CN106083773A - 3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones - Google Patents

3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones Download PDF

Info

Publication number
CN106083773A
CN106083773A CN201610378165.1A CN201610378165A CN106083773A CN 106083773 A CN106083773 A CN 106083773A CN 201610378165 A CN201610378165 A CN 201610378165A CN 106083773 A CN106083773 A CN 106083773A
Authority
CN
China
Prior art keywords
methyl
reaction
fluoro
ribo
dibenzoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201610378165.1A
Other languages
Chinese (zh)
Other versions
CN106083773B (en
Inventor
韩方津
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Huinuo Pharmaceutical Technology Co Ltd
Original Assignee
Hangzhou Huinuo Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Huinuo Pharmaceutical Technology Co Ltd filed Critical Hangzhou Huinuo Pharmaceutical Technology Co Ltd
Priority to CN201610378165.1A priority Critical patent/CN106083773B/en
Publication of CN106083773A publication Critical patent/CN106083773A/en
Application granted granted Critical
Publication of CN106083773B publication Critical patent/CN106083773B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a kind of 3; 5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones; including: starting material D mannitol is after acetone protection, sodium periodate oxidation; witting is occurred to react with homemade Ye Lide reagent; then aqueous sodium permanganate solution is used to be selectively oxidized; again through sulfonylation; and after potassium fluoride fluorination; use concentrated hydrochloric acid blocking group cyclization; finally use Benzenecarbonyl chloride. protection hydroxyl; obtaining end product 3 after purification, 5 dibenzoyls 2 deoxygenate 2 fluorine 2 methyl D ribose gamma lactones.The one 3 of the present invention; 5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones, and all raw materials are all easy to get, cheap, make production cost be substantially reduced; the coherent simplicity of technological operation simultaneously, the three wastes are less than the method for document report.

Description

3,5-dibenzoyl-2-deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of 3,5-dibenzoyl-2-deoxygenates-2-fluoro-2-methyl D-core The preparation method of sugar-gamma lactone.
Background technology
Hepatitis C (viral hepatitis type C, HC are called for short hepatitis C), is hepatitis C virus (HCV) disease caused by infection, spreads through sex intercourse in main menses source.Clinical manifestation has heating, symptom of digestive tract and abnormal liver function Deng.Similar with hepatitis B, but lighter.Majority of cases is Subclinical, and chronicity degree is the most serious, it is possible to cause fulminant Liver failure.It is more common in and other virus concurrent infection person.
According to the United Nations's news report, three, four million peoples are had to infect hepatitis C virus every year.There are about 1.5 hundred million people and suffer from chronic third Liver, and face generation liver cirrhosis or the risk of hepatocarcinoma, there are more than 350,000 people to die from the hepatic disease relevant to hepatitis C every year.China is also Shi Ge hepatitis C big country, China hepatitis C carriers about 45,000,000, account for 1/4th of whole world sum.Hepatitis C crypticity By force, if can not find in time, and give timely, correct, reasonably treat, have 10%～30% can develop into liver cirrhosis.According to defending The data that planning commission announces show, nearest 10 Nian Lai China hepatitis c virus infection reported cases numbers are in ascendant trend year by year, from 2006 70681 examples in year, rise to 201622 examples of 2012 rapidly, lift one's head 200,000 though the most stable, but general trend is still Pessimistic.
Current Domestic hepatitis C medicine is single, side effect big, the product face that urgent clinical needs cure rate is high, side effect is little Generation, Suo Feibuwei is exactly the kind of epic level in hepatitis C medicine.The hepatitis C medicine Suo Feibuwei of lucky Leadd B.V in December in 2013 obtains U.S. food Drug Administration (FDA) approval on the 6th and is used for gene 1 type, 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 medicine of scheme, when treating for specific gene type (2 types, 3 types) chronic hepatitis C, can eliminate and do conventional injection medicine Disturb the demand of element (IFN).
Sovaldi (Sofosbuvir) is NS5B AG14361, Pharmasset company by lucky moral after developing 2011 with 11,000,000,000 dollars of purchases.HCV genotype 2 (HCV GT2), HCV genotype 3 (HCV GT3) are infected, Sovaldi (Sofosbuvir) only need to be combined with ribavirin (ribavirin) day, therefore sofosbuvir becomes for the third type liver The whole world of scorching treatment is first without using the full oral combination therapy of interferon simultaneously.Sovaldi (sofosbuvir) can become A super cookle level product, the sales volume of 2014 reaches 10,300,000,000 dollars, is that first listing First Year just obtains hundred Hundred million new drugs sold.
Suo Feibuwei is hepatitis C virus (HCV) nucleotide analog NS5B AG14361, it is adaptable to as connection Composition treatment chronic hepatitis c (CHC) closed in antiviral therapy scheme infects.Have more than the chronic hcv patients of 90% at present Use this medicine to treat, and have serious adverse reaction rate ＜ 5% of this medicine of title of reporting for work.
3,5-dibenzoyl-2-deoxygenates-2-fluoro-2-methyl-D-ribo-gamma lactone It it is the key intermediate preparing Suo Feibuwei.
In the method for document report, 3,5-dibenzoyl-2-deoxygenate the conjunction of-2-fluoro-2-methyl-D-ribo-gamma lactone Route is become to have as follows:
Route one:
Patent US20080145901 and document Tetrahedron:Asymmetry, the conjunction of 2009,20,305-312 report Becoming in the chemical reaction of route the method, do not control the chirality of C-2 position, but hydrolyzed by enzyme selectivity, purification two step removes By-product, reaches the mother of fractionation, but the method to use a large amount of buffer, and preparation efficiency is the lowest, it is impossible to be applied to scale During metaplasia is produced.It addition, first step reaction uses LDA, and need-78 DEG C of reactions, severe reaction conditions, equipment requirements is compared High.
Route two:
The synthetic route of document J.Org.Chem.Vol.74, No.17,2009 report uses R-glyceraldehyde acetonide conduct Starting material, first passes through and occurs witting to react with Ye Lide reagent ethoxycarbonyl ethylidene triphenylphosphine, then use height Potassium manganate is selectively oxidized, then through sulfonylation, uses tetraethyl ammonium fluoride fluorination, uses concentrated hydrochloric acid deprotection group, And cyclization, finally use Benzenecarbonyl chloride. protection hydroxyl, obtain product after purification.R-glyceraldehyde acetonide as starting material due to It is easily polymerized, it is not easy to obtaining, ethoxycarbonyl ethylidene triphenylphosphine can not preserve for a long time, is also not readily available, four Ethyl ammonium fluoride is not conventional fluorination reagent, brings a high price, makes large-scale production cost of material be greatly improved, and totally Reaction yield is relatively low, and cost is far above 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, be selectively oxidized by aqueous sodium permanganate solution, re-use chlorination Sulfoxide is acylated through sulfurous, hypochlorite oxidation sulfonylation, uses triethylamine trihydrofluoride fluorination, uses concentrated hydrochloric acid deprotection base Group, and cyclization, finally use Benzenecarbonyl chloride. protection hydroxyl, obtain product after purification.The starting material that the method uses purifies difficulty Degree is big, therefore is difficult to buy, and uses thionyl chloride to be acylated through sulfurous, and hypochlorite oxidation sulfonylation can make the wastewater flow rate of reaction Greatly, with triethylamine trihydrofluoride fluorination, enamel still equipment being had corrosion, higher to equipment requirements, technological operation is loaded down with trivial details simultaneously, Quantity of three wastes is relatively big, does not meets large-scale production requirement.
Summary of the invention
The present invention provides a kind of 3,5-dibenzoyl-2-to deoxygenate the preparation of-2-fluoro-2-methyl-D-ribo-gamma lactone Method, all raw materials of the present invention are the most cheap and easy to get, are substantially reduced production cost, and the coherent simplicity of technological operation simultaneously, the three wastes are less than Conventional method.
A kind of 3,5-dibenzoyl-2-of the present invention deoxygenates the preparation side of-2-fluoro-2-methyl-D-ribo-gamma lactone Method, including: starting material PEARLITOL 25C, after acetone protection, sodium periodate oxidation, occurs with homemade Ye Lide reagent Witting reacts, and then uses aqueous sodium permanganate solution to be selectively oxidized, then through sulfonylation, and after potassium fluoride fluorination, Use concentrated hydrochloric acid blocking group cyclization, finally use Benzenecarbonyl chloride. protection hydroxyl, obtain end product 3,5-hexichol after purification Formoxyl-2-deoxygenates-2-fluoro-2-methyl-D-ribo-gamma lactone.
As preferred technical scheme, specifically include following steps:
1) in acetone soln, add PEARLITOL 25C and stannous chloride, be stirring evenly and then adding into 2,2-dimethoxypropane and enter Row reaction, reaction finishes, and concentrating under reduced pressure removes acetone and adds after dichloromethane stirs, and is dividedly in some parts in the first buffer, Control pH=8～9, separatory after stirring, be dried after taking organic facies pure water, obtain diacetone-PEARLITOL 25C after concentrating under reduced pressure；
2) being dissolved in dichloromethane by diacetone-PEARLITOL 25C, add sodium metaperiodate, temperature control also drips the second buffer Stirring is reacted, and reaction is finished, centrifugal, and filter cake dichloromethane washs to product-free, and filtrate is dried obtains reactant liquor 1；
3) in organic solvent, stirring adds triphenylphosphine and 2 bromopropionic acid ethyl ester, and temperature rising reflux reaction separates out white solid After be down to room temperature, centrifugal to obtain white solid；Being centrifuged after being pulled an oar with precipitant by white solid, filter cake adds in the first buffer, Controlling pH=8～9, filter after stirring reaction, filter cake dries to obtain homemade Ye Lide reagent: ethoxycarbonyl ethylidene triphenyl Phosphine；
4) mixing of reactant liquor 1 and Ye Lide reagent being carried out witting reaction, reaction is finished, centrifugal, and Cake Wash is to without producing Product, add precipitant after filtrate reduced in volume, separate out solid, centrifugal, Cake Wash to product-free, filtrate reduced in volume, decompression Distillation, collects the fraction of 108～112 DEG C, i.e. (E)-3-(2,2-dimethyl-DOX-4-base)-2-methyl-2-third Olefin(e) acid ethyl ester；
5) in organic solvent, stirring adds (E)-3-(2,2-dimethyl-1,3-dioxolanes-4-base)-2-methyl-2- Ethyl acrylate, sodium bicarbonate and ethylene glycol, cooling also temperature control adds strong oxidizer and carries out oxidation reaction when-15～10 DEG C, Reaction is finished, and heats up and temperature control 0～10 DEG C carry out cancellation reaction with quencher, centrifugal, and filtrate separatory takes organic facies, aqueous phase extraction Merging organic facies after agent extraction, dry organic facies obtains reactant liquor 2；
6) stirring in reactant liquor 2 adding triethylamine, cooling temperature control 20～25 DEG C, it is anti-that dropping sulfonic acid chloride carries out sulfonation Should, reaction is finished, and is centrifuged to obtain filtrate, for reactant liquor 3；
7) will add potassium chloride, heating reflux reaction in reactant liquor 3, reaction is finished, and adds concentrated hydrochloric acid reacting by heating, reaction Finishing, centrifugal, filtrate reduced in volume obtains yellow oil；
8) in yellow oil, add acetonitrile, after stirring and cooling down, drip DMAP, benzoyl Chlorine, stirs and rises control temp to 25～30 DEG C, dropping base catalyst reaction, and reaction is finished, and centrifugal, filtrate reduced in volume removes Removing acetonitrile, Cake Wash is dried obtains yellow solid, obtains end product 3,5-hexichol first with purificant after being purified by yellow solid Acyl group-2-deoxygenates-2-fluoro-2-methyl-D-ribo-gamma lactone.
Concrete reaction equation is as follows:
As preferred technical scheme, described first buffer includes saturated sodium carbonate.
As preferred technical scheme, described precipitant includes the one in normal hexane or 60～90 DEG C of petroleum ether.
As preferred technical scheme, described second buffer includes saturated sodium bicarbonate, saturated potassium hydrogen carbonate or 5% carbon One or more in acid sodium.
As preferred technical scheme, described organic solvent includes ethyl acetate.
As preferred technical scheme, described strong oxidizer includes the one in potassium permanganate or sodium permanganate；Oxidation is anti- The temperature answered controls as-5～0 DEG C.
As preferred technical scheme, described quencher includes the one in sodium thiosulfate or sodium sulfite；Extraction Agent includes one or more in ethyl acetate, dichloromethane or dichloroethanes.
As preferred technical scheme, described base catalyst includes triethylamine, N, N-diisopropyl ethyl amine, potassium carbonate Or one or more in sodium carbonate.
As preferred technical scheme, described purificant includes one or more in methanol, ethanol or isopropanol.
A kind of 3,5-dibenzoyl-2-of the present invention deoxygenates the preparation side of-2-fluoro-2-methyl-D-ribo-gamma lactone Method, all raw materials are all easy to get, cheap, make production cost be substantially reduced, and the coherent simplicity of technological operation simultaneously, the three wastes are low In the method for document report, have the advantages that
1, use is easy to get and cheap raw material, such as PEARLITOL 25C, triphenylphosphine, 2 bromopropionic acid ethyl ester, potassium fluoride etc.；
2, major part intermediate all need not purify, and directly carries out next step, substantially increases the continuity of technique；
3, potassium fluoride is used can to reduce fluorizating apparatus Meteorological as fluorination reagent；
4, each step reaction yield is the highest, and product quality all meets the requirements simultaneously；
5, quantity of three wastes is less, alleviates factory's environmental protection pressure, meets national conditions；
6, the purification process of final products is improved, the most efficiently.
Detailed description of the invention
It is explained the present invention below, it should be understood that example is for illustrating rather than with instantiation Limitation of the present invention, the scope of the present invention is determined according to claims with core content.
A kind of 3,5-dibenzoyl-2-of the present invention deoxygenates the preparation side of-2-fluoro-2-methyl-D-ribo-gamma lactone Method, specifically includes following steps:
1) in reactor, it is initially charged 500L acetone, is dividedly in some parts 100kg PEARLITOL 25C and 1kg stannous chloride, stir 1 Hour.Temperature control 20 DEG C-25 DEG C adds 120kg 2,2-dimethoxypropane, is warming up to 35-40 DEG C and reacts 5 hours.Reaction is finished, and subtracts Pressure concentrates and removes acetone, and residue adds dichloromethane and stirs.Saturated sodium carbonate is added water-soluble in another reactor Liquid about 500L, is dividedly in some parts above-mentioned residue to saturated aqueous sodium carbonate, controls system PH=8-9.Finishing, room temperature is stirred Mixing 30 minutes, separatory, take organic facies, organic facies purified water is washed.Organic facies anhydrous sodium sulfate is dried, and is evaporated to do Obtain off-white color solid diacetone-PEARLITOL 25C 102kg, yield: 70.9%.
2) adding 375L dichloromethane in reactor, stirring is lower adds 100kg diacetone-PEARLITOL 25C, obtains colourless Clear liquor, adds 98kg sodium metaperiodate, and temperature control 20 DEG C-25 DEG C is slowly added dropwise 30L saturated sodium bicarbonate aqueous solution, drips and finishes stirring instead Answer 1-2 hour.Reaction is finished, and centrifugal, solid with methylene chloride is washed till product-free, and filtrate is dried with anhydrous sodium sulfate stirring, centrifugal Remove desiccant, obtain product solution, be directly used in next step reaction, named reactant liquor 1.
3) in reactor, it is initially charged 900L ethyl acetate, stirring lower addition 350kg triphenylphosphine, 245kg 2 bromopropionic acid Ethyl ester, is warming up to return stirring and reacts 16 hours, separate out a large amount of white solid.Reaction is finished, and is cooled to room temperature, centrifugal, obtains white Color solid.Being pulled an oar 3 hours by solid normal hexane, centrifugal, solid joins in saturated sodium carbonate solution, controls system PH=8- 9, stir 2 hours, filter, obtain yellow solid powder, solid is dried and is obtained ethoxycarbonyl ethylidene triphenylphosphine 420kg, Yield 87%.
4) being initially charged above-mentioned reactant liquor 1 in reactor, stirring is lower adds 310kg ethoxycarbonyl ethylidene triphenyl Phosphine, 20 DEG C-25 DEG C stirrings are reacted 5 hours.Reaction is finished, centrifugal, filter cake eluent methylene chloride to product-free, filtrate 40～ 45 DEG C are evaporated to do, and concentrate is cooled to 25～30 DEG C, add 500L normal hexane and separate out solid.Centrifugal, filter cake is with just own Alkane drip washing is to product-free, and filtrate 40～45 DEG C are evaporated to do, and then oil pump decompression distillation, collects 108～112 DEG C Fraction, obtains (E)-3-(2,2-dimethyl-DOX-4-base)-2-methyl-2-ethyl acrylate 120kg yield: 73%.
5) in reactor, add 800L ethyl acetate, under stirring, add 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, be cooled to-10～-5 DEG C, Temperature control-5～0 DEG C are slowly added to 220kg 40% aqueous sodium permanganate solution.Reaction is finished, temperature control 0～10 DEG C 720L 25% sulfurous Acid hydrogen sodium solution quencher reaction, centrifugal.Filtrate separatory, takes organic facies, and aqueous phase 120L ethyl acetate extracts once.Merge organic Phase, is dried with anhydrous sodium sulfate, centrifugal, directly carries out next step reaction, named reactant liquor 2.
6) adding above-mentioned reactant liquor 2 in reactor, stirring is lower adds 73.4kg triethylamine, and system is cooled to 5～10 DEG C, In control system, temperature is at 20～25 DEG C, is slowly added dropwise 65.3kg sulfonic acid chloride.Reaction is finished, and reactant liquor is centrifuged, under filtrate is directly carried out Single step reaction, named reactant liquor 3.
7) in reactor, add above-mentioned reactant liquor 3, add 42kg potassium fluoride, be heated slowly to back flow reaction 5 hours, instead Should finish, add 42kg concentrated hydrochloric acid, be heated to 85-90 DEG C, stirring insulation reaction 2 hours.Next day, reactant liquor is centrifuged, obtains filtrate. Filtrate reduced in volume, to dry, obtains yellow oil, and purification does not directly carry out next step reaction.
8) in reactor, above-mentioned grease is added, 360L acetonitrile, stir 20 minutes, reactant liquor is cooled to 10 DEG C, and to Reaction system adds DMAP, temperature control less than 10 DEG C, is slowly added dropwise 82.7kg Benzenecarbonyl chloride., after dropping, Being warming up to 20 DEG C, temperature control 25～30 DEG C are slowly added dropwise 74.2kg triethylamine, drip and finish, insulation reaction 5 hours.Reaction is finished, will reaction Liquid is centrifuged, and filtrate reduced in volume removes the acetonitrile of 2/3, and filter cake 200L ethyl acetate washes twice, and merges organic facies, organic facies Respectively with 200L purified water, 200L saturated sodium bicarbonate, the washing of 200L saturated aqueous common salt, it is dried with anhydrous sodium sulfate, 45～50 Being evaporated at DEG C do, obtain yellow solid about 70kg, residue adds 300L methanol and is heated to 30-35 DEG C of stirring 2 hours, Slow cooling stirs 2 hours to 0-5 DEG C, cooling crystallization, filters, and 50～60 DEG C of decompression dryings obtain 3, and 5-dibenzoyl-2-goes Oxygen-2-fluoro-2-methyl-D-ribo-gamma lactone 101kg, 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 3,5-dibenzoyl-2-of the present embodiment deoxygenates the preparation of-2-fluoro-2-methyl-D-ribo-gamma lactone Method, all raw materials are all easy to get, cheap, make production cost be substantially reduced, the coherent simplicity of technological operation simultaneously, the three wastes Less than the method for document report, have the advantages that
1, use is easy to get and cheap raw material, such as PEARLITOL 25C, triphenylphosphine, 2 bromopropionic acid ethyl ester, potassium fluoride etc.；
2, major part intermediate all need not purify, and directly carries out next step, substantially increases the continuity of technique；
3, potassium fluoride is used can to reduce fluorizating apparatus Meteorological as fluorination reagent；
4, each step reaction yield is the highest, and product quality all meets the requirements simultaneously；
5, quantity of three wastes is less, alleviates factory's environmental protection pressure, meets national conditions；
6, the purification process of final products is improved, the most efficiently.
Embodiment described above is the preferably scheme of the present invention, and the present invention not makees any pro forma limit System, also has other variant and remodeling on the premise of without departing from the technical scheme described in claim.

Claims (10)

1. one kind 3,5-dibenzoyl-2-deoxygenates the preparation method of-2-fluoro-2-methyl-D-ribo-gamma lactone, and its feature exists In, including:
After acetone protection, sodium periodate oxidation, there is witting with homemade Ye Lide reagent in starting material PEARLITOL 25C Reaction, then uses aqueous sodium permanganate solution to be selectively oxidized, then through sulfonylation, and after potassium fluoride fluorination, use dense Salt acid protecting group cyclization, finally use Benzenecarbonyl chloride. protection hydroxyl, obtain end product 3 after purification, and 5-dibenzoyl- 2-deoxygenates-2-fluoro-2-methyl-D-ribo-gamma lactone.
3,5-dibenzoyl-2-the most according to claim 1 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that specifically include following steps:
1) in acetone soln, add PEARLITOL 25C and stannous chloride, be stirring evenly and then adding into 2,2-dimethoxypropane and carry out instead Should, reaction is finished, and concentrating under reduced pressure removes acetone and adds after dichloromethane stirs, and is dividedly in some parts in the first buffer, controls PH=8～9, separatory after stirring, it is dried after taking organic facies pure water, obtains diacetone-PEARLITOL 25C after concentrating under reduced pressure；
2) being dissolved in dichloromethane by diacetone-PEARLITOL 25C, add sodium metaperiodate, temperature control also drips the second buffer stirring Reacting, reaction is finished, centrifugal, and filter cake dichloromethane washs to product-free, and filtrate is dried obtains reactant liquor 1；
3) in organic solvent, stirring adds triphenylphosphine and 2 bromopropionic acid ethyl ester, and temperature rising reflux reaction is dropped after separating out white solid To room temperature, it is centrifuged to obtain white solid；Being centrifuged after being pulled an oar with precipitant by white solid, filter cake adds in the first buffer, controls PH=8～9, filters after stirring reaction, and filter cake dries to obtain homemade Ye Lide reagent: ethoxycarbonyl ethylidene triphenylphosphine；
4) mixing of reactant liquor 1 and Ye Lide reagent being carried out witting reaction, reaction is finished, centrifugal, Cake Wash to product-free, Adding precipitant after filtrate reduced in volume, separate out solid, centrifugal, Cake Wash to product-free, filtrate reduced in volume, decompression are steamed Evaporate, collect the fraction of 108～112 DEG C, i.e. (E)-3-(2,2-dimethyl-DOX-4-base)-2-methyl-2-propylene Acetoacetic ester；
5) in organic solvent, stirring adds (E)-3-(2,2-dimethyl-1,3-dioxolanes-4-base)-2-methyl-2-propylene Acetoacetic ester, sodium bicarbonate and ethylene glycol, cooling temperature control add strong oxidizer and carry out oxidation reaction when-15～10 DEG C, react Finishing, heat up and temperature control 0～10 DEG C carry out cancellation reaction with quencher, centrifugal, filtrate separatory takes organic facies, and aqueous phase extractant extracts Merging organic facies after taking, dry organic facies obtains reactant liquor 2；
6) stirring in reactant liquor 2 adding triethylamine, cooling temperature control 20～25 DEG C, dropping sulfonic acid chloride carries out sulfonating reaction, instead Should finish, be centrifuged to obtain filtrate, for reactant liquor 3；
7) will add potassium chloride, heating reflux reaction in reactant liquor 3, reaction is finished, and adds concentrated hydrochloric acid reacting by heating, and reaction is finished, Centrifugal, filtrate reduced in volume obtains yellow oil；
8) in yellow oil, add acetonitrile, after stirring and cooling down, drip DMAP, Benzenecarbonyl chloride., stir Mixing uniformly and rise control temp to 25～30 DEG C, dropping base catalyst reaction, reaction is finished, centrifugal, and filtrate reduced in volume removes second Nitrile, Cake Wash is dried obtains yellow solid, by yellow solid with obtaining end product 3 after purificant purification, 5-dibenzoyl- 2-deoxygenates-2-fluoro-2-methyl-D-ribo-gamma lactone.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described first buffer includes saturated sodium carbonate.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described precipitant includes the one in normal hexane or 60～90 DEG C of petroleum ether.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described second buffer includes in saturated sodium bicarbonate, saturated potassium hydrogen carbonate or 5% sodium carbonate One or more.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described organic solvent includes ethyl acetate.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described strong oxidizer includes the one in potassium permanganate or sodium permanganate；The temperature control of oxidation reaction It is made as-5～0 DEG C.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described quencher includes the one in sodium thiosulfate or sodium sulfite；Extractant includes acetic acid One or more in ethyl ester, dichloromethane or dichloroethanes.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates the system of-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation Method, it is characterised in that described base catalyst includes triethylamine, N, N-diisopropyl ethyl amine, potassium carbonate or sodium carbonate In one or more.
3,5-dibenzoyl-2-the most according to claim 2 deoxygenates-2-fluoro-2-methyl-D-ribo-gamma lactone Preparation method, it is characterised in that described purificant includes one or more in methanol, ethanol or isopropanol.
CN201610378165.1A 2016-05-31 2016-05-31 The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2- Active CN106083773B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610378165.1A CN106083773B (en) 2016-05-31 2016-05-31 The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610378165.1A CN106083773B (en) 2016-05-31 2016-05-31 The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-

Publications (2)

Publication Number Publication Date
CN106083773A true CN106083773A (en) 2016-11-09
CN106083773B CN106083773B (en) 2019-06-14

Family

ID=57230597

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610378165.1A Active CN106083773B (en) 2016-05-31 2016-05-31 The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-

Country Status (1)

Country Link
CN (1) CN106083773B (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN108440484A (en) * 2018-04-21 2018-08-24 江苏八巨药业有限公司 A kind of preparation method of diacetone-PEARLITOL 25C
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
CN109928901A (en) * 2017-12-15 2019-06-25 上海医药工业研究院 A kind of synthetic method of florfenicol midbody
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)

* Cited by examiner, † Cited by third party
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Title
TAKASHI HOSOYA，等: "Thermal Degradation of Methyl β-D-Glucoside.A Theoretical Study of Plausible Reaction Mechanisms", 《J.ORG.CHEM.》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN109928901A (en) * 2017-12-15 2019-06-25 上海医药工业研究院 A kind of synthetic method of florfenicol midbody
CN109928901B (en) * 2017-12-15 2020-12-11 上海医药工业研究院 Synthetic method of florfenicol intermediate
CN108440484A (en) * 2018-04-21 2018-08-24 江苏八巨药业有限公司 A kind of preparation method of diacetone-PEARLITOL 25C
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

Also Published As

Publication number Publication date
CN106083773B (en) 2019-06-14

Similar Documents

Publication Publication Date Title
CN106083773A (en) 3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones
CN104610404B (en) A kind of preparation method of ribofuranose phosphate derivative
CN110330540A (en) Nucleosides salt and preparation method thereof
CN106008603A (en) Preparation methods of tenofovir disoproxil and fumarate thereof
CN101437524B (en) Preparation of 2' ifluoro-2'- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
CN106478528A (en) The synthesis technique of Favipiravir
CN107245064B (en) The preparation method of Suo Feibuwei intermediate
CN104327138B (en) Preparation method of PSI-7977 intermediate compound
CN105541819A (en) Preparation method and intermediate of brexpiprazole and preparation method of intermediate
CN103880775B (en) Compound 2-(3-aldehyde radical-4-isobutoxy phenyl) preparation method of-4-methylthiazole-5-carboxylate and Febuxostat
CN109438432A (en) A kind of preparation method of emtricitabine
CN109422710A (en) A kind of preparation method of Suo Feibuwei fluorine lactone intermediate
CN109867673A (en) A method of synthesis Pabuk former times benefit cloth
WO2016177300A1 (en) (2'r)-2'-deoxy-2'-halo-2'-methyl uridine derivative, and preparation method and use thereof
JP2015523337A (en) Sulfilimine and sulfoxide process for producing festinavir
CN101723883A (en) Method for preparing oxycodone
CN105646626B (en) A kind of synthetic method of the fluorine of rope in high yield cloth Wei
CN105418547A (en) Preparation for sofosbuvir key intermediate
CN111454270A (en) Nucleoside compound containing six-membered ring and preparation method thereof
CN108997377B (en) Preparation method of E-type 7-ATCA
CN104892601A (en) Preparation method of antithrombotic drug Apixaban
CN104610200A (en) Preparation method of NS5B (nonstructural protein 5B) polymerase inhibitor intermediates
CN114380877A (en) Preparation method of 2' -deoxy-2 ' -beta-fluoro-4 ' -azidocytidine
CN106749248B (en) A kind of preparation method of antiviral drug of Entecavir
CN106279117A (en) A kind of synthetic method of Lei Dipawei intermediate and products thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant