NL8205065A - NEW BICYCLIC COMPOUNDS AND A PROCESS FOR THEIR PREPARATION. - Google Patents

Description

N / 31.250-Kp / Pf / vdM * -k * - 1 -

Novel bicyclic compounds and a process for their preparation.

The invention relates to new bicyclic compounds and pharmaceutical compositions containing them, as well as a process for their preparation.

The new bicyclic compounds according to the invention correspond to the general formula 1 of the formula sheet, wherein Y and Y represent a carbonyl protecting group to be removed, preferably a ketal group or a thio analog thereof, Q 'a C 1-6 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is an optionally substituted hydrocarbon radical, preferably a benzyl, 2-aminoethyl or 2-acylaminoethyl group.

The compounds of the general formula 1 are new and effective thienamycin analogs and, with the exception of the compounds wherein Q 'is an alkyl group, they can also be used as intermediates for the synthesis of thienamycin.

Thienamycin, a broad-activity center antibiotic, was first prepared by microbiological means (US Patent 3,950,357) and later by chemical means (German Patent Application 2,751,597).

The invention aims to provide a new route for the synthesis of thienamycin and its analogs, whereby the azethidinone skeleton and the α-hydroxyethyl side chain, or a side chain which can be easily converted into an α-hydroxyethyl group, are simultaneously in the early stage of the synthesis and the intermediate key product thus obtained is then converted into the desired end product.

It was found that when a dialkyl (protected 30 amino) malonate is acylated with diketene and the resulting acylated product is reacted with iodine and an alkali metal alcoholate, an azethidinone compound of the general formula 13 containing an α-acetyl side chain which can be used as a key intermediate in the synthesis.

8205065 »· - 2 -

In the above formula, R represents a removable amido protecting group, preferably a benzyl group with one or more methoxy substituents or a phenyl group, optionally. one carries more or more methoxy substituents and Z is a C 1-15-15 alkyl group.

The new intermediates of the general formula 13 and their preparation are described in detail in the older Hungarian patent application 2262/80. The preparation of these new intermediates is also described in the examples of the present application.

It was also observed that prior to the conversion of the intermediate of the general formula 13 to thienamycin or an analog thereof, it is preferable to protect the keto group of the α-C-acetyl side chain with a group, in particular a ketal group or a thio analog thereof, which can be removed at a later stage of the synthesis. Ethylene glycol or a thio analog thereof, such as mercaptoethanol, can be used particularly advantageously to form the ethylene ketal or hemithio ketal protecting group. The obtained compound of the general formula 1 2 12 of the formula sheet, wherein Y and Y together form a group for the temporary protection of the carbonyl radical, preferably ethylene ketal group or a thio analog thereof, and R and Z are defined as above. then reacted with an alkali metal halide in pyridine or a similar solvent or in aqueous dimethyl sulfoxide to give a compound of the general formula II 11 of the formula sheet wherein R, Y, Y and Z are as defined above.

The compound of the general formula II obtained is a mixture of cis and trans isomers. The isomers can be separated by chromatography or based on their different solubility. The separated trans isomer of the general formula 11a can be converted into the transcarboxylic acid of the general formula 10 of the formula sheet, by hydrolysis. However, it is more preferable to subject the isomer mixture itself to hydrolysis, since the reaction is selective, i.e. converts only the trans 8205065-3 ester to the corresponding carboxylic acid.

The separated transcarboxylic acid of the general formula 10 is first reacted with an activator for the carboxy group and then with diazomethane and the obtained compound of the general formula 9 of the formula sheet is subjected to the Wolff rearrangement in the presence of water . The resulting azethidino acetic acid of the general formula 8 of the formula sheet can be converted into the desired end products of the general formula 1 by various routes.

1 2

In general formulas 10, 9 and 8, Y, Y and R are as previously defined.

According to one of the methods for the further conversion of a compound of the general formula 8, wherein R is a phenyl group, it is nitrated and reduced thereon, yielding a compound of the general formula (1a) formula 8a, wherein Y and Y are as defined above and A represents successively a nitro group and an amino group. The resulting compound of general formula 8a is esterified thereon in a known manner to yield a compound of general formula 7a 1 2 wherein Y, Y and A are as defined above X represents a selectively removable esterification group, preferably an arylmethyl or diarylmethyl group.

The aminophenyl protecting group of the compound of the general formula 7a obtained is then removed by oxidation, preferably with chromium trioxide, in the presence of glacial acetic acid and the resulting compound of the general formula formula I, wherein Y, Y and X are defined above 30 is separated.

According to another method, a compound of the general formula 8, wherein R is a phenyl or benzyl group with one or more methoxy substituents, is esterified in a known manner to yield an ester of the general formula (7) of the formula sheet, wherein R as is defined in this paragraph and Y, Y and X are as defined above, and the protecting group R is removed thereto, yielding a compound of the general formula 6 of the formula sheet.

8205065 - 4 -

When R is a dimethoxybenzyl group it is cleaved with a peroxy disulfate compound, while when R is a methoxyphenyl group it is removed with a ceric salt in the presence of an acid.

Then the esterification group X of the obtained compound of the general formula 6 is preferably removed by reduction, in particular by catalytic hydrogenation, after which the obtained compound of the general formula (I) 2 of the formula sheet, wherein Y and Y as above be de-defined, activated on the carboxy group and reacted thereon with a salt of a malonic hemiester, preferably with the magnesium or potassium salt of an alkyl malonate or a substituted benzyl malonate. The obtained compound of the general formula 4 of the formula sheet, wherein Y and Y are as defined above and Q is an alkyl or a substituted benzyl group, is reacted with a sulfonazide in the presence of a tertiary amine to give a compound of the general formula 3 of the formula sheet, wherein Y, Y and Q are defined as above and this compound is cyclized in the presence of a rhodium salt to yield a compound of the general formula 2 of 1 2 it formula sheet, in which Y, Y and Q are defined as above. These compounds of the general formula II are the new starting materials for the thienamycin analogues according to the invention.

According to yet a further method, a compound of the general formula 8, in which R is a phenyl or benzyl group with one or more methoxy substituents, is activated on the carboxy group and reacted thereon with a salt of a malonic acid hemester, preferably with the magnesium - or potassium salt of an alkyl malonate or a substituted benzyl malonate. The resulting compound of the general formula formula I, wherein Y, Y and Q are defined as above 35 and R 'is a phenyl or benzyl group with one or more methoxy substituents, is then reacted with a sulfonazide in the presence of a tertiary amine, yielding a compound of the general formula 8205065 * - 5 - 1 2 of the formula sheet, wherein Y, Y, R 'and Q are defined as above.

The same compounds of the general formula 15 are obtained when a compound of the general formula 8, wherein R is a phenyl or benzyl group with one or more methoxy substituents, is activated on the carboxy group and reacted with a diazoacetate.

The protecting group R 'of the obtained compound of general formula 15 is split off as described above and the resulting compound of general formula 3 is converted into the starting material of general formula 2.

The compounds of the general formulas 2-15 are new and are obtained in the form of racemic mixture. Some of the compounds of general formula 12 are described in the older Hungarian patent application 2263/80. The other compounds of general formula 12 as well as compounds of general formulas 11-2, 14 and 15 are described in detail in related patent applications.

In the preparation of a compound of the general formula 1, a starting material of the general formula 2 is subjected to O-acylation and then treated with the appropriate mercaptan. When a compound of the general formula 1, wherein Q 'is a substituted benzyl group, is obtained, the substituted benzyl group can be cleaved and the resulting carboxylic acid (Q' = H) converted to an alkali metal carboxylate.

On the basis of the above, the invention relates to a process for the preparation of new bicyclic compounds of the general formula 1, wherein 1 2 Y and Y represent a removable carbonyl protecting group, preferably a ketal group or a thio analog thereof, Q ' a C 1-5 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is an optionally substituted hydrocarbon radical, preferably a benzyl, 2-aminoethyl or 2-acylaminoethyl group, such that a) a compound of the general formula 2, 1 2 in which Y and Y are as defined above and Q is an 8205065-6-C 15 alkyl group or a substituted benzyl group, is treated with a suitable O-acylating agent, preferably with a sulfonyl or phosphoryl halide, in the presence of a tertiary amine and thereon with a mercaptan, preferably with benzyl mercaptan, cysteamine or an N-acylated derivative thereof, and the product obtained with the alga Formula 1, wherein Q 'is a C 1-6 alkyl group or a substituted benzyl group, is separated, or b) from a compound of the general formula 1, 1, 2, 10 obtained in step a), wherein R ", Y and Y as defined above and Q 'represents a substituted benzyl group, ft' is removed by reduction and, if desired, the resulting carboxylic acid (Q '= H) is converted into its alkali metal salt.

In the first step of the above process, a compound of general formula 2 is reacted with an O-acylating agent in the presence of a tertiary amine. Organic carboxylic acid derivatives, or preferably sulfonyl or phosphoryl halides, can be used as reagents for this purpose. Diphenylphosphoryl chloride has been found to be a particularly preferred reagent.

The O-acylated intermediate is then reacted with a mercaptan, preferably benzyl mercaptan, cysteamine or an N-acylated derivative thereof, in the presence of a teriary amine. In this reaction, a compound of the general formula 1, wherein Q 'is a C 1-5 alkyl group or a substituted benzyl group, is formed.

The substituted benzyl group of a compound of the general formula 1, wherein Q 'is substituted benzyl, can be cleaved off by reduction, preferably by catalytic hydrogenation, to yield the corresponding carboxylic acid of the general formula 1 (Q * = H). A carboxylic acid of the general formula 1 can be converted into its alkali metal salts, the sodium salt of which, in particular, can be prepared in a simple manner by treating the free acid with sodium carbonate or sodium hydrogen carbonate. The resulting alkali metal salt can be separated from the reaction mixture by extraction and / or evaporation.

820 5 0 65 - 7 -

The new compounds of general formula 1 are therapeutically active and primarily have β-lactamase inhibitory effects.

The invention also relates to pharmaceutical compositions which, as active ingredient, comprise a compound of the general formula 1 in admixture with one or more conventional pharmaceutical additives (eg carrier, diluent, disintegrant, preservative, buffer, etc.). contain. These compositions can be prepared by well known methods.

The invention is now further illustrated by the following non-limiting examples.

EXAMPLE I

Ethyl 3- (formylaminoethylthio) -6- (2-methyl-1,2-15-dioxolan-2-yl) -7-oxo-1-azabicycloZ3.2.07hept-2-en-2-carboxylate.

Into 10 ml of dry acetonitrile and 0.61 ml (4.4 mmol) of triethylamine, 1.133 g (4.0 mmol) of ethyl 6- (2-methyl-1,3-dioxolan-2-yl) -3,7- dioxo-1-azabicyclo [3.2.3] heptane-2-carboxy-20 dissolved, followed by 0.91 ml (4.4 mmol) diphenylphosphoryl chloride, which was added to the stirred solution at 0 ° C within about 10 min. . Stirring was continued at 0 ° C and 0.61 ml (4.4 mmol) of triethylamine and 0.46 g (4.4 mmol) of N-formylcysteamine were added to the mixture. After stirring at 0 ° C for 1 hour, the mixture was evaporated in vacuo and the residue was dissolved in 20 ml of dichloromethane. The solution was washed with 10 ml of a 3% aqueous sodium hydrogen carbonate solution and then twice with 10 ml of water.

The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue weighing 2.4 g was processed by column chromatography (adsorbent: Kieselgel 60, 0.063-0.200 mm, eluent: a 7: 3 mixture of benzene and acetone. The intended product was 0.51 g (36 %) mp: 152-153 ° C (from methanol and ether).

IR (KBr): 3400, 1790, 1700, 1690 cm -1.

1 H NMR (CDCl 3): 5 = 1.35 (t, 3H), 1.45 (s, 2H), 2.82-3.65 (m, 7H), 3.95-4.5 (m, 7H), 6.1 (s, 1H), 8.20 (d, 1H) ppm.

8205065 - 8-13 C NMR (CDCl3): <S = 14.3; 23.4; 31.6; 38.6; 40.1; 52.0; 61.3; 65., 2; 65.4; 67.2; 106.8; 145.0; 161.4; 161.7; 174.1 ppm.

Mass spectrum m / e: 370, 284, 242, 197, 87 and 43.

The starting material used in this example can be prepared by the following methods;

Method I

a) A mixture of 109.8 g (0.66 mol) of 2,3-dimethoxybenzaldehyde, 72 ml (0.66 mol) of benzylamine and 660 ml of methanol was stirred at ambient temperature for 20 min, after which a clear solution was obtained from the suspension. The solution was cooled with ice water and 13.2 g (0.33 mol) of sodium borohydride were added in small portions.

The progress of the reaction was monitored by thin layer chromatography (Kieselgel G, according to Stahl; developing solvent: a 9: 1 mixture of benzene and acetone) and at the end of the reaction the mixture was evaporated in vacuo. The residue was mixed with 300 ml of water and the aqueous mixture was extracted with 500 ml, 200 ml and 200 ml portions of ether. The ether solutions were combined, dried over magnesium sulfate, filtered and 112 ml (0.66 mol) of diethyl bromomalonate and 93 ml (0.66 mol) of triethylamine were added to the filtrate. The reaction mixture was stirred at room temperature for 2-3 d. The separated triethylammonium bromide was filtered off and washed with ether. The mother liquor was evaporated to dryness and the residue was recrystallized from 150 ml of ethanol. The 210 µl crude product thus obtained was recrystallized from 400 ml ethanol, yielding 197 g (72%) diethyl N-benzyl N- (2,4-dimethoxybenzyl) aminomalonate; mp: 62-63 ° C (ethanol).

IR (KBr): 1750/1725 cm -1, d.

b) In 500 ml ethanol, 61.7 g (0.149 mol) diethyl-N-benzyl-N- (2,4-dimethoxybenzyl) aminomalonate, prepared as described under point a) of method I, was hydrogenated under atmospheric pressure in the presence of about 20 g palladium-on-carbon catalyst. The catalyst was filtered off and the filtrate was evaporated to dryness. 47.1 g (97%) of 3205065 were obtained

V

9-diethyl (2,4-dimethoxybenzylamino) malonate. The product could be converted to its hydrochloride by reaction with hydrochloric acid. The hydrochloride melted at 122-124 ° C after recrystallization from ethyl acetate.

Analysis: Calculated for C18 H24 ClNOg (361.82): C: 53.11%, H: 6.69%, Cl: 9., 90%, N: 3.87%? found: C: 52.51%, H: 6.77%, Cl: 10.30%, N: 4.09%.

IR (film): 3250, 2900, 2850, 1730, 1720 cm-1.

10 1 H NMR (CDCl 3): 6 = 1.3 (s, 6H), 3.78 (s, 3H), 3.82 (s, 3H), 4.21 (q, 4H), 6.20 ( s, 2H), 6.4-6.6 (m, 2H), 7.3-7.55 (m, 1H), 7.7 (broad s, 1H) ppm.

c) A mixture of 39.6 g (0.122 mol) diethyl (2,4-dimethoxybenzylamino) malonate prepared as described under point b) of method I, 80 ml glacial acetic acid and 12.3 g (11.2 ml, 0.146 mol) diketene was heated to boiling for 0.5 h. The solvent, the glacial acetic acid, was distilled off in vacuo over a water bath and the oily residue was triturated with 150 ml of water. The crystalline substance obtained was dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether. 29.6 g (60%) of diethyl-N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate and / or its tautomer were obtained; mp: 106-107 ° C.

Analysis: Calculated for C 20 H 27 NO 8 (409.43): C: 58.67%, H: 6.65%, N: 3.42; found: C: 58.79%, H: 6.33%, N: 3.34%.

IR (KBr): 3400, 2950, 2850, 1730 (1740, sch), 1710 cm-1.

30 XN NMR (CDCl3): δ = 1.1 (t, 3H), 1.17 (t, 3H), 1.52 (s, ~ 3H), 2.8 (<0.1H), 2.65 (broad s, 2H), 3.75 (s, 6H), 3.8-4.15 (m, 4H), 6.7 (broad s, 2H), 6.25-6.45 (m), 7.0-7.25 (m, 3H) ppm.

d) In 50 ml of dry ether, 20.5 g (50 mmol) of the product prepared as described under point c) of method I was suspended and a solution of 3.45 g (150 mmol) of metallic sodium in 100 ml of dry ethanol and a solution of 12.7 g (50 mmol) of iodine in 150 ml of dry ether were simultaneously added from two dropping funnels to the vigorously stirred suspension under cooling with ice water. Then 5 g of sodium hydrogen sulfite, dissolved in 200 ml of saturated aqueous sodium chloride solution, was added to the stirred mixture. The mixture was placed in a separatory funnel and 60 ml of water was added to dissolve the inorganic salts present. The organic phase was removed, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue, weighing 10 18.5 g, was crystallized from 30 ml of 2-propanol. 10.9 g (54%) of diethyl-3-acety1-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate were obtained; mp: 84-85 ° C (2-propanol).

Analysis: Calculated for C20 H25 NO8 (407'41): C: 58.96%, H: 6.19%, N: 3.44%; found: C: 59.99%, H: 6.04%, N: 3.57%.

1 H NMR (CDCl 3): <S = 1.12 (t, 3H), 1.21 (t, 3H), 2.31 (s, 3H), 3.76 (s, 6H), 3.8- 3.4 (m, 4H), 4.53 (d, 1H), 4.63 (d, 1H), 4.69 (s, 1H), 6.3-6.4 (m, 2H), 7 .07 (d, 1H) ppm.

E) To a vigorously stirred solution of 179 g (0.484 mol) diethyl-3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate and 107 ml (120 g, 1,936 mol) ethylene glycol in 500 µl dry dioxane was added dropwise with cooling with ice water 179 ml (206 g, 1.452 moles) of boron trifluoride diethyl ether. The reaction mixture was allowed to stand at ambient temperature for 1 day, during which time the mixture was stirred occasionally. Then, 415 g (1.452 mol) of Na2CO3.10H2O was slowly added to the stirred mixture under cooling with ice water and the mixture was stirred for 15 min. Then 1 l of ether and 1 l of water were added and the phases were separated. The aqueous phase was shaken twice with 500 ml of diethyl ether. The ether phases were dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. To the residue 35, 33.9 g (0.58 mole) of sodium chloride, 17.4 ml (0.968 mole) and 220 ml of dimethyl sulfoxide were added and the mixture was stirred on an oil bath at 180 ° C. The progress of the reaction was monitored by thin layer chromatography (adsorbent: 820 5 0 65 - 11 -

Kieselgel G according to Stahl? developing solvent: a 6: 4 mixture of benzene and ethyl acetate). At the end of the reaction, i.e. after about 15 h, the mixture was poured into 1100 ml of saturated aqueous sodium chloride solution and the resulting mixture was shaken with 1000 ml and then twice with 500 ml of diethyl ether. The ether solutions were combined # decolorized with charcoal, dried over magnesium sulfate and the filtrate was evaporated to a final volume of about 200 ml. This concentrated solution was cooled with ice-10 water to give 59 g (35%) of trans-ethyl-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) 4-oxo-2-azethidine carboxylate; mp: 95 ° C.

f) A mixture of 0.5 g (1.2 mmol) diethyl-3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azethidine dicarboxy-15 let # prepared as described under point d ) of Method I, 3 ml of dry tetrahydrofuran and 0.53 g (3.6 mmol) of mercaptoethanol were heated to boiling for 4 h and then 10 ml of water and 10 ml of chloroform were added to the reaction mixture.

The organic phase was separated, washed with 5% aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and the product was separated from the filtrate by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254 + 366; development 9SOp1 ° smi). ^: an 8: 2 mixture of toluene and acetone). 0.30 g (53%) of diethyl 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azethidine dicarboxylate were obtained .

XH NMR (CDCl3): δ = 0.8-1.55 (m, 6H), 1.72 + 1.77 (d, 3H), 2.9-3.4 (m, 2H), 3.75 (s, 6H), 4.0-5.0 (m, 9H), 6.4 (m, 2H), 7.1 (d, 1H) ppm.

30 g) A solution of 5.21 g (0.130 mole) sodium hydroxide in 60 ml of water was added to a suspension of 41.2 g (0.109 mole) trans-ethyl-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidine carboxylate, prepared as described under point e) of method I, in 50 ml ethanol under stirring and cooling with ice water and stirring was performed. continued until a clear solution was obtained (ca. 20 min). 100 ml of water was then added to the solution and the mixture was shaken with 100 ml of ether. The aqueous phase 8205065-12 - was acidified to pH = 1 with concentrated aqueous hydrochloric acid and then quickly shaken not 100 ml and twice with 50 ml dichloromethane. The dichloromethane solutions were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue was crystallized from a mixture of toluene and petroleum ether to yield 35 g (92%) of trans-1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolane) -2-yl) -4-oxo-2-azethidine carboxylic acid; mp: 117-118 ° C (toluene).

Analysis: Calculated for C 17 H 21 NO 7 (351.35): C: 58.11%, H: 6.03%, N: 3.99%; found: C: 58.17%, H: 6.30%, N: 4.24%.

IR (KBr): 3500-2500, 2900, 1760, 1720 cm-1.

15 X H NMR (CDCl 3): S = 1.39 (s, 3H), 3.50 (d, 1H, J = 2.5 Hz), 3.77 (s, 3H), 3.79 (s, 3H ), 3.86 (d, 1H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, = 15 Hz), 6.44 (m, 2H), + 7.15 (d, 1H, J = 10Hz), 7.58 (broad s, 1H) ppm.

h) To a solution of 17.6 g (50 mmol) of trans-20 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2 azethidine carboxylic acid, prepared as described under point g) of method I, in 150 ml of dry tetrahydrofuran, 7.3 ml (52.5 mmol) of triethylamine was added, and then 5.0 ml (52.5 mmol) of ethyl chloroformate under ice-cooling added to the mixture. The mixture was cooled to -15 ° C, stirred at this temperature for 20 min and the separated triethylamine salt was filtered at the same temperature under argon atmosphere. A solution of 150 mmol of diazomethane in 230 ml of cold diethyl ether was added to the filtrate. The mixture was stirred, brought to room temperature and after stirring for 2 h, it was evaporated to dryness. The brown thick residue was dissolved in 20 ml of benzene and the product was separated by column chromatography (adsorbent: 150 g Kieselgel 60.0 = 0.063-0.200 mm, eluent: a 7: 2-35 mixture of benzene and acetone). 12.0 g (64%) of trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2-azethidinone were obtained.

Analysis: 8205065 - 13 -.

calculated for c 13 H 21 N 3 ° 6 (375.37): C 57.59%, H: 5.64%; found: C: 57.78%, H: 5.39%.

IR (KBr): 2900, 2110, 1760cm * 1.

5 i) A mixture of 2.25 g (6 mmol) trans-4- (diazoacety1) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl -2-azethidinone, prepared as described under point h) of method I, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water were irradiated for 4 h with a high-pressure mercury lamp 10 (HPK 125), immersed in the reaction vessel made of pyrex glass, under argon atmosphere. The solution was evaporated in vacuo to a final volume of 50 ml and the concentrate was diluted with water to 130 ml. 2.4 ml of a 10% aqueous sodium hydroxide-15 solution was added to the aqueous mixture and the alkaline mixture was washed three times with 20 ml of dichloromethane. The aqueous phase was then acidified to pH = 2 with concentrated aqueous hydrochloric acid. The acidic solution was extracted three times with 20 ml of dichloromethane, the extracts were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was crystallized from ether. 1.82 g (83%) of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl acetic acid was obtained. Mp: 124 ° C (ether).

Analysis: Calculated for C13 H23 NO7 (365.37): C: 59.17 S, H: 6.34%, N: 3.83%? found: C: 59.22%, H: 6.49%, N: 4.07%.

IR (KBr): 3500-2300, 2900, 1730, 1700 cm * 1.

J) At room temperature, 3.05 g (15.75 mmol) diphenyldiazomethane was added to a stirred solution of 5.48 g (15 mmol) ^ trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl 1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-acetic acid, prepared as described under point i) of method I, in 50 ml of dichloromethane. When nitrogen gas evolution had ceased, a few drops of acetic acid were added to the mixture to break down excess diphenyldiazomethane. The solution was evaporated to dryness and the residue weighing 6.77 g, 8205065-14 was dissolved in 84 ml of acetonitrile. To the solution were added 16.20 g (60 mmol) potassium peroxydisulfate (K2S20g), 2lf60 g (120 mmol) disodium hydrogen phosphate monohydrate (^ 2 ^ 0 ^ .H 2 O) and 54 ml of water, the mixture was stirred vigorously for 4 h. , heated to boiling and cooled. The cold reaction mixture was filtered and the two phases of the filtrate separated. The aqueous phase was extracted three times with 30 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was dissolved in benzene and the solution was worked up by column chromatography (adsorbent: Kieselgel 60, 0.050-0.200 mm, eluent: a 7: 2 mixture of benzene and acetone), yielding 2.68 g (47%) benzhydryl-trans-3- (2-methyl-15-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl / acetate; mp: 130 ° C (ethanol).

IR (KBr): 3250, 2900, 1760, 1740 cm -1.

1 H NMR (CDCl 3): δ = 1.39 (s, 3H), 2.63 (dd, 2H, J = 4.4 Hz), 2.89 (dd, 2H, J = 9.1 Hz), 3 .97 (m, 5H), 6.12 (s, 1H), 6.9 (s, 1H), 7.28 (s, 10H), ppm.

Analysis: Calculated for C22 H23 NO5 (387.41): C: 69.27%, H: 6.08%, N: 3.67%; found: C: 69.15%, H: 6.20%, N: 3.55%.

K) A mixture of 3.80 g (10 mmol) of benzhydryl-trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-acetate, 0.4 g dry palladium-on-carbon catalyst containing 8% palladiumphen 50 ml dry ethanol was stirred under hydrogen atmosphere. Hydrogen uptake stopped after 2 h. The catalyst was filtered off and washed with 10 ml of dry ethanol. The filtrate was evaporated to dryness over a 30-40 ° C water bath, the residue was washed three times with 20 ml of ether and the liquid was decanted. 2.02 g (94%) / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-acetic acid were obtained; mp: 126-129 ° C.

Analysis: Calculated for C 1 H H NO N (215.20): N: 6.51%; found: N: 6.34%.

8205065-15 - IR (KBr): 3500-2300, 3350, 2900, 1730, 1700 cm -1.

l) A mixture of 2.15 g (10 mmol) ^ trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-acetic acid prepared as described under point k) of method I, 1.82 g of 5 (11 mmol) 98% carbonyldiimidazole and 60 ml of dry tetrahydrofuran were stirred for 30 min. 1.58 g (11 mmol) of magnesium ethyl malonate were added to the solution and the reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness under vacuum, 180 ml of di-10-chloromethane and 180 ml of 0.5 N aqueous hydrochloric acid were added to the residue, the mixture was stirred for several minutes and then the two phases were separated. The aqueous phase was extracted three times with 30 ml of dichloromethane. The organic phases were combined, washed twice with 20 ml of a 3% aqueous sodium carbonate solution, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. 2.02 g (71%) of ethyl trans-4- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-3-oxo-butanoate were obtained; mp: 65-68 ° C (ether).

IR (KBr): 3220, 1770, 1735, 1720 cm -1.

XH NMR: 5 = 1.28 (t, 3H), 1.42 (s, 3H), 2.77 (dd) and 3.10 (dd, 2H, J - 9.4 Hz and 3.6 Hz) , 3.11 (d, 1H, J = 2.6 Hz), 3.75-4.35 (m, 7H), 6.13 (2.1H) ppm.

m) To a solution of 1.426 g (5.0 mol) of 25-ethyl-trans-4- (3-(2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethi-dinyl7- 3-oxo-butanoate, prepared as described under point 1) of method I, in 15 ml of dry acetonitrile, was added 0.69 ml (5.0 mmol) of triethylamine and 0.986 g (5.0 mmol) of tosylazide under ice-cooling. The solution was allowed to warm to room temperature with stirring within 3 h. The solution was evaporated to dryness, the residue was dissolved in benzene and the solution was processed by column chromatography (adsorbent: 100 g Kieselgel 60.0 = 0.063-0.200 mm, eluent: a 7: 2 mixture of benzene and acetone). 1.12 g (72%) of 35-ethyl-2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-3- were obtained oxo-butanoate.

IR (film): 3250, 1750, 1710, 1630 cm -1.

XH NMR: δ = 1.36 (t, 3H), 1.42 (s, 3H), 2.96 and 3.44 (dd, 2H, J = 9.4 Hz and 3.6 Hz), 3, 75-4.15 (m, 5H), 8205065-16-4 / 33 (q, 2H) / 6.08 (s, 1H) ppm.

n) Dirhodium tetraacetate ^ R1 ^ (ΟΑσ) ^. 2ΤΗΡ7 was added in small portions to a boiling solution of 1.245g (4.0mmol) ethyl-2-diazo-4- ^ trans-3- (2-methyl-1, 3-5 dioxolan-2-yl) -4-oxo-2-azethidinyl7-3-oxo-butanoate, prepared as described under point m of method I, in 10 ml of benzene, until the starting material has completely reacted (this requires approx. 0.03 g of the rhodium salt). The reaction mixture was filtered through Celite cotton and the filtrate was evaporated to dryness. 1.13 g (100%) of ethyl 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo / 3.2.07-heptane-2-carboxylate were obtained. mp .: 109 ° C.

IR (KBr): 1750, 1735 cm -1.

XH NMR: 6 = 1.30 (t, 3H, J = 7.4 Hz), 1.49 (s, 15 3H), 2.4 (dd, 1H, J avg = 19.5 Hz, Jvic = 7, 5 Hz), 2.90 (dd, 1H, J = 19.5 Hz, J. = 7.0 Hz), 3.43 (d, 1H, J = 2.4 Hz), 3.97-4, 20 (m, 5H), 4.24 (q, 2H, J = 7.4 Hz), 4.63 (t, 1H, J = 0.6 Hz) ppm.

Method II

A) A mixture of 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) of diethyl bromomalonate was stirred at room temperature for 2 d. The resulting mass was triturated with 100 ml of diethyl ether, the separated 4-methoxyanisidine hydrobromide was filtered off and washed with a small amount of diethyl ether. The mother liquor was evaporated to dryness and the residue was crystallized from dilute acetic acid. 13.2 g (47%) of diethyl (4-methoxyanilino) malonate were obtained; mp: 64-65 ° C (ethanol).

Analysis: Calculated for C 1 H H NOg (281.31): C: 59.77%, H: 6.81%, N: 4.99%; found: C: 59.99%, H: 6.97%, N: 5.25%.

IR (KBr): 3300, 1775, 1725cm -1.

1 H NMR (CDCl 3): δ = 1.23 (t, 6h, J = 7.2 Hz), 35 3.67 (s, 3H), 4.2 (q, 4H, J = 7.2 Hz), 4.62 (s, 1H), 4.1-4.5 (broad s, 1H), 6.55 (2H), 6.73 (2H, AA'BB ', J = 9 Hz) ppm.

b) A mixture of 11.2 g (0.04 mol) diethyl (4-methoxyanilino) malonate prepared as described under point a) 8205065-17 of Method II, 15 ml of acetic acid and 4 g (3.7 ml, 0.048 mol) diketene was heated to boiling for 0.5 h. The solution was evaporated in vacuo, the oily residue triturated with diethyl ether and the solid filtered off.

10.5 g (72%) of diethyl-1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate and / or its tautomer? mp 136-137 ° C (ethyl acetate).

Analysis: Calculated for C 11 H 23 NO 7 (365.38): 10 C: 59.17%, H: 6.39%, N: 3.83%; found: C: 58.98%, H: 6.90%, N: 4.04%.

IR (KBr): 3600-3000, 1760, 1740, 1685cm -1.

1 H NMR (CDCl 3): δ = 1.07 (t, 3H, J = 7.2 Hz), 1.28 (t, 3H, J * 7.2 Hz), 1.58 (s, 3H), 2.76 (s, 2H), 3.64 15 (s, 1H), 3.76 (s, 3H), 4.1 (q, 2H, J * 7.2 Hz), 4.27 (q, 2H, J = 7.2 Hz), 6.7 (2H), 7.0 (2H, AA * BB ', J = 9 Hz) ppm.

c) 9.1 g (0.025 mol) of diethyl 1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate, prepared as described under point b, in 50 ml of dry diethyl ether 20 of Method II, suspended and a solution of 1.72 g of metallic sodium in 30 ml of dry ethanol and a solution of 6.35 g (0.025 mole) of iodine in 50 ml of dry diethyl ether were simultaneously suspended in the suspension with vigorous stirring and cooling dripped with ice. The mixture was then poured into 100 ml of saturated aqueous sodium chloride solution and 2 g of sodium hydrogen sulfite and 2 ml of glacial acetic acid were added. The ether phase was separated and the water phase was extracted three times with 50 ml diethyl ether. The ether phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue was triturated with 2-propanol to yield 6.2 g (68%) of crystalline diethyl-3-acetyl-1- (4-methoxyphenyl) -4-oxo-2,2-azethidine dicarboxylate; mp: 70-71 ° C (ethanol).

Analysis: Calculated for cigH21N07 (363.38): C: 59.50%, H: 5.82%, N: 3.85%; found: C: 59.04%, H: 5.84%, N: 4.08%.

IR (KBr): 1760, 1735, 1720cm -1.

8205065 - 18 - * H NMR (CDCl3): δ = 1.20 (t, 3H, J = 7.2 Hz), 1.22 (t, 3H, J = 7.2 Hz), 2.33 (s , 3H), 3.7 (s, 3H), 4.17 (q, 2H, J = 7.2 Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.7 (s , 1H), 6.7 (2H), 7.31 (2H, AA'BB ', J * 9 Hz) ppm.

D) In 20 ml of dry dioxane and 4.1 g (3.75 ml, 0.066 mol) of ethylene glycol, 6 g (0.0165 mol) of diethyl-3-acetyl-1- (4-methoxyphenyl) -4-oxo- 2,2-azethidine dicarboxylate, prepared as described under point c) of Method II, dissolved. 7.1 g (6.3 ml, 0.05 mol) of boron trifluoride-diethyl etherate complex were added dropwise to the stirred solution under ice cooling and the reaction mixture was stirred for an additional 2 h at room temperature. The solution was made alkaline with saturated aqueous sodium hydrogen carbonate solution, then 100 ml of water was added and the mixture was extracted three times with 50 ml of diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue was triturated with diethyl ether to give 6 g (89%) of crystalline diethyl-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4- oxo-2,2-azethidine dicarboxylate; smp; 82-83 ° C (ethanol).

Analysis: calculated for 2020 25 25 8 8 (407.43): C: 58.96%, H: 6.18%, N: 3.44%; Found: C: 58.70%, H: 5.68%, N: 3.63%.

IR (KBr): 1740 cm-1 (wide).

1 H NMR (CDCl 3): δ = 1.17 (t, 3H, J = 7.2 Hz), 1.26 (t, 3H, J = 7.2 Hz), 1.5 (s, 3H), 3 .7 (s, 3H), 3.9 (m, 4H), 4.2 (m, 5H), 6.67 (2H), 7.34 (2H, AA'bb ', J = 9 Hz) ppm .

E) In 20 ml dimethylsulfoxide, 11 g (0.0245 mol) diethyl-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl-4-oxo-2,2 azethidine dicarboxylate, prepared as described under point d) of method II, dissolved, 1.72 g (0.0295 mol) of sodium chloride and 0.9 ml (0.049 mol) of water were added and the mixture was stirred at 175 ° C stirred until complete reaction was obtained. The progress of the reaction was monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl development solvent: a 6: 4 mixture of 8205065-19 benzene and ethyl acetate).

The mixture was cooled, poured into 150 ml of a saturated aqueous sodium chloride solution and extracted three times with 50 ml of diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The resulting oily residue weighing 6 g was dissolved in 25 ml of 96% ethanol and a solution of 0.72 g (0.018 mol) of sodium hydroxide in 10 ml of water was added to the alcoholic mixture under cooling with ice water. The mixture was stirred for 0.5 h, then diluted with 50 ml of water and washed twice with 25 ml of dichloromethane. The aqueous phase was acidified to pH = 1 with concentrated aqueous hydrochloric acid and extracted three times with 25 ml of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue was crystallized from benzene. 4 g (54%) of trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azethidine carboxylic acid were obtained.

Analysis: Calculated for C 1 H H NOg (307.32): C: 58.63%, H: 5.57%, N: 4.56%; found: C: 58.40%, H: 5.80%, N: 4.66%.

IR (KBr): 3400-2700, 1750 (wide) cm -1.

XH NMR (CDCl3): δ * 1.5 (s, 3H), 3.7 (d, 1H, J = 2.5 Hz), 3.76 (s, 3H), 4.0 (m, 4H) , 4.38 (d, 1H, J = 2.5 Hz), 6.82 (2H), 7.26 (2H, AA'bb ', J = 9.5 Hz), 9.2 (s, 1H ) ppm.

f) To a solution of 3 g (0.01 mol) of a compound prepared as described under point e) of method II, in 20 ml dry tetrahydrofuran, 1.11 g (1.56 ml, 0.011 mol) was dried added triethylamine. The solution was cooled to -15 ° C and 1.2 g (1.06 ml, 0.011 mol) of ethyl chloroformate was added dropwise to the stirred solution. After stirring for 20 min, the separated salt was filtered off under a nitrogen atmosphere and a solution of 4.8 g (0.025 mol) of diazomethane in diethyl ether was added to the filtrate at room temperature. After stirring for 2 h, the excess diazomethane was decomposed with acetic acid and the mixture was removed.

release evaporated to dryness in vacuum. The oily residue slowly crystallized out. 3 g (90%) of trans-4- (diazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azethidinone were obtained; mp: 95-96 ° C (benzene and ether).

IR (KBr): 2200, 1760, 1640 cm -1.

XH NMR (CDCl3): 6 = 1.50 (s, 3H), 3.51 (d, 1H, J = 2.6 Hz), 3.75 (s, 3H), 4.05 (m, 4H) , 4.31 (d, 1H, J = 2.6 ^ Hz), 5.47 (s, 1H), 6.85 and 7.30 (4H, AA + BB *, J = 9 Hz) ppm.

g) In a mixture of 50 ml of water and 100 ml of tetrahydrofuran, 3.3 g (0.01 mol) of trans-4- (diazoacetyl-3- (2-methyl-1,3-dioxolan-2-yl) - 1-1 (4-methoxyphenyl) -2-azethidinone prepared as described under point f) of Method II, dissolved. The mixture was irradiated with a high pressure mercury lamp in a photoreactor under nitrogen atmosphere (the reaction was carried out at room temperature) and the progress of the reaction was monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, developing solvent) : a 7: 1 mixture of benzene and acetone). When the reaction was over, tetrahydrofuran was distilled off under vacuum, the residue was made alkaline with 20% aqueous sodium hydroxide solution and the solution was washed twice with 15 ml of dichloromethane. The aqueous phase was acidified to a pH of 1-2 with concentrated aqueous hydrochloric acid and extracted three times with 20 ml of dichloromethane. The organic phases were combined, dried over "magnesium sulfate, filtered and the filtrate was evaporated to dryness. 1.6 g (50%) / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1 were obtained. - (4-methoxyphenyl) -4-oxo-2-azethidinyl acetic acid.

Analysis: calculated for cigH19NOg (321.33): C: 59.80%, H: 5.96%, N: 4.36%; found: C: 59.60, H: 5.76%, N: 4.08%.

IR (film): 3500-2500, 1760-1700 cm -1.

H) In 10 ml of dichloromethane, 1.0 g (3.12 mmol) of the compound prepared as described under point g) of Method II was dissolved and a solution of 0.53 g (3.12 mmol) of diphenyldiazomethane in 10 ml of dichloromethane was added dropwise to the stirred solution at room temperature 8205065 »" 21 ". When gas evolution had ceased, the solution was evaporated to dryness under vacuum. 1.45 g (98%) of benzhydryl-trans-3- (2-methyl-1,3-dioxolan-2-yl) -1-5 (4-methoxyphenyl) -4-oxo-2-azethidinyl acetate were obtained.

Analysis: Calculated for C29H29N06 (487'55): C: 71.44%, H: 5.99%, N: 2.87%; found: C: 71.13%, H: 6.21%, N: 2.93%.

10 X H NMR (CDCl 3): δ - 1.35 (s, 3H), 2.7-3.1 (m, 2H), 3.38 (d, 1H, J * 2.5 Hz), 3.72 (s, 3H), 3.8-4.1 (m, 4H), 4.1-4.5 (m, 1H), 6.85 (s, 1H), 6.7-7.4 (m 14H) ppm.

i) 0.28 g (0.65 mmol) of benzhydryl-trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxy-15) in 2 ml of acetone phenyl) -4-oxo-2-azethidinyl 7acetate, prepared as described under point h) of Method II, dissolved and a solution of 0.9 g (1.6 mmol) of cerium ammonium nitrate ^ Ce (NH ^) 3 (NO ^) ^ 7 in 2 ml of 5% aqueous sulfuric acid was added dropwise at room temperature to the stirred mixture. The reaction mixture was stirred for an additional 2 min and then carefully neutralized with a 5% aqueous sodium hydrogen carbonate solution. The mixture was then extracted three times with 4 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The oily residue was purified by preparative thin layer chromatography (adsorbent: Kieselgel 60.0 = 0.050-0.200 mm, eluent: * a 7: 2 mixture of benzene and acetone), yielding 0.06 g (30% ) benzhydryl-trans-3- (2-methyl-1,3-dioxolan-2-30 yl) -4-oxo-2-azethidinyl-acetate. This compound is identical to the product prepared as described under point j) of Method I.

The product obtained could be converted into the desired starting material as described under points k) to n) of method I.

Method III

a) A mixture of 38 g (0.152 mole diethyl anilomonalonate ^ R. Blank: Ber. 31, 1815 (1898] // 38 ml glacial acetic acid and 8205065 - 22 - 15/3 g (13/9 ml / 0.182 mole) diketene was heated to boiling for 0.5 h Glacial acetic acid was evaporated in vacuo over a water bath and the oily residue was crystallized by trituration with ether 36.5 g (72%) of diethyl-5 (n-phenyl-3-) hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate) and / or its tautomer, mp .: 98-99 ° C (ethyl acetate and petroleum ether).

Analysis: Calculated for C 15 H 10 NO (335.35): 17 10 C: 60.88%, H: 6.31%, N: 4.18%; found: C: 60.83%, H: 6.15%, N: 4.43%.

IR (KBr): 3350, 2950, 1760, 1750 (d), 1700 cm -1.

1 H NMR (CDCl3): δ = 1.02 (t, 3H), 1.3 (t, 3H), 1.6 (s, 3H), 2.8 (s, 3H), 3.6 (wide s, 1H), 4-4.45 (m, 4H), 7.2 (s, 5H) ppm.

b) To a solution of 10.2 g (0.447 mol) metallic sodium in 250 ml dry ethanol, 50 g (0.149 mol) diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2- pyrrolidine dicarboxylate), prepared as described under point a) of Method III, and a solution of 37.9 g (0.149 mol) of iodine in 200 ml of dry ether was added with vigorous stirring. When the reaction was over, 8.5 ml (8.9 g, 0.149 mol) glacial acetic acid, 200 ml of water and 100 ml of ether were added to the mixture, the organic phase was separated and the aqueous phase was extracted with 100 ml ether. The ether phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue was crystallized from 50 ml 2-propanol to give 31 g (62%) diethyl (3-acetyl-1-phenyl-4-30 oxo-2,2-azethidine dicarboxylate), mp .: 55-56 ° C (2-propanol).

Analysis: Calculated for C 1 H 20 NO 5: C: 61.25%, H: 5.75%, N: 4.20%; found: C: 61.38%, H: 5.89%, N: 4.24%.

IR (KBr): 1770, 1740, 1720 cm -1.

1 H NMR (CDCl 3): δ = 1.12 (t, 6H), 2.3 (s, 3H), 4.25 (q, 4H), 4.75 (s, 1H), 7.0-7, 6 (m, 5H) ppm.

c) In a mixture of 90 ml of dry dioxane and 21 8205065 - 23 g (18.8 ml, 0.34 mol) of dry ethylene glycol, 28.5 g (0.085 mol) of diethyl-3-acetyl-1-phenyl-4 oxo-2,2-azethidine dicarboxylate, prepared as described under step d) of method III, dissolved and 36.5 g (31.5 ml, 0.255 mol) of boron trifluoride-diethyl etherate complex was added dropwise with vigorous stirring and cooling with ice water added to the solution. The solution was stirred at room temperature for an additional 2 h and then neutralized with saturated aqueous sodium carbonate solution. The neutral solution was diluted with 100 ml of water and extracted three times with 50 ml of diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness in vacuo. The oily residue was crystallized by trituration with ether. 28.5 g (90%) of diethyl-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azethidine dicarboxylate were obtained; mp: 59-61 ° C (petroleum ether).

Analysis: Calculated for C 7 H 19 N 10: G: 60.47%, H: 6.14%, N: 3.71%; Found: C: 60.74%, H: 6.21%, N: 3.79%.

IR (KBr): 1770, 1740cm * 1.

1 H NMR (CDCl 3): θ = 1.18 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz), 1.51 (s, 3H), 3.92 (m, 4H), 4.3 (m, 5H), 7.2 (m, 5H) ppm.

D) A mixture of 28.5 g (0.075 mol) diethyl-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azethidine di-carboxylate, prepared as described under point c) of method III, 44 ml of dimethyl sulfoxide, 5.6 g (0.1 mol) of sodium chloride and 3.05 ml (0.17 mol) of water were stirred at 175 ° C as the reaction proceeded. The progress of the reaction was monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, developing solvent: a 6: 4 mixture of benzene and ethyl acetate). The solution was poured into 200 ml of a saturated aqueous sodium chloride ride solution and extracted three times with 150 ml of diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The resulting 16.4 g of oily residue was dissolved in 8205065 - 24 - 100 ml of ethanol and a solution of 2.15 g (0.054 mol) of sodium hydroxide in 30 ml of water was added thereto with stirring over an ice water bath. After stirring for 0.5 h, the mixture was diluted with 150 ml of water and extracted three times with 20 ml of diethyl ether. The aqueous phase was acidified to pH = 1 with concentrated aqueous hydrochloric acid and extracted three times with 50 ml of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily-like residue was crystallized from benzene, yielding 12 g (56%) of trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2— azethidine carboxylic acid; mp: 165 ° C (benzene).

Analysis: Calculated for C 1 H H NO N (277.27): C: 60.64%, H: 5.45%, N: 5.05%; found: C: 60.64%, H: 5.72%, N: 4.99%.

IR (KBr): 3500-2700, 1770, 1730cm -1.

1 H NMR (CDCl 3): <5 = 1.5 (s, 3H), 3.69 (d, 1H, J = 3 Hz), 4.0 (m, 4H), 4.42 (d, 1H, J = 3 Hz), 7.3 (m, 5H), 7.55 (s, 1H) ppm.

e) In 100 ml of dry tetrahydrofuran, 13.8 g (0.05 mol) of trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidine carboxylic acid, prepared as described under point d) of method III, dissolved and 5.55 g (7.7 ml, 0.055 mol) of ethyl chloroformate was added to the solution at -15 ° C. After stirring for 20 min, the separated salt was filtered under nitrogen atmosphere and an ether solution of 22.6 g (0.15 mol) diazomethane was added with stirring to the filtrate. When gas evolution had ceased, the excess diazomethane was decomposed with glacial acetic acid and the solution was evaporated to dryness. The oily residue was triturated with ether to give 11.5 g (77%) of crystalline trans-4- (diazoacetyl) -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) azethi-dinon; mp: 96-97 ° C (benzene and ether).

IR (KBr): 2150, 1760, 1635 cm-1.

XH NMR (CDCl3): δ = 1.50 (s, 3H), 3.5 (d, 1H, J = 2.6 Hz), 3.50 (m, 4H), 4.34 (d, 1H, J = 2.6 Hz), 5.45 (s, 1H), 7.25 (m, 5H) ppm.

8205065 - 25 - f) In a mixture of 100 ml of tetrahydrofuran and 50 ml of water, 3.8 g (0.0126 mol) of trans-4- (diazoacetyl) -1-phenyl-3- (2-methyl-1,3) -dioxolan-2-yl) -2-azethidinone, prepared as described under point e) of method III, dissolved and the solution was irradiated with a high-pressure mercury lamp in a photo-reactor at room temperature and under nitrogen atmosphere. The progress of the reaction was monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, developing solvent: a 7: 1 mixture of benzene 10 and acetone). At the end of the reaction, tetrahydrofuran was evaporated in vacuo, the residue was made alkaline with a 20% aqueous sodium hydroxide solution and the alkaline solution was washed three times with 15 ml of dichloromethane. The aqueous phase was acidified to pH = 1-2 with concentrated aqueous hydrochloric acid and extracted three times with 20 ml of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue was triturated with ether to yield 1.8 g (50%) of crystalline / trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo -2-azethidinyl acetic acid; mp: 128-129 ° C (ethanol).

Analysis: calculated for C ^ H ^ NO. (291.29): C: 62.00%, H: 5.88%, N: 4.82%; Found: C: 61.75 *, H: 5.86%, N: 5.08%.

IR (KBr): 1760, 1740 cm -1.

XH NMR (CDCl3): <5 »1.48 (s, 3H), 2.65 (dd, 1H, +)

Jgem - 15 Hz 'Jvic = 8 Hz>' 3'12 (dd '1H' Jgem = 15 Hz '

Jvic = 8 Hz) '3'47 (d' 1H 'J * 2'5 Hz> / 3.98 4H> / 4 ^ 4 30 1H), 7.3 (m, 5H), 9.33 (wide s 1H) ppm.

g) 0.81 ml of concentrated nitric acid (p = 1.5) was added dropwise to 3 ml of acetic anhydride with constant stirring and ice-cooling, the temperature of the mixture not rising above + 5 ° C. The resulting nitration ring mixture was added dropwise at -5 ° C to a stirred solution of 2.9 g (0.01 mol) ^ trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2) -yl) -4-oxo-2-azethidinyl-7-acetic acid, prepared as described under point (f) of Method III, in 20 ml 8205065 * - 26 -

dry dichloromethane. After stirring for 1 h, the solution was poured into ice water and the phases separated. The aqueous phase was extracted twice with 25 ml of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The oily residue was triturated with ether to give 1.95 g (58%) of crystalline / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (2-nitrophenyl) - 4-oxo-2-azethidinyl acetic acid; mp .: 175-176 ° C

10 (ethanol).

Analysis: Calculated for C15 H16 N2 ° 7 (336.33): C: 53.57%, H: 4.79%, N: 8.33%; found: C: 53.31%, H: 4.68%, N: 8.21%.

IR (KBr): 3600-2900, 1740, 1540, 1340 cm -1.

h) In 15 ml of methanol, 0.336 g (1 mmol) / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (2-nitrophenyl) -4-oxo-2-azethidinyl acetic acid, prepared as described under point g) of method III, dissolved and the solution was hydrogenated under atmospheric pressure in the presence of 0.05 g of a palladium-on-carbon catalyst. The catalyst was filtered off and the filtrate was evaporated to dryness. The oily residue was dissolved in 10 ml of dichloromethane, 0.17 g (1 mmol) of diphenyldiazomethane was added and the mixture was stirred for 24 h. The mixture was then evaporated to dryness, yielding 0.4 g (90%) of benzhydryl-trans- / 1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azethidinyl-acetate.

IR (KBr): 1740, 1720cm -1.

Mass spectrum: m / e = 472 (M +).

i) In 2 ml glacial acetic acid 0.45 g (1 mmol) benzhy-dryl-trans - / - (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azethidinyl acetate dissolved and a solution of 0.2 g (2 mmol) chromium trioxide in 2 ml glacial acetic acid and 0.2 ml water was added dropwise to the above solution at room temperature. The mixture was stirred at room temperature for 3 h, then poured into 10 ml of ethyl acetate and washed with a 5% aqueous sodium hydrogen carbonate solution to neutrality. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (adsorbent: Kieselgel 60 pF254 + 5 µg, developing solvent: a 7: 3 mixture of benzene and acetone). 0.09 g (30%) of benzhydryl-trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl acetate were obtained.

The physical constants of this compound were identical to those of the product prepared according to point j) of Method I.

The obtained compound could be converted into the desired final substance, as described under points k) to n) of method I.

Method IV

A) To a solution of 0.730 g (2 mmol) / trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2- azethidinyl acetic acid in 10 ml dry tetrahydrofuran, 0.364 g (2.2 mmol) 98% carbonyldiimidazole was added and the mixture was stirred for 20 min. 0.315 g (2.2 mmol) of monoethylmalonate magnesium salt was added to the solution and this mixture was stirred for 2 h. The reaction mixture was evaporated to dryness, the residue was shaken with a mixture of 40 ml of dichloromethane and 40 ml of a 0.5 N aqueous hydrochloric acid solution and then the phases were separated. The aqueous phase was extracted with 20 ml of dichloromethane. The organic phases were combined, washed twice with 10 ml of a 3% aqueous sodium carbonate solution, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. 0.41 g (47 S) of ethyl-trans-4- (4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo- 2-azethidinyl-7-3-oxo-butanoate.

IR (film): 1750, 1740, 1720 cm * 1.

2 H NMR (CDCl 3): δ = 1.26 (t, 3H), 1.39 (s, 3H), 2.2-3.3 (m, 5H), 3.65-4.45 (m, 14H), 6.25-6.6 and 7.05-7.25 (m, 3H) ppm.

b) To a solution of 2.77 g (5.0 mmol) ethyl-trans-4- (1- (2,4-dimethoxybenzyl) -3- (2-methyl-2,3-dioxo) 8205065 -28- Lan-2-yl) -4-oxo-2-azethidinyl7-3-oxo-butanoate, prepared as described under point a) of Method IV, in 15 ml of dry acetonitrile was ice-cooled 0.69 ml (5.0 mmol) triethylamine as well as 0.986 g (5.0 mmol) tosylazide. The solution was stirred for 3 h, allowing the solution to warm to room temperature. The solution was then evaporated to dryness and the residue was further processed by column chromatography (adsorbent: Kieselgel 60,0 = 0.063-0.200 mm, eluent: a 7: 3 mixture of benzene and acetone). Obtained-10 was 1.41 g (61%) of ethyl-2-diazo-4-trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2 -yl) -4-oxo-2-azethidynyl / -3-oxo-butanoate.

IR (film): 2160, 1750, 1720, 1640 cm-1, c) To a solution of 2.340 g (5.0 mmol) of a compound prepared as described under point b) of method IV in 30 ml of acetonitrile, 5 , 4 g (20 mmol) potassium persulfate (K2S20g), 7.2 g (40 mmol) disodium hydrogen phosphate monohydrate (Na2HPC> 4 .H2 O) and 18 ml water and the mixture was heated to boiling for 10 h. The reaction mixture was cooled, filtered and the two phases of the filtrate separated. The aqueous phase was extracted three times with 10 ml of ethyl acetate each time. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was further processed by column chromatography (adsorbent: Kieselgel 60,0 = 0.063-0.200 mm, eluent: a 7: 3 mixture of benzene and acetone), yielding 0.56 g (36%) ethyl 2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-oxo-butanoate. The physical constants of this compound were identical to those of the product prepared according to point m) of Method I. The compound could be converted into the desired starting material, as described under point n) of Method I.

Method V

One drop of dimethylformamide and 0.37 ml (5.0 mmol) thionyl chloride was added to a stirred solution of 1,830 g (5.0 mmol) ^ trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl 1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-acetic acid 8205065-29 in 10 ml of dichloromethane under ice cooling and the reaction stirred under cooling for 2 h. 1.7 ml of ethyl diazoacetate was then added to the mixture and stirring was continued at ambient temperature for 24 h. The dark solution was evaporated to dryness, and the residue was processed by column chromatography (adsorbent: Kieselgel 60, 0.0 = 0.063-0.200 mm, eluent: a 7: 2 mixture of benzene and acetone). 0.17 g (7.3%) of ethyl-2-diazo-4-trans- / 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxo-10 lan-2) were obtained -yl) -4-oxo-2-azethidinyl7 "3-oxo-butanoate; the IR spectrum of this compound was identical to that of the product obtained according to point b) of Method IV.

This compound could be converted into the desired starting material, as described under point c) of Method IV.

15 Method VI

a) 0.4 g (1.24 mmol) of Ytrans-3- {2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo- in 15 ml of dry tetrahydrofuran 2-azethidinyl acetic acid, prepared as described under point g) vein method II, dissolved and 0.22 g 20 (1.36 mmol) carbonyldiimidazole was added. The resulting mixture was stirred at room temperature for about an hour. When gas evolution ceased, 0.196 g (1.36 mmol) of monoethyl malonate magnesium salt was added and the mixture was stirred for 1 h. The solution was evaporated to dryness, the residue was dissolved in 50 ml of dichloromethane and the solution was washed with 25 ml of a 2 N aqueous hydrochloric acid solution. The aqueous mixture was extracted with 25 ml of dichloromethane. The organic phases were combined, washed twice with 20 ml of a 5% aqueous sodium carbonate solution, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. 0.3 g (62%) of ethyl trans-4- (3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azethidinyl7 were obtained -3-oxo-butanoate.

Analysis: Calculated for C20 H25 NO7 (391.42): C: 61.37%, H: 6.44%, N: 3.58%; found: C: 61.20%, H: 6.59%, N: 3.72%.

IR (film): 1750-1'1.

8205065 * - 30 - b) To a stirred solution of 0.5 g (1.44 mmol) of the compound prepared according to point a) of method VI in 6 ml of dry acetonitrile, 0.28 g was cooled with ice or water (1.44 mmol) tosylazide as well as 0.2 ml (1.44 mmol) triethylamine. The reaction mixture was stirred at room temperature for 2 h and the progress of the reaction was monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, developing solvent: a 7: 3 mixture of benzene and acetone). At the end of the reaction, the mixture was evaporated to dryness, the residue was dissolved in 40 ml of dichloromethane and the solution was washed acid free with 10 ml of a 40% aqueous potassium hydroxide solution and then with 10 ml of water. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was purified by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254 + 366 'eluent: a 7: 3 mixture of benzene and acetone). 0.25 g (36%) of ethyl-2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo was obtained -2-aze-20 thidinyl7-3-oxo-butanoate; mp: 131-132 ° C (ether); IR (KBr): 2200, 1740, 1710, 1640 cm -1.

Analysis:

calculated for C20H23N3 ° 7 (417/41) J

C: 57.55%, H: 5.55%, N: 10.07%; Found: C: 57.56%, H: 5.80%, N: 10.08%.

c) In 4.5 ml of acetone, 0.45 g (0.106 mmol) of the compound was prepared as described under point b) of Method VI and a solution of 1.5 g (2.7 mmol) of cerium ammonium nitrate in 4.5 ml of a 5% aqueous sulfuric acid solution was added dropwise to the stirred mixture. The reaction mixture was stirred for an additional 5 min, after which the yellow solution was neutralized with a 5% aqueous sodium hydrogen carbonate solution and extracted three times with 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was purified as described under the previous point. 0.10 g (27%) of ethyl-2-diazo-4-trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2- 8205065 -φ c - was obtained 31 - "azethidinyl7" 3-oxo-butanoate; the IR spectrum of this compound is identical to that of the substance obtained according to point b) of Method IV.

The obtained compound could be converted into the desired starting material as described under point n) of method I.

EXAMPLE II

Ethyl 3-benzylthio-6- (2-methyl-1/3-dioxolan-2-yl) -7-oxo-1-azablcyclo / 3.2.07hept-2-en-2-carboxylate.

At 0 ° C, 0.91 ml (4.4 mmol) diphenylphosphoryl chloride (P 2 O 2 PCl) was added within 10 min to a stirred solution of 1.133 g (4.0 mmol) ethyl 6- (2- methyl 1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo [3.2.07] heptane-2-carboxylate and 0.61 ml (4.4 mmol) of triethylamine in 10 ml of dry acetonitrile.

Then 0.61 ml (4.4 mmol) of triethylamine and then 0.52 ml (4.4 mmol) of benzyl mercaptan were added to the mixture and the resulting mixture was stirred at 0 ° C for 1 h.

The mixture was evaporated to dryness under vacuum, the residue was dissolved in 50 ml of dichloromethane and the solution was washed three times with 5 ml of a 3% aqueous sodium hydrogen carbonate solution and then three times with 5 ml of water. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The oily residue, weighing 1.0 g, was further processed by column chromatography (adsorbent: Kieselgel 60.0 = 0.063-0.200 mm, eluent: a 7: 1 mixture of benzene and acetone). 0.90 g (58%) of the target compound (a fraction which crystallizes from ether) were obtained; mp: 109 ° C.

IR (KBr): 1780, 1700cm -1.

30 X H NMR (CDCl 3): δ = 1.33 (t, 3H, J = 7.5 Hz), 2.87-3.3 (m, 2H), 3.35 (d, 1H, J = 3 Hz ), 3.95-4.45 (m, 7H), 7.33 (s, 5H) ppm.

13 C-NMR (CDCl 3): 14.30; 23.35; 36.85; 40.28; 51.94; 61.15; 65.18; 65.33; 67.15; 106.85; 124.4; 127.7; 35 128.69; 128.88; 136.42; 145.93; 161.32; 173.91 ppm

Mass spectrum: m / e = 389, 303, 261, 91, 87, 43.

EXAMPLE III

p-Nitrobenzyl-3- (formylamlnoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo / 3.2.07hept-2-en-8205065 - 32 - 2- carboxylate.

At 0 ° C, 0.61 ml (4.4 mmole) of triethylamine and then, within 10 min, 0.91 ml (4.4 mmole) of diphenylphosphoryl chloride were added to a stirred solution of 1.561 g of 5 (4.0 mmole) p-nitrobenzyl-6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo / 3.2.07heptane-2-carboxylate in 10 ml dry acetonitrile. Stirring was continued and an additional 0.61 ml (4.4 mmol) of triethylamine and 0.46 g (4.4 mmol) of N-formyl cystamine were added to the mixture at 0 ° C. After stirring for 1 h, the mixture was evaporated in vacuo, the residue was dissolved in 20 ml of dichloromethane and the solution was washed with 10 ml of a 3% aqueous sodium hydrogen carbonate solution and then twice with 10 ml of water. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was processed by column chromatography (adsorbent: Kieselgel 60.0 = 0.063-0.200 mm, eluent: a 7: 3 mixture of benzene and acetone), yielding 1.05 g (64%) of the title compound; mp: 183 ° C (ether).

IR (KBr): 3330, 1750, 1680 (shoulder), 1670 cm -1.

1 H NMR (CDCl 3 + DMSO-dg): 6 = 1.43 (s, 3H), 2.85-3.45 (m, 6H), 3.58 (d, 1H, J = 3 Hz), 4, 0-4.3 (m, 5H), 5.24-5.51 (d, 2H, JAB = 13.8 Hz), 7.68 + 8.20 (d, 4H, = 11 Hz), 8, 16 (s, 1H) ppm.

P-Nitrobenzyl-6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxoazabicyclo <3.2.07heptane-2-carboxylate, the starting material of the procedure described in Example III, may be prepared from A) trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-7-acetic acid, a substance prepared as described under points a) to k) of method I points (a) to (i) of Method II plus point (k) of Method 1, or points (a) to (c) of Method III plus point (k) of Method I; or B) ^ trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-35 1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl acetic acid, a substance prepared as described under point i) of method I, or C) trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azethidinyl acetic acid, a substance 8205065 - 33 - prepared as described under point (g) of Method II.

Method A) is carried out as follows: a) A mixture of 0.645 g (3.0 mmol) ^ trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl-acetic acid, 0.535 g (3.3 mmol) carbonyldiimidazole and 15 ml dry tetrahydrofuran were stirred at room temperature for 30 min, after which 0.825 g (3.3 mmol) p-nitrobenzyl malonate magnesium salt was added to the mixture and stirring for 2 h at room temperature was continued. The mixture was allowed to stand overnight and then evaporated to dryness under vacuum. The residue was shaken with a mixture of 50 ml of dichloromethane and 50 ml of a 0.5 N aqueous hydrochloric acid solution and the organic phase was separated. The aqueous phase was extracted with 25 ml of dichloromethane. The organic solutions were combined, washed twice with 10 ml of a 3% aqueous sodium carbonate solution, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. 0.730 g (62.1%) of p-nitrobenzyl-trans-4- (3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-20-2-azethidinyl7-3-oxo- butanoate.

IR (film): 3250, 1760, 1740, 1720 cm-1.

b) In 15 ml of dry acetonitrile, 1.962 g (5.0 mmol) of the compound was prepared as described under point a) above and 0.69 ml (5.0 mmol) of triethylamine and 0.985 g (5.0 of 25 mmol) tosylazide added to the solution under ice cooling. After 5 min of the addition, a crystalline substance separated. The mixture was stirred for 20 min, after which the separated substance was filtered off, washed with ether and dried. 1.326 g (63.4%) of p-nitrobenzyl-2-30 diazo-4-trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethi- were obtained dinyl7-3-oxo-butanoate; mp: 163-164 ° C.

IR (KBr): 3320, 2160, 1750, 1710, 1630 cm -1.

XH NMR: δ = 1.41 (s, 3H), 2.98 (dd) and 3.44 (dd, 2H, J = 10 Hz and 4 Hz), 3.18 (d, 1H, J = 2, 4 Hz), 3.83-4.15 35 (m, 5H), 5.36 (s, 2H), 6.0 (s, 1H), 7.54 (d) and 8.26 (d, 4H , AB, J = 9 Hz) ppm.

c) A suspension of 1.673 g (4.0 mmol) of the compound prepared as described under point b) above in 45 ml of dry benzene was stirred and heated to boiling and 0.050 g of 8205065-34-dirhodium tetraacetate / Rh ^ (ΟΑσ) ^ .2ΤΗΡ7 was added in several portions. After boiling for 10 h, the starting material was completely reacted. The mixture was cooled, the separated substance was dissolved in dichloromethane and the solution was filtered over Celite cotton wool. The filtrate was evaporated to dryness in vacuo, the residue was mixed with ether and the suspension was filtered. 1.32 g (84.6%) of p-nitrobenzyl-6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabi-cyclo ^ 3.2.07- were obtained heptane-2-carboxylate; mp .: 167 ° C.

IR (KBr): 1760, 1735 cm -1.

XH NMR: δ = 1.48 (s, 3H), 2.47 (dd, 1H, Jgem = 19 Hz, Jvic = 8 Hz), 2.92 (dd, 1H, Jgem = 19 Hz, Jvic = 8 Hz ), 3.46 (d, 1H, J = 2.4 Hz), 4.0-4.2 (m, 5H), 4.75 (s, 1H), 5.30 (d, 2H, JAB = 14 Hz), 7.53 and 8.23 (d, 4H, JAB = 9Hz) ppm.

Method B) is analogous to method IV or V (see example I, while method C) is analogous to method VI (see example I). In both cases p-nitrobenzyl-2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azethidinyl7-3-oxo-butanoate is obtained, the physical constants of which are identical to those of the compound prepared according to point b) of method A). The compound obtained could be converted into the desired starting material, as described under point c) of method A).

EXAMPLE IV

Sodium 3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo / 3.2.07hept-2-en-2-carboxylate.

A suspension of 0.25 g of a 10% palladium-on-carbon catalyst in 70 ml of a 2: 1 mixture of 30 dioxane and water was stirred at room temperature under a hydrogen atmosphere for 20 min and a warm solution of 0.477 g was then added. (1.0 mmol) p-nitrobenzyl-3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo- / 3,2,07hept-2-ene -2-carboxylate, prepared as described in Example III, added in 30 ml peroxide-free dioxane. The reaction mixture was stirred for an additional 3 h under hydrogen atmosphere and a solution of 0.084 g (1.0 mmol) of sodium hydrogen carbonate in the minimum amount of 8205065% water was added thereto. The reaction mixture was filtered over Celite cotton wool. Dioxane was evaporated from the filtrate in vacuo and the aqueous residue was extracted three times with 10 ml of dichloromethane. The aqueous phase was then evaporated to dryness under vacuum at room temperature. The residue crystallized on cooling. The crystalline substance was mixed with 6 ml of ethanol and the crystals were filtered off. 0.25 g (73%) of the target compound are obtained; mp: 201 ° C (with decomposition).

IR (KBr): 3420, 1770 (shoulder), 1760, 1690, 1610 cm -1.

XH NMR (D20): δ - 1.42 (s, 3H), 2.7-3.6 (m, 6H), 3.65 (d, 1H, J = 3 Hz), 3.95-4, 3 (m, 5H), 8.03 (s, 1H) ppm.

15 8205065

Claims (18)

1. Process for the preparation of a new bicyclic compound of the general formula 1 of the formula sheet, in which Y and Y represent a removable carbonyl protecting group, preferably a ketal group or a thio analog thereof, Q 'a C 2 g alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is an optionally substituted hydrocarbon radical, preferably a benzyl, 2-aminoethyl or 2-acylaminoethyl group, characterized in that a) is a compound of the general formula 2 of 1 2 the formula sheet, wherein Y and Y are as defined above and Q is a C 1-6 alkyl group or a substituted benzyl group, is treated with a suitable O-acylating agent, preferably with a sulfonyl or phosphoryl halide and then with a mercaptan, preferably with benzyl mercaptan, cysteamine or an N-acylated derivative thereof, in the presence of a tertiary amine and that the obtained product of the general formula 1 of the form leaf, wherein Q 'is a C 1-6 alkyl group or a substituted benzyl group, is separated, or b) from a compound of the general formula 1 1 2 of the formula sheet obtained in step a), wherein R 1, Y and Y are as defined above and Q 'represents a substituted benzyl group, Q' is removed by reduction and, if desired, the resulting carboxylic acid (Q * = H) is converted into its alkali metal salt. A method according to claim 1, characterized in that diphenylphosphoryl chloride is used as O-acylating agent. A method according to claim 1, characterized in that N-formylcysteamine is used as an N-acylating cysteamine derivative. 4. Process according to claim 1, characterized in that the substituted benzyl group is removed by catalytic hydrogenation. Process according to claim 1, characterized in that a free carboxylic acid is converted into its alkali metal salt by reacting it with an 8205065 --··. . ..,. . ........, ....... · ΓΕΒ5 »Λ— ..., -. - - 37 - Alkali metal carbonate or hydrogen carbonate. 6. Process according to claim 1 for the preparation of ethyl-3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo ^ 3.2.ohept-2- 1-2-carboxy-5, characterized in that ethyl-6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo ^ 3.2.07heptane-2-carboxylate presence of a tertiary amine is reacted with an O-acylating agent and then with N-formylcysteamine. Process according to claim 1 for the preparation of ethyl-3-benzylthio-6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo ^ 3.2.07hept-2-ene -2-carboxylate, characterized in that ethyl-6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo ^ 3.2.07heptane-2-carboxylate in the presence of a teriary amine is reacted with an O-acylating agent and then with benzyl mercaptan. Process according to claim 1 for the preparation of p-nitrobenzyl-3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo / 3.2.07hept-2- 1- 2- carboxylate, characterized in that p-nitrobenzyl-6- (2-methyl-1,3-dioxolan-2-yl) -3-dioxo-1-azabicyclo-S. 2.07 heptane-2-carboxylate in the presence of a tertiary amine is reacted with an O-acylating agent and then with N-formyl cysteamine. Process according to claim 1 for the preparation of sodium 3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo / 3.2.ohep-2 - a 2-carboxylate, characterized in that p-nitrobenzyl-3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-30-azabicyclo ^ 3.2 .07hept-2-an-2-carboxylate is reduced and then converted to its sodium salt. 10. A process for the preparation of a pharmaceutical preparation, characterized in that a compound of the general formula 1, wherein Y, Y, Q 'and R "are defined as in claim 1, is mixed with a conventional pharmaceutical carrier, diluent and / or additive. 11. Bicyclic compound of the general formula 8205065 - 38 - 1 2 le 1 of the formula sheet, wherein Y and Y represent a removable carbonyl protecting group, preferably a ketal group or a thio analog thereof, Q 'is a C 1-6 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is an optionally substituted hydrocarbon radical, preferably a benzyl, 2-aminoethyl or 2-acyl aminoethyl group. 12. Ethyl-3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo [3.2.7hept-2-en-2- 10 carboxylate. 13. Ethyl 3-benzylthio-6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo] 3.2.07hept-2-en-2-carboxylate. 14.p-Nitrobenzyl-3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo ^ 3.2.ohept-2- 15-2-carboxylate . 15. Sodium 3- (formylaminoethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo 3.2.07hept-2-en-2-carboxylate. 16. Pharmaceutical composition containing an effective amount of a compound of the general formula 1 of the formula sheet, wherein Y, Y, Q 'and R "are as defined in claim 11. 17. A compound of the general formula 1, wherein 1 2 Y, Y, Q 'and R "are as defined in claim 1, characterized in that it is prepared by the process according to any one of claims 1-10. A pharmaceutical composition containing a compound of the general formula 1, wherein Y, Y, Q 'and R "are as defined in claim 1, together with a pharmaceutically acceptable carrier. 8205065