CN101376640B - Low irritation garlicin derivative, and synthetic method and use thereof - Google Patents
Low irritation garlicin derivative, and synthetic method and use thereof Download PDFInfo
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- CN101376640B CN101376640B CN2008100703622A CN200810070362A CN101376640B CN 101376640 B CN101376640 B CN 101376640B CN 2008100703622 A CN2008100703622 A CN 2008100703622A CN 200810070362 A CN200810070362 A CN 200810070362A CN 101376640 B CN101376640 B CN 101376640B
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- garlicin
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- garlicin derivative
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Abstract
The invention discloses a garlicin derivative having the formula of (I), wherein a broken line optionally represents bond (double bond) or does not represent bond (single bond); n1 is an integer of 1 to 20; n2 is an integer of 2 to 4; R1, R2 and R3 are hydrogen or C1-20 alkyl; R4 is hydrogen or C1-20 alkyl; and when the broken line represents bond, n1 is 1, n2 is 3, and R4 is hydrogen, at least one of R1, R2 and R3 is C1-20 alkyl. Compared with garlicin, the garlicin derivative has the characteristics of enhanced antibacterial activity, and reduced irritation; and can be used for the preparation of an antibacterial drug; and also has garlic fragrance and taste, and can be used for the preparation of a spice or a flavoring agent. The invention also discloses a synthetic method of the garlic derivative, which comprises performing nucleophilic reaction of bromide having the formula (II) as initial raw material and sodium thiosulfate and sodium sulfide as nucleophilic reagent in solvent. The method is simple.
Description
Technical field
The present invention relates to a kind of compound, particularly a kind of garlicin derivative also relates to the synthetic method and the application of this derivative.
Background technology
Garlic (Alliiridum) is the traditional food and medicament dual-purpose plant of China, and garlicin is the effective constituent that extraction separation obtains from the garlic bulb, and structural formula is CH
2=CH-CH
2-S-S-S-CH
2-CH=CH
2, chemical name is the diallyl trithioether.Scientific research is the result show, garlicin has many-sided medical treatment and health-care effect, it all has in various degree inhibition and killing action to pathogenic micro-organisms such as various bacteria, virus, fungi and tumour etc., in addition, it also has hypotensive, reducing blood-fat, hypoglycemic, enhance immunity power and pharmacologically active such as anti-oxidant.At present, garlicin uses mainly as antibacterials clinically, and the reputation of natural Broad spectrum antibiotics is arranged, and is applicable to infectation of bacteria and deep fungal infection.But there are shortcomings such as the strong and poor stability of pungency in garlicin, it is applied be very limited.
At present, Chinese scholars mainly reduces the pungency of garlicin by physical methods such as entrapping method, microwave ultrasound methods, but these methods can not tackle the problem at its root, and might reduce the pharmacologically active of garlicin.Wherein, the beta-cyclodextrin inclusion compound method is to generally acknowledge method preferably, but have also that encapsulation rate is not high, effect is undesirable, cost is than problems such as height.
Summary of the invention
In view of this, one of purpose of the present invention is to provide the garlicin derivative that a kind of anti-microbial activity is strong, pungency is low.
For reaching this purpose, garlicin derivative of the present invention has following general formula (I):
Wherein, dotted line is randomly represented key or is not represented key, is two keys when the expression key, is singly-bound when not representing key; n
1Arbitrary integer for from 1 to 20; n
2Arbitrary integer for from 2 to 4; R
1, R
2And R
3Be hydrogen or C
1-20Alkyl; R
4Be hydrogen or C
1-20Alkyl; When dotted line is represented key, n
1Be 1, n
2Be 3, R
4During for hydrogen, R
1, R
2And R
3In have one at least for C
1-20Alkyl.
Described C
1-20Alkyl is meant the alkyl of the straight or branched with one or more carbon atoms, for example: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl etc.
Further, n
1Arbitrary integer for from 1 to 12; n
2Be 2 or 3; R
1, R
2And R
3Be hydrogen or C
1-10Alkyl; R
4Be hydrogen or C
1-10Alkyl;
Further, n
1Arbitrary integer for from 1 to 6; n
2Be 3; R
1, R
2And R
3Be hydrogen, methyl or ethyl; R
4Be hydrogen.
Two of purpose of the present invention is to provide a kind of method of simple and easy to do synthetic described garlicin derivative.
For reaching this purpose, the synthetic method of described garlicin derivative is a starting raw material with general formula (II) bromide, is nucleophilic reagent with Sulfothiorine and sodium sulphite, carries out nucleophilic reaction in solvent, promptly makes corresponding garlicin derivative;
Wherein, dotted line is randomly represented key or is not represented key, is two keys when the expression key, is singly-bound when not representing key; n
1Arbitrary integer for from 1 to 20; R
1, R
2And R
3Be hydrogen or C
1-20Alkyl; R
4Be hydrogen or C
1-20Alkyl; When dotted line is represented key, n
1Be 1, R
4During for hydrogen, R
1, R
2And R
3In have one at least for C
1-20Alkyl.
Further, the reaction mol ratio of described bromide and Sulfothiorine is 1: 1～3, and the reaction mol ratio of bromide and sodium sulphite is 1: 1～2;
Further, described reaction conditions is a stirring reaction under 20～100 ℃ of conditions of temperature;
Further, described reaction solvent is selected from a kind of in dimethyl sulfoxide (DMSO), methanol aqueous solution, aqueous ethanolic solution, the water;
Further, to contain concentration expressed in percentage by volume be 10%～60% methyl alcohol to described methanol aqueous solution; It is 5%～50% ethanol that described aqueous ethanolic solution contains concentration expressed in percentage by volume.
Three of purpose of the present invention is to provide the application of described garlicin derivative in the preparation antibacterials.
Four of purpose of the present invention is to provide the application of described garlicin derivative in preparation spices or seasonings.
Beneficial effect of the present invention is: the invention discloses garlicin derivative and garlicin relatively, garlicin derivative has the advantage that anti-microbial activity strengthens, pungency reduces, and can be used for preparing antibacterials; In addition, garlicin derivative has special garlic fragrance and taste, also can be used for preparing spices or seasonings; Garlicin derivative of the present invention bromide accordingly is a starting raw material, is nucleophilic reagent with Sulfothiorine and sodium sulphite, carries out nucleophilic reaction and make in solvent, and synthetic method is simple.
The present invention subsidizes project for Chongqing City Science ﹠. Technology Commision.
Embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, will be described in further detail the preferred embodiments of the present invention below.
The preparation of embodiment 1, two (2-methacrylic) trithioether
Calculate the raw material consumption by the product theory amount of making 10.3g; Accurately take by weighing 40g Sulfothiorine, add concentration expressed in percentage by volume and be 30% aqueous ethanolic solution and make dissolving, under 20 ℃ of temperature, stirring reaction condition, slowly drip methallyl bromide 13.4g, dropwised afterreaction 4 hours, adding concentration again is the sodium sulfide solution 50mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 8.8g; Productive rate is 85.0%.
The preparation of embodiment 2, two (3-methyl-2-butene base) trithioether
Calculate the raw material consumption by the product theory amount of making 11.8g; Accurately take by weighing 40g Sulfothiorine, add concentration expressed in percentage by volume and be 40% methanol aqueous solution and make dissolving, under 30 ℃ of temperature, stirring reaction condition, slowly drip 1-bromo-3-methyl-2-butene 14.8g, dropwised afterreaction 5 hours, adding concentration again is the sodium sulfide solution 60mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 9.4g; Productive rate is 80.0%.
The preparation of embodiment 3, two (3-butenyl) trithioether
Calculate the raw material consumption by the product theory amount of making 10.4g; Accurately take by weighing 40g Sulfothiorine, use water dissolution, under 25 ℃ of temperature, stirring reaction condition, slowly drip 4-bromo-1-butylene 13.4g, dropwised afterreaction 4 hours, adding concentration again is the sodium sulfide solution 65mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 9.2g; Productive rate is 89.2%.
The preparation of embodiment 4, two (4-pentenyl) trithioether
Calculate the raw material consumption by the product theory amount of making 11.8g; Accurately take by weighing 40g Sulfothiorine, add concentration expressed in percentage by volume and be 10% methanol aqueous solution and make dissolving, under 30 ℃ of temperature, stirring reaction condition, slow Dropwise 5-bromo-1-amylene 14.8g, dropwised afterreaction 6 hours, adding concentration again is the sodium sulfide solution 40mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 10.3g; Productive rate is 87.5%.
The preparation of embodiment 5, two (5-hexenyl) trithioether
Calculate the raw material consumption by the product theory amount of making 13.2g; Accurately take by weighing 40g Sulfothiorine, the adding concentration expressed in percentage by volume is 50% methanol aqueous solution, under 60 ℃ of temperature, stirring reaction condition, slowly drips 6-bromo-1-hexene 16.3g, dropwised afterreaction 8 hours, adding concentration again is the sodium sulfide solution 55mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 10.9g; Productive rate is 82.0%.
The preparation of embodiment 6, two (3,7,11,15-tetramethyl--3-hexadecylene base) trithioether
Calculate the raw material consumption by the product theory amount of making 32.8g; Accurately take by weighing 80g Sulfothiorine, add dimethyl sulfoxide (DMSO) (DMSO) and make dissolving, under 70 ℃ of temperature, stirring reaction condition, slowly drip 1-bromo-3,7,11,15-tetramethyl--3-hexadecylene 35.8g dropwised afterreaction 24 hours, and adding concentration again is the sodium sulfide solution 100mL of 1g/mL, reaction is spent the night, last standing demix is got the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 23.0g; Productive rate is 70.1%.
The preparation of embodiment 7, dibutyl trithioether
Calculate the raw material consumption by the product theory amount of making 10.8g; Accurately take by weighing 40g Sulfothiorine, add concentration expressed in percentage by volume and be 10% aqueous ethanolic solution and make dissolving, under 80 ℃ of temperature, stirring reaction condition, slowly drip butyl bromide 13.6g, dropwised afterreaction 6 hours, adding concentration again is the sodium sulfide solution 50mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 8.9g; Productive rate is 82.4%.
The preparation of embodiment 8, dihexyl trithioether
Calculate the raw material consumption by the product theory amount of making 13.4g; Accurately take by weighing 40g Sulfothiorine, add concentration expressed in percentage by volume and be 50% aqueous ethanolic solution and make dissolving, under 90 ℃ of temperature, stirring reaction condition, slowly dripping bromine is for hexane 16.5g, dropwised afterreaction 10 hours, adding concentration again is the sodium sulfide solution 65mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 10.1g; Productive rate is 75.3%.
The preparation of embodiment 9, hexadecyl trithioether
Calculate the raw material consumption by the product theory amount of making 27.3g; Accurately take by weighing 80g Sulfothiorine, add DMSO and make dissolving, under 100 ℃ of temperature, stirring reaction condition, slowly dripping bromine is for hexadecyl 30.4g, dropwised afterreaction 18 hours, adding concentration again is the sodium sulfide solution 90mL of 1g/mL, and reaction is spent the night, last standing demix, get the upper strata, washing, anhydrous sodium sulfate drying, filtration get oily mater 19.5g; Productive rate is 71.6%.
With reference to aforesaid method, can prepare other garlicin derivative that general formula of the present invention is explained.
The bacteriostatic test of garlicin derivative
Method: adopt the minimum inhibitory concentration (MIC) of constant broth dilution method determination garlicin derivative of the present invention to streptococcus aureus, intestinal bacteria and candida albicans.
The result: see Table 1, compare with garlicin, the anti-microbial activity of garlicin derivative of the present invention improves.
The MIC of table 1, garlicin derivative of the present invention (μ g/mL)
The skin irritation test of garlicin derivative
Method: get the large ear rabbit of body weight 2.0-2.5kg, adopt the contrast of consubstantiality left and right sides self, be divided into two big groups of garlicin derivative group and garlicin control group at random, each big group is divided into intact skin group and two groups of damaged skin group, 3 of every groups again; Tame rabbit back diamond wool being cut short in preceding 24 hours in experiment, is 20% Na with mass percentage concentration
2The depilation of the S aqueous solution, the about 50cm of every side
2The making of damaged skin is to sterilize behind the rabbit unhairing, with the sand paper skin that rubs, the degree of being with the oozing of blood, left and right sides skin injury degree basically identical; Garlicin derivative of the present invention or garlicin are smeared by depilation district, every group rabbit left side, it is 1% the tween-80 aqueous solution that mass percentage concentration is smeared in depilation district, right side, every day 2 times, each 1mL, successive administration 7 days after the last administration, was observed and was write down the coating position respectively at 12,24,48,96 hours and have or not situations such as erythema and oedema, calculate skin irritation reaction average integral, make the pungency intensity evaluation.
The result: in the garlicin derivative group, the skin irritation of intact skin group rabbit reaction average integral in 12,24 hours between 0.5-1.9, show as slight pungency, in 48 hours between 0-0.4, pungency disappears; The skin irritation of damaged skin group rabbit reaction average integral in 12,24 hours between 2.0-5.9, show as the moderate pungency, in 48 hours between 0.5-1.9, show as slight pungency, in 96 hours between 0-0.4, pungency disappears; And in the garlicin control group, garlicin disappears in 96 hours to the pungency of intact skin, to pungency disappearance after 1 week of damaged skin; Compare with garlicin, garlicin derivative of the present invention reduces the pungency of skin.
Based on above-mentioned test-results, garlicin derivative of the present invention has the advantage that anti-microbial activity is strong, pungency is low, can be used for preparing antibacterials.In addition, garlicin derivative of the present invention has special garlic fragrance and taste, also can be used as spices or seasonings and uses.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to some preferred embodiment of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (8)
1. garlicin derivative has following logical formula I:
It is characterized in that: dotted line is represented two keys; n
1Be 1; n
2Be 3; R
1And R
2Be methyl, R
3And R
4Be hydrogen.
2. the synthetic method of the described garlicin derivative of claim 1 is characterized in that: with logical formula II bromide is starting raw material, is nucleophilic reagent with Sulfothiorine and sodium sulphite, carries out nucleophilic reaction in solvent, promptly makes described garlicin derivative;
In the logical formula II, dotted line is represented two keys; n
1Be 1; R
1And R
2Be methyl, R
3And R
4Be hydrogen.
3. the synthetic method of garlicin derivative according to claim 2, it is characterized in that: the reaction mol ratio of described bromide and Sulfothiorine is 1: 1～3, the reaction mol ratio of bromide and sodium sulphite is 1: 1～2.
4. the synthetic method of garlicin derivative according to claim 2 is characterized in that: described reaction conditions is stirring reaction under 20～100 ℃ of conditions of temperature.
5. the synthetic method of garlicin derivative according to claim 2 is characterized in that: described reaction solvent is selected from a kind of in dimethyl sulfoxide (DMSO), methanol aqueous solution, aqueous ethanolic solution and the water.
6. the synthetic method of garlicin derivative according to claim 5 is characterized in that: it is 10%～60% methyl alcohol that described methanol aqueous solution contains concentration expressed in percentage by volume; It is 5%～50% ethanol that described aqueous ethanolic solution contains concentration expressed in percentage by volume.
7. the application of the described garlicin derivative of claim 1 in the preparation antibacterials.
8. the application of the described garlicin derivative of claim 1 in preparation spices or seasonings.
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| CN2008100703622A CN101376640B (en) | 2008-09-24 | 2008-09-24 | Low irritation garlicin derivative, and synthetic method and use thereof |
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|---|---|---|---|
| CN2008100703622A CN101376640B (en) | 2008-09-24 | 2008-09-24 | Low irritation garlicin derivative, and synthetic method and use thereof |
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|---|---|
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| CN101376640B true CN101376640B (en) | 2011-07-20 |
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Non-Patent Citations (3)
| Title |
|---|
| Takashi Hosono,ect.Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells,.《Carcinogenesis》.2008,第29卷(第7期),1400-1406. * |
| 吴莉.韭叶中农药活性成分类似物的合成.武汉化工学院学报.2003,25(3),5-8. * |
| 楚勇等.二烯丙基硫醚化合物的合成.合成化学.2001,9(6),541-542. * |
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