FR2518998A1 - NOVEL ACETIC ACID HETEROCYCLIC DERIVATIVES AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

NEW HETEROCYCLIC COMPOUNDS OF ACETIC ACID REPRESENTED BY GENERAL FORMULA I BELOW: (CF DRAWING IN BOPI) OR Y AND Y TOGETHER FORM A DETACHABLE GROUP PROTECTING THE CARBONYL GROUP AND R IS A DETACHABLE GROUP PROTECTING RADICAL AMIDO. THEY ARE PREPARED BY ACTIVATE THE CARBOXY GROUP OF A COMPOUND REPRESENTED BY GENERAL FORMULA III BELOW: (CF DRAWING IN BOPI) OR R, Y AND Y ARE AS DEFINED ABOVE, THEN BY TREATING IT WITH DIAZOMETHANE AND SUBMITTING THE RESULTING COMPOUND REPRESENTED BY GENERAL FORMULA II BELOW: (CF DRAWING IN BOPI) OR R, Y AND Y ARE AS DEFINED ABOVE, TO REARRANGEMENT OF DIAZOCETONE IN THE PRESENCE OF WATER. THESE NEW COMPOUNDS ARE OF INTEREST, USEFUL COMPOUNDS IN THE SYNTHESIS OF THIENAMYCIN AND ITS ANALOGUES.

Description

The present invention relates to new

  calic heterocyclic derivatives of acetic acid

  by the following general formula (I): y 1 y 2 H

CHCOOH

H 3 C 2 X

  O sol N X (I) NR in which: Y 1 and y 2 together form a detachable protecting group of 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 sub-

  C 1 -C alkoxy stituents or a phenyl group optionally bearing one or more alkoxy substituents in

1 to 4 '

  and a process for preparing them.

  These compounds can be converted to thienamy-

  and related compounds, for example in the manner

felt in Diagram (A)

2 5 1 8 9 9 8

Scheme (A)

H 2 COOH

1 O

CH 2 COOH

reduction 2-esterification r X

CH 2 COO

NH 2 Z e ro

CH 2 COOX

0 NH

reduct on H

CH 2 COOH

  NH salt of the malonic semiester and 1 5 0): j Lr f 4 4 j u tu O N id p Q) 4 j U) a) v 1 salt of the malonic semiester H

: CH 2 COCH 2 COOQ

0 1 \ R

  sulfonic acid azide m H 2 COCH 2 COO 2

p a, Zj-ae

2 5 1 8 9 9 8

  Scheme (A) (Continued) 5: 00 Q 0-acylation, + mercaptan salt formation H & e

-Z, 24c.

  In the formulas indicated in Scheme (A), y 1, y 2 and R are as defined above, X is a selectively detachable esterifying group,

  Q is a C 1-5 alkyl group or a benzyl group sub-

stitutes,

  Q 'is a C 1 to C 5 alkyl group, a benzyl group sub-

  stituted, a hydrogen atom or an alkali metal ion

flax, and

  R "is a benzyl, aminoethyl or N-acyl-aminoethyl group

the.

  Thienamycin, a broad-spectrum antibiotic

  activity was first prepared microbiologically

  US Patent No. 3,850,375), and then by

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

  The purpose of the Claimant is to provide a new

  way to synthesize thienamycin and its analogs

  that the azetidinone skeleton and the chalne

  lateral r-hydroxyethyl, or a side chain susceptible

  to be easily converted to a c-hydroxyethyl group, are formed simultaneously in the first step of the

  synthesis and the resulting key-intermediate is converted into

when in final product sought.

  It has been found that when (amino-protected) -ma-

  dialkyl lonate is acylated with diketene and the resulting acylated product is treated with iodine and

  alkali metal alcoholate, an azethane compound is obtained

  dinone represented by the general formula (VI) below

HIC O C | óCOOZ) -

  a chain-side chain, which can be u-

  containing a chain α-acetyl lateral, which can be u-

  used as a key intermediate in the synthesis.

  In the above formula, R is as defined above and Z is C 1-5 alkyl. The intermediates of the general formula (VI) and their preparation are described in detail in the application for

  applicant's Hungarian patent No. 2262/80.

  These intermediates are also described in the examples below.

  It has also been observed that before converting

  intermediate of the general formula (VI) to thienamycin or one of its analogues, it is preferable to protect the ketone group of the side chain o C-acetyl with a

  group, in particular a ketal group or its thio-analog

  which can be eliminated in a later stage of

  synthesis Ethylene glycol or its thio-analogue, com-

  mercapto-ethanol, can be applied in a

  particularly preferred for forming the ethylene-ethyl group.

  Protective talith or hemithioketal The resulting compound represented by the general formula (V) below y y H H C C (co Oz) 2

O (O O 2 V

o)

  o R, Z, y 1 and y 2 are as defined above, is treated

  then with an alkali metal halide in py-

  ridine or a neighboring solvent or in dimethylsulfoxide,

  to obtain a compound represented by the general formula

  (IV) below y 1 y 2 H H H C-C t COO 2

R (IV)

  o R, y 1, y 2 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

  The separated trans-isomer of the general formula (I Va) hereinafter can be separated from one another by chromatography or according to their different solubilities.

H 5 C C OCOOZ

, (I Va)

GOLD

  can be converted to the transcarboxylic acid

  by the general formula (III) below yl y 2 H H

H 3 -0 Y COOH

0 R

  by hydrolysis It is more advantageous, however, to

  subject the isomeric mixture itself to hydrolysis,

  that the reaction is selective, that is, only the

  trans is converted to the respective carboxylic acid.

  Some of the compounds of general formulas (VI

  (IV) and (I Va) are described in the Hon.

  groise n 2263/80 of the Applicant, while the other representatives of these compounds and the compounds represented

  by the general formula (III) are described in

  Applicant's patent documents The preparation of the

  from the general formulas (VI) to (III) is also described

  in the examples of the present invention.

  The trans-carboxylic acid separated from the general formula (III) is first reacted with an activator for the carboxy group and then with diazomethane, and then the resulting compound of the general formula (II) o R, y 1 and y 2 are as defined above yy 2 HHH 3 CC T r COCHN 2

(-)

  to a rearrangement of diazoketone (Wolff transposition) in the presence of water In this last step, we obtain

  the desired products of general formula (1).

  The compounds of general formulas (I) to (VI) are obtained in the form of racemic mixtures. From these observations, the invention relates to a process for the preparation of a novel compound represented by the general formula (1), in which: Y 1 and Y 2 together form a detachable protective group, preferably a carbonyl radical, preferably a ketal group or its thio-analogue and R is a detachable protecting group of the amido radical, preferably a benzyl group carrying one or more C 1-4 alkoxy substituents or a phenyl group optionally bearing one or more C 1 -C 4 alkoxy substituents. 4 'according to which a compound of general formula (III), wherein R, Y 1 and y 2 are as defined above, is activated on the carboxy group, then reacted with diazomethane, and the resulting compound of general formula (II), o R, Y 1 and Y 2

  are as defined above, is subject to a rearrangement

  diazoketone in the presence of water, or a compound of general formula (II), o R, Y 1 and

  y 2 are as defined above, is subject to a

  diazoketone in the presence of water, and the resulting product of the general formula

(I) is then separated.

  The preparation of the starting substances of

  the general (III) is described in detail in the examples.

  Azetidine carboxylic acid of general formula

  (III) is activated first on the carboxy group A

  any activating agent compatible with the t-lac-

  can be applied in this respect It is preferred to

  the carboxy group to a mixed anhydride, for which ethyl chloroformate is particularly suitable. The mixed anhydride is formed in the presence of a

  acid-binding agent, preferably a tertiary amine.

  The salt of the tertiary amine which separates from the reaction mixture

  tional can be easily eliminated.

  The activated form of the compound of formula (III) is then reacted with diazomethane. Diazomethane is preferably prepared from N-methyl-N-nitrosourea and is added to the reaction mixture, preferably in the form of a diazomethane. ethereal solution When the release of

  gas stops, the excess diazomethane is decomposed

  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.

  Then the resulting compound of general formula

  (II) is subjected to a rearrangement of Wolff, so that the β C -diazoketone side chain first converts to ketene by removal of nitrogen and then reacts with water to form the desired product of formula

general (1).

  The rearrangement of Wolff can be primed with a catalyst, by irradiating the mixture with light

  ultraviolet, by heat treatment or their combination

  irradiation with ultraviolet light is

  particularly interesting This can be

  for example, in a photoreactor, preferably under an inert gas atmosphere, 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 phase transfer and can be purified, for example, by recrystallization, if

this is necessary.

  In addition to the foregoing, the invention also includes other arrangements which will be apparent from

the following description.

  The invention will be better understood by means of the

  description which will follow, which refers to

  examples of implementation of the method object of the present invention. It should be understood, however, that these examples of implementation are given merely by way of illustration of the subject of the invention, of which they do not constitute

  in no way constitute a limitation.

EXAMPLE 1

  Etrans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxo) acid

  lan-2-yl) -4-oxo-2-acetic azétidinylj

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

  zoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxol)

  2-2-yl) -2-azetidinone, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water are irradiated for about 4 hours with a high-pressure mercury lamp (HPK).

  125) immersed in the reactor made of Pyrex glass, under

  Argon mosphere 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 solution of sodium hydroxide are added to the solution. aqueous mixture and the alkaline mixture is washed three times with 1 ml portions of dichloromethane. Then, the aqueous phase is acidified to pH = 2 with concentrated aqueous hydrochloric acid. The acid solution is extracted three times.

  with 20 ml portions of dichloromethane and the ex-

  traits are combined, dried over magnesium sulphate,

  very, and the filtrate is evaporated to dryness. The residue is

  crystallized from ether 1.82 g (83%) of the title compound is collected as a crystalline substance.

white; mp: 124 ° C (ether).

  IR (K Br): 3500-2300, 2900, 1730, 1700 cm Analysis: Values calculated for C 18 H 23 N 07 (365.37):

C: 59.17%, H: 6.34%, N: 3.83%;

found values:

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 moles) of 2,4-dimetho-

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

borosodium hydride.

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

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

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

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

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

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

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

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

  catalyst consisting of palladium on charcoal

  The filtrate is filtered and the filtrate is evaporated. 47.1 g (97%) of diethyl (2,4-dimethoxybenzylamino) -malonate are collected. The product can be converted into its hydrochloride by reaction with hydrochloric acid. 122-124 ° C after recrystallization from ethyl acetate Analysis: Calculated for C 16 H 24 Cl NO 6 (361 82): C: 53.11%; H: 69%, C: 9 80% N, 87%; found:

  C: 52 51%, H: 67%, Cl: 30%; N: 409%.

  IR (film): 3250, 2900, 2850, 1730, 1720 cm -1 H NMR (CDCl3): δ = 13 (s, 6H), 378 (s, 3H), 382 (s, 3H), 4 21 (q, 4H), 6 (s, 2H), 6,46 (m, 2H) + 7 3-7

(m, 1H), 7 (broad s, 1H) ppm.

  c) A mixture of 39.6 g (0.122 mole) of (2-4-methoxypropionic)

  benzylamino) -diethyl malonate, prepared according to item b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 mol) of dicetene, is boiled for 0, 5 hours The solvent, glacial acetic acid, is distilled under vacuum on a water bath of water and the oily residue is triturated with 150 ml of water. The resulting crystalline substance is dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether One collects

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

  dioxo-2,2-pyrrolidine dicarboxylate and / or

tautomer, p: 106-107C

  Analysis: Value calculated for C 20 H 27 NO 8 (409.43):

C: 58.67%, H: 6.65%, N: 3.42%;

"found:

C: 58.79%, H: 6-, 33%, N: 3.34%.

  IR (K Br): 3400, 2950, 2850, 1730 (1740, sh), 1710 cm H NMR (CDCl3): 6 = 1 (t, 3H), 17 (t, 3H), 1 52 (s,% 3H), 28 (<0 1H), 265 (broad s, 2H), 375 (s, 6H), 3.8-4 (m, 4H), 67 ( broad s, 2H), 6 25-6 45 (m) + 7 0-7 25

(m, 3H) ppm.

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

  the manner described in point (c) above to the

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

  ml of a saturated aqueous solution of sodium chloride.

  The mixture is introduced into a separating funnel and 60 ml

  of water are added to dissolve the separated mineral salts.

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

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

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

  diethyl; 84-85 ° C (2-propanol).

  Analysis: Calcul calculated for C 20 H 25 NO 8 1407 41):

C: 58 96%, H: 61%, N: 44%;

found:

C: 58 99%, H: 64%, N: 577%.

  1 H NMR (CDCl3): δ = 12 (t, 3H), 121 (t, 3H), 31 (s, 3H), 376 (s, 6H), 38-3. (m, 4H), 453 (d, 1H), 463

  (d, 1H), 46 (s, 1H), 6 3-6 (m, 2H) + 70 (d, 1H) ppm.

  e) 179 ml (206 g, 1.452 moles) of boron trifluoride-diethyl etherate were added dropwise to a stirred solution of 179 g (0.484 mole) of

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

  diethyl dicarboxylate and 107 ml (120 g, 1.936 mole) of ethylheol lycol in 500 ml of dioxane to nhyd, while cooling with ice water is provided The reaction mixture is allowed to stand at room temperature One hour later, during which it is stirred periodically, 415 g (1.452 mol) of Na 2 CO 3, 10H 2 are slowly added to the stirred mixture and cooled with ice water and the mixture is stirred for a period of one hour. 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. dried on

  magnesium sulfate, filtered and the filtrate is evaporated.

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

  sulfoxide and the mixture is stirred on an oil bath at 80 ° C.

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

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

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

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

  Ethyl 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate; P f: 950 C.

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

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

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

We obtain:

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

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

diethyl dicarboxylate.

  1 H NMR (CDCl 3) δ = 0 8-155 (m, 6H), 1.72 + 1 77 (d, 3H), 29 -3 (m, 2H), 375 (s, 6). H),

  40-50 (m, 9H), 64 (m, 2H) + 7 (d, 1H) ppm.

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

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

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

  twice with 50 ml portions of dichloromethane.

  The dichloromethane solutions are combined, dried

  on magnesium sulfate, filtered and the filtrate is evaporated.

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

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

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

117-118 ° C (toluene).

  Analysis: Calculated for C 17 H 21 NO 7 (351 35):

C: 58 11%, H: 63%, N: 99%;

valuesFound:

C: 58 17%, H: 6 30%, N: 4 24%

  IR (K Br): 3500-2500, 2900, 1760, 1720 cm1.

  1 H NMR (CDCl3): 6 = 1 39 (s, 3H), 350 (d, 1H, J = 25 Hz), 377 (s, 3H, 379 (s, 3H)) , 86 (d, 1H, J = 25 Hz), 3.96 (m, 4H), 41 + 46 (d, 2H, JAB = 15Hz), 6

  1 (m, 2H) + 7 (d, 1H, J = 10Hz), 768 (broad s, 1H) ppm.

  h) 7.3 ml (52.5 mmol) of triethylamine are

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

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

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

  column chromatography (adsorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0, 200 mm, eluting agent: 7: 2 mixture of benzene

  and acetone): 12 0 g (64%) of trans-4-

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

  dioxolan-2-yl) -2-azetidinone. Analysis: Calculated Values for C 18 H 21 N 306 (375 37):

C: 57 59%, H: 64%;

  Found values C: 57 78%, H: 39%.

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

EXAMPLE 2

  Acideftrans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxy)

  phenyl) -4-oxo-2-azetidin 17-acetic acid

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

  (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone are dissolved in a mixture of 50 ml of water and 1 ml of tetrahydrofuran. The mixture is irradiated with a mercury lamp at high pressure 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;

  developer: 7: 1 mixture of benzene and acetone)

  the reaction is complete, tetrahydrofuran is

  The residue is distilled off in vacuo and the residue is made alkaline with 20% aqueous sodium hydroxide and the solution is washed twice with

  15 ml of dichloromethane The aqueous phase is acidic

  at pH 1-2 with concentrated hydrochloric acid

  and then extracted three times with

  20 ml of dichloromethane The organic phases are combined

  dried, dried over magnesium sulphate, filtered and the filtrate evaporated. 1.6 g (50%) of the desired product were collected: Analysis: calculated for C 16 H 19 N 6 O (321.33):

C: 59.80%, H: 5.96%, N: 4.36%;

found values:

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

  IR (film): 3500-2500, 1760-1700 cm The starting material can be prepared in the following manner: a) A mixture of 24.6 g (0.2 mol) of 4 methoxyaniline and 23.9 g ( 17 ml, 0.1 mole) of diethyl bromomalonate is stirred at room temperature for 2 days. The resulting mass is triturated with 100 ml of diethyl ether, the separated 4-methoxyanisidine hydrobromide is filtered and washed with a small amount of diethyl bromomalonate. Diethyl ether The mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13 g (47%) of (4-methoxyanilino) are obtained.

  diethyl malonate: mp: 64-65 ° C (ethanol).

  Analysis: Values calculated for Cl 4 H 19 NO 5 (281 31):

C: 59.77%, H: 81%, N: 499;

  Found values C: 59.99%, H: 6 97%, N: 5 25 c -1 IR (K Br): 3300, 1775, 1725 cm 1 HR 4 N (CD C 13): 6 = 1 23 (t , 6H, J = 72Hz), 367 (s, 3H), 4.2 (q, 4H, J = 72Hz), 4.62 (s, 1H), 4 1-4 5 (large

  s, 1H), 6.55 (2H) + 6 73 (2H, AA'BB ', J = 9Hz) ppm.

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

  anilino) -diethyl malonate, prepared according to item a) ci of SS u S, 5 ml of glacial acetic acid and 4 g (3.7 ml, 0.048 mole) of diketene is boiled for 0.5 hour The The solution is evaporated under vacuum, the oily residue is triturated with diethyl ether and the solid

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

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

  diethyl dicarboxylate and / or its tautomer; p f:

136-137 ° C (ethyl acetate).

  Analysis: Calculated values for C 18 H 23 N 07 (365 38):

C: 59 17%, H: 639 N: 833;

  Found values C: 58 98%, H: 6.90, N: 404%.

  IR (Y Br): 3600-3000, 1760, 1740, 1685 cm -1 H NMR (CDCl3): δ = 107 (t, 3H, J = 72 Hz), 128 (t, 3H, J); = 72 Hz), 158 (s, 3H), 276 (s, 2H), 36 (s, 1H), 376 (s, 3H), 41 (q, 2H), J = 7.2 Hz), 27 (q, 2H, J = 7.2 Hz),

  6.7 (2H) + 7O (2H, AA 'BB', J = 9Hz) ppm.

  c) 9.1 g (0 025 mole) of diethyl 1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate prepared according to (b) above are suspended in 50 ml of anhydrous diethyl ether and a solution of 1.72 g of sodium metal in 30 ml of anhydrous ethanol and a solution of 6.35 g (0.025 mole) of iodine in 50 ml The mixture is poured into 100 ml of a saturated aqueous solution of sodium chloride and 2 g of sodium hydrosulphite and the mixture is poured dropwise into the vigorously stirred suspension and cooled with ice. 2 ml of glacial acetic acid are added. The ethereal phase is separated and the

  aqueous phase is extracted three times with

  The ethereal phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated. The oily residue is triturated with methanol.

  2-propanol to obtain 6.2 g (68%) of 3-acetyl-1- (4-methoxy)

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

  crystalline; p: 70-71 ° C (ethanol). Analysis: Calculated Values for C 18 H 2 NO 7 (363 38):

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

  Found values C: 59 04%, H: 5 84, N: 4 08% _ 1

IR (K Br): 1760, 1735, 1720 cm.

  1 H NMR (CDCl 3): 6 = 1 (t, 3H, J = 7Hz), 1H (t, 3H, J = 7Hz), 23 (s, 3H), 37 (s, 3H), 17 (q, 2H, J = 7Hz), 4 (q, 2H, J = 7Hz), 47 (s, 1H), 6

  (2H) + 731 (2H, AA 'BB', J = 9Hz) ppm.

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

  Diethyl 4-oxo-2,2-azetidine-dicarboxylate, prepared according to (c) above, are dissolved in 20 ml of

  anhydrous dioxane and 4.1 g (3.75 ml, 0.066 mol) of ethylene glycol.

  7.1 g (6.3 ml, 0.95 mole) of boron trifluoride-diethyl etherate complex are added dropwise to the stirred and ice-cooled solution and the reaction mixture is stirred for 2 hours. The solution is made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, then 100 ml of water are added and the mixture is extracted three times with 50 ml portions of diethyl ether. The oily residue is triturated with diethyl ether to obtain 6 g (89%) of 3- (2-methyl-1,3-dioxolan-2-yl), and the filtrate is evaporated. crystalline diethyl 1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate;

mp: 82-83 ° C (ethanol).

  Analysis: Calculated for C 20 H 25 NO 8 (407.43):

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

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

  IR (K Br): 1740 cm-1 (broad) H NMR (CDCl3): δ = 17 (t, 3H, J = 72 Hz); 1.26 (t, 3H, J = 72Hz), 15 (s, 3H), 37 (s, 3H), 39 (m, 4H), 42 (m, 5H), 6 67 (2H) + 7 34 (2H, AAP 'BB', J =

9 Hz) ppm.

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

  Diethyl 1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate, prepared according to (d) above, are dissolved in 20 ml of dimethyl sulfoxide, then 1.72. g (0.0295 mol) of sodium chloride and 0.9 ml (0.049 mol) of water are added and the mixture is stirred at 175 ° C. until the reaction is completed. The progress of the reaction is followed by Thin layer chromatography (adsorbent: Kieselgel G according to Stahl, revealing solvent: melanae 6: 4

benzene and ethyl acetate).

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

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

  The oily residue is crystallized with benzene.

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

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

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

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

  Found C: 58 40%, H: 80-%, N: 466%.

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

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

  f) 1.11 g (155 ml, 100 mmol) of anhydrous triethylamine is added to a solution of 3 g (0.01 mol) of a compound prepared according to (e) above, in ml anhydrous tetrahydrofuran The solution is cooled to -15 ° C. and 1.2 g (1.06 ml, 0.011 mol) of ethyl chloroformate are added dropwise with stirring.

  minutes of stirring the separated salt is filtered under

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

  filtrate at room temperature After 2 hours of stirring

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

(benzene and ether).

  IR (K Br): 2200, 1760, 1640 cm H NMR (CDCl3): δ = 150 (s, 3H), 51 (d, 1H, J = 26Hz), 375 ( s, 3H 1), 405 (m, 4H), 41 (d, 1H, J = 2. 6Hz), 47 (s, 1H), 65 (2H) + 7 (2H, AA 'BB', J =

9 Hz) ppm.

EXAMPLE 3

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

oxo-2-azetidinyl L 7 acetic

  3.8 g (0.0126 mol) 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, in a photoreactor, at room temperature under a nitrogen atmosphere The progress of the reaction is monitored by thin-layer chromatography (Stahl Kieselgel G adsorbent, developer solvent, 7: 1 mixture

  benzene and acetone) At the end of the reaction, the

  Trahydrofuran is evaporated under vacuum, the residue is alkaline

  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 at pH 1-2 with concentrated hydrochloric acid

  Aqueous extract, then extracted three times with

  20 ml of dichloromethane The organic phases are

  dried, dried over magnesium sulphate, filtered and the

  The oily residue is triturated with

  ther to obtain 1.8 g (50%) of ltrans-1-phenyl-3- (2-

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

tallin; 128-129 ° C (ethanol).

  Analysis: Calculated for C 15 H 17 NO 5 (291.29):

C: 62.00%, H: 5.88%, N: 4.82%;

found values:

C: 61.75%, H: 5.86%, N: 5.08%.

  -1 IR (K Br): 1760, 1740 cm H NMR (CD C 13): = 1.48 (s, 3H), 2.65 (dd, 1H, Jgem = 15 Hz, J Vic = 8 Hz ) + 3.12 (dd, 1H, Jge = 15 Hz, J Vic = 8 Hz), 3.47 (d, 1H, J = 2.5 Hz), 3.98 (m, 4H),

  4.4 (m, 1H), 7.3 (m, 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 aniline

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

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

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

and petroleum ether).

  Analysis: Calculated for C 17 H 21 NO 6 (355 35):

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

  Found: C: 60 83%, H: 6 15%, N: 433%.

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

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

(s, 5H) ppm.

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

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

  on magnesium sulfate, filtered and the filtrate is evaporated.

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

  to obtain 31 g (62%) of 3-acetyl-11-phenyl-4-oxo-2,2-

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

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

  Found values C: 61 38%, H: 89% N: 24%.

  IR (K Br): 1770, 1740, 1720 cm H NMR (CDCl3): δ = 11 (t, 6H), 23 (s, 3H),

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

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

  diethyl oxo-2,2-azetidine-dicarboxylate, prepared according to item d) ci of S S u S, are dissolved in a mixture

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

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

  2 hours at room temperature, then neutral

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

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

  Diethyl 1,3-dioxolan-2-yl) -4-oxoazetidine dicarboxylate mp: 596 ° C (gasoline) Analysis: Calculated for C 19 H 23 NO 7:

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

  Found C: 60 74%, H: 6 21%, N: 79%.

  IR (K Br): 1770, 1740 cm H NMR (CDCl3): 6 = 1 18 (t, 3H, J = 7Hz), 1 (t, 3H, J = 7Hz) , 1, 51 (s, 3H), 392 (m, 4H), 43 (m, 5H),

7.2 (m, 5H) ppm.

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

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

  diethyl ether, prepared according to item 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 is complete 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). solution is poured into 200 ml of a saturated aqueous solution of sodium chloride and extracted three times with

  150 ml portions of diethyl ether. The organic phases

  The resulting oily residue (16.4 g) is dissolved in 100 ml of ethanol and a solution of 2.15 g (0.054 mole) of sodium hydroxide solution is added. sodium hydroxide in 30 ml of water is added to this stirred mixture and cooled with an ice-water bath. After stirring for 0.5 hour, the mixture is diluted with 150 ml of water and extracted three times with portions of water. 20 ml of diethyl ether The aqueous phase is acidified to pH = 1 with 3 C concentrated hydrochloric acid and then extracted three times with 50 ml portions of dichloroethane. The organic phases are combined, dried over sodium sulfate and dried. magnesium, filtered and the filtrate is evaporated The oily residue is crystallized

  in benzene to obtain 12 g (56%) of trans-1-acid

  phenyl-3- (2-methyl-11,3-dioxolan-2-yl) -4-oxo-2-azetidine

  carboxylic acid; 165 C (benzene).

  Analysis: values calculated for C 14 H 15 NO 5 (277 27):

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

  Found C: 60 64%, H: 72, N: 49%. IR (K Br): 3500-2700, 1770, 1730 cm H NMR (CDCl3): δ = 1.5 (s, 3H), 369 (d, 1H, J = 3 Hz), 40 (m.p. , 4H), 42 (d, 1H, J = 3Hz), 73 (m, 5H);

7.55 (s, 1H) ppm.

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

  (2-Methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid prepared according to item d) of SS u S, are dissolved in 100 ml of anhydrous tetrahydrofuran and 5.55 g. (7.7 ml 0.055 mol) of ethyl chloroformate are added to the solution at -15 ° C. For 20 minutes of stirring, the separated salt is filtered under a nitrogen atmosphere and an ethereal solution of 22.6 g (0.degree. 15 moles) of diazomethane is added

to the filtrate with stirring.

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

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

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

ether).

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

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

  As is apparent from the above, the invention is not limited to those of its modes of implementation, implementation and application which have just been described more explicitly; on the contrary, it embraces all the variants that may come to the mind of the technician in the field, without departing from the scope, the scope, the

the present invention.

Claims (11)

claims   1 compound characterized in that it is represented by the general formula (I) below y 1 y 2 H H HOC _CH 2 COOH 3 - 2 0 (I) \ R '   where y 1 and y 2 together form a detachable group   carbonyl-protecting group, preferably a ketal group or its thioanalogue, and R is a detachable protecting group of the amido group, preferably a benzyl group bearing one or more C 1 to C 4 alkoxy substituents or a phenyl group optionally carrying a or more alkoxy substituents C 1 to 4 '   Compound according to claim 1, characterized in that it is (trans-1- (2,4-dimethoxybenzyl)   3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-acetate   than. Compound according to claim 1, characterized in   what it is (trans-3- (2-methyl-1,3-dioxolan)   2-yl) -1 (4-methoxy-phenyl) -4-oxo-2-azetidinyl-acetic acid.   Compound according to claim 1, characterized in   what is ftrans-1 phenyl-3- (2-methyl)   1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl 17-acetic compound characterized in that it is represented by the general formula (II) below yl y 2 H H HOC-O C-COCH 2 H 30 to 2 o "ZNs (II)   where y 1 and y 2 together form a detachable group   protect the carbonyl group, preferably a group of   ketal or its thioanalogue, and R is a detachable protective group of the amido group,   preferably a benzyl group carrying one or more sub-   C 1 4 alkoxy stituents or a phenyl bearing group   optionally one or more C 1-4 alkoxy substituents.   Compound according to claim 5, characterized in that   what is trans-4- (diazoacetyl) -1- (2,4-dimethyl)   benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone.   Compound according to claim 5, characterized in   what is trans-4- (diazoacetyl) -3- (2-methyl-   1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone.   Compound according to claim 5, characterized in   what is trans-4- (diazoacetyl) -1-phenyl-3-   (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone.   9 Process for the preparation of a novel compound   characterized by the general formula (I) according to claim 1, characterized in that a compound represented by the general formula (III) below y 1 y 2 Y 1 Y H H   COOR H 3 O (III) wherein R 1, y 1 and y 2 are as defined above, is activated on the carboxy group, then reacted with diazomethane and the resulting compound represented by the general formula (II) according to claim 5, where R, y 1 and y 2 are such that   defined above, is subject to a rearrangement of   ketone in the presence of water, or a compound of general formula (II), where R, y 1 and y 2 are as defined more   high, is subject to a rearrangement of diazoketone in pre-   water, and the resulting product of general formula (I) is separated.   Process according to Claim 9, characterized in that the carboxy group of the compound of the general formula   (III) is activated with ethyl chloroformate.   11. Process according to claim 9, characterized in that the rearrangement of diazoketone is carried out under   irradiation with ultraviolet light.   The process according to claim 9 for the preparation of   Etrans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-   ? 1,3-dioxolan-2-yl) -4-oxo-2-acetic azétidinyll, characterized   in that trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl)   1,3-dioxolan-2-yl) -4-oxo-azetidine carboxylic acid is active   on the carboxy group and then reacts with diazo-   methane and trans-4- (diazoacetyl) -1- (2,4-dimethoxy)   benzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -2-azetidinone.   aunt is subject to a rearrangement of diazoketone, presence of water.   The process according to claim 9 for the preparation of   ration of Ltrans-3- (2-methyl-1,3-dioxolan-2-yl) -1-   (4-methoxyphenyl) -4-oxo-2-azetidinyl acetic acid, characterized   in that trans-3- (2-methyl-1,3-dioxolan-2-yl) -1-acid   (4-methoxyphenyl) -4-oxoazetidine carboxylic acid is reacted on the carboxy group and then reacts with diazomethane and   trans- (4-diazoacetyl) -3- (2-methyl-1,3-dioxolan-2-yl) -1-   (4-methoxyphenyl) -2-azetidinone is subjected to   a rearrangement of diazoketone in the presence of water.   The process according to claim 9 for the preparation of   ltrans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-)   yl) -4-oxo-2-azetidinyl-1-acetic acid, characterized in that the   trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo   2-azetidine-carboxylic acid is activated on the carboxy group   and then performs with diazomethane and then trans-4-   (diazoacetyl) -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -2-aze   tidinone is subject to a rearrangement of diazo- ketone, in the presence of water.