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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

[0017] An earlier patent application describes the preparation of bicyclic heteroaryl-2-carboxyaldehydes from a mixture of positional esters via chromatographic separation, reduction of the appropriate ester to the alcohol, and oxidation of the alcohol to the aldehyde (see U.S. Ser. No. 60 / 377052, filed May 1, 2002, Wyeth Case AM100862L1). The synthesis described herein eliminates the need for chromatography.

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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