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A kind of preparation method of tedizolid phosphate

An independent, compound technology, applied in the field of medicine and chemical industry

Active Publication Date: 2018-11-20
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] There are many defects in the synthetic method of tedizolid phosphate disclosed in the prior art, so there is still a need to prepare a new method for tedizolid phosphate

Method used

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  • A kind of preparation method of tedizolid phosphate
  • A kind of preparation method of tedizolid phosphate
  • A kind of preparation method of tedizolid phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyloxazolidine-2 - the preparation of ketone (formula V compound)

[0071] Add DMSO (100ml), (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (10g, 34.5mmol) and diboronic acid to a 250ml reaction bottle Naol ester (17.52g, 69mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.41g, 1.73mmol) and potassium acetate (13.5g , 138mmol), under the protection of nitrogen, the temperature was raised to 80°C, and the reaction was carried out for 14 hours. Stop heating, lower to room temperature, extract with water / ethyl acetate 3 times, combine organic layers, wash 3 times with saturated brine, dry over anhydrous sodium sulfate, and concentrate by suction filtration.

[0072] Add the concentrated product of the above steps to a 250ml reaction flask, add 1,4-dioxane (100ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (8.28 g, 34.5mmol), ...

Embodiment 2

[0076] Example 2 (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidine Base] the preparation of bis(benzyl ester) of methyl phosphate (compound of formula VII)

[0077] Add dichloromethane (100ml), 1H-tetrazolium (5.97g, 85.2mmol) and compound of formula V (10.5g, 28.4mmol) into a 500ml three-necked flask, and add diisopropylaminophosphorous acid dropwise under temperature control below 30°C Dibenzyl ester (19.6g, 56.8mmol) was reacted at 25-30°C for 30min. Cool down to 0-10°C, add 85% m-chloroperoxybenzoic acid (8.08g, 39.8mmol), and react at 5-10°C for 30min.

[0078] The reaction solution was sequentially washed with saturated NaHCO 3 Washed twice, washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 14.89 g of the title compound with a yield of 83.1% and a purity of 99.62% by HPLC (area normalization method).

[0079] 1 H NMR (500 MHz, DMSO-d6): δ8.9...

Embodiment 3

[0082] The preparation of embodiment 3 tedizolid phosphate (formula I compound)

[0083] Add methanol (1000ml), compound of formula VII (12.8g) and 10% Pd / C (50% water, 1.28g) into a 2L reaction flask, hydrogenate at 50°C for 12h, filter and evaporate to dryness to obtain 8.78g of the title The yield of the compound is 96.0%, and the HPLC detection purity is 99.66% (area normalization method).

[0084] 1 H NMR (500 MHz, DMSO-d6): δ8.9367(s,1H), 8.2052(m,2H), 7.72(m,2H), 7.5162(m,1H), 4.99(m,1H), 4.4961( s,3H), 4.2546(t,1H), 4.1714(m,1H), 4.1035(m,1H), 3.9521(m,1H).

[0085] 13 C NMR(125 MHz,DMSO-d6):δ163.854,159.2905,153.925,149.382,145.069,140.286,137.083,131.558,130.87,122.044,118.764,114.079,105.509,71.467,65.457,45.833,39.549。

[0086] ESI-MS m / z[M+H] + :451.0927.

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Abstract

The invention belongs to the field of medicine chemical industry and particularly relates to a preparation method for tedizolid phosphate. According to the preparation method provided by the invention, intermediates in the steps and the final product are high in purity. In addition, by using diiso-propylamido dibenzyl phosphite as a phosphorylation reagent, a dimerized product is further avoided, so that the preparation method provided by the invention is higher in yield. The preparation method provided by the invention is relatively short in route and mild in reaction condition, and further avoids use of toxic, irritant and strongly corrosive reagents, so that the preparation method is green and environmentally friendly. Meanwhile, ultralow temperature reaction is avoided, so that the preparation method is simple to operate, and the tedizolid phosphate is easy to prepare and high in production efficiency. Thereofe, the preparation method provided by the invention is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a new preparation method of tedizolid phosphate. Background technique [0002] Tedizolid phosphate, (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyl Oxazolidin-2-one dihydrogen phosphate (formula I), which is used to treat Gram-positive bacterial infections, such as acute bacterial skin infections, infections caused by MRSA, and lung infections. [0003] [0004] At present, the preparation method of disclosed tedizolid phosphate mainly contains following two kinds: [0005] Route 1: CN1894242 discloses the following preparation method: [0006] [0007] The first step reaction of this route uses toxic organotin reagents, and the second step condensation reaction prepares the key intermediate (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridine-5- Base) the yield of 3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-ketone is as l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6558C07D413/14
Inventor 朱益忠张喜全刘飞顾红梅朱波汤剑秋汤松王路路
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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