Linezolid intermediate and synthetic method of linezolid

Abstract

The present invention relates to the chemical field, and discloses a linezolid intermediate and a preparation method thereof, and a synthetic method of linezolid. The linezolid intermediate provided by the present invention has a structure shown as a formula F2, and is easy for preparation. The invention also provides the preparation method of the compound shown as the formula F2; and the compound is prepared from condensation reaction of (S)-N-(3-chloro-2-hydroxy-1-propyl) acetamide and a compound shown as a formula F4. The preparation method of the compound shown as formula F2 and the synthetic method of linezolid provided by the present invention have advantages of mild reaction system, few side reaction, high product yield and industrialization prospects. The formulas F2 and F4 are shown in the description.

Description

technical field

[0001] The invention relates to the field of chemistry, in particular to an intermediate of an antibacterial drug linezolid, a preparation method thereof and a method for synthesizing linezolid. Background technique

[0002] The chemical name of Linezolid is: (S)-N-((3-(3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl ) methyl) acetamide, structural formula is as follows:

[0003]

[0004] Linezolid is a fluorine-containing oxazolidinone antibacterial drug developed by Pharmacia & Upjohn CoMP1100611any, which was launched in the United States in 2000. The drug has a novel structure and a unique mechanism of action. It is used as an antibacterial drug to treat infections such as Gram-positive bacteria and Mycobacterium tuberculosis resistant to multiple drugs. After sulfonamides and quinolones, there is another large class of new synthetic antibacterial drugs.

[0005] There are many synthetic methods, the more important ones are:

[0006] A. Prep...

Examples

Embodiment 1

[0063] Embodiment 1: Preparation of 3-fluoro-4-morpholinylaniline (F1)

[0064] It was prepared according to the literature method (Zhao Xiaoyu et al., Improvement of Linezolid Synthesis Process, West China Pharmaceutical Journal, 2007, 22(2), 179-181). In a 1000ml four-necked flask equipped with a reflux condenser and a dropping funnel, add 36.2g (0.16mol) of 3-fluoro-4-morpholinonitrobenzene, 3.2 grams of 10% Pd / C, and 30.4 grams of ammonium formate (0.49mol) and 500 ml of acetone, stirred and reacted at 45-50°C for 4 hours, after the completion of the TLC reaction (developing solvent: ethyl acetate:petroleum ether=1:1), cool to room temperature. After suction filtration, the filtrate was distilled off the solvent under reduced pressure to obtain a crude solid product, which was recrystallized from toluene to obtain 28.1 g of solid (yield 89.5%). Confirmation of structure:

[0065]

[0066] 1 HNMR (δ, ppm, 400MHz, CDCl 3 ): 2.983(s, 4H, (-CH 2 -N) 2 ); 3.606(s, 2H, ...

Embodiment 2

[0068] Embodiment 2: Preparation of (S)-N-(3-chloro-2-hydroxyl-1-propyl)acetamide compound (compound shown in formula E3)

[0069] Prepared according to literature method (B.A. Pillman: CN1275122A, 2000-11-29; B.A. Pillman: CN101353313A, 2009-01-28). In a 500ml four-necked flask equipped with a thermometer and a dropping funnel, add 30 grams of (S)-(3-chloro-2-hydroxy-1-propyl) hydrochloride and 240ml tetrahydrofuran, and cool to -40°C in a cold bath 31.5 ml of triethylamine was added under stirring; after stirring for 5 minutes, 20.4 ml of acetic anhydride was added dropwise at -40°C, and then the temperature was raised to 20-25°C within 2 hours while stirring. Filtration, the filtrate was treated with acid magnesium silicate and filtered under reduced pressure, the solvent tetrahydrofuran was distilled off, and the residue was purified by flash chromatography (silica gel, 75-100% ethyl acetate: cyclohexane gradient elution) to obtain the target product 26.3 grams. Confirma...

Embodiment 3

[0073] Example 3: Preparation of (S)-N-(3-chloro-2-methoxycarbonyloxy-1-propyl)acetamides (F2, R is methyl)

[0074] In the 100ml four-neck flask equipped with a thermometer and a dropping funnel, add 5.1g (0.033mol) compound shown in formula E3, 4.55g (0.045mol) gram triethylamine and 15 milliliters of dichloromethane, and the water bath is kept at 15- A mixture of 3.82 g (0.04 mol) of methyl chloroformate and 8 ml of dichloromethane was added dropwise at 20°C; after the addition was complete, the reaction was continued for 3-4 hours. After adding 20ml of water, stir for 5 minutes, and let stand to separate layers. The organic layer was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and the dry solvent was recovered to obtain 5.4 g of crude product, which was the target product F2 (R was methyl, yield 78.1%), which was a colorless liquid. Confirmation of structure:

[0075]

[0076] 1 HNMR (δ, ppm, 400MHz, D 2 O): 2.008 (s, 3H, C 5 H); 3.498-3.591...

technical field

[0001] The invention relates to the field of chemistry, in particular to an intermediate of an antibacterial drug linezolid, a preparation method thereof and a method for synthesizing linezolid. Background technique

[0002] The chemical name of Linezolid is: (S)-N-((3-(3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl ) methyl) acetamide, structural formula is as follows:

[0003]

[0004] Linezolid is a fluorine-containing oxazolidinone antibacterial drug developed by Pharmacia & Upjohn CoMP1100611any, which was launched in the United States in 2000. The drug has a novel structure and a unique mechanism of action. It is used as an antibacterial drug to treat infections such as Gram-positive bacteria and Mycobacterium tuberculosis resistant to multiple drugs. After sulfonamides and quinolones, there is another large class of new synthetic antibacterial drugs.

[0005] There are many synthetic methods, the more important ones are:

[0006] A. Prep...

Examples

Embodiment 1

[0063] Embodiment 1: Preparation of 3-fluoro-4-morpholinylaniline (F1)

[0064] It was prepared according to the literature method (Zhao Xiaoyu et al., Improvement of Linezolid Synthesis Process, West China Pharmaceutical Journal, 2007, 22(2), 179-181). In a 1000ml four-necked flask equipped with a reflux condenser and a dropping funnel, add 36.2g (0.16mol) of 3-fluoro-4-morpholinonitrobenzene, 3.2 grams of 10% Pd / C, and 30.4 grams of ammonium formate (0.49mol) and 500 ml of acetone, stirred and reacted at 45-50°C for 4 hours, after the completion of the TLC reaction (developing solvent: ethyl acetate:petroleum ether=1:1), cool to room temperature. After suction filtration, the filtrate was distilled off the solvent under reduced pressure to obtain a crude solid product, which was recrystallized from toluene to obtain 28.1 g of solid (yield 89.5%). Confirmation of structure:

[0065]

[0066] 1 HNMR (δ, ppm, 400MHz, CDCl 3 ): 2.983(s, 4H, (-CH 2 -N) 2 ); 3.606(s, 2H, ...

Embodiment 2

[0068] Embodiment 2: Preparation of (S)-N-(3-chloro-2-hydroxyl-1-propyl)acetamide compound (compound shown in formula E3)

[0069] Prepared according to literature method (B.A. Pillman: CN1275122A, 2000-11-29; B.A. Pillman: CN101353313A, 2009-01-28). In a 500ml four-necked flask equipped with a thermometer and a dropping funnel, add 30 grams of (S)-(3-chloro-2-hydroxy-1-propyl) hydrochloride and 240ml tetrahydrofuran, and cool to -40°C in a cold bath 31.5 ml of triethylamine was added under stirring; after stirring for 5 minutes, 20.4 ml of acetic anhydride was added dropwise at -40°C, and then the temperature was raised to 20-25°C within 2 hours while stirring. Filtration, the filtrate was treated with acid magnesium silicate and filtered under reduced pressure, the solvent tetrahydrofuran was distilled off, and the residue was purified by flash chromatography (silica gel, 75-100% ethyl acetate: cyclohexane gradient elution) to obtain the target product 26.3 grams. Confirma...

Embodiment 3

[0073] Example 3: Preparation of (S)-N-(3-chloro-2-methoxycarbonyloxy-1-propyl)acetamides (F2, R is methyl)

[0074] In the 100ml four-neck flask equipped with a thermometer and a dropping funnel, add 5.1g (0.033mol) compound shown in formula E3, 4.55g (0.045mol) gram triethylamine and 15 milliliters of dichloromethane, and the water bath is kept at 15- A mixture of 3.82 g (0.04 mol) of methyl chloroformate and 8 ml of dichloromethane was added dropwise at 20°C; after the addition was complete, the reaction was continued for 3-4 hours. After adding 20ml of water, stir for 5 minutes, and let stand to separate layers. The organic layer was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and the dry solvent was recovered to obtain 5.4 g of crude product, which was the target product F2 (R was methyl, yield 78.1%), which was a colorless liquid. Confirmation of structure:

[0075]

[0076] 1 HNMR (δ, ppm, 400MHz, D 2 O): 2.008 (s, 3H, C 5 H); 3.498-3.591...

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