CN107011399B - The preparation method of beta comfiguration Decitabine precursor - Google Patents
The preparation method of beta comfiguration Decitabine precursor Download PDFInfo
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- CN107011399B CN107011399B CN201710370924.4A CN201710370924A CN107011399B CN 107011399 B CN107011399 B CN 107011399B CN 201710370924 A CN201710370924 A CN 201710370924A CN 107011399 B CN107011399 B CN 107011399B
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- C—CHEMISTRY; METALLURGY
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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
- C07H19/12—Triazine radicals
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The present invention provides the preparation method of beta comfiguration Decitabine precursor; including; under lewis acid catalyst effect; acylated sugar by structure for 1 alkenyl methoxyl group, 2 deoxidation, 3,5 two O acetyl group D ribofuranoses, coupling reaction is directly carried out with the silicon etherate of 5 azepine cytimidines; obtain 1 (2 deoxidations 3 of beta comfiguration; 5 two O acetyl group D ribose) 41,3,5 s-triazine of amino, 2 ketone.High selectivity of the present invention, reproducible, the molar yield and purity of product are very high.
Description
Technical field
The present invention relates to a kind of preparation method of Decitabine precursor.
Background technology
The preparation process of Decitabine disclosed in many documents, be roughly divided into isocyanic acid ester process, azacitidine deoxidation method,
Glycosylation method three classes, wherein be to be coupled pyrimidinium moiety and ribose moieties the characteristics of glycosylation method, what coupling reaction obtained
Product is the Decitabine (the application is known as Decitabine precursor) of hydroxyl protection, is most obtained afterwards through deprotection (usually hydrolyzing)
Decitabine.It is well known that Decitabine is a β type isomers, but generally yield in the preparation be α, β mixed body,
Obviously, Decitabine precursor before the content ratio of the Decitabine of β types and its complicated and simple degree of purifying are directly hydrolyzed in product
The influence of the ratio of middle β types.
Before coupling, ribose need to be subjected to a series of processing, including first be etherified ribose, then the hydroxyl of sugar is protected
Shield, for example protect to obtain the acylated sugar alleged by the application using acyl group, then, substituent C1 sugared generally has to change into halogen
Or coupling reaction could be carried out after acyl group.
People from this area changes C1 groups precisely in order to ensureing the ratio of β types in Decitabine precursor, hundreds of
Document in, only several disclose not change and are coupled, its effect is unstable and the ratio of β: α type is typically smaller than 1.
For example CN101821278 is disclosed and used acylated sugar, such as bis--O- fluorenes methoxy carbonyl acyl groups-D- of 1- methoxyl group -2- deoxidations -3,5-
Furan type ribose is corresponding using the acylated sugar protected to methyl benzoyl, is directly coupled, obtained product
It is α: β ＞ 3: 2.The US20120046457 of the method is equally used, β types account for half and unstable, β in embodiment 5 in product
Type only accounts for 47.37%.Chromatography experiment (explanations of the CN101560233 of Shanghai Qingsong Pharmaceutical Co., Ltd. only after 1 embodiment
Book subscript page 6) in α types account for 39.7%, disclose β types and account for 59.7%, but this ratio repeats the coupling reaction with the present inventor
β: α ratio is totally different (operation and the comparative example the result is shown in the application) in direct product, through analyzing, used in the patent chromatography experiment
Sample is not the product of its coupling reaction directly gained, its sample purity is more than 99%, and the coupling reaction of the embodiment is straight
Connect the system after continuing Silanization reaction to carry out, hexamethyldisilazane is much excessive in Silanization reaction, coupling reaction raw material
Also can not possibly be consumed by 100%, the silicon protection group taken off after coupling reaction with alkali on product will also produce impurity.
The raw material of CN101560233 coupling reactions is identical with US20120046457, and condition is also essentially identical, and the embodiment is only logical
Cross simple liquid separation, rather than the complicated last handling process of foregoing CN101821278, US20120046457, it is clear that can not possibly obtain
Purity is more than 99% product, β: α also can not be totally different with aforementioned patent in product, in fact, WO2008101448, paper《Ground
The preparation of his western shore α type isomers》The method is clearly directly used in and prepares α type precursors by (2012), and WO2008101448 is said
Bright book eighth row of page 5 is even more to point out that method formation α types are the selectivity for having " very high ", and CN101560233 is not carried in the whole text
And β: α the problem of, it is also not possible to directly obtain the product of high beta ratio in coupling reaction.
Above-mentioned directly coupled document, uses C1 to be carried out for the acylated sugar of methoxyl group, CN106046089 also clearly refers to
Go out that its α type impurity ratio is excessive, and CN106046089 is coupled using halogen sugar, selectivity is good, process yield is up to 89%.
Using the CN101570559 of halogen sugar, β precursor contents are more than 50%, and in the US20100249394 using halogen sugar, β: α up to 2.5,
It is unfavorable for being enriched with β type products, most literature in short, directly instructing using the directly coupled prior art of methoxyl group
It is to be changed C1 groups, usually switchs to halogen or acyl group is coupled again.
The content of the invention
The present invention overcomes the prejudice of the prior art, there is provided a kind of new method for preparing Decitabine precursor, β in product
Configuration ratio is very high.
The preparation method of the Decitabine precursor of the present invention, is included under the action of lewis acid catalyst, is by structure
The acylated sugar of bis--O- acetyl group of 1- alkenyl methoxyl group -2- deoxidations -3,5--D-RIBOSE, is etherified with the silicon of 5- azepine cytimidines
Thing is coupled, and obtains coupling product 1- (bis--O- acetyl group of 2- deoxidations -3,5--D-ribose) -4- amino -1,3 of beta comfiguration enrichment, 5-
Guanamine -one, the coupling product, that is, Decitabine precursor.After the completion of reaction, reaction can be quenched by conventional method, pass through weight
Purified by crystallisation product, recrystallization solvent can be toluene.
Optionally, the solvent of the coupling reaction is water-soluble aprotic solvent, such as acetonitrile.
Optionally, the temperature of the coupling reaction is -5 DEG C~5 DEG C, such as 0 DEG C.
Optionally, the alkenyl in the acylated sugared structure is vinyl or acrylic, i.e., with vinyl C=C- or third
Alkenyl C-C=C- is further substituted with the methyl on C1 methoxyl groups, can also order as bis--O- of 1- pi-allyl epoxide -2- deoxidations -3,5-
Acetyl group-D-RIBOSE (alkenyl in acylated sugar structure is vinyl), 1- (2- cyclobutenyls) epoxide -2- deoxidation -3,
Bis--O- acetyl group of 5--D-RIBOSE (alkenyl in acylated sugar structure is acrylic).Acylated sugar can be normal by this area
The 2- deoxy-D-ribofuranoses that 1 hydroxyl is etherified by rule method are made with hydroxy-protecting agent reaction.
Optionally, the silicon etherate is 2,4- bis--(trimethyl silicane) -5- azepine cytimidines, the acylated sugar and the silicon
The molar ratio of etherate is 1:1.2-1.8, is such as 1:1.5.
Optionally, the catalyst is trifluoromethanesulfonic acid.
Optionally, the molar ratio of the catalyst and Formulas I raw material is 0.2:1.
The beneficial effects of the invention are as follows：
The present invention overcomes the prejudice of the prior art, need not be converted into the methoxyl group of C1 before having been surprisingly found that coupling reaction
Other groups, it is only necessary to be further substituted with its methyl with alkenyl, beta comfiguration in coupling product：α configurations ratio is stablized more than 2.5,
This class reaction β: α is less than for 1 in compared with prior art, this is very surprising, and the present invention also optimizes raw material, proportioning bar
Part, further increases selectivity of reaction etc.；Step of the present invention is few, and post processing is simple, reproducible, the molar yield of product
Stablize more than 85%, purity is also stablized more than 90%, is especially advantageous for subsequently preparing Decitabine.
Embodiment
Embodiment 1：
1- (2- cyclobutenyls) epoxide -2- of 2, the 4- bis- of 60mmol-(trimethyl silicane) -5- azepines cytimidine and 50mmol take off
Bis--O- acetyl group of oxygen -3,5--D-RIBOSE is dissolved in 500mL acetonitriles, and temperature control adds the trifluoromethanesulfonic acid of 10mmol to 0 DEG C,
Continue to be kept for 0 DEG C, when stirring reaction 2 is small, HPLC monitoring reactions are completed.Quickly it is quenched with 500mL saturated sodium bicarbonate aqueous solutions
Reaction and washing reaction mixed liquor, isolate organic layer, are evaporated to drying under vacuo, then with re crystallization from toluene, obtain
Solid 14.75g, be identified as 1- (bis--O- acetyl group of 2- deoxidations -3,5--D-ribose) -4- amino -1,3,5- guanamines -
Ketone, it is 90% that HPLC, which detects its purity, and the content ratio of wherein beta comfiguration and α configurations is 2.5.
1H-NMR(DMSO-d6)δ：2.0 (s, 6H), 2.2-3.0 (m, 2H), 4.1 (m, 1H), 4.3 (m, 1H), 4.8 (m,
1H), 5.2 (m, 1H), 6.1 (m, 1H), 7.5 (s, 1H), 7.6 (s, 1H), 8.4 (s, 1H)
Embodiment 2-4：
Coupling reaction, each bar are directly carried out with bis--O- acetyl group of 1- pi-allyl epoxide -2- deoxidations -3,5--D-RIBOSE
Part is different with reference to 1,2,4- bis--(trimethyl silicane) -5- azepine cytimidines dosage of embodiment cytimidine raw material, is as a result summarized as follows：
Comparative example：
The methoxyl group of C1 is not also switched to other groups by CN101560233 embodiments 5, and directly carries out coupling reaction,
Its catalyst and the application are closest, repeat the embodiment, and corresponding its product of detection and analysis completely below.
The citation of operation original text is as follows：
Addition 5- azepines cytimidine (50.7g, 452.1mmol) in 1000ml three-necked bottles, hexamethyldisilazane (500ml,
2.4mol), ammonium sulfate (2g), heated under nitrogen are back to clarification, and decompression evaporates solvent, is dissolved in dichloromethane (250ml), cold
To 5 DEG C, trimethyl silicane triflate (TMSOTf) (140ml, 770mmol) is added dropwise.Then be added dropwise formula III (100g,
Dichloromethane (500ml) solution 430.6mmol), is stirred overnight at room temperature.Saturated sodium bicarbonate solution is added dropwise and is washed till neutrality, takes out
Filter, filtrate are washed with saturated sodium bicarbonate solution (500ml), and liquid separation, organic phase is dried with anhydrous sodium sulfate, filter solvent evaporated
Obtain Formula V.
Note：According to patent specification, Formula V refers to 3 ', 5 '-diacetoxy -5-aza-2'-deoxycytidine, completely with this Shen
Decitabine precursor please；Formula III refers to 1- methyl -3,5- diacetoxy -2-deoxy-D-ribose, corresponding to the acyl of the application
Change sugar.
Through measurement, the common 90g of Decitabine precursor reacted, its purity is 75%, wherein β：α=0.9, calculating to rub
Your yield is 50%, it is clear that its selectivity, yield are far below the present invention.
Claims (6)
1. the preparation method of beta comfiguration Decitabine precursor, it is characterized in that, under lewis acid catalyst effect, by 1- alkenyl first
Bis--O- acetyl group of epoxide -2- deoxidations -3,5--D-RIBOSE, directly carries out being coupled anti-with the silicon etherate of 5- azepine cytimidines
Should, obtain 1- (bis--O- acetyl group of 2- deoxidations -3,5--D-ribose) -4- amino -1,3 of beta comfiguration, 5- guanamine -one；It is described
Alkenyl is vinyl or acrylic.
2. preparation method according to claim 1, it is characterized in that, the solvent of the coupling reaction is water-soluble non-proton molten
Agent.
3. preparation method according to claim 1, it is characterized in that, the temperature of the coupling reaction is -5 DEG C~5 DEG C.
4. preparation method according to claim 1, it is characterized in that, the temperature of the coupling reaction is 0 DEG C.
5. preparation method according to claim 1, it is characterized in that, the silicon etherate is 2,4- bis--(trimethyl silicane) -5-
Azepine cytimidine.
6. preparation method according to claim 1, it is characterized in that, the catalyst is trifluoromethanesulfonic acid.
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| CN1968605A (en) * | 2004-06-15 | 2007-05-23 | 默克公司 | C-purine nucleoside analogs as inhibitors of RNA-dependent RNA viral polymerase |
| WO2007097643A1 (en) * | 2006-02-22 | 2007-08-30 | Industrial Research Limited | Analogues of coformycin and their use for treating protozoan parasite infections |
| CN101307084A (en) * | 2008-07-08 | 2008-11-19 | 贵州大学 | Synthetic process of decitabine |
| CN101311184A (en) * | 2007-05-25 | 2008-11-26 | 上海医药工业研究院 | 2-deoxy-D-ribose derivates, preparation method and use thereof |
| CN101787046A (en) * | 2010-02-11 | 2010-07-28 | 上海百灵医药科技有限公司 | Preparation method of intermediate compound of Decitabine |
| WO2017053216A2 (en) * | 2015-09-23 | 2017-03-30 | Merck Sharp & Dohme Corp. | 4'-substituted nucleoside reverse transcriptase inhibitors and preparations thereof |
-
2017
- 2017-05-24 CN CN201710370924.4A patent/CN107011399B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1968605A (en) * | 2004-06-15 | 2007-05-23 | 默克公司 | C-purine nucleoside analogs as inhibitors of RNA-dependent RNA viral polymerase |
| WO2007097643A1 (en) * | 2006-02-22 | 2007-08-30 | Industrial Research Limited | Analogues of coformycin and their use for treating protozoan parasite infections |
| CN101311184A (en) * | 2007-05-25 | 2008-11-26 | 上海医药工业研究院 | 2-deoxy-D-ribose derivates, preparation method and use thereof |
| CN101307084A (en) * | 2008-07-08 | 2008-11-19 | 贵州大学 | Synthetic process of decitabine |
| CN101787046A (en) * | 2010-02-11 | 2010-07-28 | 上海百灵医药科技有限公司 | Preparation method of intermediate compound of Decitabine |
| WO2017053216A2 (en) * | 2015-09-23 | 2017-03-30 | Merck Sharp & Dohme Corp. | 4'-substituted nucleoside reverse transcriptase inhibitors and preparations thereof |
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| Pentenyl Ribosides: New Reagents for Purine Nucleoside Synthesis;Marie-Christine Chapeau，等;《J. Org. Chem.》;19931231;第58卷;第7258-7262页 * |
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