IE49408B1 - Azetidinone derivatives - Google Patents

Description

The invention relates to azetidinone derivatives and to 5 processes for their preparation.

The invention provides azetidinone derivatives of the general formula I wherein n is 0 or 1, Ph represents a phenyl croup, R represents a hydrogen atom, an alkyl group having from 1 to carbon atoms, a 2,2,2-trichloroethyl, benzyl, acetonyl, t £.nitrobenzyl, £.methoxybenzyl, phenyl, p.nitrophenyl, ber.zhycrvl, acetoxymethyl, pivaloyloxymethyl or phthalidyl oroup cr a croup of the formula -CH(CH,).OCOOC,H. or J Z 5 -CH^NHCORj wherein Rj represents an alkyl croup having from. to i carbon atoms or a cycloalkyl or aryl group; X represents a group cf the formula CHgZ or CKj^' wherein Z represents a hydroxy, amino or carbamoyloxy croup, or a group of the formula OR^ or OCOR^ wherein represents an alkyl group having from 1 to 4 csrfcff, atoms and 2' represents a mercapto or pyricinium croup or a croup of the formula wherein represents an alkyl croup having - 3 from 1 to 4 carbon atoms or a 5-methyl-l,3,4-thiadiezol-2-yl, l-methyl-lh-tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl group; Y represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a cyano or alkoxycarbonyl group or a group of the formula CH^Z in which Z is as above defined; and R' represents · an alkyl, alkoxy, or hydroxyalkyl group, each of which has from 1 to 4 carbon atoms, the alcoholic function of the hydroxyalkyl group being free or protected by a p-nitrobenzyloxycarbonyl croup. The 3-substituent may have the a- or g-configuration. 3a-substitution is preferred.

Preferred groups which R‘ may represent are methyl, ethyl, methoxy, 1-hydroxy-ethyl and 1-(p. nitrohenzyl oxy carbcny loxy) -ethyl groups.

The azetidinone derivatives according to the invention are useful as intermediates in the preparation of certain penem-carboxylic acids and esters wh h have a wide spectrum of antibacterial activity as well as β-lactamase inhibiting activity (see specification of Irish Application No. 338/80, from which this Application is divided). It should be pointed out that the stereochemistry et of tr.e compounds according to the invention, as well as that of all the intermediates of their preparation, is the same as in naturally occurring penicillins and cepholosporins. 494-08 - 4 The invention further provides a process for the preparation of compounds of the general formula I in which n, R' and R, Y and Ph are as above defined and X represents a group of the formula CHjZ in which Z is as above defined. Such compounds of the general formula I are hereinafter referred to as compounds of the formula (9). The process is illustrated by the following reaction scheme, in which R', R, Y, Ph, Z and n are as above defined and R represents an alkyl group. 4-94-08 (2) COOR l.5) (0) (9) The process comprises condensing, in an inert solvent at elevated temperature, a penicillanic acid Sroxide ester of the general formula (2) with an acetylenic compound of the general formula ZCHjCzCY, iaomerising the resultant compound of the general formula (3), preferably in basic conditions, and converting the resultant * azetidinone derivative of the general formula (4) into one of the general formula (9J by the Steps pf (a) ozonolysis of the 1-substftuent of the formula CH. (b) COOR in solution at removal of the reduced temperature, 1-substituent of the formula v° COOR resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO.COOR by refluxing in a solvent, (d) chlorination of the 1-substituent of the formula introduced in step (c) by the action of a chlorinating agent, and (e) conversion of the 1-substituent of the formula COOR Introduced In step (d) into one of the formula COOR by reaction with triphenylphosphine, the steps (a) to (e) being carried out in the order given, and the optional step of (f) reduction of the 4β-(substituted vinylsulphinyl) group by the action of a reducing agent the step (f) being carried out (if at all) immediately after step (a) or step (e), and if carried out after step (e) then being carried out in acidic conditions.

The reaction sequence (a) , (b), (c), (d), (e,, (f) is possible when Y is not a strong electron withdrawing group. Then the compound (6, n=l) is surprisingly stable.

The optional reduction step (f) may be carried out using phosphorus tribro.mide or sodium iodide in acetyl chloride as reducing agent.

When R' represents a hydroxyalkyl group in the desired compound of the general formula 1, the reaction sequence is preferably carried out with the alcoholic function protected. 9 4 0 8 - 8 Compounds of the general formula I in which P. represents a hydrogen atom can be obtained by hydrolysis or hydrogenolylis of corresponding esterified compounds.

The preparation of compounds of the general formula I in whichn, R', R”, y and Ph are as herein defined and X represents a group of the formula CHgZ1 in which Z' is as above defined is carried out according to the above process with the additional step of converting the substituent Z into a substituent of Z'. The additional §tep may be carried out at any stage in the above process after the condensation of the penicillanic acid S-oxide ester (2) with the acetylenic compound ZCHgC=CY, and is necessary because of the difficulty of condensing the penicillanic acid S-oxide ester (2) directly with an acetylenic compound HSCHg-CeCY, R^CH CgCi or PyCH2~C=CY in which Py represents a pyridinium ion. This process is also within the scope of the invention.

The starting materials of the general formula (2) in which R' represents a hydrogen atom may be prepared from (5R)-620 -aminopenicillanic acid following known procedures (see CIGNARELLA et al., Journal of Organic chemihtry, 27, 2668 and EVRARD et al., Nature, 201, 1124).

When R' represents an alkyl or hydroxyalkyl group, it can be introduced according to the procedure of Di Ninno et al., Journal of Organic Chemistry 42 , 2960 (1977). When R' <*9408 represents an alkoxy group, it may be introduced according to the procedures of Hauser et al., Helv. Chem. Acta, 50, 1327 (19671 and Giddings et al., Tetrahedron Letters, 11,995, (1978). Alternatively compounds of general formula (2) in which R' represents a hydrogen atom can be converted to compounds of the general formula (2) in which R' represents an alkyl or hydroxyalkyl group by introducing the substituent into the 6-position using a strong base, as illustrated in the following Examples.

Compounds of the general formula (2) in which R' represents an alkyl or hydroxyalkyl group can also be prepared starting from a suitable, es'ter of penicillanic acid S-oxide, as illustrated in the following Examples. The substitution at the 3-position is stereospecifically directed to the 3a-derivatives. 8 - 10 The following Examples illustrate the invention.

EXAMPLE 1 methyl 6-(1-hydroxyethyl)-3-peni cillanate To a solution of 2.2 g of methyl pencillanate in 30 ml of anhydrous tetrahydrofuran, a slight excess of lithium diisopropylamide was added at -78°C under nitrogen. An excess of acetaldehyde was dropped in and the mixture was stirred for 5 minutes, he reaction was then quenched with a trace of acetic acid; the mixture was poured into water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulphate and evaporated in vacuo to give 0.8 g of the title compound., EXAMPLE 2 methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-penicillante. 1.2 g of methyl G-(l-hydroxyethyl)-3-penicillanate, prepared as described in Example 1 , were dissolved in ml of tetrahydrofuran cooled to -7S°C and treated with one equivalent of butyl lithium. 1.2 equivalents of p-nitrobenzyloxycarbony1 chloride were added to the mixture. After 30 minutes at -78OC, the reaction mixture was left at room temperature for 60 minutes, pourec into water and extracted with dichloromethane. 1.4 g of the title compound were obtained after drying over anhydrous sodium sulphate and evaporating off the solvent. - 11 EXAMPLE 3 methyl 6-(l-p-nitrobenzyloxycarbonyloxyethyl-3-penicillanate-S-oxide (2) : R=CH3, R'=CH3CH.O.LoCH2 NC>2 1.8 g of methyl 6-/l-p-nitrobenzyloxycarbonyloxyethyl/-3-penicillante, prepared as described in Example 2, were dissolved in 50 ml of dichloromethane and treated at O°C with 1.5 equivalents of m-chloroperbenzoic acid. The organic phase was shaken with a saturated solution of sodium bicarbonate, extracted, dried over anhydrous sodium sulphate and evaporated: 1.4 g of the expected sulphoxide were obtained.

EXAMPLE 4 46-(l-acetoxymethyl-3-acetoxy-l-propenylsulphinyl)-315 -(1-p-nitrobenzyloxycarbonyloxyethyl)-l-(l-methoxycarbor.y 1-2-methyl-allyl) -a2etidin-2-one (3) :R=CH3, R'=CH3CH.O.C.OCH2 (ol N02> Y=CH2O.CO.CH3, Z=OCOCH3 A solution of 2.0 g of the compound prepared in Example and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatography eluting with 9:1 by volume dichloromethane:ethyl acetate. 1.1 g of the title compound were obtained. 408 - 12 EXAMPLE 5 4B-(l-acetoxymethyl-3-acetoxy-l-propenylsulphinyl)-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonvl-2-methyl-1-proper.yl) -azetidin-2-one ’ r\ (4) : R=CH3, R’=CH3CH,O.C.OCH2 (oj NOj,Y=CH2O.CO.CH3, Z=OOOCH3 1.3 g of the compound prepared in Example 4 were dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine were added and the mixture was left at room temperature for 2 hours. The title compound was obtained in pure form in quantitative yield by evaporating off the solvent.

EXAMPLE 6 48-(l-acetoxymethyl-3-acetoxy-l-propenylsulphinyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-methoxyoxalyl-azetidin-2-one O ' 11 ΛΛ (5) : R=CH3, R'=CH3CH.0.C.0CH2/o\N02, Y=CH2O.CO.CH3, Z=OOOCH3, n=l A solution of 1.1 g of the compound prepared in Example 5 in 100 ml of dichloromethane was cooled to -78°C.

Ozone in oxygen was then bubbled through the solution until a blue colour appeard. The solution was shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate. 0.5 g of the title compound were obtained after evaporation off of the solvent. - 13 ~ EXAMPLE 7 4S-(1-acetoxymethyl-3-acetoxy-l-propenvlthio)-3-(1-p-nitrobenzyloxycarbonyloxyefhyl)-l-ffiethoxyaxalyl-azetidin-2-one.

I (5): R=CH3, R'=CH3CH.O.C.OCH2 /o\N02, Y=CH2O.CO.CH3, Z=OCOCH3< n=0 A solution of 0.8 g of the compound prepared in Example 6 in 15 ml of anhydrous dimethylformamide was cooled to -20°C and 0.6 ml of phosphorus tribromide were added.

The reaction mixture was diluted with ethyl acetate after 10 minutes and washed twice with a solution of sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate and the solvent was then evaporated off giving 0.4 g of the title compound.

EXAMPLE 8 48-(l-acetoxvmethvl-3-acetoxy-l-propenylthio)-3-(l-p-nitrobenzvloxycarbonyloxyethyl)-azetidin-2-one 11 (6): R’=CH3CH .O.C.OCH2 (o>NO2, Y=CH2O.CO.CH3, ZOCOCHj, n=0 1.2 g of the compound prepared in Example 7 were dissolved in methanol and 2 g of silica gel were added to the solution. After 60 minutes the insoluble matter was filtered off and the organic phase was evaporated: a short column chromatography afforded 0.4 g of the title compound. - 14 EXAMPLE 9 4E-(1-acetoxymethyl-3-acetoxy-1-progeny1thio)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-acetoxymethoxycarbonyl-l-hydroxymethyl)-azetidin-2-one. (7) : R'=CH3CH.O.C.OCH2 Zo\N02, R=Y=CH2O.CO.CH3, Z=OOOCH3< n=0 0.6 g of the compound prepared in Example 8, dissolved in 30 ml of benzene, and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate), were refluxed together. The reaction was completed after two hours. The condensation product can be used for the next step without further purification.

EXAMPLE 10 4g-(l-acetoxymefhyl-3-acetoxy-l-propenylthio)-3-(1-p-nitrobenzvloxycarbonyloxyethyl) -1-(1-acetoxymethoxv carbony1-1-chloromethyl)-azetjdin-2-one.

II /-Λ (8) : R'=CH3CH.O.C.OCH2/o\N02, R=Y=CH2O.CO.CH3, Z=OCOCH3, n=0 0.5 g of the compound prepared in Example 9 were dissolved in 12 ml of anhydrous tetrahydrofuran and cooled to 0°C. 1.1 Equivalents of pyridine and 1.1 equivalents of thionyl chloride were added and the mixture was left under stirring for 10 minutes. The insoluble matter was filtered off and the solvent was evaporated off at room temperature to give the title compound in nearly quantitative yield. The product can - 15 be used without further purification for the next step.

EXAMPLE 11 46-(l-acetoxymefhyl-3-acetoxy-l-propenylthio)-3-(1-p-nitrobenzvloxycarbonyloxyethyl)-1-(acetoxytnethoxy5 carbonyl-1-triphenylphosphoranvlidenemethyl)-azetidin-2one (9): R'=CH3CH.O.C.OCH2 ^o^N02, Ru=Y=^2O.CO.CH3,Z=OCCCK3,n=0 A solution of 0.760 g of the compound prepared in Example 10 in 10 ml of tetrahydrofuran and 10 ml of dioxan was stirred overnight at 50°C with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine. The phosphorane was purified by silica gel column chromatography, eluting with 70:30 by volume dichloromethane: ethyl acetate. 0.480 g of the title compound were obtained.

Claims (7)

1. An azetidinone derivative having the general formula I as herein defined.

2. . 4g-(l-acetoxymethyl-3-acetoxy-l-propenylthio)5 -3-(l-£.nitrobenzyloxvcarbonyloxyethyl)-1-(acetoxymethoxy-carbonyl-l-triphenylphosphoranyli-denemethyl)-azdetidin-2-one.

3. . A process for the preparation of an azetidinone derivative having the general formula I wherein 0 R,R, Y, and Ph and n are as herein defined and X represents a group of the formula CHjZ wherein Z is as herein defined, the process comprising condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) as herein defined with an acetylenic compound of the general formula ZCHg C===CY wherein Y and Z are as herein defined, - 17 isomerising the resultant compound of the general formula (3) as herein defined and converting the resultant azetidinone derivative of the general formula (

4. ) as herein defined into one of the general 5 formula 6) as herein defined by the steps of (a) ozonolysis of the 1-substituent of the formula in solution at reduced temperature, (b) removal of the 1-substituent of the 10 formula v° COOR resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO.COOR wherein R is as herein defined by refluxing in a solvent, 19 4 0 8 - 18 (d) chlorination of the 1-substituent of the formula COOR introduced in step (c) by the action of a chlorinating agent, and (e) conversion of the l-substituent of the formula iiiuiuuuceu m step iaj into one of the formula r COOR' -PPh. by reaction with triphenylphosphine, the steps (a) to (e) being carried out in the order given, and the optional step of (f) reduction of the 4g-(substituted vinylsulphinyl) group Ly the action of a reducing agent, the step (f) being carried out (if at all) immediately after step (a) or step (e), and if carried out after step (e) then being carried out in acidic conditions. - 19 4. A process for the preparation of an azetidinone derivative having the general formula I wherein R,B, Y, Ph and n as herein defined and X represents a group of the formula CHjZ' wherein

5. Z' is as herein defined, the process being as defined in claim 3 with the additional step of converting the substitutent Z into a substitutent Z' as herein defined, the additional step being carried out at any stage in the process after

6. 10 the condensation of the pencillanic acid S-oxide ester with the acetylenic compound. 5. A process according to claim 3 or claim 4 in which the isomerisation is carried out in basic conditions .

7. 15 6 . A process according to claim 3, the process being substantially as described herein with reference to Examples 4 to 11.