LU84567A1 - PROCESS FOR THE PREPARATION OF HETEROCYCLIC DERIVATIVES OF ACETIC ACID - Google Patents

Description

NOT

The present invention relates to a process for the preparation of heterocyclic derivatives of acetic acid, represented by the general formula (I) below:

5 \ ^ CïïpCOOX

H ^ O - 0-3-Y 2 J-KH i1) (Γ 1 2 10 where Y and Y together form a detachable group protecting the carbonyl group, preferably a ketal group or its thioanalogue, and X is a detachable esterifying group selectively, preferably an arylmethyl or diarylmethyl group.

The compounds of formula (I) constitute intermediate intermediates in the synthesis of thienamycin and its analogs. Another process for the preparation of these compounds is described in a patent application filed at the same time as the present application.

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

The object of the present invention is to develop a new pathway for the synthesis of thienamycin and its analogs, according to which the aze- skeleton. tidinone and the side OC-hydroxyethyl chain or a side chain which can be easily converted to an o'-hydroxyethyl group, are formed simultaneously in the first step of the synthesis and the resulting key intermediate is then converted to desired end product.

It has been found that by acylating with diketene a malonate. (protected amino group) of dialkyl and by reacting the resulting acylated product with iodine and an alkali metal alcoholate, an azetidium compound is obtained. none represented by the general formula (VIII) below 2, Ο Hÿj - c-- | (C00Z) 2

mTO

containing a "C-acetyl side chain, which can be: used as a key intermediate in the synthesis.

In the above formula, R 'represents a detachable group protecting the amido radical, preferably 10' / a phenyl or benzyl group carrying one or more alkoxy at 1 ^ and Z is an alkyl group at 5 ·

The intermediates of general formula (VIII) 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 examples of the present invention.

It has also been observed that, before converting the intermediate of general formula (VIII) into thienamycin or one of its analogs, it is preferable to protect the ketone group of the oO-C-acetyl chain lateral to the using a group, in particular a ketal group or its thioanalogue which can be eliminated during a later stage of the synthesis. Ethylene glycol or its thioanalogue, such as mercaptoethanol, can be particularly preferably applied to form the ethylene ketal or hemithioketal protecting group. The resulting compound of general formula (VII) below ï1 ï2 H, C - (COOZ) ä 30 5 ά SS- ^ {VJI) ^ R »Λ 1 2 wherein Y and Y together form a group to temporarily protect the carbonyl part, preferably an ethylene ketal group or a thioanalogue thereof and R 'and Z are as defined above, is then treated with 3.

an alkali metal halide in pyridine or a neighboring solvent or in aqueous dimethyl sulfoxide, to obtain a compound represented by the general formula (VI) below:

ï1 Y2 H H

H? C -V-j-y 0002 A-i (TI) 10

AT

in which R ', Z, Y and γ2 are as defined above.

The resulting compound of general formula (VI) is a mixture of the cis and trans isomers. The isomers can be separated from each other by chromatography or, thanks to their different solubility. The separate trans isomer represented by the general formula (Via) below

20 Y1 Y2 H H

V / W r ·. COOZ h5c - C - f 4-IL (Via) 25 can be converted into trans-carboxylic acid represented by the general formula (V) below

Y1 Y2 H H

\ / * C00H

H ^ C - C-1 ^ 30 0J-V (V) by hydrolysis. It is more advantageous, however, to subject the isomeric mixture itself to hydrolysis, since

The reaction is selective, that is to say that only the ester \\ ί 4 trans is converted into the respective carboxylic acid.

The separated trans-carboxylic acid, represented by formula (V) is treated first with an activator for the carboxy group, then with diazomethane and the resulting compound, represented by the general formula (IV) below ttI -y-2 tt rr

h3o I yL-ï — V

10 J-H (IV) 0 'is subjected to a Wolff transposition in the presence of water.

In this way, an azetidinoacetic acid is obtained represented by the general formula (III) below Y \ J2 J? ® CHpCOOH H c - C - Y ά 5 (= d 0 ^ \ E '20 which constitutes the starting material for the process according to the present invention. In the general formulas (V), (IV) and (III), R ', Y1 and are as described above.

Some of the compounds of general formula (VII) are described in patent application No. 2263/80 of the applicant, while the other compounds of general formula (VII) as well as the 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.

The compounds of general formula (III) can be converted into new esters represented by the general formula (II) below ü · 5 γΐ ν2 \? Η Η

HjC Λ_ί ^ CH? COOX

5 cJ- "V (ΙΙ) · R" according to methods known in themselves and the protective group R 'of the resulting esters is then removed -> to give the compounds of general formula (I). These latter compounds can be converted to thienamycin or its analogs as indicated in Scheme A. In the formulas listed in Scheme A or X, Y and Y are as defined above, Q is a C1 N c alkyl group or a substituted benzyl group, Q 'is a C 1-6 alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is a benzyl, aminoethyl or N-acylaminoethyl group . ^ j ‘6 I Diagram (A)

Y1 Y2 H H ”CHpCOOH

uC> c <—3-MH2C00X / -V

5 H7 / Pd / C f

_WH I._NH

O * 0 ^ salt of the semiester 10 maIonique y H h r ^ CHpCOCNpCOOQ = nu œ / —1 / —f "15 J sulfonic azide ^ 2 0 * - NH C00" | salt! 20 Rh I v j

! H

1 „/ '"' X, o! “H f

I // ^ COOQ

0 i I 30 -i.

0-acylation + formation of y ‘mercaptan salt

H

î S -___ SR "if 35 f 1 ^ a N ^ COOQ5 L · i ° i

i i

7 On the basis of these data, the present invention relates to a process for the preparation of a compound of general formula (I), in which: 1 2 Y and Y together form a detachable group protecting the carbonyl radical, preferably a ketal group or one of its thio-analogs, and X is a selectively detachable esterifying group, preferably an arylmethyl or diarylmethyl group, according to which 1 2

10 a compound of general formula (III), where Y and Y

are as defined above and R 'is a detachable group protecting the amido radical other than a phenyl group, preferably a phenyl or benzyl group carrying one or more alkoxy substituents at 4 / / is conver-15 ti to a ester of general formula (II), where X, R ', Y ** and Y are as defined above, according to a method known per se and the protective group R' of the resulting ester is then removed, or the protecting group R 'of a compound of general formula (II) where X, R', Y and Y are as defined more! high, is eliminated.

In the first step of the above process, an azetidine acetic acid of general formula (III) is reacted with an esterifying agent which provides a selectively detachable esterifying group. It is preferred to apply esterifying agents which provide a group X, in particular an arylmethyl or diaryl-methyl group which can be removed later by reduction.

Phenyl diazomethane and diphenyl diazomethane are particularly useful as esterifying agents.

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

The protective group R 'can be eliminated by 8 oxidizing methods. When a protective dimethoxybenzyl group has to be removed, a compound of the peroxydisulfate type, preferably potassium or sodium peroxydisulfate (K2S20g, Na2S20g) is applied as the oxidizing agent. The reaction is carried out in the presence of water and an organic solvent and the mixture is buffered to pH ^.

When a methoxyphenyl protecting group is to be removed, it is preferred to apply a cerium (IV) salt as an oxidizing agent in the presence of an acid.

A solution of ceric ammoniacal nitrate in dilute aqueous sulfuric acid proves particularly suitable for this purpose. The oxidation is carried out in the presence of an organic solvent.

In addition to the foregoing provisions, the invention I 15 also comprises other provisions, which will emerge from the description which follows.

The invention will be better understood with the aid of the! additional description which follows, which refers to examples of implementation of the method which is the subject of the present invention.

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

25 EXAMPLE 1

Trans- £ 3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azetidinyl7 I -benzhydryl acetate 3.05 g (15.75 mmol) diphenyl diazomethane are added at temperature ambient to a stirred solution of 5.48 g (15 mmol) acid / trans-1- (2,4-dimethoxyben-zyl) -3- (2-methyl-1,3-dioxolan-2-yl ) -4-oxo-2-azetidinylJ7-acetic in 50 ml of dichloromethane. When the nitrogen evolution ceases a few drops of acetic acid are added to the mixture to destroy the excess diphenyl-diazomethane in I35. The solution is evaporated to dryness and the residue (weighing 6.77 g) is dissolved in 84 ml of acetonitrile. 16.20 g (60 iranoles) of potassium peroxydisulfate (K2S20g), 21.60 g (120 mmoles) of disodium phosphate monohydrate (Na ^ PO ^ / H20) and 54 ml 'water and the mixture is stirred vigorously for 45 hours', brought to a boil, then cooled. The cold reaction mixture is filtered and the two phases of the filtrate are separated from each other. The aqueous phase is extracted three times with 30 ml portions of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The residue is dissolved in benzene and the solution is sent to a chromatography column (adsorbent: Kielselgel 60, 0 = 0.050 to 0.200 mm, eluent: 7: 2 mixture of benzene and acetone) to provide 2 , 68 g 15 (47%) of the product whose name is indicated in the title; m.p .: 130uC (ethanol) - Analysis: values calculated for ^ 22H23N ^ 5 (387.41): C: 69.27%, H: 6.08%, N: 3.67%; values found: 20 C: 69.15%, H: 6.20%, N: 3.55%.

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

1H NMR (CDC12): 1.39 (s, 3H), 2.63 (dd, 2H, J = 4.4 Hz), 2.89 (dd, 2H, J = 9.1 Hz), 5.97 (m, 5H), 6.12 (s, 1H), 6.9 (s, 1H), 7.28 (ε, 10H) ppm.

The starting material is prepared as follows: a) A mixture of 109.8 g (0.66 mole) of 2,4-dimetho-xybenzaldehyde, 72 ml (0.66 mole) of benzylamine and 660 ml The ethanol 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) fl of borosodium hydride.

: | The progress of the reaction is monitored by chromatography on a Λ J thin layer (Kieselgel G according to Stahl; revealing solvent:! 110 9: 1 mixture of benzene and acetone) and at the end of the reaction, the mixture is evaporated to dry, under vacuum. The residue 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: 5 The ethereal solutions are combined, dried over magnesium sulphate, filtered, then the filtrate 112 ml (0.66 mole) of diethyl bromomalonate and 33 ml (0.66 mole) of triethylamine are added. The reaction mixture is stirred at room temperature for 2 to 3 days. The separated triethylammonium bromide is filtered and then washed with ether. The mother liquor is evaporated and the residue is recrystallized from 150 ml of ethanol. The resulting crude product: (210 g) is again recrystallized from 400 ml of ethanol and provides 197 g (72%) of diethyl N-benzyl-N- (2,4-dimethoxybenzyl) -15 amino-malonate; m.p. : 62-63 ° C (ethanol).

IR (KBr): 1750f1725 cm'1, d.

b) 61.7 g (0.149 mole) of diethyl N-benzyl-N- (2,4-dimetho-xybenzyl) -amino-malonate, prepared according to point (s) above, are hydrogenated in 500 ml of ethanol 20 under atmospheric pressure in the presence of about 20 g of catalyst consisting of palladium on charcoal. The catalytic converter 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:

Calculated values for C ^ gE ^ ClNOg (361.82): '30 C: 53.11%; H: 6.69%, Cl: 9.80%; N: 3.87%; jf s ”found:: C: 52.51%, H: 6.77%, Cl: 10.30%; N: 4.09%.

| IR (film): 3250, 2900, 2850, 1730, 1720 cm "1, d 1H NMR (CDC13): 6 = 1.3 (t, 6H), 3.78 (s, 3H), 3.82 J 35 (s, 3H), 4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H) + 7.3-7.

j (m, 1H), 7.7 (broad s, 1H) ppm.

B

i 111 c) A mixture of 39.6 g (0.122 mol) of (2,4-dimethox benzÿlamino) -methylate diethylate, prepared according to point b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 mole) of diketene is brought to the boil for 0.5 hour. The 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. 10 29T6 g (60%) of diethyl N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer, are collected. f. î 106-107 ° C.

Analysis:

Values calculated for C20H27N ^ 8 (409.43): 15 C: 58.67%, H: 6.65%, N: 3.42%; "‘ Found: C: 58.79%, H: 6.33%, N: 3.34%.

IR (KBr): 3400, 2950, 2850, 1730 (1740, sh), 1710 cm 'r 12 d 1H NMR (CDC13): δ = 1.1 (t, 3H), 1.17 (t, 3H), 1.52 (s, ^ 3H), 2.8 (<0.1 H), 2.65 (large s, 2h), 3.75 (s, 6H), 3.8-4.15 (m, 4H), 6.7 (large s, 2H), 6.25-6.45 (m) + 7.0-7.25 (m, 3H) ppm.

D) 20.5 g (50 mmol) of the product prepared as described in point c) above are suspended in 50 ml of anhydrous ether and a solution of 3.45 g (150 g) is simultaneously added mmol) of metallic sodium in 100 ml of anhydrous ethanol and a solution of 12.7 g 10 (50 mmol) of iodine in 150 ml of anhydrous ether, from two dropping funnels, to the suspension vigorously stirred and cooled by ice water. Next, 5 g of sodium hydrosulfite, dissolved in 200 ml of a saturated aqueous solution of 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 C20H25NO8 || 25 C: 58.96%, H: 6.19%, N: 3.44%; "found: c: 58.99%, H: 6.04%, N: 3.57% IR (KBr): 2900, 1780, 1740, 1710 cm“ 1 1H NMR (CDC13): δ = 1.12 (t, 3H), 1.21 (t, 3H), 2.31 (s, 3H), 3.76 (s, 6H), 3.8-3.4 (m, 4H), 4.53 (d, 1H), 4.63! 30 (d, 1H), 4.69 (s, 1H), 6.3-6.4 (m, 2H) + 7.07 (d, 1H) ppm.

e) 17 g ml (206 g, 1.452 μmol) of boron trifluoride-diethyl etherate are added dropwise to a j; vigorously stirred solution of 179 g (0.484 mole) of 3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine- | 35 diethyl dicarboxylate and 107 ml (120 g, 1.936 mole) i a

B

wm

“I B

r B

|! H

13 ethylene glycol in 500 ml of anhydrous dioxane, while gu * 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, 1010 was added slowly to the stirred mixture and cooled with ice water and the mixture was stirred for 15 minutes. Then, 1 liter of ether and 1 liter of water are added and the phases are separated from each other. The aqueous phase 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. 180 ° C.

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).

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 500 ml portions of diethyl ether. ethereal solutions are combined, discolored. with charcoal, dried over magnesium sulfate and the filtrate is evaporated to a final volume of about 200 ml. This concentrated solution is cooled with ice water and provides 59 g (35%) of trans-1- (2,4-dimethoxybenzyl) - 3- (2-methyl-1,3-dioxolan-2-yl) - Ethyl 4-oxo-2-azetidine carboxylate; P.f. : 95 ° C.

F) A mixture of 0.5 g (1.2 mmol) of 3-acetyl-1 - (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine-diethyl dicarboxylate prepared according to point d) above, 3 ml of anhydrous tetrahydrofuran and 0.53 g (3.6 mmol) of mercapto-ethanol is brought to the boil for 4 hours, I i 14 I then 10 ml <3 * water and 10 ml of chloroform are added to | 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 PF254 + 366 revealing mixture: 8: 2 mixture of toluene and acetone).

0.30 g (53%) of 1- (2,4-dimethoxybenzyl) -3- ^ (2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azetidine-dicarboxylate are obtained diethyl.

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

g) A solution of 5.21 g (0.130 mole) of sodium hydroxide in 60 ml of water is added to a suspension of 41r2 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 (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 to pH = 1 with concentrated aqueous hydrochloric acid, then quickly shaken with 100 ml, then twice with 50 ml portions of dichloromethane.

The dichloromethane solutions are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated.

The oily residue is crystallized from a mixture of k toluene and petroleum ether to provide 35 g (92%) of trans-1- (2,4-dimethoxybenzyl) -3- (2 -methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic; m.p. : È 117-118 ° C (toluene). .

"\ ·’ 15

Analysis:

Values calculated for ci7H2iN07 (351.35): C: 58.11%, H: 6.03%, N: 3.99%;

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

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 -f 4.56 (d, 2H, J = 15 Hz), 6.44

Ad 10 (m, 2H) + 7.15 (d, 1H, J = 10 Hz), 7.58 (large s, 1H) ppm.

h) 7.3 ml (52.5 mmol) of triethyl amine are added to a solution of 17.6 g (50 mmol) of trans- 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1 acid) , 3-dioxolan-2-yl) -15 4-oxo-2-azetidine-carboxylic acid prepared according to point g) above, in 150 ml of anhydrous tetrahydrofuran, then 5.0 ml (52.5 mmol) of chloroformate ethyl are added to the mixture, cooled with ice. The mixture is cooled to -15 ° C., stirred at this temperature for 20 minutes and the separated triethylamine salt is filtered at the same temperature under an argon atmosphere. A solution of 150 mmol of diazomethane in 230 ml of cold diethyl ether 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. (adsorbent: 150 g of Kieselgel 60, 0 = 0.063 to 0.200 mm, eluting agent: 7: 2 mixture of benzene and acetone) .We collect: 12.0 g (64%) of trans-4-30 (diazoacetvl) - 1 - (2,4-dimethoxybenzyl) -3- (2-methyl-1,3)

Idioxolan-2-yl) -2-azetidinone.

Analysis: Value calculated for C28H21K3 ° 6 (375.37): C: 57.59%, H: 5.64%; ï Values found C: 57.78%, H: 5.39%.

at

S - T

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

ji 16 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) above, 100 ml of tetrahydrofuran devoid of peroxide 5 and 50 ml of water, is irradiated for approximately 4 hours, with a high-pressure mercury lamp (HPX 125) , immersed in a pyrex reactor, under an argon atmosphere. The solution is evaporated in vacuo to a final volume of 50 ml and the concentrate is diluted with water to 130 ml. 2.4 ml of a 10% aqueous sodium hydroxide solution are added to the aqueous mixture and the alkaline mixture is washed three times with 20 ml portions of dichloromethane. Then, the aqueous phase is acidified to pH = 2 using concentrated aqueous hydrochloric acid. The acid solution is extracted three times with 20 ml portions of dichloromethane. The extracts are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated at [eec. The residue is crystallized from ether. Lt82 g (83%) of acid / trans-1- (2,4-dimethoxybenzyl) -3-20 (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl_7 are collected. ~ acetic acid mp: 124 ° C (ether).

Analysis:

Values calculated for C18 23N07 (365'37): C: 59.17%, H: 6.34%, N: 3.83%; 25 Values found C: 59.22%, H: 6.49%, N: 4.07%.

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

Example 2 Î Trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azétiainyl7-benzhydryl acetate 0.28 g (0.65 mole ) of trans- / 3- (2-methyl-1,3-dioxo-f '\ lan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinylJ7- acetate f of benzhydryl is dissolved in. 2 ml of acetone and a solution of 0.9 g (1.6 mole) of crude ammonium nitrate f _ I / Ce (NH ^) 2 (NO ^) g7 in 2 ml of acid 5% aqueous sulfuric is added dropwise to the stirred mixture at temperature

! I

17 t ambient. The reaction mixture is stirred for an additional 2 minutes, then carefully neutralized with a 5% aqueous solution of sodium hydrogen carbonate. Then the mixture is extracted three times with 4 ml portions of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The oily residue is purified by preparative thin layer chromatography (adsorbent: Kieselgel 60, 0 = 0.050-0.200 mm; eluting agent 10: 7: 2 mixture of benzene and acetone) to obtain 0.06 g (30%) of the desired compound . This compound is identical to that which is prepared as described in Example 1.

The starting material is prepared in this way.

15 following:; -1 i 18 a) A mixture of 24.6 g (0.2 mole) of 4-methoxyanilin 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-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 acetic acid. 13.2 g (47%) of (4-methoxyanilino) -] o-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 S, N: 5.25%.

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

1H NMR (CDC13): δ = 1.23 (t, 6H, J = 7.2 Hz), 3.67 (s, 3H), 4.2 (q, 4H, J = 7.2 Hz), 4.62 (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-methoxv-20 anilino) -methylate diethyl, prepared according to point a) above, 15 ml of glacial acetic acid and 4 g ( 3.7 ml, 0.048 mole) of diketene is brought to the boil for 0.5 hour. The solution is evaporated in vacuo, the oily residue is triturated with diethyl ether and the solid is filtered and separated. 10.5 g (72%) of 1- (4-methoxyphenul) -3-hydroxy-3-methvl-5-oxo-2,2-pyrrolidine-> diethyl dicarboxylate and / or its tautomer are collected; mp: 136-137 ° C (ethyl acetate).

Analysis:

Values calculated for cigH23N07 (365.38): C: 59.17%, H: 6.39? .. N: 3.83%; ί 19

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

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

1H NMR (CDC13): 6 = 1.07 (t, 3H, J = 7.2 Hz), 1.28 (t, 3H, J = 7.2 Hz), 1.58 (s, 3H), 2.76 (s, 2H), 3.64 (s, 1H), 5 3.76 (ε, 3H), 4.1 (g, 2H, J = 7.2 Hz), 4.27 (q, 2H, J = 7.2 Hz), 6.7 (2H) + 7.0 (2H, AA 'BB', J = 9 Hz) ppm.

c) 9rl g (0.025 mole) âe 1- (4-methyloxyphenyl) -3-hydroxy -3-methyl-5-oxo-2,2-pyrrolain-diethyl dicarboxylate, prepared according to point b) above are suspended in 50 ml of anhydrous diethyl ether and a solution of 1.72 g of metallic sodium in 30 ml of anhydrous ethanol, as well as a solution of 6.35 g (0.025 mol) of iodine in 50 ml of anhydrous diethyl ether are poured simultaneously into the vigorously stirred suspension and cooled with ice. Then, the mixture is poured into 100 ml of a saturated aqueous solution of sodium chloride and 2 g of sodium hydrosulfite and 2 ml of glacial acetic acid are added. The ethereal phase is separated and the aqueous phase is extracted three times with 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 6.2g (68%). crystalline diethyl 3-acetyl-1- (4-metho-xyphenyl) -4-oxo-2,2-azetidine dicarboxylate; mp: 70-71 ° C (ethanol).

Analysis: * Values calculated for C ^ g ^^ NO ^ (363.38): C: 59.50%, H: 5.82%, N: 3.85%;

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

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

D) 6 g (0.0165 mole) of 3-acetyl-1- (4-methoxyphenyl) - 20 4-oxo-2,2-azetidine-dicarboxylate, prepared according to 4 point c) above, are dissolved in 20 ml of anhydrous dioxane and 4.1 g (3.75 ml, 0.066 Mole) of ethylene glycol.

7.1 g (6.3 ml, 0.05 mole) of boron trifluoride-diethyl etherate complex are added dropwise to the solution stirred and cooled with ice and the reaction mixture is stirred for 2 additional hours at room temperature. The solution is basified with a saturated, aqueous solution of sodium hydrogen carbonate, then added with 100 ml of water and the mixture is 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 residue t (oily is triturated with diethyl ether to obtain 1 15 6 g (89%) of 3- (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl)? -4-ΟΧΟ-2,2-azetidine-crystalline diethyl dicarboxylate; c mp: 82-83 ° C (ethanol).

^ - Analysis: t Values calculated for C20H25NO8: £ 20 C: 58.96%, H: 6.18%, N: 3.44%; ^ Values found C: 58.70%, H: 5.68%, N: 3.63%.

: £ IR (KBr): 1740 cm ”1 (wide) ιΛ 1H NMR (CDCl3): δ = 1.17 (t, '3H, J = 7.2 Hz); l * 1.26 (t, 3H, J = 7.2.Hz), 1.5 (s, 3H), 3.7 (s, 3H), 3.9? 25 (m, 4H), 4.2 (m, 5H), 6.67 (2H) + 7.34 (2H, AA 'BB', J = 9 Hz) ppm.

e) 11 g (0.0245 mole) of 3- (2-methyl-1,3-dioxolan— '2-yl) -1- (4-methoxyphenyl) -4-oxo-2,2-azetidine-dicarboxylate diethyl, prepared according to point d) of Method II, are dissolved in 20 ml of dimethyl sulfoxide, then 1.72 g (0.0295 mole) of sodium chloride and 0.9 ml (0.049 mole) of water are added and the mixture is stirred at 175 ° C until the reaction is complete. The progress of the reaction is monitored by thin layer chromatography (adsorbent: 35 Kieselgel G according to Stahl; revealing solvent: 6: 4 mixture of 421 (benzene and ethyl acetate).

The mixture is cooled, poured into 150 ml of a saturated aqueous solution of sodium chloride and extracted three times with 50 ml portions of diethyl ether. The 5 organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The resulting oily residue, weighing 6 g, is dissolved in 25 ml of 96% ethanol, then added with a solution of 0.72 g (0.018 mole) i of sodium hydroxide in 10 ml of water, with cooling r 10 with ice water. The mixture is stirred for 0.5 hour,

L

then diluted with 50 ml of water and washed twice with 25 ml portions of dichloromethane. The aqueous phase is acidified to pH = 1 with concentrated hydrochloric acid, then extracted three times with 25 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized with benzene.

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

20 Analysis:

Calculated values for C ^ H ^ NO ^ (307.32): C: 58.63%, H: 5.57%, N: 4.56%;

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

IR (KBr): 3400-2700, 1750 (wide) cm "1 * 25 1H NMR (CDC13): δ = 1.5 (s, 3H), 3.7 (d, 1H, J = 2.5

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

f) 1.11 g (1.56 ml, 0.011 mole) of anhydrous triethyl amine 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 to -15 ° C and 1.2 g (1.06 ml, 0.011 mole) of ethyl chloroformate is added dropwise, with stirring. After. 20 minutes of stirring, the separated salt is filtered under nitrogen and a solution of 4.8 g (0.025 mole) of 22! diazomethane in diethyl ether is added to the filtrate at room temperature. After 2 hours of agi-. tation, the excess diazomethane 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-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azetidinone are obtained; mp: 95-96 ° C d (benzene and ether).

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

10 1H NMR (CDC13): δ = 1.50 (s, 3H), 3.51 (d, 1H, J = 2.6 Hz), 3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, 1H , J = ^ 2.6 Hz), 5.47 (s, 1H), 6.85 (2H) + 7.30 (2H, AA 'BB', J = 9 Hz) ppm.

g) 3.3 g (0.01 mole) trans-4- (diazoacetyl) -3-15 (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -2-azé tidinone prepared according to point f) above, are dissolved in a mixture of 50 ml of water and 100 ml of tetrahydrofuran. The mixture is irradiated with a high-pressure mercury lamp in a photoreactor under nitrogen atmosphere (the reaction is carried out at room temperature) and the progress of the reaction is monitored by thin layer chromatography (adsorbent : Kieselgel G according to Stahl; revealing solvent: 7: 1 mixture of benzene and, acetone). When the reaction is complete, the tetrahydro-furan is distilled under vacuum, the residue is basified with a 20% aqueous solution of sodium hydroxide and the solution is washed twice with 15 ml portions of dichloromethane. . The aqueous phase is acidified to dII = 1-2 with concentrated aqueous hydrochloric acid, then extracted three times with 20 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate i is evaporated. 1.6 g (50%) of acid / trans-3- are obtained.

iC

(2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinylJ7-acetic. ^ i »23

Analysis:

Calculated values for ci5Hi9N06 (321.33): C: 59.80%, H: 5.96%, N: 4.36% #

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

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

h) 1.0 g (3.12 mmol) of the compound prepared according to point g) above is dissolved in 10 ml of dichloromethane and a solution of 0.53 g (3, 12 mmol) of diphenyl diazomethane in 10 ml of dichlo-10 romethane with stirring, at room temperature. When the evolution of gas stops, the solution is evaporated under vacuum. 1.45 g (98%) of trans- / f ~ 3- (2-methyl-1, 3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2-azetidinvl7 -acetate are obtained. benzhydryl.

Analysis:

Calculated values for ^ 29 ^ 29 ^ 6 (487.55): C: 71.44%, H: 5.99%, N: 2.87%;

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

1H NMR (CDC13): δ = 1.35 (s, 3H), 2.7-3.1 (m, 2H), 20 3.38 (d, 1H, J "= 2.5 Hz), 3.72 (s, 3H), 3.8-4.1 (m , 4H), 4.1-4.5 (m, 1H), 6.85 (s, 1H), 6.7-7.4 (m, 14H) ppm.

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

Claims (9)

24 - Claims 1. Process for the preparation of a compound represented by the general formula (I) below:] 2 Υχ Y TT ττ \ / “CH COOZ 2. Method according to claim 1, characterized in that a compound of general formula (III), where R ', Y and Y are as defined above, is caused to react with phenyl-diazomethane or diphenyl diazomethane . 3. Method according to claim 1, characterized in that the protective group R 'of a compound of general formula (II) is eliminated with a compound of the peroxy-disulfate type or with a ceric salt in the presence of an acid. 4. Method according to claim 1, for the preparation of trans-Z3- (2-methyl-1,3-dioxolan-2-yl) -4-OXO-2-azetidinyl / -benzhydryl acetate, characterized in that * reacting the acid / trans- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azétidinyl_7-acétique with diphenyl diazomethane, then with a peroxydisulfa-te. 2n 5. Process according to claim 1, for the preparation of trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4-OXO-2-azetidinyl7 ~ benzhydryl acetate, characterized in that reacted / trans-3- (2-methyl-1,3-dioxolan-2-yl) - 1- (4-methoxyphenyl) -4-oxo-2-azetidinyl7 ~ acetic acid with 25 diphenyldiazomethane, then with a ceric salt in an acid medium. 5 E? C - C - "- Y 2 L-ira (i) o ^ 1 2 in which Y and Y together form a detachable group protecting the carbonyl radical, preferably a group or 10 ketal or a thioanalogue thereof ci, and X is a selectively detachable esterifying group, preferably an arylmethyl or diarvlmethyl group, characterized in that a compound represented by the general formula (III) below: 15 ï1 Ί2 HHH? C -V - * - y CH2C ° 0H J-1 (III) υ · ^ ri 1 2 20 in which Y1 and Y are as defined above and R 'is a detachable group protecting the amido radical other than a phenyl group, preferably a group phenyl or benzyl carrying one or more C1 to 4 alkoxy substituents, is converted into an ester represented by the general formula (II) below ï1 Y2 HH HjC -V-ï-Y CE2C00ï cJ- (II) 30. R> 1 2 where X, R ', Y and Y are as defined above, in a manner known per se and the group R' protecting the resulting ester is eliminated, or else the group protector R 'of a compound of general formula (II), where 1 2 X, R', Y 'and Y are as defined above, is eliminated. 6. Compound characterized in that it is represented by the general formula (II) below 30 ï1 ï2 HH Hrf -V_î_CH2000X P 0J- * (H) ^ R »1 y 35 in which Y and Y together form a group detach- (I * 26 ble protective carbonyl radical, preferably a ketal group or its thioanalogue, X is a selectively detachable esterifying group, preferably an aryl-methyl or diarylmethyl group, and R * is a detachable group pro -5 protector of the amido radical other than a phenyl group, preferably a phenyl or benzyl group carrying one or more C1 ^ 4 alkoky substituents · 7. Compound according to Claim 6, characterized in that it is trans / 3- (2-methyl-1,3-dioxolan-2-yl) -1-10 (4-methoxyphenyl) -4-oxo -2-benzhydryl azetidinyl / -acetate. 8. A compound according to claim 6, characterized in that it is trans / 1-2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo -2-azetidinyl7 ~ benzhydryl acetate. 9. Compound according to the general formula (I), where Y ^, Y ^ and X are as defined in claim 1, characterized in that it is prepared by the process according to any one of claims 1 to 5.