CN105884846B - A kind of synthetic method of 2'-deoxyadenosine - Google Patents
A kind of synthetic method of 2'-deoxyadenosine Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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Abstract
The invention discloses a kind of synthetic methods of 2 ' desoxyadenossines, and by adenosine through esterification, the acylation of acylating agent and acid binding agent obtains acylate；Gained acylate obtains 2 ' desoxyadenossines using reduction and purification process；Wherein, the esterifying agent used in esterification process is dialkyltin.The reaction selectivity of the method for the present invention is high, be not necessarily to chromatographic isolation, at low cost, yield is high, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis and intermediate preparing technical fields, and in particular to a kind of synthesis of 2'-deoxyadenosine
Method.
Background technology
2'-deoxyadenosine is also 2 '-deoxyadenine ribonucleotide, and (2 '-deoxyadenosine, also referred to as β-D-2 '-are de-
Oxygen adenosine), it is a kind of natural dezyribonucleoside, is the structure fragment of DNA DNA, with other natural nucleus glycoside
The transmission of the same hereditary information for almost participating in all biological cells, affects the synthesis of protein and the metabolism of polysaccharide, and
There is highly important regulating and controlling effect to the growth of organism inner cell, proliferation, differentiation and inhibition etc..Its not still genomic medicine
With the important raw and processed materials of genetic engineering research, and it also itself have good physiological activity, 2'-deoxyadenosine can inhibit by
The insulin releasing of sugar induction, and specific Pimobendane or adenosine cyclase activator promotion pancreas can be reduced
The effect of island element secretion.In addition, 2'-deoxyadenosine is alternatively arranged as antiviral, anticancer, the important intermediate of anti-AIDS drug,
For example, 2 '-fluoro- 2'-deoxyadenosines, Cladribine (2 '-chloro- 2'-deoxyadenosine) have excellent antitumous effect, double deoxidation
Adenosine (ddA) has inhibiting effect pole of the higher active, acyclovir to HSV-1 and HSV-2 viruses to HIV and HBV viruses
By force.These are prodigious important drugs of dosage in the world.
Since 2'-deoxyadenosine has a very wide range of applications in biotechnology and pharmaceutical field, people increasingly recognize
To nucleoside compound importance, therefore the demand of nucleosides material is also increasingly increased.Most products come from DNA degradation, but
Limited natural resources can be increasingly confined to by being the method for this traditional mode of production deoxyribonucleoside substance, and separation and Extraction is pure
Product are difficult, and it is still main stream approach that chemical synthesis at present, which prepares 2'-deoxyadenosine,.
Such as, 1, Morris J.Robins et al. use fusion method, utilize the catalytic action heat condensation system of acidic catalyst
Standby a variety of nucleoside compounds (J Am Soc Chem.1964,86,125), with 1,3, the 5- triacetyl -2- deoxidations of chloroethene acid catalysis
Ribose and 6-chloropurine are condensed into glycosides in a heated condition, then react deacetylate with ammonia methanol and obtained 2 '-deoxidation glands
Glycosides.The synthetic line square formula 1：
Equation 1
This method is easy to operate, but glycosylated stereoselectivity is poor, and obtained 2'-deoxyadenosine product is α, β-core
The mixture of glycosides, while the regioselectivity of the reaction is not high, therefore obtained synthetic product is complicated, even if using column chromatography for separation
It also is difficult to obtain the product of single configuration, causes the difficulty isolated and purified.
2, Robert.K.Ness et al. uses the new method synthesis 2'-deoxyadenosine of base heavy metallic salt, chloro- with 1-
3,5- bis- (p-nitrophenyl formoxyl) -2-deoxyribosyls and the condensation of 6- benzamide purine mercury chloride, then in barium methoxide-methanol
Solution in deprotection obtain 2'-deoxyadenosine (J Am Chem Soc.1960,82,3434).The synthetic line square formula 2
(the R=p-nitrophenyls formoxyl in equation 2)：
Equation 2
The disadvantages of this method is that its raw material is rare, and reaction process has used mercury salt, and toxicity is big, and difficult during purifying
To remove remaining mercury salt, this method is rarely needed at present.
3, Zygmunt kazimierczuk et al. with 6-chloropurine and sodium hydride reaction generate sodium salt, then with 1- chloro- 3,
After the condensation of 5- bis- (p-nitrophenyl formoxyl) -2-deoxyribosyl, 2'-deoxyadenosine (J Am Chem are obtained through ammonolysis
Soc.1984,106 (21), 6379).The synthetic line square formula 3 (the R=p-nitrophenyls formoxyl in equation 3)：
Equation 3
The disadvantages of this method is that raw material is rare, operating difficulties, and sodium hydride has been used in reaction process, causes reaction not easily-controllable
System, and yield is low (first step reaction only 32%, overall yield of reaction 27.2%), is not easy to realize industrialized production.
To sum up, there are many methods of existing synthesis 2'-deoxyadenosine, but the cost having in big multi-method is too high, some originals
Expect rare and toxic, some yields are low, some operating difficulties, inevitable column chromatography the shortcomings of, therefore can not all apply
In large batch of industrial production.
Invention content
The object of the present invention is to provide a kind of reaction selectivity height, high income, at low cost, and are relatively suitable for industrialized production
2'-deoxyadenosine synthetic method.
A kind of synthetic method of 2'-deoxyadenosine, by adenosine through esterification, the acylation of acylating agent and acid binding agent obtains
Acylate；Gained acylate obtains 2'-deoxyadenosine using reduction and purification process；Wherein, the ester used in esterification process
Agent is dialkyltin.
Using adenosine, as starting material, 2 '-deoxidation glands are made through over-churning, acylation, reduction process (step) in the present invention
Glycosides；Wherein, esterification process can effectively improve the selectivity of purpose product, improve it using dialkyltin as esterifying agent
Yield and purity, in addition, each step intermediate of route of the present invention be not necessarily to purification process, purpose product (2'-deoxyadenosine) also without
Chromatography separating method need to be used to purify, it is easy to operate, it can effectively reduce cost, be suitble to industry's enlarging production.
The improvement of present invention method more described above, mainly in former method reaction selectivity difference and operation
The problems such as complicated, such as the acylation reaction in the present invention, no matter to the inventory of acylating agent (such as toluene sulfochloride) how much, only
2 ' position hydroxyls of adenosine are acylated and are acylated without the hydroxyl to 3 ' or 5 ' positions, then again to the acyl ester bond (example of 2 ' positions
Such as p-methyl benzenesulfonic acid ester group) it is restored, to solve the problems, such as that reaction selectivity is poor.In addition, to the whole of 2 '-desoxyadenossines
A building-up process post-processing is not cumbersome, is not necessarily to pillar layer separation, simplifies the operation entirely synthesized.
The synthetic line square formula 4 of the present invention：
Equation 4
Adenosine ((I) of structural formula square formula 4), esterifying agent ((a) of structural formula square formula 4) and solvent are mixed,
Temperature reaction obtains carboxylate ((b) of structural formula square formula 4).
Preferably, the alkyl of dialkyltin is selected from the alkyl of C1-6.
The molecular formula of the dialkyltin is R1R2SnO, wherein R1And R2It is independently selected from the alkyl of C1-6.R1And R2
Identical alkyl is can be selected from, also selected from different alkyl.
Further preferably, esterifying agent be dimethyl tin oxide, di-nbutyltin oxide, in di-n-octyl tin oxide at least
It is a kind of.
In esterification reaction process, esterifying agent adds mole slightly than adenosine excess, preferably, adenosine and esterifying agent
Molar ratio is 1: 1.1~1.2.
Esterification reaction temperature has influence to esterification,
Esterification reaction temperature is 60~80 DEG C.
Preferably, esterification reaction temperature is 75~80 DEG C.
Preferably, the solvent of esterification is methanol or dichloromethane.The preferred solvent and reaction temperature next time
Stream reaction, it is possible to increase the solubility of reactant in a solvent, the progress more conducively reacted.
Esterification is carried out under the material, temperature and solvent, reaction time of esterification is preferably 2-3h.
After esterification, without further concentration, purification of intermediate processing, directly by the esterification reaction solution into
Acylate ((c) of structural formula square formula 4 is made in row acylation reaction.In structural formula (c) ,-O-X refers to acylating agent and 2 '-hydroxyls
The acyl ester that acylation reaction is formed is strong.
Contain carboxylate in esterification reaction solution, which carries out acylation reaction with acylating agent under acid binding agent catalysis.
Preferably, acylating agent is acyl chlorides, acylbromide or acid anhydrides.Structural formula is, for example, X-Cl；X-Br；X-O-X.It is further excellent
Choosing, acylating agent is acyl chlorides.Acylating agent is sulfonic acid chloride.
More preferably, acylating agent is paratoluensulfonyl chloride.
Preferably, the mole that feeds intake of acylating agent is 2-3 times of the adenosine added.
The present invention is using organic base as acid binding agent.
Preferably, acid binding agent is fat or aromatic amine.
Further preferably, acid binding agent is fat or fragrant tertiary amine.
Most preferably, the acid binding agent is triethylamine or pyridine.
Preferably, the mole that feeds intake of the acid binding agent is 2-3 times of the adenosine added.
Acylation reaction is stirred to react in room temperature or less than room temperature at a temperature of, such as to carry out the acylation at room temperature anti-
It answers, reaction time 3-5h；After acylation reaction, it is stored at room temperature a period of time (such as 1h), is then separated by solid-liquid separation.Gu
Liquid isolation technics uses existing conventional techniques, such as filtering, centrifugation.After separation of solid and liquid, is washed with solvent and be separated by solid-liquid separation collection
Solid portion, the solvent are preferably acylation reaction solvent, that is to say solvent used by esterification.After the completion of washing, solid
Part precipitation drying, is made acylate.
Reducing agent is added after acylate is dissolved and carries out reduction reaction under inert gas shielding atmosphere, to remove acylate
In 2 ' positions on acyl ester group (in structural formula c ,-the O-X of 2 ' positions).
Preferably, reduction reaction carries out in dimethyl sulfoxide (DMSO), tetrahydrofuran or n,N-Dimethylformamide.This is preferably
Reduction reaction solvent need to use anhydrous solvent.
Preferably, the reducing agent is hydride-ion-transfer reducing agent.
The present invention is using the compound of 1-3 hydrogen in the alkyl of lithium borohydride or C1-5 substitution lithium borohydride as catalysis
Agent.
The reducing agent molecular formula is R3R4R5HB-LI+；Wherein, R3、R4、R5It is independently selected from the alkyl of H, C1-5.
The structural formula of the reducing agent is
Still more preferably, the reducing agent is lithium borohydride, lithium triethylborohydride or 3-sec-butyl lithium borohydride.
The ratio that adds of acylate and reducing agent has certain influence to the product yield of reduction reaction, preferably, acyl
The molar ratio of compound and reducing agent is 1: 5~1: 7.
(such as 0~5 DEG C) adds reducing agent dilution at a lower temperature, and it is 0.5-1.5h to add the time.Reducing agent is thrown
After the completion of adding, continues stirring a period of time (such as 2h), then raise temperature to and continue to be stirred to react at room temperature.
After reduction reaction, is extinguished with alcohol (such as methanol) or water and reacted, in subsequent concentration and recovery, elimination reaction liquid
Solvent, obtained concentrate are 2'-deoxyadenosine crude product, purification process are carried out to 2'-deoxyadenosine crude product, at the purifying
Reason includes recrystallization, and 2'-deoxyadenosine (sterling) is made after recrystallization.
In the present invention, recrystallisation solvent used by recrystallizing is ethyl alcohol.
In recrystallization process, the solid-liquid ratio that adds of recrystallisation solvent is 1g/2-6mL.That is to say, 2'-deoxyadenosine crude product and
The solid-liquid ratio of recrystallisation solvent is 1g/2-6mL.
In the present invention, a kind of preferred embodiment includes the following steps：
Step (1)：Preparation that adenosine (I) and di-nbutyltin oxide are flowed back in methyl alcohol contains 2 ', 3 '-di-n-butyl first tin
The reaction solution of alkylidene adenosine (II)；Wherein, the molar ratio of adenosine and di-nbutyltin oxide is 1: 1.1~1.2；Reaction
Temperature is 75~80 DEG C；
Step (2)：Paratoluensulfonyl chloride reaction is added in the reaction solution obtained to step (1), triethylamine as acid binding agent,
2 '-O- p-toluenesulfonyls adenosines (III) are made；
Step (3)：2 '-O- p-toluenesulfonyls adenosines (III) are dissolved with THF, and lithium triethylborohydride is then added dropwise
THF dilutions react under atmosphere of inert gases；After reaction, it concentrates, recycle THF, ethyl alcohol progress is added into concentrate
2'-deoxyadenosine (IV) is made in recrystallization.
The reaction equation square formula 5 of the preferred embodiment：
Equation 5
The present invention program has the characteristics that：
(1), various raw materials are easy to get, are at low cost；
(2), reaction selectivity is high, and reaction dosage is few (raw material input 5mmol can react), product quality stabilization, yield
High (total recovery 77.3%)
(3), synthetic route is reasonable, and reaction step is few, is not necessarily to chromatographic isolation, simplifies operation, is suitable for industrialized production.
Description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 2 '-O- p-toluenesulfonyls adenosines (III)；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of 2'-deoxyadenosine (IV).
Specific implementation mode
Following embodiment is implemented by aforesaid operations method：
With reference to example, further illustrate the present invention.Example is merely to illustrate the present invention rather than limitation originally herein
The range of invention.
Embodiment 1
(1) 2 '-O- p-toluenesulfonyls adenosines (III) are synthesized by adenosine (I)
Adenosine 1.34g, di-nbutyltin oxide 1.37g, methanol 35ml are weighed, above-mentioned raw materials, which are placed in 100ml round bottoms, to be burnt
In bottle, it is heated to reflux 2h, the 2 ' of generation, 3 '-di-n-butyl stannylene adenosines (II) directly carry out next step reaction, to anti-
It answers mixture that paratoluensulfonyl chloride 3.10g, triethylamine 2ml is added, is stirred to react 3-5h at room temperature, 1h is stored at room temperature after reaction,
It filters, filter residue is washed with methanol, and then filter residue is placed in vacuum drying chamber dry, final to obtain 2 '-O- pairs of white powdery solids
Tosyl adenosine 1.71g, yield 81.2%.HPLC purity is 98.1%.
(2) 2'-deoxyadenosine (IV) is synthesized by 2 '-O- p-toluenesulfonyls adenosines (III)
It weighs 2 '-O- p-toluenesulfonyls adenosine 1.69g, anhydrous dimethyl sulphoxide 10ml and above-mentioned raw materials is placed in 50ml
In round-bottomed flask, the tetrahydrofuran solution 20ml, 1h of 1mol/L lithium triethylborohydrides are slowly added dropwise at 0~5 DEG C for nitrogen protection
It drips off and continues to stir 1h, be then transferred to 4~6h of stirring at room temperature, extinguished with 5~6ml methanol after reaction and reacted, first rotation is steamed
Hair removes tetrahydrofuran, and then decompression boils off dimethyl sulfoxide (DMSO), finally can obtain White crystal product 0.85g with ethyl alcohol recrystallization,
Yield is 84.6%.HPLC detects purity ＞ 99.0%.
Embodiment 2
(1) 2 '-O- p-toluenesulfonyls adenosines (III) are synthesized by adenosine (I)
Adenosine 2.67g, di-nbutyltin oxide 2.99g, methanol 50ml are weighed, above-mentioned raw materials, which are placed in 100ml round bottoms, to be burnt
In bottle, it is heated to reflux 3h, rotary evaporation removes methanol, the 2 ' of generation, 3 '-di-n-butyl stannylene adenosines (II) after reaction
Next step reaction is directly carried out, paratoluensulfonyl chloride 3.10g, triethylamine 2ml, dichloromethane 50ml is added to reaction mixture,
It is stirred to react 5~7h at room temperature, concentrated by rotary evaporation after reaction is added 15ml methanol, is stored at room temperature 1h, filters, and filter residue is washed with methanol
It washs, then filter residue is placed in vacuum drying chamber dry, final to obtain 2 '-O- p-toluenesulfonyl adenosines of white powdery solids
3.76g, yield 89.2%.HPLC purity is 98.6%.
(2) 2'-deoxyadenosine (IV) is synthesized by 2 '-O- p-toluenesulfonyls adenosines (III)
2 '-O- p-toluenesulfonyls adenosine 1.69g, anhydrous tetrahydro furan 30ml are weighed, above-mentioned raw materials are placed in 100ml circles
In the flask of bottom, tetrahydrofuran solution 25ml, the 1h drop of 1mol/L lithium triethylborohydrides is slowly added dropwise at 0~5 DEG C for nitrogen protection
It is complete to continue to stir 2h, it is then transferred to 6~8h of stirring at room temperature, is extinguished with 6~8ml methanol after reaction and is reacted, first rotary evaporation
Tetrahydrofuran is removed, then decompression boils off dimethyl sulfoxide (DMSO), finally can obtain White crystal product 0.89g with ethyl alcohol recrystallization, receives
Rate is 86.7%.It is ＞ 99.0% that HPLC, which detects purity,.
Claims (8)
1. a kind of synthetic method of 2'-deoxyadenosine, which is characterized in that by adenosine through esterification, acylating agent and acid binding agent are in room temperature
Under acylation, obtain acylate；Gained acylate obtains 2'-deoxyadenosine using reduction and purification process；
Wherein, the esterifying agent used in esterification process is dialkyltin；
The reducing agent molecular formula that reduction reaction uses is R3R4R5HB-Li+；Wherein, R3、R4、R5It is independently selected from the alkyl of H, C1-5；
The molar ratio of acylate and reducing agent is 1:5~1:7；Reducing agent adds at 0~5 DEG C, and it is 0.5- to add the time
1.5h；After reducing agent adds completion a period of time, then raises temperature to and continue to be stirred to react at room temperature.
2. the synthetic method of 2'-deoxyadenosine as described in claim 1, which is characterized in that point of the dialkyltin
Minor is R1R2SnO, wherein R1And R2It is independently selected from the alkyl of C1-6.
3. the synthetic method of 2'-deoxyadenosine as claimed in claim 2, which is characterized in that esterifying agent be dimethyl tin oxide,
At least one of di-nbutyltin oxide, di-n-octyl tin oxide.
4. the synthetic method of 2'-deoxyadenosine as described in claim 1, which is characterized in that adenosine and feeding intake for esterifying agent are rubbed
You are than being 1:1.1~1.2.
5. the synthetic method of 2'-deoxyadenosine as described in claim 1, which is characterized in that esterification reaction temperature is 75~80
℃。
6. the synthetic method of 2'-deoxyadenosine as described in claim 1, which is characterized in that acylating agent is sulfonic acid chloride；Acid binding agent
For fat or aromatic amine.
7. the synthetic method of 2'-deoxyadenosine as described in claim 1, which is characterized in that the purification process includes weight
Crystallization, used recrystallisation solvent are ethyl alcohol.
8. the synthetic method of 2'-deoxyadenosine as claimed in claim 7, which is characterized in that in recrystallization process, recrystallisation solvent
Add solid-liquid ratio be 1g/2-6mL.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993023413A1 (en) * | 1992-05-13 | 1993-11-25 | Ribozyme Pharmaceuticals, Inc. | Synthesis of nucleotide monomers |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993023413A1 (en) * | 1992-05-13 | 1993-11-25 | Ribozyme Pharmaceuticals, Inc. | Synthesis of nucleotide monomers |
Non-Patent Citations (4)
| Title |
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| 2"-脱氧腺苷全合成研究;蒋忠良，等;《同济大学学报（自然科学版）》;20070930;第35卷(第9期);第1264-1268页 * |
| A Deoxygenative [1,2]-Hydride Shift Rearrangement Converting Cyclic cis-Diol Monotosylates to Inverted Secondary Alcohols;Fritz Hansske，等;《J. Am. Chem. SOC.》;19831231;第105卷;第6736-6737页 * |
| Facile Conversion of Adenosine into New 2’-Substitlited-2’ -Deoxy-Arabinofuranosyladenine Derivatives: Stereospecific Syntheses of 2’-Azido-2’-Deoxy-, 2’-Amino-2’-Deoxy-, And 2’-Mercapto-2’-Deoxy-β-D-Arabinofuranosyladenine;R. Ranganathan，等;《Tetrahedron Letters》;19781231;第19卷(第45期);第4341-4344页 * |
| Preparation and Synthetic Utility of Some Organotin Derivatives of Nucleosides;Daniel Wagner，等;《J. Org. Chem.》;19741231;第39卷(第1期);第24-30页 * |
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