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Preparation method of oxazolidinone antibiotic intermediate

An intermediate and system technology, which is applied in the field of preparation of tedizolid phosphate intermediate, can solve problems such as unfavorable industrial scale-up, and achieve the effect of easy-to-obtain raw materials and simple process

Active Publication Date: 2020-03-31
NANJING YOUKE BIOLOGICAL MEDICAL RES +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, this method still cannot avoid the use of expensive palladium catalysts and corresponding ligands, which is also not conducive to industrial scale-up

Method used

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  • Preparation method of oxazolidinone antibiotic intermediate
  • Preparation method of oxazolidinone antibiotic intermediate
  • Preparation method of oxazolidinone antibiotic intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1. Preparation of 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid (compound 3)

[0029]

[0030] Under a nitrogen atmosphere, add 5-bromo-2-(2-methyltetrazol-5-yl)pyridine (compound 2, 20g, 0.083mol) in a 500mL three-neck reaction flask with an additional funnel and a nitrogen inlet connector , THF (200 mL) and triisopropyl borate (17.17 g, 0.091 mol, 1.1 equiv), and the mixture was cooled to -72°C. Add n-butyllithium (15.3ml, 0.183mol, 2.2eq) in batches to the external funnel, and drop it in about 2 hours, and control the temperature not to exceed -65°C during the dropwise addition. After the completion of the reaction was determined by HPLC, the reaction solution was quenched with 100 ml of 20% (w / w) ammonium chloride aqueous solution. When the temperature of the reaction solution rose to room temperature (two-phase separation), the THF layer was separated and concentrated to dryness under reduced pressure. The crude product was slurried with 30 mL of d...

Embodiment 2

[0031] Example 2. Preparation of 5-(2-fluoro-4-nitrophenyl)-2-(2-methyltetrazol-5-yl)pyridine (compound 4)

[0032]

[0033] Under nitrogen atmosphere, compound 3 (12.50g, 0.061mol), 1,2-difluoro-4-nitrobenzene (7.48g, 0.047mol, 0.77 equivalent), CuI (4.48g, 0.024mol, 0.39 eq), tetrabutylammonium bromide TBAB (3.03 g, 0.009 mol, 0.15 eq), cesium carbonate (30.62 g, 0.094 mol, 1.54 eq) and DMSO (120 mL). The mixture was heated and stirred at 145-150° C. until the substrate concentration did not change as monitored by HPLC. The reaction solution was cooled to room temperature, filtered, and the filtrate was poured into 300 mL of ether for extraction. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was further slurried with ethanol (30ml), filtered, and the filter cake was vacuum-dried to obtain 12.85g of compound 4, with a yield...

Embodiment 3

[0034] Example 3. Preparation of 3-fluoro-4-(6-(2-methyltetrazol-5-yl)pyridin-3-yl)aniline (compound 5)

[0035]

[0036] Add compound 4 (12.49g, 0.042mol), ethanol (120ml) and water (40ml) in reaction flask, then continue to add ammonium chloride solid (13.48g, 0.252mol, 6 equivalents) and iron powder ( 11.73 g, 0.210 mol, 5 equivalents). The reaction mixture was heated to 80° C. until the reaction was completed as monitored by HPLC. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Water (50ml) was added to the obtained residue, extracted with ethyl acetate (100ml×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The resulting product was used directly in the next step without isolation.

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Abstract

The invention provides a preparation method of a tedizolid phosphate intermediate compound 3-fluoro-4-(6-(2-methyltetrazole-5-yl)pyridine-3-yl)phenyl benzyl carbamate. The method comprises the following steps: carrying out a reaction on 5-bromo-2-(2-methyltetrazole-5-yl)pyridine as a raw material and triisopropyl borate under the action of n-butyllithium to prepare a boric acid intermediate, coupling the boric acid intermediate and 1,2-difluoro-4-nitrobenzene, and finally performing nitro reduction and amidation to obtain the required target product. Compared with the method in the prior art,the preparation method disclosed by the invention has the advantages of easily available raw materials, simple process, economy, environmental protection and suitability for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a tedizolid phosphate intermediate. Background technique [0002] Tedizolid phosphate is an oxazolidinone antibiotic developed by Cubist, which was approved by the FDA on June 10, 2014. Its trade name is Sivextro, and it is used for the treatment of Acute bacterial skin and skin structure infections caused by Staphylococcus aureus and gram-positive bacteria such as various Streptococcus species and Enterococcus faecalis. Tedizolid phosphate is an oxazolidinone antibiotic. By binding to the 50S subunit of bacterial ribosome, it inhibits bacterial protein synthesis and exerts antibacterial effect. It is not easy to produce cross-resistance with other types of antibiotics. It is the same as the first oxazolidine Compared with the ketone antibiotic linezolid, it has better efficacy and higher safety. [0003] Tedizolid phosphate, chemical name ((5R)-3-(4-(6-(2-...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 不公告发明人
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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