MXPA98006936A - Process for the preparation of 2-halometil-penemsy its use for the preparation of penems antibacteria - Google Patents

Abstract

The present invention relates to: A process for the preparation of 2-halomethyl-penems (in particular 2-chloromethyl-penems) comprising, as an intermediate step, the formation of 2-haloacetylthio-azetidone corresponding to

Description

Process for the preparation of 2-halomethyl-penems and its use for the preparation of antibacterial penems.

Field of the Invention The present invention relates to a process for the preparation of 2-halomethyl-penems (in particular 2-chloromethyl-penems) useful for the preparation of antibacterial penems.

Background of the Invention It is known that the derivatives of penems are compounds endowed with a broad spectrum of activity against bacteria [see for example Wise R "the Carbapenem and Penem Antibiotics - A Brief Review" - Antimicrob. Newsl. 7. 73-80 (1990)]. It is also known that the 2-halomethyl-penems of the formula (I) (in particular 2-chloromethyl-penems) are useful intermediates for the preparation of antibacterial penems [G. Pentassuglia and collaborators J of Antibiotics Vol. 48, 399 - 407 (nineteen ninety five)]. The processes for the preparation of 2-halomethyl-penems (I) known hitherto [see for example Alta ura M. et al. J. Org. Chem.

REF. 28096 1993, 58, 272-274] comprises a step involving the corresponding 2-hydroxymethyl-penem (II): wherein Ri and R2 are as defined below in the present. The preparation of compound (II) requires a long series of complicated steps, giving low yields and involving the use of protective groups and expensive reagents, which are not suitable for industrial protection. In addition, the synthesis of (II) requires many chromatographic separations for the purification of the obtained compounds, since their use as raw products in the following acidic or basic reaction conditions, is not suitable due to their low stability.

Brief description of the invention The present invention relates to a process for the preparation of 2-halomethyl-penems (in particular 2-chloromethyl-penems) of the formula (I) wherein Ri is a protecting group for the alcoholic hydroxyl, R2 is a protective group for the carboxyl and X is a halogen, in particular chlorine, comprising, as an intermediate step, the formation of 2-haloacetylthio-azetidone.

Detailed description of the invention It was found now, and this is an objective of the present invention, a process that allows to obtain the 2-halomethyl-penems (I) (in particular 2-chloromethyl-penems) with only three steps using as a starting product a product that is easily commercially available. The synthesis route, described in the attached Scheme, allows obtaining the compounds of the formula (I) without requiring intermediary steps involving the protection and deprotection and the use, for the construction of the final product, of all the aggregated carbon atoms during the synthesis. In addition, the objective process of the present invention does not involve the complicated methods of separation or purification of the intermediates, and therefore allows the compounds of the formula (I) to be obtained in high yields. Furthermore, the reaction conditions make it possible to obtain the compounds (I) with high tereoselectivity, since during the process according to the invention only the desired optical isomer is formed. The 2-halomethyl-penems of the formula (I) can be directly transformed, after removing the protective groups, into the desired final products. As reported in the Scheme, the process according to the invention comprises the reaction between a compound of the formula (III), (3R, 4R) -4-acetoxy-3- [Ri 0 -ethyl] -2-azetidinone, wherein Ri is as defined above, and a 2-halothioacetic acid (IV) where X is a halogen, prepared, for example, as described in: Arndt, Bekir Berichte, 63B, 2390 (1930). The reaction is carried out in a non-protic organic solvent, preferably dioxane, tetrahydrofuran, chloroform at a temperature of -10 ° C to + 40 ° C, in the presence of an organic base, such as triethylamine or diisopropylethylamine, and an Lewis, such as zinc iodide, zinc bromide, zinc chloride, aluminum chloride. The 2-haloacetylthio azetidone (V) can be reacted, without further purification, with an oxalyl chloride ester (VI). Such a reaction is carried out in a non-protic organic solvent, preferably dioxane, tetrahydrofuran, toluene, chloroform, at a temperature of -60 ° C to + 20 ° C, preferably -20 ° C to + 10 ° C, in the presence of a base organic, such as triethylamine or diisopropylethylamine. The intermediate (VII), acylated on the β-lactam nitrogen, is cyclized in the corresponding 2-halomethyl-penem (I), under the action of an organic phosphite, such as triethyl phosphite or trimethyl phosphite, or phosphonite, such as dimethoxymethylphosphine , in an organic solvent, such as toluene, xylene, chloroform, methylene chloride, at a temperature of 20 ° C to 140 ° C, for a time of 1 to 120 hours.

The reaction mixture containing the 2-halomethyl-penem (I) can be used directly, without further purification, to obtain the desired penem derivatives (for example as described in US Pat. No. 4,794,109). In particular, the present invention relates to a process for the preparation of 2-chloromethyl-penems [compounds of the formula (I) wherein X = Cl, Ri and R2 are as defined above]. According to the invention, the group Rx, which protects the alcoholic hydroxyl group, is preferably a tri- (alkyl of 1 to 6 carbon atoms) -silyl (in particular tert-butyl-dimethyl-silyl and trimethylsilyl), allyloxycarbonyl, -nitrobenzyloxycarbonyl; while the group R2, which protects the carboxyl group, is preferably allyl, benzyl (possibly substituted with a methoxy or nitro group), CH2OCO (0) mR4 wherein R is an alkyl group of 1 to 6 carbon atoms and m is 0 or 1. The halogen according to the present invention is: chlorine, bromine, iodine, in particular chlorine. The following examples are reported to better illustrate the invention.

EXAMPLE 1 (35.4R) -3 - [(R)] tert-Butyldimethylsiloxy) ethyl] -4- (2-chloroacetylthio) -2-azetidone 83.3 g (0.261 mol) of zinc iodide are added at 20 ° C under nitrogen atmosphere in a solution of 50 g (0.174 mol) of (3R, 4R) -4-acetoxy-3- [(R) - terbutyldimethylsilyloxy) ethyl] -2-azetidone: after 15 minutes 38.3 g (0.346 moles) of 2-chloroacetic acid are added. The mixture is cooled to 12 ° C and after that, in 1 hour, a solution of 26.5 ml (0.190 mol) of triethylamine in dioxane (50 ml) is added. The mixture is stirred for 2 hours at the same temperature. 5.0 ml (0.036 mole) of triethylamine are added and the mixture is stirred for 30 minutes. The solution is drained in a cold 3% NaHS0 solution and extracted with ethyl acetate. The organic phase is washed with 3% NaHS03, 5% sodium hydrogen carbonate, water, 10% sodium chloride, and dried over anhydrous sodium sulfate. Upon evaporation of the solvent, in vacuo, a yellow-brown solid is obtained. Ethyl ether is added, the solvent is evaporated and a pale yellow solid is obtained. Yield 75 g (97%).

X H NMR (200 MHz) (CDC13): d 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.21 (3H, d, j = 6.3 Jz), 3.23 (1H, dd, J = 2.3, 4.0 Hz) 4.22 (2H, s) 4.27 (1H, qd, J = 3.7, 6.3 Hz), 5.32 (1H, d, J = 2.3 Hz), 6.4 (1H, s broad). 13 C NMR (50 MHz) (CDC13): d -4.3, -5.1, 17.9, 22. 3, 25.7, 48.0, 52.4, 64.6, 65.4, 166.1 194.8 Mass spectrum (MS) TS (m / z): (M + H) + 338, (M + NH4) * 355.

EXAMPLE 2 (3S, 4R) -1- (allyloxyoxalyl) -3- [(R) -ter-butyldimethylsilyloxy) -ethyl] -4- (2-chloroacetylthio) -2-azetidone To a solution of 57 g (0.169 moles) of (3S, 4R) -3- [(R) -ter-butyldimethylsilyloxy) ethyl] -4- (2-chloroacetylthio) -2-azetidone in anhydrous tetrahydrofuran (500 ml), 42.3 ml (0.338 mol) of aliloxyoxalyl chloride at 0 ° - 3 ° C, under nitrogen atmosphere. The mixture is stirred for a few minutes and then a solution of 43.4 ml (0.254 mol) of diisopropylethylamine in tetrahydrofuran is added. (40 ml), drop by drop, in 45 minutes. The mixture is stirred for 30 minutes at the same temperature, 15 ml (0.087 mol) of diisopropylethylamine are added, the solution is stirred 30 minutes and filtered. The filtrate is drained in a cold solution of 5% NaHC03 and extracted with n-hexane, washing with the same solvent the solid that remains on the filter. The organic phases are combined, washed with water and with 10% sodium chloride and dried over anhydrous sodium sulfate. Upon evaporation of the solvent, a brown oil is obtained which is used in the next step without further purification. Yield: 73.0 g (96%). 1U-NMR (200 MHz) (CDC13): d -0.04 (3H, s), -0.09 (3H, s), 0.85 (9H, s), 1.24 (3H, d, J = 6.3 Hz) 3.52 (1H, t , J = 3 Hz), 4.25 (2H, s), 4.38 (1H, qd, J = 3. 6.3 Hz), 4.70-4.82 (2H,), 5.22-5.46 (2H,), 5.80-6.06 (1H, m), 5.97 (1H, d, J = 3 Hz) 13C NMR (50 MHz) (CDCI3): d -5.2, -4.3, 17.8, 21.7 25.6, 47.9, 53.8, 64. 7, 66.3, 67.4, 120.1, 130.5, 154.5, 159.0, 162.9, 190.7. Mass spectrum (MS) TS (m / z): (M + NH4) + 467.

EXAMPLE 3 (5R, 6S) -2-chloromethyl-6- ((R) -1-tert-butyldimethylsilyloxy-ethyl) -penem-3-allylcarboxylate.

To a solution of 73 g (0.162 mol) of (3S, 4R) -1- (allyloxyoxalyl) -3- [(R) -tert-butyldimethyl-1-silyloxy) -ethyl] -4- (2-chloroacetylthio) - 2-azetidone in 730 ml of toluene, 59 g (0.356 mol) of triethyl phosphite are added. The solution is heated to reflux for 3 hours. The solution is cooled and concentrated in vacuo to give, after column chromatography (silica gel; cyclohexane / ethyl acetate 3: 1 v / v), (5R, 6S) -2-chloromethyl-6- ( (R) - 1-tert-Butyldimethylsilyloxy-ethyl) -penem-3-carboxylate of desired allyl, as a yellow oil. Performance 82%. High resolution liquid chromatography (HPLC: 1) column: Hypersil 5 ODS 5 mm C? 8, 4.6 x 250 mm; mobile phase: water / acetonitrile 20:80 v / v; flow = 1 ml / min., 1 = 220, 320 nm; tR = 8.4 min. 2), column: BondClone 10, 10 mm, C? 8, 3.9 x 300 mm, mobile phase: water / acetonitrile 20:80 v / v, flow = 1 ml / min., 1 -205, 245 nm); tR = 9.6 minutes. X H NMR (200 MHz) (CDC13): d 0.07 (6H, s), 0.87 (9H, s), 1.23 (3H, d, J = 6.2 Hz), 3.73 (1H, dd, J = 1.6, 4.3 Hz) , 4.60-4.81 (2h, m) 4.62 and 4.94 (2H, ABq, J = 14 Hz), 5.20-5.47 (2H, m), 5.63 / 1H, d, J = 1.6 Hz), . 81-6.03 (1H,), RNM 1JC (50 MHz) (CDC13): d -5.3, -4.7, 17.9, 22.3, 25.6, 37.6 (CH2-Cl), 62.4, 64.9, 65.9, 72.0, 118.6, 121.8, 131.2, 150.9 158.9, 172.3, Mass spectrum (MS) El: (m / z) 417 (M +).

EXAMPLE 4 To a solution of 19 g (0.056 moles) of (3S, 4R) -l- (allyloxyoxalyl) -3- [(R) -tert-butyldimethyl-silyl) ethyl) -4- (2-chloroacetylthio) -2 -zetidone in anhydrous toluene (150 ml), 14.1 ml (0.113 mole) of allyloxyoxalyl chloride are added under a nitrogen atmosphere at 0 ° -3 ° C. The solution is stirred for a few minutes and then a solution of 11. 7 ml (0.084 moles) of triethylamine in toluene (10 ml) dropwise. The solution is stirred for 90 minutes at the same temperature. 3.9 ml are added (0.028 moles) of triethylamine, the solution is stirred at 90 minutes and filtered. The filtrate is washed with a cold aqueous solution of 5% NaHCO 3, with water and with a 10% sodium chloride solution; after this the solution is dried over anhydrous sodium sulfate and filtered. 20.4 g (0.123 mol) of triethyl phosphite are added and the mixture is heated to reflux for 3 hours. The solution is cooled, concentrated in vacuo and purified by column chromatography (silica gel; cyclohexane / ethyl acetate 3: 1 v / v) to give (5R, 6S) -2-chloromethyl-6- ( (R) -1,5-tert-butyldimethylsilyoxy-ethyl) -penem-3-carboxylate of allyl, as a yellow oil. Performance: 71% COCÍ COOR2 (VI) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (8)

RE IVINDI CATIONS

1. A process for the preparation of 2-halomethyl-penems of the formula (I) (I) wherein Ri is a protective group for the alcoholic hydroxyl, R2 is a protective group for the carboxyl and X is a halogen, characterized in the process because it comprises, as an intermediate step, the formation of the corresponding 2-haloacetylthio-azet idone (V) (V) where X is halogen

2. The process according to claim 1, characterized in that: a) the compounds of the formula (III) (ip: • where Rx is as defined above, it is reacted with a 2-halothioacetic acid in an organic solvent, in the presence of an organic base and a Lewis acid, at a temperature of -10 ° C to 40 ° C, for giving the compounds of the formula (V) as defined in accordance with claim 1; b) the aforementioned compounds of the formula (V) are reacted by an ester of axalyl chloride in an organic solvent, in the presence of an organic base at a temperature of -60 ° C to + 20 ° C, preferably -20 ° C to + 10 ° C, to give the compounds of the formula (VII) wherein Ri, R2 and X are as defined above; c) the compounds of the formula (VII) are finally cyclized in an appropriate solvent at 20 ° -140 ° C for 1 to 120 hours, under the action of an organic phosphite or phosphonite.

3. The process according to claim 1, for the preparation of derivatives of the general formula (I), characterized in that the protecting group Ri is selected from the group consisting of: tert-butyldimethylsilyl, trimethylsilyl, allyloxycarbonyl, p-nitrobenzyloxycarbonyl; and the R2 group is selected from the group consisting of: allyl, benzyl (possibly substituted with a methoxy or nitro group), CH2OCO (0) mR4 wherein R4 is an alkyl group of 1 to 6 carbon atoms and m is 0 or 1; the organic base is preferably triethylamine or diisopropylethylamine, the Lewis acid is selected from the group consisting of: zinc iodide, zinc bromide, zinc chloride, aluminum chloride and the organic phosphite or phosphonite is a trimethyl or triethyl phosphite , or a di ethoxymethylphosphine.

4. The process according to claims 1 and 2, characterized in that the 2-halothioacetic acid is 2-chlorothioacetic acid.

5. The process according to claim 3, characterized in that the compound (I) obtained is a compound of the formula (I) according to claim 1 wherein: Ri = tert-butyldimethylsilyl, R2 = allyl, X = chloro.

The compound of the formula (V) (V) characterized in that R and X are as defined above.

7. The compound of the formula (VII) characterized in that Ri, R2 and X are as defined above.

8. The compounds according to claims 5 and 6, characterized in that X is chlorine.