The preparation method of Suo FeibuweiTechnical field
The preparation method that the present invention relates to a kind of anti-HCV medicament, the preparation method particularly relating to a kind of Suo Feibuwei.
Background technology
Suo Feibuwei, Sofosbuvir, chinesization formal name used at school is N-［ (S)-2-(S)-(2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl oxolane-2-base) methoxyl group) (phenoxy group) phosphinylidyne amino) isopropyl propionate (structural formula is as shown in Equation 2); CAS registration number: 1193037-88-0. Suo Feibuwei is developed by beautiful Pharmasset pharmacy corporation, and exploitation listing after lucky Deco (GileadSci) corporate buyout, code name is GS-7977. FDA (Food and Drug Adminstration) (FoodandDrugAdministration, FDA) ratifies listing on 6th first in December in 2013, and preparation is tablet 400mg, trade name Sovaldi. Structure is formula 1 such as:
It is a kind of viral hepatitis being infected by hepatitis C virus (HCV) and causing that hepatitis C (is called for short hepatitis C, hepatitis C). Adding up according to World Health Organization (WHO), the infection rate of whole world hepatitis C 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, may result in that liver chronic inflammatory disease is downright bad and fibrosis, has 1%～5% can develop into liver cirrhosis even hepatocarcinoma (HCC) and dead in 100 patients.
Suo Feibuwei is the first anti-HCV medicament that can be used for the full oral treatment regimes of hepatitis C. Before Suo Feibuwei comes out, hepatitis C patient must accept the treatment of at least 6 months, including injectable drug interferon and ribavirin, and both medicines can cause serious similar flu-like symptom and the side effect such as erythra, anemia respectively, its cure rate is only 45% simultaneously, and the cure rate of Suo Feibuwei is more than 90%, revolutionize the low cure rate situation of hepatitis C.
Ji Leadd B.V of the U.S. of Yuan Yan enterprise reports the synthesis of Suo Feibuwei product in patent US2013029929, is prepared with the fluoro-2'-MU glycosides of (2'R)-2'-deoxidation-2'-and phosphate ester side chain for raw material and forms.Owing to Suo Feibuwei building-up process being taken off a part Pentafluorophenol, and Pentafluorophenol is be worth higher industrial chemicals, and there is certain toxicity and environment is had impact by it because of it, the former recovery grinding not mentioned Pentafluorophenol in patent and utilization, therefore the recovery of Pentafluorophenol has great importance.
Accordingly, it is desirable to provide a kind of new technical scheme solves the problems referred to above.
Summary of the invention
The preparation method that the technical problem to be solved in the present invention is to provide a kind of Suo Feibuwei, is the new drug for treating chronic hepatitis c.
For solving above-mentioned technical problem, the preparation method of the Suo Feibuwei of the present invention, comprise the following steps:
(1) preparation of Suo Feibuwei:
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When anhydrous and oxygen-free, (2'R) the fluoro-2'-MU glycosides of-2'-deoxidation-2'-, N-[(S)-(2, 3, 4, 5, 6-phenyl-pentafluoride oxygen base) phenoxy group phosphoryl]-ALANINE isopropyl ester and grignard reagent react under reaction dissolvent existence condition, after completion of the reaction, dropping concentrated hydrochloric acid and shrend are gone out reaction, remove reaction dissolvent under reduced pressure, then extract, merge organic facies, dry again, sucking filtration, concentrating under reduced pressure, obtain grease crude product, dichloromethane is added in grease crude product, add thermosol clear, then stirring and crystallizing at being cooled to 0-10 DEG C, after sucking filtration mother liquid obtained for reclaiming Pentafluorophenol, filter cake dries to obtain white solid product Suo Feibuwei,
(2) mother solution of the recovery of Pentafluorophenol: Suo Feibuwei dissolves in a solvent, it is subsequently added adsorbent, is evaporated to dry, again add solvent, pull an oar in room temperature, sucking filtration, collects filtrate, and evaporated under reduced pressure obtains grease, solvent is added again in grease, add thermosol clear, be then cooled to 0-5 DEG C of crystallize, obtain the Pentafluorophenol of recovery;
(3) preparation of formula II compound: D-alanine isopropyl ester and dichloro-phenyl phosphate, reacts at-70～-80 DEG C, adds solvent solution and the alkali of Pentafluorophenol, and reaction prepares formula II compound.
In step (1); (2'R) the fluoro-2'-MU glycosides of-2'-deoxidation-2'-, N-[(S)-(2,3,4; 5,6-phenyl-pentafluoride oxygen bases) phenoxy group phosphoryl]-ALANINE isopropyl ester, grignard reagent charge ratio be 1:1.05:1.1～1:1.5:1.8.
In step (2), the mass ratio adding adsorbent, adsorbent and mother solution in the mother solution of Suo Feibuwei is 1:2～1:5.
In step (3), D-alanine isopropyl ester, dichloro-phenyl phosphate, Pentafluorophenol charge ratio are 1:0.9:1.05～1:1.3:1.6.
In technique scheme, the grignard reagent in step (1) is tert-butyl group magnesium chloride, isopropylmagnesium chloride; Reaction dissolvent in step (1) is oxolane, toluene, dimethylformamide or dimethyl sulfoxide.
Adsorbent in step (2) is silica gel; Solvent in step (2) is diisopropyl ether, methyl tertiary butyl ether(MTBE), normal hexane, ethyl acetate or dichloromethane.
Alkali in step (3) is triethylamine, piperidines; Solvent in step (3) is dichloromethane, toluene, methyl tertiary butyl ether(MTBE), ethyl acetate, normal hexane.
Beneficial effects of the present invention: applying grignard reagent in the Suo Feibuwei building-up process of the present invention and carry out the Butt-coupling of master chain, easy and simple to handle, impurity is easily controllable, is beneficial to large-scale production. And course of reaction is taken off a part Pentafluorophenol, and Pentafluorophenol has been reclaimed, Pentafluorophenol is for the preparation of one of Suo Feibuwei synthesis material intermediate so that Pentafluorophenol recycling, reduces the impact on environment.
Detailed description of the invention
In order to deepen the understanding of the present invention, below the invention will be further described, this embodiment is only used for explaining the present invention, is not intended that the restriction to protection scope of the present invention.
Embodiment 1
The preparation method of the Suo Feibuwei of the present invention, comprises the following steps:
The preparation of Suo Feibuwei:
In reaction bulb, when anhydrous and oxygen-free, add the fluoro-2'-MU glycosides of 120g (2'R)-2'-deoxidation-2'-, 600mL oxolane, stirring, be cooled to-30 DEG C, drip 268g1.7M tert-butyl group magnesium chloride; Drip and finish, stirring reaction 1 hour, then heat to-10 DEG C, the 500mL tetrahydrofuran solution of dropping 230gN-[(S)-(2,3,4,5,6-phenyl-pentafluoride oxygen base) phenoxy group phosphoryl]-ALANINE isopropyl ester; Dripping and finish, react 1 hour, then heat to room temperature reaction at-10 DEG C, TLC monitors reaction. React complete, be cooled to 0 DEG C, start to drip concentrated hydrochloric acid/water (100mL/600mL) cancellation reaction; Removing oxolane under reduced pressure, be subsequently adding 800mL ether, stir separatory, water layer ether (300mL × 3) extracts, and merges organic facies, and with saturated sodium bicarbonate solution, saturated sodium-chloride, anhydrous sodium sulfate dries, sucking filtration, concentrating under reduced pressure, obtains 195g grease crude product; In grease crude product, add 3 times amount dichloromethane, add thermosol clear, stirring and crystallizing at being then cooled to 0-10 DEG C, sucking filtration, dry to obtain 176g white solid product.
The recovery of Pentafluorophenol:
By the mother liquor concentrations liquid of 220g Suo Feibuwei, add in 800mL diisopropyl ether and dissolve, add silica gel 440g, after stirring, it is evaporated to dry, adds 800mL diisopropyl ether, pull an oar in room temperature (20-25 DEG C), sucking filtration, filter cake diisopropyl ether rinses, and collects filtrate; Filter cake is pulled an oar at 800m diisopropyl ether again, sucking filtration, collects filtrate; Repeat aforesaid operations once, merging filtrate, evaporated under reduced pressure obtains 95g grease; In this grease, add 100mL dichloromethane and 200mL methyl tertiary butyl ether(MTBE), stirring, add thermosol clear, be then cooled to 0-5 DEG C of crystallize, sucking filtration, dry to obtain 45g yellow solid.
The preparation of formula II compound:
In reaction bulb, add 30gD-alanine isopropyl ester grease, 200ml dichloromethane and 20g anhydrous sodium sulfate, stirring, be cooled to-70～-80 DEG C, the 500ml dichloromethane solution of dropping 48g dichloro-phenyl phosphate; Drip and finish, insulation reaction 1 hour at-70～-80 DEG C, then drip dichloromethane solution and the 45g triethylamine of the Pentafluorophenol (42g) of above-mentioned recovery successively; Drip and finish, warm naturally to 0-5 DEG C, stirring, filter, filter cake 200ml dichloromethane, filtrate reduced in volume is concentrated into dry, obtains grease; Adding the making beating of 800mL methyl tertiary butyl ether(MTBE) in this grease, filter, filtrate reduced in volume, to dry, obtains 85g crude product; In this crude product, add 200ml ethyl acetate and 300ml normal hexane, stirring, be warming up to 50 DEG C, be then cooled to room temperature crystallize, sucking filtration, dry to obtain 72g white solid product.
Embodiment 2
The preparation method of the Suo Feibuwei of the present invention, comprises the following steps:
The preparation of Suo Feibuwei:
In reaction bulb, when anhydrous and oxygen-free, add the fluoro-2'-MU glycosides of 95g (2'R)-2'-deoxidation-2'-, 500mL oxolane, stirring, be cooled to-30 DEG C, drip 213g2.0M isopropylmagnesium chloride; Drip and finish, stirring reaction 1 hour, then heat to-10 DEG C, the 400mL tetrahydrofuran solution of dropping 198gN-[(S)-(2,3,4,5,6-phenyl-pentafluoride oxygen base) phenoxy group phosphoryl]-ALANINE isopropyl ester; Dripping and finish, react 1 hour, then heat to room temperature reaction at-10 DEG C, TLC monitors reaction.React complete, be cooled to 0 DEG C, start to drip concentrated hydrochloric acid/water (200mL/500mL) cancellation reaction; Removing oxolane under reduced pressure, be subsequently adding 600mL ether, stir separatory, water layer ether (200mL × 3) extracts, and merges organic facies, and with saturated sodium bicarbonate solution, saturated sodium-chloride, anhydrous sodium sulfate dries, sucking filtration, concentrating under reduced pressure, obtains 152g grease crude product; In grease crude product, add 3 times amount dichloromethane, add thermosol clear, stirring and crystallizing at being then cooled to 0-10 DEG C, sucking filtration, dry to obtain 136g white solid product.
The recovery of Pentafluorophenol:
By the mother liquor concentrations liquid of 160g Suo Feibuwei, add in 600mL methyl tertiary butyl ether(MTBE) and dissolve, add silica gel 480g, after stirring, it is evaporated to dry, adds 600mL methyl tertiary butyl ether(MTBE), pull an oar in room temperature (20-25 DEG C), sucking filtration, filter cake methyl tertiary butyl ether(MTBE) rinses, and collects filtrate; Filter cake is pulled an oar at 600m methyl tertiary butyl ether(MTBE) again, sucking filtration, collects filtrate; Repeat aforesaid operations once, merging filtrate, evaporated under reduced pressure obtains 70g grease; In this grease, add 80mL dichloromethane and 150mL methyl tertiary butyl ether(MTBE), stirring, add thermosol clear, be then cooled to 0-5 DEG C of crystallize, sucking filtration, dry to obtain 35g yellow solid.
The preparation of formula II compound:
In reaction bulb, add 23gD-alanine isopropyl ester grease, 150ml toluene and 10g anhydrous sodium sulfate, stirring, be cooled to-70～-80 DEG C, the 300ml toluene solution of dropping 42g dichloro-phenyl phosphate; Drip and finish, insulation reaction 1 hour at-70～-80 DEG C, then drip toluene solution and the 40g piperidines of the Pentafluorophenol (34g) of above-mentioned recovery successively; Drip and finish, warm naturally to 0-5 DEG C, stirring, filter, filter cake 150ml toluene rinses, and filtrate reduced in volume is concentrated into dry, obtains grease; Adding the making beating of 500mL methyl tertiary butyl ether(MTBE) in this grease, filter, filtrate reduced in volume, to dry, obtains 58g crude product; In this crude product, add 100ml ethyl acetate and 250ml normal hexane, stirring, be warming up to 50 DEG C, be then cooled to room temperature crystallize, sucking filtration, dry to obtain 53g white solid product.
Embodiment 3
The preparation method of the Suo Feibuwei of the present invention, comprises the following steps:
The preparation of Suo Feibuwei:
In reaction bulb, when anhydrous and oxygen-free, add the fluoro-2'-MU glycosides of 140g (2'R)-2'-deoxidation-2'-, 600mL dimethyl sulfoxide, stirring, be cooled to-30 DEG C, drip 339g2.0M isopropylmagnesium chloride; Drip and finish, stirring reaction 1 hour, then heat to-10 DEG C, the 500mL dimethyl sulphoxide solution of dropping 50gN-[(S)-(2,3,4,5,6-phenyl-pentafluoride oxygen base) phenoxy group phosphoryl]-ALANINE isopropyl ester; Dripping and finish, react 1 hour, then heat to room temperature reaction at-10 DEG C, TLC monitors reaction. React complete, be cooled to 0 DEG C, start to drip concentrated hydrochloric acid/water (250mL/700mL) cancellation reaction; Removing dimethyl sulfoxide under reduced pressure, be subsequently adding 800mL ether, stir separatory, water layer ether (300mL × 3) extracts, merging organic facies, with saturated sodium bicarbonate solution, saturated sodium-chloride, anhydrous sodium sulfate dries, sucking filtration, concentrating under reduced pressure, obtain 224g grease crude product; In grease crude product, add 3 times amount dichloromethane, add thermosol clear, stirring and crystallizing at being then cooled to 0-10 DEG C, sucking filtration, dry to obtain 202g white solid product.
The recovery of Pentafluorophenol:
By the mother liquor concentrations liquid of 240g Suo Feibuwei, add in 800mL normal hexane and dissolve, add silica gel 960g, after stirring, it is evaporated to dry, adds 800mL normal hexane, pull an oar in room temperature (20-25 DEG C), sucking filtration, filter cake normal hexane rinses, and collects filtrate;Filter cake is pulled an oar in 800m normal hexane again, sucking filtration, collects filtrate; Repeat aforesaid operations once, merging filtrate, evaporated under reduced pressure obtains 125g grease; In this grease, add 130mL dichloromethane and 250mL methyl tertiary butyl ether(MTBE), stirring, add thermosol clear, be then cooled to 0-5 DEG C of crystallize, sucking filtration, dry to obtain 64g yellow solid.
The preparation of formula II compound:
In reaction bulb, add 34gD-alanine isopropyl ester grease, 300ml methyl tertiary butyl ether(MTBE) and 20g anhydrous sodium sulfate, stirring, be cooled to-70～-80 DEG C, the 500ml t-butyl methyl ether solution of dropping 72g dichloro-phenyl phosphate; Drip and finish, insulation reaction 1 hour at-70～-80 DEG C, then drip t-butyl methyl ether solution and the 55g piperidines of the Pentafluorophenol (63g) of above-mentioned recovery successively; Drip and finish, warm naturally to 0-5 DEG C, stirring, filter, filter cake 300ml methyl tertiary butyl ether(MTBE) rinses, and filtrate reduced in volume is concentrated into dry, obtains grease; Adding the making beating of 800mL methyl tertiary butyl ether(MTBE) in this grease, filter, filtrate reduced in volume, to dry, obtains 98g crude product; In this crude product, add 200ml ethyl acetate and 400ml normal hexane, stirring, be warming up to 50 DEG C, be then cooled to room temperature crystallize, sucking filtration, dry to obtain 75g white solid product.