CN1865272A - Glucosamine felbinac derivative synthesis method - Google Patents
Glucosamine felbinac derivative synthesis method Download PDFInfo
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- CN1865272A CN1865272A CN 200610034564 CN200610034564A CN1865272A CN 1865272 A CN1865272 A CN 1865272A CN 200610034564 CN200610034564 CN 200610034564 CN 200610034564 A CN200610034564 A CN 200610034564A CN 1865272 A CN1865272 A CN 1865272A
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Abstract
The invention discloses a synthetic method of amino glucose biphenyl acetate derivant, which comprises the following steps: adopting amino glucose hydrochlorate (1) as raw material to produce medium body of 1,3,4,6-four-O- acetyl-2- deoxidation-2-amino-beta-D-glucose (2); reacting the medium body and biphenyl acetate to form amido bond under the activating anhydrating agent action of N, N'-bicyclohexyl carbodiimide; generating the product of 1,3,4,6-four-O- acetyl-2- deoxidation-2-biphenyl acetoamino-beta-D-glucose (3); Removing acetyl base of (3) to produce 2-deoxidation-2- biphenyl acetoamino-beta-D-glucose (4). The compound (3) and (4) possesses plus or multiplied action new-drug compound, whose structures are affirmed through 1HNMR and 13CNMR detection.
Description
Technical field
The present invention relates to the synthetic method of two kinds of glucosamine derivatives, particularly the synthetic method of two kinds of glucosamine felbinac derivatives.
Background technology
Felbinac is a kind of anti-inflammatory analgesic, active metabolite for fenbufen, be usually used in the analgesia and the anti-inflammatory of endemic osteoarthritis, tenosynovitis, intramuscular pain, wound and swelling, pain, has the performance that table absorbs, but take orally and can cause gastral obstacle, therefore often make the ointment of Transdermal absorption, medicine is directly divided a word with a hyphen at the end of a line in inflammation part, have higher curative effect and security.Glucosamine is a kind of natural product, be the composition of the poly-glucosamine in human articular cartilage matrix and the synovia, the human body external source absorbs glucosamine, can stimulate the chondrocyte to recover normal metabolic function, produce polymer structural protein polysaccharide, with form, the structure of keeping cartilage.Thereby, in recent years, aspect the treatment osteoarthritis, begun to use glucosamine, in the hope of preventing from pathomechanism and the treatment osteoarthritis.
Summary of the invention
Purpose of the present invention just provides the method that a kind of four acidylate glucosamines and felbinac are carried out binding, makes the new preceding drug compound with the two kinds of compound additions or the drug action of multiplying each other that promptly takes stopgap measures and effect a permanent cure.
The present invention is realized by following method: glucosamine hydrochloride (1) is obtained tetrem amido glucose (2) through four step chemical conversions, its inventive point is: 1. with 0.5～50 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (2) and the stupid acetate of 0.5～30 gram connection are dissolved in 20～1000 milliliters the methylene dichloride, be dissolved with in the solution of 2～250 milliliters of methylene dichloride of 0.2～25 gram dicyclohexylcarbodiimide in 0～40 ℃ of adding, insulated and stirred 2～24 hours, the adularescent solid is separated out, suction filtration, collect filtrate, rotary evaporation gets the white solid thing; 2. use silica gel column chromatography, eluent is a chloroform-methanol volumetric ratio 10～500: 1, obtains 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3).
The present invention is all right: with 0.1～50 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3) is dissolved in 5～300 milliliters of anhydrous methanols, adds 6～60 milligrams of sodium methylates, and 0～40 ℃ was stirred 1～24 hour; Add acidulous cation resin, it is neutral transferring PH, the elimination resin, and filtrate rotary evaporation, residue dehydrated alcohol recrystallization obtains 2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (4).
The present invention synthesized as follows:
The present invention N; N '-dicyclohexylcarbodiimide makes four acidylate glucosamines and felbinac binding for the activation dewatering agent, obtains product: four acidylate biphenyl acetylglucosamines (3); this product behind deacetylation, can get biphenyl acetylglucosamine (4) again.In the hope of obtaining a kind of can taking orally, can external application have addition or the new preceding drug compound of the drug action of multiplying each other again, its structure is nucleus magnetic resonance
1HNMR,
13CNMR confirms, is two kinds of new preceding drug compounds.
Embodiment
Below in conjunction with embodiment, the present invention is further described.
Embodiment one
Getting glucosamine hydrochloride (1) is raw material, through four steps synthetic 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (2).
Get 0.5 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (2) and 0.5 gram felbinac are dissolved in 20 milliliters of methylene dichloride, stir down, contain 2 milliliters of the dichloromethane solutions of 0.2 gram dicyclohexylcarbodiimide 0 ℃ of adding, in 0 ℃ of reaction 2 hours, the adularescent solid was separated out, suction filtration, the filtrate rotary evaporation removes and desolvates, and gets the white solid thing; Residue is refining with silicagel column, and eluent is chloroform-methanol volumetric ratio 10: 1, obtains white crystal 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D-glucose (3).
Through nucleus magnetic resonance
1HNMR,
13CNMR measures and has confirmed its structure.Gained compound (3) is a kind of new preceding drug compound.
Embodiment two
Getting 50 grams (2) is dissolved in 1000 milliliters of methylene dichloride, stir and add 30 gram felbinac down, after the dissolving, slowly add 250 milliliters of dichloromethane solutions containing 25 gram dicyclohexylcarbodiimides under 40 ℃, in 40 ℃ of reactions 24 hours, the adularescent solid was separated out, suction filtration, the filtrate rotary evaporation removes and desolvates.Residue is refining with silicagel column, and eluent is chloroform-methanol volumetric ratio 500: 1, gets white crystal, and 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3).
By
1HNMR,
13CNMR measures the gained compound structure and confirms, and gained compound (3) is a kind of new preceding drug compound.
Embodiment three
Get 0.5 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (2) and 0.2 gram felbinac are dissolved in 20 milliliters of methylene dichloride, stir down, contain 2 milliliters of the dichloromethane solutions of 0.2 gram dicyclohexylcarbodiimide 0 ℃ of adding, in 0 ℃ of reaction 2 hours, when the adularescent solid is separated out, suction filtration, the filtrate rotary evaporation removes and desolvates, and gets the white solid thing; Residue is refining with silicagel column, and eluent is chloroform-methanol volumetric ratio 10: 1, obtains white solid 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D-glucose (3); Get 0.1 gram 1,3,4; 6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3) is dissolved in 5 milliliters of anhydrous methanols, adds 6 milligrams of sodium methylates; 0 ℃ was reacted 1 hour; add a small amount of acidulous cation resin, it is neutral transferring pH value, the elimination resin; the filtrate rotary evaporation; residue dehydrated alcohol recrystallization gets the white powder solid, is 2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D-glucose (4).
By
1HNMR,
13CNMR measures the gained compound structure and confirms, and gained compound (4) is a kind of new preceding drug compound.
Embodiment four
Get 50 grams 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (2), be dissolved in 1000 milliliters of methylene dichloride, stir adding felbinac 30 grams down, after the dissolving, slowly add 250 milliliters of dichloromethane solutions containing 25 gram dicyclohexylcarbodiimides under 40 ℃, in 40 ℃ of stirrings 24 hours, when the adularescent solid is separated out, suction filtration, the filtrate rotary evaporation removes and desolvates; Residue is refining with silicagel column, and eluent is chloroform-methanol volumetric ratio 500: 1, gets white solid 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3); With 50 grams 1,3,4; 6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3); be dissolved in 300 milliliters of anhydrous methanols, add 60 milligrams of sodium methylates, 40 ℃ were reacted 24 hours; add a small amount of acidulous cation resin; it is neutral regulating pH value, leaches resin, the filtrate rotary evaporation; residue dehydrated alcohol recrystallization, getting white solid is 2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (4).
By
1HNMR,
13CNMR measures the gained compound structure and confirms, and gained compound (4) is a kind of new preceding drug compound.
1; 3; 4; 6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3), the medicine antibacterial active testing that is carried out through Sichuan microbiotic industrial research shows, in 13 given the test agent; the 13# sample is compound (3); its anti-microbial activity the best is better than ornidazole, metronidazole, morpholine nitre azoles and clarithromycin, and significant difference is arranged.See test report for details.
The test report of " the antibacterial activity in vitro screening of anti-Hp series of samples "
[experiment purpose] [test material] [test method] omitted
[test-results] 1 test-results is omitted
2 test result analysis evaluations
2.1 the analytical test data, these 13 sample samples testing have the strong and weak antibacterial activity in vitro that does not wait to the clinical separation Hp of being tested.Wherein samples such as 3#, 9#, 13# are better to the antibacterial activity in vitro of institute's test strain, its MIC50 is 8 μ g/m1, the MIC90 value is respectively 32,8,32 μ g/ml, little 1～3 times than the MIC90 of other samples, demonstrating these three samples all has the good in-vitro anti-microbial activity to most strain subject.
2.2 change the inoculum density of bacterium liquid, to the not obviously influence of vitro antibacterial activity of the sample tested, its MIC value does not change because of the change that the inoculation bacterium is measured.The MIC data of this test gained are carried out statistical procedures with SPSS software, and whether the antibacterial activity in vitro of institute's test sample there are differences as can be seen, and analytical results shows:
1) under this test conditions, given the test agent to the external Hangzhoupro of clinical separation Hp bacterium effect best be the 13# sample, secondly be 9# sample and 3# sample.The antibacterial activity in vitro of these three samples is suitable, does not have significant difference (P＞0.05), but these three samples all significantly are better than other given the test agent (P＜0.05).
2) under this test conditions, 13#, 9# and 3# sample are better than control drug ornidazole, metronidazole, morpholine nitre azoles and clarithromycin to the vitro antibacterial activity of clinical separation Hp, and significant difference (P＜0.05) is arranged.
Claims (2)
1, a kind of synthetic method of glucosamine felbinac derivative is characterized in that:
1. with 0.5～50 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (2) and the stupid acetate of 0.5～30 gram connection are dissolved in 20～1000 milliliters the methylene dichloride, are dissolved with in the solution of 2～250 milliliters of methylene dichloride of 0.2～25 gram dicyclohexylcarbodiimide in 0～40 ℃ of adding, insulated and stirred 2～24 hours, the adularescent solid is separated out, and suction filtration is collected filtrate, rotary evaporation gets the white solid thing;
2. use silica gel column chromatography, eluent is a chloroform-methanol volumetric ratio 10～500: 1, obtains 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3).
2, according to the synthetic method of right 1 described glucosamine felbinac derivative, it is characterized in that:
1. get 0.1～50 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (3) is dissolved in 5～300 milliliters of anhydrous methanols, adds 6～60 milligrams of sodium methylates, and 0～40 ℃ was stirred 1～24 hour;
2. add acidulous cation resin, it is neutral transferring PH, the elimination resin, and filtrate rotary evaporation, residue dehydrated alcohol recrystallization obtains 2-deoxidation-2-biphenyl acetylaminohydroxyphenylarsonic acid β-D glucose (4).
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| CN 200610034564 CN1865272A (en) | 2006-03-27 | 2006-03-27 | Glucosamine felbinac derivative synthesis method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104017030A (en) * | 2014-06-19 | 2014-09-03 | 资阳顺兴制药有限公司 | Glucosamine derivatives |
| CN104017029A (en) * | 2014-06-19 | 2014-09-03 | 四川大学 | Glucosamine derivatives or pharmaceutically acceptable salts thereof |
-
2006
- 2006-03-27 CN CN 200610034564 patent/CN1865272A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104017030A (en) * | 2014-06-19 | 2014-09-03 | 资阳顺兴制药有限公司 | Glucosamine derivatives |
| CN104017029A (en) * | 2014-06-19 | 2014-09-03 | 四川大学 | Glucosamine derivatives or pharmaceutically acceptable salts thereof |
| CN104017029B (en) * | 2014-06-19 | 2017-06-06 | 四川大学 | Aminoglucose sugar derivatives or its pharmaceutically acceptable salt |
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