CN100509860C - Chitin sulfuric-ester hydroxy-benzene disulfonic acid derivative and production thereof - Google Patents
Chitin sulfuric-ester hydroxy-benzene disulfonic acid derivative and production thereof Download PDFInfo
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- CN100509860C CN100509860C CNB2007100101110A CN200710010111A CN100509860C CN 100509860 C CN100509860 C CN 100509860C CN B2007100101110 A CNB2007100101110 A CN B2007100101110A CN 200710010111 A CN200710010111 A CN 200710010111A CN 100509860 C CN100509860 C CN 100509860C
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Abstract
A chitose sulfuric ester hydroxyl-benzene-disulfo-amine derivative and its production are disclosed. In the chemical formula, n=12-621. The process is carried out by reacting chitose sulfuric ester with different molecular weight with hydroxyl-benzene-disulfo-chlorine and synthesizing into final products. Its advantages include better solubility, synergistic and antiviral functions and excellent biological activity. It can be used in medicinal, cosmetics and agricultural industries.
Description
Technical field
The present invention relates to the marine chemical industry field of engineering technology, is hydroxybenzene disulfonic acid amide analog derivative of a kind of chitosan C-6 position sulfuric ester and preparation method thereof concretely.
Background technology
The research and development of new veterinary drug be one expensive big, the cycle is long, technical requirements is high, the systems engineering that has a big risk.A kind of new drug of developed countries comes out and needs the 10-15 year, expensive more than one hundred million dollars.Prospect new veterinary drug research and development of 21 century trend, development along with pollution-free food, the safety problem of animal products is subject to people's attention day by day, market promptly presents the requirement for height to safety, efficient, low cytotoxic drug, be that veterinary drug is not only little to the medication animal toxicity, and require residual in animal body few.For satisfying this requirement, veterinary drug production now is tending towards greenization substantially, and natural product is carried out the research of deep chemistry and physiologically active, has the structure novel type of DEVELOPMENT PROSPECT as lead compound great chance to be arranged clinically for finding.The fact shows that the natural drug of development is better efficacy not only, and toxic side effect is littler, and its development cost are also than the synthetic much less of pure chemistry.
Chitosan is a large amount of class natural biological polysaccharide that exist of nature, and itself is biodegradable, has excellent biological compatibility.Because of containing active hydroxyl in its molecular structure (OH) and amino (NH
2), can form derivative by various chemical modifications and modification with different structure and function.Chitosan is introduced SO through sulphating
3 -Group makes it have enhancing body immunizing power, suppresses tumour, suppresses the effect of aspects such as virus, and is very active to its development research both at home and abroad.At present, existing report is applied in the veterinary drug chitosan as additive, immunity function that can enhancing body, improves the resistance against diseases of cultivated animals, but effect is all bad.
Hydroxybenzene disulfonic acid amide compounds has bacteriostatic activity preferably, sulfanilamide (SN) is as a kind of effect antibiotics preferably, in veterinary drug, use more extensively, but be to use in animal body residual of sulfa drugs to occur acute and chronic poisoning seriously, clinically easily.Sulfonyl compound is the important intermediate in the organic synthesis, it is inserted form the bacteriostatic activity that new sulfonic acid amide derivatives can significantly strengthen this compounds in the compound molecule.At present, relevant report is not seen in the research of the hydroxybenzene disulfonic acid amide analog derivative of relevant sulfated chitosan.
Summary of the invention
Purpose of the present invention just provides the hydroxybenzene disulfonic acid amide analog derivative and the preparation method of a kind of good water solubility, sulfated chitosan that bacteriostatic activity is high.
For achieving the above object, the technical scheme taked of the present invention is:
Derivative is formula (1) or formula (2):
Formula (1) formula (2)
N=12-621 wherein.
The preparation method of derivative: sulfated chitosan is reacted with the hydroxybenzene disulfonic acid chloride in acetate solvate, and temperature of reaction is 50-80 ℃, and the reaction times is 4-8 hour; Adopt organic solvent that reaction product is precipitated behind the cool to room temperature, throw out is used organic solvent washing, drying after filtration and with it, then be derivative by organic solvent extraction, vacuum-drying, the mol ratio of described sulfated chitosan and hydroxybenzene disulfonic acid chloride is 1:1-3; Described hydroxybenzene disulfonic acid chloride is: 2-hydroxyl-5-chloro-1,3-benzene-disulfo-chloride or 4-hydroxyl-5-chloro-1,3-benzene-disulfo-chloride.
Described sulfated chitosan is a chitosan C-6 position sulfuric ester, and its molecular weight is between 0.4-20 ten thousand, and deacetylation is 80-96%, sulphur content weight percent meter 9.55%-12.54%.
The add-on of described acetic acid is 50-80mL, and its HAc solvent strength is 1-3%.
The described organic solvent that is used to precipitate and washs is acetone or dehydrated alcohol, and consumption is 200-400mL.
Described drying temperature is 50-60 ℃.Described extraction is to adopt Soxhlet to extract, and organic solvent was a hexanaphthene when it extracted.
Principle: contain active-NH in the chitosan structure
2On N, can introduce other active group, can on the sulfuric ester molecule of chitosan C-6 position, introduce hydroxybenzene disulfonic acid amide group by chitosan C-6 position sulfuric ester and the reaction of hydroxybenzene disulfonic acid chloride, produce synergy, significantly strengthen its biological activity with the chitosan sulfate ester molecule.
The hydroxybenzene disulfonic acid chloride mainly is and chitosan C among the present invention
2Amino (the NH of position
2) reaction.Wherein the substitution value of sulfuryl amine group is 36.5-61.2% in the hydroxybenzene disulfonic acid amide analog derivative of sulfated chitosan.
The advantage that the present invention had:
1. the present invention effectively combines chitosan C-6 position sulfuric ester molecule and hydroxybenzene disulfonic acid amide group, the two-way interaction can produce synergistic function, strengthen distinctive separately biological activity, have multiple biological activitys such as anti-oxidant, antiviral, antibacterial.Wherein Fan Ying amino group accounts for the 36.5-61.2% of amino total amount in the chitosan.
2. the hydroxybenzene disulfonic acid amide derivative of the chitosan C-6 position sulfuric ester prepared of the present invention easily is absorbed, has good water-solubility, be dissolvable in water in the multiple inorganic and organic solvent, overcome the shortcoming of chitosan solubility property difference, enlarged its Application Areas, the general using value of factory has been arranged in fields such as agricultural, medicine, healthcare products and makeup.
Description of drawings
Fig. 1 is the infrared spectrogram of raw materials of chitosan sulfuric ester; Its characteristic infrared (cm
-1): 3425.61,2934.85,1629.29,1216.24 (S=O), 1086.38,871.07,815.60,583.44.
Fig. 2 is the sulfone amide derivative infrared spectrogram of the embodiment of the invention 1 gained; Its characteristic infrared (cm
-1): 3458.92,1672.54,1543.16,1396.02,1225.67,1067.63,1005.24,813.69,686.77,586.28.
Fig. 3 is the sulfone amide derivative infrared spectrogram of the embodiment of the invention 2 gained; Its characteristic infrared (cm
-1): 3424.36,1684.75,1530.48,1391.15,1219.73,1067.42,1003.56,808.36,688.00,584.07.
Fig. 4 is the sulfone amide derivative infrared spectrogram of the embodiment of the invention 3 gained; Its characteristic infrared (cm
-1): 3443.94,1684.94,1653.18,1398.06,1260.65,1060.80,1008.97,810.75,689.53.
Fig. 5 is the sulfone amide derivative infrared spectrogram of the embodiment of the invention 4 gained; Its characteristic infrared (cm
-1): 3467.83,1686.60,1532.50,1391.74,1249.67,1078.17,808.27.
Fig. 6 is the sulfone amide derivative infrared spectrogram of the embodiment of the invention 5 gained; Its characteristic infrared (cm
-1): 3402.86,1686.81,1539.47,1395.35,1225.63,1065.20,799.44.
Fig. 7 is the sulfone amide derivative infrared spectrogram of the embodiment of the invention 6 gained; Its characteristic infrared (cm
-1): 2986.00,1692.11,1615.18,1485.01,1390.71,1234.62,1057.67,759.46,684.88.
Embodiment
Further describe below in conjunction with accompanying drawing, protection scope of the present invention not only is confined in following examples.
The 1g molecular weight is that 160,000 chitosan C-6 position sulfuric ester is dissolved in 50mL2%HAc, wherein said chitosan C-6 position sulfuric ester is referring to Concepts for improved regioselective placementof O-suifo, N-sulfo, N-acetyl, and N-carboxymethyl groups inchitosan derivatives; Hanno Baumann, Volker Faust; CarbohydrateResearch, 2001,331, the currently known methods of 43-57. prepares; Stir adding 1.8g2-hydroxyl-5-chloro-1 down, the 3-benzene-disulfo-chloride, 65 ℃ were reacted 5 hours.Behind the cool to room temperature, 300mL precipitates it in the acetone fully with the reaction mixture impouring, obtain throw out and exceed use acetone, use washing with acetone behind the sedimentation and filtration, and obtain brown ceramic powder 50 ℃ of following dryings, extract the hydroxybenzene disulfonic acid amide derivative that the 8h final vacuum is drying to obtain chitosan with the hexanaphthene for the solvent Soxhlet, structural formula is referring to formula 1, wherein n=496.
Infrared spectroscopy shows that the hydroxybenzene disulfonic acid amide derivative (referring to Fig. 2) of sulfated chitosan is compared with sulfated chitosan (referring to Fig. 1), appearance 1543.16 and 1396.02cm
-1New absorption peak, this is the charateristic avsorption band of hydroxybenzene disulfonic acid amide group: are SO about 1370
2The asymmetric stretching vibration absorption peak of-N group; 1540cm
-About be the skeleton stretching vibration absorption peak of phenyl ring, prove the formation of target compound.
Difference from Example 1 is:
The 2g molecular weight is that 0.4 ten thousand chitosan C-6 position sulfuric ester is dissolved in 50mL1%HAc, stirs to add 3.45g2-hydroxyl-5-chloro-1 down 3-benzene-disulfo-chloride, 75 ℃ of reactions 4 hours.After the cooling, precipitation will be obtained in the reaction mixture impouring 400mL dehydrated alcohol, use absolute ethanol washing behind the sedimentation and filtration, dry down for 55 ℃ and obtain brown ceramic powder, extract the hydroxybenzene disulfonic acid amide derivative that the 8h final vacuum is drying to obtain sulfated chitosan with the hexanaphthene for the solvent Soxhlet, structural formula is referring to formula 1, wherein n=12.
Infrared spectroscopy shows, the hydroxybenzene disulfonic acid amide derivative (referring to Fig. 3) of sulfated chitosan is compared with sulfated chitosan (referring to Fig. 1), 1530.48 and 1391.15 two new absorption peaks occur, this is the charateristic avsorption band of hydroxybenzene disulfonic acid amide group: are SO about 1370
2The asymmetric stretching vibration absorption peak of-N group, 1540cm
-1About be the skeleton stretching vibration absorption peak of phenyl ring, prove the formation of target compound.
Embodiment 3
Difference from Example 1 is:
The 2g molecular weight is that 50,000 chitosan C-6 position sulfuric ester is dissolved in 60mL1%HAc, stirs to add 2.25g2-hydroxyl-5-chloro-1 down 3-benzene-disulfo-chloride, 65 ℃ of reactions 5 hours.After the cooling, precipitation will be obtained in the reaction mixture impouring 300mL dehydrated alcohol, use absolute ethanol washing behind the sedimentation and filtration, dry down for 60 ℃ and obtain brown ceramic powder, extract the hydroxybenzene disulfonic acid amide derivative that the 8h final vacuum is drying to obtain sulfated chitosan with the hexanaphthene for the solvent Soxhlet, structural formula is referring to formula 1, wherein n=155.
Infrared spectroscopy shows that the hydroxybenzene disulfonic acid amide derivative (referring to Fig. 4) of sulfated chitosan is compared with sulfated chitosan (referring to Fig. 1), 1398.06cm occurs
-1New absorption peak, this is the charateristic avsorption band of hydroxybenzene disulfonic acid amide group: are SO about 1370
2The asymmetric stretching vibration absorption peak of-N group proves the formation of target compound.
Embodiment 4
Difference from Example 1 is:
The 2g molecular weight is that 150,000 chitosan C-6 position sulfuric ester is dissolved in 80mL1%HAc, stirs to add 3.5g4-hydroxyl-5-chloro-1 down 3-benzene-disulfo-chloride, 70 ℃ of reactions 3 hours.After the cooling, precipitation will be obtained in the reaction mixture impouring 250mL dehydrated alcohol, use absolute ethanol washing behind the sedimentation and filtration, 55 ℃ of following dryings obtain brown ceramic powder, extract the hydroxybenzene disulfonic acid amide derivative that the 8h final vacuum is drying to obtain the low-molecular weight chitoglycan sulfuric ester with the hexanaphthene for the solvent Soxhlet, structural formula is referring to formula 2, wherein n=465.
Infrared spectroscopy (referring to Fig. 5) shows that the hydroxybenzene disulfonic acid amide derivative of chitosan is compared with sulfated chitosan (referring to Fig. 1), 1532.50 and 1391.74 two new absorption peaks occur, and this is the charateristic avsorption band of sulfuryl amine group: 1395-1360cm
-1Be SO
2The asymmetric stretching vibration absorption peak of-N group, 1540cm
-1About be phenyl ring skeletal vibration absorption peak, prove the formation of target compound.
Difference from Example 1 is:
The 2g molecular weight is that 1.2 ten thousand chitosan C-6 position sulfuric ester is dissolved in 70mL3%HAc, stirs to add 4.0g4-hydroxyl-5-chloro-1 down 3-benzene-disulfo-chloride, 60 ℃ of reactions 6 hours.After the cooling, reaction mixture impouring 350mL is obtained precipitation in the acetone, use washing with acetone behind the sedimentation and filtration, 50 ℃ of following dryings obtain brown ceramic powder, extract the hydroxybenzene disulfonic acid amide analog derivative that the 8h final vacuum is drying to obtain sulfated chitosan with the hexanaphthene for the solvent Soxhlet, structural formula is referring to formula 2, wherein n=37.
Infrared spectroscopy (referring to Fig. 6) shows that the hydroxybenzene disulfonic acid amide derivative of sulfated chitosan is compared with sulfated chitosan (referring to Fig. 1), appearance 1395.35 and 1539.47cm
-1Two new absorption peaks, this is the charateristic avsorption band of sulfuryl amine group: 1395-1360cm
-1Be SO
2The asymmetric stretching vibration absorption peak of-N group, 1540cm
-1About be phenyl ring skeletal vibration absorption peak, prove the formation of target compound.
Embodiment 6
Difference from Example 1 is:
The 2g molecular weight is that 0.7 ten thousand chitosan C-6 position sulfuric ester is dissolved in 80mL2%HAc, stirs to add 3.5g4-hydroxyl-5-chloro-1 down 3-benzene-disulfo-chloride, 70 ℃ of reactions 3 hours.After the cooling, precipitation will be obtained in the reaction mixture impouring 250mL dehydrated alcohol, use absolute ethanol washing behind the sedimentation and filtration, 55 ℃ of following dryings obtain brown ceramic powder, extract the hydroxybenzene disulfonic acid amide derivative that the 8h final vacuum is drying to obtain the low-molecular weight chitoglycan sulfuric ester with the hexanaphthene for the solvent Soxhlet, structural formula is referring to formula 2, wherein n=21.
Infrared spectroscopy (referring to Fig. 7) shows that the hydroxybenzene disulfonic acid amide derivative of sulfated chitosan is compared with sulfated chitosan (referring to Fig. 1), 1390.71 new absorption peaks occur, and this is the charateristic avsorption band of sulfuryl amine group: 1395-1360cm
-1Be SO
2The asymmetric stretching vibration absorption peak of-N group proves the formation of target compound.
Claims (7)
1. the hydroxybenzene disulfonic acid amide analog derivative of a sulfated chitosan is characterized in that derivative is formula (1) or formula (2):
Formula (1) formula (2)
N=12-621 wherein.
2. the preparation method of the hydroxybenzene disulfonic acid amide analog derivative of claims 1 described sulfated chitosan, it is characterized in that: sulfated chitosan is reacted with the hydroxybenzene disulfonic acid chloride in acetum, temperature of reaction is 50-80 ℃, and the reaction times is 4-8 hour; The cooling back adopts organic solvent that reaction product is precipitated, throw out is used organic solvent washing, drying after filtration and with it, then be derivative by organic solvent extraction, vacuum-drying, the mol ratio of described sulfated chitosan and hydroxybenzene disulfonic acid chloride is 1:1-3; Described hydroxybenzene disulfonic acid chloride is: 2-hydroxyl-5-chloro-1,3-benzene-disulfo-chloride or 4-hydroxyl-5-chloro-1,3-benzene-disulfo-chloride.
3. according to the described preparation method of claim 2, it is characterized in that: described sulfated chitosan is a chitosan C-6 position sulfuric ester, and its molecular weight is between 0.4-20 ten thousand, and deacetylation is 80-96%, sulphur content weight percent meter 9.55%-12.54%.
4. according to the described preparation method of claim 2, it is characterized in that: the add-on of described acetic acid is 50-80mL, and its HAc strength of solution is 1-3%.
5. according to the described preparation method of claim 2, it is characterized in that: the described organic solvent that is used to precipitate and washs is acetone or dehydrated alcohol, and consumption is 200-400mL.
6. according to the described preparation method of claim 2, it is characterized in that: described drying temperature is 50-60 ℃.
7. according to the described preparation method of claim 2, it is characterized in that: described extraction is to adopt Soxhlet to extract, and organic solvent was a hexanaphthene when it extracted.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1229071A (en) * | 1997-12-30 | 1999-09-22 | 武汉可太安生物工程有限公司 | Water-soluble heparin type chitosan sulfanilamide anticoagulation agent |
| EP1127574A1 (en) * | 2000-02-22 | 2001-08-29 | Food Industry Research and Development Institute | Use of chitinous materials for inhibiting cellular nitric oxide production |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1229071A (en) * | 1997-12-30 | 1999-09-22 | 武汉可太安生物工程有限公司 | Water-soluble heparin type chitosan sulfanilamide anticoagulation agent |
| EP1127574A1 (en) * | 2000-02-22 | 2001-08-29 | Food Industry Research and Development Institute | Use of chitinous materials for inhibiting cellular nitric oxide production |
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