2-(2-AZETIDINON-N-YL)-2- AND 3-BUTENOIC ACIDS DERIVATIVES AND THEIR USE IN THE CEPHALOSPORINE SYNTHESIS

Abstract: Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula (I), wherein X is an acylamino group, Y is a S-substituted dithio group or a sulfonylthio group, or X and Y are joined to form a group (a), wherein R<1> is the aliphatic, aromatic or arylaliphatic residue bound to the carbonyl of said acylamino group and R<2> represents a carboxy-protecting group. The compounds (I) are intermediates in the preparation of cephem derivatives unsubstituted in the 3-position.

Description: "2-(2-AZE-Tm-D WI-YL)-2- AND 3-BUI-ENDIC ACIDS DERIVAT-I-VES AMD THEIR USE IN THE CEFHA -U---6P0R----N-I SYN-M-SCS" The present invention concerns novel esters of 2-(2-azetidinon-N- yl)-2 and 3-butenoic acids, a process for their preparation and their use for manufacturing cephem derivatives unsubstituted in the 3- position. Methods for the preparation of cephem derivatives unsubstituted in the 3-position are described in the literature. For example a series of reactions starting from penicillin G through its degradation is described by S. Kukolja et al. in Chemistry and Biology of β- actam Antibiotics, Ed. Morin and Gorman, 1982, Vol.l, pages 170-176, who, in their turn, refer to Helv. Chim. Acta, 1972, pages 423 and following. A decarbonylation of the corresponding 3-formylcephem is described in Helv. Chim. Acta, 1974, pages 2044 and following. The reduction of 3-hydroxy-3-cephems with sodium borohydride and further dehydratation is illustrated in Helv. Chim. Acta, 1974, pages 1919 and following, whilst a reduction to 3-cephem unsubstituted in the 3-position of 3- chloro, -bromo or -sulfonyloxy derivatives with zinc and acids is described in DE 2.651.595. However, all the known methods have drawbacks due to the number of steps to arrive to the desired compound or to the obtention of mixtures of [_ 2 and [_3 derivatives. It has now been found that the cephem derivatives unsubstituted in the 3-position can be obtained in one or two steps only, starting from a 2-azetidinone via novel intermediates. It has also been found that, by reacting said 2-azetidinone with an ester of 2-bromo-3-butenoic acid in the presence of a base, an acylation is performed in high yields. Finally, it has been found that the novel intermediates obtained by said alkylation allow the obtention of cephem derivatives unsubstituted in the 3-position in high yields. Thus, it is an object of the present invention to provide novel esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I wherein the dotted lines indicate a double bond in the 2- or 3- pos it ion, X represents an acylamino group, Y represent s a S- substituted dithio group or a sul fonylthio group , or X and Y , together, form a group ( a) in which R represents the residue bond to the carbonyl of X and R represents a carboxy-protecting group. The compounds of formula I above are designated as "2 and 3 2 -3 butenoic acids" because they appear as mixtures of [_ and derivatives. Preferably, the acylamino group represented by X is a group of structure (b) R 1 -CO-NH- (b) in which R represents a phenyl, phenoxymethyl or benzyl radical, unsubstituted or substituted on the benzene ring with one or two atoms of a halogen, preferably chlorine, with one or two alkyl groups of from 1 to 4 carbon atoms, preferably methyl, or with one or two alkoxy groups containing from 1 to 4 carbon atoms, preferably methoxy. Thus, the radical R of the above mentioned group (a) has preferably the hereinabove defined meaning. 2 The carboxy-protecting group represented by R may be an ester group selected among the unsubstituted or substituted (C--C. )alkyl, unsubstituted or substituted phenyl, unsubstituted or on the aromatic ring substituted benzyl, or diphenylmethyl groups. Preferably R represents phenyl, 4-methylphenyl, 2-methylphenyl, 4- chlorophenyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, phenoxymethyl, 2 4-methylphenoxymethyl, 4-chlorophenoxymethyl, and R represents methyl, ethyl, t-butyl, 2,2,2-trichloroethyl, penta luorophenyl, penta chlorophenyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl. The S-substituted dithio group is preferably represented by the radical (c) of structure -S-S-R 3 (c) in which R is a unsubstituted or substituted phenyl or a unsubstituted or substituted heterocyclic group. In the radical (c) R advantageously represents a phenyl; a phenyl substituted with a (C.- C.)alkyl, preferably methyl, with one or two atoms of a halogen, preferably chlorine, with a nitro group or with a (C..-C.)alkoxy group, preferably methoxy; a 1-naphthyl; a 2-naphthyl; a 6-methoxy-2- naphthyl; a 4-biphenylyl; a 2-benzimidazolyl; a 2-benzothiazolyl; a 2- indolyl; a 3-indolyl; a 2-(1-methyl)indolyl; a l-methyl-3-indolyl. The preferred s-substituted dithio group is represented by the 2-benzo thiazolyldithio radical of structure (c) in which R is 2-benzo thiazolyl. The sulfonylthio group is preferably represented by the radical (d) -S-Sθ 2 -R 4 (d) 4 in which R is a (C.-C,)alkyl, an unsubstituted or substituted aryl or a unsubstituted or substituted heterocyclic group. In the radical (d) R advantageously represents methyl, ethyl, n-propyl, n-butyl, phenyl, phenyl substituted with a (C,-C^)alkyl, with a (C,-C.)alkoxy group, with a halogen or with a nitro group, 1-naphthyl, 2-naphthyl. The preferred sulfonylthio group is a radical of structure (d) in which R is p-methylphenyl, p-chlorophenyl, p-nitrophenyl or phenyl. It is another object of the present invention to provide a process for the preparation of 2-(2-azetidinon-N-yl)-2 and 3-butenoic acids derivatives of formula I which comprises treating a 2-azetidinone of formula II wherein X and Y are as defined above, with an ester of 2-bromo-3- butenoic acid of formula III CH =CH-CH-C0OR 2 (III) * I Br wherein is as defined above, in a polar aprotic solvent at a temperature of from -40°C to +35°C in the presence of a base. The reaction is carried out using substantially equimolecular amounts of the compounds II and III, by adding compound III to the azetidinone II at low temperature, preferably between -40°C and -10°C in the selected solvent and by allowing the temperature to rise firstly at 0°C and then at room temperature. The employed solvent may be a polar aprotic derivative such as N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like. The base is used in eguimolecular amounts, but an excess in respect of the azetidinone II does not modify the course of the reaction. The employed base may be organic or inorganic, for example trimethylamine, triethylamine, N-methylmorpholine, N-methylpiperidine, N-benzyltrj. methylaπmonium hydroxide (hereinbelow designated Triton B), sodium hydride, sodium acetate. When the reaction is over, the ester of the 2-(2-azetidinon-N-yl)- 2- and 3-butenoic acids thus obtained is isolated by neutralization of the excess of base. The 2-azetidinones of formula II used as starting material for the preparation of the compounds of the present invention are known in the literature and can be prepared using well known methods. The preparation of azetidinones of formula II in which X and Y, together, form a group (a), is described in Tetrahedron, 1983, 39, 2493-2503 or in J. Chem. Soc. The preparation of 2-azetidinones of formula II in which X represents an acylamino group, more particularly a group of structure (b), and Y represents a S-substituted dithio group, more particularly a group of structure (c), is described in WO 84/00960. The preparation of 2-azetidinones of formula II in which X represents an acylamino group, more particularly a group of structure (b) , and Y represents a substituted sulfonylthio group, more particularly a group of structure (d), is described in DE 3.443.225. The esters of 2-bromo-3-butenoic acid, corresponding to formula III, are prepared according to a method which comprises treating the 2-bromo-2-butenoyl chloride with the corresponding alcohol in the presence of a base in an apolar solvent. The novel esters of the 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I are key intermediates for the preparation of cephem derivatives unsubst ituted in the 3-position . It is a further object of the present invention to provide the use of the esters of the 2- ( 2-azetidinon-N-yl ) -2- and 3-butenoic acids corre sponding to the formu la I , for the preparation o f cephem derivatives unsubstituted in the 3-position of formula VIII 2 wherein X and R are as defined above. Preferably, the present invention also provides the use of compounds of formula I above, wherein X represents a group of the structure (b) , for the preparation of cephem derivatives unsubstituted in the 3-position of formula IV wherein R 1 and R2 are as defined above. For this use, the esters of the 2-(2-azetidinon-N-yl)-2- and 3- butenoic acids of formula I are subjected to a cyclization reaction. The compounds of formula I, wherein X and Y, together, form a group (a) are firstly treated with an excess of 2-benzothiazolylsulfenyl chloride in dioxane/water at room temperature or with a slight excess of 2-benzothiazolyl disulfide in tetrahydrofurane in the presence of an aqueous acid such as 5% hydrochloric acid, 25+30% p-toluene sulfonic acid or 10+20% perchloric acid, still at room temperature, to obtain a compound of formula V wherein X is acylamino and Y is a group of structure (c) in which R~ is 2-benzothiazolyle. Still starting from the novel compounds of formula I wherein X and Y, together, form a group of structure (a), the opening of the thiazoline ring is obtained by a reaction with a sulfonyl chloride, particularly with a compound of formula VI R 4 -Sθ 2 -Br (VI) wherein R is as defined above, to afford a compound of formula VII wherein X represents an acylamino group, more particularly a group of 2 structure (b), R represents a carboxy-protecting group and Z represents hydrogen, methyl, chloro or nitro. For example, the compound of formula I, wherein X and Y, together, form a group of structure (a), is treated with benzenesulfonyl bromide, p- toluenesulfonyl bromide or p-nitrobenzenesulfonyl bromide in a solvent such as methanol, acetone, tetrahydrofurane, methylene chloride or their mixtures at a temperature of 10+15°C to obtain the corresponding 2 compound of formula VII wherein X, and Z have the above-stated meaning. The compounds of formula I wherein X represents an acylamino group, particularly a group of structure (b), and Y represents a substituted dithio group, particularly a group of structure (c), and preferably the compounds of formula V are straightforward transformed into the corresponding cephem derivatives, unsubstituted in the 3-position, of formula IV, by treatment with a base. The cyclization occurs in a polar aprotic solvent such as dimethylformamide, or in a ether solvent such as tetrahydrofurane or dioxane, by using a base such as gaseous ammonia, sodium or potassium acetate, triethylamine, sodium or potassium carbonate or bicarbonate, sodium or potassium hydroxide, 1,5-diazabicyclot5.4.0]undec-5-ene o tetramethylguanidine. Analogously, the compounds of formula I wherein X represents an acylamino group, particularly a group of structure (b), and Y represents a sulfonylthio group, more particularly a group of structure (d) , and preferably the compounds of formula VII are straightforward transformed into the corresponding cefem derivatives, unsubstituted in the 3-position, by treatment with a base, as set forth for the compounds of formula V. Thus, it is a further object of the present invention to provide a process for the preparation of 3-cephem derivatives unsubstituted in the 3-position of formula VIII wherein X and are as defined above, which comprises (a) treating an azetidinone of formula II wherein X and Y are as defined above, with an ester of 2-bromo-3- butenoic acid of formula III CH 2 =CH-CH-COOR 2 (III) Br 2 wherein R is as defined above, in a polar aprotic solvent in the presence of a base; and (b) subjecting the ester of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids thus obtained of formula I wherein the dotted lines indicate a double bond with 2- or 3-position, 2 X, Y and R are as defined above, to a cyclization n a basic medium. Preferably as starting material a 2-azetidinone of formula II, wherein X represents a group of structure (b), is used, in order to obtain a cephem derivative, unsubstituted in the 3-position, of formula IV as final product. The following example illustrates the invention without, however, limiting it. Esempio [a] Benzyl 2-bromo-3-butenoate (III, R 2 = PhCH_) A solution of 0.52 ml of benzyl alcohol and 1.39 ml of triethylami. ne in 5 ml of anhydrous ethyl ether is prepared at -78°C and under argon. After a 10-minute stirring, a solution of 1.38 g of 2-bromo-3- butenoyl chloride in 5 ml of anhydrous ethyl ether is added dropwise. After a 1-hour stirring the reaction mixture is treated with 5 ml of diluted HC1 (1:1 v/v);the aqueous phase is separated and extracted with 10 ml of ethyl ether. The combined ethereal phases are evaporated under vacuum to an oil. Thus, 1.89 g of the oil sufficiently pure for the next step are obtained. [b] Benzyl 2-(3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6- yl-7-oxo)-2-butenoate (I, X-Y=a, R 1 ** PhCH 2 , R 2 =PhCH 2 ). To a solution of 2.18 of 3-benzyl-4-thia-2,6-diazabicyclo(3.2.0] hept-2-en-7-one in 100 ml of tetrahydrofurane, at 0°C, a suspension of 0.24 g of sodium hydride (80% oil dispersion) in 10 ml of tetrahydro furane are added. A solution of 2.39 g of benzyl 2-bromo-3-butenoate in 50 ml of tetrahydrofurane is slowly added. After a 24-hour stirring, the reaction mixture is treated with ice and extracted with 15 ml of ethyl acetate. The organic phase is separated, dried and evaporated under vacuum. The residue is purified by chromatography on a silica gel column (ethyl acetate/petroleum ether = 3:1 v/v) . After evaporation of the eluate under vacuum, 1.77 g of the desired product are obtained. 1 H-NMR (300 MHz)(ppm): 1.56 (d, 3H, methyl); 3.90 (dd, 2H, CH 2 benzyl); 5.18 (dd, 2H, CH 2 ester); 6.04 (s, 2H, CH in 1 and 5); 7.0 (q, 1H, =CH); 7.27+7.37 (m, 10H, aromatic). [c] Benzyl 2-(l-azetidin-2-(2-benzothiazolylthio)-3-benzyl-4-oxo)- 2-butenoate (V, X = PhCH 2 CONH, R 2 = PhCH 2 ) 4.32 g of benzothiazolyldisulfide are suspended in a mixture of 40 ml of tetrahydrofurane and 10 ml of 5% HC1. Under stirring, 3.92 g of the intermediate [b] are added and the obtained suspension is stirred at 18÷20°C per 1 hour. The obtained solution is partially evaporated, then diluted with 20 ml of methylene chloride. After concentration under vacuum of the separated organic phase, the residue is purified by column chromatography of silica gel, eluted with methylene chloride/ethyl acetate (3:2 v/v). The collected fractions are concentrated to afford 2.44 g of the desired product. [d] Benzyl 2-[l-azetidin-2-(4-methylphenilsulfonylthio)-3-benzyl-4- oxo]-2-butenoate (VII, X = PhCH 2 CONH, R 2 = PhCH 2 , Z = CH 3 ) To a solution of 5.76 g of the intermediate [c] in 200 ml of a mixture acetone/water (9:1 v/v), in portions in 1 hour, 3.8 g of p- toluenesulfonyl bromide are added. The suspension is stirred for another hour, the insoluble residue is removed by filtration and the filtrate is evaporated under vacuum. The residue is extracted with 50 ml of ethyl acetate and the phases are separated; the organic phase is evaporated under vacuum to afford a oil. The residual oil is purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (3:1 v/v). The fractions containing the desired product are concentrated under vacuum to afford 3.88 g. [e] Benzyl 7-phenylacetamido-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2- en-2-carboxylate (IV, R 1* * Ph, R 2 = PhCH 2 ) To a solution of 2.88 g of the intermediate [c] in 150 ml of tetrahydrofurane, cooled to -65+-70°C, 1.5 g of DBU are added. After a 1-hour stirring at the same temperature the reaction mixture is acidified with 35% HC1, then diluted with 60 ml of ethyl acetate. The phases are separated and the organic one is washed with water and evaporated under vacuum to afford an oil. The residual oil is purified by chromatography on a silica gel colomn, eluted with methylene chloride/ethyl acetate (3:1 v/v). The collected fractions are evaporated to obtain 1.44 g of the desired product. [f] Benzyl 7-phenylacetamido-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2- ene-2-carboxylate (IV, R 1 = Ph, R 2 = PhCH 2 ) To a solution of 2.13 of the intermediate [d] in 120 ml of tetrahydrofurane, 1.32 ml of DBU at 0÷+5°C are added. After a 2-hour stirring the temperature is let to reach to 20°c. By proceeding according to [e], 1.31 g of the desired product are obtained.

Claims: CLAIMS 1. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I wherein X represents an acylamino group, Y represents a S-substituted dithio group or a sulfonylthio group, or X and Y, together, form a group (a) in which R 1 represents the residue bond to the carbonyl of X and R2 represents a carboxy-protecting group. 2. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claim 1, in which X is a group of structure (b) R 1 -CO-NH- (b) in which represents a phenyl, phenoxymethyl or benzyl radical, unsubstituted or substituted on the benzene ring with one or two atoms of a halogen, with one or two alkyl groups of from 1 to 4 carbon atoms, or with one or two alkoxy groups containing from 1 to 4 carbon atoms. 3. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claim 1, wherein X and Y, together, form a group of structure (a), in which R is as defined in claim 2. 4. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claims 1 to 3, wherein Y is a S-substituted dithio group of structure (c) -S-S-R 3 (c) in which R is a phenyl, a phenyl substituted with a (C 1 ~C 4 )alkyl, preferably methyl, with one or two atoms of a halogen, with a nitro group or with a (C,-C 4 )alkoxy group; a 1-naphthyl; a 2-naphthyl; a 6- methoxy-2-naphthyl; a 4-biphenylyl; a 2-benzimidazolyl; a 2- benzothiazolyl; a 2-indolyl; a 3-indolyl; a 2-(1-methyl)indolyl; a 1- methyl-3-indolyl. 5. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claims 1 to 4, wherein Y is a s-substituted dithio group of structure (c) in which R is 2-benzothiazolyl. 6. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claims 1 to 3, wherein Y is a sulfonylthio group of structure (d) -S-Sθ 2 -R 4 (d) 4 in which R represents methyl, ethyl, n-propyl, n-butyl, phenyl, phenyl substituted with a (C.-C * )alkyl, with a (C.-C.)alkoxy group, with a halogen or with a nitro group, 1-naphthyl, 2-naphthyl. 7. Esters of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claims 1 to 3 and 6, wherein Y is a 4 sulfonylthio group of structure (d) , in which R represents phenyl, p- methylphenyl, p-chloropheyl or p-nitrophenyl. 8. A process for the preparation of esters of 2-(2-azetidinon-N- yl)-2- and 3-butenoic acids of formula I according to claim 1, which comprises treating a 2-azetidinone of formula II wherein X and Y are as defined in claim 1, with an ester of 2-bromo-3- butenoic acid of formula III CH 2 =CH-CH-COOR 2 (III) Br 2 wherein R is as defined in claim 1, in a polar aprotic solvent at a temperature of from -40°C to +35°C in the presence of a base. 9. A process according to claim 8, in which sodium hydride is used as a base. 10. Use of esters of the 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I for the preparation of the corresponding cephem derivatives unsubstituted in the 3-position of formula VIII wherein X and R are as defined in claim 1. 11. Use of esters of the 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids of formula I according to claims 2 to 7 for the preparation of cephem derivatives unsubstituted in the 3-position of formula IV wherein R 1 is as defined in claim 2 and R 2 is as defined in claim 1. 12 . A process for the preparation of 3-cephem derivatives unsubstituted in the 3-position of formula VIII 2 wherein X and R are as defined in claim 1, which comprises: (a) treating an azetidinone of formula II wherein X and Y are as defined in claim 1, with an ester of 2-bromo-3- butenoic acid of formula III CH-,«CH-CH-C0OR' 2 I (HI) Br 2 wherein R is as defined in claim 1, in a polar aprotic solvent in the presence of a base; and (b) subjecting the ester of 2-(2-azetidinon-N-yl)-2- and 3-butenoic acids thus obtained of formula I wherein the dotted lines indicate a double bond with 2- or 3-position, 2 X, Y and R are as defined in claim 1, to a cyclization in a basic medium. 13. A process according to claim 11, in which a 2-azetidinone of formula II, wherein X is a group of structure (b) R 1 -CO-NH- (b) in which R represents a phenyl, phenoxymethyl or benzyl radical, unsubstituted or substituted on the benzene ring with one or two atoms of a halogen, with one or two (C.-C.)alkyl groups or with one or two (C.-C.Jalkoxy groups is used as starting material.

Inventors: CAINELLI GIANFRANCO, CONTENTO MICHELE, DA COL MARCO, DALL ASTA LEONE, PANUNZIO MAURO, RESTA IRENE, SANDRI SERGIO, UMANI RONCHI ACHILLE, CAINELLI, GIANFRANCO, CONTENTO, MICHELE, DA COL, MARCO, DALL'ASTA, LEONE, PANUNZIO, MAURO, RESTA, IRENE, SANDRI, SERGIO, UMANI RONCHI, ACHILLE
Applicants: CAINELLI GIANFRANCO, CONTENTO MICHELE, DA COL MARCO, DALL ASTA LEONE, OPOS BIOCHIMICA SRL, PANUNZIO MAURO, RESTA IRENE, SANDRI SERGIO, UMANI RONCHI ACHILLE, BIOCHIMICA OPOS S.P.A., CAINELLI, GIANFRANCO, CONTENTO, MICHELE, DA COL, MARCO, DALL'ASTA, LEONE, PANUNZIO, MAURO, RESTA, IRENE, SANDRI, SERGIO, UMANI RONCHI, ACHILLE
Application year: 1995
Main classification: C07D205
IPC codes: C07D205, C07D417, C07D501, C07D513