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A kind of preparation method of bacterial protein synthesis inhibitor

A solvent and compound technology, which is used in the preparation of bacterial protein synthesis inhibitors and the preparation of tedizolid phosphate

Active Publication Date: 2018-12-21
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 bacterial protein synthesis inhibitor
  • A kind of preparation method of bacterial protein synthesis inhibitor
  • A kind of preparation method of bacterial protein synthesis inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Preparation of Example 1 (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphate bis(benzyl ester) (compound of formula VIII)

[0078] Add dichloromethane (50ml), 1H-tetrazolium (7.24g, 103.41mmol) and (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazole in 250ml there-necked flask Alkan-2-one (10.0g, 34.47mmol), temperature controlled below 30°C, add dropwise dibenzyl diisopropylamino phosphite (23.81g, 68.94mmol), keep the temperature at 25-30°C for 30min, cool down to 0-10°C, add 85% m-chloroperoxybenzoic acid (9.8g, 48.26mmol), and react at 5-10°C for 30min.

[0079] The reaction solution was sequentially washed with saturated NaHCO 3 Washed twice, washed once with saturated NaCl solution, anhydrous NaCl 2 SO 4 Drying, filtration, concentration in vacuo and purification by column chromatography afforded 17.11 g of the title compound in 90.2% yield and 99.24% purity by HPLC (area normalized method).

[0080] 1 H NMR (500MHz, DMSO-d6): δ7.6892(m,1...

Embodiment 2

[0083] Preparation of Example 2B-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl]boronic acid (compound of formula VI)

[0084] 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 2 Under 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).

[0085] 1 H NMR (500 MHz, DMSO-d6): δ 8.9245 (s, 1H), 8.2169 (dd, 1H), 8.1549 (dd, 1H), 4.4811 (s, 3H).

[0086] 13 C NMR (125 MHz, DMSO-d6): δ 163.901, 154.885, 148.290, 143.277, 121.612,...

Embodiment 3

[0088] 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)

[0089] Add 1,4-dioxane (60ml), compound of formula VIII (17.0g, 30.89mmol), compound of formula VI (6.97g, 33.98mmol), [1,1'-bis(diphenyl Phosphine) ferrocene] dichloropalladium dichloromethane complex (0.51g, 0.62mmol), sodium carbonate aqueous solution (30ml, containing 10.8g sodium carbonate, 101.94mmol), N 2 Under protection, the temperature was raised to 70°C, reacted for 3h, added dichloromethane for extraction, and the separated organic phase was washed with saturated NaCl solution, anhydrous NaCl 2 SO 4 Dehydration, filtration, vacuum concentration and purification by column chromatography yielded 15.31 g of a solid with a yield of 78.6% and a purity of 98.43% by HPLC (area normalization method).

[0090] 1 H NMR (500MHz, DMSO-d6): δ8.9318(s,1H),8.241(m,1H),8.1938(m,1H),7.7457(t,1H),7....

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Abstract

The present invention belongs to the field of medicine and chemical industry, relates to a bacterial protein synthesis inhibitor preparation method, and specifically relates to a tedizolid phosphate preparation method. According to the method, intermediates of every steps and a final product are high in purity. Further, by the use of diisopropylamine dibenzyl phosphite as a phosphorylating agent, a dimerization product can be avoided, and the preparation method has a higher yield. The preparation method is shorter in route and mild in reaction conditions, avoids the use of toxic, irritating and strongly-corrosive reagents, is green and environmentally-friendly, meanwhile avoids the use of ultra-low temperature reaction, and is simple and easy in preparation and high in production efficiency. Therefore, the preparation method is particularly adapted to 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 bacterial protein synthesis inhibitor, in particular to a 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 yiel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6558C07F5/02C07F9/653
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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