CN100999449A - Preparation method of aliphatic cyclo benzylether - Google Patents
Preparation method of aliphatic cyclo benzylether Download PDFInfo
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- CN100999449A CN100999449A CN 200610155832 CN200610155832A CN100999449A CN 100999449 A CN100999449 A CN 100999449A CN 200610155832 CN200610155832 CN 200610155832 CN 200610155832 A CN200610155832 A CN 200610155832A CN 100999449 A CN100999449 A CN 100999449A
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- benzyl
- cycloaliphatic ring
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- benzylic ether
- chloride
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Abstract
This invention involves a preparation method of cyclo-fat benzyl ether. It take cyclo-fat alcohol as raw material, non-water-soluble organic as solvent, at 50% solids alkaline aqueous solution environment, by adding benzyl reagent, stirring and refluxing to obtain cyclo-fat benzyl ether. This invention obtain the product by using phase transfer catalyst to synthesize benzyl, adding small amount of phase-transfer catalyst in the two-phase reaction system, without joining alumina, and taking toluene and dichloromethane etc. common solvent as solvents, mixing in 50% alkaline environment. Through the optimization of processes, the reaction time is shortened considerably; Chromatography absorption rate can achieve 85% to 100%, suit for industrial production.
Description
Technical field:
The present invention relates to the synthetic method of compound, particularly the synthetic method of cycloaliphatic ring benzylic ether.
Background technology:
The synthetic general A.W.Willianson method that adopts of cycloaliphatic ring benzylic ether forms sodium alkoxide by fatty cyclic alcohol in the presence of highly basic such as sodium hydride, hydrolith, potassium tert.-butoxide or sodium tert-butoxide etc., form ether with the reaction of benzyl haloalkane again.But the side reaction that usually can eliminate reaction and produce alkene.And to control the reaction system anhydrous and oxygen-free, and add expensive anhydrous solvent or polar aprotic solvent, though reaction can be carried out, severe reaction conditions is operated inconvenience, the aftertreatment complexity, side reaction simultaneously is many, and yield is low, the cost height.
People such as Nouguier (Elsevier Science B.V., Amsterdam, CarbohydrateResearch, 252 (1994) 149-157) methyl-α-D-glucopyranoside is adsorbed on the aluminum oxide, the Aliquat 336 that adds 4eq bromobenzyl and 10%, stir under the alkaline environment of KOH or cesium fluoride, reaction yield can bring up to 60%.But because the existence of aluminum oxide increases post-reaction treatment and filters a step, aftertreatment bothers, and yield is still waited to improve.
Summary of the invention:
The objective of the invention is to overcome above-mentioned not enough problem, a kind of preparation method of cycloaliphatic ring benzylic ether is provided, raw material is cheap and easy to get, the reaction conditions gentleness, and easy and simple to handle, aftertreatment is simple, and by product is few, suitability for industrialized production productive rate height.
The technical scheme that the present invention is adopted for achieving the above object is: a kind of preparation method of cycloaliphatic ring benzylic ether, with fatty cyclic alcohol is raw material, adopts water-insoluble organic solvent, in 50% solid caustic soda aqueous environment, add benzyl reagent, the stirring and refluxing reaction makes the cycloaliphatic ring benzylic ether.
In being installed, the exsiccant stainless steel cauldron (gauge pressure 0-1Mpa) of thermometer, mechanical stirring and condenser adds entry, stir and add solid caustic soda down, the control mixture temperature is not higher than 40 ℃, the solid caustic soda adding finishes, temperature of reaction system is reduced to 20～25 ℃, add phase-transfer catalyst, the water-insoluble organic solvent solution of naphthenic hydrocarbon alcohol, benzyl reagent, stir, and 0～100 ℃ of the control reaction temperature of heating up gradually, stir 3～4h after, back flow reaction finishes, and cooling is left standstill aftertreatment and got the cycloaliphatic ring benzylic ether.
Described aftertreatment is specially: layering, tell alkali lye, and the concentrated solvent layer, product can be by adding the normal hexane making beating, and centrifugal, washing or underpressure distillation obtain.
Described proportioning raw materials is: fatty cyclic alcohol: benzyl reagent: phase-transfer catalyst: the mol ratio of solid caustic soda is 1: 1.1～1.5: 0.1～0.3: 15～25.
Described fatty cyclic alcohol is cyclopentanol, hexalin, 2-nitrine cyclopentanol, 2-nitrine hexalin, 2-N-Boc-cyclopentamine alcohol, 2-N-Boc-hexahydroaniline alcohol or 2-N-protecting group-cyclopentamine alcohol or 2-N-protecting group-hexahydroaniline alcohol.
Described benzyl reagent is cylite, Benzyl Chloride, to the methyl benzyl chloride, to the methoxyl group benzyl chloride, to the methyl bromobenzyl, to the methoxyl group bromobenzyl, to fluorobenzyl chloride, to fluorine bromobenzyl, 4-chlorobenzyl chloride, to chlorine bromobenzyl, a methyl-benzyl chlorine, meta-methylbenzyl bromide, a chlorobenzyl chloride, m-chloro bromotoluene, a fluorobenzyl chloride, a fluoro benzyl bromide, meta-methoxy benzyl chloride, meta-methoxy bromotoluene, adjacent fluoro benzyl bromide, adjacent fluorobenzyl chloride, o-chlorobenzyl bromine or o-chlorobenzyl chlorine.
Described phase-transfer catalyst is one of following quaternary ammonium salt: tri-n-octyl methyl ammonium chloride, TBAH, Tetrabutyl amonium bromide, tri-methyl benzyl ammonium bromide, trimethylphenyl brometo de amonio, triethyl benzyl brometo de amonio, 4-butyl ammonium hydrogen sulfate, tetraethyl-monoammonium sulfate, four heptyl monoammonium sulfates.
Described solid caustic soda is sodium hydroxide and potassium hydroxide.
Described water-insoluble organic solvent is methylene dichloride, benzene, toluene, chlorobenzene etc.
Described temperature of reaction is 40～80 ℃ and is more suitable for, especially with 60-70 ℃ of the best.Stirring velocity is 300～400 rev/mins.
The structural formula of described products obtained therefrom cycloaliphatic ring benzylic ether is as follows:
Wherein R1=-H ,-F ,-Cl ,-CH3 or-OCH3
R2＝-H、-N3、-N?HCOOtert-C
4H
9
n＝1，2。
The industrialized preparing process that the present invention utilizes phase-transfer catalyst catalysis benzyl to be combined to, in two-phase reaction system, add a small amount of phase-transfer catalyst, need not to add aluminum oxide, is solvent with common solvents such as toluene, methylene dichloride, stirs to make in 50% alkali lye environment.The reaction conditions gentleness, easy and simple to handle, do not need expensive anhydrous solvent or protonic solvent, reaction solvent for use low toxicity; Do not require waterless operation, do not need to add highly basic such as sodium hydride, hydrolith, potassium tert.-butoxide or sodium tert-butoxide, and suppress the side reaction generation, the feed stock conversion height improves yield.In fact whole, raw material is cheap and easy to get, and processing condition are wide in range, suitability for industrialized production productive rate height, and by technology is optimized, the reaction times shortens greatly, and the chromatogram yield reaches 85%～100%, and raw material almost carries out main reaction entirely.Aftertreatment is simple, and phase-transfer catalyst and alkali lye are all recyclable simultaneously utilizes again, and whole reaction system almost no waste is got rid of environmental friendliness.The present invention is by process optimization, and it is wide in range progressively to set up a cover reaction and post-processing operation temperature, and control makes things convenient for aftertreatment easily, is fit to suitability for industrialized production.
Embodiment:
The present invention is described in further detail below in conjunction with specific embodiment, but be not limited to following embodiment.
Embodiment 1
In the 5L four-hole round-bottomed flask that mechanical stirring, thermometer and spherical condenser are housed, add the pure and mild 429.5g (2.21mol of 450g (1.84mol) N-Boc guard ring hexylamine, 1.2eq) cylite, 148.7g (0.368mol, 0.2eq) tri-n-octyl methyl ammonium chloride, the 1000ml methylene dichloride stirs; Stir down, gradation adds the sodium hydroxide solution of 3.2kg 50% in reactor, and the control mixture temperature is not higher than 40 ℃.After 50% sodium hydroxide solution dropwises, be warming up to 40 ℃, 3～4h refluxes; After reaction finished, cooling stopped to stir.Layering keeps dichloromethane layer.Dichloromethane layer, with the 300ml water washing once.(minimum volume) behind most of methylene dichloride removed in all dichloromethane layer underpressure distillation, add normal hexane, solvent exchange, solid appears in cooling, and making beating 1h disperses solid fully.With the solid filtering in the slurries, solid is used the washing of 2 * 300ml normal hexane again.Product purity is 99.4006%.(efficient liquid phase chromatographic analysis) weight 360g product, separation yield is 74% for the first time; Mother liquor reclaims product 107g, and purity is 85%; The product calculated yield that obtains for twice is 82%.
Embodiment 2
In the 2L four-hole round-bottomed flask that mechanical stirring, thermometer and spherical condenser are housed, add 200g potassium hydroxide and 200g water, stirring and dissolving, be cooled to 40 ℃, add 52.6g (0.354mol) nitrine hexalin and 24.1g (0.07mol again, 0.2eq) 4-butyl ammonium hydrogen sulfate, 500ml toluene stirs.Stir down, drip the 49.2g Benzyl Chloride in reaction mixture, the control reaction mixture temperature is at 40 ± 2 ℃.After benzyl chloride dropwises, be warming up to 60 ℃, heated and stirred 4h, cooling stops to stir layering.The toluene solution that collection obtains washs with 300ml semi-saturation salt solution, and nitrine benzyl rings hexyl ether chromatogram content is 70%, chromatogram yield 90%.
Embodiment 3
In the 1L four-hole round-bottomed flask that mechanical stirring, thermometer and spherical condenser are housed, add 120g sodium hydroxide and 120g water, stirring and dissolving, be cooled to 40 ℃, add 26.7g (0.21mol) 2-nitrine cyclopentanol and 9.7g (0.042mol again, 0.2eq) tri-methyl benzyl ammonium bromide, 35.2g (0.25mol 1.2eq) stirs methyl benzyl chloride and 500ml chlorobenzene, and the control reaction mixture temperature is at 70 ± 2 ℃.After reaction finished, cooling stopped to stir layering.The toluene solution that collection obtains washs with 150ml semi-saturation salt solution, and nitrine benzyl rings amyl ether chromatogram content is 68%, chromatogram yield 89%.
Embodiment 4
In the 1L four-hole round-bottomed flask that mechanical stirring, thermometer and spherical condenser are housed, add 160g potassium hydroxide and 160g water; stirring and dissolving; be cooled to 40 ℃; add the pure and mild 10.9g (0.04mol of 40.2g (0.2mol) N-Boc guard ring amylamine again; 0.2eq) triethyl benzyl brometo de amonio; 49.3g (0.24mol, 1.2eq) p-chlorobenzyl bromine and 500ml toluene stir, and the control reaction mixture temperature is at 60 ± 2 ℃.After reaction finished, cooling stopped to stir layering.The toluene solution that collection obtains washs with 150ml semi-saturation salt solution, underpressure distillation, and the making beating dispersing and filtering, solid is used the washing of 2 * 100ml normal hexane again.Product purity is 99.2%.(efficient liquid phase chromatographic analysis) separation yield is 85%.
The present invention is applicable to that also other fatty cyclic alcohol (as 2-nitrine hexalin, 2-N-Boc-cyclopentanol, 2-N-Boc-hexalin or 2-N-protecting group-cyclopentanol or 2-N-protecting group-hexalin) is a raw material production cycloaliphatic ring benzylic ether in addition; method is identical, and yield all can reach more than 85%.
Claims (10)
1, a kind of preparation method of cycloaliphatic ring benzylic ether is characterized in that: it is a raw material with fatty cyclic alcohol, adopts water-insoluble organic solvent, in 50% solid caustic soda aqueous environment, adds benzyl reagent, and the stirring and refluxing reaction makes the cycloaliphatic ring benzylic ether through aftertreatment.
2, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1, it is characterized in that: thermometer is being installed, add entry in the exsiccant stainless steel cauldron of mechanical stirring and condenser, stir and add solid caustic soda down, the control reaction mixture temperature is not higher than 40 ℃, the solid caustic soda adding finishes, temperature of reaction system is reduced to 20～25 ℃, add phase-transfer catalyst, the water-insoluble organic solvent solution of fat cyclic alcohol, benzyl reagent stirs, heat up gradually and control reaction temperature 0-100 ℃, after stirring 3～4h, back flow reaction finishes, and cooling is left standstill aftertreatment and got the cycloaliphatic ring benzylic ether.
3, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2, it is characterized in that: aftertreatment is specially: layering, tell alkali lye, the concentrated solvent layer, product can be by adding the normal hexane making beating, and centrifugal, washing or underpressure distillation obtain.
4, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: proportioning raw materials is: fatty cyclic alcohol: benzyl reagent: phase-transfer catalyst: the mol ratio of solid caustic soda is 1: 1.1～1.5: 0.1～0.3: 15～25.
5, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: phase-transfer catalyst is one of following quaternary ammonium salt: tri-n-octyl methyl ammonium chloride, TBAH, Tetrabutyl amonium bromide, tri-methyl benzyl ammonium bromide, trimethylphenyl brometo de amonio, triethyl benzyl brometo de amonio, 4-butyl ammonium hydrogen sulfate, tetraethyl-monoammonium sulfate, four heptyl monoammonium sulfates.
6, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: solid caustic soda is solid sodium hydroxide or solid potassium hydroxide.
7, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: fatty cyclic alcohol is cyclopentanol, hexalin, 2-nitrine cyclopentanol, 2-nitrine hexalin, 2-N-Boc-cyclopentamine alcohol, 2-N-Boc-hexahydroaniline alcohol or 2-N-protecting group-cyclopentamine alcohol or 2-N-protecting group-hexahydroaniline alcohol; Benzyl reagent is cylite, Benzyl Chloride, to the methyl benzyl chloride, to the methoxyl group benzyl chloride, to the methyl bromobenzyl, to the methoxyl group bromobenzyl, to fluorobenzyl chloride, to fluorine bromobenzyl, 4-chlorobenzyl chloride, to chlorine bromobenzyl, a methyl-benzyl chlorine, meta-methylbenzyl bromide, a chlorobenzyl chloride, m-chloro bromotoluene, a fluorobenzyl chloride, a fluoro benzyl bromide, meta-methoxy benzyl chloride, meta-methoxy bromotoluene, adjacent fluoro benzyl bromide, adjacent fluorobenzyl chloride, o-chlorobenzyl bromine or o-chlorobenzyl chlorine.
8, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: water-insoluble organic solvent is methylene dichloride, benzene, toluene or chlorobenzene.
9, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: temperature of reaction is 40～80 ℃.
10, the preparation method of a kind of cycloaliphatic ring benzylic ether according to claim 1 and 2 is characterized in that: the structural formula of product cycloaliphatic ring benzylic ether is as follows:
Wherein R1=-H ,-F ,-Cl ,-CH3 or-OCH3
R2＝-H、-N3、-NHCOOtert-C
4H
9
n＝1，2。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114867708A (en) * | 2020-12-04 | 2022-08-05 | 泉州海创医药科技有限公司 | Method for synthesizing benzyl ether from polyhydroxyphenol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114867708A (en) * | 2020-12-04 | 2022-08-05 | 泉州海创医药科技有限公司 | Method for synthesizing benzyl ether from polyhydroxyphenol |
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Effective date of registration: 20160310 Address after: 116600, No. seven, 18 street, Liaohe West Road, Dalian economic and Technological Development Zone, Liaoning, Dalian Patentee after: Allychem Co., Ltd., Dalian, China Address before: 116620, Liaoning, Dalian double D port, double D5 street, 18, bio pharmaceutical R & D center, C Patentee before: Dalian Lianhua Medical Technology Co., Ltd. |