CN111116652A

CN111116652A - A kind of preparation method of high-purity tedizolid phosphate

Info

Publication number: CN111116652A
Application number: CN201911241003.3A
Authority: CN
Inventors: 王振国; 齐冬梅; 阴启明; 付先军; 王晓龙
Original assignee: Shandong University of Traditional Chinese Medicine
Current assignee: Shandong University of Traditional Chinese Medicine
Priority date: 2019-12-06
Filing date: 2019-12-06
Publication date: 2020-05-08
Also published as: CN111518135B; CN111518135A

Abstract

A preparation method of high-purity tedizolid phosphate comprises the following steps: the method comprises the following steps: taking 2-methyl-5- (5-bromopyridine-2-yl) tetrazole as an initial material, taking tetrakis (triphenylphosphine) palladium (Pd (PPh3) 4) as a catalyst, and reacting with pinacol diboron to generate bromine of a compound shown in a formula 1, and converting the bromine into pinacol borate; step two: the compound of formula 3 is coupled with (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone by Suzuki under the catalysis of tetrakis (triphenylphosphine) palladium (Pd (PPh3) 4) to obtain (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine; step three: the compound of the formula 5 is prepared under the condition of the phosphorylation of phosphorus oxychloride to obtain tedizolid phosphate.

Description

Preparation method of high-purity tedizolid phosphate

Technical Field

The invention belongs to the field of preparation of tedizolid phosphate, and particularly relates to a preparation method of high-purity tedizolid phosphate.

Background

Tedizolid phosphate (1) with the chemical name (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl]-3-fluorophenyl group]-5-hydroxyMethyl oxazolidin-2-one phosphate ester with the structure

The drug is a prodrug of a novel oxazolidinone antibacterial drug developed by Cubist pharmaceutical company, is approved by FDA to be on the market in 7 months in 2014, and has two administration modes of oral administration and injection. The product can be used for treating acute bacterial skin and skin tissue structure infection caused by gram-positive bacteria in vivo by removing phosphate group through serum phosphatase action and converting into active form tedizolid. Unlike chloramphenicol and lincomycin, the product does not hinder the formation of formylmethionine tRNA and is not easy to generate cross drug resistance with other drugs.

Because of the existing process steps of using high-toxicity organic tin reagent in the currently reported synthesis process of tedizolid phosphate; some process steps are used under the condition of ultralow temperature (-78 ℃), the reaction conditions are harsh, the yield is low due to more by-products in product quality, the purity is generally low below 70%, and the purity of the tedizolid phosphate obtained after the reaction is generally lower than 95%. In addition, a new process is reported in a document (a new synthesis method of tedizolid phosphate [ J ] application chemistry 2015 32 volume 11 period), wherein (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone (a compound shown in a formula 4) is used as a starting material, boronized, coupled with 2-methyl-5- (5-bromopyridin-2-yl) tetrazole (a compound shown in a formula 1) Suzuki, finally subjected to dibenzyl N, N-diisopropylphosphoramidite serving as a phosphorylation reagent, and finally subjected to debenzylation to obtain the tedizolid phosphate; the method finally removes benzyl through hydrogenation reaction, and has great potential safety hazard.

Disclosure of Invention

The invention provides a preparation method of high-purity tedizolid phosphate, which is used for overcoming the defects in the prior art.

The invention is realized by the following technical scheme:

a preparation method of high-purity tedizolid phosphate comprises the following steps:

the method comprises the following steps: adding 2-methyl-5- (5-bromopyridine-2-yl) tetrazole, pinacol diboron, potassium acetate and 1, 4-dioxane into a reactor, starting stirring, replacing with nitrogen twice, adding palladium tetrakis (triphenylphosphine) under the protection of nitrogen, heating to 65-75 ℃, reacting for 4 hours, stopping heating after the reaction is finished, adding n-heptane, cooling to 0-10 ℃, keeping the temperature and stirring for 1 hour, removing the protection of nitrogen, discharging and filtering, leaching a filter cake once with n-heptane, leaching until no filtrate drips, collecting the filter cake, drying at 45-55 ℃ in a vacuum drying oven, collecting and weighing after 8 hours to obtain pinacol borate;

step two:

step 1: adding pinacol borate, (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-one, 1, 4-dioxane and a potassium carbonate solution into a reactor, starting stirring, replacing twice with nitrogen, adding tetrakis (triphenylphosphine) palladium under the protection of nitrogen, heating to 55-65 ℃, reacting for 5 hours, removing nitrogen after the reaction is finished, cooling to 20-30 ℃, adding purified water, cooling to 5-15 ℃, keeping the temperature and stirring for 0.5 hour, performing throw filtration, leaching a filter cake for 1 time by using 1, 4-dioxane, performing throw filtration until no liquid flows out, and collecting the filter cake;

step 2: adding the filter cake obtained in the step (1) and N, N-dimethylacetamide into a reactor, starting stirring, heating to 55-65 ℃, keeping the temperature and stirring for 1h, cooling to 15-25 ℃, filtering, leaching the filter cake with N, N-dimethylacetamide, and collecting filtrate;

and step 3: adding the filtrate obtained in the step 2, L-cysteine and triethylamine into a reactor, starting stirring, reacting in a dark place, replacing with nitrogen once, heating to 55-65 ℃, reacting for 16h, cooling to 15-25 ℃, reacting for 0.5h, performing suction filtration, leaching a filter cake for 1 time by using N, N-dimethylacetamide, and collecting filtrate;

and 4, step 4: adding the filtrate obtained in the step 3 into a reactor, starting stirring, cooling to 5-15 ℃, adding purified water, controlling the temperature below 35 ℃ in the process of adding the purified water, stirring for 1h at the temperature of 15-25 ℃ after adding the purified water, performing throw filtration, leaching filter cakes respectively for 1 time by using an N, N-dimethylacetamide/purified water mixed solution and anhydrous methanol, performing throw filtration until no liquid flows out, and collecting the filter cakes;

and 5: adding the filter cake obtained in the step (4) and anhydrous methanol into a reactor, starting stirring, controlling the temperature to be 20-30 ℃, keeping the temperature and stirring for 1h, performing filtration in a throwing manner, leaching the filter cake for 1 time by using the anhydrous methanol, performing filtration in a throwing manner until no liquid flows out, collecting the filter cake, putting the filter cake into a vacuum drier, drying for 5h at the temperature of 55-65 ℃ under the condition that the vacuum degree is more than or equal to 0.09MPa, collecting and weighing to obtain (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridine-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine;

step three: adding (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridine-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine, triethylamine and tetrahydrofuran into a reactor under the protection of nitrogen, starting stirring, cooling to-5-5 ℃, adding phosphorus oxychloride/tetrahydrofuran solution, controlling the temperature to-5-5 ℃ after the addition is finished, stirring for 5 hours, taking out the mixed solution, adding purified water into the reactor, cooling to 0-10 ℃, starting stirring, adding the mixed solution, controlling the system temperature to 0-10 ℃ during the addition process, heating to 20-30 ℃ after the addition is finished, stirring for 1 hour, performing swing filtration, leaching a filter cake for 1 time by using purified water, performing swing filtration until no liquid flows out, collecting a filter cake; and (3) putting the filter cake into a reactor, adding methanol and purified water, keeping the temperature, stirring for 0.5h, performing spin filtration, leaching the filter cake for 1 time by using methanol, performing spin filtration until no liquid flows out, collecting the filter cake, putting the filter cake into a hot air circulation drying box, heating to 35-45 ℃, and drying for 4h to obtain the tedizolid phosphate.

The preparation method of the high-purity tedizolid phosphate comprises the following steps of:

4.3 parts of 2-methyl-5- (5-bromopyridine-2-yl) tetrazole, 5.4 parts of pinacol diboron, 3.5 parts of potassium acetate, 35 parts of 1, 4-dioxane and 0.29 part of tetrakis (triphenylphosphine) palladium.

pinacol borate 3.8 parts, (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyloxazolidine-2-one 4.7 parts, 1, 4-dioxane 24.3 parts, potassium carbonate solution 13.8 parts, tetrakis (triphenylphosphine) palladium 0.67 part, L-cysteine 1.4 parts, triethylamine 1.4 parts.

1 part of (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine, 0.82 part of triethylamine, 17.8 parts of tetrahydrofuran and 2.14 parts of phosphorus oxychloride/tetrahydrofuran solution.

In the preparation method of high-purity tedizolid phosphate, the mass ratio of the solute to the solvent of the potassium carbonate solution in the second step is 4.5: 9.3.

According to the preparation method of the high-purity tedizolid phosphate, the N, N-dimethylacetamide/purified water mixed solution is prepared by mixing N, N-dimethylacetamide and purified water according to the mass ratio of 1: 1.

According to the preparation method of the high-purity tedizolid phosphate, the phosphorus oxychloride/tetrahydrofuran solution is prepared by mixing and dissolving phosphorus oxychloride and tetrahydrofuran according to the mass ratio of 1.26: 0.88.

The preparation method of the high-purity tedizolid phosphate, wherein in the first step, the mass of the n-heptane added into the reactor is not more than the mass of the reaction liquid;

in the preparation method of the high-purity tedizolid phosphate, the mass of the n-heptane for washing the filter cake in the first step is not more than that of the filter cake.

In the preparation method of high-purity tedizolid phosphate, the mass of the purified water added into the reactor in the step 1 of the step two is not more than that of the reaction liquid;

according to the preparation method of the high-purity tedizolid phosphate, in the step 1 of the step two, the mass of 1, 4-dioxane of the filter cake washed is not more than that of the filter cake;

in the preparation method of the high-purity tedizolid phosphate, the mass of the N, N-dimethylacetamide added into the reactor together with the filter cake in the step 2 of the step two is 1-4 times of the mass of the filter cake;

in the preparation method of high-purity tedizolid phosphate, the mass of the N, N-dimethylacetamide for washing the filter cake in the step 2 of the second step is not more than that of the filter cake;

in the preparation method of high-purity tedizolid phosphate, the mass of the N, N-dimethylacetamide for washing the filter cake in the step 3 of the step two is not more than that of the filter cake;

in the preparation method of high-purity tedizolid phosphate, the mass of the N, N-dimethylacetamide/purified water mixed solution and the anhydrous methanol for leaching the filter cake in the step 4 of the step two is not more than that of the filter cake;

in the preparation method of the high-purity tedizolid phosphate, the mass of the anhydrous methanol added into the reactor together with the filter cake in the step 5 of the step two is 1-4 times of the mass of the filter cake;

in the preparation method of the high-purity tedizolid phosphate, the mass of the anhydrous methanol for washing the filter cake in the step 5 of the step two is not more than that of the filter cake.

The method for preparing high-purity tedizolid phosphate comprises the following steps that in the third step, the mass of purified water added into the reactor together with the reaction liquid is 0.8-1.5 times of the mass of the reaction liquid;

in the preparation method of the high-purity tedizolid phosphate, the mass of the purified water for washing the filter cake for the first time in the third step is not more than that of the filter cake;

the method for preparing high-purity tedizolid phosphate comprises the following steps that in the third step, the mass of the purified water added into the reactor together with the filter cake is not more than that of the filter cake, and the weight of the methanol added into the reactor together with the filter cake in the third step is 2-5 times that of the filter cake;

in the preparation method of the high-purity tedizolid phosphate, the mass of the methanol in the filter cake rinsed for the second time in the third step is not more than that of the filter cake.

The invention has the advantages that: the process method reported by the invention firstly provides that 2-methyl-5- (5-bromopyridine-2-yl) tetrazole (a compound shown as a formula 1 in a figure 1) is used as a starting material, tetrakis (triphenylphosphine) palladium (Pd (PPh3) 4) is used as a catalyst, bromine of the compound shown as the formula 1 is reacted with pinacol diboron (a compound shown as a formula 2 in the figure 1) to generate pinacol borate (a compound shown as a formula 3 in the figure 1), the bromine is converted into pinacol borate, and the pinacol borate is subjected to Suzuki coupling with (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-one (a compound shown as a formula 4 in the figure 1) under the catalytic action of tetrakis (triphenylphosphine) palladium (Pd (PPh3)4 to obtain (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridine -5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine (compound of formula 5 in figure 1), (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine is prepared to tedizolid phosphate (compound of formula 6 in figure 1) by phosphatization.

The process method for preparing tedizolid phosphate has the advantages of no need of ultralow temperature operation and simple reaction; the purity is high and can reach more than 95 percent; the by-products are few, and the yield is high and is higher than 70%; the process is stable and has strong operability, avoids high-toxicity organic tin reagents and harsh reaction conditions, also avoids high-risk processes such as hydrogenation reaction and the like, and can realize safe industrial production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.

FIG. 1 is a reaction scheme of the present invention;

FIG. 2 is a purity detection spectrum of doxazosin phosphate.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

A preparation method of high-purity tedizolid phosphate is characterized by comprising the following steps: comprises the following steps:

the method comprises the following steps: adding 2-methyl-5- (5-bromopyridine-2-yl) tetrazole, 5.4kg pinacol diboron, 3.5kg potassium acetate and 35.0kg1, 4-dioxane into a reactor, starting stirring, replacing with nitrogen twice, adding 0.29kg palladium tetrakis (triphenylphosphine) under the protection of nitrogen, heating to 70 ℃, reacting for 4 hours, stopping heating after the reaction is finished, adding 22.0kg n-heptane, cooling to 5 ℃, keeping the temperature and stirring for 1 hour, removing the protection of nitrogen, discharging and pumping, leaching a filter cake once by using 4.0kg n-heptane, pumping and filtering until no filtrate drips, collecting the filter cake, drying at 50 ℃ in a vacuum drying oven, weighing after 8 hours, and obtaining the pinacol borate;

step two:

step 1: adding 3.8kg of pinacol borate, 4.7kg of (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-one, 24.3kg of 1, 4-dioxane and 13.8kg of potassium carbonate solution into a reactor, starting stirring, replacing with nitrogen twice, adding 0.67kg of tetrakis (triphenylphosphine) palladium under the protection of nitrogen, heating to 60 ℃, reacting for 5 hours, removing nitrogen after the reaction is finished, cooling to 25 ℃, adding 9.3kg of purified water, cooling to 10 ℃, keeping the temperature, stirring for 0.5 hour, performing spin filtration, leaching a filter cake with 4.7kg of 1 and 4-dioxane for 1 time, performing spin filtration until no liquid flows out, and collecting the filter cake;

step 2: adding the filter cake obtained in the step (1) and 55.0kg of N, N-dimethylacetamide into a reactor, starting stirring, heating to 60 ℃, keeping the temperature and stirring for 1h, cooling to 20 ℃, filtering, leaching the filter cake with 4.3kg of N, N-dimethylacetamide, and collecting filtrate;

and step 3: adding the filtrate obtained in the step (2), 1.4 kgL-cysteine and 1.4kg triethylamine into a reactor, starting stirring, reacting in a dark place, replacing with nitrogen once, heating to 60 ℃, reacting for 16h, cooling to 20 ℃, reacting for 0.5h, performing suction filtration, leaching the filter cake with 13.0kgN, N-dimethylacetamide for 1 time, and collecting the filtrate;

and 4, step 4: adding the filtrate obtained in the step 3 into a reactor, starting stirring, cooling to 10 ℃, adding purified water, controlling the temperature at 15 ℃ in the process of adding the purified water, stirring for 1h at the temperature of 20 ℃, performing throw filtration, leaching a filter cake for 1 time by using 4.7kg of N, N-dimethylacetamide/purified water mixed solution and 3.7kg of anhydrous methanol respectively, and collecting the filter cake until no liquid flows out;

and 5: adding the filter cake obtained in the step (4) and 55.0kg of anhydrous methanol into a reactor, starting stirring, controlling the temperature to be 25 ℃, keeping the temperature and stirring for 1h, performing filter throwing, leaching the filter cake for 1 time by using 18.0kg of anhydrous methanol, performing filter throwing until no liquid flows out, collecting the filter cake, putting the filter cake into a vacuum drier, drying for 5h at the temperature of 60 ℃ under the condition that the vacuum degree is more than or equal to 0.09MPa, collecting and weighing to obtain (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine;

step three: adding 1.0kg of (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridine-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine, 0.32kg of triethylamine and 17.8kg of tetrahydrofuran into a reactor under the protection of nitrogen, starting stirring, cooling to 0 ℃, slowly adding 2.14kg of phosphorus oxychloride/tetrahydrofuran solution, controlling the temperature to 0 ℃ after the addition is finished, stirring for reacting for 5 hours, taking out the mixed solution, adding 20.0kg of purified water into the reactor, cooling to 5 ℃, starting stirring, adding the mixed solution, controlling the temperature of the system in the feeding process to 5 ℃, controlling the temperature to 25 ℃ after the addition is finished, stirring for 1 hour, performing swing filtration, leaching a filter cake for 1 time by using 1.0kg of purified water, performing the swing filtration until no liquid flows out, and collecting the filter cake; and (2) putting the filter cake into a reactor, adding 5.9kg of methanol and 0.7kg of purified water, keeping the temperature, stirring for 0.5h, performing spin filtration, leaching the filter cake for 1 time by using 0.7kg of methanol, performing spin filtration until no liquid flows out, collecting the filter cake, putting the filter cake into a hot air circulation drying box, heating to 40 ℃, and drying for 4h to obtain the tedizolid phosphate, wherein the calculated yield is 75.68% and the purity is 99.95%.

The yield and the purity of the tedizolid phosphate prepared by the method are higher than those of the tedizolid phosphate prepared by the existing preparation method, the operation is simple, the process is stable, the operability is strong, high-toxicity organic tin reagents and harsh reaction conditions are avoided, high-risk processes such as hydrogenation reaction and the like are also avoided, and the safe industrial production can be realized.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. a preparation method of high-purity tedizolid phosphate, is characterized in that: bag following steps:

Step 1: Add 2-methyl-5-(5-bromopyridin-2-yl) tetrazolium, biboronic acid pinacol ester, potassium acetate, 1,4-dioxane to the reactor, start stirring , nitrogen was replaced twice, under nitrogen protection, tetrakis (triphenylphosphine) palladium was added, heated to 65-75 ° C, reacted for 4 h, after the reaction was completed, the heating was stopped, n-heptane was added, and cooled to 0-10 ° C , keep stirring for 1h, remove nitrogen protection, discharge and suction filter, filter cake with n-heptane rinsing once, suction filter until no filtrate drips, collect filter cake and put it into vacuum drying oven to dry at 45-55℃, and collect after 8h. The material is weighed to obtain pinacol borate;

Step 2:

Step 1: Add pinacol borate, (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one, 1,4-diol into the reactor Oxane and potassium carbonate solution, turn on stirring, replace with nitrogen twice, under nitrogen protection, add tetrakis (triphenylphosphine) palladium, heat up to 55-65 ℃, react for 5h, the reaction is complete, remove nitrogen, cool to 20 -30°C, add purified water, then cool down to 5-15°C, keep stirring for 0.5h, shake off for filtration, rinse the filter cake with 1,4-dioxane once, shake and filter until no liquid flows out, and collect the filter cake ;

Step 2: Add the filter cake obtained in step 1 and N,N-dimethylacetamide into the reactor, start stirring, heat up to 55-65 °C, keep stirring for 1 h, cool down to 15-25 °C, filter, filter The cake was rinsed with N,N-dimethylacetamide, and the filtrate was collected;

Step 3: Add the filtrate obtained in step 2, L-cysteine and triethylamine into the reactor, start stirring, react in the dark, replace with nitrogen once, heat up to 55-65 ° C, react for 16 h, cool down to 15 -25°C, reacted for 0.5h, suction filtered, the filter cake was rinsed once with N,N-dimethylacetamide, and the filtrate was collected;

Step 4: Add the filtrate obtained in step 3 into the reactor, turn on stirring, cool down to 5-15°C, add purified water, control the temperature below 35°C during the process of adding purified water, and finish adding purified water, at 15-25°C. At the temperature of ℃, stir for 1 h, shake off and filter, the filter cake is washed with N,N-dimethylacetamide/purified water mixed solution and anhydrous methanol respectively once each, shake and filter until no liquid flows out, and collect the filter cake;

Step 5: Add the filter cake obtained in step 4 and anhydrous methanol into the reactor, start stirring, control the temperature to 20-30 ° C, keep stirring for 1 h, shake off for filtration, rinse the filter cake with anhydrous methanol once, and shake and filter to no The liquid flows out, the filter cake is collected, and the filter cake is placed in a vacuum dryer, dried for 5 hours at a temperature of 55-65 °C and a vacuum degree of 0.09 MPa or more, collected and weighed to obtain (R)-3- [4-[2-(2-Methyltetrazol-5-yl)pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidine;

Step 3: Under nitrogen protection, add (R)-3-[4-[2-(2-methyltetrazol-5-yl)pyridin-5-yl]-3-fluorophenyl] into the reactor -5-Hydroxymethyloxazolidine, triethylamine and tetrahydrofuran, turn on stirring, cool down to -5-5°C, add phosphorus oxychloride/tetrahydrofuran solution, complete the addition, control the temperature to -5°C-5°C, and stir the reaction 5h, take out the mixed solution, add purified water to the reactor, cool down to 0-10°C, turn on stirring, add the above-mentioned mixed solution, control the feeding process and control the temperature of the system to 0-10°C, after the feeding is completed, heat up to 20-30°C , stirred for 1 h, shaken and filtered, the filter cake was rinsed once with purified water, shaken and filtered until no liquid flowed out, and the filter cake was collected; put the filter cake into the reactor, add methanol and purified water, keep the temperature at 20-30 °C and stir for 0.5 h, shake off the filter, rinse the filter cake with methanol once, shake off the filter until no liquid flows out, collect the filter cake, place the filter cake in a hot air circulating drying oven, heat it up to 35-45 ° C, and dry it for 4 hours to obtain phosphoric acid. azolamide.

2. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that: in the described step 1, the parts by weight of each reactant are as follows:

4.3 parts of 2-methyl-5-(5-bromopyridin-2-yl)tetrazolium, 5.4 parts of pinacol biboronate, 3.5 parts of potassium acetate, 35 parts of 1,4-dioxane, tetrakis( 0.29 part of triphenylphosphine) palladium.

3. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that: in the described step 2, the parts by weight of each reactant are as follows:

3.8 parts of pinacol borate, 4.7 parts of (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one, 24.3 parts of 1,4-dioxane parts, 13.8 parts of potassium carbonate solution, 0.67 parts of tetrakis(triphenylphosphine)palladium, 1.4 parts of L-cysteine, and 1.4 parts of triethylamine.

4. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that: in the described step 2, the parts by weight of each reactant are as follows:

1 part of (R)-3-[4-[2-(2-methyltetrazol-5-yl)pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidine, three 0.82 parts of ethylamine, 17.8 parts of tetrahydrofuran, 2.14 parts of phosphorus oxychloride/tetrahydrofuran solution.

5. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1 and 3, is characterized in that: the mass ratio of the solute of the potassium carbonate solution in the described step 2 and solvent is 4.5:9.3.

6. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that: described N,N-dimethylacetamide/purified water mixed solution is made of N,N-dimethylacetamide The mixed solution of acetamide and purified water was prepared according to the mass ratio of 1:1.

7. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1 and 4, is characterized in that: described phosphorus oxychloride/tetrahydrofuran solution is mixed solution by phosphorus oxychloride and tetrahydrofuran according to mass ratio 1.26 : 0.88 ratio preparation.

8. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that:

The quality of the n-heptane added in the reactor in the described step one is not greater than the quality of the reaction solution;

In the described step 1, the quality of the n-heptane leaching the filter cake is not more than twice the quality of the filter cake.

9. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that:

The quality of the purified water added to the reactor in the step 1 of the second step is not greater than the quality of the reaction solution;

In the step 2 of the described step 2, the quality of the N,N-dimethylacetamide of the leaching filter cake is not more than twice the quality of the filter cake;

In the step 3 of the described step 2, the quality of the N,N-dimethylacetamide of the leaching filter cake is not more than twice the quality of the filter cake;

In the step 4 of the described step 2, the quality of the N,N-dimethylacetamide/purified water mixed solution and the anhydrous methanol of the leaching filter cake is not more than twice the quality of the filter cake;

In the step 5 of the described step 2, the quality of the anhydrous methanol added to the reactor together with the filter cake is between 1-4 times of the quality of the filter cake;

In the step 5 of the second step, the quality of the anhydrous methanol used to wash the filter cake is not greater than the quality of the filter cake.

10. the preparation method of a kind of high-purity tedizolid phosphate according to claim 1, is characterized in that:

The quality of the purified water added to the reactor together with the reaction solution in the step 3 is 0.8-1.5 times the quality of the reaction solution;

In the described step 3, the quality of the purified water of the first leaching filter cake is not greater than the quality of the filter cake;

In the described step 3, the quality of the purified water added in the reactor together with the filter cake is that the quality of the reaction solution is not greater than the quality of the filter cake, and the weight of the methanol added in the reactor together with the filter cake in the described step 3 is: 2-5 times the filter cake;

In the described step 3, the quality of the methanol in the second rinsing filter cake is not more than twice the quality of the filter cake.