Tedizolid phosphate, preparation method of intermediate of tedizolid phosphate and injection

A technology of tedizolid phosphate and intermediates, applied in the field of preparation methods and injections of tedizolid phosphate and intermediates thereof, can solve the problems of unsuitability for industrialized production, harsh reaction conditions, low production costs and the like, and achieve improved selectivity. and catalytic, low production cost, easy separation effect

Pending Publication Date: 2022-04-12
山西振东泰盛制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The present invention overcomes the disadvantages of the preparation method of tedizolid phosphate intermediate in the prior art, such as harsh reaction conditions, dangerous operation, need to use highly toxic reagents, serious environmental pollution, low reaction yield, unsuitable for industrialized production, etc., and proposes a phosphoric acid The preparation method and injection of tedizolid and its intermediates, the preparation method has mild reaction conditions, high catalytic efficiency, safe operation, environmental friendliness, high yield (78%~82%), and the obtained product has high purity (HPLC purity greater than 98.5%), low production cost

Method used

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  • Tedizolid phosphate, preparation method of intermediate of tedizolid phosphate and injection

Examples

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preparation example 1Pd

[0035] The preparation of preparation example 1Pd series catalyst

[0036] S1. Preparation of silica magnetic microspheres: Add 10g of γ-aminopropyltrimethoxysilane and 4g of ferrous chloride into water, add dropwise 25wt% ammonia solution, adjust the pH to 9, heat to 80°C, and Ultrasonic while dropping, the power is 1000W, after 2 hours of reaction, magnet separation, washing, to obtain silica magnetic microspheres;

[0037] S2. Preparation of Pd-loaded silica magnetic microspheres: Disperse 1 g of silica magnetic microspheres in water, disperse evenly by ultrasonic, add 0.82 g of PdCl 2 , heated to 50° C., reacted for 1 h, separated by a magnet, and washed to obtain a Pd-based catalyst, and the amount of Pd-containing substances per g of the Pd-based catalyst was 0.001 mol. figure 1 It is a SEM image of the Pd-based catalyst, and it can be seen from the image that the particle size of the microspheres is between 100-500nm.

Embodiment 1

[0039] synthetic route:

[0040]

[0041] Step 1, the synthesis of intermediate T1:

[0042] Add 2-methyl-5-(5-bromopyridin-2-yl)tetrazolium 20.00g, biboronic acid pinacol ester 27.51g, the Pd-based catalyst prepared in Preparation Example 1 to a dry 500mL four-necked flask 3g, KOAc 24.53g, 1,4-dioxane 300mL, stirring, N 2 Replace three times. Replacement completed, N 2 Under protection, the temperature was raised to 90° C., and the reaction was incubated for 2 hours. The reaction was monitored by TLC (2-methyl-5-(5-bromopyridin-2-yl)tetrazolium spots disappeared). Under nitrogen protection, 150 mL of purified water, 22.96 g of (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one, K 2 CO 3 32.82g stirred and reacted for 2h. After the reaction is complete, turn off the heating, lower the temperature naturally, stir and crystallize, filter for 18 hours, and rinse the filter cake with 100 mL of 1,4-dioxane: water = 1:1 mixture and 100 mL of purified water. ...

Embodiment 2

[0049] Step 1, the synthesis of intermediate T1:

[0050] Add 40.00 g of 2-methyl-5-(5-bromopyridin-2-yl)tetrazolium, 55.2 g of pinacol ester of diboronic acid, and the Pd-based catalyst prepared in Preparation Example 1 into a dry 1000 mL four-necked flask 5g, KOAc 49.06g, 1,4-dioxane 600mL, stirred, replaced with Ar gas three times. After the replacement, the temperature was raised to 90° C. under the protection of Ar gas, and the reaction was incubated for 3 hours. TLC monitored the completion of the reaction (2-methyl-5-(5-bromopyridin-2-yl)tetrazolium spots disappeared). Under the protection of Ar gas, 300 mL of purified water and 45.92 g of (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one were added to the above reaction mixture 、K 2 CO 3 65.64g stirred and reacted for 2h. After the reaction is complete, turn off the heating, lower the temperature naturally, stir and crystallize, filter for 20 hours, and wash the filter cake with 200 mL of 1,4-dioxane...

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Abstract

The invention provides tedizolid phosphate, a preparation method of an intermediate of tedizolid phosphate and an injection, and belongs to the technical field of organic synthesis.The preparation method comprises the steps that 1, 2-methyl-5-(5-bromopyridine-2-yl) tetrazole, bis (pinacolato) diboron, a Pd catalyst and KOAc are mixed and heated for a reaction, water, (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyl oxazolidine-2-ketone and K2CO3 are added for a reaction, a reaction is conducted, and a reaction solution is obtained; cooling, crystallizing, filtering, washing and drying to obtain an intermediate T1; and (2) mixing the intermediate T1, triethylamine and phosphorus oxychloride for reaction, performing cold water quenching reaction, filtering, washing, drying and refining to obtain tedizolid phosphate. The preparation method disclosed by the invention is mild in reaction condition, high in catalytic efficiency, safe to operate, environment-friendly, high in yield, high in purity of the prepared product and low in production cost.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of tedizolid phosphate and an intermediate thereof and an injection. Background technique [0002] The treatment of infectious diseases such as skin and soft tissue infections (SSSIs), pneumonia, sepsis, and endocarditis caused by Gram-positive bacteria is still facing severe challenges in today's advanced modern medicine. Taking methicillin-resistant Staphylococcus aureus (MRSA) as an example, MRSA appeared 2 years after the clinical application of methicillin, and after more than 50 years, the bacteria has been widely spread in hospitals all over the world. Since the early 1990s, community-acquired MRSA (CA-MRSA) appeared and spread globally, changing the old idea that MRSA infection only occurs in hospital settings. The problem of drug resistance in Gram-positive bacteria is not limited to MRSA, including challenges posed by vancomycin-resistant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07D413/14A61K31/675A61P17/00A61P31/04A61K9/00B01J23/89B01J35/08
Inventor 高治华韩佩莲沈达
Owner 山西振东泰盛制药有限公司
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