CN105130989B - A kind of 2 fluoroadenine synthetic methods - Google Patents
A kind of 2 fluoroadenine synthetic methods Download PDFInfo
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- CN105130989B CN105130989B CN201510620892.XA CN201510620892A CN105130989B CN 105130989 B CN105130989 B CN 105130989B CN 201510620892 A CN201510620892 A CN 201510620892A CN 105130989 B CN105130989 B CN 105130989B
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Abstract
The invention discloses a kind of 2 fluoroadenine synthetic method.Using 6 cheap chloropurines as raw material, THP trtrahydropyranyl protections are carried out to 9 NH, then with trifluoromethanesulfonic acid anhydride reactant, nitros are introduced at 2, then and NH4F reacts, while nitro is converted into fluorine atom, removes THP trtrahydropyranyl, finally in by the methanol solution of ammonia saturation, 6 chlorine atoms are converted into amino, 2 fluoroadenines, total recovery 58% are obtained.This method raw material is cheap and easy to get, it is to avoid use expensive and poisonous and hazardous reagent, it is to avoid the dangerous and corrosive operating procedure of use, and reaction scale is when being expanded to 200g scales, and yield is without being decreased obviously.The present patent application provides a new route of synthesis for the synthesis of 2 fluoroadenines, with potential application prospect.
Description
Technical field
The present invention relates to the new synthetic method of medicine intermediate, and in particular to a kind of 2- fluoroadenines synthetic method.
Background technology
2- fluoroadenines (1) are a kind of important medicine intermediates, be widely used in anti-viral nucleoside medicine fludarabine,
The synthesis of fludarabine phosphate, 2- fluorine adenosine and other nucleoside medicines, domestic and international demand is huge.Its traditional synthetic method
All it is using diazo-reaction as committed step.Such as obtained with 2,6- diaminopurines for raw material by fluoboric acid diazo-reaction,
Yield only 0.7%-6.0%.After descendant improves, with anhydrous hydrogen fluoride as Fluorine source, yield brings up to 22%, but anhydrous fluorination
Hydrogen-type corrosion is strong, operation inconvenience, big [Calley N.Eaton, the George H.Denny Jr.Synthesis of environmental pollution
of2-fluoroadenine.J.Org.Chem.,1969,34(3),747–748].The report such as Chen Jianbing is fast from 2- amino -6- chlorine
Purine sets out, and 2 amino -6- nitrine purine is synthesized by azido reaction, then in fluoboric acid and NaNO2The lower generation of effect is uncommon graceful anti-
Should, azido reduction is finally obtained into 2- fluoroadenines, (Wang Jiangjie, Sun little Yan, old to build soldier synthesis 2- fluorine glands fast for yield 39%
The new method synthesis chemistry of purine, 2007,15,506-507.).Diazo-reaction explosive, used sodium azide has play
The synthesis step of poison, operation inconvenience, 2,6- diaminopurines or 2- amido-6-chloropurines is more, such as [Chen Wenhua FCVs
Synthesis chemical reagent, 2006,28 (28):185-186.], cost is high, and these shortcomings limit the expansion of reaction scale.
The content of the invention
In order to solve the deficiencies in the prior art, the invention provides a kind of 2- fluoroadenines synthetic method.
The technical scheme is that：A kind of 2- fluoroadenines synthetic method, it is characterised in that comprise the following steps, step
Rapid 1：Using 6-chloropurine as the chloro- 9- pyranoses purine of Material synthesis 6-；Step 2：The chloro- 9- pyranoses purine of 6- that step 1 is obtained
With trifluoromethanesulfonic acid anhydride reactant, introduce nitro at 2 and obtain the chloro- 2- nitros -9- pyranose purine of 6-；Step 3：By in step 2
The obtained chloro- 2- nitros -9- pyranoses purine of 6- and NH4While nitro is converted into fluorine atom by F reactions, deprotection base；
Step 4：The fluoro- 6-chloropurines of 2- that finally step 3 is obtained ammonolysis in by the methanol solution of ammonia saturation, by 6 chlorine atoms
Amino is converted into, 2- fluoroadenines are obtained.
Further improvement of the present invention includes：
Described protection group is THP trtrahydropyranyl.
Step 2 is specifically included：Tetrabutyl ammonium nitrate (10.1g, 33mmol) is dissolved in 50mL anhydrous methylene chlorides, cooling
To 0 DEG C, trifluoromethanesulfanhydride anhydride (4.6mL, 33mmol) is added, is stirred 20 minutes, the freshly prepd chloro- 9- pyranoses purine of 6- is added
(3,5.24g, 22mmol), is maintained at 0 DEG C, reacts 5 hours, adds 100mL saturated sodium bicarbonate solutions, and stirring is separated organic
Phase, aqueous phase is extracted with dichloromethane (20mL × 2), collects organic phase, is dried, and removal of solvent under reduced pressure obtains pale yellow oil,
The chloro- 2- nitros -9- pyranoses purine (4) of as 6-.
Step 3 is specifically included：The chloro- 2- nitros -9- pyranoses purine of 6- (, 4,5.6g, 20mmol) and NH4F (1.1g,
30mmol) it is added in DMF (50mL), is stirred at room temperature, reacts 10 hours, activated carbon decolorizing is removed under reduced pressure
Solvent, obtained thick substances are recrystallized with water, obtain white powder, the fluoro- 6-chloropurines of as 2- (5).
Step 4 is specifically included：The fluoro- 6-chloropurines of 2- (5,10g, 58mmol), are added to 100mL by the methanol of ammonia saturation
In solution, it is heated to 50 DEG C and reacts 10 hours, cooling, activated carbon decolorizing, removal of solvent under reduced pressure obtains grease, tied again with water
Crystalline substance, obtains white solid, as 2- fluoroadenines (1).
Then and trifluoro the present patent application carries out THP trtrahydropyranyl protections using cheap 6-chloropurine as raw material to 9 NH,
Methanesulfonic acid acid anhydride is reacted, and nitro, and NH are introduced at 24Nitro is converted into fluorine atom by F reactions, while removing THP trtrahydropyranyl, most
Afterwards in by the methanol solution of ammonia saturation, 6 chlorine atoms are converted into amino, 2- fluoroadenines, total recovery 58% is obtained.This
Method raw material is cheap and easy to get, it is to avoid use expensive and poisonous and hazardous reagent, it is to avoid use dangerous and corrosive behaviour
Make step, and reaction scale is when being expanded to 200g scales, yield is without being decreased obviously.The present patent application is the synthesis of 2- fluoroadenines
There is provided a new route of synthesis, with potential application prospect.Synthetic route is as follows：
.Wherein, the prior art of the synthesis chloro- 9- pyranoses purine 3 of 6- is specially (Purine Nucleosides.I.The
Synthesis of Certain 6-Substituted-9-(tetrahydro-2-pyranyl)-purines as Models
of Purine Deoxynucleosides[J].Roland K.Robins,Erik F.Godefroi,Edward
C.Taylor,Leland R.Lewis,and Alvin Jackson.J.Am.Chem.Soc.,1961,83(11),2574-
2579.) synthetic method described in.
Embodiment
The present invention is elaborated with reference to embodiment.
Embodiment 1
A kind of 2- fluoroadenines synthetic method, it is characterised in that comprise the following steps, step 1：Using 6-chloropurine as raw material
Synthesize the chloro- 9- pyranoses purine of 6-；Step 2：The chloro- 9- pyranoses purine of 6- and trifluoromethanesulfonic acid anhydride reactant that step 1 is obtained,
2 introducing nitros, obtain the chloro- 2- nitros -9- pyranose purine of 6-；Step 3：By the chloro- 2- nitros -9- of the 6- obtained in step 2
Pyranose purine and NH4Nitro is converted into fluorine atom by F reactions, while deprotection base；Step 4：Finally step 3 is obtained
6 chlorine atoms are converted into amino by the fluoro- 6-chloropurines of 2- ammonolysis in by the methanol solution of ammonia saturation, obtain 2- fluorine glands fast
Purine.
Embodiment 2
Key instrument and reagent
Type NMR (the CDCl of AC 4003Or DMSO-d6For solvent, TMS is internal standard, Bruker companies)；Kofler shows
Micro- melting point detector, thermometer is not calibrated；6-chloropurine (Xinxiang Tuoxin Biochemical Co., Ltd.)；Agents useful for same is point
Analysis is pure.Synthetic route is as follows：
Synthetic method
The synthesis of the chloro- 9- pyranoses purine (3) of 6-
Synthesized according to document, yield 96%, product fusing point,1HNMR data are consistent (Purine with document report
Nucleosides.I.The Synthesis of Certain 6-Substituted-9-(tetrahydro-2-
pyranyl)-purines as Models of Purine Deoxynucleosides.Roland K.Robins,Erik
F.Godefroi,Edward C.Taylor,Leland R.Lewis,and Alvin Jackson.J.Am.Chem.Soc.,
1961,83(11),2574-2579.)。
The synthesis of the chloro- 2- nitros -9- pyranoses purine (4) of 6-
Tetrabutyl ammonium nitrate (10.1g, 33mmol) is dissolved in anhydrous methylene chloride (50mL), is cooled to 0 DEG C, adds three
Fluorine methanesulfonic acid acid anhydride (4.6mL, 33mmol), is stirred 20 minutes, the freshly prepd chloro- 9- pyranoses purine of 6- of addition (3,5.24g,
22mmol), 0 DEG C is maintained at, is reacted 5 hours, saturated sodium bicarbonate (100mL) solution is added, stirring separates organic phase, aqueous phase
Extracted with dichloromethane (20mL × 2), collect organic phase, dried, removal of solvent under reduced pressure obtains pale yellow oil, as mesh
Mark product 4, yield 85%.
The synthesis of the fluoro- 6-chloropurines of 2- (5)
The chloro- 2- nitros -9- pyranoses purine (4,5.6g, 20mmol) of 6- and NH4F (1.1g, 30mmol) is added to N, N-
In dimethylformamide (50mL), it is stirred at room temperature, reacts 10 hours, activated carbon decolorizing, removal of solvent under reduced pressure, obtained dope
Matter is recrystallized with water, obtains white powder, the fluoro- 6-chloropurines of as 2- (5), yield 83%.
2- fluoroadenines (1) are synthesized
The fluoro- 6-chloropurines of 2- (5,10g, 58mmol), are added in the methanol solution (100mL) by ammonia saturation, heating
Reacted 10 hours to 50 DEG C, cooling, activated carbon decolorizing, removal of solvent under reduced pressure obtains grease, recrystallized with water, obtains white
Solid, as 2- fluoroadenines (1), yield 86%.
Described protection group is THP trtrahydropyranyl.6-chloropurine polarity is larger, and solubility is limited in organic solvent, simultaneously
9 NH can influence nitration reaction, so, 9 NH must be protected in denitrification step.Inventor examines or check by lot of experiments
A variety of protection groups, but all undesirable, as benzyl is difficult to remove, acetyl group be difficult with 9 NH reactions, trimethyl silicon substrate is in nitre
Change and easily taken off in course of reaction.Finally we filter out THP trtrahydropyranyl, and it can both increase its in organic solvent molten
Xie Du, can relatively easily be sloughed again.In fluoro-reaction, due to the acidity of tetrabutyl ammonium fluoride, deprotection and fluoro can
With one pot of completion, reactions steps are shortened.
Influence of the reaction scale to yield
The synthesis of the chloro- 9- pyranoses purine (3) of 6- and 2- 6 ammonolysis of fluoro- 6-chloropurine can be relatively easy in laboratory
The synthesis of feather weight is realized on ground, and technical difficulty is little.Committed step is the nitrification and fluoro-reaction of the chloro- 9- pyranoses purine of 6-.
Reaction scale to nitrification and fluoro is examined or check, and the results are shown in Table 1.
Influence of the differential responses scale of table 1 to yield
As shown in Table 1, reaction scale is extended to ten grams of levels to hectogram level, after conventional separating-purifying, nitrification is received
Rate is reduced to 80%, when reaction scale reaches 200g, and the yield of fluoro step can still reach 83%, add and mother liquor is returned
Receive and utilize, yield can also increased, so, the application of generally whole piece route is very strong.
Then and trifluoro the present patent application carries out THP trtrahydropyranyl protections using cheap 6-chloropurine as raw material to 9 NH,
Methanesulfonic acid acid anhydride is reacted, and nitro, and NH are introduced at 24Nitro is converted into fluorine atom by F reactions, while removing THP trtrahydropyranyl, most
Afterwards in by the methanol solution of ammonia saturation, 6 chlorine atoms are converted into amino, 2- fluoroadenines, total recovery 58% is obtained.This
Method raw material is cheap and easy to get, it is to avoid use expensive and poisonous and hazardous reagent, it is to avoid use dangerous and corrosive behaviour
Make step, and reaction scale is when being expanded to 200g scales, yield is without being decreased obviously.The present patent application is the synthesis of 2- fluoroadenines
There is provided a new route of synthesis, with potential application prospect.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (1)
1. a kind of 2- fluoroadenines synthetic method, it is characterised in that comprise the following steps,
Step 1：Using 6-chloropurine as the chloro- 9- of Material synthesis 6- (oxinane -2- bases) purine；
Step 2：The chloro- 9- of 6- (oxinane -2- bases) purine and trifluoromethanesulfonic acid anhydride reactant that step 1 is obtained, nitre is introduced at 2
Base, obtains the chloro- 2- nitros -9- of 6- (oxinane -2- bases) purine：10.1g tetrabutyl ammonium nitrate is dissolved in 50mL anhydrous two
In chloromethanes, 0 DEG C is cooled to, 4.6mL trifluoromethanesulfanhydride anhydrides are added, stirred 20 minutes, the freshly prepd chloro- 9- of 5.24g 6- are added
(oxinane -2- bases) purine, is maintained at 0 DEG C, reacts 5 hours, adds 100mL saturated sodium bicarbonate solutions, and stirring has been separated
Machine phase, aqueous phase is extracted twice with anhydrous methylene chloride, collects organic phase, is dried, and removal of solvent under reduced pressure obtains faint yellow oily
The chloro- 2- nitros -9- of thing, as 6- (oxinane -2- bases) purine；
Step 3：By the chloro- 2- nitros -9- of the 6- obtained in step 2 (oxinane -2- bases) purine and NH4F is reacted, and nitro is turned
While turning to fluorine atom, oxinane -2- bases are removed：With the chloro- 2- nitros -9- of 5.6g 6- (oxinane -2- bases) purine and
1.1g NH4F is added in 50mL DMFs, is stirred at room temperature, and is reacted 10 hours, activated carbon decolorizing, decompression is removed
Solvent is removed, obtained thick substances are recrystallized with water, obtain white powder, the fluoro- 6-chloropurines of as 2-；
Step 4：The fluoro- 6-chloropurines of 2- that finally step 3 is obtained ammonolysis in by the methanol solution of ammonia saturation, by 6 chlorine
Atom is converted into amino, obtains 2- fluoroadenines：It is molten by the methanol of ammonia saturation that the fluoro- 6-chloropurines of 10g 2- are added to 100mL
In liquid, it is heated to 50 DEG C and reacts 10 hours, cooling, activated carbon decolorizing, removal of solvent under reduced pressure obtains grease, recrystallized with water,
Obtain white solid, as 2- fluoroadenines.
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Non-Patent Citations (4)
| Title |
|---|
| Convenient Synthesis of 2-Fluoroadenine;CALLEY N.EATON et al.;《The Journal of Organic Chemistry》;19690331;第34卷(第3期);747-748 * |
| Purine Nucleosides.I.The Synthesis of Certain 6-Substituted-9-(tetrahydro-2-pyrany1)-purines as Models of Purine Deoxynucleosides;ROLAND K.ROBINS et al.;《Journal of the American Chemical Society》;19610605;第83卷;2574-2579 * |
| Synthesis of Potential Anticancer Agents.XX.2-Fluoropurines;JOHN A.MONTGOMERY et al.;《Journal of the American Chemical Society》;19600120;第82卷;463-468 * |
| 合成2-氟腺嘌呤的新方法;汪江节等;《合成化学》;20071231;第15卷(第4期);506-507 * |
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