CN104610404B - A kind of preparation method of ribofuranose phosphate derivative - Google Patents
A kind of preparation method of ribofuranose phosphate derivative Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of ribofuranose phosphate derivative, its preparation process comprises: with ALANINE isopropyl ester hydrochloride, phenol either dichlorophosphate and fortified phenol for starting raw material, carries out docking reaction under the effect of alkali; (2R) the fluoro-2-methyl D-erythro form pentonic acid of-2-deoxidation-2-? GAMMA-lactone? carbonyl reduction is alcoholic extract hydroxyl group through strong reductant effect by 3,5-dibenzoate in methylene dichloride or ether solvent; Intermediate formula 2-1, under alkali effect, is obtained by reacting p-toluenesulfonic esters with Tosyl chloride; Intermediate formula 2-2 and benzoyl cytosine derivative carry out docking reacting under condensing agent effect; Cytosines is uridylic by intermediate formula 2-3 under organic acid effect; Intermediate formula 2-4 sloughs benzoyl protection under alkali reagent effect; Intermediate formula 2-5 and formula 1 are docked and are obtained Sofosbuvir under grignard reagent effect.
Description
Technical field
The present invention relates to a kind of preparation method of ribofuranose phosphate derivative, belong to pharmaceutical chemistry synthesis field.
Background technology
Hepatitis C (being called for short hepatitis C, the third liver) is that one infects by hepatitis C virus (HCV) viral hepatitis caused.According to World Health Organization's statistics, the infection rate of global third liver is about 3%, about 1.8 hundred million people's HCV infection, annual new hepatitis C case about 3.5 ten thousand example.Hepatitis C is global prevalence, can cause the downright bad and fibrosis of liver chronic inflammatory diseases, has 1% ~ 5% can develop into liver cirrhosis even hepatocellular carcinoma (HCC) and dead in 100 patients.
At present, HCV virus has 6 kinds of genotype.Standard regimens is that Peg-IFN alpha-2b (Peg-IFN) combines ribavirin (RBV), and total cure rate, less than 50%, need adhere to sufficient dosage continued treatment more than 1 year.There is the shortcomings such as many untoward reactions, drug interaction and patient compliance difference as the Peg-IFN injecting 1 time for 1 week, its Clinical practice is limited to some extent.Therefore, improve curative ratio, shorten treatment time and adopt entirely oral and direct antiviral (DAAs) that is that do not use Peg-IFN to treat the third liver constantly occurs.Suo Feibuwei is the precursor medicine of fluorine-containing nucleotide analog, very high inhibition effect is had to hepatitis C virus (HCV) NS5B polysaccharase, one of component for the treatment of chronic hepatitis C (CHC) the antiviral combination treatment that can be used as, HCV genotype 2 (GT2), HCV genotype 3 (GT3) are infected, Suo Feibuwei only need with RBV coupling, become the whole world first without the need to using the full oral therapeutic drug of Interferon, rabbit (IFN) simultaneously, and treat HCV genotype 1 and 4 the infected must with RBV and Peg-IFN coupling.
Suo Feibuwei is ribofuranose phosphate derivative, English name Sofosbuvir, Chinese N-［ (S)-2-(S)-(2R by name, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl tetrahydrofuran (THF)-2-base) methoxyl group) (phenoxy group) phosphinylidyne amino) isopropyl propionate, structural formula is
。
There is following shortcoming in the preparation method of current Suo Feibuwei: main chain side chain segments docking reaction yield is low, and product is purifying not easily, affects subsequent reactions quality mostly; Operational path is long, complex operation; Material solvent species used is many, is difficult to recycle; Suo Feibuwei finished product reaction yield is low, and content of isomer is bigger than normal, and purity is wayward.
For this reason, be badly in need of a kind of new technical scheme and solve above-mentioned technical problem.
Summary of the invention
The object of this invention is to provide the preparation method that a kind of ribofuranose phosphate derivative is new.
The technical solution used in the present invention is:
A preparation method for ribofuranose phosphate derivative, its preparation process comprises:
The preparation of a, intermediate formula 1:
With ALANINE isopropyl ester hydrochloride, phenol either dichlorophosphate and fortified phenol for starting raw material, under the effect of alkali, carry out docking reaction;
The preparation of b, intermediate formula 2-1:
(2R) carbonyl reduction is alcoholic extract hydroxyl group through strong reductant effect by the fluoro-2-methyl D of-2-deoxidation-2--erythro form pentonic acid GAMMA-lactone 3,5-dibenzoate in methylene dichloride or ether solvent;
The preparation of c, intermediate formula 2-2:
Intermediate formula 2-1, under alkali effect, is obtained by reacting p-toluenesulfonic esters with Tosyl chloride;
The preparation of d, intermediate formula 2-3:
Intermediate formula 2-2 and benzoyl cytosine derivative carry out docking reacting under condensing agent effect;
The preparation of e, intermediate formula 2-4:
Cytosines is uridylic by intermediate formula 2-3 under organic acid effect;
The preparation of f, intermediate formula 2-5:
Intermediate formula 2-4 sloughs benzoyl protection under alkali reagent effect;
The preparation of g, Sofosbuvir:
Intermediate formula 2-5 and formula 1 are docked and are obtained Sofosbuvir under grignard reagent effect.
The chemical structural formula of intermediate formula 1, formula 2-1, formula 2-3, formula 2-4 and formula 2-5 is respectively:
.
Further, in a step, described fortified phenol is the one in 4-chlorophenol, 4-bromophenol, 4-nitrophenols or perfluor phenol; Described alkali is the one in DIPEA, triethylamine or piperidines; Described temperature of reaction is-78 ~ 0 DEG C; Described reaction solvent is methylene dichloride, tetrahydrofuran (THF), toluene or ether.
Further, in a step, intermediate formula 1 crude product obtained after docking reaction obtains fine work through purification step, and purification step solvent for use is the mixture of one or more in methyl tertiary butyl ether, normal hexane, ethyl acetate or isopropyl ether.
Further, in b step, described strong reductant is three tertiary butyoxy aluminium lithiums, RED-AL toluene solution or DIBAL-H solution; Described temperature of reaction is-30 ~ 30 DEG C; Described ether solvent is tetrahydrofuran (THF) or ether.
Further, in step c, described alkali is triethylamine, DIPEA or DMAP; Described temperature of reaction is-10 ~ 30 DEG C; Described reaction solvent is methylene dichloride, toluene or isopropyl ether.
Further, in Step d, interpolation hexamethyldisilazane or two (trimethyl silicon based) ethanamide of N, O-are hydroxy-protecting agent; Described condensing agent is tin tetrachloride or Trimethylsilyl trifluoromethanesulfonate; Described temperature of reaction is-10 ~ 100 DEG C; Described reaction solvent is methylene dichloride or acetonitrile.
Further, in step e, described organic acid is Glacial acetic acid; Described temperature of reaction is 30 ~ 120 DEG C.
Further, in f step, described alkali reagent is sodium methylate or ammonia methyl alcohol; Described temperature of reaction is 0 ~ 30 DEG C; Described reaction solvent is methyl alcohol;
Further, in g step, described grignard reagent is tertiary butyl magnesium chloride; Described temperature of reaction is-50 ~ 30 DEG C; Described reaction solvent is tetrahydrofuran (THF), toluene, DMF or DMSO.
Advantage of the present invention is: with the fluoro-2-methyl D of (2R)-2-deoxidation-2--erythro form pentonic acid GAMMA-lactone 3, the 5-dibenzoate that is easy to get for starting raw material, and through six step synthesis Suo Feibuwei, route is brief; Each intermediate purity is easy to control, and is beneficial to control foreign matter content; It is high that starting raw material and intermediate formula 1 dock reaction yield, avoids the too much loss of material; Each step reaction technique is easy and simple to handle, and solvent is all recyclable to be applied mechanically, and pollutes little; The Suo Feibuwei purity of preparation is high, and each impurity is easy to control, and technique is suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is process route chart of the present invention.
Embodiment
Embodiment 1:
The preparation of intermediate formula 1:
In reaction flask, add 200mL methylene dichloride, 50gL-alanine isopropyl ester hydrochloride and 38.3gDIPEA, stir, be cooled to-78 DEG C, reaction 30min, then drips the dichloromethane solution (63g/120mL) of phenol either dichlorophosphate; Drip and finish, stirring reaction 30min, be then warming up to-10 DEG C of reactions 3 hours.55.4g perfluor phenol, 35.2gDIPEA are dissolved in 200mL methylene dichloride, are added drop-wise in above-mentioned reaction solution; Drip and finish, stirring reaction, TLC monitors reaction; React complete, suction filtration, filter cake 50mL washed with dichloromethane, merge organic phase, concentrating under reduced pressure, then dissolve making beating with 500mL methyl tertiary butyl ether, suction filtration, filter cake 50mL methyl tertiary butyl ether washing, merge organic phase, concentrating under reduced pressure, obtains 123.5g off-white color crude product.This crude product ethyl acetate and normal hexane polishing purification, obtain 65.6 fine work.Yield: 48%.
The preparation of intermediate formula 2-1:
In reaction flask, under anhydrous and oxygen-free condition, add 45g (2R)-2-deoxidation-2-fluoro-2-methyl D-erythro form pentonic acid GAMMA-lactone 3,5-dibenzoate and 150mL tetrahydrofuran (THF), stirring and dissolving, is cooled to-20 DEG C, drip the tetrahydrofuran solution (46g/150mL) of three tertiary butyoxy aluminium lithiums, stirring reaction 30min, is then warming up to 0 DEG C of reaction, TLC detection reaction; React complete, add saturated ammonium chloride solution and carry out cancellation, then remove tetrahydrofuran (THF) under reduced pressure, add 300mL ethyl acetate, leave standstill separatory, aqueous layer with ethyl acetate (50mL × 2) extracts, and merges organic phase, washs organic phase with saturated nacl aqueous solution, use anhydrous sodium sulfate drying again, suction filtration, concentrating under reduced pressure, obtains intermediate formula 2-1 product.This product is not purified directly carries out next step.
The preparation of intermediate formula 2-2:
Intermediate formula 2-1 is added, 200mL methylene dichloride and 24.6g triethylamine in reaction flask, stir; Be cooled to 0 ~ 5 DEG C, add 23.8g Tosyl chloride, stirring reaction 1h, then be warming up to room temperature reaction, TLC monitors reaction; React complete, reaction solution use water (100mL × 2) washs, and anhydrous sodium sulfate drying, less than 40 DEG C evaporates to dryness, obtain solid crude product.This crude product 3-4 times amount Virahol is refined, and obtains 56.8g intermediate formula 2-2 solid phase prod.
The preparation of intermediate formula 2-3:
32g hexamethyldisilazane is added, 100mL chlorobenzene, 2g ammonium sulfate in reaction flask, and 21.5g benzoyl cytosine, stir, be warming up to back flow reaction, TLC monitors reaction; React complete, concentrating under reduced pressure, add 300mL methylene dichloride stirring and dissolving, then add 55g intermediate formula 2-2, stir, add 78.1g tin tetrachloride, be warming up to back flow reaction, TLC monitors reaction: react complete, be cooled to room temperature, add 32g sodium bicarbonate and 60g diatomite, stir, suction filtration, filter cake uses methylene dichloride (200mL × 3) to pull an oar again, merges organic phase, washs with saturated nacl aqueous solution, anhydrous sodium sulfate drying, is evaporated to dry, obtains 63.6g intermediate formula 2-3 crude product.This crude product 4 times amount Virahols are refined, and obtain 47.8g white solid product.
The preparation of intermediate formula 2-4:
In reaction flask, add Glacial acetic acid 300g, water 100g, input 45g intermediate formula 2-3, stirring and dissolving, is warming up to backflow, about 90 ~ 105 DEG C; TLC detection reaction, reacts complete, is down to room temperature, adds water 300g; Stir 30min, suction filtration, filter cake saturated sodium bicarbonate solution washs, and dries, obtains 32.7g white solid product.
The preparation of intermediate formula 2-5:
In reaction flask, add 30g intermediate formula 2-4,300mL methyl alcohol, stirring and dissolving, add 3.5g sodium methylate, stir, be then warming up to back flow reaction, TLC monitors reaction; React complete, be cooled to room temperature, add citric acid and shrend and to go out reaction, stir, remove methyl alcohol under reduced pressure, then use ethyl acetate (100mL × 3) extract, merging organic phase, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, obtains 24.4g off-white color solid crude product.Crude product 120mL Virahol is refined, and obtains 12.8g white solid product.Yield: 78%.
The preparation of Sofosbuvir:
In reaction flask, under anhydrous and oxygen-free condition, add 12g intermediate formula 2-5,120mL tetrahydrofuran (THF), stir, be cooled to-30 DEG C, drip 53.2g1.7M tertiary butyl magnesium chloride; Drip and finish, stirring reaction 1 hour, is then warming up to-10 DEG C, drips the 100mL tetrahydrofuran solution of 21.3gN-[(S)-(2,3,4,5,6-penta fluoro benzene oxygen base) phenoxy group phosphoryl]-ALANINE isopropyl ester; Drip and finish, react 1 hour at-10 DEG C, be then warming up to room temperature reaction, TLC monitors reaction.React complete, be cooled to 0 DEG C, start to drip concentrated hydrochloric acid/water (50mL/300mL) cancellation reaction; Remove tetrahydrofuran (THF) under reduced pressure, then add 200mL ether, stir separatory, water layer ether (50mL × 3) extraction, merge organic phase, with saturated sodium bicarbonate solution, saturated sodium-chloride, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, obtains 19.7g oily matter crude product.Oily matter crude product 5 times amount methylene dichloride are refined, and obtain 13.5g white solid product.
Embodiment 2:
The preparation of intermediate formula 1:
In reaction flask, add 200mL methylene dichloride, 50gL-alanine isopropyl ester hydrochloride and 30g triethylamine, stir, be cooled to-78 DEG C, reaction 30min, then drips the dichloromethane solution (63g/1200mL) of phenol either dichlorophosphate; Drip and finish, stirring reaction 30min, be then warming up to-10 DEG C of reactions 3 hours.42.7g4-nitrophenols, 30.6g triethylamine are dissolved in 200mL methylene dichloride, are added drop-wise in above-mentioned reaction solution; Drip and finish, stirring reaction, TLC monitors reaction; React complete, suction filtration, filter cake 50mL washed with dichloromethane, merge organic phase, concentrating under reduced pressure, then dissolve making beating with 500mL isopropyl ether, suction filtration, filter cake 50mL isopropyl ether washing, merge organic phase, concentrating under reduced pressure, obtains 116.2g off-white color crude product.This crude product ethyl acetate and normal hexane polishing purification, obtain 52.3g fine work.Yield: 43%.
The preparation of intermediate formula 2-1:
Under anhydrous and oxygen-free condition, in reaction flask, under nitrogen protection, add 17.4g trifluoroethanol and 60mL toluene, stir, be cooled to-20 DEG C, stir lower dropping 52.8gRED-AL toluene solution; Drip and finish, stir 1 hour, be then warming up to room temperature preservation stand-by.
In reaction flask, add the fluoro-2-methyl D of 45g (2R)-2-deoxidation-2--erythro form pentonic acid GAMMA-lactone 3,5-dibenzoate, 200mL methylene dichloride, stirring and dissolving, is cooled to-15 ~-20 DEG C, drips the RED-AL solution prepared; Drip and finish, react at-15 ~-20 DEG C, TLC monitors reaction; React complete, add aqueous citric acid solution and carry out cancellation, be warming up to room temperature, leave standstill separatory, water layer methylene dichloride (50mL × 2) extracts, merge organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, obtains intermediate formula 2-1 product, directly carries out next step reaction.
The preparation of intermediate formula 2-2:
Intermediate formula 2-1 is added, 200mL toluene and 31.6gDIPEA in reaction flask, stir; Be cooled to 0 ~ 5 DEG C, add 23.1g Tosyl chloride, stirring reaction 1h, then be warming up to room temperature reaction, TLC monitors reaction; React complete, reaction solution use water (100mL × 2) washs, and anhydrous sodium sulfate drying, less than 40 DEG C evaporates to dryness, obtain solid crude product.This crude product 3-4 times amount Virahol is refined, and obtains 58.4g intermediate formula 2-2 solid phase prod.
The preparation of intermediate formula 2-3:
In reaction flask, add 21.5g benzoyl cytosine, two (trimethyl silicon based) ethanamide of 20.5gN, O-and 100mL acetonitrile, stir, be warming up to back flow reaction, TLC monitors reaction; React complete, be cooled to room temperature, then add 55g intermediate formula 2-2, stir, add 78.5g tin tetrachloride, be warming up to back flow reaction, TLC monitors reaction: react complete, be cooled to room temperature, adds 32g sodium bicarbonate and 60g diatomite, stir, suction filtration, filter cake uses acetonitrile (200mL × 3) to pull an oar again, merge organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, be evaporated to dry, obtain 68.8g intermediate formula 2-3 crude product.This crude product 4 times amount Virahols are refined, and obtain 48.9g white solid product.
The preparation of intermediate formula 2-4:
In reaction flask, add Glacial acetic acid 300g, water 100g, input 45g intermediate formula 2-3, stirring and dissolving, is warming up to backflow, about 90 ~ 105 DEG C; TLC detection reaction, reacts complete, is down to room temperature, adds water 300g; Stir 30min, suction filtration, filter cake saturated sodium bicarbonate solution washs, and dries, obtains 32.6g white solid product.
The preparation of intermediate formula 2-5:
In reaction flask, add 30g intermediate formula 2-4,300mL methyl alcohol, stirring and dissolving, add 3g sodium methylate, stir, be then warming up to back flow reaction, TLC monitors reaction; React complete, be cooled to room temperature, add citric acid and shrend and to go out reaction, stir, remove methyl alcohol under reduced pressure, then use ethyl acetate (100mL × 3) extract, merging organic phase, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, obtains 24.5g off-white color solid crude product.Crude product 120mL Virahol is refined, and obtains 12.8g white solid product.Yield: 78%.
The preparation of Sofosbuvir:
In reaction flask, under anhydrous and oxygen-free condition, add 12g intermediate formula 2-5,120mL tetrahydrofuran (THF), stir, be cooled to-30 DEG C, drip 53.6g1.7M tertiary butyl magnesium chloride; Drip and finish, stirring reaction 1 hour, is then warming up to-10 DEG C, drips the 120mL tetrahydrofuran solution of 19.6gN-[(S)-(4 ,-nitro-phenoxy) phenoxy group phosphoryl]-ALANINE isopropyl ester; Drip and finish, react 1 hour at-10 DEG C, be then warming up to room temperature reaction, TLC monitors reaction.React complete, be cooled to 0 DEG C, start to drip concentrated hydrochloric acid/water (50mL/300mL) cancellation reaction; Remove tetrahydrofuran (THF) under reduced pressure, then add 200mL methyl tertiary butyl ether, stir separatory, water layer methyl tertiary butyl ether (50mL × 3) extracts, merge organic phase, with saturated sodium bicarbonate solution, saturated sodium-chloride, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, obtains 22.9g oily matter crude product.Oily matter crude product 5 times amount methylene dichloride are refined, and obtain 14.8g white solid product.
Embodiment 3:
The preparation of intermediate formula 1:
In reaction flask, add 200mL toluene, 50gL-alanine isopropyl ester hydrochloride and 26.4g piperidines, stir, be cooled to-78 DEG C, reaction 30min, then drips the toluene solution (63g/120mL) of phenol either dichlorophosphate; Drip and finish, stirring reaction 30min, be then warming up to-10 DEG C of reactions 3 hours.46.5g4-bromophenol, 25g piperidines are dissolved in 100mL toluene, are added drop-wise in above-mentioned reaction solution; Drip and finish, stirring reaction, TLC monitors reaction; React complete, suction filtration, filter cake 50mL toluene wash, merge organic phase, concentrating under reduced pressure, then dissolve making beating with 500mL methyl tertiary butyl ether, suction filtration, filter cake 50mL methyl tertiary butyl ether washing, merge organic phase, concentrating under reduced pressure, obtains 119.6g off-white color crude product.This crude product ethyl acetate and normal hexane polishing purification, obtain 60.5g fine work.Yield: 46%.
Prepared by intermediate formula 2-1:
In reaction flask, under anhydrous and oxygen-free condition, add 45g (2R)-2-deoxidation-2-fluoro-2-methyl D-erythro form pentonic acid GAMMA-lactone 3,5-dibenzoate and 150mL tetrahydrofuran (THF), stirring and dissolving, is cooled to-20 DEG C, add the DIBAL-H solution of 180mL1M, stirring reaction 30min, is then warming up to 0 DEG C of reaction, TLC detection reaction; React complete, add saturated ammonium chloride solution and carry out cancellation, then remove tetrahydrofuran (THF) under reduced pressure, add 300mL ethyl acetate, leave standstill separatory, aqueous layer with ethyl acetate (50mL × 2) extracts, and merges organic phase, washs organic phase with saturated nacl aqueous solution, use anhydrous sodium sulfate drying again, suction filtration, concentrating under reduced pressure, obtains intermediate formula 2-1 product.This product is not purified directly carries out next step.
The preparation of intermediate formula 2-2:
Intermediate formula 2-1 is added, 200mL isopropyl ether and 29gDMAP in reaction flask, stir; Be cooled to 0 ~ 5 DEG C, add 23g Tosyl chloride, stirring reaction 1h, then be warming up to room temperature reaction, TLC monitors reaction; React complete, reaction solution use water (100mL × 2) washs, and anhydrous sodium sulfate drying, less than 40 DEG C evaporates to dryness, obtain solid crude product.This crude product 3-4 times amount Virahol is refined, and obtains 57.3g intermediate formula 2-2 solid phase prod.
The preparation of intermediate formula 2-3:
32g hexamethyldisilazane is added, 100mL chlorobenzene, 2g ammonium sulfate in reaction flask, and 21.5g benzoyl cytosine, stir, be warming up to back flow reaction, TLC monitors reaction; React complete, concentrating under reduced pressure, add 300mL acetonitrile stirring and dissolving, be cooled to 0 ~ 5 DEG C, then add 55g intermediate formula 2-2, stir, add 66.4g Trimethylsilyl trifluoromethanesulfonate, stir, be warming up to 65 DEG C of reactions, TLC monitors reaction: react complete, add saturated sodium bicarbonate solution, extracts by ethyl acetate (200mL × 3), merge organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, be evaporated to dry, obtain 62.9g intermediate formula 2-3 crude product.This crude product 4 times amount Virahols are refined, and obtain 46.8g white solid product.
The preparation of intermediate formula 2-4:
In reaction flask, add Glacial acetic acid 300g, water 100g, input 45g intermediate formula 2-3, stirring and dissolving, is warming up to backflow, about 90 ~ 105 DEG C; TLC detection reaction, reacts complete, is down to room temperature, adds water 300g; Stir 30min, suction filtration, filter cake saturated sodium bicarbonate solution washs, and dries, obtains 32.3g white solid product.
The preparation of intermediate formula 2-5:
In reaction flask, add 90g ammonia methyl alcohol, be cooled to about 5 DEG C, add 30g intermediate formula 2-4; Finish and be slowly warming up to room temperature, TLC monitors reaction; React complete, remove solvent under reduced pressure, add the making beating of 150mL ethyl acetate, suction filtration, obtains 21.7g solid crude product; This solid 100mL Virahol is refined, and obtains 12.5g white solid product.Yield: 75%.
The preparation of Sofosbuvir:
In reaction flask, under anhydrous and oxygen-free condition, add 12g intermediate formula 2-5,120mL tetrahydrofuran (THF), stir, be cooled to-30 DEG C, drip 53g tertiary butyl magnesium chloride; Drip and finish, stirring reaction 1 hour, is then warming up to-10 DEG C, drips the 150mL tetrahydrofuran solution of 20.9gN-[(S)-(4-bromine phenoxy group) phenoxy group phosphoryl]-ALANINE isopropyl ester; Drip and finish, react 1 hour at-10 DEG C, be then warming up to room temperature reaction, TLC monitors reaction.React complete, be cooled to 0 DEG C, start to drip concentrated hydrochloric acid/water (50mL/300mL) cancellation reaction; Remove tetrahydrofuran (THF) under reduced pressure, then add 200mL ether, stir separatory, water layer ether (50mL × 3) extraction, merge organic phase, with saturated sodium bicarbonate solution, saturated sodium-chloride, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, obtains 24.5g oily matter crude product.Oily matter crude product 5 times amount methylene dichloride are refined, and obtain 15.5g white solid product.
Claims (7)
1. a preparation method for ribofuranose phosphate derivative, is characterized in that: preparation process comprises:
The preparation of a, intermediate formula 1:
With ALANINE isopropyl ester hydrochloride, phenol either dichlorophosphate and fortified phenol for starting raw material, under the effect of alkali, carry out docking reaction;
The preparation of b, intermediate formula 2-1:
(2R) carbonyl reduction is alcoholic extract hydroxyl group through strong reductant effect by the fluoro-2-methyl D of-2-deoxidation-2--erythro form pentonic acid GAMMA-lactone 3,5-dibenzoate in methylene dichloride or ether solvent;
The preparation of c, intermediate formula 2-2:
Intermediate formula 2-1, under alkali effect, is obtained by reacting p-toluenesulfonic esters with Tosyl chloride;
The preparation of d, intermediate formula 2-3:
Intermediate formula 2-2 and benzoyl cytosine derivative carry out docking reacting under condensing agent effect;
The preparation of e, intermediate formula 2-4:
Cytosines is uridylic by intermediate formula 2-3 under organic acid effect;
The preparation of f, intermediate formula 2-5:
Intermediate formula 2-4 sloughs benzoyl protection under alkali reagent effect;
The preparation of g, Suo Feibuwei:
Intermediate formula 2-5 and formula 1 are docked and are obtained Suo Feibuwei under grignard reagent effect;
The chemical structural formula of described intermediate formula 1, formula 2-1, formula 2-3, formula 2-4 and formula 2-5 is respectively:
;
In b step, described strong reductant is three tertiary butyoxy aluminium lithiums, two (2-methoxy ethoxy) the sodium aluminate toluene solution of dihydro or diisobutyl aluminium hydride solution; Described temperature of reaction is-30 ~ 30 DEG C; Described ether solvent is tetrahydrofuran (THF) or ether;
In step c, described alkali is triethylamine, DIPEA or DMAP; Described temperature of reaction is-10 ~ 30 DEG C; Described reaction solvent is methylene dichloride, toluene or isopropyl ether.
2. the preparation method of a kind of ribofuranose phosphate derivative according to claim 1, is characterized in that: in a step, and described fortified phenol is the one in 4-chlorophenol, 4-bromophenol, 4-nitrophenols or perfluor phenol; Described alkali is the one in DIPEA, triethylamine or piperidines; Described temperature of reaction is-78 ~ 0 DEG C; Described reaction solvent is methylene dichloride, tetrahydrofuran (THF), toluene or ether.
3. the preparation method of a kind of ribofuranose phosphate derivative according to claim 1 and 2, it is characterized in that: in a step, intermediate formula 1 crude product obtained after docking reaction obtains fine work through purification step, and purification step solvent for use is the mixture of one or more in methyl tertiary butyl ether, normal hexane, ethyl acetate or isopropyl ether.
4. the preparation method of a kind of ribofuranose phosphate derivative according to claim 1, is characterized in that: in Step d, and interpolation hexamethyldisilazane or two (trimethyl silicon based) ethanamide of N, O-are hydroxy-protecting agent; Described condensing agent is tin tetrachloride or Trimethylsilyl trifluoromethanesulfonate; Described temperature of reaction is-10 ~ 100 DEG C; Described reaction solvent is methylene dichloride or acetonitrile.
5. the preparation method of a kind of ribofuranose phosphate derivative according to claim 1, is characterized in that: in step e, and described organic acid is Glacial acetic acid; Described temperature of reaction is 30 ~ 120 DEG C.
6. the preparation method of a kind of ribofuranose phosphate derivative according to claim 1, is characterized in that: in f step, and described alkali reagent is sodium methylate or ammonia methyl alcohol; Described temperature of reaction is 0 ~ 30 DEG C; Described reaction solvent is methyl alcohol.
7. the preparation method of a kind of ribofuranose phosphate derivative according to claim 1, is characterized in that: in g step, and described grignard reagent is tertiary butyl magnesium chloride; Described temperature of reaction is-50 ~ 30 DEG C; Described reaction solvent is tetrahydrofuran (THF), toluene, DMF or dimethyl sulfoxide (DMSO).
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| PCT/CN2015/095524 WO2016112746A1 (en) | 2015-01-16 | 2015-11-25 | Method for preparing ribofuranose phosphate derivatives |
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| CN104610404B (en) * | 2015-01-16 | 2016-04-06 | 南通常佑药业科技有限公司 | A kind of preparation method of ribofuranose phosphate derivative |
| CN106146588A (en) * | 2015-03-26 | 2016-11-23 | 常州制药厂有限公司 | A kind of preparation method of Suo Feibuwei |
| CN104829672B (en) * | 2015-05-19 | 2018-03-13 | 江苏福瑞生物医药有限公司 | A kind of synthetic method of pharmaceutical intermediate |
| CN105061535A (en) * | 2015-09-02 | 2015-11-18 | 江苏科本医药化学有限公司 | Synthetic method of sofosbuvir intermediate |
| CN106565805B (en) * | 2015-10-10 | 2020-04-14 | 常州市勇毅生物药业有限公司 | Preparation method of sofosbuvir |
| CN105503983B (en) * | 2015-12-17 | 2019-06-28 | 江苏阿尔法药业有限公司 | The preparation method of Suo Feibuwei intermediate and its derivative |
| CN105461775B (en) * | 2015-12-24 | 2018-03-13 | 江苏阿尔法药业有限公司 | A kind of Suo Feibuwei preparation method |
| CN105566422B (en) * | 2015-12-29 | 2019-06-25 | 江苏阿尔法药业有限公司 | The preparation method of Suo Feibuwei intermediate or derivatives thereof |
| CN105503787A (en) * | 2015-12-31 | 2016-04-20 | 阜阳欣奕华材料科技有限公司 | Sofosbuvir intermediate purification method |
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| CN105906673A (en) * | 2016-05-05 | 2016-08-31 | 精华制药集团南通有限公司 | Synthetic method for sofosbuvir intermediate |
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| CN107880089B (en) * | 2017-11-29 | 2021-02-12 | 昆明科麦德科技有限公司 | Trimethylsilylation method of saccharide compound |
| WO2022088161A1 (en) * | 2020-11-02 | 2022-05-05 | 南京正大天晴制药有限公司 | METHOD FOR PREPARING HIGHLY STEREOSELECTIVE β-GLYCOSIDE COMPOUND |
| CN113105329B (en) * | 2021-04-22 | 2023-10-03 | 成都道合尔医药技术有限公司 | Synthesis method of (E) -methyl ester 3- (3, 5-difluoro-4-formylphenyl) acrylic acid |
| CN115433194B (en) * | 2022-09-13 | 2023-06-23 | 上海毕得医药科技股份有限公司 | Synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
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