CN103664653B - 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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- CN103664653B CN103664653B CN201310706001.3A CN201310706001A CN103664653B CN 103664653 B CN103664653 B CN 103664653B CN 201310706001 A CN201310706001 A CN 201310706001A CN 103664653 B CN103664653 B CN 103664653B
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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, specifically, the present invention relates to the novel method that one prepares efonidipine intermediate 2-[(N-benzyl-N-phenyl) amido] ethanol.
Background technology
Efonidipine is a kind of dihydropyridines new calcium antagonist of Nissan Chemical Ind Ltd's synthesis exploitation in 1985.Efonidipine is L-type and T-shaped heavy Ca
2+channel blocker, the permeability of film can be affected, optionally vasoactive unstriated muscle, there is effective vasodilation and negative chronotropic action, negative inotropic action is slight, less on myocardial cell's impact, step-down improves myocardium oxygen balance simultaneously, maintains cardiac output, does not affect heart function, do not cause or minimumly causes reflex tachycardia.In addition, efonidipine can improve glomerular filtration rate(GFR and not increase pressure in renal glomerulus, simultaneously diastole goal and efferent glomerular arteriole, thus reduces the generation of albuminuria, has more renal protection than other calcium antagonist.
2-[(N-benzyl-N-phenyl) amido] ethanol is the important intermediate preparing efonidipine, has reported that the method preparing 2-[(N-benzyl-N-phenyl) amido] ethanol has following two kinds:
1. react obtained with N-β-anilino-ethanol and Benzyl Chloride, yield is about 56%(J Med Chem, 1999,42(9): 1587-1603)
2. react obtained with Phenhenzamine and ethylene chlorhydrin, yield is about 87.2%(China pharmaceutical chemistry magazine, 2008,18(1): 35-37).
But the aftertreatment of above-mentioned two kinds of preparation methods all will carry out high vacuum rectification, higher to equipment requirements.
Therefore, this area needs the novel method of a kind of comparatively easy preparation 2-[(N-benzyl-N-phenyl) amido] ethanol.
Summary of the invention
The invention provides the novel method that one prepares 2-[(N-benzyl-N-phenyl) amido] ethanol, the method is for raw material with aniline and Benzyl Chloride, first obtained Phenhenzamine, then obtains 2-[(N-benzyl-N-phenyl) amido] ethanol with reacting ethylene oxide.
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 the higher 2-of purity [(N-benzyl-N-phenyl) amido] ethanol, overcomes the deficiencies in the prior art.
In embodiments of the invention, the invention provides the method for 2-[(N-benzyl-N-phenyl) amido] ethanol of a kind of preparation formula (I), comprise the steps:
Step 1: reacted by aniline (II) and Benzyl Chloride (III) and prepare Phenhenzamine (IV)
Step 2: prepare 2-[(N-benzyl-N-phenyl) amido] ethanol (I) by Phenhenzamine (IV) and reacting ethylene oxide
In embodiments of the invention, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, the aftertreatment of step 1 and step 2 does not need rectification under vacuum.
In embodiments of the invention, the method of 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, step 1 is: mixed by aniline, alkaline carbonate or supercarbonate and water, be heated under the condition of 80-97 DEG C, dripping 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, add activated carbon decolorizing, heat filter, cooling crystallization, filtration, obtain Phenhenzamine.
In embodiments of the invention, the method of 2-provided by the invention [(N-benzyl-N-phenyl) amido] 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, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, being heated to 80-97 DEG C in step 1, preferably, is 90-95 DEG C.
In embodiments of the invention, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, the boiling point of the sherwood oil described in step 1 is preferably 60-90 DEG C.
In embodiments of the invention, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, the mol ratio that in step 1, Benzyl Chloride (III) and aniline (II) react is 1:1-10, is preferably 1:4-6.The mol ratio of the consumption of Benzyl Chloride (III) and alkaline carbonate or supercarbonate is 1:1-2.
In embodiments of the invention, the method of 2-provided by the invention [(N-benzyl-N-phenyl) amido] 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 DEG C, reaction times 2-48 hour, reaction is finished, at ambient pressure or 40-50 DEG C with recycling design under-0.08MPa to dry; Remaining oily matter is dissolved in chloroform, respectively with 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, the method of 2-provided by the invention [(N-benzyl-N-phenyl) amido] 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, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] 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, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, in step 2, temperature of reaction is preferably 40-60 DEG C.
In embodiments of the invention, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, reaction described in step 2 is carried out under 5 normal atmosphere at normal pressure or normal pressure.
In embodiments of the invention, the method for 2-provided by the invention [(N-benzyl-N-phenyl) amido] ethanol, wherein, in step 2, the mol ratio of Phenhenzamine and reacting ethylene oxide is 1:1-10, is more preferably 1:2-6.
The method of 2-[(N-benzyl-N-phenyl) amido] ethanol provided of the present invention, compared to prior art, tool has the following advantages:
First, post-reaction treatment of the present invention is simple, and can obtain without the need to rectification under vacuum 2-[(N-benzyl-N-phenyl) amido] ethanol that purity is greater than 90.0%, 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; need at this it is emphasized that; 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 according to the invention described above content to the present invention.
The present invention is raw materials used all from Chemical Reagent Co., Ltd., Sinopharm Group;
The analytical instrument used in the present invention is:
Proton nmr spectra: DRX500Bruker
Liquid chromatography: Agilent1100Series
The purity detecting condition of 2-[(N-benzyl-N-phenyl) amido] ethanol (I) is: moving phase is methanol-water (80: 20), determined wavelength is 251nm, chromatographic column is C18 post (4.6 × 250mm, 5 μm), flow velocity is 1.mL0mL/min, concentration 0.5mg/mL, sample introduction 20 μ L.
The synthesis of embodiment 1 Phenhenzamine (IV)
In reaction flask, add 372g aniline, 108g sodium bicarbonate and 108g water, reaction solution is heated, at 90-95 DEG C, drip 126g Benzyl Chloride wherein, within about 1 hour, drip off.Drip and finish, continue reaction 3 hours at 90-95 DEG C.Be cooled to room temperature, filtration, separatory, organic phase washes twice with 300mL saturated aqueous common salt respectively, anhydrous sodium sulfate drying.Filter, the excessive aniline of reclaim under reduced pressure, adds 300mL sherwood oil (60-90 DEG C), heating for dissolving, 10g activated carbon decolorizing in raffinate, heat filter, cooling crystallization, filter solid dries heavily about 135g.
Carry out nuclear magnetic resonance spectroscopy to gained solid, gained hydrogen nuclear magnetic resonance modal data is 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).Be Phenhenzamine (IV) by gained proton nmr spectra determination gained solid.
The synthesis of embodiment 2 2-[(N-benzyl-N-phenyl) amido] ethanol (I)
In reaction flask, add the Phenhenzamine 10g, dehydrated alcohol 50mL and the 5g oxyethane that are obtained by embodiment 1, under 45 DEG C and 0.1MPa, react about 24 hours, reaction is finished, and decompression and solvent recovery is to dry.Remaining oily matter is dissolved in 100mL chloroform, and wash with saturated sodium bicarbonate aqueous solution 30mL, water 30mL and saturated aqueous common salt 30mL respectively, last chloroform layer anhydrous sodium sulfate drying, filters out siccative, and decompression and solvent recovery, to dry, obtains thick liquid 11.5g.
Carry out nuclear magnetic resonance spectroscopy to gained thick liquid, gained hydrogen nuclear magnetic resonance modal data is 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）。Be 2-[(N-benzyl-N-phenyl) amido] ethanol by gained proton nmr spectra determination gained thick liquid.
The purity of gained 2-[(N-benzyl-N-phenyl) amido] ethanol is 91.5%(HPLC), yield: 92.7%.
The synthesis of embodiment 3 2-[(N-benzyl-N-phenyl) amido] ethanol (I)
The Phenhenzamine 10g, methyl alcohol 50mL and the 5g oxyethane that are obtained by embodiment 1 is added in reaction flask, closed reactor, about 48 hours are reacted under 20 DEG C and 0.2MPa, reaction is finished, decompression and solvent recovery is to dry, the oily matter obtained 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%.
The nmr analysis data consistent of gained 2-[(N-benzyl-N-phenyl) amido] ethanol and embodiment 2 products therefrom.
The synthesis of embodiment 4 2-[(N-benzyl-N-phenyl) amido] ethanol (I)
The Phenhenzamine 10g, dehydrated alcohol 50mL and the 10g oxyethane that are obtained by embodiment 1 is added in reaction flask, closed reactor, about 12 hours are reacted under 60 DEG C and 0.3MPa, reaction is finished, decompression and solvent recovery is to dry, the oily matter obtained 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%.
The nmr analysis data consistent of gained 2-[(N-benzyl-N-phenyl) amido] ethanol and embodiment 2 products therefrom.
The synthesis of embodiment 5 2-[(N-benzyl-N-phenyl) amido] ethanol (I)
The Phenhenzamine 10g and methyl alcohol 50mL that are obtained by embodiment 1 is added in reaction flask, be warming up to 60 DEG C, the methanol solution containing 20g oxyethane is dripped in reaction solution, drip and finish, continue to react about 2 hours under 60 DEG C and 0.1MPa, reaction is finished, and decompression and solvent recovery is to dry, the oily matter obtained 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%.
The nmr analysis data consistent of gained 2-[(N-benzyl-N-phenyl) amido] ethanol and embodiment 2 products therefrom.
Claims (11)
1. prepare a method for efonidipine intermediate 2-[(N-benzyl-N-phenyl) amido] alcohol cpd, comprise the steps:
Step 1. is mixed by aniline, alkaline carbonate or supercarbonate and water, is being heated under the condition of 80-97 DEG C, drips 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, add activated carbon decolorizing, heat filter, cooling crystallization, filtration, obtain Phenhenzamine;
Phenhenzamine and oxyethane react by step 2. in C1-C4 alkanol or chloro C1-C4 alkane, and temperature of reaction is 20-80 DEG C, reaction 2-48 hour, and reaction is finished, and normal pressure or decompression and solvent recovery are to dry; Remaining oily matter is dissolved in chloroform, respectively with 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.
2. method according to claim 1, wherein, the alkanol of C1-C4 described in step 2 is methyl alcohol, ethanol, Virahol or butanols.
3. method according to claim 2, wherein, the alkanol of C1-C4 described in step 2 is methyl alcohol or ethanol.
4. method according to claim 3, wherein, the alkanol of C1-C4 described in step 2 is dehydrated alcohol.
5. method according to claim 1, wherein, the C1-C4 of chloro described in step 2 alkane is methylene dichloride or chloroform.
6. method according to claim 1, wherein, in step 2, temperature of reaction is 40-60 DEG C.
7. method according to claim 1, wherein, in step 2, reaction pressure is that normal pressure is to 5 normal atmosphere.
8. method according to claim 1, wherein, in step 2, the mol ratio of Phenhenzamine and reacting ethylene oxide is 1:1-10.
9. method according to claim 8, wherein, in step 2, the mol ratio of Phenhenzamine and reacting ethylene oxide is 1:2-6.
10. method according to claim 1, 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.
11. methods according to claim 10, wherein, the alkali metal hydrocarbonate described in step 1 is sodium bicarbonate.
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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 |
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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)
| Title |
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| 盐酸依福地平合成工艺改进;郭以猛等;《中国药物化学杂志》;20080228;第18卷(第1期);35-37 * |
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