CN104513171A - Synthetic method and application of MACAmide - Google Patents
Synthetic method and application of MACAmide Download PDFInfo
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Abstract
The invention relates to a synthetic method of MACAmide. The method includes following steps: with a fatty acid and benzylamine or m-methoxybenzylamine as reaction raw materials, mixing the raw materials in a dichloromethane solution in which HOAt, EDC.HCl and DIPEA are dissolved; performing a reaction with stirring; washing a reaction product with water; and drying a substance being undissolved in water to obtain the MACAmide. The method is simple in processes and the raw materials are easy to obtain. Operation conditions of the method are easy to control. The reaction product can reach a purity of 95% without purification. The invention provides basis for industrialized synthesis of the MACAmide. In addition, the MACAmide has effects of enhancing male reproductive ability and treating male sexual dysfunction. The invention provides market prospects to application of the MACAmide.
Description
Technical field
The invention belongs to field of biological pharmacy, relate to a kind of preparation method and use of macamide, particularly a kind of synthetic method of the macamide without the need to purification step and the purposes of macamide that prepared by the method.
Background technology
Agate coffee (Lepidium meyenii Walp.) is Cruciferae Lepidium annual herb plant, originates in the Andes of South America height above sea level 3500 ~ 4500m.China started to introduce a fine variety plantation at Lijiang, yunnan in 2002, had become the agate coffee planting base that the whole world is maximum at present.Agate coffee has abundant nutritive value and pharmaceutical use.Research shows that agate coffee has raising people and animals Fertility, improvement function, suppresses prostate gland increase, antifatigue, antidepressant, improves the effects such as sclerotin is loose, raising memory.
Macamide (Macamides) is combined by amido linkage for benzylamine (or methoxybenzylamine) and lipid acid, and a series of compounds only found in agate coffee at present, its basic structure is
wherein R is H base or methoxyl group, and R ' is saturated or undersaturated straight-chain paraffin, or the saturated or undersaturated straight-chain paraffin containing ketone group.
Agate coffee growing environment requires harsh, yield poorly, the content of macamide extremely low (< 0.2%) in agate coffee, and complicated components in agate coffee, make with agate coffee as raw material, bio-chemistry separation prepares the method for macamide because separation and purification difficulty, and raw material sources limit to, and cannot to prepare etc. being restricted on a large scale.Therefore, obtain macamide by chemosynthesis mode, solve its raw material resources deficient, purification step waste of solvent, the problems such as the utilization ratio of agate coffee raw material is low.
In prior art, there is report with benzylamine and palmityl chloride synthesis macamide, but due to the restriction of fatty acid chloride raw material, multiple macamide cannot be synthesized; Have report under dicyclohexylcarbodiimide starts pyrollidinopyridine katalysis, to synthesize macamide with benzylamine or methoxybenzylamine and lipid acid, but in its product, the purity of macamide is low.
Therefore, it is few that a kind of synthesis step is urgently developed in this area, and reaction conditions is simple, without raw material restriction, and the synthetic method of the macamide that product purity is high.
Summary of the invention
It is few that an object of the present invention is to provide a kind of synthesis step, and reaction conditions is simple, without raw material restriction, and the synthetic method of the macamide that product purity is high.
The present invention is achieved through the following technical solutions:
A synthetic method for macamide, is characterized in that, described method is:
With lipid acid, be reaction raw materials with benzylamine or meta-methoxy benzylamine, be dissolved with HOAt(1-hydroxyl-7-azo benzotriazole), EDCHCl(1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) and DIPEA(N, N'-diisopropylethylamine) dichloromethane solution in mix, stirring is reacted, then reaction product is washed, water-insoluble is drying to obtain macamide.
Reaction provided by the invention just can synthesize macamide by a step, and reaction raw materials is easy to obtain, and the by product after reaction is water-soluble, and therefore without the need to the purge process of complexity, after washing, water-insoluble drying can obtain the higher macamide of purity.The purity of the macamide that the method for the invention prepares is more than 95%.
In reaction solution of the present invention, HOAt, EDCHCl, DIPEA, benzylamine or methoxybenzylamine, and the mol ratio of lipid acid is (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10): 1, typical but non-limiting 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.; Preferably (1 ~ 3): (1 ~ 4): (1 ~ 4): (1 ~ 3): 1, further preferably 3:4:6:2:2.
In described reaction solution, reaction raw materials quality and methylene chloride volume are (0.5 ~ 50) than m:v: 100, such as: 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, preferred 15:100 further.
Lipid acid of the present invention is the saturated of straight chain or undersaturated lipid acid, preferably from Palmiticacid, stearic acid, oleic acid, linolic acid, linolenic acid, 5 oxygen-6 are anti-, the combination of any a kind or at least 2 kinds in 8 trans-octadecadienoic acids, described combination such as Palmiticacid and linolenic combination, 5 oxygen-6 are anti-, 8 trans-octadecadienoic acids and stearic combination, oleic acid and linolenic combination, oleic acid, the combination of linolic acid and Palmiticacid, with combination, stearic acid, oleic acid, the combination of linoleic acid plus linolenic acid, Palmiticacid, stearic acid, oleic acid and 5 oxygen-6 anti-, the combination etc. of 8 trans-octadecadienoic acids.
The temperature of reaction of the present invention is 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, more preferably 20 ~ 30 DEG C, most preferably 30 DEG C.
Stirring of the present invention is carried out the solvent reacted in reaction solution and is volatilized, and preferably stirring the time of carrying out reacting is 0.5 ~ 20h, such as 0.5h, 1h, 7h, 10h, 12h, 16h, 19h etc., further preferably 6 ~ 12h, particularly preferably 12h.
The mode of drying of the present invention is selected from oven dry, air-dry or nitrogen blows.
In building-up process of the present invention, when lipid acid is Palmiticacid, the macamide obtained is N-benzyl-palmitoyl amine (N-benzyl-hexadecanamide), and concrete structure is
its molecular formula is C
23h
39nO;
When lipid acid is stearic acid, the macamide obtained is N-benzyl-octadecanoyl amine (N-benzyl-octadecanamide), and concrete structure is
its molecular formula is C
25h
43nO;
When lipid acid is oleic acid, the macamide obtained is N-benzyl-9 cis-oleic acid acid amides (N-benzyl-9Z-octadecenamide), and concrete structure is
its molecular formula is C
25h
41nO;
When lipid acid is linolic acid, the macamide obtained is that N-benzyl-9 is suitable, and 12 cis-linoleamide (N-benzyl-9Z, 12Z-octadecadienamide), concrete structure is
its molecular formula is C
25h
39nO;
When lipid acid is linolenic acid, the macamide obtained is that N-benzyl-9 is suitable, and 12 is suitable, and 15 cis-linolenamide (N-benzyl-9Z, 12Z, 15Z-octadecatrienamide), concrete structure is
its molecular formula is C
25h
37nO;
When lipid acid is that 5 oxygen-6 are anti-, during 8 trans-octadecadienoic acid, the macamide obtained is that N-benzyl-5 oxygen-6 is anti-, and 8 trans-octadecadienoic acid acid amides (N-benzyl-5-oxo-6E, 8E-octadecadienamide), concrete structure is
its molecular formula is C
25h
37nO
2.
When lipid acid is linolic acid, when reacting with meta-methoxy benzylamine, the macamide obtained is that between N-, methoxybenzyl-9 is suitable, and 12 cis-linoleamide (N-(m-methoxybenzyl)-9Z, 12Z-octadecadienamide), concrete structure is
its molecular formula is C
26h
41nO
2;
When lipid acid is linolenic acid, when reacting with meta-methoxy benzylamine, the macamide obtained is that between N-, methoxybenzyl-9 is suitable, 12 is suitable, 15 cis-linolenamide (N-(m-methoxybenzyl)-9Z, 12Z, 15Z-octadecadienamide), concrete structure is
its molecular formula is C
26h
39nO
2;
Two of object of the present invention is to provide the purposes of the macamide that a kind of synthetic method as described in one of object prepares, and it is characterized in that, described macamide for improving male fecundity, or is used for the treatment of male sexual disorder.
Typical case but without limitation, the synthetic method of macamide of the present invention comprises the steps:
By 0.075mol HOAt, 0.1mol EDCHCl, 0.15mol DIPEA adds in 150mL methylene dichloride and stirs, add 0.05mol lipid acid, then add the benzylamine of 0.05mol, 40 DEG C of stirring reaction liquid react, 20h reaction solution solvent swings, add water washed product, by water-insoluble vacuum-drying after filtration, obtains macamide;
Or, 0.02mol HOAt, 0.02mol EDCHCl, 0.03mol DIPEA are added in 30mL methylene dichloride and stirs, add 0.01mol lipid acid, add 0.01mol meta-methoxy benzylamine again, overnight at room temperature stirring reaction liquid reacts, and reaction solution solvent swings, add water washed product, chloroform extraction water-insoluble, nitrogen blows and no longer reduces to extract layer volume, obtains macamide.
Compared with prior art, the present invention has following beneficial effect:
The method of synthesis macamide of the present invention, step is simple, and raw material is easy to get, and operational condition is easily controlled, and product can reach more than 95% without the need to purifying purity; For industrialization synthesis macamide provides the foundation; In addition, the macamide of the present invention's synthesis has the effect improving male fecundity and treatment male sexual disorder, for the application of macamide provides market outlook.
Embodiment
For better the present invention being described, be convenient to understand technical scheme of the present invention, typical but non-limiting embodiment of the present invention is as follows:
Embodiment 1
A kind of one-step synthesis method macamide---the method for N-benzyl-palmitoyl amine:
Take 0.01mol HOAt respectively, 0.01mol EDCHCl and 0.01mol DIPEA is in 7.3mL DCM(methylene dichloride) in, then add 0.01mol benzylamine, 0.01mol Palmiticacid, and reaction raw materials and DCM are than being 50%(w/v), stirred overnight under 10 DEG C of conditions; Add deionized water 50mL, stirred at ambient temperature 30min, filter also vacuum-drying and obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, peak value is V
max=3303 (N-H), 2917,2849,1639 (C=O), 1549(N-C), 1454 (N-C=O), 730 and 696(phenyl ring) cm
-1;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z346.2;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer
1h composes (600MHz, CDCl
3), 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, can confirm that the macamide that the present embodiment prepares is N-benzyl-palmitoyl amine, its structural formula is as follows:
N-benzyl-palmitoyl amine (N-benzyl-hexadecanamide, C
23h
39nO).
Embodiment 2
A kind of single stage method chemosynthesis macamide---the method for N-benzyl-octadecanoyl amine:
Take 0.1mol HOAt respectively, 0.1mol EDCHCl and 0.1mol DIPEA in 2730mL DCM, then adds 0.1mol benzylamine, 0.01mol stearic acid, and reaction raw materials and DCM are than being 0.5%(w/v) stir under 40 DEG C of conditions and spend the night, revolve solvent evaporated; Add deionized water 200mL, stirred at ambient temperature 30min, filter also vacuum-drying and obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, peak value is V
max=3306(N-H), 2918,2849,1639(C=O), 1552(N-C), 1455(N-C=O), 1428,743,730 and 699(phenyl ring) cm
-1;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z374.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer
1h composes (600MHz, CDCl
3), 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, can confirm that the macamide that the present embodiment prepares is N-benzyl-octadecanoyl amine, its structural formula is as follows:
N-benzyl-octadecanoyl amine (N-benzyl-octadecanamide, C
25h
43nO).
Embodiment 3
A kind of single stage method chemosynthesis macamide---the method for N-benzyl-9 cis-oleic acid acid amides:
Take 0.015mol HOAt respectively, 0.02mol EDCHCl and 0.03mol DIPEA in 30mLDCM, then adds 0.01mol benzylamine, and 0.01mol oleic acid stirs 12h under 30 DEG C of conditions; Add deionized water 50mL, stirred at ambient temperature 30min, filter also vacuum-drying and obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, V
max=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);
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z372.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer
1h composes (600MHz, CDCl
3), 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, can confirm that the macamide that the present embodiment prepares is N-benzyl-amine hydroxybenzene, its structural formula is as follows:
N-benzyl-amine hydroxybenzene (N-benzyl-9Z-octadecenamide, C
25h
41nO).
Embodiment 4
A kind of single stage method chemosynthesis macamide---N-benzyl-9 is suitable, the method for 12 cis-linoleamide:
Take 0.015mol HOAt respectively, 0.02mol EDCHCl and 0.03mol DIPEA in 30mLDCM, then adds 0.01mol benzylamine, 0.01mol linolic acid, stirred overnight under 25 DEG C of conditions; Add deionized water 50mL, stirred at ambient temperature 30min, filter also vacuum-drying and obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, V
max=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;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z370.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer, 1H composes (600MHz, CDCl
3), 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, can confirm that the macamide that the present embodiment prepares is that N-benzyl-9 is suitable, 12 cis-linoleamide, its structural formula is as follows:
N-benzyl-9 is suitable, 12 cis-linoleamide, and its structural formula is as follows:
N-benzyl-9 is suitable, 12 cis-linoleamide (N-benzyl-9Z, 12Z-octadecadienamide, C
25h
39nO).
Embodiment 5
A kind of single stage method chemosynthesis macamide---between N-, methoxybenzyl-9 is suitable, the method for 12 cis-linoleamide:
Take 0.02mol HOAt respectively, 0.02mol EDCHCl and 0.02mol DIPEA in 30mL DCM, then adds 0.01mol benzylamine, and 0.01mol linolic acid stirs 30min, revolves solvent evaporated under 40 DEG C of conditions; Add deionized water 50mL, stirred at ambient temperature 30min, volatilizes DCM, adds chloroform extraction, and extract layer nitrogen blows to volume and no longer reduces to obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, V
max=3290(N-H), 3064,3006(C=C-H), 2929,2850,1632(C=O) and, 1554(N-C), 1464(N-C=O) and, 776,696(methoxyl group phenyl ring) cm
-1;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z400.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer, 1H composes (600MHz, CDCl
3), 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, can confirm that the macamide that the present embodiment prepares is that between N-, methoxybenzyl-9 is suitable, 12 cis-linoleamide, its structural formula is as follows:
between N-, methoxybenzyl-9 is suitable, 12 cis-linoleamide (N-(m-methoxybenzyl)-9Z, 12Z-octadecadienamide, C
26h
41nO
2).
Embodiment 6
A kind of single stage method chemosynthesis macamide---N-benzyl-9 is suitable, and 12 is suitable, the method for 15 cis-linolenamide:
Take 0.02mol HOAt respectively, 0.02mol EDCHCl and 0.02mol DIPEA in 30mL DCM, then adds 0.01mol benzylamine, 0.01mol linolenic acid, and under 15 DEG C of conditions, 20h stirs; Add deionized water 50mL, stirred at ambient temperature 30min, filtration product obtains product in vacuum-drying;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, V
max=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;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z368.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer, 1H composes (600MHz, CDCl
3), 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, can confirm that the macamide that the present embodiment prepares is that N-benzyl-9 is suitable, 12 is suitable, 15 cis-linolenamide, and its structural formula is as follows:
n-benzyl-9 is suitable, and 12 is suitable, 15 cis-linolenamide (N-benzyl-9Z, 12Z, 15Z-octadecatrienamide, C
25h
37nO).
Embodiment 7
A kind of single stage method chemosynthesis macamide---between N-, methoxybenzyl-9 is suitable, and 12 is suitable, the method for 15 cis-linolenamide:
Take 0.02mol HOAt respectively, 0.02mol EDCHCl and 0.02mol DIPEA in 30mL DCM, then adds 0.01mol meta-methoxy benzylamine, 0.01mol linolenic acid, stirs in overnight at room temperature; Add deionized water 50mL, stirred at ambient temperature 30min, adds chloroform extraction, and extract layer nitrogen blows to volume and no longer reduces to obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, V
max=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;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z398.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer, 1H composes (600MHz, CDCl
3), 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, can confirm that between the N-that the present embodiment prepares, methoxybenzyl-9 is suitable, 12 is suitable, 15 cis-linolenamide, and its structural formula is as follows:
between N-, methoxybenzyl-9 is suitable, and 12 is suitable, 15 cis-linolenamide (N-(m-methoxybenzyl)-9Z, 12Z, 15Z-octadecatrienamide, C
26h
39nO
2).
Embodiment 8
A kind of single stage method chemosynthesis macamide---N-benzyl-5 oxygen-6 is anti-, the method for 8 trans-octadecadienoic acid acid amides:
Take 0.02mol HOAt respectively, 0.02mol EDCHCl and 0.02mol DIPEA in 30mL DCM, then adds 0.01 meta-methoxy benzylamine, and 0.01mol N-benzyl-5 oxygen-6 is anti-, and 8 trans-octadecadienoic acids, stir in overnight at room temperature; Add deionized water 50mL, stirred at ambient temperature 30min, adds chloroform extraction, and extract layer nitrogen blows to volume and no longer reduces to obtain product;
Performance test:
Infrared: FT/IR-660 radar stealthy materials, V
max=3311(N-H), 2928,2845,1639(C=O), 1545(N-C), 1239(N-C=O), 1000,731 and 697(phenyl ring) cm
-1;
The LCQ DECAXP ion hydrazine mass spectrum of mass spectrum: Thermo, m/z384.3;
Nuclear-magnetism: in Bruker AVANCE III600 nuclear magnetic resonance spectrometer, 1H composes (600MHz, CDCl
3), 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, can confirm that N-benzyl-5 oxygen-6 that the present embodiment prepares is anti-, 8 trans-octadecadienoic acid acid amides, its structural formula is as follows:
n-benzyl-5 oxygen-6 is anti-, 8 trans-octadecadienoic acid acid amides (N-benzyl-5-oxo-6E, 8E-octadecadienamide, C
25h
37nO
2).
Application example 1 macamide is on the impact of Kunming mouse antifatigue effect
Select Kunming mouse in five week age, be divided into 10 groups at random, often organize 9, be respectively control group (physiological saline), the macamide group (macamide concentration is 2.0mg/10mL) that each embodiment prepares, and macamide mixture group (mixture concentration is 2.0mg/10mL), described macamide mixture is that 15%N-benzyl-9 is suitable, 12 cis-linoleamide and 85%N-benzyl-9 suitable, 12 is suitable, the mixture of 15 cis-linolenamide;
To Kunming mouse gavage every day often organized 1 time, gavage volume is 10mL/kg body weight (namely given low is 2.0mg/kg), each group of successive administration 7 days, after last gavage 1h, mouse is placed in depth of water 40cm, in the large basin of water temperature 25 DEG C, 10% of afterbody heavy burden own wt, record mouse starts from swimming to sinking 10s, no longer swim out of the water surface time (X ± SEM) (n=9); The results are shown in Table 1:
Table 1 macamide is on the impact of kunming mice swimming time
Note: compare with blank group, * P<0.05, * * P<0.01.
Experimental result shows that the macamide that the present invention synthesizes can obviously extend the mice burden swimming time, has antifatigue effect.
Application example 2 macamide is on the impact of rat mating ability
Choose male SD rat and carry out castration postoperative recovery 5 days, be divided into 10 groups at random, often organize 6, be respectively blank group (physiological saline), the macamide group (macamide concentration is 2.0mg/10mL) that each embodiment prepares, and macamide mixture group (mixture concentration is 2.0mg/10mL), described macamide is that 15%N-benzyl-9 is suitable, 12 cis-linoleamide and 85%N-benzyl-9 suitable, 12 is suitable, the mixture of 15 cis-linolenamide;
To SD rat gavage every day often organized 1 time, gavage volume is 10mL/kg body weight (namely given low is 2.0mg/kg), and continuous gavage 21 days, freely takes food and drink water; After 21st day gavage, every 1 male rat and 2 virgin's female rats are placed in a cage by 30min, observe in 3h number of copulations (X ± SEM) (n=6).The results are shown in Table 2:
Table 2 macamide is on the impact of male rat mating ability
Note: compare with blank group, * P<0.05, * * P<0.01.
Experimental result shows that synthesis macamide can significantly improve male rat mating ability.
The impact that application example 3 macamide occurs SD rat spermatozoa
Choose three monthly age SD rats, be divided into 10 groups at random, often organize 6, be respectively control group (physiological saline), the macamide group (macamide concentration is 2.0mg/10mL) that each embodiment prepares, and macamide mixture group (mixture concentration is 2.0mg/10mL), described macamide is that 15%N-benzyl-9 is suitable, 12 cis-linoleamide and 85%N-benzyl-9 suitable, 12 is suitable, the mixture of 15 cis-linolenamide;
To SD rat gavage every day often organized 1 time, gavage volume is 10mL/kg body weight (namely given low is 2.0mg/kg), each group of continuous gavage 7 days, freely take food and drink water, after last gavage, 24h ether is put to death, measure its day sperm production, epididymal sperm number (X ± SEM) (n=6) respectively, the results are shown in Table 3:
Table 3: the impact that macamide occurs SD rat spermatozoa
Note: compare with blank group, * P<0.05, * * P<0.01.
Experimental result shows that synthesis macamide obviously increases SD rat day sperm production and epididymal sperm number, but does not make significant difference to motility of sperm.
Application Example 4 macamide is to the clinical observation on the therapeutic effect of sexual dysfunction patient
To 36 sexual dysfunctions and volunteer carried out preparing clinical trial check the clinical effectiveness synthesizing macamide.Subject's mean age is 40 ± 5.9 years old, is 4.6 months between period of disease.Volunteer is divided into two groups at random, A group (give macamide essence sheet, containing macamide 10mg/ grain, 2 tablets/time, every day 1 time), B group (give JINGUI SHENQI WAN, 20 (4g)/time, every day 2 times), each oral 1 month.Experimenter before and after take medicine by international index of erectile function grade form-5(IIEF-5) evaluate ED light and heavy degree and fill in sexual function questionnaire respectively, be divided into 2 groups of each 18 examples at random, two groups of state of an illness weights divide stage to compare without significant difference (P>0.05).Suitable containing 15%N-benzyl-9 in described macamide essence sheet, 12 cis-linoleamide and 85%N-benzyl-9 suitable, 12 is suitable, 15 cis-linolenamide.Described JINGUI SHENQI WAN is the pharmacy of Beijing Tongrentang.Observation of curative effect the results are shown in Table 4:
Table 4: macamide is to the clinical observation on the therapeutic effect of sexual dysfunction patient
Note: international index of erectile function grade form-5(IIEF-5) with reference to Liu Zhaoxu, model doctor east. the Clinics and Practices [M] of sexual dysfunction. Jinan: Shandong Science Press, 2002.387.
Experimental group total effective rate is 94%, and control group total effective rate is that 77%, two groups of total effective rates compare, and difference has significant (P<0.05), and experimental group is better than control group, and macamide has significant curative effect to sexual dysfunction patient.
Application Example 5 macamide is to the clinical observation on the therapeutic effect of sexual dysfunction patient
According to the macamide of embodiment 1-8 synthesis, be mixed to get macamide mixture, clinical observation on the therapeutic effect is carried out to sexual dysfunction patient
To 36 sexual dysfunctions and volunteer carried out preparing clinical trial check the clinical effectiveness synthesizing macamide.Subject's mean age is 40 ± 5.9 years old, is 5 months between period of disease.Volunteer is divided into two groups at random, A group (give macamide essence sheet, containing macamide 10mg/ grain, 2 tablets/time, 1 times/day), B group (give JINGUI SHENQI WAN, 20 (4g)/time, 2 times/day), each oral 1 month.Experimenter before and after take medicine by international index of erectile function grade form-5(IIEF-5) evaluate ED light and heavy degree and fill in sexual function questionnaire respectively, be divided into 2 groups of each 18 examples at random, two groups of state of an illness weights divide stage to compare without significant difference (P>0.05).The macamide prepared containing the embodiment of the present invention 1 ~ 8 in described macamide essence sheet, and the mass ratio of 8 kinds of macamide is: embodiment 1: embodiment 2: embodiment 3: embodiment 4: embodiment 5: embodiment 6: embodiment 7: embodiment 8 is 1:1:2:2:2:3:3:1.Described B group JINGUI SHENQI WAN is the pharmacy of Beijing Tongrentang.Observation of curative effect the results are shown in Table 5:
Table 5: macamide is to the clinical observation on the therapeutic effect of sexual dysfunction patient
Note: international index of erectile function grade form-5(IIEF-5) with reference to Liu Zhaoxu, model doctor east. the Clinics and Practices [M] of sexual dysfunction. Jinan: Shandong Science Press, 2002.387.
Experimental group total effective rate is 94%, and control group total effective rate is that 77%, two groups of total effective rates compare, and difference has significant (P<0.05), and experimental group is better than control group, and macamide has significant curative effect to sexual dysfunction patient.
As can be seen from application implementation 1 ~ 5, the macamide of the present invention's synthesis for antifatigue, improvement function, improves male fertility ability and has useful effect.
It should be noted that and understand, when not departing from the spirit and scope of the present invention required by accompanying claim, various amendment and improvement can be made to the present invention of foregoing detailed description.Therefore, the scope of claimed technical scheme is not by the restriction of given any specific exemplary teachings.
Applicant states, the present invention illustrates method detailed of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned method detailed, does not namely mean that the present invention must rely on above-mentioned method detailed and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (9)
1. a synthetic method for macamide, is characterized in that, described method is:
With lipid acid, and benzylamine or meta-methoxy benzylamine are reaction raw materials, mix in the dichloromethane solution being dissolved with HOAt, EDCHCl and DIPEA, stir and react, and then reaction product washed, water-insoluble is drying to obtain macamide.
2. the method for claim 1, it is characterized in that, in described reaction solution, HOAt, EDCHCl, DIPEA, benzylamine or methoxybenzylamine, and the mol ratio of lipid acid is (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10): 1, preferably (1 ~ 3): (1 ~ 4): (1 ~ 4): (1 ~ 3): 1, further preferably 3:4:6:2:2.
3. method as claimed in claim 1 or 2, it is characterized in that, in described reaction solution, reaction raw materials quality and methylene chloride volume are (0.5 ~ 50) than m:v: 100, preferably (10 ~ 20): 100, preferred 15:100 further.
4. the method as described in one of claims 1 to 3, it is characterized in that, described lipid acid is the saturated or undersaturated lipid acid of straight chain, preferably anti-from Palmiticacid, stearic acid, oleic acid, linolic acid, linolenic acid, 5 oxygen-6, the combination of any a kind or at least 2 kinds in 8 trans-octadecadienoic acids.
5. the method as described in one of Claims 1 to 4, is characterized in that, the temperature of described reaction is 10 ~ 40 DEG C, preferably 15 ~ 35 DEG C, more preferably 20 ~ 30 DEG C, most preferably 30 DEG C.
6. the method as described in one of Claims 1 to 5, is characterized in that, described stirring is carried out the solvent reacted in reaction solution and volatilized, and preferably stirring the time of carrying out reacting is 0.2 ~ 20h, further preferably 6 ~ 12h, particularly preferably 12h.
7. the method as described in one of claim 1 ~ 6, is characterized in that, the mode of described drying is selected from oven dry, air-dry or nitrogen blows.
8. the method as described in one of claim 1 ~ 7, is characterized in that, when lipid acid is Palmiticacid, the macamide obtained is N-benzyl-palmitoyl amine;
When lipid acid is stearic acid, the macamide obtained is N-benzyl-octadecanoyl amine;
When lipid acid is oleic acid, the macamide obtained is N-benzyl-9 cis-oleic acid acid amides;
When lipid acid is linolic acid, the macamide obtained is that N-benzyl-9 is suitable, 12 cis-linoleamide;
When lipid acid is linolenic acid, the macamide obtained is that N-benzyl-9 is suitable, and 12 is suitable, 15 cis-linolenamide;
When lipid acid is that 5 oxygen-6 are anti-, during 8 trans-octadecadienoic acid, the macamide obtained is that N-benzyl-5 oxygen-6 is anti-, 8 trans-octadecadienoic acid acid amides;
When lipid acid is linolic acid, when reacting with meta-methoxy benzylamine, the macamide obtained is that between N-, methoxybenzyl-9 is suitable, 12 cis-linoleamide;
When lipid acid is linolenic acid, when reacting with meta-methoxy benzylamine, the macamide obtained is that between N-, methoxybenzyl-9 is suitable, and 12 is suitable, 15 cis-linolenamide.
9. a purposes for the macamide that the synthetic method as described in one of claim 1 ~ 8 prepares, is characterized in that, described macamide for improving male fecundity, or is used for the treatment of male sexual disorder.
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| CN106674038A (en) * | 2016-11-08 | 2017-05-17 | 广东药科大学 | Method for compounding and purifying macamides |
| 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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| CN106674038A (en) * | 2016-11-08 | 2017-05-17 | 广东药科大学 | Method for compounding and purifying macamides |
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| 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 |
| CN110845780A (en) * | 2019-10-31 | 2020-02-28 | 浙江比例聚合科技股份有限公司 | PE colorful heat shrinkable film and preparation method thereof |
| CN110845780B (en) * | 2019-10-31 | 2021-12-21 | 浙江比例聚合科技股份有限公司 | PE colorful heat shrinkable film and preparation method thereof |
| CN116135208A (en) * | 2021-11-18 | 2023-05-19 | 中国科学院大连化学物理研究所 | Use of compounds and ACLY inhibitors or anticancer drugs |
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