Preparation method for tedizolid, tedizolid intermediate, and preparation method therefor

Description

This application claims priority to Chinese patent application No. 201510739910.6 filed with SIPO on Nov. 3, 2015, entitled “PREPARATION METHOD FOR TEDIZOLID AND INTERMEDIATE THEREOF”, the content of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The invention relates to a preparation method for a novel oxazolidinone antibiotic tedizolid or its phosphates, and its intermediate compounds and the preparation method thereof.

BACKGROUND ART

Tadizolid phosphate has a strong antibacterial activity to pathogens of human and animal, including gram-positive bacteria such as Staphylococcus, Enterococcus and Streptococcus, anaerobic microorganisms such as bacteroid and Clostridium, and acidotolerant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium complex. Tadizolid (formerly called torezolid) was jointly developed by the Cubist Pharmaceuticals company (a subsidiary of Merck Corporation) and Bayer. It was originally found as an antibacterial drug precursor by Dong-A Pharmaceutical (Dong-A ST) and used for the treatment of gram-positive bacterial infections. Tedizolid is rapidly transformed into its active form TR 700 (DA 7157) in plasma.

WO2005058886A1 discloses the synthesis of 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone, wherein 3-fluoroaniline is used as raw material and reacts with glycidyl butyrate after being protected by Cbz to obtain compound 3. Compound 3 is then iodinated and converted into tin reagent 5, which is Suzuki coupled with 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine to produce the key intermediate K. The reaction scheme is depicted as follows:

The reaction procedure of the original drug of Dong-A Pharmaceutical is long, and the total yield is not high. In terms of cost, relatively expensive reagents such as CF₃COOAg are needed, and Pd catalyst are needed twice for respectively preparing intermediates 5 and K in the scheme. The reaction conditions are harsh, which is not easy for a large scale production.

Later, the synthetic scheme of the original compound was improved by an licensee Trius Therapeutics company, in whose patent WO2010042887, 4-bromo-3-fluoroaniline is employed as the starting material, first to synthesize boric acid ester 10, which is then Suzuki coupled with 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine to generate intermediate 11. Intermediate 11 then reacts with glycidyl butyrate to obtain the oxazolidinone intermediate K. The reaction scheme is depicted as follows:

Compared with the patented method of Dong-A Pharmaceutical, this scheme is short in reaction procedure with an improved total yield. However, the reaction conditions are still rather harsh. Butyl lithium is needed, and the reaction needs to be carried out at ultra-low temperature (−65° C.). The use of n-BuLi and LiHMDS requires strict anhydrous condition.

In addition, CN104496979A discloses a method for preparing tedizolid, which is as depicted in the reaction scheme below:

wherein R is hydrogen or a hydroxyl protective group; one of L and R₁ is a leaving group, while the other one is BF₃ or BR₂R₃, wherein R₂ and R₃ are independently selected from a group consisting of OH, and optionally substituted C₁-C₆ monohydric alcohol and C₁-C₆ diol, and wherein R₂ and R₃ can form a ring. Pd is employed in this scheme to catalyze the synthesis of borate intermediate II. After separation and purification, the intermediate II is Suzuki coupled with compound I under catalysis of Pd to obtain the compound of formula H. In this scheme, the reaction operations are complicated, since the intermediate II needs to be separated out before Suzuki coupling.

The methods of prior art for preparing tedizolid intermediates all suffer from complex operation, long reaction time, low total yield and low purity.

SUMMARY OF THE INVENTION

One purpose of the invention is to provide a preparation method of tedizolid, which has low production cost, simple operation, relatively high yield and high purity, and is suitable for industrial production. In particular, the invention relates to a novel method for preparing tedizolid by using novel intermediates.

To achieve the above purpose, the invention provides a method for preparing a tedizolid compound of the formula below

• • wherein R is selected from a group consisting of hydrogen,

• •  benzyl or benzyl substituted by a substituent (the substituent is selected from a group consisting of halogen, nitro, C₁-C₆ alkyl and C₁-C₆ alkoxy), and R₁ is C₁-C₆ alkyl or C₁-C₆ alkyl substituted by halogen;
    wherein the method comprises reacting the compound of the formula below

• • wherein X is a leaving group (the leaving group includes chlorine, bromine, iodine, and sulfonyloxy such as trifluoromethane sulfonyloxy, methane sulfonyloxy, benzenesulfonyloxy, or benzene sulfonyloxy substituted by one or more substituents, and the substituents are selected from the group consisting of halogen, C₁-C₆ alkyl and C₁-C₆ alkoxy; preferably, the leaving group is chlorine, bromine or iodine; and more preferably, the leaving group is bromine or iodine),
    with the compound of the formula below

by catalysis of a metal catalyst by a coupled reaction, wherein the substituent R is as defined above.

In a preferred embodiment of the present invention, the metal catalyst is a copper catalyst. The copper catalyst is preferably selected from a group consisting of Cu powder, CuI, CuBr, Cu₂O, CuO, Cu₂O, CuSO₄, Cu(OAc)₂ or Cu(OTf)₂, and more preferably CuI and Cu(OAc)₂.

In addition to using a copper catalyst alone, in some instances, ligands are also required for the reaction. Diamine ligands, diketone ligands, phenanthroline ligands, amino acid ligands, or Phos ligands can be used. The diamine ligands are preferably selected from a group consisting of:

The diketone ligands are preferably selected from a group consisting of:

The phenanthroline ligands are preferably selected from a group consisting of:

The amino acid ligands are preferably selected from a group consisting of:

The Phos ligands are preferably selected from a group consisting of: X-Phos, XantPhos, RuPhos, BrettPhos, SPhos, DavePhos, JohnPhos and tBuXPhos.

In other embodiments of the present invention, the metal catalyst is a palladium catalyst, such as palladium chloride, palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, dichloro [1,1′-Bis(diphenylphosphino)-ferrocene] palladium, dichlorobis(tricyclohexylphosphine)palladium or dichlorobis(triphenylphosphine)palladium, and preferably, tris-(dibenzylideneacetone)dipalladium, palladium chloride or palladium acetate.

Generally, the reaction can be promoted in alkaline environment (such as potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium hydroxide, potassium hydroxide, potassium phosphate or sodium phosphate, or the like). The solvent is selected from a group consisting of aromatic hydrocarbons, ethers, alcohols, ethers, nitriles, amides and the like, preferably toluene, chlorobenzene, tetrahydrofuran (THF), N,N-dimethyl-formamide (DMF), dimethyl sulfoxide (DMSO), dioxane, isopropanol, ethanol or acetonitrile; more preferably N,N-dimethylformamide (DMF) and dioxane. The reaction temperature is preferably 60-110° C., and more preferably 90-110° C.

When being not

the protective group R can be optionally removed (where R is as defined above, excluding hydrogen), to obtain the compound of the formula below:

The compound of the formula above can be further phosphorylated to obtain tedizolid phosphate of the formula below:

The invention also provides a preparation method of a novel tedizolid intermediate of the formula below:

• • wherein X is a leaving group as defined above;
    wherein the method includes reacting the compound of the formula below

• • wherein C is hydroxyl group or amino group;
    1) with sulfochloride compounds (such as trifluoroformic anhydride, methanesulfonyl chloride or benzenesulfonyl chloride, or the like), when C is hydroxyl, to obtain the compound of the formula below:

• • wherein X is a leaving group (the leaving group is sulfonyloxy such as trifluoromethane sulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, or benzenesulfonyloxy substituted by one or more substituents, and the substituents are selected from a group consisting of halogen, C₁-C₆ alkyl and C₁-C₆ alkoxy);
  • in this circumstance, addition of alkaline substances, such as potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium phosphate, or the like, can promote the reaction.
    2) to obtain diazonium compounds in the presence of sodium nitrite, when C is amino group, and the diazonium compounds are then substituted by halogen ions to form the compound with of a structure of the formula below:

• • wherein X is a leaving group, which is selected from a group consisting of chlorine, bromine and iodine;
  • in this circumstance, under acidic conditions such as in the presence of acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid or camphosulfonic acid, it is reacted with sodium nitrite to form diazonium. Diazonium is then substituted by halogen ions to obtain the compound of the formula above. Donors of the halogen ions can be chlorine, bromine or iodine. Taking iodine as an example, the donors may include iodine element or Iodide salt such as sodium iodide, potassium iodide, or the like.

The invention also provides a method for preparing a novel tedizolid intermediate, i.e. the compound of the formula below:

wherein the method includes reacting the compound of the formula below

with the compound of the formula below

by catalysis of palladium catalyst by a coupled reaction,
wherein C is a hydroxyl or amino group; one of A and B is a leaving group, and the other one is BF₃ or BR₂R₃, wherein R₂ and R₃ are independently selected from a group consisting of OH and C₁-C₆ monohydric alcohol and C₁-C₆ diol or C₁-C₆ monohydric alcohol and C₁-C₆ diol substituted by halogen, and wherein R₂ and R₃ can form a ring.

In one embodiment, preferably A is a leaving group, B is BF₃ or BR₂R₃, wherein R₂ and R₃ can be independently selected from a group consisting of OH and C₁-C₆ monohydric alcohol and C₁-C₆ diol or C₁-C₆ monohydric alcohol and C₁-C₆ diol substituted by halogen, and wherein R₂ and R₃ can form a ring.

In another embodiment, preferably B is a leaving group, A is BF₃ or BR₂R₃, wherein R₂ and R₃ can be independently selected from a group consisting of OH and C₁-C₆ monohydric alcohol and C₁-C₆ diol or C₁-C₆ monohydric alcohol and C₁-C₆ diol substituted by halogen, and wherein R₂ and R₃ can form a ring.

The leaving groups include halogens such as chlorine, bromine, or iodine, and sulfonyloxy such as trifluoromethane sulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, or benzenesulfonyloxy substituted by one or more substituents, and the substituents are selected from a group consisting of halogen, C₁-C₆ alkyl and C₁-C₆ alkoxy; preferably the leaving group is chlorine, bromine or iodine; and more preferably the leaving group is bromine or iodine.

Preferably, BR₂R₃ is B(OH)₂ or

In one embodiment, C is a hydroxyl or amino group; preferably B is bromine or iodine, and A is BF₃, B(OH)₂ or

In an embodiment, the catalyst for reaction is palladium catalyst. The palladium catalyst is palladium chloride, palladium acetate, bis(dibenzylideneacetone) palladium, tetrakis(triphenylphosphine) palladium, dichloro[1,1′-bis-(diphenylphosphino)ferrocene] palladium, dichlorobis(tricyclohexylphosphine) palladium or dichlorobis(triphenylphosphine) palladium, or the like.

The reaction can be promoted in the presence of alkaline substances, such as potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, potassium phosphate or sodium phosphate. The solvent can be a combination of one or more selected from the group consisting of water, toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, isopropanol, ethanol, acetonitrile, or the like, and preferably toluene, water and dioxane, or isopropanol. The reaction temperature is preferably 50-120° C., and more preferably 70-100° C.

In another embodiment, C is a hydroxyl or amino group; and preferably A is bromine or iodine, and B is BF₃, B(OH)₂ or

In one embodiment, the reaction is carried out preferably in the presence of palladium catalyst. The solvent is preferably water and dioxane, and the reaction temperature is about 60-80° C. Then the tedizolid intermediate compound below is prepared:

The invention also provides a novel tedizolid intermediate, i.e. the compound of the chemical formula below:

or the compound of the chemical formula below:

wherein X is a leaving group (the leaving group includes chlorine, bromine, iodine, and sulfonyloxy such as trifluoromethane sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, or benzene sulfonyloxy substituted by one or more substituents selected from the group consisting of halogen, C₁-C₆ alkyl and C₁-C₆ alkoxy); preferably the leaving group is bromine or iodine. The compound is preferably as follows:

The invention achieves the following technical effects: by comparison with the prior art, the present invention provides a novel method for preparing tedizolid, having the advantages of material availability, low cost, a high yield for each step, simple process, easy operation and environmental friendliness, economical efficiency and being conducive to industrial production. The preparation method of the present invention involves the use of a key intermediate 5-(4-substituent group-2-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine which allows the preparation scheme of tedizolid being carried out.

DETAILED DESCRIPTION OF THE INVENTION

Examples

In order to make the technical problems solved by the invention, the technical solutions and the beneficial effects more clearly, the invention will be further illustrated in combination with specific examples. The specific examples given are preferred examples of the invention.

Experiments and Data Analysis

Reagents are purchased from commercial sources and they are directly used without treatment. ¹H-NMR spectra were measured on a Bruker AVANCE 400 spectrometer operating at 400 MHz. MS data were recorded by Agilent HPLC 1260 Infinity and 6120 Duadrupole LC/MS.

Example 1: Preparation of 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 1 eq), bis(pinacolato)-diboron (42.3 g, 2.0 eq), potassium acetate (24.5 g, 3.0 eq) and toluene (400 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (0.6 g, 3% w/w) was added, followed by purging with N₂ again, and the mixture was reacted under stirring at 80-85° C. for 12 h. The completion of the reaction was monitored by HPLC. The reaction liquid was cooled to 40-50° C., suction filtered at this temperature. 5 g activated carbon was added to the filtrate. The mixture was then heated to 70-80° C. under stirring for 1-2 h for decoloration, cooled to 40-50° C., and suction filtered at this temperature. The obtained filtrate was distillated under reduced pressure to 40-60 mL, cooled to 10-15° C. to separate out white solid. The white solid was filtered and the filter cake was oven dried at 50° C. to obtain 19.5 g white solid product with a yield of 81.5% and an HPLC purity of 98.5%. LCMS[M+H]=288.1, NMR(CDCl₃, 400 MHz): 9.15 (t, 1H), 8.22 (m, 2H), 4.44 (s, 3H), 1.25 (s, 12H).

Example 2: Preparation of 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)-aniline

2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (50 g, 1 eq), 4-bromo-3-fluoroaniline (36.4 g, 1.1 eq), Na₂CO₃ (36.9 g, 2.0 eq), water (300 mL) and dioxane (1000 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (1.5 g, 3% w/w) was added, followed by purging with N₂ again, and the mixture was reacted under stirring at 70-80° C. for 12 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the dioxane, added with 500 mL water, stirred at room temperature for 2-3 h; and then filtered. The filter cake was pulped with ethanol (100 mL), and then filtered. The obtained filter cake was oven dried at 50° C. to obtain 42.3 g offwhite solid products with a yield of 90% and an HPLC purity of 99.1%. LCMS[M+H]=271.0, NMR (DMSO-d6, 400 MHz): 9.01 (t, 1H), 8.54 (s, 2H), 8.18 (m, 2H), 7.75 (t, 1H), 7.59 (d, 1H), 7.29 (d, 1H), 4.41 (s, 3H).

Example 3: Preparation of 5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine

3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl)aniline (30.0 g, 1 eq) and acetic acid (600 mL) were added into a three-necked flask equipped with agitator and thermometer, and dissolved under stirring at room temperature. Then, camphorsulfonic acid (30.9 g, 1.2 eq), potassium iodide (36.9 g, 2.0 eq) and sodium nitrite (9.2 g, 1.2 eq) were successively added. The mixture obtained was stirred for 16 h at room temperature. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the acetic acid, then added with 300 mL water and 500 mL dichloromethane, stirred and separated. The dichloromethane layer was washed with water, and then distilled under reduced pressure to remove solvent. 20.8 g brown solid product was obtained with a yield of 49% and an HPLC purity of 96.7%. LCMS[M+H]=381.9, NMR (DMSO-d6, 400 MHz): 8.85 (s, 1H), 8.28 (d, 1H), 8.01 (d, 1H), 7.65 (t, 1H), 7.56 (dd, 1H), 7.19 (d, 1H), 4.42 (s, 3H).

Example 4: Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine (50.0 g, 1 eq), (R)-5-(hydroxymethyl)oxazolidin-2-one (23.0 g, 1.5 eq), cyclohexanediamine (1.5 g, 0.1 eq), cuprous iodide (1.3 g, 0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, the mixture obtained was reacted under stirring at 100-110° C. for 16 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the solvent. 1000 mL water was added into the residues, heated to reflux for 1-2 h, then cooled to 70° C., and suction filtered. The filter cake was pulped with DMF (150 mL) for 2 h, and then filtered. The filter cake was pulped again with water (300 mL) and then filtered. The filter cake was oven dried at 65° C. to obtain offwhite solid products with a yield of 79.2% and an HPLC purity of 97.9%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

Example 5: Preparation of 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenol

2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (25 g, 1 eq), 4-bromo-3-fluorophenol (19.9 g, 1.2 eq), Na₂CO₃ (18.5 g, 2.0 eq), water (120 mL) and dioxane (600 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (0.75 g, 3% w/w) was added, followed by purging with N₂ again, and the mixture was reacted under stirring at 70-80° C. for 12 h. The completion of the reaction was monitored by HPLC. The mixture was distilled under reduced pressure to remove most of the dioxane. 500 mL water was added, stirred at room temperature for 2-3 h, and then filtered. The filter cake was pulped with isopropanol (70 mL). The mixture obtained was filtered, and the filter cake was oven dried at 50° C. to obtain 18.2 g white solid product with a yield of 77% and an HPLC purity of 99.5%. LCMS[M+H]=272.0, NMR (DMSO-d6, 400 MHz): 10.20 (s, 1H), 9.11 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.75 (t, 1H), 7.59 (d, 1H), 7.29 (d, 1H), 4.39 (s, 3H).

Example 6: Preparation of 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl trifluoromethanesulfonate

3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenol (15 g, 1 eq), trifluoromethanesulfonic anhydride (23.4 g, 1.5 eq), pyridine (6.6 g, 1.5 eq), and tetrahydrofuran (150 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, the mixture obtained was heated to reflux and react for 5 h under stirring. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the tetrahydrofuran. Then, 100 mL ethyl acetate and 100 mL water were added, and stirred at room temperature. Liquids were separated. The organic phase was dried and distilled to remove solvent. 20.0 g white solid product was obtained with a yield of 90% and an HPLC purity of 96.3%. LCMS[M+H]=403.9, NMR (DMSO-d6, 400 MHz): 9.12 (s, 1H), 8.44 (d, 1H), 8.08 (d, 1H), 7.85 (t, 1H), 7.67 (d, 1H), 7.28 (d, 1H), 4.33 (s, 3H).

Example 7: Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl trifluoromethanesulfonate (10.0 g, 1 eq), (R)-5-(hydroxymethyl)oxazolidin-2-one (3.8 g, 1.3 eq), Pd(dppf)Cl₂ (300 mg, 3% w/w), XantPhos (300 mg, 3% w/w), potassium carbonate (6.9 g, 2.0 eq) and dioxane (80 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, the mixture obtained was reacted under stirring at 100-110° C. for 16 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the solvent. The residue was added with 100 mL water, heated to reflux for 1-2 h, cooled to 70° C., and filtered under reduced pressure. the filter cake was pulped with DMF (150 mL) for 2 h. The obtained mixture was filtered, and the filter cake was pulped with water (150 mL) again. The obtained mixture was filtered, and the filter cake was oven dried at 65° C. to obtain 6.1 g offwhite solid product with a yield of 66% and an HPLC purity of 96.9%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

Example 8: Preparation of Tedizolid Phosphate

(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-5-(hydroxy methyl)-oxazolidin-2-one (10.0 g, 1 eq) and tetrahydrofuran (200 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, the mixture obtained was cooled to 0° C. Triethylamine (8.2 g, 3 eq) was added dropwise. Phosphorus oxychloride was added dropwise at 0-10° C. under stirring. After the addition was completed, the reaction mixture was warmed to room temperature slowly and reacted for 20 h. The completion of the reaction was monitored by HPLC. The reaction liquid was added into 100 mL ice water dropwise slowly, stirred overnight, and filtered. The solid product was washed with 50 mL to obtain filter cake. The filter cake was oven dried at 65° C. for 20 h and obtained crude white solid, which was then pulped with 40 mL methanol, and filtered. The filter cake was oven dried at 65° C. to obtain 6.8 g pure product of white solid with a yield of 56% and an HPLC purity of 99.7%. LCMS[M+H]=451.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

Example 9: Preparation of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-bromo-3-fluoroaniline (50.0 g, 1 eq), bis(pinacolato)diboron (100.2 g, 1.5 eq), potassium acetate (77.5 g, 3.0 eq) and toluene (500 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (1.5 g, 3% w/w) was added, followed by purging with N₂ again, and the mixture was reacted under stirring at 80-85° C. for 8 h. The completion of the reaction was monitored by HPLC. The reaction liquid was cooled to 40-50° C., and filtered under reduced pressure at this temperature. 10 g activated carbon was added to the filtrate. The filtrate was heated to 70-80° C. under stirring for 1-2 h for decoloration, then cooled to 40-50° C., and filtered under reduced pressure at this temperature. The filtrate was distilled under reduced pressure to 80-100 mL, cooled to 10-15° C. to separate out white solid, and filtered. The filter cake was oven dried at 50° C. to obtain 54 g white solid product with a yield of 87% and an HPLC purity of 98.9%. LCMS[M+H]=238.1, NMR (DMSO-d6, 400 MHz): 7.51 (d, 1H), 7.02 (s, 1H), 6.87 (d, 1H), 6.51 (s, 2H), 1.25 (s, 12H).

Example 10: Preparation of 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)aniline

3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline (15 g, 1 eq), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (18.2 g, 1.2 eq), Na₂CO₃ (13.4 g, 2.0 eq), water (60 mL) and dioxane (300 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (450 mg, 3% w/w) was added, followed by purging with N₂ again. The mixture was reacted under stirring at 70-80° C. for 12 h. The completion of the reaction was monitored by HPLC. The obtained mixture was distilled under reduced pressure to remove most of the dioxane, added with 150 mL water, stirred at room temperature for 2-3 h, and filtered. The filter cake was pulped with ethanol (80 mL). The mixture obtained was filtered, and the filter cake was oven dried at 50° C. to obtain 14.8 g offwhite solid product with a yield of 87% and an HPLC purity of 98.3%. LCMS[M+H]=271.0, NMR (DMSO-d6, 400 MHz): 9.01 (t, 1H), 8.54 (s, 2H), 8.18 (m, 2H), 7.75 (t, 1H), 7.59 (d, 1H), 7.29 (d, 1H), 4.41 (s, 3H).

Example 11: Preparation of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

4-Bromo-3-fluorophenol (30.0 g, 1 eq), bis(pinacolato)diboron (59.8 g, 1.5 eq), potassium acetate (46.3 g, 3.0 eq) and toluene (300 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (0.9 g, 3% w/w) was added, followed by purging with N₂ again, and the mixture was reacted under stirring at 80-85° C. for 8 h. The completion of the reaction was monitored by HPLC. The reaction liquid was cooled to 40-50° C., filtered under reduced pressure at this temperature. 10 g activated carbon was added to the filtrate. The filtrate was heated to at 70-80° C. under stirring for 1-2 h for decoloration, then cooled to 40-50° C., and filtered under reduced pressure at this temperature. The filtrate was distilled under reduced pressure to 60-80 mL, cooled to 0-10° C. to separate out white solid, and filtered. The filter cake was oven dried at 50° C. to obtain 29.8 g white solid product with a yield of 80% and an HPLC purity of 99.5%. LCMS[M+H]=239.0, NMR (DMSO-d6, 400 MHz): 10.50 (s, 1H), 7.65 (d, 1H), 7.42 (s, 1H), 7.01 (d, 1H), 1.26 (s, 12H).

Example 12: Preparation of 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenol

3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenol (18.0 g, 1 eq), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (21.8 g, 1.2 eq), Na₂CO₃ (16.0 g, 2.0 eq), water (54 mL) and dioxane (270 mL), were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, Pd(dppf)Cl₂ (540 mg, 3% w/w) was added, followed by purging with N₂ again, and the mixture was reacted under stirring at 70-80° C. for 12 h. The completion of the reaction was monitored by HPLC. The obtained mixture was distilled under reduced pressure to remove most of the dioxane, added with 300 mL water, stirred at room temperature for 2-3 h, and filtered. The filter cake was pulped with isopropanol (90 mL). The obtained mixture was filtered, and the filter cake was oven dried at 50° C. to obtain 16.0 g white solid product with a yield of 78% and an HPLC purity of 98.9%. LCMS[M+H]=272.0, NMR (DMSO-d6, 400 MHz): 10.20 (s, 1H), 9.11 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.75 (t, 1H), 7.59 (d, 1H), 7.29 (d, 1H), 4.39 (s, 3H).

Example 13: Preparation of (R)-2-((benzyloxy)methyl)ethylene oxide

Benzyl alcohol (50 g, 1 eq), potassium hydroxide aqueous solution 300 mL (50% w/w), TBAB (14.9 g, 0.1 eq) and dichloromethane (300 mL) were added into a three-necked flask equipped with agitator and thermometer, and cooled to 0-10° C. Epoxy chloropropane (64.2 g, 1.5 eq) was added dropwise slowly. After the addition was completed, the mixture obtained was warmed to room temperature and reacted for 16 h. The completion of the reaction was monitored by HPLC. The stir was stopped and the liquids were separated. The aqueous phase was extracted once with 300 mL dichloromethane; and the organic phases were combined and directly used in the next step without purification.

Example 14: Preparation of (R)-1-amino-3-(benzyloxy)isopropanol

A solution of (R)-2-((benzyloxy)methyl)oxirane in dichloromethane and 100 mL aqueous ammonia were added into a hydrogenated bottle equipped with agitator, heated to 35° C. after sealing, stirred and reacted for 16 h. The completion of the reaction was monitored by HPLC. The stir was stopped, and 300 mL water was added, and stirred. The liquids were separated. The organic phase was washed with 0.1M HCl solution (100 mL), and dichloromethane was separated and discarded. The aqueous phase was adjusted with NaOH to pH 9-10, extracted with (300 mL) dichloromethane and concentrated to obtain 55.0 g colorless liquid product, with a two-step yield of 66% and an HPLC purity of 98.4%. LCMS[M+H]=182.0, NMR (DMSO-d6, 400 MHz): 7.42-7.25 (m, 5H), 5.11 (s, 2H), 4.54 (s, 2H), 3.68 (m, 1H), 3.50-3.34 (m, 2H), 3.12-3.06 (br, 1H), 3.00-2.89 (m, 2H).

Example 15: Preparation of (R)-5-((benzyloxy)methyl)oxazolidin-2-one

(R)-1-amino-3-(benzyloxy)isopropanol (20 g, 1 eq) and tetrahydrofuran (200 mL) were added into a three-necked flask equipped with agitator, heated to 35° C., added with CDI (26.8 g, 1.5 eq). The obtained mixture was stirred and reacted for 16 h while keeping the temperature. The completion of the reaction was monitored by HPLC. The stir was stopped and the tetrahydrofuran-containing solution was concentrated. 200 mL ethyl acetate and 100 mL 1M hydrochloric acid were added, and stirred. The liquids were separated. The organic phase was washed with water and the ethyl acetate-containing phase was concentrated to obtain a colorless liquid product 21.0 g with yield of 92% and HPLC purity of 99.0%. LCMS[M+H]=208.0, NMR (DMSO-d6, 400 MHz): 8.05 (s, 1H), 7.44-7.22 (m, 5H), 4.56 (s, 2H), 4.28-4.20 (m, 1H), 3.77-3.69 (m, 1H), 3.42-3.29 (m, 2H), 3.11-3.06 (m, 1H).

Example 16: Preparation of (R)-5-(hydroxymethyl)oxazolidin-2-one

(R)-5-((benzyloxy)methyl)oxazolidin-2-one (15 g, 1 eq), tetrahydrofuran (150 mL) and Pd/C (1.5 g, 10% w/w) were added into a three-necked flask equipped with agitator. After purging with H₂, the mixture obtained was heated to 45° C., stirred and reacted for 3 h by keeping this temperature. The completion of the reaction was monitored by HPLC. The mixture obtained was filtered without stir to remove Pd/C. The tetrahydrofuran-containing phase was concentrated to obtain 8.4 g colorless oil product with a yield of 99% and an HPLC purity of 98.6%. LCMS[M+H]=117.9, NMR (DMSO-d6, 400 MHz): 7.92 (s, 1H), 4.68-4.60 (m, 1H), 3.97-3.90 (m, 1H), 3.70 (br, 1H), 3.62-3.55 (m, 2H), 3.11-3.06 (m, 1H).

Example 17: Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine (50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5 eq), cyclohexanediamine (1.5 g, 0.1 eq), copper sulfate (1.05 g, 0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL) were added into a three-necked flask equipped with agitator and thermometer. The mixture obtained was stirred and reacted at 100-110° C. for 16 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the solvent. 1000 mL water was added into the residue, heated to reflux for 1-2 h, then cooled to 70° C., and filtered under reduced pressure. The filter cake was pulped with DMF (150 mL) for 2 h. The mixture obtained was filtered, and the filter cake was pulped with water (300 mL) again. The mixture obtained was filtered; the filter cake was oven dried at 65° C. to obtain 36.3 g offwhite solid product with a yield of 74.7% and an HPLC purity of 98.3%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

Example 18: Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine (50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5 eq), cyclohexanediamine (1.5 g, 0.1 eq), Cu(OAc)₂ (1.19 g, 0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, the mixture obtained was stirred and reacted at 100-110° C. for 16 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the solvent. 1000 mL water was added into the residue, heated to reflux for 1-2 h, cooled to 70° C., and filtered under reduced pressure. The filter cake was pulped with DMF (150 mL) for 2 h. The mixture obtained was filtered; and the filter cake was pulped with water (300 mL) again. The mixture obtained was filtered; and the filter cake was oven dried at 65° C. to obtain 39.9 g offwhite solid products with a yield of 82.1% and an HPLC purity of 97.8%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

Example 19: Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine (50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5 eq), cyclohexanediamine (1.5 g, 0.1 eq), tris(dibenzylideneacetone)dipalladium (1.5 g, 3% w/w), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL) were added into a three-necked flask equipped with agitator and thermometer. The mixture obtained was stirred and reacted at 100-110° C. for 16 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of the solvent. 1000 mL water was added into the residue, heated to reflux for 1-2 h, cooled to 70° C., and filtered under reduced pressure. The filter cake was pulped with DMF (150 mL) for 2 h. The mixture obtained was filtered; and the filter cake was pulped with water (300 mL) again. The mixture obtained was filtered; and the filter cake was oven dried at 65° C. to obtain 36.7 g offwhite solid product with a yield of 75.5% and an HPLC purity of 98.0%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

Example 20: Preparation of (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine (50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5 eq), cyclohexanediamine (1.5 g, 0.1 eq), cuprous iodide (1.3 g, 0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and DMF (500 mL) were added into a three-necked flask equipped with agitator and thermometer. After purging with N₂, the mixture obtained was stirred and reacted at 100-110° C. for 16 h. The completion of the reaction was monitored by HPLC. The mixture obtained was distilled under reduced pressure to remove most of solvent. 1000 mL water was added into the residue, heated to reflux for 1-2 h, cooled to 70° C., and filtered under reduced pressure. The filter cake was pulped with DMF (150 mL) for 2 h. The mixture obtained was filtered; and the filter cake was pulped with water (300 mL) again. The mixture obtained was filtered; and the filter cake was oven dried at 65° C. to obtain 36.9 g offwhite solid product with a yield of 76.0% and an HPLC purity of 99.5%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).

The description above was only preferred embodiments of the present invention, which is not limited thereto. Any modification, substitution and improvement made within the spirit and scope of the present invention should fall into the scope claimed by the present invention.