CN102452995A - Synthesizing method of oxazolidine compound - Google Patents

Synthesizing method of oxazolidine compound Download PDF

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CN102452995A
CN102452995A CN2010105293481A CN201010529348A CN102452995A CN 102452995 A CN102452995 A CN 102452995A CN 2010105293481 A CN2010105293481 A CN 2010105293481A CN 201010529348 A CN201010529348 A CN 201010529348A CN 102452995 A CN102452995 A CN 102452995A
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alkyl
substituted
methylene radical
compound
benzyl
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许羚
陈文杰
李平
筒井英之
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Toray Fibers and Textiles Research Laboratories China Co Ltd
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Toray Fibers and Textiles Research Laboratories China Co Ltd
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Abstract

The invention provides a synthesizing method of an oxazolidine compound. In the method, a phenylethylamine derivative performs oxidation to prepare the oxazolidine compound by virtue of an organic oxidant, wherein the organic oxidant is one of benzoquinone oxidant, hypervalent iodide oxidant or halogenated imide oxidant. The product prepared by the method is an important bioactive substance, and plays an important role in medicament synthesis and application; and compared with the prior art, the synthesizing method has the characteristics of mild condition, wide raw material practicality, high yield, easily available reaction raw materials, is simple in operation and the like, and is suitable for laboratory preparation and industrial scale production.

Description

The compound method of Yi Zhong oxazolidone compound
Technical field
The present invention relates to the compound method of Yi Zhong oxazolidone compound, be specially a kind of compound method of the organic oxidizing agent Zhi of utilization oxazolidinones compound.
Background technology
The oxazolidone compound is a kind of important biological material, has important effect the synthetic of medicine with in using.
At present the method for He Cheng oxazolidone compound mainly contains: in the mixed solvent of water and acetonitrile, the mixed system of use Potassium Persulphate and copper sulfate carries out oxidizing reaction Sheng Chengs oxazolidone compound (as: Tetrahedron Letter, 1988; 29,5177-5180; Japanese Patent, the spy opens flat 1-228946); In the mixing solutions of water and acetone, use ceric ammonium nitrate and cupric salt as oxygenant, Zhi oxazolidinones compound (Japanese Patent, the spy opens and puts down 8-231518);
In the method for existing Zhi oxazolidinones compound, be use an inorganic oxidizer.Yet it is obviously not enough to use an inorganic oxidizer Zhi oxazolidinones compound to exist.For example with under the situation of carbamate as raw material, use the inorganic salts mixed system to require to have the existence of water as oxygenant, the mixture that utilizes water and organic solvent is as solvent, and this has strict demand to the stability of raw material in water.In addition, because reaction is for two-phase system, so speed of response also receives influence to a certain degree.
Summary of the invention
The objective of the invention is to overcome the deficiency of an inorganic oxidizer in the prior art, provide a kind of under the effect of suitable organic oxidizing agent, make as the phenylethylamine derivative of raw material oxidizedly, De is Dao the compound method of oxazolidone compound.Compare with existing method, the characteristics of the inventive method are: avoided an inorganic oxidizer and in oxidising process, must make water or contain the limitation of water mixed liquid as reaction solvent, to the raw material of water sensitive possible compound method is provided to part; In addition; Hydroxyl can be retained in the process of oxidation Zhi oxazolidinones compound, and the present invention also provides a kind of raw material that needn't protect hydroxyl, compound method that just can direct oxidation Zhi oxazolidinones compound; Thereby reached the simplification synthesis step, improved the purpose of yield.
In order to solve the problems of the technologies described above, the present invention is achieved by the following technical solutions.
The phenylethylamine derivative of said formula (I) synthesizes said formula (II) De oxazolidone compound as raw material below the use under the effect of organic oxidizing agent;
Figure BSA00000329861300021
Wherein, R 1And R 5Identical, a kind of in hydrogen, alkoxyl group, alkyl sulfide hydroxyl or the alkyl amine group;
R 2And R 6Identical, a kind of in hydrogen, alkyl, aryl or the substituted aryl;
R 3And R 7Identical, a kind of in alkyl, substituted alkyl, aryl or the substituted aryl;
R 4A kind of in alkyl or the aralkyl.
Described organic oxidizing agent is a kind of in benzoquinones class oxygenant, the inferior amides oxygenant of high price iodide class oxygenant or halo.
Described benzoquinones class oxygenant is preferably 2,3-two chloro-5, a kind of in 6-dicyan para benzoquinone (DDQ) or its analogue; High price iodide class oxygenant is preferably a kind of in iodobenzene diacetate (PIDA) or its analogue; The inferior amides oxygenant of halo is preferably a kind of in n-halogenated succinimide imide or its analogue.
Substituted aryl described in the formula (I) is substituted-phenyl, naphthyl or replaces fragrant heterocycle; Wherein substituted-phenyl be the palkoxy benzene base, to alkyl phenyl, o-alkoxyl phenyl, adjacent alkyl phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N; The TMSDMA N dimethylamine base) phenyl or 3, a kind of in the 4-dialkyl phenyl organic; Naphthyl is a kind of in Alpha-Naphthyl or the betanaphthyl; Replace fragrant heterocycle and be a kind of in substituted pyridinyl, substituted azole base or the substituted furan base, wherein substituted pyridinyl is a kind of in 4-Alkylpyridyl or the 2-Alkylpyridyl, and the substituted azole base is a kind of in 3-alkyl pyrryl or the 2-alkyl pyrryl; The substituted furan base is a kind of in 3-alkyl furan base or the 2-alkyl furan base.
R in the formula (I) 4Alkyl be preferably the alkyl of C1-C8; Said aralkyl is selected from benzyl, substituted benzyl or replaces a kind of in the assorted methylene radical of virtue; Wherein substituted benzyl is to alkoxybenzyl, to alkyl benzyl, o-alkoxyl benzyl, adjacent alkyl benzyl, to luorobenzyl, adjacent luorobenzyl, p-chlorobenzyl, o-chlorobenzyl, to bromobenzyl, adjacent bromobenzyl, right-(trifluoromethyl) benzyl, right-(N; The TMSDMA N dimethylamine base) benzyl or 3, a kind of in the 4-dimethyl benzyl; Replace the assorted methylene radical of virtue and be a kind of in substituted pyridines methylene radical, substituted azole methylene radical, the substituted furan methylene radical; Wherein the substituted pyridines methylene radical is a kind of in 4-alkyl pyridine methylene radical or the 2-alkyl pyridine methylene radical; The substituted azole methylene radical is a kind of in 3-alkyl pyrroles's methylene radical or the 2-alkyl pyrroles methylene radical, and the substituted furan methylene radical is a kind of in 3-alkyl furan methylene radical or the 2-alkyl furan methylene radical.
R in the said formula (I) 4During for alkyl, this R 4Further be preferably the tertiary butyl; So R in the formula (I) 4Further be preferably the tertiary butyl or benzyl.
Said analogue is with the compound of its structure similar or is its verivate.
Said substituted alkyl is meant and contains heteroatomic alkyl on the carbochain.
The main compound method of Zhong De oxazolidone compound of the present invention is following:
In room temperature nitrogen protection downhill reaction bottle, add raw material, organic oxidizing agent and solvent are processed reaction solution; After being heated to backflow, follow the tracks of reaction with thin plate chromatography chromatogram (TLC); React and finish postcooling to room temperature, through washing, extraction, after merging organic phase and the drying, separation and purification can obtain target compound.
The present invention is to not restriction of reaction conditions, and preferred Heating temperature is 60 ℃-90 ℃.
In the above-mentioned experimental procedure, solvent preferably uses toluene, benzene, 1, one or more in 4-dioxane, methylene dichloride or the water.
In the above-mentioned washing step, preferably use in saturated sodium carbonate solution, saturated sodium bicarbonate solution, saturated nacl aqueous solution or the water one or more.
In the above-mentioned extraction step, preferably use in ETHYLE ACETATE or the methylene dichloride one or more.
Compound method mild condition of the present invention, the raw material practicality is wider, and productive rate is higher; Mixed solution with organic solvent or organic solvent and water is made solvent, and applied widely, reaction raw materials is easy to get, and is easy and simple to handle, is applicable to prepared in laboratory and industrial-scale production.The prepared product of the present invention is a kind of important biological material, has important effect the synthetic of medicine with in using.
Embodiment
The preparation method of employed phenylethylamine derivative is following among the present invention: with city dealer to anisole ethamine or Uteramin and phenyl aldehyde reaction, the secondary amine of generation can make after protecting with tert-butoxycarbonyl chlorine or Carbobenzoxy Chloride.
The various organic oxidizing agents that the present invention uses are city dealer article, do not carry out purifying, directly use.
The NMR model that the present invention uses is: the JNM-ECX400P of NEC (JOEL).
Embodiment 1
Figure BSA00000329861300041
Under the room temperature nitrogen protection, in 100mL single port bottle, add raw material 240mg, toluene 15mL, 2; 3-two chloro-5,6-dicyan para benzoquinone (DDQ) 175mg processes reaction solution, stirs post-heating to 86 ℃; Follow the tracks of reaction to most of raw material with thin-layer chromatography (TLC) and disappear, stop heating and be cooled to room temperature, reaction solution washs with saturated sodium carbonate solution, ethyl acetate extraction; Organic phase is used anhydrous sodium sulfate drying, filters, and after solvent is removed in underpressure distillation, obtains red solid 124mg through the silicagel column separation; Yield 60% is accredited as target compound through nuclear-magnetism, is main with trans-compound wherein.
1H?NMR(400MHz，CDCl 3)δ7.29-7.38(m，5H)，7.09(d，J＝8.0Hz，2H)，6.82(d，J＝8.0Hz，2H)，6.08(s，1H)，4.86(d，J＝7.8Hz，1H)，4.81(d，J＝15.1Hz，1H)，4.17(d，J＝15.1Hz，1H)，3.46-3.52(m，1H)，1.24(d，J＝6.4Hz，3H)
Embodiment 2
Figure BSA00000329861300042
In the 25mL there-necked flask, adding raw material 170mg under the room temperature nitrogen protection, 2,3-two chloro-5,6-dicyan para benzoquinone (DDQ) 113mg, 1,4-dioxane 6mL and water 0.6mL process reaction solution.Be heated to backflow, reaction solution is a brown solution.Utilize TLC to follow the tracks of reaction to end, be cooled to room temperature, add the 10mL saturated sodium bicarbonate solution to reaction solution; The 20mL ethyl acetate extraction merges organic phase, with twice of 20mL water washing organic phase; Anhydrous sodium sulfate drying is behind the pressure reducing and steaming ETHYLE ACETATE, through column chromatography for separation purification (sherwood oil: ETHYLE ACETATE=3: 1); Obtain 116mg colorless oil compound, yield 79% is accredited as target compound through nuclear-magnetism.
1H?NMR(400MHz，CDCl 3)δ7.22-7.39(m，7H)，6.88(d，J＝8.2Hz，2H)，5.42(t，J＝8.2Hz，1H)，4.54(d，J＝14.2Hz，1H)，4.41(d，J＝14.2Hz，1H)，3.80(s，3H)，3.72(t，J＝8.8Hz，1H)，3.30(t，J＝8.0Hz，1H)
Embodiment 3
Figure BSA00000329861300051
In the 100mL there-necked flask, adding raw material 1.08g under the room temperature nitrogen protection, methylene dichloride 40mL, water 4mL adds 2 under stirring at room, 3-two chloro-5,6-dicyan para benzoquinone (DDQ) 1.59g processes reaction solution.Be heated to backflow, utilize TLC to follow the tracks of reaction, in reaction solution, add saturated sodium carbonate solution 20mL, tell organic phase to no longer changing; Water adds methylene chloride and extracts three times, merges organic phase, adds saturated nacl aqueous solution 20mL washing, water 20mL washing; Add anhydrous sodium sulfate drying, filter, steaming obtains yellow oil after removing organic solvent, through the silicagel column separation and purification; Get colorless oil 0.35g, yield 39% is accredited as target compound through nuclear-magnetism, and nuclear magnetic data is identical with embodiment 2.
Embodiment 4
Figure BSA00000329861300052
In the 100mL there-necked flask, adding raw material 170mg under the room temperature nitrogen protection, benzene 5mL, N-bromo-succinimide (NBS) 98mg processes reaction solution.Be heated to backflow, utilize TLC to follow the tracks of reaction, add ethyl acetate extraction to no longer changing; In reaction solution, add saturated nacl aqueous solution 20mL washing, water 20mL washing adds anhydrous sodium sulfate drying; Filter, steaming obtains pale brown look oily matter 31mg, yield 22% after removing organic solvent; Be accredited as target compound through nuclear-magnetism, nuclear magnetic data is identical with embodiment 2.
At last, it is also to be noted that what more than enumerate only is specific embodiment of the present invention, obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.

Claims (8)

1. the compound method of Yi Zhong oxazolidone compound is characterized in that: the phenylethylamine derivative of use formula (I) is as raw material, (the II) De oxazolidone compound of synthesis type under the effect of organic oxidizing agent;
Figure FSA00000329861200011
Wherein, R 1And R 5Identical, a kind of in hydrogen, alkoxyl group, alkyl sulfide hydroxyl or the alkyl amine group;
R 2And R 6Identical, a kind of in hydrogen, alkyl, aryl or the substituted aryl;
R 3And R 7Identical, a kind of in alkyl, substituted alkyl, aryl or the substituted aryl;
R 4A kind of in alkyl or the aralkyl.
2. according to the compound method of claim 1 Suo Shu De oxazolidone compound, it is characterized in that: described organic oxidizing agent is a kind of in benzoquinones class oxygenant, the inferior amides oxygenant of high price iodide class oxygenant or halo.
3. the compound method of the oxazolidone compound of stating according to claim 2, it is characterized in that: described benzoquinones class oxygenant is 2,3-two chloro-5, a kind of in 6-dicyan para benzoquinone or its analogue.
4. according to the compound method of claim 2 Suo Shu De oxazolidone compound, it is characterized in that: described high price iodide class oxygenant is a kind of in iodobenzene diacetate or its analogue.
5. according to the compound method of claim 2 Suo Shu De oxazolidone compound, it is characterized in that: the inferior amides oxygenant of described halo is a kind of in N-halogenated succinimide imide or its analogue.
6. according to the compound method of claim 1 or 2 Shu De oxazolidone compounds; It is characterized in that: said substituted aryl is substituted-phenyl, naphthyl or replaces a kind of in the fragrant heterocycle; Wherein substituted-phenyl be the palkoxy benzene base, to alkyl phenyl, o-alkoxyl phenyl, adjacent alkyl phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N; The TMSDMA N dimethylamine base) phenyl or 3, a kind of in the 4-dialkyl phenyl organic; Naphthyl is a kind of in Alpha-Naphthyl or the betanaphthyl; Replace fragrant heterocycle and be a kind of in substituted pyridinyl, substituted azole base or the substituted furan base; Wherein substituted pyridinyl is a kind of in 4-Alkylpyridyl or the 2-Alkylpyridyl; The substituted azole base is a kind of in 3-alkyl pyrryl or the 2-alkyl pyrryl, and the substituted furan base is a kind of in 3-alkyl furan base or the 2-alkyl furan base.
7. according to the compound method of claim 1 Suo Shu De oxazolidone compound, it is characterized in that: the R in the said formula (I) 4Alkyl be the alkyl of C1-C8; Said aralkyl comprises benzyl, substituted benzyl or replaces a kind of in the assorted methylene radical of virtue; Wherein substituted benzyl is to alkoxybenzyl, to alkyl benzyl, o-alkoxyl benzyl, adjacent alkyl benzyl, to luorobenzyl, adjacent luorobenzyl, p-chlorobenzyl, o-chlorobenzyl, to bromobenzyl, adjacent bromobenzyl, right-(trifluoromethyl) benzyl, right-(N; The TMSDMA N dimethylamine base) benzyl or 3, a kind of in the 4-dimethyl benzyl; Replace the assorted methylene radical of virtue and be a kind of in substituted pyridines methylene radical, substituted azole methylene radical or the substituted furan methylene radical; Wherein the substituted pyridines methylene radical is a kind of in 4-alkyl pyridine methylene radical or the 2-alkyl pyridine methylene radical; The substituted azole methylene radical is a kind of in 3-alkyl pyrroles's methylene radical or the 2-alkyl pyrroles methylene radical, and the substituted furan methylene radical is a kind of in 3-alkyl furan methylene radical or the 2-alkyl furan methylene radical.
8. according to the compound method of claim 7 Suo Shu De oxazolidone compound, it is characterized in that: the R in the said formula (I) 4Be the tertiary butyl or benzyl.
CN2010105293481A 2010-10-21 2010-10-21 Synthesizing method of oxazolidine compound Pending CN102452995A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533707A (en) * 2020-05-21 2020-08-14 中国科学院长春应用化学研究所 Preparation method of polysubstituted oxazole-2 (3H) -ketone compound
CN115215815A (en) * 2022-08-17 2022-10-21 扬州工业职业技术学院 Method for efficiently preparing oxazolidinone derivative

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533707A (en) * 2020-05-21 2020-08-14 中国科学院长春应用化学研究所 Preparation method of polysubstituted oxazole-2 (3H) -ketone compound
CN115215815A (en) * 2022-08-17 2022-10-21 扬州工业职业技术学院 Method for efficiently preparing oxazolidinone derivative
CN115215815B (en) * 2022-08-17 2024-03-15 扬州工业职业技术学院 Method for efficiently preparing oxazolidone derivative

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Application publication date: 20120516