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Tedizolid crystal and preparation method thereof

A technology of tedizolid and crystals, which is applied in the field of medicinal chemistry, can solve the problems of unfavorable industrial production of tedizolid phosphate, increase the preparation cost of tedizolid phosphate, and cumbersome preparation process, etc., and achieve easy large-scale production , stable quality and simple process

Active Publication Date: 2016-11-23
SHANGHAI DESANO CHEM PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The patented process is cumbersome to operate, and the intermediates in each step need to be purified, and the impurities contained therein are difficult to remove in the subsequent preparation of tedizolid phosphate, and the purity of the obtained tedizolid phosphate is only 95.3% (see the Example 7 of the patent specification), it is necessary to undergo salt formation and acidification treatment to obtain tedizolid phosphate with a purity of 99.5% (see Example 9 of the patent specification), which not only increases the tedizolid phosphate The preparation cost also makes the preparation process very cumbersome, so it is also unfavorable for the industrialized production of tedizolid phosphate

Method used

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  • Tedizolid crystal and preparation method thereof
  • Tedizolid crystal and preparation method thereof
  • Tedizolid crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] At room temperature, add 1.0 g of compound of formula I, 1.2 g of compound of formula II, 0.8 g of potassium carbonate, 60 mg of tricyclohexylphosphine and 72 mg of tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ) catalyst, then add 4mL water and 15mL 1,4-dioxane, heat to reflux after vacuum and nitrogen replacement, keep warm and carry out SUZUKI coupling reaction under reflux state; when SUZUKI coupling reaction is complete (about 4 hours) , to end the reaction, filter the reaction solution while hot with diatomaceous earth, and naturally cool down and crystallize the collected filtrate to obtain 1.0g tedizolid crystals (off-white solid), the HPLC purity is 99.5%, and the molar yield is 78%.

[0042] figure 1For the XRD spectrogram of the obtained tedizolid crystals, by figure 1 It can be seen that under X-ray powder diffraction, the crystal has a main characteristic peak with a peak intensity of 100% at a diffraction angle 2θ of 14.1±0.2°, and at a diffractio...

Embodiment 2

[0046] At room temperature, add 1.0 g of compound of formula I, 1.5 g of compound of formula II, 1.0 g of sodium carbonate, 60 mg of triphenylphosphine and 60 mg of Pd(PPh 3 ) 4 Catalyst, then add 10mL water and 5mL tetrahydrofuran, heat to reflux after vacuum and nitrogen replacement, keep warm and carry out SUZUKI coupling reaction under reflux state; when the SUZUKI coupling reaction is complete (about 8 hours), end the reaction, use diatomaceous earth The reaction solution was filtered while it was hot, and the collected filtrate was naturally cooled and crystallized to obtain 0.9 g of tedizolid crystals (off-white solid), with an HPLC purity of 99.1% and a molar yield of 70%.

[0047] The tedizolid crystals obtained in this example also have figure 1 The XRD spectrum features shown and figure 2 The characteristics of the DSC spectrum shown and image 3 Characteristic TGA spectra shown.

Embodiment 3

[0049] At room temperature, add 1.0 g of compound of formula I, 1.1 g of compound of formula II, 1.0 g of triethylamine, 30 mg of triphenylphosphine and 30 mg of PdCl into the vessel 2 (PPh 3 ) 2 Catalyst, then add 2mL water and 20mL toluene, heat to reflux after vacuum and nitrogen replacement, keep warm and carry out SUZUKI coupling reaction under reflux state; when SUZUKI coupling reaction is complete (about 8 hours), end the reaction, use diatomaceous earth The reaction solution was filtered while it was hot, and the collected filtrate was naturally cooled and crystallized to obtain 1.0 g of tedizolid crystals (off-white solid), with an HPLC purity of 99.3% and a molar yield of 78%.

[0050] The tedizolid crystals obtained in this example also have figure 1 The XRD spectrum features shown and figure 2 The characteristics of the DSC spectrum shown and image 3 Characteristic TGA spectra shown.

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Abstract

The invention discloses a tedizolid crystal and a preparation method thereof. The preparation method comprises that pinacol 2-(2-methyl-2H-tetrazyl-5-yl)pyridyl-5-boronate shown in the formula I and (R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one shown in the formula II undergo a SUZUKI coupling reaction to produce tedizolid. Under X-ray powder diffraction, the tedizolid crystal has a main characteristic peak with intensity of 100% at a diffraction angle 2 theta of 14.1+ / -0.2 degrees. The preparation method has the advantages of simple processes, high product purity, stable quality and large scale production easiness and has a significant value of tedizolid phosphate raw material industrial production and corresponding preparation quality guarantee.

Description

technical field [0001] The invention relates to a method for preparing tedizolid and the obtained tedizolid crystal, belonging to the technical field of medicinal chemistry. Background technique [0002] Tedizolid Phosphate is a second-generation oxazolidinone antibiotic that was approved by the FDA on June 20, 2014. The chemical name of tedizolid phosphate is: (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5 -Hydroxymethyloxazolidin-2-one dihydrogen phosphate, the molecular formula is: C 17 h 16 FN 6 o 6 P, the molecular weight is 450.32, the CAS number is 856867-55-5, and its structural formula is: [0003] [0004] Tedizolid, chemical name: (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxy Methyloxazolidin-2-one is a key intermediate in the synthesis of tedizolid phosphate, and its structural formula is: [0005] [0006] East Asia Pharmaceutical Co., Ltd. reported the preparation method of tedizolid in Example 1 on ...

Claims

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Application Information

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IPC IPC(8): C07D413/14
Inventor 安晓霞刘军周吴胡猛
Owner SHANGHAI DESANO CHEM PHARMA
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