CN105418710B - A kind of method using inosine as Material synthesis 2,6- dichloropurine nucleosides - Google Patents
A kind of method using inosine as Material synthesis 2,6- dichloropurine nucleosides Download PDFInfo
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- CN105418710B CN105418710B CN201510953581.5A CN201510953581A CN105418710B CN 105418710 B CN105418710 B CN 105418710B CN 201510953581 A CN201510953581 A CN 201510953581A CN 105418710 B CN105418710 B CN 105418710B
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- 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
- C07H19/16—Purine radicals
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a kind of method using inosine as 2,6 dichloropurine nucleosides of Material synthesis.The present invention is using cheap inosine as raw material; pass through acetylation and chlorination; obtain 6 chlorine triacetyl purine nucleosides; then with trifluoromethanesulfonic acid anhydride reactant, nitro is introduced at 2, finally in the ethanol solution for being chlorinated hydrogen saturation; removing acetyl group and nitroxyl chloride are completed for two-step reaction; obtain 2,6 dichloropurine nucleosides, total recovery 63%.This method raw material is cheap and easy to get, avoids using expensive reagent and poisonous and hazardous heavy metal catalyst, and when reaction scale is expanded to 200g scales, and yield is without being decreased obviously.The present invention provides a new route of synthesis for the synthesis of 2,6 dichloropurine nucleosides, has potential application prospect.
Description
Technical field
The present invention relates to the synthetic method of 2,6-dichloropurine riboside, and in particular to one kind is using inosine as Material synthesis 2,6-
The method of dichloropurine nucleosides.
Background technology
2,6-dichloropurine riboside has significant antitumor and antiviral drugs active, is especially drawn to treating by mycoplasma
The infection tool risen has a better effect.Meanwhile it or a kind of widely used medicine intermediate, a series of have for synthesizing
The nucleosides material of good pharmacological activity, such as cancer therapy drug 2- chlorine adenosine, adenosine A 3 receptor agonists.Therefore 2,6- dichloropurines
The synthesis of nucleosides has great importance.
At present, the synthetic method of the 2,6-dichloropurine riboside of document report mainly has：1st, condensation method.Such as Schaefe
Deng[4]It is condensed with the mercury salt and chloro- 2,3,5- tri-benzoyl ribose of 1- of 2,6- dichloropurines, obtained intermediate is deprotected
To 2,6- dichloropurine nucleosides.Shen bright red etc. is in SnCl4Under catalysis, 2,6- dichloropurines and 1,2,3,5-Tetra-O-Acetyl-D-Ribose condensation, obtain
Intermediate removing acetyl group obtains 2,6- dichloropurines nucleosides (Shen bright red, Liu Qibin, Li Shujun, canal osmanthus honor .2,6- dichloropurines
The synthesising process research fine-chemical intermediates of nucleosides, 2007,37:35-37.).The shortcomings that these methods is：(1) 2,6- bis-
The higher price of chloropurine, preparation process are more；(2) heavy metal catalyst mercury salt or SnCl4Toxicity is big, easily residual, environmental pollution
Greatly.2nd, semi-synthesis method.This method uses existing nucleoside compound, and target product is obtained by functional group conversions.Use
Nucleoside compound has 2- amido-6-chloropurines nucleosides and 2- chloro -6- hydroxyls -2,3,5- triacetyls-purine nucleosides.The former needs
The diazotation step of explosive is used, the latter's synthesis step is more, higher price.
So method cost of material for the synthesis 2,6-dichloropurine riboside (about 20000 yuan/Kg of market price) reported
High, synthesis technique complexity, limits production-scale expansion.
The content of the invention
In order to solve the deficiencies in the prior art, the present invention for raw material, is passed through with cheap inosine (100 yuan/Kg of market price)
Simple chemical conversion, target product is obtained with 4 steps and 63% total recovery.
The technical scheme is that：A kind of method using inosine as Material synthesis 2,6-dichloropurine riboside, its feature
It is, using cheap inosine as raw material, 6- chlorine triacetyl purine nucleosides is made；Then nitration reaction is carried out, nitro is introduced at 2
Obtain 2- nitro -6- chlorine triacetyl purine nucleosides；Finally in the ethanol solution for being chlorinated hydrogen saturation, removing acetyl is completed
Base and nitroxyl chloride obtain 2,6-dichloropurine riboside for two-step reaction.
Further improvement of the present invention includes：
The synthesis step of 2- nitro -6- chlorine triacetyl purine nucleosides includes：Tetrabutyl ammonium nitrate is dissolved in anhydrous dichloromethane
In alkane, 0 DEG C is cooled to, adds trifluoromethanesulfanhydride anhydride, is stirred 20 minutes, 6- chlorine triacetyl purine nucleosides is added, is maintained at 0 DEG C,
React 5 it is small when, add saturated sodium bicarbonate solution, stirring, separate organic phase, water is mutually extracted twice with dichloromethane, and collection has
Machine phase, it is dry, solvent is removed under reduced pressure, obtains pale yellow oil, to obtain the final product.
The synthesis step of 2- nitro -6- chlorine triacetyl purine nucleosides includes：Tetrabutyl ammonium nitrate (10.1g, 33.0mmol)
It is dissolved in 50mL anhydrous methylene chlorides, is cooled to 0 DEG C, add trifluoromethanesulfanhydride anhydride (4.6mL, 33.0mmol), stirs 20 points
Clock, adds 6- chlorine triacetyl purine nucleosides (9.1g, 22mmol), is maintained at 0 DEG C, when reaction 5 is small, adds 100mL unsaturated carbonates
Hydrogen sodium solution, stirring, separates organic phase, and water is mutually extracted twice with 20mL dichloromethane, collects organic phase, dry, is removed under reduced pressure
Solvent, obtains pale yellow oil, to obtain the final product.
The synthesis step of 2,6- dichloropurine nucleosides includes：2- nitro -6- chlorine triacetyl purine nucleosides is added to saturation
It is chlorinated in the ethanol solution of hydrogen saturation, is stirred at room temperature, when reaction 10 is small, solvent is removed under reduced pressure, obtained thick substances
Recrystallized with absolute ethyl alcohol, that is, obtain 2,6-dichloropurine riboside.
The synthesis step of 2,6- dichloropurine nucleosides includes：2- nitro -6- chlorine triacetyl purine nucleosides (4.6g, 10mmol)
Being chlorinated in the ethanol solution of hydrogen saturation for 20mL saturations is added to, is stirred at room temperature, when reaction 10 is small, is removed under reduced pressure molten
Agent, obtained thick substances are recrystallized with absolute ethyl alcohol, that is, obtain 2,6-dichloropurine riboside.
The nitration reaction is the NO that is formed after trifluoromethanesulfanhydride anhydride and the reaction of tetrabutyl ammonium nitrate2 +。
The nitration reaction is the NO that is formed after trifluoromethanesulfanhydride anhydride and the reaction of tetramethyl ammonium nitrate2 +。
This method raw material is easy to get, and simple process, total recovery is higher, and cost is low, easily amplification, avoids using expensive
Reagent and poisonous and hazardous heavy metal catalyst, and when reaction scale is expanded to 200g scales, yield is without being decreased obviously.The present invention
A new route of synthesis is provided for the synthesis of 2,6-dichloropurine riboside, there is potential application prospect, is scale metaplasia
Production is laid a good foundation.Synthetic route is as follows：
Embodiment
Elaborate with reference to embodiment to the present invention.
Embodiment 1
A kind of method using inosine as Material synthesis 2,6-dichloropurine riboside, it is characterised in that using cheap inosine as
Raw material, is made 6- chlorine triacetyl purine nucleosides；Then nitration reaction is carried out, introducing nitro at 2 obtains three second of 2- nitro -6- chlorine
Acyl purine nucleosides；Finally in the ethanol solution for being chlorinated hydrogen saturation, complete removing acetyl group and nitroxyl chloride two steps of generation are anti-
Should, obtain 2,6-dichloropurine riboside.
Embodiment 2
Synthetic route of the present invention is as follows：
Wherein
The synthesis of 6- chlorine triacetyl purine nucleosides (3)
According to document (Zhou Le, Shi Yuangang, king build the chloro- 9- β-D-RIBOSE purine of occasion .6- synthesis chemistry circular,
1996,5:31-32.) synthesize, product1HNMR data are consistent with document report.
The synthesis of 2- nitro -6- chlorine triacetyl purine nucleosides (4)
Tetrabutyl ammonium nitrate (10.1g, 33.0mmol) is dissolved in anhydrous methylene chloride (50mL), is cooled to 0 DEG C, is added
Trifluoroacetic anhydride (4.6mL, 33.0mmol), stir 20 minutes, add freshly prepd 6- chlorine triacetyl purine nucleosides (3,9.1g,
22mmol), 0 DEG C, when reaction 5 is small is maintained at, adds saturated sodium bicarbonate solution (100mL), stirring, separates organic phase, water phase
It is extracted twice with anhydrous methylene chloride (20mL), collects organic phase, it is dry, solvent is removed under reduced pressure, obtains pale yellow oil, i.e.,
For target product 4, yield 81%.
The synthesis of 2,6- dichloropurines nucleosides (1)
What 2- nitro -6- chlorine triacetyl purine nucleosides (4,4.6g, 10mmol) was added to saturation is chlorinated hydrogen saturation
Ethanol solution (20mL) in, be stirred at room temperature, reaction 10 it is small when, solvent is removed under reduced pressure, obtained thick substances absolute ethyl alcohol
Recrystallization, that is, obtain 2,6-dichloropurine riboside, yield 82%.
Nitro source
Inosine synthesis 6- chlorine triacetyl purine nucleosides document report of the present invention is more, and method is ripe.Committed step is purine
The function dough of 2, ring.The method that the present invention takes is nitrification.The source of nitro is trifluoromethanesulfanhydride anhydride and tetrabutyl ammonium nitrate
The NO formed after reaction2 +, its detailed process see document (P.F.Deghati, M.J.Wanner and G.-J.Koomen,
Tetrahedron Lett.2000,41:1291-1295.)。
The present invention examines influence of the different nitrate for yield by a large number of experiments, as a result such as table 1.
Influence of the different nitrate of table 1 to yield
As shown in Table 1, tetramethyl ammonium nitrate and ammonium nitrate can obtain product, but yield is reduced to 65% and 32%.Nothing
Machine salt sodium nitrate cannot obtain product.Tetrabutyl ammonium nitrate yield highest.Reason is tetrabutyl ammonium nitrate solubility in a solvent
Preferably, it can effectively promote NO2 +Generation.
Chlorine atom source is examined or check
According to the prior art, chlorine is converted into 2 nitros, can be using ethanol as solvent, with NH4Cl reacts at room temperature to obtain.
In NH4In Cl- ethanol systems, the acetyl group in saccharide ring is unaffected, obtains 2,6- dichloropurine triacetyl purine nucleosides (5),
Also need to remove acetyl group in acid condition, obtain target product.Which adds reactions steps.And it is chlorinated hydrogen
The Alcohol system of saturation be once used for remove acetyl group, and chlorion therein then can and nitroso reaction, one pot completion
Two steps chemically react, and obtain target product 1.Reaction scheme below figure：
Influence of the reaction scale to yield
Reaction scale in nitrification and chloro step is examined or check, the results are shown in Table 2.
Influence of the 2 differential responses scale of table to yield
As shown in Table 2, reaction scale is extended to ten grams of levels to hectogram level, after conventional separating-purifying, nitrification and
The yield of chloro step without reduction, can once obtain the 2,6-dichloropurine riboside more than 100g.Due to experimental facilities
Limitation, is not expanded further.Because inosine synthesis 6- chlorine triacetyl purine nucleosides is highly developed, whole
The application of route is very strong.
The present invention using cheap inosine as raw material, by simply reacting, obtain 6- chlorine triacetyl purine nucleosides, then and
Trifluoromethanesulfonic acid anhydride reactant, nitro is introduced at 2, finally in the ethanol solution for being chlorinated hydrogen saturation, completes removing second
Acyl group and nitroxyl chloride obtain 2,6-dichloropurine riboside, total recovery 63% for two-step reaction.This method raw material is cheap and easy to get, keeps away
Exempt to use expensive reagent and poisonous and hazardous heavy metal catalyst, and when reaction scale is expanded to 200g scales, yield
Nothing is decreased obviously.The present invention provides a new route of synthesis for the synthesis of 2,6-dichloropurine riboside, potentially should have
Use prospect.
The basic principles, main features and the advantages of the invention have 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 above embodiments and description only describe this
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 (7)
- A kind of 1. method using inosine as Material synthesis 2,6-dichloropurine riboside, it is characterised in that using inosine as raw material, be made 6- chlorine triacetyl purine nucleosides；Then nitration reaction is carried out, introducing nitro at 2 obtains 2- nitro -6- chlorine triacetyl purine cores Glycosides；Finally in the ethanol solution for being chlorinated hydrogen saturation, removing acetyl group and nitroxyl chloride are completed for two-step reaction, obtains 2, 6- dichloropurine nucleosides.
- 2. a kind of method using inosine as Material synthesis 2,6-dichloropurine riboside according to claim 1, its feature exist In the synthesis step of 2- nitro -6- chlorine triacetyl purine nucleosides includes：Tetrabutyl ammonium nitrate is dissolved in anhydrous methylene chloride, 0 DEG C is cooled to, adds trifluoromethanesulfanhydride anhydride, is stirred 20 minutes, adds 6- chlorine triacetyl purine nucleosides, is maintained at 0 DEG C, reaction 5 Hour, saturated sodium bicarbonate solution is added, stirring, separates organic phase, and water is mutually extracted twice with dichloromethane, collects organic phase, It is dry, solvent is removed under reduced pressure, obtains pale yellow oil, up to intermediate 2- nitro -6- chlorine triacetyl purine nucleosides.
- 3. a kind of method using inosine as Material synthesis 2,6-dichloropurine riboside according to claim 2, its feature exist In the synthesis step of 2- nitro -6- chlorine triacetyl purine nucleosides includes：Tetrabutyl ammonium nitrate (10.1g, 33.0mmol) is dissolved in In 50mL anhydrous methylene chlorides, 0 DEG C is cooled to, adds trifluoromethanesulfanhydride anhydride (4.6mL, 33.0mmol), is stirred 20 minutes, is added 6- chlorine triacetyl purine nucleosides (9.1g, 22mmol), is maintained at 0 DEG C, when reaction 5 is small, it is molten to add 100mL saturated sodium bicarbonates Liquid, stirring, separates organic phase, and water is mutually extracted twice with 20mL dichloromethane, collects organic phase, dry, and solvent is removed under reduced pressure, obtains To pale yellow oil, up to intermediate 2- nitro -6- chlorine triacetyl purine nucleosides.
- 4. a kind of method using inosine as Material synthesis 2,6-dichloropurine riboside according to claim 1, its feature exist In the synthesis step of 2,6-dichloropurine riboside includes：2- nitro -6- chlorine triacetyl purine nucleosides is added to being chlorinated for saturation In the ethanol solution of hydrogen saturation, it is stirred at room temperature, when reaction 10 is small, solvent is removed under reduced pressure, obtained thick substances is with anhydrous Ethyl alcohol recrystallization, that is, obtain 2,6-dichloropurine riboside.
- 5. a kind of method using inosine as Material synthesis 2,6-dichloropurine riboside according to claim 4, its feature exist In the synthesis step of 2,6-dichloropurine riboside includes：2- nitro -6- chlorine triacetyl purine nucleosides (4.6g, 10mmol) adds To being chlorinated in the ethanol solution of hydrogen saturation for 20mL saturations, it is stirred at room temperature, when reaction 10 is small, solvent is removed under reduced pressure, obtains To thick substances recrystallized with absolute ethyl alcohol, that is, obtain 2,6-dichloropurine riboside.
- 6. a kind of method using inosine as Material synthesis 2,6-dichloropurine riboside according to claim 1, its feature exist In the source of nitro is the NO that is formed after trifluoromethanesulfanhydride anhydride and the reaction of tetrabutyl ammonium nitrate in the nitration reaction2 +。
- 7. a kind of method using inosine as Material synthesis 2,6-dichloropurine riboside according to claim 1, its feature exist In the source of nitro is the NO that is formed after trifluoromethanesulfanhydride anhydride and the reaction of tetramethyl ammonium nitrate in the nitration reaction2 +。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012260A (en) * | 2007-01-31 | 2007-08-08 | 河南师范大学 | Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method |
| CN105085595A (en) * | 2015-09-15 | 2015-11-25 | 安阳工学院 | Method for synthesizing 2,6-hologenated purine nucleoside by deacylation protection |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012260A (en) * | 2007-01-31 | 2007-08-08 | 河南师范大学 | Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method |
| CN105085595A (en) * | 2015-09-15 | 2015-11-25 | 安阳工学院 | Method for synthesizing 2,6-hologenated purine nucleoside by deacylation protection |
Non-Patent Citations (2)
| Title |
|---|
| 《2-氯腺苷的合成路线研究》;申艳红;《精细与专用化学品》;20070621;第15卷(第12期);全文 * |
| 《无金属催化合成2，6-二氯嘌呤核苷和2-氯腺苷》;夏然;《应用化学》;20151210;第32卷(第12期);全文 * |
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