CN106083961A - A kind of preparation method of (2 ' R) 2 ' deoxidation 2 ' fluorine 2 ' MU glycosides - Google Patents
A kind of preparation method of (2 ' R) 2 ' deoxidation 2 ' fluorine 2 ' MU glycosides Download PDFInfo
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- CN106083961A CN106083961A CN201610546211.4A CN201610546211A CN106083961A CN 106083961 A CN106083961 A CN 106083961A CN 201610546211 A CN201610546211 A CN 201610546211A CN 106083961 A CN106083961 A CN 106083961A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses the preparation method of one (2 ' R) 2 ' deoxidation 2 ' fluorine 2 ' MU glycosides, with 2 C methyl D ribonic acids 1,4 lactones are initiation material, through silanization, fluoro, reduce, be etherified, dock, hydrolysis step prepares (2 ' R) 2 ' deoxidation 2 ' fluorine 2 ' MU glycosides.The invention have the advantage that route is brief, it is to avoid use the severe toxicity harmful substances such as barium chloride, it is to avoid produce such as a large amount of solid waste such as triphenylphosphine oxides；The acid using catalytic amount carries out deprotection reaction; avoid using substantial amounts of ammonia methanol to carry out de-ester protection group; reduce solvent usage amount and the volume of production of trade waste, and the αisomer recoverable of target product, reduce the generation of solid waste to greatest extent；This route overall yield is high, the easy polishing purification of intermediate, is suitable for large-scale industrial and produces.
Description
Technical field
The present invention relates to the preparation method of intermediate important for a kind of Suo Feibuwei, specifically, relate to one (2 ' R)-
2 '-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides.
Background technology
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides be synthesis Suo Feibuwei important intermediate, CAS registration number:
863329-66-2, as shown in formula IV.
At present synthesis (2 ' R)-2 '-deoxidation-2 ' process route of-fluoro-2 '-MU glycosides is complicated, needs to use barium chloride
Deng extremely toxic substance, and produce substantial amounts of solid waste, be unsuitable for large-scale industrial and produce.Accordingly, it would be desirable to a kind of new technology
Scheme solves above-mentioned technical problem.
Summary of the invention
The invention aims to solve above-mentioned technical problem, it is provided that a kind of process route is brief, avoid barium chloride etc.
The use of noxious substance, it is to avoid (2 ' R)-the 2 '-deoxidation-2 of the generation of solid waste ' the preparation side of-fluoro-2 '-MU glycosides
Method.
The technical solution used in the present invention is:
A kind of (2 ' R)-2 '-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides, it is with 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-interior
Ester is initiation material, through silanization, fluoro, reduce, be etherified, dock, hydrolysis step prepares (2 ' R)-2 '-deoxidation-2 '-
Fluoro-2 '-MU glycosides.Specifically comprise the following steps that
A, the preparation of intermediate formula I
Under the conditions of anhydrous and oxygen-free, with 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone as raw material, under organic base catalytic, warp and hydroxyl
Base protective agent reacts under conditions of 15-20 DEG C, after completion of the reaction through distill, stand, wash, sucking filtration, concentration prepared
Crude product, crude product is through preparing intermediate formula I, described 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone and hydroxyl protection with isopropanol is refined
The mol ratio of agent is 1:2～2.2；
B, intermediate formula II prepare intermediate formula I under base reagent effect, through reacting with fluoro reagent, alcoholic extract hydroxyl group is carried out
Fluorine replaces, and described intermediate formula I is 1:1.05:2～1:1.8:2.5 with the mol ratio of fluoro reagent and base reagent；
C, the preparation of intermediate formula III
Under the conditions of anhydrous and oxygen-free, intermediate formula II is after carbonyl reduction is alcoholic extract hydroxyl group by strong reductant effect, through lewis acid
Catalysis is reacted with methanol and is obtained intermediate formula III crude product, it is not necessary to purification directly carries out next step reaction；Described intermediate formula II with
The mol ratio of strong reductant and methanol is 1:1.2:1.5～1:2.5:3；
D, (2 ' R)-2 '-deoxidation-2 ' preparation of-fluoro-2 '-MU glycosides
Uracil and silanes hydroxy-protecting agent react and prepare uracil derivative, intermediate formula III and described uracil derivative
Carrying out docking reaction under lewis acid catalyst effect, docking product is hydrolyzed instead under phase transfer catalyst effect
Target product should be obtained；
E, αisomer reclaim
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides αisomer occurs under trifluoromethyl sulfonic acid trimethylsilyl ester effect
Reaction, the configuration reversal of αisomer is (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides；
The structural formula of described intermediate formula I, intermediate formula II and intermediate formula III is as follows:
。
Reaction equation is:
The invention have the advantage that
1) route is brief, it is to avoid use the severe toxicity harmful substances such as barium chloride, it is to avoid produces a large amount of solids such as triphenylphosphine oxide such as and gives up
Gurry；
2) acid of catalytic amount is used to carry out deprotection reaction, it is to avoid to use substantial amounts of ammonia methanol to carry out de-ester protection group, reduce
Solvent usage amount and the volume of production of trade waste, and the αisomer recoverable of target product, reduce solid to greatest extent
The generation of body garbage；
3) this route overall yield is high, the easy polishing purification of intermediate, is suitable for large-scale industrial and produces.
Detailed description of the invention
Embodiment 1
1. the preparation of intermediate I
Under the conditions of anhydrous and oxygen-free, reaction bulb adds 80g 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone, 4g 4-diformazan ammonia
Yl pyridines, 187g 1, chloro-1,1,3,3-tetra isopropyl diformazan silica ether and the 1500mL acetonitrile of 3-bis-, stirring, it is cooled to 15-20
DEG C reaction, TLC monitors reaction；React complete, remove acetonitrile under reduced pressure, add 1000mL ethyl acetate and 300mL unsaturated carbonate hydrogen
Sodium solution, stirring, stand separatory, aqueous layer with ethyl acetate (800mL × 2) extracts, and merges organic facies, washes with sodium chloride solution
Washing, anhydrous sodium sulfate is dried, sucking filtration, is evaporated to do, and obtains yellow-brown solid crude product.This crude product refines with 5 times amount isopropanols,
Obtain 169g faint yellow solid product.Yield: 85%.
2. the preparation of intermediate II
169g intermediate I it is separately added in reaction bulb, 93g triethylamine, 71g Fluohydric acid. triethylamine salt, 1500mL oxolane,
Stirring, is warming up to back flow reaction, and TLC monitors reaction；Raw material reaction is complete, is down to room temperature, removes oxolane under reduced pressure, adds
1000mL ethyl acetate and 300mL 1N hydrochloric acid solution, stirring, stand separatory, aqueous layer with ethyl acetate (500mL × 2) extracts,
Merging organic facies, wash with sodium chloride solution, anhydrous sodium sulfate is dried, sucking filtration, is evaporated to do, and obtains 155g faint yellow solid
Product.Yield: 91%.
3. the preparation of intermediate III
In reaction bulb, under the conditions of anhydrous and oxygen-free, add 155g intermediate II and 1000mL oxolane, stirring and dissolving, cooling
To-20 DEG C, drip the tetrahydrofuran solution (120g/500mL) of three tertiary butyoxy aluminum lithiums, stirring reaction 30min, then rise
Temperature is to 0 DEG C of reaction, and TLC detects reaction；React complete, add 1000mL saturated ammonium chloride solution and carry out cancellation, steaming of then reducing pressure
Except oxolane, adding 1000mL ethyl acetate, stand separatory, aqueous layer with ethyl acetate (500mL × 2) extracts, and merges organic
Phase, washs organic facies with saturated nacl aqueous solution, then is dried with anhydrous sodium sulfate, sucking filtration, and concentrating under reduced pressure obtains oily intermediate,
Being subsequently adding 1500mL methanol and 15g p-methyl benzenesulfonic acid, stir, keep room temperature reaction, TLC monitors reaction；React complete,
Reactant liquor saturated sodium bicarbonate solution (500mL × 2) washs, and saturated nacl aqueous solution (500mL × 2) washs, anhydrous slufuric acid
Sodium is dried, less than 40 DEG C concentrating under reduced pressure, obtains solid crude product.This crude product, without purification, directly carries out next step reaction.
4. (2 ' R)-2 '-deoxidation-2 ' preparation of-fluoro-2 '-MU glycosides
In reaction bulb, add 168g HMDS, 1000mL chlorobenzene, 5g ammonium sulfate, and 71g uracil, stirring, rise
Temperature is to back flow reaction, and TLC monitors reaction；React complete, be down to room temperature, be subsequently adding previous step reaction intermediate III, stirring, add
Entering 163g butter of tin, be warming up to 50 DEG C of reactions, TLC monitors reaction: react complete, is cooled to room temperature, adds 105g bicarbonate
Sodium and 100g kieselguhr, stirring, sucking filtration, filter cake is pulled an oar with chlorobenzene (500mL × 3) again, merges organic facies, molten with saturated sodium-chloride
Liquid washs, and anhydrous sodium sulfate is dried, and is evaporated to do, obtains intermediate.This intermediate is placed in 6 times amount oxolanes, stirs
Mixing dissolving, add 20g tetrabutyl ammonium fluoride, be warming up to 55-60 DEG C, insulation reaction, TLC monitors reaction.Reacting complete, decompression is steamed
Dry solvent, obtains crude product.This crude product refines with 5 times amount isopropanols, obtains 72g white solid product.Refinement mother liquor is stand-by.Yield:
72%。
5. αisomer reclaims
In reaction bulb, add refinement mother liquor and 3 times amount methanol, heat up, stirring and dissolving, after 1 hour, it is cooled to room temperature, has solid
Body separates out, and sucking filtration obtains 23g off-white color solid.Such white solid is placed in 150mL acetonitrile, stirring, adds 9g trifluoromethyl
Sulfonic acid trimethylsilyl group, is warming up to back flow reaction, and TLC monitors reaction: reacts complete, is cooled to room temperature, is evaporated to do, adds
Enter 2 times amount methanol making beating, sucking filtration, dry, obtain 12g white solid product.
Embodiment 2
1. the preparation of intermediate I
Under the conditions of anhydrous and oxygen-free, adding 65g 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone, 8g N in reaction bulb, N-bis-is different
Propylethylamine, 150g 1, chloro-1,1,3,3-tetra isopropyl diformazan silica ether and the 1000mL oxolane of 3-bis-, stirring, it is cooled to
15-20 DEG C of reaction, TLC monitors reaction；React complete, remove oxolane under reduced pressure, add 600mL toluene and 100mL saturated carbon
Acid hydrogen sodium solution, stirring, stand separatory, water layer toluene (400mL × 2) extracts, and merges organic facies, washes with sodium chloride solution
Washing, anhydrous sodium sulfate is dried, sucking filtration, is evaporated to do, and obtains yellow-brown solid crude product.This crude product refines with 5 times amount isopropanols,
Obtain 137g faint yellow solid product.Yield: 86%.
2. the preparation of intermediate II
137g intermediate I it is separately added in reaction bulb, 69g piperidines, 74g diethylin sulfur trifluoride, 1200mL dichloromethane,
Stirring, is warming up to back flow reaction, and TLC monitors reaction；Raw material reaction is complete, is down to room temperature, adds 100mL 1N hydrochloric acid solution, stirs
Mixing, stand separatory, water layer dichloromethane (300mL × 2) extracts, and merges organic facies, washs with sodium chloride solution, anhydrous slufuric acid
Sodium is dried, sucking filtration, is evaporated to do, and obtains 127g faint yellow solid product.Yield: 93%.
3. the preparation of intermediate III
In reaction bulb, under the conditions of anhydrous and oxygen-free, add 127g intermediate II and 800mL ether, stirring, be cooled to-20 DEG C, drip
Add the toluene solution (110g/300mL) of double (2-methoxyethoxy) sodium aluminate of dihydro, stirring reaction 30min, then heat to 0
DEG C reaction, TLC detects reaction；React complete, add 800mL saturated ammonium chloride solution and carry out cancellation, stand separatory, water layer first
Benzene (300mL × 2) extracts, and merges organic facies, washs organic facies with saturated nacl aqueous solution, then be dried with anhydrous sodium sulfate, take out
Filter, concentrating under reduced pressure, obtain oily intermediate, be subsequently adding 1000mL methanol and 20g boron trifluoride diethyl etherate, stir, keep room
Temperature reaction, TLC monitors reaction；Reacting complete, reactant liquor saturated sodium bicarbonate solution (300mL × 2) washs, saturated sodium-chloride
Solution (300mL × 2) washs, and anhydrous sodium sulfate is dried, less than 40 DEG C concentrating under reduced pressure, obtains solid crude product.This crude product without purification,
Directly carry out next step reaction.
4. (2 ' R)-2 '-deoxidation-2 ' preparation of-fluoro-2 '-MU glycosides
In reaction bulb, add 85g trim,ethylchlorosilane, 600mL isopropyl acetate, 5g ammonium sulfate, and 56g uracil, stir,
Being warming up to back flow reaction, TLC monitors reaction；React complete, be down to room temperature, be subsequently adding previous step reaction intermediate III, stirring,
Adding 83g trifluoromethyl sulfonic acid trimethylsilyl ester, be warming up to 50 DEG C of reactions, TLC monitors reaction: reacts complete, is cooled to room temperature,
Adding 76g sodium bicarbonate and 100g kieselguhr, stirring, sucking filtration, filter cake is pulled an oar with dichloromethane (300mL × 3), is merged organic
Phase, washs with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and is evaporated to do, obtains intermediate.This intermediate is placed in 6
In times amount acetonitrile, stirring and dissolving, add 15g tetrabutyl ammonium bromide, be warming up to 55-60 DEG C, insulation reaction, TLC monitors reaction.Instead
Should be complete, evaporated under reduced pressure solvent, obtain crude product.This crude product, with 5 times amount refining methanols, obtains 56g white solid product.Refinement mother liquor is treated
With.Yield: 70%.
5. αisomer reclaims
In reaction bulb, add refinement mother liquor and 3 times amount methanol, heat up, stirring and dissolving, after 1 hour, it is cooled to room temperature, has solid
Body separates out, and sucking filtration obtains 18g off-white color solid.Such white solid is placed in 150mL acetonitrile, stirring, adds 7g trifluoromethyl
Sulfonic acid trimethylsilyl group, is warming up to back flow reaction, and TLC monitors reaction: reacts complete, is cooled to room temperature, is evaporated to do, adds
Enter 2 times amount methanol making beating, sucking filtration, dry, obtain 9.5g white solid product.
Embodiment 3
1. the preparation of intermediate I
Under the conditions of anhydrous and oxygen-free, reaction bulb adds 48g 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone, 8g piperidines, 112g
1,3-bis-chloro-1,1,3,3-tetra isopropyl diformazan silica ether and 800mL acetonitrile, stirring, it is cooled to 15-20 DEG C of reaction, TLC monitors
Reaction；React complete, remove acetonitrile under reduced pressure, add 800mL ethyl acetate and 200mL saturated sodium bicarbonate solution, stirring, stand
Separatory, aqueous layer with ethyl acetate (300mL × 2) extracts, and merges organic facies, washs with sodium chloride solution, and anhydrous sodium sulfate is dried,
Sucking filtration, is evaporated to do, and obtains yellow-brown solid crude product.This crude product refines with 5 times amount isopropanols, obtains 101g faint yellow solid and produces
Product.Yield: 85%.
2. the preparation of intermediate II
101g intermediate I it is separately added in reaction bulb, 41g pyridine, 38g Fluohydric acid. pyridiniujm, 1000mL isopropyl acetate, stir
Mixing, be warming up to back flow reaction, TLC monitors reaction；Raw material reaction is complete, is down to room temperature, 200mL 1N hydrochloric acid solution, stirs, quiet
Putting separatory, water layer isopropyl acetate (500mL × 2) extracts, and merges organic facies, washs with sodium chloride solution, anhydrous sodium sulfate
It is dried, sucking filtration, is evaporated to do, obtains 93g faint yellow solid product.Yield: 90%.
3. the preparation of intermediate III
In reaction bulb, under the conditions of anhydrous and oxygen-free, add 93g intermediate II and 600mL oxolane, stirring and dissolving, be cooled to-
20 DEG C, the tetrahydrofuran solution (42g/500mL) of dropping diisobutyl aluminium hydride, stirring reaction 30min, then heat to 0 DEG C
Reaction, TLC detects reaction；React complete, add 600mL saturated ammonium chloride solution and carry out cancellation, then remove tetrahydrochysene furan under reduced pressure
Muttering, add 600mL ethyl acetate, stand separatory, aqueous layer with ethyl acetate (300mL × 2) extracts, and merges organic facies, with saturated
Sodium chloride solution washing organic facies, then be dried with anhydrous sodium sulfate, sucking filtration, concentrating under reduced pressure, obtain oily intermediate, be subsequently adding
800mL methanol and 8g p-methyl benzenesulfonic acid, stir, and keeps room temperature reaction, and TLC monitors reaction；Reacting complete, reactant liquor is with full
Washing with sodium bicarbonate solution (300mL × 2), saturated nacl aqueous solution (300mL × 2) washs, and anhydrous sodium sulfate is dried, 40 DEG C
Following concentrating under reduced pressure, obtains solid crude product.This crude product, without purification, directly carries out next step reaction.
4. (2 ' R)-2 '-deoxidation-2 ' preparation of-fluoro-2 '-MU glycosides
Double (trimethyl is silica-based) acetamide of addition 116gN, O-in reaction bulb, 800mL 1,2-dichloroethanes, 3g ammonium sulfate, and
42g uracil, stirring, it is warming up to back flow reaction, TLC monitors reaction；React complete, be down to room temperature, be subsequently adding previous step anti-
Answer intermediate III, stirring, add 98g butter of tin, be warming up to 50 DEG C of reactions, TLC monitors reaction: reacts complete, is cooled to room
Temperature, adds 60g sodium bicarbonate and 80g kieselguhr, stirring, sucking filtration, and filter cake is pulled an oar with dichloromethane (300mL × 3), is associated with
Machine phase, washs with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and is evaporated to do, obtains intermediate.This intermediate is placed in
In 6 times amount diisopropyl ethers, stirring and dissolving, add 10g tetrabutylammonium iodide, be warming up to 55-60 DEG C, insulation reaction, TLC monitoring is anti-
Should.React complete, evaporated under reduced pressure solvent, obtain crude product.This crude product, with 5 times amount refining methanols, obtains 43g white solid product.Refined
Mother solution is stand-by.Yield: 71%.
5. αisomer reclaims
In reaction bulb, add refinement mother liquor and 3 times amount methanol, heat up, stirring and dissolving, after 1 hour, it is cooled to room temperature, has solid
Body separates out, and sucking filtration obtains 13g off-white color solid.Such white solid is placed in 150mL acetonitrile, stirring, adds 6g trifluoromethyl
Sulfonic acid trimethylsilyl group, is warming up to back flow reaction, and TLC monitors reaction: reacts complete, is cooled to room temperature, is evaporated to do, adds
Enter 2 times amount methanol making beating, sucking filtration, dry, obtain 8g white solid product.
Claims (8)
1. one kind (2 ' R)-2 '-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides, it is characterised in that: with 2-C-methyl D core
Saccharic acid-Isosorbide-5-Nitrae-lactone is initiation material, through silanization, fluoro, reduce, be etherified, dock, hydrolysis step prepare (2 ' R)-
2 '-deoxidation-2 '-fluoro-2 '-MU glycosides.
The preparation method of one the most according to claim 1 (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides, its feature
It is: specifically comprise the following steps that
A, the preparation of intermediate formula I
Under the conditions of anhydrous and oxygen-free, with 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone as raw material, under organic base catalytic, warp and hydroxyl
Base protective agent reacts under conditions of 15-20 DEG C, after completion of the reaction through distill, stand, wash, sucking filtration, concentration prepared
Crude product, crude product is through preparing intermediate formula I, described 2-C-methyl D ribonic acid-Isosorbide-5-Nitrae-lactone and hydroxyl protection with isopropanol is refined
The mol ratio of agent is 1:2～2.2；
B, the preparation of intermediate formula II
Alcoholic extract hydroxyl group, under base reagent effect, through reacting with fluoro reagent, is carried out fluorine replacement, described intermediate formula I by intermediate formula I
It is 1:1.05:2～1:1.8:2.5 with the mol ratio of fluoro reagent and base reagent；
C, the preparation of intermediate formula III
Under the conditions of anhydrous and oxygen-free, intermediate formula II is after carbonyl reduction is alcoholic extract hydroxyl group by strong reductant effect, through lewis acid
Catalysis is reacted with methanol and is obtained intermediate formula III crude product, it is not necessary to purification directly carries out next step reaction；Described intermediate formula II with
The mol ratio of strong reductant and methanol is 1:1.2:1.5～1:2.5:3；
D, (2 ' R)-2 '-deoxidation-2 ' preparation of-fluoro-2 '-MU glycosides
Uracil and silanes hydroxy-protecting agent react and prepare uracil derivative, intermediate formula III and described uracil derivative
Carrying out docking reaction under lewis acid catalyst effect, docking product is hydrolyzed instead under phase transfer catalyst effect
Target product should be obtained；
E, αisomer reclaim
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides αisomer occurs under trifluoromethyl sulfonic acid trimethylsilyl ester effect
Reaction, the configuration reversal of αisomer is (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides；
The structural formula of described intermediate formula I, intermediate formula II and intermediate formula III is as follows:
。
The preparation method of one the most according to claim 2 (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides, its feature
Being: in described a step, described hydroxy-protecting agent is 1, chloro-1,1,3, the 3-tetra isopropyl diformazan silica ether of 3-bis-, described organic
Alkali is DMAP, piperidines, DIPEA or triethylamine, reaction dissolvent used be oxolane, acetonitrile,
Toluene, diisopropyl ether or dimethyl sulfoxide.
The preparation method of one the most according to claim 2 (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides, its feature
Being: in described b step, described fluorination reagent is Fluohydric acid. triethylamine salt, Fluohydric acid. pyridiniujm or diethylin sulfur trifluoride,
Described base reagent is piperidines, triethylamine or pyridine；Reaction dissolvent used is oxolane, acetonitrile, isopropyl acetate or dichloromethane
Alkane.
The preparation method of one the most according to claim 2 (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides, its feature
Being: in described step c, described strong reductant is three tertiary butyoxy aluminum lithiums, double (2-methoxyethoxy) sodium aluminate of dihydro
Or diisobutyl aluminium hydride；Described lewis acid catalyst is boron trifluoride diethyl etherate or p-methyl benzenesulfonic acid, described reaction temperature is-
20-25 DEG C, reaction dissolvent used is dichloromethane, oxolane, ether, toluene or diisopropyl ether.
The preparation method of one the most according to claim 2 (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides, its feature
It is: during described d is rapid, described hydroxy-protecting agent is HMDS, N, double (trimethyl the is silica-based) acetamide of O-or front three
Base chlorosilane, described lewis acid catalyst is butter of tin or Trimethylsilyl trifluoromethanesulfonate；Described reaction temperature is-20
- 100℃；Described phase transfer catalyst is tetrabutyl ammonium fluoride, tetrabutyl ammonium bromide or tetrabutylammonium iodide；Reaction used is molten
Agent is dichloromethane, 1,2-dichloroethanes, acetonitrile, chlorobenzene, toluene, isopropyl acetate or diisopropyl ether.
7. the preparation method of '-deoxidation-2 '-fluoro-2 '-MU glycosides according to the one (2 ' R)-2 described in claim 2 or 6, its
Being characterised by: during described d is rapid, described intermediate formula III is 1:1.1～2.2 with the mol ratio of lewis acid catalyst.
The preparation method of one the most according to claim 2 (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides, its feature
It is: during described e is rapid, described reaction temperature is 25-100 DEG C；Reaction dissolvent used is acetonitrile, oxolane, toluene or chlorine
Benzene.
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| CN108440613A (en) * | 2018-03-26 | 2018-08-24 | 上海仁实医药科技有限公司 | The synthesis technology of one kind fluoro- 2`- methylurea glycosides of (2`R) -2`- deoxidations -2`- |
| CN111285876A (en) * | 2018-12-06 | 2020-06-16 | 重庆圣华曦药业股份有限公司 | Linagliptin intermediate isomer impurity, preparation method and application thereof |
| CN111892636A (en) * | 2020-08-07 | 2020-11-06 | 山东大学 | Synthesis method of azvudine |
| CN114940676A (en) * | 2022-07-06 | 2022-08-26 | 天津全和诚科技有限责任公司 | Synthesis method of pseudouridine |
| CN115745953A (en) * | 2022-06-29 | 2023-03-07 | 上海凌凯医药科技有限公司 | Hydroxyl fluorination reagent and hydroxyl fluorination method |
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| CN111285876A (en) * | 2018-12-06 | 2020-06-16 | 重庆圣华曦药业股份有限公司 | Linagliptin intermediate isomer impurity, preparation method and application thereof |
| CN111892636A (en) * | 2020-08-07 | 2020-11-06 | 山东大学 | Synthesis method of azvudine |
| CN115745953A (en) * | 2022-06-29 | 2023-03-07 | 上海凌凯医药科技有限公司 | Hydroxyl fluorination reagent and hydroxyl fluorination method |
| CN114940676A (en) * | 2022-07-06 | 2022-08-26 | 天津全和诚科技有限责任公司 | Synthesis method of pseudouridine |
| CN114940676B (en) * | 2022-07-06 | 2024-01-26 | 天津全和诚科技有限责任公司 | Synthesis method of pseudouridine |
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