CN102199176A - Preparation method for 2-amino-2-deoxy-D-glucose and salt thereof - Google Patents
Preparation method for 2-amino-2-deoxy-D-glucose and salt thereof Download PDFInfo
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Abstract
The invention discloses a preparation method for 2-amino-2-deoxy-D-glucose and hydrochloride or sulfate thereof, which comprises the following steps: carrying out acylation, bromination, protection, esterification, substitution, reduction and other processes on D-glucose used as a raw material to obtain 2-amino-2-deoxy-D-glucose; and adding sulfuric acid or hydrochloric acid to the 2-amino-2-deoxy-D-glucose used as a raw material, thus forming 2-amino-2-deoxy-D-glucose and hydrochloride or sulfate thereof in an organic solvent. The preparation method has the advantages that the used chemical raw materials are easily available, the quality of the in-process intermediate product and final product of the prepared glucosamine is easy to control, the product has high yield and purity and is easy to separate and purify, the used organic solvents are recoverable, and the cost is lowered. Besides, the preparation method is simple in process and is easy to realize industrial mass production.
Description
Technical field
The present invention relates to the synthetic method of a kind of 2-amino-2-deoxidation-D-glucosamine; The invention still further relates to the preparation method of aforementioned 2-amino-2-deoxidation-D-glucosamine hydrochloride or vitriol.
Background technology
Glucosamine hydrochloride or vitriol (also being 2-amino-2-deoxy-D-glucose hydrochloride or vitriol) are treatment bone and joint diseases medicine and microbiotic synergistic agent; be again sweeting agent, the antioxidant of food; also can make the nutrition accessory agent for the diabetic subject; but the also growth of anticancer simultaneously; being the main raw material of synthesizing new antitumor drug NSC-178248, also is the important source material of the active substance N-formamyl glucosamine of anti-gram negative bacterium and fungi.Glucosamine sugar hydrochloride or vitriol and derivative thereof the background that has a wide range of applications in fields such as medical science, chemical industry, makeup.
D-2-glucosamine hydrochloride vitriol of the prior art all is by chitin preparation, generally adopts the hydrochloric acid hydrolysis method, promptly adds chitin in certain density hydrochloric acid, through operations such as hydrolysis, concentrated, decolouring and crystallizations.Thereby obtain the glucosamine sugar hydrochloride or the sulphate crystal powder of white, but glucosamine hydrochloride or vitriol are under the acid solution and the situation of being heated of higher concentration, can cause complicated compound and decomposition reaction, not only make the color burn of crude product, and reduce finished product purity and the recovery rate that reduces finished product, thereby increase the cost of preparation.
Summary of the invention
Technical problem to be solved by this invention is at the deficiencies in the prior art, provides that a kind of method is more reasonable, the preparation method of finished product purity height, 2-amino-2-deoxy-D-glucose that cost is low.
Another technical problem to be solved by this invention has provided the preparation method of a kind of 2-amino-2-deoxy-D-glucose and hydrochloride thereof.
Another technical problem to be solved by this invention has provided the preparation method of a kind of 2-amino-2-deoxy-D-glucose and vitriol thereof.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is a kind of preparation method of 2-amino-2-deoxy-D-glucose, is characterized in, its step is as follows:
(1) with D-glucose in the presence of perchloric acid or sulfuric acid with acetic anhydride, make penta-acetyl glucose, penta-acetyl glucose is without separation, directly in the presence of phosphorus with the bromine reaction or directly feed bromize hydrogen gas and obtained compound 3;
(2) compound 3 is dissolved in the organic solvent, at alkaline matter, phase-transfer catalyst exists down and 4-penten-1-alcohol, reacting generating compound 4;
(3) compound 4 is dissolved in the organic solvent, under alkaline condition, with bromobenzyl reacting generating compound 5;
(4) compound 5 is dissolved in the organic solvent, reacting generating compound 6 in the presence of silicon ester;
(5) compound 6 is dissolved in organic solvent or the mixed solvent, under alkaline condition,, generates compound 7 with the SULPHURYL CHLORIDE reaction;
(6) compound 7 is dissolved in the organic solvent, with trinitride reacting generating compound 8;
(7) compound 8 is dissolved in the organic solvent, in the presence of 10% palladium charcoal and hydrogen, shortening is also sloughed benzyl simultaneously, and obtaining compound 1 is 2-amino-2-deoxy-D-glucose.
The synthetic route of 2-amino-2-deoxy-D-glucose of the present invention is as follows:
In the following synthetic route, mark 1,3,4,5,6,7,8 structural formula below and be respectively compound 1(2-amino-2-deoxy-D-glucose), the structural formula of compound 3, compound 4, compound 5, compound 6, compound 7, compound 8.
In the scheme, optimized technical scheme is in above-described 2-amino-2-deoxy-D-glucose preparation method technology:
1, in step (1), D-glucose in the presence of perchloric acid with acetic anhydride, temperature of reaction is-10 ℃～30 ℃, the reaction times is 1～4 hour, the mol ratio of D-glucose, diacetyl oxide and perchloric acid is 1:5～12:0.01～0.1; Five acetyl glucose in the presence of phosphorus with bromine temperature of reaction-10～25 ℃, the reaction times is 1～4 hour, the mol ratio of D-glucose, phosphorus and bromine is 1:1～2.5:1～2.5.
2, in step (1), D-glucose in the presence of sulfuric acid with acetic anhydride, temperature is-10 ℃～30 ℃, the reaction times is 1～4 hour, D-glucose, diacetyl oxide and vitriolic mol ratio are 1:5～12:0.01～0.1; Five acetyl glucose in the presence of phosphorus with bromine temperature of reaction-10～25 ℃, the reaction times is 1～4 hour, the mol ratio of D-glucose, phosphorus and bromine is 1:1～2.5:1～2.5.
3, in step (2), described alkaline matter is selected from pyridine, triethylamine, Trimethylamine 99,3-aminopyridine, trimethylpyridine or 4-aminopyridine; Phase-transfer catalyst is selected from Tetrabutyl amonium bromide, tetraethylammonium bromide, triethyamino Benzyl Chloride or triethyamino cylite.
4, in step (4), described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), methane amide, methyl alcohol, ethanol, the mixture of one or more compositions in propyl alcohol or the butanols; Described silicon ester is selected from monobromo-acetic acid trimethyl silane ester, silica-based ethyl acetate of front three or trifluoromethanesulfonic acid trimethyl silane ester.
5, in step (5), compound 6 reacts with SULPHURYL CHLORIDE under alkaline condition, and temperature of reaction is-20 ℃～20 ℃, and the reaction times is 13～18 hours; Described alkaline matter is selected from salt of wormwood, yellow soda ash, Trimethylamine 99, triethylamine, pyridine or piperidines; Described SULPHURYL CHLORIDE is selected from methane sulfonyl chloride, benzene sulfonyl chloride or Tosyl chloride.
6, in step (6), described solvent is selected from water, ethyl acetate, methyl acetate, methylene dichloride, trichloromethane, dioxane, the mixture of one or more compositions in tetrahydrofuran (THF) or the acetone; Described trinitride is sodiumazide or potassium azide; Temperature of reaction is 60 ℃～160 ℃, and the reaction times is 3～8 hours.
7, in step (7), described organic solvent is selected from the mixture of one or more compositions in methyl alcohol, ethanol, n-propyl alcohol, ethyl acetate, formic acid or the acetate; Temperature of reaction is 0 ℃～120 ℃, and pressure is 0.1MPa～20Mpa.
The invention also discloses the preparation method of a kind of 2-amino-2-deoxy-D-glucose hydrochloride, be characterized in: it is salify in organic solvent or water with prepared 2-amino-2-deoxy-D-glucose of the preparation method of any one described 2-amino-2-deoxy-D-glucose in the above technical scheme and hydrochloric acid, obtains 2-amino-2-deoxy-D-glucose hydrochloride; Refining obtaining made with extra care 2-amino-2-deoxy-D-glucose hydrochloride in solvent then, and described solvent is a water, methyl alcohol, ethanol, the mixture of one or more compositions in the acetone.
The invention also discloses the preparation method of a kind of 2-amino-2-deoxy-D-glucose vitriol, be characterized in: it is salify in organic solvent or water with prepared 2-amino-2-deoxy-D-glucose of the preparation method of any one described 2-amino-2-deoxy-D-glucose in the above technical scheme and sulfuric acid, obtains 2-amino-2-deoxy-D-glucose vitriol; Refining obtaining made with extra care 2-amino-2-deoxy-D-glucose vitriol in solvent then, and described solvent is a water, methyl alcohol, ethanol, the mixture of one or more compositions in the acetone.
Compared with prior art, the used chemical feedstocks of the inventive method is easy to get, and intermediate and end product quality are controlled easily in the glucosamine process for preparing, product yield is higher, and purity is good, is easy to separate purify, and all recyclable utilization of organic solvent that the present invention is used can reduce cost.And the inventive method technology is simple, is easy to industrialized production.
Embodiment
Below further describe concrete technical scheme of the present invention,, and do not constitute restriction its right so that those skilled in the art understands the present invention further.Used various chemical and reagent are commercially available purchase if no special instructions among the embodiment.
Embodiment 1.A kind of preparation method of 2-amino-2-deoxy-D-glucose, its step is as follows:
(1) with D-glucose in the presence of perchloric acid or sulfuric acid with acetic anhydride, make penta-acetyl glucose, penta-acetyl glucose is without separation, directly in the presence of phosphorus with the bromine reaction or directly feed bromize hydrogen gas and obtained compound 3;
(2) compound 3 is dissolved in the organic solvent, at alkaline matter, phase-transfer catalyst exists down and 4-penten-1-alcohol, reacting generating compound 4;
(3) compound 4 is dissolved in the organic solvent, under alkaline condition, with bromobenzyl reacting generating compound 5;
(4) compound 5 is dissolved in the organic solvent, reacting generating compound 6 in the presence of silicon ester;
(5) compound 6 is dissolved in organic solvent or the mixed solvent, under alkaline condition,, generates compound 7 with the SULPHURYL CHLORIDE reaction;
(6) compound 7 is dissolved in the organic solvent, with trinitride reacting generating compound 8;
(7) compound 8 is dissolved in the organic solvent, in the presence of 10% palladium charcoal and hydrogen, shortening is also sloughed benzyl simultaneously, and obtaining compound 1 is 2-amino-2-deoxy-D-glucose.
Embodiment 2.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of perchloric acid with acetic anhydride, temperature of reaction is-10 ℃, the reaction times is 1 hour, the mol ratio of D-glucose, diacetyl oxide and perchloric acid is 1:5:0.01; Five acetyl glucose in the presence of phosphorus with bromine temperature of reaction-10 ℃, the reaction times is 1 hour, the mol ratio of D-glucose, phosphorus and bromine is 1:1:1.
Embodiment 3.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of perchloric acid with acetic anhydride, temperature of reaction is 30 ℃, the reaction times is 4 hours, the mol ratio of D-glucose, diacetyl oxide and perchloric acid is 1:12:0.1; Five acetyl glucose in the presence of phosphorus with 25 ℃ of bromine temperature of reaction, the reaction times is 4 hours, the mol ratio of D-glucose, phosphorus and bromine is 1:2.5:2.5.
Embodiment 4.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of perchloric acid with acetic anhydride, temperature of reaction is 20 ℃, the reaction times is 2 hours, the mol ratio of D-glucose, diacetyl oxide and perchloric acid is 1:8:0.05; Five acetyl glucose in the presence of phosphorus with 15 ℃ of bromine temperature of reaction, the reaction times is 2 hours, the mol ratio of D-glucose, phosphorus and bromine is 1:1.5:2.0.
Embodiment 5.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of sulfuric acid with acetic anhydride, temperature is-10 ℃, the reaction times is 1 hour, D-glucose, diacetyl oxide and vitriolic mol ratio are 1:5:0.01; Five acetyl glucose in the presence of phosphorus with bromine temperature of reaction-10 ℃, the reaction times is 1 hour, the mol ratio of D-glucose, phosphorus and bromine is 1:1:1.
Embodiment 6.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of sulfuric acid with acetic anhydride, temperature is 30 ℃, the reaction times is 4 hours, D-glucose, diacetyl oxide and vitriolic mol ratio are 1:12:0.1; Five acetyl glucose in the presence of phosphorus with 25 ℃ of bromine temperature of reaction, the reaction times is 4 hours, the mol ratio of D-glucose, phosphorus and bromine is 1:2.5:2.5.
Embodiment 7.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of sulfuric acid with acetic anhydride, temperature is 30 ℃, the reaction times is 4 hours, D-glucose, diacetyl oxide and vitriolic mol ratio are 1:12:0.1; Five acetyl glucose in the presence of phosphorus with 25 ℃ of bromine temperature of reaction, the reaction times is 4 hours, the mol ratio of D-glucose, phosphorus and bromine is 1:2.5:2.5.
Embodiment 8.In embodiment 1 described preparation method's the step (1): D-glucose in the presence of sulfuric acid with acetic anhydride, temperature is 15 ℃, the reaction times is 1.5 hours, D-glucose, diacetyl oxide and vitriolic mol ratio are 1:7:0.06; Five acetyl glucose in the presence of phosphorus with 15 ℃ of bromine temperature of reaction, the reaction times is 2.5 hours, the mol ratio of D-glucose, phosphorus and bromine is 1:2:1.5.
Embodiment 9.In any one described preparation method's of embodiment 1-8 the step (2): described alkaline matter is selected from pyridine, triethylamine, Trimethylamine 99,3-aminopyridine, trimethylpyridine or 4-aminopyridine; Phase-transfer catalyst is selected from Tetrabutyl amonium bromide, tetraethylammonium bromide, triethyamino Benzyl Chloride or triethyamino cylite.
Embodiment 10.In any one described preparation method's of embodiment 1-9 the step (4): described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), methane amide, methyl alcohol, ethanol, the mixture of one or more compositions in propyl alcohol or the butanols; Described silicon ester is selected from monobromo-acetic acid trimethyl silane ester, silica-based ethyl acetate of front three or trifluoromethanesulfonic acid trimethyl silane ester.
Embodiment 11.In any one described preparation method's of embodiment 1-10 the step (5): compound 6 reacts with SULPHURYL CHLORIDE under alkaline condition, and temperature of reaction is-20 ℃, and the reaction times is 13 hours; Described alkaline matter is selected from salt of wormwood, yellow soda ash, Trimethylamine 99, triethylamine, pyridine or piperidines; Described SULPHURYL CHLORIDE is selected from methane sulfonyl chloride, benzene sulfonyl chloride or Tosyl chloride.
Embodiment 12.In any one described preparation method's of embodiment 1-10 the step (5): compound 6 reacts with SULPHURYL CHLORIDE under alkaline condition, and temperature of reaction is 20 ℃, and the reaction times is 18 hours; Described alkaline matter is selected from salt of wormwood, yellow soda ash, Trimethylamine 99, triethylamine, pyridine or piperidines; Described SULPHURYL CHLORIDE is selected from methane sulfonyl chloride, benzene sulfonyl chloride or Tosyl chloride.
Embodiment 13.In any one described preparation method's of embodiment 1-10 the step (5): compound 6 reacts with SULPHURYL CHLORIDE under alkaline condition, and temperature of reaction is 10 ℃, and the reaction times is 15 hours; Described alkaline matter is selected from salt of wormwood, yellow soda ash, Trimethylamine 99, triethylamine, pyridine or piperidines; Described SULPHURYL CHLORIDE is selected from methane sulfonyl chloride, benzene sulfonyl chloride or Tosyl chloride.
Embodiment 14.In any one described preparation method's of embodiment 1-13 the step (6): described solvent is selected from water, ethyl acetate, methyl acetate, methylene dichloride, trichloromethane, dioxane, a kind of in tetrahydrofuran (THF) or the acetone; Described trinitride is sodiumazide or potassium azide; Temperature of reaction is 60 ℃, and the reaction times is 3 hours.
Embodiment 15.In any one described preparation method's of embodiment 1-13 the step (6): described solvent is selected from water, ethyl acetate, methyl acetate, methylene dichloride, trichloromethane, dioxane, the mixture of any two kinds of compositions in tetrahydrofuran (THF) or the acetone; Described trinitride is sodiumazide or potassium azide; Temperature of reaction is 160 ℃, and the reaction times is 8 hours.
Embodiment 16.In any one described preparation method's of embodiment 1-13 the step (6): described solvent is selected from water, ethyl acetate, methyl acetate, methylene dichloride, trichloromethane, dioxane, the mixture of one or more compositions in tetrahydrofuran (THF) or the acetone; Described trinitride is sodiumazide or potassium azide; Temperature of reaction is 100 ℃, and the reaction times is 5 hours.
Embodiment 17.In any one described preparation method's of embodiment 1-16 the step (7); Described organic solvent is selected from the mixture of one or more compositions in methyl alcohol, ethanol, n-propyl alcohol, ethyl acetate, formic acid or the acetate; Temperature of reaction is 0 ℃, and pressure is 0.1MPa.
Embodiment 18.In any one described preparation method's of embodiment 1-16 the step (7); Described organic solvent is selected from the mixture of one or more compositions in methyl alcohol, ethanol, n-propyl alcohol, ethyl acetate, formic acid or the acetate; Temperature of reaction is 120 ℃, and pressure is 20Mpa.
Embodiment 19.In any one described preparation method's of embodiment 1-16 the step (7); Described organic solvent is selected from the mixture of one or more compositions in methyl alcohol, ethanol, n-propyl alcohol, ethyl acetate, formic acid or the acetate; Temperature of reaction is 30 ℃, and pressure is 5Mpa.
Embodiment 20.The preparation method of a kind of 2-amino-2-deoxy-D-glucose hydrochloride, it obtains 2-amino-2-deoxy-D-glucose hydrochloride with any one described 2-amino-2-deoxy-D-glucose among the embodiment 1-19 and hydrochloric acid salify in organic solvent or water; Refining obtaining made with extra care 2-amino-2-deoxy-D-glucose hydrochloride in solvent then, and described solvent is a water, methyl alcohol, ethanol, the mixture of one or more compositions in the acetone.
Embodiment 21.The preparation method of a kind of 2-amino-2-deoxy-D-glucose vitriol, it obtains 2-amino-2-deoxy-D-glucose vitriol with any one described 2-amino-2-deoxy-D-glucose among the embodiment 1-19 and sulfuric acid salify in organic solvent or water; Refining obtaining made with extra care 2-amino-2-deoxy-D-glucose vitriol in solvent then, and described solvent is a water, methyl alcohol, ethanol, the mixture of one or more compositions in the acetone.
Embodiment 22.The preparation method of 2-amino-2-deoxidation-D-glucosamine hydrochloride or vitriol.
(1) preparation of compound 3:
D-glucose 55mol slowly is added in the stirring the mixture of diacetyl oxide 440mol and perchloric acid 400ml, control reaction temperature is no more than 40 ℃, after 2 hours, phosphorus 90mol is joined in the reaction soln, reaction mixture is cooled to 0 ℃ of-10 ∽, and under this temperature, add bromine 130mol, after bromine drips, drip pure water 200mol again, control reaction temperature, after being added dropwise to complete, reaction is 2.5 hours under stirring at room.Methylene dichloride and frozen water, organic layer washing secondary, anhydrous magnesium sulfate drying, at last yellow soup compound compound 3, yield 88.1%.
(2) preparation of compound 4:
Compound 3 40mol with gained of last step, be dissolved among the trichloromethane 70L, stir and add trimethylpyridine 1mol N-Bu4NBr 0.5mol down, keep the reaction soln temperature at 10--15 ℃, drip the trichloromethane 96L solution of 4-penten-1-alcohol 44mol, after being added dropwise to complete, in 42--48 ℃ of reaction handled in 8 hours compound 4, yield 83.2%.Through potassium hydroxide, handle, and can make pure compound 5, yield 84.1% by bromobenzyl in tetrahydrofuran (THF) for compound 4.
(3) preparation of compound 6:
Compound 5 16mol of above-mentioned preparation are dissolved among the methylene dichloride 20L icy salt solution cooling down, make solution temperature below 0 ℃, and control reaction soln temperature is in below 0 ℃, be added dropwise to the methylene dichloride 40L solution of trifluoromethanesulfonic acid trimethyl silane ester 20mol, after dropwising, continue reaction 3 hours, reaction soln is handled with methanol solution of sodium methylate, obtain compound 6, yield 84.5%.
(4) preparation of compound 7:
6 10mol are dissolved among the trichloromethane 50L with compound, are cooled to below-5 ℃, stir to drip pyridine 11mol down, and keep dripping the trichloromethane 10L solution of Tosyl chloride 11mol, after dropwising below-5 ℃, naturally heat up, continue reaction 13 hours under the room temperature, solution is used frozen water, saturated sodium bicarbonate solution successively, the saturated common salt water washing, anhydrous magnesium sulfate drying filters the compound 7 of concentrating under reduced pressure.Yield 77.5%.
(5) preparation of compound 8:
Compound 7 5mol are dissolved among the dimethyl formamide 25L, stir and add powdery sodiumazide 7.5mol, heating reflux reaction 5 hours, concentrating under reduced pressure down, residue adds ethyl acetate 8L ⅹ 5, merge organic layer, pure water 10L ⅹ 3 washings, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure gets compound 8, yield 79.1%.
(6) preparation of glucosamine (1):
8 1mol are dissolved in the methyl alcohol with compound, add 10% palladium charcoal, 20 grams, vacuumize, and exchange three times with nitrogen, hydrogen exchange three times, with be hydrogenated under the normal temperature and pressure do not inhale hydrogen till, vacuumize and nitrogen exchange three times discharging, filter, methanol wash is removed the palladium catalyst charcoal, gets colourless solution and handles with triethylamine 1mol, must contain the solution of 2-amino-2-deoxidation-D-glucosamine.
(7) get above-mentioned solution and transfer pH ≈ 2 back concentrating under reduced pressure to get thick 2-amino-2-D-glucosamine hydrochloride with 2N hydrochloric acid, water and methyl alcohol volume ratio 1:1 are refining and obtain 2-amino-2-deoxidation-D-glucosamine hydrochloride again.Gained 2-amino-2-deoxidation-D-glucosamine hydrochloride quality index: content HPLC 99.6%, chlorion 16.4, pH 4.1, optically-active 72.2, iron ion 3PPM, ignition residue 0.07, weight loss on drying 0.22.
Perhaps transfer pH ≈ 2 back concentrating under reduced pressure to get thick 2-amino-2-deoxidation-D-glucosamine vitriol with 4N sulfuric acid above-mentioned solution, water and ethanol volume ratio 1:1.5 are refining and obtain 2-amino-2-deoxy-D-glucose vitriol again.Gained 2-amino-2-deoxidation-D-glucosamine vitriol quality index: content HPLC 99.4%, sulfate ion 33.4, pH 3.2, optically-active 52.5, iron ion 2PPM, ignition residue 21.2, weight loss on drying 0.34.
Embodiment 23.The preparation method of 2-amino-2-deoxidation-D-glucosamine hydrochloride or vitriol.
(1) preparation of compound 3:
D-glucose 55mol slowly is added in the stirring the mixture of diacetyl oxide 440mol and perchloric acid 400ml, control reaction temperature is no more than 40 ℃, after 2 hours, reaction mixture is cooled to 0 ℃ of-10 ∽, and under this temperature, feed the bromize hydrogen gas control reaction temperature, after finishing, under stirring at room, continue reaction 2.5 hours.Add methylene dichloride and frozen water, organic layer washing secondary, anhydrous magnesium sulfate drying, at last yellow soup compound compound 3, yield 87.8%.
(2) preparation of compound 4:
The preparation method can make pure compound 5 with embodiment 22, yield 84.5%.
(3) preparation of compound 6:
Compound 5 16mol of above-mentioned preparation are dissolved among the methylene dichloride 20L icy salt solution cooling down, make solution temperature below 0 ℃, and control reaction soln temperature is in below 0 ℃, be added dropwise to the methylene dichloride 40L solution of monobromo-acetic acid trimethyl silane ester 20mol, after dropwising, continue reaction 3 hours, reaction soln is handled with methanol solution of sodium methylate, obtain compound 6, yield 85.2 %.
(4) preparation of compound 7:
6 10mol are dissolved among the trichloromethane 50L with compound, are cooled to below-5 ℃, stir to drip piperidinyl-1 1mol down, and keep dripping the trichloromethane 10L solution of methylsulfonyl chloride 11mol, after dropwising below-5 ℃, naturally heat up, continue reaction 14 hours under the room temperature, solution is used frozen water, saturated sodium bicarbonate solution successively, the saturated common salt water washing, anhydrous magnesium sulfate drying filters the compound 7 of concentrating under reduced pressure.Yield 78.4%.
(5) preparation of compound 8:
Compound 7 5mol are dissolved among the dimethyl formamide 25L, stir and add powdery sodiumazide 7.5mol, heating reflux reaction 5 hours, concentrating under reduced pressure down, residue adds ethyl acetate 8L ⅹ 5, merge organic layer, pure water 10L ⅹ 3 washings, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure gets compound 8, yield 78.7%.
(6) preparation of glucosamine (1):
8 1mol are dissolved in the ethanol with compound, add 10% palladium charcoal, 20 grams, vacuumize, and exchange three times with nitrogen, hydrogen exchange three times, with be hydrogenated under the normal temperature and pressure do not inhale hydrogen till, vacuumize and nitrogen exchange three times discharging, filter, washing with alcohol is removed the palladium catalyst charcoal, gets colourless solution and handles with triethylamine 1mol, must contain the solution of 2-amino-2-deoxidation-D-glucosamine.
(7) above-mentioned solution transfers pH ≈ 2 back concentrating under reduced pressure to get thick 2-amino-2-D-glucosamine hydrochloride with 2N hydrochloric acid, and water and methyl alcohol volume ratio 1:1 are refining and obtain 2-amino-2-deoxidation-D-glucosamine hydrochloride again.Gained 2-amino-2-deoxidation-D-glucosamine hydrochloride quality index: content HPLC 99.8%, chlorion 16.5, pH 4.0, optically-active 71.6, iron ion 2PPM, ignition residue 0.06, weight loss on drying 0.25.
Perhaps above-mentioned solution transfers pH ≈ 2 back concentrating under reduced pressure to get thick 2-amino-2-deoxidation-D-glucosamine vitriol with 4N sulfuric acid, and water and ethanol volume ratio 1:1.5 are refining and obtain 2-amino-2-deoxy-D-glucose vitriol again.Gained 2-amino-2-deoxidation-D-glucosamine vitriol quality index: content HPLC99.5%, sulfate ion 32.4, pH 3.1, optically-active 53.5, iron ion 4PPM, ignition residue 20.8, weight loss on drying 0.30.
Claims (10)
1. the preparation method of a 2-amino-2-deoxy-D-glucose is characterized in that, its step is as follows:
(1) with D-glucose in the presence of perchloric acid or sulfuric acid with acetic anhydride, make penta-acetyl glucose, penta-acetyl glucose is without separation, directly in the presence of phosphorus with the bromine reaction or directly feed bromize hydrogen gas and obtained compound 3;
(2) compound 3 is dissolved in the organic solvent, at alkaline matter, phase-transfer catalyst exists down and 4-penten-1-alcohol, reacting generating compound 4;
(3) compound 4 is dissolved in the organic solvent, under alkaline condition, with bromobenzyl reacting generating compound 5;
(4) compound 5 is dissolved in the organic solvent, reacting generating compound 6 in the presence of silicon ester;
(5) compound 6 is dissolved in organic solvent or the mixed solvent, under alkaline condition,, generates compound 7 with the SULPHURYL CHLORIDE reaction;
(6) compound 7 is dissolved in the organic solvent, with trinitride reacting generating compound 8;
(7) compound 8 is dissolved in the organic solvent, in the presence of 10% palladium charcoal and hydrogen, shortening is also sloughed benzyl simultaneously, and obtaining compound 1 is 2-amino-2-deoxy-D-glucose;
The structural formula of compound 1,3-8 is as follows:
2. preparation method according to claim 1, it is characterized in that: in step (1), D-glucose in the presence of perchloric acid with acetic anhydride, temperature of reaction is-10 ℃～30 ℃, reaction times is 1～4 hour, and the mol ratio of D-glucose, diacetyl oxide and perchloric acid is 1:5～12:0.01～0.1; Five acetyl glucose in the presence of phosphorus with bromine temperature of reaction-10～25 ℃, the reaction times is 1～4 hour, the mol ratio of D-glucose, phosphorus and bromine is 1:1～2.5:1～2.5.
3. preparation method according to claim 1, it is characterized in that: in step (1), D-glucose in the presence of sulfuric acid with acetic anhydride, temperature is-10 ℃～30 ℃, reaction times is 1～4 hour, and D-glucose, diacetyl oxide and vitriolic mol ratio are 1:5～12:0.01～0.1; Five acetyl glucose in the presence of phosphorus with bromine temperature of reaction-10～25 ℃, the reaction times is 1～4 hour, the mol ratio of D-glucose, phosphorus and bromine is 1:1～2.5:1～2.5.
4. preparation method according to claim 1 is characterized in that: in step (2), described alkaline matter is selected from pyridine, triethylamine, Trimethylamine 99,3-aminopyridine, trimethylpyridine or 4-aminopyridine; Phase-transfer catalyst is selected from Tetrabutyl amonium bromide, tetraethylammonium bromide, triethyamino Benzyl Chloride or triethyamino cylite.
5. preparation method according to claim 1 is characterized in that: in step (4), described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), methane amide, methyl alcohol, ethanol, the mixture of one or more compositions in propyl alcohol or the butanols; Described silicon ester is selected from monobromo-acetic acid trimethyl silane ester, silica-based ethyl acetate of front three or trifluoromethanesulfonic acid trimethyl silane ester.
6. preparation method according to claim 1 is characterized in that: in step (5), compound 6 reacts with SULPHURYL CHLORIDE under alkaline condition, and temperature of reaction is-20 ℃～20 ℃, and the reaction times is 13～18 hours; Described alkaline matter is selected from salt of wormwood, yellow soda ash, Trimethylamine 99, triethylamine, pyridine or piperidines; Described SULPHURYL CHLORIDE is selected from methane sulfonyl chloride, benzene sulfonyl chloride or Tosyl chloride.
7. preparation method according to claim 1 is characterized in that: in step (6), described solvent is selected from water, ethyl acetate, methyl acetate, methylene dichloride, trichloromethane, dioxane, the mixture of one or more compositions in tetrahydrofuran (THF) or the acetone; Described trinitride is sodiumazide or potassium azide; Temperature of reaction is 60 ℃～160 ℃, and the reaction times is 3～8 hours.
8. preparation method according to claim 1 is characterized in that: in step (7), described organic solvent is selected from the mixture of one or more compositions in methyl alcohol, ethanol, n-propyl alcohol, ethyl acetate, formic acid or the acetate; Temperature of reaction is 0 ℃～120 ℃, and pressure is 0.1MPa～20Mpa.
9. the preparation method of 2-amino-2-deoxy-D-glucose hydrochloride, it is characterized in that: it obtains 2-amino-2-deoxy-D-glucose hydrochloride with any one described 2-amino-2-deoxy-D-glucose among the claim 1-8 and hydrochloric acid salify in organic solvent or water; Refining obtaining made with extra care 2-amino-2-deoxy-D-glucose hydrochloride in solvent then, and described solvent is a water, methyl alcohol, ethanol, the mixture of one or more compositions in the acetone.
10. the preparation method of 2-amino-2-deoxy-D-glucose vitriol, it is characterized in that: it obtains 2-amino-2-deoxy-D-glucose vitriol with any one described 2-amino-2-deoxy-D-glucose among the claim 1-8 and sulfuric acid salify in organic solvent or water; Refining obtaining made with extra care 2-amino-2-deoxy-D-glucose vitriol in solvent then, and described solvent is a water, methyl alcohol, ethanol, the mixture of one or more compositions in the acetone.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102516329A (en) * | 2011-11-25 | 2012-06-27 | 上海现代哈森（商丘）药业有限公司 | Gastrodin synthesizing method |
| CN107325133A (en) * | 2017-08-11 | 2017-11-07 | 济南山目生物医药科技有限公司 | A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 |
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| CN102516329A (en) * | 2011-11-25 | 2012-06-27 | 上海现代哈森（商丘）药业有限公司 | Gastrodin synthesizing method |
| CN102516329B (en) * | 2011-11-25 | 2014-03-26 | 上海现代哈森（商丘）药业有限公司 | Gastrodin synthesizing method |
| CN107325133A (en) * | 2017-08-11 | 2017-11-07 | 济南山目生物医药科技有限公司 | A kind of synthetic method of the deoxidation D ribose of 1,2,3 3 O acetyl group 5 |
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