GB2112393A

GB2112393A - Azetidinone derivatives

Info

Publication number: GB2112393A
Application number: GB08236917A
Authority: GB
Inventors: Karoly Lempert; Gabor Doleschall; Jozsef Fetter; Gyula Hornyak; Peter Huszthy; Jozsef Nyitrai; Gyula Simig; Karoly Zauer; Tibor Gizur; Kalman Harsanyi; Gyorgy Fekete; Laszlo Szporny; Gyorgy Hajos
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1981-12-30
Filing date: 1982-12-30
Publication date: 1983-07-20
Also published as: ZA829593B; DE3248672A1; AT379147B; SE8207475L; GB2112393B; HU184495B; AU9196882A; ES8405761A1; IT1210968B; FR2518998A1; SE8207475D0; SE453083B; JPS58118566A; GR78428B; ATA450782A; FI824516L; FI824516A0; LU84568A1; CH655926A5; PL239885A1

Abstract

New heterocyclic acetic acid compounds of the general formula (I), <IMAGE> wherein Y<1> and Y<2> form together a removable carbonyl protecting group, and R is a removable amido protecting group, are prepared in the way that a compound of the general formula (II), <IMAGE> wherein R, Y<1> and Y<2> are as defined above, is activated on the carboxy group and then reacted with diazomethane, and the resulting new compound of the general formula (II), <IMAGE> wherein R, Y<1> and Y<2> are as defined above, is subjected to diazoketone rearrangement in the presence of water. The new compounds according to the invention can be incorporated into pharmaceutical preparations and are valuable intermediates in the synthesis of thienamycin and thienamycin analogues.

Description

SPECIFICATION New heterocyclic acetic acid derivatives and a process for the preparation thereof The invention relates to new heterocyclic acetic acid derivatives of the general formula (I),

wherein Y' and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents.

These compounds can be converted into thienamycin and related compounds e.g. as shown on Scheme (A).

In the formulae shown on Scheme (A) Y1, Y2 and R are as defined above, X is a selectively removable esterifying group, Q is a C15 alkyl group or a substituted benzyl group, Q' is a C15 alkyl group, a substituted benzyl group, hydrogen atom or an alkali metal ion, and R" is a benzyl, aminoethyl or N-acyl-aminoethyl group.

Thienamycin, an antibiotic of broad spectrum of activity, was prepared first on microbiological way (US patent specification No. 3,950,375) and later on by chemical synthesis (German Offenlegungsschrift No. 2,751,597).

Our aim was to provide a new route for the synthesis of thienamycin and its analogues, wherein the azethidinone skeleton and the a-hydroxyethyl side chain or a side chain which can be converted easily into a-hydroxyethyl group, are formed simultaneously at the early stage of the synthesis, and the resulting key intermediate is converted then into the desired end-product.

It has been found that when a dialkyl (protected amino)-malonate is acylated with diketene and the resulting acylated product is reacted with iodine and an alkali metal alcoholate, an azethidinone compound of the general formula (Vl),

containing an ct-acyl side chain, is obtained, which can be utilized as key intermediate in the synthesis.

In the above formula R has the same meaning as given above and Z is a Cur~5 alkyl group.

The intermediates of the general formula (VI) and their preparation are described in detail in our previous Hungarian patent application No. 2262/80. The preparation of these intermediates is also described in the examples of the present application.

It has also been observed that, prior to converting the intermediate of the general formula (VI) into thienamycin or an analogue thereof, it is preferable to protect the keto group of the c4-C-acetyl side chain with a group, particularly a ketal group or a thioanalogue thereof, which can be removed at a later stage of the synthesis. Ethylene glycol or a thioanalogue thereof, such as mercapto-ethanol, can be applied particularly preferably to form the ethyleneketal or hemithioketal protecting group.The resulting compound of the general formula (V),

wherein R, Z, Y' and y2 are as defined above, is reacted then with an alkali metal halide in pyridine or a related solvent or in aqueous diemethyl sulfoxide to obtain a compound of the general formula (lV),

wherein R, Y', Y2 and Z are as defined above.

The resulting compound of the general formula (IV) is a mixture of cis and trans isomers. The isomers can be separated from each other by chromatography or on the basis of their different solubilities. The separated trans isomer of the general formula (IVa)

can be converted into the trans carboxylic acid of the general formula (Ill)

by hydrolysis. It is more preferable, however, to subject the isomeric mixture itself to hydrolysis, since the reaction is selective, i.e. only the trans ester converts into the respective carboxylic acid.

Some of the compounds of the general formulae (V), (IV) and (IVa) are described in our previous Hungarian patent application No. 2263/80, whereas the other representatives of these compounds and the compounds of the general formula (Ill) are described in our co-pending patent applications. The preparation of the compounds of the general formulae (VI) to (Ill) is also described in the examples of the present application.

The separated trans carboxylic acid of the general formula (Ill) is reacted first with an activator for the carboxy group and then with diazomethane, and the resulting compound of the general formula (II), wherein R, Y' and Y2 are as defined above,

is subjected to diazoketone exchange (Wolff rearrangement) in the presence of water. In this latter step the desired products of the general formula (I) are obtained.

The compounds of the general formulae (I) to (VI) are racemic mixtures.

Based on the above, the invention relates to a process for the preparation of a new compound of the general formula (I), wherein Y1 and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof and R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents, in such a way that a compound of the general formula (III), wherein R, Y' and Y2 are as defined above, is activated on the carboxy group and then reacted with diazomethane, whereafter the resulting compound of the general formula (II), wherein R, Y1 and Y2 are as defined above, is subjected to diazoketone exchange in the presence of water, or a compound of the general formula (II), wherein R, Y1 andY2 are as defined above, is subjected to diazoketone exchange in the presence of water, and the resulting product of the general formula (I) is separated.

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

The azethidinecarboxylic acid of the general formula (III) is activated first on the carboxylic group.

Any activating agent compatible with the i3-lactam ring can be applied for this purpose. It is preferred to activate the carboxy group as a mixed anhydride, for which purpose ethyl chloroformate proved to be a particularly suitable reactant. The mixed anhydride is formed in the presence of an acid binding agent, preferably a tertiary amine. The salt of the tertiary amine which separates from the reaction mixture can be removed easily.

The activated form of the compound of formula (III) is reacted then with diazomethane.

Diazomethane is prepared preferably from N-methyl-N-nitroso-urea and is added to the reaction mixture, preferably as an ethereal solution. When the gas evolution ceases, the excess of diazomethane is decomposed preferably with acetic acid, and the resulting compound of the general formula (II) is separated from the reaction mixture. If necessary, this product can be purified e.g; by column chromatography.

Thereafter the resulting compound of the general formula (II) is subjected to Wolff rearrangement, whereupon the cr-diazoketone side chain converts first into ketene by nitrogen elimination, and then it reacts with water to form the desired product of the general formula (I).

Wolff rearrangement can be promoted with a catalyst, by irradiating the mixture with ultraviolet light, by thermal treatment, and any combination thereof. Irradiation with ultraviolet light proved to be particularly preferable. Irradiation can be performed e.g. in a photoreactor, preferably under inert gas atmosphere, in the presence of water and optionally an inert organic solvent.

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

The invention is elucidated in detail by the aid of the following non-limiting Examples.

Example 1 [trans-I -(2,4-Dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo-2-azathidinyl]-acetic acid A mixture of 2.25 g (6 mmoles) of trans-4-(diazoacetyl)-1-(2,4-dimethoxybenzyl)-3-(2-methyl1 ,3-dioxolan-2-yl)-2-azethidinone, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water is irradiated for about 4 hours with a high-pressure mercury lamp (HPK 125), immersed into the reaction vessel made of pyrex glass, under 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 thrice with 20 ml of dichloromethane, each. Thereafter the aqueous phase is acidified to pH=2 with concentrated aqueous hydrochloric acid.The acidic solution is extracted thrice with 20 ml of dichloromethane, each, the extracts are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated to dryness. The residue is crystallized with ether.1.82 g (83%) of the aimed compound are obtained as a white, crystalline substance; m.p.: 1 240C (ether).

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

Analysis: calculated for C18H23NO, (365.37): C: 59.17%, H: 6.34%, N: 3.83%; found: C: 59.22%, H: 6.49%, N: 4.07%.

The starting substance can be prepared as follows: a) A mixture of 109.7 g (0.66 mole) of 2,4-dimethoxybenzaldehyde, 72 ml (0.66 mole) of benzylamine and 660 ml of methanol is stirred at room temperature for 20 minutes, whereupon a clear solution is obtained from the suspension. The solution is cooled with ice water, and 13.2 g (0.33 mole) of sodium borohydride are added to it in small portions.

The progress of the reaction is monitored by thin layer chromatography (Kieselgel G according to Stahl; developing solvent: a 9:1 mixture of benzene and acetone), and at the end of the reaction the mixture is evaporated to dryness in vacuo. The residue is admixed with 300 ml of water, and the aqueous mixture is extracted with 500 ml, 200 ml and 200 ml portions of ether. The ethereal solutions are combined, dried over magnesium sulfate, filtered, and then 112 ml (0.66 mole) of diethyl bromomalonate and 93 ml (0.66 mole) of triethyl amine are added to the filtrate. The reaction mixture is stirred at room temperature for 2-3 days. The separated triethyl ammonium bromide is filtered off and washed with ether. The mother liquor is evaporated, and the residue is recrystallized from 1 50 ml of ethanol.The resulting 210 g of crude product are recrystallized again from 400 ml of ethanol to obtain 1 97 g (72%) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate; m.p.: 62-630C (ethanol).

IR (KBr): 1750/1725 cm-', d.

b) 61.7 g (0.149 mole) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate, prepared as described in point a) above, are hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of about 20 g of palladium-on-charcoal catalyst. The catalyst is filtered off and the filtrate is evaporated. 47.1 g (97%) of diethyl (2,4-dimethoxybenzylamino)-malonate are obtained. The product can be converted into its hydrochloride by reacting it with hydrochloric acid. The hydrochloride melts at 122-1 240C after recrystallization from ethyl acetate.

Analysis: calculated for C16H24CINOf, (361.82): C: 53.1 19/0, H: 6.69%, Cl: 9.80%, N: 3.87%; found: C: 52.51%, H: 6.77%, Cl: 10.30%, N: 4.09%.

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

'H NMR (CDCl3): =1 S=1.3 6H), 3.78 (s,3H),3.82 (s, 3H), 4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H)+7.3-7.55 (m, 1 H), 7.7 (broad s, 1 H) ppm.

c) A mixture of 39.6 g (0.122 mole) of diethyl (2,4-dimethoxybenzylamino)-malonate, prepared as described in point b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 mole) of diketene is boiled for 0.5 hour. Glacial acetic acid is distilled off in vacuo over water bath, and the oily residue is triturated with 1 50 ml of water. The resulting crystalline substance is dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether. 29.6 g (60%) of diethyl N-(2,4-dimethoxybenzyl) 3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or its tautomer are obtained; m.p.: 1061070C.

Analysis: calculated for C20H27NO8 (409.43): 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), 1710cm1.

1H NMR (CDCl3): S=1.1 (t, 3H), 1.17 (t, 3H), 1.52 (s, 3H), 2.8 ( < 0.1 H), 2.65 (broad s, 2H), 3.75 (s, 6H), 3.8-4.15 (m, 4H), 6.7 (broad s, 2H), 6.25--6.45 (m)+7.0--7.25 (m, 3H) ppm.

d) 20.5 g (50 mmoles) of the product prepared as described in point c) above are suspended in 50 ml of dry ether, and a solution of 3.45 g (150 mmoles) of metallic sodium in 100 ml of dry ethanol and a solution of 12.7 g (50 mmoles) of iodine in 1 50 ml of dry ether are added simultaneously, from two dropping funnels, to the vigorously stirred suspension under cooling with ice water. Thereafter 5 g of sodium hydrosulfite, dissolved in 200 ml of a saturated aqueous sodium chloride solution, are added to the stirred mixture. The mixture is filled into a separating funnel and 60 ml of water are added to dissolve the separated inorganic salts. The organic phase is removed, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue, weighing 1 8.5 g, is crystallized from 30 ml of 2 propanol. 10.9 g (54%) of diethyl 3-acetyl-1 -(2,4-dimethoxybenzyl)-4-oxo-2,2-azethidine dicarboxylate are obtained; m.p.: 84-850C (2-propanol).

Analysis: calculated for C20H25NO8 (407.41): C: 58.96%, H: 6.19%, N: 3.44%; found: C: 58.99%, H: 6.04%, N: 3.57%.

'H NMR (CDCI3):a=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, 1 H), 4.63 (d, 1 H), 4.69 (s, 1 H), 6.3-6.4 (m, 2H)+7.07 (d, 1 H) ppm.

e) 1 79 ml (206 g, 1.452 moles) of boron trifluoride-diethyl etherate are added dropwise to a vigorously stirred solution of 179 g (0.484 mole) of diethyl 3-acetyl-1-(2,4-dimethoxybenzyl)-4-oxo- 2,2-azethidine-dicarboxylate and 107 ml (120 g, 1.936 moles) of ethylene glycol in 500 ml of dry dioxane under cooling with ice water. The reaction mixture is allowed to stand at room temperature for one day, during this period the mixture is occasionally stirred. Thereafter 415 g (1.452 moles) of Na2CO3.10H2O are added slowly to the stirred mixture under cooling with ice water, and the mixture is stirred for 1 5 minutes. Thereafter 1 litre of ether and 1 litre of water are added, and the phases are separated from each other.The aqueous phase is shaken twice with 500 ml of diethyl ether, each. 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 at 1 800C. The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl; developing solvent: a 6:4 mixture of benzene and ethyl acetate). At the end of the reaction, i.e. after about 1 5 hours, the mixture is poured into 1100 ml of saturated aqueous sodium chloride solution, and the resulting mixture is shaken with 1000 ml and then twice with 500 ml of diethyl ether, each.The ethereal solutions are combined, decolourized with charcoal, dried over magnesium sulfate, and the filtrate is evaporated to a final volume of cca. 200 ml. This concentrated solution is cooled with ice water to obtain 59 g (35%) of trans-ethyl 1 -(2,4-dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-4- oxo-2-azethidine-carboxylate; m.p.: 950C.

f) A mixture of 0.5 g (1.2 mmoles) of diethyl 3-acetyl-1 -(2,4-dimethoxybenzyl)-4-oxo-2,2- azethidine-dicarboxylate, prepared as described in point d) above, 3 ml of dry tetrahydrofuran and 0.53 g (3.6 mmoles) of mercapto-ethanol is boiled for 4 hours, and 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 sodium hydrocarbonate solution, dried over magnesium sulfate, filtered, and the product is separated from the filtrate by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254+358, developing solvent: a 8:2 mixture of toluene and acetone). 0.30 g (53%) of diethyl 1-(2,4dimethoxybenzyl)-3-(2-methyl- 1 ,3-oxathiolan-2-yl)-4-oxo-2,2-azethidine-dicarboxylate are obtained.

rH NMR (CDCl3): 6=0.8--1.55 (m, 6H), 1.72+1.77 (d, 3H), 2.9-3.4 (m, 2H), 3.75 (s, 6H), 4.0- 5.0 (m, 9H), 6.4 (m, 2H)+7.1 (d, 1 H) ppm.

g) A solution of 5.21 g (0.130 mole) of sodium hydroxide in 60 ml of water is added to a suspension of 41.2 g (0.109 mole) of trans-ethyl 1 -(2,4-dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan2-yl)-4-oxo-azethidine-carboxylate, prepared as described in point e) above, in 50 ml of ethanol under stirring and cooling with ice water, and stirring is continued until a clear solution is obtained (about 20 minutes). 100 ml of water are added then 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, and then shaken quickly with 100 ml and twice with 50 ml of dichloromethane, each. The dichloromethane solutions are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue is crystallized from a mixture of toluene and petroleum ether to obtain 35 g (92%) of trans-1 (2,4-dimethoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid; m.p.: 117-11 80C (toluene).

Analysis: calculated for C17H2'NO7 (351.35): C: 58.11%, H: 6.03%, N: 3.99%; found: C: 58.17%, H: 6.30%, N: 4.24%.

IR (KBr): 3500--2500, 2900, 1760, 1720 cm~'.

1H NMR (CDCl3): =1 b=1.39 3H), 3.50 (d, 1 j=2.5 Hz), 3.77 (s, 3H), 3.79 (s, 3H), 3.86 (d, 1 H, J=2.5 Hz), 3.96 (m, 4H), 4.21+4.56 (d, 2H, JAB=15 Hz), 6.44 (m, 2H)+7.15 (d, 1 H, J=10 Hz), 7.58 (broad s, 1 H) ppm.

h) 7.3 ml (52.5 mmoles) of triethyl amine are added to a solution of 17.6 g (50 mmoles) of trans1 -(2,4-dimethoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, prepared as described in point g) above, in 1 50 ml of dry tetrahydrofuran, and then 5.0 ml (52.5 mmoles) of ethyl chloroformate are added to the mixture under cooling with ice. The mixture is cooled to -1 50C, stirred at this temperature for 20 minutes, and the separated triethyl amine salt is filtered off at the same temperature under argon atmosphere. A solution of 1 50 mmoles of diazomethane in 230 ml of cold diethyl ether is added to the filtrate. The mixture is stirred, allowed to warm to room temperature, and after 2 hours of stirring it is evaporated to dryness.The brown, thick residue is dissolved in 20 ml of benzene, and the product is separated by column chromatography (adsorbent: 1 50 g of Keiselgel 60, =0.063--0.200 mm, eluting agent: a 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-azethidinone are obtained.

Analysis: calculated for C18H2,N308 (375.37): C: 57.59%, H: 5.64%; found: C: 57.78%, H: 5.39%.

IR (KBr): 2900,2110, 1760 cm~'.

Example 2 [trans-3-(2-Methyl-1 ,3-dioxolan-2-yl)-1 -(4-methoxyphenyl)-4-oxo-2-azethidinyl1-acetic acid 3.3 g (0.01 mole) of trans-4-(diazoacetyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-1 -(4-methoxyphenyl)- 2-azethidinone 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 at room temperature, and the progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl; developing solvent: a 7:1 mixture of benzene and acetone). When the reaction is over, tetrahydrofuran is distilled off in vacuo, the residue is rendered alkaline with 20% aqueous sodium hydroxide solution, and the solution is washed twice with 1 5 ml of dichloromethane, each.The aqueous phase is acidified to pH 1-2 with concentrated aqueous hydrochloric acid and then extracted thrice with 20 ml of dichloromethane, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. 1.6 g (50%) of the aimed compound are obtained.

Analysis: calculated for C18H19N08 (321.33): C: 59.80%, H: 5.96%, N: 4.36%; found: C: 59.60%, H: 5.76%, N: 4.08%.

1R (film): 3500-2500, 1760-1700 cm~'.

The starting substance can be prepared as follows: a) A mixture of 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) of diethyl bromomalonate is stirred at room temperature for 2 days. The resulting mass is triturated with 100 ml of diethyl ether, the separated 4-methoxy-anisidine hydrobromide is filtered off 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 diethyl (4-methoxyanilino)-malonate are obtained; m.p.: 64--650C (ethanol).

Analysis: calculated for C14H19NO5 (281.31): C: 59.77%, H: 6.81%, N: 4.99% found: C: 59.99%, H, 6.97%, N: 5.25%.

IR (KBr): 3300, 1775, 1725 cm-2.

'H NMR (CDC13): 8=1.23 (t, 6H, J=7.2 Hz), 3.67 (s. 3H), 4.2 (q, 4H, J=7.2 Hz), 4.62 (s, 1 H), 4.14.5 (broad 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 diethyl (4-methoxyanilino)-malonate, prepared as described in point a) above, 1 5 ml of glacial acetic acid and 4 g (3.7 ml, 0.048 mole) of diketone is boiled for 0.5 hour. The solution is evaporated in vacuo, the oily residue is triturated with diethyl ether, and the solid is filtered off. 10.5 g (72%) of diethyl 1 -(4-methoxyphenyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine- dicarboxylate and/or its tautomer are obtained; m.p.: 136-1 370C (ethyl acetate).

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

Analysis: calculated for C18H23NO7 (365.38): C: 59.17%, H: 6.39%, N: 3.83%; found: C: 58.98%, H: 6.90%, N: 4.04%.

1H NMR (CDC13): ô=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, 1 H), 3.76 (s, 3H), 4.1 (q, 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) 9.1 g (0.025 mole) of diethyl 1-(4-methoxyphenyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine- dicarboxylate, prepared as described in point b) above, are suspended in 50 ml of dry diethyl ether, and a solution of 1.72 g of metallic sodium in 30 ml of dry ethanol and a solution of 6.35 g (0.025 mole) of iodine in 50 ml of dry diethyl ether are simultaneously dropped into the suspension under vigorous stirring and cooling with ice. Thereafter the mixture is poured into 100 ml of a saturated aqueous sodium chloride solution, 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 thrice with 50 ml of diethyl ether, each. 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 6.2 g (68%) of crystalline diethyl 3 acetyl-1 (4-methoxyphenyl)-4-oxo-2,2-azethidine-dicarboxylate; m.p.: 70-71 0C (ethanol).

Analysis: calculated for Cl8H2lNO7 (363.38): C: 59.50%, H: 5.82%, N: 3.85%; found: C: 59.04%, H: 5.84%, N: 4.08%.

IR (KBr): 1760, 1735, 1720 cm-l.

1H NMR (CDCl3): 8=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=2 Hz), 4.7 (s, 1 H), 6.7 (2H)+7.31 (2H, AA'BB', J=9 Hz) ppm.

d) 6 g (0.0165 mole) of diethyl 3-acetyl-1 -(4-methoxyphenyl)-4-oxo-2,2-azethidinedicarboxylate, prepared as described in point c) above, are dissolved in 20 ml of dry 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 stirred solution under ice cooling, and the reaction mixture is stirred for additional 2 hours at room temperature. The solution is rendered alkaline with saturated aqueous sodium hydrocarbonate solution, thereafter 100 ml of water are added, and the mixture is extracted thrice with 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue is triturated with diethyl ether to obtain 6 g (89%) of crystalline diethyl 3-(2-methyl-1 ,3-dioxolan-2-yl)-l -(4-methoxyphenyl)-4-oxo-2,2- azethidine-dicarboxylate; m.p.: 82-830C (ethanol).

Analysis: calculated for C20H25NO,^ (407.43): C: 58.96%, H: 6.18%, N: 3.44%; found: C: 58.70%, H: 5.68%, N: 3.63%.

IR (KBr): 1 740 cm-l (broad).

1H NMR (CDCl3): d=1.17 (t, 3H, J=7.2 Hz), 1.26 (t, 3H, J=7.2 Hz), 1.5(s, 3H), 3.7 (5, 3H) 3.9 (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 diethyl 3-(2-methyl-1 ,3-dioxolan-2-yl)-1 -(4-methoxyphenyl)-4-oxo2,2-azethidine-dicarboxylate, prepared as described in point d) above, are dissolved in 20 ml of dimethyl sulfoxide, 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 1 750C until a complete reaction is obtained. The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl; developing solvent: a 6:4 mixture of benzene and ethyl acetate).

The mixture is cooled, poured into 1 50 ml of a saturated aqueous sodium chloride solution, and extracted thrice with 50 ml of diethyl ether, each. 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, and a solution of 0.72 g (0.018 mole) of sodium hydroxide in 10 ml of water is added to the alcoholic mixture under cooling with ice water. The mixture is stirred for 0.5 hour, then diluted with 50 ml of water and washed twice with 25 ml of dichloromethane, each. The aqueous phase is acidified to pH=1 with concentrated aqueous hydrochloric acid, and then extracted thrice with 25 ml of dichloromethane, each. 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-azethidine-carboxylic acid are obtained.

Analysis: calculated for C15H"NO (307.32): C: 58.63%, H: 5.57%, N: 4.56%; found: C: 58.40%, H: 5.80%, N: 4.66%.

IR (KBr): 3400--2700, 1750(broad) cm-l.

1H NMR (CDCl3): S=1.5 (s, 3H), 3.7 (d, 1 H, J=2.5 Hz), 3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, 1 H, J=2.5 Hz), 6.82 (2H)+7.26 (2H, AA'BB', J=9 Hz), 9.2 (s, 1 H) ppm.

f) 1.11 g (1.56 ml, 0.011 mole) of dry triethyl amine are added to a solution of 3 g (0.01 mole) of a compound prepared as described in point e) above in 20 ml of dry tetrahydrofuran. The solution is cooled to -1 50C, and 1.2 g (1.06 ml, 0.011 mole) of ethyl chloroformate are added dropwise to the stirred solution. After 20 minutes of stirring the separated salt is filtered off under nitrogen atmosphere, and a solution of 4.8 g (0.025 mole) of diazomethane in diethyl ether is added to the filtrate at room temperature. After 2 hours of stirring the excess of diazomethane is decomposed with acetic acid, and the solution is evaporated in vacuo. The oily residue slowly crystallizes. 3 g (90%) of trans-4 (diazoacetyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)- 1 -(4-methoxyphenyl)-2-azethidinone are obtained; m.p.: 95-960C (benzene and ether).

IR (KBr): 2200, 1760, 1640 cm-l.

1H NMR (CDCl3): =1 b=1.50 3H), 3.51 (d, 1 H, J=2.6 Hz), 3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, 1 H, J=2.6 Hz), 5.47 (s, 1H), 6.85 (2H)+7.30 (2H, AA'BB', J=9 Hz) ppm.

Example 3 [trans-1-Phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl]-acetic acid 3.8 g (0.0126 mole) of trans-4-(diazoacetyl)-1 -phenyl-3-(2-methyl-1 ,3-dioxolan-2-yl)-2- azethidinone 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 nitrogen atmosphere. The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, developing solvent: a 7:1 mixture of benzene and acetone).

At the end of the reaction tetrahydrofuran is evaporated in vacuo, the residue is rendered alkaline with a 20% aqueous sodium hydroxide solution, and the alkaline solution is washed thrice with 15 ml of dichloromethane, each. The aqueous phase is acidified to pH=1-2 with concentrated aqueous hydrochloric acid and then extracted thrice with 20 ml of dichloromethane, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is triturated with ether to obtain 1.8 g (50%) of crystalline [trans-1 -phenyl-3-(2-methyl-1 ,3-dioxolan-2- yl)-4-oxo-2-azethidinyl]-acetic acid; m.p.: 128-1 290C (ethanol).

Analysis: calculated for C,5H"NOs (291.29): C: 62.00%, H: 5.88%, N: 4.82%; found: C: 61.75%, H: 5.86%, N: 5.08%.

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

1H NMR (CDCI3): =1.48 S=1.48 (s,3H), 2.65 (dd, 1 H, gem=15 Hz, Hz,Jvic=8 Hz)+3.12 (dd, 1H,Jgem=15 Hz, JVIC=8 Hz), 3.47 (d, 1 H, J=2.5 Hz), 3.98 (m, 4H), 4.4 (m, 1 H), 7.3 (m, 5H), 9.33 (broad s, 1 H) ppm.

The starting substance can be prepared as follows: a) A mixture of 38 g (0.152 mole) of diethyl anilinomalonate [Fl. Blank: Ber. 31, 1815 (1898)], 38 ml of glacial acetic acid and 15.3 g (13.9 ml, 0.182 mole) of diketene is boiled for 0.5 hour. Glacial acetic acid is evaporated in vacuo over a water bath, and the oily residue is crystallized by triturating it 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; m.p.: 98-990C (ethyl acetate and petroleum ether).

Analysis: calculated for C"H2,NO6 (335.35): C: 60.88%, H: 6.31%, N: 4.18%; found: C: 60.83%, H: 6.15%, N: 4.43%.

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

'H NMR (CDCl3): 8=1.02 (t, 3H), 1.3 (t, 3H), 1.6 (s, 3H), 2.8 (s, 3H), 3.6 (broad s, 1 H), 4.45 (m, 4H), 7.2 (s, 5H) ppm.

b) 50 g (0.149 mole) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate), prepared as described in point a) above, are added to a solution of 10.2 g (0.447 mole) of metallic sodium in 250 ml of dry ethanol, thereafter a solution of 37.9 g (0.149 mole) of iodine in 200 ml of dry ether is added under vigorous stirring. When the reaction is over, 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 diethyl (3-acetyl-1-phenyl-4-oxo-2,2- azethidine-dicarboxylate), m.p.: 55--560C (2-propanol).

Analysis: calculated for C1,H1gNO 5: C: 61.25%, H: 5.75%, N: 4.20%; found: C: 61.38%, H: 5.89%, N: 4.24%.

IR (KBr): 1770,1740, 1720 cm-1.

H NMR (CDCl3): 8=1.12 (t, 6H), 2.3 (s, 3H), 4.25 (q, 4H), 4.75 (s, 1 H), 7.0-7.6 (m, 5H) ppm.

c) 28.5 g (0.085 mole) of diethyl 3-acetyl-1 -phenyl-4-oxo-2,2-azethidine-dicarboxylate, prepared as described in point d) above, are dissolved in a mixture of 90 ml of dry dioxane and 21 g (18.8 ml, 0.34 moie) of dry ethylene glycol, and 36.5 g (31.5 ml, 0.255 mole) of boron trifluoride--diethyl etherate complex are added dropwise to the solution under vigorous stirring and cooling with ice water. The solution is stirred for additional 2 hours at room temperature and then neutralized with saturated aqueous sodium carbonate solution. The neutral solution is diluted with 100 ml of water and then extracted thrice with 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo.The oily residue is crystallized by triturating it with ether. 28.5 g (90%) of diethyl 1 -phenyl-3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo-2,2- azethidine-dicarboxylate are obtained; m.p.: 59-61 C (petrol).

Analysis: calculated for C,9H23NO,: C: 60.47%, H: 6.14%, N: 3.17%; found: C: 60.74%, H: 6.21%, N: 3.79%.

IR (KBr): 1770, 1740 cm-l.

1H NMR (CDCl3): 6=1.18(t, 3H, J=7.2 Hz), 1.24 (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 mole of diethyl 1 -phenyl-3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo- 2,2-azethidine-dicarboxylate, prepared as described in point c) above, 44 ml of dimethyl sulfoxide, 5.6 g (0.1 mole) of sodium chloride and 3.05 ml (0.17 mole) of water is stirred at 1 750C until the reaction proceeds. The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl, developing solvent: a 6:4 mixture of benzene and ethyl acetate). The solution is poured into 200 ml of a saturated aqueous sodium chloride solution and extracted thrice with 1 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The resulting 1 6.4 g of oily residue are dissolved in 100 ml of ethanol, and a solution of 2.15 g (0.054 mole) of sodium hydroxide in 30 ml of water is added to it under stirring over an ice bath. After 0.5 hour of stirring the mixture is diluted with 1 50 ml of water and extracted thrice with 20 ml of diethyl ether, each. The aqueous phase is acidified to pH=1 with concentrated aqueous hydrochloric acid and extracted then thrice with 50 ml of dichloromethane, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is crystallized from benzene to obtain 12 g (56%) of trans -phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4- oxo-2-azethidine-carboxylic acid; m.p.: 1 650C (benzene).

Analysis: calculated for C,4H,5NO5 (277.27): C: 60.64%, H: 5.45%, N: 5.05%; found: 60.64%, H: 5.72%, N: 4.99%.

1H NMR (CDCl3): d=1.5 (s, 3H), 3.69 (d, 1 H, J=3 Hz), 4.0 (m, 4H), 4.42 (d, 1 H, J=3 Hz), 7.3 (m, 5H), 7.55 (s, 1 H) ppm.

e) 13.8 g (0.05 mole) of trans-1 -phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine- carboxylic acid, prepared as described in point d) above, are dissolved in 100 ml of dry tetrahydrofuran, and 5.55 g (7.7 ml, 0.055 mole) of ethyl chloroformate are added to the solution at --150C. After 20 minutes of stirring the separated salt is filtered off under nitrogen atmosphere, and an ethereal solution of 22.6 g (0.1 5 mole) of diazomethane is added to the filtrate under stirring. When the gas evolution ceases, the excess of diazomethane is decomposed with glacial acetic acid, and the solution is evaporated. The oily residue is triturated with ether to obtain 11.5 g (77%) of crystalline trans-4 (diazoacetyl)-i -phenyl-3-(2-methyl-1 ,3-dioxolan-2-yl)-azethidinone; m.p.: 96-970C (benzene and ether).

IR (KBr):2150, 1760,1635 cm-l.

1H NMR (CDCl3): =1.50 .50(s, 3H), 3.5 (d, 1 H, J=2.6 Hz), 3.50 (m, 4H), 4.34 (d, 1 H, J=2.6 Hz), 5.45 (d, 1 H), 7.25 (m, 5H) ppm.

Claims

1. A process for the preparation of a new compound of the general formula (I),

wherein Y1 and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents, characterized in that a compound of the general formula (III),

wherein R, Y1 and Y2 are as defined above, is activated on the carboxy group and then reacted with diazomethane, whereafter the resulting compound of the general formula (II),

wherein R, Y1 and Y2 are as defined above, is subjected to diazoketone exchange in the presence of water, or a compound of the general formula (II), wherein R, Y' and Y2 are as defined above, is subjected to diazoketone exchange in the presence of water, and the resulting product of the general formula (I) is separated.

2. A process as claimed in claim 1, characterized in that the carboxy group of the compound of the general formula (III) is activated with ethyl chloroformate.

3. A process as claimed in claim 1, characterized in that the diazoketone exchange is performed under irradiation with ultraviolet light.

4. A process as claimed in claim 1 for the preparation of [trans-1-(2,4-dimethoxybenzyl)-3-82- methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidinyl]-acetic acid, characterized in that trans -(2,4 dimethoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-azethidine-carboxylic acid is activated on the carboxy group and reacted then with diazomethane, and the resulting trans-4-(diazoacetyl)-1-(2,4- dimethoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-2-azathidinone is subjected to diazoketone exchange in the presence of water.

5. A process as claimed in claim 1 for the preparation of [trans-3-(2-methyl-1 ,3-dioxolan-2-yl)-1- (4-methoxyphenyl)-4-oxo-2-azethidinyl]-acetic acid, characterized in that trans-3-(2-methyl-1 ,3- dioxolan-2-yl)- 1 -(4-methoxyphenyl)-4-oxo-azethidine-carboxylic acid is activated at the carboxy group and reacted then with diazomethane, and the resulting trans-(4-diazoacetyl)-3-(2-methyl-1 ,3dioxolan-2-yl)-1-(4-methoxyphenyl)-2-azethidinone is subjected to diazoketone exchange in the presence of water.

6. A process as claimed in claim 1 for the preparation of [trans-l -phenyl-3-(2-methyl-1 ,3- dioxolan-2-yl)-4-oxo-azethidinyl]-acetic acid, characterized in that trans -phenyl-3-(2-methyl- 1 3- dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid is activated on the carboxy group and reacted then with diazomethane, and the resulting trans-4-(diazoacetyl)- 1 -phenyl-3-(2-methyl- 1 ,3-dioxolan-2-yl)- 2-azethidinone is subjected to diazoketone exchange in the presence of water.

7. A compound of the general formula (I),

wherein Y' and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and R is a removable amido protecting group, preferably a benzyl group bearing one or more C 1-4 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substitutents.

8. [trans-l -(2,4-Dimethoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2- azethidinyl]-acetic acid.

9. [tra ns-3-(2-Methyl- 1 ,3-dioxolan-2-yl)- 1 -(4-methoxyphenyl)-4-oxo-2-azathidinyll- acetic acid.

10. [trans-i-P henyl-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidinyl]-acetic acid.

11. A compound of the general formula (II),

wherein Y1 and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents.

1 2. trans-4-(Diazoacetyl)-1 -(2,4-dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-2- azethidinone.

1 3. trans-4-(Diazoacetyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-1 -(4-methoxyphenyl)-2-azethidinone.

14. trans-4-(Diazoacetyl)- 1 -phenyl-3-(2-methyl-1 ,3-dioxolan-2-yl)-2-azethidinone.

15. A process substantially as hereinbefore described in any one of Examples 1 to 3.

1 6. A compound of the general formula (I), wherein Y1, Y2 and R are as defined in claim 1, whenever prepared by the process of any one of claims 1 to 6.

17. A pharmaceutical preparation containing a compound of the general formula (I), wherein Y', y2 and R are as defined in claim 1 , together with a pharmaceutically acceptable carrier.