CN110804038B - Preparation method of tedizolid phosphate and intermediate thereof - Google Patents

Preparation method of tedizolid phosphate and intermediate thereof Download PDF

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CN110804038B
CN110804038B CN201810883176.4A CN201810883176A CN110804038B CN 110804038 B CN110804038 B CN 110804038B CN 201810883176 A CN201810883176 A CN 201810883176A CN 110804038 B CN110804038 B CN 110804038B
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tedizolid phosphate
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陈健
刘振峰
应述欢
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Shanghai Xinlitai Pharmaceutical Co ltd
Shanghai Yunshengyan Neoplasm Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07F9/02—Phosphorus compounds
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Abstract

The invention discloses a preparation method of tedizolid phosphate and an intermediate thereof. A preparation method of tedizolid phosphate intermediate II, which comprises the following steps of 1: reacting 3-fluoro-4-bromophenyl benzyl carbamate in an organic solvent in the presence of a catalyst and zinc powder to obtain a solution of a tedizolid phosphate intermediate III; step 2: and (2) in an organic solvent, in the presence of a palladium catalyst and alkali, carrying out coupling reaction on the solution of the tedizolid phosphate intermediate III obtained in the step (1) and 2-methyl-5- (5-bromopyridine-2-yl) tetrazole to obtain a tedizolid phosphate intermediate II. The preparation method of the invention does not use highly toxic reagents, has mild reaction conditions, safe operation, environmental protection, high yield, high purity of the prepared product and low production cost. The tedizolid phosphate prepared from the tedizolid phosphate intermediate II has high yield and high purity, can reach the standard of raw material medicaments, and is suitable for industrial production.

Description

Preparation method of tedizolid phosphate and intermediate thereof
Technical Field
The invention relates to a preparation method of tedizolid phosphate and an intermediate thereof.
Background
The novel antibacterial drug Tedizolid phosphate (I) is a second generation oxazolidinone antibiotic developed by the east asia pharmaceutical industry, and the commercial development of Cubist Pharmaceuticals and Bayer is authorized and approved by FDA on the market at 6/20 th of 2014. Tedizolid phosphate is used for treating adult patients with skin infections, for treating acute bacterial skin and skin tissue infections (abssi) caused by certain susceptible bacteria, such as staphylococcus aureus (including methicillin-resistant strains and methicillin-susceptible strains), various streptococci and enterococcus faecalis, by intravenous injection and oral administration. Phase III clinical trials of tedizolid phosphate show that the clinical effect of the tedizolid phosphate is equivalent to that of linezolid, the adverse reaction in the aspects of gastrointestinal tract and platelet reduction is less than that of linezolid, and the incidence rate of drug resistance is lower. Tests have shown that the tolerance of tedizolid is also superior to that of vancomycin. The FDA approved preparation comprises injections and tablets, is convenient for clinical switching, and is used for six days once a day, which is more convenient for clinical use than the two times a day of linezolid for ten days.
Figure BDA0001754956030000011
Tedizolid phosphate is a compound with a chiral center, and published methods for synthesizing tedizolid phosphate under the prior art conditions are reported in patent documents CN200480037612, CN200980140144 and the like.
The method reported in patent document CN200480037612 is as follows: preparing a tedizolid phosphate intermediate from 3-fluoro-4-bromophenyl carbamic acid benzyl ester and hexabutylditin, and coupling with 2-methyl-5- (5-bromopyridine-2-yl) tetrazole in the presence of a palladium catalyst to obtain a tedizolid phosphate intermediate II. Because a tin reagent which is expensive and has high toxicity needs to be used, and the tin reagent is easy to remain in the bulk drug; meanwhile, the production is also limited, and the harm to human bodies is very large when tin reagents are used in large scale; it is necessary to replace the tin and use other safer metal catalysts. The total reaction yield of the tin intermediate is lower, and is only 24 percent reported in the literature, and is also only 42 percent after the process is optimized.
Figure BDA0001754956030000021
The patent document CN200980140144 reports the following method: 3-fluoro-4-bromophenyl benzyl carbamate is added dropwise with n-butyl lithium in tetrahydrofuran in the presence of borate under the environment of ultralow temperature (-78 ℃) to obtain a tedizolid phosphate borate intermediate, and then coupled with 2-methyl-5- (5-bromopyridine-2-yl) tetrazole in the presence of a palladium catalyst to obtain a tedizolid phosphate intermediate II.
The disadvantages of this operation are: (1) because the reaction temperature requirement is extremely low (-78 ℃), special cooling equipment is required to be used, and the preparation is not carried out in most common pharmaceutical enterprises, so the implementation cost is higher; (2) the n-butyl lithium is extremely flammable and dangerous for large-scale use, and is generally used only in laboratories; (3) the total yield of the reaction of the borate intermediate is low, and is only 55%.
Figure BDA0001754956030000022
Therefore, the prior art conditions need to be changed urgently, a method which is simple and convenient to operate is needed to be found for preparing the tedizolid phosphate intermediate II, the use of highly toxic metal tin is avoided, the use of ultralow temperature and the use of extremely flammable materials are avoided, and the method is suitable for the requirement of industrial production.
Disclosure of Invention
The invention aims to overcome the defects of harsh reaction conditions, dangerous operation, need of using highly toxic reagents, serious environmental pollution, low reaction yield, unsuitability for industrial production and the like of the preparation method of the tedizolid phosphate intermediate in the prior art. The preparation method of the invention does not use highly toxic reagents, has mild reaction conditions, safe operation, environmental protection, high yield (72-74%), high purity of the prepared product (HPLC purity is more than 98.0%) and low production cost. The tedizolid phosphate prepared from the tedizolid phosphate intermediate II has high yield and high purity, can reach the standard of raw material medicaments (the HPLC purity is more than 99.5 percent, and the maximum single impurity is less than 0.10 percent), and is suitable for industrial production.
The invention provides a preparation method of a tedizolid phosphate intermediate II, which comprises the following steps:
step 1: reacting 3-fluoro-4-bromophenyl benzyl carbamate in an organic solvent in the presence of a catalyst and zinc powder to obtain a solution of a tedizolid phosphate intermediate III;
step 2: in an organic solvent, in the presence of a palladium catalyst and alkali, carrying out a coupling reaction on the solution of the tedizolid phosphate intermediate III obtained in the step 1 and 2-methyl-5- (5-bromopyridine-2-yl) tetrazole to obtain a tedizolid phosphate intermediate II:
Figure BDA0001754956030000031
step 1 may be carried out by a method conventional in the art for such reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in step 1, the organic solvent is preferably an ether solvent and/or a nitrile solvent. The ether solvent is preferably one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and dioxane. The nitrile solvent is preferably acetonitrile.
In step 1, the volume-to-mass ratio of the organic solvent to the benzyl 3-fluoro-4-bromophenylcarbamate is preferably 1mL/g to 20mL/g, more preferably 4mL/g to 10mL/g, such as 7.5mL/g, 10mL/g, or 5 mL/g.
In step 1, the zinc powder may be a commercially available zinc powder reagent that is conventional in the art.
In the step 1, the molar ratio of the zinc powder to the benzyl 3-fluoro-4-bromophenyl carbamate is preferably 1.0 to 10.0, more preferably 2 to 8, such as 2.5, 6.1, or 4.
In step 1, the catalyst is preferably a metallocene transition metal catalyst. The "metallocene transition metal catalyst" is a complex of a metallocene and a transition metal, a complex of an acyl metallocene and a transition metal, or a complex of an alkyl metallocene and a transition metal. The "transition metal" in the "metallocene-type transition metal catalyst" may be a transition metal conventional in the art, i.e., a series of metal elements in the d-block of the periodic table, preferably cobalt, nickel, iron. The "complex of the metallocene and the transition metal" is preferably cobaltocene and/or nickelocene; the complex of the acyl dicyclopentadienyl and the transition metal is preferably acetyl ferrocene and/or benzoyl ferrocene; the "complex of an alkylmetallocene and a transition metal" is preferably 1,1 '-diethylcobaltocene, 1' -diethylnickelocene, ethylferrocene or butylferrocene.
In step 1, the molar ratio of the catalyst to the benzyl 3-fluoro-4-bromophenylcarbamate is preferably 0.001 to 0.1, more preferably 0.005 to 0.02, such as 0.01, 0.02 or 0.005.
In step 1, the reaction temperature is preferably 0 to 60 ℃, more preferably 5 to 50 ℃, for example 20 to 30 ℃, 10 to 20 ℃ or 35 to 45 ℃.
In step 1, the progress of the reaction can be monitored by conventional monitoring methods in the art, and is generally determined as the end point of the reaction when the benzyl 3-fluoro-4-bromophenyl carbamate is almost disappeared (for example, TLC monitors the content of benzyl 3-fluoro-4-bromophenyl carbamate to be less than 1%), and the reaction time is preferably 1 hour to 10 hours, more preferably 2 hours to 8 hours, such as 4 hours to 5 hours, 5 hours to 6 hours, 5.5 hours to 6.5 hours, or 7 hours to 8 hours.
The reaction in step 1 is preferably carried out under the protection of a protective gas, and the protective gas is preferably nitrogen and/or argon.
Step 1 preferably employs the following reaction steps: adding zinc powder and a catalyst into a mixture formed by 3-fluoro-4-bromophenyl benzyl carbamate and an organic solvent for reaction to obtain a solution of the tedizolid phosphate intermediate III.
Step 2 may be carried out by methods conventional in the art for such coupling reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in step 2, the organic solvent is preferably an ether solvent and/or a nitrile solvent. The ether solvent is preferably one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and dioxane. The nitrile solvent is preferably acetonitrile.
In the step 2, the volume-to-mass ratio of the organic solvent to the 2-methyl-5- (5-bromopyridin-2-yl) tetrazole is preferably 1mL/g to 20mL/g, more preferably 4mL/g to 10mL/g, for example 12.3mL/g, 19.4mL/g or 9 mL/g.
In step 2, the palladium catalyst is preferably one or more of tris (dibenzylideneacetone) dipalladium, tetratriphenylphosphine palladium, bis (tricyclohexylphosphine) palladium and bis (tri-tert-butylphosphine) palladium.
In step 2, the molar ratio of the palladium catalyst to the benzyl 3-fluoro-4-bromophenyl carbamate is preferably 0.0005 to 0.05, more preferably 0.001 to 0.005, for example, 0.005, 0.001, or 0.002.
In step 2, the alkali is preferably an organic alkali or an inorganic alkali. The organic base is preferably triethylamine and/or diethylisopropylamine. The inorganic base is preferably one or more of cesium carbonate, potassium phosphate and sodium carbonate.
In the step 2, the molar ratio of the base to the benzyl 3-fluoro-4-bromophenylcarbamate is preferably 1.1 to 8.0, more preferably 1.5 to 4.0, for example, 2.0, 1.5 or 4.0.
In the step 2, the molar ratio of the 2-methyl-5- (5-bromopyridin-2-yl) tetrazole to the 3-fluoro-4-bromophenyl benzyl carbamate is preferably 1.0 to 2.0, more preferably 1.0 to 1.2, for example, 1.2, 1.0 or 1.1.
In step 2, the temperature of the coupling reaction is preferably 45 ℃ to the boiling point of the solvent, more preferably 55 ℃ to 85 ℃, for example, 65 ℃ to 70 ℃, 55 ℃ to 65 ℃, or 75 ℃ to 85 ℃.
In step 2, the progress of the coupling reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and is generally regarded as the end point of the reaction when the tedizolid phosphate intermediate III disappears, and the time of the coupling reaction is preferably 2 hours to 12 hours, more preferably 3 hours to 8 hours, such as 3 hours to 4 hours, 7 hours to 8 hours, or 5 hours to 6 hours.
Step 2 preferably employs the following post-treatment steps: and after the reaction is finished, cooling, filtering, extracting, washing, drying and concentrating to obtain a crude product of the tedizolid phosphate intermediate II.
The cooling, filtration, extraction, drying, concentration may be carried out by methods conventional in the art for such procedures. The filtration is preferably carried out by means of kieselguhr. The solvent used for extraction is preferably an ether solvent and/or an ester solvent. The ether solvent is preferably tetrahydrofuran. The ester solvent is preferably ethyl acetate. The washing is preferably performed with a saline solution. The concentration of the saline solution is preferably 10-30%, for example 15%, and the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution. The drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 45-55 ℃; the time for vacuum drying is preferably 8 hours to 20 hours, for example 8 hours to 12 hours or 16 hours; the pressure of the vacuum drying is preferably-0.01 MPa to-0.1 MPa.
And preferably recrystallizing the crude product of the tedizolid phosphate intermediate II to obtain the tedizolid phosphate intermediate II. The recrystallization preferably adopts the following steps: and (3) cooling and crystallizing a solution formed by the crude product of the tedizolid phosphate intermediate II and an organic solvent to obtain the tedizolid phosphate intermediate II.
The organic solvent is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The temperature of the solution formed by the crude product of the tedizolid phosphate intermediate II and the organic solvent is preferably 50-100 ℃, and is further preferably 70-90 ℃, for example 70-75 ℃. The cooling crystallization temperature is preferably-5 ℃ to 20 ℃, and more preferably 0 ℃ to 15 ℃, for example 0 ℃ to 10 ℃. The cooling crystallization time is preferably 1 hour to 2 hours.
The invention also provides a preparation method of the tedizolid phosphate intermediate V, which comprises the following steps: after the tedizolid phosphate intermediate II is prepared according to the preparation method, carrying out condensation reaction on the tedizolid phosphate intermediate II and R-glycidyl butyrate in an organic solvent in the presence of a catalyst and alkali to obtain a tedizolid phosphate intermediate V;
Figure BDA0001754956030000061
the preparation method of the tedizolid phosphate intermediate V can adopt a conventional method for the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the tedizolid phosphate intermediate V, the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the preparation method of tedizolid phosphate intermediate V, the volume-to-mass ratio of the organic solvent to the tedizolid phosphate intermediate II is preferably 1mL/g to 50mL/g, more preferably 10mL/g to 30mL/g, such as 19.2 mL/g.
In the preparation method of the tedizolid phosphate intermediate V, the base is preferably an organic base; the organic base is preferably lithium hexamethyldisilazide. The lithium hexamethyldisilazide is preferably used in the form of a solution, and the solvent is preferably an ether solvent, and the ether solvent is preferably tetrahydrofuran. The solution of lithium hexamethyldisilazide is preferably a solution of lithium hexamethyldisilazide in tetrahydrofuran. The molar concentration of the "tetrahydrofuran solution of lithium hexamethyldisilazide" is preferably 1mol/L to 3mol/L, for example, 1mol/L, and the molar concentration refers to the ratio of the molar amount of lithium hexamethyldisilazide to the volume of the tetrahydrofuran solution of lithium hexamethyldisilazide.
In the preparation method of tedizolid phosphate intermediate V, the molar ratio of the alkali to the tedizolid phosphate intermediate II is preferably 1-3, more preferably 1.1-1.5, such as 1.1.
In the preparation method of the tedizolid phosphate intermediate V, the catalyst is preferably 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidone (DMPU).
In the preparation method of tedizolid phosphate intermediate V, the molar ratio of the catalyst to the tedizolid phosphate intermediate II is preferably 1-3, more preferably 1.1-1.5, such as 1.1.
In the preparation method of the tedizolid phosphate intermediate V, the condensation reaction temperature is preferably 5-40 ℃, for example 10-15 ℃.
In the preparation method of tedizolid phosphate intermediate V, the progress of the condensation reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and generally the time for the condensation reaction is preferably 5 hours to 24 hours, more preferably 10 hours to 15 hours, such as 12 hours, with the time for the tedizolid phosphate intermediate II to almost disappear as the end point of the reaction (such as TLC monitoring the content of the tedizolid phosphate intermediate II is less than 1%).
The invention also provides a preparation method of tedizolid phosphate I, which comprises the following steps: after the tedizolid phosphate intermediate V is prepared according to the preparation method, the tedizolid phosphate intermediate V and phosphorus oxychloride are subjected to condensation reaction in an organic solvent in the presence of alkali to obtain the tedizolid phosphate I;
Figure BDA0001754956030000081
in the present invention, the preparation method of tedizolid phosphate I can adopt the conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
in the preparation method of tedizolid phosphate I, the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.
In the preparation method of tedizolid phosphate I, the volume-to-mass ratio of the organic solvent to the tedizolid phosphate intermediate V is preferably 1mL/g to 50mL/g, more preferably 10mL/g to 30mL/g, such as 20 mL/g.
In the preparation method of tedizolid phosphate I, the base is preferably an organic base; the organic base is preferably triethylamine.
In the preparation method of tedizolid phosphate I, the molar ratio of the alkali to the tedizolid phosphate intermediate V is preferably 1.5-5.5, more preferably 2.0-4.1, such as 3.0.
In the preparation method of tedizolid phosphate I, the molar ratio of the phosphorus oxychloride to the tedizolid phosphate intermediate V is preferably 1.5-5.0, more preferably 2.0-4.0, such as 3.0.
In the preparation method of tedizolid phosphate I, the condensation reaction temperature is preferably 0-40 ℃, for example 0-10 ℃.
In the preparation method of tedizolid phosphate I, the progress of the condensation reaction can be detected by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and generally the time for the condensation reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 5 hours, such as 3 hours, with the time when the tedizolid phosphate intermediate V is almost disappeared as the end point of the reaction (such as TLC monitoring the content of the tedizolid phosphate intermediate V is lower than 1%).
In the invention, the preparation method of tedizolid phosphate I preferably adopts the following route:
Figure BDA0001754956030000091
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method of the invention does not use highly toxic reagents, has mild reaction conditions, safe operation, environmental protection, high yield (72-74%), high purity of the prepared product (HPLC purity is more than 98.0%), low production cost and suitability for industrial production. The tedizolid phosphate prepared from the tedizolid phosphate intermediate II has high yield and high purity, can reach the standard of raw material medicaments (the HPLC purity is more than 99.5 percent, and the maximum single impurity is less than 0.10 percent), and is suitable for industrial production.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Detailed Description
Example 1: preparation of tedizolid phosphate intermediate II
Figure BDA0001754956030000101
Under the protection of nitrogen, adding 4.7Kg (14.5mol) of benzyl 3-fluoro-4-bromophenyl carbamate into 35.3L of tetrahydrofuran, stirring at 20-30 ℃, adding 3.8Kg (58.1mol) of zinc powder and 27.4g (0.145mol) of cobaltocene, stirring at 20-30 ℃ for 4-5 hours, filtering, and washing with 11.7L of tetrahydrofuran to obtain a solution which is a solution of tedizolid phosphate intermediate III and is stored under nitrogen. Stirring the solution of the tedizolid phosphate intermediate III at the temperature of between 20 and 30 ℃, adding 3.83Kg (15.95mol) of 2-methyl-5- (5-bromopyridine-2-yl) tetrazole, 3.1Kg (29.2mol) of sodium carbonate and 26.5g (0.029mol) of tris (dibenzylideneacetone) dipalladium, heating to between 65 and 70 ℃, and stirring for 5 to 6 hours. Cooling, filtering by diatomite 2.5Kg, adding tetrahydrofuran 10L and saline solution with mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution) 4L into the mother solution, layering, separating out the organic phase, drying, vacuum concentrating (the temperature is 35-55 ℃, and the pressure is-0.08 MPa-0.1 MPa) to dryness, pumping ethyl acetate 30L, heating to 70-75 ℃, stirring for 0.5-1 hour, cooling to 0-10 ℃, stirring for 1-2 hours, centrifuging, leaching with ethyl acetate 3L for three times, vacuum drying (the vacuum degree is-0.01 MPa-0.1 MPa, and the temperature is 45-55 ℃) for 16 hours, obtaining the midbody II of the white-like solid tedizolid phosphate, wherein the total yield is 74.4 Kg. HPLC purity 98.74%.
Example 2: preparation of tedizolid phosphate intermediate II
Under the protection of nitrogen, adding 40g (0.123mol) of benzyl 3-fluoro-4-bromophenylcarbamate into 400mL of acetonitrile, stirring at 10-20 ℃, adding 49g (0.749mol) of zinc powder and 0.60g (0.00245mol) of 1,1' -diethyl nickelocene, stirring at 10-20 ℃ for 7-8 hours, filtering, washing with 200mL of acetonitrile to obtain a solution, and storing under nitrogen to obtain the solution of the tedizolid phosphate intermediate III. Stirring the solution of the tedizolid phosphate intermediate III at 10-20 ℃, adding 31.0g (0.129mol) of 2-methyl-5- (5-bromopyridine-2-yl) tetrazole, 18.6g (0.184mol) of triethylamine and 0.15g (0.000129mol) of tetrakistriphenylphosphine palladium, heating to 55-65 ℃, and stirring for 7-8 hours. Cooling, filtering by filling 25g of diatomite, vacuum-concentrating the mother liquor (the temperature is 45-65 ℃, the pressure is-0.08 MPa-0.1 MPa) to dryness, adding 1L of a mixture with the volume ratio of tetrahydrofuran to ethyl acetate being 1:1 and saline water with the mass concentration being 15% (the mass concentration refers to the mass percentage of the mass of sodium chloride to the total mass of the saline water), layering, separating an organic phase, drying, vacuum-concentrating (the temperature is 35-55 ℃, the pressure is-0.08 MPa-0.1 MPa), adding 255mL of ethyl acetate, heating to 70-75 ℃, stirring for 0.5-1 hour, cooling to 0-10 ℃, stirring for 1-2 hours, filtering, leaching by using 30mL of ethyl acetate for three times, drying a wet product in a vacuum (the pressure is-0.01 MPa-0.1 MPa) drying box for 8-12 hours at 45-55 ℃, obtaining 35.9g of a white-like solid tedizolid intermediate II phosphate, the total yield is 72.0%. HPLC purity 98.49%.
Example 3: preparation of tedizolid phosphate intermediate II
Adding 80g (0.247mol) of benzyl 3-fluoro-4-bromophenyl carbamate into 400mL of dioxane under the protection of nitrogen, stirring at 35-45 ℃, adding 40.5g (0.619mol) of zinc powder and 0.36g (0.00124mol) of benzoyl ferrocene, stirring at 35-45 ℃ for 5.5-6.5 hours, cooling, filtering, and washing with 240mL of dioxane to obtain a solution which is a solution of tedizolid phosphate intermediate III and is preserved under nitrogen. Stirring the solution of the tedizolid phosphate intermediate III at 35-45 ℃, adding 71.1g (0.296mol) of 2-methyl-5- (5-bromopyridin-2-yl) tetrazole, 209g (0.984mol) of potassium phosphate and 0.83g (0.00124mol) of bis (tricyclohexylphosphine) palladium, heating to 75-85 ℃, and stirring for 3-4 hours. Cooling, filtering by using 60g of diatomite, adding 80mL of ethyl acetate and saline water with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline water) for layering, separating an organic phase, drying, concentrating in vacuum (the temperature is 35-65 ℃, and the pressure is-0.08 MPa-0.1 MPa), adding 510mL of ethyl acetate, heating to 70-75 ℃, stirring for 0.5-1 hour, cooling to 0-10 ℃, stirring for 1-2 hours, filtering, leaching for three times by using 60mL of ethyl acetate, drying a wet product in a vacuum (the pressure is-0.01 MPa-0.1 MPa) drying oven at 45-55 ℃ for 8-12 hours to obtain 73.1g of a white-like solid tedizolid intermediate II phosphate, wherein the total yield is 73.3%. HPLC purity 98.50%.
Example 4: preparation of tedizolid phosphate I (method according to patent CN 200980140140144)
Figure BDA0001754956030000121
Under the protection of nitrogen, 2.60Kg (6.43mol) of tedizolid phosphate intermediate II and 50L of anhydrous tetrahydrofuran were added to a 100L reactor and stirred to dissolve. 7.07L of a 1mol/L solution of lithium hexamethyldisilazide in tetrahydrofuran was added dropwise. Stirring for 2 hours at 10-15 ℃, adding 0.83Kg of 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidinone (DMPU), and cooling to 0-5 ℃. 0.97Kg of glycidyl R-butyrate was added. Stirring overnight at 10-15 ℃ to obtain light yellow slurry. Sodium methoxide 33g of a solution dissolved in 330mL of methanol was added thereto, and the mixture was stirred for 1 hour. Adding 17L of ammonium chloride solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the ammonium chloride in the total mass of the ammonium chloride water). Concentrating the two-phase mixture, adding water (13L,5 vol) into the concentrated slurry, cooling to room temperature, filtering, pulping the filter cake with methanol and water (the volume ratio is 4:1) (70L), filtering again, rinsing the filter cake with 12L of methanol and 12L of water, and drying the wet product in a vacuum (the pressure is-0.01 MPa to-0.1 MPa) drying oven at 45-55 ℃ for 8-12 hours to obtain a white solid, namely a tedizolid phosphate intermediate V2.01 Kg, with the yield of 84.4%. HPLC purity: 99.21 percent.
2.01Kg (5.41mol) of tedizolid phosphate intermediate V, 40L of tetrahydrofuran and 1.67Kg (16.5mol) of triethylamine are added into a 100L reaction kettle. Adding 2L of tetrahydrofuran and 2.48Kg (16.2mol) of phosphorus oxychloride into the mixture at the temperature of 0-5 ℃. Stirring for 3 hours at 0-10 ℃. Adding 40L of water, cooling to 0-10 ℃, stirring and filtering, and washing a filter cake with 20L of methanol and 20L of water. And drying the wet product in a vacuum (pressure of-0.01 MPa to-0.1 MPa) drying oven at 15-25 ℃ for 12-16 hours to obtain 2.03Kg of a white-like solid which is a tedizolid phosphate I crude product, wherein the yield is 83.0%. HPLC purity 99.49%, maximum single impurity 0.17%.
2.00kg of crude tedizolid phosphate I and 10L of water are added into a 50-liter reaction kettle and cooled to 5-10 ℃. 4.44L of sodium hydroxide solution with the mass concentration of 1% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide) is added into the free acid slurry drop by drop, and the pH value at the end point of the dropping is about 9. 10L of ethanol was added slowly, stirred at room temperature for 1 hour, filtered, rinsed with 3.3L of ethanol and drained. The filter cake was redissolved in 10L of water, 10L of ethanol was slowly added, stirred at room temperature for 1 hour, filtered, rinsed with 3.3L of ethanol and drained. The filter cake was redissolved in 10L of water, 10L of acetone was slowly added, stirred at room temperature for 1 hour, filtered, rinsed with 3.3L of acetone and drained. The filter cake was dissolved in water (10L), cooled to 5-10 deg.C and 4.44L of freshly prepared 2mol/L hydrochloric acid solution was added dropwise until the pH was 1.34, stirred at room temperature for 1 hour, filtered and rinsed with 7L of water. The wet product is dried for 12 to 16 hours in a vacuum (pressure of minus 0.01 to minus 0.1MPa) drying oven at the temperature of between 45 and 55 ℃ to obtain the off-white solid which is 1.21Kg of tedizolid phosphate I with the yield of 60.5 percent. HPLC purity 99.87%, maximum single impurity 0.04%.
Comparative example 1: preparation of tedizolid phosphate intermediate II (method according to patent CN 200980140144)
Figure BDA0001754956030000131
69.2g of benzyl 3-fluoro-4-bromophenylcarbamate, 0.67L of anhydrous Tetrahydrofuran (THF) and 443g of triisopropyl borate were added under nitrogen protection. The mixture was stirred and cooled to-70 ℃ to-75 ℃ in a dry ice/acetone bath. 0.18L of 2.5mol/L n-butyllithium was added dropwise. The reaction is quenched by 0.27L of an ammonium chloride aqueous solution with a mass concentration of 20% (the mass concentration refers to the mass percentage of ammonium chloride in the total mass of the ammonium chloride aqueous solution), so that the reaction is heated to 0-5 ℃. Separating the two phases, concentrating the organic phase in vacuum (the temperature is 45-65 ℃, the pressure is-0.08 MPa-0.1 MPa) until the organic phase is dry, adding 0.20L of mixed solvent of n-heptane/dichloromethane (the volume ratio is 10:1), stirring for L hour, filtering the mixture, and washing the filter cake by 0.05L of mixed solvent of n-heptane/dichloromethane (the volume ratio is 10: 1). The wet product was dried in a vacuum (pressure-0.01 MPa-0.1 MPa) oven at 45 ℃ to 55 ℃ for 8 hours to 12 hours to obtain 40.3g of a borate intermediate (yield 65.3%).
Under the protection of nitrogen, 17.7g of 2-methyl-5- (5-bromopyridine-2-yl) tetrazole, 27.7g of borate intermediate, 0.663g of tricyclohexylphosphine and 0.23L of dioxane are sequentially added and stirred to be dissolved; adding 70mL of water solution of 175g of potassium carbonate at a time; adding 0.88g of tris (dibenzylideneacetone) dipalladium, carrying out vacuum-nitrogen replacement for three times, heating and reacting to 70 ℃, keeping the temperature for 1 hour, filtering the reaction solution, leaching, adding 100mL of saline solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride to the total mass of the saline solution), layering, separating out an organic phase, carrying out vacuum concentration (the temperature is 45-65 ℃, and the pressure is-0.08 MPa-0.1 MPa) to dryness, stirring the crude product in 120mL of ethyl acetate for 12-16 hours, filtering, drying the wet product in a vacuum (the pressure is-0.01 MPa-0.1 MPa) drying box at the temperature of 45-55 ℃ for 8-12 hours, obtaining a white-like solid which is tedizolid intermediate II, and the total yield is 55.1% (calculated by 3-fluoro-4-bromophenyl benzyl carbamate). HPLC purity 96.23%.
Comparative example 2: preparation of tedizolid phosphate intermediate II (method according to patent CN 200480037612)
Figure BDA0001754956030000141
Under nitrogen protection, 5.44g of benzyl 3-fluoro-4-bromophenylcarbamate, 67mL of dioxane, 5.76g of hexabutylditin, and 0.93g of palladium dichlorobistriphenylphosphine were added. Stirring for 2-3 hours at 10-15 ℃, filtering and washing with dioxane to obtain a dioxane solution of a tributyltin intermediate. The dioxane solution of tributyltin intermediate is stirred at 35-45 deg.c, added with 4.23g of 2-methyl-5- (5-bromopyridin-2-yl) tetrazole, 2.09g of potassium phosphate and 0.083g of tetrakis (triphenylphosphine) palladium, heated to 75-85 deg.c and stirred for 3-4 hr. Cooling, filtering by using 6g of diatomite, adding 40mL of ethyl acetate and saline water with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline water) for layering, separating an organic phase, drying, concentrating in vacuum (the temperature is 35-65 ℃, and the pressure is-0.08 MPa-0.1 MPa), adding 26mL of ethyl acetate, heating to 70-75 ℃, stirring for 0.5-1 hour, cooling to 0-10 ℃, stirring for 1-2 hours, filtering, leaching for three times by using 12mL of ethyl acetate, drying a wet product in a vacuum (the pressure is-0.01 MPa-0.1 MPa) drying oven at 45-55 ℃ for 8-12 hours, and obtaining a white-like solid which is 2.91g of a tedizolid intermediate II, the total yield is 42.9%, and the HPLC purity is 97.18%.

Claims (10)

1. A preparation method of tedizolid phosphate intermediate II is characterized by comprising the following steps: step 1: reacting 3-fluoro-4-bromophenyl benzyl carbamate in an organic solvent in the presence of a catalyst and zinc powder to obtain a solution of a tedizolid phosphate intermediate III;
step 2: in an organic solvent, in the presence of a palladium catalyst and alkali, carrying out a coupling reaction on the solution of the tedizolid phosphate intermediate III obtained in the step 1 and 2-methyl-5- (5-bromopyridine-2-yl) tetrazole to obtain a tedizolid phosphate intermediate II:
in the step 1, the catalyst is a metallocene transition metal catalyst, and the "metallocene transition metal catalyst" is a complex of a metallocene and a transition metal, a complex of an acyl metallocene and a transition metal, or a complex of an alkyl metallocene and a transition metal; the "complex of the metallocene and the transition metal" is cobaltocene and/or nickelocene; the complex of the acyl dicyclopentadienyl and the transition metal is acetyl ferrocene and/or benzoyl ferrocene; the "complex of alkyl dicyclopentadienyl and transition metal" is 1,1 '-diethyl cobaltocene, 1' -diethyl nickelocene, ethyl ferrocene or butyl ferrocene; the reaction temperature is 0-60 ℃;
Figure FDA0002719644740000011
2. the process for the preparation of tedizolid phosphate intermediate II according to claim 1, wherein: in the step 1, the organic solvent is an ether solvent and/or a nitrile solvent;
and/or the presence of a gas in the gas,
in the step 1, the volume-to-mass ratio of the organic solvent to the benzyl 3-fluoro-4-bromophenyl carbamate is 1mL/g to 20 mL/g;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the zinc powder to the 3-fluoro-4-bromophenyl benzyl carbamate is 1.0-10.0;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the catalyst to the 3-fluoro-4-bromophenyl benzyl carbamate is 0.001-0.1;
and/or the presence of a gas in the gas,
in the step 1, the reaction time is 1-10 hours;
and/or the presence of a gas in the gas,
the reaction in the step 1 is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
the step 1 adopts the following reaction steps: adding zinc powder and a catalyst into a mixture formed by 3-fluoro-4-bromophenyl benzyl carbamate and an organic solvent for reaction to obtain a solution of the tedizolid phosphate intermediate III.
3. The process for the preparation of tedizolid phosphate intermediate II according to claim 2, wherein: in the step 1, the ether solvent is one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and dioxane;
and/or the presence of a gas in the gas,
in the step 1, the nitrile solvent is acetonitrile;
and/or the presence of a gas in the gas,
in the step 1, the volume-to-mass ratio of the organic solvent to the benzyl 3-fluoro-4-bromophenyl carbamate is 4mL/g to 10 mL/g;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the zinc powder to the 3-fluoro-4-bromophenyl benzyl carbamate is 2-8;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the catalyst to the 3-fluoro-4-bromophenyl benzyl carbamate is 0.005-0.02;
and/or the presence of a gas in the gas,
in the step 1, the reaction temperature is 5-50 ℃;
and/or the presence of a gas in the gas,
in the step 1, the reaction time is 2-8 hours;
and/or the presence of a gas in the gas,
when the reaction in step 1 is performed under the protection of a protective gas, the protective gas is nitrogen and/or argon.
4. The process for the preparation of tedizolid phosphate intermediate II according to claim 3, wherein: in the step 1, the volume-to-mass ratio of the organic solvent to the benzyl 3-fluoro-4-bromophenyl carbamate is 7.5mL/g, 10mL/g or 5 mL/g;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the zinc powder to the 3-fluoro-4-bromophenyl benzyl carbamate is 2.5, 6 or 4;
and/or the presence of a gas in the gas,
in the step 1, the molar ratio of the catalyst to the benzyl 3-fluoro-4-bromophenyl carbamate is 0.01, 0.02 or 0.005;
and/or the presence of a gas in the gas,
and/or the presence of a gas in the gas,
in the step 1, the reaction temperature is 20-30 ℃, 10-20 ℃ or 35-45 ℃;
and/or the presence of a gas in the gas,
in the step 1, the reaction time is 4 to 5 hours, 5 to 6 hours, 5.5 to 6.5 hours or 7 to 8 hours.
5. The process for the preparation of tedizolid phosphate intermediate II according to claim 1, wherein: in the step 2, the organic solvent is an ether solvent and/or a nitrile solvent;
and/or the presence of a gas in the gas,
in the step 2, the volume-to-mass ratio of the organic solvent to the 2-methyl-5- (5-bromopyridine-2-yl) tetrazole is 1 mL/g-20 mL/g;
and/or the presence of a gas in the gas,
in the step 2, the palladium catalyst is one or more of tris (dibenzylideneacetone) dipalladium, tetratriphenylphosphine palladium, bis (tricyclohexylphosphine) palladium and bis (tri-tert-butylphosphine) palladium;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the palladium catalyst to the benzyl 3-fluoro-4-bromophenyl carbamate is 0.0005-0.05;
and/or the presence of a gas in the gas,
in the step 2, the alkali is organic alkali or inorganic alkali;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the alkali to the 3-fluoro-4-bromophenyl benzyl carbamate is 1.1-8.0;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the 2-methyl-5- (5-bromopyridine-2-yl) tetrazole to the 3-fluoro-4-bromophenyl benzyl carbamate is 1.0-2.0;
and/or the presence of a gas in the gas,
in the step 2, the temperature of the coupling reaction is 45-boiling point of the solvent;
and/or the presence of a gas in the gas,
in the step 2, the coupling reaction time is 2-12 hours;
and/or the presence of a gas in the gas,
the step 2 adopts the following post-treatment steps: and after the reaction is finished, cooling, filtering, extracting, drying and concentrating to obtain a crude product of the tedizolid phosphate intermediate II.
6. The process for preparing tedizolid phosphate intermediate II according to claim 5, wherein: in the step 2, the ether solvent is one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and dioxane;
and/or the presence of a gas in the gas,
in the step 2, the nitrile solvent is acetonitrile;
and/or the presence of a gas in the gas,
in the step 2, the volume-to-mass ratio of the organic solvent to the 2-methyl-5- (5-bromopyridine-2-yl) tetrazole is 4 mL/g-10 mL/g;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the palladium catalyst to the 3-fluoro-4-bromophenyl benzyl carbamate is 0.001-0.005;
and/or the presence of a gas in the gas,
in the step 2, the organic base is triethylamine and/or diethylisopropylamine;
and/or the presence of a gas in the gas,
in the step 2, the inorganic base is one or more of cesium carbonate, potassium phosphate and sodium carbonate;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the alkali to the 3-fluoro-4-bromophenyl benzyl carbamate is 1.5-4.0;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the 2-methyl-5- (5-bromopyridine-2-yl) tetrazole to the 3-fluoro-4-bromophenyl benzyl carbamate is 1.0-1.2;
and/or the presence of a gas in the gas,
in the step 2, the temperature of the coupling reaction is 55-85 ℃;
and/or the presence of a gas in the gas,
in the step 2, the coupling reaction time is 3-8 hours;
and/or the presence of a gas in the gas,
recrystallizing the crude product of the tedizolid phosphate intermediate II to obtain the tedizolid phosphate intermediate II.
7. The process for preparing tedizolid phosphate intermediate II according to claim 6, wherein: in the step 2, the volume-to-mass ratio of the organic solvent to the 2-methyl-5- (5-bromopyridine-2-yl) tetrazole is 12.3mL/g, 19.4mL/g or 9 mL/g;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the palladium catalyst to the benzyl 3-fluoro-4-bromophenyl carbamate is 0.005, 0.001 or 0.002;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the alkali to the benzyl 3-fluoro-4-bromophenylcarbamate is 2.0, 1.5 or 4.0;
and/or the presence of a gas in the gas,
in the step 2, the molar ratio of the 2-methyl-5- (5-bromopyridine-2-yl) tetrazole to the 3-fluoro-4-bromophenyl benzyl carbamate is 1.2, 1.0 or 1.1;
and/or the presence of a gas in the gas,
in the step 2, the temperature of the coupling reaction is 65-70 ℃, 55-65 ℃ or 75-85 ℃;
and/or the presence of a gas in the gas,
in the step 2, the coupling reaction time is 3 to 4 hours, 7 to 8 hours or 5 to 6 hours;
and/or the presence of a gas in the gas,
the recrystallization adopts the following steps: and (3) cooling and crystallizing a solution formed by the crude product of the tedizolid phosphate intermediate II and an organic solvent to obtain the tedizolid phosphate intermediate II.
8. The process for preparing tedizolid phosphate intermediate II according to claim 7, wherein: in the step of recrystallization, the organic solvent is an ester solvent;
and/or the presence of a gas in the gas,
in the recrystallization step, the temperature of the solution formed by the crude product of the tedizolid phosphate intermediate II and the organic solvent is 50-100 ℃;
and/or the presence of a gas in the gas,
in the recrystallization step, the cooling crystallization temperature is-5 ℃ to 20 ℃;
and/or the presence of a gas in the gas,
in the recrystallization step, the cooling crystallization time is 1-2 hours.
9. A preparation method of tedizolid phosphate intermediate V is characterized by comprising the following steps: after the tedizolid phosphate intermediate II is prepared by the preparation method according to any one of claims 1 to 8, carrying out condensation reaction on the tedizolid phosphate intermediate II and R-glycidyl butyrate in an organic solvent in the presence of a catalyst and alkali to obtain a tedizolid phosphate intermediate V;
Figure FDA0002719644740000071
10. the preparation method of tedizolid phosphate I is characterized by comprising the following steps: after the tedizolid phosphate intermediate V is prepared according to the preparation method of claim 9, carrying out a condensation reaction on the tedizolid phosphate intermediate V and phosphorus oxychloride in an organic solvent in the presence of alkali to obtain the tedizolid phosphate I;
Figure FDA0002719644740000072
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