CN105566406A

CN105566406A - Preparation method of fluorodesoxyribofuranose

Info

Publication number: CN105566406A
Application number: CN201511020367.0A
Authority: CN
Inventors: 叶敏; 刘锐; 叶方国
Original assignee: Jiangxi Shengfu Chemical Co Ltd
Current assignee: Jiangxi Shengfu Chemical Co Ltd
Priority date: 2015-12-30
Filing date: 2015-12-30
Publication date: 2016-05-11

Abstract

The invention provides a preparation method of fluorodesoxyribofuranose. The structure of the fluorodesoxyribofuranose is represented by general formula 1 shown in the description; and the general formula 1, 1a:R = F, and R' = Me; and 1b:R = Me, and R' = F. The fluorodesoxyribofuranose prepared through the brand new preparation method can be used in researching of new medicines, or can be used in researches as a research model. The method adopts glyceraldehyde acetonide as a raw material and allows enantiomers in all intermediates to be effectively separated through a four-step reaction by adopting a rectification or distillation and re-crystallization technology, and a 2-posiion single optical isomer in the target product is directly constructed through an enol addition reaction, so the preparation of the target compound is smooth completed, and the method has the advantages of high yield, simple operation, and suitableness for promotion and application.

Description

A kind of preparation method of fluorodeoxy ribofuranose

Technical field

The present invention relates to the field of chemical synthesis, be specifically related to a kind of preparation method, particularly relate to a kind of preparation method of fluorodeoxy ribofuranose.

Background technology

D-2-ribodesose is a derivative that 2 hydroxyls are replaced by hydrogen of ribose.It as the component of thymus nucleic acid DNA, has a very important role in cell.In DNA, due to r-ray or containing the antibiotic stimulation of alkene-acetylene bond, cause the damage of oxidisability DNA sometimes, namely ribodesose damage occurs, thus causes pathology.

Fluorodeoxy ribofuranose, owing to introducing more stable carbon-fluorine bond, is introduced in DNA, ribodesose can be made to damage and be difficult to occur; This result for the damage of further investigation ribodesose and biological action provide more stable research model, meanwhile, also make this compounds be widely used in the research and development of new drug.Fluorodeoxy ribofuranose as shown in summary of the invention Chinese style (1a), as the key component of anti-third liver star medicine Suo Feibuwei, is pharmacologically playing vital role.Therefore, the preparation method researching and developing this compounds has outstanding meaning.

In fact, for compound 1a, in prior art, openly report multiple synthetic method, but there is the shortcomings such as synthetic route is long, yield is low, stereoselectivity is poor in these methods, is not suitable for scale operation usually.Such as:

Early stage method take L-arabinose as raw material, and just can prepare the analogue 11 of compound 1a through 11 step reactions, concrete synthetic route is:

In addition, most method take glyceraldehyde acetonide as raw material, is first obtained by reacting compound 13 by two hydroxyl oxidize, on this basis, different methods has prepared different intermediates, then prepares compound 1a by fluoro-reaction and ring closure reaction, and concrete synthetic route is:

Also a kind of method is the method being widely used in industrialized production compound 1a at present, this method with the triethylamine salt of hydrofluoric acid for fluoro reagent replaces expensive diethylaminosulfurtrifluoride (DAST) and compound reacts for committed step, successfully achieve the scale operation of compound 1a, concrete synthetic route is:

Another kind method obtains compound by the Reformatsky condensation reaction of glyceraldehyde acetonide, compound is prepared through reactions such as peroxidation, fluoro, reduction, but this method route is long, need the oxidation-reduction state adjustment through twice, and the diastereomer 27 generated need be separated and could obtain 27a by purifying by chromatographic column, concrete synthetic route is:

Also have bibliographical information a kind of the short-cut method needing three-step reaction to prepare compound 1a, but, this method stereoselectivity is poor, four diastereomers producing are difficult to separation and purification, wherein, the method that in document, trial enzyme splits carrys out separate targets product 1a, but effect bad, and concrete synthetic route is:

Therefore, at present, a kind of method of easier, efficient synthesizing fluoro desoxyribofu-is those skilled in the art in the urgent need to.

Summary of the invention

Based on above-mentioned background technology, the invention provides a kind of novel method preparing fluorodeoxy ribofuranose, wherein, take glyceraldehyde acetonide as raw material, by four-step reaction, rectifying or distillation is adopted to have effectively achieved being separated of enantiomer in each intermediate with the method for recrystallization, especially, the single optical isomer of 2-position in target product by enol addition reaction direct construction, thus complete the preparation of target compound smoothly.

Theme of the present invention is a kind of preparation method of fluorodeoxy ribofuranose, and wherein, the structure of described fluorodeoxy ribofuranose is as shown in general formula 1: (1), wherein, 1a:R=F, R'=Me; 1b:R=Me, R'=F; It is characterized in that, its synthetic route is:

Its synthesis step comprises:

(1) glyceraldehyde acetonide and ethyl ester compound carry out condensation reaction and obtain each other 31 of enantiomer and the mixture of 32;

(2) compound 33 is obtained with acid treatment compound 31;

(3) compound 33 carries out the mixture that benzoylation obtains 34 and 35;

(4) described 34 and 35 mixture tertiary butyl dimethyl silyl triflate and triethylamine process, obtain enol form compound 36;

(5) there is trans nucleophilic addition in compound 36 under the effect of nucleophilic reagent, obtains compound 1.

Wherein, the mixture employing rectifying of 31 and 32 or the method for distillation of the described enantiomer each other obtained in step (1) carry out separating-purifying.

In one embodiment of the invention, described ethyl ester class is the bromo-2-ethyl fluoroacetate of 2-or ethyl propionate.Because condensation reaction has higher trans selective, the primary product therefore in step (1) is compound 31; Further preferably, present inventor surprisingly finds, adopts the method for rectifying or distillation, carries out further separating-purifying, can obtain the higher compound of purity 31 to the mixture of 31 and 32 of described enantiomer each other.

In another embodiment of the present invention, compound 31, in alcohol reagent, obtains compound 33 with acid treatment; Further preferably, described alcohol reagent selects ethanol; Hydrochloric acid, sulfuric acid, tosic acid etc. are selected in described acid.The compound 33 obtained in this step is directly used in next step reaction, and without the need to carrying out the operation of isolation andpurification.

In an embodiment of the present invention, compound 33 preferably carries out benzoylation reaction in acetonitrile reagent; Further, the mixture to obtained 34 and 35 carries out recrystallization, not only obtains highly purified product, and thoroughly eliminates simultaneously and derive by cis-product 32 by product got off.Preferably, described crystallization adopts Virahol to carry out.

In one embodiment, described nucleophilic reagent is methyl iodide or 1-chloromethyl-4-fluoro-Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt.

Further, in step (5), preferably carry out recrystallization to reaction product, thus obtain highly purified the finished product, be i.e. compound 1, wherein, more preferably, described recrystallization adopts Virahol to carry out as solvent.

In a preferred embodiment of the invention, a kind of preparation method of fluorodeoxy ribofuranose, the structural formula of described fluorodeoxy ribofuranose is as shown in general formula 1a: (1a); It is characterized in that, its synthesis step is:

(1) in containing the tetrahydrofuran solution of zinc powder, drip bromo-2 ethyl fluoroacetates of 2-and glyceraldehyde acetonide, be obtained by reacting compound 31a;

(2) compound 31a, ethanol and concentrated hydrochloric acid hybrid reaction, obtain compound 33a;

(3) compound 33a, acetonitrile, DMAP and Benzoyl chloride hybrid reaction, obtain the mixture of 34a and 35a;

(4) in the dichloromethane solution of mixture being dissolved with 34a and 35a, drip triethylamine and tertiary butyl dimethyl silyl triflate, be obtained by reacting compound 36a;

(5) in the DMF solution being dissolved with compound 36a, add methyl iodide, be obtained by reacting compound 1a.

In a preferred embodiment of the invention, a kind of preparation method of fluorodeoxy ribofuranose, the structural formula of described fluorodeoxy ribofuranose is as shown in general formula 1b: (1b); It is characterized in that, its synthesis step is:

(1) in the tetrahydrofuran solution of Diisopropylamine, drip n-Butyl Lithium form lithium diisopropylamine, then drip ethyl propionate and glyceraldehyde acetonide, be obtained by reacting compound 31b;

(2) compound 31b, ethanol and concentrated hydrochloric acid hybrid reaction, obtain compound 33b;

(3) compound 33b, acetonitrile, DMAP and Benzoyl chloride hybrid reaction, obtain the mixture of 34b and 35b;

(4) in the dichloromethane solution of mixture being dissolved with 34b and 35b, drip triethylamine and tertiary butyl dimethyl silyl triflate, be obtained by reacting compound 36b;

(5) in the DMF solution being dissolved with compound 36b, add 1-chloromethyl-4-fluoro-Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, be obtained by reacting compound 1b.

In one particular embodiment of the present invention, the preparation method of described 1a is:

(1) under nitrogen protection, zinc powder and anhydrous tetrahydro furan are put in reaction flask, then slowly drip the bromo-2 ethyl fluoroacetate solution of 2-being dissolved in tetrahydrofuran (THF), more slowly drip (the R)-glyceraldehyde acetonide solution being dissolved in tetrahydrofuran (THF), be obtained by reacting compound 31a;

(2) gained compound 31a, ethanol and concentrated hydrochloric acid are put in reaction flask, be obtained by reacting compound 33a, be directly used in next step reaction;

(3) under nitrogen protection, compound 33a, acetonitrile, DMAP and Benzoyl chloride are put in reaction flask, drip triethylamine, after reaction terminates, obtain compound 34a/35a with recrystallisation from isopropanol;

(4) compound 34a/35a and methylene dichloride are dropped in reaction flask, slowly drip triethylamine, then drip tertiary butyl dimethyl silyl triflate, be obtained by reacting compound 36a;

(5) compound 36a is dissolved in DMF, adds methyl iodide, after reaction terminates, obtain compound 1a with recrystallisation from isopropanol.

In one particular embodiment of the present invention, the preparation method of described 1b is:

(1) under nitrogen protection, tetrahydrofuran (THF), Diisopropylamine are put in reaction flask, slowly drip 2.5M n-Butyl Lithium, then the toluene solution of ethyl propionate and R-glyceraldehyde acetonide is dripped, after reaction terminates, rectifying or distillation, collect 90-110 DEG C of cut and obtain compound 31b;

(2) compound 31b, ethanol and concentrated hydrochloric acid are put in reaction flask, be obtained by reacting compound 33b;

(3) under nitrogen protection, compound 33b, acetonitrile, DMAP and Benzoyl chloride are put in reaction flask, drip triethylamine, after reaction terminates, obtain compound 34b/35b with recrystallisation from isopropanol;

(4) under nitrogen protection, compound 34b/35b and methylene dichloride are dropped in reaction flask, slowly drips triethylamine, then add tertiary butyl dimethyl silyl triflate, obtain compound 36b;

(5) compound 36b is dissolved in DMF, adds 1-chloromethyl-4-fluoro-Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, after reaction terminates, obtain compound 1b with recrystallisation from isopropanol.

In preparation method, except necessary post-processing step described above, the present invention does not get rid of other auxiliary post-processing step, and wherein, in a preferred specific embodiment of the present invention, the preparation method of described 1a is:

(1) under nitrogen protection, zinc powder is put in advance in dry anhydrous reaction flask, anhydrous tetrahydro furan is added with syringe, slow dropping is dissolved in the 2-bromo-2-ethyl fluoroacetate solution of tetrahydrofuran (THF), after adding, stirring at room temperature reaction 30min, slowly drips (the R)-glyceraldehyde acetonide solution being dissolved in tetrahydrofuran (THF), after adding, stirring at room temperature reaction 1h; Water and isopropyl ether are joined in reaction system, leave standstill separatory, aqueous phase isopropyl ether extracting twice, merge organic phase, with dilute hydrochloric acid and water washing once, then use anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain compound 31a;

(2) put in reaction flask by gained compound 31a, ethanol and concentrated hydrochloric acid, room temperature reaction spends the night, and is evaporated to toluene evaporate to dryness under 60 DEG C of conditions, gained compound 33a, can be directly used in next step reaction;

(3) under nitrogen protection, put in reaction flask by the crude product of compound 33a, acetonitrile, DMAP and Benzoyl chloride, ice bath is cooled to 0 DEG C-5 DEG C, starts to drip triethylamine, after dripping off, is naturally warming up to room temperature reaction 30min; Add ethyl acetate, water stirs 30min, stratification, collected organic layer, use saturated sodium bicarbonate solution, saturated common salt water washing organic phase successively, layering, organic layer is dry with Sodium sulfate anhydrous.min(99), after filtration, under 60 DEG C of conditions, concentrating under reduced pressure is done, and adds Virahol, be warming up to 80 DEG C, stir 10min, be cooled to 0 DEG C-10 DEG C, crystallization 1h, filters, filter cake washed with isopropyl alcohol cold on a small quantity, 50 DEG C of decompression dryings, obtain compound 34a/35a;

(4) under nitrogen protection, compound 34a/35a and methylene dichloride are dropped in reaction flask, stirring and dissolving, is cooled to 0 DEG C, slowly drips triethylamine, then drips tertiary butyl dimethyl silyl triflate, drips, stirring reaction 30min at 0 DEG C; In reactant, add shrend to go out reaction, stratification, aqueous phase uses dichloromethane extraction three times again, merges organic phase, with anhydrous sodium sulfate drying, after filtration, is evaporated to dry, obtains compound 36a;

(5) compound 36a is dissolved in DMF, in cooling-40 DEG C, adds methyl iodide, after adding, rise to room temperature, stirring reaction 1h; In reactant, add shrend to go out reaction, be extracted with ethyl acetate three times, merge organic phase, with anhydrous sodium sulfate drying, after filtration, be evaporated to dry, gained crude product recrystallisation from isopropanol, obtains compound as white solid 1a.

In another one specific embodiment of the present invention, the preparation method of described 1b is:

(1) under nitrogen protection, tetrahydrofuran (THF), Diisopropylamine are put in reaction flask, liquid nitrogen cooling is to-78 DEG C, slow dropping 2.5M n-Butyl Lithium, drips off and is slowly warming up to-10 DEG C afterwards, stirs 30min, again with liquid nitrogen cooling extremely-78 DEG C, drip the toluene solution of ethyl propionate and R-glyceraldehyde acetonide, drip off rear insulation reaction 30min, be naturally warming up to room temperature reaction 2h; Control temperature less than 20 DEG C, with 28% potassium dihydrogen phosphate cancellation reaction, add ethyl acetate and extract 3 times, layering, merge organic layer concentrated dry, underpressure distillation, collects 90 DEG C of-110 DEG C of fractions, obtains compound 31b;

(2) put in reaction flask by compound 31b, ethanol and concentrated hydrochloric acid, room temperature reaction spends the night, 60 DEG C of concentrating under reduced pressure, and toluene evaporate to dryness, obtains compound 33b;

(3) under nitrogen protection, put in reaction flask by compound 33b, acetonitrile, DMAP and Benzoyl chloride, ice bath is cooled to 0 DEG C-5 DEG C, starts to drip triethylamine, after dripping off, is naturally warming up to room temperature reaction 30min; Add ethyl acetate, water stirs 30min, stratification, collected organic layer, use saturated sodium bicarbonate solution, saturated common salt water washing organic phase successively, layering, organic layer is dry with Sodium sulfate anhydrous.min(99), after filtration, 60 DEG C of concentrating under reduced pressure are done, and add Virahol, be warming up to 80 DEG C, stir 10min, be cooled to 0 DEG C-10 DEG C, crystallization 1h, filters, filter cake washed with isopropyl alcohol cold on a small quantity, 50 DEG C of decompression dryings, obtain compound 34b/35b;

(4) under nitrogen protection, compound 34b/35b and methylene dichloride are dropped in reaction flask, stirring and dissolving, is cooled to 0 DEG C, slowly drips triethylamine, then adds tertiary butyl dimethyl silyl triflate, after adding, and stirring reaction 30min at 0 DEG C; In reactant, add shrend to go out reaction, stratification, aqueous phase uses dichloromethane extraction three times again, merges organic phase, with anhydrous sodium sulfate drying, after filtration, is evaporated to dry, obtains compound 36b;

(5) compound 36b is dissolved in DMF, is cooled to-40 DEG C, add 1-chloromethyl-4-fluoro-Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, after adding, rise to room temperature, stirring reaction 1h, in reactant, add shrend to go out reaction, be extracted with ethyl acetate three times, merge organic phase, with anhydrous sodium sulfate drying, after filtration, be evaporated to dry, gained crude product recrystallisation from isopropanol, obtains compound as white solid 1b.

Further, embody particularly in a particular embodiment of the present invention in technical solution of the present invention, certainly, theme of the present invention is a kind of preparation method of compound, mainly lays particular emphasis on the innovation of method, therefore, the general introduction of synthetic route and synthesis step is technical characteristics of the present invention, in addition, present inventor is also unexpected has found the post-treating method being especially adapted to each synthesis step of the present invention, can obtain highly purified corresponding reaction product.On this basis, those skilled in the art can be optimized it according to routine techniques means, but its net result is still encompassed in theme of the present invention, the above-mentioned embodiment about concrete preparation method or preferred embodiment, only for making technician understand theme of the present invention further, and be not limit the present invention.

Relative to prior art, the present invention is by a kind of brand-new preparation method, prepare a kind of fluorodeoxy ribofuranose, may be used for new drug research and development and as research model for studying use, wherein said method take glyceraldehyde acetonide as raw material, pass through four-step reaction, rectifying or distillation is adopted to have effectively achieved being separated of enantiomer in each intermediate with the method for recrystallization, especially, the single optical isomer of 2-position in target product by enol addition reaction direct construction, thus complete the preparation of target compound smoothly, yield is high, easy and simple to handle, be suitable for promotion and application.

Embodiment

Its synthesis step comprises:

(2) compound 33 is obtained with acid treatment compound 31;

(3) compound 33 carries out the mixture that benzoylation obtains 34 and 35;

(5) there is trans nucleophilic addition in compound 36 under the effect of nucleophilic reagent, obtains compound 1;

In a preferred embodiment of the invention, a kind of preparation method of fluorodeoxy ribofuranose, the structural formula of described fluorodeoxy ribofuranose is as shown in general formula 1b: (1b); It 20 is characterised in that, its synthesis step is:

(1) under nitrogen protection, zinc powder is put in advance in dry anhydrous reaction flask, anhydrous tetrahydro furan is added with syringe, slow dropping is dissolved in the bromo-2 ethyl fluoroacetate solution of 2-of tetrahydrofuran (THF), after adding, stirring at room temperature reaction 30min, slowly drips (the R)-glyceraldehyde acetonide solution being dissolved in tetrahydrofuran (THF), after adding, stirring at room temperature reaction 1h; Water and isopropyl ether are joined in reaction system, leave standstill separatory, aqueous phase isopropyl ether extracting twice, merge organic phase, with dilute hydrochloric acid and water washing once, then use anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain compound 31a;

According to technique scheme provided by the invention, existing by following examples content of the present invention explained further and illustrate.

Embodiment 1---the synthesis of compound 31b

Under nitrogen protection, by tetrahydrofuran (THF) (500mL), Diisopropylamine (66.1g, 0.65mol) put in reaction flask, liquid nitrogen cooling is to-78 DEG C, slow dropping 2.5M n-Butyl Lithium (261mL, 0.65mol), drip off and be slowly warming up to-10 DEG C afterwards, stir 30min, again with liquid nitrogen cooling extremely-78 DEG C, drip ethyl propionate (58.8g, 0.58mol) with R-glyceraldehyde acetonide (50.0g, toluene (250mL) solution 0.49mol), drip off rear insulation reaction 30min, naturally room temperature reaction 2h is warming up to, control temperature less than 20 DEG C, react with 28% potassium dihydrogen phosphate (600mL) cancellation, add ethyl acetate (200mL) and extract 3 times, layering, merge organic layer concentrated dry, decompression (50pa-100pa) distillation, collect 90 DEG C of-110 DEG C of fractions, obtain 31b (54.2g, yield 60.8%, configuration ratio is 31b/32b=89.4:10.6).

Embodiment 2---the synthesis of compound 33b

Put in reaction flask by compound 31b (15g, 0.065mol), ethanol (75mL) and concentrated hydrochloric acid (5mL), room temperature reaction spends the night, 60 DEG C of concentrating under reduced pressure.Toluene band evaporate to dryness, obtains 33b (8.7g, yield 92.2%).

Embodiment 3---the synthesis of compound 34b/35b

Under nitrogen protection, by compound 33b (7.4g, 50.6mmol), acetonitrile (50mL), DMAP (0.3g, 2.5mmol) with Benzoyl chloride (17.8g, 126.6mmol) put in reaction flask, ice bath is cooled to 0 DEG C-5 DEG C, start to drip triethylamine (12.8g, 0.1266mol), after dripping off, naturally room temperature reaction 30min is warming up to, add ethyl acetate (50mL), water (50g) stirs 30min, stratification, collected organic layer, use saturated sodium bicarbonate solution (20mL) successively, saturated aqueous common salt (20mL) washs organic phase, layering, organic layer is dry with Sodium sulfate anhydrous.min(99), after filtration, 60 DEG C of concentrating under reduced pressure are done, add Virahol (70mL), be warming up to 80 DEG C, stir 10min, be cooled to 0 DEG C-10 DEG C, crystallization 1h, filter, filter cake washed with isopropyl alcohol cold on a small quantity, 50 DEG C of decompression dryings, obtain compound 34b/35b (8.1g, yield 54.4%).1HNMR(400MHz,CDCl3)δ8.08–7.97(m,4H),7.60(dt,J＝21.2,7.4Hz,2H),7.45(dt,J＝20.7,7.8Hz,4H),5.42–5.35(m,1H),4.81(dd,J＝8.5,5.0Hz,1H),4.69(qd,J＝12.3,4.1Hz,2H),3.02(dt,J＝14.8,7.4Hz,1H),1.50(d,J＝7.5Hz,3H)。

Embodiment 4---the synthesis of compound 1b

Under nitrogen protection, the mixture (3.54g, 10mmol) of 34b/35b and methylene dichloride (100mL) are dropped in reaction flask, stirring and dissolving.Be cooled to 0 DEG C, slowly drip triethylamine (4.7mL, 35mmol), then add tertiary butyl dimethyl silyl triflate (4.23g, 16mmol).Add, stirring reaction 30min at 0 DEG C, in reactant, add 120mL shrend to go out reaction, stratification, aqueous phase uses dichloromethane extraction three times again, merge organic phase, with anhydrous sodium sulfate drying, after filtration, be evaporated to dry, products therefrom is dissolved in N, in dinethylformamide (100mL), in cooling-40 DEG C, add 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt (7.08g, 20mmol), after adding, rise to room temperature, stirring reaction 1h, in reactant, add 300mL shrend to go out reaction, be extracted with ethyl acetate three times (3x200mL), merge organic phase, with anhydrous sodium sulfate drying, after filtration, be evaporated to dry, gained crude product recrystallisation from isopropanol, obtain compound as white solid 1b (2.1g, 56.4%).Optical value: [α]=+ 24.9 (c1.0, CH2Cl2) .1HNMR (400MHz, CDCl3): δ 8.03 (d, J=7.6Hz, 4H), 7.63 (d, J=7.6Hz, 1H), 7.56 (d, J=7.6Hz, 1H), 7.51-7.40 (m, 4H), 5.84 (dd, J=18.8Hz, 5.2Hz, 1H), 4.76-4.74 (m, 2H), 4.60 (d, J=5.4Hz, 1H), 1.78 (d, J=23.2Hz, 3H).

Embodiment 5---the synthesis of compound 33a

Under nitrogen protection, by zinc powder (24.2g, 0.37mol) input in advance dry anhydrous reaction flask.Anhydrous tetrahydro furan (300mL) is added with syringe, slow dropping is dissolved in the bromo-2 ethyl fluoroacetate (46.9g of 2-of 80mL tetrahydrofuran (THF), 0.25mol) solution, after adding, stirring at room temperature reaction 30min, slow dropping is dissolved in (R)-glyceraldehyde acetonide (33g of 80mL tetrahydrofuran (THF), 0.253mol) solution, after adding, stirring at room temperature reaction 1h, water and isopropyl ether are joined in reaction system, leaves standstill separatory.Aqueous phase isopropyl ether extracting twice, merge organic phase, with dilute hydrochloric acid and water washing once, organic phase anhydrous sodium sulfate drying, filters, be evaporated to dry, put in reaction flask by gained compound 31a, ethanol (165mL) and concentrated hydrochloric acid (10mL), room temperature reaction spends the night, 60 DEG C of concentrating under reduced pressure, toluene band evaporate to dryness, products therefrom is directly used in next step reaction.

Embodiment 6---the synthesis of compound 34a/35a

Under nitrogen protection, by previous step gained crude product (7.4g, 50.6mmol), acetonitrile (140mL), DMAP (0.83g, 7.0mmol) with Benzoyl chloride (49.3g, 350mmol) put in reaction flask, ice bath is cooled to 0 DEG C-5 DEG C, start to drip triethylamine (35.5g, 350mmol), after dripping off, naturally room temperature reaction 30min is warming up to, add ethyl acetate (150mL), water (150g) stirs 30min, stratification, collected organic layer, use saturated sodium bicarbonate solution (60mL) successively, saturated aqueous common salt (60mL) washs organic phase, layering, organic layer is dry with Sodium sulfate anhydrous.min(99), after filtration, 60 DEG C of concentrating under reduced pressure are done, add Virahol (200mL), be warming up to 80 DEG C, stir 10min, be cooled to 0 DEG C-10 DEG C, crystallization 1h, filter, filter cake washed with isopropyl alcohol cold on a small quantity, 50 DEG C of decompression dryings, obtain compound 34a/35a (20.8g, three step total recoverys 23.3%).1HNMR(400MHz,CDCl3)δ8.13–8.01(m,3H),7.99–7.94(m,1H),7.64–7.57(m,1H),7.56–7.50(m,1H),7.49–7.40(m,4H),5.70(d,J＝8.1Hz,1H,minor),5.65(d,J＝8.1Hz,1H,minor),5.55(d,J＝18.8Hz,1H,major),5.47–5.38(m,1H,major,1H,minor),4.81–4.76(m,1H,minor),4.71–4.62(m,1H,major),4.62–4.49(m,1H,major,1H,minor),1.68(d,J＝22.0,3H,major),1.66(d,J＝22.0,3H,minor)。

Embodiment 7---the synthesis of compound 1a

Under nitrogen protection, the mixture (7.16g, 20mmol) of 34a/35a and methylene dichloride (200mL) are dropped in reaction flask, stirring and dissolving.Be cooled to 0 DEG C, slowly drip triethylamine (9.4mL, 70mmol), drip tertiary butyl dimethyl silyl triflate (8.46g, 32mmol) again, drip, stirring reaction 30min at 0 DEG C, adds 200mL shrend and to go out reaction, stratification in reactant, aqueous phase uses dichloromethane extraction three times again, merges organic phase, with anhydrous sodium sulfate drying, after filtration, be evaporated to dry, products therefrom is dissolved in DMF (200mL).In cooling-40 DEG C, add methyl iodide (5.68g, 40mmol).After adding, rise to room temperature, stirring reaction 1h, in reactant, add 300mL shrend to go out reaction, be extracted with ethyl acetate three times (3x300mL), merge organic phase, with anhydrous sodium sulfate drying, after filtration, be evaporated to dry, gained crude product recrystallisation from isopropanol, obtains compound as white solid 1a (3.5g, 47%).Fusing point: 135-137 DEG C; Optical value: [α]=+ 24.9 (c1.0, CH2Cl2) .1HNMR (400MHz, DMSO) δ 8.03 (d, J=7.2Hz, 2H), 7.95 (d, J=7.1Hz, 2H), 7.73 (t, J=7.4Hz, 1H), 7.66 (t, J=7.4Hz, 1H), 7.57 (t, J=7.8Hz, 2H), 7.49 (t, J=7.8Hz, 2H), 5.77 (dd, J=18.5,7.1Hz, 1H), 5.15 (td, J=6.7,3.7Hz, 1H), 4.70 (ddd, J=18.9,12.4,5.1Hz, 2H), 1.70 (d, J=24.4Hz, 3H).

Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.

Claims

1. a preparation method for fluorodeoxy ribofuranose, wherein, the structure of described fluorodeoxy ribofuranose is as shown in general formula 1: wherein, 1a:R=F, R'=Me; 1b:R=Me, R'=F; It is characterized in that, its synthetic route is:

its synthesis step comprises:

(2) compound 33 is obtained with acid treatment compound 31;

(3) compound 33 carries out the mixture that benzoylation obtains 34 and 35;

2. preparation method according to claim 1, is characterized in that, ethyl ester compound described in step (1) is the bromo-2-ethyl fluoroacetate of 2-or ethyl propionate.

3. preparation method according to claim 1, is characterized in that, the compound 33 obtained in step (2) is directly used in next step reaction, and without the need to carrying out the operation of isolation andpurification.

4. preparation method according to claim 1, is characterized in that, in step (3) and step (5), carries out recrystallization process to reaction product, obtains mixture and the described compound 1 of described 34 and 35 respectively.

5. preparation method according to claim 1, is characterized in that, in step (5), described nucleophilic reagent is methyl iodide or 1-chloromethyl-4-fluoro-Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt.

6. a preparation method for fluorodeoxy ribofuranose, the structural formula of described fluorodeoxy ribofuranose is as shown in general formula 1a: it is characterized in that, its synthesis step is:

7. preparation method according to claim 6, is characterized in that, described synthesis step is:

8. a preparation method for fluorodeoxy ribofuranose, the structural formula of described fluorodeoxy ribofuranose is as shown in general formula 1b: it is characterized in that, its synthesis step is:

(1) in the tetrahydrofuran solution of Diisopropylamine, drip n-Butyl Lithium form lithium diisopropylamine, and then drip ethyl propionate and glyceraldehyde acetonide, be obtained by reacting compound 31b;

9. preparation method according to claim 8, is characterized in that, described synthesis step is: