LU84568A1 - NOVEL HETEROCYCLIC DERIVATIVES OF ACETIC ACID AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

- »• 1 *

The present invention relates to new heterocyclic derivatives of acetic acid represented by the general formula (I) below:

5 Y H H

Hrf-'c - J-VCH2C ° 0H 'O --Γ (X)

VE

in which: Y and Y together form a detachable group protecting the carbonyl group, preferably a ketal group or a thioanalogue radical thereof and R is a detachable group protecting the amido group, preferably a benzyl group carrying one or more C 15 alkoxy substituents or a phenyl group optionally bearing one or more C 1 to 4 'alkoxy substituents and a process for their preparation.

These compounds can be converted to thienamy-ein and related compounds, for example as shown in Scheme (A) ^

j S

Ί%

Diagram (A) 2

H / CH2COOX J — N

5 0 aR

./ y ch2cooh f Π no2 10 -, <f

Ύ M iP

Υ2μ u / çc 1. reduction *

15 H3C-C4- ^ CH2C00H V 2. esterification J

—-— I I u rJ-H. VH -h o | nr Jj? ch2coox a sel du / j * "malonic semiester I m ^^ 2 20 I Cf: c έ ο ο) o Lv_yj I I CH2COCH2COOQ g g

g / l ip ’vCH2C00X

25 g v — N a / -T

.30 . 'R 1 I

10 I J — 1NH

M U

(D azide of ra sulfonic acid reduction

3. ’(H / itcH2COOH

* _ * / CH2C0CN2C00Q

J — N salt âu ^ \ r η malonic semiester

35 ^ g ^ CH ^ OCH ^ COOQ

\ & 0 ^ - NH

a'®1 '’^ I

* 3 *

Schema (A) (Continued) r _ Ä $ / -. \ 0- ^ ^ * - u

VCH2COCN2COOQ

fl

10 J— NH

0

Sei's

Rh ”tTY0

CT N COOQ

9 n O-acylation- + formation of sei 1 'of mercaptan 25 f-hrSR "λ — M— (0 COOQ *

30 I

"

V

4

In the formulas indicated in Scheme (A), 1 2 Y, Y and R are as defined above, X is a selectively detachable esterifying group, Q is a C1 ^ 5 alkyl group or a sub-5 substituted benzyl group , Q 'is a C 1-6 alkyl group, ^ a substituted benzyl group, a hydrogen atom or a metal alkalin ion, and R "is a benzyl, aminoethyl or N-acyl-aminoethyl-10 le group * 'Thienamycin, an antibiotic with a broad spectrum of activity, was first prepared by microbiological means (American patent n ° 3,850,375), then then by chemical synthesis (German patent n ° 2,751,597).

The aim of the Applicant is to provide a new pathway for synthesizing thienamycin and its analogs, according to which the azetidinone skeleton and the side chain of-hydroxy ethyl, or a side chain capable of being easily converted to cC-hydroxyethyl group, 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 that when a dialkyl (amino-protected) -ma-lonate is acylated with diketene and the resulting acylated product is treated with iodine and an alkali metal alcoholate, a compound of azeti-dinone represented by the general formula (VI) below 0 EUC - Or —-. (COOZ) 30 5 2 oJ — V, ™ containing a ° C-acetyl side chain, which can be used as an intermediate- key in the synthesis.

In the above formula, R is as defined above and Z is a C 1-6 alkyl group.

I ci D

V

% 5

The intermediates of general formula (VI) and their preparation are described in detail in the applicant's Hungarian patent application no. 2262/80. The preparation of these intermediates is also described in the 5 examples below.

It has also been observed that before converting the intermediate of general formula (VI) into thienamycin or one of its analogs, it is preferable to protect the ketone group of the C-acetyl side chain with a group , in particular a ketal group or its thio-analog, which can be eliminated during a later stage of the synthesis. Ethylene glycol or its thio-analog, such as mercaptoethanol, can be applied in a particularly preferred way to form the ethylene-ce-tal or hemithioketal group for protection. The resulting compound represented by the general formula (v) below Y1 y2 H ^ C. -V ^ - 1 (C00Z) 2, »» J — ro 1 2 where R, Z, Y and Y are as defined above, is then treated with an alkali metal halide in py-ridine or a neighboring solvent or in dimethyl sulfoxide, to obtain a compound represented by the general formula (IV) below Y1 y2 H h h3c -V-ï-Y 0002 30 JK (IV) 1 2 where R, Y, Y and Z are as defined above.

The resulting compound of general formula (IV) is a mixture of cis and trans isomers. The isomers can be separated from each other, either by chromatography or according to their different solubilities. The l η isomer

V

6 separate trans, of general formula (IVa) below h3o | .....- · γ 0002 5 I- (IVa) '0 * Xt-,

R

can be converted to the trans-carboxylic acid represented by the general formula (III) below

10 Y1 Y2 H H

H ^ C JY-5-y C00ïï J-J (III)

XR

15 by hydrolysis. It is more advantageous, however, to subject the isomeric mixture itself to hydrolysis, since the reaction is selective, that is, only the trans ester converts to the respective carboxylic acid.

Some of the compounds of general formulas (V) (IV) and (IVa) are described in Hungarian patent application No. 2263/80 of the Applicant, while the other representatives of these compounds and the compounds represented by the general formula (III) are described in patent applications of the applicant. The preparation of the compounds of general formulas (VI) to (III) is also described in the examples of the present invention.

The separate trans-carboxylic acid of general formula (III) is first reacted with an activator for the carboxy group and then with diazomethane, then the resulting compound of general formula (II) is subjected where R, 1 9 Y and YA are as defined above V y2 „Tj H3C _Y -” - yCCßBKz 35 J_1 (n)

^ I

V

7 to a rearrangement of diazoketone (Wolff transposition) in the presence of water. In this last step, the desired products of general formula (I) are obtained.

The compounds of general formulas (I) to (VI) 5 are obtained in the form of racemic mixtures.

On the basis of these observations, the invention relates to a process for the preparation of a new compound represented by the general formula (I), in which: Y and Y together form a detachable protective group, preferably of the carbonyl radical, preferably a ketal group or its thio-analog and R is a detachable protective group, of the amido radical, preferably a benzyl group carrying one or more alkoxy substituents in ^ or a phenyl group optionally carrying one or more alkoxy substituents in which: Ί

a compound of general formula (III), where R, Y

2 and Y are as defined above, is activated on the carboxy group, then reacted with diazomethane, then the resulting compound of general formula (II), where R, Y1 and Y are as defined above , is subject to a rearrangement of diazoketone in the presence of water, or - | a compound of general formula (II), where R, Y and Y are as defined above, is subjected to a rearrangement of diazoketone in the presence of water, and the resulting product of general formula (I) is then separate.

The preparation of the starting substances of general formula (III) is described in detail in the examples.

The azetidine carboxylic acid of general formula (III) is activated first on the carboxy group. Any activating agent compatible with the ß-lac-tame cycle can be applied in this connection. It is preferred to activate the carboxy group to a mixed anhydride, for which purpose ethyl chloroformate is found to be particularly suitable. The mixed anhydride is formed in the presence of an i% 8 acid-binding agent, preferably a tertiary amine.

The salt of the tertiary amine which separates from the reaction mixture can be easily removed.

The activated form of the compound of formula (III) is then ► 5 reacted with diazomethane. Diazomethane is preferably prepared from N-methyl-N-nitrosourea: and is added to the reaction mixture, preferably in the form of an ethereal solution. When the evolution of gas stops, the excess of diazomethane is decomposed preferably with acetic acid and the resulting compound of general formula (II) is separated from the reaction mixture.

If necessary, this product can be purified, for example, by column chromatography.

Next, the resulting compound of gene formula (II) is subjected to a Wolff rearrangement, so that the side "C-diazoketone chain first converts to ketene by elimination of nitrogen and then it reacts with water. to form the desired product of general formula (I).

The Wolff rearrangement can be initiated with: a catalyst, by irradiation of the mixture with ultraviolet light, by heat treatment or their combination. The irradiation with ultraviolet light turns out to be particularly interesting. This can be carried out, for example, in a photoreactor, preferably under an atmosphere of inert gas, in the presence of water and optionally an inert organic solvent.

The resulting product can be separated from the reaction mixture by evaporation and / or by phase transfer and can be purified, for example, by recrystallization, if necessary.

In addition to the preceding arrangements, the invention also comprises other arrangements 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! 9! · L · i examples of implementation of the process 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

Jtrans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxo-lan-2-y1) -4-oxo-2-azetidinyl / -acetic acid 10 A mixture of 2.25 g (6 mmol) of trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan- 2-2-yl) -2-azetidinone, 100 ml of tetrahydrofuran devoid of peroxide and 50 ml of water is irradiated for approximately 4 hours with a mercury lamp under high pressure (HPK 15 125) immersed in the reactor made of Pyrex glass, under an argon atmosphere. The solution is evaporated in vacuo 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 with aqueous hydrochloric acid; concentrated. The acid solution is extracted three times with 20 ml portions of dichloromethane and the ex-25 lines are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness. The residue is recrystallized from ether. 1.82 g (83%) of the desired compound are collected in the form of a white crystalline substance; mp: 124 ° C (ether).

f, 30 IR (KBr): 3500-2300, 2900, 1730, 1700 cm "1.

i | - Analysis: | calculated values for C ^ gH ^ NO ^ (365.37): C: 59.17%, H: 6.34%, N: 3.83%; values found: 35 C: 59.22%, H: 6.49%, N: 4.07%.

The starting material can be prepared as follows: a) A mixture of 109.7 g (0.66 mole) of 2,4-dimetho-j. 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 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 the reaction, the mixture is evaporated to dryness under vacuum. The residue 15 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 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 and provides 197 g (72%) of diethyl N-benzyl-K- (2,4-dimethoxybenzyl) -amino-malonate; m.p. : 62-63 ° C (ethanol).

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

b) 61.7 g (0.149 mole) of diethyl K-benzyl-N- (2,4-dimetho-xybenzyl) -amino-malonate, prepared according to point a) above, are stored in 500 ml ethanol Iat atmospheric pressure in the presence of approximately 20 g of catalyst consisting of palladium on charcoal. 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 C ^ H ^ ClNOg (361.82): * C: 53.11%; H: 6.69%, Cl: 9.80%; K: 3.87%; "found: C: 52.51%, H: 6.77%, Cl: 10.30%; N: 4.09%.

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

15 IH NMR (CDC13): 6 = 1.3 (ε, 6H), 3.78 (s, 3H), 3.82 (ε, 3H), 4.21 (σ, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H) + 7.3-7.55 (m, 1H), 7.7 (large s, 1H) ppm.

c) A mixture of 39.6 g (0.122 mol) of (2-4-dimethoxv-benzylamino) -methylate diethylate, prepared according to point b); - 20 above, 80 ml of glacial acetigue acid and 12.3 g (11.2 ml, 0.146 mole) of dicetene, 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 ^ 20 ^ 27 ^ 8 (409.43): C: 58.67%, H: 6.65%, N: 3.42%; "found: C: 58.79%, H: 6.33%, N: 3.34 l.

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

1 H NMR (CDC13): 6 * 1.1 (t, 3H), 1.17 (t, 3H), 1.52 (s, ^ 3H), 2.8 (<0.1 H), 2.65 (large s, 2H), 3.75 (ε, 6H ), 3.8-4.15 (m, 4H), 6.7 (large s, 2H), 6.25-6.45 (m) + 7.0-7.25 (m, 3H) ppm.

5 d) 20.5 g (50 mmol) of the product prepared as described in point c) above are put in the suspension 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 vigorously stirred suspension and cooled by ice water. Next, 5 g of sodium hydrosulfite, dissolved in 200 ml of an aqueous solution, saturated with sodium chloride, are added to the stirred mixture. 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:

Calculated values for ^ 2QH25NOe (407.41): 25 C: 58.96%, H: 6.19%, N: 3.44%; "found: C: 58.99%, H: 6.04%, N: 3.57%.

1H NMR (CDC13): 6 = 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) 4 7.07 (d, 1H) ppm.

e) 179 ml (206 g, 1.452 mole) of boron trifluoride-diethyl etherate are added dropwise to a solution: vigorously stirred of 179 g (0.484 mole) of 3-acetyl-1- (2,4-dimethoxybenzvl) ) -4-oxo-2,2-azetidine-35 diethyl dicarboxvlate and 107 ml (120 g, 1.936 mole) i

The 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 NaCO 4, 10H 3 O is added slowly to the stirred mixture and cooled with ice water and the mixture is 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 is shaken twice, with 500 ml portions 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. 180cC. 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, 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-dimethoxybenzvl) -3- (2-methyl-1,3-dioxolan-2-yl) - Ethyl 4-oxo-2-azetidine carboxylate; P.f. : 95 ° C.

F) UK 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 c ) above, 3 ml of anhydrous tetrahydrofuran and 0.53 g (3.6 mmol) of mercauto-ethanol is brought to the boil for 4 hours,! 14 '* 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 'revealing mixture: 8: 2 mixture of toluene and acetone.).

We obtain: 0.30 g (53%) of 1- (2,4-dimethoxybenzyl) -3-10v "· (2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azetidine -diethyl dicarboxylate.

1H NMR (CDC13): 6 = 0.8-1.55 (m, 6H), 1.72+ 1.77 (at, 3H), 2.9 -3.4. (m, 2H), 3.75 '(ε, 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 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 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 shaken quickly with 100 ml, then twice with 50 ml portions of cichloromethane.

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-azeticine-carboxylic; m.p. : 117-118 ° C (toluene).

35 15.

"/ Analysis:

Values calculated for (351.35): * C: 58.11%, H: 6.03%, N: 3.99%;

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

1H NMR (CDC13): δ = 1.39 (s, 3H), 3.50 (d, 1H, J = 2.5 Hz), 3.77 (s, 3H, 3.79 (s, 3H), 3.86 (d, 1H, J = 2.5 Hz ), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JAß = 15 Hz), 6.44 30 (m, 2H) + 7.15 (d, 1H, J = 10 Hz), 7.58 (large s, lH) 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-dimethoxybenzvl) -3- (2-methyl- 1,3-dioxolan-2-yl) -15 4-oxo-2- £ zetidine-cerboxylic prepared according to point g) above, in 150 rI of anhydrous tetrahydrofuran, then 5.0 ml (52.5 mmol} this ethyl chloroformate is 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 atmosphere of Argon 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 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 column chromatography [absorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0.200 mm, eluent: 7: 2 mixture of benzene and a ketone). 12.0 g (64 -a) of trans-4-30 (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2- are collected. azetidinone.

Analysis: Value calculated for ΕΗ21Κ3 ^ 6 (375.37): C-.57.59 ï, H: 5.64%;

Values found 0: 57.76%, H: 5.39%.

35 IR (KBr): 2900, 2110, 1760 cm ”1.

»16 EXAMPLE 2

Acid / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxy-pheryl) -4 ~ oxo-2-azetidinyl7-acetic 3.3 g (0.01 mole ) of trans-4- (diazoacetyl) -3-5 (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azéti-dinone 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, 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 tetrahydrofuran is distilled off in vacuo, the residue is basified with 20% aqueous sodium hydroxide solution and the solution is washed twice with 15 ml portions of dichloromethane. The aqueous phase is acidified to pH 1-2 with concentrated 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 the desired product are collected r

Analysis: 25 values calculated for Ο ^ Η ^ ΝΟ ^ (321, 33): C: 59.80%, H: 5.96%, N: 4.36%; values found: C: 59.60%, H: 5.76%, N: 4.08%.

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

The starting material can be prepared as follows: 35 i 117 7a) A mixture of 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) of diethyl bromomalonate is stirred at room temperature for 2 days. The mass ç. resulting is triturated with 100 ml of diethyl ether, the separated 4-methoxy-anisidine hydrobromide is filtered and washed with a small amount of diethyl ether. The mother liquor is evaporated and the residue is crystallized from dilute acetigue acid. 13.2 g (47%) of (4-methoxyanilino) -j q-diethyl malonate are obtained (mp: 64-65 ° C (ethanol).

Analysis:

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

Values found C: 59.99%, H: 6.97%, K: 5.25? ..

15 IR (KBr): 3300, 1775, 1725 cm.

1B 1ÏMN (CDC13): δ = 1.23 (t, 6H, J = 7.2 H2), 3.67 (s, 3H), 4.2 (q, 4H, 3 = 7.2 Hz), 4.62 (ε, 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 mole) of (4-methoxy-20 anilino) -methylate diethyl, prepared according to point a) above,. 5 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 c (72 l) of 1- (4-methoxyphenyl) -3-hycroxy-3-methyl-5-oxc-2,2-pvrrolidine- * diethyl cicarboxylate and / or its tautomer are collected; mp:] 36-137 ° C (ethyl acetate).

Analysis:

Calculated values for C1oK - N0 “(365.38): 1 o Z ό / C: 59.17 t, H: 6.39 t. K: 3.83? ; 18

Values found C: 58.98%, H: 6.90%, K: 4.04 £.

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

7 1H NMR (CDC13): 6 = 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 (s , 1H), 5 3.76 (s, 3H), 4.1 (q, 2H, J = 7.2 Hz), 4.27 (ç, 2H, J = 7.2 Hz), 6.7 (2H) + 7.0 (2H, AA 'BB', J = 9 Hz) ppm.

c) 9rl g (0.025 mol 1- (4-methoxyphenyl) ~ 3-hydroxy-3-methvl-5-oxo-2,2-pyrroliain-diethyl dicarboxylate, prepared according to point b) above are set to 10 suspension 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 mole) 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 portions of 50 ml of 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 6.2c (68%) of crystalline diethyl 3-acetyl-1- (4-metho-xyphenyl) -4-oxo-2,2-azetidine dicarboxylate ; mp: 70-71 ° C (ethanol).

Analysis:

Calculated values for CigH21N07 (363.38): C: 59.50%, H: 5.82%, K: 3.85%;

Values found C: 59.04%, K: 5.84%, N: 4.08%, 30 IR (KBr): 1760, 1735, 1720 cm "3.

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

I 35 d) 6 c (0.0165 mole) of 3-acetvl-1- (4-methoxvphenyl) - 19 * 4-oxo-2,2-azetidine-diethyl dicarboxylate, prepared according to point c) above, are dissolved in 20 ml of anhydrous dioxane and 4.1 g (3.75 ml, 0.066 mole) of ethylene qlvcol. * 7.1 g (6.3 ml, 0.05 mole) of boron trifluoride-diethyl etherate complex are added dropwise to the solution stirred and cooled by 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, then 10 "added with 100 ml of water and the mixture is extracted three times with 50 ml portions of diethyl ether. The I organic phases are combined , dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is triturated with diethyl ether to obtain 15 6 c (89 l) of 3- (2-methyl-1,3-dioxolan-2- yl) -1- (4-methoxypheny1) -4-oxo-2,2-azetidine-diethyl crystalline dicarboxylate; m.p .: 82-83 ° C (ethanol).

Analysis:

Calculated values for C20H25NO8 (^ 7.43): 20 C: 58.96%, H: 6.18%, K: 3.44%;

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

IR (KBr): 1740 cm 1 (wide) 1H NMR (CDC13): δ = 1.17 (t, 3H, J = 7.2 Hz); 1.26 (t, 3H, J = 7.2 Hz), 1.5 (s, 3K), 3.7 (s, 3H), 3.9 25 (ir., 4K), 4.2 (m, 5H), 6.67 (2H) 4 7.34 (2H , AA 'BE', J = 9 Hz) ppm.

e) 11 g (0.0245 mole) of 3- (2-methyl-1,3-dioxolan - 2-y1) -1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate , prepared according to point d) above, 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) this is water added and the mixture is stirred at 175 ° C until completion of the reaction. The progress of the reaction is monitored by thin layer chromatography (adsorbent: 35 Kieselgel G according to Stahl; revealing solvent: 6: 4 mixture of 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 sium, filtered and the filtrate is evaporated. The resulting oily residue, weighing 6 gf, 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 at pH = 1 with concentrated hydrochloric acid, then extracted three times with 25 ml portions of dichicrome-thane. The organic phases are combined, dried over this magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized with benzene.

* 4 a (54%) of trans-3- (2-methyl-1,3-dioxolai -2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidine-carboxylic acid are collected.

20 Analysis:

Calculated values for C ^ H ^ NOg (307.32): C: 5B.63%, H: 5.57%, N; 4.56%;

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

IR (KBr): 3400-2700, 1750 (large) year "1.25 -1¾ NMR (CDC1?): 6 = 1.5 (s, 3H), 3.7 (d, 1H, J = 2.5 m Kz), 3.76 ( s, 3H), 4.0 (m, 4H), 4.38 (c, 1H, J = 2.5 Hz), 1 6.82 (2H) + 7.26 (2H, AA 'BE', J = 9 Hz), 9.2 (s , 1H) ppm.

H ”f) 1.11 g (1.56 ml, 0.011 mole) of anhydrous triethyl amine H is added to a solution of 3 g (0.01 mole) of a compound prepared according to point e) above , in 20 ml of anhydrous tetrahydrofuran. The solution is cooled. s -15 ° C and added dropwise 1.2 g (1.06 ml, d 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 i

21 diazometharïe in diethyl ether is added to the filtrate at room temperature. After 2 hours of stirring, the excess of diazomethane is decomposed with acetigue acid and the solution is evaporated under vacuum. The oily residue crystallizes slowly. 3 g- (90%) trans-4-fdiazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone are obtained; mp: 95-96 ° C (benzene and ether).

IR (KBr): 2200, 1760, 1640 cm ”1.

10 1H NMR (CDC13): 6 = 1.50 (ε, 3H), 3.51 (d, 1H, J = 2.6 Hz), 3.75 (ε, 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.

EXAMPLE 3 Acid / trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyf7 acetic 3.8 g (0.0126 mole) of trans- 4- (diazoacetyl) -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone are dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml of water and the solution is irradiated with a high-pressure mercury lamp, in a photoreactor, at room temperature under a nitrogen atmosphere. The progress of the reaction is monitored by thin layer chromatography (Kieselgel G adsorbent according to Stahl, revealing solvent; 7: 1 mixture of benzene and acetone). At the end of the reaction, the tetrahydrofuran is evaporated in vacuo, the residue is alkali-nized 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 30 is acidified to pH 1-2 with aqueous concentrated 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 e-35 ther to obtain 1.8 g (50%) of acid / trans-1-phenyl-3- (2-methyl-1, 3-dioxolan-2-yl) -4-oxo-2-azetidinylJ / '- crystalline acetic acid; m.p. : 128-129 ° C (ethanol).

Analysis:

Calculated values for C ^ H ^ NO ^ (291, 29): C: 62.00%, H: 5.88%, N: 4.82%; 1 5 values found: C: 61.75%, H: 5.86%, N: 5.08%.

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

^ NMR (CDC13): <f = 1.48 (s, 3H), 2.65 (dd, 1H, J = 15 Hz, J, .. = 8 Hz) + 3.12 (dd, 1H, J = 15 Hz, gern Vxc gern 1 ° Jyic = 8 Hz), 3.47 (d, 1H, J = 2.5 Hz), 3.98 (m, 4H), 4.4 (m, 1H), 7, 3 (κι, 5H), 9.33 (broad s, 1H) ppm.

The starting material can be prepared as follows: a) A mixture of 38 g (0.152 mol) of diethyl anilino-malonate ^ R. Blank: Ber. 32_, 1815 (1898 ^^, 38 ml of glacial acetic acid and 15.3 g (13.9 ml, 0.182 mole) of ciicetene, is brought to the boil for 0.5 hour.

The glacial acetic acid is evaporated in vacuo on a water bath and the oily residue is crystallized by trituration with ether. 36.5 g (72%) of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer are obtained; mp: 98-99 ° C (ethyl acetate and petroleum ether).

25 Analysis:

Calculated values for ^ 7 ^ 21 ^ 6 (355.35): C: 60.88%, H: 6.31%, N: 4.18%;

Values found: C: 60.83%, H: 6.15%, N: 4.43%.

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

30 1H NMR (CDC13): δ = 1.02 (t, 3H), 1.3 (t, 3K), 1.6 ”(s, 3H), 2.8 (s, 3H), 3.6 (large s, 1H), 4-4.45 ( m, 4H), 7.2 (ε, 5H) ppm.

b) 50 g (0.149 mol) of diethyl N-phenyl-3-hydroxy-3-methyl-5-ΟΧΟ-2,2-pyrrolidine-dicarboxylate, prepared according to point a) above, 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 (0.149 mole) of iodine in 200 ml of anhydrous ether is added 1 23 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 5.300 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, nNOf: 1/1 y b 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-phenvl-4-oxo-2,2-azetidine-diethyl dicarboxylate, prepared according to

M

point d) above, are dissolved in a mixture of 90 ml of anhydrous dioxane and 21 g (18.8 ml, 0.34 mole) of anhydrous ethylene glycol, then 36.5 g (31, 5 ml, 0.255 mol) of boron trifluoride-diethyl etherate complex are added 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 diethyl 1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-azetidine-dicarboxylate are obtained; mp: 59-61 ° C (petrol) ^ 24 îj Analysis:

Values calculated for cigH23NC) 7: C: 60.47%, H: 6.34%, N: 3.71%,

Values found C: £ 60.74, H: 6.21%, N: 3.79%.

J * 5 IR (KBr): 1770, 1740 cm "1.

1 H NMR (CDC13): 6 = 1.18 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz), 1.51 (ε, 3H) χ 3.92 (m, 4H), 4.3 (m, 5H), 7.2 (m, 5H) ppm. ' â) A mixture of 28.5 g (0.075 mole) of 1-phenyl-3 0 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine-dicarboxy- diethyl late, prepared according to point c) above, 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 followed 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 20 ml portions of 150 ml of ethyl 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> with 20 ml portions of diethyl ether. The aqueous phase is acidified to pH = 1 with concentrated aqueous hydrochloric acid 3C and then extracted three times with 50 ml portions of cichloromethane. The organic phases [j are combined, dried over magnesium sulfate, filtered J 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-1.25 carboxylic; mp: 165 ° C (benzene).

Analysis:

Calculated values for C-.H, cNO, - (277.27):

* 14 lD D

C: 60.64%, H: 5.45%, N: 5.05 '%, 5 Values found C: 60.64%, H: 5.72%, N: 4.99%.

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

1H NMR (CDC13): 6 = 1.5 (ε, 3H), 3.69 (ä, 1H, J = 3 Hz), 4.0 (m, 4H), 4.42 (d, 1H, J = 3 Hz), 7.3 (m, 5H); 7.55 (s, 1H) ppm.

E) 13.8 g (0.05 mole) of trans-1-phenyl-3- (2-methylvl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid according to point d) above, 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 1 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).

I IR (KBr): 2150, 1760, 1635 cm “1.

| j 'αΗ 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), h. 30. 5.45 (s, 1H), 7.25 (m, 5H) ppm.

y * As is apparent from the above, the invention is in no way limited to those of its modes of implementation, of! realization and application which have just been described in a more explicit manner; 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 (15)

1. Compound characterized in that it is represented by the general formula (I) below? HHH, C - C_ T CH.COOH 5 5 2 'n, in which and Y2 together form a detachable group protecting the carbonyl group, preferably a ketal group or its thioanalogue, and R is a detachable group protecting the amido group, preferably a benzyl group carrying one or more alkoxy substituents at ^ or a phenyl group optionally carrying one or more substituents a] coxy at 15 C1 to 4 ’ 2. Compound according to claim 1, characterized in that it is acid / trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl ) -4-oxo-2-azetidinyl_7-acéti-que. 3. Compound according to claim 1, characterized in that it is acid / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxy-phenyl ) -4-oxo-2-azétidinyly-acétique. 4. Compound according to claim 1, characterized in that it is acid / trans-1 - ph e n yl-3- (2-methyl-1,3-dioxolan-2-yl) - 4-oxo-2-azetidinyl7-acetic 5. Compound characterized in that it is represented by the general formula (II) below γ · * · g dd 30 h5c -V-ί-pcocHK2 J_ ïï (II) i - St i! 1 2 j in which Y and Y together form a detached group! 11 I! 28 protecting the carbonyl group, preferably a ketal group or its thioanalogue, and R is a detachable protecting group of the amido group, preferably a benzyl group carrying one or more alkoxy substituents at ^ or a phenyl group optionally carrying a or several C ^^ alkoxy substituents. 6. Compound according to claim 5, characterized in that it is trans-4 - (.. diazoacetyl) -1 - (2,4-nüinethoxy-benzyl) -3- (2-methyl ~ 1, 3-dioxolan-2-yl) -2-azetidinone. 7. Compound according to claim 5, characterized in that it is trans-4- (diazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -1- (4- methoxyphenyl) -2-azetidinone. 8. Compound according to claim 5, characterized in that it is trans-4- (diazoacetyl) -1-phenyl-3-15 (2-methyl-1,3-dioxolan-2-yl) - 2-azetidinone. 9. Process for the preparation of a new compound represented by the general formula (I) according to claim 1, characterized in that a compound represented by the general formula (III) below 20 -1 2 I T1 Y ' - UH h5c -Y-1_J- C00H 0J-tni) 25 1 2 where R, Y1 and Y are as defined above, is activated on the carboxy group, then reacted with diazomethane and the resulting compound represented by general formula (IX) according to claim 5, in which R, Y ′ and Y are as defined above, is subjected to a rearrangement of diazo-ketone in the presence of water, or else a compound of general formula 12 (II), where R, Y and Y are as defined above, is subject to a rearrangement of diazoketone in pre- | sence of water, and the resulting product of general formula (I) i 35 is separated. 110. Process according to claim 9, characterized in that the carboxy group of the compound of general formula (III) is activated with ethyl chloroformate. 11. Method according to claim 9, characterized in that the rearrangement of diazoketone is carried out under irradiation with ultraviolet light. 12. The method of claim 9, for the preparation of acid / trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl- ^ 1, 3-dioxolan-2-yl) -4-oxo- 2-azetidinyl_7-acetic, characterized in that trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-azetidine- carboxylic is activated on the carboxy group and then reacts with diazo-methane and trans-4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2- yl) -2-azetidinone resul-aunt is subjected to a rearrangement of diazoketone, in the presence of water. 13. The method of claim 9, for the preparation of acid / trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinylJ7 ~ acetic, characterized in that trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-azetidine-carboxylic acid is activated on the carboxy group and then reacts with diazomethane and the resulting trans- (4-diazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone is subjected to 25 a rearrangement of diazoketone in the presence of water. 14. The method of claim 9, for the preparation of acid / trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7 ~ acetic, characterized in that trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4 ~ oxo-30 2-azetidine-carboxylic acid is activated on the carboxy group ^ and then produced with diazomethane, then the resulting trans-4- (diazoacetyl) -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone is subjected to a diazo- rearrangement | ketone, in the presence of water. I ‘ï