CN101805380A - Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate - Google Patents
Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate Download PDFInfo
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Abstract
The invention discloses a synthesis method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate which is shown in formula B. The method comprises the following step of: under the protection of inert gas, in polar organic solvent, leading compound A and acetylation reagent to have reaction under the action of protonic acid and/or lewis base; wherein Ac is acetyl. The method has simple operation, mild reaction condition and high yield, and the products B and C have industrial application valve and are in accordance with the green chemistry standard with atom economy. The subsequent products of the method are separated by the post-treatment methods such as filtering, rectification under vacuum and the like. Therefore, the method is simple and feasible, thus being applicable to not only laboratory small-scale preparation, but also large-scale industrialized production.
Description
Technical field
The present invention relates to a kind of novelty preparation (3S, 5S)-2, the methodology of organic synthesis of 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate.
Background technology
(3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate has suc as formula the structure shown in the B:
Wherein, Ac is an ethanoyl.
This compound is a kind of derived structure of sugar, can be converted into the nucleoside medicine parent, is the synthetic field of medicine intermediate commonly used, particularly at the antibiotic of preparation treatment infectation of bacteria, has a wide range of applications in the diagnostic medicine of anti-AIDS medicine and cancer.
At present, the synthetic method of this compound need adopt silicagel column to separate and obtain product (Tetrahedron Vol.50.1994, pp.1435-1448; Journal of Organic Chemistry; 38; 1973; 3622-3623).Owing to there is the cost height, shortcoming such as complicated operation and solvent load are big, so far, the method for existing synthetic this compound is difficult to obtain gratifying result in preparation of industrialization.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome existing synthetic (3S, 5S)-2, the method of 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate (formula B) need adopt the silicagel column separated product, make solvent load big, complicated operation, cost is high and be difficult to industrialized defective, and provide a kind of simple possible, cost is lower, and is suitable for the novel method of suitability for industrialized production, and this method can also reach higher yield.
Method of the present invention comprises the steps: under the protection of inert gas, in polar organic solvent, under the effect of protonic acid and/or Lewis base, compd A and acetylation reagent reaction is got final product;
Wherein, Ac is an ethanoyl.
Wherein, compd B comprises two kinds of isomer that absolute configuration is different in fact, promptly comprise furans parent nucleus 2-position acetoxyl group be configured as axial bond or equatorial bond the time two kinds of isomer forming.
Among the present invention, described acetylation reagent forms the reagent of acetic ester for hydroxyl can be carried out acetylize, and preferable is Acetyl Chloride 98Min., acetyl bromide or aceticanhydride; What the mol ratio of compd A and described acetylation reagent was preferable is 1: 1.1～1: 20.0, and better is 1: 3～1: 5.
Described protonic acid and/or Lewis base are as catalyzer.That described Lewis base is preferable is sodium-acetate, N, one or more in the nitrogenous compounds such as N-dimethyl-4-aminopyridine, pyridine, quinoline, imidazoles and triethylamine; What the mol ratio of compd A and Lewis base was preferable is 1: 0.05～1: 0.2.Described protonic acid can be inorganic proton acid (as in sulfuric acid, hydrochloric acid and the phosphoric acid one or more) and/or organic protonic acid (as in acetic acid, propionic acid, tosic acid and the methylsulfonic acid one or more), preferred acetic acid.What the mol ratio of compd A and protonic acid was preferable is 1: 0.25～1: 20.0, and better is 1: 10～1: 13.
That described polar organic solvent is preferable is N, in dinethylformamide, glycol dimethyl ether, dimethylbenzene, N-Methyl pyrrolidone, methyl-phenoxide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetic acid and the aceticanhydride one or more, better not only makes reactant but also make solvent with aceticanhydride.The consumption of polar organic solvent generally can be 3 times to 20 times of compd A quality.
Among the present invention, described rare gas element can be nitrogen and/or argon gas; What the temperature of described reaction was preferable is 80～160 ℃, and better is 145 ℃.The time of reaction can by detection reaction fully till, preferred HPLC and/or LC-MS detect, the reaction times was generally 3～24 hours.
Among the present invention, can also control the upright and calm ratio of furans 2 bit substituents by control reaction temperature.As under the oil bath heating, temperature of reaction is more than 145 ℃, and the reaction times shortens, and two kinds of upright and calm configuration ratios of 2 bit substituents increase; Temperature of reaction is below 140 ℃, and the reaction times prolongs, and two kinds of upright and calm configuration ratios of 2 bit substituents reduce.
After reaction of the present invention is finished, be cooled to 5 ℃～10 ℃, separate out precipitation; be precipitated as Compound C, filter, reaction solvent and excessive acetylation reagent are removed in the filtrate decompression distillation; get final product target compound (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate.Preferable, in underpressure distillation, promptly remove most of reaction solvent and acetylation reagent after, residual solution is carried out rectification under vacuum again, further purified product.Described precipitated product used water or weak acid are washed, and to remove residual catalyzer protonic acid and/or Lewis base, the Compound C of gained also has industrial application value.
The synthetic method of compd A can be with reference to Chinese patent application " synthetic method of deoxyadenosine compounds " among the present invention, and application number 200710036293.9 is January 9 2007 applying date, specific as follows:
Under 50～120 ℃ of the temperature, in the solvent, will under the radical initiator effect,, make suc as formula acidylate bromo adenosine compounds and the reductive agent shown in the I suc as formula the acidylate deoxyadenosine compounds shown in the II through debromination; The reaction that is hydrolyzed under the mineral alkali effect afterwards gets final product;
Formula I formula II formula III
Wherein, R is for replacing or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, ring penta, cyclohexyl, phenyl or benzyl preferable methyl, ethyl, propyl group, butyl, phenyl or benzyl.
What wherein, described free radical initiation base was preferable is azo isobutyl cyanogen (AIBN) or Benzoyl Peroxide (BPO); What the usage quantity of described free radical was preferable is suc as formula 5～20% of the acidylate bromo adenosine compounds weight shown in the I; That described reductive agent is preferable is Bu
3SnH or H
3PO
2The molar weight of described reductive agent is 1～30 times suc as formula the acidylate bromo adenosine compounds shown in the I, and better is 5～15 times.The preferred solvents of described debromination be selected from following one or more: benzene, toluene, ethylbenzene, propyl benzene, trimethylphenylmethane, dimethylbenzene, chlorobenzene, dichlorobenzene, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, oil of mirbane and methyl-phenoxide, wherein preferred tetrahydrofuran (THF) or 1, the 4-dioxane.What the temperature of described debromination was preferable is 75～95 ℃; The reaction times of described debromination is 1～12 hour, and better is 1～6 hour.Before described debromination began, the preferable alkaline matter that also adds in reactant was beneficial to the carrying out that reacts.Described alkaline matter is preferable is selected from following one or more: butylamine, amylamine, hexylamine, diethylamine, dibutylamine, diamylamine, triethylamine, Tributylamine, triamylamine, aniline, methylphenylamine, monomethylaniline, pyridine, imidazoles, pyrroles, piperidines, piperazine and pyrazine.
Wherein, the mineral alkali that uses in the described hydrolysis reaction is preferable is selected from following one or more: salt of wormwood, potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, hydrated barta, yellow soda ash, Quilonum Retard, cesium carbonate, volatile salt, sodium bicarbonate, saleratus and bicarbonate of ammonia, wherein preferred salt of wormwood, yellow soda ash, volatile salt, potassium hydroxide or sodium hydroxide.Described mineral alkali with can be 1: 5 suc as formula the mole ratio of the acidylate deoxyadenosine compounds shown in the II, preferable is 1.5: 3.The solvent of described hydrolysis reaction can be selected from one or more in following: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, second eyeball, tetrahydrofuran (THF) and 1,4-dioxane.Wherein, what the temperature of described hydrolysis reaction was preferable is 0～50 ℃, and better is 20～30 ℃.
Wherein, it is starting raw material that described acidylate bromo adenosine compounds (formula I) can adopt adenosine (formula IV), synthetic as follows obtaining, and the concrete steps embodiment 1～3 that sees reference:
Formula IV formula V formula I
Wherein, R
1Be methyl, ethyl, propyl group or butyl; R is for replacing or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, ring penta, cyclohexyl, phenyl or benzyl preferable methyl, ethyl, propyl group, butyl, phenyl or benzyl.
The present invention is raw materials used and reagent is all commercially available gets.
Positive progressive effect of the present invention is: synthetic method of the present invention is simple to operate, and the reaction conditions gentleness can realize high yield, technology is easy, and the liquid chromatographic detection product (3S, 5S)-2, purity＞90% of 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate, productive rate 25-83%.The subsequent products of this method separates the method that adopts filtration and underpressure distillation, has avoided existing method to need massive laundering and post separation processes, and is simple and feasible, is not only applicable to the laboratory and prepares on a small scale, but also be fit to industrialized production.In addition, except that target product, another separating obtained product Compound C also has industrial application value, meets the Green Chemistry standard of Atom economy.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Reference example 1 preparation acetylize bromo adenosine (compound shown in the formula I, R are methyl)
At room temperature, with adenosine (2000g, tosic acid (1706g 7.48mol), 9.9mol) (4.1L is 32.07mol) and in the mixing solutions of acetonitrile (15L), behind the stirring 3h to add trimethyl orthoacetate, methanol solution (8M with carbinolamine, 800mL) neutralize pH, leave standstill after stirring, filter for neutral, filtrate is with 1, the washing of 2-ethylene dichloride merges organic layer, and concentrating under reduced pressure gets the 3500g yellow solid.
(3500g 9.28mol) is dissolved in 1, and in the 2-ethylene dichloride (1500L), (3000g, 24.4mol), it is complete up to raw material reaction slowly to be heated to the reflux state reaction after stirring to drip acetyl bromide after being cooled to 0 ℃ with above-mentioned yellow solid.Pour into behind the reaction solution cool to room temperature in the frozen water (10L); adding saturated sodium hydroxide neutralization reaction liquid arrives neutral to pH; tell organic layer; water layer is with 1; (3 * 5L) extractions merge organic layer to the 2-ethylene dichloride, use anhydrous magnesium sulfate drying; filter, concentrating under reduced pressure obtains 3000g acetylize bromo adenosine.
Reference example 2 preparation propionyl bromo adenosines (compound shown in the formula I, R are ethyl)
Method with reference to reference example 1 replaces with propionyl bromide with acetyl bromide, gets final product.
Reference example 3 preparation benzyl acidylate bromo adenosines (compound shown in the formula I, R are phenyl)
With reference to the method for reference example 1, acetyl bromide is replaced with the benzyl acylbromide, get final product.
Reference example 4 deoxyadenosine compounds (formula III compound)
The acetylize bromo adenosine (0.1mol that reference example 1 is made; 37.2g) add in the toluene (100mL); add 50% ortho phosphorous acid (1.0mol after stirring successively; 132g), triethylamine (0.3mol) and azo isobutyl cyanogen (AIBN) are (3.72g); after fully stirring, slowly be heated to 95 ℃ and react 6 hours to the disappearance of HPLC tracking raw material.Behind the reaction solution cool to room temperature, (3 * 150mL) extract, and merge organic layer, use anhydrous sodium sulfate drying, and filtration, concentrating under reduced pressure obtain yellow needle-like crystal acetylize Desoxyadenosine, and productive rate is 78% with methylene dichloride.
(0.1mol 29.3g) joins in the methyl alcohol (200mL), adds yellow soda ash (0.15mol) then, and reaction is complete up to HPLC detection raw material reaction down in room temperature (20-25 ℃) in the back that stirs with the acetylize Desoxyadenosine.Behind the reaction solution concentrating under reduced pressure, add entry (150mL), (3 * 150mL) extractions, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure obtain yellow needle-like crystal, and productive rate is 88% with methylene dichloride.
Reference example 5 deoxyadenosine compounds (formula III compound)
The propionyl bromo adenosine (0.1mol that reference example 2 is made; 38.6g) add in the tetrahydrofuran (THF) (100mL); add 50% ortho phosphorous acid (0.5mol after stirring successively; 66g) and azo isobutyl cyanogen (AIBN) (1.93g); after fully stirring, slowly be heated to 75 ℃ and react 4 hours to the disappearance of HPLC tracking raw material.Behind the reaction solution cool to room temperature, (3 * 100mL) extract, and merge organic layer, use anhydrous sodium sulfate drying, and filtration, concentrating under reduced pressure obtain yellow needle-like crystal propionyl Desoxyadenosine, and productive rate is 83% with methylene dichloride.
(0.1mol 30.7g) joins in the ethanol (150mL), adds salt of wormwood (0.20mol) then, and reaction is complete up to HPLC detection raw material reaction down in 0-5 ℃ in the back that stirs with the propionyl Desoxyadenosine.The reaction solution pressure reducing and steaming adds entry (150mL) after concentrating, and (3 * 150mL) extractions, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure obtain yellow needle-like crystal, and productive rate is 78% with methylene dichloride.
Reference example 6 deoxyadenosine compounds (formula III compound)
The benzyl acidylate bromo adenosine (0.1mol that reference example 3 is made; 44.8g) add in the acetonitrile (100mL); add 50% ortho phosphorous acid (1.5mol after stirring successively; 198g), pyridine (1.5mol) and azo isobutyl cyanogen (AIBN) are (8.96g); after fully stirring, slowly be heated to 75 ℃ and react 3 hours to the disappearance of HPLC tracking raw material.Behind the reaction solution cool to room temperature, (3 * 100mL) extract, and merge organic layer, use anhydrous sodium sulfate drying, and filtration, concentrating under reduced pressure obtain yellow needle-like crystal benzyl acidylate Desoxyadenosine, and productive rate is 89% with methylene dichloride.
(0.1mol 36.9g) joins in the ethanol (200mL), adds potassium hydroxide (0.30mol) then, and slowly being heated to 25-30 ℃ of reaction after stirring, to detect raw material reaction up to HPLC complete with benzyl formylation Desoxyadenosine.Add entry (150mL) behind the reaction solution concentrating under reduced pressure, (3 * 150mL) extractions, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure obtain yellow needle-like crystal, and productive rate is 90% with methylene dichloride.
Embodiment 1 preparation (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (105 the gram, 0.4mol), N, N-dimethyl-4-aminopyridine (5 the gram, 0.04mol) be dissolved in acetic anhydride (400ml, 3.9mol) in, add the vitriol oil (mass concentration 98%, 10g, 0.1mol), the mol ratio of compd A and aceticanhydride and the vitriol oil is 1: 10: 0.25.
Under nitrogen protection, be heated to 145 ℃, reacted 24 hours.
Be cooled to more than 0 ℃, below 10 ℃, filter, solid obtains white solid C with cold ethyl acetate rinsing.Organic phase merges, vacuum distillation recovered solvent.1～2mmHg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B 40 grams, yield 39%, and liquid chromatography (HPLC) detects purity 95%.
Embodiment 2 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (105 grams, 0.4mol), N, N-dimethyl-4-aminopyridine (5 grams, 0.04mol) be dissolved in acetic anhydride (300ml, 2.9mol) in, (300mL, 5.0mol), the mol ratio of compd A and aceticanhydride and acetic acid is 1: 7.2: 12.5 to add acetic acid.
Under nitrogen protection, be heated to 145 ℃, reacted 24 hours.
Be cooled to more than 0 ℃, below 10 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B 80 grams, yield 78%, and liquid chromatography (HPLC) detects purity 95%.
Embodiment 3 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (105 grams, 0.4mol), pyridine (5 grams, 0.06mol) be dissolved in acetic anhydride (300ml, 2.9mol) in, (300mL, 5.0mol), the mol ratio of A and aceticanhydride and acetic acid is 1: 7.2: 12.5 to add acetic acid.
Under nitrogen protection, be heated to 145 ℃, reacted 24 hours.
Cool to 80 ℃, reclaim aceticanhydride and acetic acid to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to more than 0 ℃, below 10 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, vacuum distillation recovered solvent.The residue rectification under vacuum obtains compd B, 85 grams, and yield 83%, liquid chromatography (HPLC) detects purity 94%.
Embodiment 4 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (105 grams, 0.4mol), sodium-acetate (5 grams, 0.06mol) be dissolved in acetic anhydride (300ml, 2.9mol) in, (300mL, 5.0mol), the mol ratio of A and aceticanhydride and acetic acid is 1: 7.2: 12.5 to add acetic acid.
Under nitrogen protection, be heated to 145 ℃, reacted 24 hours.
Cool to 90 ℃, reclaim aceticanhydride and acetic acid to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to more than 0 ℃, below 10 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 68 grams, and yield 65%, liquid chromatography (HPLC) detects purity 92%.
Embodiment 5 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 the gram, 0.04mol), N, N-dimethyl-4-aminopyridine (0.5 the gram, 0.004mol) be dissolved in acetic anhydride (30ml, 0.29mol) in, (17.2,0.1mol), the mol ratio of A and aceticanhydride and tosic acid is 1: 7.2: 2.5 to add tosic acid.
Under nitrogen protection, be heated to 145 ℃, reacted 24 hours.
Cool to 90 ℃, reclaim aceticanhydride to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to more than 0 ℃, below 10 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 2.4 grams, and yield 25%, liquid chromatography (HPLC) detects purity 92%.
Embodiment 6 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 grams, 0.04mol), N, (0.5 gram 0.004mol) is dissolved in acetic anhydride (30ml to N-dimethyl-4-aminopyridine, 0.29mol) in, adding acetic acid (6ml, 0.1mol), dimethyl formamide (30ml, 0.6mol), the mol ratio of A and aceticanhydride, acetic acid and dimethyl formamide is 1: 7.2: 2.5: 15.
Under nitrogen protection, be heated to 145 ℃, reacted 10 hours.
Cool to 90 ℃, reclaim aceticanhydride and dimethyl formamide to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to more than 0 ℃, below 10 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 2.4 grams, and yield 25%, liquid chromatography (HPLC) detects purity 92%.
Embodiment 7 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 the gram, 0.04mol), quinoline (0.258 the gram, 0.002mol) and Acetyl Chloride 98Min. (3.14g, 0.04mol) in the adding hydrochloric acid (3.7ml, 0.044mol), glycol dimethyl ether (30ml), the mol ratio of A and Acetyl Chloride 98Min. and hydrochloric acid is 1: 1: 1.1.
Under nitrogen protection, be heated to 160 ℃, reacted 12 hours.
Reclaim solvent then to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to 5 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 4.8 grams, and yield 50%, liquid chromatography (HPLC) detects purity 93%.
Embodiment 8 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 the gram, 0.04mol), imidazoles (0.272 the gram, 0.004mol) and acetyl bromide (98.4g, 0.8mol) in the adding phosphoric acid (0.8mol), dimethylbenzene (30ml), the mol ratio of A and acetyl bromide and phosphoric acid is 1: 20: 20.
Under nitrogen protection, be heated to 80 ℃, reacted 24 hours.
Reclaim solvent then to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to 5 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 3.12 grams, and yield 30%, liquid chromatography (HPLC) detects purity 90%.
Embodiment 9 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 the gram, 0.04mol), triethylamine (0.404 the gram, 0.004mol) and aceticanhydride (30ml, 0.29mol) in the adding propionic acid (0.8mol), N-Methyl pyrrolidone (30ml), the mol ratio of A and second aceticanhydride and propionic acid is 1: 7.2: 20.
Under nitrogen protection, be heated to 120 ℃, reacted 10 hours.
Reclaim solvent then to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to 5 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 3.12 grams, and yield 30%, liquid chromatography (HPLC) detects purity 93%.
Embodiment 10 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 the gram, 0.04mol), sodium-acetate (5 the gram, 0.06mol) and aceticanhydride (0.12mol) in the adding methylsulfonic acid (0.8mol), N-Methyl pyrrolidone (30ml), the mol ratio of A and aceticanhydride and methylsulfonic acid is 1: 3: 10.
Under nitrogen protection, be heated to 120 ℃, reacted 10 hours.
Reclaim solvent then to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to 5 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 4.16 grams, and yield 40%, liquid chromatography (HPLC) detects purity 91%.
Embodiment 11 preparations (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate
With compd A (10.5 the gram, 0.04mol), sodium-acetate (5 the gram, 0.06mol) and aceticanhydride (0.20mol) in the adding acetic acid (0.4mol), dimethyl sulfoxide (DMSO) (30ml), the mol ratio of A and aceticanhydride and acetic acid are 1: 5: 10.
Under nitrogen protection, be heated to 120 ℃, reacted 10 hours.
Reclaim solvent then to doing.Cool to room temperature adds ethyl acetate, stirs.Be cooled to 7 ℃, filter, solid is with cold that the ethyl acetate rinsing obtains white solid C.Organic phase merges, and solvent is washed till neutrality with 1% hydrochloric acid and saturated sodium bicarbonate.Vacuum distillation recovered solvent.1～2mm Hg is collected in the residue rectification under vacuum, and the cut that boiling point is 120～125 ℃ obtains compd B, 3.64 grams, and yield 35%, liquid chromatography (HPLC) detects purity 90%.
Claims (14)
1. one kind prepares suc as formula the compound (3S shown in the B, 5S)-2, the synthetic method of 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate, it is characterized in that comprising the steps: under the protection of inert gas, in polar organic solvent, under the effect of protonic acid and/or Lewis base, compd A and acetylation reagent reaction are got final product;
Wherein, Ac is an ethanoyl.
2. the method for claim 1, it is characterized in that: described acetylation reagent is Acetyl Chloride 98Min., acetyl bromide or aceticanhydride.
3. the method for claim 1, it is characterized in that: the mol ratio of described compd A and acetylation reagent is 1: 1.1～1: 20.0.
4. method as claimed in claim 3 is characterized in that: the mol ratio of described compd A and acetylation reagent is 1: 3～1: 5.
5. the method for claim 1, it is characterized in that: described Lewis base is sodium-acetate, N, one or more in N-dimethyl-4-aminopyridine, pyridine, quinoline, imidazoles and the triethylamine.
6. the method for claim 1, it is characterized in that: the mol ratio of described compd A and Lewis base is 1: 0.05～1: 0.2.
7. the method for claim 1, it is characterized in that: described protonic acid is one or more in sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, propionic acid, tosic acid and the methylsulfonic acid.
8. the method for claim 1, it is characterized in that: the mol ratio of described compd A and protonic acid is 1: 0.25～1: 20.0.
9. method as claimed in claim 8 is characterized in that: the mol ratio of described compd A and protonic acid is 1: 10～1: 13.
10. the method for claim 1, it is characterized in that: described polar organic solvent is N, one or more in dinethylformamide, glycol dimethyl ether, dimethylbenzene, N-Methyl pyrrolidone, methyl-phenoxide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetic acid and the aceticanhydride.
11. the method for claim 1 is characterized in that: the temperature of described reaction is 80～160 ℃.
12. the method for claim 1 is characterized in that: the time of described reaction with detection reaction fully till.
13. the method for claim 1 is characterized in that: described reaction is cooled to 5 ℃～10 ℃ after finishing, and separates out precipitation, filter, the gained precipitation is Compound C, and filtrate decompression is distilled, get final product (3S, 5S)-2,3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate.
14. method as claimed in claim 13 is characterized in that: after the described underpressure distillation, carry out rectification under vacuum again, with further purified product.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103588840A (en) * | 2013-11-20 | 2014-02-19 | 武汉佰福泰制药有限公司 | Method for synthetizing cordycepin |
| CN107033205A (en) * | 2017-06-12 | 2017-08-11 | 上海兆维科技发展有限公司 | A kind of preparation method of 3 ' BrdUs |
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| DE1518259C3 (en) * | 1965-10-29 | 1975-04-10 | Papierwerke Waldhof-Aschaffenburg Ag, 8000 Muenchen | Process for the preparation of i-acetyl ^^ S-benzoyl-D-ribose |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103588840A (en) * | 2013-11-20 | 2014-02-19 | 武汉佰福泰制药有限公司 | Method for synthetizing cordycepin |
| CN107033205A (en) * | 2017-06-12 | 2017-08-11 | 上海兆维科技发展有限公司 | A kind of preparation method of 3 ' BrdUs |
| CN107033205B (en) * | 2017-06-12 | 2020-05-19 | 上海兆维科技发展有限公司 | Preparation method of 3' -deoxyuridine |
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