METHOD FOR SYNTHESIZING N-SUBSTITUTED PHENYL-5-HYDROXYMETHYL-2-OXAZOLIDINONE

Abstract

The disclosure discloses a method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone, wherein the method comprises: reacting from raw materials, 3-R2-4-R1-aniline and epichlorohydrin, and allowing the resulting product to react under alkaline conditions in a CO.sub.2 atmosphere to obtain N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone, wherein R.sub.1 is a morpholine group, a morpholin-3-one group or a piperazine group, and derivative groups thereof, and R.sub.2 is halogen, hydrogen or lower alkyl. The method provided by the disclosure has such advantages as few steps, simple operation, cheap and easily available raw materials, mild reaction conditions, and high product yield, and is especially suitable for industrial production of antibiotic linezolid intermediates and antithrombotic drug rivaroxaban intermediates.

Claims

1. A method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone, wherein the method comprises: reacting from raw materials, 3-R.sub.2-4-R.sub.1-aniline and epichlorohydrin, and allowing the resulting product to react under alkaline conditions in a CO.sub.2 atmosphere to obtain N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone, wherein R.sub.1 is a morpholine group, a morpholin-3-one group or a piperazine group, and derivative groups thereof, and R.sub.2 is halogen, hydrogen or lower alkyl.

2. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 1, wherein the method is a one-pot process comprising: preparing 1-chloro-3-(3-R.sub.2-4-R.sub.1-phenylamino)-2-propanol from 3-R.sub.2-4-R.sub.1-aniline and epichlorohydrin as raw materials, wherein R.sub.1 is a morpholine group, a morpholin-3-one group or a piperazine group, and derivative groups thereof, and R.sub.2 is halogen, hydrogen or lower alkyl; adding an inorganic or organic base and introducing CO.sub.2 to allow 1-chloro-3-(3-R.sub.2-4-R.sub.1-phenylamino)-2-propanol and CO.sub.2 to undergo cyclization to obtain N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone.

3. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 1, wherein with (S)-epichlorohydrin as a raw material, (R)-N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained; with (R)-epichlorohydrin as a raw material, (S)-N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained; and with racemic epichlorohydrin as a raw material, racemic N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained.

4. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 2, wherein the 1-chloro-3-(3-R.sub.2-4-R.sub.1-phenylamino)-2-propanol is prepared by dissolving 3-R.sub.2-4-R.sub.1-aniline, epichlorohydrin and boron trifluoride diethyl ether into an organic solvent to react at 30-70° C. for 12-24 h.

5. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 4, wherein the molar ratio of 3-R.sub.2-4-R.sub.1-aniline, epichlorohydrin and boron trifluoride diethyl ether is 0.8-5:1:0.05-0.2.

6. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 2, wherein the cyclization is carried out at a temperature of 20-100° C.

7. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 2, wherein the molar ratio of 3-R.sub.2-4-R.sub.1-aniline to the inorganic or organic base is 1:1-20.

8. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 7, wherein the organic base is selected from one or a combination of at least two of organic amines, sodium methoxide or sodium ethoxide.

9. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 8, wherein the organic amine is one or a combination of at least two of triethylamine, tetramethylguanidine, 1,8-diazabicycloundec-7-ene, pyridine, piperidine, quinoline, 4-dimethylaminopyridine or N-methylmorpholine.

10. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 7, wherein the inorganic base is selected from one or a combination of at least two of sodium carbonate, potassium carbonate, trisodium phosphate or tripotassium phosphate.

11. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 1, wherein the method comprises preparing (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone or (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3 -yl)-phenyl] -morpholin-3 -one using 3-R.sub.2-4-R.sub.1-aniline and (S)-epichlorohydrin as raw materials, wherein 3-R.sub.2-4-R.sub.1-aniline is 3-fluoro-4-morpholinoaniline or 4-(4-aminophenyl)-morpholin-3 -one.

12. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 2, wherein with (S)-epichlorohydrin as a raw material, (R)-N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained; with (R)-epichlorohydrin as a raw material, (S)-N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained; and with racemic epichlorohydrin as a raw material, racemic N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 is the NMR spectrum of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone prepared in the examples;

[0034] FIG. 2 is the NMR spectrum of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one prepared in the examples.

DESCRIPTION OF THE EMBODIMENTS

[0035] In order to make the objective, technical solution and advantages of the disclosure more clear, the disclosure will be further described in detail below with reference to the drawings and examples. It should be understood that the specific embodiments described here are only for explaining the disclosure rather than limiting the scope of protection of the disclosure.

Example 1 Preparation of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone

[0036] 20.0 g of 3-fluoro-4-morpholinoaniline, 9.5 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 50° C. for 16 h to prepare (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)-2-propanol. Then, 32.1 g of triethylamine was added into the system which was then heated to 90° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was filtered and then concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 85° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 22.6 g of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidone, yield 74.8%, ee>99% as analyzed by chiral HPLC.

[0037] The NMR data of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone prepared in this example: .sup.1H NMR (500 MHz, Chloroform-d) δ 7.43 (dd, 1H), 7.09 (dd, 1H), 6.90 (t, 1H), 4.72 (ddt, 1H), 4.02-3.90 (m, 3H), 3.89-3.83 (m, 4H), 3.72 (q, 2H), 3.03 (dd, 4H); .sup.13C NMR (126 MHz, CDC13) δ 156.35, 154.95, 154.39, 136.21, 133.27, 133.19, 118.82, 118.79, 113.91, 113.88, 107.49, 107.28, 77.35, 77.30, 77.10, 76.85, 73.12, 66.90, 62.49, 62.44, 50.98, 50.96, 46.37.

Example 2 Preparation of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone

[0038] 20.0 g of 3-fluoro-4-morpholinoaniline, 9.5 g of (S)-epichlorohydrin and 1.2 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 40° C. for 24 h to prepare (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)-2-propanol. Then, 20.0 g of a 28% sodium methoxide solution in methanol was added to the system which was then heated to 95° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was filtered and then concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 85° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 21.8 g of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone, yield 72.2%, ee>99% as analyzed by chiral HPLC.

Example 3 Preparation of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone

[0039] 20.0 g of 3-fluoro-4-morpholinoaniline, 9.5 g of (S)-epichlorohydrin and 0.4 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 60° C. for 12 h to prepare (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)-2-propanol. Then, 33.5 g of trisodium phosphate was added into the system which was then heated to 90° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was filtered and then concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 85° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 22.3 g of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone, yield 73.8%, ee>99% as analyzed by chiral HPLC.

Example 4 Preparation of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone

[0040] 20.0 g of 3-fluoro-4-morpholinoaniline, 9.5 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 60° C. for 16 h to prepare (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)-2-propanol. Then, 12.9 g of tetramethylguanidine was added into the system which was then heated to 55° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 85° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 22.7 g of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone, yield 75.2%, ee>99% as analyzed by chiral HPLC.

Example 5 Preparation of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone

[0041] 20.0 g of 3-fluoro-4-morpholinoaniline, 9.5 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 60° C. for 16 h to prepare (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)-2-propanol. Then, 17.0 g of DBU was added into the system which was then heated to 55° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 85° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 22.3 g of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone, yield 73.8%, ee>99% as analyzed by chiral HPLC.

Example 6 Preparation of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone

[0042] 20.0 g of 3-fluoro-4-morpholinoaniline, 9.5 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 50° C. for 18 h to prepare (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)-2-propanol. Then, 15.4 g of quinoline was added into the system which was then heated to 70° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 85° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 22.1 g of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone, yield 72.9%, ee>99% as analyzed by chiral HPLC.

Example 7 Preparation of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one

[0043] 20.0 g of 4-(4-aminophenyl)-morpholin-3-one, 9.7 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 60° C. for 14 h to prepare (S)-4-(4-((3-chloro-2-hydroxypropyl)amino)phenyl)morpholin-3-one. Then, 45 g of potassium carbonate was added into the system which was then heated to 90° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was filtered and then concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 80° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 21.8 g of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one, yield 71.7%, ee>99% as analyzed by chiral HPLC.

[0044] The NMR data of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one prepared in this example: .sup.1H NMR (500 MHz, DMSO-d6) δ 7.63-7.56 (m, 2H), 7.44-7.37 (m, 2H), 5.23 (t, 1H), 4.70 (ddt, 1H), 4.20 (s, 2H), 4.09 (t, 1H), 4.00-3.94 (m, 2H), 3.84 (dd, 1H), 3.68 (td, 2H), 3.57 (ddd, 1H); .sup.13C NMR (126 MHz, DMSO) δ 165.94, 154.45, 136.80, 136.66, 125.92, 117.99, 73.14, 67.69, 63.45, 61.62, 48.99, 46.00, 40.05, 39.96, 39.88, 39.79, 39.71, 39.62, 39.55, 39.46, 39.38, 39.29, 39.12, 38.96.

Example 8 Preparation of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one

[0045] 20.0 g of 4-(4-aminophenyl)-morpholin-3-one, 9.7 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 50° C. for 16 h to prepare (S)-4-(4-((3-chloro-2-hydroxypropyl)amino)phenyl)morpholin-3-one. Then, 13.1 g of tetramethylguanidine was added into the system which was then heated to 20° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 80° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 22.3 g of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one, yield 73.3%, ee>99% as analyzed by chiral HPLC.

Example 9 Preparation of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one

[0046] 20.0 g of 4-(4-aminophenyl)-morpholin-3-one, 9.7 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 70° C. for 13 h to prepare (S)-4-(4-((3-chloro-2-hydroxypropyl)amino)phenyl)morpholin-3-one. Then, 27.1 g of pyridine was added into the system which was then heated to 30° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 80° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 25.3 g of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one, yield 83.2%, ee>99% as analyzed by chiral HPLC.

Example 10 Preparation of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl] -morpholin-3 -one

[0047] 20.0 g of 4-(4-aminophenyl)-morpholin-3-one, 9.3 g of (S)-epichlorohydrin and 2.8 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 70° C. for 13 h to prepare (S)-4-(4-((3-chloro-2-hydroxypropyl)amino)phenyl)morpholin-3-one. Then, 43.0 g of piperidine was into the system which was then heated to 50° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 80° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 26.9 g of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl] -morpholin-3 -one, yield 88.4%, ee>99% as analyzed by chiral HPLC.

Example 11 Preparation of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl] -morpholin-3 -one

[0048] 20.0 g of 4-(4-aminophenyl)-morpholin-3-one, 9.7 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 60° C. for 14 h to prepare (S)-4-(4-((3-chloro-2-hydroxypropyl)amino)phenyl)morpholin-3-one. Then, 17.3 g of DMAP was added into the system which was then heated to 30° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 80° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 20.9 g of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one, yield 68.9%, ee>99% as analyzed by chiral HPLC.

Example 12 Preparation of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one

[0049] 20.0 g of 4-(4-aminophenyl)-morpholin-3-one, 9.7 g of (S)-epichlorohydrin and 0.9 g of boron trifluoride diethyl ether were dissolved in 200.0 g of N,N-dimethylformamide to react at 30° C. for 24 h to prepare (S)-4-(4-((3-chloro-2-hydroxypropyl)amino)phenyl)morpholin-3-one. Then, 26.8 g of N-methylmorpholine was added into the system which was then heated to 50° C. CO.sub.2 was introduced into the solution, and after the reaction was finished, the reaction mixture was concentrated under reduced pressure. 100 ml of water and 200 ml of dichloromethane were added, and the system was layered. The organic layer was concentrated under reduced pressure, and then 100 g of ethyl acetate was added thereto. The mixture was heated to 80° C., slowly cooled to 5° C. to crystallize, filtered and dried, thereby obtaining 21.9 g of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one, yield 72.2%, ee>99% as analyzed by chiral HPLC.

[0050] Among others, the NMR spectrum of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone prepared in Examples 1-6 is as shown in FIG. 1, and the NMR spectrum of (R)-4-[4-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenyl]-morpholin-3-one prepared in Examples 7-12 is as shown in FIG. 2.

[0051] The specific embodiments described above have described the technical solution and beneficial effects of the disclosure in detail. It should be understood that the above-described embodiments are only the most preferred embodiments of the disclosure, and are not used to limit the disclosure. Any modifications, supplements and equivalent replacements within the principle and scope of the disclosure should be included in the protection scope of the disclosure.