New synthesis process of oxazolinone antibiotic

A new synthesis and compound technology, applied in the new synthesis field of tedizolid intermediates, can solve the problems of industrialized production, hidden dangers of large-scale production safety, insufficient process robustness, etc., to ensure quality and continuous supply, increase Process robustness, cost reduction effects

Active Publication Date: 2016-03-02
BEIJING CHEMPION BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the boric acid required for the Suzuki reaction needs to be prepared using butyllithium, which poses a huge hidden danger to the safety of large-scale production
In addition, the Suzuki reaction needs to use tricyclohexylphosphine, which is extremely sensitive to oxygen, which puts forward high requirements for process operation and process control, and the process is not robust enough, leaving hidden dangers for industrial production

Method used

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  • New synthesis process of oxazolinone antibiotic
  • New synthesis process of oxazolinone antibiotic
  • New synthesis process of oxazolinone antibiotic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Synthesis of benzyl 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenylcarbamate (Compound 1)

[0032]

[0033] Put compound 2 (2.4g, 10mmol), potassium acetate (2.9g, 30mmol) and pinacol diboron (3g, 12mmol) in a 500mL three-necked flask, add 1,4-dioxane (70mL) and Pd (dppf) 2 Cl 2 ·CH 2 Cl 2 (800mg, 1mmol). After nitrogen protection, heat to 80°C and react for 3 hours. After LC / MS detection confirmed that compound 2 was completely converted into compound 3, compound 4 (2.93g, 9mmol), Pd(dppf) were added 2 Cl 2 ·CH 2 Cl 2 (800mg, 1mmol), potassium carbonate (3.45g, 25mmol) and water (20mL), protected by nitrogen again, heated to 80°C for 12 hours. LCMS confirmed that the reaction was complete. Suction filtration was performed to remove the solid material. The obtained filtrate was evaporated under reduced pressure on a rotary evaporator to remove 1,4-dioxane, and then extracted with dichloromethane (100 mL×2), and the organic phases were combined and...

Embodiment 2

[0034] Example 2: Synthesis of benzyl 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenylcarbamate (Compound 1)

[0035]

[0036] Put compound 2 (120g, 0.5mol), potassium acetate (145g, 0.5mol) and pinacol diboron (150g, 0.6mol) in a 10L four-neck flask, and add 1,4-dioxane (3L) And Pd(dppf) 2 Cl 2 ·CH 2 Cl 2 (20g, 25mmol). After nitrogen protection, heat to 80°C and react for 3 hours. After LC / MS detection confirmed that compound 2 was completely converted into compound 3, compound 4 (146g, 0.45mol), potassium carbonate (173g, 1.2mol) and water (1L) were added, re-protected with nitrogen, and heated to 80℃ for 12 hours. . LCMS confirmed that the reaction was complete. Suction filtration was performed to remove solid materials. The obtained filtrate was evaporated under reduced pressure on a rotary evaporator to remove 1,4-dioxane, 500 mL of ethanol was added to the water phase, and the slurry was beaten overnight. After suction filtration, the filter cake was washed...

Embodiment 3

[0037] Example 3: Synthesis of benzyl 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenylcarbamate (Compound 1)

[0038] Step 1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-methyl-2H-tetrazole- Synthesis of 5-yl)pyridine

[0039]

[0040] Put compound 2 (2.4g, 10mmol), potassium acetate (2.9g, 30mmol) and pinacol diboron (3g, 12mmol) in a 250mL three-necked flask, add 1,4-dioxane (70mL) and Pd (dppf) 2 Cl 2 ·CH 2 Cl 2 (800mg, 1mmol). After nitrogen protection, heat to 80°C and react for 3 hours. After LC / MS detection confirmed that compound 2 was completely converted into compound 3, the temperature of the reaction system was lowered to room temperature, filtered, and the filtrate was evaporated to dryness. Add 50 mL of water and extract with ethyl acetate. The organic phases were combined, washed with saturated brine (200 mL×1), and dried with anhydrous sodium sulfate. Suction filtration, and the filtrate was evaporated to dryness under reduced pressure with...

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PUM

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Abstract

According to the method of the present invention, a methyl tetrazole pyridine bromide (2) and pinacol diboron are subjected to a reaction under catalysis of a transition metal to obtain a boronic acid pinacol ester (3), the compound (3) is separated or is not separated, and the separated compound (3) or the un-separated compound (3) and Cbz-protected bromobenzene (4) are subjected to a reaction under catalysis of a transition metal to obtain a key intermediate (1) of tedizolid. According to the present invention, the compound (3) is not subjected to separation purification, and reacts with the compound (4) in a kettle to generate the compound (1).

Description

Technical field [0001] The invention relates to a new synthetic method of Tedizolamide intermediate. Background technique [0002] Tedizolamide phosphate was approved by the US FDA in June 2014 for use in complex skin and soft tissue infections caused by methicillin-resistant Chrysococcus. Tedizolid phosphate is an inhibitor of bacterial protein synthesis and an upgraded version of linezolid. Unlike traditional antibiotics, Tedizolamide Phosphate selectively binds to the 50S subunit ribosomes of bacteria and interferes with the formation of 70S initiation complexes including mRNA, 30S ribosomes and initiation factors, thereby inhibiting bacterial protein synthesis. Because this inhibition process is in the early stage of protein translation, it is not easy to cross-resistance with antibiotics of other mechanisms. [0003] The patent WO2005058886 and the document Eur.J.Med.Chem., 2011, 46, 1027-1039 report the synthesis process of Tedizolamide phosphate. The patent first construct...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 蔡苹任婧
Owner BEIJING CHEMPION BIOTECHNOLOGY CO LTD
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