CN1271079C - Method for synthesizing ramification of diclofenac of glucosamine - Google Patents
Method for synthesizing ramification of diclofenac of glucosamine Download PDFInfo
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- CN1271079C CN1271079C CN 200410077358 CN200410077358A CN1271079C CN 1271079 C CN1271079 C CN 1271079C CN 200410077358 CN200410077358 CN 200410077358 CN 200410077358 A CN200410077358 A CN 200410077358A CN 1271079 C CN1271079 C CN 1271079C
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- diclofenac
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Abstract
The present invention relates to a method for synthesizing aminoglucose diclofenac derivatives. The aminoglucose acid and the diclofenac carry out bonding by a chemical method. A novel prodrug compound with the function of addition or multiplication on the medicine property is synthesized. The present invention uses aminoglucose hydrochlorate to serve as raw material, and thus, an intermediate of 1, 3, 4, 6-four-O-acetyl-2-deoxidation-2-amino-belta-D-glucose is prepared. Under the activation dehydration function of N, N'-dicyclohexylcarbodiimide, a compound of 2-[1, 3, 4, 6-four-O-acetyl-2-deoxidation-2-amino-belta-D-glucosyl]-diclofenac with amido links is formed from the intermediate of 1, 3, 4, 6-four-O-acetyl-2-deoxidation-2-amino-belta-D-glucose and diclofenac. After tested by [1]HNMR, [13]CNMR and MS, the compound of 2-[1, 3, 4, 6-four-O-acetyl-2-deoxidation-2-amino-belta-D-glucosyl]-diclofenac is a novel prodrug compound.
Description
Technical field
The present invention relates to a kind of synthetic method of derivative, the one-tenth method that particularly a kind of ramification of diclofenac of glucosamine closes.
Background technology
Diclofenac sodium belongs to the non-steroidal antalgic anti-inflammatory agent, and osteoarthropathy is treated in many clinically being applied to, and is characterized in that produce effects is fast, but because it has significant side effects to stomach and intestine, thereby clinical application has been subjected to very big restriction.Glucosamine is a kind of natural amino monose, is the composition of poly-glucosamine in cartilage matrix and the synovia.Ectogenic glucosamine can stimulate chondrocyte's synthetic proteins polysaccharide, replenishes the composition of losing of cartilage matrix, and can suppress expression of MMPs mRNA, thereby promote the reparation of cartilage.Clinical test results shows that glucosamine not only has the doing well,improving effect to osteoarthritis, but also has state of an illness control action kou, is the choice drug of the prophylactic treatment osteoarthritis of present world affirmation.2003, prestige pharmaceutcal corporation, Ltd far away in China approved Shanxi produced glucosamine hydrochloride (No. the 20020306th, the accurate word of traditional Chinese medicines) listing, medicine name " capsule founds in the Portugal ".
Summary of the invention
Purpose of the present invention just provides a kind of diclofenac and glucosamine carries out binding, obtains a kind of toxic side effect that can reduce diclofenac sodium, has the new preceding drug compound of the two drug effect addition of diclofenac sodium and glucosamine or synergism again.
The present invention can be realized by following mode: diclofenac sodium is changed into diclofenac; Glucosamine hydrochloride (1) is condensed into schiff base compound (2) with phenyl aldehyde; Amido protecting on the sugar ring is got up, and acetylize gets full acetylated glucosamine schiff bases (3); Behind hydroxyl protection on the sugar ring, slough phenyl aldehyde, obtain full acetylated glucosamine hydrochloride (4), take off hydrochloric acid, get intermediate 1,3,4,6-four-O-ethanoyl 2-deoxidation-2-amino-beta--D-grape sugar (5); Its inventive point is: 1. with 1～500 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-ammonia-β-D-glucose (5) and 1～500 gram diclofenac add in 200～10000 milliliters of methylene dichloride, 0～40 ℃ is stirred down, add 1～100 gram N, N '-dicyclohexylcarbodiimide is when white precipitate is separated out, restir 1～36 hour, leach precipitation, filtrate concentrates, and gets white solid substance; 2. use silica gel column chromatography, eluent is trichloromethane-methyl alcohol volume ratio 10～1500: 1, and concentrating under reduced pressure, drying obtain 2-[1,3,4, and 6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac (6).
When the present invention selects diclofenac and glucosamine binding; consider in the diclofenac molecule to have bifunctional, adopt chloride method, have a lot of side reactions and take place; so select N for use; N '-dicyclohexylcarbodiimide is the activation dewatering agent, and methylene dichloride is a solvent, and the two is bonding at a certain temperature; obtain compound 2-[1; 3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac (6).Through nucleus magnetic resonance
1HNMR,
13CNMR and mass spectrum MS measure, and have proved conclusively 2-[1, and 3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac is a kind of preceding drug compound.
Building-up process of the present invention is as follows:
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment one
Add 31.9 gram diclofenac sodium and 120 ml distilled waters in the reaction flask, heated and stirred makes its dissolving, 1 mole hydrochloride is stirred slow down the adding in the above-mentioned solution, the adularescent solid is separated out, and continues to stir 10 minutes, is cooled to room temperature, suction filtration, filter cake wash PH=6 with water, pump, conventional drying gets diclofenac; Get 10 gram glucosamine hydrochlorides (1), under 0 ℃, be added in the 47 ml water solution that contain 1.84 gram sodium hydroxide, stir down, slowly add 5.4 milliliters of phenyl aldehydes, when separating out white solid, continue to stir 1 hour, placed 12 hours down, filter in 0 ℃, water, ether successively: the mixed solvent washing in 1: 1 of ethanol volume ratio, dry schiff base compound (2); Getting 11.9 gram schiff base compounds (2) is added in 70 milliliters of pyridines, stir down in 0 ℃, slowly add 42 milliliters of diacetyl oxides, intensification 35-40 ℃, be incubated 6 hours, reactant is poured in the frozen water, the adularescent solid is separated out, and stirs 1 hour, filters, water, petroleum ether successively, dry the full acetylated amino grape schiff bases of white solid thing (3); Getting the 4.4 full acetylated amino grape schiff bases of gram (3) is added in 100 milliliters the acetone, stir under the room temperature, slowly adding contains in the 5 ml methanol solution of 0.84 milliliter of hydrochloric acid, separates out white solid, reacts 1 hour, add the ether stopped reaction, be cooled to 0 ℃, be incubated 1 hour, filter, filter cake washs with ether, the dry full acetylated glucosamine hydrochloride (4) that gets; Getting the 3.9 full acetylated glucosamine hydrochlorides of gram (4) is dissolved in 20 ml waters; add sodium-acetate 1.64 grams, normal temperature stirred 1 hour down, folded white solid; chloroform extraction; the extraction liquid underpressure distillation gets white solid, washs with ether; dry 1; 3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (5).
Get 1 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (5) and 1 gram diclofenac place the exsiccant round-bottomed flask, add 200 milliliter methylene dichloride, 0 ℃ is stirred down, adds 1 gram N, N '-dicyclohexylcarbodiimide, when white precipitate is separated out, stirred 1 hour, leach precipitation, filtrate concentrates, and gets white solid substance; Use silica gel column chromatography, eluent is trichloromethane-methyl alcohol volume ratio 10: 1, and concentrating under reduced pressure, drying obtain 2-[1,3,4, and 6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac (6).
Through nucleus magnetic resonance
1HNMR,
13CNMR and mass spectrum MS measure, and have proved conclusively gained compound 2-[1, and 3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac is a kind of new preceding drug compound.
Embodiment two
Change into diclofenac from diclofenac sodium, arrive intermediate 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (5) is identical with embodiment one, no longer the narration.
Get 50 grams 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (5) and 50 gram diclofenacs place the exsiccant round-bottomed flask, add 10000 milliliters of methylene dichloride, 40 ℃ are stirred down, add 100 gram N, N '-dicyclohexylcarbodiimide, when white precipitate is separated out, stirred 36 hours, leach precipitation, filtrate concentrates, and gets white solid substance; Use silica gel column chromatography, eluent is trichloromethane-methyl alcohol volume ratio 1500: 1, obtains 2-[1,3,4, and 6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac (6).
Through nucleus magnetic resonance
1HNMR,
13CNMR and mass spectrum MS measure, and have proved conclusively gained compound 2-[1, and 3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac is a kind of new preceding drug compound.
Claims (1)
1, a kind of synthetic method of ramification of diclofenac of glucosamine is characterized in that:
1. with 1～500 gram 1,3,4,6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucose (5) and 1～500 gram diclofenac add in 200～10000 milliliters of methylene dichloride, 0～40 ℃ is stirred down, add 1～100 gram N, N '-dicyclohexylcarbodiimide is when white precipitate is separated out, stirred 1～36 hour, leach precipitation, filtrate concentrates, and gets white solid substance;
2. use silica gel column chromatography, eluent is trichloromethane-methyl alcohol volume ratio 10～1500: 1, obtains 2-[1,3,4, and 6-four-O-ethanoyl-2-deoxidation-2-amino-beta--D-glucosyl group]-diclofenac (6).
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410077358 CN1271079C (en) | 2004-12-08 | 2004-12-08 | Method for synthesizing ramification of diclofenac of glucosamine |
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| CN 200410077358 CN1271079C (en) | 2004-12-08 | 2004-12-08 | Method for synthesizing ramification of diclofenac of glucosamine |
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| CN1660870A CN1660870A (en) | 2005-08-31 |
| CN1271079C true CN1271079C (en) | 2006-08-23 |
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| CN100460413C (en) * | 2006-01-16 | 2009-02-11 | 中国药科大学 | Chemical compound synthesized by carboxylic acid analog non-steroid anti-inflammatory agent and aminoglucose or its salt, and its synthesis method and uses |
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