PROCESS FOR PREPARING A CARBAPENEM ANTIBIOTIC

Abstract

A process for the preparation of a carbapenem, includes the step of treating a solution of a protected carbapenem with hydrogen gas in the presence of a heterogeneous catalyst to form the carbapenem, wherein the heterogeneous catalyst includes at least two platinum group metals.

Claims

1. A process for the preparation of a carbapenem, said process comprising the step of treating a solution of a protected carbapenem with hydrogen gas in the presence of a heterogeneous catalyst to form the carbapenem, wherein the heterogeneous catalyst comprises at least two platinum group metals.

2. A process according to claim 1, wherein the protected carbapenem and carbapenem are selected from the group consisting of: TABLE-US-00004 Protected Carapenem Carbapenem Protected Meropenem Meropenem Protected Imipenem Imipenem Protected Ertapenem Ertapenem Protected Thienamycin Thienamycin Protected Panipenem Panipenem Protected Doripenem Doripenem

3. A process according to claim 1, wherein the protected carbapenem comprises one or more protecting groups selected from the group consisting of unsubstituted benzyl, substituted benzyl, unsubstituted-carboxybenzyl, substituted-carboxybenzyl groups, and a combination thereof.

4. A process according to claim 1, wherein the heterogeneous catalyst comprises at least two platinum group metals on a solid support.

5. A process according to claim 4, wherein the solid support is selected from the group consisting of carbon, alumina, calcium carbonate, barium carbonate, barium sulfate, titania, silica, zirconia, ceria and a combination thereof

6. A process according to claim 4, wherein the solid support is selected from the group consisting of activated carbon, carbon black or graphite.

7. A process according to claim 1, wherein the platinum group metals are selected from two or more of ruthenium, rhodium, palladium, iridium and platinum.

8. A process according to claim 7, wherein the platinum group metals are palladium and platinum.

9. A process according to claim 1, wherein the solvent is selected from the group consisting of water, protic solvents, aprotic solvents and a mixture thereof.

10. A process according to claim 9, wherein the solvent is selected from the group consisting of water, alcohol solvents, ether solvents, ester solvents, chlorinated solvents, amide solvents and mixtures thereof.

11. A process according to claim 9, wherein the solvent is selected from the group consisting of water, methanol, ethanol, propanols, butanols, pentanols, hexanols, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethyl acetate, methyl acetate, dichloromethane, dimethylformamide, dimethylacetamide and mixtures thereof.

12. A process according to claim 1, wherein the process further comprises a base.

13. A process according to claim 12, wherein the base is an inorganic or organic base.

14. A process according to claim 13, wherein the organic base is lutidine.

15. A process according to claim 2, wherein the protected carbapenem comprises one or more protecting groups selected from the group consisting of unsubstituted benzyl, substituted benzyl, unsubstituted-carboxybenzyl, substituted-carboxybenzyl groups, and a combination thereof.

16. A process according to claim 2, wherein the heterogeneous catalyst comprises at least two platinum group metals on a solid support.

17. A process according to claim 5, wherein the solid support is selected from the group consisting of activated carbon, carbon black or graphite.

18. A process according to claim 10, wherein the solvent is selected from the group consisting of water, methanol, ethanol, propanols, butanols, pentanols, hexanols, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethyl acetate, methyl acetate, dichloromethane, dimethylformamide, dimethylacetamide and mixtures thereof.

Description

[0057] The invention will now be further illustrated by the following Examples, which are for illustrative purposes and as such do not serve to limit the scope of the protection as defined by the claims and with reference to the following Figures in which:

[0058] FIG. 1 is a graph illustrating the conversions and selectivities achieved in the synthesis of meropenem with 2.5 wt % (Pd.sub.xPt.sub.2.5-x)/C catalysts.

[0059] FIG. 2 details the results that are obtained utilising nine different Pd,Pt/C catalyst in which the wt % ratio of Pd:Pt are varied (5% total metal), together with the carbon support.

[0060] FIGS. 3 and 4 detail the results obtained utilising six different Pd,Pt/C catalyst in which the wt % ratio of Pd:Pt are varied (10% total metal), together with the carbon support. The results for two comparative Pd only catalysts are also provided.

[0061] FIG. 5 illustrates the isolated meropenem mole yield (%) vs. % Pt in Pd.sub.10-xPt.sub.x/C catalysts where the carbon support is Ceca L4S.

[0062] FIG. 6 illustrates the isolated meropenem mole yield (%) vs. % Pt in Pd.sub.10-xPt.sub.x/C catalysts where the carbon support is Ceca ENO.

EXAMPLES

[0063] Palladium(II) nitrate solution (having 15.06 wt % Pd by assay), platinum (IV) nitrate solution (having 16.44 wt % Pt by assay), 4-Methylmorpholine (99%), Diisopropylamine (99+%), 1-Methyl-2-pyrrolidinone, anhydrous (99.5%) are obtainable from Alfa Aesar. The carbon support (Ceca ENO, Ceca L4S and Ceca CPL) are commercially available.

[0064] The protected meropenem of formula 2 may be prepared according to literature procedure (Sunagawa et al, Journal of Antibiotics, 1990, 43, 519-532; U.S. Pat. No. 4,888,344).

[0065] HPLC analysis may be carried out according to the procedure described in N. Tewari et al, Organic Process Research & Development 2007, 11, 773-775.

Example 1

[0066] Catalyst Preparation

[0067] The metal precursor(s) are deposited onto a Ceca ENO activated carbon support by an incipient wetness process.

[0068] A 25 ml aqueous solution containing 0.25 g in total of metal by weight is added to 9.75 g of Carbon and this is stirred by hand for one minute so that all of the moisture is taken up. Experiments demonstrate that this is the maximum amount of water that can be added to the activated carbon without observing liquid that is not absorbed.

[0069] The solution added varies according to the desired weight loading of the catalyst:

TABLE-US-00002 Amount of Amount of Platinum(IV) Palladium(II) Amount of nitrate nitrate water (ml) solution (g) solution (g) 2.5 wt % Pd/C* 25 0 1.66 2.4 wt % Pd; 0.1 wt % Pt/C 25 0.06 1.59 2.25 wt % Pd; 0.25 wt % Pt/C 25 0.15 1.49 2.0 wt % Pd; 0.5 wt % Pt/C 25 0.30 1.33 1.25 wt % Pd; 1.25 wt % Pt/C 25 0.76 0.83 2.5 wt % Pt/C* 25 1.52 0 *not according to the invention

[0070] The mixture is then dried in an oven at 105 C. for 24 hours. After this time, 5.0 g of the resulting black powder is transferred to a silica crucible and placed in a Carbolite STF tube furnace and a flow of 5% H.sub.2/N.sub.2 of approximately 0.5 L/minute is passed over the sample. After dwelling for ten minutes, the furnace is programmed to heat at a ramp rate of 10 C./minute up to 200 C. It is held at this temperature for one hour before cooling back to room temperature.

[0071] Diprotected Meropenem Screening Reactions

##STR00008##

[0072] The equipment used for the reaction screening is an HEL Chemscan unit, which has eight individual reaction tubes.

[0073] The buffer solution is made as follows. 1.06 g 4-Methylmorpholine+0.43 g g-Acetic acid and made up to 100 ml with water. The buffer is required to be in the pH 7.0-pH 7.5 range. This is achieved by adjusting either component. In this case approximately 20 uL of 4-methylmorpholine is added to bring the pH back up to 7.1.

[0074] The catalytic reaction is undertaken using 35 mg of the dry mixed metal catalyst (equating to 25% catalyst loading by weight with respect to the substrate). To this is added 0.140 g of the substrate, 3 ml of ethyl acetate and 2 ml of buffer solution. Prior to the reaction, the vessels are purged 5 times at room temperature (without stirring) with nitrogen and subsequently hydrogen gas. The reaction is then run at 26 C., 6.48 bar of hydrogen, a stirring rate of 900 rpm for 90 minutes. During the reaction, the temperature and pressure values are maintained and the hydrogen uptake is recorded.

[0075] The reaction tubes are removed from the Chemscan and the contents of each is separately decanted into individually numbered test tubes. Each reaction tube is washed twice with 5.0 ml of methanol and the washings added to the appropriate numbered test tube. All the test tubes are then sonicated for 15 minutes. Sample filters are made up by taking about 10 cm.sup.2 of single ply Kimtech Science paper tissue and packing it tightly into a glass Pasteur pipette down to the tip end. Then approximately 1 ml of each sonicated solution is filtered under gravity.

[0076] Results

TABLE-US-00003 Amount of Pd in 2.5 wt % Conversion (%) (after Selectivity (%) (after (Pd.sub.xPt.sub.2.5x)/C catalyst 90 mins reaction time) 90 mins reaction time) 2.5* 51.1 46.2 2.4 76.4 70.1 2.25 68.5 66.4 2 92.6 81.0 1.5 92.1 84.0 1.25 93.6 85.5 0* 88.7 89.8 *not according to the invention

[0077] The data presented in the table above is illustrated graphically in FIG. 1. From the data it is seen that replacing palladium for platinum in the metal on carbon catalysts results in both an increase in the conversion of the starting material and the selectivity towards the desired product. However, this increase is not linear and it is observed that the yield (i.e. conversionselectivity) of the desired product is greatest for the mixed-metal materials. For example, the conversion of the mixed metal catalysts that contain 1.25, 1.5, and 2% Pd within the 2.5 wt % (Pd.sub.xPt.sub.2.5-x)/C materials have the highest values. Here, it appears that the metals are synergistically combining to give enhanced performance. Furthermore, the selectivities of the mixed metal catalysts are significantly greater than a weighted average of the two monometallic analogues, again exhibiting synergistic behaviour.

Example 2

[0078] The Pd,Pt/C catalysts utilised in this Example may be obtained commercially from Johnson Matthey Catalysis and Chiral Technologies or may be prepared by aqueous slurry impregnation of metal salt components onto an activated carbon support followed by reduction using methods known in the art, for example, as described by G. J. K. Acres et al in The Design and Preparation of Supported Catalysts, Catalysis Volume 4, pages 1-30, Royal Society of Chemistry, January 1981.

[0079] Process Followed for Hydrogenation:

##STR00009##

[0080] Protected meropenem of formula 1 above (2.5 g), tetrahydrofuran (THF) (63.5 mL), water (50 mL), 2,6-lutidine (0.5 mL) and a Pd,Pt/C paste (30% dry wt basis) (based on the catalysts identified in FIG. 2) are added and the mixture is hydrogenated at 260 psi for 70 minutes and 40 C. At the end of the reaction, the H.sub.2 pressure is released and the mass is filtered over celite bed. The catalyst bed is washed with minimum amount of water (10 mL).

[0081] Isolation of Product from Solution:

[0082] The obtained filtrate is cooled in ice (0-2 C.) and meropenem of formula 2 above is crystallized out by the drop wise addition of pre-cooled acetone (188.5 mL) over 1 hour. Meropenem precipitates out as a solid. The solution containing meropenem is allowed to stir at 0-2 C. for a further 30 minutes and is filtered, washed with a cooled mixture of acetone (12.5 mL) and water (4 mL). The product is dried under vacuum for 30 minutes.

[0083] Purification of Crude Meropenem:

[0084] The product is dissolved in THF-water mixture (1.3:1) by warming to 40 C. and is filtered. The filtrate is cooled and the product is crystallized by addition of acetone. The solid obtained is dried under vacuum.

[0085] Results

[0086] FIG. 2 details the results that are obtained utilising nine different Pd,Pt/C catalyst in which the wt % ratio of Pd:Pt are varied (5% total metal), together with the carbon support. The conversions are high in all cases, as well as the yields and HPLC purities of the isolated meropenem. The mixed metal catalysts, therefore, demonstrate an increased rate of conversion and/or selectivity resulting in good to excellent isolated yields.

Example 3

[0087] The Pd,Pt/C catalysts utilised in this Example may be obtained commercially from Johnson Matthey Catalysis and Chiral Technologies or may be prepared by aqueous slurry impregnation of metal salt components onto an activated carbon support followed by reduction using methods known in the art, for example, as described by G. J. K. Acres et al in The Design and Preparation of Supported Catalysts, Catalysis Volume 4, pages 1-30, Royal Society of Chemistry, January 1981.

[0088] Process Followed for Hydrogenation:

##STR00010##

[0089] Protected meropenem of formula 1 above (2.5 g), tetrahydrofuran (THF) (63.5 mL), water (50 mL), 2,6-lutidine (0.5 mL) and a Pd,Pt/C paste (50% dry wt basis) (based on the catalysts identified in FIGS. 3 and 4) are added and the mixture is hydrogenated at 150 psi for 120 minutes and 30 C. At the end of the reaction, the H.sub.2 pressure is released and the mass is filtered over celite bed. The catalyst bed is washed with minimum amount of water (10 mL).

[0090] Isolation of Product from Solution:

[0091] The obtained filtrate is cooled in ice (0-2 C.) and meropenem of formula 2 above is crystallized out by the drop wise addition of pre-cooled acetone (188.5 mL) over 1 hour. Meropenem precipitates out as a solid. The solution containing meropenem is allowed to stir at 0-2 C. for a further 30 minutes and is filtered, washed with a cooled mixture of acetone (12.5 mL) and water (4 mL). The product is dried under vacuum for 60 minutes and under vacuum with a N.sub.2 purge for 30 minutes.

[0092] Results

[0093] FIGS. 3 and 4 detail the results obtained utilising six different Pd,Pt/C catalyst in which the wt % ratio of Pd:Pt are varied (10% total metal), together with the carbon support. The results for two comparative Pd only catalysts are also provided. FIGS. 5 and 6 illustrate the isolated meropenem mole yield (%) vs. % Pt in Pd.sub.10-xPt.sub.x/C catalysts where the carbon support is Ceca L45 (FIG. 5) or Ceca ENO (FIG. 6). The conversions are high in all cases, as well as the yields and HPLC purities of the isolated meropenem. However, the mixed metal catalysts give higher isolated meropenem product yields than the Pd only catalysts.