LU84565A1 - NOVEL HETEROCYCLIC DERIVATIVES OF ACETIC ACID AND A PROCESS FOR THEIR PREPARATION - Google Patents

Description

"

The present invention relates to new heterocyclic derivatives of acetic acid, represented by the general formula (I) below: y1 Y2 HH Hq VT. ^ OHpOOqt o '10 in which: l 2 Y and Y together form a group detachable protector of the carbonyl radical, preferably a ketal group or a thio-analog thereof, and X is a selectively detachable esterifying group, preferably an arylmethyl or diarylmethyl group, as well as a process for their preparation .

The azetidine acetic acid derivatives of general formula (I) as well as their precursors of general formulas (II) and (II) below, in which Y, Y and X are as defined above and A represents a nitro- or amino- group

Y1 Y2 H H

HXC _V-ï-yCH2C00X

25 5 HH

° ^ VS lII)

3 0 -irl -y2 TT TT

\ z1 “. CHpCOOH

% c-c — J — r Α „_Ί Λ (III)

35k ^ J

2 are new compounds and can be used mainly as intermediates in the synthesis of thienamycin and its analogs.

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

It has been found that by acylating a di-alkyl malonate with an amino group protected with diketene and by reacting the resulting acylated product with iodine and an alkali metal alcoholate, a 20 Azetidinone compound represented by the general formula (IX) below, containing a side α-acetyl chain, which can be used as a key intermediate in the synthesis. In this formula, Z represents a C1-C6 alkyl group.

25 f 0 H, C - C -, -, ((ίΟΟΖ) 2 0 ^ (IX) 30

The intermediates of formula (IX) and their oration are described in detail in a previous Application] of Hungarian Patent No. 2262/80 of the Applicant. The preparation of these intermediates is also described in the examples of the present invention.

It has also been noted that before converting the intermediate of general formula (IX) into thienamycin or its analog, it is preferable to protect the ketone group 5 of the lateral α-C-acetyl chain with a group, preferably a ketal group or its thioanalogue, which can be removed in a later stage of the synthesis. Ethylene glycol or its thioanalogue, such as mercaptoethanol, can be particularly preferably applied to form the protective ethylene ketal or hemithiocetal group. The resulting compound, represented by the general formula (VIII) below: γ1 ^ 2 15 HjC - C -j-1C00Z) 2 20 where Y and Y 'together form a group for the temporary protection of the carbonyl part, preferably an ethylene ketal group or a thioanalogue thereof, and Z is as defined above, is then treated with an alkali metal halide in pyridine or a related solvent or in dimethyl sulfoxide, to obtain a compound represented by the general formula (VII) below:

Y1 f H H

h3c -Y —- 4 —- Vcooz o) n / \ (VU) 4 1 '► 1 2 where Z, Y and Y are as defined above.

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

A ^ = ïï, COOZ

H ^ C - C-4- 10 Ί ^ * of- (VIIa)

K J

can be converted to the trans carboxylic acid of general formula (VI) below:

ÏN / 2 “î / COOH

h5 ο - 0-i- <20 0 ^ - (VI) K? by hydrolysis. It is more advantageous, however, to subject the isomeric mixture itself to hydrolysis, since the reaction is selective, i.e. only the trans ester converts to the respective carboxylic acid.

The separate trans carboxylic acid represented by the general formula (VI) is first treated with an activator for the carboxy group, then with diazomethane and the resulting compound, represented by the general formula (V) below: 5 Γ ι * ”] \ / 2? = C0CHN2 η3 ° - ο — γ—].

. Μφ “is subjected to a Wolff transposition in the presence of water to obtain an azetidineacetic acid represented by the general formula (IV) below:

^ ® CHÿOOH

H, C - C-1- “T

0J- (IV)

. U

which can serve as a starting substance in the process according to the present invention. In the compounds of general formulas (VI) to (IV), Y * and are as defined above.

The new compounds of general formulas (VIII) to (IV) and their preparation are described in detail in the Applicants' Patent Applications. The preparation of these new compounds is also described in the examples of the present invention.

In the next step of the synthesis, the protective phenyl group is removed from the amido portion. This is accomplished in accordance with the present invention by an indirect method, such that the phenyl group is first nitrated, the resulting nitrophenyl group is then converted to the aminophenyl group by reduction and the latter protecting group is removed after est-; rification of the lateral acetic acid chain. To the knowledge of the Applicant, no method is known hitherto for removing a phenyl protecting group from the nitrogen atom from a β-lactam ring, so that these process steps according to present invention are considered to provide a new solution.

On the basis of these facts, the present invention relates to a process for the preparation of new compounds represented by the general formula If in which: 10 ′ Y and Y * together form a detachable group protecting the carbonyl radical, preferably a ketal group or a thioanalogue thereof, and X is a selectively detachable esterifying group, preferably an arylmethyl or diarylmethyl group, according to which a compound of general formula (IV), where 1 2 Y and Y are as defined more above, is nitrated, then reduced, the resulting compound of general formula (III), 1 2 where Y and Y are as defined above and A represents a nitro- group, then an amino- group, is con- 1 2 verti in an ester of general formula (II), where YY and X are as defined above, according to a method known in itself and the protective aminophenyl group of the resulting compound of general formula (II) is detached, or 25 good 1 2

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

are as defined above and A is an amino group, is converted into an ester of general formula (II), where 1 2 Y, Y and X are as defined above, according to a method known in it -same, and the aminophenyl protecting group of the resulting compound of general formula (II) is detached, or else the aminophenyl protecting group of a compound of 12 general formula (II) where Y, Y and X are such as challenge-35 above, is detached.

i

F

\ \ \ I * '1, 7

The new compounds of general formulas (III), (II) and (I) which are racemic mixtures, can be converted into thienamycin or analogues thereof, for example as represented by scheme (A), 1 2 5 Y, Y and X being as defined above, Q is a C1-alkyl group or a substituted benzyl group, Q 'is a C1-alkyl group, a substituted benzyl group, a hydrogen atom or an alkali metal ion and R "is a benzyl, aminoethyl or N-acylaminoethyl group.

H

ί '6 * Diagram (A)

., 1., 2 tt H

Y Y H H P CHpCOOH

HC> c ^ -J- ^ H2COOX S-f

H ^ / Pd / c v fP

_hJH "i_NH * '5 0 ^ 0 * salt of the malonic semiester

10 "V

H H

! ^ CH2C0CN2C00Q J f ^ CHpCO

^ sulfonic azide f ^ ‘2

15 -NH ^ -NH C00Q

salt of T? h-20 Y

H

fTï

25 J-- N - L

^ ^ ^ COOD

O

O-acylation + formation ce 30 mercaDtan salt

• Y

H

35 / -SR "\ - N --- x i

J ^ COOQ I

9 ΐ * d

The compounds of general formula (IV), bearing a phenyl group protecting the nitrogen atom of the amido radical, are firstly nitres. It is preferred to apply a mixture of nitric acid and acetic anhydride as the nitrating mixture. The reaction is carried out at a temperature of approximately 0 ° C, preferably between -10 and + 5 ° C. Acetyl nitrate which is formed by interaction of nitric acid or acetic acid and is soluble in excess acetic acid, serves as the nitrating agent in this reaction.

The resulting compound of general formula (III) where A is a nitro- group is then preferably reduced by catalytic hydrogenation. Then, the amino derivative of general formula (III) is separated from the reaction mixture or, more preferably, it is directly esterified in the reaction mixture in which it is formed, to provide a compound of general formula ( II).

It is preferred to apply phenyldiazomethane or diphenyldiazomethane as the esterifying agent, to introduce the selectively detachable esterifying group X into the molecule.

Then, the protective amidophenyl group of the intermediate of general formula (II) is eliminated. Oxidizing agents, such as a mixture of a ceric salt and a mineral acid, or more preferably chromium oxide in glacial acetic acid, can be applied in this connection. The resulting product of general formula (I) is then separated from the reaction mixture.

In addition to the foregoing provisions, the invention 30 further comprises other provisions, which will emerge from the description which will follow.

The invention will be better understood with the aid of the additional description which follows, which refers to an example of implementation of the method which is the subject of the present 10 I .. ·· ·.

! It should be understood, however, that this example; implementation, is given only by way of illustration of the object of the invention, of which it in no way constitutes a limitation.

5 EXAMPLE

_ - - - ^

Trans- / 3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azetidinyl7- benzhydryl acetate 0.45 g (1 mmol) trans- ^ î- (2-amino -phenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7_acetate 10 is dissolved in 2 ml of glacial acetic acid and a solution of 0.2 g (2 mmol) of chromium trioxide in 2 ml of glacial acetic acid and 0.2 ml of water, is added dropwise to the above solution at room temperature. The mixture is stirred at room temperature for 3 hours, then poured into 10 ml of ethyl acetate and washed with a 5% aqueous solution of sodium hydrogen carbonate until neutral. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by preparative chromatography on a thin layer (adsorbent: Kieselgel 60 PF 254 + 366 "developer solvent: 7: 3 mixture of benzene and acetone). 0.09 g (30%) of the sought product is collected; m.p. : 129-130 ° C (ethanol).

XH NMR (CDC13): 6 1.39 (s, 3H), 2.63 (dd, 2H, J = 25 4.4 Hz) and 2.89 (dd, 2H, J = 9.1 Hz), 3 , 97 (m, 5H), 6.12 (s, 1H), 7.28 (s, 10H) ppm.

The starting material is prepared as follows: a) A mixture of 38 g (0.152 mol) of diethyl anilino-malonate ^ __ R. Blank: Ber. 31_, 1815 (1893) ^, 38 ml of glacial acetic acid and 15.3 g (13.9 ml, 0.182 mole) of diketene, is brought to the boil for 0.5 hours.

| The glacial acetic acid is evaporated in vacuo on a water bath and the oily residue is crystallized by trituration

ί I

I \ with ether. 36.5 g (72%) of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and / or its tautomer are obtained; mp: 98-99 ° C (ethyl acetate and petroleum ether).

5 Analysis:

Values calculated for Cj7H21N06 (355.35): C: 60.88%, H: 6.31%, N: 4.18%;

Found values C: 60.83%, H: 6.15%, N: 4.43%.

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

10. 1H NMR (CDC13): 6 = 1.02 (t, 3H), 1.3 '(t, 3K), 1/6 (s, 3H), 2.8 (s, 3H), 3.6 (broad s, 1H), 4-4., 45 (m, 4K), 7.2 (s, 5H) ppm.

b) 50 g (0.149 mol) of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate, prepared according to point a) above, are added to a solution of 10.2 g (0.447 mol) of metallic sodium in 250 ml of anhydrous ethanol, then a solution of 37.9 g (0.149 mole) of iodine in 200 ml of anhydrous ether is added with vigorous stirring. When the reaction is complete, 8.5 ml (8.9 g, 0.149 mole) of glacial acetic acid, 200 ml of water and 100 ml of ether are added to the mixture; the organic phase is separated and the aqueous phase is extracted with 100 ml of ether. The ethereal phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized from 50 ml of 2-propanol to obtain 31 g (62%) of 3-acetyl-1-phenyl-4- diethyl oxo-2,2-azetidine dicarboxylate, mp; 55-56 ° C (2-propar Analysis:

Calculated values for C ^ H ^ NO ^: 30 C: 61.25%, H: 5.75%, N: 4.20%;

Values found C: 61.38%, H: 5.89%, .N: 4.24% IR (KBr): 1770, 1740, 1720 cm ”1.

j 1K NMR (CDC13): δ = 1.12 (t, 6H), 2.3 (ε, 3H), 4.25 (q, 4H), 4.75 (s, 1H), 7.0-7.6 (m, 5H) ppm.

".

he - ! 12 c) 28.5 g (0.085 mol) of diethyl 3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate, prepared according to point b) above, are dissolved in a mixture of 90 ml of anhydrous dioxane and 21 g (18.8 ml, 0.34 mole) of ethylene glycol and then 36> 5 g (31> 5 ml, 0.255 mole) of boron trifluoride-diethyl etherate complex are added dropwise to the vigorously stirred solution and cooled with ice water. The solution is stirred for an additional 2 hours at room temperature, then neutralized with an aqueous solution saturated with sodium carbonate. The neutral solution is diluted with 100 ml of water, then extracted three times with 50 ml fractions of diethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The oily residue is crystallized by trituration with ether. 28.5 g (90%) of diethyl 1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-azetidine-dicarboxylate are obtained; mp: 59-61 ° C (petrol).

Analysis: 20 Values calculated for H23N07: C: 60.47 ", H: 6.14%, N: 3.71%,

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

IR (KBr): 1770, 1740 cm *.

1H NMR (CDC13): 6 = 1.18 (t, 3H, J = 7.2 Hz), 1.24 25 (t, 3H, J = 7.2 Hz), 1.51 (s, 3H) # 3.92 (m, 4H), 4.3 (m, 5H), 7.2 (m, 5H) ppm.

d) A mixture of 28.5 g (0.075 mol) of 1-phenyl- 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine-dicarboxy-late of diethyl, prepared according to point c) above, 30 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. that the reaction ends. The progress of the! reaction is followed by thin layer chromatography (adsorbent: Kieselgel G according to Stahl; revealing solvent:

if

13 6: 4 mixture of benzene and ethyl acetate). The solution is poured into 200 ml of an aqueous saturated solution of sodium chloride and extracted three times with 1 portions of 150 ml of diethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The resulting oily residue (16.4 g) is. dissolved in 100 ml of ethanol and a solution of 2.15 g (0.054 mol ·) · of sodium hydroxide in 30 ml of water is added to this stirred mixture and cooled by an ice-water bath. After 0.5 hours of stirring, the mixture is diluted with 150 ml of water and extracted three times with 20 ml portions of diethyl ether. The aqueous phase is acidified to pH = 1 with concentrated aqueous hydrochloric acid and then extracted three times with 50 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated. The oily residue is crystallized from benzene to obtain 12 g (56%) of trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine acid -20 carboxylic; mp: 165 ° C (benzene).

Analysis:

Calculated values for ci 4 ^ 5 ^ 5 (277.27): C: 60.64%, H: 5.45%, N: 5.05%,

Values found C: 60.64%, H: 5.72%, N: 4.99%.

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

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

e) 13.8 g (0.05 mole) of trans-1-phenyl-3-30 (2-methvl-1, 3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid according to point d) above, are dissolved in 100 ml of anhydrous tetrahydrofuran and 5.55 g (7.7 ml 0.055 mole) of ethyl chloroformate are added to the solution at -15 ° C. After 20 minutes of stirring, the separated salt is filtered under a nitrogen atmosphere and a solution! ! “22.6 g (0.15 mole) of diazomethane is added to the filtrate with stirring.

5 "When the evolution of the gas stops, the excess of diazomethane is decomposed by glacial acetic acid and the solution is evaporated. The oily residue is triturated with ether to obtain 11.5 g (77 %) of crystalline trans-4- (diazoacetyl) -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -azetidinone; mp: 96-97 ° C (benzene and ether).

10 IR (KBr): 2150, 1760, 1635 cm "1.

1H NMR (CDC13): δ = 1.50 (s, 3H), 3.5 (d, 1H, J = 2.6 Hz), 3.50 (m, 4H), 4.34 (d, 1H, J = 2.6 Hz), 5.45 (s, 1H), 7.25 (m, 5H) ppm.

f) 3.8 g (0.0126 mol) of trans-4- (diazoacetyl) -15 l-phenyl-3- (2-methylvl-1,3-dioxolan-2-yl) -2-azetidinone prepared according to point e) above, are dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml of water and the solution is irradiated with a high-pressure mercury lamp, in a photoreactor at room temperature, under an atmosphere of nitrogen. 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). At the end of the reaction, the tetrahydrofuran is evaporated in vacuo, then the residue is basified with a 20% aqueous solution of sodium hydroxide and the alkaline solution is washed three times with 15 ml portions of dichloromethane. The aqueous phase is acidified to pH = 1-2 with concentrated aqueous hydrochloric acid, then extracted three times with 30 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is triturated; with ether to obtain 1γ8 g (50%) of acid / -trans-l-pheny1-3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azétidinyl_7- · § 35 crystalline acetic acid; mp: 128-129 ° C (ethanol).

! _.

i * 115

Analysis:

Values calculated for C15H17NC> 5 (291.29): C: 62.00%, H: 5.88%, N: 4.82%;

Values found C: 61.75%, H: 5.86% f N: 5.08%.

5 IR (KBr): 1760, 1740 cm-1.

1H NMR (CDC13) î.6 = 1.48 (ε, 3H), 2.65 (dd, 1H,

Jgeirf 15 Hz 'Jvic = 8 Hz) + 3 * 12 <dd' 1H 'JgenT 15 Hz'

Jvic = 8 Hz), 3.47 (d, 1H, J = 2.5 Hz), 3.98 (m, 4H), 4.4.

(m, 1H), 7.3 (m, 5H), 9.33 (large s, 1H) ppm.

10 g) 0.81 ml of concentrated nitrigue acid (P = 1.5) is added dropwise, with constant stirring and with cooling by ice, to 3 ml of acetic anhydride, so that the temperature of the mixture does not rise above + 5 ° C. The resulting nitrating mixture is added dropwise, at -5 ° C, to a stirred solution of 2.9 g (0.01 mole) of trans-1-phenyl-3- (2-methyl-1, 3-dioxolan-2-y]) - 4 ^ oxo-2-azetidinyl_-7-acetic, prepared according to point f) of Method III, in 20 ml of anhydrous dichloroethane. After one hour of stirring, the solution 20 is poured onto ice water and the phases are separated from each other. The aqueous phase is extracted twice with 25 ml portions of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The oily residue is triturated with ether to obtain 1/95 g (58%) of trans-3- (2-methvl-1,3-dioxolan-2-yl) -1- acid. (2-nitrophenyl) -4-oxo-2-azetidinyl_7-acetic crystal -, mp: 175-176 ° C (ethanol).

Analysis: 30 Values calculated for Ci5Hi6K2 ° 7 (336.33): C: 53.57%, H: 4.79%, N: 8.33%; Values found C: 53.31%, H: 4.68%, N: 8.21%.

IR (KBr): 3600-2900, 1740, 1540, 1340 cm "1.

16 h) 0.336 g (Immole) of acid / ftrans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (2-nitrophény)) -4-oxo-2-azétidinyl_7-acétigue prepared according to point g) above, is dissolved in 15 ml of methanol and the solution is hydrogenated under atmospheric pressure, in the presence of 0.05 g of a catalyst consisting of palladium on charcoal. The catalyst is filtered and the filtrate is evaporated. The oily residue is dissolved in 10 ml of dichloromethane, 0.17 g (immole) of diphenyl diazo-methane is added and the mixture is stirred for 24 hours.

Then the mixture is evaporated to obtain 0.4 g (90%) of trans - / ”l- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo- 2-azetidinyl_y-acetate · benzhydryl.

IR - (KBr); 1740, 1720 cm “1 Mass spectrum: m / z: 472 (M) 15 As it appears from this preceding mistletoe, 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 can come to the mind of the technician: 20 know in the matter, without departing from the framework or the scope! of the present invention. Λ! } \ - i i i

Claims (7)

1 17 1 ° - Compound characterized in that it is represented by the general formula (I) below: 5 ï * / 2 ^ ® CHoCOOX H, C - C-1-fd J_L U) in which: 10 y1 and Y * together form a detachable group of the carbonyl radical, preferably a ketal group or a thioanalogue thereof, and X is a selectively detachable esterifying group, preferably an arylmethyl or diarylmethyl group. 2 ° - Compound according to Claim 1, characterized in that it is trans- ^ 3- (2-methyl-l, 3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -acetate benzhydryl. 3 ° - Compound characterized in that it is represented by the general formula (II) below: Y \? ? ch2coox HC _ c-3-Y 5 m2 25 0 ^ M in which:, Y ^ and Y2 together form a detachable group protecting the carbonyl radical, preferably a v ketal group or a thioanalogue thereof, and X is a selectively detachable esterifying group, preferably an arylmethyl or diarylmethyl group. 35 4 ° - Compound according to Claim 3, characterized \. '> »18 in that it is trans- ^ 1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl / -benzhydryl acetate. 5 ° - Compound characterized in that it is represented 5 by the general formula (III) below: Y1 Y2 HH CH „COOH n ^ ψ = / 2 H ^ C - C-3-T 10 cJ T ^ l (III) in which: Y and Y * together form a detachable group protecting the carbonyl radical, preferably a ketal group or a thioanalogue thereof, and A is a nitro- or amino group . 6 ° - Compound according to Claim 5, characterized in that it is the acid ^ trans-1- (2-aminophenyl) -3-20 (2-methyl-1,3-dioxolan-2-yl ) -4 “OXO-2-azetidinyl / -acetic. 7 ° - Compound according to Claim 5, characterized in that it is the acid ^ trans-3- (2-methyl-l, 3-di-oxolan-2-yl) -1- (2- nitrophenyl) -4-oxo-2-azetidinyl / -aceous. 8 ° - Process for the preparation of a new compound represented by the general formula (I) according to Claim 1, characterized in that: a compound represented by the general formula (IV) below: _ 30. YHH QHpCOOH HjC - C-- (iv) XJ I * 19 * k 1 2 where Y and Y are as defined above, is nitrated and then reduced, the resulting compound represented by the general formula (III) ci- after: 5 Y1 ï2 HH CH-COOH h5c - cX-γ 2 0 * (Iix) 10 ^ 1 where Y and Y ^ are as defined above and A is a nitro- group, then amino- is converted into an ester of formula general (II) below: 15 • jl ^ 2 H h CH ^ C00Z ÏÏ5C - c '^ M2 oJ H (11) IX 2 where Yx, Y ^ and X are as defined above, in a manner known per se, and the amino-phenyl protecting group of the resulting compound of formula (II) is removed, or 1 2 un compound of general formula (III), where Y and Y are as defined above and A is an amino group- is converted into an ester of general formula (II), where 1 2 Y, Y and X are as defined above, according to a method known per se and the protective aminophenyl group of the resulting compound of general formula (II) is eliminated, or the protective aminophenyl group of a compound of 1 2 35 general formula (II), where Y, Y and X are such that 20! defined above, is eliminated. 9 ° - Process according to Claim 8, characterized in that a compound of general formula (IV) is nitrated with a mixture of nitric acid and acetic anhydride. 10. Method according to Claim 8, characterized in that a compound of general formula (III) where A is a nitro group, is reduced by catalytic hydrogenation. Il0- Process according to Claim 8, characterized in that a compound of general formula (III) where A is an amino group is esterified with an aryl or diaryldiazomethane. 12 ° - Process according to Claim 8, characterized | in that the protective aminophenyl group is detached with the aid of a suitable oxidizing agent. 13. Method according to any one of Claims 8 to 12, characterized in that the protective aminophenyl group is detached with chromium trioxide in glacial acetic acid. 14 ° - Process according to Claim 8 for the preparation of trans-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azeti <benzyl 7-acetate acetate , characterized in that the / trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4 -ox -2-azetidinyl7-acetic acid is nitrated and then reduced, that ^ trans-3- (2-methyl-1,3-dioxolan-2-yl) -1- (2-aminophenyl) -4-oxo-2-azetidinylÿ-acetic acid is treated with diphenyldiazomethane and the Protective aminophenyl group of trans- / 1- (2-aminophenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinyl7-acetate of the resulting benzhydryl, is detached. I [