, dried and evaporated to a dry residue to give 3,3-dibromo-2-methoxy- alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid identical to that described in example 2a).

Example 3

Benzyl ester of 2,3,3-tribromo-alpha-(1-bromomethylethylidene)-4-oxo-1-azetidine of acetic acid

Benzyl ester of 3,3-dibromo-alpha-(1-methylethenyl)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-1-azetidine-acetic acid (5.61 g; 0.01 mol ) is suspended in chloroform (210 mL), bromine (4.1 mL, 12.78 g, 0.08 mol) is added and stirred at room temperature for two hours. Then the reaction mixture is evaporated to dryness (6.4 g) and passed through a silk gel column with a methylene chloride-petroleum ether mixture (6:4). 4.46g (77.6%) of the mixture of isomers was obtained. Further purification by chromatography on a silica gel column isolated the less polar isomer with Tt 84-5°C.

Rf 0.60 methylene chloride-petroleum ether (6:4)

IR (film) v: 1790 (vs), 1720(vs), 1640(m), 1390(m), 1370(s), 1240(s), 1100(s), 810(s)cm-l.

1H NMR (CDC13,300 MHz) δ: 2.12 (3H, s, Me), 4.39 and 4.71 (each 1H d, J=9.4 Hz, CH2Br), 5.20 and 5.31 (each 1H d, J=12 Hz, CH2Ph) , 6.31 (s, 1H, C2-H), and 7.38 (5H, s, Ar) ppm.

13C (CDC13, 300 MHz) APT δ: 20.40 (Me), 29.72 (CH2Br), 55.29 (CBr2), 67.98 (CH2Ph), 73.15 (C2-H) and 119.10; 128.80; 134.29 154.71; 157.160 161.09.

MH+576, M+(Br4)575.

Anal. C15H13Br4NO3; Ráč.: C 31.33; H 2.28; N 2.44. %

Found.: C 31.63; H 2.09; N 2.27. %

The more polar isomer (oil) was isolated by passing the methylene chloride-petroleum ether (6:4) solvent mixture further.

Rf 0.50 methylene chloride-petroleum ether (6:4)

IR (film) v: 1800 (vs), 1725(vs), 1625(m), 1450(m), 1390-60 (s), 1210 (vs), 1105 (s), 810(s)cm-1 .

1H NMR (CDCl3, 300MHz)δ: 2.42 (3H, s, Me), 4.00 (s, 2H, CH2Br), 5.18 and 5.27 (each 1H d, J=12 Hz, CH2Ph), 6.30 (s, 1H, C2 -H), and 7.36 (5H, s, Ar) ppm.

13C APT (CDC13, 300 MHz) APT δ: 19.39 (Me), 31.38 (CH2Ph), 55, 22 (CBr2), 67.87 (CH2Br), 72.97(C2-H) and 118.23(C2); 128.78(Ph),; 134.37; 154.59; 158.29; and 161.21 ppm.

Example 4

3,3,4-Tribromo-1-(4-methyl-2-oxo-2,5-dihydro-furan-3-yl)-azetidin-2-one

A solution of benzyl ester 2,3,3-tribromo-alpha-(1-bromomethylethylidene)- 4-oxo-1-azetidine acetic acid 0.575 g, 0.001 mol) and anisole (2.59g; 2.6 ml, 0.024 mol) for one hour and then stirred at room temperature for another hour. Ethyl acetate (15 mL) and 0.1 N hydrochloric acid to pH 1 and sodium chloride are added to the reaction mixture, the layers are separated. The aqueous layer is extracted again with ethyl acetate, the combined ethyl acetate is dried and evaporated to a dry residue. The dry residue was purified by chromatography on a silica gel column first with the solvent system methylene chloride-methanol (9:1). 0.33 g (73%) of the product was obtained, which was further purified by chromatography on a silica gel column with methylene chloride.

The product T t was obtained. m.p. 164-66°C.

Rf 0.55 (methylene chloride)

Rf 0.25 (methylene chloride-petroleum ether 6:4)

IR (KBr) v : 1785(vs), 1700(s) 1630(m), 1425(m) 1370(s), 1115(s) 815(m) cm-1.

1H NMR (300 MHz, CDCl3) δ: 2.26 (s, 3H, Me), 4.77 and 4.84 (2d, 2H, J=17.8 Hz, -CH2) and 6.92 (1H, s, C2-H) ppm.

13C NMR APT(300 MHz, CDCl3) δ: 13.02 (Me), 55.53(CBr2), 69.789 (C2'-H), 72.01 (-CH2), 118.31(C2), 153.99, 156.49 and 167.67 (C3, C4' and C1).

Example 5

Acetic acid 3,3-dibromo-2-chloro-alpha-(1-methylethylidene)-4-oxo-1-azetidine benzylamide

3,3-dibromo-2-chloro-alpha-1-(1-methylethylidene)-4-oxo-1-azetidine acetic acid (0.180 g, 5 mmol) was dissolved in methylene chloride (10 mL), cooled to -10 °C, add thionyl chloride (2 mL) and stir for one hour at -10°C and then another hour at room temperature. Then the reaction mixture is evaporated, benzene (2 times 10 mL each) is added to the dry residue and evaporated each time. Benzylamine (0.22 mL; 0.21 g; 20 mmol) was added to the residue dissolved in methylene chloride (10 ml) and stirred at room temperature for 2 hours. The precipitate is filtered off with suction, and the lye is evaporated to a dry residue (0.205 g). The obtained product was purified by "flash" chromatography with methylene chloride as eluent, after which an oily product was isolated, which turned into a foam after drying at 0.01 mm Hg (0.09 g; 44.0%).

Rf 0.33 (methylene chloride)

IR (film) v max: 3300(s), 1800 (vs), 1660 (vs), 1640 (vs), 1520 (vs), 1365 (vs), 1130 (s) 1100 (s),812 (s) 700 (s) cm-1.

1H NMR (CDCl3, 300 MHz) δ: 1.86 and 2.07 (6H, 2s, 2Me), 4.49 (2H, m, N-CH2), 6.07(1H, s, C2-H), 6.19 (1H, s, NH-C) and 7.29-7.36 (5H, m, Ar) ppm.

1H NMR (CDCl3+D2O, 300 MHz) δ: 1.86 and 2.07 (6H, 2s, 2Me), 4.49 (2H, ABq, N-CH2), 6.07 (1H, s, C2-H) and 7.28-7.37(5H , m, Ar) ppm.

Example 6

Benzylamide 3,3-dibromo-2-chloro-alpha-(1-methylethenyl)-4-oxo-1-azetidine acetic acid

N-chlorosuccinimide (0.40 g, 3 mmol) was added to a solution of 6,6-dibromopenicillanic acid benzylamide sulfoxide (0.70 g, 1.5 mmol) in dry toluene (75 ml) and refluxed for 3 hours. The reaction mixture was evaporated to a dry residue, then ether was added and the precipitate was suctioned off, and the lye was evaporated to dryness. (0.68 g). The obtained product was purified by chromatography on a silica gel column with methylene chloride as eluent. An oily syrupy product (0.20 g, 29.9%) was obtained.

Rf 0.28 methylene chloride

IR (film) v max: 3300(m), 1795(vs), 1705(vs), 1525(m), 1345(m), 1180(s), 700(m)cm-1.

1H NMR (CDCl3, 300 MHz) δ:1.81(3H, s, Me), 4.42 and 4.32 (each 1H, dd J 5.5, 6.0, and 15 Hz NH-CH2), 4.73 (1H, s, CH-CON) , 5.16 and 5.21 (2H, 2s, =CH2), 6.36 (1H, s, C2-H), 6.50 (1H, m, NH) and 7.27-7.36 (5H, m, Ar) ppm.

1H NMR (D2O) (300 MHz) δ: 1.85 (3H, s, Me), 4.39 and 4.50 (2H, for each 1H d, J 15 Hz, N-CH2Ph), 4.73 (1H, s, CH-CON) , 5.16 and 5.21(2H, 2s, =CH2), 6.35(1H, s, C2-H), 7.28-7.36 (5H, m, Ar) ppm

Example 7

Benzyl ester-3,3-dibromo-alpha-(1-methylethylidene)-2-nitroxy-4-oxo-azetidine of acetic acid

a) 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (0.744 g; 0.0015 mol) is dissolved in 2-propanol (20 mL) and silver nitrate (1.01 g; 0.0060 mol) and heated in a stream of nitrogen at boiling temperature for one hour. After that, the reaction mixture is filtered and the lye is evaporated to dryness. Methylene chloride is added to the evaporated residue, the precipitate is filtered off with suction and the alkali is evaporated to dryness (0.466 g; 65%). The obtained product is passed through a column of silica gel with methylene chloride, after which a substance is isolated that crystallizes on standing (0.42 g; 58.13%).

d.p. 69-710 ̊C;

Rf = 0.75 (methylene chloride);

IR(KBr) v:1805(vs), 1730(vs), 1660(vs), 1390(m), 1375(m), 1285(vs), 1225 (vs), 1140(s), 1080(m) , 830(s), 760(m), 700(m) cm-1.

1H NMR (CDCl3) (300 MHz) δ: 1.99(3H, s, Me), 2.32 (3H, s, Me), 5.16 and 5.27 (each 1H d, J 12 Hz, CH2Ph), 6.42 (1H, s, C2-H), 7.37 (5H, s, Ar) ppm.

13C (CDC13) APT: 21.97 and 23.70 (2 Me), 52.93 (C3-Br2), 67.34 (CH2Ph), 90.89 (C2-H), 116.65(N-C=), 128.61 (Ph), 134.66(C-Ph) , 158.29 (COO), 159.63 (=C(Me)2), 161.67 (C=O).

Mole. mass 478.11; m/e 432 (-NO2), 398 (-Br), 352 (-NO2).

b) Benzyl ester 3,3-dibromo-alpha-(1-methylethylidene)-2-nitroxy-4-oxo-1-azetidine of acetic acid can be obtained in an analogous way as in example a), only the starting substance is benzyl ester 3 ,3-dibromo-2-chloro-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid (0.676g, 0.0015 mol).

Example 8

3-bromo-2-chloro-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid methyl ester

3-Bromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-1-azetidine-acetic acid methyl ester (4.06 g; 0.01 mol) was suspended in chloroform (110 mL), added N-chlorosuccinimide (5.34 g; 0.04 mol) and stirred at room temperature for 8 hours. The reaction mixture is processed as under 1 e) and purified by chromatography on a silica gel column eluting with methylene chloride, after which 2 isomeric products are isolated: First, the "trans" isomer (oil) is isolated

Rf 0.50 (methylene chloride)

IR (film) v max: 1800(vs), 1730(vs),1640(m) 1435(m) 1380(vs), 1370(vs), 1270(s), 1225(vs), 1125-1070(bm) ), 810(s) cm-1.

1H NMR (CDCl3) (90 MHz) δ: 2.03 (3H, s, Me), 2.32 (3H, s, Me), 3.30 (3H, s, OCH3), 5.05 and 5.95 (each 1H d, J=0.9, C2-H and C3-H) ppm.

and then the "cis" isomer (oil)

Rf 0.40 (methylene chloride)

IR (film) v max: 1800(vs), 1730(vs), 1640(m), 1435(m), 1380(vs), 1370(vs),

1270(s), 1225(vs), 1125-1070(bm), 810(s) cm-1.

1H NMR (CDCl3) (300 MHz) δ: 2.04 (3H, s, Me), 2.31 (3H, s, Me), 3.79 (3H,

s, OCH3), 5.33 and 6.10 (each 1H d, J=4Hz, C2-H and C3-H) ppm.

Mole. mass: 294.960534

Example 9

Benzyl ester of 3-bromo-2-chloro-alpha-(1-methylethylidene)-4-oxo-1-azetidine of acetic acid

3-Bromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazol-3-yl)-aminosulfinyl]-4-oxo-1-azetidine-acetic acid benzyl ester (4.82 g; 0.01 mol) was suspended in chloroform (110 mL), added N-chlorosuccinimide (5.34 g; 0.04 mol) and stirred at room temperature for 8 hours. The reaction mixture is processed as under 1e) and purified by chromatography on a silica gel column eluting with methylene chloride, after which 2 isomeric products are isolated:

The "trans" isomer (oil) was eluted first.

Rf 0.66 (methylene chloride)

IR (film) v max: 1795(vs), 1730(s), 1635(m) 1390(m), 1375(m), 1265(m9), 1220(s), 1120-1070(bm), 815( m) and 700(m) cm-1.

1H NMR (CDCl3) (300 MHz) δ: 2.03 and 2.34 (6H, 2s, 2Me), 4.86 and 5.76(each 1H d, J=0.8 Hz, C2-H and C3-H), and 7.37( 5H, s , Ar) ppm

and then the "cis" isomer (oil)

Rf 0.53 (methylene chloride)

IR (film) v max: 1795 (vs), 1730(s), 1635(m), 1390(m), 1375(m), 1265(m9), 1220(s), 1120-1070(bm), 815 (m) and 700(m) cm-1.

1H NMR (CDCl3) (300 MHz) δ: 2.04 (3H, s, Me), 2.31 (3H, s, Me), 5.14 and 5.26 (each 1H d, J=12 Hz, CH2Ph), 5.19 and 5.9 (each 1H d, J=4 Hz, C2-H and C3-H), 7.31-7.42 (5H, m, Ar) ppm.

Mole. mass: 370.991834

Claims (11)

1. New derivatives of 3-bromo- and 3,3-dibromo-4-oxo-1-azetidine of general formula I [image] where radicals have meaning R 1 is hydrogen or bromine R 2 is hydrogen or bromine [image] at what R4 is hydrogen, methyl, benzyl or some other protecting group, a R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring Y is a halogen atom X is a halogen atom, an alkoxy group, a nitroxy group 2. Compound according to claim 1, characterized in that R1 bromine, R2 bromine, R3 -C(COOR4)=C(Me)CH2 Y, R4 benzyl, Y is bromine, X bromine [image] Xbrom 3. Compound according to claim 1, characterized in that R1 is bromine, R2 is bromine, R3 4. Compound according to claim 1, characterized in that R1 bromine, R2 bromine, R3 Me2C=C-CONHR5, R5 benzyl, X chlorine 5. Compound according to claim 1, characterized in that R1 bromine, R2 bromine, R3 -CH(CONHR5)-C(Me)=CH2, R5 benzyl, X chlorine 6. Compound according to claim 1, characterized in that Rl bromine, R2 bromine, R3 Me2C=C-COOR4, R4 benzyl, X methoxy 7. The compound according to claim 1, characterized in that Rl bromine, R2 bromine, R3 Me2C=C-COOR4, R4 hydrogen, X methoxy 8. Compound according to claim 1, characterized in that Rl hydrogen, R2 bromine, R3 Me2C=C-COOR4, R4 methyl, X chlorine 9. Compound according to claim 1, characterized in that Rl hydrogen, R2 bromine, R3 Me2C=C-COOR4, R4 benzyl, X chlorine 10. Process for the preparation of new derivatives of 3-bromo- and 3,3-dibromo-4-oxo-1-azetidine of the general formula I in which the radicals have R1 is hydrogen or bromine R 2 is hydrogen or bromine R3 is hydrogen, Me2-C=C-COOR4, -C(COOR4)=C(Me)CH2 Y [image] at what Me2-C=C-CONHR5; CH(CONHR5)-C(Me)=CH2; R4 is hydrogen, methyl, benzyl or some other protecting group R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring, a Y is a halogen atom X is a halogen atom, an alkoxy group, a nitroxy group starts from derivatives of sulfinic acids of the general formula II in which the radicals have a meaning [image] R1 is hydrogen or bromine R 2 is hydrogen or bromine [image] at what R4 is hydrogen, methyl, benzyl or some other protecting group R5 is hydrogen, alkyl, alkylaryl, heterocyclic ring Y is a halogen atom and R6 is halogen, -OR7; or -NH-R8, in which R7 is hydrogen, alkyl or alkylaryl, or an alkali metal or DBN group, while R8 is hydrogen, alkyl, alkylaryl or a substituted heterocyclic ring, which by reaction with tetrabutylammonium halide, e.g. bromide, halogen e.g. bromine or bromine on a polymer support or some halogenating agent in which the halogen has a positive charge, e.g. with N-chlorosuccinimide or N-bromo-succinimide in an organic solvent, e.g. chloroform, tetrahydrofuran, methylene chloride or a mixture of methylene chloride and dioxane, by stirring the reaction solution at room temperature for one to twelve hours, and by evaporating to a dry residue, 2-halo derivatives of the general formula I are formed in which X is a halogen, and the other radicals are as stated in claim 1, which are then subjected to a reaction with silver tetrafluoroborate and alcohols, whereby a derivative of the general formula I is formed, in which X is an alkoxy group, and the radicals are as stated in claim 1, or 2-halo derivatives of the general formula I in which X is a halogen, and the radicals as specified in claim 1, undergo a reaction with silver nitrate in 2-propanol, whereby a derivative of the general formula I is formed in which X is a nitroxy group, and the radicals as specified in claim 1, or the derivatives of the general formula I in which R 1 is hydrogen or bromine R 2 is hydrogen or bromine R3 is Me2-C=C-COOR4, C(COOR4)=C(Me)CH2 Y at what R4 is benzyl or some other protecting group, a X is a halogen atom, an alkoxy group, a nitroxy group subjected to a protective group removal reaction, e.g. of benzyl with aluminum trichloride and anisole, resulting in product I in which R 1 is hydrogen or bromine R 2 is hydrogen or bromine R3 is hydrogen, Me2-C=C-COOR4, -C(COOR4)=C(Me)CH2 Y R4 is hydrogen Y is a halogen atom X is a halogen atom, an alkoxy group, a nitroxy group 11. A pharmaceutical mixture effective in antibacterial or antitumor therapy, which contains as an active substance new derivatives of 4-oxo-azetidine of the general formula I specified in patent claim 1, carrier and adjuvants.