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Preparation method of compound for preventing gram-positive bacteria

A compound and complex technology, applied in the field of medicine and chemical industry

Active Publication Date: 2016-04-20
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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  • Preparation method of compound for preventing gram-positive bacteria
  • Preparation method of compound for preventing gram-positive bacteria
  • Preparation method of compound for preventing gram-positive bacteria

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] The preparation of embodiment 1B-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl]boronic acid (formula III compound)

[0073] DMSO (100ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (10.0g, 41.66mmol), pinacol diborate (12.69g, 49.99mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.7g, 2.08mmol) and potassium acetate (16.35g, 166.64mmol), N 2Under protection, the temperature was raised to 80°C, and the reaction was carried out for 3h. Dichloromethane / water extraction, the separated organic phase was washed with saturated NaCl solution, anhydrous Na 2 SO 4 Dehydration, filtration, vacuum concentration and purification by column chromatography afforded 8.11 g of solid with a yield of 95.0% and a purity of 98.2% by HPLC (area normalization method).

[0074] 1 HNMR (500 MHz, DMSO-d6): δ 8.9245 (s, 1H), 8.2169 (dd, 1H), 8.1549 (dd, 1H), 4.4811 (s, 3H).

[0075] 13 CNMR (125MHz, DMSO-d6): δ 163.901, 154.885, 148.290, 143.277, 121.612...

Embodiment 2

[0077] Example 2 (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyloxazolidine-2 - the preparation of ketone (formula V compound)

[0078] Add 1,4-dioxane (100ml), compound of formula III (8g, 39mmol), (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxane into 250ml reaction flask Oxazolidin-2-one (11.3 g, 39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.64 g, 0.78 mmol) and cesium carbonate Aqueous solution (60ml, containing 41.93g cesium carbonate, 128.7mmol), N 2 Under protection, the temperature was raised to 70°C, reacted for 3 hours, and extracted with dichloromethane. The separated organic phase was washed with saturated NaCl solution, anhydrous Na 2 SO 4 Dehydration, filtration, vacuum concentration and purification by column chromatography afforded 12.16 g of solid with a yield of 84.2% and a purity of 98.39% by HPLC (area normalization method).

[0079] 1 HNMR (500MHz, DMSO-d6): δ8.9328(s,1...

Embodiment 3

[0082] Example 3 (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazole Preparation of Alkyl]methyl Phosphate Bis(benzyl Ester) (Compound of Formula VII)

[0083] Add dichloromethane (100ml), 1H-tetrazolium (5.67g, 81.0mmol) and compound of formula V (10g, 27.0mmol) into a 500ml three-necked flask, and add diisopropylaminophosphite dropwise at a temperature below 30°C. Benzyl ester (18.65g, 54.0mmol), keep the temperature at 25-30°C for 30min. Cool down to 0-10°C, add 85% m-chloroperoxybenzoic acid (7.67g, 37.8mmol), and react at 5-10°C for 30min.

[0084] The reaction solution was sequentially washed with saturated NaHCO 3 solution was washed twice, saturated NaCl solution was washed once, anhydrous NaCl 2 SO 4 Drying, filtration, concentration in vacuo and purification by column chromatography afforded 14.1 g of the title compound in 82.8% yield and 99.49% purity by HPLC (area normalized method).

[0085] 1 HNMR (500MHz, DMSO-d6): δ8.9318(s,1...

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Abstract

The invention belongs to the field of pharmaceutical chemical engineering, relates to a preparation method of a compound for preventing gram-positive bacteria, and specifically relates to a preparation method of tedizolid. According to the preparation method, the purities of intermediates in each step and final product are very high. Moreover, diisopropylamino dibenzyl phosphite is taken as the phosphorylation reagent, dimerization is avoided, and thus the preparation method has a higher yield. The preparation method has the advantages that the route is short; the reaction conditions are mild; no toxic, irritant, or corrosive reagent is used; the preparation method is green and environment-friendly; at the same time, ultralow temperature reaction is avoided, the operation is simple and convenient, the production efficiency is high, and the preparation method is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of a compound against Gram-positive bacteria, in particular to a new preparation method of tedizolid phosphate. Background technique [0002] Tedizolidphosphate (tedizolidphosphate), (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)p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558
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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