阅读说明：本技术 一种高纯度磷酸特地唑胺的制备方法 (Preparation method of high-purity tedizolid phosphate ) 是由 王晓龙 阴启明 于 2020-06-10 设计创作，主要内容包括：一种高纯度磷酸特地唑胺的制备方法,包括如下步骤：步骤一：以2-甲基-5-(5-溴吡啶-2-基)四氮唑为起始物料,以四(三苯基膦)钯(Pd(PPh3)4)为催化剂,与联硼酸频那醇酯反应生成式1化合物的溴转化为硼酸频那醇酯；步骤二：式3化合物在四(三苯基膦)钯(Pd(PPh3)4)的催化作用下经过与(5R)-3-(4-溴-3-氟苯基)-5-羟甲基恶唑烷-2-酮经过Suzuki偶联,得到(R)-3-[4-[2-(2-甲基四唑-5-基)吡啶-5-基]-3-氟苯基]-5-羟甲基噁唑烷；步骤三：式5化合物在三氯氧磷的磷酸酯化条件下制备得到磷酸特地唑胺。本发明的制备的磷酸特地唑胺的工艺方法具有无需超低温操作,反应简单；高纯度,纯度可以达到95％以上；副产物少,收率高收率高于70％；工艺稳定、可操作性强。(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. 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 the operability is strong.)

1. 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, 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; putting the filter cake into a reactor, adding methanol and purified water, keeping the temperature at 20-30 ℃, stirring for 0.5h, performing throw filtration, leaching the filter cake for 1 time by using methanol, performing throw 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.

2. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps: in the step one, the weight parts of each reactant are as follows:

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.

3. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps: the weight parts of the reactants in the second step are as follows:

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.

4. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps: the weight parts of the reactants in the second step are as follows:

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.

5. The method for preparing tedizolid phosphate with high purity according to claim 1 or 3, characterized in that: and the mass ratio of the solute to the solvent of the potassium carbonate solution in the second step is 4.5: 9.3.

6. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps: the N, N-dimethylacetamide/purified water mixed solution is prepared by mixing N, N-dimethylacetamide and purified water according to a mass ratio of 1: 1.

7. The method for preparing tedizolid phosphate with high purity according to claim 1 or 4, wherein the reaction is carried out in the presence of a solvent: the phosphorus oxychloride/tetrahydrofuran solution is prepared by mixing phosphorus oxychloride and tetrahydrofuran according to the mass ratio of 1.26: 0.88.

8. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps:

the mass of the n-heptane added into the reactor in the first step is not more than that of the reaction liquid;

the mass of the n-heptane for washing the filter cake in the first step is not more than two times of the mass of the filter cake.

9. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps:

the mass of the purified water added into the reactor in the step 1 in the second step is not more than that of the reaction liquid;

the mass of the N, N-dimethylacetamide for leaching the filter cake in the step 2 of the second step is not more than twice that of the filter cake;

the mass of the N, N-dimethylacetamide for leaching the filter cake in the step 3 of the second step is not more than twice that of the filter cake;

the mass of the N, N-dimethylacetamide/purified water mixed solution and the anhydrous methanol which are used for leaching the filter cake in the step 4 of the second step is not more than twice that of the filter cake;

in the step 5 of the second step, the mass of the anhydrous methanol added into the reactor together with the filter cake is 1-4 times of the mass of the filter cake;

and in the step 5 of the second step, the mass of the anhydrous methanol for leaching the filter cake is not more than that of the filter cake.

10. The method for preparing tedizolid phosphate with high purity according to claim 1, wherein the method comprises the following steps:

in the third step, the mass of the 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 third step, the mass of the purified water for leaching the filter cake for the first time is not more than that of the filter cake;

the mass of the purified water added into the reactor together with the filter cake in the third step is that the mass of the reaction liquid 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;

and in the third step, the mass of the methanol for leaching the filter cake for the second time is not more than twice that of the filter cake.

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 of (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidin-2-one phosphate has the structure that the medicine is a prodrug of a novel oxazolidinone antibacterial medicine developed by Cubist pharmaceutical company, is approved by FDA to be marketed in 7 months 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.

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

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.

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

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.