CN105130989A - 2-fluoroadenine synthetic method - Google Patents
2-fluoroadenine synthetic method Download PDFInfo
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- CN105130989A CN105130989A CN201510620892.XA CN201510620892A CN105130989A CN 105130989 A CN105130989 A CN 105130989A CN 201510620892 A CN201510620892 A CN 201510620892A CN 105130989 A CN105130989 A CN 105130989A
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- fluoroadenine
- pyranyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
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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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- 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
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Abstract
The invention discloses a 2-fluoroadenine synthetic method. The 2-fluoroadenine synthetic method comprises the steps of taking cheap 6-chloropurine as a raw material, and carrying out tetrahydropyranyl protection on a 9-position NH; then enabling a product obtained in step one to react with trifluoromethanesulfonic anhydride, and introducing nitryl at 2-position; continuously enabling a product obtained in step two to react with NH4F, and removing tetrahydropyranyl while converting the nitryl into fluorine atoms; finally, converting the 6-position fluorine atom into amidogen in methanol solution which is saturated by ammonia gas, thus obtaining 2-fluoroadenine, wherein the total yield is 58 percent. According to the2-fluoroadenine synthetic method disclosed by the invention, the raw material is cheap and easy to obtain, a reagent which has expensive cost and is toxic and harmful is prevented from being used, risky and corrosive operating steps are prevented from being used, and the yield is not obviously reduced when the reaction scale is enlarged to be 200g; a new synthetic path is provided for synthesizing of the 2-fluoroadenine, and a potential application prospect is obtained.
Description
Technical field
The present invention relates to the synthetic method that medicine intermediate is new, be specifically related to a kind of 2-fluoroadenine synthetic method.
Background technology
2-fluoroadenine (1) is a kind of important medicine intermediate, and be widely used in the synthesis of anti-viral nucleoside medicine fludarabine, fludarabine phosphate, 2-fluorine adenosine and other nucleoside medicines, domestic and international demand is huge.Its traditional synthetic method is all take diazotization reaction as committed step.As taken 2,6-diaminopurine as raw material, obtained by fluoroboric acid diazotization reaction, yield is 0.7%-6.0% only.After descendant improves, with anhydrous hydrogen fluoride as fluorine source, yield brings up to 22%, but anhydrous hydrogen fluoride corrodibility is strong, operation inconvenience, the large [CalleyN.Eaton of environmental pollution, GeorgeH.DennyJr.Synthesisof2-fluoroadenine.J.Org.Chem., 1969,34 (3), 747 – 748].The report such as Chen Jianbing, from 2-amido-6-chloropurine, synthesizes 2 amino-6-nitrine purine, then at fluoroboric acid and NaNO by azido reaction
2there is schiemann reaction under effect, finally azido-reduction is obtained 2-fluoroadenine, yield 39% (Wang Jiangjie, Sun little Yan, Chen Jianbing. the novel method of synthesis 2-fluoroadenine. synthetic chemistry, 2007,15,506-507.).Diazotization reaction explosive, the sodiumazide used has severe toxicity, operation inconvenience, the synthesis step of 2,6-diaminopurine or 2-amido-6-chloropurine is many, and such as [Chen Wenhua. the synthesis of Famciclovir. chemical reagent, 2006,28 (28): 185-186.], cost is high, and these shortcomings limit the expansion of reaction scale.
Summary of the invention
In order to solve the deficiencies in the prior art, the invention provides a kind of 2-fluoroadenine synthetic method.
Technical scheme of the present invention is: a kind of 2-fluoroadenine synthetic method, is characterized in that, comprise the following steps, step 1: take 6-chloropurine as Material synthesis 6-chloro-9-pyranyl purine; Step 2: the 6-that step 1 obtains chloro-9-pyranyl purine and trifluoromethanesulfonic acid anhydride reactant, introduces nitro at 2 and obtains the chloro-2-nitro of 6--9-pyranyl purine; Step 3: by the chloro-2-nitro of the 6--9-pyranyl purine that obtains in step 2 and NH
4while nitro is converted into fluorine atom by F reaction, deprotection base; 6 chlorine atoms are converted into amino, obtain 2-fluoroadenine by step 4: the fluoro-6-chloropurine of the 2-finally step 3 obtained is ammonia solution in the methanol solution saturated by ammonia.
Further improvement of the present invention comprises:
Described protecting group is THP trtrahydropyranyl.
Step 2 specifically comprises: tetrabutyl ammonium nitrate (10.1g, 33mmol) be dissolved in 50mL anhydrous methylene chloride, be cooled to 0 DEG C, add trifluoromethanesulfanhydride anhydride (4.6mL, 33mmol), stir 20 minutes, add freshly prepd 6-chloro-9-pyranyl purine (3, 5.24g, 22mmol), remain on 0 DEG C, react 5 hours, add 100mL saturated sodium bicarbonate solution, stir, separate organic phase, aqueous phase methylene dichloride (20mL × 2) extracts, collect organic phase, dry, removal of solvent under reduced pressure, obtain pale yellow oil, be the chloro-2-nitro of 6--9-pyranyl purine (4).
Step 3 specifically comprises: the chloro-2-nitro of 6--9-pyranyl purine (, 4,5.6g, 20mmol) and NH
4f (1.1g, 30mmol) joins in DMF (50mL), stirring at room temperature, react 10 hours, activated carbon decolorizing, removal of solvent under reduced pressure, the thick substances water recrystallization obtained, obtains white powder, is the fluoro-6-chloropurine of 2-(5).
Step 4 specifically comprises: the fluoro-6-chloropurine (5 of 2-, 10g, 58mmol), join 100mL by the saturated methanol solution of ammonia, be heated to 50 DEG C of reactions 10 hours, cooling, activated carbon decolorizing, removal of solvent under reduced pressure, obtain oily matter, use water recrystallization, obtain white solid, be 2-fluoroadenine (1).
The present patent application for raw material, carries out THP trtrahydropyranyl protection to 9 NH with the 6-chloropurine of cheapness, then with trifluoromethanesulfonic acid anhydride reactant, introduces nitro at 2, and NH
4nitro is converted into fluorine atom by F reaction, removes THP trtrahydropyranyl simultaneously, finally in the methanol solution saturated by ammonia, 6 chlorine atoms is converted into amino, obtains 2-fluoroadenine, total recovery 58%.Present method cheaper starting materials is easy to get, and avoids use expensive and poisonous and hazardous reagent, avoid using dangerous and corrosive operation steps, and when reaction scale expands 200g scale to, yield is without obvious decline.The present patent application is that the synthesis of 2-fluoroadenine provides a new route of synthesis, has potential application prospect.Synthetic route is as follows:
。Wherein, the prior art of synthesis 6-chloro-9-pyranyl purine 3 is specially (PurineNucleosides.I.TheSynthesisofCertain6-Substituted-9-(tetrahydro-2-pyranyl)-purinesasModelsofPurineDeoxynucleosides [J] .RolandK.Robins, ErikF.Godefroi, EdwardC.Taylor, LelandR.Lewis, andAlvinJackson.J.Am.Chem.Soc., 1961,83 (11), 2574-2579.) synthetic method recorded in.
Embodiment
Below in conjunction with embodiment, the present invention is elaborated.
Embodiment 1
A kind of 2-fluoroadenine synthetic method, is characterized in that, comprise the following steps, step 1: take 6-chloropurine as Material synthesis 6-chloro-9-pyranyl purine; Step 2: the 6-that step 1 obtains chloro-9-pyranyl purine and trifluoromethanesulfonic acid anhydride reactant, introduces nitro at 2, obtains the chloro-2-nitro of 6--9-pyranyl purine; Step 3: by the chloro-2-nitro of the 6--9-pyranyl purine that obtains in step 2 and NH
4nitro is converted into fluorine atom by F reaction, simultaneously deprotection base; 6 chlorine atoms are converted into amino, obtain 2-fluoroadenine by step 4: the fluoro-6-chloropurine of the 2-finally step 3 obtained is ammonia solution in the methanol solution saturated by ammonia.
Embodiment 2
Key instrument and reagent
AC400 type nuclear magnetic resonance analyser (CDCl
3or DMSO-d
6for solvent, TMS is interior mark, Bruker company); Kofler micro melting point apparatus, thermometer is not calibrated; 6-chloropurine (Xinxiang Tuoxin Biochemical Co., Ltd.); Agents useful for same is analytical pure.Synthetic route is as follows:
Synthetic method
The synthesis of 6-chloro-9-pyranyl purine (3)
According to document synthesis, yield 96%, product fusing point,
1hNMR data conform to bibliographical information (PurineNucleosides.I.TheSynthesisofCertain6-Substituted-9-(tetrahydro-2-pyranyl)-purinesasModelsofPurineDeoxynucleosides.RolandK.Robins, ErikF.Godefroi, EdwardC.Taylor, LelandR.Lewis, andAlvinJackson.J.Am.Chem.Soc., 1961,83 (11), 2574-2579.).
The synthesis of the chloro-2-nitro of 6--9-pyranyl purine (4)
Tetrabutyl ammonium nitrate (10.1g, 33mmol) be dissolved in anhydrous methylene chloride (50mL), be cooled to 0 DEG C, add trifluoromethanesulfanhydride anhydride (4.6mL, 33mmol), stir 20 minutes, add freshly prepd 6-chloro-9-pyranyl purine (3, 5.24g, 22mmol), remain on 0 DEG C, react 5 hours, add saturated sodium bicarbonate (100mL) solution, stir, separate organic phase, aqueous phase methylene dichloride (20mL × 2) extracts, collect organic phase, dry, removal of solvent under reduced pressure, obtain pale yellow oil, be target product 4, yield 85%.
The synthesis of the fluoro-6-chloropurine of 2-(5)
The chloro-2-nitro of 6--9-pyranyl purine (4,5.6g, 20mmol) and NH
4f (1.1g, 30mmol) join N, in dinethylformamide (50mL), stirring at room temperature, reacts 10 hours, activated carbon decolorizing, removal of solvent under reduced pressure, the thick substances water recrystallization obtained, obtains white powder, be the fluoro-6-chloropurine of 2-(5), yield 83%.
2-fluoroadenine (1) synthesizes
The fluoro-6-chloropurine of 2-(5,10g, 58mmol), join by the saturated methanol solution (100mL) of ammonia, be heated to 50 DEG C of reactions 10 hours, cooling, activated carbon decolorizing, removal of solvent under reduced pressure, obtain oily matter, use water recrystallization, obtain white solid, be 2-fluoroadenine (1), yield 86%.
Described protecting group is THP trtrahydropyranyl.6-chloropurine polarity is comparatively large, and solubleness is limited in organic solvent, and 9 NH can affect nitration reaction simultaneously, so, 9 NH must be protected in denitrification step.Contriver examines multiple protecting group through lot of experiments, but all undesirable, and as benzyl is difficult to remove, ethanoyl not easily with 9 NH reaction, trimethyl silicon basedly easily takes off in nitration reaction process.Finally we filter out THP trtrahydropyranyl, and it both can increase its solubleness in organic solvent, can relatively easily slough again.In fluoro-reaction, due to the acidity of tetrabutyl ammonium fluoride, deprotection and fluoro can one pot complete, shorten reactions steps.
Reaction scale is on the impact of yield
The synthesis of 6-chloro-9-pyranyl purine (3) and the fluoro-6-chloropurine of 2-6 ammonia solutions relatively easily can realize the synthesis of feather weight in laboratory, technical difficulty is little.Committed step is the nitrated and fluoro-reaction of 6-chloro-9-pyranyl purine.Reaction scale that is nitrated and fluoro is examined or check, the results are shown in Table 1.
Table 1 differential responses scale is on the impact of yield
As shown in Table 1, reaction scale is extended to ten grams of levels to hectogram level, after the separating-purifying of routine, nitrated yield is reduced to 80%, and when reaction scale reaches 200g, the yield of fluoro step still can reach 83%, add the recycling to mother liquor, yield also can increase to some extent, so the applicability of whole piece route is very strong generally.
The present patent application for raw material, carries out THP trtrahydropyranyl protection to 9 NH with the 6-chloropurine of cheapness, then with trifluoromethanesulfonic acid anhydride reactant, introduces nitro at 2, and NH
4nitro is converted into fluorine atom by F reaction, removes THP trtrahydropyranyl simultaneously, finally in the methanol solution saturated by ammonia, 6 chlorine atoms is converted into amino, obtains 2-fluoroadenine, total recovery 58%.Present method cheaper starting materials is easy to get, and avoids use expensive and poisonous and hazardous reagent, avoid using dangerous and corrosive operation steps, and when reaction scale expands 200g scale to, yield is without obvious decline.The present patent application is that the synthesis of 2-fluoroadenine provides a new route of synthesis, has potential application prospect.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (5)
1. a 2-fluoroadenine synthetic method, is characterized in that, comprises the following steps,
Step 1: take 6-chloropurine as Material synthesis 6-chloro-9-pyranyl purine;
Step 2: the 6-that step 1 obtains chloro-9-pyranyl purine and trifluoromethanesulfonic acid anhydride reactant, introduces nitro at 2, obtains the chloro-2-nitro of 6--9-pyranyl purine;
Step 3: by the chloro-2-nitro of the 6--9-pyranyl purine that obtains in step 2 and NH
4f reacts, while nitro is converted into fluorine atom, and deprotection base;
6 chlorine atoms are converted into amino, obtain 2-fluoroadenine by step 4: the fluoro-6-chloropurine of the 2-finally step 3 obtained is ammonia solution in the methanol solution saturated by ammonia.
2. a kind of 2-fluoroadenine synthetic method according to claim 1, it is characterized in that, described protecting group is THP trtrahydropyranyl.
3. a kind of 2-fluoroadenine synthetic method according to claim 1, it is characterized in that, step 2 specifically comprises: tetrabutyl ammonium nitrate (10.1g, 33mmol) be dissolved in 50mL anhydrous methylene chloride, be cooled to 0 DEG C, add trifluoromethanesulfanhydride anhydride (4.6mL, 33mmol), stir 20 minutes minutes, add freshly prepd 6-chloro-9-pyranyl purine (5.24g, 22mmol), remain on 0 DEG C, react 5 hours, add 100mL saturated sodium bicarbonate solution, stir, separate organic phase, aqueous phase anhydrous methylene chloride extracting twice, collect organic phase, dry, removal of solvent under reduced pressure, obtain pale yellow oil, be the chloro-2-nitro of 6--9-pyranyl purine.
4. a kind of 2-fluoroadenine synthetic method according to claim 1, it is characterized in that, step 3 specifically comprises: with 6-chloro-2-nitro-9-pyranyl purine (5.6g, 20mmol) and NH
4f (1.1g, 30mmol) joins in DMF (50mL), stirring at room temperature, react 10 hours, activated carbon decolorizing, removal of solvent under reduced pressure, the thick substances water recrystallization obtained, obtains white powder, is the fluoro-6-chloropurine of 2-.
5. a kind of 2-fluoroadenine synthetic method according to claim 1, it is characterized in that, step 4 specifically comprises: the fluoro-6-chloropurine (10g of 2-, 58mmol), join in the saturated methanol solution saturated by ammonia of 100mL, be heated to 50 DEG C of reactions 10 hours, cooling, activated carbon decolorizing, removal of solvent under reduced pressure, obtains oily matter, uses water recrystallization, obtain white solid, be 2-fluoroadenine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180130073A (en) * | 2017-05-26 | 2018-12-06 | 에스티팜 주식회사 | The Method For Adenine Derivative |
| CN112661758A (en) * | 2020-12-29 | 2021-04-16 | 天津全和诚科技有限责任公司 | Preparation method of fludarabine antitumor drug intermediate |
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Non-Patent Citations (4)
| Title |
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| CALLEY N.EATON ET AL.: "Convenient Synthesis of 2-Fluoroadenine", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| JOHN A.MONTGOMERY ET AL.: "Synthesis of Potential Anticancer Agents.XX.2-Fluoropurines", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| ROLAND K.ROBINS ET AL.: "Purine Nucleosides.I.The Synthesis of Certain 6-Substituted-9-(tetrahydro-2-pyrany1)-purines as Models of Purine Deoxynucleosides", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| 汪江节等: "合成2-氟腺嘌呤的新方法", 《合成化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180130073A (en) * | 2017-05-26 | 2018-12-06 | 에스티팜 주식회사 | The Method For Adenine Derivative |
| KR101930908B1 (en) | 2017-05-26 | 2019-01-24 | 에스티팜 주식회사 | The Method For Adenine Derivative |
| CN112661758A (en) * | 2020-12-29 | 2021-04-16 | 天津全和诚科技有限责任公司 | Preparation method of fludarabine antitumor drug intermediate |
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