856867-55-5

Usage

Uses

Used in Pharmaceutical Industry:
Tedizolid Phosphate is used as an intracellular antibacterial drug for the treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive pathogens, including MRSA. It is administered both orally and intravenously, providing a convenient once-daily dosing option for patients.

A new antibacterial drug

Tedizolid phosphate is a new anti-bacterial drug developed by CUBIST PHARMS company. Tedizolid phosphate is a prodrug of Tedizolid. After oral or intravenous administration, Tedizolid phosphate is converted to Tedizolid by phosphatase. Tedizolid is the second generation of oxazolidinone antibiotics, a protein synthesis inhibitors. binding the 50S subunit of bacterial ribosomes, it can inhibit protein synthesis and play a role of antibacterial. It? is not easy to have? cross-resistance with other types of antibiotics, and has a longer half-life compared to linezolid. On June 20, 2014, the US Food and Drug Administration (FDA) approved Tedizolid phosphate for use in certain sensitive bacterial-induced adult acute bacterial skin and skin structure infections (ABSSSI), with trade name SIVEXTRO, specification 200 mg. Tedizolid phosphate has been submitted a listing application in Europe and Canada currently, while the drug has not yet listed in China. Tedizolid's listing application is based on clinical trials ESTABLISH 1 and ESTABLISH 2. The results showed that Tedizolid achieved its primary endpoint and secondary endpoint in clinical trials of ABSSSI (defined by the FDA and the European Medicines Agency). Clinical studies have shown that Tedizolid not only has a better clinical efficacy, and but shortened the treatment cycle by 40% compared with linezolid. In addition, the study of Tedizolid for hospital acquired/ventilator-associated bacterial pneumonia (HABP/VABP) has entered the clinical phase II. Analyst Larry Smith predicts the drug will sell more than $ 1 billion by 2020. This information was edited by Xiao Nan from lookchem (2015-08-14).

Indications

Tedizolid (Tedizolid Phosphate, Tidizolamide) is oxazolidinone compounds for serious Gram-positive bacterial infection treatment: Acute bacterial skin and skin structure infections and complex skin and soft tissue infections (absssi/cSSTI, IV/oral) (to be approved). Hospital Acquired/Ventilator-Associated Bacterial Pneumonia (HABP/VABP) (Clinical Phase II). SIVEXTRO is a class of oxazolidinone-based antimicrobials designed for Acute bacterial skin and skin structure infections (ABSSSI). In order to reduce the development of resistant bacteria and to maintain the effectiveness of SIVEXTRO and other antimicrobial agents, SIVEXTRO should only be used to treat or prevent infections that have been proven or strongly suspected to be bacterial-induced.

Clinical Use

Reversible non-selective MAO inhibitor: Antibacterial agent

Synthesis

Commercial 5-bromo-2-cyanopyridine (260) was treated with sodium azide and ammonium chloride in DMF to produce tetrazole 261, which was isolated by precipitation of the tetrazole ammonium salt. Subsequent methylation with methyl iodide in THF/DMF (3:1) afforded a 3.85:1 mixture of 262 and the corresponding N1-regioisomer. Acidification with 6 M HCl followed by treatment with 50% aqueous NaOH (to pH 10.6) enabled isolation of 262 in 96% isomeric purity; crude 262 was further purified by recrystallization from isopropyl acetate and obtained in 33% yield from 261. A Suzuki reaction of 262 with boronic acid 263 (which was prepared from commercial 4-bromo-3-fluoroaniline (267) as described in Scheme, via carboxybenzyl (Cbz) protection and lithiation/borylation) followed by recrystallization from ethyl acetate produced triaryl system 264. Deprotonation of the carbamate within 264 using lithium hexamethyldisilazide (LiHMDS) followed by reaction with R-(-)-glycidyl butyrate (265) in the presence of 1,3-dimethyl tetrahydropyrimidin-2 (1H)-one (DMPU) generated tedizolide 266 in 85% yield. Reaction with POCl3 in THF at 1–2 ℃ followed by subjection to sodium hydroxide and subsequent acidification furnished tedizolid phosphate (XXXIII) in 76% yield across the three steps.

Drug interactions

Potentially hazardous interactions with other drugs Alcohol: some alcoholic and de-alcoholised drinks contain tyramine which can cause hypertensive crisis. Alpha-blockers: avoid concomitant use with indoramin; enhanced hypotensive effect. Analgesics: CNS excitation or depression with pethidine, other opioids and nefopam - avoid; increased risk of serotonergic effects and convulsions with tramadol - avoid. Antidepressants: enhancement of CNS effects and toxicity; avoid MAOIs, SSRIs and vortioxetine for 2 weeks after use; care with all antidepressants. Antiepileptics: antagonism of anticonvulsant effect; avoid carbamazepine with or within 2 weeks of MAOIs. Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol. Antipsychotics: effects enhanced by clozapine. Atomoxetine: possible increased risk of convulsions - avoid concomitant use and for 2 weeks after use. Bupropion: avoid with or for 2 weeks after MAOIs. Dapoxetine: increased risk of serotonergic effects, avoid with or for 2 weeks after MAOIs. Dexamfetamine and lisdexamfetamine: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs. Dopaminergics: avoid concomitant use with entacapone and tolcapone; hypertensive crisis with levodopa and rasagiline - avoid for at least 2 weeks after stopping MAOI; hypotension with selegiline. 5HT1 agonist: risk of CNS toxicity with sumatriptan, rizatriptan and zolmitriptan - avoid sumatriptan and rizatriptan for 2 weeks after MAOI. Metaraminol: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs. Methyldopa: avoid concomitant use. Opicapone: avoid concomitant use. Sympathomimetics: hypertensive crisis with sympathomimetics - avoid. Tetrabenazine: risk of CNS excitation and hypertension - avoid.

Metabolism

Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to the microbiologically active moiety, tedizolid. Tedizolid is eliminated in excreta, primarily as a noncirculating sulfate conjugate. Following single oral administration of [14C]-labelled tedizolid under fasted conditions, the majority of elimination occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% in urine.

Upstream product

• 856866-72-3 (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridra-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazoiidin-2-one 
• 1188330-70-2 (R)-3-(4-bromo-3-fluoro-phenyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-oxazolidin-2-one 
• 1220910-89-3 3-fluoro-4-(6-(2-methyl-2H-tetrazole-5-yl)pyridin-3-yl)phenyl-carbamic acid benzylester 
• 510729-01-8 (4-bromo-3-fluorophenyl)carbamic acid benzyl ester 
• 874290-59-2 2-fluoro-4-(benzyloxycarbonyl)aminophenylboronic acid 
• 444335-16-4 (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one 
• 487041-08-7 (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one 
• 149524-42-5 (5R)-3-(3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one 
• 72755-13-6 (3-fluoro-phenyl)-carbamic acid methyl ester 
• 372-19-0 meta-fluoroaniline 
• 380380-60-9 2-(1,2,3,4-tetrazol-5-yl)-5-bromopyridine 
• 380380-64-3 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine 
• 97483-77-7 2-Cyano-5-bromopyridine 

Relevant academic research and scientific papers

Preparation method of tedizolid phosphate

The invention discloses a preparation method of tedizolid phosphate, and belongs to the technical field of medicines. The preparation method of tedizolid phosphate comprises the following steps: 1, synthesizing a compound IV; 2, synthesizing a compound II

Refining process of tedizolid and preparation method of tedizolid phosphate

The invention belongs to the field of medicine synthesis, and discloses a refining process of tedizolid. According to the invention, a mixed solution of dichloromethane, toluene and ethanol is prepared, tedizolid generated through Suzuki reaction is purified through steps of liquid separation, filtration and the like, and the obtained tedizolid pure product is used for tedizolid phosphate synthesis. While the purity of tedizolid is ensured, the consumption of tedizolid in the refining process is reduced, the yield of tedizolid is improved, the utilization rate of raw materials is improved, the production cost is saved, the tedizolid with higher purity participates in synthesis of tedizolid phosphate, the side reaction in the tedizolid phosphate synthesis process is reduced, the purification difficulty of tedizolid phosphate is reduced, and the purity and the yield of tedizolid phosphate are improved. The method is suitable for refining tedizolid compounds, and is especially suitable for refining an intermediate tedizolid in a tedizolid phosphate synthesis process.

Purification method of tedizolid phosphate

The invention relates to the technical field of medicinal chemistry, in particular to a purification method of tedizolid phosphate. The method comprises the following steps: firstly, crude tedizolid phosphate is creatively mixed with absolute ethyl alcohol, impurities with lower polarity than tedizolid phosphate in the crude tedizolid phosphate are dissolved in the absolute ethyl alcohol, then the impurities are removed by filtering, and tedizolid phosphate is left in a filtered solid; and other impurities can be removed by combining the subsequent steps of converting tedizolid phosphate solid into tedizolid phosphate disodium salt, acidifying, crystallizing and the like. The tedizolid phosphate obtained through purification is high in purity, the sodium hydroxide solution is clear, and a high-boiling-point solvent which is difficult to remove does not need to be used in the purification process of the purification method. The method is simple, convenient and beneficial to industrial production.

Preparation method of high-purity tedizolid phosphate

The invention discloses a preparation method of high-purity tedizolid phosphate. The preparation method comprises the following steps: 1, with 2-methyl-5-(5-bromopyridin-2-yl)tetrazole as a starting material and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) as a catalyst, and reacting the starting material and the catalyst with bis(pinacolato)diboron to generate a compound as shown in a formula 1, namely bromine-converted pinacol borate; 2, subjecting a compound shown in a formula 3 and (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one to Suzuki coupling under the catalyticaction of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to obtain (R)-3-[4-[2-(2-methyltetrazol-5-yl)pyridin-5-yl]-3-fluorophenyl]-5-one; and 3, preparing tedizolid phosphate from a compound as shown in a formula 5 under the condition of phosphorylation of phosphorus oxychloride.

Preparation method of tedizolid phosphate and intermediate thereof

The invention discloses a preparation method of tedizolid phosphate and an intermediate thereof. The preparation method of a tedizolid phosphate intermediate II comprises the following steps: 1, in anorganic solvent, under a condition of presence of a catalyst and zinc powder, performing a reaction on 3-fluorine-4-bromophenyl amino benzyl formate so as to obtain a solution of a tedizolid phosphate intermediate III; and 2, in an organic solvent, under a condition of presence of a palladium catalyst and a base, performing a coupling reaction on the solution of the tedizolid phosphate intermediate III obtained in the step 1 with 2-methyl-5-(5-bromopyridine-2-yl) tetrazole, so as to obtain the tedizolid phosphate intermediate II. The preparation method disclosed by the invention is free of toxic reagent, mild in reaction condition, safe to operate, environmentally friendly, high in yield, high in prepared product purity and low in production cost. Tedizolid phosphate prepared from the tedizolid phosphate intermediate II disclosed by the invention is high in yield, high in purity, capable of meeting raw material medicine standards and applicable to industrial production.

Nickel catalyzed tedizolid phosphate synthesis method

The invention discloses a nickel catalyzed tedizolid phosphate synthesis method. The method includes that methyl tetrazolium bromopyridine serving as an electrophilic reagent and N-oxazolidinone phenyl zinc halide serving as a nucleophilic reagent are subjected to nickel catalyzed Negishi coupling reaction and in-situ deprotection to obtain pharmaceutically active molecular tedizolid through a two-step one-pot process, and tedizolid is subjected to phosphoric acid esterification to obtain tedizolid phosphate. The method has advantages that 1) by in-situ synthesis and utilization of the organiczinc reagent, a complex step of metal reagent separation is avoided; 2) a cheap nickel catalyzing system is applied to establishment of a tedizolid phosphate core framework for the first time, and efficiency of nickel catalyzed Negishi coupling reaction is equivalent to that of palladium catalyzed Suzuki coupling reaction in current industrial synthesis of tedizolid phosphate. The remarkable advantages are beneficial to improvement of efficiency in tedizolid phosphate synthesis and production cost reduction, and the nickel catalyzed tedizolid phosphate synthesis method has a promising industrial application prospect.

Preparation method of tedizolid phosphate

The invention belongs to the field of pharmaceutical and chemical industry, and specifically relates to a preparation method of tedizolid phosphate. The compound shown as a formula Z1 is a tedizolid phosphate precursor, and is obtained in a cyclization reaction through catalyst catalysis by using X3 as a raw material. The preparation method of the compound shown as the formula Z1 comprises the following steps: carrying out the cyclization reaction on a compound shown as a formula X2 and a compound shown as a formula R under the existence of a catalyst and a solvent, so as to obtain the compound shown as a formula Z1; carrying out a phosphorylation reaction on the compound shown as the formula Z1 so as to obtain tedizolid phosphate. According to the preparation method disclosed by the invention, the compound with high boiling point such as DMPU is prevented from being used as the catalyst, and the dissolubility of the reaction system is improved through the addition of a mixed solvent,so that the reaction time is greatly shortened, and the compound is applicable for industrial production.

A high-purity extreme zuozuo amine phosphorus ester preparation method

The invention discloses a preparation method for high-purity tedizolid phosphate. The method is characterized by comprising the following steps: subjecting starting materials tedizolid and phosphorus oxychloride to a reaction so as to produce a tedizolid phosphorus oxychloride intermediate; then reacting the tedizolid phosphorus oxychloride intermediate with benzyl alcohol so as to produce a tedizolid dibenzyl phosphate intermediate; and carrying out debenzylation under the action of a catalyst so as to obtain tedizolid phosphate. Meanwhile, all the parameters of procedures are systematically adjusted. The introduced dibenzyl phosphate intermediate has good stability; benzyl protection removal reaction conditions are mild; compared with conventional preparation methods for tedizolid, by-reactions and generation of impurities are greatly reduced in the invention; the purity of the prepared tedizolid phosphate can reach more than 99.9%; and the preparation method omits the step of product purification, has more simplified steps and improves preparation efficiency of the tedizolid phosphate.

A process for the preparation of key intermediate thiazolylamine specially phosphate and its preparation method (by machine translation)

The invention discloses a key intermediate for preparing tedizolid phosphate. The key intermediate has a structure shown in formula I: R is any one of R1 or R2, and the R1 and R2 are independently selected from aryl groups or replaced aryl groups. The invention further discloses a preparation method of the key intermediate, and a method for preparing tedizolid phosphate by the key intermediate. The key intermediate disclosed by the invention is a solid compound and is easy to purify; besides, dipolymers, multimers and hydrolysis impurities cannot be generated during the preparation of tedizolid phosphat, the reaction temperature is moderate, the operation is simple, a strong-acidity reagent (phosphorus oxychloride) is prevented from being used, and the preparation method belongs to an environment-friendly production technology.

Method for preparing tedizolid phosphate

The invention discloses a method for preparing tedizolid phosphate, wherein the method specifically includes the steps: with N-[3-fluoro-4-[6-(2-methyl-2H-tetrazole-5-yl)-3-pyridyl]phenyl]benzyqcarbamate as a starting raw material, in the presence of R1-O-M, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, carrying out a reaction with R-glycidyl butyrate, and then esterfying with POCl3 phosphoric acid to obtain a tedizolid phosphate crude product; and adjusting the pH value to 7-9 with an alkali solution, converting the tedizolid phosphate crude product into a salt, and adjusting the pH value to 1-2 with hydrochloric acid to obtain the refined tedizolid phosphate. The method has the advantages of mild reaction conditions, relatively low cost, simple and convenient operation, less side reaction, high yield, good reaction reproducibility, economy and environmental protection, and is suitable for industrialized production.