BETA-LACTAMS SYNTHESIS USING A METAL COMPOUND AS CATALYST

Abstract: Trans-β-lactams are prepared by the reaction of a glycine alkyl ester and an imine, in the presence of an alkali metal base and a metal compound catalyst.

Description: The present invention relates to a process for the preparation of trans-β-lactams by reacting an N,N-diprotected glycine ester with an imine in the presence of a metal compound. Considerable research effort has been, and continues to be expended on the development of new synthetic methods for the production of both new and known antibiotics. The azetidinones or β-lactams have received the most attention in recent years since they are generally well tolerated by humans. The determination of their mode of action on a molecular scale, i.e. their ability to inhibit the synthesis of bacterial cell walls, has further served to stimulate and focus the interest of investigators searching for new synthetic schemes. In the European patent application EP-A-0281177 a route was described to synthesize 1,3,4-trisubstituted trans-2-azetidinones in which the atom linked to the C-3 carbon atom is nitrogen, as follows: a process was provided for the preparation of trans-β-lactams of formula I' wherein R₂ and R₃ are each hydrogen, alkyl, aryl, aralkyl, each optionally substituted with alkyl, aryl or aralkyl, or are where R₆, R₇ and R₈ are each alkyl, aryl, aralkyl, each optionally substituted and R₆, R₇ and R₈ are the same or different, and R₂ and R₃ are the same or different and R₂ and R₃ are not both methyl or benzyl, or R₂ and R₃ together with the nitrogen atom to which they are attached form a ring with up to 8 ring atoms, each optionally substituted with alkyl, aryl or aralkyl, R₁ is hydrogen, halogen, alkyl, alkenyl, alkoxy, aryl or aralkyl, or is where R₉, R₁₀ and R₁₁ are each alkyl, aryl, aralkyl, each optionally substituted, and R₉, R₁₀ and R₁₁ are the same or different, R₄ is alkyl, hydroxy, halogen, sulfonyl, alkoxy, alkenyl, alkynyl or aryl, each optionally substituted, or is where R₅ is alkyl, by a condensation reaction of a metal enolate wherein R₁₂ is alkyl, aryl or aralkyl, each optionally substituted with alkyl, aryl or aralkyl, M is zinc, aluminum, zirconium, boron, tin or titanium, P is alkali metal, W, X, Y and Z are alkyl, aryl, halide, alkoxide, thiolate, triflate or any other substituted sulfonate or any other suitable anionic group, and W, X, Y and Z are the same or different, and a, b, c and m = 0-1, n = 1-6, all being integers, R₂' and R₃' is R₂ and R₃ respectively, with the proviso that when R₂ and R₃ are hydrogen, R₂' and R₃' form together with the nitrogen atom to which they are attached a ring of formula III' wherein R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are each alkyl, aryl, aralkyl and R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are the same or different, with an imine of formula IV' where R₄ is as defined above, and R₁' is R₁ with the proviso that when R₁ is hydrogen, R₁' is where R₆, R₇ and R₈ are defined as above which group is hydrolysed after the reaction by acid or base, and with the proviso that when R₂ and R₃ are both hydrogen, the ring of formula III' is converted into NH₂ by acid or base catalysed hydrolysis, after the reaction. To carry out this process as a one-pot process starting from an R₂'R₃'N-glycine ester (V'), an imine (IV'), an alkali metal base (VI') and a metal compound (VII') was also disclosed in EP-A-0281177. Both the reaction starting from the metal enolate (II') and the one starting from the R₂'R₃'N-glycine ester (V') and the metal compound (VII') have been displayed in the following scheme (with all variable substituents as defined above): The supposed intermediates VIII' and IX' have not been isolated. Summarizing: besides this above-mentioned one-pot process, EP-A-0281177 discloses the two-step process comprising the isolation of the intermediate zinc enolate (II') and the reaction of this intermediate with an imine (IV') which results in the formation of trans-β-lactams compounds of formula I'. Therefore equimolar amounts of the metal compound MW(X) a (Y) b (Z) c compared to the other starting materials were used. Also in the non-prepublished European patent application No. 89201666.8 wherein similar reactions yielding enantioselective compounds have been disclosed, equimolar amounts of the metal compound MW(X) a (Y) b (Z) c compared to the starting materials were used. It has now surprisingly been found that also β-lactams are formed in substantially similar yields if these reactions are carried out in the presence of lower amounts of the suitable metal compound MW(X) a (Y) b (Z) c . Therefore, according to the invention a process is provided for the preparation of a trans-β-lactam compound of formula I, wherein R₂ and R₃ are each hydrogen, (1-8C)alkyl, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, each optionally substituted with (1-8C)alkyl, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, or are where R₆, R₇ and R₈ are each (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, each optionally substituted and R₆, R₇ and R₈ are the same or different, and R₂ and R₃ are the same or different, or R₂ and R₃ together with the nitrogen atom to which they are attached form a ring with up to 8 ring atoms, each optionally substituted with (1-8C)alkyl, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, R₁ is hydrogen, halogen, (1-8C)alkyl, (2-8C)alkenyl, (1-8C)alkoxy, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, or is where R₉, R₁₀ and R₁₁ are each (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, each optionally substituted, and R₉, R₁₀ and R₁₁ are the same or different, or is where R₂₁, R₂₂ and R₂₃ are each hydrogen, (1-8C)alkyl, (1-8C)alkoxy, (1-18C)aryl, (1-18C)aryloxy, (1-8C)-alkyl(1-18C)aryl, (1-18C)(1-8C)aralkoxy or heterocyclic, each optionally substituted, and R₂₁, R₂₂ and R₂₃ are the same or different, R₄ is (1-8C)alkyl, hydroxy, halogen, sulphonyl, (1-8C)alkoxy, (2-8C)alkenyl, (2-8C)alkynyl or (1-18C)aryl, each optionally substituted, or is where R₅ is (1-8C)alkyl, or R₄ is where R₅ is (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, or a heterocyclic group, each optionally substituted, or R₅ is where R₂₄, R₂₅ and R₂₆ are each hydrogen, (1-8C)alkyl, (1-8C)alkoxy, (1-18C)aryl, (1-18C)aryloxy, (1-8C)alkyl(1-18C)aryl, (1-18C)(1-8C)aralkoxy or heterocyclic, each optionally substituted, and R₂₄, R₂₅ and R₂₆ are the same or different, or R₄ is a heterocyclic group, optionally substituted, by reacting a R₂'R₃'N-glycine ester of formula wherein R₁₂ is (1-8C)alkyl, (1-8C)cycloalkyl(1-18C)aryl or (1-8C)alkyl(1-18C)aryl, each optionally substituted with (1-8C)alkyl, (1-8C)cycloalkyl(1-18C)aryl or (1-8C)alkyl(1-18C)aryl, R₂' and R₃' is R₂ and R₃ respectively, with the proviso that when R₂ and R₃ are hydrogen, R₂' and R₃' form together with the nitrogen atom to which they are attached a ring of formula III wherein R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are each (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, and R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are the same or different, with an imine of formula IV, where R₄' is R₄, with the proviso that when R₄ is which group is hydrolysed by acid after the reaction, and R₁' is R₁ with the proviso that when R₁ is hydrogen R₁' is where R₉, R₁₀ and R₁₁ are defined as above, which group is hydrolysed by acid or base after the reaction, where R₁, R₄ and R₅ are defined as for figure I, and with the proviso that when R₂ and R₃ are both hydrogen, the ring of formula III is converted into NH₂ by acid or base catalysed hydrolysis, in the presence of an alkali metal base and a metal compound of the formula MW(X) a (Y) b (Z) c , wherein M is zinc, aluminum, zirconium, boron, tin or titanium, X, Y and Z are (1-8C)alkyl, (1-18C)aryl, halide, alkoxide, thiolate, triflate or any other substituted sulfonate or any other suitable anionic group, W is halide, thiolate, triflate or any other substituted sulfonate or any other suitable anionic group, and X, Y and Z are the same or different, and a, b and c = 0-1, with the proviso that one of a, b or c is 1, all being integers, characterized in that the reaction is carried out in the presence of an amount of MW(X) a (Y) b (Z) c which is lower than equimolar compared to the R₂'R₃'N-glycine ester. The reactions are preferably carried out in inert, weakly polar solvents as for instance diethyl ether or tetrahydrofuran. M in the metal compound MW(X) a (Y) b (Z) c is preferably zinc; as metal compound preferably ZnCl₂ is used. The values of a, b and c depend on the valency of M. Advantageously, the compound ZnW(X) a (Y) b (Z) c is used in an amount of 0.1 to 0.5 equivalent compared to that of the R₂'R₃'N-glycine ester, preferably in an amount of 0.2 to 0.3 equivalent. By the term "optionally substituted" unsubstituted or substituted with one or more groups "generally present in organic compounds" is meant, such as (1-8C)alkyl, particularly methyl, ethyl, propyl or butyl; (1 18C)aryl, particularly phenyl or naphthyl; (1-8C)alkyl(1-18C)aryl, particularly benzyl or xylyl; (1-8C)alkoxy, particularly methoxy, ethoxy, propoxy or butoxy; (1-18C)aryloxy, particularly phenoxy or naphthoxy; (1-18C)(1-8C)aralkoxy, particularly benzyloxy or xylyloxy; heterocyclic, particularly pyridyl, furyl or thienyl; halogen, nitro, protected hydroxy or cyano. With a heterocyclic group a 5 or 6 membered heterocyclic group is meant, particularly comprising a nitrogen, oxygen or sulfur atom. A suitable anionic group comprises all anionic groups appropriate to form as ligand a complex with zinc, aluminum, zirconium, boron, tin or titanium, as indicated in formula II, or to form a salt with an alkali metal, such as halide, thiolate, triflate etc. When an amount of metal compound lower than equimolar compared to the other starting materials is used, not only the yields are generally maintained on the same, nearly quantitative level, but the stereoselectivity, in favour of the trans compound, is even enhanced. Apparently, the metal compound behaves as a catalyst resulting in a good yield and even a better stereoselectivity than when the reaction is carried out with a stoichiometric amount of metal compound as described in EP-A-0281177. Another advantage is the use of less metal compound MW(X) a (Y) b (Z) c compared to the amount needed in the above-mentioned applications. It is very important that the metal compounds (with the formula MW(X) a (Y) b (Z) c ) used in these reactions essentially are free of water. When small amounts of water are present, lower yields may be obtained and the stereoselectivity decreases. The following non-limitative examples illustrate the invention. General procedure All reactions were carried out in an atmosphere of dry nitrogen using standard Schlenk-techniques ("Manipulations of air-sensitive compounds", D.F. Shriver, editor Mc. Graw Hill, New York, 1969). Solvents were distilled from sodium prior to use. 2,2,5,5-tetramethyl-1-aza-2,5-disilylacyclopentane-1-acetic acid ethyl ester was prepared according to the method described in Tetrahedron Lett., 22 , 1787 (1981). Solutions of n-butyllithium in n-hexane and diethyl-zinc in n-hexane were obtained commercially. It is very important to use a dry metal compound to prepare the metal enolates. Therefore for instance zinc dichloride was either prepared from zinc and dry hydrogen chloride in diethyl ether or commercially available zinc dichloride was dehydrated in refluxing thionyl chloride. Example I Preparation of 1-methyl-3-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentyl)-4-phenyl-2-azetidinone employing various amounts of zinc dichloride. 10 mmoles of n-butyllithium (6.67 ml of a 1.5 molar solution in hexane) was added to a stirred solution containing diisopropylamine (1.40 ml; 10 mmoles) and 25 ml of diethyl ether at -70°C. This reaction mixture was stirred for 10 min and then 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-acetic acid ethylester (2.45 g; 10 mmoles) was added. The solution was stirred for another 15 min at -70°C and then 2.5 mmoles of zinc dichloride (2.5 ml of a 1.0 molar solution in diethyl ether) was added. After stirring for another 15 min at -70°C 10 mmoles of N-(benzylidene)methylamine (1.19 g) was added. After 5 min at -70°C the reaction mixture was slowly warmed to room temperature and stirred for another 8 hours, whereafter it was quenched with 20 ml of a saturated aqueous ammonium chloride solution. The water layer was extracted with diethyl ether. The diethyl ether extract was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3.19 g (100%) of the pure 2-azetidinone product as a pale yellow solid. The ¹H NMR spectrum revealed that the product was a mixture of cis- and trans-isomers (cis/trans ratio 2:98). The results of experiments using other amounts of zinc dichloride are given in Table I. Example II Preparation of 1-benzyl-3-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentyl)-4-methyl-2-azetidinone employing a catalytic amount of zinc dichloride. 10 mmoles of n-butyllithium (6.67 ml of a 1.5 molar solution in hexane) was added to a stirred solution containing diisopropylamine (1.40 ml; 10 mmoles) and 25 ml of diethyl ether at -70°C. This reaction mixture was stirred for 10 min and then 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-acetic acid ethylester (2.45 g; 10 mmoles) was added. The solution was stirred for another 15 min at -70°C and then 2.5 mmoles of zinc dichloride (2.5 ml of a 1.0 molar solution in diethyl ether) was added. After stirring for another 15 min at -70°C 10 mmoles of N-(ethylidene)benzylamine (1.33 g) was added. After 5 min at -70°C the reaction mixture was slowly warmed to room temperature and stirred for another 8 hours, whereafter it was quenched with 20 ml of a saturated aqueous ammonium chloride solution. The water layer was extracted with diethyl ether. The diethyl ether extract was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3.00 g (90%) of the 2-azetidinone product as a pale yellow oil. The ¹H NMR spectrum revealed that the product was exclusively the trans-isomer. Example III Preparation of 1-methyl-3-(diethylamino)-4-phenyl-2-azetidinone employing a catalytic amount of zinc dichloride. 10 mmoles of n-butyllithium (6.67 ml of a 1.5 molar solution in hexane) was added to a stirred solution containing diisopropylamine (1.40 ml; 10 mmoles) and 30 ml of tetrahydrofuran at room temperature. This solution was stirred for 10 min and then N,N-diethylglycine ethylester (1.59 g; 10 mmoles) was added, which resulted in a pale yellow suspension. After stirring for another 15 min 2.5 mmoles of zinc dichloride (2.5 ml of a 1.0 molar solution in diethyl ether) were added, which resulted in a clear yellow solution. This solution was stirred for 30 min, whereafter some material (LiCl) precipitated. Then 10 mmoles of N-(benzylidene)methylamine (1.19 g) were added and the mixture was refluxed for 16 hours, whereafter it was quenched with 20 ml of a saturated aqueous ammonium chloride solution. The water layer was extracted with diethyl ether. The combined extracts were dried with sodium sulfate and concentrated in vacuo to give 2.09 g (90%) of the 2-azetidinone product as a yellow solid. The ¹H NMR spectrum revealed that the product was a mixture of cis- and trans-isomers (cis/trans ratio 27:73). Employing one equivalent of zinc dichloride in tetrahydrofuran a cis/trans ratio of 58:42 was found; yield 90%. Example IV Preparation of trans-1-t-butyl-3-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentyl)-4-N-t-butylimino-2-azetidinone 10 mmoles of n-butyllithium (6.67 ml of a 1.5 molar solution in hexane) was added to a stirred solution containing diisopropylamine (1.40 ml; 10 mmoles) and 25 ml of diethyl ether at -70°C. This reaction mixture was stirred for 10 min and then 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-acetic acid ethylester (2.45 g; 10 mmoles) was added. The solution was stirred for another 15 min at -70°C and then 2.5 mmoles of zinc dichloride (2.5 ml of a 1.0 molar solution in diethylether) was added. After 5 min at -70°C, a white solid (LiCl) began to precipitate. Then bis-t-butyl-1,4-diaza-1,3-butadiene (1.68 g; 10 mmoles) was added. The reaction mixture was stirred for another 15 min at -70°C and, after being warmed to room temperature, quenched with 20 ml of a saturated aqueous ammonium chloride solution. The water layer was extracted with diethyl ether. The diethyl ether extract was washed with water, dried with sodium sulfate and concentrated in vacuo to give 2.87 g (78%) of the pure 2-azetidinone product as a pale yellow solid. Following the same procedure and using the same reaction conditions as used above, one more 3-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentyl) trans-β-lactam was obtained, see Table II. The ¹H NMR and ¹³C NMR spectra revealed that substantially only the respective trans-compounds were formed. yield cis trans R₁ = t-butyl R₄ = (t-butyl)imino 78% 0% 100% R₁ = t-butyl R₄ = 2-pyridyl 97% 0% 100%

Claims: A process for the preparation of a trans-β-lactam compound of formula I, wherein R₂ and R₃ are each hydrogen, (1-8C)alkyl, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, each optionally substituted with (1-8C)alkyl, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, or are where R₆, R₇ and R₅ are each (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, each optionally substituted and R₆, R₇ and R₈ are the same or different, and R₂ and R₃ are the same or different, or R₂ and R₃ together with the nitrogen atom to which they are attached form a ring with up to 8 ring atoms, each optionally substituted with (1-8C)alkyl, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, R₁ is hydrogen, halogen, (1-8C)alkyl, (2-8C)alkenyl, (1-8C)alkoxy, (1-18C)aryl or (1-8C)alkyl(1-18C)aryl, or is where R₉, R₁₀ and R₁₁ are each (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, each optionally substituted, and R₉, R₁₀ and R₁₁ are the same or different, or is where R₂₁, R₂₂ and R₂₃ are each hydrogen, (1-8C)alkyl, (1-8C)alkoxy, (1-18C)aryl, (1-18C)aryloxy, (1-8C)alkyl(1-18C)aryl, (1-18C)(1-8C)aralkoxy or heterocyclic, each optionally substituted, and R₂₁, R₂₂ and R₂₃ are the same or different, R₄ is (1-8C)alkyl, hydroxy, halogen, sulphonyl, (1-8C)alkoxy, (2-8C)alkenyl, (2-8C)alkynyl or (1-18C)aryl, each optionally substituted, or is where R₅ is (1-8C)alkyl, or R₄ is where R₅ is (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, or a heterocyclic group, each optionally substituted, or R₅ is where R₂₄, R₂₅ and R₂₆ are each hydrogen, (1-8C)alkyl, (1-8C)alkoxy, (1-18C)aryl, (1-18C)aryloxy, (1-8C)alkyl(1-18C)aryl, (1-18C)(1-8C)aralkoxy or heterocyclic, each optionally substituted, and R₂₄, R₂₅ and R₂₆ are the same or different, or R₄ is a heterocyclic group, optionally substituted, by reacting a R₂'R₃'N-glycine ester of formula wherein R₁₂ is (1-8C)alkyl, (1-8C)cycloalkyl(1-18C)aryl or (1-8C)alkyl(1-18C)aryl, each optionally substituted with (1-8C)alkyl, (1-8C)cycloalkyl(1-18C)aryl or (1-8C)alkyl(1-18C)aryl, R₂' and R₃' is R₂ and R₃ respectively, with the proviso that when R₂ and R₃ are hydrogen, R₂' and R₃' form together with the nitrogen atom to which they are attached a ring of formula III wherein R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are each (1-8C)alkyl, (1-18C)aryl, (1-8C)alkyl(1-18C)aryl, and R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are the same or different, with an imine of formula IV, where R₄' is R₄, with the proviso that when R₄ is which group is hydrolysed by acid after the reaction, and R₁' is R₁ with the proviso that when R₁ is hydrogen R₁' is where R₉, R₁₀ and R₁₁ are defined as above, which group is hydrolysed by acid or base after the reaction, where R₁, R₄ and R₅ are defined as for figure I, and with the proviso that when R₂ and R₃ are both hydrogen, the ring of formula III is converted into NH₂ by acid or base catalysed hydrolysis, in the presence of an alkali metal base and a metal compound of the formula MW(X) a (Y) b (Z) c , wherein M is zinc, aluminum, zirconium, boron, tin or titanium, X, Y and Z are (1-8C)alkyl, (1-18C)aryl, halide, alkoxide, thiolate, triflate or any other substituted sulfonate or any other suitable anionic group, W is halide, thiolate, triflate or any other substituted sulfonate or any other suitable anionic group, and X, Y and Z are the same or different, and a, b and c = 0-1, with the proviso that one of a, b or c is 1, all being integers, characterized in that the reaction is carried out in the presence of an amount of MW(X) a (Y) b (Z) c which is lower than equimolar compared to the R₂'R₃'N-glycine ester. A process according to claim 1, characterized by the preparation of a trans-β-lactam of formula I, as depicted in claim 1, wherein R₂ and R₃ together with the nitrogen atom to which they are attached form 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentyl or R₂ and R₃ are hydrogen, and R₁ is methyl and R₄ is phenyl or R₁ is benzyl and R₄ is methyl or R₁ is butyl and R₄ is N-t-butylimino or R₁ is butyl and R₄ is 2-pyridyl, R₂ is ethyl, R₃ is ethyl and R₁ is methyl, R₄ is phenyl. A process according to claim 1 or 2, characterized in that the reaction is carried out in an inert, weakly polar solvent. A process according to claim 3, characterized in that the reaction is carried out in diethyl ether or tetrahydrofuran. A process according to any one of the claims 1-4, characterized in that in the formula MW(X) a (Y) b (Z) c M is zinc. A process according to claim 5, characterized in that ZnW(X) a (Y) b (Z) c is ZnCl₂. A process according to claim 5 or 6, characterized in that ZnW(X) a (Y) b (Z) c is used in an amount of 0.1 to 0.5 equivalent compared to the amount of the R₂'R₃'N-glycine ester, where W, X, Y, Z, a, b, c, R₂' and R₃' are as defined in claim 1. A process according to claim 7, characterized in that ZnW(X) a (Y) b (Z) c is used in an amount of 0.2 to 0.3 equivalent compared to the amount of the R₂'R₃'N-glycine ester.

Inventors: JASTRZEBSKI, JOHAN TOENS BARTHOLD HEINRICH, VAN DER STEEN, FREDERIK HENDRIK, VAN KOTEN, GERARD, Jastrzebski, Johan Töns Barthold Heinrich
Applicants: RIJKSUNIVERSITEIT UTRECHT
Application year: 1989
Main classification: C07F7
IPC codes: C07D205, C07B61, C07F7, B01J27