MXPA98000041A - Improved procedure to synthetic carbape intermediaries - Google Patents

Abstract

A method is described for synthesizing a compound of the formula (1) or (2), wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl, a compound of the formula (3) or (4) is reacted with P-CI wherein P is such as defined above, in the presence of a base and a substantially non-reactive solvent, to produce (1) or (2). (see formula

Description

IMPROVED PROCEDURE TO SYNTHETIZE CARBAPENEM INTERMEDIARIES BACKGROUND OF THE INVENTION The present invention relates to an improved synthesis of carbapenem intermediates and, in particular, the following compounds: wherein R represents hydrogen or methyl and P represents triethylsilyl or trimethylsilyl. Similar intermediates have been used in the past in order to synthesize carbapenem antibiotics. However, at present, the path of synthesis for these antibiotics has required the use of extremely stable intermediaries. Additionally, the syntheses described in the past result in low yields and require numerous separation and purification steps. The intermediates for the carbapenem antibiotics described herein are referred to, for example, in U.S. Patent No. 4,350,631, issued to Chr? S- < ensen and co-inventors, on September 21, 1982 and U.S. Patent No. 4,994,568, issued to Christensen on February 19, 1991. In the process described in each of these patents, a diazo compound of the formula is cyclized: using a catalyst or irradiation. This generates a mixture of the l-a and 1-ß-methyl isomers which, in turn, requires separation before further chemical modification. Finally, many of the previous procedures for synthesizing carbapenem antibiotics use an intermediate of the formula: which has an active substitutable group in position 2, that is, triflate. This compound is extremely unstable and can not be used in a large-scale synthesis, with an acceptable level of efficiency. Thus, one of the objects of the present invention is to avoid that intermediary. The present invention solves these disadvantages by providing a scheme that avoids unstable intermediates. In many cases, producing intermediates that are in crystalline form requires little or no purification before further use.

BRIEF DESCRIPTION OF THE INVENTION A method for synthesizing a compound of the formula is described: B wherein R represents H or methyl and P represents triethylsilyl or trirnethylsilyl. The process comprises treating a compound of the formula: with P-Cl, wherein P is as defined above, in the presence of a base and a substantially non-reactive solvent to produce: DETAILED DESCRIPTION OF THE INVENTION The 1-β-methyl isomer of the diazo compound 1 and the bicyclic ketoester 2 (R = methyl) shown above are highly desirable and useful as carbapenem intermediates, because the antibiotics of 1-β-rnetyl carbapene have a reduced tendency to biological inactivation by the enzyme dehydropeptidase, when administered to a mammalian patient to treat a bacterial infection. In general, the 1-β-methyl isomer of the final product is more resistant to deactivation than 1H or the 1-methyl-isomer. The bicyclic ketoester 2_ can be reacted further in the 2-position to establish a substitutable group, for example, L, which represents: difamid phosphate, tp-flate, tosylate, rnesylate, fluorosulfonate, chloride and the like, to form the activated carbapenene intermediate , appropriate. The activated carbapenem intermediate is suitable for coupling to its carrier at position 2, for example, by the use of a palladium catalyst, for example, P 2 (dba) 3 -CHC 13, and tr? S (2, 4,6-tpmetox? Phen? L) phosphma, in a suitable solvent. Other details that relate to the coupling reaction can be obtained from US Pat. No. 5,034,384. In a preferred embodiment of the invention, a compound of the formula 3 is reacted, wherein R represents H or methyl, with P-Cl in the presence of base and a non-reactive solvent, to produce a compound of the formula 1 : In an embodiment of the invention which is more preferred, a compound of the formula 3 is reacted with P-Cl, where P represents triethyl silyl, to produce a compound of the formula la: In another embodiment of the invention that is still more preferred, a compound of the formula 3 is reacted with P-Cl, where P represents trimethylsilyl, to produce a compound of the formula lb: In another preferred embodiment, a compound of the formula t * _ wherein R represents H or methyl, is reacted with P-Cl, in the presence of a base and a substantially non-active solvent, to produce a compound of the Formula 2: In another more preferred embodiment of the invention, a compound of the formula k_ is reacted with P-Cl, where P represents triethylsilyl, to produce a compound of the formula 2a: In another more preferred embodiment of the invention, a compound of the formula is reacted with P-Cl, wherein P represents trirnethylsilyl, to produce a compound of the formula 2b: In another preferred embodiment, the substituted azetidinone is cyclized before the protection of the hydroxyethyl side chain. After cyclization, the side chain is protected with P ..}.

As used herein, PNB refers to the para-nitrobenzyl protecting group. The abbreviation THF refers to tetrahydrofuran. The abbreviation OAc refers to acetate, CH3C (0) 0-. Accordingly, the solvent ethyl acetate is abbreviated as EtOAc and the isopropyl acetate is abbreviated as lPrOAc. TES refers to the t-riet isilyl group. TMS refers to the t-rimethylsilyl group. Et.3 refers to tethylamine. dba refers to dibenzyli denacetone. In general, the objects of the present invention are to use crystalline intermediates to avoid unstable intermediates. Additionally, stereospecific fidelity and regiospecific reactions are favored. The following schemes are representative: SCHEME 1 CO PNB P-Cl Solvent (Crystalline) Cyclization (Crystalline) (Stable) Copulation Reaction 2-Substituted Carbapenems SCHEME 2 NB Cyclization (Crystalline) / («E.sta ub-l, e) C02 ¿PNB 2-Substituted Carbapenems The starting materials for schemes 1 and 2 can be obtained in accordance with US Pat. Nos. 4,454,332 (issued June 12, 1984) and 4,312,871 (issued on January 26, 1982). For each of the schemes noted above, by entering the compound 3_ or _4 with P-Cl in the presence of a base, you get stable intermediaries, and even cns-t almos. This is an unexpected and surprising advantage with respect to other procedures for synthesizing * carbapenems. There are numerous methods for cyclizing the diazo intermediates noted above to produce ketoeeter 2 or 4 bicycles. The preferred method of cyclization involves a reaction in the presence of rhodium catalyst, such as rhodium acetate or rhodium octanoate. Similarly, when bicyclic ketoester 2 is activated in position 2, the L2O or L-Cl halide anhydride can be combined with the bicyclic ketoester in the presence of a nitrogen-containing base, and in a substantially unreactive solvent to produce activated carbapenem 5_. Activated carbapenem 5_, with the appropriate group L in position 2, can then be coupled to an appropriate substituent according to the procedures set forth in U.S. Patent No. 5,034,384. The carbapenems that can be synthesized according to the process described therein are described, and groups that are suitable for such binding can be found in, for example, U.S. Patent No. 5,034,384. The preferred substantially non-reactive solvents used herein are dimethiifornarnide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate and full rnei chloride. Iluy preferably, mixtures thereof are used. The preferred base used in the methods described herein is irnidazole. The nitrogen-containing bases, for use in the activation reaction with L2O or L-Cl, include triethylamine, diisopropylethylamine and diisopropylamine. Preferred values for L include substitutable sulphonate groups, such as trifluorornetansulfonate (tp flato), rnetansulfonate (mesylate), toluensulphonate (tosylate) and fluorosulfonate.; phosphonic acid residues, such as di phenyl phosphonate, and substitutable halide groups, such as chloride, bromide or iodide. Most preferred are tri-flute (OTf), fluorosulfonate (OSO2F), rnesylate (Ols), difluoryl phosphate and tosylate (OTs).

EXAMPLE ONE 7.8 g of compound 3a and 3.4 g of irnidazole are dissolved in 70 ml of ethyl acetate, dried on a sieve, and the solution is stirred for 10 minutes at room temperature. The solution is cooled and 2.57 nl of trirnethylsilyl chloride is added, while maintaining the temperature at -10 to -1 ° C. A white-yellow suspension is formed. The suspension is allowed to warm to room temperature and is stirred at room temperature for 1.5 hours. Pour 80 rnl, 0.01 mole, of phosphate buffer, pH 6.8. The phases are separated and the organic phase is washed with aqueous sodium bicarbonate solution (40 ml, saturated). Dry over sodium sulfate. Filter and evaporate the filtrate to dryness. The filtrate is loaded onto a rapid silica column (40 cm diameter x 180 cm high), packed with 30% EtOAc and hexane (+ 0.025% Et3N). Fractions 18 to 55 contained the compound le.

EXAMPLE TWO A 250 ml, three-necked flask equipped with an inlet for 2, a thermocouple probe and a dropping funnel was charged with 20 rnl of THF (KFUI <80 ug / ml), 90 rnl of isopropyl acetate ( IPAC, KF <80 ug / ml), 15 g, 38.4 mmol, of compound 3a and 4.7 g, 69.0 mmol, of imidazole. The suspension was stirred at room temperature for 10 minutes until the solution was complete (KF <140 ug / rnl). The solution was maintained at 18-22 ° C, as 9.0 rnl, 53-6 rnmoles, of TESC1 were slowly added over 100 minutes. After the addition was complete, the charge was aged at 20 ° C for 2 hours. The reaction mixture was analyzed by HPLC. The starting material should be less than 0.15% area at 254 nm. The reaction mixture was quenched to a mixture of 30 rnl of heptanes and 100 rnl of 0.01 mole of phosphate buffer, pH 6.8, at room temperature. After stirring for 30 minutes at room temperature, the organic layer was separated.

The organic layer was washed twice with 100 ml each of 0.01 mole of phosphate buffer, pH 6.8. The organic layer was concentrated at about 35 rnl at 18-20 ° C / 110-80 rnrn Hg (GC chromatography showed 6.3 vol / vol of heptanes). 30 ml of heptanes were added slowly during the additional concentration at 18-20 ° C / 110-80 rnm of Hg, maintaining the volume at approximately 40 ml. After the crystallization was carried out, another 90 ml of heptane was slowly added at room temperature and the suspension was aged at 20 ° C for 1 hour, then at 0 ° C for 1 hour. The crystals were filtered and washed (suspension then displacement) with a mixture of IPAC and heptane (3:97 v / v, 100 rnl), and then dried under a stream of nitrogen. A yield of 18 g, 93% of the product, 99.6% of the area, was obtained as a white crystalline solid.

EXAMPLE THREE Starting from the compound 3_b, and using the procedure indicated in example one, the compound le is obtained.

EXAMPLE FOUR It was added to a solution of 245 mg of 3_b in a mixture of 1 ml of THF and 2 ml of EtOAc, 80 mg of imidazole and 0.15 ml of TESC1 at room temperature. After stirring for 2 hours, the reaction mixture was diluted with 3 ml of hexanes and washed twice with 6 rnl of phosphate buffer, pH 7.0. The organic layer was dried over magnesium sulfate and concentrated to give crude lf, which was further purified by silica gel column chromatography using a mixture of hexanes and EtOAc (3: 2 to 1: 1) to give 310 rng of lf pure. 1. 8 EXAMPLE FIVE Dry 16.0 kg of compound Id, .123 kg of rhodium octanoate, 71 g of anhydrous zinc bromide and 63.42 liters of dichloromethane (KF <100 μg / ml) in a dry reactor. The solution is deoxygenated with three cycles of vacuum / nitrogen filling; then it is heated under reflux under nitrogen for 90 minutes to give a solution of compound 2d.

EXAMPLE SIX Starting from compound ^ c, and using the procedure indicated in example five, compound 2c is obtained.

EXAMPLE SEVEN TESCI Imidazole A solution of 1.1 g of compound 3a in 4 ml of rnnilene chloride, together with 10 mg of zinc bromide and 10 mg of rhodium octanoate, was heated at reflux for 4 hours. The solution containing Compound 4ja was cooled to -78 ° C. A mixture of 0.65 nrl of triethylsilyl chloride and 285 nrg of imidazole at -78 ° C was added to this solution. After aging for 1 hour at -78 ° C, the reaction mixture was slowly warmed to 0 ° C. Nuclear magnetic resonance and HPLC analysis showed that the solution contained mainly the. 2d compound EXAMPLE EIGHT B A solution of 291 rng of ljf in 5 rnl of methylene chloride, with 10 rng of the rhodium octanoate dimer at 30 ° C, is heated for 3 hours. The reaction mixture was concentrated under reduced pressure to give 260 rng of crude 2.

EXAMPLE NINE Starting from the compound LE, using the procedure of example eight, intermediate 2e protected with TUS is obtained.

EXAMPLE TEN To a solution of 0.97 g of 4a and 343 mg of irnidazole in a mixture of 5 rnl of THF and 5 ml of EtOAc, 0.66 ml of TESC1 was slowly added at room temperature. After stirring for 2 hours, the reaction mixture was diluted with 10 nmol EtOAc and washed twice with 15 rnl of regulator-phosphate, pH 7.0. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, to give 1.235 g of crude 2f.

Claims (13)

00 NOVELTY OF THE INVENTION CLAIMS

1. - A method for synthesizing - a compound of the formula: B wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl, characterized in that it comprises treating a compound of the formula: B with P-Cl, where P is as defined above, in the presence of a base and a substantially non-reactive solvent, to produce:

2. - A process for synthesizing a compound of the formula: NB wherein R represents H or methyl, characterized in that it comprises treating a compound of the formula: with triethylsilyl chloride, in the presence of a base and a substantially non-reactive solvent, to produce: B

3. - A method according to claim 1, further characterized in that the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or rnetylene chloride.

4. A method according to claim 3, further characterized in that the base is imidazole.

5. A process for synthesizing a compound of the formula: wherein R represents H or methyl, characterized in that it comprises treating a compound of the formula: with triethylsilyl chloride, in the presence of a nitrogen-containing base and a substantially non-reactive solvent, to produce:

6. - A process according to claim 5, further characterized in that the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.

7. A method according to claim 6, further characterized in that the base is imidazole.

8. A process for synthesizing a compound of the formula: wherein R represents H or methyl, characterized in that it comprises treating a compound of the formula. with trirne diisilyl chloride, in the presence of a base and a substantially unreactive solvent, to produce:

9. - A method according to claim 8, further characterized in that the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or rnetylene chloride.

10. - A method according to claim 9, further characterized in that the base is irnidazole.

11. A process for synthesizing a compound of the formula: COPNB wherein R represents H or methyl, characterized in that it comprises treating a compound of the formula. with trimethylsilyl chloride, in the presence of a base and a substantially non-reactive solvent, to produce: COPNB

12. - A method according to claim 11, further characterized in that the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.

13. A method according to claim 12, further characterized in that the base is imidazole.