CN101638392A - Novel preparation method of netaglinide oxazolone - Google Patents
Novel preparation method of netaglinide oxazolone Download PDFInfo
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Abstract
The invention discloses a novel preparation method of netaglinide oxazolone shown in the formula (IV), which comprises the following steps: under the action of a catalyst A, enabling 3-fluorine-4-morpholine phenyl isocyanate shown in the formula (I) to react with (R)-epoxy chloropropane to obtain a compound (II), wherein the catalyst A is magnesium diiodide, magnesium dibromide, magnesium dichloride, magnesium perchlorate or magnesium trifluoromethanesulfonic acid; enabling the compound (II) to react with sodium azide to obtain a compound (III); reducing the compound (III) by hydrogenation, and then, acetylating the reduced compound (III) to obtain the compound (IV). In the invention, the low-cost and environment-friendly catalyst (Lewis acid magnesium) is used for catalyzing the cycloaddition reaction of the (R)-epoxy compound and the isocyanate to establish a mother nucleus structure of the netaglinide oxazolone by one step, thus the prepared netaglinide oxazolone has high stereoselectivity, does not need rigorous operation conditions, such as low temperature, no water, no oxygen and the like, has the advantages of moderate reaction conditions, simple and convenient operation, high utilization ratio of atoms, environment protection, low production cost and the like, and is suitable for industrialized production.
Description
(1) technical field
The present invention relates to the synthetic field of medicine, be specifically related to antibacterials and how be listed as the novel preparation method of oxazolone.
(2) background technology
In recent years, the resistant organism development of all kinds of microbiotic and antiseptic-germicide rapidly, for example, methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), penicillin resistant streptococcus pneumoniae (PRSP), multi-drug resistant tubercule bacillus, especially the appearance of vancomycin-resistant enterococcus (VRE) has caused difficulty to clinical treatment.Because this type of medicine bacterium of the still difficult effectively control of existing medicine infects, so Pharmaceutical Chemist just making great efforts to develop the medicine of novel anti resistant organism, and design also screening has the new antimicrobial drug of new chemical structure, new role mechanism or new role target position.
Linezolid is the oxazolidine ketone antimicrobial drug of first full chemosynthesis of listing in 2000, and chemical name is: (S)-N-((3-(3-fluoro-4-(4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl) ethanamide, CAS number:
Linezolid is the one the oxazolidine ketone medicine of being developed by Pharmacia UpJohn company, and go on the market in the U.S. in April, 2000, is mainly used in the infectious diseases that treatment is caused by the resistance gram-positive microorganism.This medicine is good to the characteristics of pharmacokinetics of the perviousness of bone, lung, cerebrospinal fluid etc. and tissue concentration, also can be used for the surgical infection treatment of diseases.Linezolid anti-microbial effect mechanism is different with other antiseptic-germicide, system is by combining with 50S ribosomal subunit, suppressing the gram-positive microorganism messenger RNA(mRNA) shifts, thereby act on the commitment of protein synthesis, using, these product stop protein synthesis even before it began, this may be to limit a kind of mechanism that it causes resistance and reduction and other antimicrobial drug crossing drug resistant risk trend.
At present how bibliographical information is listed as that the synthetic method of oxazolone has following several:
People (J.Med.Chem.1996 such as patent US 5837870 and Steven J.Brickner; 39; 673-679) openly reported with N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholine N-methyl-p-nitroaniline (78 ℃) under the cold condition in the presence of n-Butyl Lithium with (R)-condensation of Racemic glycidol butyric ester; generate (R)-[3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol; sulfonylation, amination, reduction and acetylize again; how obtain being listed as oxazolone, as follows.
Chinese patent CN200510048548.4 discloses with the synthetic 3-fluoro-4-morpholine benzene isocyanic ester of phosgenation; Generate (R)-N-(3-fluoro-4-morpholinyl phenyl)-oxazolone-5-methylbutyrate with the cyclisation of (R)-Racemic glycidol butyric ester then; Generate (R)-N-(3-fluoro-4-morpholinyl phenyl)-oxazolone-5-methyl alcohol with the sodium methylate reaction; How sulfonylation, amination, reduction and acetylize then obtain being listed as oxazolone, as follows.
W02007/116284 has proposed S-epoxy chloropropane and 4-chlorobenzaldehyde under ammoniacal liquor, generate (S)-1-chloro-3-[(4-chloro-E-Ben Yajiaji)-amino]-propionic aldehyde-2-alcohol, with (3 '-fluoro-4 '-morpholine-4-phenyl)-benzyl carbamate under the effect of tert-butyl lithium, generate (S)-5-{[(4-chloro-benzal)-amino]-methyl }-3-(3 '-fluoro-4 '-morpholine-4-phenyl)-oxazolidone, generation (S)-N-[3-under the hydrochloric acid effect (3 '-fluoro-4 '-morpholine-4-phenyl]-2 oxazolidines-5-methyl)-semicarbazide hydrochloride, regulate the pH value to neutrality with sodium hydroxide, add aceticanhydride, how generation is listed as oxazolone, as follows.
Document (Tetrahedron Lett, 1990,40,4855-4866) reported to be raw material with N.F,USP MANNITOL, obtain 5-hydroxymethyl oxazolidone with 3-fluoro-4-morpholine aniline through three-step reaction, how diazotization again obtain being listed as oxazolone with the Thiovanic acid reaction then.
Aforesaid method uses dangerous reaction reagent butyllithium or tert-butyl lithium, and the poisonous reagent phosgene perhaps use expensive raw material, and reaction scheme is longer, and environmental pollution is serious, and cost is higher, is unfavorable for suitability for industrialized production.
(3) summary of the invention
The technical problem to be solved in the present invention provides that a kind of step is simple, reaction conditions is gentle, row easy and simple to handle, the eco-friendly novel preparation method of oxazolone how.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of row are the novel preparation method of oxazolone how, comprises the steps:
Steps A: under the catalyst A effect, make the 3-fluoro-4-morpholinyl phenyl isocyanic ester shown in the formula (I) with (R)-epichlorohydrin reaction obtains compound (II); Described catalyst A is two magnesium iodides, dibrominated magnesium, magnesium dichloride, magnesium perchlorate or trifluoromethanesulfonic acid magnesium;
Step B: compound (II) obtains compound (III) with reaction of sodium azide;
Step C: compound (III) hydrogenating reduction obtains compound (IV) through acetylize then;
Reaction equation is as follows:
Below above-mentioned three-step reaction is elaborated.
Among the present invention, the described reaction of steps A specifically can be carried out according to following steps: under condition of no solvent or in the organic solvent A, compound (I) in the presence of catalyst A with (R)-epoxy chloropropane in 25～60 ℃ the reaction 2～8 hours, separation and purification obtains compound (II); Described catalyzer is two magnesium iodides, dibrominated magnesium, magnesium dichloride, magnesium perchlorate or trifluoromethanesulfonic acid magnesium, preferred two magnesium iodides or dibrominated magnesium; It is one of following that described organic solvent A is selected from: tetrahydrofuran (THF), 2-methyltetrahydrofuran, isopropyl ether, methyl tertiary butyl ether, methylene dichloride, 1,2-ethylene dichloride, chloroform, benzene,toluene,xylene, acetonitrile, preferably from one of following: tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, toluene.
In the steps A, preferred 40～60 ℃ of temperature of reaction, preferred 3～5 hours of reaction times.
Molar ratio compound (I) among the preferred steps A of the present invention: (R)-epoxy chloropropane is 1: 1～4, more preferably 1: 1～1.5.The molar ratio of preferred catalyst A and compound (I) is 0.1～1: 1, more preferably 0.4～0.7: 1.The volumetric usage of organic solvent A is recommended as 5～20ml/g in the quality of compound (I), preferred 7～15ml/g.
The described separation and purification of steps A can be adopted ordinary method, carry out separation and purification as adopting extraction, step concentrated, recrystallization, extraction agent generally can use methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, ethyl acetate, methyl acetate, propyl acetate or butylacetate; Recrystallization solvent can be selected from a kind of or several mixing arbitrarily in methylene dichloride, chloroform, ethyl acetate, sherwood oil, isopropyl ether, the methyl tertiary butyl ether, and preferred recrystallization solvent is a kind of or several mixing arbitrarily in ethyl acetate, sherwood oil, the methyl tertiary butyl ether.
The present invention is concrete to recommend described steps A to react according to following: add 3-fluoro-4-morpholinyl phenyl isocyanic ester, (R)-epoxy chloropropane (not solubilizing agent or adding organic solvent A) in reaction vessel, add two magnesium iodides or dibrominated magnesium then, 40～60 ℃ of heated and stirred reaction 3～5h, after finishing, reaction adds 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying, concentrate, crude product obtains pale solid and is compound (II) with ethyl acetate-sherwood oil recrystallization.
Among the present invention, the described reaction of step B specifically can be carried out according to following steps: in organic solvent B, compound (II) and sodiumazide separate obtaining compound (III) in 30～90 ℃ of reactions 6～12 hours; Described organic solvent B is selected from following a kind of or any several combinations: N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) (DMSO), dioxane, acetonitrile.
Among the step B, the molar ratio preferred 1: 1～6, preferred 1: 2～4 of compound (II) and sodiumazide.。The volumetric usage of organic solvent B is recommended as 3～20ml/g in the quality of compound (II), preferred 5～10ml/g.
The described separation of step B can be adopted routine operation, and such as adopting extraction, enrichment step to separate, general extraction agent can use methylene dichloride, chloroform or ethyl acetate.
Among the step C of the present invention; compound (III) can adopt that existing technology is carried out hydrogenating reduction, acetylize obtains compound (IV); such as people (J.Med.Chem.1996,39,673-679) disclosed methods such as patent US 5837870 and Steven J.Bri ckner.
Concrete, the described reaction of step C of the present invention can be carried out according to following steps: compound (III) is dissolved among the organic solvent C, adds catalyzer C, hydrogenating reduction removes by filter catalyzer C and obtains hydrogenation products then; Hydrogenation products in organic solvent C under the alkali effect and acetylation reagent reaction, fully stirring reaction after extraction, concentrate, recrystallization obtains compound (IV); Described catalyzer C is palladium carbon or Raney's nickel; Described organic solvent C is selected from a kind of or several mixing arbitrarily in methyl alcohol, ethanol, Virahol, ethyl acetate, methyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), the 2-methyltetrahydrofuran.
After step C hydrogenating reduction finishes; removing by filter behind the catalyzer C gained filtrate can not steam to desolventize and directly carry out next step acetylization reaction; can steam to desolventize does not need purifying directly to carry out next step acetylization reaction yet, and this moment, the acetylization reaction process need add organic solvent C again as reaction solvent.
The described reaction of step C of the present invention is preferably carried out under 20～40 ℃ temperature condition, more preferably carries out under 25～30 ℃ temperature condition.Described hydrogenating reduction condition optimization is: hydrogenation reaction is 8～15 hours under 20～40 ℃, condition of normal pressure; Described acetylization reaction condition optimization was: 20～40 ℃ of reactions 1～5 hour.
The catalyzer C that the present invention uses is palladium carbon or Raney's nickel, and wherein the preferred palladium content of palladium charcoal is 5～10%, and the preferred nickel content of Raney's nickel is 80～90%; The quality consumption of preferred described catalyzer C be compound (III) quality 1～10%, more preferably 3～5%.
Molar ratio compound (III) among the step C: acetylation reagent is preferably 1: 1～and 6, more preferably 1: 2～4.The preferred acetic acid of described acetylation reagent, aceticanhydride or Acetyl Chloride 98Min..
Alkali among the step C can be organic bases or mineral alkali, and organic bases can be: diethylamine, triethylamine, diisopropyl ethyl amine, pyridine, 2,6-picoline, piperidines; Mineral alkali can be: yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, calcium hydroxide.Its molar ratio compound (III): alkali is preferably 1: 1～and 3, more preferably 1: 1～2.
The present invention recommends the volumetric usage of organic solvent C to count 8～20ml/g with the quality of compound (III), preferred 10～15ml/g.
The described extraction of step C, concentrate, recrystallization can adopt routine operation, general extraction agent can use methylene dichloride, chloroform, ethyl acetate, methyl acetate, propyl acetate, butylacetate, and recrystallization solvent can use one or more the mixture in methylene dichloride, chloroform, ethyl acetate, sherwood oil, isopropyl ether, the methyl tertiary butyl ether.
Compared with prior art, novelty of the present invention is embodied in:
The present invention adopts the cycloaddition reaction one step foundation of cheap and environmentally friendly catalyzer lewis acidity magnesium catalysis (R)-epoxy compounds and isocyanic ester how to be listed as the oxazolone mother nucleus structure, stereoselectivity with height, do not need harsh operational condition such as low temperature and anhydrous, anaerobic, have reaction conditions gentleness, easy and simple to handle, advantage such as atom utilization is high, environmental friendliness, production cost are low, be suitable for suitability for industrialized production.
(4) specific embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail; But the present invention is not limited to these embodiment.
Synthesizing of embodiment 13-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL tetrahydrofuran (THF) stirring and dissolving to epoxy chloropropane, adds MgI then
2(2.5mmol), 50 ℃ of stirring reaction 4h add the reaction of going out of 5% sulphur thiosulfuric acid sodium water solution temper, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.47g, yield 93% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 23-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL tetrahydrofuran (THF) stirring and dissolving to epoxy chloropropane, adds MgBr then
2(2.5mmol), 50 ℃ of heated and stirred reaction 5h add 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.50g, yield 95% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 33-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL tetrahydrofuran (THF) stirring and dissolving to epoxy chloropropane, adds MgCl then
2(2.5mmol), 50 ℃ of heated and stirred reaction 8h add 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 0.94g, yield 60% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 43-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL methylene dichloride stirring and dissolving to epoxy chloropropane, adds MgI then
2(2.5mmol), stirring at room reaction 6h adds 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.35g, yield 86% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 53-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL methylene dichloride stirring and dissolving to epoxy chloropropane, adds MgBr then
2(2.5mmol), stirring at room reaction 8h adds 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.40g, yield 90% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 63-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL methylene dichloride stirring and dissolving to epoxy chloropropane, adds MgCl then
2(2.5mmol), stirring at room reaction 12h adds 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 0.98g, yield 63% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 73-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL acetonitrile stirring and dissolving to epoxy chloropropane, adds MgI then
2(2.5mmol), 50 ℃ of heated and stirred reaction 4h add 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.18g, yield 75% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 83-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL toluene stirring and dissolving to epoxy chloropropane, adds MgI then
2(2.5mmol), 50 ℃ of heated and stirred reaction 4h add 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.13g, yield 72% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 93-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(0.51g 5.5mmol) in 25mL single port flask, adds 10mL 1 to epoxy chloropropane, and 2-ethylene dichloride stirring and dissolving adds MgI then
2(2.5mmol), 50 ℃ of heated and stirred reaction 10h add 5% sodium thiosulfate solution, dichloromethane extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.07g, yield 68% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 103-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (1.11g, 5mmol) and (R)-(1.85g 20mmol) in 25mL single port flask, adds MgI to epoxy chloropropane then
2(2.5mmol), 60 ℃ of heated and stirred reaction 3h add 5% sodium thiosulfate solution, ethyl acetate extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.53g, yield 96% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 113-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (0.44g, 2mmol) and (R)-(0.93g 10mmol) in 25mL single port flask, adds MgI to epoxy chloropropane then
2(0.4mmol), 60 ℃ of heated and stirred reaction 6h add 5% sodium thiosulfate solution, ethyl acetate extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.43g, yield 94% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 123-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (0.44g, 2mmol) and (R)-(0.93g 10mmol) in 25mL single port flask, adds MgBr to epoxy chloropropane then
2(1.0mmol), 60 ℃ of heated and stirred reaction 4h add 5% sodium thiosulfate solution, ethyl acetate extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.43g, yield 96% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 133-fluoro-4-morpholinyl phenyl oxazolidone
Take by weighing 3-fluoro-4-morpholinyl phenyl isocyanic ester (0.44g, 2mmol) and (R)-(0.93g 10mmol) in 25mL single port flask, adds MgBr to epoxy chloropropane then
2(0.4mmol), 60 ℃ of heated and stirred reaction 6h add 5% sodium thiosulfate solution, ethyl acetate extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, (V/V=1: 15) recrystallization obtains pale solid 1.41g, yield 93% to crude product with ethyl acetate-sherwood oil.
Synthesizing of embodiment 143-fluoro-4-morpholinyl phenyl oxazolidone trinitride
In 25mL single port bottle, add 3-fluoro-4-morpholinyl phenyl oxazolidone 629mg (2mmol), sodiumazide 390mg (6mmol) and DMF (10mL), be heated to 80 ℃ of reaction 12h, add water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, concentrate not purified next step reaction, the yield 85% of directly carrying out.
Synthesizing of embodiment 153-fluoro-4-morpholinyl phenyl oxazolidone trinitride
In 25mL single port bottle, add 3-fluoro-4-morpholinyl phenyl oxazolidone 629mg (2mmol), sodiumazide 390mg (6mmol) and 1,4-dioxane (10mL) is heated to 80 ℃ of reaction 12h, adds water, ethyl acetate extraction, the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, not purified next step reaction, the yield 81% of directly carrying out.
Synthesizing of embodiment 163-fluoro-4-morpholinyl phenyl oxazolidone trinitride
In 25mL single port bottle, add 3-fluoro-4-morpholinyl phenyl oxazolidone 629mg (2mmol), sodiumazide 390mg (6mmol) and DMSO (10mL), be heated to 80 ℃ of reaction 12h, add water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, concentrate not purified next step reaction, the yield 80% of directly carrying out.
Embodiment 17 is listed as the synthetic of oxazolone how
Add (R)-3-fluoro-4-morpholinyl phenyl oxazolidone trinitride 642mg (2mmol) to 50ml single port bottle, use the 20ml dissolve with ethanol, add 5%Pd-C (120mg), normal temperature and pressure hydrogenation 12h, remove by filter catalyzer then, steaming desolventizes, use acetic acid ethyl dissolution, add triethylamine 242mg (2.4mmol) and aceticanhydride 250mg (2.4mmol), stirring at room 5h adds water, ethyl acetate extraction, (V/V=1: 10) how recrystallization obtains being listed as oxazolone, total recovery 91%, fusing point 178.8-179.0 ℃ (document 181.5-182.5 ℃) with ethyl acetate-sherwood oil.
Embodiment 18 is listed as the synthetic of oxazolone how
Add (R)-3-fluoro-4-morpholinyl phenyl oxazolidone trinitride 642mg (2mmol) to 50ml single port bottle, add 5%Pd-C (120mg) with the 20ml ethyl acetate, normal temperature and pressure hydrogenation 12h, remove by filter catalyzer then, in filtrate, directly add triethylamine 242mg (2.4mmol) and aceticanhydride 250mg (2.4mmol), stirring at room 3h, add water, ethyl acetate extraction, (V/V=1: 10) how recrystallization obtains being listed as oxazolone with ethyl acetate-sherwood oil, total recovery 88%, fusing point 178.8-179.0 ℃ (document 181.5-182.5 ℃).
Embodiment 19 is listed as the synthetic of oxazolone how
Add (R)-3-fluoro-4-morpholinyl phenyl oxazolidone trinitride 642mg (2mmol) to 50ml single port bottle, use the 20ml dissolve with ethanol, add 80-90% Raney's nickel catalyst (120mg), normal temperature and pressure hydrogenation 12h, remove by filter catalyzer then, steaming desolventizes, use acetic acid ethyl dissolution, add triethylamine 242mg (2.4mmol) and aceticanhydride 250mg (2.4mmol), stirring at room 3h adds water, ethyl acetate extraction, (V/V=1: 10) how recrystallization obtains being listed as oxazolone, total recovery 84%, fusing point 178.8-179.0 ℃ (document 181.5-182.5 ℃) with ethyl acetate-sherwood oil.
Embodiment 20 is listed as the synthetic of oxazolone how
Add (R)-3-fluoro-4-morpholinyl phenyl oxazolidone trinitride 642mg (2mmol) to 50ml single port bottle, add 5%Pd-C (120mg) with the 20ml ethyl acetate, normal temperature and pressure hydrogenation 12h, remove by filter catalyzer then, in filtrate, directly add triethylamine 242mg (2.4mmol) and Acetyl Chloride 98Min. 190mg (2.4mmol), frozen water cooling and stirring 4h, add water, ethyl acetate extraction, (V/V=1: 10) how recrystallization obtains being listed as oxazolone with ethyl acetate-sherwood oil, total recovery 83%, fusing point 178.8-179.0 ℃ (document 181.5-182.5 ℃).
Embodiment 21 is listed as the synthetic of oxazolone how
Add (R)-3-fluoro-4-morpholinyl phenyl oxazolidone trinitride 321mg (1mmol) to 50ml single port bottle, add 5%Pd-C (120mg) with the 10ml ethyl acetate, normal temperature and pressure hydrogenation 12h, remove by filter catalyzer then, in filtrate, directly add pyridine 158mg (2.0mmol) and aceticanhydride 126mg (1.2mmol), frozen water cooling and stirring 5h, add water, ethyl acetate extraction, (V/V=1: 10) how recrystallization obtains being listed as oxazolone with ethyl acetate-sherwood oil, total recovery 87%, fusing point 178.8-179.0 ℃ (document 181.5-182.5 ℃).
Embodiment 22 is listed as the synthetic of oxazolone how
Add (R)-3-fluoro-4-morpholinyl phenyl oxazolidone trinitride 642mg (2mmol) to 50ml single port bottle, add 5%Pd-C (120mg) with the 20ml ethyl acetate, normal temperature and pressure hydrogenation 12h, remove by filter catalyzer then, in filtrate, directly add diisopropyl ethyl amine 387mg (3.0mmol) and aceticanhydride 250mg (2.4mmol), frozen water cooling and stirring 4h, add water, ethyl acetate extraction, (V/V=1: 10) how recrystallization obtains being listed as oxazolone with ethyl acetate-sherwood oil, total recovery 90%, fusing point 178.8-179.0 ℃ (document 181.5-182.5 ℃).
Claims (10)
1, suc as formula the preparation method of oxazolone how of the row shown in (IV), comprises the steps:
Steps A: under the catalyst A effect, make the 3-fluoro-4-morpholinyl phenyl isocyanic ester shown in the formula (I) with (R)-epichlorohydrin reaction obtains compound (II); Described catalyst A is two magnesium iodides, dibrominated magnesium, magnesium dichloride, magnesium perchlorate or trifluoromethanesulfonic acid magnesium;
Step B: compound (II) obtains compound (III) with reaction of sodium azide;
Step C: compound (III) hydrogenating reduction obtains compound (IV) through acetylize then;
Reaction equation is as follows:
2, preparation method as claimed in claim 1, it is characterized in that the described reaction of steps A specifically carries out according to following steps: under condition of no solvent or in the organic solvent A, compound (I) in the presence of catalyst A with (R)-epoxy chloropropane in 25～60 ℃ the reaction 4～12 hours, separation and purification obtains compound (II); Described catalyzer is two magnesium iodides, dibrominated magnesium, magnesium dichloride, magnesium perchlorate or trifluoromethanesulfonic acid magnesium; It is one of following that described organic solvent A is selected from: tetrahydrofuran (THF), 2-methyltetrahydrofuran, isopropyl ether, methyl tertiary butyl ether, methylene dichloride, 1,2-ethylene dichloride, chloroform, benzene,toluene,xylene, acetonitrile.
3, preparation method as claimed in claim 1 or 2 is characterized in that the molar ratio compound (I) of steps A: (R)-epoxy chloropropane: catalyst A is 1: 1～4: 0.1～1.
4, preparation method as claimed in claim 1 is characterized in that the described reaction of step B specifically carries out according to following steps: in organic solvent B, compound (II) and sodiumazide separate obtaining compound (III) in 30～90 ℃ of reactions 6～12 hours; Described organic solvent B is selected from following a kind of or any several combinations: N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), dioxane, acetonitrile; Described compound (II) is 1: 1～6 with the molar ratio of sodiumazide.
5, preparation method as claimed in claim 1, it is characterized in that the described reaction of step C specifically carries out according to following steps: compound (III) is dissolved among the organic solvent C, add catalyzer C, hydrogenating reduction removes by filter catalyzer C and obtains hydrogenation products then; Hydrogenation products in organic solvent C under the alkali effect and acetylation reagent reaction, fully stirring reaction after extraction, concentrate, recrystallization obtains compound (IV); Described catalyzer C is palladium carbon or Raney's nickel; Described organic solvent C is selected from a kind of or several mixing arbitrarily in methyl alcohol, ethanol, Virahol, ethyl acetate, methyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), the 2-methyltetrahydrofuran.
6, preparation method as claimed in claim 5, the quality consumption that it is characterized in that described catalyzer C be compound (III) quality 1～10%.
7, preparation method as claimed in claim 5, it is characterized in that the molar ratio compound (III) among the step C: acetylation reagent is 1: 1～6; Described acetylation reagent is acetic acid, aceticanhydride or Acetyl Chloride 98Min..
8, preparation method as claimed in claim 5, it is one of following to it is characterized in that described alkali is selected from: diethylamine, triethylamine, diisopropyl ethyl amine, pyridine, 2, the 6-picoline, piperidines, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, calcium hydroxide; Its molar ratio compound (III): alkali is 1: 1～3.
9, as the described preparation method of one of claim 5～8, it is characterized in that described hydrogenating reduction condition is: hydrogenation reaction is 8～15 hours under 20～40 ℃, condition of normal pressure.
10, as the described preparation method of one of claim 5～8, it is characterized in that described acetylization reaction condition is: 20～40 ℃ of reactions 1～5 hour.
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| WO2011137222A1 (en) | 2010-04-30 | 2011-11-03 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
| CN102321041A (en) * | 2011-07-20 | 2012-01-18 | 北京赛科药业有限责任公司 | Preparation method of linezolid |
| CN102702125A (en) * | 2012-05-10 | 2012-10-03 | 浙江工业大学 | Chemical synthesis method for linezolid |
| WO2013001096A1 (en) | 2011-06-30 | 2013-01-03 | Dsm Ip Assets B.V. | Silicone-containing monomer |
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| CN1772750A (en) * | 2005-11-15 | 2006-05-17 | 郑州大学 | Prepn process of (R)-N-(3-fluoro-4-morpholinyl phenyl)-oxazolone-5-methyl alcohol |
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| WO2011137222A1 (en) | 2010-04-30 | 2011-11-03 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
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