BACKGROUND OF THE INVENTION

The present invention is related 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 such intermediates have been used in the past to synthesize carbapenem antibiotics. However, to date, the synthesis pathway for these antibiotics has required the use of extremely unstable intermediates. Additionally, the syntheses disclosed in the past result in low yields and require numerous separation and purification steps. The intermediates for carbapenem antibiotics described herein are addressed in, e.g., U. S. Pat. No. 4,350,631 issued to Christensen, et aL on September 21 , 1982 and U. S. Pat. 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 1-α and 1-β methyl isomers, which in turn requires separation prior to further chemical modification.

Lastly, many of the prior processes of synthesizing carbapenem antibiotics utilize an intermediate of the formula:

which has an active leaving group at position 2, namely the triflate. This compound is extremely unstable, and cannot be utilized in large scale synthesis with an acceptable level of efficiency. As such, one of the objectives of the present invention is to avoid this intermediate.

The present invention overcomes these disadvantages, providing a scheme which avoids unstable intermediates, and in many instances, producing intermediates which are in crystalline form, requiring little or no purification before futher use.

SUMMARY OF THE INVENTION

A process of synthesizing a compound of the formula:

B

is disclosed wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl. The process comprises treating a compound of the formula:

with P-Cl wherein P is as defined above, in the presence of 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) which are shown above are highly desired and useful as carbapenem intermediates, because 1-β methyl carbapenem antibiotics have a reduced tendency toward biological inactivation by the enzyme dehydropeptidase when administered to a mammalian patient to treat a bacterial infection. Generally, the 1 -β methyl isomer of the final product is more resistant to deactivation than the IH or the 1-α methyl isomer.

The bicyclic ketoester 2 can be further reacted at the 2- position to establish a leaving group, e.g., L, which represents diphenyl phosphate, triflate, tosylate, mesylate, fluorosulfonate, chloride and the like, to form the appropriate activated carbapenem intermediate. The

activated carbapenem intermediate is suitable for coupling to a substituent at position 2, for example, through the use of a palladium catalyst, e.g., Pd2(dba)3*CHCl3, and tris(2, 4, 6- trimethoxyphenyl)phosphine in a suitable solvent. Further details regarding coupling reactions can be obtained from U.S. Patent No. 5,034,384.

In one preferred embodiment of the invention, a compound of formula 3 wherein R represents H or methyl is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 1 :

In a more preferred embodiment of the invention, a compound of formula 3 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula la:

In another more preferred embodiment of the invention, a compound of formula 3 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula lb:

In another preferred embodiment, a compound of formula 4 wherein R represents H or methyl, is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 2:

In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula 2a:

In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula 2b:

_2b CO PNB

In another preferred embodiment, the substituted azetidinone is cyclized before protection of the hydroxyethyl side chain. After cyclization, the side chain is protected with P.

As used herein, PNB refers to the protecting group para- nitrobenzyl.

The abbreviation THF refers to tetrahydrofuran.

The abbreviation OAc refers to acetate, CH3C(0)0-. Hence, the solvent ethyl acetate is abbreviated as EtOAc and isopropyl acetate is abbreviated iPrOAc. TES refers to the group triethylsilyl.

TMS refers to the group trimethylsilyl.

Et3N refers to triethylamine. dba refers to dibenzylideneacetone.

Generally, the objects of the present invention are to utilize crystalline intermediates and to avoid unstable intermediates. Additionally, stereospecificity and regiospecific reactions are favored. The following schemes are representative.

SCHEME 1

(Crystalline)

Cyclize B

(Crystalline)

C0 ₂ PNB _{χ = |Θavjng group} C0 ₂ PNB (Stable)

Coupling Reaction 2-Substituted Carbapenems

SCHEME 2

B Cyclize

(Crystalline)

(Stable)

(Stable) ^C ° ^{2P N B}

2-Substituted Carbapenems

The starting materials for schemes 1 and 2 can be obtained in accordance with U.S. Patent Nos. 4,454,332 (issued on June 12, 1984) and 4,312,871 (issued on January 26, 1982). For each of the schemes noted above, by reacting compound 3 or 4 with P-Cl in the presence of base, stable and even crystalline intermediates are realized. This is an unexpected and suφrising advantage over other processes of synthesizing carbapenems.

There are numerous methods of cyclizing the diazo intermediates noted above to produce the bicyclic ketoester 2 or 4. The preferred method of cyclization involves a reaction in the presence of a rhodium catalyst, such as rhodium acetate or rhodium octanoate. Likewise, when activating the bicyclic ketoester 2 at position two, the anhydride L2O or the halide L-Cl can be combined with the bicyclic ketoester in the presence of a nitrogen containing base and in a substantially non-reactive solvent to produce the activated carbapenem 5. The activated carbapenem 5, with the appropriate group L at position 2, can then be coupled to an appropriate substituent according to the procedures set forth in U. S. Pat. No. 5,034,384. Carbapenems which can be synthesized in accordance with the process described herein are disclosed, and the groups which are appropriate for such attachment, can be found, e.g., in U.S. Pat. No. 5,034,384. The preferred substantially non-reactive solvents used herein are dimethylformamide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate and methylene chloride. Most preferably, mixtures thereof are used.

The preferred base used in the processes described herein is imidazole.

The nitrogen containing bases for use in the activating reaction with L2O or L-Cl include triethylamine, diisopropylethylamine and diisopropylamine.

Preferred values for L include the sulfonate leaving groups, such as trifluoromethanesulfonate (triflate), methanesulfonate (mesylate), toluenesulfonate (tosylate) and fluorosulfonate, the phosphonic acid residues, such as diphenylphosphonate and the halide leaving groups, such as chloride, bromide or iodide. Most preferred are triflate (OTf), flurorosulfonate (OSO2F), mesylate (OMs), diphenyl phosphate and tosylate (OTs).

EXAMPLE ONE

Compound Ja (7.8 g.) and imidazole (3.4 g.) are dissolved in ethyl acetate (70 mL, sieve dried) and the solution is stirred for 10 min. at room temperature. The solution is cooled and trimethylsilyl chloride (3.57 mL) is added while maintaining the temperature at -10 to -1 °C. A white-yellow suspension formed.

The suspension is allowed to warm to room temperature and stirred at room temperature for 1.5 hrs. Pour into phosphate buffer (0.0 IM, 80 mL, pH 6.8). Separate phases and wash the organic phase with aq. NaHCθ3 solution (saturated, 40 mL). Dry over Na2Sθ4. Filter and evaporate the filtrate to dryness. Load the filtrate onto a flash silica column (40 cm diam x 180 cm high), packed in 30% EtOAc and hexane (+ 0.025% E13N). Fractions 18 - 55 contained compound lc

EXAMPLE TWO

A 250 mL 3 -neck flask equipped with a N2 inlet, a thermocouple probe, and a dropping funnel was charged with THF (20 mL; KF < 80 μg/mL), isopropy lacetate (IPAC; 90 mL; KF < 80 μg/mL), compound 3α (15 g; 38.4 mmol) and imidazole (4.7 g; 69.0 mmol). The slurry was stirred at room temperature for 10 minutes until dissolution

was complete (KF < 140 μg/mL). The solution was maintained at 18-22

°C as TESC1 (9.0 mL; 53.6 mmol) was added slowly over 100 minutes.

After the addition was completed, the batch was aged at 20 °C for 2 hr.

The reaction mixture was assayed by HPLC. The starting material should be less than 0.15 area % at 245 nm.

Reaction mixture was quenched into a mixture of heptanes

(30 mL) and 0.01 M phosphate buffer (100 mL; pH 6.8) at room temperature. After 30 minutes of stirring at room temperature, the organic layer was separated. The organic layer was washed twice with 0.01 M phosphate buffer (pH 6.8; 100 mL each).

The organic layer was concentrated to about 35 mL at 18 -

20°C/1 10 - 80 mm Hg (GC showed 6.3 v/v % heptanes). Heptanes (30 mL) was slowly added during further concentration at 18 - 20°C/1 10 - 80 mm Hg keeping the volume at about 40 mL. After crystallization took place, additional heptane (90 mL) was added slowly at room temperature and the suspension was aged at

20°C for 1 hr then 0°C for 1 hr.

The crystals were filtered and washed (slurry then displacement) with a mixture of IPAC and heptane (3 : 97 v/v; lOOmL), and then dried under a nitrogen stream. The product (18 g; 93 % yield;

99.6 area %.) was obtained as a white crystalline solid.

EXAMPLE THREE

Starting from compound 3b, using the procedure set forth in Example One, compound le is obtained.

EXAMPLE FOUR

To a solution of 3b (245 mg) in a mixture of THF ( 1 mL) and EtOAc (2 mL) was added imidazole (80 mg) and TESCl (0.15 mL) at room temperature. After stirring for 2 hrs, the reaction mixture was diluted with hexanes (3 mL) and washed with phosphate buffer (pH 7.0; 6 mL) twice. The organic layer was dried over MgS04 and concentrated to give crude If, which was further purified by silica gel column chromatography using a mixture of hexanes and EtOAc (3 : 2 to 1 : 1 ) to give pure 7/(310 mg).

EXAMPLE FIVE

Compound Id (16.0 kg), rhodium octanoate (0.123 kg), anhydrous zinc bromide (71 g), and dry dichloromethane (63.42 L; KF < lOOμg/mL) are charged to a dry reactor. The solution is deoxygenated with three vacuum/nitrogen-fill cycles, then heated to reflux under nitrogen for 90 min to give a solution of Compound 2d.

EXAMPLE SIX

Starting from compound lc, using the procedure set forth in

Example Five, compound 2c is obtained.

EXAMPLE SEVEN

OoPNB

TESCl Imidazole

A solution of Compound 3α (1.1 g) in methylene chloride (4 mL) was heated under reflux with zinc bromide (10 mg) and rhodium octanate (10 mg) for 4 hours. The solution containing Compound 4α was cooled down to -78 °C. To this solution was added a mixture of triethylsilyl chloride (0.65 mL) and imidazole (285 mg) at -78 °C. After aged for 1 hr at -78 °C. The reaction mixture was slowly warmed up to 0

°C. From NMR and HPLC analysis, the solution contained mainly Compound 2d.

EXAMPLE EIGHT

A solution of If (291 mg) in methylene chloride (5 mL) is heated with 10 mg of rhodium octanoate dimer at 30°C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give crude 2f (260 mg).

EXAMPLE NINE

Starting from compound le, using the procedure set forth in Example Eight, the TMS protected intermediate 2e is obtained.

EXAMPLE TEN

To a solution of 4α (0.97 g) and imidazole (343 mg) in a mixture of THF (5 mL) and EtOAc (5 mL) was slowly added TESCl (0.66 mL) at room temperature. After stirring for 2 hrs, the reaction mixture was diluted with 10 mL of EtOAc and washed with phosphate buffer (pH 7.0; 15 mL) twice. The organic layer was dried over MgS04, concentrated under reduced pressure to give crude 2f (1.235 g).