CN103664653A - Method for preparing 2-[(N-benzyl-N-phenyl)amino]ethanol - Google Patents
Method for preparing 2-[(N-benzyl-N-phenyl)amino]ethanol Download PDFInfo
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- CN103664653A CN103664653A CN201310706001.3A CN201310706001A CN103664653A CN 103664653 A CN103664653 A CN 103664653A CN 201310706001 A CN201310706001 A CN 201310706001A CN 103664653 A CN103664653 A CN 103664653A
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Abstract
The invention discloses a method for preparing an efonidipine hydrochloride intermediate of a 2-[(N-benzyl-N-phenyl)amino]ethanol compound of the formula (I). The method comprises the following steps: a formula (II) compound and a formula (III) compound are condensed in presence of alkali carbonate or bicarbonate to prepare a formula (IV) compound; then the formula (IV) compound reacts with ethylene oxide to prepare the formula (I) compound. Through the adoption of the method, the formula (I) compound with high yield can be prepared; post-processing is simple.
Description
Technical field
The present invention relates to organic chemistry filed, particularly, the present invention relates to a kind of efonidipine intermediate 2-[(N-benzyl-N-phenyl of preparing) amido] novel method of ethanol.
Background technology
Efonidipine is a kind of dihydropyridines new calcium antagonist of Nissan Chemical Ind Ltd's synthetic exploitation in 1985.Efonidipine is L-type and T-shaped heavy Ca
2+channel blocker, can affect the permeability of film, vasoactive unstriated muscle optionally, there is effective vasodilation and negative chronotropic action, negative inotropic action is slight, less on myocardial cell impact, step-down improves myocardium oxygen balance simultaneously, maintains cardiac output, does not affect heart function, does not cause or minimum causes reflex tachycardia.In addition, efonidipine can improve glomerular filtration rate(GFR and not increase pressure in renal glomerulus, while diastole goal and efferent glomerular arteriole, thus the generation of minimizing albuminuria has more kidney provide protection than other calcium antagonist.
2-[(N-benzyl-N-phenyl) amido] ethanol is an important intermediate preparing efonidipine, reported and prepared 2-[(N-benzyl-N-phenyl) amido] method of ethanol has following two kinds:
1. with N-β-anilino-ethanol, react and make with Benzyl Chloride, the about 56%(J Med of yield Chem, 1999,42(9): 1587-1603)
2. with Phenhenzamine, react and make with ethylene chlorhydrin, the about 87.2%(of yield China pharmaceutical chemistry magazine, 2008,18(1): 35-37).
But above-mentioned two kinds of preparation methods' aftertreatment all will be carried out high vacuum rectification, higher to equipment requirements.
Therefore, this area needs a kind of comparatively easy preparation 2-[(N-benzyl-N-phenyl) amido] novel method of ethanol.
Summary of the invention
The invention provides a kind of 2-[(N-of preparation benzyl-N-phenyl) amido] novel method of ethanol, the method is that to take aniline and Benzyl Chloride be raw material, first make Phenhenzamine, then make 2-[(N-benzyl-N-phenyl with reacting ethylene oxide) amido] ethanol.
Due under certain reaction conditions, oxyethane can more fully react with Phenhenzamine, and is gas under oxyethane normal temperature, and excessive oxyethane and reaction solvent can be removed easily.Therefore, reaction only needs simple aftertreatment can obtain 2-[(N-benzyl-N-phenyl that purity is higher) amido] ethanol, overcome the deficiencies in the prior art.
In embodiments of the invention, the invention provides 2-[(N-benzyl-N-phenyl of a kind of preparation formula (I)) amido] method of ethanol, comprise the steps:
Step 1: react and prepare Phenhenzamine (IV) with Benzyl Chloride (III) by aniline (II)
Step 2: prepare 2-[(N-benzyl-N-phenyl by Phenhenzamine (IV) and reacting ethylene oxide) amido] ethanol (I)
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, the aftertreatment of step 1 and step 2 does not need rectification under vacuum.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, step 1 is: by aniline, alkaline carbonate or supercarbonate and water, mixed, be heated to, under the condition of 80-97 ℃, to drip Benzyl Chloride; About 1-5 hour drips.After dropwising, continue reaction 1-10 hour; Be cooled to room temperature, filter, separatory, wherein organic phase saturated common salt water washing, dry, filter, the aniline that reclaim under reduced pressure is excessive, adds sherwood oil in raffinate, and heating for dissolving, adds activated carbon decolorizing, and hot filter, cooling crystallization, filtration, obtain Phenhenzamine.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, alkaline carbonate described in step 1 or supercarbonate are selected from one or more the mixture in salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate, preferably, be sodium bicarbonate.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, in step 1, be heated to 80-97 ℃, preferably, be 90-95 ℃.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, the boiling point of the sherwood oil described in step 1 is preferably 60-90 ℃.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, Benzyl Chloride in step 1 (III) is 1:1-10 with the mol ratio that aniline (II) reacts, and is preferably 1:4-6.Benzyl Chloride (III) is 1:1-2 with the mol ratio of the consumption of alkaline carbonate or supercarbonate.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, step 2 is: Phenhenzamine and oxyethane are reacted in C1-C4 alkanol or chloro C1-C4 alkane, temperature of reaction is 20-80 ℃, reaction times 2-48 hour, reaction is finished, under normal pressure or 40-50 ℃ with-0.08MPa under reclaim solvent to dry; Remaining oily matter is dissolved in chloroform, use respectively saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, last chloroform layer anhydrous sodium sulfate drying, filters out siccative, decompression and solvent recovery, to dry, obtains 2-[(N-benzyl-N-phenyl) amido] ethanol.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, the alkanol of C1-C4 described in step 2 is methyl alcohol, ethanol, Virahol or butanols, being preferably methyl alcohol or ethanol, is more preferably dehydrated alcohol.The mass ratio of the alkanol of C1-C4 described in step 2 and Phenhenzamine is 1:3-7.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, the C1-C4 of chloro described in step 2 alkane is preferably methylene dichloride or chloroform.The mass ratio of the C1-C4 alkane of chloro described in step 2 and Phenhenzamine is 1:8-16.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, in step 2, temperature of reaction is preferably 40-60 ℃.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, reaction described in step 2 is carried out under normal pressure or normal pressure to 5 normal atmosphere.
In embodiments of the invention, 2-[(N-benzyl-N-phenyl provided by the invention) amido] method of ethanol, wherein, in step 2, the mol ratio of Phenhenzamine and reacting ethylene oxide is 1:1-10, is more preferably 1:2-6.
2-[(N-benzyl-N-the phenyl providing of the present invention) amido] method of ethanol, than prior art, tool has the following advantages:
First, post-reaction treatment of the present invention is simple, without rectification under vacuum, can obtain 2-[(N-benzyl-N-phenyl that purity is greater than 90.0%) amido] ethanol, yield is also more than 87.0%;
Secondly, the present invention uses oxyethane as reaction raw materials, because its consumption is few, greatly reduces production cost.
Embodiment
Below by embodiment, the present invention will be further described; what need to particularly point out at this is; following examples are only for the invention will be further described; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make nonessential improvement and adjustment to the present invention according to the invention described above content.
The present invention is raw materials used all from Chemical Reagent Co., Ltd., Sinopharm Group;
The analytical instrument of using in the present invention is:
Proton nmr spectra: DRX500Bruker
Liquid chromatography: Agilent1100Series
2-[(N-benzyl-N-phenyl) amido] the purity detecting condition of ethanol (I) is: moving phase is methanol-water (80: 20), and detection wavelength is 251nm, and chromatographic column is C18 post (4.6 * 250mm, 5 μ m), flow velocity is 1.mL0mL/min, concentration 0.5mg/mL, sample introduction 20 μ L.
Synthesizing of embodiment 1 Phenhenzamine (IV)
In reaction flask, add 372g aniline, 108g sodium bicarbonate and 108g water, by reaction solution heating, at 90-95 ℃, drip wherein 126g Benzyl Chloride, within approximately 1 hour, drip off.Drip and finish, at 90-95 ℃, continue reaction 3 hours.Be cooled to room temperature, filtration, separatory, organic phase is used respectively 300mL saturated aqueous common salt washed twice, anhydrous sodium sulfate drying.Filter, the excessive aniline of reclaim under reduced pressure, adds 300mL sherwood oil (60-90 ℃) in raffinate, heating for dissolving, and 10g activated carbon decolorizing, hot filter, cooling crystallization, filters to such an extent that solid dries heavily about 135g.
Gained solid is carried out to nuclear magnetic resonance spectroscopy, and gained proton nmr spectra data are as follows:
1h-NMR (CDCl
3) 7.396-6.678(m, 10H, Ar-H), 4.370(s, 2H, Ar-CH
2), 4.196 (brs, 1H, Ar-H, NH).By gained proton nmr spectra, determine that gained solid is Phenhenzamine (IV).
Embodiment 2 2-[(N-benzyl-N-phenyl) amido] ethanol (I) synthetic
In reaction flask, add Phenhenzamine 10g, dehydrated alcohol 50mL and the 5g oxyethane being obtained by embodiment 1, under 45 ℃ and 0.1MPa, react approximately 24 hours, reaction is finished, and decompression and solvent recovery is to dry.Remaining oily matter is dissolved in 100mL chloroform, and with saturated sodium bicarbonate aqueous solution 30mL, water 30mL and saturated aqueous common salt 30mL washing, last chloroform layer anhydrous sodium sulfate drying, filters out siccative respectively, and decompression and solvent recovery, to dry, obtains thick liquid 11.5g.
Gained thick liquid is carried out to nuclear magnetic resonance spectroscopy, and gained proton nmr spectra data are as follows:
1H-NMR(CDCl
3)7.348-6.761（m，10H，Ar-H），4.650（s，2H，Ar-CH
2），3.869-3.637(m，4H，2×CH
2)，1.630（brs，1H，-OH）。By gained proton nmr spectra, determine that gained thick liquid is 2-[(N-benzyl-N-phenyl) amido] ethanol.
Gained 2-[(N-benzyl-N-phenyl) amido] purity of ethanol is 91.5%(HPLC), yield: 92.7%.
Embodiment 3 2-[(N-benzyl-N-phenyl) amido] ethanol (I) synthetic
In reaction flask, add Phenhenzamine 10g, methyl alcohol 50mL and the 5g oxyethane being obtained by embodiment 1, closed reactor, under 20 ℃ and 0.2MPa, react approximately 48 hours, reaction is finished, decompression and solvent recovery is to dry, the oily matter obtaining carries out aftertreatment by the method for embodiment 2, finally obtains 2-[(N-benzyl-N-phenyl) amido] ethanol 10.9g.Purity is 92.1%(HPLC), yield: 87.9%.
Gained 2-[(N-benzyl-N-phenyl) amido] the nmr analysis data consistent of ethanol and embodiment 2 products therefroms.
Embodiment 4 2-[(N-benzyl-N-phenyl) amido] ethanol (I) synthetic
In reaction flask, add Phenhenzamine 10g, dehydrated alcohol 50mL and the 10g oxyethane being obtained by embodiment 1, closed reactor, under 60 ℃ and 0.3MPa, react approximately 12 hours, reaction is finished, decompression and solvent recovery is to dry, the oily matter obtaining carries out aftertreatment by the method for embodiment 2, finally obtains 2-[(N-benzyl-N-phenyl) amido] ethanol 11.2g.Purity is 91.8%(HPLC), yield: 90.3%.
Gained 2-[(N-benzyl-N-phenyl) amido] the nmr analysis data consistent of ethanol and embodiment 2 products therefroms.
Embodiment 5 2-[(N-benzyl-N-phenyl) amido] ethanol (I) synthetic
In reaction flask, add Phenhenzamine 10g and the methyl alcohol 50mL being obtained by embodiment 1, be warming up to 60 ℃, in reaction solution, drip the methanol solution containing 20g oxyethane, drip and finish, continuation is reacted approximately 2 hours under 60 ℃ and 0.1MPa, and reaction is finished, and decompression and solvent recovery is to dry, the oily matter obtaining carries out aftertreatment by the method for embodiment 2, finally obtains 2-[(N-benzyl-N-phenyl) amido] ethanol 11.0g.Purity is 92.5%(HPLC), yield: 88.7%.
Gained 2-[(N-benzyl-N-phenyl) amido] the nmr analysis data consistent of ethanol and embodiment 2 products therefroms.
Claims (10)
1. efonidipine intermediate 2-[(N-benzyl-N-phenyl of preparation formula (I)) amido] method of alcohol cpd, comprise the steps:
Step 1. is reacted and is prepared Phenhenzamine (IV) with Benzyl Chloride (III) by aniline (II)
Step 2. is prepared 2-[(N-benzyl-N-phenyl by Phenhenzamine (IV) and reacting ethylene oxide) amido] ethanol (I)
2. method according to claim 1, wherein, the aftertreatment of step 1 and step 2 does not comprise rectification under vacuum.
3. method according to claim 1, wherein, step 2 is: Phenhenzamine and oxyethane are reacted in C1-C4 alkanol or chloro C1-C4 alkane, and temperature of reaction is 20-80 ℃, reaction 2-48 hour, reaction is finished, and normal pressure or decompression and solvent recovery are to dry; Remaining oily matter is dissolved in chloroform, use respectively saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, last chloroform layer anhydrous sodium sulfate drying, filters out siccative, decompression and solvent recovery, to dry, obtains 2-[(N-benzyl-N-phenyl) amido] ethanol.
4. method according to claim 3, wherein, the alkanol of C1-C4 described in step 2 is methyl alcohol, ethanol, Virahol or butanols, is preferably methyl alcohol or ethanol, is more preferably dehydrated alcohol.
5. according to the method for claim 3, wherein, the C1-C4 of chloro described in step 2 alkane is methylene dichloride or chloroform.
6. according to the process of claim 1 wherein, in step 2, temperature of reaction is 40-60 ℃.
7. according to the process of claim 1 wherein, in step 2, reaction pressure is normal pressure to 5 normal atmosphere.
8. according to the process of claim 1 wherein, in step 2, the mol ratio of Phenhenzamine and reacting ethylene oxide is 1:1-10, is more preferably 1:2-6.
9. according to the method described in arbitrary claim in claim 1 to 8, wherein, step 1 is: by aniline, alkaline carbonate or supercarbonate and water, mixed, be heated to, under the condition of 80-97 ℃, to drip Benzyl Chloride; After dropwising, continue reaction 1-10 hour; Be cooled to room temperature, filter, separatory, wherein organic phase saturated common salt water washing, dry, filter, the aniline that reclaim under reduced pressure is excessive, adds sherwood oil in raffinate, and heating for dissolving, adds activated carbon decolorizing, and hot filter, cooling crystallization, filtration, obtain Phenhenzamine.
10. according to the method for claim 9, wherein, the alkaline carbonate described in step 1 or supercarbonate are selected from one or more the mixture in salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate, preferably, are sodium bicarbonate.
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| CN109320519A (en) * | 2018-08-27 | 2019-02-12 | 北京化工大学 | A kind of synthetic method of double hydroxyls or trihydroxy Rhodamine Derivatives |
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| CN102040527A (en) * | 2010-11-26 | 2011-05-04 | 西北师范大学 | Preparation method of N,N-benzyl diphenylamine |
| CN103373929A (en) * | 2012-04-20 | 2013-10-30 | 罗门哈斯公司 | Dibenzylamine hydrophobe |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102040527A (en) * | 2010-11-26 | 2011-05-04 | 西北师范大学 | Preparation method of N,N-benzyl diphenylamine |
| CN103373929A (en) * | 2012-04-20 | 2013-10-30 | 罗门哈斯公司 | Dibenzylamine hydrophobe |
Non-Patent Citations (1)
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| 郭以猛等: "盐酸依福地平合成工艺改进", 《中国药物化学杂志》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109320519A (en) * | 2018-08-27 | 2019-02-12 | 北京化工大学 | A kind of synthetic method of double hydroxyls or trihydroxy Rhodamine Derivatives |
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