LU84570A1 - PROCESS FOR THE PREPARATION OF NEW BICYCLIC COMPOUNDS AND COMPOUNDS THUS OBTAINED - Google Patents

Description

bed b πΗ "^ 9

The present invention relates to a process for the preparation of new bicyclic compounds represented by the general formula (I) below: I 5 π o V * | ] - ^ r ° IK ^ qqo ^ I in which: I 10 y · * - and Y2 represent a protective acetyl group to the carbonyl radical, preferably a ketal group I or a thioanalogue thereof, and Q is an alkyl group in to ^ or a substituted 9 'zyl group.

Some of the compounds represented by the general formula 9 (I) constitute useful inhibitors of 9 ß-lactamase, others are interesting intermediates B of the synthesis of thienamycin and its analogues.

[1 The new compounds of general formula (I), as well as H 20 and another process for preparing them, are protected in 9 another Applicant's Patent Application.

9 Thienamycin, a broad spectrum antibiotic, was first prepared microbiologically (American Patent 3,950,357 and then by chemical synthesis 9 (German Patent Application 2 751 597).

The aim of the present invention is to provide a new pathway 9 for the synthesis of thienamycin and 9 of its analogs, according to which the backbone azetidinone 9 and the side α-hydroxyethyl chain, or a side chain which can be easily converted to group B α-hydroxyethyl, are formed simultaneously in the first step of the synthesis and the resulting key intermediate is then converted into the desired final product.

H It has been found that by acylating a dialkyl malonate 9 35 of which the amino group is protected, with diketene, 2 ".

then reacting the resulting acylated product with iodine and an alkali metal alcoholate, an azetidinone compound is obtained represented by the general formula * (X) below:

HvC - C -. (COOZ) 3 1 2 {X) \ R ’10 containing an α-acetyl chain chain, 'which may be used as a key intermediate in synthesis.

In the above formula, R 'represents a detachable group protecting the amido- radical, other than a phenyl group, preferably a phenyl or benzyl group bearing one or more C1-C6 alkoxy substituents and Z is a group alkyl in to.

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

It has also been observed that before converting the intermediate of general formula (X) into thienamycin or its analogs, it is preferable to protect the ketone group from 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 stage of the synthesis. Ethylene glycol or a thioanalogue thereof 30, such as mercaptoethanol, can be particularly preferably applied to form a protective ethylene ketal or hemithioketal group. The resulting compound I I is represented by the general formula (IX) | below:

V

! ".

s.

3 ï1 ï2. H3C 1-i (COOZ) 2 _ ·, (ΙΣ) 5 '-H * I *> where Y and Y "together form a group for the temporary protection of the carbonyl part, preferably an ethylene ketal group or a thioanalogue of that -ci and R 'and Z 10 are as defined above, and it is then reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide to obtain a compound represented by the formula general (VIII) below:

~ 15 γΐ y2 H H

h5C _v -] - ycooz „(wine)

! Cr V

U \ P »1 2 20 in which R ', Y and Y and Z are as defined above.

The resulting compound of general formula (VIII) is a mixture of cis and trans isomers. The isomers can be separated from each other by chromatography or by virtue of their different solubilities. The separate trans isomer represented by the general formula (Villa) below -: ï1 ï2 H? GOOZr

£ v / f -X

II · 3o h5c, -c --- J

_.¾ (Villa) n S \ u R * can "be converted into the trans-carboxylic acid represented by the general formula (VII) below: * v" 4 Y \ yY?? Cooh

HjC - C-- O * —- \ (VII) 5 H "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 10 converts to the respective carboxylic acid.

The separate trans-carboxylic acid of general formula (VII) reacts first with an activator for the carboxyl group, then with diazomethane and the resulting compound represented by the formula (VI) below: \ / ^ 2 f ϊί COCHE ,, H * C - C-1-X ά l {VI) o ^ \ R> 20 is subjected to a Wolff transposition in the presence of water to obtain an azetidinoacetic acid represented by the general formula (V) ci -after: \ / Ύ E? CHpCOOK H * C - C - ^ ^ J_r (V)

0 * R

R "which can be applied as a starting material in the process according to the present invention.

In the general formulas (VII), (VI) and (V), 1 2 R ', Y and Y are as defined above.

; Some of the new compounds of general formula (IX) are described in Applicant's Hungarian Patent Application No. 2263/80. The other compounds of general formula (IX) as well as the new 5 A.

% composed of general formulas (VIII) to (V) are described in detail in the Applicant's Patent Applications.

The compounds of general formula (V) can be converted into the desired end products of generic formula (I) by two methods.

In accordance with a method of the present invention, a compound of general formula (V) is reacted with a salt of a malonic hemiester and the resulting compound of general formula (IV) is treated below:

. Y J- yÉ- JJ JJ

\ ^ / y CHpCOCHpCOOQ

H ^ C - C

J-K ’(IV) \, 1

E

1 2 15 where R ', O, Y and Y are such rrue defined above, with a sulfonic azide in the presence of a tertiary amine to obtain a compound of general formula (III) below: ï1 Y2 p rj 20 H , C -V_s_§ / CH2C0CN2C003 0 J --- K (III) ^ E »1 2 where R *, Q, Y and Y are as defined above. The compounds of general formulas (IV) and (III) are new, and also included within the scope of the present invention.

In accordance with the other method of the present invention, a compound of general formula (V) is activated - on its carboxy group - and then caused to react with a diazoacetic ester, to obtain a compound of general formula (III).

The protective group R ′ of the compound resulting from! formula (III) is then eliminated and the resulting compound 35 represented by the general formula (II) below: i i ·, yl γ2 Η Η

\ CHPC0CN2C00Q

Η “C

_: m · s.

1 2 where Q, Y and Y are as defined above, is subjected to a cycle closure to obtain the desired compound of general formula (I).

The compounds represented by general formulas (I) to (V) are racemic mixtures.

From these considerations, the present invention relates to a process for the preparation of a compound of general formula (I), in which: 1 2 15 Y and Y represent a detachable group protecting the carbonyl radical, preferably a group ketal or a thioanalogue thereof, and Q is a C1-alkyl or a substituted benzyl group, wherein:

• 1 2 a) a compound of general formula (V) where Y and Y

are as defined above and R ′ is a detachable group protecting the amido- radical, other than the phenyl group, preferably a phenyl or benzyl group carrying one or more alkoxy substituents; carboxy- group, then reacted with a malonic hemiester salt, in which the alcohol component is a C 1 to ς aliphatic alcohol or a substituted benzyl alcohol; x D 12 the resulting compound of general formula (IV), where Y, Y, 130 R * and Q are as defined above, is then reacted with a sulfonic azide in the presence of a tertiary amine,; then the protecting group R ′ of the resulting compound of general formula (III) is eliminated and the resulting compound l of general formula (II) is subjected to a closure of f | 35 cycle, preferably in the presence of a rhodium salt, or i 1 j (7.

1 2 a compound of general formula (IV), where Y, Y, R 'and Q are as defined above, is reacted with a sulfonic azide in the presence of a tertiary amine, then the protective group R' of resulting compound of general formula 5 (11¾ is eliminated and the resulting compound of general formula (II) is subjected to ring closure, preferably in the presence of a rhodium salt, or the protective group R 'of a compound of general formula 1 2 (III) where R ', Q, Y and Y are as defined above, is eliminated and the resulting compound of general formula (II) is subjected to ring closure, preferably in the presence of a rhodium salt, or a compound of general formula (II), where Q, Y1 and 2 Y are as defined above, is subjected to a ring iron, preferably in the presence of a salt of rhodium; or b) a compound of general formula (V), where R ', Q, 1 2 Y and Y are as defined above, is activated on its carboxy group and then reacts with a diazoacetic ester, the protecting group R 'of the resulting compound of general formula (III), where R', Q, Y and Y are as defined above, is eliminated and the resulting compound of formula general (II) where Q, Y and Y are as defined above, is subjected to cy-key closure, preferably in the presence of a rhodium salt, and the resulting compound of general formula (I) is then separated.

In accordance with method A) of the present invention, a compound of general formula (V) is first activated on its carboxy group. Any activating agent compatible with the & -lactam cycle can be used. for this purpose, and, among others, carbonyldiimidazole | is particularly preferable.

The activated compound then reacts with a salt of a malonic hemiester, preferably a salt of malonate i I *.

V

ethyl or (p-nitrobenzyl) malonate.

The resulting compound of general formula (IV) is then treated, in the presence of a tertiary amine, with a sulphonic azide, preferably tosylazide, to form a compound of general formula (III), then the protective group R 'is removed from the resulting compound.

The protective group R 'can be removed by oxidative methods. When the protective methyloxybenzyl group must be removed, a compound of the peroxy-10 disulfate type is applied, preferably potassium or sodium peroxydisulfate (K2S20g.or Ν32ε208) as an oxidizing agent. The reaction is carried out in the presence of water and an organic solvent and the mixture is buffered to pH-7.

When a methophenyl protecting group is to be removed, it is preferred to apply a cerium (IV) salt as an oxidizing agent in the presence of an acid. A solution of cerriuri-amrionium nitrate in dilute aqueous sulfuric acid appears to be particularly suitable for this purpose. The oxidation is carried out in the presence of an organic solvent.

In the final stage of the synthesis, the resulting compound of general formula (II) is subjected to a cycle closure. This reaction is carried out in an inert solvent, with heating, in the presence of a rhodium salt, preferably dirhodium tetraacetate. The product is separated from the reaction mixture, preferably by evaporation.

In accordance with method B) of the present invention, a compound of general formula (V) is first activated on the carboxy group with an activator compatible with the β-lactam ring. Activators which form acyl chlorides are particularly advantageous.

The activated compound is then reacted with a diazoacetic ester, preferably with ethyl diazoacetate. The resulting compound of general formula (III) 9 is then converted into the desired end product of general formula (I) as described above.

Among the compounds represented by the general formula (I), those in which Q is a substituted benzyl group can be converted into thienamycin or an analog thereof, as illustrated by scheme (A):

Diagram (A) H5c - ^ -— 4 — V ^ t °

0J- N-L-COOQ

1. O-acylation 15 o "d-, + mercaptan 3 · salt formation Λ1 / *

20 H5C - ° [I

0J-® ^ rooster »1 2

In the above formulas, Y and Y represent a detachable group protecting the carbonyl radical, Q is a C 1 to C 4 alkyl group or substituted benzyl, Q * 25 is a C 1 to C 4 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is a benzyl, aminoethyl or N-acyl-aminoethyl group.

The compounds of general formula (I) in which Q is an alkyl group are pharmacologically active.

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.

It should be understood, however, that these working examples are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.

EXAMPLE_1 6- (2-methyl-I, 3-dioxolan-2-yl) -3,7-dioxo-1-azabicyclo / 3,2,07heptane-2-ethyl carboxylate 10 Dirhodium tetraacetate (OAc) 4, 2THF7is added to a boiling solution of 1.245 g (4.0 mmol) of 2-diazo-4- ^ trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -3-ethyl oxo-butanoate in 10 ml of benzene, in small portions, until the starting substance has completely reacted (this requires approximately 0.03 g of the rhodium salt). The reaction mixture is filtered through a pad of Celite and the filtrate is evaporated. The residue crystallizes on standing. 1.13 g (100%) of the sought product are thus collected; m.p. : 109 ° C.

20 IR (KBr): 1750, 1735 cm “1.

2H NMR: δ = 1.30 (t, 3H, J = 7.4 Hz), 1.49 (s, 3H,) 2.41 (dd, 1H, Jgem = 19.5 Hz, Jvic = 7.5 Hz), 2.90 (dd, 1H,

Jgem = 19.5 HZ / Jvic = 7 '° Hz)' 3'43 (from 1H 'J = 2'4 Hz) / 3.97-4.20 (m, 5H), 4.24 (q, 2H, J = 7.4 Hz), 4.63 (t, 1H, 25 J = 0.6 Hz) ppm.

The starting material can thus be prepared from a compound bearing a 2,4-dimethoxybenzyl group - protecting, see below: a) A mixture of 109.8 g (0.66 mole) of 2,4-dimetho-30 xybenzaldehyde, 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 j ·; ice water and gradually added 13.2 g (0.33 mole)

P

I 35 borosodium hydride.

Γ t * ιι The progress of the reaction is monitored by thin layer chromatography (Kieselgel G according to Stahl; revealing solvent: mixture 9; 1 of benzene and acetone) and at the end of the: reaction, the mixture is evaporated S dry, under vacuum. The residue 5 is mixed with 300 ml of water and the aqueous mixture is extracted with portions of 500 ml, 200 ml and 200 ml of ether The ethereal solutions are combined, dried over magnesium sulfate, filtered, then the filtrate is supplemented 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 and provides 197 g (72%) of diethyl N-benzyl-N- (2,4-dimethoxybenzy1) -amino-malonate; m.p. : 62-63 ° C (ethanol).

IR (KBr): 1750/1725 cm “1, d.

b) 61.7 a (0.149 mol) of diethyl N-benzyl-N- (2,4-dimetho-xybenzyl) -amino-malonate, prepared according to point a) described above, 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 catalyzer 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.

30 Analysis:

Values calculated for C ^ g ^^ ClNOg (361.82): C: 53.11%; H: 6.69%, Cl: 9, .80%; N: 3; 87%; "found: j | C: 52 d 51%, H: 6.77 l, Cl: 10.30%; K: 4.09 l.

I i k

V

k 12 IR (film): 3250, 2900, 2850, 1730, 1720 cm "1.

1H NMR (CDC13): δ = 1.3 (t, 6H), 3.78 (s, 3H), 3.82 (s, 3H), 4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H) + 7 ^ -7 ,! (m, 1H), Ί (large s, 1H) ppm.

C) A mixture of 39.6 g (0.122 mol) of diethyl (2,4-dimethoxybenzylamino) -malonate, prepared according to point b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 mole) of diketene, is brought to the boil for 0.5 hour · The 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-ΟΧΟ-2,2-pyrrolidine-dicarboxylate and / or its tautomer are collected. pf Mp: 106-107 ° C.

Analysis:

Values calculated for ^ Q ^ yNOg (409.43): C: 58.67%, H: 6.65%, N: 3.42%; 20 „.

found: C: 58.79%, H: 6.33%, N: 3.34%.

IR (KBr): 3400, 2950, 2850, 1730 (1740, sh), 1710 cm '1H NMR (CDC13): 6 = 1.1 (t, 3H), 1.17 (t, 3H), 1.52.

25 (s, ^ 3H), 2.8 (<0.1 H), 2.65 (large ε, 2H), 3.75 (ε, 6H), 3.8-4.15 (m, 4H), 6.7 (large ε, 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) above are put in suspension in 50 ml of anhydrous ether and the 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 (50 mmol) of iodine in 150 ml of anhydrous ether, from two vigorously stirred bromine vials 35 and cooled by ice water. Then we add to the b

V

b 13 stirred mixture, 5 g of sodium hydrosulfite, dissolved in 200 ml of a saturated aqueous solution of sodium chloride. The mixture is introduced into a separatory funnel and 60 ml of water are added to dissolve the separated mineral salts.

The organic phase is removed, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue, weighing 18.5 g, is crystallized from 30 ml of 2-propanol. Obtained: 10.9 g (54%) of 3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine-diethyl dicarboxylate; m.p. : 84-85 ° C (2-propanol).

Analysis:

Values calculated for C20H25NO8 C: 58.96, £, H: 6.19 £, K: 3.44%; "found: 15 C: £ 58.99, H: 6.04%, N: £ 3.57.

1H NMR (CDC13): δ = 1.12 (t, 3H), 1.21 (t, 3H), 2.33 (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 20 mole) of boron trifluoride-diethyl etherate are added dropwise to a vigorously stirred solution of 379 g (0.484 mole) of 3-acetyl-3 - (2,4-dimethoxybenz .yl) -4-oxo-2,2-azetidine-dicarboxylate. diethyl and 107 ml (120 g, 1.936 mole) of 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) NaCO 2, 10H 2 was added slowly to the stirred mixture and cooled with ice water and the mixture was stirred for 15 minutes. Then, 1 liter of ether and 1 liter of water are added and the phases are separated from each other. The aqueous phase I is shaken twice with 500 ml portions of diethyl ether. The ethereal phase is dried over! "; l! - * 14 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 betnzene and ethyl acetate).

At the end of the reaction, that is to say after approximately 15 hours, the mixture is poured into 1100 ml of saturated aqueous solution of saturated sodium chloride, the resulting mixture is shaken with 1000 ml, then twice with portions, from 500 ml 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; P.f. : 95 ° C.

f) A mixture of 0.5 g (1.2 mmol) of 3-acetyl-20 i- (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, 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 is separated from the filtrate by preparative thin layer chromatography (adsorbent: Kieselgel 60 ^ 254 + 366 ' Developer 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-I diethyl dicarboxylate. "\\.

| 15 1H NMR (CDC13): 6 = 0.8-1.55 (m, 6H), 1.72 + 1.77 (d, 3H), 2.9 -3.4. (m, 2H) f 3.75 (s, 6H), 4.0r5.0 (m, 9H), 6.4. (m, 2H) + 7.1 (d # 1H) ppm.

g) A solution of 5.21 g (0f130 mole) of sodium hydroxide in 60 ml of water is added to a suspension of 41r2 g (0.109 mole) of trans-1- (2,4-dimethoxybenzyl) - 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylate of ethyl 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%) of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl- 1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic; m.p. : 117-118 ° C (toluene).

Analysis:

Values calculated for C17H21N07 (351‘35): 25 C: 58.11%, H: 6.03%, N: 3.99%;

Valems found: C: 58.17%, H: 6.30%, N: 4.24% IR (KBr): 3500-2500, 2900, 1760, 1720 cm 1.

NMR (CDC13): 6 = 1.39 (s, 3H), 3.50 (d, 1H, 30 J = 2.5 Hz), 3.77 (s, 3H), 3.79 (s, 3H), 3.86 (d, 1H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JAß = 15 Hz), 6.44 (m, 2ή) + 7.15 (d, 1H, J = 10 Hz), 7.58 (large s, lH) ppm.

ü%: 3 »» J. 6 h) 7.3 ml (52.5 mmoles) of triethyl amine are added to a solution of 17.6 g (50 mmoles) of trans-1- (2,4-dimethoxybenzyl) acid -3- (2-methyl-1,3-dioxolan ~ 2-yl) - 4-oxo-2-azetidine-carboxylic prepared according to point g) 5 above, in 150 ml of anhydrous tetrahydrofuran, then 5.0 ml (52.5 ml) of ethyl chloroformate 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 ml of diazomethane in 230 ml of diethyl ether the mixture is stirred, allowed to warm to ambient temperature and after 2 hours of stirring, evaporated to dryness, the thick brown residue is dissolved in 20 ml of benzene and the product is separated by chromatography on column {adsorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0.200 mm, eluting agent: 7: 2 mixture of benzene and acetonel Collect: 12.0 g (64%) of trans-4- / (diazoacetyl) -1 - (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-20 dioxolan-2-yl) -2-azetidinone.

Analysis: Value calculated for (375.37): C-.57.59%, H: 5.64%;

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

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

I) A mixture of 2.25 g (6 mmoles) of trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone prepared according to point h) above, 100 ml of tetrahydrofuran devoid of peroxide and 50 ml of water, is irradiated for approximately 4 hours, with a high-pressure mercury lamp (HPX 125), immersed in a Pyrex reactor, under an argon atmosphere. The solution is evaporated in vacuo to a final volume of 50 ml and the concentrate I is diluted with water to 130 ml. 2.4 ml of a 10% aqueous solution of sodium hydroxide 117 are added to the stirring 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 5 is extracted three times with 20 ml portions of dichloromethane. The extracts are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated to eec. The residue is crystallized from ether. We collect lt82 g (83%) of acid / trans-1- (2,4-dimethoxybenzyl) -3-10 (2-methyl-l, 3-dioxolan-2-yl) -4-oxo ~ 2-azétidinyl_7 -acetigue mp: 124 ° C (ether).

Analysis:

Calculated values for C] _8H23N07 (365.37): C: 59.17%, H: 6.34%, N: 3.83%; 15 Values found C: 59.22%, H: 6.49%, N: 4.07%.

IR (KBr): 3500-2300, 2900, 1730, 1700 cm-1, j) 0.364 'g (2.2 mmoles of 98% carbonyl-diimidazole) is added to a solution of 0.730g (2 minutes) / trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -20 4-oxo-2-azetidinyl / -acetigue, prepared according to point i ) above, in 10 ml of anhydrous tetrahydrofuran and the mixture is stirred for 20 minutes. 0.315 g (2.2 mmol) of the magnesium salt of monoethyl malonate is added to this solution and stirred for 2 hours. The reaction mixture is evaporated, the residue is shaken with a mixture of 40 ml of dichloromethane and 40 ml of 0.5N aqueous hydrochloric acid, 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 sulfate, filtered and the filtrate is evaporated. 0.41 g (47%) of trans-4- / ï- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dicxolan-2-yl) -4-oxo-2- is obtained. Ethyl az-etidinyl7-3-oxo-butanoate.

i (18 IR (film): 1750, 1740, 1720 cm “1.

XH NMR (CDCI3): 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.

5 k) 0.69 ml (5.0 mmol) of triethylamine and 0.986 g (5.0 mmol) of tosylazide are added to a solution of 2.177 g (5.0 mmol) of trans-4- ^ 1- (2 , 4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-ethyl oxo-2-azetidinyl7_3-oxo-butanoate, prepared according to point j) described above, in 15 ml of anhydrous acetonitrile under ice 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, 0 = 0.063 to 0.200 mm, eluent: 1: 3 mixture of benzene and acetone). 1.41 g (61%) of 2-diazo-4-trans- / 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) - 4- are obtained. ethyl oxo-2-azetidinyl7 ~ 3-oxo-butanoate.

120 1) 5.4 g (20 mmoles) of potassium peroxydisulfate (K ^ S ^ Og), 7.2 g (40 irmoles) of disodium acid phosphate mondhydrate (1 ^ 2 ^^) 4.1 ^ 0) and 18 mL of water, are added to a solution of 2.340 g (5.0 irmoles) of 2-diazo-4-trans- / l- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3) ethyl dioxolan-2-yl) -4-oxo-2-az-etidinyl / -3-oxo-butanoate prepared according to point k described above, in 30 ml of acetonitrile and the mixture is brought to boiling for 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

Ides 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, j 0 = 0.063 to 0.200 mm, eluent: 7: 3 mixture of benzenine and acetone) to obtain 0.56 g (36%) from 2-diazo-! 35 4-trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -

! 'I

Î 19 1 ethyl 3-oxo-butanoate.

I ’IR (film): 3280, 2160, 1760, 1720, 1640 cm“ 1.

ro) The product obtained in point k) above can also be prepared in accordance with method B) of the invention, according to the following procedure:

One 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-dimethoxybenzyl) acid. ) -3- (2-methyl-1,3-dioxolan-2-yl) - 10 4-oxo ~ 2-azétidinyl7 ~ acetic acid prepared according to point i) I above, in 10 ml. Of dichloromethane while cooling - dissant with ice. 1.7 ml of ethyl 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 H benzene and acetate). 0.17 g (7.3%) of I2-diazo-4-trans- / l- (2,4-dimethoxybenzyl) -3- (2-methyl-20,3,3-dioxolan-2-yl) is obtained -4-oxo-2-azetidinyl7 ~ 3-ethyl oxo-butanoate. The IR spectrum of this compound is indicated below: h IR (film): 2160, 1750, 1720, 1640 cm 1.

The starting material of Example 1 can also be prepared from a compound in which R 'is 9 a protective 4-methoxyphenyl group, according to the following procedure: 9, A) A mixture of 24.6 g (0.2 mole) of 4-methoxyan 9 and 23.9 g (17 ml, 0.1 mole) of diethyl bromomalonate are stirred at room temperature for 2 days. The resulting mass is triturated with 100 ml of diethyl ether, 1 separate 4-methoxy-anisidine hydrobromide is filtered and washed with a small amount of diethyl ether. The liquor is evaporated and the residue is crystallized from dilute acetic acid. 13.22 g (47%) of diethyl (4-methoxyanilino) -malonate are obtained: mp .: 64-65DC (ethanol).

Analysis:

Values calculated for Hi9N05 (281.31): 5 C: 59.77%, H: 6.81%, N: 4.99%;

Values found C: 59.99%, H: 6.97%, N: 5.25%.

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

ΧΗ 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 (ε, 1H ), 4.1-4 ^ 5 (wide 10 s, 1H), 6.55 (2H) + 6 ^ 3 (2H, AA'BB ', J = 9 Hz) ppm.

B) A mixture of 11.2 g (0.04 mole) of (4-methoxy-anilino) -methylate diethyl, prepared according to point A) described above, 15 ml of glacial acetic acid and 4 g (3 , 7 ml, 0.048 mole) of diketene is boiled 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-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer are collected; mp: 20 136-137 ° C (ethyl acetate).

'Analysis:

Calculated values for C28H23N07 (365.38): C: 59.17%, H; 6.39? .. N: 3y83%; 2ii 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 (ε, 3H), 2.76 (s, 2H), 3.64 (ε, 1H), 3.76 (s, 3H), 4.1 (q, 2H, J = 7.2 Hz), 4.27 (q, 2H, J = 7.2 H: 30 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-pyrrolidine-dicarboxylate, prepared according to point 3) described above, are suspended in 50 ml of anhydrous diethyl ether and a solution of 1.72 g of metallic sodium in 30 ml of ethanol

! I

4 "; 8 i S tb fcB% anhydrous, so that a solution of 6.35 g (0.025 mol) of iodine I 'in 50 ml of anhydrous diethyl ether is poured dropwise simultaneously into the vigorously stirred suspension and cooled with ice. Then, the mixture is poured I 5 into 100 ml of a saturated, aqueous solution of sodium chloride I 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 50 ml portions of diethyl ether. The ethereal phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is triturated with 8 2-propanol to obtain 6.2 g (68%) of crystalline diethyl I crystalline 3-acetyl-1- (4-metho-xyphenyl) -4-oxo-2,2-azetidine-dicarboxylate; mp: 70-71 ° C (ethanol).

B 15 Analysis: B Values calculated for CiDHo1N0t (363.38): B C: 59.50%, H: 5.82%, N: 3.85%; I Values found C: 59.04 H ,, H: 5.84%, K: 4.08%, 1 IR (KBr): 1760, 1735, 1720 cm “1.

1 20 1H NMR (CDC13): 6 = 1.20 (t, 3H, J = 7.2. Hz), 1.22 1 (t, 3H, J = 7.2 Hz), 2.33 (s, 3H), 3.7 (ε, 3H), 4.17 (g, 2H, 9 J = 7.2..-Hz), 4.19 (g, 2H, J = 7.2 Hz), 4.7 (ε, 1H), 6.7 1 (2H) + 7.31 (2H, AA 'BB', J = 9 Hz) ppm.

B D.) 6 g (0.0165 mol) of 3-acetyl-1- (4-methoxyphenyl) B 25 4-oxo-2,2-azetidine-diethyl dicarboxylate, prepared according to I point C) described above, are dissolved in 20 ml of 1 anhydrous dioxane and 4.1 g (3.75 ml, U, ü & 6 drown) of ethylene glycol.

B 7.1 g (6.3 ml, 0.05 mole) of 1 boron trifluoride-diethyl etherate complex are added dropwise to the stirred solution, cooled with ice and the reaction mixture: is stirred for an additional 2 hours at room temperature. The solution is made alkaline with an aqueous solution saturated with sodium hydrogen carbonate, then added with 100 ml of water and the mixture is extracted! 35 times with 50 ml portions of diethyl ether. The i S * t / 22 organic phases are combined, dried over magnesium sulphate, 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-yl) -1- (4-methoxypheny 5 -4-OXO- Crystalline diethyl 2,2-azetidine-dicarboxylate; mp: 82-83 ° C (ethanol).

Analysis:

Calculated values for ^ 20 ^ 25NO8 (407.43): C: 58.96%, H: 6.18%, N: 3.44%; 10 Values found C: 58.70%, H: 5.68%, N: 3.63%.

IR (KBr): 1740 cm 1 (wide) 1H NMR (CDC13): ό = 1.17 (t, 3H, J = 7.2 Hz); 1.26 (t, 3H, 3 = 7.2.Hz), 1.5 (s, 3H), 3.7 (s, 3H), 3.9 (m, 4H), 4.2 (m, 5H), 6.67 (2H) + 7.34 (2H, AA * BB ', J = 15, _9 Hz) ppm.

E) 2 3 g (0.0245 mole) of 3- (2-methyl-1,3-dioxolan 2-yl) -1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate , prepared according to point D) described above, SOr dissolved in 20 ml of dimethyl sulfoxide, then 1.72 g 20 (0.0295 mole) of sodium chloride and 0.9 ml (0.049 mole) of water are 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: Kieselgel G according to Stahl; revealing solvent: mixed ¢,: 4 cc. 25 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; The organic phases are combined, dried over magnesium sulphate, 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 I / 23 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 concentrated aqueous 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.

4 g (54%) of trans-3- (2-methyl-1,3-dioxol <10 -2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidine-carboxylic acid are collected. .

Analysis:

Calculated values for C25H27N0g (307.32): C: 58.63%, H: 5.57%, N: 4.56%;

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

15 IR (KBr): 3400-2700, 1750 (wide) cm "1 * 1H NMR (CDC13): δ = 1.5 (s, 3H), 3.7 (d, 1H, J = 2.5

Hz), 3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, 1H, J = 2.5 Hz), 6.82 (2H) + 7.26 (2H, AA 'BB *, J = 9.5 Hz) , 9.2 (s, 1H) ppm.

F) 1.11 g (1.56 ml, 0.011 mole) of anhydrous triethylamine, is added to a solution of 3 g (0.01 mole) of a compound prepared according to point E) above, in 20 ml anhydrous tetrahvdrofuran. 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 stirring for 20 minutes, the separated salt is filtered under a nitrogen atmosphere and a solution of 4.8 g (0.025 mole) of 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 in vacuo. The oily residue slowly crystallizes. 3 g (90%) of trans-4-fdiazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) are obtained.

-1- (4-methoxyphenyl) -2-azetidinone; mp: 95-96 ° C

124 IR (KBr): 2200, 1760, 1640 cm “1.

1H NMR (CDC13) ϊ δ = 1.50 (s, 3Η), 3.51 (d, 1Η, J = 2.6 Hz), 3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, 1H J = 2.6 Hz ), 5.47 (s, 1H), 6.85 (2H) + 7.30 (2H, AA 'BB', J = 5 9 Hz) ppm.

G) 3.3 g (0.01 mole) trans-4- (diazoacetyl) -3- (2-methyl-1, 3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-aze-tidinone prepared according to point F) described above, are dissolved in a mixture of 50 ml of water and 100 ml of tetrahydrofuran. The mixture is irradiated with a high-pressure mercury lamp in a photoreactor under a nitrogen atmosphere (the reaction is carried out at room temperature) and the progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to 15 Stahl; revealing solvent: 7: 1 mixture of benzene and acetone). When the reaction is complete, the tetrahydrofuran is distilled in vacuo, the residue is basified with a 20% aqueous solution of sodium hydroxide and the solution is washed twice with 15 ml portions of aichloromethane. 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 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-2-azetidinyl are obtained. J? -Acetic.

Analysis:

Calculated values for ^ 26 ^ 19 ^^ 6 (321.33): 30 C: 59.80%, H: 5.96%, N: 4.36

Values found C: 59.60% f H: 5.76%, N: 4.08 ÏR (film): 3500-2500, 1760-1700 cm "1.

»» 25 H) 0.4 g (1.24 mmol) of acid / trans- 3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl-4-) is dissolved. oxo ~ 2-az-etidinyl / -acetic prepared according to point G) described above, 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 one hour. When the evolution of gas stops, 0.196 g (1.36 mmol) of the magnesium salt of the 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 an aqueous solution of 2N hydrochloric acid. The aqueous phase is extracted with 25 ml of dichloromethane. The organic phases are combined, washed at two repri-ses with 20 ml portions of a 5% aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and the filtrate is evaporated. 0.3 g (62%) of trans-4- / 3- (2-methyl-1,3-dioxolan-2-ylj-l- (4-methoxyphenyl) -4-oxo-2-azetidinyl7-3 is obtained. -ethyl oxo-butanoate.

20 Analysis:

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

IR (film): 1750 cm 25 I) 0.28 g (1.44 mmol) of tosyl azide and 0.2 ml (1.44 moles) of anhydrous triethylamine are added to a stirred solution of 0.5 g (1 , 44 mmol) of the compound prepared according to point H) described above, in 6 ml I of anhydrous acetonitrile, with cooling by ice or water. The progress of the reaction is monitored by thin layer chromatography (adsorbent:

Kieselgel G according to Stahl, revealing solvent: 7: 3 mixture of benzene and acetone). After two hours of stirring at room temperature, the mixture is evaporated, the residue is dissolved “26 ft a 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 hydroxide, then with 10 ml of water. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is purified by preparative thin layer chromatography (adsorbent: Kieselgel 60 ^ 254 + 366 's revealing developer: 7: 3 mixture of benzene and acetone). 0.25 g (36%) of 2-diazo-4-trans- / 3- (2-methyl-1,3-dioxolan-10 2-yl) -1- (4-methoxyphenyl) -4-oxo- is obtained. Ethyl 2-azetidinyl7-3-oxo-butanate; m.p. : 131-132 ° C (ether).

Analysis:

Values calculated for C2QH23N3O7 (417.41): C: 57.55%, H: 5.55%, N: 10.07%; 15 Values found C: 57.56%, H: 5.80%, N: 10.08%.

IR (KBr): 2200, 1740, 1710, 1640 cm “1.

J) 0.45 g (0.106 mmol) of the compound prepared according to point I) described above is dissolved in 4.5 ml of acetone and a dropwise solution is added to the stirred solution. solution of 1.5 g (2.7 mmol) of cerium ammonium nitrate in 4.5 ml of 5% aqueous sulfuric acid, the reaction mixture is stirred for a further 5 minutes, then the yellow solution is neutralized with a 5% aqueous sodium bicarbonate solution, 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 oily residue is purified as indicated in point I above. 0.10 g (27%) of 2-diazo-trans-4- / 3- (2-methyl-1,3-dioxolan- 2-yl) -4-oxo-2-azetidinyl7 ethyl 3-oxo-butanoate; the IR spectrum of the product is identical to that of the product which is prepared according to point 1).

I "* *" 27 EXAMPLE_2 6- (2-methyl-I, 3-dioxolan-2-yl) -3,7-dioxo-l-aza-bicyclo / 3/2 / 07heptane-2-carboxylate of (p- nitrobenzyle) 0.050 g of dirhodium tetraacetate 5 / Rh2 (0Ac) ^, 2THF7 is added in several portions to a suspension at boiling point and stirred, 1.673 g (4.0 mmol) of trans-2-diazo -4- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-3-p-nitrobenzyl oxo-butanoate in 45 ml of anhydrous benzene. After 10 hours of boiling, the starting material has completely reacted. The mixture is cooled, the separated substance is dissolved in dichloromethane and the solution is filtered through a pad of Cëlite. The filtrate is evaporated in vacuo, the residue is suspended in ether and the suspension is filtered. 1.32 g (84.6%) of the desired compound are collected, m.p. 167 ° C.

IIR (KBr) Î 1760, 1735 cm “1.

1H NMR: 6 = 1.48 (s, 3H), 2.47 (dd, 1H, J = 19 Hz, gern

Jvic = 8 Hz), 2.92 (dd, 1H, Jge, m = 19 Hz, Jyic = 8 Hz), 20 3.46 (d, 1H, J = 2.4 Hz), 4.0-4, 2 (m, 5H), 4.75 (ε, 1H), 5.30 (d, 2H, JAB = 14 Hz), 7.53 and 8.23 (d, 4H, JAß = 9 Hz) ppm.

The starting material can be prepared as follows: a) a mixture of 2.92 g (8.0 mmol) of acid / trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl -1.3-dioxolan-2-yl) -4-oxo-2-az-etidinyl / -acetic, prepared according to point i) of Example 1, 1.45 g (8.8 mmol) of carbonyl- Idiimidazole 98% and 30 ml of anhydrous tetrahydrofuran, 30 is stirred at room temperature for 30 minutes, then 2.20 g (8.8 mmol of (p-nitrobenzyl) -malonate of: l magnesium are added to the mixture and l stirring is continued at room temperature for 2 hours.

| The mixture is evaporated to dryness under vacuum, the residue is | Shaken with a mixture of 150 ml of dichloromethane and 150 ml of 0.5N aqueous hydrochloric acid and the phases are separated from each other. The aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, washed twice with 25 ml of a 5% aqueous solution of 3% sodium hydrogen carbonate, dried over magnesium sulfate, filtered and the filtrate is evaporated. 3.4 g (78%) of trans-4- ^ 1 - ^, 4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-OXO-2-azetidinyl are collected. / -3-oxo-butanoate of p-nitrobenzyl.

10 IR (film): 1740, 1730, 1710 cm-1.

b) 0.69 ml (5.0 mmol) of triethylamine and 0.99 g (5.0 mmol) of tosyl azide are added to a stirred solution of 2.71 g (5.0 mmol) of trans-4- ^ ï- (2,4-dimethoxy-benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azétidinyl / -15 3-oxo-butanoate de (p- nitrobenzyl) prepared according to point a) above, in 15 ml of anhydrous acetonitrile with cooling by ice. The solution is stirred for 3 hours, during which time it is allowed to warm to room temperature. Then, the mixture 20 is evaporated to dryness and the residue is treated in a chromatography column (adsorbent: Kieselgel 60, 0 = 0.063 to 0.200 mm, eluting agent; 7: 2 mixture of benzene and acetone). 2.7 g (80%) of 2-diazo-4- / trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-25 2-yl) are thus collected. (P-nitro benzyl) 4-oxo-2-azetidinyl / -3-oxo-butanoate; m.p. : 45-46 ° C (acetone).

IR (KBr): 2200, 1750, 1730, 1650 cm “1, c) A mixture of 2.84 g (5.0 mmol) of 2-diazo-4- / trans-l- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-30 2-yl) -4-oxo-2-azetidinyl7-3-oxo-butanoate (p-nitro-benzyl) prepared according to point b) above , 5.4 g! (20 mmol) of potassium peroxidisulfate (K2S20g), 7.2 g (40 mmol) of disodium acid phosphate monohydrate (Na2HP0 ^, H2O), 30 ml of acetonitrile and 18 ml of water, is brought to the boil and stirred for about 10 hours. The reaction mixture is then cooled, filtered and the 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 5 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: 2 mixture of benzene and acetone) to obtain 0.67 g (32%) of 10 2-diazo -4- ^ trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -3-oxo-butanoate (p-nitrobenzyl); m.p. : 163-164 ° C (ether-).

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

1H NMR: δ = 1.41 (s, 3H), 2.98 (dd) and 3.44 (dd, 15 2H, J = 10 Hz and 4 Hz), 3.18 (d, 1H, J = 2 , 4 Hz), 3.83-4.15 (m, 5H), 5.36 (ε, 2H), 6.0 (s, 1H), 7.54 (d) and 8.26 (d, 4H , AB, J = 9 Hz) ppm.

As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application 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.

Claims (4)

5. H?, CH COCH 000¾ H, C - C -i-T 2 2 5 | _J (XV) 0 <! %> in which î ---- Y1 and Y2 represent a detachable group protecting the carbonyl radical, preferably a ketal group or a thioanalogue thereof, Q is a C1-alkyl group or a substituted benzyl group, and R 'is a detachable group protecting the amido- radical, other than a phenyl group, preferably a phenyl or benzyl group carrying one or more C1 to 4 alkoxy- substituents. 8 ° - Compound according to Claim 7, characterized 20 in that it is trans-4- ^ ï- (2,4-dimethoxybenzyl) - 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7 -3-ethyl oxo-butanoate. 9 ° - Compound according to Claim 7, characterized in that it is trans-4- / 3 = (2-methyl-1,3-dioxolan-25 2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl / -3-ethyl oxo-butanoate. 10 ° - Compound characterized by the general formula (III) below: 30 y2 HH cEpC0CKpC003 tx n _ n -S -— Ύ '' - \ j î 1 r (m) O ** \ Il E * î 35 î 34% * * in which: i 12 Y and Y represent a detachable group protecting the carbonyl radical, preferably a ketal group "or a thioanalogue thereof, 5 Q. is a C1-alkyl group or a substituted benzyl group, and R 'is a detachable group protecting the amido- radical, other than a phenyl group, preferably a phenyl or benzyl group carrying one or more C- alkoxy- substituents at 11 ° - Compound according to Claim 10, characterized in that it is 2-diazo-4-trans- / ï- (2,4-dimethoxy-benzyl) -3- (2-methyl-1, Ethyl 3-dioxolan-2-yl) -4-oxo-2-azetidinyl7- 3-oxo-butanoate. 15 12 ° - Compound according to Claim 10, characterized in that it is 2-diazo-4-trans ~ 73- (2-methyl-l, 3-dioxolan-2-yl) -1- (4 -methoxyphenyl) -4-ethyl oxo-2-azetidinyl / -3-oxo-butanoate. 13 ° - Compound according to Claim 10, characterized in that it is 2-diazo-4-trans- / ï- (2,4-dimethoxy-benzyl) -3- (2-methyl-1, P-nitrobenzyl 3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -3-oxo-butanoate. 14 ° - Compound according to Claim 10, characterized in that it is 2-diazo-4-trans “73- (2-methyl-l, 3-25 dioxolan-2-yl) -1- (4 -methoxyphenyl) -4-oxo-2-azetidinyl7-3-p-nitrobenzyl oxo-butanoate. "f