SK176597A3 - Improved process for synthesizing carbapenem intermediates - Google Patents

Abstract

A process of synthesizing a compound of formula (1) or (2) is disclosed wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl. A compound of formula (3) or (4) is reacted with P-C1 wherein P is as defined above, in the presence of base and a substantially non-reactive solvent to produce (1) or (2).

Description

Process for the synthesis of carbapenem intermediates

Technical field

The present invention relates to an improved process for the synthesis of carbapenem intermediates, in particular the following compounds

wherein R is hydrogen or methyl and P is triethylsilyl or trimethylsilyl. Intermediates similar to these compounds have been used in the past for the synthesis of carbapenem antibiotics. However, the method of synthesis of these antibiotics required the use of extremely unstable intermediates. In addition, the previously described synthesis had low yields and required numerous separation and purification steps.

BACKGROUND OF THE INVENTION

The carbapenem antibiotic intermediates described herein are disclosed, for example, in U.S. Pat. No. 4,350,631 to Christensen et al., Sep. 21, 1982; and U.S. Pat. No. 4,994,568, Christensen, Feb. 19, 1991. In the method described in both of these patents, a compound of formula is cyclized using a catalyst or irradiation.

ABOUT

CO ₂ R

This creates a mixture of 1-α and 1-β methyl isomers, which must be separated before further chemical modification. Recently, in many methods for the synthesis of carbapenem antibiotics, an intermediate of formula has been utilized

which has an active leaving group at the 2-position, namely triflate. This compound is extremely unstable and cannot be used in large-scale synthesis with an acceptable level of efficacy. It is one object of the present invention to provide a synthesis without using this intermediate. The present invention overcomes this drawback by providing a scheme in which there are no unstable intermediates and in many cases intermediates are formed which are in crystalline form and require little or no purification before reuse.

SUMMARY OF THE INVENTION

Described is a method of synthesizing a compound of formula

wherein R is hydrogen or methyl and P is triethylsilyl or trimethylsilyl. The method comprises treating a compound of formula P-Cl, wherein P is as defined above

(3) (4) in the presence of a base and a substantially non-reactive solvent to form the compound

The 1-β-methyl isomer of diazo compound 1 and the bicyclic ketoester 2 (R = methyl) shown above are highly desirable and useful compounds as carbapenem intermediates since 1-β-methyl carbapenem antibiotics have a reduced propensity for biological inactivation by enzyme dehydropeptidase when administered to a mammal in the treatment of a bacterial infection. Generally, the 1-β methyl isomer of the final product is more resistant to inactivation than the 1H or 1- and methyl isomer.

The bicyclic ketoester 2 can be further reacted at the 2-position to form a leaving group, for example L, which may be diphenylphosphate, triflate, tosylate, mesylate, fluorosulfonate, chloride and the like to form a suitably activated carbapenem intermediate. The activated carbapenem intermediate is suitable for binding to the substituent at the 2-position, for example using a palladium catalyst such as Pd 2 (dba) 3 CHCl 3 and tris (2,4,6-trimethoxyphenyl) phosphine in a suitable solvent. Further details regarding the coupling reactions can be obtained from US Patent 5,034,384.

In a preferred embodiment of the invention, the compound of formula 3 wherein R is hydrogen or methyl is reacted with the compound P-Cl in the presence of a base and v. a substantially non-reactive solvent to form a compound of Formula 1

In a more preferred embodiment of the invention, compound 3 is reacted with compound P-Cl, wherein P is triethylsilyl to form a compound of formula 1a

(1a)

In another more preferred embodiment of the invention, the compound of formula 3 is reacted with a compound of formula P-CI, wherein P is trimethylsilyl, to form a compound of formula 1b

(1b)

In another preferred embodiment, the compound of formula IV wherein R is hydrogen or methyl is reacted with P-Cl in the presence of a base and a substantially non-reactive solvent to form compound 2

co ₂ pnb (3)

In a more preferred embodiment of the invention, the compound of formula IV is reacted with a compound of formula P-Cl, wherein P is triethylsilyl to form a compound of formula 2a

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

In another preferred embodiment, the substituted azetidinone is cyclized prior to protection of the hydroxyethyl side chain. After cyclization, the P group is bound to the side chain.

co ₂ pnb

As used herein, the abbreviation PNB refers to the paranitrobenzyl protecting group.

The abbreviation THF refers to tetrahydrofuran.

OAc stands for acetate, CH 3 C (O) O -.

Therefore, the solvent ethyl acetate is designated as EtOAc and the isopropyl acetate is shortened to iPrOAc.

TES refers to a triethylsilyl group.

TMS refers to a trimethylsilyl group.

Et 3 N refers to triethylamine. dba refers to dibenzylideneacetone.

In general, it is an object of the present invention to use crystalline intermediates and thereby avoid unstable intermediates. In addition, sterospecific and site specific reactions are preferred. Representative schemes include the following schemes.

Scheme 1

co ₂ pnb co ₂ pnb

P-Cl solvent cyclization

(stable) coupling reaction group

2-substituted carbapenems

- Scheme 2

cyclization

P-CI solvent

L ₂ O or L-Cl base solvent

2-substituted carbapenems

The starting materials for Schemes 1 and 2 can be obtained according to U.S. Pat. 4,454,332 (Jan. 12, 1984) and 4,312,871 (Jan. 26, 1982). For both of the above schemes, stable and even crystalline intermediates are formed by reacting compounds 3 or 4 with compound P-Cl in the presence of a base. This is an unexpected and surprising advantage in the synthesis of carbapenems over other prior art processes.

There are a number of methods for cyclizing the diazo intermediates listed above to form a bicyclic ketoester 2 or 4. A preferred cyclization method involves reaction in the presence of a radio catalyst such as radium acetate or rhodium octanoate.

Similarly, when the bicyclic ketoester 2 is activated at the 2-position, the L ₂ O anhydride or L-Cl halide may be combined with the bicyclic ketoester in the presence of a nitrogenous base and essentially in a non-reactive solvent to form activated carbapenem. it can then react from binding to a suitable substituent according to the procedures disclosed in U.S. Pat. 5,034,384. Carbapenems which can be synthesized according to the procedure described above are listed and groups suitable for this attachment can be found, for example, in U.S. Patent No. 5,201,549. 5,034,384.

Preferred substantially non-reactive solvents used in the described process are dimethylformamide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate, and methylene chloride. Most preferably, mixtures thereof are used.

The preferred base used in the methods described above is imidazole. Nitrogen bases for use in the L ₂ O or L-Cl activation reaction are triethylamine, diisopropylethylamine and diisopropylamine.

Preferred L groups are leaving groups such as trifluoromethanesulfonate (triflate), methanesulfonate (mesylate), toluenesulfonate (tosylate) and fluorosulfonate, phosphonic acid residues such as diphenylphosphonate, and halide leaving groups such as chloride, bromide or iodine. Most preferred are triflate (OTf), fluorosulfonate (OSO2F), mesylate (OMs), diphenylphosphate and tosylate (OTs).

DETAILED DESCRIPTION OF THE INVENTION

Compound 3a (7.8 g) and imidazole (3.4 g) were dissolved in ethyl acetate (70 mL, molecular sieve dried) and the solution was stirred at room temperature for 10 minutes. solution

Cool and add trimethylsilyl chloride (3.57 mL) maintaining the temperature in the range of 10-1 ° C. A light yellow suspension is formed.

The suspension was allowed to warm to room temperature and stirred at room temperature for 1.5 hours. It is then poured into phosphate buffer (0.01 M, 80 ml, pH 6.8). The phases were separated and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate (40 ml). The solution was dried over Na 2 SO 4. It is then filtered and the filtrate is evaporated to dryness. The filtrate was then loaded onto a flash silica gel column (40 cm diameter, 180 cm height) with 30% EtOAc and hexane (+ 0.025% ΕίβΝ). Compound 1c contains fractions 18 to 55.

THF (20 mL, KF <80 pg / mL), isopropyl acetate (IPAC, 90 mL, KF <80 pg / mL), Compound 3a (15 g, 50 mL) was added to a 250 mL three-necked flask equipped with nitrogen inlet, thermocouple and addition funnel. 38.4 mmol) and imidazole (4.7 g, 69.0 mmol). The slurry was stirred at room temperature for 10 minutes until complete dissolution (KF < 140 Mg / ml). The solution was maintained at 18-22 ° C and TESCI (9.0 mL, 53.6 mmol) was added slowly over 100 minutes. After the addition was complete, the flask was allowed to stand at 20 ° C for 2 hours. The reaction mixture was analyzed by HPLC. The starting material content should be less than 0.15 area% at 245 nm.

The reaction is terminated by pouring into a mixture of heptanes (30 mL) and 0.01 M phosphate buffer (100 mL, pH 6.8) at room temperature. After stirring at room temperature for 30 minutes, the organic layer was separated. The organic layer was washed twice with 100 mL of 0.01 M phosphate buffer pH 6.8.

The organic layer is concentrated under vacuum at 18-20 ° C / 110-80 mm Hg (14.6-10.6 kPa) (GC heptane content of 6.3% v / v). During

Subsequent concentrations under the same conditions were slowly added heptanes (30 mL) while maintaining the volume at approximately 40 mL.

Once crystallization has taken place, additional heptane (90 mL) is slowly added at room temperature and the suspension is aged for 1 hour at 20 ° C and then for 1 hour at 0 ° C.

The crystals were filtered off and washed with a mixture of IPAC and heptane (3:97 by volume, 100 ml) and dried under a stream of nitrogen. The product was obtained as a white crystalline solid (18 g, 93% yield, area 99.6%).

Example 3

(3b)

(1a)

Starting from compound 3b and following the procedure of Example 1, compound 1e is obtained.

Example 4

To a solution of 3b (245 mg) in a mixture of THF (1 mL) and EtOAc (2 mL) was added imidazole (80 mg) and TESCI (0.15 mL) at room temperature. After stirring for 2 hours, the reaction mixture was diluted with hexanes (3 mL) and washed twice with phosphate buffer (pH 7.0, 6 mL). The organic layer was dried over MgSO 4 and

- 11 concentrated to give crude 1f which was further purified on a silica gel column using hexanes and EtOAc (3: 2 to 1: 1) to give pure 1f (310 mg).

Compound 1d (16.0 kg), rhodium octanoate (0.123 kg), anhydrous zinc bromide (71 g) and dry dichloromethane (63.42 L, KF < 100 pg / mL) were charged to a dry reactor. Oxygen was removed from the solution by three vacuum / nitrogen purge cycles and then heated at reflux under nitrogen for 90 minutes to give a solution of 2d.

Starting from 1c and using the procedure of Example 5, 2c was obtained.

Example 7

CO ₂ PNB

(4a) ch ₂ or ₂

TESCl

imidazole

A solution of 3a (1.1 g) in methylene chloride (4 mL) was refluxed with zinc bromide (10 mg) and rhodium octanoate (10 mg) for 4 hours. The solution containing 4a was cooled to -78 ° C. To this solution was added a mixture of triethylsilyl chloride (0.65 mL) and imidazole (285 mg) at -78 ° C. The solution was aged at -78 ° C for 1 hour. The reaction mixture is slowly warmed to 0 ° C. In particular, the NMR analysis and HPLC solution contained 2d.

Example 8

(2f)

A solution of 1f (291 mg) in methylene chloride (5 mL) was heated with 10 mg of dimerium rhodium octanoate at 30 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure to give crude compound 2f (260 mg).

Example 9

TMSO

Starting from compound 1e and using the procedure of Example 8, intermediate 2e protected by TMS was obtained.

Example 10

(4a) (2f)

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

Claims (13)

PATENT CLAIMS wherein R is hydrogen or methyl and P is triethylsilyl or trimethylsilyl, wherein the compound of the formula is treated with a compound of the formula P-CI, wherein P is as defined above, in the presence of a base and a substantially non-reactive solvent to form a compound 2. A process for the synthesis of a compound of formula OPNB - 15 where R is a hydrogen atom or methyl, wherein the compound of the formula is treated with triethylsilyl chloride in the presence of a base and a substantially non-reactive solvent to form the compound The process according to claim 1, wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride. The process of claim 3, wherein the base is imidazole. A process for the synthesis of a compound of the formula wherein R is hydrogen or methyl, which is treated with triethylsilyl chloride in the presence of a nitrogen-containing base and a substantially non-reactive solvent to form a compound The process according to claim 5, wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride. The method of claim 6, wherein the base is imidazole. A process for the synthesis of a compound of the formula wherein R is a hydrogen atom or methyl, comprising reacting a compound of the formula - 17 with trimethylsilyl chloride in the presence of a base and a substantially non-reactive solvent to form a compound The process of claim 8, wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate, or methylene chloride. The process of claim 9, wherein the base is imidazole. A process for the synthesis of a compound of the formula wherein R is hydrogen or methyl, comprising reacting a compound of the formula with trimethylsilyl chloride in the presence of a base and a substantially non-reactive solvent to form the compound The process of claim 11, wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate, or methylene chloride. The method of claim 12, wherein the base is imidazole.