CN106674038A - Method for compounding and purifying macamides - Google Patents
Method for compounding and purifying macamides Download PDFInfo
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- CN106674038A CN106674038A CN201610982391.0A CN201610982391A CN106674038A CN 106674038 A CN106674038 A CN 106674038A CN 201610982391 A CN201610982391 A CN 201610982391A CN 106674038 A CN106674038 A CN 106674038A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
Abstract
The invention discloses a method for compounding and purifying macamides. The method comprises the following steps: 1) adding fatty acid, EDC.HCl, HOBT.H2O and triethylamine into a dichloromethane liquid and stirring for 10-24 hours; 2) adding benzylamine or substituted benzylamine into the reaction liquid and reacting for 2-10 hours; and 3) drying the compound reaction liquid by distillation and then purifying. The macamides prepared according to the preparation method disclosed by the invention is higher in purity, the compounding steps are simple and convenient and the method is suitable for industrial large-scale production.
Description
Technical field
The invention belongs to field of biological pharmacy, more particularly to a kind of method of synthesis and purification macamide.
Background technology
Lepidinm meyenii Walp (Lepidium meyenii Walp.) is Cruciferae separate row Vegetable spp, is grown in more than 3500 meters of height above sea level
In environment, 1 year or biennial herbaceous plant are tired with the edible history of thousand of years and extensive biological effect-alleviation muscle power
Labor, improves sexual function, improves sclerotin loose and improve memory ability etc..
Macamide class compound is the minimum amide alkaloid of alkalescence in nitrogenous Alkaloid, in Lepidinm meyenii Walp, Lepidinm meyenii Walp
Amide is formed by benzylamine and fatty acid molecule bioconversion, right with very long carbochain and polynary insatiable hunger.In Lepidinm meyenii Walp
In dry root, the content of macamide is in 0.06%-0.52%, and content is very low, so proposing the requirement of a large amount of synthesis.N-(4-
Hydroxy-benzvl) -5 oxygen -6E, 8E- octadecadienoic acids amide compared with common macamide, in structure, its phenyl ring parent nucleus
Middle hydrogen atom is optionally substituted by a hydroxyl group.Such macamide is generous et al. by height first, in 2013, finds.To hydroxyl benzyl
Amine alkaloid and common macamide, the difference on biological effect and pharmaceutical usage, also do not have document report, so carrying
Its preparation and purification method is gone out, has been that drug efficacy study provides material base.According to《Lepidinm meyenii Walp dry productss quality standard》(DBS 53/
001-2015) five kinds of macamides, are mainly included in Lepidinm meyenii Walp, is successively meta-methoxy-benzyl-linolenamide (397.60), benzyl
Base-linolenamide (367.57), meta-methoxy-benzyl-Asia oleamide (399.62), benzyl-Asia oleamide (369.59) and benzyl
Base-palmitic amide (345.57).
The technique of synthesis macamide is mainly synthesizing amide key, and the synthesis of current amido link is mainly the contracting of carbodiimide class
Mixture method, carbodiimide class condensing agent mainly includes three kinds of dicyclohexylcarbodiimides (DCC), DIC
(DIC) and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDCI), the hydrochlorate of EDCI is the more commonly used, is water solublity
, finished product purification is also easy to, mainly play a part of activated carboxyl.Due to activated carboxyl formed intermediate it is unstable, easily
Stable by-product is formed, so must be added to amide catalysts (HOBT, HOAT etc.) to form intermediate.In course of reaction
It is also required to add acid binding agent, the yield of product is improved especially with the hydrochlorate of EDCI, although the chemistry of this material point
Minor structure has been determined, but because it does not have canonical biometric alkali characteristic, the content in Lepidinm meyenii Walp is relatively low and extraction and separation process
Complexity, there is presently no the chemical synthesis process and extensive preparation technology of maturation.
The content of the invention
It is an object of the invention to provide a kind of preparation method of macamide.
The technical solution used in the present invention is：
A kind of preparation method of macamide, comprises the following steps：1) in dichloromethane solution add fatty acid,
EDC·HCl、HOBT·H2O and triethylamine are mixed, and are stirred 10~24 hours；2) state reactant liquor then up to add benzylamine or take
For benzylamine, react 2~10 hours；3) reactant liquor of above-mentioned synthesis is evaporated, and purification.
The macamide chemical structure of general formula is：
(1)Or (2)
Preferably, the fatty acid of preparing raw material is respectively：Palmitic acid, stearic acid, linoleic acid, linolenic acid, 5 oxygen -6E, 8E-
Octadecadienoic acid.
Preferably, reaction solution, benzylamine or alpha substituted benzylamine, fatty acid, EDCHCl, HOBT in step one and step 2
H2The mol ratio of O and triethylamine is (1-10)：(1-10)：(1-10)：(1-10)：(1-10).
It is further preferred that alpha substituted benzylamine is gumbix or m-anisidine.
It is further preferred that gumbix, fatty acid, EDCHCl, HOBTH2The mol ratio of O and triethylamine is 1：
1：1：1：2.5.
Preferably, the step of purification in macamide preparation process is：
1) acid solution and organic solvent are added, after ultrasonic wave added dissolving, organic layer is taken；
2) by organic layer aqueous slkali fully shaking, reaction is complete；
3) add acid solution to be washed, and take organic layer solution low temperature crystallization or silica gel crosses post.
It is further preferred that low temperature crystallization temperature is -30 DEG C -10 DEG C.
The invention has the beneficial effects as follows：There is provided a kind of preparation method of macamide, the product purity of the method synthesis
Higher, step is easy, can be used for industrialization extensive.
Description of the drawings
Fig. 1 is that after dilute filtration, loading is obtained according to synthetic method, the reactant liquor for obtaining in the embodiment of the present invention 1
High-efficient liquid phase chromatogram.
Fig. 2 is that after methanol dissolving is a certain amount of, loading is obtained according to purification process, the crystallization for obtaining in the embodiment of the present invention 1
High-efficient liquid phase chromatogram.
Specific embodiment
By following specific embodiment and its accompanying drawing, the present invention is described in further detail, readily appreciates the present invention's
Technical scheme, but embodiments of the present invention not limited to this.
Comparative example
In the vial equipped with 300mL DCM (dichloromethane), HOAt (11.4mmol), EDCHCL are added
(15.2mmol, 1456.92mg) and DIPEA (22.8mmol), adds palmitic acid (7.6mmol, 1950mg), benzylamine
(7.6mmol, 830 μ L), their mol ratio is 3：6：4：2：Stirring reaction 12h under conditions of 2, with 30 DEG C；Add ionized water
30min is stirred under 100mL, room temperature, is filtered and vacuum drying product；
Performance detection
Mass spectrum：The LCQ DECAXP ion hydrazine mass spectrums of Thermo, m/z 346.2；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (600MHz, CDCl3), δ=2.20 (t, J=
7.65Hz, 2H), δ=1.65 (t, J=7.05Hz, 2H), δ=1.26 (s, br, 24H), δ=0.88 (t, J=6.75Hz, 3H),
δ=4.43 (d, J=7.65Hz, 2H), δ=7.29 (m, 5H), δ=5.73 (s, 1H).
Thus, it is possible to confirm that the macamide that this comparative example is prepared is N- benzyls-palmitoyl amine (N-
Benzyl-hexadecanamide, C23H39NO), its chemical formula is
Detectable concentration is 50.45%, and after purification purity is 61.93%.
Embodiment 1
In the vial equipped with 300mL dichloromethane, addition palmitic acid (1950mg), EDCHCL (1456.92mg),
HOBt·H2O (1030mg) and triethylamine (2633.7 μ L), the mol ratio of each of which is 1：1：1：2.5, then stirred with magnetic force
Mix and stir 20h under device, room temperature.Benzylamine (830 μ L) is subsequently added into afterwards, 4h is reacted at identical conditions, you can synthesized
Whole liquid.After above-mentioned reactant liquor Rotary Evaporators are evaporated to dryness, 10%HCL (100mL) and normal hexane are added immediately
(250mL), dissolved with ultrasonic assistant, normal hexane layer is obtained by extraction；Flushed three times with 10%NaOH (50mL), then with 10%
HCL (50mL) washed once, and finally hexane solution is transferred in 4 DEG C of low temperature environment overnight；Analysed with defecator
The crystallization for going out, gets product after being dried.
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value be Vmax=3306.47 (N-H), 2917.51,2849.64,1638.42
(C=O) (phenyl ring) cm of, 1551.30 (N-C), 1454.83 (N-C=O), 729.10 and 698.72-1；
Mass spectrum：The ESI positive ion mass spectrums of Waters, m/z=346.31；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (400MHz, CDCL3),7.32–7.36(m,2H),
7.26-7.30 (m, 3H), 5.72 (br s, 1H), 4.45 (d, J=6.0Hz, 2H), 2.21 (t, J=7.2Hz, 2H), 1.61-
1.67 (m, 2H), 1.25-1.34 (m, 24H), 0.88 (t, J=6.8Hz, 3H)；13C NMR(CDCl3,100MHz)d 173.21,
138.66,128.92,128.05,127.71,43.80,37.06,32.16,29.92,29.89,29.84,29.73,29.59,
29.56,26.01,22.93,14.36；
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is N- benzyls-palmitoyl amine (N-
Benzyl-hexadecanamide, C23H39NO), its chemical formula is
Detectable concentration is 61.64%, and after purification concentration is 97.63%.
Embodiment 2
In the vial equipped with 50mL dichloromethane, linoleic acid (2363.32 μ L), EDCHCL are added
(1457.41mg), HOBtH2O (1030mg) and triethylamine (2633.7 μ L), the mol ratio of each of which is 1：1：1：2.5,
Then magnetic stirring apparatuss are used, under room temperature 15h is stirred.Benzylamine (830 μ L) is subsequently added into afterwards, and 5h is reacted at identical conditions,
Can obtain synthesizing whole liquid.After above-mentioned reactant liquor Rotary Evaporators are evaporated to dryness, 5% sulphuric acid (50mL) and just is added immediately
Hexane (50mL), is dissolved with ultrasonic assistant, and acetone layer is obtained by extraction；Flushed three times with 10%CaOH (50mL), then with 10%
HCL (50mL) washed once, and finally hexane solution is transferred in -10 DEG C of low temperature environment overnight；Obtained with defecator
The crystallization of precipitation, gets product after being dried.
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value be Vmax=3302.23 (N-H), 2921.31,2850.64,1642.42
(C=O) (phenyl ring) cm of, 1551.68 (N-C), 1452.83 (N-C=O), 720.10 and 695.72-1；
Mass spectrum：The ESI positive ion mass spectrums of Waters, m/z=370.31；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (400MHz, CDCL3),d 7.26–7.36(m,5H),
5.73 (br s, 1H), 5.30-5.40 (m, 4H), 4.44 (d, J=5.6Hz, 2H), 2.77 (t, J=6.4Hz, 2H), 2.21 (t,
J=8.0Hz, 2H), 2.02-2.07 (m, 4H), 1.63-1.67 (m, 2H), 1.26-1.37 (m, 14H), 0.89 (t, J=
6.4Hz,3H)；13C NMR(CDCl3,100MHz)d 173.15,138.64,130.46,130.27,128.94,128.27,
128.13,128.06,127.74,43.82,37.03,31.75,29.82,29.57,29.51,29.48,29.37,27.42,
25.98,25.85,22.81,14.31；
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is that N- benzyls -9 are suitable, 12 cis- linoleic acid acyls
Amine (N-benzyl-9Z, 12Z-octadecadienamide, C25H39NO), its chemical formula is
Detectable concentration is 63.24%, and after purification concentration is 95.13%.
Embodiment 3
In the vial equipped with 50mL dichloromethane, linoleic acid (2363.32 μ L), EDCHCl are added
(1457.41mg), HOBtH2O (103mg) and triethylamine (2634 μ L), the mol ratio of each of which is 1：1：1：2.5, then
10h is stirred with magnetic stirring apparatuss, room temperature.Meta-methoxy benzylamine (984.31 μ L) is subsequently added into afterwards, at identical conditions
Reaction 4h, you can obtain synthesizing whole liquid.After above-mentioned reactant liquor Rotary Evaporators are evaporated to dryness, acetic acid (50mL) is added immediately
With ether (50mL), dissolved with ultrasonic assistant, ether layer is obtained by extraction；Flushed three times with 10%KOH (50mL), then use acetic acid
(50mL) washed once, diethyl ether solution is crossed into silicagel column, with petroleum ether and ethyl acetate silicon (1：1) mixed solution is used as solvent,
Solvent evaporated obtains final product synthetic product.
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value be Vmax=3290.12 (N-H), 2929.24,2850.14,1632.32
(C=O) (phenyl ring) cm of, 1554.48 (N-C), 1464.23 (N-C=O), 776.21 and 695.82-1；
Mass spectrum：The ESI positive ion mass spectrums of Waters, m/z=400.32；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (400MHz, CDCL3)d 7.23–7.27(m,1H),
6.86 (d, J=7.2Hz, 1H), 6.81-6.83 (m, 2H), 5.67 (br s, 1H), 5.29-5.40 (m, 4H), 4.42 (d, J=
5.6Hz, 2H), 3.80 (s, 3H), 2.77 (t, J=6.8Hz, 2H), 2.21 (t, J=7.6Hz, 2H), 2.02-2.07 (m, 4H),
1.61-1.68 (m, 2H), 1.27-1.39 (m, 14H), 0.89 (t, J=6.8Hz, 3H)；13C NMR(CDCl3,100MHz)
d173.10,160.13,140.23,130.46,130.27,129.98,128.28,128.13,120.25,113.62,
113.18,55.46,43.78,37.05,31.75,29.83,29.57,29.52,29.49,29.37,27.42,25.98,
25.85,22.81,14.31；
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is that N- meta-methoxies benzyl -9 is suitable, 12 is cis-
Linoleamide (N- (m-methoxybenzyl) -9Z, 12Z-octadecadienamide, C26H41NO2), its chemical formula is
Detectable concentration is 59.65%, and after purification concentration is 96.21%.
Embodiment 4
In the vial equipped with 50mL dichloromethane, addition linolenic acid (2325 μ L), EDCHCl (1457.41mg),
HOBt·H2O (1030mg) and triethylamine (2634 μ L), the mol ratio of each of which is 1：1：1：2.5, then use magnetic agitation
23h is stirred under device, room temperature.Benzylamine (830 μ L) is subsequently added into afterwards, 3h is reacted at identical conditions, you can obtain synthesis eventually
Liquid.After above-mentioned reactant liquor Rotary Evaporators are evaporated to dryness, malic acid (50mL) and methanol (50mL) are added immediately, with ultrasound
Ripple auxiliary dissolving, is obtained by extraction methanol layer；Flushed three times with ammonia (50mL), then be washed once with malic acid (50mL), finally
Methanol solution is transferred in -20 DEG C of low temperature environment overnight；The crystallization for obtaining separating out with defecator, obtains final product into after being dried
Product.
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value be Vmax=3302.32 (N-H), 2920.14,2849.24,1639.12
(C=O) (phenyl ring) cm of, 1550.78 (N-C), 1453.23 (N-C=O), 720.31 and 696.42-1；
Mass spectrum：The ESI positive ion mass spectrums of Waters, m/z=368.31；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (400MHz, CDCL3)d 7.26–7.35(m,5H),
5.73 (br s, 1H), 5.30-5.41 (m, 6H), 4.44 (d, J=5.2Hz, 2H), 2.80 (t, J=6.4Hz, 4H), 2.21 (t,
J=7.6Hz, 2H), 2.02-2.11 (m, 4H), 1.62-1.67 (m, 2H), 1.30-1.36 (m, 8H), 0.97 (t, J=7.6Hz,
3H)；13C NMR(CDCl3,100MHz)d 173.14,138.64,132.20,130.49,128.94,128.51,128.48,
128.06,127.95,127.74,127.34,43.82,37.03,29.80,29.51,29.47,29.36,27.43,25.98,
25.85,25.75,20.78,14.51；
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is that N- benzyls -9 are suitable, 12 is suitable, 15 cis- Caulis et Folium Lini
Sour amide (N-benzyl-9Z, 12Z, 15Z-octadecatrienamide, C25H37NO),
Detectable concentration 63.51%, after purification concentration is 95.71%.
Embodiment 5
In the vial equipped with 50mL dichloromethane, addition linolenic acid (232.5 μ L), EDCHCL (145.7mg),
HOBt·H2O (103mg) and triethylamine (263.4 μ L), the mol ratio of each of which is 1：1：1：2.5, then use magnetic agitation
20h is stirred under device, room temperature.Meta-methoxy benzylamine (98.4 μ L) is subsequently added into afterwards, is reacted at identical conditions, you can obtain
The whole liquid of synthesis.After above-mentioned reactant liquor Rotary Evaporators are evaporated to dryness, citric acid (50mL) and acetonitrile (50mL) are added immediately,
Dissolved with ultrasonic assistant, acetonitrile layer is obtained by extraction；Flushed three times with sodium bicarbonate (50mL), then with citric acid 50mL) wash
Once, acetonitrile solution is crossed into silicagel column, with petroleum ether and ethyl acetate silicon (1：1) used as solvent, solvent evaporated is mixed solution
Obtain synthetic product.
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value be Vmax=3302.12 (N-H), 2920.24,2849.74,1639.21
(C=O) (phenyl ring) cm of, 1551.23 (N-C), 1453.41 (N-C=O), 776.11 and 696.22-1；
Mass spectrum：The ESI positive ion mass spectrums of Waters, m/z=398.36；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (400MHz, CDCL3)d 7.23–7.27(m,1H),
6.86 (d, J=7.2Hz, 1H), 6.81-6.83 (m, 2H), 5.67 (br s, 1H), 5.29-5.41 (m, 6H), 4.42 (d, J=
6.0Hz, 2H), 3.80 (s, 3H), 2.80 (t, J=6.8Hz, 4H), 2.21 (t, J=7.6Hz, 2H), 2.02-2.10 (m, 4H),
1.61-1.68 (m, 2H), 1.30-1.36 (m, 8H), 0.97 (t, J=7.6Hz, 3H)；13C NMR(CDCl3,100MHz)
d173.10,160.13,140.22,132.21,130.50,129.98,128.52,128.48,127.96,127.34,
120.26,113.63,113.18,55.46,43.78,37.05,29.81,29.52,29.48,29.36,27.43,25.98,
25.85,25.75,20.78,14.51；
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is that N- meta-methoxies benzyl -9 is suitable, 12 is suitable, 15
Cis- linolenamide (N- (m-methoxybenzyl) -9Z, 12Z, 15Z-octadecatrienamide, C26H39NO2), its
Chemical formula is
Detectable concentration 60.75%, after purification concentration is 95.92%.
Claims (8)
1. a kind of preparation method of macamide, comprises the following steps：
1) fatty acid, EDCHCl, HOBTH are added in dichloromethane solution2O and triethylamine are mixed, and stirring 10~24 is little
When；
2) reactant liquor is stated then up and adds benzylamine or alpha substituted benzylamine, react 2~10 hours；
3) reactant liquor of above-mentioned synthesis is evaporated, and purification.
2. macamide preparation method according to claim 1, it is characterised in that the macamide chemical structure of general formula
For：
3. macamide preparation method according to claim 1, it is characterised in that the fatty acid difference of the preparing raw material
For：Palmitic acid, stearic acid, linoleic acid, linolenic acid, 5 oxygen -6E, 8E- octadecadienoic acids.
4. the preparation method of macamide according to claim 1, it is characterised in that react in the step one and step 2
Solution, benzylamine or alpha substituted benzylamine, fatty acid, EDCHCl, HOBTH2The mol ratio of O and triethylamine is (1-10)：(1-
10)：(1-10)：(1-10)：(1-10).
5. macamide preparation method according to claim 1, it is characterised in that the alpha substituted benzylamine be gumbix or
M-anisidine.
6. the preparation method of macamide according to claim 5, it is characterised in that react in the step one and step 2
Solution, gumbix, fatty acid, EDCHCl, HOBTH2The mol ratio of O and triethylamine is 1：1：1：1：2.5.
7. the preparation method of macamide according to claim 1, it is characterised in that be the step of the purification：
1) acid solution and organic solvent are added, after ultrasonic wave added dissolving, organic layer is taken；
2) by organic layer aqueous slkali fully shaking, reaction is complete；
3) add acid solution to be washed, and take organic layer solution low temperature crystallization or silica gel crosses post.
8. the preparation method of macamide according to claim 7, it is characterised in that the low temperature crystallization temperature is -30
DEG C -10 DEG C.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107353219A (en) * | 2017-07-25 | 2017-11-17 | 四川省农业科学院农产品加工研究所 | A kind of macamide compound and its synthetic method, application |
| CN110722857A (en) * | 2019-10-31 | 2020-01-24 | 浙江比例聚合科技股份有限公司 | PE vacuum aluminized composite film and preparation method thereof |
| CN113893809A (en) * | 2021-10-14 | 2022-01-07 | 丽江英煌集生物工程有限公司 | Device and method for synthesizing and purifying macamide |
| CN115233225A (en) * | 2022-07-25 | 2022-10-25 | 威海翔宇环保科技股份有限公司 | Amphoteric environment-friendly high-temperature corrosion inhibitor and preparation method thereof |
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| CN104513171A (en) * | 2013-09-30 | 2015-04-15 | 中国科学院过程工程研究所 | Synthetic method and application of MACAmide |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107353219A (en) * | 2017-07-25 | 2017-11-17 | 四川省农业科学院农产品加工研究所 | A kind of macamide compound and its synthetic method, application |
| CN110722857A (en) * | 2019-10-31 | 2020-01-24 | 浙江比例聚合科技股份有限公司 | PE vacuum aluminized composite film and preparation method thereof |
| CN113893809A (en) * | 2021-10-14 | 2022-01-07 | 丽江英煌集生物工程有限公司 | Device and method for synthesizing and purifying macamide |
| CN115233225A (en) * | 2022-07-25 | 2022-10-25 | 威海翔宇环保科技股份有限公司 | Amphoteric environment-friendly high-temperature corrosion inhibitor and preparation method thereof |
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Application publication date: 20170517 |