Preparation method for tedizolid phosphate

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

Active Publication Date: 2016-03-23
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Abstract
  • Description
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Problems solved by technology

[0011] There are many defects in the synthetic method of tedizolid phosphate disclose...

Method used

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  • Preparation method for tedizolid phosphate
  • Preparation method for tedizolid phosphate
  • Preparation method for 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 - Preparation of ketones (compounds of formula V)

[0071] Add DMSO (100ml), (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (10g, 34.5mmol), biboronic acid to a 250ml reaction flask. Natrol ester (17.52 g, 69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.41 g, 1.73 mmol) and potassium acetate (13.5 g) , 138 mmol), under nitrogen protection, the temperature was raised to 80 °C, and the reaction was carried out for 14 hours. The heating was stopped, cooled to room temperature, extracted three times with water / ethyl acetate, and the organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated by suction filtration.

[0072] The concentrated product of the above step was added to a 250ml reaction flask, 1,4-dioxane (100ml), 5-bromo-2-(2-methyl-2H-te...

Embodiment 2

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

[0077] Dichloromethane (100ml), 1H-tetrazolium (5.97g, 85.2mmol) and formula V compound (10.5g, 28.4mmol) were added to the 500ml there-necked flask, and diisopropylamino phosphorous acid was added dropwise under temperature control at 30°C Dibenzyl ester (19.6 g, 56.8 mmol) was kept at 25-30 °C for 30 min. The temperature was lowered to 0-10°C, 85% m-chloroperoxybenzoic acid (8.08 g, 39.8 mmol) was added, and the reaction was carried out at 5-10°C for 30 min.

[0078] The reaction solution was successively 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% detected by HPLC (area norma...

Embodiment 3

[0082] The preparation of embodiment 3 Tedizolid Phosphate (formula I compound)

[0083] Methanol (1000ml), compound of formula VII (12.8g) and 10% Pd / C (50% water, 1.28g) were added to the 2L reaction flask, hydrogenation reaction was carried out at 50°C under normal pressure for 12h, filtered and evaporated to dryness to obtain 8.78g of the title. The yield of the compound was 96.0%, and the purity detected by HPLC was 99.66% (area normalization method).

[0084] 1 HNMR (500MHz, 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 CNMR (125MHz, 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, 45.493, 65.559, 45.497

[0086] ESI-MSm / 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] Tedizolidphosphate, (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyl Oxazolidin-2-one dihydrogen phosphate (formula I), the medicine is used for the treatment of 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 the following two kinds: [0005] Route 1: CN1894242 discloses the following preparation method: [0006] [0007] The first step of this route uses toxic organotin reagents, and the second step is condensation to prepare the key intermediate (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridine-5- (R)-[3-(4-(2-(2-(R)-[3-(4-(2-(2-(R)-[3-(4-(2-(2- Methyltetrazol-5-yl...

Claims

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Application Information

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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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