CN1428345A - Chemical synthesis process for preparing gastrodin and its analogous henolic glycoside formula (I) - Google Patents
Chemical synthesis process for preparing gastrodin and its analogous henolic glycoside formula (I) Download PDFInfo
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Abstract
The present invention relates to a chemical synthesis process for preparing gastrodin and its similar phenolic glycoside formula (I), and is characterized by that it uses industrially easily available raw material acetic anhydride and acetyl bromide or phosphorus tribromide or phosphorus pentabromide to implement hydroxyl protection of glycosyl and bromization reaction of hemiacetal hydroxyl so as to solve the problem of that the use of red phosphorus and bromide in the existent production process of gastrodin raw material medicine can damage health of human body and contaminated environment. Said invention mainly includes two key reactions: firest, synthesis of bromoacetyl glycosyl compound; and second, condensation of bromoacetyl glycosyl compound and phenolic compound to produce acetyl-protected phenolic glycoside compound.
Description
Field that the present invention belongs to:
The present invention relates to chemical synthesis process suc as formula Gastrodine shown in (I) and similar phenol glucoside thereof.
Glycosyl is glucoside unit part partly
Formula (I)
Wherein, but glycosyl part monose, disaccharide, trisaccharide etc., monose can be five-carbon sugar, hexose or substituted monosaccharide, for example: ribose, ribodesose, wood sugar, pectinose, glucose, allose, seminose, semi-lactosi, glucosamine, lactose, maltose, raffinose or the like.But R1 C1～C6 alkyl alcohol or aldehyde, hydrogen atom can be at the ortho positions, a position, contraposition.But R2 C1～C6 alkyl, C1～C6 haloalkyl, C3～C6 cycloalkyl, aryl, hydrogen atom, amino, nitro, substituted-amino, halogen, hydroxyl can be at the ortho positions, a position, contraposition.The glycoside bond that generates can be α type glycoside bond or β type glycoside bond.
Background technology:
There are numerous small molecules phenol glycoside compounds with specific physiologically active in occurring in nature, for example: salicyl alcohol glucoside, small molecules phenol glycoside compound such as thizoma curculiginis glucoside, salicin benzoate, ursin, Gastrodine, Hilieidum, Arctiin, Phillyrin, be widely used in the pharmaceutical preparation that is used for health care of body or treatment disease that the people of other countries use, wherein, there is chemical compound lot to be considered to the main component or the effective constituent of these pharmaceutical preparations, caused correlative study personnel's concern.Because this kind compound content is lower in the natural product, generally speaking, content is lower than one of percentage, and directly extraction cost is very high from natural product, people expect to rely on the method for chemosynthesis, obtain a large amount of inexpensive small molecules phenol glycoside compounds for human used.
The chemical synthesis process of glycoside compound started from the beginning of last century, form glycosyl halides activatory method very important effect is arranged on the carbohydrate chemistry development history, foremost reaction has Koenigs-Knorr reaction [Koenigs, W.And Knorr, E. (1901), Ber.Dtsch.Chem.Ges., 34,957], generally all need to add heavy metal silver or mercury salt etc. in this type of reaction.Other method; for example; form glycosyl trichloroacetamide activation method (trichloroacetimidate Method) [Schmidt; R.R.and Kinzy; W. (1994) .Adv.Carbohydr.Chem.Biochem.; 50; 21], form glycosyl sulphur and replace (thioglycoside), glycosyl selenium replaces [Garegg such as (selenoglycoside) activation method; P.J. (1997) .Adv.Carbohydr.Chem.Biochem.; 52,179.Witczak, Z.J.and Czernecki; S. (1998) .Adv.Carbohydr.Chem.Biochem.; 53,143.], need to use severe toxicity and expensive chemical reagent; only limit to the usefulness that the laboratory makes a search, be difficult to be used for large-scale production.
In recent decades, chemical synthesis process about this type of small molecules glucoside compound has many research reports, mainly contain: the 1. chemosynthesis [Zhou Jun etc. of Gastrodine, the chemical research II of rhizoma Gastrodiae " Gastrodine and analogue thereof synthetic " chemical journal vol.38, No.2, in April, 1980], the synthetic route of this compound, with diacetyl oxide under perchloric acid catalysis, generate five acetyl glucose with the glucose effect, with red phosphorus and bromine reaction, obtain the bromo acetyl glucosamine again, bromo acetyl glucosamine and p-Hydroxybenzaldehyde condensation, condensation product is through reduction, acetylize, saponification, steps such as recrystallization are finished the chemosynthesis of Gastrodine; 2. chemosynthesis [the Li Wen etc. of ursin, " Synthesis of Arbutin by Phase-transter Catalysis Method ", Zhengzhou Polytechnical Univ.'s journal, 1999 the 20th the 2nd phases of volume], the synthetic route of this compound, with diacetyl oxide under perchloric acid catalysis, generate five acetyl glucose with the glucose effect, again with red phosphorus and bromine reaction, obtaining the bromo acetyl glucosamine, is catalyzer with the Tetrabutyl amonium bromide, bromo acetyl glucosamine and the condensation of single acetyl Resorcinol in two-phase system (trichloromethane/water), condensation product obtains the final product ursin through steps such as saponification, recrystallizations; 3. the improvement of the chemosynthesis of rhodioloside [Li Guoqing etc., " rhodioloside synthetic method ", Chinese pharmaceutical chemistry magazine; Vol.6; No.2, Jun.1996], the synthetic route of this compound; raw material 4-benzyloxy phenylethyl alcohol is dissolved in methylene dichloride and the ether mixing solutions; feed nitrogen protection, add bromo acetyl glucosamine and silver carbonate, to reacting completely; condensation product obtains the final product rhodioloside through saponification, shortening.4. the chemosynthesis of Hyperoside is [with faithful and upright person etc., " study on the synthesis of Hyperoside ", Acta Pharmaceutica Sinica, 1994; 29 (11)]; this synthetic route is in the presence of pyridine; semi-lactosi and acetic anhydride, the thick liquid of generation is dissolved in glacial acetic acid, feeds dry hydrogen bromide; finish bromo-reaction; obtain α-D-acetyl bromide for semi-lactosi, in reaction flask, add 5 successively under stirring; 7; 3 ', 4 '-four benzoyl quercetins, α-D-acetyl bromide are for semi-lactosi, anhydrous pyridine, silver suboxide, and afterreaction was complete in 86 hours; separate the product that obtains; under nitrogen protection, refluxed hcl acidifying 20 minutes with methyl alcohol, potassium hydroxide; 50% ethyl alcohol recrystallization is finished the chemosynthesis of Hyperoside.
The chemosynthesis of Gastrodine comes from people such as late nineteen seventies Zhou Jun in last century and be separated to a new compound from the Chinese medicine rhizoma Gastrodiae, be accredited as 4-hydroxymethyl phenyl-β-D-glucopyanoside through structure, pharmaceutical research shows that this compound has calmness, soporific function, think the effective constituent of Chinese medicine rhizoma Gastrodiae, called after Gastrodine (gastrodin).People such as Zhou Jun in 1980 have finished the chemosynthesis [Zhou Jun etc. of Gastrodine, the chemical research II of rhizoma Gastrodiae " Gastrodine and analogue thereof synthetic " chemical journal vol.38, No.2, in April, 1980], in this synthetic route, use the bigger red phosphorus of toxicity, bromine in a large number, exist the serious three wastes to handle problems, production safety and environmental safety are all brought unfavorable factor, and total yield is lower, and production cost is higher.This synthetic route is still adopted by the synthetic main manufacturing enterprise of Gastrodine bulk drug of China so far.People such as Pang Qijie in 1984 propose [the people such as Pang Qijie that improves one's methods of Gastrodine synthesis technique, " improvement of Gastrodine synthetic method ", medicine industry, 1984,3:3～4], in people's such as Pang Qijie the method, still use red phosphorus and bromine, just change one step of potassium borohydride reduction into Raney nickel shortening, do not have bigger actual application value, but also face the problem of new introducing heavy metal.
Summary of the invention: at the deficiency of prior art existence; the present invention proposes the chemical synthesis process of a kind of preparation Gastrodine and analogous henolic glycoside formula (I) thereof; it finishes the hydroxyl protection of glycosyl and the bromo-reaction of hemiacetal hydroxyl with industrial raw acetic acid acid anhydride and the acetyl bromide or phosphorus tribromide or phosphorus pentabromide of being easy to get, solved use in the existing Gastrodine production of raw medicine that red phosphorus, bromine bring destroy problem to the injury of direct labor's body and mind with to the pollution of environment.
Mainly comprise two step committed steps in the technology that the present invention proposes, the first step: bromo acetyl glycosyl compound synthetic; Second step: bromo acetyl glycosyl compound and phenoloid condensation generate the phenol glycoside compound that ethanoyl is protected.Adopt the present invention to generate the reaction conditions of glucoside, improved generation glucoside single step reaction yield, reduced production cost, raise labour productivity.
1. the chemical synthesis process of chemical formula (I) phenol glucoside comprises the steps: that with diacetyl oxide and acetyl bromide or phosphorus tribromide or phosphorus pentabromide be reagent, by with the reaction of glycosyl, both protected the hydroxyl in the glycosyl, simultaneously, bromo hemiacetal hydroxyl obtains bromo acetyl glycosyl compound; 2. in acetone and water reaction system, the iodide ion that adds catalytic amount, with sodium hydroxide or potassium hydroxide is alkali reagent, bromo acetyl glycosyl compound and phenoloid react in 3: 1～1: 3 ratio, TLC detection reaction process, after reaction finishes, obtain the phenol glycoside compound of ethanoyl protection; 3. in sodium methylate and methyl alcohol or sodium ethylate and ethanolic soln, slough the acetyl protection base, obtain final product-phenol glycoside compound.Chemical synthesis process is as follows:
x＝3or?5
The bromo-reaction of above-mentioned glycosyl protection and hemiacetal hydroxyl is to finish with diacetyl oxide and acetyl bromide reagent, and the consumption of diacetyl oxide and acetyl bromide reagent is 1: 0.1～4.
The reaction of above-mentioned generation phenol glucoside in acetone and water reaction system, is used the iodide ion of catalytic amount, and its consumption is 0～1.0 equivalent of phenoloid.
In the mixed system of above-mentioned acetone and water, the proportional range of acetone and water is 5～1: between 1～5, the ratio of alkali consumption and phenoloid is between 1: 5～0.2, and temperature is at 10～40 ℃;
The bromo-reaction of the protection of above-mentioned glycosyl and hemiacetal hydroxyl can be finished as reagent with diacetyl oxide and phosphorus tribromide or phosphorus pentabromide, and the consumption of diacetyl oxide and phosphorus tribromide or phosphorus pentabromide bromide reagent is 1: 0.1～4;
The acetyl protection radical reaction that takes off of the phenol glycoside compound of above-mentioned ethanoyl protection is finished in sodium methylate and methanol solution or sodium ethylate and ethanolic soln.
Below just the present invention specifically describe as follows:
The first step, the preparation of the synthetic embodiment 1 bromo acetyl glycosyl compound of bromo acetyl glycosyl compound divides two steps, and acetylize and bromine replace.Add the diacetyl oxide of 1.5mol in the clean there-necked flask of 500ml, the perchloric acid of 0.5ml is made catalyzer, under the stirring at room; add glucose 0.2mol, control reaction temperature is no more than 40 ℃ in batches, adds in about 30 minutes; add the back and continue to stir 30 minutes, TLC detects, and acetylize is finished.Drip phosphorus tribromide or phosphorus pentabromide 0.10mol in above-mentioned reaction flask, added in about 30 minutes, the water-bath control reaction temperature is no more than 40 ℃, after phosphorus tribromide or phosphorus pentabromide add, slowly add 15ml water, add ice-water bath, control reaction temperature is no more than 40 ℃, adds the back and continues to stir 2～3 hours, and TLC detects, bromine replaces to be finished, after reaction finishes, reaction solution is poured in an amount of frozen water into stirred for several minute, filter 5%NaHCO
3Cold soln is washed till neutrality, gets white solid, can directly do next step reaction, total recovery＞95%.Embodiment 2 acetylize steps are identical in embodiment 1, but the diacetyl oxide consumption is 1.0mol, and raw material is semi-lactosi (0.20mol).After acetylize finishes, drip acetyl bromide 0.34mol (1.7 equivalent) in reaction flask, added in about 30 minutes, the water-bath control reaction temperature is no more than 40 ℃, after acetyl bromide adds, continues to stir 2～3 hours, and TLC detects, and bromine replaces finishes total recovery＞95%.Embodiment 3 acetylize steps are identical with embodiment 2, but raw material is D-ribose (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.36mol (1.8 equivalent).Total recovery＞95%.Embodiment 4 acetylize steps are identical with embodiment 2, and still, raw material is lactose (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.38mol (1.9 equivalent).Total recovery＞95%.Embodiment 5 acetylize steps are identical with embodiment 2, and still, raw material is seminose (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.42mol (2.1 equivalent).Total recovery＞95%.Embodiment 6 acetylize steps are identical with embodiment 2, and still, raw material is sorbose (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.44mol (2.2 equivalent).Total recovery＞95%.Embodiment 7 acetylize steps are identical with embodiment 2, and still, raw material is wood sugar (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.48mol (2.4 equivalent).Total recovery＞95%.Embodiment 8 acetylize steps are identical with embodiment 2, and still, raw material is fructose (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.48mol (2.4 equivalent).Total recovery＞95%.Embodiment 9 acetylize steps are identical with embodiment 2, and still, raw material is rhamnosyl (0.20mol).After acetylize finishes, in reaction flask, drip acetyl bromide 0.48mol (2.4 equivalent).Total recovery＞95%.
In second step, bromo acetyl glycosyl compound and phenoloid condensation generate the phenol glycoside compound that ethanoyl is protected,
Wherein, but glycosyl part monose, disaccharide, trisaccharide etc., monose can be five-carbon sugar, hexose or substituted monosaccharide, for example: ribose, ribodesose, wood sugar, pectinose, glucose, allose, seminose, semi-lactosi, glucosamine, lactose, maltose, raffinose or the like.R1 can be C1～C6 alkyl alcohol or aldehyde, hydrogen atom, can be at the ortho position, a position, contraposition.R2 can be C1～C6 alkyl, C1～C6 haloalkyl, C3～C6 cycloalkyl, aryl, hydrogen atom, amino, nitro, substituted-amino, halogen, hydroxyl, can be at the ortho position, a position, contraposition.The glycoside bond that generates can be α type glycoside bond or β type glycoside bond.
Generate in the step of glycoside compound at bromo acetyl glycosyl compound and phenoloid condensation, carried out big quantity research, improved existing Gastrodine chemical synthesis process for selecting best experiment condition.1, proportioning raw materials
Two kinds of raw materials that participate in condensation reaction are bromo acetyl glycosyl compound (A) and phenoloid (B), at solvent systems is acetone and water (3: 2), potassiumiodide consumption (0.02 equivalent), under the condition of sodium hydroxide concentration (with the phenoloid equivalent), proportioning raw materials is from A: B=3: all test at 1～1: 3, and with A: B=2: 3 proportioning is the best.2, solvent systems
There are two main side reactions in condensation reaction, hydrolysis reaction and the reaction of the elimination under the anhydrous condition under the water participation condition are promptly arranged, so the selection of solvent systems is crucial, at potassiumiodide consumption (0.02 equivalent), sodium hydroxide concentration (with the phenoloid equivalent), proportioning raw materials A: B=2: under 3 the condition, the selection of solvent systems is from acetone: water=5: 1～all test at 1: 5, with acetone: the system of water=2: 1 is the best.3, KI consumption
With acetone=2: 1 was solvent, and proportioning raw materials is A: B=2: 3, and sodium hydroxide concentration (with the phenoloid equivalent), the potassiumiodide consumption is all tested from 0～1.0 equivalent, and yield is the highest when participating in reaction with 0.02 equivalent.4, alkali consumption
With acetone and water=2: 1 was solvent, and proportioning raw materials is A: B=2: 3, and potassiumiodide consumption (0.02 equivalent), sodium hydroxide is all tested from 0～2 equivalent, and yield is the highest when participating in reaction with sodium hydroxide and phenoloid equivalent.
In sum, the top condition of condensation reaction is: with acetone and water=2: 1 was solvent, and proportioning raw materials is
A: B=2: 3, potassiumiodide consumption (0.02 equivalent), sodium hydroxide and phenolic compound equivalent participate in reaction.Embodiment 1 is load weighted p-Hydroxybenzaldehyde 0.30mol (1.5 equivalent), sodium hydroxide or potassium hydroxide 0.30mol (1.5 equivalent), and 0.004mol KI (0.02 equivalent) is transferred in the reactor, and adds 50ml H
2O, the room temperature lower magnetic force stirs, and reactant is fully dissolved.After bromo acetyl glucosamine (0.20mol) fully dissolved with 100ml acetone, in 30 minutes, splash in the reactor.Stirred under the room temperature 4～5 hours, reaction soln has the colourless limpid turbid liquid that becomes brown.TLC detects, and adds 500ml H after the bromo acetyl glucosamine reacts completely
2O stirred 2 hours under the room temperature, and the adularescent solid is separated out, and behind the filtration under diminished pressure, uses diluted sodium hydroxide solution respectively, and the saturated common salt water washing gets white crystal.Ethyl alcohol recrystallization, in the bromo acetyl glucosamine, yield is 46.5%.Under embodiment 2 room temperatures, embodiment 1 gained white crystals 20mmol is dissolved in 100ml methyl alcohol or the ethanol, add 2mmol sodium methylate or sodium ethylate, stirring at room stoichiometric number hour, after reaction finished, reaction soln suitably concentrated, add the chloroform crystallization, filter dry white solid (4-carboxaldehyde radicals-phenyl-β-D-glucopyanoside), the yield 94.8% of getting.Embodiment 3 methods are identical with embodiment 1, and still, raw material is bromo acetyl glucosamine 0.20mol, p-aminophenol (amino is protected) 0.30mol (1.5 equivalent), and alkali is potassium hydroxide 0.30mol (1.5 equivalent), and KI4.0mmol, yield are 30.4%.Embodiment 4 methods are identical with embodiment 1, and still, raw material is bromo acetyl glucosamine 0.20mol, 3-isopropyl-phenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), and KI 4.0mmol, yield are 28.1%.Embodiment 5 methods are identical with embodiment 1, and still, raw material is bromo acetylated mannan sugar 0.20mol, 4-isopropyl-phenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), and KI 4.0mmol, yield are 33.4%.Embodiment 6 methods are identical with embodiment 1, and still, raw material is bromo acetylated mannan sugar 0.20mol, ethyl p-hydroxybenzoate 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), and KI 4.0mmol, yield are 47.2%.Embodiment 7 methods are identical with embodiment 1, and still, raw material is bromo acetyl glucosamine 0.20mol, 2-bromophenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI 4.0mmol (0.02 equivalent), and yield is 67.3%.Embodiment 8 methods are identical with embodiment 1, and still, raw material is bromo acetyl wood sugar 0.20mol, 3-bromophenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI 4.0mmol (0.02 equivalent), and yield is 30.6%.Embodiment 9 methods are identical with embodiment 1, and still, raw material is bromo acetyl semi-lactosi 0.20mol, 4-bromophenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 27.5%.Embodiment 10 methods are identical with embodiment 1, and still, raw material is bromo acetyl semi-lactosi 0.20mol, 4-nitrophenols 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI 4.0mmol (0.02 equivalent), and yield is 24.3%.Embodiment 11 methods are identical with embodiment 1, and still, raw material is bromo acetyl lactose 0.20mol, 2-nitrophenols 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 22.1%.Embodiment 12 methods are identical with embodiment 1, and still, raw material is bromo acetyl semi-lactosi 0.20mol, 2-benzene phenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 18.6%.Embodiment 13 methods are identical with embodiment 1, and still, raw material is bromo acetyl glucosamine sugar 0.20mol, 4-benzene phenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 27.6%.Embodiment 14 methods are identical with embodiment 1, and still, raw material is bromo acetylated mannan sugar 0.20mol, 4-fluorophenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 29.4%.Embodiment 15 methods are identical with embodiment 1, and still, raw material is bromo acetyl sorbose 0.20mol, 3-benzene phenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 22.6%.Embodiment 16 methods are identical with embodiment 1, but raw material is bromo acetyl fructose 0.20mol, Vanillin (4-hydroxy 3-methoxybenzene formaldehyde) 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), yield is 47.2%.Embodiment 17 methods are identical with embodiment 1, and still, raw material is bromo acetyl lactose 0.20mol, 3-methoxyphenol 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), and yield is 28.4%.Embodiment 18 methods are identical with embodiment 1, but raw material is L-bromo acetyl sorbose 0.20mol, thymol (2-sec.-propyl-5-methyl-phenol) 0.30mol (1.5 equivalent), and alkali is sodium hydroxide 0.30mol (1.5 equivalent), KI4.0mmol (0.02 equivalent), yield is 21.7%.
By as above describing in detail, the scope of chemical synthesis process of the present invention and this operational path of application clearly has been described, the numerous embodiment that enumerate just for the further concrete content of the present invention of setting forth, do not limit the present invention's meaning.This chemical synthesis process suitability for industrialized is produced, and each batch produced phenol glycoside compound quality can be between 1～500 kilogram, little to the pollution of environment, with short production cycle, the starting material source of using is abundant, and low production cost, product have extraordinary competitive power.
Claims (6)
1. the chemical synthesis process for preparing Gastrodine and analogous henolic glycoside formula (I) thereof
Glycosyl is glucoside unit part partly
Formula (I)
Wherein, glycosyl part can be a monose; disaccharide; trisaccharide etc.; monose can be five-carbon sugar; hexose; or substituted monosaccharide; for example: ribose; ribodesose; wood sugar; pectinose; glucose; allose; seminose; semi-lactosi; glucosamine; lactose; maltose; raffinose or the like; R1 can be C1～C6 alkyl alcohol or aldehyde; hydrogen atom; can be at the ortho position; between the position; contraposition; R2 can be C1～C6 alkyl; C1～C6 haloalkyl; C3～C6 cycloalkyl; aryl; hydrogen atom; amino; nitro; substituted-amino; halogen; hydroxyl; can be at the ortho position; between the position; contraposition; the glycoside bond that generates can be α type glycoside bond or β type glycoside bond; the chemical synthesis process that it is characterized in that chemical formula (I) phenol glucoside; comprise the steps: that 1. with diacetyl oxide and acetyl bromide or phosphorus tribromide or phosphorus pentabromide be reagent; by with the reaction of glycosyl; both protected the hydroxyl in the glycosyl; simultaneously; bromo hemiacetal hydroxyl; obtain bromo acetyl glycosyl compound; 2. in acetone and water reaction system; the iodide ion that adds catalytic amount; with sodium hydroxide or potassium hydroxide is alkali reagent; bromo acetyl glycosyl compound and phenoloid react in 3: 1～1: 3 ratio; TLC detection reaction process; after reaction finishes; obtain the phenol glycoside compound of ethanoyl protection; 3. in sodium methylate and methyl alcohol or sodium ethylate and ethanolic soln; slough the acetyl protection base; obtain final product-phenol glycoside compound, chemical synthesis process is as follows:
x＝3or?5
2. chemical synthesis process according to claim 1 is characterized in that: the bromo-reaction of the protection of glycosyl and hemiacetal hydroxyl is to finish with diacetyl oxide and acetyl bromide reagent, and the consumption of diacetyl oxide and acetyl bromide reagent is 1: 0.1～4.
3. chemical synthesis process according to claim 1 is characterized in that: generate the reaction of phenol glucoside, in acetone and water reaction system, use the iodide ion of catalytic amount, its consumption is 0～1.0 equivalent of phenoloid.
4. chemical synthesis process according to claim 1 is characterized in that: in the mixed system of acetone and water, the proportional range of acetone and water is 5～1: between 1～5, the ratio of alkali consumption and phenoloid is between 1: 5～0.2, and temperature is at 10～40 ℃.
5. chemical synthesis process according to claim 1; it is characterized in that: the bromo-reaction of the protection of glycosyl and hemiacetal hydroxyl can be finished as reagent with diacetyl oxide and phosphorus tribromide or phosphorus pentabromide, and the consumption of diacetyl oxide and phosphorus tribromide or phosphorus pentabromide bromide reagent is 1: 0.1～4.
6. chemical synthesis process according to claim 1 is characterized in that: the reaction of taking off the acetyl protection base is finished in sodium methylate and methyl alcohol or sodium ethylate and ethanolic soln.
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| CN101029064B (en) * | 2007-04-11 | 2010-06-23 | 昆明贝克诺顿制药有限公司 | Bean-curd pectin analogues, and its use in preparation of medicine for preventing senile dementia |
| CN101933932A (en) * | 2010-03-16 | 2011-01-05 | 云南大学 | Application of 4-cyan-beta-D-glucoside in treating chronic neurogenic pain |
| CN101810632A (en) * | 2010-03-16 | 2010-08-25 | 云南大学 | Purpose of 4-cyan-beta-D-glucoside for curing tristimania |
| CN101933932B (en) * | 2010-03-16 | 2012-05-23 | 云南大学 | Application of 4-cyan-beta-D-glucoside in treating chronic neurogenic pain |
| CN101933933A (en) * | 2010-03-16 | 2011-01-05 | 云南大学 | Application of 2-fluoro-beta-D-glucoside in treating depression |
| CN101829127B (en) * | 2010-05-18 | 2012-02-08 | 云南大学 | Application of 3-carbethoxyphenyl-beta-D-acetylated glucoside in treating depression |
| CN101829128A (en) * | 2010-05-18 | 2010-09-15 | 云南大学 | Application of 4-formylphenyl-beta-D-glucoside compounds in treating chronic neuropathic pains |
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| CN101829128B (en) * | 2010-05-18 | 2012-05-23 | 云南大学 | Application of 4-formylphenyl-beta-D-glucoside compounds in treating chronic neuropathic pains |
| 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 |
| CN102977161A (en) * | 2012-12-17 | 2013-03-20 | 青岛农业大学 | Method for chemically synthesising gastrodin |
| CN102977161B (en) * | 2012-12-17 | 2015-03-25 | 青岛农业大学 | Method for chemically synthesising gastrodin |
| CN104447902A (en) * | 2013-09-17 | 2015-03-25 | 昆明制药集团股份有限公司 | High yield and easy purification preparation method of gastrodin derivative |
| CN104231013A (en) * | 2014-08-26 | 2014-12-24 | 上海现代哈森（商丘）药业有限公司 | Gastrodin ferulate compound and preparation method and application of gastrodin ferulate compound |
| CN110317129A (en) * | 2019-05-30 | 2019-10-11 | 杭州迈世腾药物科技有限公司 | The synthetic method of the bromo- 5- metoxyphenol of 2- |
| CN111018928A (en) * | 2019-12-06 | 2020-04-17 | 北京悦康科创医药科技股份有限公司 | Synthetic method and application of gastrodin hemihydrate |
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