SE453082B - AZETIDINON CARBOXYLIC ACIDS AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

diazoacetic acid ester UV-light Reaction Scheme A 1. * 'Coon H_ 5 cH coox N / f 2 \ RN \ RH f -fl cnzcoon N NO2' F 1. reduction removal of RE 5 CHZCOOH 2. esterification \ H o IR 5 CH coox '2 malonic acid- _ semiestersalt $ 4D N N32 ° 'š.

H ~ fi 5 cnzcocuzcooQ gg / r. fl>> N \ J'_N H 0 I \ R ä! CH 2 COOX I sulfonic acid-4; - NH azide 0. reduction J, H H E CHZCOOH E CHZCOCNZCOOQ _____._ 04L_'NH malonic acid \ semiestersalt O * L R Eg å; ., cazcocnzcoog Ü (i: o 3 453 082 Reaction Scheme A (continuedJ 1 Rh-salt O-acylation, mercaptan, salt formation.

H ..: _ SRI! In the formulas shown in Reaction Scheme A, Y1, Y2 and R have the meanings given above and X is a selectively removable esterification group: Q is a C1-5 alkyl group or a substituted benzyl group, Q 'is a C 1-5 alkyl group, a substituted benzyl group, hydrogen atom or an alkali metal ion and R "is a benzyl, aminoethyl or N-acylaminoethyl group.

Thienamycin, a broad-spectrum antibiotic, was first prepared microbiologically (US 3,950,375) and later by chemical synthesis (DE-OS 2,751,597).

The object of the inventions is to provide a new way of synthesizing thienamycin and its analogues, in which the azetidinone backbone and the (hydroxyethyl side chain or a side chain which can be easily converted to a hydroxyethyl group are simultaneously formed at an early stage of the synthesis and the obtained the key intermediate is then converted to the desired end product.

It has been found that, when dialkyl (protected amino) malonate is acylated with the diketene and the resulting acylated product is reacted with iodine and an alkali metal alcoholate, 1 contains an azetidinone compound of the general formula IV O 1 in H 3c -c - (cooz) 2 In Iv 4 N o \ R containing a ° L-acetyl side chain, which compound can be used as a key intermediate in the synthesis.

In the above formula, R has the same meaning as given above and Z is a C 1-5 alkyl group.

The intermediates of the general formula IV and their preparation are described in detail in Hungarian patent application 2262/80. The preparation of these intermediates is also described in the working examples below. It has also been found that prior to the conversion of the intermediate of general formula IV to thienamycin or an analogue thereof, it is preferable to protect the keto group in it. The C-acetyl side chain has a group, in particular a ketal group or a thio analogue thereof, which can be easily removed at a later stage of the synthesis. Ethylene glycol or a thio analogue thereof, such as mercaptoethanol, can be used in particular to form the ethylene ketal or hemithioketal protecting group. The obtained compound of the general formula III 1 z R) nc - c --- (cooz) 3 I 2 III 04 N 1 ~ R 1 and Y 2 has the meaning given above, wherein R, Z, Y are then added with a alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide to give a compound of general formula II wherein R 1, Y 1, Y 2 and Z 2 have R 1, Y 1, Y 2 and Z 2 meanings given above.

The resulting compound of general formula II 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 IIa 1 2 ï / Y E! H cooz H - c-ïßïr / 3C Ira% '_ “- ~ N o \ 10 20 25 30 35 453 082 can be converted to the trans-carboxylic acid of the general formula I by hydrolysis. However, it is more preferable to subject the isomer mixture itself to hydrolysis because the reaction is selective, i.e. only the trans ester is converted to the respective carboxylic acid.

The compounds of the general formulas III, II and IIa, in which R is a dimethoxybenzyl group, Y1 and Y2 together form an ethylene ketal or hemithioketal group and Z is ethyl, are described in Hungarian patent application 2263/80 but their preparation is also described in embodiments below. The other compounds of the general formulas III, II and IIa are new. The compounds of the general formulas I-IV are racemic mixtures.

Based on the above, the invention also relates to a process for the preparation of novel heterocyclic carboxylic acids of the general formula I, wherein Y 1 and Y together are an ethylene ketal group or a thio analogue thereof and R is a benzyl group bearing one or more C 1-4 alkoxy substituents or a phenyl group bearing optionally one or more C 1-4 alkoxy substituents, which process is characterized in that a compound of the general formula IV, in which Z is a C 1-5 alkyl group and R has the meaning given above, is reacted with ethylene glycol or a thio analogue thereof in the presence of boron trifluoride. diethyl etherate or an arylsulfonic acid, that the obtained compound of general formula III, wherein Z, R, Y and Y have the meanings given above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide and that the resultant compound of the general formula II, wherein Z, R, Y and Y have the meanings given above and which is a mixture of cis- and 453,452 trans isomers, a) is selectively hydrolyzed or b) is separated into its components and the trans isomer of the general formula IIa is hydrolyzed; or that a compound of general formula III, wherein Z, R, Y1 and Y2 have the meanings given above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide and that the resulting compound of 1 and Y2 has the meanings given above and which is a mixture of cis and trans isomers, a) the general formula II is selectively hydrolyzed, wherein Z, R, Y or b) is separated into its components and the trans isomer of the general formula IIa hydrolyzed; or that a compound of general formula II, wherein Z, R, Y1 and Y2 have the meanings given above and which is a mixture of cis and trans isomers, a) is selectively hydrolyzed or b) is separated into its components and trans the isomer of general formula IIa is hydrolyzed, after which the trans compound of general formula I is separated from the reaction mixture.

In the process of the invention, a compound of general formula IV is first converted to a compound of general formula III. The reaction is carried out in the presence of boron trifluoride diethyl etherate or an arylsulfonic acid (for example p-toluenesulfonic acid or naphthalenesulfonic acid), which facilitates the conversion.

The reaction is carried out in an organic solvent such as benzene, toluene, dioxane, tetrahydrofuran, etc. at a temperature from room temperature to the boiling point of the reaction mixture.

Then a compound of general formula III is reacted with an alkali metal halide, preferably sodium or lithium chloride, in the presence of pyridine, quinoline, a homologue or a mixture thereof or preferably in aqueous dimethyl sulfoxide to give holding of a compound of general formula II.

If desired, this step can also be carried out without separating the compound of general formula III from the reaction mixture in which it has been formed.

The compounds of general formula II are isomer mixtures. The trans component of the mixture can be used to prepare thienamycin or thienamycin analogs.

The isomer mixture of the general formula II can be hydrolyzed with alkali, the trans compound of the general formula I being selectively formed. The alkaline hydrolyzate is used in an equivalent molar amount or in a moderate excess.

If desired, the isomer mixture of general formula II is first separated into its components. The individual isomers of compounds in which R is 2,--di-1 and Y2 is a 1,3-dioxomethoxybenzyl, Z is ethyl and Y is lanyl group can be separated from each other, for example by chromatography using Kieselgel 60 (0 = 0.063-0.200 mm) as adsorbent and benzene with gradually increasing acetone content (the elution begins with benzene and then the acetone content is increased to a ratio of benzene acetone of 9: 1) as eluent. The individual isomers can also be separated from each other on the basis of their different solubilities since only the cis-esters are soluble in ether-type solvents such as diethyl ether.

Thereafter, the separated trans isomer of general formula IIa is hydrolyzed to obtain the trans product of general formula I.

The invention is further illustrated by the following working examples.

E2emEe1'1 trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid 10 15 20 25 30 35 453 082 A solution of 5.21 g (0.130 mol) of sodium hydroxide in 60 ml of water is added to a suspension of 41.2 g (0.69 mol) of trans-ethyl 1- (2,4-dimethoxybenzyl) -3- (2-methyl -1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate in 50 ml of ethanol while stirring and cooling with ice water and stirring is continued until a clear solution is obtained (about 20 minutes). 100 ml of water are then added to the solution and the mixture is shaken with 100 ml of ether.

The aqueous phase is acidified to pH = 1 with a concentrated aqueous solution of hydrochloric acid and then shaken rapidly with 100 ml and twice each with 50 ml of dichloromethane.

The dichloromethane solutions are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated. The oily residue is crystallized from a mixture of toluene and petroleum ether to give 35 g (92%) of trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolane-2- yl) -4-oxo-2-azetidinecarboxylic acid, m.p. 117-118 ° C (toluene). Analysis: calculated for C 17 H 21 NO 7 (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, 1120 cm -1.

'H man tcncl3> = J = 1.39 (s, an), 3.50 (d, m, J = 2.5 H2), 3.77 (s, 3H), 3.79 (s, 3H) , 3.86 (d, 1H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JAB = 15 Hz), 6.44 (m, 2H) + fl, 15 (d, 1H, J = 10 Hz), 7.58 (broad s, 1H) ppm.

The starting material is prepared as follows: a) A mixture of 109.8 g (0.66 mol) of 2,4-dimethoxybenzaldehyde, 72 ml (0.66 mol) of benzylamine and 660 ml of methanol is stirred for 20 minutes at room temperature, clear solution is obtained from the suspension. The solution is cooled with ice water and 13.2 g (0.33 mol) of sodium borohydride are added in small portions.

The course 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 mixed with 300 ml of water and the aqueous mixture is extracted with 500 ml, 200 ml and 200 ml ether portions. The ether solutions are combined, dried over magnesium sulphate and filtered, then 112 ml (0.66 mol) of diethyl bromomalonate and 93 ml (0.66 mol) of triethylamine are added to the filtrate. The reaction mixture is stirred at room temperature for 2-3 days. The separated triethylammonium bromide is filtered off and washed with ether. The mother liquor is evaporated and the residue is recrystallized from 150 ml of ethanol. The resulting crude product of 210 g is recrystallized from 400 ml of ethanol to give 197 (72%) of diethyl N-benzyl-N- (2,4-dimethoxybenzyl) aminomalonate, m.p. 62-63 ° C ( ethanol). 'n: (Can: 1750/1725 cm -1). b) 61.7 g (0.149 mol) of diethyl N-benzyl-N- (2,4-dimethoxybenzyl) -aminomalonate, prepared as described under a) above , hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of about 20 g of a palladium catalyst on charcoal. The catalyst is filtered off and the filtrate is evaporated. 47.1 g (97%) of diethyl (2,4-dimethoxybenzylamino) - 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 for 116H 24 ClNO 6 (361.82): C: 53.11%, 1H: 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 -1. NMR (s, 3H), 4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H) + 7.3-7.55 (m, 1H), 7.7 (broad s, 1H) ppm. c) A mixture of 39.6 g (0.122 mol) of diethyl (2,4-dimethoxybenzylamino) malonate, prepared as described in b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 mol) diketen is boiled for 0.5 hours. The glacial acetic acid is distilled off in vacuo over a water bath and the oily residue is triturated with 150 ml of water. The crystalline substance obtained is dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether. 29.6 g (60%) of diethyl ethyl acetate (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate and / or its tautomer are obtained. with a melting point of 106-17 ° C.

Analysis: calculated for C 20 H 27 NO 8 (409.43): Found: IR 1 3.8-4.15 (m, 7.0-7.25 (m, d) 20.5 C: 58.67%, H: C: 58.79%, H: (KBr) = 3400, zeso, zsso, 1730 (174o sh). 1110 cm -1 H NMR (cnc13) = α '= 1.1 ft, sn), 1.17 (t, sn ), 1.52 4H), 6.7 (broad s, 2H), 6.25-6.45 (m) + 3H) ppm. 6.65%, N: 6.33%, N: 3.34%. g (50 mmol) of the product prepared under c) above is suspended in 50 ml of dry ether and a solution of 3.45 g (150 mmol) of metallic sodium in 100 ml of dry ethanol and a solution of 12.7 g (50 mmol) mmol) of iodine in 150 ml of dry ether is added simultaneously from two separatory funnels to the vigorously stirred suspension while cooling with ice water. Then 5 g of sodium hydrosulfite, dissolved in 200xd 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 precipitated inorganic salts. The organic phase is removed, dried over magnesium sulphate and filtered and the filtrate is evaporated.

The oily residue, weighing 18.5 g, is crystallized from 30 ml of 2-propanol. 10.9 g (54%) of 3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate with a melting point of 84-85 ° C (2- propanol).

Analysis: calculated for C 20 H 25 NO Found: C:% | H: C: 58.99%, H: 8 (407.41): 6.19%; N: 6.04%, N: 3.44%; 3.57%. 1 to 10 15 20 25 30 35 12 453 082 1: 1 Nm (cnc13> = J = 1.12 (t, sm, 1.21 (t, an), 2.31 Ås, 3H), 3.76 ( s, 6H), 3.8-3.4 (m, 4H), 4.53 (d, 1H), 4.63 (d, 1H), 4.69 (s, 1H), 6.3-6 .4 (m, 2H) + 7.07 (d, 1H) PPm. E) 179 ml (206 g, 1.452 mol) of boron trifluoride diethyl ether are added dropwise to a vigorously stirred solution of 179 g (0.484 mol) of diethyl-3-acetyl -1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate and 107 ml (120 g, 1.936 mol) of ethylene glycol in 500 ml of dry dioxane under ice-cooling. The reaction mixture is allowed to stand at room temperature for 1 day and during this time the mixture is stirred occasionally. Then 415 g (1¿452 mol) are added. Na 2 CO 3. 10H 2 O slowly to the stirred mixture while cooling with ice water and the mixture is 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 each with 500 ml of diethyl ether. The ether phase is dried over magnesium sulphate and filtered and the filtrate is evaporated. 33.9 g (0.58 mol) of sodium chloride, 17.4 ml (0.968 mol) of water and 220 ml of dimethyl sulfoxide are added to the residue and the mixture is stirred on an oil bath at 180 ° C. The course 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). Towards the end of the reaction, ie. after about 15 hours, the mixture is kept in 1100 ml of a saturated aqueous solution of sodium chloride and the resulting mixture is shaken with 1000 ml and then twice each with 500 ml of diethyl ether. The ether solutions are combined, decolorized with charcoal and dried over magnesium sulphate and the filtrate is evaporated to a final volume of about 200 ml. This concentrated solution is cooled with ice water to give 59.9 (35%) trans-ethyl-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azetidine carboxylate, m.p. 95 ° C. f) A mixture of 0.5 g (1.2 mmol) of diethyl 3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate, prepared as described under d ) above, 10 ml of dry tetrahydrofuran and 0.53 g (3.6 mmol) of mercaptoethanol are 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 solution of sodium hydrogencarbonate, dried over magnesium sulphate and filtered and the product is separated from the filtrate by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254 + 366, developing solvent: 8: 2- mixture of toluene and acetone). 0.30 g (53%) of diethyl-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2- azetidine dicarboxylate. U nun (cnc13) = á '= o, a-1, ss (m, en), 1.72 + 1.77 (d, 3H), 2.9-3.4 (m, ZH), 3 , 75 (s, 6H), 4.0-5.0 (m, 9H), 6.4 (m, 2H) + 7.1 (d, 1H) PPm.

Example 2 Trans-1- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid 11 g (0.0245 mol) of diethyl-3 - (2-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2,2-azetidine dicarboxylate is dissolved in 20 ml of dimethyl sulfoxide, 1.72 g (0.0295 mol) of sodium chloride and 0.9 ml (0.049 mol) of water are added and the mixture is stirred at 175 ° C until the reaction is complete. The course 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 and kept in 150 ml of a saturated aqueous solution of sodium chloride and extracted three times each with 50 ml of diethyl ether. The organic phases are combined, dried over magnesium sulphate and 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 mol) of sodium hydroxide in 10 ml of water is added to the alcohol mixture while cooling with ice water. The mixture is stirred for 0.5 hours, then diluted with 50 ml of water and washed twice each with 25 ml of dichloromethane. The aqueous phase is acidified to pH = 1 with a concentrated aqueous solution of hydrochloric acid and then extracted three times each with 25 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated.

The oily residue is crystallized from benzene. 4 g (54%) of the desired product with a melting point of 131-132 ° C (benzene) are obtained.

Analysis: Calculated for C 15 H 17 NO 6 (307.32): C 58.63%, H: 5.57%, N: 4.56%; Found: C: 58.40%, H: 5.80%, N: 4.66%; IR (Carp 3400-2700, 1750 (broad) cx fi. 111 mm (cnc13) = J = 1.5 (s, 311), 3.7 (a, 111, J = 2.3 Hz), 3.76 ( s, BHL, 4.0 (m, 4H), 4.38 (d, 1H, J = 2.5 Hz), 6.82 (ZH) + 7.26 (2H, AA'BB'¿ J = 9 , 5 Hz), 9.2 (S, 1H) ppm.

The starting substance is prepared as follows: a) A mixture of 24.6 g (0.2 mol) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mol) of diethyl bromomalonate is stirred for two days at room temperature. The resulting mass is triturated. with 100 ml of diethyl ether, the precipitated 4-methoxyanisidine 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 with a melting point of 64-65 ° C (ethanol) are obtained.

Analysis: Calculated for C 14 H 19 NO 5 (281.31): C: 59.77%, H: 6.81%, N: 4.99%; Found: C: 59.99%, H: 6.97%, N: 5.25%.

IR (λ max 3300, 1775, 1725 om). N man (cnc13) = J = 1.23 (t, en, J = 7.2 Hz), 3.67 (s, 3H), 4.2 (q , 4H, J = 7.2 Hz), 4.62 (s, 1H), 4.1-4.5 (broad s, 1H), 6.55 (2H) + 6.73 (2H, AA'BB B) A mixture of 11.2 g (0.04 mol) of diethyl (4-methoxyanilino-malonate, prepared as described under a) above, 15 ml of glacial acetic acid and 4 g (3 , 7 ml, 0.048 mol) 10 15 20 25 30 35 15 455 082 diketene is boiled for 0.5 hours. 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 with melting point 136 are obtained. 137 ° C (ethyl acetate).

Analysis: calculated for C 18 H 23 NO 7 (365.38): C: 59.17%, H: 6.39%, N: 3.83%; found = c = 58.98%, H: 6.90%, N; 4.04%.

IR (Kßr) = 3600-sooo, 1760, 1740, 1685 cm-1.

1 H NMR (cDc13): J '= 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), 3.76 (s, 3H), 4.1 (q, 2H, J = 7.2 Hz), 4.27 (q, za, J = 7.2 Hz). 6.7 (2H) + 7.0 (za, AA'BB ', J = 9 Hz) ppm. c) 9.1 g (0.025 mol) of diethyl 1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate, prepared as described in 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 mol) of iodine in 50 ml of dry diethyl ether are simultaneously introduced dropwise into the suspension with vigorous stirring and cooling with is. 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 ether phase is separated and the aqueous phase is extracted three times with 50 ml of diethyl ether each. The ether phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated. The oily residue is triturated with 2-propanol to give 6.2 g (680 crystalline diethyl 3-acetyl-1- (4-methoxyphenyl) -4-oxo42,2-azetidinedicarboxylate, m.p. 70-71 ° C ( ethanol).

Analysis: Calculated for C 18 H 21 NO 7 (363.38): C: 59.50%, H: 5.82%, N: 3.85%; Found: C: 59.04%, H: 5.84%, N: 4.08%. 10 15 '20 25 30 35 16 453 082 IR (KBr) = 1760. 1735, 1720 cm -1. 1H una (cDc13) = ¿'= 1.20 1 :, au, 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 mol) of diethyl 3-acetyl-1- (4-methoxyphenyl) -4-oxo-2,2-azetidine dicarboxylate, prepared as described in c) above, are dissolved in 20 ml dry dioxane and 4.1 g (3.75 ml, 0.066 mol) of ethylene glycol. 7.1 g (6.3 ml, 0.05 mol) of boron trifluoride diethyl etherate complex are added dropwise to the stirred solution under ice-cooling and the reaction mixture is stirred for a further 2 hours at room temperature. The solution is alkalized with a saturated aqueous solution of sodium hydrogencarbonate and then 100 ml of water are added and the mixture is extracted three times with 50 ml of diethyl ether each. The organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated. The oily residue is triturated with diethyl ether to give 6 g (89%) of crystalline diethyl-3: 12-methyl-1,3-dioxolan-2-yl) -1- (4-methoxyphenyl) -4-oxo-2. 2-Azetidetine dicarboxylate, m.p. 82-83 ° C (ethanol).

: R (Kßr) = 1140 cmf1 (broad) - 1 H NMR (cnc13) = ä '= 1.17 (t, sn, J = 7.2 Hz). 1.26 (t, 3H, J = 7.2 Hz), 1.5 (s, 3H), 3.7 (s, 3H), 3.9 (m, 4H), 4.2 (m, SH ), 6.67 (2H) + 7.34 (2H, AA'BB ', J, = 9 Hz) ppm.

Analysis: calculated for C 20 H 25 NO 8 (407.43): C: 58.96%, H: 6.18%, N: 3.44%; Found: C: 58.70%, H: 5.68%, N: 3.63%.

Example 3 Trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid A mixture of 28.5 g (0.075 mol) of diethyl-1- phenyl 3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine dicarboxylate, 44 ml of dimethylsulfoxide, 5.6 g (0.1 mol) of sodium 10 15 20 25 30 35 17 453 032 chloride and 3, os m1 10.17 moi) water is stirred at 17 ° C until the reaction is completed. The course 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 solution of sodium chloride and extracted three times with 150 ml of diethyl ether each. The organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated. The resulting oily residue, weighing 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 with stirring over an ice-water bath. After stirring for 0.5 hour, the mixture is diluted with 150 ml of water and extracted three times with 20 ml of diethyl ether each. The aqueous phase is acidified to pH = 1 with a concentrated aqueous solution of hydrochloric acid and then extracted three times with 50 ml of dichloromethane each. The organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated. The oily residue is crystallized from benzene to give 12 g (56%) of the desired compound, m.p. 165 ° C (benzene).

Analysis: Calculated for C 14 H 15 NO 5 (277.27): C 60.64%, H: 5.45%, N: 5.05%; Found: C: 60.64%, H: 5.72%, N: 4.99%.

: R (man: 3500-2700, 1770, 1730 01:51. 111 mm (cnc13h Q = 3 Hz), 4.0 (m, 4H), 4.42 (d, 1H, J = 3 Hz). 7 Δ (m, 9H), 7.55 (s, 1H) ppm.

The starting material is prepared as follows: a) a mixture of 38 g (0.152 mol) of diethylanilino malonate (n. Blank = Ber. 31 (1898) 1815], see m1 glacial acetic acid and 15.3 g (13.9 ml, 0.182 mol ) the vinegar is boiled for 0.5 hours. Glacial acetic acid is evaporated in vacuo over a water bath and the oily residue is crystallized by trituration thereof with ether 36.5 g (72%) of diethyl are obtained. 15 15 20 25 30 35 18 453 082 (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate) and / or its tautomer, m.p. 98-99 ° C (ethyl acetate and petroleum ether).

Analysis: calculated for C 17 H 21 NO 6 (335.35): C: 60.88%, H: 6.31%, N: 4.18%; Found: C: 60.83%, H: 6.15%, N: 4.43%.

IR (xBr) = 3350, 2950, 1760, 1750 (d), 1700 cm -1. 1 H NMR (cDc13) = δ '= 1.02 (t, 3H), 1.3 (t, 3H), 1.6 (s, 3H), 2.8 (s, 3H), 3.6 (broad s, 1H), 4-4.45 (m, 4H), 7.2 (s, SH) ppm. b) 50 g (0.149 mol) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate, prepared as described in a) above, are added to a solution of 10 .2 g (0.447 mol) of metallic sodium in 250 ml of dry ethanol and then a solution of 37.9 g (0.149 mol) of iodine in 200 ml of dry ether is added with vigorous stirring. When the reaction is complete, 8.5 ml (8.9 g, 0.149 mol) 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 ether phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated. The oily residue is crystallized from 50 ml of 2-propanol to give 31 g (62%) of diethyl (3-acetyl-1-phenyl-4-oxo-2,2-azetidine-dicarboxylac), m.p. ss ° c (2-propanol).

Analysis: calculated for C 17 H 19 NO 6: 61.25%, H: 5.75%, N: 4.20%; Found: C: 61.38%, H: 5.89%, N: 4.24%.

IR (Kßr) = 1770, 1740, 1720 cm -1.

1 H NMR (cDc 13) = J = 1.12 (e, en), 2.3 (S, an), 4.25 (q, 4H), 4.75 (s, 1H), 7.0-7 Δ (m, 5H) ppm. c) 28.5 g (0.085 mol) of diethyl 3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate, prepared as described in b) above, are dissolved in a mixture of 90 ml of dry dioxane and 21 g (18.8 ml, 0.34 mol) of dry ethylene glycol and 36.5 g (31.5 ml, 0.255 mol) of boron trifluoride-diethyl etherate complex are added dropwise to the solution. - vigorous stirring and cooling with ice water. The solution is stirred for a further 2 hours at room temperature and then neutralized with a saturated aqueous solution of sodium carbonate. The neutral solution is diluted with 100 ml of water and then extracted three times with 50 ml of diethyl ether each. The organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is evaporated in vacuo. The oily residue is crystallized by trituration thereof with ether. 28.5 g (90%) of diethyl 1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine dicarboxylate, m.p. C (benzene).

Analysis: calculated for C 19 H 23 NO 7: C: 60.47%, H: 6.14%, N: 3.71%; Found: C: 60.74%, H: 6.21%, N: 3.79%.

IR (λmax 1770, 1740 cm -1. 111 NMR (cnc13) = J = 1.18 (t, 311, - J = 7.2 Hz), 1.24 (t, 311,.: R = 7.2 Hz) , 1.51 (s, an), 3.92 (m, 4: 1), 4.3 (m, SH), 7.2 (m, SH) ppm.

Claims (11)

10 15 20 25 30 35 4 ss f morsa “° PATENT REQUIREMENTS Compounds of the general formula I 1 2 vn H \ j coon H3C - C '"" J! "____ 1, I 04" - N \ R wherein Y1 and Y2 together are an ethylene ketal group or a thio analogue thereof and R is a benzyl group bearing one or more C 1-4 alkoxy substituents or a phenyl group optionally bearing one or more C 1-4 alkoxy substituents 1-4. Trans-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid according to claim 1. Trans-1- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid according to claim 1. Trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid according to claim 1. A process for the preparation of novel heterocyclic carboxylic acids according to claim 1 having the general formula I wherein the Y1 and Y2 together are an ethylene ketal group or a thio analogue thereof and R is a benzyl group bearing one or more C 1-4 alkoxy substituents or a phenyl group bearing optionally one or more C 1-4 alkoxy substituents, characterized in that (a) reacting a compound of the general formula IV - 10 15 20 25 30 21 Wherein Z is a C 1-5 alkyl group and R is as defined above, with ethylene glycol or a thio analogue thereof in the presence of boron trifluoride diethyl etherate or an arylsulfonic acid, to react the obtained compound of the general formula III 21 22 / Hae - c --_ |. wherein Z, R, Y1 and Y2 have the meanings given above, with an alkali metal halide in pyridine or a related solvent or in an aqueous solution of dimethyl sulfoxide and that the obtained compound of the general formula Wherein Z, R, Y and Y2 have the meanings given above and which are a mixture of cis and trans isomers, a) selectively hydrolyzed or b) separated into their components and that the trans isomer of the general formula IIa 10 15 20 25 30 35 Y1 YZ HH Hsc fc 'cooz Ira N _ / ø o I \ is hydrolyzed; or reacting (b) a compound of general formula III, wherein Z, R, Y1 and Y2 have the meanings given above, with an alkali metal halide in pyridine or a related solvent or in an aqueous solution of dimethyl sulfoxide and the resulting compound of the general formula II, in which Z, R, Y1 and Y2 have the meanings given above and which are a mixture of cis and trans isomers, a) are selectively hydrolysed or b) are separated into their components and that the trans isomer with the general formula IIa is hydrolyzed; or that (c) a compound of general formula II, wherein ZJLY1 a a1 Y2 has the meanings given above and which is a mixture of cis and trans isomers, a) is selectively hydrolyzed or b) is separated into its components, and that the trans isomer of the general formula IIa is hydrolysed, after which the trans compound of the general formula I is separated from the reaction mixture. Process according to Claim 5, characterized in that the hydrolysis is carried out in the presence of a molar equivalent of alkali, calculated on the compound of the general formula II or IIa, or that alkali is used in a moderate excess. 10 15 20 25 30 “453 082 ' 7. A process according to claim 5, characterized in that the trans isomer of the general formula IIa is separated from the cis isomer by dissolving it in an ether-type solvent. A process according to claim 5 for the preparation of trans -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid , characterized in that ethyl 1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate or trans- the isomer thereof is hydrolyzed. A process according to claim 5 for the preparation of trans-1- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidine-carboxylic acid, k This means that ethyl 1- (4-methoxyphenyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate is hydrolyzed. Process according to Claim 1 for the preparation of trans-1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylic acid, characterized in that ethyl -1-phenyl-3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2-azetidinecarboxylate is hydrolyzed. 11. ll. Pharmaceutical composition containing a compound according to claim 1 of the general formula I, wherein: Y 1, Y 2 and R have the meanings given in claim 1, together with a pharmaceutically acceptable carrier.