CN114933596B - Preparation method of tedizolid - Google Patents
Preparation method of tedizolid Download PDFInfo
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- CN114933596B CN114933596B CN202210518265.5A CN202210518265A CN114933596B CN 114933596 B CN114933596 B CN 114933596B CN 202210518265 A CN202210518265 A CN 202210518265A CN 114933596 B CN114933596 B CN 114933596B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of medicines, in particular to a preparation method of tedizolid, which takes (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone as a starting material and 2- (2-methyltetrazole-5-yl) pyridine-5-boric acid pinacol ester to be synthesized under the action of a palladium catalyst, improves the utilization rate of raw materials through optimizing the process steps, and improves the yield of the tedizolid to more than 85 percent; and a recovery process is designed for the palladium catalyst, palladium introduced by the palladium catalyst is reduced into palladium simple substance, and then stirred for decoloration, the palladium is adsorbed by utilizing the adsorption effect of active carbon on the palladium simple substance, so that the removal rate of palladium ions reaches more than 99.2%, the palladium ions in the product are efficiently removed, the palladium content in the tedizolid product is reduced to below 1ppm, the purity of the product is improved, and the method has extremely high popularization significance.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tedizolid.
Background
Tertrazolamide phosphate (Telizolid phosphate, english trade name Sivextro), chemical name (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridin-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidin-2-one phosphate; is a second generation oxazolidinone antibacterial agent developed by the eastern Asia pharmaceutical company of Korea, can be used for converting into active form of tedizolid by removing phosphate group through serum phosphatase in vivo, and is clinically mainly used for treating adult acute bacterial skin tissue infection caused by gram positive bacteria such as staphylococcus aureus (including methicillin-resistant strain and methicillin-sensitive strain), various streptococcus, enterococcus and the like.
In the existing preparation process of the tedizolid phosphate, the (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone is taken as a starting material, and is reacted with 2- (2-methyl-2H-tetrazole-5-yl) pyridine-5-pinacol borate under the action of a palladium catalyst to synthesize the tedzollid, and then the tedzollid phosphate is reacted with phosphorus oxychloride to prepare the technical route of the tedzollid phosphate. The yield of the intermediate product, namely the tedizolid, prepared by the process route is only about 60%, and the residual solvent and palladium ions in the tedizolid are difficult to separate, so that the tedizolid is low in purity, the palladium ion content is high, and the safety of clinical medication is seriously influenced.
Disclosure of Invention
Aiming at the technical problems that in the prior art, the yield of the tedizolid is low, the solvent and the palladium catalyst are difficult to separate, so that the purity of the product is poor, and the medication safety is affected, in the process of synthesizing the tedzolamide by the reaction of (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone and 2- (2-methyl-2H-tetrazole-5-yl) pyridine-5-boric acid pinacol ester under the action of the palladium catalyst, the preparation method provided by the invention has the characteristics of simplicity and convenience in operation, high purity of the prepared product and high yield.
In order to achieve the above purpose, the embodiment of the invention adopts the following technical scheme:
the embodiment of the invention provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: sequentially adding a compound III, (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-one and an acid binding agent into a solvent, uniformly mixing, removing oxygen in the solvent, adding a palladium catalyst, heating under the protection of nitrogen to perform suzuki reaction, cooling to room temperature after the reaction is finished, adding water, stirring, and carrying out solid-liquid separation to obtain a solid which is a wet crude product of the tebuconazole;
s2: and (3) dissolving the wet crude product of the tedizolid obtained in the step (S1) in a recrystallization solvent, adding a reducing agent and active carbon, heating, stirring for decoloration, separating the hot liquid, crystallizing, and separating the solid from the liquid to obtain the purified tedizolid.
Compared with the prior art, the preparation method of the tedizolid improves the utilization rate and conversion efficiency of raw materials and improves the yield of the tedizolid to more than 85% through optimizing the process steps in the preparation process of the tedizolid; and a recovery process of the palladium catalyst is designed aiming at the palladium catalyst added in the reaction process, the palladium element introduced by the palladium catalyst is reduced into palladium simple substance by using a reducing agent, then the palladium simple substance is stirred and decolored by using activated carbon under the heating condition, the palladium simple substance is adsorbed by using the adsorption effect of the activated carbon, so that the removal rate of palladium ions reaches more than 99.2%, the palladium ions existing in the product are efficiently removed, the palladium content in the tedizolid product is reduced to below 1ppm, conditions are created for realizing recovery of the palladium ions and the solvent in the tedizolid product, and the purity of the product is also improved.
Preferably, the reducing agent is sodium bisulphite, sodium sulfite or sodium sulfide, and the mass ratio of the reducing agent to the 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester is 1:1 to 10, and the further preferable mass ratio is 1:2 to 5.
Sodium bisulphite, sodium sulfite and sodium sulfate not only have certain reducibility, but also can effectively reduce palladium ions in the products into palladium simple substance, and the reducing agent and oxidation products thereof have good solubility in water, are not easy to remain in the final product, namely the tedizolid, and are beneficial to improving the purity of the final product.
Preferably, the molar ratio of (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidin-2-one to 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester is 1:1 to 2; further preferred molar ratios are 1:1.05 to 1.2.
The ratio of the preferable raw materials is favorable for controlling the reaction completion rate, avoiding excessive raw material residues while ensuring the overall conversion rate, reducing the difficulty of purifying the reaction product in the later period, reducing the cost and improving the purity of the product.
Preferably, the solvent is one of 1,4 dioxane and acetonitrile or an aqueous solution of one of them.
The boiling points of the 1,4 dioxane and acetonitrile are relatively low, and the 1,4 dioxane and acetonitrile can be separated and recovered by adopting simple reduced pressure distillation after the reaction is finished, so that the purity of the tedizolid is improved, and the production cost is reduced.
Preferably, the acid-binding agent is potassium fluoride dihydrate, potassium acetate or potassium carbonate, and the molar ratio of the acid-binding agent to 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester is 1:2 to 4, and a further preferred molar ratio is 1:2.5 to 3.5.
The solubility of the potassium fluoride dihydrate, the potassium acetate and the potassium carbonate in water is higher, so that the acid generated in the reaction process can be neutralized, the reaction is pushed to proceed towards the direction of producing the tedizolid, no impurity is introduced into the product, and the purity of the product is improved.
Preferably, the palladium catalyst is palladium acetate, palladium chloride or PdCl 2 dppfDCM (1, 1' -bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex), the molar ratio of palladium catalyst to 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester was 0.5% -1.5%: 1, further preferred molar ratio is 0.8% -1.2%: 1.
the preferential palladium catalyst and the preferential catalyst dosage can fully improve the reaction rate, simultaneously reduce the residual risk of the catalyst in the organism, reduce the separation difficulty of the palladium catalyst at the later stage, improve the purity of the product and ensure the medication safety.
Preferably, the recrystallization solvent is a mixture obtained by mixing acetonitrile and water in an arbitrary volume ratio, and further preferably the volume ratio is 40:60; the activated carbon is wood dust activated carbon or coconut shell activated carbon; the amount of the recrystallization solvent is 20-80 ml of the recrystallization solvent corresponding to each gram of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester, and the more preferable amount of the recrystallization solvent is 35-65 ml of the recrystallization solvent corresponding to each gram of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester; the amount of the activated carbon is 5-30% of the mass of the 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester, and the more preferable amount is 15-25% of the mass of the 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester.
Preferably, the means for removing oxygen from the solvent is nitrogen substitution.
Preferably, the Suzuki reaction temperature in S1 is 70 to 100℃and more preferably 90 to 100 ℃.
Preferably, the decolorization temperature is 70 to 80 ℃.
Preferably, the crystallization temperature is 5 to 25 ℃, and more preferably, the crystallization temperature is 10 to 20 ℃.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The chemical name of the phosphoric acid tertrazolamide is (R) -3- [4- [2- (2-methyltetrazol-5-yl) pyridine-5-yl ] -3-fluorophenyl ] -5-hydroxymethyl oxazolidine-2-ketone phosphate, belongs to a second generation oxazolidinone antibacterial agent, can be converted into the active form tertrazolamide through in-vivo serum phosphatase dephosphorylation, plays a role, and is clinically mainly used for treating adult acute bacterial skin tissue infection and the like caused by gram-positive bacteria such as staphylococcus aureus (including methicillin-resistant strains and methicillin-sensitive strains), various streptococcus, enterococcus and the like.
The synthesis route of the tedizolid phosphate is a plurality of routes, most of the routes are used for an organotin reagent, the reaction is required to be carried out under the ultralow temperature condition, the energy consumption is huge, meanwhile, certain harm is brought to human bodies, and the like, under the large environment, the intermediate of the tedizolid phosphate is synthesized by (5R) -3- (2-methyltetrazole-5-yl) pyridine-5-pinacol borate in a DMF solvent under the catalysis condition of a palladium catalyst, and the intermediate of the tedizolid phosphate is reacted with phosphorus oxychloride, so that the technical problem is avoided, the process route is more and more popular in pharmaceutical factories, but the process route has no defects of operation difficulty and danger, but the yield of the prepared intermediate of the tedizolid is only about 60%, and the solvent and the palladium catalyst are difficult to separate from products. At present, the best palladium removal effect in the prior art is that an organic amine compound or a sulfur-containing compound is used for removing palladium after complexing, but practice shows that the organic amine compound or the sulfur-containing compound has good complexing effect on palladium, but the substance obtained after complexing is difficult to separate from the tedizolid, so that new impurities are introduced into the tedizolid, and the purification difficulty of the tedizolid is increased. The purity of the product is seriously affected by the problem that the solvent and the palladium catalyst in the tedizolid product are difficult to recycle, and the medication safety is also affected to a certain extent.
In order to solve the technical problems of low product yield, poor product purity caused by difficult recovery and separation of solvent and catalyst and influence on medication safety in the process for preparing the terozolomide in the prior art,
the invention provides a preparation method of tedizolid, which improves the utilization rate and conversion efficiency of raw materials and improves the yield of the tedizolid to more than 85% through optimizing the process steps in the preparation process of the tedizolid; the recovery process of the palladium catalyst is specially designed, the palladium element introduced by the palladium catalyst is reduced into palladium simple substance by using a reducing agent, then stirring and decoloring are carried out, the adsorption effect of the active carbon on the palladium simple substance is utilized to adsorb, so that the removal rate of palladium ions reaches more than 99.2%, the palladium ions existing in the product are efficiently removed, the palladium content in the tebuconazole product is reduced to below 1ppm, and conditions are created for realizing recovery of the palladium ions and the solvent in the tebuconazole product, and the purity of the product is also improved. The preparation method of the tedizolid specifically comprises the following steps:
s1: sequentially adding 2- (2-methyl-2H-tetrazole-5-yl) pyridine-5-boric acid pinacol ester, (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone and an acid binding agent into an organic solvent, removing oxygen in the solvent, adding a palladium catalyst, heating under the protection of nitrogen to perform Suzuki reaction, cooling to room temperature after the reaction is finished, adding purified water, stirring, and carrying out solid-liquid separation to obtain a solid which is a wet crude product of the tedizolid;
s2: and (3) adding the wet crude product of the tedizolid obtained in the step (S1) into a recrystallization solvent for dissolution, adding a reducing agent and active carbon, stirring for decoloration at 60-90 ℃, separating the hot liquid, and crystallizing to obtain the purified tedizolid.
The reducing agent preferably adopts sodium bisulphite, sodium sulfite and sodium sulfate, and the reducing agent not only has certain reducibility, but also can reduce palladium ions remained in the terozolomide into palladium simple substance, and has good solubility in water of the self and salt generated by oxidation of the self, so that the residual in the product can be avoided, and the purity of the product is improved.
In order to control the reaction rate, ensure the conversion rate, avoid excessive raw material residues, reduce the purification difficulty and the production cost of the post-reaction product, improve the purity of the product, and have the mole ratio of (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-one to 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester of 1: 1-2, more preferably the molar ratio is 1:1.05 to 1.2.
The traditional DMF and other reaction solvents have better dissolution performance on reaction raw materials, but are unfavorable for separation from the reaction product, namely the tedizolid, and influence the purity of the product.
The solubility of the potassium fluoride dihydrate, the potassium acetate and the potassium carbonate in water is higher, the potassium fluoride dihydrate, the potassium acetate and the potassium carbonate can be used as acid generated in the neutralization reaction process of an acid binding agent, the reaction is pushed to proceed towards the direction of producing the tedizolid, no impurity is introduced into the product, and the purity of the product is improved.
Equivalent to 0.5 to 1.5 percent of palladium acetate, palladium chloride or PdCl by mass of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester 2 dppfDCM catalyst can fully improve reaction rate, reduce residual risk of catalyst in the organism and reduce late palladium catalystThe difficulty of separation improves the purity of the product and ensures the medication safety.
The invention is further illustrated below in the form of a number of examples.
Example 1
The embodiment provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: to a reaction vessel were added 76ml of 1, 4-dioxane and 190ml of water at room temperature, 0.33mol total of 95g of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester, 0.35mol total of 100.8g of (5R) -3- (4-bromo-3-fluorophenyl) -5-methylol oxazolidin-2-one and 0.99mol total of 93.4g of potassium fluoride dihydrate, 3.3mmol total of 2.6g of PdCl was added after three nitrogen substitutions to remove oxygen in the solvent 2 Heating dppfDCM to 90 ℃ under the protection of nitrogen, reacting for 5 hours at constant temperature, cooling to room temperature after the reaction is completed, adding purified water, stirring for 1 hour, and filtering to obtain a wet crude product of the tedizolid, wherein the palladium content in the wet crude product is 3896ppm through inspection;
s2: 4L acetonitrile and 2L purified water are added into a reaction vessel, 28.5g sodium sulfite and 19g active carbon are added into the wet crude product of the tebuconazole obtained by S1 under stirring, the temperature is raised to 80 ℃ and the mixture is stirred for 8 hours for decoloration, the filtrate obtained after hot filtration is cooled to 20 ℃, the solid obtained after filtration is purified tebuconazole, and the tebuconazole has the quality of 104g, the purity of 99.9 percent, the palladium content of 0.3ppm and the comprehensive yield of 85 percent after weighing inspection.
Example 2
The embodiment provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: 1.6L of 1, 4-dioxane and 0.4L of water were charged into a reaction vessel at room temperature, 200g of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester in total, 212.73 mol of (5R) -3- (4-bromo-3-fluorophenyl) -5-methyloxazolid-2-one in total and 169.7g of potassium fluoride dihydrate in total were added in total, and after replacing three times of nitrogen to remove oxygen in the solvent, 5.6mmol of PdCl in total of 4.6g was added 2 Heating dppfDCM to 90 ℃ under the protection of nitrogen gas, reacting for 5 hours at constant temperature, cooling to room temperature after the reaction is completed, adding purified water, stirring for 1 hour, filtering to obtain a wet crude product of the tebuconazole, and checking that the palladium content in the wet crude product is3470ppm；
S2: 8L of acetonitrile and 4L of purified water are added into a reaction vessel, the wet crude product of the tebuconazole obtained by S1 is added under stirring, 60g of sodium sulfite and 40g of active carbon are added, the temperature is raised to 70 ℃ and the mixture is stirred for 8 hours for decolorization, the filtrate obtained after hot filtration is cooled to 10 ℃, and the solid obtained after filtration is the purified tebuconazole. Through weighing inspection, the mass of the tedizolid is 220g, the purity is 99.9%, the palladium content is 0.2ppm, and the comprehensive yield is 85.3%.
Comparative example 1
The comparative example provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: 1.6L of 1, 4-dioxane and 0.4L of water were charged into a reaction vessel at room temperature, a total of 200g of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester, 0.73mol of 212.6g of (5R) -3- (4-bromo-3-fluorophenyl) -5-methylol oxazolidin-2-one and 2.09mol of 169.7g of potassium fluoride dihydrate were added, and after replacing three times of nitrogen to remove oxygen in the solvent, 5.6mmol of PdCl of 4.6g was added 2 Heating dppfDCM to 90 ℃ under the protection of nitrogen, reacting for 5 hours at constant temperature, cooling to room temperature after the reaction is completed, adding purified water, stirring for 1 hour, and filtering to obtain a wet crude product of the tedizolid, wherein the palladium content in the wet crude product is 3804ppm through inspection;
s2: adding 8L of acetonitrile and 4L of purified water into a reaction vessel, adding the wet crude product of the tedizolid obtained by S1 under stirring, adding 40g of active carbon, heating to 70 ℃, stirring for 8 hours for decoloring, filtering while the active carbon is hot, cooling the obtained filtrate to 10 ℃, and filtering to obtain a solid, namely the purified tedizolid.
Through weighing inspection, the mass of the tedizolid is 218g, the purity is 99.2%, the palladium content is 162ppm, and the comprehensive yield is 84.5%.
Comparative example 2
The comparative example provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: 1.6L of 1, 4-dioxane and 0.4L of water were charged into a reaction vessel at room temperature, 0.7mol together of 200g of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester, 0.73mol together of 212.6g of (5R) -3- (4-bromo-3-fluorophenyl) -5-methylol oxazolidin-2-one and 2.09mol together of 169.7g of dihydrate were addedPotassium fluoride was replaced three times with nitrogen to remove oxygen from the solvent, and 5.6mmol of PdCl was added together with a total of 4.6g 2 Heating dppfDCM to 90 ℃ under the protection of nitrogen, reacting for 5 hours at constant temperature, cooling to room temperature after the reaction is completed, adding purified water, stirring for 1 hour, and filtering to obtain a wet crude product of the tedizolid, wherein the palladium content in the wet crude product is 3789ppm through inspection;
s2: adding 8L of acetonitrile and 4L of purified water into a reaction vessel, adding the wet crude product of the tedizolid obtained by S1 under stirring, adding 20g of 1, 3-propanediamine and 40g of active carbon, heating to 70 ℃, stirring for 8 hours for decolorization, filtering while the mixture is hot, cooling the filtrate to 10 ℃, and filtering to obtain a solid which is the purified tedizolid.
Through weighing inspection, the mass of the tedizolid is 210g, the purity is 96.7%, the palladium content is 42ppm, and the comprehensive yield is 81.4%.
Comparative example 3
The comparative example provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: 1.6L of 1, 4-dioxane and 0.4L of water were charged into a reaction vessel at room temperature, a total of 200g of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester, 0.73mol of 212.6g of (5R) -3- (4-bromo-3-fluorophenyl) -5-methylol oxazolidin-2-one and 2.09mol of 169.7g of potassium fluoride dihydrate were added, and after replacing three times of nitrogen to remove oxygen in the solvent, 5.6mmol of PdCl of 4.6g was added 2 Heating dppfDCM to 90 ℃ under the protection of nitrogen for constant temperature reaction for 5 hours, cooling to room temperature after the reaction is completed, adding purified water, stirring for 1 hour, and filtering to obtain a wet crude product of the tedizolid, wherein the palladium content in the wet crude product is 3690ppm through inspection;
s2: adding 6L of DMF solvent into a reaction vessel, adding the wet crude product of the tedizolid obtained by S1 under stirring, adding 60g of sodium sulfite and 40g of active carbon, heating to 70 ℃, stirring for 8h for decolorization, filtering while the mixture is hot, cooling the filtrate to 10 ℃, and filtering to obtain a solid, namely the purified tedizolid.
Through weighing inspection, the mass of the tedizolid is 153g, the purity is 98.5%, the palladium content is 12ppm, and the comprehensive yield is 59.3%.
Comparative example 4
The comparative example provides a preparation method of tedizolid, which specifically comprises the following steps:
s1: 1.6L of 1, 4-dioxane and 0.4L of water were charged into a reaction vessel at room temperature, a total of 200g of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester, 0.73mol of 212.6g of (5R) -3- (4-bromo-3-fluorophenyl) -5-methylol oxazolidin-2-one and 2.09mol of 169.7g of potassium fluoride dihydrate were added, and after replacing three times of nitrogen to remove oxygen in the solvent, 5.6mmol of PdCl of 4.6g was added 2 Heating dppfDCM to 90 ℃ under the protection of nitrogen, reacting for 5 hours at constant temperature, cooling to room temperature after the reaction is completed, adding purified water, stirring for 1 hour, and filtering to obtain a wet crude product of the tedizolid, wherein the palladium content in the wet crude product is 3750ppm through inspection;
s2: adding DMF solvent 6L into a reaction vessel, adding wet crude product of the tedizolid obtained by S1 under stirring, adding 20g of 1, 3-propylene diamine, heating to 70 ℃ after 40g of active carbon, stirring for 8h for decolorization, cooling filtrate obtained after hot filtration to 10 ℃, and filtering to obtain solid, namely the purified tedizolid.
Through weighing test, the mass of the tedizolid is 150g, the purity is 97.3%, the palladium content is 25ppm, and the comprehensive yield is 58.1%.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the particular embodiments disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (7)
1. The preparation method of the tedizolid is characterized by comprising the following steps of:
s1: sequentially adding 2- (2-methyl-2H-tetrazole-5-yl) pyridine-5-boric acid pinacol ester, (5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-ketone and an acid binding agent into a solvent, uniformly mixing, removing oxygen in the solvent, adding a palladium catalyst, heating under the protection of nitrogen to perform a suzuki reaction, cooling to room temperature after completion, adding water, stirring, and carrying out solid-liquid separation, wherein the obtained solid is a tertiary azole wet crude product;
s2: dissolving the wet crude product of the tedizolid in a recrystallization solvent, adding a reducing agent and active carbon, heating, stirring for decoloration, separating the hot liquid, crystallizing, and separating the solid from the liquid to obtain the solid of the tedizolid;
wherein the reducing agent in S2 is sodium bisulphite, sodium sulfite or sodium sulfide; the solvent in S1 is one of 1,4 dioxane, DMSO and acetonitrile, or an aqueous solution of one of the two solvents; s1, the acid binding agent is potassium fluoride dihydrate, potassium acetate or potassium carbonate; the palladium catalyst is palladium acetate, palladium chloride or PdCl 2 dppfDCM; and S2, the recrystallization solvent is a mixture obtained by mixing acetonitrile and water in any volume ratio.
2. The method for preparing tedizolid according to claim 1, wherein the mass ratio of the reducing agent to 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester is 1: 1-10.
3. The process for the preparation of tedizolamine according to claim 1, wherein the molar ratio of S1 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester to (5R) -3- (4-bromo-3-fluorophenyl) -5-methylol oxazolidin-2-one is 1: 1-2.
4. The method for preparing tedizolid according to claim 1, wherein the molar ratio of the palladium catalyst S1 to the 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester is 0.5% -1.5%: 1, a step of; and/or
The molar ratio of the dosage of the acid binding agent to the 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boric acid pinacol ester is 1: 2-4.
5. The method for preparing tedizolid according to claim 1, wherein the activated carbon is wood dust activated carbon or coconut shell activated carbon.
6. The method for preparing tedizolid according to claim 5, wherein the amount of the recrystallization solvent is 20-80 ml of the recrystallization solvent per gram of 2- (2-methyl-2H-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester; and/or
The dosage of the activated carbon is 5% -30% of the mass of the 2- (2-methyl-2H-tetrazole-5-yl) pyridine-5-boric acid pinacol ester.
7. The method for preparing tedizolid according to claim 1, wherein the reaction temperature of S1 is 70-100 ℃; and/or
S2, the decoloring temperature is 70-80 ℃; and/or
The crystallization temperature is 5-25 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210518265.5A CN114933596B (en) | 2022-05-12 | 2022-05-12 | Preparation method of tedizolid |
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| CN105418678A (en) * | 2014-09-17 | 2016-03-23 | 正大天晴药业集团股份有限公司 | Preparation method for tedizolid phosphate |
| CN112961186A (en) * | 2021-02-04 | 2021-06-15 | 海南通用康力制药有限公司 | Method for purifying tedizolid phosphate |
| CN113214239A (en) * | 2021-04-06 | 2021-08-06 | 海南通用康力制药有限公司 | Tedizolid refining process and preparation method of tedizole phosphate |
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| CN105418678A (en) * | 2014-09-17 | 2016-03-23 | 正大天晴药业集团股份有限公司 | Preparation method for tedizolid phosphate |
| CN112961186A (en) * | 2021-02-04 | 2021-06-15 | 海南通用康力制药有限公司 | Method for purifying tedizolid phosphate |
| CN113214239A (en) * | 2021-04-06 | 2021-08-06 | 海南通用康力制药有限公司 | Tedizolid refining process and preparation method of tedizole phosphate |
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