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

Abstract

The present invention relates to a preparation method for a tedizolid compound in Formula I. In Formula I, R is selected from hydrogen, formula A, formula B, benzyl or benzyl substituted by a substituent, the substituent is selected from a group consisting of halogen, nitryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy, and R.sub.1 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl substituted by halogen. The method comprises: generating a compound having a structure as shown in Formula C and a compound having a structure as shown in Formula D by a coupled reaction under the catalysis of a metal catalyst, a substituent of R being defined as above, where X is a leaving group, the leaving group comprising chlorine, bromine, iodine, and sulfonyl oxy such as trifluoromethane sulfonic oxy, methylsulfonyl oxy and benzenesulfonyl oxy, or benzenesulfonyl oxy substituted by one or more substituents, the substituent being selected from a group consisting of halogen, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy. ##STR00001##

Claims

1. A preparation method for tedizolid compound of the formula below ##STR00050## wherein R is selected from the group consisting of hydrogen, ##STR00051## benzyl and benzyl substituted by a substituent selected from the group consisting of halogen, nitro, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, and R.sub.1 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl substituted by halogen; wherein the preparation method comprises reacting the compound having a structure of the formula below ##STR00052## wherein X is a leaving group selected from the group consisting of chlorine, bromine, iodine, and sulfonyloxy; with the compound having a structure of the formula below ##STR00053## under the catalysis of metal catalyst in the presence of an alkaline substance as a promoter, in a reaction solvent selected from the group consisting of toluene, chlorobenzene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, isopropanol, ethanol and acetonitrile, at a reaction temperature of 60-110 C. to produce the tedizolid compound by a coupled reaction, and wherein substituent R is as defined above.

2. The preparation method according to claim 1, wherein the metal catalyst is a copper catalyst or a palladium catalyst.

3. The preparation method according to claim 1, wherein when the metal catalyst is a copper catalyst, the copper catalyst acts together with ligands selected from the group consisting of a diamine ligand, a diketone ligand, a phenanthroline ligand, an amino acid ligand, and a Phos ligand.

4. The preparation method according to claim 1, wherein the sulfonyloxy is selected from the group consisting of trifluoromethane sulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, and benzenesulfonyloxy substituted by one or more substituent(s) selected from the group consisting of halogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy.

5. The preparation method according to claim 2, wherein the copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, CuO, Cu.sub.2O, CuSO.sub.4, Cu(OAc).sub.2, Cu(OTf).sub.2 and Cu powder; and/or the palladium catalyst is selected from the group consisting of palladium chloride, palladium acetate, bis(dibenzylideneacetone) palladium, tetrakis(triphenylphosphine) palladium, tris(dibenzylideneacetone) dipalladium, dichloro [1, 1-bis(diphenylpho sphino)ferrocene] palladium, dichlorobis(tricyclohexylphosphine) palladium and dichlorobis(triphenylphosphine) palladium.

6. The preparation method according to claim 1, wherein the alkaline substance is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, potassium phosphate and sodium phosphate.

7. The preparation method according to claim 1, wherein the reaction temperature is 90-110 C.

8. The preparation method according to claim 3, wherein the diamine ligand is selected from the group consisting of: ##STR00054## the diketone ligand is selected from the group consisting of: ##STR00055## the phenanthroline ligand is selected from the group consisting of: ##STR00056## the amino acid ligand is ##STR00057## and the Phos ligand is selected from the group consisting of X-Phos, XantPhos, RuPhos, BrettPhos, SPhos, DavePhos, JohnPhos and tBuXPhos.

Description

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLES

(1) 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.

(2) Experiments and Data Analysis

(3) Reagents are purchased from commercial sources and they are directly used without treatment. .sup.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

(4) ##STR00030##

(5) 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 N.sub.2, Pd(dppf)Cl.sub.2 (0.6 g, 3% w/w) was added, followed by purging with N.sub.2 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(CDCl.sub.3, 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

(6) ##STR00031##

(7) 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), Na.sub.2CO.sub.3 (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 N.sub.2, Pd(dppf)Cl.sub.2 (1.5 g, 3% w/w) was added, followed by purging with N.sub.2 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

(8) ##STR00032##

(9) 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

(10) ##STR00033##

(11) 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 N.sub.2, 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

(12) ##STR00034##

(13) 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), Na.sub.2CO.sub.3 (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 N.sub.2, Pd(dppf)Cl.sub.2 (0.75 g, 3% w/w) was added, followed by purging with N.sub.2 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

(14) ##STR00035##

(15) 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 N.sub.2, 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

(16) ##STR00036##

(17) 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)Cl.sub.2 (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 N.sub.2, 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

(18) ##STR00037##

(19) (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 N.sub.2, 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

(20) ##STR00038##

(21) 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 N.sub.2, Pd(dppf)Cl.sub.2 (1.5 g, 3% w/w) was added, followed by purging with N.sub.2 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

(22) ##STR00039##

(23) 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), Na.sub.2CO.sub.3 (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 N.sub.2, Pd(dppf)Cl.sub.2 (450 mg, 3% w/w) was added, followed by purging with N.sub.2 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

(24) ##STR00040##

(25) 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 N.sub.2, Pd(dppf)Cl.sub.2 (0.9 g, 3% w/w) was added, followed by purging with N.sub.2 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

(26) ##STR00041##

(27) 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), Na.sub.2CO.sub.3 (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 N.sub.2, Pd(dppf)Cl.sub.2 (540 mg, 3% w/w) was added, followed by purging with N.sub.2 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

(28) ##STR00042##

(29) 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

(30) ##STR00043##

(31) 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

(32) ##STR00044##

(33) (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

(34) ##STR00045##

(35) (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 H.sub.2, 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

(36) ##STR00046##

(37) 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

(38) ##STR00047##

(39) 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).sub.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 N.sub.2, 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

(40) ##STR00048##

(41) 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

(42) ##STR00049##

(43) 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 N.sub.2, 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).

(44) 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.