CN104402945A - Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose - Google Patents
Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose Download PDFInfo
- Publication number
- CN104402945A CN104402945A CN201410706530.8A CN201410706530A CN104402945A CN 104402945 A CN104402945 A CN 104402945A CN 201410706530 A CN201410706530 A CN 201410706530A CN 104402945 A CN104402945 A CN 104402945A
- Authority
- CN
- China
- Prior art keywords
- isopropylidene
- furyl xylose
- deoxidation
- benzoyl
- xylofuranose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose. The 3-deoxy-1,2-O-isopropylidene-D-xylofuranose is obtained by alkalifying 5-O-benzoyl-3-deoxy-1,2-D-isopropylidene-D-xylofuranose to remove 5-paraben protection. According to the synthesis method, reaction raw materials of the whole route are low in cost and readily available, and reaction conditions are safer and more moderate; the main innovation is the removal of 3-hydroxyl, the utilization of the conventional free radical initiation principle is avoided, and a high-toxicity or difficult-to-obtain reagent such as tributyltin hydride is avoided; D-xylose is used for preparing the 3-deoxy-1,2-O-isopropylidene-D-xylofuranose, and the total yield reaches 34 percent.
Description
Technical field
The present invention relates to field of medicaments, relate to the synthesis of pharmaceutical intermediate, be specifically related to the synthesis of 3-deoxidation-1,2-O-isopropylidene-D-furyl xylose.
Background technology
Atorvastatin (Lipitor) is a kind of hypolipidemic that Pfizer produces.The anticholesteremic agent maximum as global recipe quantity and the prescription drugs ranked the first, it can significantly reduce low density lipoprotein cholesterol and triglyceride levels.3-deoxidation-1,2-O-isopropylidene-D-furyl xylose, be the chiral intermediate that synthesis atorvastatin produces drug effect side chain, it still synthesizes the key of many other drug intermediates.
In prior art, be that raw material synthesizes mainly with D-wood sugar and D-Glucose.There are some areas for improvement.As with D-wood sugar for raw material, first react under copper sulfate and sulfuric acid catalysis with D-wood sugar and acetone and its four hydroxyls two acetonylidenes are protected, selectively removing 3 in diluted acid again, the acetonylidene protection of 5-position obtains the compound of two free hydroxyl, in the presence of a base 5-position hydroxyl protection is obtained 3-free hydroxyl compound with Benzoyl chloride again, again 3-position hydroxyl dithiocarbonic anhydride and methyl iodide are become xanthate under sodium hydride effect, then under Diisopropyl azodicarboxylate causes, carry out free radical reaction with tributyl tin hydrogen 3-position hydroxyl sloughed to obtain 3-deoxy compound, slough the target compound that benzoic ether protection obtains acetonylidene protection again.In present method, subject matter is that reagent toxicity is very big, deoxidation process complicated operation, needs strict anhydrous condition.
Summary of the invention
Given this, the object of the invention is the synthetic method providing a kind of five poisonous creatures: scorpion, viper, centipede, house lizard, toad, 3-deoxidation-1,2-O-isopropylidene-D-furyl xylose easy and simple to handle.
For solving above technical problem; technical scheme provided by the invention is; a kind of 3-deoxidation-1 is provided; the synthetic method of 2-O-isopropylidene-D-furyl xylose; 3-deoxidation-1; 2-O-isopropylidene-D-furyl xylose by 5-O-benzoyl-3-deoxidation-1,2-D-isopropylidene-D-furyl xylose add alkali slough 5-position benzoic ether protect obtain.
Further, allusion quotation base removing in 3-position is obtained by iodo-1, the 2-D-isopropylidene-D-furyl xylose reduction of 5-O-benzoyl-3-by described 5-O-benzoyl-3-deoxidation-1,2-D-isopropylidene-D-furyl xylose.
Further, iodo-1, the 2-D-isopropylidene-D-furyl xylose of described 5-O-benzoyl-3-adds Iod R by 5-O-benzoyl-1,2-O-isopropylidene-D-furyl xylose and obtains, the hydroxyl reaction of iodine and 3-position.
Further, the hydroxyl selective protection of 5-position is obtained by 1,2-D-isopropylidene-D-furyl xylose formyl chloride by described 5-O-benzoyl-1,2-O-isopropylidene-D-furyl xylose.
Further, described 1,2-D-isopropylidene-D-furyl xylose is prepared by D-wood sugar, and D-wood sugar four hydroxyl acetonylidenes are protected, at 0.1molL
-1hCl in optionally remove the acetonylidene of 3,5-position.
Compared with prior art, a technical scheme tool in technique scheme has the following advantages:
Whole piece route reaction raw material of the present invention is more cheap and easy to get, the safer gentleness of reaction conditions.Main innovative point is removing of 3-position hydroxyl, does not utilize common free radical to cause principle, avoids reactant that is as large in toxicity such as tributyl tin hydrogen or that be not easy to obtain.
The present invention utilizes D-wood sugar to prepare 3-deoxidation-1,2-O-isopropylidene-D-furyl xylose, and total recovery reaches 34%.
Embodiment
In 500mL round-bottomed flask, add D-wood sugar (15.0g, 0.1mol) and anhydrous cupric sulfate (34.4g, 0.216mol), then add 98% vitriol oil of 150mL acetone and 3mL wherein, react in stirred at ambient temperature.Mixture is the muddy shape of yellow-green colour, and when leaving standstill, upper strata is weak yellow liquid, and lower floor is pale blue solid.Along with carrying out corresponsively, muddy solution progressively becomes tawny.Reaction 24h, by the mixture decompress filter be obtained by reacting, filter cake is light blue, and with acetone filter wash cake, merging filtrate, obtains yellow transparent liquid.Strong aqua is dripped to pH-7.0, neutralisation of sulphuric acid in filtrate.Generate white flock precipitate (NH
4)
2s0
4.Filter (NH
4)
2s0
4, filter cake washing with acetone, obtains colourless liquid.Merging filtrate, is spin-dried for (temperature≤50 DEG C) with Rotary Evaporators in single port flask, concentrates to obtain tawny syrupy shape material.
The 0.1molL of 100mL is added in two acetonylidene D-wood sugars obtained in the previous step
-1dilute hydrochloric acid, product is insoluble.Stirring at room temperature, solution dissolves gradually, reaction 1.5h.TLC follows the tracks of, and uses CH
2cl
2developping agent.Add solid sodium bicarbonate after reaction terminates and be adjusted to pH 7.2 ~ 7.5, mixture is poured in separating funnel, add about 30mL ether, vibration layering, organic layer glassy yellow, separatory.Repeat again to wash twice, until organic phase is colourless.Be spin-dried for (temperature≤50 DEG C) with Rotary Evaporators, concentrate to obtain colorless syrup material.
Appropriate CH is added in syrupy shape material
2c1
2, then add anhydrous sodium sulphate, dried overnight, and filter, concentrated.By 1,2-D isopropylidene-D-furyl xylose (15.82g, 0.082mol), anhydrous pyridine (12.70mL, 0.166mol) is dissolved in the CH of about 150mL
2c1
2in (adding anhydrous sodium sulphate dried overnight), stirring reaction, carries out in ice-water-bath, at the uniform velocity drips Benzoyl chloride (9.70mL, 0.082mol) wherein in 40min, and insulation reaction is about l h.TLC follows the tracks of, and developping agent is sherwood oil: ethyl acetate (3/1).After end, be poured in 500mL separating funnel, add the 0.1molL of appropriate about 30mL
-1hydrochloric acid, vibration layering, quick separatory, taking off layer has phase, three times repeatedly; Again with saturated sodium bicarbonate solution washing, take off layer equally in triplicate; Finally use saturated common salt water washing three times, take off layer.With anhydrous sodium sulfate drying, filter, concentrate to obtain yellowish syrup dope.Column chromatography for separation, the granularity of silica gel is 300-400 order, sherwood oil 60-90 DEG C: ethyl acetate adds with the order of 5/1,4/1,3/1,2/1, collects the component of 2/1, concentrates to obtain colorless syrup dope (slightly cooling becomes white solid).
HNMR(CDCl
3)δ:8.04(d,J=4.7Hz,2H);7.59(t,J=8.2Hz,lH);7.45(t,J=8.5Hz,2H);5.98(d,J=6.5Hz,lH);4.78(m,J=12.2Hz,lH;4.60(d,J=6.5Hz,1H);4.41(m,J=6.7Hz,2H);4.22(d,J=4.0Hz,lH;2.04(s,1H;1.51(s,3H);1.32(s,3H)。
By colorless syrup dope (1.32g, 4.5mmol) be dissolved in 10mL anhydrous pyridine, add Tosyl chloride (1.27g, 6.7mmol), add micro-DMAP (N again, N-Dimethylamino pyridine) fully shake up, make dissolution of solid, in colourless solution (or micro-band is faint yellow).Stirring at normal temperature reaction 24h.TLC follows the tracks of, and developping agent is sherwood oil: ethyl acetate (3/1).After reaction terminates, with about 50mL CH
2c1
2dilution, is poured in 150mL separating funnel, adds the 0.1molL of appropriate about 30mL
-1hydrochloric acid, vibration layering, quick separatory, taking off layer has phase, three times repeatedly; Again with saturated sodium bicarbonate solution washing, take off layer equally in triplicate: finally use saturated common salt water washing three times, take off layer.With anhydrous sodium sulfate drying, filter, concentrate to obtain yellowish syrup dope.Column chromatography for separation, the granularity of silica gel is 300-400 order, sherwood oil 60-90 DEG C: ethyl acetate with 5/1,4/1,3/l, 2/1 order add, collect the component of 3/l, concentratedly to obtain brilliant white solid.
1HNMR(CDCl
3)δ:7.95(d,J=7.6Hz,2H);7.81(d,J=8.1Hz,2H);7.61(t,J=7.4Hz,1H);7.46(t,J=7.7Hz,2H);7.27(d,J=12.1Hz,2H);6.03(d,J=3.5Hz,1H);4.97(d,J=2.6Hz,1H);4.86(d,J=3.5Hz,1H);4.58(m,J=3.0Hz,lH);4.44(m,J=5.8Hz,1H);4.32(m,J=6.0Hz,1H);2.31(s,3H);1.55(s,3H);1.37(s,3H).
The DMF (DMF) brilliant white solid (0.10g, 0.29mmol) being dissolved in about 10mL adds sodium iodide (0.67g again, 4.66mmol), solution is faint yellow, reacts and be heated to 90 DEG C in oil bath, stirs and carries out about 12h.TLC follows the tracks of, and developping agent is sherwood oil: ethyl acetate (3/1).After end, by solvent evaporate to dryness, then add about 30mL CH2C12 and again dissolve: pour in 125mL separating funnel, add the saturated brine of appropriate about 10mL, wash three times, taking off layer has phase; With anhydrous sodium sulfate drying, filter, concentrate to obtain faint yellow solid.Column chromatography for separation, the granularity of silica gel is 300.400 orders, sherwood oil 60.90 DEG C: ethyl acetate adds with the order of 6/1,4/1,3/1,2/1,1/1, collects the component of 3/1, concentrates to obtain faint yellow solid.
Faint yellow solid (1.72g, 5.85mmol) is dissolved in 20mLCH
2c1
2in (Non-aqueous processing), add anhydrous pyridine (0.71mL, 8.78mmol) with micro-DMAP (N, N-Dimethylamino pyridine), finally add Methanesulfonyl chloride (0.69g, 8.77mmol), fully shake up, in colourless solution (or micro-band is faint yellow).Stirring at normal temperature reaction 12h.TLC follows the tracks of, and developping agent is sherwood oil: ethyl acetate (3/1).After reaction terminates, with the CH of about 30mL
2c1
2dilution, is poured in 150mL separating funnel, adds the 0.1molL of appropriate about 20mL
-1with hydrochloric acid, vibration layering, quick separatory, taking off layer has phase, three times repeatedly; Again with saturated sodium bicarbonate solution washing, take off layer equally in triplicate: finally use saturated common salt water washing three times, take off layer.With anhydrous sodium sulfate drying, filter, concentrate to obtain yellowish syrup dope.Column chromatography for separation, the granularity of silica gel is 300-400 order, sherwood oil 60-90 DEG C: ethyl acetate adds with the order of 5/1,4/1,2/1, collects the component of 2/1, concentrates to obtain white solid.
White solid (1.07g, 3.63mmol) is dissolved in the toluene solution of 10mL, adds triphenyl phosphorus (2.39g, 9.08mmol); Imidazoles (0.6l g, 9.07mmol): fully shake up, makes dissolution of solid (some may be had to remain insoluble having not big harm), then adds iodine (1.84g, 7.25mmol).Solution yellow has chocolate to precipitate (iodine solvability is not good), reacts and be heated to 120 DEG C in oil bath, toluene is evenly refluxed, and stirs anti-about 5h.TLC follows the tracks of, and developping agent is sherwood oil 60--90 DEG C: ethyl acetate (3/1).Reaction terminates rear to be cooled to room temperature, adds isopyknic saturated sodium bicarbonate and stirs 5min, have a large amount of bubble to release: continue to stir the dilution with toluene adding about 20mL again, adds iodine gradually and makes organic phase keep iodine look; Pour separating funnel into, separatory; Organic phase saturated sodium thiosulfate is washed, and has grey flocks to separate out, and 3-5 time until solution becomes clean faint yellow repeatedly; Wash three times again with water, separatory; Yellow-brown solid is concentrated to obtain with anhydrous sodium sulfate drying; Wash with appropriate ether, on a small quantity repeatedly, filtering and concentrating obtains faint yellow solid again.Column chromatography for separation, the granularity of silica gel is 300-400 order, sherwood oil 60-90 DEG C: ethyl acetate with 7/1,6/1,5/I, 4/1, the order of 3/1 adds, component when collecting 5/1, concentratedly to obtain faint yellow solid.
Be dissolved in by faint yellow solid (1.45g, 5.22mmol) in about 20mL methyl alcohol (anhydrous) solution, add sodium methylate (0.61g, 11.32mmol), stirring at room temperature reacts about 2.5h.TLC follows the tracks of, and developping agent is sherwood oil 60-90 DEG C: ethyl acetate (3/1).After reaction terminates, concentrate to obtain thick white thing.Column chromatography for separation, the granularity of silica gel is 300-400 order, sherwood oil 60-90 DEG C: ethyl acetate adds with the order of 6/1,4/1,3/1,2/1, component when collecting 2/1, concentratedly to obtain white solid.
White solid (0.61g, 1.78mmol) is dissolved in about 20mL methyl alcohol (anhydrous) solution, adds iron cyanide (0.58g, 1.81mmol), adding trace P d/C is again catalyzer, and heating in water bath makes methanol eddy to 70 DEG C, and stirring reaction is about 20h.TLC follows the tracks of, and developping agent is sherwood oil 60 ~ 90 DEG C: ethyl acetate (3/1).Finally obtain 3-deoxidation-1,2-O-isopropylidene-D-furyl xylose, productive rate is 34%.
Claims (5)
1. a 3-deoxidation-1; the synthetic method of 2-O-isopropylidene-D-furyl xylose, is characterized in that, 3-deoxidation-1; 2-O-isopropylidene-D-furyl xylose by 5-O-benzoyl-3-deoxidation-1,2-D-isopropylidene-D-furyl xylose add alkali slough 5-position benzoic ether protect obtain.
2. 3-deoxidation-1 according to claim 1; the synthetic method of 2-O-isopropylidene-D-furyl xylose; it is characterized in that; described 5-O-benzoyl-3-deoxidation-1; allusion quotation base removing in 3-position is obtained by iodo-1, the 2-D-isopropylidene-D-furyl xylose reduction of 5-O-benzoyl-3-by 2-D-isopropylidene-D-furyl xylose.
3. 3-deoxidation-1 according to claim 2; the synthetic method of 2-O-isopropylidene-D-furyl xylose; it is characterized in that; described 5-O-benzoyl-3-iodo-1; 2-D-isopropylidene-D-furyl xylose is by 5-O-benzoyl-1; 2-O-isopropylidene-D-furyl xylose adds Iod R and obtains, the hydroxyl reaction of iodine and 3-position.
4. 3-deoxidation-1 according to claim 3; the synthetic method of 2-O-isopropylidene-D-furyl xylose, is characterized in that, described 5-O-benzoyl-1; the hydroxyl selective protection of 5-position is obtained by 1,2-D-isopropylidene-D-furyl xylose formyl chloride by 2-O-isopropylidene-D-furyl xylose.
5. the synthetic method of 3-deoxidation-1,2-O-isopropylidene-D-furyl xylose according to claim 4, is characterized in that, described 1,2-D-isopropylidene-D-furyl xylose is prepared by D-wood sugar, and D-wood sugar four hydroxyl acetonylidenes are protected, at 0.1molL
-1hCl in optionally remove the acetonylidene of 3,5-position.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410706530.8A CN104402945A (en) | 2014-11-27 | 2014-11-27 | Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410706530.8A CN104402945A (en) | 2014-11-27 | 2014-11-27 | Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose |
Publications (1)
Publication Number | Publication Date |
---|---|
CN104402945A true CN104402945A (en) | 2015-03-11 |
Family
ID=52640624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410706530.8A Pending CN104402945A (en) | 2014-11-27 | 2014-11-27 | Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104402945A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5637688A (en) * | 1994-12-13 | 1997-06-10 | Eli Lilly And Company | Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride |
US20080032999A1 (en) * | 2006-06-22 | 2008-02-07 | Anadys Pharmaceuticals, Inc. | Prodrugs of 5-amino-3-(3'-deoxy-b-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidin-2,7-dione |
CN101182342A (en) * | 2007-12-07 | 2008-05-21 | 合肥学院 | Method for synthesizing 1,2,3-O-tri-acetyl-5-deoxidation-D-ribose |
CN101735285A (en) * | 2008-11-18 | 2010-06-16 | 上海睿智化学研究有限公司 | Preparation method of 1,2,5-O-triacyl-3-deoxy-alpha-D-xylofuranose |
CN103242386A (en) * | 2013-04-11 | 2013-08-14 | 中国中化股份有限公司 | Method for preparing alpha-1-methoxy-2-deoxyribofuranose derivatives |
-
2014
- 2014-11-27 CN CN201410706530.8A patent/CN104402945A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5637688A (en) * | 1994-12-13 | 1997-06-10 | Eli Lilly And Company | Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride |
US20080032999A1 (en) * | 2006-06-22 | 2008-02-07 | Anadys Pharmaceuticals, Inc. | Prodrugs of 5-amino-3-(3'-deoxy-b-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidin-2,7-dione |
CN101182342A (en) * | 2007-12-07 | 2008-05-21 | 合肥学院 | Method for synthesizing 1,2,3-O-tri-acetyl-5-deoxidation-D-ribose |
CN101735285A (en) * | 2008-11-18 | 2010-06-16 | 上海睿智化学研究有限公司 | Preparation method of 1,2,5-O-triacyl-3-deoxy-alpha-D-xylofuranose |
CN103242386A (en) * | 2013-04-11 | 2013-08-14 | 中国中化股份有限公司 | Method for preparing alpha-1-methoxy-2-deoxyribofuranose derivatives |
Non-Patent Citations (1)
Title |
---|
陈怡欣: "3-脱氧-1,2-O-异丙叉-D-呋喃木糖的合成", 《南京理工大学硕士学位论文》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103458689B (en) | The preparation method of 4-amino-5-fluorine-3-halo-6-(replacement) pyridine-2-manthanoate | |
CN106928055B (en) | A method of aspirin is catalyzed and synthesized using choline eutectic solvent | |
CN103980263B (en) | The synthesis technique of canagliflozin | |
CN101792400A (en) | Synthetic method for agomelatine | |
CN102516078A (en) | Preparation methods of glyoxylic acid L-menthyl alcohol ester and monohydrate of glyoxylic acid L-menthyl alcohol ester | |
CN105566215B (en) | A kind of Rui Gefeini preparation method | |
CN104672157A (en) | Method for preparing aryl triazolinone | |
CN104016924A (en) | One-pot method for synthetizing enzalutamide | |
CN106117216A (en) | A kind of method of atmospheric high efficiency synthesis 6H iso-indoles [2,1 a] indole 6 ketone compounds | |
CN104402945A (en) | Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose | |
CN103992261B (en) | 2-bromine carbazole industrial preparation process | |
CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
CN110105302B (en) | Preparation method of aromatic thioether compound containing benzoheterocycle | |
CN101486676B (en) | Preparation method of cyano-methyl-pyridyl compound | |
CN104829588B (en) | A kind of Preparation Method And Their Intermediate of benzo [b] thiophene | |
CN100460416C (en) | Method for preparing adenosine | |
CN104478852A (en) | Novel diazo benzothiapyrone photosensitive protecting groups and synthesis method thereof | |
CN105924390A (en) | Synthesis method of metafenib | |
CN104650160A (en) | Novel synthesis method of capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose | |
CN105017284A (en) | Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates | |
CN110143861A (en) | A kind of preparation method of brufen | |
CN103864679B (en) | A kind of preparation method of 3-methyl-2-pyridine carboxylic acid methyl esters | |
CN103910668B (en) | A kind of preparation method of 3 alkyl-indol | |
CN102329237A (en) | Production process of 2-chloro-5-nitrobenzoic acid | |
CN104177386B (en) | A kind of nitrogen-bridged three aryloxy rare earth metal compounds and its preparation method and application |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150311 |