CN104513171B - A kind of preparation method and use of macamide - Google Patents
A kind of preparation method and use of macamide Download PDFInfo
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- CN104513171B CN104513171B CN201310462602.4A CN201310462602A CN104513171B CN 104513171 B CN104513171 B CN 104513171B CN 201310462602 A CN201310462602 A CN 201310462602A CN 104513171 B CN104513171 B CN 104513171B
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Abstract
The present invention relates to a kind of synthetic method of macamide, methods described is：With aliphatic acid, and benzylamine or meta-methoxy benzylamine are reaction raw materials, are mixed in the dichloromethane solution for be dissolved with HOAt, EDCHCl and DIPEA, and stirring is reacted, and then washes reaction product, water-insoluble is drying to obtain into macamide.The method of synthesis macamide of the present invention, step is simple, and raw material is easy to get, and operating condition is easily-controllable, and product need not purify purity i.e. up to more than 95%；Macamide is combined to for industry to provide the foundation；In addition, the macamide that the present invention is synthesized has the effect for improving male fecundity and treatment male sexual disfunction, market prospects are provided for the application of macamide.
Description
Technical field
The invention belongs to field of biological pharmacy, it is related to a kind of preparation method and use of macamide, more particularly to one
The purposes for the macamide that kind is prepared without the synthetic method of the macamide of purification step and by this method.
Background technology
Maca（Lepidium meyenii Walp.）For Cruciferae Lepidium annual herb plant, South America is originated in
Continent 3500~4500m of height above sea level Andes.China started to introduce a fine variety plantation in Lijiang, yunnan in 2002, had become at present
Global maximum maca planting base.Maca has abundant nutritive value and medical value.Research shows that maca has raising
People and animals' fecundity, the sexual function that improves, the prostatitis hylperadenosis that suppresses, antifatigue, antidepression, improvement sclerotin are loose, raising memory
Deng effect.
Macamide（Macamides）For benzylamine（Or methoxybenzylamine）Combined with aliphatic acid by amido link, at present
A series of compounds only found in maca, its basic structure isWherein R is H bases
Or methoxyl group, R ' is saturation or undersaturated linear paraffin, or the saturation containing ketone group or undersaturated linear paraffin.
Maca growing environment requires harsh, yields poorly, the content of macamide is extremely low in maca（＜ 0.2%）, and in maca
Complicated components so that using maca as raw material, bio-chemistry separation prepares the method for macamide because isolating and purifying difficulty, raw material sources
Limitation, it is impossible to which extensive preparation etc. is restricted.Therefore, macamide is obtained by chemical synthesis mode, solves its raw material
Scarcity of resources, purification step waste of solvent, the low problem of utilization rate of maca raw material.
In the prior art, have been reported that with benzylamine and palmitoyl chloride synthesis macamide, but due to fatty acid chloride raw material
Limitation, it is impossible to synthesize a variety of macamides；Have been reported that with benzylamine or methoxybenzylamine and aliphatic acid in dicyclohexylcarbodiimide
The purity that macamide in macamide, but its product is synthesized under startup pyrollidinopyridine catalytic action is low.
Therefore, urgently to develop a kind of synthesis step few for this area, and reaction condition is simple, and no raw material limitation, product purity is high
Macamide synthetic method.
The content of the invention
An object of the present invention is to provide a kind of synthesis step few, and reaction condition is simple, and no raw material limitation, product is pure
The synthetic method of the high macamide of degree.
The present invention is achieved through the following technical solutions：
A kind of synthetic method of macamide, it is characterised in that methods described is：
With aliphatic acid, and benzylamine or meta-methoxy benzylamine are reaction raw materials, are being dissolved with HOAt（1- hydroxyls -7- is even
Nitrogen BTA）、EDC·HCl（1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate）And DIPEA（N,
N'- diisopropylethylamine）Dichloromethane solution in mix, stirring reacted, then reaction product is washed, water is insoluble
Thing is drying to obtain macamide.
The reaction that the present invention is provided can just synthesize macamide by a step, and reaction raw materials are easily obtained, and react it
Accessory substance afterwards is water solubility, therefore without complicated purge process, after washing, it is higher that water-insoluble drying can obtain purity
Macamide.The purity for the macamide that the method for the invention is prepared is more than 95%.
In reaction solution of the present invention, HOAt, EDCHCl, DIPEA, benzylamine or methoxybenzylamine, and aliphatic acid
Mol ratio is（1~10）:（1~10）:（1~10）:（1~10）:1, it is typical but non-limiting to have 2:3:2:1:1、1:2:3:
4:1、5:6:8:9:1、3:7:9:10:1、1:5:3:8:1 etc.；It is preferred that（1~3）：（1~4）:（1~4）:（1~3）:1, further
It is preferred that 3:4:6:2:2.
In the reaction solution, reaction raw materials quality compares m with methylene chloride volume:V is（0.5~50）:100, for example:0.7:
100、1.3:100、2.3:100、4.8:100、9:100、16:100、31:100、38:100、45:100、49:100, preferably（10
~20）:100, further preferably 15:100.
Aliphatic acid of the present invention is the saturated or undersaturated aliphatic acid of straight chain, preferably is selected from palmitic acid, stearic acid, oil
Acid, linoleic acid, leukotrienes, 5 oxygen -6 are anti-, any a kind or at least two kinds of of combination in 8 trans- octadecadienoic acids, the combination
Such as palmitic acid and linolenic combination, 5 oxygen -6 are anti-, 8 trans- octadecadienoic acids and stearic combination, oleic acid and leukotrienes
Combination, the combination of oleic acid, linoleic acid and palmitic acid, and combination, stearic acid, oleic acid, the combination of linoleic acid plus linolenic acid are soft
Resin acid, stearic acid, oleic acid and 5 oxygen -6 are anti-, combination of 8 trans- octadecadienoic acids etc..
The temperature of reaction of the present invention be 10~40 DEG C, such as 13 DEG C, 18 DEG C, 24 DEG C, 26 DEG C, 30 DEG C, 33 DEG C, 36
DEG C, 39 DEG C etc., preferably 15~35 DEG C, most preferably more preferably 20~30 DEG C, 30 DEG C.
The solvent of the present invention that reacted into reaction solution of stirring is volatilized, and is preferably stirred the time reacted and is
0.5~20h, such as 0.5h, 1h, 7h, 10h, 12h, 16h, 19h, further preferred 6~12h, particularly preferred 12h.
The mode of drying of the present invention is selected from drying, air-dried or nitrogen and blown.
In the building-up process of the present invention, when aliphatic acid is palmitic acid, obtained macamide is the phosphinylidyne of N- benzyls-ten six
Amine（N-benzyl-hexadecanamide）, concrete structure is
Its molecular formula is C23H39NO；
When aliphatic acid is stearic acid, obtained macamide is the phosphoamide of N- benzyls-ten eight（N-benzyl-
octadecanamide）, concrete structure isIts molecule
Formula is C25H43NO；
When aliphatic acid is oleic acid, obtained macamide is the cis-oleic acid acid amides of N- benzyls -9（N-benzyl-9Z-
octadecenamide）, concrete structure isIts point
Minor is C25H41NO；
When aliphatic acid is linoleic acid, obtained macamide is that N- benzyls -9 are suitable, 12 cis- linoleamides（N-benzyl-
9Z,12Z-octadecadienamide）, concrete structure is
Its molecular formula is C25H39NO；
When aliphatic acid is leukotrienes, obtained macamide is that N- benzyls -9 are suitable, and 12 is suitable, 15 cis- leukotrienes acid amides（N-benzyl-
9Z,12Z,15Z-octadecatrienamide）, concrete structure is
Its molecular formula is C25H37NO；
When aliphatic acid is that 5 oxygen -6 are anti-, during 8 trans- octadecadienoic acid, obtained macamide is that the oxygen -6 of N- benzyls -5 is anti-, 8
Trans- octadecadienoic acid acid amides（N-benzyl-5-oxo-6E,8E-octadecadienamide）, concrete structure isIts molecular formula is C25H37NO2。
When aliphatic acid is linoleic acid, when being reacted with meta-methoxy benzylamine, obtained macamide is methoxybenzyl -9 between N-
It is suitable, 12 cis- linoleamides（N-(m-methoxybenzyl)-9Z,12Z-octadecadienamide）, concrete structure isIts molecular formula is C26H41NO2；
When aliphatic acid is leukotrienes, when being reacted with meta-methoxy benzylamine, obtained macamide is methoxybenzyl -9 between N-
Suitable, 12 is suitable, 15 cis- leukotrienes acid amides（N- (m-methoxybenzyl) -9Z, 12Z, 15Z-octadecadienamide）, tool
Body structure isIts molecular formula is C26H39NO2；
The second object of the present invention is to provide the macamide that a kind of synthetic method as described in the first purpose is prepared
Purposes, it is characterised in that the macamide is used to improve male fecundity, or for treating male sexual disfunction.
Typical case but without limitation, the synthetic method of macamide of the present invention comprises the following steps：
0.075mol HOAt, 0.1mol EDCHCl, 0.15mol DIPEA are added in 150mL dichloromethane and stirred
Uniformly, 0.05mol aliphatic acid is added, 0.05mol benzylamine is added, 40 DEG C of stirring reaction liquid are reacted, and 20h reaction solutions are molten
Agent swings, and add water washed product, is dried in vacuo water-insoluble after filtering, produces macamide；
Or, 0.02mol HOAt, 0.02mol EDCHCl, 0.03mol DIPEA are added in 30mL dichloromethane
Stir, add 0.01mol aliphatic acid, add 0.01mol meta-methoxy benzylamines, stirred overnight reaction solution is carried out at room temperature
Reaction, reaction solution solvent swings, and add water washed product, chloroform extraction water-insoluble, and nitrogen is blown to extract layer volume and no longer subtracted
It is few, produce macamide.
Compared with prior art, the present invention has the advantages that：
The method of synthesis macamide of the present invention, step is simple, and raw material is easy to get, and operating condition is easily-controllable, and product need not
Purity is purified i.e. up to more than 95%；Macamide is combined to for industry to provide the foundation；In addition, the maca acyl that the present invention is synthesized
Amine has the effect for improving male fecundity and treatment male sexual disfunction, is provided for the application of macamide before market
Scape.
Embodiment
For the present invention is better described, technical scheme is readily appreciated, of the invention is typical but non-limiting
Embodiment is as follows：
Embodiment 1
A kind of method of the phosphoamide of one-step synthesis method macamide --- N- benzyls-ten six：
0.01mol HOAt, 0.01mol EDCHCl and 0.01mol DIPEA are weighed respectively in 7.3mL DCM（Dichloro
Methane）In, 0.01mol benzylamines are added, 0.01mol palmitic acid, reaction raw materials are 50% with DCM ratios（w/v）, in 10 DEG C of conditions
Lower stirred overnight；Deionized water 50mL is added, 30min is stirred at room temperature, product is filtered and be dried in vacuo and to obtain；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value is Vmax=3303 (N-H), 2917,2849,1639 (C=O), 1549（N-
C）, 1454 (N-C=O), 730 and 696（Phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z346.2；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (600MHz, CDCl3), δ=2.20 (t, J=7.65Hz,
2H, H=2), δ=1.65 (t, J=7.05Hz, 2H, H=3), δ=1.26 (s, br, 24H, H=4-15), δ=0.88 (t, J=6.75Hz,
3H, H=16), δ=4.435 (d, J=7.65Hz, 2H, H=1`), δ=7.29 (m, 5H, H=3`-7`), δ=5.73 (s, 1H, N-H).
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is the phosphoamide of N- benzyls-ten six, its structural formula is such as
Shown in lower：
The phosphoamide of N- benzyls-ten six（N-benzyl-hexadecanamide, C23H39NO）.
Embodiment 2
A kind of method of the phosphoamide of one-step method chemical synthesis macamide --- N- benzyls-ten eight：
0.1mol HOAt, 0.1mol EDCHCl and 0.1mol DIPEA are weighed respectively in 2730mL DCM, then are added
Enter 0.1mol benzylamines, 0.01mol stearic acid, reaction raw materials are 0.5% with DCM ratios（w/v）It is stirred overnight, revolves under the conditions of 40 DEG C
Solvent evaporated；Deionized water 200mL is added, 30min is stirred at room temperature, product is filtered and be dried in vacuo and to obtain；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, peak value is Vmax=3306（N-H）, 2918,2849,1639（C=O）, 1552（N-
C）, 1455（N-C=O）, 1428,743,730 and 699（Phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z374.3；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (600MHz, CDCl3), δ=2.20 (t, J=7.65Hz,
2H, H=2), δ=1.65 (t, J=7.05Hz, 2H, H=3), δ=1.29 (s, br, 24H, H=4-17), δ=0.88 (t, J=6.75Hz,
3H, H=18), δ=4.44 (d, J=7.65Hz, 2H, H=1`), δ=7.29 (m, 5H, H=3`-7`), δ=5.723 (s, 1H, N-H).
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is the phosphoamide of N- benzyls-ten eight, its structural formula is such as
Shown in lower：
The phosphoamide of N- benzyls-ten eight（N-benzyl-octadecanamide, C25H43NO）.
Embodiment 3
A kind of method of the cis-oleic acid acid amides of one-step method chemical synthesis macamide --- N- benzyls -9：
0.015mol HOAt, 0.02mol EDCHCl and 0.03mol DIPEA are weighed respectively in 30mLDCM, then are added
Enter 0.01mol benzylamines, 0.01mol oleic acid stirs 12h under the conditions of 30 DEG C；Deionized water 50mL is added, is stirred at room temperature
30min, filters and is dried in vacuo and to obtain product；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, Vmax=3299（N-H）, 3002（C=C-H）, 2919,2849,1640（C=O）,
1554（N-C）, 1463.98（N-C=O）, 725 and 696（Phenyl ring）；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z372.3；
Nuclear-magnetism：In Bruker AVANCE III600 nuclear magnetic resonance spectrometers1H composes (600MHz, CDCl3), δ=2.21 (t, J=7,65Hz,
2H, H=2), δ=1.66 (m, J=6,45Hz, 2H, H=3), δ=1.28 (s, br, 8H, H=4-7), δ=2.047 (m, J=3,90Hz,
4H, H=8,11), δ=5.34 (m, J=2,00Hz, 2H, H=9,10), δ=1.30 (s, br, 12H, H=12-17), δ=0.879 (t, J=
6,60Hz, 3H, H=18), δ=4,13 (q, J=7,10Hz, 2H, H=1`), δ=7,319 (m, 5H, H=3`-7`), δ=5,65 (s, 1H,
N-H)。
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is N- benzyls-oleamide, its structural formula is as follows
It is shown：
N- benzyls-oleamide（N-benzyl-9Z-octadecenamide, C25H41NO）.
Embodiment 4
A kind of one-step method chemical synthesis macamide --- N- benzyls -9 are suitable, the method for 12 cis- linoleamides：
0.015mol HOAt, 0.02mol EDCHCl and 0.03mol DIPEA are weighed respectively in 30mLDCM, then are added
Enter 0.01mol benzylamines, 0.01mol linoleic acid, the stirred overnight under the conditions of 25 DEG C；Deionized water 50mL is added, is stirred at room temperature
30min, filters and is dried in vacuo and to obtain product；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, Vmax=3302（N-H）, 3064,3007（C=C-H）, 2920,2850,1642（C=
O）, 1552（N-C）, 1453（N-C=O）, 1417,720 and 696（Phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z370.3；
Nuclear-magnetism：1H composes (600MHz, CDCl in Bruker AVANCE III600 nuclear magnetic resonance spectrometers3), δ=2.20 (t, 2H, 2), δ=
1.66 (s, 3H, 3), δ=1.32 (m, 14H, 4-7,15-17), δ=2.04 (m, 4H, 8,14), δ=5.35 (m, 4H, 9,10,12,
13), δ=2.77 (t, J=6.8Hz, 2H, 11), δ=0.89 (t, J=7.0Hz, 3H, 18), δ=4.44 (d, J=5.7Hz, 2H, 1 '), δ
=7.30 (m, 5H, H=3`-7`), δ=5.72 (s, 1H, N-H).
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is suitable for N- benzyls -9,12 cis- linoleamides,
Its structural formula is as follows：
N- benzyls -9 are suitable, and 12 cis- linoleamides, its structural formula is as follows：
N- benzyls -9 are suitable, 12 cis- linoleamides（N-benzyl-9Z, 12Z-octadecadienamide,
C25H39NO）.
Embodiment 5
A kind of one-step method chemical synthesis macamide --- methoxybenzyl -9 is suitable between N-, the method for 12 cis- linoleamides：
0.02mol HOAt, 0.02mol EDCHCl and 0.02mol DIPEA are weighed respectively in 30mL DCM, then are added
Enter 0.01mol benzylamines, 0.01mol linoleic acid stirs 30min under the conditions of 40 DEG C, revolves solvent evaporated；Add deionized water
50mL, stirs 30min at room temperature, volatilizes DCM, adds chloroform extraction, and extract layer nitrogen is blown to volume and no longer reduces to obtain product；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, Vmax=3290（N-H）, 3064,3006（C=C-H）, 2929,2850,1632（C=
O）, 1554（N-C）, 1464（N-C=O）, 776,696（Methoxyl group phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z400.3；
Nuclear-magnetism：1H composes (600MHz, CDCl in Bruker AVANCE III600 nuclear magnetic resonance spectrometers3), δ=2.20 (t, 2H, 2), δ=
1.66 (s, 3H, 3), δ=1.32 (m, 14H, 4-7,15-17), δ=2.04 (m, 4H, 8,14), δ=5.35 (m, 4H, 9,10,12,
13), δ=2.77 (t, J=6.8Hz, 2H, 11), δ=0.89 (t, J=7.0Hz, 3H, 18), δ=4.44 (d, J=5.7Hz, 2H, 1 '), δ
=7.01 (m, 3H, H=3 ', 5 ', 7 '), δ=7.20（s,1H,6’）, δ=3.82 (t, 3H, OMe), δ=5.72 (s, 1H, N-H).
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is suitable for methoxybenzyl -9 between N-, 12 cis- linoleic acid
Acid amides, its structural formula is as follows：
Methoxybenzyl -9 is suitable between N-,
12 cis- linoleamides（N- (m-methoxybenzyl) -9Z, 12Z-octadecadienamide, C26H41NO2）.
Embodiment 6
A kind of one-step method chemical synthesis macamide --- N- benzyls -9 are suitable, and 12 is suitable, the method for 15 cis- leukotrienes acid amides：
0.02mol HOAt, 0.02mol EDCHCl and 0.02mol DIPEA are weighed respectively in 30mL DCM, then are added
Enter 0.01mol benzylamines, 0.01mol leukotrienes, the 20h stirrings under the conditions of 15 DEG C；Deionized water 50mL is added, is stirred at room temperature
30min, filtration product is in being dried in vacuo to obtain product；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, Vmax=3302（N-H）, 3064,3006（C=C-H）, 2920,2849,2850,
1639（C=O）, 1551（N-C）, 1453（N-C=O）, 1417,720 and 696（Phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z368.3；
Nuclear-magnetism：1H composes (600MHz, CDCl in Bruker AVANCE III600 nuclear magnetic resonance spectrometers3), δ=7.20（s,1H,6’）, δ
=7.01 (m, 3H, H=3 ', 5 ', 7 '), δ=3.82 (t, 3H, OMe), δ=5.76 (s, 1H, N-H), δ=5.35 (m, 4H, 9,10,12,
13,15,16), δ=4.443 (d, J=5.7Hz, 2H, 1 '), δ=2.778 (t, J=6.8Hz, 2H, 11,14), δ=2.20 (t, 2H,
2), δ=2.04 (m, 4H, 8,14), δ=1.64 (m, 3H, 3), δ=1.31 (m, 14H, 4-7), δ=0.97 (t, J=7.5HZ, 3H, H=
18)。
Thus, it is possible to confirm that the macamide that the present embodiment is prepared is suitable for N- benzyls -9,12 is suitable, 15 cis- leukotrienes
Acid amides, its structural formula is as follows：
N- benzyls -9 are suitable, and 12 is suitable, 15 cis- Asias
Numb acid acid amides（N-benzyl-9Z, 12Z, 15Z-octadecatrienamide, C25H37NO）.
Embodiment 7
A kind of one-step method chemical synthesis macamide --- methoxybenzyl -9 is suitable between N-, and 12 is suitable, 15 cis- leukotrienes acid amides
Method：
0.02mol HOAt, 0.02mol EDCHCl and 0.02mol DIPEA are weighed respectively in 30mL DCM, then are added
Enter 0.01mol meta-methoxy benzylamines, 0.01mol leukotrienes, at room temperature stirred overnight；Deionized water 50mL is added, at room temperature
30min is stirred, chloroform extraction is added, extract layer nitrogen is blown to volume and no longer reduces to obtain product；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, Vmax=3302（N-H）, 3064,3006（C=C-H）, 2920,2849,2850,
1639（C=O）, 1551（N-C）, 1453（N-C=O）, 1417,776 and 696（Methoxyl group phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z398.3；
Nuclear-magnetism：1H composes (600MHz, CDCl in Bruker AVANCE III600 nuclear magnetic resonance spectrometers3), δ=7.21（s,1H,6’）, δ
=7.01 (m, 3H, H=3 ', 5 ', 7 '), δ=3.82 (t, 3H, OMe), δ=5.76 (s, 1H, N-H), δ=5.35 (m, 4H, 9,10,12,
13,15,16), δ=4.443 (d, J=5.7Hz, 2H, 1 '), δ=2.778 (t, J=6.8Hz, 2H, 11,14), δ=2.20 (t, 2H,
2), δ=2.04 (m, 4H, 8,14), δ=1.64 (m, 3H, 3), δ=1.31 (m, 14H, 4-7), δ=0.97 (t, J=7.5HZ, 3H, H=
18)。
Thus, it is possible to confirm that methoxybenzyl -9 is suitable between the N- that the present embodiment is prepared, 12 is suitable, 15 cis- leukotrienes acid amides,
Its structural formula is as follows：
Methoxybenzyl -9 is suitable between N-,
12 is suitable, 15 cis- leukotrienes acid amides（N- (m-methoxybenzyl) -9Z, 12Z, 15Z-octadecatrienamide,
C26H39NO2）.
Embodiment 8
A kind of oxygen -6 of one-step method chemical synthesis macamide --- N- benzyls -5 is anti-, the side of 8 trans- octadecadienoic acid acid amides
Method：
0.02mol HOAt, 0.02mol EDCHCl and 0.02mol DIPEA are weighed respectively in 30mL DCM, then are added
Enter 0.01 meta-methoxy benzylamine, the oxygen -6 of 0.01mol N- benzyls -5 is anti-, 8 trans- octadecadienoic acids, at room temperature stirred overnight；
Deionized water 50mL is added, 30min is stirred at room temperature, chloroform extraction is added, extract layer nitrogen is blown to volume and no longer reduced
Product；
Performance test：
It is infrared：FT/IR-660 radar stealthy materials, Vmax=3311（N-H）, 2928,2845,1639（C=O）, 1545（N-C）, 1239
（N-C=O）, 1000,731 and 697（Phenyl ring）cm-1；
Mass spectrum：Thermo LCQ DECAXP ion hydrazine mass spectrums, m/z384.3；
Nuclear-magnetism：1H composes (600MHz, CDCl in Bruker AVANCE III600 nuclear magnetic resonance spectrometers3), δ=7.26 (m, 3H, H=3 '-
7 '), δ=7.09 (ddd, J=3.0,9.7,15.4Hz.1H, 7), δ=6.13 (m, 2H, 8,9), δ=6.04 (d, J=15.4Hz, 1H,
6), δ=5.76 (s, 1H, N-H), δ=4.41 (d, J=5.6Hz, 2H, 1 '), δ=1.29 (m, 12H, 11-16), δ=1.24 (m, 2H,
17), δ=2.13 (m, 2H, 10), δ=2.17 (m, 2H, 2), δ=1.61 (m, 3H, 3), δ=2.50 (t, J=7.3Hz, 2H, 4), δ=
0.87(t,J=7.0Hz,3H,H=18)。
Thus, it is possible to confirm that the oxygen -6 of N- benzyls -5 that the present embodiment is prepared is anti-, 8 trans- octadecadienoic acid acid amides, its
Structural formula is as follows：
The oxygen -6 of N- benzyls -5 is anti-, 8 trans- 18 carbon
Dienoic acid acid amides（N-benzyl-5-oxo-6E, 8E-octadecadienamide, C25H37NO2）.
Influence of the macamide of application example 1 to Kunming mouse antifatigue effect
Five week old Kunming mouses are selected, 10 groups, respectively every group 9, control group are randomly divided into（Physiological saline）, it is each to implement
The macamide group that example is prepared（Macamide concentration is 2.0mg/10mL）, and macamide mixture group（Mixture is dense
Spend for 2.0mg/10mL）, the macamide mixture is that 15%N- benzyls -9 are suitable, 12 cis- linoleamide and 85%N- benzyls -
9 is suitable, and 12 is suitable, the mixture of 15 cis- leukotrienes acid amides；
Daily to every group of Kunming mouse gavage 1 time, gavage volume is 10mL/kg body weight（I.e. given low is
2.0mg/kg）, mouse after last time gavage 1h, is placed in depth of water 40cm, the big basin that 25 DEG C of water temperature by each group successive administration 7 days
In, the 10% of afterbody heavy burden own wt, record mouse from swimming to the time that the water surface is no longer swum out of in sinking 10s（X±
SEM）（n=9）；It the results are shown in Table 1：
Influence of the macamide of table 1 to kunming mice swimming time
Note：Compared with blank control group, * P<0.05, * * P<0.01.
Test result indicates that the macamide that the present invention is synthesized can be obviously prolonged the mice burden swimming time, with anti-tired
Work is used.
Influence of the macamide of application example 2 to rat mating ability
Choose male SD rat and carry out castration postoperative recovery 5 days, be randomly divided into 10 groups, respectively every group 6, blank pair
According to group（Physiological saline）, the macamide group that each embodiment is prepared（Macamide concentration is 2.0mg/10mL）, and maca
Amide blend group（Mixture concentration is 2.0mg/10mL）, the macamide is that 15%N- benzyls -9 are suitable, 12 cis- linoleic acid
Acid amides and 85%N- benzyls -9 are suitable, and 12 is suitable, the mixture of 15 cis- leukotrienes acid amides；
Daily to every group of SD rats gavage 1 time, gavage volume is 10mL/kg body weight（I.e. given low is 2.0mg/
kg）, continuous gavage 21 days freely takes food and drinks water；30min is by every 1 male rat and 2 virgin's females after 21st day gavage
Rat is placed in number of copulations in a cage, observation 3h（X±SEM）（n=6）.It the results are shown in Table 2：
Influence of the macamide of table 2 to male rat mating ability
Note：Compared with blank control group, * P<0.05, * * P<0.01.
Test result indicates that synthesis macamide can significantly improve male rat mating ability.
The influence that SD rat spermatozoas occur the macamide of application example 3
Three monthly age SD rats are chosen, 10 groups, respectively every group 6, control group are randomly divided into（Physiological saline）, each embodiment
The macamide group prepared（Macamide concentration is 2.0mg/10mL）, and macamide mixture group（Mixture concentration
For 2.0mg/10mL）, the macamide is that 15%N- benzyls -9 are suitable, and 12 cis- linoleamide and 85%N- benzyls -9 are suitable, 12
It is suitable, the mixture of 15 cis- leukotrienes acid amides；
Daily to every group of SD rats gavage 1 time, gavage volume is 10mL/kg body weight（I.e. given low is 2.0mg/
kg）, each group continuous gavage 7 days freely taken food and drinks water, and 24h ether is put to death after last gavage, and sperm production in its day is determined respectively
Amount, epididymal sperm number（X±SEM）（n=6）, the results are shown in Table 3：
Table 3：The influence that SD rat spermatozoas occur macamide
Note：Compared with blank control group, * P<0.05, * * P<0.01.
Test result indicates that synthesis macamide substantially increases SD rats day sperm production and epididymal sperm number, but to sperm
Dynamic role does not make significant difference.
Clinical observation on the therapeutic effect of the macamide of Application Example 4 to sex dysfunction patient
Prepared clinical test is carried out to 36 sex dysfunctions and volunteer to examine synthesis macamide to face
Bed effect.Subject's average age is 40 ± 5.9 years old, is 4.6 months during morbidity.Volunteer is randomly divided into two groups, A groups
（Give macamide smart piece, 10mg/ containing macamide, 2 tablets/time, one time a day）, B groups（Give chinkuei shin chewan pills, 20
（4g）/ time, 2 times a day）, each oral 1 month.Subject presses international index of erectile function grade form -5 before and after medication（IIEF-
5）Evaluation ED light and heavy degrees fill in sexual function questionnaire respectively, are randomly divided into 2 groups each 18, two groups of state of an illness weights are classified degree ratio
Compared with without significant difference（P>0.05）., 12 cis- linoleamides and 85% suitable containing 15%N- benzyls -9 in the smart piece of the macamide
N- benzyls -9 are suitable, and 12 is suitable, 15 cis- leukotrienes acid amides.The chinkuei shin chewan pills is the pharmacy of Beijing Tongrentang.Observation of curative effect result is shown in
Table 4：
Table 4：Clinical observation on the therapeutic effect of the macamide to sex dysfunction patient
Note：International index of erectile function grade form -5（IIEF-5）With reference to Liu Zhaoxu, model cures the diagnosis of east sex dysfunctions
With treatment [M] Jinan:Shandong Science Press, 2002.387.
Experimental group total effective rate is 94%, and control group total effective rate is 77%, and two groups of total effective rates compare, and difference has conspicuousness
Meaning（P<0.05）, experimental group is better than control group, and macamide has significant curative effect to sex dysfunction patient.
Clinical observation on the therapeutic effect of the macamide of Application Example 5 to sex dysfunction patient
The macamide synthesized according to embodiment 1-8, is mixed and obtains macamide mixture, and sex dysfunction is suffered from
Person carries out clinical observation on the therapeutic effect
Prepared clinical test is carried out to 36 sex dysfunctions and volunteer to examine synthesis macamide to face
Bed effect.Subject's average age is 40 ± 5.9 years old, is 5 months during morbidity.Volunteer is randomly divided into two groups, A groups（Give
Give the smart piece of macamide, 10mg/ containing macamide, 2 tablets/time, 1 times/day）, B groups（Give chinkuei shin chewan pills, 20（4g）/
It is secondary, 2 times/day）, each oral 1 month.Subject presses international index of erectile function grade form -5 before and after medication（IIEF-5）Evaluation
ED light and heavy degrees fill in sexual function questionnaire respectively, are randomly divided into 2 groups each 18, two groups of state of an illness weight classification degree compare without aobvious
Write difference（P>0.05）.The macamide prepared in the smart piece of the macamide containing the embodiment of the present invention 1~8, and 8 kinds
The mass ratio of macamide is：Embodiment 1:Embodiment 2:Embodiment 3:Embodiment 4:Embodiment 5:Embodiment 6:Embodiment 7:It is real
It is 1 to apply example 8:1:2:2:2:3:3:1.The B groups chinkuei shin chewan pills is the pharmacy of Beijing Tongrentang.Observation of curative effect the results are shown in Table 5：
Table 5：Clinical observation on the therapeutic effect of the macamide to sex dysfunction patient
Note：International index of erectile function grade form -5（IIEF-5）With reference to Liu Zhaoxu, model cures the diagnosis of east sex dysfunctions
With treatment [M] Jinan:Shandong Science Press, 2002.387.
Experimental group total effective rate is 94%, and control group total effective rate is 77%, and two groups of total effective rates compare, and difference has conspicuousness
Meaning（P<0.05）, experimental group is better than control group, and macamide has significant curative effect to sex dysfunction patient.
The macamide that the present invention is synthesized it can be seen from 1~5 by application implementation for it is antifatigue, improve sexual function, carry
High male fecundity has beneficial effect.
It should be noted that and understand, in the feelings for not departing from the spirit and scope of the present invention required by appended claims
Under condition, various modifications and improvements can be made to the present invention of foregoing detailed description.It is therefore desirable to the model of the technical scheme of protection
Enclose and do not limited by given any specific exemplary teachings.
Applicant states that the present invention illustrates the method detailed of the present invention, but not office of the invention by above-described embodiment
It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implemented.Art
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, selection of concrete mode etc., within the scope of all falling within protection scope of the present invention and being open.
Claims (13)
1. a kind of purity that need not purify is up to more than 95% macamide synthetic method, it is characterised in that methods described is：
With aliphatic acid, and benzylamine or meta-methoxy benzylamine are reaction raw materials, are being dissolved with HOAt, EDCHCl and DIPEA
Dichloromethane solution in mix, stirring reacted, then reaction product is washed, water-insoluble is drying to obtain maca acyl
Amine；
In the reaction solution, HOAt, EDCHCl, DIPEA, benzylamine or methoxybenzylamine, and the mol ratio of aliphatic acid is (1
~3): (1~4): (1~4): (1~3): 1；
The temperature of the reaction is 10~40 DEG C；
Reaction raw materials quality is (0.5~50) than m: v with methylene chloride volume: 100；
The aliphatic acid is that palmitic acid, stearic acid, oleic acid, linoleic acid, leukotrienes, 5 oxygen -6 are anti-, in 8 trans- octadecadienoic acids
Any a kind or at least two kinds of of combination.
2. the method as described in claim 1, it is characterised in that in the reaction solution, HOAt, EDCHCl, DIPEA, benzylamine
Or methoxybenzylamine, and the mol ratio of aliphatic acid is 3: 4: 6: 2: 2.
3. the method as described in claim 1, it is characterised in that in the reaction solution, reaction raw materials quality and dichloromethane body
Product is (10~20) than m: v: 100.
4. method as claimed in claim 3, it is characterised in that in the reaction solution, reaction raw materials quality and dichloromethane body
Product is 15: 100 than m: v.
5. the method as described in claim 1, it is characterised in that the temperature of the reaction is 15~35 DEG C.
6. method as claimed in claim 5, it is characterised in that the temperature of the reaction is 20~30 DEG C.
7. method as claimed in claim 6, it is characterised in that the temperature of the reaction is 30 DEG C.
8. the method as described in claim 1, it is characterised in that the solvent that the stirring is reacted into reaction solution is volatilized.
9. method as claimed in claim 8, it is characterised in that the time that the stirring is reacted is 0.2~20h.
10. method as claimed in claim 9, it is characterised in that the time that the stirring is reacted is 6~12h.
11. method as claimed in claim 10, it is characterised in that the time that the stirring is reacted is 12h.
12. the method as described in claim 1, it is characterised in that the mode of the drying is selected from drying, air-dried or nitrogen and blown.
13. the method as described in claim 1, it is characterised in that when aliphatic acid is palmitic acid, obtained macamide is N-
The phosphoamide of benzyl-ten six；
When aliphatic acid is stearic acid, obtained macamide is the phosphoamide of N- benzyls-ten eight；
When aliphatic acid is oleic acid, obtained macamide is the cis-oleic acid acid amides of N- benzyls -9；
When aliphatic acid is linoleic acid, obtained macamide is that N- benzyls -9 are suitable, 12 cis- linoleamides；
When aliphatic acid is leukotrienes, obtained macamide is that N- benzyls -9 are suitable, and 12 is suitable, 15 cis- leukotrienes acid amides；
When aliphatic acid is that 5 oxygen -6 are anti-, during 8 trans- octadecadienoic acid, obtained macamide is that the oxygen -6 of N- benzyls -5 is anti-, and 8 is trans-
Octadecadienoic acid acid amides；
When aliphatic acid is linoleic acid, when being reacted with meta-methoxy benzylamine, obtained macamide is suitable for methoxybenzyl -9 between N-, and 12
Cis- linoleamide；
When aliphatic acid is leukotrienes, when being reacted with meta-methoxy benzylamine, obtained macamide is suitable for methoxybenzyl -9 between N-, and 12
It is suitable, 15 cis- leukotrienes acid amides.
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| CN106974955A (en) * | 2017-04-12 | 2017-07-25 | 云南省药物研究所 | A kind of Maca extract for improving sex dysfunction and its preparation method and application |
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