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Process for synthesizing beta-lactamase inhibitor intermediates

a technology of beta-lactamase and intermediates, which is applied in the field of synthesizing beta-lactamase inhibitor intermediates, can solve the problems of loss of antibacterial activity, damage to the effective treatment of bacterial infections,

Inactive Publication Date: 2008-01-10
WYETH HOLDINGS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new process for the preparation of bicyclic heteroaryl carboxaldehydes, which are useful for the synthesis of bicyclic heteroaryl substituted 6-alkylidene penems. The process involves nitrosating an amino acid to form a nitroso compound, which is then reacted with a thiol to form a thioether. The resulting thioether is then oxidized to form the carboxaldehyde. The process is advantageously selective and avoids the need for chromatography. The invention also provides a method for the preparation of bicyclic heteroaryl carboxaldehydes from a mixture of positional esters via aqueous base hydrolysis of the desired ester and isolation of the product as the potassium salt. The invention solves the problem of the existing methods and provides a new method for the preparation of bicyclic heteroary carboxaldehydes.

Problems solved by technology

However, the development of resistance to β-lactam antibiotics by different pathogens has had a damaging effect on maintaining the effective treatment of bacterial infections.
These enzymes degrade the β-lactam antibiotics, resulting in the loss of antibacterial activity.

Method used

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  • Process for synthesizing beta-lactamase inhibitor intermediates
  • Process for synthesizing beta-lactamase inhibitor intermediates
  • Process for synthesizing beta-lactamase inhibitor intermediates

Examples

Experimental program
Comparison scheme
Effect test

example 1

(2S)-1-Nitrosoproline

[0144]

[0145] To a solution of L-proline (2.50 kg, 21.6 moles) and sodium nitrite (2.10 kg, 30.4 moles) in water (5.0 L) maintained at 0-10° C. is added concentrated hydrochloric acid (2.53 L) and the resulting slurry is stirred for 16 hours at ambient temperature. The reaction mixture is extracted with t-butyl methyl ether (1×6 L+2×3 L) and the organic solution is concentrated using a rotary evaporator with a bath temperature below 35° C. Residual water is removed by evaporation with 2.0 L of toluene. The resulting (2S)-1-nitrosoproline (3.25 kg, 105%) is isolated as a yellow solid and dried under vacuum at 25° C., m.p. 100-102° C., HPLC purity, 96.3% (area % HPLC conditions described in Example 7) and residual toluene, 4%. The product of the example is used directly, without further purification, in the next step (see example 2).

example 2

3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium Ylide

[0146]

[0147] Trifluoroacetic anhydride (3.86 kg, 18.4 moles) is added slowly to a slurry of (2S)-1-nitrosoproline (1.75 kg, 12.2 moles from example 1) in toluene (6 L) below 10° C. The resulting dark-red solution is stirred for 2 hours at ambient temperature and the reaction is quenched by adding the dark-red solution to a stirred mixture of potassium carbonate (2.70 kg, 19.6 moles), dichloromethane (3.5 L) and water (2.0 L) below 25° C. Following complete addition and after separating the upper organic layer, the aqueous layer is extracted with dichloromethane (3×3.0 L). The combined organic extracts are concentrated under vacuum using a rotary evaporator with a bath temperature at 35-45° C. Residual water is removed by evaporation with toluene (2.0 L) to afford the title compound as a dark liquid, which solidified upon standing (0.91 kg, 58% yield over 2 steps). The product of the example, 3a,4,5,6-tetrahydro-...

example 3

3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium Ylide

[0148]

[0149] To a solution of (2S)-1-nitroso-proline (9.20 g, 0.0638 mol) in dichloromethane (50 mL) under nitrogen at 0-5° C. is added trifluoroacetic anhydride (12 mL, 0.0850 mol) dropwise over a period of 10 minutes. After 15 minutes all the solid had dissolved and the solution started to turn colored. After a total reaction time of 20 minutes the dark solution is poured into a magnetically stirred mixture of potassium bicarbonate (22 g) and water (50 ml) using dichloromethane (50 mL) as a rinse. The lower organic phase is separated and the dark colored, aqueous phase is extracted with dichloromethane (3×50 mL). The combined organic extracts are dried over anhydrous magnesium sulfate overnight. The drying agent is collected on a filter and washed with dichloromethane (50 mL). The dark red filtrate and washings are evaporated to a dark red, mobile, oil (7.17 g, 89%) which crystallized on seeding with material ...

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Abstract

There is provided a process for the preparation of bicyclicheteroaryl carboxaldehydes having the structural Formula I where X and Y are defined in the specification The bicyclic heteroaryl carboxaldehydes are useful as intermediates in the preparation of β-lactamase inhibitors.

Description

[0001] This application is a divisional application of copending application, application Ser. No. 10 / 844,243 filed May 12, 2004 which claims priority from provisional application, Application No. 60 / 471,458 filed on May 16, 2003. These applications are herein incorporated by reference in their entireties.FIELD OF THE INVENTION [0002] The invention relates to a process for synthesizing intermediate bicyclic heteroaryl carboxaldehydes useful in the synthesis of β-lactamase inhibitors which are useful in antibiotic therapy. BACKGROUND OF THE INVENTION [0003] New improved antibiotics are continually in demand, for the treatment of diseases in man. According to the World Health Organization, more than 95% of the Staphylococcus aureus isolates worldwide are now resistant to penicillin and up to 60% are resistant to methicillin (Breithaupt, H. Nat Biotechnol. 17(12), 1165-9 (1999) and the references therein). Resistance is spreading from hospital-acquired infections to community-acquired ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D277/60C07D487/04C07D513/12
CPCC07D498/04C07D487/04A61P31/04
Inventor WINKLEY, MICHAEL WILLIAMCHAN, ANITA WAI-YINJIRKOVSKY, IVO L.KREMER, KENNETH ALFRED MARTINZELDIS, JOSEPHNIKITENKO, ANTONIA ARISTOTELEVNASTRONG, HENRY LEEMANSOUR, TAREKKHAFIZOVA, GULNAZVENKATESAN, ARANAPAKAM M.
Owner WYETH HOLDINGS CORP
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