LU84564A1 - NOVEL BICYCLIC COMPOUNDS AND PROCESS FOR PREPARING THEM - Google Patents

Description

1 - ‘'* 1 Λ *

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

The new compounds according to the present invention are represented by the general formula (I) below:

- "ï * f H H

LC -

I - (D

In which: 12 Y and Y form a detachable group protecting the carbonyl radical, preferably a ketal group or a thioanalogue thereof; Q 'is a ^ alkyl group. 5, a substituted benzyl group, a hydrogen atom or an alkali metal ion, and, v R "is an optionally substituted hydrocarbon residue, preferably a benzyl, 2-aminoethyl or 2-acylaminoethyl group.

The compounds of general formula (I) are new and effective analogues of thienamycin and with the exception of compounds in which Q1 is an alkyl group, they can also serve as intermediates in the synthesis of thienamycin.

Thienamycin, a broad spectrum antibiotic, was first prepared microbiologically (US Patent No. 3,950,357), then thereafter by chemical synthesis (German Patent No. 2,751,597).

The object of the present invention is to provide a new pathway for the synthesis of thienamycin and its analogs, whereby the backbone azetidinone and the side α-hydroxyethyl chain or a side chain which can be easily converted to the α-hydroxyethyl group , 2

X

* * are formed simultaneously in the first stage of the synthesis and the resulting key intermediate is then converted into the desired end product.

It has been found gu * by acylating a dialkyl malonate 5 of which the amino group is protected, with diketene, then reacting the resulting acylated product with iodine and an alkali metal alcoholate, an azetidinone compound is obtained. represented by the general formula (XIII) below: V-.

- 10 HjC-C-1- (cooz) 0 ^ · \ E (XIII) containing a side α-acetyl chain, which can be used as a key intermediate in the synthesis.

In the above formula, R represents a detachable group protecting the amido radical, preferably a benzyl group bearing one or more methoxy substituents ΊΧ or a phenyl group optionally bearing one or more methoxy substituents, and Z is a C alkyl group - c * î ad

The new intermediates of general formula (XIII) and their preparation are described in detail in the applicant's previous Hungarian patent application No. 2262/80. The preparation of these new intermediates 25 is also described in the examples of the present invention.

It has also been observed that before converting the intermediate of general formula (XIII) into thienamycin or its analogs, it is preferable to protect the ketone group of the lateral α-C-acetyl chain with a group, in particular a ketal group or a thioanalogue thereof, which can be removed in a later step of the synthesis. Ethylene glycol or a thioanalog thereof, such as mercaptoethanol, can be applied in a particularly preferred manner to form an ethylene-ketal r t 3 *, or protective hemithioketal. The resulting compound is represented by the general formula (XII) below: yl γ2 \ / 5 'H3C ~ c -, (C00Z) p I (XII) * - \

N R

"12 where Y and Y together form a group for the temporary protection of the carbonyl part, preferably an ethylenecetal group or a thioanalogue thereof and R and Z are as defined above, and it is then reacts with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide to obtain a compound represented by the general formula (XI) below:

γΐ y-2 h H

H ,,.-Θ '-! _ L' rn 20 "12 in which R, Y t Y and Z are as defined above.

The resulting compound of general formula (XI) is a mixture of cis and trans isomeæs. The isomers can be separated from each other by chromatography or by virtue of their different solubility. The separate trans isomer represented by the general formula (Xla) below:

y1 y2 H H

HO -V— | —yr0002 30 oJ-1 (Da)

^ R

- * "V

m ·· can be converted into the trans-carboxylic acid represented by the general formula (X) below: h *!

It

V

4 4

H H

HjC - C __! _ J ^ .OOOR

I · (X) 0iJ- by hydrolysis. 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 separate trans-carboxylic acid of general formula (X) is first treated with an activator for the carboxy group, then with diazomethane and the resulting compound represented by the general formula (IX) below: 15 h 5c ! y "2 | t C0C ™ 2 '™

R

20 is subjected to a Wolff transposition in the presence of water.

The resulting azetidinoacetic acid, represented by the general formula (VIII) below: yl y2

V y H H

u r r 1, ^ <J% 00CB

25 h 5 ° - o-1-r (VIII) oJ- can be converted into the desired end products, of general formula (I), in several ways.

In the general formulas (X), (IX) and (VIII), r 12 Y, Y and R are as defined above.

According to one of the methods used to carry out the subsequent conversion, a compound of general formula (VIII), where R is a phenyl group, is nitrated, then Μ 1 5

[J

> reduced to provide a compound represented by the general formula (Villa) below: yl y2

's /? ? ^ .CHpCOÔH

5 HjC - C -—-- γ '2 Q -? - H f (Villa): X) 10 1 2 in which Y and Y are as defined above and A is a nitro group, then an amino group. The resulting compound of general formula (Villa) is then esterified according to a known method to obtain a compound of general formula (VIIa) below:

\ X / H H

H ^ C - C _ | _L · - CH2C00X

0J

I (VIIa) 12 in which Y, Y and A are as defined above and X is a selectively detachable esterifying group, preferably an arylmethyl or diarylmethyl group.

The aminophenyl protecting group of the resulting compound of general formula (Vlla) is then removed by oxidation, preferably with chromium trioxide in the presence of glacial acetic acid and the resulting compound, represented by general formula (VI) ci -after:

• Ï *, Y2 H H

h, c -c__ p ch2coox V (VI) oJ- »H«

V

r; 6 Λ is then separated.

According to another method, a compound of general formula (VIII), where R is a phenyl or benzyl group carrying one or more methoxy substituents, is esterified in a known manner to an ester represented by the general formula (VII) below ;

Y1 y2 H H

, 'H * C - C _! _ Ch2coox 5 (VII) 10 oJ-h.

; R

1 2 where R is as defined in this paragraph and Y, Y and X are as defined above, then the protective group R is removed and this provides a compound of general formula (VI). When R is a dimethoxybenzyl group, it is detached with a peroxydisulfate compound, while in J if R is a methoxyphenyl group, this is removed with a ceric salt in the presence of an acid.

Next, 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 general formula (V) 1 below: I 25 V1 v2

Y \ / H H

H, C - C __L— CH2000H

P

(V)

1 0 - KH

2 where Y and Y are as defined above, is activated on the carboxy group, then treated with a salt of a malonic hemiester, preferably with a potassium or magnesium salt of alkyl malonate or a malonate of substituted benzyl. The resulting compound represented by the general formula (IV) below: t * "7 ï1 ï2 h. 5

y n - π 1? CH- ^ COCH ^ GOOS

(IV) O J-Hh 1 2 5 where Y and Y are as defined above and Q is an alkyl group | 5 or substituted benzyl, is treated with a sulphonic azide in the presence of a tertiary amine to obtain a compound represented by the general formula (III) below: 10 ïl ï2

> / H H

H, C - C __—- ch2coch2cooq 0 J- ™ (III) 1 2 15 where Υ, Υ and Q are as defined above and this compound is subjected to ring closure in the presence of a salt of rhodium to obtain a compound represented by the general formula (II) below: i yl y2

20 v y- H H

HjC - C _T

____J_I (n) ° "^ cooq X 2 * 25 where Y, Y and Q are as defined above. These compounds of general formula (II) are the new starting substances for thienamycin analogs, in accordance with the present invention .

According to yet another method, a compound of general formula (VIII) in which R is a benzyl or phenyl group carrying one or more methoxy substituents, is activated on the carboxy group, then treated with a salt of a malonic hemiester, preferably with the magnesium or potassium salt of a substituted alkyl or benzyl malonate. The resulting compound represented by the embarrassed formula - "7 1" v s 4 8 line (XIV) below:

Υΐ ï2 H H

H C Xc / —— 1 — CïïpCOCHpCOOQ

5 “Γ (XIV)

5 I

0 ^ r »1 2; where Y, Y and Q are as defined above and R 'is "a phenyl or benzyl group carrying one or more methoxy substituents, is then treated with a sulfonic azide in the presence of a tertiary amine to obtain a compound represented by the general formula (XV) below: yl y2

x 1 H H

15 H, C - ff --- I_p0H2C0CH2C00Q

QJ-H. (T}) "1 2 where Y, Y, 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 carrying one or more methoxv 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 in the manner described above and the resulting compound of general formula (III) is converted into the starting material of general formula (II).

30. The compounds of general formulas (II) to (XV) are new and obtained in the form of racemic mixtures. Certain compounds of general formula (XII) are described in a previous Hungarian patent application of the Applicant No. 2263/80. The other compounds of general formula (XII), as well as the compounds of general formulas i • '9 I 1 (XI) to- (II), (XIV) and (XV) are described in detail in patent applications. of the plaintiff.

When preparing a compound of general formula (I), a starting material of general formula (II) 5 is subjected to O-acylation and then treated with an appropriate mercaptan. When a compound of general formula (I) is obtained, where Q 'is a substituted benzyl group, the substituted benzyl group can be detached and the resulting carboxylic acid can be (Q' = H) then converted to alkali carboxylate .

From these data, the present invention relates to a process for the preparation of new bicyclic compounds of general formula (I), in which: 1 2 Y and Y represent a detachable group protecting the carbonyl radical, preferably a group ketal or a thioanalogue thereof, Q 'is a C 5 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and u R "is an optionally substituted hydrocarbon residue of preferably a benzyl group, 2-aminoethylsou 2-acylaminoethyl, according to which: ~~ 1 a) a compound of general formula (II), where Y and 2 Y are as defined above and Q is an alkyl group ^ en ^ 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, then with a mercaptan, preferably with benzyl mercaptan, cysteamine or an N-acylated derivative thereof and p resulting product of general formula (I), where Q 'is a C 1-4 alkyl group or a substituted benzyl group, is separated, or b) from a compound of formula (I) obtained 1 2 in step a), where R ", Y and Y are as defined above and-Q 'represents a substituted benzyl group, Q' is eliminated by reduction and optionally, the resulting carboxylic acid is converted (Q '= H) in its alkali metal salt.

! _.

ι °

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. Derivatives of organic carboxylic acids or preferably sulfonyl or phosphoryl halides can be applied as reagents therefor. Diphenyl phosphoryl chloride appears to be a particularly advantageous reagent.

- The O-acylated intermediate is then treated with a mercaptan, preferably benzylmercaptan, cysteamine or an N-acyl derivative thereof, in the presence of a tertiary amine. forms a compound of general formula (I), where Q 'is a 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 removed by reduction, preferably by catalytic "Ns" hydrogenation, to obtain the respective carboxylic acid of general formula (I) (Q ′ = H) A carboxylic acid of general formula (I) can be converted into its alkali metal salts, among which the sodium salt can be prepared particularly easily by treatment of 1 * 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.

The new compounds of general formula (I) are active in therapy and have mainly inhibitory (3-lactamase) effects.

The present invention also relates to pharmaceutical compositions which contain, as active agent, a compound of general formula (I) in admixture with one or more conventional pharmaceutical additives (for example, carrier, diluent, disintegration aid, agent preservative, buffer etc ...). These compositions can be prepared by methods well known in the art.

111

In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows.

The invention will be better understood with the aid of the additional description which follows, which refers to examples of implementation of the method which is the subject of the present invention, which are not limiting.

Example 1 - 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan- 10-yl) -7-oxo-l-azabicyclo / 3,2,0 _7hept-2-en-2 - ethyl carboxylate.

1.133 g (4.0 mmol) of ethyl 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo / 3,2, Oj7heptane-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 0 ° C. about 10 minutes. Stirring is continued at 0 ° C., then 0.61 ml (4.4 mmol) of triethylamine and 0.46 g (4.4 mmol) of N-formyl-20 cysteamine are added to the mixture. After one hour of stirring at 0 ° C, the mixture is evaporated in vacuo 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, then twice with 10 ml portions of water. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated.

The residue, weighing 2.4 g, is treated by column chromatography (adsorbent: Kieselgel 60, 0 = 0.063 to 0.200 mm; eluting agent "7: 3 mixture of benzene and acetone). 0.51 g is collected ( 36%) of the product sought; mp = 152-153 ° C (from methanol and ether).

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

^ 1H NMR (CDCI 3) î δ = 1.35 (t, 3H), 1.45 (s, 2H), 2.82-3.65 (m, 7H), 3.95-4.5 (m, 7H), 6.1 d, 1H), 8.20 ΐ 35 (d, 1H) ppm.

! I. 12 '13C NMR (CDC13): 6 = 14r3, 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-dimethoxybenzaldehyde, 72 ml (0.66 mole) of benzylamine and 660 ml of methanol is stirred at room temperature for | 20 minutes, so that a clear solution is obtained from the suspension. The solution is cooled with ^. ice water and gradually added 13.2 g (0.33 mole) of borosodium hydride.

The progress of the reaction is monitored by thin layer chromatography (Kieselgel G according to Stahl; revealing solvent: 9: 1 mixture of benzene and acetone) and at the end of; 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, 200 ml and 200 ml ether portions. The ethereal solutions are combined, dried over magnesium sulphate, filtered, then the filtrate is added with 112 ml (0.66 mole) of diethyl bromomalonate and 33 ml (0.66 mole) of triethylamine. The reaction mixture is stirred at room 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 again recrystallized from 400 ml of ethanol i 30 and provides 197 g (72%) of N-benzyl-N- (2,4-dimethoxybenzy 1) - diethyl amino malonate; pf. : 62-63 ° C (ethanol).

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

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

Diethyl Ixybenzyl) -amino-malonate, prepared according to point 35 a) of Method I, are hydrogenated in 500 ml of ethanol 13! .

i at atmospheric pressure in the presence of approximately 20 g of catalyst consisting of palladium on carbon. The catalyst is filtered and the filtrate is evaporated. 47/1 g (97%) of diethyl (2/4-dimethoxybenzylamino) -malonate are collected. The product can be converted to its hydrochloride by reaction with hydrochloric acid. The hydrochloride melts at 122-124 ° C after recrystallization from ethyl acetate.

Analysis: 10 Value calculated for ci5H24C1N06 (361 82): ^ 'C: 53/11%; H: 6.69%, Cl: 9.80%; N: 3.87%; i "" found: C: 52.51%, H: 6.77%, Cl: 10.30%; N: 4.09%.

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

15 1H NMR (CDC13): δ = 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.

ic) A mixture of 39.6 g (0.122 mol) of diethyl (2,4-dimethoxybenzinolamino) -malonate, prepared according to point b) of Method I, 80 ml of glacial acetal acid and 12, 3 g (11.2 ml, 0.146 mole) of diketene is brought to the boil for 0.5 hour. The solvent, glacial acetic acid, is distilled in vacuo on a water bath 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. 29.6 g (60%) of diethyl N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer are collected. Mp: 106-107 ° C.

30 Analysis:

Calculated values for C20H27NO8 (^ 09.43): C: 58.67%, H: 6.65%, N: 3.42%; & "-Found: C: 58.79%, H: 6.33%, N: 3.34%.

35 IR (KBr): 3400, 2950, 2850, 1730 (1740, sh), 1710 cm ”1.

1½ NMR (CDC13): 6 = 1.1 (t, 3H), 1.17 (t # 3H), 1.52 '' (s ^ H), 2.8 (<0.1 H), 2.65 (large s, 2H), 3.75 (s, 6H), 3.8-4.15 (m, 4H), 6.7 (large s, 2H), 6.25-6.45 (m) + 7.0-7.25 (m, 3H) ppm.

D) 20.5 g (50 mmol) of the product prepared as described in point c) of Method I are suspended in 50 ml of anhydrous ether and a solution of 3.45 g is added simultaneously. (150 mmol) of metallic sodium in 100 ml of anhydrous ethanol and a solution of 12.7 g 10 (50 mmol) of iodine in 150 ml of anhydrous ether, from two dropping funnels, to the suspension vigorously stirred and cooled with ice water, then 5 g of sodium hydrosulfite, dissolved in 200 ml of a saturated aqueous solution of sodium chloride, are added to the stirred mixture. decant 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 from 30 ml of 2-propanol: 10.9 g (54%) of diethyl 3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate are obtained; .f. : 84-85 ° C (2-propanol).

Analysis:

Values calculated for ^ 20 ^ 25 ^ 8 1 ^ 07.41): 25 C: 58.96%, H: 6.19%, N: 3.44%; "found: C: 58.99%, H: 6.04%, N: 3.57%.

XH NMR (CDC13): Ô = 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 30 (d, 1H), 4.69 (s, 1H), 6.3-6.4 (m, 2H) + 7.07 (d, 1H) ppm.

e) 179 ml (206 g, 1.452 mole) of boron trifluoride-diethyl etherate are added dropwise to a vigorously stirred solution of 179 g (0.484 mole) of 3-acetyl-1- (2,4-dimethoxybenzyl). ) -4-OXO-2,2-azetidine-35 diethyl dicarboxylate and 107 ml (120 g, 1.936 moles) 15 ".

ethylene glycol in 500 ml of anhydrous dioxane, while cooling with ice water is ensured. The reaction mixture is allowed to stand at room temperature for one day, during which it is stirred from time to time. Then 415 g (1.452 mole) of NaCO3, 10H2O are slowly added to the stirred mixture and cooled with ice water and the mixture is stirred for ς 15 minutes. Then add 1 liter of ether and 1 liter. of water and .the phases are separated from each other. The aqueous phase is shaken twice with portions of. 500 ml of diethyl ether. The ethereal phase is dried over magnesium sulfate, filtered and the filtrate is evaporated.

33.9 g (0.58 mole) of sodium chloride, 17.4 ml (0.968 mole) of water and 220 ml of dimethyl sulfoxide are added to the residue and the mixture is stirred on an oil bath. at 180 ° C. 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).

At the end of the reaction, that is to say after about 15 hours, ~ 20 the mixture is poured into 1100 ml of saturated aqueous sodium chloride solution, the resulting mixture is shaken with 1000 ml, then twice with 500 ml portions of diethyl ether. the ethereal solutions are combined, bleached 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-ethyl oxo-2-azetidine carboxylate; mp: 95 ° C.

F) A mixture of 0.5 g (1.2 mmol) of 3-acetyl- 1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine-diethyl dicarboxylate prepared according to point d) above, 3 ml of anhydrous tetrahydrofuran and 0.53 g (3.6 mmol) of mercapto-ethanol is brought to the boil for 4 hours, “16 then 10 ml of water and 10 ml of chloroform are added to the mixture of reaction. The organic phase is separated, washed with a 5% aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and the product is separated from the filtrate by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254 +366 '* revealing mixture: 8: 2 mixture of toluene and acetone.

\ We obtain: 0.30 g (53%) of 1- (2,4-dimethoxybenzyl) -3- ^ '(2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azetidine -diethyl dicarboxylate.

1H NMR (CDC13): δ = 0.8-1.55 (m, 6H), 1.72 + 1.77 (d, 3H), 2.9 -3.4. (m, 2H), 3.75 (s, 6H), 15 4.0-5.0 (m, 9H), 6.4. (m, 2H) + 7.1 (d, 1H) ppm.

g) A solution of 5.21 g (0.130 mole) of sodium hydroxide in 60 ml of water is added to a suspension of r 41.2 g (0.109 mole) of trans-1- (2,4-dimethoxybenzyl ) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-ethyl carboxylate - 20 prepared according to point e) above, in 50 ml of ethanol with stirring and with cooling with ice water and stirring is continued until a clear solution is obtained (about 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 to pH = 1 with "concentrated aqueous hydrochloric acid, then quickly shaken with 100 ml, then twice with 50 ml portions of dichloromethane.

The dichloromethane solutions are combined, dried over 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%) f of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl acid -1.3-dioxolan'-2-yl) -4-oxo-2-azetidine-carboxylic; m.p. : 117-118 ° C (toluene).

I i 17 7

Analysis:

Calculated values for ci7H2iN07 (351 · 35): C: 58.11%, H: 6.03%, N: 3.99%?

Found value: 5 C: 58.17%, H: 6.30%, N: 4.24% ^ IR (KBr): 3500-2500, 2900, 1760, 1720 cm "1.

H NMR (CDC13): δ = 1.39 (s, 3H), 3.50 (d, 1H, J = 2.5 Hz), 3.77 (ε, 3H), 3.79 (s, 3H), 3.86 (d, 1H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, J = 15 Hz), 6.44 'io (m, 2H) + 7.15 (d, 1H, J = 10 Hz), 7.58 (large s, 1H) ppm.

h) 7.3 ml (52.5 mmol) of triethyl amine are added to a solution of 17.6 g (50 mmol) of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1 acid) , 3-dioxolan-2-yl) -15 4-oxo-2-azetidine-carboxylic acid prepared according to point g) above, in 150 ml of anhydrous tetrahydrofuran, then 5.0 ml (52.5 mmol) of chloroformate ethyl are added to the mixture, cooled with ice. 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 150 mmol of diazomethane in 230 ml of cold diethyl ether is added to the filtrate. The mixture is. stirred, allowed to warm to room temperature and after 2 hours 25 of stirring, evaporated to dryness. The thick brown residue is dissolved in 20 ml of benzene and the product is separated by column chromatography (adsorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0.200 mm, eluting agent: 7: 2 mixture of benzene and acetone) .We collect: 12.0 g (64%) of trans-4-30 (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2- azetidinone.

Analysis: Value calculated for C18H2A ° 6 (375.37): C: 57.59%, H: 5.64%;

Values found C: 57.78%, H: 5.39%.

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

1 18 ij ·, / I i) A mixture of 2.25 g (6 mmol) of trans-4- § '(diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1, 3- I dioxolan-2-yl) -2-azetidinone prepared according to point h) above I, 100 ml of tetrahydrofuran devoid of peroxide 5 and 50 ml of water, is irradiated for approximately 4 hours with a flashlight. high pressure mercury (HPX 125), immersed in a Pyrex reactor, under an argon atmosphere. The solution 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 sodium hydroxide solution are added to the aqueous mixture and the alkaline mixture is washed three times with 20 ml portions of dichloromethane.

Then, the aqueous phase is acidified to pH = 2 using concentrated aqueous hydrochloric acid. The acid solution is extracted three times with 20 ml portions of dichloromethane. The extracts are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness. The residue is crystallized from ether. Lt82 g (83%) of ^ trans-1- (2,4-dimethoxybenzyl) -3-20 (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl_7 acid is collected. -acetic mp: 124 ° C (ether).

Analysis:

Calculated values for C ^ gï ^ gNO ^ (365.37): C-.59.17%, H: 6.34%, N: 3.83%, -25 Values found 0: 59.22%, _ H: 6.49%, N: 4.07% .

IR (KBr): 3500-2300, 2900, 1730, 1700 cm-1, j) 3.05 g (15.75 mmol) of diphenyl diazomethane are added at room temperature to a stirred solution of 5.48 g (15 mmol) of acid / trans-1- (2,4-dimé-30 thoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azétidinyl ^ 7-acetic, prepared according to point 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 diphenyl-diazomethane. The solution is evaporated to dryness! 119 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 (^ 2 ^ 2 ^ 8 ^ · 21.60 g (120 mmol) disodium acid phosphate monohydrate (Na2HPO4, I ^ O) and 54 ml of water; the mixture is stirred vigorously for 4 hours, brought to the boil and then cooled. The cold reaction mixture is filtered and both The phases of the filtrate are separated from each other. The aqueous phase is extracted three times with 30 ml portions of ethyl acetate. 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, 15 0 = 0.05 to 0.200 mm, eluent: mixture 7; 2 of benzene and acetone) to obtain 2.68 g (47%) of trans- ^ 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl_7 ~ benzhydryl acetate; mp: 130 ° C (eth anol).

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

20 1H NMR (CDC13): 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: 25 Values calculated for C22H23N05 (387.41): C: 69.27%, H: 6.08%, N: 3.67%;

Values found C: 69.15%, H: 6.20%, N: 3.55%.

20. \

Il * k) A mixture of 3.80 g (10 mmol) of trans- 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinylJ ^ -benzhydryl acetate, 0 , 4 g of an anhydrous catalyst consisting of 8% palladium on charcoal and 50 ml of anhydrous ethanol 5 is stirred under a hydrogen atmosphere. Hydrogen absorption Stops after 2 hours. The catalyst is filtered and washed with 10 ml of anhydrous ethanol. The filtrate is evaporated on a water bath at 30-40 ° C, the residue is washed three times with 20 ml portions of ether and the liquid is decanted.

10 2.02 g (94%) of i / ”trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl_7-acetic acid are collected pf: 126-129 ° C.

Analysis:

Calculated values for CgH13N05 (215.20): N: 6.51%; 15 values found N: 6.34%.

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

l) A mixture of 2.15 g (10 mmol) of trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -acetic acid prepared according to point k) of Method I, 1.82 g (11 mmol) of 98% carbonvldiimidazole and 60 ml of anhydrous tetrahydrofuran is stirred for 30 minutes. 1.58 g (11 mmol) of ethyl magnesium malonate is added to the solution and the reaction mixture is stirred at room temperature for 2 hours. The mixture is evaporated in vacuo, 180 ml of dichloromethane and 180 ml of 0.5N aqueous hydrochloric acid are added to the residue, then this mixture * is stirred for a few minutes and the two phases are separated from one another. the other. The aqueous phase is extracted three times with 30 ml fractions of dichloromethane.

The organic phases are combined, washed twice with 20 ml portions of 3% aqueous sodium carbonate solution, dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness. We collect | 2.02 g (71%) of trans-4- ^ 3- (2-methyl-1,3-dioxolan-2-yl) j 35 -4-oxo-2-azétidinyl_7-3-ethoxylbutanoate ; mp. 65-68 ° C (ether) - 21 IR (KBr): 3220, 1770, 1735, 1720 cm ”1.

XH NMR: δ = 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 (s, 1H) ppm.

5 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 (5.0 mmol) of trans-4- ^ 3- (2-methyl- 1,3-dioxolan-2-yl) -4-oxo-2-azetidinylJ7-3-ethyl oxo-butanoate, prepared according to step 1) of Method I, in 15 ml of anhydrous acetonitrile, with ice cooling. The solution is allowed to warm to room temperature over three hours with stirring. The solution is evaporated to dryness, the residue is dissolved in benzene and the solution is treated by column chromatography (adsorbent: 100 g of Kieselgel 60, 0 = 15 0.063 to 0.200 mm, eluent agent 7: 2 mixture of benzene and d 1.12 g (72%) of 2-diazo-4- / trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / r -3-oxo-? ethyl butanoate.

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

20 1H 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), 4.33 (q, 2H), 6.08 (s, 1H) ppm.

n) Dirhodium tetraacetate £ _ Rh2 (OAc) ^ is added in small portions to a boiling solution of 1.425 g (4.0 mmol) of 2-diazo-4- ^ trans-3- (2- ethyl methyl-3, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -3-oxo-butanoate, prepared according to point m) of Method I, in 10 ml of benzene. until the starting material has completely reacted (this requires approximately 0.03 g of rhodium salt). The reaction mixture is filtered through a pad of Celite and the filtrate is evaporated. 1.13 g (100%) of 6- (2-methyl ν -1,3-dioxolan-2-yl) -3.7-dioxo-1-azabicyclo- ^ 3 are collected. 2.0 Ethyl jieptane-2-carboxylate: m.p .: 109 ° C.

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

135 1H NMR: δ = 1.30 (t, 3H; J = 7.4. Hz), 1.49 (s, 3H) y, 22 2.41 (dd, 1H, J = 19.5 Hz, J. = 7.5. Hz), 2.90 (dd , 1H), gem vie

Jgem = 19 * 5 Hz 'Jvic = 7.0 Hz)' 3.43 (from 1H 'J = 2.4 Hz)' 3.97-4.20 (m, 5H), 4.24 (g, 2H, J = 7.4 Hz ), 4.63 (t, 1H, J - 0.6 Hz) ppm.

i

5 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 added. * stirred at room temperature for 2 days. The resulting mass is triturated with 100 ml of diethyl ether, the 10 '4-methoxy-anisidine hydrobromide separated is filtered and washed with a small amount of diethyl ether. The mother liquor

It is evaporated and the residue is crystallized from dilute acetic acid. 13.2 g (47%) of diethyl (4-methoxyanilino) -malonate are obtained: mp: 64-65 ° C (ethanol), analysis:

Calculated values for H ^ NO, - (281.31): C: 59.77%, H: 6.81%, N: 4.99%; c Values found C: 59.99%, H: 6.97%, N: 5.25%.

IR (KBr): 3300, 1775, 1725 cm “1.

20 1H NMR (CDC13): δ = 1.23 (t, 6H, J = 7.2 Hz), 3.67 (S, 3H), 4.2 (q, 4H, J = 7.2 Hz), 4.62 (s, 1H) , 4.1-4.5 (large s, 1H), 6.55 (2H) + 6.73 (2H, AA'BB ', J = 9 Hz) ppm.

b) A mixture of 11.2 g (0.04 mol) of diethyl (4-methoxy-anilino) -malonate, prepared according to point a) of Method II, 15 ml of glacial acetic acid and 4 g (3.7 ml, 0.048 mole) of diketene is brought to the boil for 0.5 hour. The solution is evaporated in vacuo, the oily residue is triturated with diethyl ether and the solid is filtered and separated. 10.5 g (72%) of diethyl 1- (4-30 methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer are collected; mp: 136-137 ° C (ethyl acetate).

• Analysis: | ^ Values calculated for C ^ g ^^ NO ^ (365.38): 35 C: 59.17%, H: 6.39?. N: 3.83%; 23

Values found C: 58.98%, H: 6.90%, N: 4.04%.

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

1H NMR (CDC13): 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 (s, 1H), 5 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) 9rl g (0.025 mole) of 1- (4-methoxyphenyl) -3-hydroxy * -3-methyl-5-oxo-2,2-pvrrolidine-dicarboxylate, prepared according to point b) of Method II , are suspended in 50 ml of anhydrous diethyl ether and a solution of 1.72 g of metallic sodium in 30 ml of anhydrous ethanol, as well as a solution of 6.35 g (0.025 mol) of iodine in 50 ml of anhydrous diethyl ether are poured simultaneously into the vigorously stirred suspension and cooled with ice. Then, the mixture is poured into 100 ml of a saturated aqueous solution of sodium chloride and 2 g of sodium hydrosulfite and 2 ml of glacial acetic acid are added. The ethereal phase is separated and the aqueous phase is extracted three times with por-i; 20 x 50 ml diethyl ether. The ethereal phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is triturated with 2-propanol to obtain 6.2 g (68%) of crystalline diethyl 3-acetyl-1- (4-metho-xyphenyl) -4-oxo-2,2-azetidine dicarboxylate; mp: 70-7l ° C (ethanol).

Analysis:

Calculated values for C18H21N07 (363.38): C: 59.50%, H: 5.82%, N: 3.85%;

Values found C: 59.04%, H: 5.84%, N: 4.08%, 30 IR (KBr): 1760, 1735, 1720 cm "1.

1H NMR (CDC13): 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) 6 g (0.0165 mole) of 3-acetyl-1- (4-methoxyphenyl) - ^ * 24 »4-oxo-2,2-azetidine-diethyl dicarboxylate, prepared according to point 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, 0.05 mole) of boron trifluoride-diethyl etherate complex are added dropwise to the solution stirred and cooled with ice and the reaction mixture is stirred for 2 additional hours at room temperature. The solution is basified with a saturated aqueous solution of sodium hydrogen carbonate, followed by addition of 100 ml of water and the mixture is extracted three times with 50 ml portions of diethyl ether. The j organic phases are combined, dried over i- sulfate! magnesium, filtered and the filtrate is evaporated. The oily residue is triturated with diethyl ether to obtain | 15 6 g (89%) 3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) | -4-OXO-2,2-azetidine-crystalline diethyl dicarboxylate; mp: 82-83 ° C (ethanol).

Analysis:

Calculated values for C20H25NO8 (407.43): 20 C: 58.96%, H: 6.18%, N: 3.44%;

Values found C: 58.70%, H: 5.68%, N: 3.63%.

IR (KBr): 1740 cm * (wide) 1H NMR (CDC13): 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 25 (m, 4H), 4.2 (m, 5H), 6.67 (2H) + 7.34 ( 2H, AA ', BB', J = 19 Hz) ppm.

e) 11 g (0.0245 mole) of 3- (2-methyl-1,3-dioxolane-- 2-yl) -1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate diethyl, prepared according to point d) of Method II, are dissolved in 20 ml of dimethyl sulfoxide, then 1.72 g (0.0295 mole) of sodium chloride and 0.9 ml (0.049 mole) - d Water is added and the mixture is stirred at 175 ° C until the reaction is complete. The progress of the reaction is monitored by thin layer chromatography (adsorbent: 35 Kieselgel G according to Stahl; revealing solvent: 6: 4 mixture of 25 "I benzene and ethyl acetate).

The mixture is cooled, poured into 150 ml of a saturated aqueous solution of sodium chloride and extracted three times with 50 ml portions of diethyl ether. The 5 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 mole) of sodium hydroxide in 10 ml of water, with cooling by ice water. The mixture is stirred for 0.5 hour, 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 aqueous concentrated hydrochloric acid, then extracted three times with 25 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized with benzene. r 4 g (54%) of trans-3- (2-methyl-1,3-dioxolan -2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidine-carboxylic acid are collected.

20 Analysis:

Values calculated for Ci5H17NOg (307.32); VS; 58.63%, H: 5.57%, N: 4.56%;

Values found C: 58.40%, H: 5.80%, N; 4.66%.

IR (KBr): 3400-2700, 1750 (wide) cm 1, 25 1H NMR (CDC13); 6 = 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) 1.11 g (1.56 ml, 0.011 mole) of anhydrous triethyl amine is added to a solution of 3 g (0.01 mole) of a compound prepared according to point e) of Method II, in 20 ml of anhydrous tetrahydrofuran. The solution is cooled to -15 ° C and added dropwise 1.2 g (1.06 ml, 0.011 mole) of ethyl chloroformate with stirring. After 20 minutes of stirring, the separated salt is filtered under an atmosphere of nitrogen and a solution of 4.8 g (0.025 mole) of i 26! "Diazomethane in diethyl ether is added to the filtrate at room temperature. After 2 hours of stirring, the excess of diazomethane is decomposed with acetic acid and the solution is evaporated under vacuum. The oily residue crystallizes slowly. We obtain 3 g (90%) of trans-4-fdiazoacetyl) -3- (2-methyl-lr3-dioxolan-2-yl)! -L- (4-methoxyphenyl) -2-azetidinone? mp: 95-96 ° C (benzene and ether).

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

10 1H NMR (CDC13) î 6 = 1.50 (s, 3H), 3.51 (d, 1H, IJ = 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 (2H) + 7.30 (2H, AA ', BB', J = 9 Hz) ppm.

g) 3d, 3g (0.01 mole) of prepared trans-4- (diazoacetyl) -3-15 (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone according to point f) of Method II, are dissolved in a mixture of 50 ml of water and 100 ml of r tetrahydrofuran. The mixture is irradiated with a high-pressure mercury lamp in a photoreactor under an atmosphere of nitrogen (the reaction is carried out at ambient temperature) and the progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl - revealing solvent: 7: 1 mixture of benzene and acetone). When the reaction is complete, the tetrahydro-25 furan is distilled in vacuo, the residue is made alkaline with a 20% aqueous solution of sodium hydroxide and the solution is washed twice with 15 ml portions of dichloromethane. The aqueous phase is acidified to ni! = 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 sulfate, filtered and the filtrate is evaporated. 1.6 g (50%) of acid / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-35_ 2-azetidinylrf_7 are obtained. -acetic.

; . 27 t

Analysis:

Calculated values for ^ g ^ g ^ g (321.33): C: 59.80%, H: 5.96% f N: 4.36%,

Values found C: 59.60%, H: 5.76%, N: 4.08%.

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

h) 1.0 g (3.12 mmol) of the compound prepared according to point g) of Method II is dissolved in 10 ml of dichloromethane and a solution of 0.53 g is added thereto dropwise. 3.12 mmol) of diphenyl diazomethane in 10 ml of dichlo-10 romethane with stirring, at room temperature. When the evolution of gas stops, the solution is evaporated under vacuum. 1.45 g (98%) of trans- ^ 3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl7-benzhvdryl acetate are obtained.

15 Analysis:

Values calculated for (487.55): C: 71.44%, H: 5.99%, N: 2.87%;

Values found C: 71.13.%, H: 6.21%, N: 2.93%.

1H NMR (CDC13): δ = 1.35 (s, 3E), 2.7-3.1 (m, 2H), 20 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) trans- / ~ 3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinylJ7 ~ benzhydrile acetate, prepared according to point 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 ^) 2 (NO ^) ^ 7 in 2 ml of 5% aqueous sulfuric acid is added dropwise to the solution stirred at room temperature The reaction mixture is stirred for an additional 2 minutes and then neutralized carefully with a 5% aqueous solution of sodium hydrogen carbonate. Then the mixture is extracted three times ·; with 4 ml portions of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, 35 filtered and the filtrate is evaporated in vacuo The oily residue 28 is purified by preparative thin layer chromatography (adsorbent: Kieselgel 60, 0 = 0.050 to 0.200 mm, eluting agent; 7: 2 mixture of benzene and acetone) for get 0.06 g (30%) of trans- / 3- (2-methyl-1,3-dioxolan-2-yl) 5 -4-oxo-2-azetidinyl7-benzhydryl acetate.

This compound is identical to that which is prepared j as described in point j) of Method I.

! * The resulting product can be converted into the desired starting substance according to the procedure described in - io points k) to n) of Method I.

Method III - a) A mixture of 38 g (0.152 mol) of diethyl anilino-malonate ^ / _ R. Blank: Ber. 31 ^ 1815 (1898 ^ / ^, 38 ml of glacial acetic acid and 15.3 g (13.9 ml, 0.182 mole) of diketene, is brought to the boil for 0.5 hour.

The glacial 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-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate of diethyl and / or its tautomer are obtained; mp: 98-99 ° C (ethyl acetate and petroleum ether).

Analysis:

Values calculated for ci7H21N06 ^ 335.35): C: 60.88%, H: 6.31%, N: 4.18%; 25 Value found C: 60.83%, H: 6.15%, N: 4.43%.

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

1H NMR (CDC13): 6 = 1.02 (t, 3H), 1.3 (t, 3H), 1.6, (s, 3H), 2.8 (s, 3H), 3.6 (large s, 1H), 4-4.45 (m , 4H), 7.2 (s, 5H) ppm.

B) 50 g (0.149 mol) of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate, prepared according to point a) of Method III, are added to a solution of 10.2 g (0.447 mol) of metallic sodium in 250 ml of anhydrous ethanol, then a solution of 37.9 g 35 (0.149 mol) of iodine in 200 ml of anhydrous ether is added 29 under vigorous agitation. When the reaction is complete, 8.5 ml (8.9 g, 0.149 mole) of glacial acetic acid, 200 ml of water and 100 ml of ether are added to the mixture; the organic phase is separated and the aqueous phase is extracted with 100 ml of ether. The ethereal phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated.

The oily residue is crystallized from 50 ml of 2-propanol to obtain 31 g (62%) of diethyl 3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate, m.p .; 55-56 ° C (2-propanol) - 10 Analysis:

Calculated values for C ^ H ^ NO ^: C: 61.25%, H: 5.75%, N: 4.20%;

Values found C: 61.38%, H: 5.89%, .N: 4.24%.

IR (KBr): 1770, 1740, 1720 cm ”1.

1 H NMR (CDCI 3): 6 = 1.12 (t, 6H), 2.3 (s, 3H), 4.25 (g, 4H), 4.75 (s, 1H), 7.0-7.6 (m, 5H) ppm.

c) 28.5 g (0.085 mole) of 3-acetyl-1-phenyl-4-oxo-2,2-azetidine-dicarboxylate, prepared according to point d) of Method III, are dissolved in a mixture of 90 ml of anhydrous dioxane and 21 g (18.8 ml, 0.34 mole) of ethylene glycol and then 36> 5 g (31.5 ml, 0.255 mole) of boron trifluoride-diethyl etherate complex are added dropwise dropwise to the vigorously stirred solution and cooled with ice water. The solution is stirred for an additional 2 hours at room temperature, then neutralized with a saturated aqueous solution of sodium carbonate. The neutral solution is diluted with 100 ml of water, then extracted three times with 50 ml fractions of diethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The oily residue is crystallized by trituration with ether. 28.5 g (90%) of 1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-azetidine-diethyl dicarboxylate are obtained; mp: 59-61 ° C (petrol).

! 30 d ♦

Analysis:

Values calculated for C19H23 "° 7 = C: 60.47%, H: 6.14%, N: 3.71%, I Values found C: 60.74%, H: 6.21%, N: 3.79%.

5 IR (KBr): 1770, 1740 cm “1.

NMR (CDCI3): 6 = 1.18 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz), 1.51 (s, 3Η); 3.92 (m, 4H), 4.3 (m, 5H), * 7.2 (m, 5H) ppm.

d) A mixture of 28.5 g (0.075 mole) of 1-phenyl-10 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine-dicarboxy-- diethyl late, prepared according to point 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 stirred at 175 ° C until the reaction ends. 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 are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The resulting oily residue (16.4 g) is dissolved in 100 ml of ethanol and a solution of 2.15 g (0.054 mol ·) · of sodium hydroxide in 30 ml of water is added to this stirred mixture and cooled by an ice water bath. After 0.5 hours of stirring, the mixture * is diluted with 150 ml of water and extracted three times t with 20 ml portions of diethyl ether. The aqueous phase is acidified to pH = 1 with concentrated aqueous hydrochloric acid and then extracted three times with 50 ml portions of dichlaromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized from benzene to obtain 12 g (56%) of trans-1-35 phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2- acid. azetidine- »31 carboxylic; mp: 165 ° C (benzene).

Analysis:

Calculated values for CL .H, .. NO, - (277.27): 14 15 5 C: 60.64%, H: 5.45%, N: 5.05 '%, 5 Found values C: 60.64%, H: 5.72%, N: 4.99%.

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

1H NMR (CDC13): δ = 1.5 (s, 3H), 3.69 (d, 1H, * J = 3 Hz), 4.0 (m, 4H), 4.42 (d, 1H, J = 3 Hz), 7.3 (in , 5H); 7.55 (s, 1H) ppm, * 10 e) 13.8 g (0.05 mole) of trans-1-phenyl-3- (2-methvl-1, 3-dioxolan-2-yl) -4 acid -oxo-2-azetidine-carboxylic acid prepared according to point d) of Method III, are dissolved in 100 ml of anhydrous tetrahydrofuran and 5.55 g (7.7 ml 0.055 mole) of ethyl chloroformate are added to the solution at -15 ° C. After 20 minutes of stirring, the separated salt is filtered under a nitrogen atmosphere and an ethereal solution of 22.6 g (0.15 mole) of diazomethane is added to the filtrate with stirring.

When the evolution of the gas stops, the excess of diazomethane is decomposed by glacial acetic acid and the solution is evaporated. The oily residue is triturated with ether to obtain 11.5 g (77%) of trans-4- (diazoacetyl) -l-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -azetidinone crystalline; mp: 96-97 ° C (benzene and 25 ether).

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

, ΧΗ NMR (CDC13): 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), 30. 5.45 (s, 1H), 7.25 (m, 5H) ppm.

g 32 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 point e) of Method III, are dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml.

5 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; revealing solvent: mixture

H

10 7: 1 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 concentrated aqueous hydrochloric acid, then extracted three times with 20 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is triturated with ether to obtain 1T8 g (50%) of / trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4- acid. oxo-2-azetidinyl_J7-> crystalline acetic; mp: 128-129 ° C (ethanol).

Analysis:

Calculated values for C ^ H ^ NO ^ (291.29): 25 C: 62.00%, H: 5.88%, N: 4.82%; v Values found C: 61.75%, H: 5.86%, N: 5.08%.

IR (KBr): 1760, 1740 cm ”1.

1H NMR (CDC13): 6 = 1.48 (s, 3H), 2.65 (dd, 1H, J = 15 Hz, J. = 8 Hz) + 3.12 (dd, 1H, J = 15 Hz, gern 'vie' gern 30 J. = 8 Hz), 3.47 (d, 1H, J = 2.5 Hz), 3.98 (m, 4H), 4.4.

V10 (m, 1H), 7.3 (m, 5H), 9.33 (large s, 1H) ppm.

V g) 0.81 ml of concentrated nitric acid (p = 1.5) is added dropwise, with constant stirring and with ice cooling, to 3 ml of acetic anhydride, so that the temperature of the mixture does not rise above 33 ° C. The resulting nitrating mixture is added dropwise, at -5 ° C, to a stirred solution of 2.9 g (0.01 mole) of trans-1-pheny 1-3- (2-methyl-1) acid. , 3-dioxolan-2-yl) -4-oxo-2-azetidinyl__7-acetic t prepared according to point f) of Method III, in 20 ml of anhydrous dichlo-romethane. After one hour of stirring, 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, filtered and the filtrate is evaporated under vacuum. The oily residue is triturated with ether to obtain 1.95 g (58%) of trans-3- ( Crystalline 2-methyl-1,3-dioxolan-2-yl) -1- (2-nitrophenyl) -4-oxo-2-azetidinyl_7-acetic; 15 mp: 175-176 ° C (ethanol).

Analysis:

Values calculated for ci5HigN2 ° 7 (336.33): .. C: 53.57%, H: 4.79%, N: 8.33%;

Values found C: 53.31%, H: 4.68%, N: 8.21%.

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

h) 0.336 g (mmol) of acid / ptrans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (2-nitrophényJ ·) -4-oxo-2-azetidinyl_7-acetic acid according to point g) of Method III, is dissolved in 15 ml of methanol and the solution is hydrogenated under atmospheric pressure, 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. 10 ml of dichloromethane, 0.17 g (immole) of diphenyl diazomethane is added and the mixture is stirred for 24 hours. Then the mixture is evaporated to obtain 0.4 g (90%) of trans - / "" l- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl)> -4- oxo-2-azetidinyl __ / - benzhydryl acetate.

i - 34 IR (KBr); 1740, 1720 cm ”1.

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

i) 0.45 g (1 mmol) of trans- / 1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl __ / -.

5 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 dropwise to the above solution at room temperature. 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 neutral. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated under vacuum. The residue is purified by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF PF254 + 366 'revealing solvent 7: 3 mixture of benzene and acetone). 0.09 g (30%) of trans - / ^ 3 is obtained. - (2-methyl-1,3-dioxolan-2 ~ yl) -4-oxo-2-azetidinylJ7-benzhydryl acetate. The physical constants of this compound are identical to those determined for the product prepared according to point j) of Method I.

The resulting compound can be converted to the desired final substance according to the procedure which is described in points k) to n) of Method I.

Method IV

a) 0.364 g (2.2 mmol) of carbonyl, diimidazole 98% is added to a solution of 0.730 g (2 mmol) of trans-1- (2,4-dimethoxybenzyl) -3- (2) acid -methyl-l, 3-30 dioxolan-2-yl) -4-oxo-2-azetidinyl__7_acétique in 10 ml of anhydrous tetrahydrofuran and the mixture is stirred for 20 minutes. To this solution is added 0.315 g (2.2 mmol · ) magnesium salt of monoethyl malonate and stirred for 2 hours The reaction mixture is evaporated, the residue is shaken with a mixture of 40 ml of cichlorarethane and 40 ml of 0.5N aqueous hydrochloric acid, then the phases are U. separated from each other. The aqueous phase is extracted

Iwith 20 ml of dichloromethane. The organic phases are combined, washed twice with 5-10 ml portions of a 3% aqueous solution of sodium carbonate, dried over magnesium sulfate, filtered and the filtrate is evaporated. 0.41 g (47%) of trans-4 - ^ / ”” l- (2,4-dimethoxvbenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo- are obtained. Ethyl 2-azetidinyl_y-3-oxo-butanoate.

10 IR (film): 1750, 1740, 1720 cm "'1.

1H NMR (CDC13): 6 = 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) 0.69 ml (5.0 mmol) of triethyl amine and 0.986 g (5.0 mmol) of tosyl azide are added to a solution of 2.77 g (5.0 mmol) of trans-4- / 1- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-ethyl oxo-2-azetidinyl_7- 3-oxo-butanoate, prepared according to point a) of Method IV, in 15 ml of anhydrous acetonitrile under cooling by ice. 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: Kiéselgel 60, 0 = 0.063 to 0.200 mm, agent - eluent: 7: 2 mixture of benzene and acetone). We obtain 1.41 g (61%) of 2-diazo-4-trans- / 1- (2,4-dimethoxybenzyl), -3- (2-methyl-1,3-dioxolan-2-yl) -4- ethyl oxo-2-azetidinyl_7 -3-oxo-butanoate.

IR (film): 2160, 1750, 1720, 1640 cm "1 30 c) 5 ^ 4 g (20 mmol) of potassium persulfate (K2S2Ûg), 7.2 g (40 mmol) of disodium phosphate monahydrate (Na2HPO ^ , H2O) and 18 ml of water are added to a solution of 2.340 g (5.0 mmol) of a compound I prepared according to point b) of Method IV, in 30 ml of acetonitrile and the mixture is brought to the boil for 36 1 - 10 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 10 ml portions 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, 0 = 0.063 to 0.200 mm, eluent: 7: 3 mixture of benzene and acetone) to obtain 0.56 g (36%) of 2-diazo-4- ethyl trans / -3- (2-methyl- 110 1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl __ / r-3-oxo-butanoate. The physical constants of this compound are identi-

These are those of the product which is prepared according to point m) of Method I. The compound can be converted into the desired starting material, according to the procedure which is described in point n) of Method I.

Method V

A drop of dimethylformamide and 0.37 ml (5.0 mmol) of thionyl chloride are added to a stirred solution of 1.830 g (5.0 mmol) of trans-1- (2,4-dimetho-20) acid. xybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl _ / - acetic in 10 ml of dichloromethane while cooling —with ice and stirred reaction mixture for two hours while cooling, 1.7 ml of ethyl diazoacetate are then added to the mixture and the stirring is continued at room temperature for 24 hours. The dark solution is evaporated and the residue is treated by column chromatography (adsorbent: Kieselgel 60, 0 = 0.063. To 0.200 mm, eluent: 7: 2 mixture of benzene and acetate. 0.17 g is obtained (7.3% ) of 2-diazo-4-trans- / T1- (2,4-30 dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl_7-3- ethyl oxo-butanoate The IR spectrum of this compound is identical to that of the compound prepared according to point b) of Method IV.

The compound can be converted to the desired starting material according to the procedure described in point c) of Method IV.

37 ”

Method VI

a) Dissolve 0.4 g (1.24 mitiole) of ^ / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) - 4-oxo acid -2-azetidinyl__7r-acetic prepared according to point g) 5 of Method II, in 15 ml of anhydrous tetrahydrofuran and 0.22 g (1.36 mmol) of carbonyldiimidazole is added thereto.

'- The resulting mixture is stirred at room temperature | * for about an hour. When the evolution of gas stops, 0.196 g (1.36 mmol) of the magnesium salt of monoethyl malonate is added and stirring is continued for one hour. The solution is evaporated, the residue is dissolved in 50 ml of dichloromethane and the solution is washed with 25 ml of 2N aqueous hydrochloric acid. The aqueous mixture is extracted with 25 ml of 15-dichloromethane. The organic phases are combined, washed twice with 20 ml portions of a 5% aqueous solution of sodium carbonate, dried over magnesium sulphate, filtered and the filtrate is evaporated. __ 0.3 g (62%) of trans-4 - ^ “3- (2-methyl-1,3-dioxolan-2-yl) - 20 1- (4-methoxyphenyl) -4-oxo-2 are obtained. -azetidinyl_7-3-ethyl oxo-butanoate.

Analysis:

Values calculated for C20H25NO7 (391.42): C: 61.37%, H: 6.44%, N: 3.58%; \ 25 Values found C: 61.20%, K: 6.59%, N: 3.72%.

IR (film): 1750 cm “1.

b) 0.28 g (1.44 mmol) of tosyl azide and 0.2 ml (1.44 mmol · / of triethyl amine 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 by ice or water. The reaction mixture is stirred at ambient temperature for 2 hours and the progress of the reaction is followed by thin layer chromography (adsorbent, Kieselgel G according to Stahl 35, revealing solvent: 7: 3 mixture of benzene and V * 38 acetone). 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 is freed from the acid, with 10 ml of a 40% aqueous solution. % of potassium 5-hydroxide, then with 10 ml of water. The organic phase is dried over magnasium sulphate, filtered and the filtrate is evaporated. The residue is purified by preparative thin layer chromatography (Kieselgel adsorbent 60 ^ 254 + 366 'eluting agent: 7: 3 mixture of benzene and acetone). 0.25 g (36%) of 2-diazo-4 - / ^ trans-3-, (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4- is obtained. ethyl oxo-2-azetidinyljy-3-oxo-butanoate; mp: 131-132 ° C (ether).

IR (KBr); 2200, 1740, 1710, 1640 cm "1.

15 Analysis:

Values calculated for C20H23N3 ° 7 (4l7 · 41): C: 57.55 S, H: 5.55%, N: 10.07%;

Values found C: 57.56%, H: 5.80%, N: 10.08%.

c) 0.45 g (0.106 mmol) of the compound 20 prepared according to point b) of Method VI is dissolved in 4.5 ml of acetone and a solution of 1 is added dropwise to the stirred solution. 5 g (2.7 mmol) of ceric ammonium nitrate in 4.5 ml of 5% aqueous sulfuric acid. The reaction mixture is stirred for an additional 5 minutes, then the yellow solution is neutralized with a 5% aqueous solution of sodium hydrogen carbonate, then extracted three times with 10 ml portions of ethyl acetate. The organic phases are combined, »dried over magnesium sulfate, filtered and the filtrate J 30 is evaporated. The residue is purified as indicated in the previous point: 0.10 g (27%) of i „2-diazo-4- / ~ 'trans-3- (2-methvl-1,3-dioxolan - is obtained. 2-yl) -4-oxo-

! - '2-Azetidinyl ^ 7-3-ethyl oxo-butanoate; the IR spectrum

! of this compound is identical to that of the substance | "35 prepared according to the procedure in point b) of Method IV.

39 ".

The resulting compound can be converted to the desired starting material, according to the procedure in point n) of Method I.

Example 2 5 3-Benzylthio-6- (2-methyl-1,3-dioxolan-2-yl) - 7-oxo-l-azabicycloZ "" 3,2,0, J7hept-2-ene-2-carboxylate d1 ethyl.

0.91 ml (4.4 mmol) of diphenyl phosphoryl chloride (Ph ^ O ^ PCl) is added at 0 ° C, over a period of 10 minutes, to a stirred solution of 1.133 g (4.0 mmol) 10 of ethyl 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-l-azabicyclo Z ^. 2.0.0_7heptane-2-carboxylate and 0.61 ml (4.4 mmol) of triethyl amine in 10 ml of anhydrous acetonitrile. Next, 0.61 ml (4.4 mmol) of triethylamine is added to the mixture, then 0.52 ml (4.4 mmol) of benzyl mercap-tan and the resulting mixture is stirred at 0 ° C for one hour . The mixture is evaporated in vacuo 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 5 ml portions of water. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue weighing 1.0 g is treated by column chromatography (adsorbent: Kieselgel 60, 0 = 0.063 to 0.200 mm; eluting agent: 7: 1 mixture of benzene and acetone). 0.90 g (58%) of the desired compound are obtained; m.p. = 109 ° C.

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

1H NMR (CDC13): 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), 30 7.33 (s, 5H) ppm.

13C RMN (CDC13): 14.30, 23.35, 36.85, 40.28, 51.94, 61.15, 65.18, 65.33, 67.15, 106.85, 124.4, 127.7, 128.69, 7 128.88, .136.42, 145.93, 161.32, 173.91 ppm.

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

40! ' ·! "

Example 3 3- (formylamino-ethvTthio) -6- (2-methyl-l, 3- \ '^ dioxolan-2-yl) -7-oxo-1 u'a'zabicycio /. 3.2. Oj hept-2-ene-2-carboxylate of p-nitrobenzyl.

5 0.61 ml (4.4 mmol) of triethyl amine and then, over a period of 10 minutes, 0.91 ml (4.4 mmol) of chloride, of diphenylphosphoryl are added at 0 ° C. to a stirred solution of 1.561 g (4.0 mmol) of 6- (2-methyl-1,3-dioxolan-. 2-vl) -3,7-dioxo-l-a2abicyclo / 73- 2.0 ^ heptane-2-carboxylate p -nitrobenzyl in 10 ml of anhydrous acetonitrile. The stirring is continued, then another quantity of 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 in vacuo, the residue is dissolved in 20 ml of dichloromethane and the solution is washed with 10 ml of a 3% aqueous solution of sodium hydrogen carbonate, then twice with 10 ml portions of water. The organic phase is dried over magnesium sulphate, filtered and the filtrate is evaporated. The residue is treated by column chromatography (adsorbent »Kieselgel 60, 0 = 0.063 v to 0.200 mm, eluent: mixture 7; 3 of benzene and acetone) to obtain 1.05 g (64%) of the compound including name is mentioned in the title; mp 183 ° C (ether).

IR (KBr): 3330, 1750, 1680 shoulder ', 1670 cm 1H NMR (CDCl3) + DMSO-dg): £ = 1.43 (ε, 3H); s 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, JAß = 13.8 Hz), 7.68 + 8.20 (d , 4H, JAB = 11 Hz), 8.16 (ε, 1H) ppm.

P-Nitrobenzyl 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo-30 azabicvclo / ~ 3.2.0 / .heptane-2-carboxylate described in Example 3, - can be prepared from: A) acid / Îrans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl J7- acetic, a substance i prepared as described in i 35 points a) to k) of Method I, points a) to i) of% 41 Method II, plus point k) of Method I , or points a) to c) of Method III, then point k) of Method I; or B- Trans-1- (2,4-dimethoxybenzyl) -3- (2-5 methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl _ / - acetic acid, a \ substance prepared according to point i) of Method I, or C- Acid / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4- oxo-2-azetidinyl / acetic, a substance prepared according to the procedure described in point q) of Method II.

Method (A) is carried out as follows a) A mixture of 0.645 g (3.0 mmol) of * / trans-3- (2-methyl-1,3-dioxolan-2-y1) acid -4-oxo-2-azetidinylJ-acetic, 0.535 g (3.3 mmol) of carbonyl diimidazole and 15 ml of anhydrous tetrahydrofuran, is stirred at room temperature for 30 minutes, then 0.825 g (3.3 mmol) of magnesium salt of p-nitrobenzvle malonate is added? mixing and stirring is continued at room temperature for 2 hours. The mixture is left to stand for 16 hours, then evaporated under vacuum. The residue is shaken with a mixture of 50 ml of dichloromethane and 50 ml of 0.5N 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. 0.730 g (6 2.1%) of trans-4- / T * 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-30 2-azetidinyl_7-3-oxo-butanoate are obtained. p-nitrobenzyl.

IB (film): 3250, 1760, 1740, 1720 cm “1.

b) 1.962 g (5.0 mmol) of the compound prepared according to point a) above, is dissolved in 15 ml of anhydrous acetonitrile, then 0.69 ml (5.0 mmol) of triethylamine and 0.985 g (5.0 mmol) of tosyl azide are added to the solution sT 'I * I',.

42 cooled by ice. After 5 minutes of addition, a crystalline substance separates. The mixture is stirred for 20 minutes, then the separated substance is filtered and washed with ether, then dried. 1.326 g (63.4%) 5 of 2-diazo-4 - / _ 'trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl_7 ~ 3-oxo are obtained p-nitrobenzyl butanoate? m.p. : 3 163-164 ° C.

- »IR (KBr): 3220, 2160, 1750, 1710, 1630 cm“ 1.

1H NMR: = 1.41 (s, 3 ^, 2.98 (dd) and 3.44 (dd, 2H, * 10 J = 10 Hz and 4 Hz), 3.18 (d, 1H, J = 2.4 Hz), 3.83-4.15 I ( m, 5H), 5.36 (s, 2H), 6.0 (s, 1H), 7.54 (d) and 8.26 (d, 4H, 9 AB, J = 9 Hz) ppm.

I ”c) A suspension of 1.673 g (4.0 mmol) of! compound prepared according to point b) above, in 45 ml of anhydrous benzene, is stirred and brought to the boil, then 0.050 g of dirhodium tetraacetate Rh (OAc) ^ f2THF_7 is introduced in several portions. After 10 minutes of boiling, the starting material reacted completely. The ? mixture is cooled, the separated substance is dissolved in 20 chlorine adorned thane and the solution is filtered through a pad of Celite. The filtrate is evaporated in vacuo, 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-l-azabicyclo are obtained. F "3.2.0.J7“ hePtane P-nitrobenzyl 2- carboxylate; mp: 167 ° C.

i IR (KBr) λ 1760. 1735 enf1 AH RMN: j = 1.48 s, 3H), 2.47 dd, 1H, J = i gern „19 Hz, J. = 8 Hz), 2.92 (dd, 1H, J = 19 Hz, J. = 8 Hz), '' vie '' 'gem' vie '3.46 (d, 1H, J = 2.4. Hz), 4.0.14.2 (m, 5H), 4.75 (s, 1H), 30 5.30 (d, 2H, JAß = 14 Hz), 7.53 and 8.23 (d, 4H, 9 Hz) 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- <l / trans-3- (2-methyl-1,3-dioxolan 35 -2-yl) -4-oxo-2-azé, tidinyl_7 is obtained. -3-oxo-butanoate of p-nitrobenzyl, the physical constants of which are identical to those of l "43 Ί" compound prepared according to point b) of Method a). The resulting compound can be converted into the desired starting substance, as described in point c) of Method A.

5 Example 4 3- (formylamino-ethylthio) -6- (2-methyl-l, 3- 'dioxolan-2-yl) -7-oxo-l-azabicyclo / T'3.2.0J hept-2-ene-2 - * sodium carboxylate.

A suspension of 0.25 g of a catalyst consisting of 10% palladium on charcoal in 70 ml of a 2: 1 mixture of dioxane and water is stirred in an atmosphere. hydrogen sphere at room temperature for 20 minutes, then a hot solution of 0.477 g (1.0 rmole) of 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl ) -7-oxo-l -azabicvclo / 3,2 .O ^ hept- 15-p-nitrobenzyl 2-ene-2-carboxylate prepared in this way! described in Example 3, in 30 ml of dioxane devoid of! peroxide is added. The reaction mixture is stirred in - an atmosphere of hydrogen for an additional 3 hours, C and then added with a solution of 0.084 g (1.0 mmol) of Γ 20 sodium hydrogen carbonate in the minimum amount of water. The reaction mixture is filtered through a pad of Celite.

The dioxane is evaporated in vacuo from the filtrate and the aqueous residue is extracted three times with 10 ml portions of dichloromethane. Then, the aqueous phase is evaporated in vacuo at room temperature. The residue * crystallizes upon cooling. The crystal line substance is mixed with 6 ml of ethanol and the crystals are separated by filtration. 0.25 g (73%) of the desired compound is collected; m.p. 201 ° C (with decomposition).

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

1H NMR (D20): 0 = 1.42 (ε, 3H), 2.7t3.6 (m, 6H), 3.65 (d, ΊΗ, J = 3 Hz), 3.95-4.3 (m, 5H), 8.03 (s, 1H) ppm.

As is apparent from the above, the invention is in no way limited to those of its embodiments, embodiments and applications which have just been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the framework, or the scope, of the present invention. -

I

I * '! * *

Claims (15)

1. Bicyclic compound characterized in that it is represented by the general formula (I) below yl y2 5. vs HH -SR "v- ° —1 — rr, o: t COOQ * ► 1 2 10 or Y and Y represent a detachable group protecting the carbonyl radical, preferably a ketal group or a thioanalogue thereof, Q ′ is an alkyl group; in v a benzyl group substituted “a hydrogen atom or an alkali metal ion, and R "is an optionally substituted hydrocarbon residue, preferably a benzyl, 2-amino-ethyl or 2-acylamino-ethyl group. 2. Compound according to claim 1, characterized n in that it is 3- (formylamino-ethylthio) -6- (2-methyl-> 20 l, 3-dioxolan-2-yl) -7-oxo -l-azabicyclo / "~ 3.2.0 7 hept-2-ene-2-ethyl carboxylate. 3. Compound according to claim 1, characterized in that it is, 3-benzylthio-6- (2-methyl-l, 3-dioxolan-2-yl) -7-oxo-l-azabicylo. /3.2.0 7 'ethyl hept-2-ene-2-carboxylate. 4. Compound according to claim 1, characterized in that it is 3- (formylamino-ethylthio-6- (2-methyl- # 1,3-dioxolan-2-yl) -7-oxo- l-azabicyclo ^ 3.2.0 ~ I hept-2-ene-2-carboxylate of p-nitrobenzyl. 5. Compound according to claim 1, characterized in that it is 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-l- azabicyclo. /3.2.0 7 sodium hept-2-ene-2-carboxylate. 6. Process for the preparation of a new bicyclic compound represented by the general formula (I) according to Γ · “B Λ 46; ; claim 1, characterized in that: | a) treating a compound represented by the [- general formula (II) below: j i. t c yl γ2! 5 / h 5 ^. 0 | ;; . Ïï5 ° -C - [] '(II) \ f ®' ^ COOQ, L * t ,: F '12 f | 10 in which Y and Y are as defined above and! Q is a C 1-6 alkyl group or a benzyl group substituted by a suitable O-acylating agent, preferably by a sulfonyl or phosphoryl halide, then by a mercaptan, preferably by benzyl merceptan, la 'la cysteamine or an N-acyl derivative thereof, in the presence of a tertiary amine and the resulting product is separated from general formula (I), where Q 'is a group, "- C1-6alkyl or substituted benzyl ; or, b) from a compound of general formula (I) ^ 12 dd ^ 20 obtained in step a), where R ", Y and Y are as defined | above and Q ’is a substituted benzyl group, I Q’ is removed by reduction and, if desired, the resulting carboxylic acid (Q ’= H) is converted to its 1: alkali metal salt. f ·· ί 25 7. Method according to claim 6, characterized î * in that the diphenyl phosphoryl chloride is applied f as O-acylating agent. 8. Method according to claim 6, characterized t in that the N-formyl-cysteamine is applied as 3. N-acylated derivative of cysteamine. * 9. Method according to claim 6, characterized -f *! in that the substituted benzyl group is removed by | <catalytic hydrogenation. | - 10. Method according to claim 6, characterized I 35 in that a free carboxylic acid is converted to its salt * * 47! of alkali metal by reaction with an alkali metal carbonate or acid carbonate. 11. The method of claim 6, for the preparation of 3- (formylamino-ethylthio) -6- (2-methyl-l, 3-5 dioxolan-2-yl) -7-oxo-l-azabicyclo / "3.2. O.J7hept ~ 2-ene-2-ethyl carboxylate, characterized in that one reacts v the 6- (2-methyl-l, 3-dioxolan-2-yl)) - 3,7-dioxo- l-azabicyclo rh JL 3.2.0_7'heptane-2-ethyl carboxylate, in the presence of a - - tertiary amine, with an O-acylating agent, then with * 10 N-formyl-cststeamine. 12. The method of claim 6 for the preparation of 3-benzylthio-6- (2-methyl-1,3-dioxolan-2-yl) -7-oxo-1-azabicyclo / -3.2.Q7; hept- Ethyl 2-ene-2-carboxylate, characterized in that the 6- (2-methyl-1,3-dioxolan-15 2-yl) -3,7-dioxo-l-azabicyclq / ~ is reacted 3.2.07 ethyl heptane-2-carboxylate, in the presence of a tertiary amine, with an O-acylating agent, then with benzyl mercaptan. 13. The method of claim 6 for the preparation of 3- (formylamino-ethylthio) -6- (2-methyl-1,3-dioxolan i 20 -2-yl) -7-oxo-l-azabicyclo2T 3.2 .J7hept-2-ene-2-p-nitrobenzyl carboxylate, characterized in that 6- (2-methyl-1,3-dioxolan-2-yl) -3,7-dioxo- 1- is reacted azabicyclo / -3.2.0 DD? p-nitrobenzyl heptane-2-carboxylate, in the presence of 1; tertiary amine, with an 0-acylating agent, then with N-formyl-cysteamine. 14. The method of claim 6, for the preparation of 3- (formylamino-ethylthio) -6_ (2-methyl-1,3-dioxolan-2-yl) -7-oxo-l-azabicyclo /. " '3.2.0_7hept-2-enne-2-carboxylate! Of sodium, characterized in that 3- (formylamino-ethvlthio) -6- (2-methyl-1,3-dioxolan-2-yl) is reduced -7-oxo-l-azabicyclo-JT3.2.0 J ^ hept-2 -in -2-carboxylate of p-nitrobenzyl, then in this •. There that it is converted to its sodium salt. -15. Pharmaceutical composition, characterized in that it contains an effective amount of a compound represented by the general formula (I) or Y1 (Y2, Q 'and B "are as defined in claim. L