FR2519002A1 - NEW BICYCLIC COMPOUNDS AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

NEW ANALOGUES OF THIENAMYCIN REPRESENTED BY GENERAL FORMULA I BELOW: (CF DRAWING IN BOPI) OR Y AND Y REPRESENT A DETACHABLE GROUP PROTECTING RADICAL CARBONYL, Q IS AN ALKYL GROUP IN CAC A BENZYL GROUP A SUBSTITUTE HYDROGEN OR AN ION OF METAL ALKALINE AND R IS A POSSIBLY SUBSTITUTED HYDROCARBYL RESIDUE, AND THEIR PREPARATION METHODS. THESE NEW COMPOUNDS OF GENERAL FORMULA I CAN BE USED THERAPEUTICALLY, PRIMARILY AS B-LACTAMASE INHIBITORS.

Description

The present invention relates to novel bicyclic compounds and to

pharmaceutical compositions

  containing them, as well as a process for preparing them.

  The novel compounds according to the present invention are represented by the following general formula (I): ## STR2 ##

HC-C H

\ Ij R I

O

  Wherein Y 1 and Y 2 form a detachable protecting group of the carbonyl radical, preferably a ketal group or a thioanalogue thereof;

  Q 'is a C 1 to C 5 alkyl group; a benzyl substituted group;

  killed, a hydrogen atom or an alkali metal ion, and R "is an optionally substituted hydrocarbon residue, preferably a benzyl, 2-aminoethyl or 2-acylaminoethyl group.The compounds of the general formula (I) are novel and effective analogues of thienamycin and with the exception of those compounds in which Q 'is an alkyl group, they may

  also serve as intermediaries in the synthesis of

  namycine. Thienamycin, a broad-spectrum antibiotic, was first prepared microbiologically (US Patent No. 3,950,357) and then chemically synthesized.

(German Patent No. 2,751,597).

  It is an object of the present invention to provide a novel route for the synthesis of thienamycin and its analogs, wherein the azetidinone backbone and the α-hydroxyethyl side chain or a side chain which can easily be converted to the α-hydroxyethyl group are formed simultaneously in the first step of the synthesis and the resulting key-intermediate is then converted into

final product sought.

  It has been found that by acylating a dialkyl malonate whose amino group is protected, with diketene, and then reacting the resulting acylated product with iodine

  and an alkali metal alcoholate, an azene compound is obtained.

  tidinone represented by the following general formula (XIII):

HC (CZ)

  R 'containing an a-acetyl side chain, which can be used

  as a key intermediary in the synthesis.

  In the above formula, R represents a detachable protecting group of the amido radical, preferably a benzyl group bearing one or more methoxy substituents or a phenyl group optionally bearing one or more methoxy substituents, and Z is a C 1 -C 4 alkyl group. The novel intermediates of the general formula (XIII) and their preparation are described in detail in the applicant's earlier Hungarian patent application No. 2262/80. Preparation of these new intermediates

  is also described in the examples of the present invention.

  tion. It has also been observed that before converting the intermediate of the general formula (XIII) to thienamycin or its analogs, it is preferable to protect the ketone group of the lateral α-acetyl chain with a group, in particular a group ketal or a thioanalogue thereof, which may be removed in a subsequent step of

  synthesis Ethylene glycol or a thioanalogue of this

  ci, such as mercapto-ethanol, can be applied particularly preferably to form an ethylene-ketal or hemithioketal protection The resulting compound is represented by the following general formula (XII): yl y 2 /

HOC-C ^ (COOZ) 2

(XIII)

R

  o y 1 and y 2 together form a group for temporary protection

  porary part of the carbonyl part, preferably an ethyl group

  Necetal or a thioanalogue thereof and R and Z are as defined above, and then reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethylsulfoxide to obtain a compound represented by the general formula (XI) below: yl 2 HH

*% C / -YC COOZ (XI)

GOLD

  wherein R, y 2 and Z are as defined above.

  The resulting compound of the general formula (XI) is a mixture of cis and transisomers. The isomerscan be separated from each other by chromatography or by their different solubility. The separated trans isomer represented by the general formula (X Ia) ) hereinafter: yi y 2 HH

\ C COOZ

HOC-C "I (-)

  O (X Ia) O-R can be converted to the transcarboxylic acid represented by the following general formula (X): yl y 2 H

C C COOH

  It is more advantageous, however, to subject the isomeric mixture itself to hydrolysis, since the reaction is selective, i.e., only the trans ester is converted.

to the respective carboxylic acid.

  The separated transcarboxylic acid of the general formula (X) is first treated with an activator for the carboxy group, then with diazomethane and the resulting compound represented by the following general formula (IX): 1 y 2

H H

HOC COC Hi 00012 (IX)

  is subject to Wolff transposition in the presence of water.

  The resulting azetidinoacetic acid represented by the following general formula (VIII) can be converted into the desired end products, from

  general formula (I) in several ways.

  In the general formulas (X), (IX) and (VIII), y 1 y 2

  y, Y 2 and R are as defined above.

  In accordance with one of the methods used to carry out the subsequent conversion, a compound of the general formula (VIII 'o R is a phenyl group, is nitrated, then

  reduced to provide a compound represented by the general formula

(VII Ia) below: yi y 2

H / E H C 2 COÈH

HC-C -

  Where Y 1 and y 2 are as defined above and A is a nitro group and then an amino group. The resulting compound of general formula (VII Ia) is then esterified according to a known method to obtain a compound of general formula (VI Ia) below: yy 2 HH

H 3 C CH 2 NECK

  3-2 A j {1 | (VI Ia) 1 2 wherein y, y 2 and A are as defined above and X is a selectively detachable ester group,

  preferably an arylmethyl or diarylmethyl group.

  The aminophenyl protecting group of the resulting compound

  so much of the general formula (VI Ia) is then removed by

  oxidation, preferably with chromium trioxide in the form of

  of glacial acetic acid and the resulting compound represented by the following general formula (VI): yl y 2 H H

H C -C CH 2000 X

(VI) 0 -X

is then separated.

  In accordance with another method, a compound of

  general mule (VIII), wherein R is a phenyl or benzyl group bearing one or more methoxy substituents, is esterified in a known manner to an ester represented by the general formula (VII) below; y 1 y 2 H H

HC-CH 20 COX

  i 3 (VII) R o R is as defined in this paragraph and Y, y 2 and X

  are as defined above, then the group R of protection

  tion is eliminated and this provides a compound of general formula

  (VI) When R is a dimethoxybenzyl group, it is detached with a peroxydisulphate compound, whereas in the case where R is a methoxyphenyl group, it is

  removed with a ceric salt in the presence of an acid.

  Then, the esterifying group X of the resulting compound of general formula (VI) is preferably removed by reduction, in particular by catalytic hydrogenation; the resulting compound represented by the following general formula (V): y 1 y 2

H H

HO-c CH 2000 H

H 3 C \ / A HCO

  (V) wherein Y and Y are as defined above, is activated on the carboxy group, and then treated with a salt of a malonic half ester, preferably with a potassium or magnesium salt of alkyl malonate or a malonate substituted benzyl compound The resulting compound represented by the following general formula (IV):

2519 OO 2

y 1 y 2

H 3 H'2 COCH 2 COOQ

  And wherein Q is C 1 to C 5 alkyl or substituted benzyl, is treated with a sulfonic azide in the presence of a tertiary amine to give a compound represented by the following general formula (III): yl y 2

1 / H H

H 30 -C CH 2 C 00 N 2000 Q

  o y 1 y 2 and Q are as defined above and this component

  is subjected to a ring closure in the presence of a rhodium salt to obtain a compound represented by the following general formula (II)

0 GOOQ

  wherein the compounds of the general formula (II) are the novel starting materials of the thienamycin analogs, which conform to the

present invention.

  According to yet another method, a compound of general formula (VIII) where R is benzyl or phenyl bearing one or more methoxy substituents, is activated on the carboxy group, and then treated with a salt of a malonic half ester, preferably with magnesium salt

  or potassium of an alkyl malonate or benzyl

  The resulting compound represented by the general formula

(XIV) below: yl y 2 H H

\ R

  13 \ c CH 2000 2 C O Q o Y y and Q are as defined above and R 'is

  a phenyl or benzyl group carrying one or more

  methoxy, is then treated with an azosulfonic acid in the presence of a tertiary amine to obtain a compound represented by the following general formula (XV): yl y 2 1

H 3 C 0 -C CH 2 00 N 20 Q

O, J N (x V) R '

  o y 2 R 'and Q are as defined above.

  The same compounds of general formula (XV) are obtained when a compound of general formula (VIII) where R is a phenyl or benzyl group bearing one or more methoxy substituents, is activated on the carboxy group, and

  then treated with a diazoacetate.

  The protecting group R 'of the resulting compound of general formula (XV) is then detached as described above and the resulting compound of general formula (III) is converted to the starting material of general formula (II). Compounds of the general formulas (II) to (XV)

  are new and obtained as racemic mixtures.

  Certain compounds of general formula (XII) are described in a previous Hungarian patent application of Applicant N 2263/80. The other compounds of general formula (XII), as well as the compounds of general formulas (XI) to (II), ( XIV) and (XV) are described in detail in

  patent applications of the plaintiff.

  When a compound of the general formula (I) is prepared, a starting substance of the general formula (II) is subjected to O-acylation, and then treated with a suitable mercaptan When a compound of the general formula (I) is obtained, where Q 'is a substituted benzyl group, the benzyl group

  substituted can be detached and the resulting carboxylic acid

  as much may be (Q '= H) then converted to alkaline carboxylate.

  From these data, the present invention relates to a process for the preparation of novel bicyclic compounds of general formula (I), wherein: Y 1 and Y 2 represent a detachable group protecting the carbonyl radical, preferably a ketal group or a thioanalogue of it,

  Q 'is a C1 to 5 alkyl group, a benzyl group

  a hydrogen atom or an alkali metal ion and R "is an optionally substituted hydrocarbon residue, preferably a benzyl, 2-aminoethyl or 2-acylaminoethyl group, wherein: a) a compound of the general formula (II), Y 1 and y 2 are as defined above and Q is a C 1 -C 5 alkyl group or a substituted benzyl group, is treated with

  an appropriate O-acylating agent, preferably with a halogen

  sulfonyl ether or phosphoryl, in the presence of a tertiary amine, then with a mercaptan, preferably with benzyl mercaptan, cysteamine or an N-acyl derivative thereof and the resulting product of general formula (I) wherein Q 'is a C 1-5 alkyl group or a substituted benzyl group, is separated, or b) from a compound of formula (I) obtained in step a), o R ", Y 1 and y 2 are as defined above and Q 'represents a substituted benzyl group, Q' is removed by reduction and optionally converted

  the resulting carboxylic acid (Q '= H) is an alkali metal salt.

  In the first step of the above process, a compound of general formula (II) is reacted with an O-acylating agent in the presence of a tertiary amine. Organic carboxylic acid derivatives or preferably sulfonyl or phosphoryl halides. may be applied as reagents in this regard.

  diphenyl phosphoryl is found to be a particular reagent

advantageously.

  The O-acylated intermediate is then treated with a

  mercaptan, preferably benzyl mercaptan, cyste-

  amine or an N-acyl derivative thereof, in the presence of a tertiary amine. In this reaction, a compound of general formula (I) is formed, where Q 'is a C 1 -C 5 alkyl group.

or substituted benzyl.

  The substituted benzyl group of a compound of general formula (I) where Q 'is a substituted benzyl radical may be reduced by reduction, preferably by catalytic hydrogenation, to obtain the respective carboxylic acid of

  general formula (I) (Q '= H) A carboxylic acid of

  The general formula (I) can be converted to its alkali metal salts, of which the sodium salt can be prepared particularly easily by treating the free acid with sodium carbonate or sodium hydrogen carbonate. The alkali metal salt resulting can be separated

  of the reaction mixture by extraction and / or evaporation.

  The new compounds of general formula (I) are active in therapy and possess mainly β-lactamase inhibiting effects. The present invention also relates to pharmaceutical compositions which contain, as active agent, a compound of general formula (I) in mixture with one or more conventional pharmaceutical additives (for example, carrier, diluent, disintegrating aid, preservative, buffer etc.).

  be prepared by methods well known in the art.

  In addition to the foregoing provisions, the invention also includes other provisions which will emerge

of the following description.

  The invention will be better understood by means of the

  description which will follow, which refers to

  examples of implementation of the method, object of the present invention, which are non-limiting

Example 1

  3- (Formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan)

  Ethyl 2-yl) -7-oxo-1-azabicyclo 3,2,0 hept-2-ene-2-carboxylate.

  1.133 g (4.0 mmol) of 6- (2-methyl-1,3-dioxol)

  Ethyl 2-yl) -3,7-dioxo-1-azabicyclo [3,2,0] heptane-2-carboxylate is dissolved in 10 ml of anhydrous acetonitrile and 0.61 ml (4.4 mmol) of triethylamine. then 0.91 ml (4.4 mmol) of diphenyl phosphoryl chloride are

  added to the stirred solution at 00 C in about 10 minutes.

  Stirring is continued at 0 ° C., then 0.61 ml (4.4 mmol)

  triethylamine and 0.46 g (4.4 mmol) of N-formyl

  cysteamine are added to the mixture After one hour of

  The solution is evaporated under vacuum and the residue is dissolved in 20 ml of dichloromethane. The solution is washed with 10 ml of a 3% aqueous solution of sodium hydrogen carbonate and then twice with 10 parts of sodium chloride. ml of water The organic phase is dried

  magnesium sulfate, filtered and the filtrate is evaporated.

  The residue, weighing 2.4 g, is treated by column chromatography (adsorbent: Kieselgel 60, O = 0.063 to 0.200 mm, eluent: benzene-acetone 7: 3 mixture). %) of the desired product; p f =

  152-153 ° C (from methanol and ether).

  IR (K Br): 3400, 1790, 1700, 1690 cm H NMR (CDCl3): δ = 1.35 (t, 3H), 1.45 (s, 2H), 2.82-3.65 (m, 7H), 3.95-4.5 (m, 7H), 6.1 is, 1H), 8.20

(d, 1H) ppm.

  1 C NMR (CDCl 3): δ = 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 / z: 370, 284, 242, 197, 87, 43.

  The starting material used in this example can be prepared according to the following methods: Method I

  a) A mixture of 109.8 g (0.66 mole) of 2,4-dimetho-

  xylbenzaldehyde, 72 ml (0.66 mol) of benzylamine and 660 ml of methanol is stirred at room temperature for minutes, so that a clear solution is obtained from the suspension The solution is cooled with ice water and added little by little 13.2 g (0.33 mol)

borosodium hydride.

  The progress of the reaction is monitored by thin-layer chromatography (Stahl Kieselgel G, revealing solvent: 9: 1 mixture of benzene and acetone) and at the end of the reaction, the mixture is evaporated to dryness under vacuum. The residue is mixed with 300 ml of water and the aqueous mixture is

  extracted with 500 ml portions, 200 ml and 200 ml of ether.

  The ethereal solutions are combined, dried over magnesium sulphate, filtered and the filtrate is then added with 112 ml (0.66 mol) of diethyl bromomalonate and 33 ml (0.66 mol) of triethylamine. the ambient temperature for 2 to 3 days The separated triethylammonium bromide is filtered and then washed with ether The mother liquor is evaporated and the residue is recrystallized from 150 ml of ethanol The resulting crude product (210 g) is new recrystallized in 400 ml of ethanol

  and provides 197 g (72%) of N-benzyl-N- (2,4-dimethoxybenzyl) -

  amino-mnalonate diethyl; mp: 62-630 ° C (ethanol).

-1

IR (K Br): 1750/1725 cm, d.

  (b) 61.7 to (0.149 mole) of N-benzyl-N- (2,4-dimetho-

  Diethyl xybenzyl) -amino malonate, prepared according to item a) of Method I, are hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of approximately 20 g of

  catalyst consisting of palladium on charcoal

  The filtrate is filtered and the filtrate is evaporated. 47.1 g (97%) of diethyl (2,4-dimethoxybenzylamino) -malonate are collected. The product can be converted into its hydrochloride by reaction with hydrochloric acid. 122-124 ° C. after recrystallization from ethyl acetate. Analysis: Calculated for C 16 H 24 C 1 NO 6 (361.82): C, 53.11%; H: 6.69%, Cl: 9.80%; 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.

  1 H NMR (CD C 13): 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 mole) of (2,4-dimethoxy)

  diethyl benzylamino) -malonate, prepared according to item b) of Method I, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 mol) of diketene, is boiled for 0.5 hour The solvent, glacial acetic acid, is distilled under vacuum on a water bath of water and the oily residue is triturated with 150 ml of water The resulting crystalline substance is dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether We collected

  29.6 g (60%) of N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-

  dioxo-2,2-pyrrolidine dicarboxylate and / or

tautomer, p: 106-107C

  Analysis: Value 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 (K Br): 3400, 2950, 2850, 1730 (1740, sh), 1710 cm -1 IR (K Br): 3400, 2950, 2850, 1730 (1740, sh), 1710 cm H NMR (M. CDC 13): 6 = 1 1 (t, 3H), 1 17 (t, 3H), 1 52 (s,% 3H), 28 (<0 1H), 265 (broad s, 2 H), 37 (s, 6H), 3.8-4 (m, 4H), 67 (broad s, 2H), 6-25-6 (m) ± 7 0-7.

(m, 3H) ppm.

  d) 20.5 g (50 mmol) of the product prepared from

  the method described in point c) of Method I in addition to

  The solution is dissolved in 50 ml of anhydrous ether and a solution of 3.45 g (150 mmol) of sodium metal in 100 ml of anhydrous ethanol and a solution of 12.7 g (50 mmol) of iodine in 150 ml. ml of anhydrous ether, from two dropping funnels, to the vigorously stirred suspension and cooled with ice water. Then, 5 g of sodium hydrosulphite, dissolved in

  ml of a saturated aqueous solution of sodium chloride.

  The mixture is introduced into a separating funnel and 60 ml

  of water are added to dissolve the separated mineral salts.

  The organic phase is removed, dried over magnesium sulphate, filtered and the filtrate is evaporated. The oily residue, weighing 18.5 g, is crystallized in 30 ml of

  2-propanol There are obtained: 10 9 g (54%) of 3-acetyl-1- (2,4-

  dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate

  diethyl; 84-85 ° C (2-propanol).

  Analysis: Calculated Values for C 20 H 25 NO 8 1407 41):

C: 58.96%, H: 6.19%, N: 3144%;

"found:

C: 58.99%, H: 6.04%, N: 3.57%.

  1 H NMR (CDCl3): δ = 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) 179 ml (206 g, 1.452 mol) of boron trifluoride-diethyl etherate were added dropwise to a vigorously stirred solution of 179 g (0.484 mol) of

  3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine

  diethyl dicarboxylate and 107 ml (120 g, 1.936 moles) of ethylene glycol in 500 ml of anhydrous dioxane while cooling with ice water is provided. The reaction mixture is allowed to stand at room temperature for a period of one hour. During which time 415 g (1.452 mol) of Na 2 CO 3, 10H 2 are slowly added to the stirred mixture and cooled with ice-water and the mixture is stirred for a further minute. 1 liter of ether and 1 liter of water are added and the phases are separated from each other. The aqueous phase is shaken twice with 500 ml portions of diethyl ether. The ether phase is dried over

  magnesium sulfate, filtered and the filtrate is evaporated.

  The residue is supplemented with 33.9 g (0.58 mol) of sodium chloride, 17.4 ml (0.968 mol) of water and 220 ml of dimethyl

  sulfoxide and the mixture is stirred on a 180 C oil bath.

  The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, solvent

  developer: 6: 4 mixture of benzene and ethyl acetate).

  At the end of the reaction, i.e. after about 15 hours, the mixture is poured into 1100 ml of saturated aqueous sodium chloride solution, the resulting mixture is shaken with 1000 ml, then twice with portions. 500 ml of diethyl ether The ether solutions are combined, decolorized with charcoal, dried over magnesium sulfate and the filtrate is evaporated to a final volume of about 200 ml This concentrated solution is cooled with ice water

  and provides 59 g (35%) of trans-1- (2,4-dimethoxybenzyl)

  3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine carboxylate

ethyl; P f: 95 C.

  f) A mixture of 0.5 g (1.2 mmol) of 3-acetyl-

  Diethyl 1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine-dicarboxylate prepared according to (d) above, 3 ml of anhydrous tetrahydrofuran and 0.53 g (3.6 mmol) of The mercaptoethanol is boiled for 4 hours, then 10 ml of water and 10 ml of chloroform are added to the reaction mixture. The organic phase is separated, washed with a 5% aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and the product separated from the filtrate by preparative thin-layer chromatography (adsorbent: Kieselgel 60 PF 254 + 366,

  developer mixture: 8: 2 mixture of toluene and acetone.

We obtain:

  0 030 g (53%) of 1- (2,4-dimethoxybenzyl) -3-

  (2-Methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azetidine

diethyl dicarboxylate.

  1 H NMR (CDCl3): δ = 0.8-1.55 (m, 6H), 1.72 + 1177 (d, 3H), 2.9 -3.4 (m, 2H), 3.75 (s, 6H),

  4.0-5.0 (m, 9H), 6 r (m, 2H) + 7 r 1 (d, 1H) ppm.

  g) A solution of 5.21 g (0.130 mol) of sodium hydroxide in 60 ml of water is added to a suspension of

  41.2 g (0 109 mol) of trans-1- (2,4-dimethoxybenzyl) -3- (2-

  ethyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate prepared in accordance with (e) above, in 50 ml ethanol with stirring and cooling with ice water and stirring is continued until a clear solution is obtained (approximately 20 minutes) 100 ml of water are added to the solution and the mixture is shaken with 100 ml of ether. The aqueous phase is acidified with water. = 1 with aqueous concentrated hydrochloric acid, then shaken rapidly with 100 ml, then

  twice with 50 ml portions of dichloromethane.

  The dichloromethane solutions are combined, dried

  on magnesium sulfate, filtered and the filtrate is evaporated.

  The oily residue is crystallized from a mixture of toluene and petroleum ether to provide 35 g (92%)

  trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-

  dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid; p f:

117-118C (toluene).

  Analysis: Calculated for C 17 H 21 NO 7 (351 35): C: 58 R 11%, H: 6.03%, N: 3; 99%; valuesFound:

C: 58; 17%, H: 6.30%, N: 4.24%

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

  1 H NMR (CDCl3): δ = 1 39 (s, 3H), 50 (d, 1H, J = 2.5 Hz), 3.77 (s, 3H), 3.79 (s). , 3H), 3.86 (d, 1H, J = 2.5Hz), 3196 (m, 4H), 4T 21 + 4156 (d, 2H, JAB = 15Hz), 6.44

  (m, 2H) + 7.15 (d, 1H, J = 10Hz), 7.58 (broad s, 1H) ppm.

  h) 7.3 ml (52.5 mmol) of triethylamine are

  added to a solution of 17 6 g (50 mmol) of trans-

  1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl)

  4-oxo-2-azetidinecarboxylic acid prepared according to item g) above, in 150 ml of anhydrous tetrahydrofuran, then 0 ml (52.5 mmol) of ethyl chloroformate are added to the mixture, cooled with The mixture is cooled to -15 ° C., stirred at this temperature for 20 minutes and the separated triethylamine salt is filtered at the same temperature under an argon atmosphere. A solution of mmoles of diazomethane in 230 ml of cold diethyl ether is added to the mixture. The mixture is stirred, allowed to warm to room temperature and after stirring for 2 hours, evaporated to dryness. The thick brown residue is dissolved.

  in 20 ml of benzene and the product is separated by chroma-

  column chromatography (adsorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0, 200 mm, eluting agent: 7: 2 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-azetidinone. Analysis: Value calculated for C 18 H 21 N

306 (375-37):

C: 57.59%, H: 5.64%;

  Found values C: 57.78%, H: 5; 39%.

IR (K Br): 2900, 2110, 1760 cm -1 IR (K Br): 2900, 2110, 1760 cm

  i) A mixture of 2.25 g (6 mmol) of trans-4-

  (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-

  dioxolan-2-yl) -2-azetidinone prepared in accordance with (h) above

  100 ml of peroxide-free tetrahydrofuran and 50 ml of water are irradiated for about 4 hours with a high-pressure mercury lamp (HPX 125) immersed in a Pyrex reactor under an argon atmosphere. is evaporated under vacuum to a final volume of 50 ml and the concentrate is diluted with water to 130 ml 2.4 ml of a 10% aqueous solution of sodium hydroxide is added to the aqueous mixture and the alkaline mixture is washed at three

  times with 20 ml portions of dichloromethane.

  Then, the aqueous phase is acidified at pH = 2 with concentrated aqueous hydrochloric acid. The acid solution is extracted three times with 20 ml portions of dichloromethane. The extracts are combined, dried over magnesium sulphate and filtered. and the filtrate is evaporated to dryness. The residue is crystallized in ether.

  1.82 g (83%) of trans-1- (2,4-dimethoxybenzyl) -3-

  (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidin 11-acetic acid

mp: 124C (ether).

  Analysis: Calculated for C 18 H 23 N 07 (365.37): C, 59.17%, H: 6134%, N: 3, 83%;

  Found values C: 59 22%, H: 6.49%, N: 4.07%.

  IR (K Br): 3500-2300, 2900, 1730, 1700 cm3) 3.05 g (15 L 75 mmol) of diphenyl diazomethane are added at room temperature to a solution

  stirred with 5.48 g (15 mmol) of trans-1- (2,4-dimethyl

  thoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-

  azetidinyl 7-acetic acid, prepared according to item i) of Method I, in 50 ml of dichloromethane When the evolution of nitrogen stops, a few drops of acetic acid are added to the mixture to destroy the excess of diphenyl diazomethane The solution is evaporated to dryness and the residue, weighing 6.77 g, is dissolved in 84 ml of acetonitrile. This solution is supplemented with 16.20 g (60 mmol) of potassium peroxydisulfate (K 25208), 21.60 g. (120 mmol) of disodium hydrogen phosphate monohydrate (Na 2 HPO 4, H 2 O) and 54 ml of water; the mixture is stirred vigorously for 4 hours, brought to boiling then cooled. The cold reaction mixture is filtered and the two phases of the filtrate are separated from each other. The aqueous phase is extracted three times with 30 ml portions. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The residue is dissolved in benzene and the solution is sent to a chromatography column (adsorbent: Kieselgel 60, O = 0 , 05 to 0.200 mm, eluent: benzene mixture 7: 2

  and acetone) to obtain 2.68 g (47%) of trans-E 3-

  (2-Methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-7-acetate

  benzhydryl; p: 130 C (ethanol).

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

  1 H NMR (CDCl3): δ = 1139 (s, 3H), 263 (dd, 2H, J = 4, 4Hz), 2; 89 (dd, 2H, J = 9.1Hz), 97 (m, 5H), 6; 12

  (s, 1H), 6.9 (s, 1H), 7.28 (s, 10H) ppm.

  Analysis: Calculated for C 22 H 23 NO 5 (387 41):

C: 69.27%, H: 608%, N: 677%;

  Found values C: 69715%, H: 6.20%, N: 3/55%.

  (k) A mixture of 3.80 g (10 mmol) of

  E 23- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl 7 benzhydryl acetate, 0.4 g of an anhydrous catalyst consisting of 8% palladium on charcoal and 50 ml of anhydrous ethanol is stirred under an atmosphere of hydrogen The absorption of hydrogen stops after 2 hours The catalyst is filtered and washed with 10 ml of anhydrous ethanol The filtrate is evaporated on a 30 ml water bath -400 C, the residue is washed three times

  with 20 ml portions of ether and the liquid is decanted.

  20 g (94%) of trans-3- (2-methyl)

  1,3-dioxolan-2-yl) -4-oxo-2-azétidinylt-acetic acid; p f:

126-129 C.

  Analysis: Calculated for C 9 H 13 NO 5 (215%): N: 51%;

found values N: 6 34%.

  IR (K Br): 3500-2300, 3350, 2900 1730, 1700 cm -1.

  1) A mixture of 2.15 g (10 mmol) of trans-acid

  3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-acetic acid prepared according to item (k) of Method I, 1.82 g (11 mmol) of carbonyl di % and 60 ml of anhydrous tetrahydrofuran is stirred for 30 minutes. 1.58 g (11 mmol) of ethyl malonate-magnesium are added to the solution and the reaction mixture is stirred at room temperature for 2 hours. The mixture is evaporated. under vacuum, the residue is supplemented with 180 ml of dichloromethane and 0.5N aqueous hydrochloric acid, and this mixture is stirred for a few minutes and the two phases are separated from each other The aqueous phase is extracted at three

  repeated with 30 ml fractions of dichloromethane.

  The organic phases are combined, washed twice with portions of 20 ml of aqueous 3% sodium carbonate solution, dried over magnesium sulphate, filtered and the filtrate is evaporated to dryness. 2.02 g (71%) are collected. ) Trans-4-J 3- (2-methyl-1,3-dioxolan-2-yl)

  Ethyl 4-oxo-2-azetidinyl-3-oxo-butanoate; 65-68 ° C (ether)

  IR (K Br): 3220, 1770, 1735, 1720 cm -1 H NMR: 6 = 1 28 (t, 3H), 1 42 (s, 3H), 277 (dd) and 3 ( dd, 2H, J = 9 4 Hz and 36 Hz), 3 11 (d, 1H, J =

  2.6 Hz), 75-4 (m, 7H), 6 (s, 1H) ppm.

  m) 0.69 ml (5.0 mmol) of triethylamine and 0.986 g (5.0 mmol) of tosyl azide are added to a solution of

  1.426 g (50 mmol) of trans-4-1 3- (2-methyl-1,3-dioxolan-2-

  ethyl yl) -4-oxo-2-azetidinyl-3-oxo-butanoate, prepared according to step 1) of Method I, in 15 ml of anhydrous acetonitrile, with cooling with ice The solution is left to warm to room temperature in three hours with stirring The solution is evaporated to dryness, the residue is

  dissolved in benzene and the solution is treated by chroma-

  columnography (adsorbent: 100 g of Kieselgel 60, O = 0.063 to 0, 200 mm, 7: 2 mixture of benzene and

  acetone) 1.12 g (72%) of 2-diazo-4-Ltrans-3 were collected.

  (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-3-oxo

Ethyl butanoate.

  -1 IR (film: 3250, 1750, 1710, 1630 cm 1 H NMR: 6 = 1 36 (t, 3H), 1 42 (s, 3H), 2 96 and 44 Idd, 2H, J = 9 4 Hz and 36 Hz), 75-4 (m, 5 H), 4 33

(q, 2H), 6.88 (s, 1H) ppm.

  n) Dirhodium tetraacetate t kh 2 (O Ac) 4, 2THF 7 is added in small portions to a boiling solution of

  1.425 g (4.0 mmol) of 2-diazo-4-ltrans-3- (2-methyl-1-l, 3-

  ethyl dioxolan-2-yl) -4-oxo-2-azetidinyl-3-oxo-butanoate, prepared according to item m) of Method I, in 10 ml of benzene until the starting material has completely reacted (this requires about 0.03 g of rhodium salt) The reaction mixture is filtered through a pad of Celite and the filtrate is evaporated. 13 g (100%) of 6- (2-methyl) are collected.

  -1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo-3-O-heptane

  Ethyl 2-carboxylate: mp: 109.degree.

  IR (K Br): 1750, 1735 cm -1 H NMR: 6 = 1 (t, 3H, J = 74Hz), 14 (s, 3H) 2.41 (dd, 1H, Jgem = 19 Hz, Jvic = 75 Hz), 290 (dd, 1 H), Jgem = 19 5 Hz, Jvic = 70 Hz), 43 (d, 1 H, J = 2.4 Hz), 3.97- 4 (m, 5H), 42 (q, 2H, J = 74Hz), 46 (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 is stirred at room temperature for 2 days. The resulting product is triturated with 100 ml of diethyl ether, the separated 4-methoxy-anisidine hydrobromide is filtered and washed with a small amount of diethyl ether. The mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13 g (47%) of (4-methoxyanilino) are obtained

  diethylmalonate: mp: 64-65 ° C (ethanol).

  Analysis: Calculated for C 14 H 19 NO 5 (281 31):

C: 59 77%, H: 61%, N: 49%;

  Value V found C: 59 99%, H: 97%, N 25%.

  IR (K Br): 3300, 1775, 1725 cm -1 H NMR (CDCl3): 6 = 1 23 (t, 6H, J = 72Hz), 36 (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 = 9Hz) ppm.

  b) A mixture of 11.2 g (0.04 mole) of (4-methoxy)

  anilino) -diethyl malonate, prepared according to item a) of Method II, 15 ml of glacial acetic acid and 4 g (3.7 ml, 0.048 mol) of diketene is boiled for 0.5 hour The solution is evaporated under vacuum, the oily residue is triturated with diethyl ether and the solid

  is filtered and separated. 10 g (72%) of 1- (4-

  methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine

  diethyl dicarboxylate and / or its tautomer; p f:

136-137 ° C (ethyl acetate).

  Analysis: Calculated values for C 18 H 23 NO 7 (365 38):

C: 59 17%, H: 6 39% N: 833%;

  Found C: 58 98%, H: 6 90%, N: 404%.

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

  1 H NMR (CD C 13): 6 = 107 (t, 3H, J = 72 Hz), 128 (t, 3H, J = 72 Hz), 158 (s, 3H), 76 (s, 2H), 36 (s, 1H), 376 (s, 3H), 41 (q, 2H, J = 72Hz), 42 (q, 2H, J = 7.2 Hz),

  6.7 (2H) + 70 (2H, AA 'BB', J = 9Hz) ppm.

  c) 9.1 g (0 025 mole) of diethyl 1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate, prepared according to item b) of the Method II, are suspended in 50 ml of anhydrous diethyl ether and a solution of 1.72 g of sodium metal in 30 ml of anhydrous ethanol and a solution of 6.35 g (0.025 mol) of The mixture is poured into 100 ml of saturated aqueous sodium chloride solution and 2 g sodium hydrosulfite and 2 ml of glacial acetic acid are added. The ether phase is separated and the

  aqueous phase is extracted three times with

  The ether phases are evaporated, dried over magnesium sulphate, filtered and the filtrate is evaporated. The oily residue is triturated with water.

  2-propanol to obtain 6 2 g (68%) of 3-acetyl-1- (4-methoxy)

  xyphenyl) -4-oxo-2,2-azetidine-diethyl dicarboxylate

  crystalline; p: 70-71 ° C (ethanol).

  Analysis: Calculated values for C 18 H 21 NO 7 (363 38):

C: 59 50%, H: 82%, N: 85%;

  Found C: 59 04%, H: 84%, N: 408%, IR (K Br): 1760, 1735, 1720 cm H NMR (CDCl3): d = 1 (t, 3H) , J = 72 Hz), 22 (t, 3H, J = 72 Hz), 23 (s, 3H), 37 (s, 3H), 17 (q, 2H, J); = 7 2 Hz), 4 19 (q, 2 H, J = 7 2 Hz), 47 (s, 1 H), 6 7

  (2H) + 31 (2H, AA ', BB', J = 9Hz) ppm.

  d) 6 g (0 0165 mol) of 3-acetyl-1- (4-methoxyphenyl) -

  Diethyl 4-oxo-2,2-azetidine-dicarboxylate, prepared according to item c) of Method II, are dissolved in 20 ml of

  dry dioxane and 4.1 g (3.75 ml, 0.066 mole) of ethylene glycol.

  7.1 g (6.3 ml, 0.5 mol) of boron trifluoride-diethyl etherate complex are added dropwise to the stirred and ice-cooled solution and the reaction mixture is stirred for 2 hours. additional hours at room temperature The solution is basified with a saturated aqueous solution of sodium hydrogen carbonate, then added with 100 ml of water and the mixture is extracted three times with 50 ml portions of diethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is triturated with diethyl ether to obtain 6 g (89%) of 3- (2-methyl-1,3-dioxolan-2- crystalline diethyl yl) (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate;

mp: 82-83 ° C (ethanol).

  Analysis: Values calculated for C 20 H 25 N 08 (407 43):

C: 58 96%, H: 18%, N: 44%;

  Found values C: 58 70%, H: 688, N: 633.

  IR (K Br): 1740 cm (broad) H NMR (CDCl3): δ = 17 (t, 3H, J = 72 Hz); 1.26 (t, 3H), J = 72 Hz), 15 (s, 3H), 37 (s, 3H), 39 (m, 4H), 42 (m, 5H); , 67 (2H) + 734 (2H, AA ', BB', J 9 Hz) ppm

  e) 11 g (0.0245 mol) of 3- (2-methyl-1,3-dioxolane)

  Diethyl 2-yl) -1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate, prepared according to item d) of Method II, are dissolved in 20 ml of dimethyl sulfoxide, then 1, 72 g (0.0295 mol) of sodium chloride and 0.9 ml (0.049 mol) of water are added and the mixture is stirred at 175 ° C. until the reaction is completed. The progress of the reaction is monitored by chromatography. thin layer (adsorbent: Kieselgel G according to Stahl, revealing solvent: 6: 4 mixture of

benzene and ethyl acetate).

  The mixture is cooled, poured into 150 ml of a solution

  Saturated aqueous solution of sodium chloride and extracted three times with 50 ml portions of diethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The resulting oily residue, weighing 6 g is dissolved in 25 ml of 96% ethanol, then added with a solution of 0.72 g (0.018 mol) of sodium hydroxide in 10 ml of water, with cooling with ice water. The mixture is It is stirred for 0.5 hours, then diluted with 50 ml of water and washed twice with 25 ml portions of dichloromethane. The aqueous phase is acidified to pH = 1 with acylated concentrated hydrochloric acid and then extracted three times with portions of 25 ml of dichloromethane The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is

  The oily residue is crystallized with benzene.

  4 g (54%) of trans-3- (2-methyl-1,3-dioxolan) acid are collected

  -2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinecarboxylic acid.

  Analysis: Calculated for C 15 H 17 NO 6 (307 32):

C: 58 63%, H: 57%, N: 466%;

  Found values C: 58 40%, H: 80%, N: 466%.

  IR (K Br): 3400-2700, 1750 (broad) cm 1 H NMR (CDCl 3): 6 = 1 (s, 3H), 37 (d, 1H, J = 25 Hz), 3 76 (s, 3H), 40 (m, 4H), 438 (d, 1H, J = 25 Hz),

  6.82 (2H) + 7 (2H, AA ', BB', J = 95Hz), 9 (s, 1H) ppm.

  f) 1.11 g (155 ml, 100 mmol) of anhydrous triethylamine is added to a solution of 3 g (0.01 mol) of a compound prepared according to e) of Method II, in ml of anhydrous tetrahydrofuran The solution is cooled to -15 ° C. and 1.2 g (1.06 ml, 0.01 mol) of ethyl chloroformate are added dropwise with stirring.

  minutes of stirring the separated salt is filtered under

  of nitrogen and a solution of 4.8 g (0.025 mol) of diazomethane in diethyl ether is added to

  filtrate at room temperature After 2 hours of stirring

  The excess diazomethane is decomposed with acetic acid and the solution is evaporated under vacuum. The oily residue slowly crystallizes. 3 g (90%) of trans-4- (diazoacetyl) -3- (2-methyl) are obtained. -1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone; p f: 95-96 C

(benzene and ether).

  IR (K Br): 2200, 1760, 1640 cm H NMR (CDCl3): δ = 150 (s, 3H), 51 (d, 1H, J = 26Hz), 375 ( s, 3H), 405 (m, 4H), 41 (d, 1HJ = 2.6Hz), 47 (s, 1H), 68 (2H) + 7 (2H, AA). ', BB', J =

9 Hz) ppm.

  g) 3 v 3 g (0.01 mol) of trans-4- (diazoacetyl) -3-

  (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azole

  tidinone prepared according to item f) of Method II, are dissolved in a mixture of 50 ml of water and 100 ml of tetrahydrofuran. The mixture is irradiated with a fluorescent lamp.

  mercury at high pressure in a photoreactor under atmospheric pressure

  nitrogen (the reaction is carried out at room temperature

  ambient) and the progress of the reaction is followed by

  Thin-film chemistry (adsorbent: Stahl Kieselgel G, developer solvent: 7: 1 mixture of benzene and

  When the reaction is complete, the tetrahydrofuran

  furan is distilled under vacuum, the residue is basified with a 20% aqueous solution of sodium hydroxide and the solution is washed twice with portions of 1 ml of dichloromethane The aqueous phase is acidified to DH = 1-2 with concentrated aqueous hydrochloric acid, then extracted three times with 20 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is filtered off.

  is evaporated. 1.6 g (50%) of Ztrans-3- acid are obtained.

  (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo

2-azetidin 17-acetic acid.

  Analysis: Calculated values nour C 16 H 19 N 06 (321 33):

C: 59 80%, H: 59%, N: 36%,

  Found C: 59 60%, H: 5.76%, N: 4.08%.

  IR (film): 3500-2500, 1760-1700 cm-1. h) 1.0 g (3.12 mmol) of the prepared compound is dissolved

  according to item g) of Method II, in 10 ml of dichloro-

  methane and a solution of 0.53 g is added dropwise

  (3.12 moles) of diphenyl diazomethane in 10 ml of dichloromethane

  romethane with stirring at room temperature When the gas evolution stops, the solution is evaporated under

  Vacuum gives 1 45 g (98%) of trans-r 3- (2-methyl)

  1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl

-benzyl acetate.

  Analysis: Calculated for C 29 H 29 NO 6 (487.55):

C: 71 44%, H: 99%, N: 87%;

  Found C: 71 13%, H: 6 21%, N: 2 93%.

  1 H NMR (CDCl3): 6 = 1 (s, 3 u), 27-3 (m, 2H), 38 (d, 1H, J = 25 Hz), 372 (s). , 3H), 38-4-1 (m, 4H),

  4.1-4 (m, 1H), 65 (s, 1H), 67-7 (m, 14H) ppm.

  i) 0; 28 g (0.65 mmol of trans - / - 3- (2-methyl-1,3-

  dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl 7-

  benzhydryl acetate, prepared according to item h) of Method II, is dissolved in 2 ml of acetone and a solution of 0.9 g (1.6 mmol) of ceric ammonium nitrate Ce (NH 4) 2 (No. 3) in 2 ml of% aqueous sulfuric acid is added dropwise to the stirred solution at room temperature.

  room temperature The reaction mixture is agitated

  2 minutes, then neutralized with precau-

  The mixture is extracted three times with 4 ml portions of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is filtered off. evaporated under vacuum The oily residue is purified by preparative thin layer chromatography (adsorbent: Kieselgel 60, O = 0.050 ± 0.200 mm, eluent, 7: 2 mixture of benzene and acetone) to obtain 0 06 g (30%) trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-benzhydryl acetate. This compound is identical to that prepared in the manner described in item (j) of Method I. The resulting product can be converted to the desired starting material according to the procedure described in items (k) to (n) of the Method I. Method III

  a) A mixture of 38 g (0.152 mol) of aniline

  Diethyl malonate DR Blank: Ber 31, 1815 (18983, 38 ml of glacial acetic acid and 15.3 g (13.9 ml, 0.182 mol) of diketene, is heated to boiling for 0.5 hour Acetic acid is evaporated under vacuum on a water bath and the oily residue is crystallized by trituration

  with ether 36.5 g (72%) of N-phenyl-3 are obtained.

  diethyl hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer; p: 98-99 ° C (ethyl acetate

and petroleum ether).

  Analysis: Calculated for C 17 H 21 NO 6 (335.35):

C: 60 88%, H: 61%, N: 18%;

  Found values C: 60 83%, H: 6 15%, N: 43%.

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

  1 H NMR (CDCl3): δ = 1 O2 (t, 3H), ¹3 (t, 3H), 16 (s, 3H), 28 (s, 3H), 36 (broad , 1H), 4-4 45 (m, 4H), 7 2

(s, 5H) ppm.

  b) 50 g (0.149 mol) of N-phenyl-3-hydroxy-3-methyl-

  Diethyloxo-2,2-pyrrolidine-dicarboxylate, prepared according to item a) of Method III, are added to a solution of 10.2 g (0.447 mol) of sodium metal in 250 ml of anhydrous ethanol, then a solution of 37.9 g (0.149 mol) of iodine in 200 ml of anhydrous ether is added with vigorous stirring. When the reaction is complete, 8.5 ml (8.9 g, 0.149 mol) of the mixture are added to the mixture. glacial acetic acid, 200 ml of water and 100 ml of ether; the organic phase is separated and the aqueous phase is extracted with 100 ml of ether. The ethereal phases are combined, dried

  on magnesium sulfate, filtered and the filtrate is evaporated.

  The oily residue is crystallized in 50 ml of 2-propanol

  to obtain 31 g (62%) of 3-acetyl-1-phenyl-4-oxo-2,2-

  azetidine-diethyl dicarboxylate, p; 55-56 C (2-propanol) Analysis: Calculated for C 17 H 19 NO 6:

C: 61%, H: 75%, N: 20%;

  Found C: 61 38%, H: 89%, N: 24%.

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

  1 H NMR (CDCl3): δ = 12 (t, 6H), 23 (s, 3H),

  4.25 (q, 4H), 45 (s, 1H), 70- (m, 5H) ppm.

  c) 28 5 g (0.085 mol) of 3-acetyl-1-phenyl-4-

  diethyl oxo-2,2-azetidine-dicarboxylate, prepared according to item d) of Method III, are dissolved in a mixture

  90 ml of anhydrous dioxane and 21 g (18.8 ml, 0.34 mole) of ethyl

  glycol and then 36.5 g (31.5 ml, 0.255 moles) of boron trifluoride-diethyl etherate complex are added dropwise to the vigorously stirred solution and cooled with ice-water. The solution is agitated.

  2 hours at room temperature, then neutral

  The neutral solution is diluted with 100 ml of water and then extracted three times with 50 ml portions of diethyl ether. The organic phases are combined, dried over magnesium sulphate and filtered. and the filtrate is evaporated under vacuum The oily residue is crystallized by trituration with

  of the ether 28.5 g (90%) of 1-phenyl-3- (2-methyl)

  Diethyl 1,3-dioxolan-2-yl) -4-oxoazetidine-dicarboxylate; m.p .: 59 61 C (gasoline) Analysis: Calculated for C 19 H 23 NO 7:

C: 60 47%, H: 614%, N: 71%,

  Found C: 60 74%, H: 6 21%, N: 79%.

  -1 IR (K Br): 1770, 1740 cm -1 H NMR (CD 13): 6 = 1 18 (t, 3H, J = 7 2 Hz), 1 24 (t, 3H, J = 7 Hz) ), 1, 51 (s, 3H), 392 (m, 4H), 43 (m, 5H),

7.2 (m, 5H) ppm.

  d) A mixture of 28.5 g (0.075 mole) of 1-phenyl-

  3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine dicarboxyl

  diethylate, prepared according to item c) of Method III / 44 ml of dimethyl sulfoxide, 5.6 g (0.1 mole) of sodium chloride and 3.05 ml (0.17 mole) of water is The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, revealing solvent: 6: 4 mixture of benzene and ethyl acetate). The solution is poured into 200 ml of a saturated aqueous solution of sodium chloride and extracted three times with

  150 ml portions of diethyl ether. The organic phases

  The resulting oily residue (16.4 g) is dissolved in 100 ml of ethanol and a solution of 2.15 g (0.054 mole) of sodium hydroxide solution is added. sodium hydroxide in 30 ml of water is added to this stirred mixture and cooled with an ice-water bath. After stirring for 0.5 hour, the mixture is diluted with 150 ml of water and extracted three times with portions of water. 20 ml of diethyl ether The aqueous phase is acidified to pH = 1 with aqueous concentrated hydrochloric acid and then extracted three times with portions of 50 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated The oily residue is crystallized

  in benzene to obtain 12 g (56%) of trans-l-

  phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine

  carboxylic acid; 165 C (benzene).

  Analysis: Values calculated for C 14 H 15 N 05 (277 27):

C: 60 64%, H: 45%, N: 055%,

  Found C: 60 64%, H: 72%, N: 49%.

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

  1 H NMR (CDCl3): δ = 1.5 (s, 3H), 69 (d, 1H, J = 3Hz), 40 (m, 4H), 42 (d, 1H, J); = 3 Hz), 73 (m, 5H);

7.55 (s, 1H) ppm.

  e) 13.8 g (0.05 mol) of trans-1-phenyl-3- acid

  (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid prepared according to item d) of Method III are dissolved in 100 ml of anhydrous tetrahydrofuran and 5.55 g ( 7.7 ml 0.055 mol) of ethyl chloroformate are added to the solution at -15 ° C. After stirring for 20 minutes, the separated salt is filtered under a nitrogen atmosphere and an ethereal solution of 22.6 g (0.15 g) is added. mole) of diazomethane is added

to the filtrate with stirring.

  When gas evolution stops, the excess diazomethane is decomposed with glacial acetic acid and the solution is evaporated. The oily residue is triturated with ether to obtain 11.5 g (77%).

  trans-4- (diazoacetyl) -1-phenyl-3- (2-methyl-11,3-dioxolan)

  Crystalline 2-yl) azetidinone; p: 96-97 C (benzene and

ether).

  IR (K Br): 2150, 1760, 1635 cm -1 H NMR (CDCl3): 6 = 150 (s, 3H), 35 (d, 1H, J = 26Hz), 350 (m, 4H), 434 (d, 1H, J = 26Hz),

45 (s, 1H), 7 (m, 5H) ppm.

  f) 3.8 g (0.0126 mol) of trans-4- (diazoacetyl) -

  1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone prepared according to item e) of Method III are dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml of water and the solution is irradiated with a high-pressure mercury lamp in a photoreactor at room temperature under a nitrogen atmosphere The progress of the reaction is monitored by thin-layer chromatography (adsorbent: Kieselgel G according to Stahl; developer: 7: 1 mixture of benzene and acetone) At the end of the reaction, the tetrahydrofuran is evaporated under vacuum, then the residue is basified with a 20% aqueous solution of sodium hydroxide and the alkaline solution is washed. three times with 15 ml portions of dichloromethane The aqueous phase is acidified to pH = 1-2 with aqueous concentrated hydrochloric acid and then extracted three times with 20 ml portions of dichloromethane The organic phases are combined dried on sulphate of agnesium, filtered and the filtrate is evaporated The oily residue is triturated

  with ether to obtain 1.8 g (50%) of acid / trans-1

  phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl 7-.

  crystalline acetic acid; 128-129 ° C (ethanol). Analysis: values calculated for C 15 H 17 NO 5 (291 29):

C: 6200%, H: 88%, N: 822%;

  Found C: 61 75%, H: 86%, N: 088%.

  -1 IR (K Br): 1760, 1740 cm H NMR (CDCl3): 6 = 148 (s, 3H), 265 (dd, 1H, Jgem = 15Hz, Jvic = 8Hz) +3 12 (dd, 1H, Jgem = 15 Hz,

  Jvic = 8 Hz), 47 (d, 1H, J = 25 Hz), 398 (m, 4H), 4.

  (m, 1H), 73 (m, 5H), 33 (broad s, 1H) ppm.

  g) 0.81 ml of concentrated nitric acid (p = 1.5), with constant stirring and with cooling with ice, is added dropwise to 3 ml of acetic anhydride, so that the temperature of the mixture does not rise above + 5 C The resulting nitrating mixture is added dropwise at -5 C to a stirred solution

  2.9 g (0.01 mol) of trans-1-phenyl-3- (2-methyl)

  1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-7-acetic acid, prepared according to item f) of Method III, in 20 ml of anhydrous dichloromethane After one hour of stirring, the The solution is poured into ice water and the phases are separated from each other. The aqueous phase is extracted twice with 25 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulphate and filtered. and the filtrate is evaporated in vacuo The oily residue is triturated with ether to give 1.95 g (58%) of trans-3- (2-methyl-1,3-dioxolan-2-yl) acid. Crystalline -1- (2-nitrophenyl) -4-oxo-2-azetidinyl] acetic acid;

mp: 175-176 ° C (ethanol).

  Analysis: Values calculated for C 15 H 16 N 20 (336 33): 1

C: 53 57%, H: 79%, N: 33%;

  Found values C: 53 31%, H: 688, N: 8 21%.

  -1 IR (K Br): 3600-2900, 1740, 1540, 1340 cm

  h) 0.336 g (lmmole) of _-trans-3- (2-methyl-1,3-

  dioxolan-2-yl) -1- (2-nitrophenyl) -4-oxo-2-azetidinyl-7-acetic acid, prepared according to item g) of Method III, is dissolved in ml of methanol and the solution is hydrogenated under pressure atmospheric, in the presence of 0.05 g of a catalyst consisting of palladium on charcoal The catalyst is filtered and the filtrate is evaporated The oily residue is dissolved in

  ml of dichloromethane, 0.17 g (immole) of diphenyl diazo-

  methane is added and the mixture is stirred for 24 hours.

  Then, the mixture is evaporated to obtain 0 4 g (90%) of trans 1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl)

  Benzhydryl 4-oxo-2-azetidin 11-acetate.

IR (K Br); 1740, 1720 cm 1.

Mass spectrum: m / z: 472 (M +).

  i) 0.45 g (1 mmol) trans / 1- (2-aminophenyl)

  3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl

  benzhydryl acetate is dissolved in 2 ml of glacial acetic acid and a solution of 0.2 g (2 mmol) of chromium trioxide in 2 ml of glacial acetic acid and 0.2 ml of water is added dropwise to The mixture is stirred at room temperature for 3 hours, then poured into 10 ml of ethyl acetate and washed with a 5% aqueous solution of sodium hydrogen carbonate until the mixture is stirred at room temperature. The organic phase is dried over magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is purified by preparative chromatography N thin layer (adsorbent: Kieselgel 60 PF PF 254 + 366, developer solvent: mixture 7: 3 of benzene and

  acetone). 0.09 g (30%) of trans 3- (2-methyl)

  Benzhydryl 1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl J-acetate The physical constants of this compound are the same as those determined for the product prepared according to item j) of Method I. The resulting compound can be converted to the desired end-material according to the procedure described in items k) to n) of Method I. Method IV a) 0.364 g (2.2 mmol) of carbonyl diimidazole at 98% are added to a solution of 0.730 g (2 mmol)

  of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-

  dioxolan-2-yl) -4-oxo-2-azetidinyl-11-acetic acid in 10 ml of anhydrous tetrahydrofuran and the mixture is stirred for minutes. This solution is supplemented with 0.315 g (2.2 mmol) of the magnesium salt of the sodium malonate. The reaction mixture is evaporated, the shake is shaken with a 40 liter of cichlorohydrin and 40 ml of 0.5 N aqueous hydrochloric acid, and then the phases are separated from each other. The aqueous phase is extracted with 20 ml of dichloromethane. The organic phases are combined, washed twice with 10 ml portions of a 3% aqueous solution of sodium carbonate, dried over magnesium sulphate, filtered and filtered. filtrate

  is evaporated. 0 41 g (47%), trans-4-f 1 (2,4-

  dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-

  ethyl azetidinyl-3-oxo-butanoate.

IR (film): 1750, 1740, 1720 cm H NMR (CDCl3): δ = 26 (t, 3H), 19 (s, 3H), 2.2-3 (m, 5H) ), 65-445 (m, 14H), 6-25-6 and

7.05-7 (m, 3H) ppm.

  b) 0.69 ml (5.0 mmol) of triethyl amine and

  0.986 g (5.0 mmol) of tosyl azide are added to a solution.

  2.77 g (5.0 mmol) of trans-4 / T- (2,4-dimethoxy)

  henzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl 7

  Ethyl 3-oxo-butanoate, prepared in accordance with point (a) of

  M 4 ethod IV, in 15 ml of anhydrous acetonitrile under cooling.

  The solution is stirred for 3 hours, while being allowed to warm to room temperature. Then, the solution is evaporated to dryness and the residue is treated by column chromatography (adsorbent: Kieselgel 60, O = 0.063 to 100.degree. 0.200 mm, eluent: 7: 2 mixture of benzene and acetone) 1.41 g (61%) of 2-diazo4-trans - / - 1- (2,4-dimethoxybenzyl) -3- (2-methyl) are obtained -1,3 dioxolan-2-yl) -4-oxo2-azetidinyl

Ethyl 3-oxo-butanoate.

  IR (film): 2160, 1750, 1720, 1640 cm. (C) 4 g (20 mmol) of potassium persulfate (K 25208), 7.2 g (40 mmol) of monohydrated disodium hydrogen phosphate (Na 2 HPO). 4, H20) and 18 ml of water are added to a solution of 2.40 g (5.0 mmol) of a compound prepared according to item b) of Method IV, in 30 ml of acetonitrile and the mixture is boiled for hours The reaction mixture is cooled, filtered and

  the two phases of the filtrate are separated from each other.

  The aqueous phase is extracted three times with portions of 10 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The residue is treated by column chromatography (adsorbent: Kieselgel 60 , O = 0.063 to 0.200 mm, eluent: 7: 3 mixture of benzene and acetone) for

  obtain 0 56 g (36%) of 2-diazo-4-trans E-3- (2-methyl)

  1,3-dioxolan-2-yl) -4-oxo-2-azétidinylj-3-oxo-butanoate

  The physical constants of this compound are identically

  those of the product which is prepared according to item (m) of Method I The compound may be converted into the desired starting material according to the procedure described in item (n) of Method I. Method V A drop of dimethylformamide and 0.37 ml (5.0 mmol) of thionyl chloride to a solution

  stirred with 1.830 g (5.0 mmol) of acid / trans-1- (2,4-dimethoxy)

  xybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl

  acetic acid in 10 ml of dichloromethane while cooling

  with ice and stir the reaction mixture

  2 hours while cooling, add 1.7 ml

  of ethyl diazoacetate to the mixture and the stirring

  The solution is evaporated and the residue is treated by column chromatography (adsorbent: Kieselgel 60, O = 0.063).

  at 0.200 mm, eluent: 7: 2 mixture of benzene and acetylene

  This gives 0 17 g (73%) of 2-diazo-4-trans-ú 1-

  dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-

  Ethyl azetidinyl-3-oxo-butanoate The IR spectrum of this compound is identical to that of the compound prepared according to item b) of Method IV The compound can be converted to the starting material

  desired according to the procedure described in point c) of Method IV.

  Method VI a) 0.4 g (1.24 mmol) of acid are dissolved

  ftrans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -

  4-oxo-2-azetidinyl 7-acetic acid prepared according to item g) of Method II in 15 ml of anhydrous tetrahydrofuran

  and 0.22 g (1.36 mmol) of carbonyldiimidazole are added thereto.

  The resulting mixture is stirred at room temperature for about one hour. When the evolution of gas stops, 0.196 g (1.36 mmol) of the monoethyl malonate magnesium salt is added and stirring is continued for a period of one hour. hour The solution is evaporated, the residue is dissolved in 50 ml of dichloromethane and the solution is washed with 25 ml of aqueous hydrochloric acid

  2 N The aqueous mixture is extracted with 25 ml of dichloromethane

  methane The organic phases are combined, washed twice with 20 ml portions of an aqueous solution

  5% sodium carbonate, dried over magnesium sulphate

  sium, filtered and the filtrate is evaporated

  0.3 g (62%) of trans-4 3- (2-methyl-1,3-dioxolan-2-yl)

  Ethyl 1- (4-methoxyphenyl) -4-oxo-2-azetidinyl 7-3-oxo-butanoate. Analysis: Calculated for C 20 H 25 NO 7 (391 42):

C: 61 37%, H: 64%, N: 588%;

  Found values C: 61 20%, H: 59%, N: 72%.

IR (film): 1750 cm 1.

  b) 0.28 g (1.44 mmol) tosyl azide and 0.2 ml (1.44 mmol triethylamine) are added 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 anhydrous acetonitrile with cooling with ice or water. The reaction mixture is stirred at room temperature

  2 hours and the progress of the reaction is followed by chroma-

  Thin layer film (adsorbent, Kieselgel G according to Stahl, revealing solvent: 7: 3 mixture of benzene and

19002

  At the end of the reaction, the mixture is evaporated, the residue is dissolved in 40 ml of dichloromethane and the solution is washed until it has been freed from

  the acid, with 10 ml of a 40% aqueous solution of hydro-

  The organic phase is dried over magnesium sulphate, filtered and the filtrate is evaporated. The residue is purified by preparative chromatography in a thin layer (Kieselgel adsorbent 60).

  PF 254 + 366, eluting agent: 7: 3 mixture of benzene and

  tone) 0.25 g (36%) of 2-diazo-4- / trans-3 are obtained

  (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo

  Ethyl 2-azetidinyl-3-oxo-butanoate; mp: 131-132 ° C (ether). -1 IR (K Br); 2200, 1740, 1710, 1640 cm. Analysis: Values calculated for C 20 H 23 N 307 (417 41):

C: 57 55%, H: 55%, N: 107%;

  Found values C: 57.56%, H: 80%, N: 10.08%.

  c) 0.45 g (0.106 mmol) of the compound prepared according to item b) of Method VI is dissolved in 4.5 ml of acetone and a solution of 1.5 g is added dropwise to the stirred solution; (2.7 mmol) of ceric ammonium nitrate in 4.5 ml of 5% aqueous sulfuric acid. The reaction mixture is stirred for a further 5 minutes and then the yellow solution is neutralized with a 5% aqueous solution of carbonate. sodium acid, then extracted three times with 10 ml portions of ethyl acetate The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated The residue is purified as indicated in point Previous: 0.10 g (27%) of

  2-diazo-4-1-trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo

  Ethyl 2-azetidin 113-3-oxo-butanoate; the IR spectrum of this compound is identical to that of the substance

  prepared in accordance with the procedure of item (b) of Method IV.

  The resulting compound can be converted into

  desired starting point, according to the procedure of item n) of Method I.

Example 2

  3-Benzylthio-6- (2-methyl-1,3-dioxolan-2-yl)

  Ethyl 7-oxo-1-azabicyclo [7-3,2] ohept-2-ene-2-carboxymate.

  0.91 ml (4.4 mmol) of diphenyl phosphoryl chloride (Ph 203 PCl) is added to OC over a period of minutes to a stirred solution of 1.133 g (4.0 mmol) of (2-Methyl-1,3-dioxolan-2-yl) -3,7-dioxo-lazabicycloethyl 2,2-heptane-2-carboxymate and 0.61 ml (4.4

  mmol) of triethylamine in 10 ml of anhydrous acetonitrile.

  Then, 0.61 ml (4.4 mmol) of

  triethylamine, then 0.52 ml (4.4 mmol) of benzyl mercaptan

  The mixture is evaporated in vacuo and the residue is dissolved in 50 ml of dichloromethane and the solution is washed twice with 5 ml portions of a 3% aqueous solution. of sodium hydrogen carbonate, then three times with portions of 5 ml of water. The organic phase is dried over magnesium sulphate, filtered and the filtrate is evaporated. The oily residue weighing 1.0 g is treated by column chromatography. (adsorbent: Kieselgel 60, 0.063 to 0.200 mm, eluent: 7: 1 mixture of benzene and acetone) 0.90 g (58%) of the title compound is obtained;

mp = 109 C.

  IR (K Br): 1780, 1700 cm H NMR (CDCl3): 6 = 13 (t, 3H, J = 75 Hz), 2.87-3 (m, 2H), 33 ( d, 1H, J = 3Hz), 95-445 (m, 7H),

33 (s, 5H) ppm.

  13 C NMR (CDCl3): 1430, 2335, 3685, 40-28, 51-94,

  61.15, 65 18, 65 33, 67 15, 106 85, 124 4, 127 7, 128.69,

  128.88, 136 42, 145 93, 161 32, 173 91 ppm.

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

Exem Section 3

  3- (Formylaminoethylthio) -6- (2-methyl-1-l, 3-

  dioxolan-2-yl) -7-oxo-1-azabicyclo [3-hept-2-ene-2-

p-nitrobenzyl carboxylate.

  0.61 ml (4.4 mmol) of triethyl amine and then, over a period of 10 minutes, 0.91 mi (4.4 mmol) of diphenylphosphoryl chloride are added to 0 C, to a solution of

  stirred with 1.561 g (4.0 mmol) of 6- (2-methyl-1,3-dioxol)

  2-yl) -3,7-dioxo-1-azabicyclo [2] heptane-2-carboxylate

  of p-nitrobenzyl in 10 ml of anhydrous acetonitrile.

  The addition is continued, then another 0.61 ml (4.4 mmol) of triethylamine and 0.46 g (4.4 mmol) of N-formyl-cysteamine are added to the mixture at 0 ° C. After one hour of stirring. the mixture is evaporated under vacuum, the

  The residue is dissolved in 20 ml of dichloromethane and the solution

  The organic phase is washed with 10 ml of a 3% aqueous solution of sodium hydrogen carbonate and then twice with portions of ml of water. The organic phase is dried over magnesium sulphate, filtered and the filtrate is evaporated. column chromatography (adsorbent: Kieselgel, O = 0.063 to 0.200 mm, eluent: mixture 7, 3 of benzene and acetone) to obtain 1.05 g (64%) of the compound of which

  name is mentioned in the title; mp: 183 C (ether).

-1

  IR (K Br): 3330, 1750, 1680 shoulder, 1670 cm.

  1 H NMR (CD Ci 3) + DMSO-d 6): δ = 14 (s, 3H); 2.85-345 (m, 6H), 358 (d, 1H, J = 3Hz), 40-4 (m, 5H), 5.24-551 (d, 2H, JAB = 13). 8 Hz), 688 + 8 (d, 4H, JAB =

11 Hz), 8 16 (s, 1 H) ppnm.

  6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo

  p-nitrobenzyl azabicyclol 3,207 heptane-2-carboxylate, the starting material of the process described in Example 3,

  can be prepared from: A) Atrans-3- (2-methyl)

  1,3-dioxolan-2-yl) -4-oxo-2-azetidin 12-acetic acid, a substance prepared in the manner described in items a) to k) of Method I, items a) to i ) Method II, plus Method I (k), or Method III (a) through (c), and then Method I (k); or

  B ftrans-1- (2,4-dimethoxybenzyl) -3- (2-

  methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-acetic acid, a substance prepared according to item i) of Method I, or C Ztrans-3- (2-methyl-1) acid; 3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl / acetic acid, a substance prepared according to the procedure described in

q) Method II.

  Method (A) is carried out as follows: a) A mixture of 0.645 g (3.0 mmol) of acid

  trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl

  acetic acid, 0.535 g (3.3 mmol) of carbonyl diimidazole and ml of anhydrous tetrahydrofuran, is stirred at room temperature for 30 minutes, then 0.825 g (3.3 mmol) of the magnesium salt of pnitrobenzyl malonate is added to the mixture and the stirring is continued at ambient temperature for 2 hours. The mixture is left to stand for 16 hours and then evaporated under vacuum. The residue is shaken with a mixture of 50 ml of dichloromethane and 50 ml of acid.

  0.5 N aqueous hydrochloric acid and the organic phase is separated.

  The aqueous phase is extracted with 25 ml of dichloromethane.

  The organic solutions are combined, washed twice with 10 ml portions of a 3% aqueous solution of sodium carbonate, dried over magnesium sulphate, filtered and the filtrate is evaporated to give 0.730 g.

  (62 1%) trans-4-f- (2-methyl-1,3-dioxolan-2-yl) -4-oxo

  P-nitrobenzyl 2-azetidinyl 7-3-oxo-butanoate.

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

  b) 1.962 g (5.0 mmol) of the compound prepared according to item a) above, is dissolved in 15 ml of anhydrous acetonitrile, followed by 0.69 ml (5.0 mmol) of triethylamine and 0.985 g (5 mmol). 0 mmoles) of tosyl azide are added to the ice-cooled solution. After 5 minutes of addition, a crystalline substance separates. The mixture is stirred for 20 minutes, then the separated substance is filtered off and washed with ether. then dried (326 g, 634%) of 2-diazo-4-trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl. p-nitrobenzyl oxobutanoate; p f:

163-164 C.

  IR (K Br): 3220, 2160, 1750, 1710, 1630 cm -1 H NMR: = 1 41 (s, 3 HI / 2 98 (dd) and 34 (dd, 2H, J = 10 Hz and 4 Hz ), 3 18 Id, 1H, J = 24Hz), 3834 (m, 5H), 36 (s, 2H), 60 (s, 1H), 744 (d) and 26 (d, 4H,

AB, J = 9 Hz) ppm.

  c) A suspension of 1.673 g (4.0 mmol) of the compound prepared according to item b) above in 45 ml of anhydrous benzene is stirred and boiled, then 0.050 g of dirhodium tetraacetate -Rh 2 ( O Ac) 4 T 2THF is

  introduced in several portions After 10 minutes of ebul-

  The reaction mixture is cooled, the separated substance is dissolved in dichloromethane and the solution is filtered through a pad of celite. The filtrate is evaporated under vacuum, the residue is mixed with ether and the suspension is

  filtered. 1.32 g (84.6%) of 6- (2-methyl-1,3-

  dioxolan-2-yl) -3,7-dioxo-1-azabicyclo C-3 2 O-7-heptane-2

  p-nitrobenzyl carboxylate; p: 167 C.

1 IR (K Br): 1760 1535 c 1 n

  H NMR: = 1 4 b (s, 3 CH), 247 (dd, 1H, Jgem = 19 Hz, Jvic = 8 Hz), 292 (dd, 1H, Jgem = 19 Hz, Jvic = 8 Hz ), 3.46 (d, 1H, J = 24Hz), 40 (m, 5H), 45 (s, 1H),

  (D, 2H, JAB = 14Hz), 733 and 823 (d, 4H, JAB = 9Hz) ppm.

  Method B) is analogous to Methods IV or V (see Example 1), while Method C is analogous to Method VI (see Example 1). In both cases, 2-diazo-4- / p-nitrobenzyl trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl] -3-oxo-butanoate, the physical constants of which are identical to those of

  compound prepared in accordance with (b) of Method A).

  The resulting product can be converted to the desired starting material in the manner described in c) of Method A.

Example 4

  3- (Formylamino-ethylthio) -6- (2-methyl-1,3-

  dioxolan-2-yl) -7-oxo-1-azabicyclo [2,7] hept-2-ene-2-

sodium carboxylate.

  A suspension of 0.25 g of a catalyst constituting

  with 10% palladium on charcoal, in 70 ml

  2: 1 mixture of dioxane and water, is stirred in an atmosphere

  hydrogen at room temperature for 20 minutes,

  then a hot solution of 0.477 g (1.0 mnol) of 3- (formylamino)

  ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo Z 3 e 2 O O

  P-nitrobenzyl 2-ene-2-carboxylate prepared in the manner described in Example 3 in 30 ml of dioxane free of peroxide is added. The reaction mixture is stirred in an atmosphere of hydrogen for a further 3 hours and then added. a solution of 0.084 g (1.0 mmol) of sodium hydrogen carbonate in the minimum amount of water

  reaction mixture is filtered through a pad of Celite.

  The dioxane is evaporated under vacuum from the filtrate and the aqueous residue is extracted three times with 1 ml portions of dichloromethane. The aqueous phase is then evaporated under vacuum at room temperature.

  crystallises on cooling. The crystalline substance

  line is mixed with 6 ml of ethanol and the crystals are separated by filtration. 0.25 g (73%) of

  desired compound; p f 201 C (with decomposition).

  IR (K Br): 3420, 1770, (shoulder), 1760, 1690, -1 1610 cm H NMR (D 20): = 42 (s, 3H), 273 (m, 6H); )

  3.65 (d, 1H, J = 3Hz), 95-4 (m, 5H), 803 (s, 1H) ppm.

  As is apparent from the above, the invention is not limited to those of its modes of implementation, implementation and application which have just been described more explicitly; on the contrary, it embraces all the variants that may come to the mind of the technician in the

  subject matter, without departing from the scope, scope,

this invention.

Claims (11)

  Bicyclic compound, characterized in that it is represented by the following general formula (I): ## STR2 ## H 5 C C, (I) H O 0 COQ '   oy 1 and y 2 represent a detachable protecting group of the carbonyl radical, preferably a ketal group or a thioanalogue thereof, Q 'is a C 1 to B alkyl group, a substituted benzyl group, a hydrogen or an alkali metal ion, and R "is an optionally substituted hydrocarbon residue of   preferably a benzyl, 2-aminoethyl or 2-acylamino group.   ethyl. Compound according to claim 1, characterized   in that it is 3- (formylamino-ethylthio) -6- (2-methyl)   1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo [3.2.2] hept-2-ene 2-ethyl carboxylate.   Compound according to claim 1, characterized   in that it is 3-benzylthio-6- (2-methyl-1,3-dioxolan)   2-yl) -7-oxo-1-azabicyclo [3-O] hept-2-ene-2-carboxylate ethyl.   Compound according to claim 1, characterized   in that it is 3- (formylamino-ethylthio-6- (2-methyl)   1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo [322] hept-2-ene P-nitrobenzyl 2-carboxylate.   Compound according to claim 1, characterized   in that it is 3- (formylamino-ethylthio) -6- (2-methyl)   1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo, 3-20-hept-2-ene Sodium 2-carboxylate.   Process for the preparation of a novel bicyclic compound represented by the general formula (I) according to Claim 1, characterized in that: a) a compound represented by the following general formula (II) is treated: yl y 2 x / H H 3 CCC (I) 0 -COOQ 1 2   wherein Y and Y are as defined above and Q is a C 1-5 alkyl group or a substituted benzyl group, with a suitable O-acylating agent, preferably a sulfonyl or phosphoryl halide, and then a mercaptan, preferably with benzyl merceptan, cysteamine or an N acyl derivative thereof, in the presence of a tertiary amine and the resulting product of the general formula (I) is separated, where O 'is an alkyl group C 1 -C 5 or substituted benzyl; or, b) from a compound of general formula (I) obtained in step a), where R ", Y 1 and Y 2 are as defined above and Q 'is a substituted benzyl group, it eliminates By reduction and, if desired, converting the resulting carboxylic acid (Q '= H) to its alkali metal salt. 7. Process according to claim 6, characterized in that diphenylphosphoryl chloride is applied. as O-acylating agent.   Process according to claim 6, characterized in that N-formylcysteamine is applied as a   N-acyl derivative of cysteamine.   Process according to claim 6, characterized in that the substituted benzyl group is removed by catalytic hydrogenation.   Process according to Claim 6, characterized in that a free carboxylic acid is converted into its salt 1900 2   of alkali metal by reaction with a carbonate or carbonate alkali metal acid.   The process according to claim 6, for   preparation of 3- (formylaminoethylthio) -6- (2-methyl-1,3-   Ethyl dioxolan-2-yl) -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate, characterized in that 6- (2-methyl-1,3-dioxolan) is reacted with 2-yl)) - ethyl 3,7-dioxo-1-azabicyclo Z 73 2 O-heptane-2-carboxylate, in the presence of a tertiary amine, with an O-acylating agent, then with N-formyl-cysteamine.   The method according to claim 6 for the prepa-   3-Benzylthio-6- (2-methyl-1,3-dioxolan-2-yl) -7-   oxo-1-azabicyclo (-3 2 Q 7, hept-2-ene-2-carboxylic acid ethyl ester,   characterized in that the 6- (2-methyl-1,3-dioxolan) is reacted   Ethyl 2-yl) -3,7-dioxo-1-azabicyclo L-3 2 O 2 heptane-2-carboxylate, in the presence of a tertiary amine, with an agent   0-acylating, then with benzyl mercaptan.   13. Process according to claim 6 for the prepa-   of p-nitrobenzyl 3- (formylamino thylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-azabicyclo [2-methyl-2-ene-2-carboxylic acid, characterized in that p-nitrobenzyl 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo [2] heptane-2-carboxylate is reacted in the presence of a tertiary amine, with a 0-acylating agent, then with N-formyl-cysteamine.   The process according to claim 6 for the preparation of   3- (formylaminoethylthio) -6 (2-methyl-1,3-dioxolan)   2-yl) -7-oxo-1-azabicyclo [3-yl] hept-2-ene-2-carboxylate   of sodium, characterized in that 3- (formylamino)   ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo   C 3 2 O p-Nitrobenzyl ohèpt-2-ene-2-carboxylate, and then   convert it to its sodium salt.   Pharmaceutical composition, characterized in that it contains an effective amount of a compound represented by the general formula (I) or y 1 Y 2, Q 'and R "are such that defined in the claim.