CN106083773B - The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- - Google Patents
The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- Download PDFInfo
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Abstract
The invention discloses one kind 3; the preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 5- dibenzoyl -2- deoxidation -2-; it include: starting material PEARLITOL 25C after acetone protection, sodium periodate oxidation; witting occurs with homemade Ye Lide reagent to react; then it is selectively oxidized using aqueous sodium permanganate solution; using sulfonylation; and after potassium fluoride fluorination; use concentrated hydrochloric acid blocking group and cyclization; finally hydroxyl is protected using chlorobenzoyl chloride; final product 3, the fluoro- 2- methyl-D-ribo-gamma lactone of 5- dibenzoyl -2- deoxidation -2- are obtained after purification.One kind 3 of the invention; the preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 5- dibenzoyl -2- deoxidation -2-, all raw materials are all easy to get, are cheap, substantially reduce production cost; the coherent simplicity of technological operation simultaneously, the three wastes are lower than method reported in the literature.
Description
Technical field
The invention belongs to field of medicaments, and in particular to the fluoro- 2- methyl D-core of one kind 3,5- dibenzoyl -2- deoxidation -2-
Sugar-gamma lactone preparation method.
Background technique
Viral hepatitis type C (viral hepatitis type C, HC abbreviation hepatitis C), is Hepatitis C Virus
(HCV) the caused disease of infection, main menses source is spread through sex intercourse.Clinical manifestation has fever, symptom of digestive tract and dysfunction of liver
Deng.It is similar with hepatitis B but relatively light.Majority of cases is in Subclinical, and chronicity degree is more serious, may also lead to fulminant
Hepatic failure.It is more common in and other viral combined infections.
According to the United Nations's news report, there are three, four million peoples to infect hepatitis C virus every year.There are about 1.5 hundred million people to suffer from chronic third
Liver, and the risk that cirrhosis or liver cancer occurs is faced, there are more than 350,000 people to die of liver diseases relevant to hepatitis every year.China
It is a hepatitis big country, China hepatitis C carriers about 45,000,000, account for a quarter of global sum.Hepatitis C crypticity
By force, if cannot find in time, and timely, correct, reasonable treatment is given, there is 10%~30% can develop as cirrhosis.According to defending
The data that planning commission announces show that most China's hepatitis c virus infection reported cases number is in trend is risen year by year in the past 10 years, from 2006
70681 of year, rapidly rise to 201622 in 2012, though lifting one's head slightly stable later 200,000, general trend is still
It is pessimistic.
Current Domestic hepatitis therapeutic agent is single, side effect is big, the product face of urgent clinical needs cure rate height, Small side effects
Generation, Suo Feibuwei are exactly the kind of epic grade in hepatitis therapeutic agent.The hepatitis C drug Suo Feibuwei of lucky Leadd B.V in
Acquisition U.S. Food and Drug Administration on December 6 (FDA) approval in 2013 is used for 1 type of gene, and 2 types, 3 types and 4 types are chronic
The treatment of hepatitis C (Hepatitis C) adult patient.Sovaldi is first granted to can be used for the full oral medication of hepatitis C
The drug of scheme can be eliminated dry to conventional injection drug when for the treatment of specific genotype (2 types, 3 types) chronic hepatitis C
Disturb the demand of plain (IFN).
Sovaldi (Sofosbuvir) is NS5B polymerase inhibitors, by lucky moral after being developed by Pharmasset company
It is purchased with 11,000,000,000 dollars within 2011.For HCV genotype 2 (HCV GT2), HCV genotype 3 (HCV GT3) infection, Sovaldi
(Sofosbuvir) it need to be only combined with Ribavirin (ribavirin) day, therefore sofosbuvir becomes for the third type liver
The first full oral combination therapy being not necessarily to while using interferon in the whole world of inflammation treatment.Sovaldi (sofosbuvir) can become
A super cookle grade product, sales volume in 2014 reach 10,300,000,000 dollars, are that first listing First Year just obtains hundred
The new drug of hundred million sale.
Suo Feibuwei is Hepatitis C Virus (HCV) nucleotide analog NS5B polymerase inhibitors, is suitable as joining
Close composition treatment chronic hepatitis C (CHC) infection in antiviral therapy scheme.90% chronic hcv patients are had more than at present
It is treated using the drug, and has to register and claim the serious adverse reaction rate < 5% of the drug.
The fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-It is the key intermediate for preparing Suo Feibuwei.
In method reported in the literature, the conjunction of 3, the 5- fluoro- 2- methyl-D-ribo-gamma lactones of dibenzoyl -2- deoxidation -2-
Have at route as follows:
Route one:
The conjunction of patent US20080145901 and document Tetrahedron:Asymmetry, 2009,20,305-312 report
In chemical reaction at route this method, C-2 chiralitys are not controlled, but are hydrolyzed by enzyme selectivity, and two steps of purifying remove
By-product reaches the mother of fractionation, but this method will use a large amount of buffers, and preparation efficiency is very low, can not be applied to scale
During metaplasia produces.In addition, first step reaction uses LDA, and needs -78 DEG C of reactions, severe reaction conditions compare equipment requirement
It is high.
Route two:
The synthetic route of document J.Org.Chem.Vol.74, No.17,2009 report use R- glyceraldehyde acetonide as
Starting material is first passed through and is reacted with Ye Lide reagent ethoxycarbonyl ethylidene triphenylphosphine generation witting, then using height
Potassium manganate is selectively oxidized, and using sulfonylation, is fluorinated using tetraethyl ammonium fluoride, deprotects group using concentrated hydrochloric acid,
And cyclization, hydroxyl finally is protected using chlorobenzoyl chloride, obtains product after purification.R- glyceraldehyde acetonide as starting material due to
It is easy polymerization, it is not easy to obtain, ethoxycarbonyl ethylidene triphenylphosphine can not save for a long time, also be not readily available, four
Ethyl ammonium fluoride is also not conventional fluorination reagent, brings a high price, and greatly improves large-scale production cost of material, and overall
Reaction yield is lower, and cost is much higher than the market price.
Route three:
The synthetic route of patent WO2008/045419 report uses (E) -3- (2,2- dimethyl -1,3- dioxolanes -4-
Base) -2- methyl -2- ethyl acrylate as starting material, is selectively oxidized with aqueous sodium permanganate solution, reuses chlorination
Sulfoxide is acylated by sulfurous, and hypochlorite oxidation sulfonylation is fluorinated using triethylamine trihydrofluoride, deprotects base using concentrated hydrochloric acid
Group, and cyclization finally protect hydroxyl using chlorobenzoyl chloride, obtain product after purification.The starting material that the method uses purifies difficult
Degree is big, therefore is not easy to buy, and acylated by sulfurous using thionyl chloride, hypochlorite oxidation sulfonylation can make the wastewater flow rate of reaction
Greatly, there is corrosion to enamel still equipment with triethylamine trihydrofluoride fluorination, it is relatively high to equipment requirement, while technological operation is cumbersome,
Quantity of three wastes is larger, does not meet large-scale production requirement.
Summary of the invention
The present invention provides a kind of preparation of fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-
Method, all raw materials of the present invention are cheap and easy to get, substantially reduce production cost, while the coherent simplicity of technological operation, the three wastes are lower than
Conventional method.
A kind of preparation side of fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- of the invention
Method, comprising: starting material PEARLITOL 25C is protected by acetone, after sodium periodate oxidation, is occurred with homemade Ye Lide reagent
Witting reaction, is then selectively oxidized using aqueous sodium permanganate solution, after sulfonylation and potassium fluoride fluorination,
Using concentrated hydrochloric acid blocking group and cyclization, hydroxyl finally is protected using chlorobenzoyl chloride, obtains final product 3,5- hexichol after purification
The fluoro- 2- methyl-D-ribo-gamma lactone of formoxyl -2- deoxidation -2-.
Specifically comprise the following steps: as a preferred technical solution,
1) PEARLITOL 25C and stannous chloride are added in acetone soln, be stirring evenly and then adding into 2,2-dimethoxypropane into
Row reaction, reaction are finished, and are concentrated under reduced pressure and are removed acetone and methylene chloride is added after mixing evenly, are added portionwise in the first buffer,
Control pH=8~9, liquid separation after stirring, take after organic phase pure water it is dry, be concentrated under reduced pressure after obtain diacetone-PEARLITOL 25C；
2) diacetone-PEARLITOL 25C is dissolved in methylene chloride, sodium metaperiodate is added, simultaneously the second buffer is added dropwise in temperature control
It is stirred to react, reaction is finished, centrifugation, and filter cake is washed with methylene chloride to no product, obtains reaction solution 1 after filtrate is dry；
3) triphenylphosphine and 2 bromopropionic acid ethyl ester is added in stirring in organic solvent, and white solid is precipitated in temperature rising reflux reaction
After be down to room temperature, be centrifuged to obtain white solid；It being centrifuged after white solid is beaten with precipitating reagent, filter cake is added in the first buffer,
PH=8~9 are controlled, are filtered after being stirred to react, filter cake dries to obtain homemade Ye Lide reagent: ethoxycarbonyl ethylidene triphenyl
Phosphine；
4) reaction solution 1 and Ye Lide reagent are mixed and carries out witting reaction, reaction is finished, centrifugation, Washing of Filter Cake to no production
Precipitating reagent is added after filtrate decompression concentration in product, and solid, centrifugation, Washing of Filter Cake to no product, filtrate decompression concentration, decompression is precipitated
108~112 DEG C of fraction, i.e. (E) -3- (2,2- dimethyl -1,3-dioxolane -4- base) -2- methyl -2- third are collected in distillation
Olefin(e) acid ethyl ester；
5) (E) -3- (2,2- dimethyl -1,3- dioxolanes -4- base) -2- methyl -2- is added in stirring in organic solvent
Ethyl acrylate, sodium bicarbonate and ethylene glycol, cool down and strong oxidizer is added at -15~10 DEG C and carries out oxidation reaction for temperature control,
Reaction is finished, and heats up and 0~10 DEG C of temperature control carries out quenching reaction with quencher, be centrifuged, and filtrate liquid separation takes organic phase, water phase extraction
Merge organic phase after agent extraction, dry organic phase obtains reaction solution 2；
6) triethylamine is added in stirring in reaction solution 2, cooled down simultaneously 20~25 DEG C of temperature control, it is anti-that dropwise addition sulfonic acid chloride carries out sulfonation
It answers, reaction is finished, and filtrate is centrifuged to obtain, and is reaction solution 3；
7) potassium chloride will be added in reaction solution 3, heating reflux reaction, reaction is finished, and concentrated hydrochloric acid is added and heats reaction, reacts
Finish, centrifugation, filtrate decompression is concentrated to give yellow oil；
8) acetonitrile is added in yellow oil, after stirring evenly and cooling down, 4-dimethylaminopyridine, benzoyl is added dropwise
Chlorine, stirs evenly and the temperature control that heats up is to 25~30 DEG C, and basic catalyst reaction is added dropwise, and reaction is finished, centrifugation, and filtrate decompression concentration removes
It goes to obtain yellow solid after acetonitrile, Washing of Filter Cake are dry, final product 3,5- hexichol first is obtained after yellow solid is purified with purificant
The fluoro- 2- methyl-D-ribo-gamma lactone of acyl group -2- deoxidation -2-.
Specific reaction equation is as follows:
First buffer includes saturated sodium carbonate as a preferred technical solution,.
The precipitating reagent includes one of n-hexane or 60~90 DEG C of petroleum ethers as a preferred technical solution,.
Second buffer includes saturated sodium bicarbonate, saturated potassium hydrogen carbonate or 5% carbon as a preferred technical solution,
One or more of sour sodium.
The organic solvent includes ethyl acetate as a preferred technical solution,.
The strong oxidizer includes one of potassium permanganate or sodium permanganate as a preferred technical solution,；Oxidation is anti-
The temperature control answered is -5~0 DEG C.
The quencher includes one of sodium thiosulfate or sodium hydrogensulfite as a preferred technical solution,；Extraction
Agent includes one or more of ethyl acetate, methylene chloride or dichloroethanes.
The basic catalyst includes triethylamine, N, N- diisopropyl ethyl amine, potassium carbonate as a preferred technical solution,
Or one or more of sodium carbonate.
The purificant includes one or more of methanol, ethyl alcohol or isopropanol as a preferred technical solution,.
A kind of preparation side of fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- of the invention
Method, all raw materials are all easy to get, are cheap, substantially reduce production cost, while the coherent simplicity of technological operation, the three wastes are low
In method reported in the literature, have the advantages that
1, using being easy to get and cheap raw material, such as PEARLITOL 25C, triphenylphosphine, 2 bromopropionic acid ethyl ester, potassium fluoride etc.；
2, most of intermediate does not all need to purify, and directly carries out in next step, substantially increasing the continuity of technique；
3, use potassium fluoride that can reduce fluorizating apparatus Meteorological as fluorination reagent；
4, respectively step reaction yield is all higher, while product quality all meets the requirements；
5, quantity of three wastes is less, mitigates factory's environmental protection pressure, meets national conditions；
6, the purification process for improving final products, is simple and efficient.
Specific embodiment
The present invention is explained with specific example below, it should be understood that example is for illustrating rather than
Limitation of the present invention, the scope of the present invention are determined with core content according to claims.
A kind of preparation side of fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- of the invention
Method specifically comprises the following steps:
1) to 500L acetone is first added in reaction kettle, 100kg PEARLITOL 25C and 1kg stannous chloride is added portionwise, stirring 1
Hour.20 DEG C of -25 DEG C of addition 120kg 2,2-dimethoxypropanes of temperature control are warming up to 35-40 DEG C and react 5 hours.Reaction is finished, and is subtracted
Pressure concentration removes acetone, and residue is added methylene chloride and stirs evenly.It is water-soluble that saturated sodium carbonate is added in another reaction kettle
Liquid about 500L, above-mentioned residue is added portionwise into saturated aqueous sodium carbonate, control system PH=8-9.It finishes, room temperature is stirred
It mixes 30 minutes, liquid separation, takes organic phase, organic phase purifying water washing.Organic phase is dry with anhydrous sodium sulfate, is concentrated to dryness
Obtain off-white powder diacetone-PEARLITOL 25C 102kg, yield: 70.9%.
2) to addition 375L methylene chloride in reaction kettle, it is added with stirring 100kg diacetone-PEARLITOL 25C, is obtained colourless
98kg sodium metaperiodate is added in clarified solution, and 20 DEG C -25 DEG C of temperature control are slowly added dropwise 30L saturated sodium bicarbonate aqueous solution, drips and finishes stirring instead
It answers 1-2 hours.Reaction is finished, centrifugation, and solid is washed till no product with methylene chloride, and filtrate stirs drying, centrifugation with anhydrous sodium sulfate
Desiccant is removed, product solution is obtained, is directly used in and reacts in next step, be named as reaction solution 1.
3) to 900L ethyl acetate is first added in reaction kettle, is added with stirring 350kg triphenylphosphine, 245kg 2 bromopropionic acid
Ethyl ester is warming up to return stirring and reacts 16 hours, a large amount of white solids are precipitated.Reaction is finished, and is cooled to room temperature, and is centrifuged, is obtained white
Color solid.Solid n-hexane is beaten 3 hours, centrifugation, solid is added in saturated sodium carbonate solution, control system PH=8-
9, it stirs 2 hours, filtering obtains yellow solid powder, and solid dries to obtain ethoxycarbonyl ethylidene triphenylphosphine 420kg,
Yield 87%.
4) to above-mentioned reaction solution 1 is first added in reaction kettle, it is added with stirring 310kg ethoxycarbonyl ethylidene triphenyl
Phosphine, 20 DEG C -25 DEG C are stirred to react 5 hours.Reaction is finished, centrifugation, until filter cake eluent methylene chloride to no product, filtrate 40~
45 DEG C are concentrated to dryness, and concentrate is cooled to 25~30 DEG C, 500L n-hexane are added, solid is precipitated.Centrifugation, filter cake use just oneself
Alkane elutes until no product, and 40~45 DEG C of filtrate are concentrated to dryness, and then oil pump is evaporated under reduced pressure, and collects 108~112 DEG C
Fraction is to get (E) -3- (2,2- dimethyl -1,3-dioxolane -4- base) -2- methyl -2- ethyl acrylate 120kg yield:
73%.
5) 800L ethyl acetate is added into reaction kettle, is added with stirring 120kg (E) -3- (2,2- dimethyl -1,3- bis-
Butyl oxide link -4- base) -2- methyl -2- ethyl acrylate, 140kg sodium bicarbonate, 139.2kg ethylene glycol, -10~-5 DEG C are cooled to,
Temperature control -5~0 DEG C is slowly added to 40% aqueous sodium permanganate solution of 220kg.Reaction is finished, 0~10 DEG C of temperature control, 25% sulfurous of 720L
Sour hydrogen sodium solution quenching reaction, centrifugation.Filtrate liquid separation, takes organic phase, and water phase 120L ethyl acetate extracts primary.Merge organic
Phase, centrifugation dry with anhydrous sodium sulfate, directly progress next step reaction are named as reaction solution 2.
6) above-mentioned reaction solution 2 is added into reaction kettle, is added with stirring 73.4kg triethylamine, system is cooled to 5~10 DEG C,
65.3kg sulfonic acid chloride is slowly added dropwise at 20~25 DEG C in temperature in control system.Reaction is finished, and reaction solution centrifugation, filtrate directly carries out down
Single step reaction is named as reaction solution 3.
7) above-mentioned reaction solution 3 is added into reaction kettle, 42kg potassium fluoride is added, is heated slowly to back flow reaction 5 hours, instead
It should finish, 42kg concentrated hydrochloric acid is added, be heated to 85-90 DEG C, stir insulation reaction 2 hours.Next day, reaction solution centrifugation obtain filtrate.
Filtrate decompression is concentrated to dryness, and obtains yellow oil, is not purified and is directly carried out next step reaction.
8) it is added above-mentioned grease into reaction kettle, 360L acetonitrile stirs 20 minutes, and reaction solution is cooled to 10 DEG C, and to
4-dimethylaminopyridine is added in reaction system, 10 DEG C of temperature control is hereinafter, be slowly added dropwise 82.7kg chlorobenzoyl chloride, after being added dropwise,
20 DEG C are warming up to, 25~30 DEG C of temperature control are slowly added dropwise 74.2kg triethylamine, and drop finishes, and insulation reaction 5 hours.Reaction is finished, and will be reacted
Liquid centrifugation, filtrate decompression concentration remove 2/3 acetonitrile, and filter cake is washed twice with 200L ethyl acetate, merge organic phase, organic phase
200L purified water, 200L saturated sodium bicarbonate, 200L saturated common salt water washing are used respectively, it is dry with anhydrous sodium sulfate, 45~50
It being concentrated to dryness at DEG C, obtains yellow solid about 70kg, residue is added 300L methanol and is heated to 30-35 DEG C of stirring 2 hours,
Slow cooling stirs 2 hours to 0-5 DEG C, and cooling crystallization, filtering, 50~60 DEG C of decompression dryings obtain 3,5- dibenzoyl -2- and go
The fluoro- 2- methyl-D-ribo-gamma lactone 101kg of oxygen -2-, yield: 48.4%, purity is with (E) -3- (2,2- dimethyl -1,3- bis-
Butyl oxide link -4- base) -2- methyl -2- ethyl acrylate meter, product purity 98.7%.
A kind of preparation of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- of the present embodiment
Method, all raw materials are all easy to get, are cheap, substantially reduce production cost, while the coherent simplicity of technological operation, the three wastes
Lower than method reported in the literature, have the advantages that
1, using being easy to get and cheap raw material, such as PEARLITOL 25C, triphenylphosphine, 2 bromopropionic acid ethyl ester, potassium fluoride etc.；
2, most of intermediate does not all need to purify, and directly carries out in next step, substantially increasing the continuity of technique；
3, use potassium fluoride that can reduce fluorizating apparatus Meteorological as fluorination reagent；
4, respectively step reaction yield is all higher, while product quality all meets the requirements；
5, quantity of three wastes is less, mitigates factory's environmental protection pressure, meets national conditions；
6, the purification process for improving final products, is simple and efficient.
Embodiment described above is preferable scheme of the invention, not makees limit in any form to the present invention
System, there are also other variations and modifications on the premise of not exceeding the technical scheme recorded in the claims.
Claims (5)
1. one kind 3, the preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 5- dibenzoyl -2- deoxidation -2-, feature exist
In, comprising:
Starting material PEARLITOL 25C is protected by acetone, after sodium periodate oxidation, and witting occurs with homemade Ye Lide reagent
Reaction, is then selectively oxidized using potassium permanganate solution, and after sulfonylation and potassium fluoride fluorination, use is dense
Salt acid protecting group and cyclization finally protect hydroxyl using chlorobenzoyl chloride, obtain final product 3,5- dibenzoyl-after purification
The fluoro- 2- methyl-D-ribo-gamma lactone of 2- deoxidation -2-；
Specifically comprise the following steps:
1) PEARLITOL 25C and stannous chloride are added in acetone soln, is stirring evenly and then adding into 2,2-dimethoxypropane and carries out instead
It answers, reaction is finished, and is concentrated under reduced pressure and is removed acetone and methylene chloride is added after mixing evenly, is added portionwise in the first buffer, is controlled
PH=8~9, liquid separation after stirring, take after organic phase pure water it is dry, be concentrated under reduced pressure after obtain diacetone-PEARLITOL 25C；
2) diacetone-PEARLITOL 25C is dissolved in methylene chloride, sodium metaperiodate is added, simultaneously the stirring of the second buffer is added dropwise in temperature control
It reacts, reaction is finished, centrifugation, and filter cake is washed with methylene chloride to no product, obtains reaction solution 1 after filtrate is dry；
3) triphenylphosphine and 2 bromopropionic acid ethyl ester is added in stirring in organic solvent, and temperature rising reflux reaction is dropped after white solid is precipitated
To room temperature, it is centrifuged to obtain white solid；It is centrifuged after white solid is beaten with precipitating reagent, filter cake is added in the first buffer, control
PH=8~9 are filtered after being stirred to react, and filter cake dries to obtain homemade Ye Lide reagent: ethoxycarbonyl ethylidene triphenylphosphine；
4) reaction solution 1 and Ye Lide reagent being mixed and carries out witting reaction, reaction is finished, centrifugation, Washing of Filter Cake to no product,
Precipitating reagent is added after filtrate decompression concentration, solid is precipitated, centrifugation, Washing of Filter Cake to no product, filtrate decompression concentration, decompression are steamed
It evaporates, collects 108~112 DEG C of fraction, i.e. (E) -3- (2,2- dimethyl -1,3-dioxolane -4- base) -2- methyl -2- propylene
Acetoacetic ester；
5) (E) -3- (2,2- dimethyl -1,3- dioxolanes -4- base) -2- methyl -2- propylene is added in stirring in organic solvent
Acetoacetic ester, sodium bicarbonate and ethylene glycol, cool down and strong oxidizer potassium permanganate is added at -15~10 DEG C and aoxidize instead for temperature control
It answers, reaction is finished, and heats up and 0~10 DEG C of temperature control carries out quenching reaction with quencher, be centrifuged, and filtrate liquid separation takes organic phase, and water phase is used
Merge organic phase after extractant extraction, dry organic phase obtains reaction solution 2；
6) triethylamine is added in stirring in reaction solution 2, cools down simultaneously 20~25 DEG C of temperature control, sulfonic acid chloride is added dropwise and carries out sulfonating reaction, instead
It should finish, be centrifuged to obtain filtrate, be reaction solution 3；
7) potassium fluoride being added in reaction solution 3, heating reflux reaction, reaction is finished, and concentrated hydrochloric acid is added and heats reaction, and reaction is finished,
Centrifugation, filtrate decompression are concentrated to give yellow oil；
8) acetonitrile is added in yellow oil, after stirring evenly and cooling down, 4-dimethylaminopyridine, chlorobenzoyl chloride is added dropwise, stirs
It mixes uniformly and the temperature control that heats up is to 25~30 DEG C, basic catalyst reaction is added dropwise, reaction is finished, centrifugation, and filtrate decompression concentration removes second
Nitrile obtains yellow solid after Washing of Filter Cake is dry, final product 3,5- dibenzoyl-is obtained after yellow solid is purified with purificant
The fluoro- 2- methyl-D-ribo-gamma lactone of 2- deoxidation -2-；
First buffer is saturated sodium carbonate；The precipitating reagent is one of n-hexane or 60~90 DEG C of petroleum ethers；Institute
Stating the second buffer is one or more of saturated sodium bicarbonate, saturated potassium hydrogen carbonate or 5% sodium carbonate.
2. the system of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- according to claim 1
Preparation Method, which is characterized in that the organic solvent is ethyl acetate.
3. the system of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- according to claim 2
Preparation Method, which is characterized in that the quencher is one of sodium thiosulfate or sodium hydrogensulfite；Extractant is acetic acid second
One or more of ester, methylene chloride or dichloroethanes.
4. the system of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- according to claim 2
Preparation Method, which is characterized in that the basic catalyst is triethylamine, N, in N- diisopropyl ethyl amine, potassium carbonate or sodium carbonate
One or more.
5. the system of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- according to claim 2
Preparation Method, which is characterized in that the purificant is one or more of methanol, ethyl alcohol or isopropanol.
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| CN106810541A (en) * | 2016-12-30 | 2017-06-09 | 苏州诚和医药化学有限公司 | A kind of method that one-step method prepares Suo Feibuwei intermediates |
| CN109422789A (en) * | 2017-08-28 | 2019-03-05 | 常州制药厂有限公司 | A kind of preparation process amelioration method of Suo Feibuwei |
| CN109928901B (en) * | 2017-12-15 | 2020-12-11 | 上海医药工业研究院 | Synthetic method of florfenicol intermediate |
| CN108440484B (en) * | 2018-04-21 | 2020-04-07 | 江苏八巨药业有限公司 | Preparation method of diacetone-D-mannitol |
| CN112430224A (en) * | 2020-11-17 | 2021-03-02 | 江西国化实业有限公司 | Preparation process of 5-dibenzoyl-2-deoxy-2-fluoro-2 methyl-D-ribose-r-lactone |
| CN114805428A (en) * | 2022-05-05 | 2022-07-29 | 上海予君生物科技发展有限公司 | Synthesis process of physostigmine intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417533A (en) * | 2011-10-28 | 2012-04-18 | 江苏正大清江制药有限公司 | Synthesis method of gemcitabine hydrochloride |
| CN102933570A (en) * | 2010-06-03 | 2013-02-13 | 中央硝子株式会社 | Method for producing (2r)-2-fluoro-2-c-methyl-d-ribono-y-lactone precursor |
| CN103420955A (en) * | 2012-05-23 | 2013-12-04 | 上海汇林医药科技有限公司 | Preparation method for fluoro ribose lactone |
| CN105073766A (en) * | 2012-12-21 | 2015-11-18 | 艾丽奥斯生物制药有限公司 | Substituted nucleosides, nucleotides and analogs thereof |
-
2016
- 2016-05-31 CN CN201610378165.1A patent/CN106083773B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933570A (en) * | 2010-06-03 | 2013-02-13 | 中央硝子株式会社 | Method for producing (2r)-2-fluoro-2-c-methyl-d-ribono-y-lactone precursor |
| CN102417533A (en) * | 2011-10-28 | 2012-04-18 | 江苏正大清江制药有限公司 | Synthesis method of gemcitabine hydrochloride |
| CN103420955A (en) * | 2012-05-23 | 2013-12-04 | 上海汇林医药科技有限公司 | Preparation method for fluoro ribose lactone |
| CN105073766A (en) * | 2012-12-21 | 2015-11-18 | 艾丽奥斯生物制药有限公司 | Substituted nucleosides, nucleotides and analogs thereof |
Non-Patent Citations (1)
| Title |
|---|
| Thermal Degradation of Methyl β-D-Glucoside.A Theoretical Study of Plausible Reaction Mechanisms;Takashi Hosoya，等;《J.Org.Chem.》;20090727;第74卷(第17期);第6891-6894页 |
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