FR2518995A1 - PROCESS FOR THE PREPARATION OF ACETIC ACID HETEROCYCLIC DERIVATIVES AND DERIVATIVES THUS OBTAINED - Google Patents

Abstract

DERIVATIVES OF HETEROCYCLIC ACETIC ACID REPRESENTED BY GENERAL FORMULA I BELOW: (CF DRAWING IN BOPI) OR Y AND Y TOGETHER FORM A DETACHABLE GROUP PROTECTING RADICAL CARBONYL AND X IS AN ESTERIFYING GROUP DETACHABLE SELECTIVELY SELECTIVELY, PREPARATION COMPOUND OF GENERAL FORMULA III BELOW: (CF DRAWING IN BOPI) OR X, R, Y AND Y ARE AS DEFINED ABOVE. THESE COMPOUNDS OF GENERAL FORMULA I CONSTITUTE INTERMEDIATE INTERESTS IN THE SYNTHESIS OF THIENAMYCIN AND ITS ANALOGUES.

Description

The present invention relates to a process for the preparation of derivatives

  heterocyclic acetic acid, represented by the general formula (I) below: 2 y 1 / X H H

H -C | C CH 2000 X

I} NH (I)

0s

  o y 1 and y 2 together form a detachable protective group

  carbonyl group, preferably a ketal group or its thioanalogue, and X is a selectively detachable ester group,

  preferably an arylmethyl or diarylmethyl group.

  The compounds of formula (I) constitute

  intermediates in the synthesis of thienamycin and its analogues Another process for the preparation

  of these compounds is described in a patent application de-

  asked at the same time as this application.

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

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

  The present invention aims to bring

  point a new way for the synthesis of thiéna-

  mycine and its analogues, according to which the azene skeleton

  tidinone and the side chain "-hydroxyethyl or chain

  which can be easily converted into a group

  C-hydroxyethyl, are formed simultaneously in the first

  first step of the synthesis and the resulting key-intermediate

  is then converted into the desired end product.

  It has been found that by acylating with diketene a malonate (protected amino group) of dialkyl and

  react the resulting acylated product with iodine and a

  alkali metal coolate, an azetidine compound is obtained.

  none represented by the general formula (VIII) below

H 3 C C (COO 2) 2

N RI (VIII)

  containing a lateral e-acetyl chain, which can be

  used as a key intermediate in the synthesis.

  In the formula above, R 'represents a group

  detachable protector of the amido radical, preferably; a phenyl or benzyl group bearing one or more C 1 to C 4 alkoxy and Z is a C 1 to C 5 alkyl group. The intermediates of the general formula (VIII) and their preparation are described in detail in the application for

  applicant's Hungarian patent No. 2262/80.

  ration of these intermediates is also described in

  examples of the present invention.

  It has also been observed that before converting

  intermediate of the general formula (VIII) to thienamycin or one of its analogues, it is preferable to protect the ketone group of the lateral α-acetyl chain by means of a group, in particular a ketal group or its

  thioanalogue that can be eliminated in a subsequent step

  ethylene glycol or its thioanalo-

  As the mercaptoethanol may be particularly preferably applied to form the ethylene-ketal or hemithioketal protective group. The resulting compound of the general formula (VII) hereinafter: ## STR2 ##

  where Y 1 and y 2 together form a group for

  temporarily templating the carbonyl part, preferably an ethylene ketal group or a thioanalogue thereof and R 'and Z are as defined above, is then treated with an alkali metal halide in pyridine or a neighboring solvent or in aqueous dimethylsulfoxide, to obtain a compound represented by the following general formula (VI): ## STR2 ## in which R ', Z, y 1 and y 2 are such The resulting compound of the general formula (VI) is a mixture of the cis and trans isomers. The isomers can be separated from one another by chromatography or, due to their different solubility. The separated trans isomer represented by the general formula (V Ia) below y 1 HHH 50 -O E 3 a C o N (V Ia)

0 RI

  can be converted to transcarboxylic acid represented by the following general formula (V) y 1 Y H H

\ / W C 000 H

H 30 C

4 * (V)

_____ (y)

  by hydrolysis It is more advantageous, however, to submit

  the isomer mixture itself to hydrolysis, since the reaction is selective, that is to say that only the ester

  trans is converted to the respective carboxylic acid.

  The separated transcarboxylic acid represented by the formula (V) is treated first with an activator for the carboxy group, then with diazomethane and the resulting compound represented by the following general formula (IV)

I -COCHN

J (Iv)

  is subject to Wolff transposition in the presence of water.

  In this way, an azetidinoacetic acid is obtained.

  presented by the following general formula (III)

Y Y 2 H H H 20

\ HCO

EH C 2

  (III) R 'which constitutes the starting material of the process according to the present invention In the general formulas (V), (IV) and (III), R', Y 1 and y 2 are as described above. Some of the compounds of general formula (VII) are described in our patent application No. 2263/80, while the other compounds of formula

  (VII) as well as compounds of general formulas

  (VI) to (III) are described in other patent applications of the Applicant The preparation of these compounds

  is also described in the examples of the present invention.

  tion. The compounds of general formula (III) can

  be converted into new esters represented by the

  general mule (II) hereinafter yl Y H H

H 3 C-C CH 2 CX

  by methods known per se and the protecting group R 'of the resulting esters is then removed.

  give the compounds of the general formula (I)

  The compounds listed may be converted to thienamycin or its analogues, as shown in scheme A. In the formulas listed in Scheme AOX, Y 1 and y 2 are as defined above, Q is a C 1 to C 1 alkyl group. Or a substituted benzyl group, Q 'is a C 1-5 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is a group

  benzyl, aminoethyl or N-acylaminoethyl.

2 5 1 8 9 9 5

Diagram (A) y 1 y 2 H H Cc

3 1

  H, HCOOH E.H.H.sub.2 H.sub.5, / Pd / c Malonic semiester salt HCO 2 COCINJ 2 COOQ azide sulfonic acid and H DQ 1 5 salt of Rh H 0 -acylation formation of mercaptan salt H '

- 1 SR ##

q C 00 Q 3 f, O

I 12 CO.

_r, CH.

l 1 '

C) 4 '

  From these data, the present invention

  relates to a process for the preparation of a compound

  SE of general formula (I), wherein:

  y 1 and y 2 together form a detachable protecting group

  carbonyl radical, preferably a ketal group or a thio-analogue thereof, and X is a selectively detachable ester group,

  preferably an arylmethyl or diarylmethyl group

  1a, according to which a compound of general formula (III), where y 1 and 2

  are as defined above and R 'is a group

  protector of the radical amido other than a

  nyl, preferably a phenyl or benzyl group bearing

  one or more C 1-4 alkoxy substituents is converted into

  ti to an ester of general formula (II), where X, R ', Y 1 and

  y 2 are as defined above, according to a method con-

  in itself and the protective group R 'of the ester

sultant is then eliminated, or

  the protecting group R 'of a compound of general formula

  neral (II) o X, R ', Yi and y 2 are as defined more

high, is eliminated.

  In the first step of the above process,

  reacts an azetidine-acetic acid of general formula

  (III) with a esterifying agent which provides a selectively releasable esterifying group. It is preferred to apply esterifying agents which provide a

  group X, in particular an arylmethyl or diaryl group.

  methyl which can be removed later by reduction.

  Phenyl diazomethane and diphenyl diazomethane are

  particularly interesting as estéri-

  cants. The resulting ester of general formula (II) is separated from the reaction mixture, optionally, or it is subjected to the subsequent step directly in the medium

  reaction in which it is formed.

  The protecting group R 'can be removed by

  oxidative methods When a dimethoxybenzyl

  must be removed, a compound of the peroxidisulphon

  fate, preferably potassium peroxydisulphate or

  sodium (K 25208, Na 25208) is applied as an oxy-

  The reaction is carried out in the presence of water and a

  organic solvent and the mixture is buffered at pH 7.

  When a methoxyphenyl protecting group is to be removed, it is preferred to apply a salt of

  cerium (IV) as an oxidizing agent in the presence of an acid.

  A solution of ammoniacal ceric nitrate in

  dilute aqueous sulfuric acid is particularly

  oxidation is carried out in advance.

presence of an organic solvent.

  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 which is the subject of this

invention.

  It should be understood, however, that these examples of implementation are given solely for the purpose of

  illustration of the subject of the invention, of which they do not

  in no way constitute a limitation.

EXAMPLE 1

  Benzyl-trans-1 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl-7-acetate 3.05 g (15.75 mmol) diphenyl diazomethane is added at room temperature to a stirred solution

  5.48 g (15 mmol) of Ztrans-1- (2,4-dimethoxybenzoic acid)

  zyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidin 17-acyl

  tick in 50 ml of dichloromethane When clearing

  of nitrogen ceases a few drops of acetic acid are added

  The solution is evaporated to dryness and the residue (weighing 6.77 g) is dissolved in 84 ml of acetonitrile. The solution is supplemented with 16.20 g (60 mmol) of peroxydisulphate.

  potassium (K 25208), 21.60 g (120 mmol) of phos-

  Disodium flask monohydrate (Na 2 HP 04, H 20) and 54 ml of water and the mixture is stirred vigorously for 4 hours, brought to boiling, then cooled. The cold reaction mixture is filtered and the two phases of the filtrate are filtered off.

  are separated from each other The aqueous phase is ex-

  treated three times with 30 ml

  The organic phases are combined, dried

  on magnesium sulphate, filtered and the filtrate is

  The residue is dissolved in benzene and the solution is sent to a chromatography column (adsorbent:

  Kielselgel 60, O = 0.050 to 0.200 mm, eluent agent:

  7: 2 benzene-acetone) to provide 2.68 g (47%) of the title product; Mp: 130 ° C (ethanol) Analysis: Calculated for C 22 H 23 NO 5 (387.41):

C: 69.27%, H: 6.08%, N: 3.67%;

found values:

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

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

  1H NMR (CDCl2): = 1.39 (s, 3H), 2.63 (dd, 2H, J = 4.4Hz), 2.89 (dd, 2H, J = 9.1 Hz), 5.97 (m, 5H), 6.12

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

  The starting material is prepared as follows:

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

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

borosodium hydride.

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

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

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

  and provides 197 g (72%) of N-benzyl-N- (2, A-d 4 imethoxybenzyl) -

  amino-mnalonate diethyl; p: 62-63 ° C (ethanol).

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

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

  diethylamino malonate, prepared according to item a) of S su S, are hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of approximately 20 g of

  catalyst consisting of palladium on charcoal

  The filtrate is filtered and the filtrate is evaporated. 47.1 g (97%) of diethyl (2,4-dimethoxybenzylamino) -malonate are collected. The product can be converted into its hydrochloride by reaction with hydrochloric acid. 122-124 ° C after recrystallization from ethyl acetate E: Analysis: Calculated for C 16 H 24 C 1 N O 6 (361 82): C: 53.11%; H: 69%, C: 9 80 %; N: 87%; "found

  C: 52%, H: 77%, C: 30%; N: 409%.

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

  1 H NMR (CDCl3): δ = 13 (t, 6H), 378 (s, 3H), 382 (s, 3H), 421 (q, 4H), 6 (s). , 2H), 6 4-6 6 (m, 2H) + 7 3-7 55

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

  c) A mixture of 39.6 g (0.122 mole) of diethyl (2,4-dimethoxbenzylamino) malonate, prepared according to item (b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 g). 2 ml, 0.146 mol) of diketene 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 material is dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether.

  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: Calculated Values 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), 1H (t, 3H), 1H NMR (CDCl3):? 52 (s, 3H), 28 (<1H), 265 (broad s, 2H), 37 (s, 6H), 3.8-4 (m, 4H), 6 7 (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 in addition to

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

  ml of a saturated aqueous solution of sodium chloride.

  The mixture is introduced into a separating funnel and 60 ml

  of water are added to dissolve the separated mineral salts.

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

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

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

  diethyl; 84-85 ° C (2-propanol).

  Analysis: Values calculated for C 20 H 25 NO 8 407 41):

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

  Found: C: 58.99%, H: 6.04%, N: 3.57% IR (K Br): 2900, 1780, 1740, 1710 c M-1 H NMR (CD C 13): 6 = 1 12 (t, 3H), 121 (t, 3H), 31 (s, 3H), 376 (s, 6H), 38-3 (m, 4H), 453 ( d, 1H), 4 63

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

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

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

  diethyl dicarboxylate and 107 ml (120 g, 1.936 moles) of ethyl ene glycol in 500 ml of anhydrous dioxane, while cooling with ice water is provided. The reaction mixture is allowed to stand at room temperature for one day. During which time 415 g (1.452 mol) of Na 2 CO 3 .0 10 H 20 are added slowly to the stirred mixture and cooled with ice-water and the mixture is stirred for a minute. 1 liter of ether and 1 liter of water are added and the phases are separated from each other. The aqueous phase is shaken twice with 500 ml portions of diethyl ether. The ether phase is dried over

  magnesium sulfate, filtered and the filtrate is evaporated.

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

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

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

  developer: 6: 4 mixture of enzene 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 and the ether solutions are combined, decolorized with charcoal, dried over magnesium sulphate and the filtrate is evaporated to a final volume of about 200 ml. This concentrated solution is cooled with ice water.

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

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

ethyl; P f: 95 C.

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

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

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

We obtain:

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

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

diethyl dicarboxylate.

  1H NMR (CDCl3): δ = 0 8-155 (m, 6H), 1.72 + 1 77 (d, 3H), 29-38 (m, 2H), 375 (s, 6H),

  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:

117-1189 C (toluene).

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

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

Value found:

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

  IR (K Br) 3500-2500, 2900, 1760, 1720 cm-1 1H NMR (CDCl3): δ = 1 39 (s, 3H), δ -50 (d, 1H, J = 25 Hz ), 377 (s, 3H), 379 (s, 3H), 86 (d, 1H, J = 25 Hz), 3.96 (m, 4H), 4 +4 (d) , 2H, JAB = 15Hz), 6

  (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 mmoles of diazomethane in 230 ml of cold diethyl ether is added to the mixture. The mixture is stirred, allowed to warm to room temperature and stirred for 2 hours, evaporated to dryness. The thick brown residue is dissolved.

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

  column chromatography (adsorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0, 200 mm, eluent: 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 for C 18 H 21 N 306 (375 37):

C: 57 59%, H: 64%;

  Found values C: 57 78%, H: 39%.

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

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

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

* dioxolan-2-yl) -2-azetidinone prepared according to point (h)

  100 ml of peroxide-free tetrahydrofuran and 50 ml of water are irradiated for about 4 hours with a high-pressure mercury lamp (HPX 125) immersed in a Pyrex reactor under an argon atmosphere. 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 is added to the aqueous mixture and the alkaline mixture is washed at three

  times with 20 ml portions of dichloromethane.

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

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

  (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidin 117-acetic acid

mp: 124C (ether).

  Analysis: Calculated for C 18 H 23 NO 7 (365.37):

C: 59 17%, H: 34%, N: 833%;

  Found values C: 59 22%, H: 6 49%, N: 407%.

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

EXAMPLE 2

  Trans-D- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidin; 7-acetic

benzhydryl tate

  0.28 g (0.65 moles) of trans-E 3- (2-methyl-1,3-dioxo)

  lan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinyl acetate

  benzhydryl is dissolved in 2 ml of acetone and a solution of

  0.9 g (1.6 mole) of ceric ammonium nitrate (NH 4) 2 (NO 3) 6 l in 2 ml of 5% aqueous sulfuric acid is added dropwise to the mixture. agitated, at the temperature

  The reaction mixture is stirred for 2 minutes.

  extra, then neutralized carefully, with

  a 5% aqueous solution of sodium hydrogen carbonate.

  The mixture is then extracted three times with 4 ml portions of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated under vacuum. The oily residue

  is purified by preparative layer chromatography.

  (adsorbent: Kieselgel 60, O = 0.050-0.200 mm, eluent: benzene-acetone 7: 2 mixture) to obtain

  0.06 g (30%) of the compound of interest This compound is identical

  than that prepared in the manner described in the e-

xample 1.

  The starting material is prepared in the way.

  following: a) A mixture of 24.6 g (0.2 mol) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mol) of diethyl bromomalonate is stirred at room temperature for 2 days. The resulting product is triturated with 100 ml of difthyl ether, the separated 4-methoxy-anisidrine hydrobromide is filtered and washed with a small amount of diethyl ether. The mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13 g (47%) of (4-methoxyanilino) are obtained

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

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

C: 59 77%, H: 6 81%, N: 49%

  Found C 59% 99%, H 97%, N 25%.

  IR (K Br): 3300, 1775, 1725 cm -1 NMR (CDCl 3): 6 = 1 23 (t, 6H, J = 7Hz), 36 (s, 3H), 4, 2 (q 4 H, J = 7 2 Hz), 4.62 (s, 1 H), 4 1-4 5 (broad

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

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

  anilino) -diethyl malonate, prepared according to item a) 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 under vacuum, the oily residue is triturated with diethyl ether and the solid

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

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

  diethyl dicarboxylate and / or its tautomer; p f:

136-137 ° C (ethyl acetate).

  Analysis: Calculated Values for C 18 H 23 NO 7 (365 38): C: 59 17%, H: 6 39 g N: 833%

  Found C: 58 98%, H: 6 90%, N: 404%.

  IR (K Br): 3600-3000, 1760, 1740, 1685 cm-1. 1H NMR (CD C 13): δ = 107 (t, 3H, J = 72 Hz), 128 (t, 3H, J = 72 Hz),

  1 58 (s, 3H), 276 (s, 2H), 36 (s, 1H), 376 (s, 3H), 41 (q, 2H, J = 7Hz) , 27 (q, 2H, J = 7 Hz)

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

  c) 9.1 g (0 025 mole) of diethyl 1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate, prepared according to item b) cide-s su S 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 of anhydrous diethyl ether are poured dropwise simultaneously into the vigorously stirred suspension and cooled with ice. The mixture is then poured into 100 ml of a saturated aqueous solution of sodium chloride and 2 g of hydrosulphite. Sodium and 2 ml of glacial acetic acid are added. The ether phase is separated and the

  aqueous phase is extracted three times with

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

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

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

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

  Analysis: Calculated values for C 18 H 21 N 07 (363 38):

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

  Found C: 59 04%, H: 84%, N: 408% -1 IR (K Br): 1760, 1735, 1720 cm H NMR (CDCl3): δ = 1 (t, 3) H, J = 72 Hz), 22 (t, 3H, J = 72 Hz), 23 (s, 3H), 37 (s, 3H), 41 (q, 2H, J = 7.2 Hz), 19 (q, 2H, J = 72 Hz), 47 (s, 1H), 67

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

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

18995

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

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

  7.1 g (6.3 ml, 0.05 mol) of boron trifluoride-diethyl etherate complex are added dropwise to the stirred and ice-cooled solution and the reaction mixture is stirred for 2 hours. 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) 1H 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, AA 'BB', J =

9 Hz) ppm.

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

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

benzene and ethyl acetate).

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

  Saturated aqueous solution of sodium chloride and extracted three times with 50 ml portions of diethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The resulting oily residue, weighing 6 g is dissolved in 25 ml of 96% ethanol, then added with a solution of 0.72 g (0.018 mole) of sodium hydroxide in 10 ml of water, with cooling with ice water. 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 at pH = 1 with concentrated hydrochloric acid and extracted with three times. The organic phases are combined with 25 ml portions of dichloromethane, dried over magnesium sulphate, filtered and the filtrate is filtered off.

  The oily residue is crystallized with benzene.

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

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

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

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

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

1.

  IR (K Br): 3400-2700, 1750 (broad) cm 1.

  1H NMR (CDCl3): 6 = 1 (s, 3H), 37 (d, 1H, J = 25Hz), 376 (s, 3H), 40 (m, 4H). ), 38 (d, 1H, J = 25 Hz),

  6.82 (2H) + 726 (2H, AA 'BB', J = 9.5Hz), 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 mole) 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 diazomethane solution is decomposed with acetic acid and the solution is evaporated under vacuum. The oily residue crystallizes slowly. 3 g (90%) of trans-4- (diazoacetyl) -3- (2-methyl) are obtained. -1,3-dioxanan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone; p f: 95-96 C

(benzene and ether).

  IR (K Br): 2200, 1760, 1640 cm H NMR (CDCl3): δ = 150 (s, 3H), 51 (d, 1H, J = 26Hz), 375 ( s, 3H), 405 (m, 4H), 311 (d, 1H, J = 2.6Hz), 47 (s, 1H), 65 (2H) + 7 (2H). , AA 'BB', J =

9 Hz) ppm.

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

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

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

  mercury at high pressure in a photoreactor under atmospheric pressure

  nitrogen (the reaction is carried out at room temperature

  ambient) and the progress of the reaction is followed by

  thin-film matography (adsorbent: Stahl Kieselgel G; developer solvent: 7: 1 mixture of benzene and acetone> When the reaction is complete, the tetrahydrofuran is distilled in vacuo, the residue is basified with an aqueous solution of 20% sodium hydroxide and the solution is washed twice with portions of 1 ml of dichloromethane The aqueous phase is acidified to D = 1-2 with aqueous concentrated hydrochloric acid, and then extracted three times with portions 20 ml of dichloromethane The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate

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

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

2-Azetidinyl 3 -acetic acid.

  Pnalysis: Calculated for C 6 H 19 NO 6 (321 33):

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

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

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

  according to point (g) of S su S, in 10 ml of dichloromethane

  methane and a solution of 0.53 is added dropwise

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

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

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

  1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidin 17

-benzyl acetate.

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

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

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

  H NMR (CDCl 3): 6 = 1 (s, 3 P), 27-3 (m, 2H), 3.38 (d, 1H, J = 25 Hz), 372 (FIGS. s, 3H), 38-4-1 (m, 4H),

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

  As is apparent from the foregoing, the invention

  tion is not limited to those of its modes of implementation, of realization and of application which have just been

  described more explicitly; it embraces the contrary

  all variants that may come to the mind of the techni-

  in this respect, without departing from the scope or scope,

of the present invention.

Claims (5)

claims   1 Process for the preparation of a representative compound   by the following general formula (I): y 1 y 2 yy H H 3 C CH 2 COOX 0 (I o-.   where y 1 and y 2 together form a detachable group   protecting the carbonyl radical, preferably a group   ketal or a thioanalogue thereof, and X is a selectively detachable ester group, preferably an arylmethyl or diarylmethyl group, characterized in that   that a compound represented by the general formula (III) after: y 1 H H / wa CH 2 C 00 H O R III)   wherein y 1 and y 2 are as defined above and R 'is a detachable protecting group of the amido radical other than a phenyl group, preferably a phenyl or benzyl group bearing one or more C 1-4 alkoxy substituents. is converted to an ester represented by the following general formula (II) y 1 y 2 HH Hs CC CHCOOX O X, (II) RI   X, R ', y 1 and y 2 are as defined above, in a manner known per se and the protecting group R' of the resulting ester is eliminated, or the protecting group R 'd' a compound of general formula (II),   X, R ', y 1 and y 2 are as defined above, is eli-   mine. Process according to Claim 1, characterized in that a compound of the general formula (III), where R ', y 1 and y 2 are as defined above, is reacted with   phenyl diazomethane or diphenyl diazomethane.   Process according to Claim 1, characterized in that the protective group R 'of a compound of formula   (II) is removed with a compound of the peroxy-   disulfate or with a ceric salt in the presence of an acid.   4. Process according to claim 1 for the preparation   trans-D 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-   azetidinyl-benzhydryl acetate, characterized in that   etrans- (2,4-dimethoxybenzyl) -3- (2-   methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidin 11-acetic acid   with diphenyl diazomethane and then with a peroxydisulfa   you. Process according to Claim 1 for the preparation   trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-   azetidin 17-benzhydryl acetate, characterized in that   reacts acid / trans-3- (2-methyl-1,3-dioxolan-2-yl) -   1- (4-Methoxyphenyl) -4-oxo-2-azetidinyl-β-acetic acid with diphenyldiazomethane and then with a ceric salt in an acidic medium.   A compound characterized in that it is represented by the following general formula (II) y 1 Y H H Ca 2 CHCH 000 XOO o 2 i (TT)   where y 1 and y 2 together form a detachable group   W 2518995; protecting the carbonyl radical, preferably a ketal group or its thioanalogue, X is an esterifying group   selectively detachable, preferably an aryl group   methyl or diarylmethyl, and R 'is a detachable group   tector of the radical amido other than a phenyl group,   preferably a phenyl or benzyl group carrying one or more   C 1 -C 4 alkoky substituents A compound according to Claim 6, characterized in that   that it is trans / 3- (2-methyl-1,3-dioxolan-2-yl) -1-   Benzhydryl (4-methoxyphenyl) -4-oxo-2-azetidinyl 17-acetate.   Compound according to claim 6, characterized in   what is trans / 1-2,4-dimethoxybenzyl) -3- (2-methyl-   Benzyl 1,3-dioxolan-2-yl) -4-oxo-2-azetidin 17-acetate   hydryle. Compound according to general formula (I), wherein Y 1, y 2   and X are as defined in claim 1, characterized   in that it is prepared by the following process   any of claims 1 to 5.