CN101497639A - Preparation of decitabine - Google Patents
Preparation of decitabine Download PDFInfo
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- CN101497639A CN101497639A CNA2009100198149A CN200910019814A CN101497639A CN 101497639 A CN101497639 A CN 101497639A CN A2009100198149 A CNA2009100198149 A CN A2009100198149A CN 200910019814 A CN200910019814 A CN 200910019814A CN 101497639 A CN101497639 A CN 101497639A
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- deoxidation
- ribofuranose
- decitabine
- toluyl
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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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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- 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 relates to a preparation method of decitabine. The method comprises the following steps: a double-silicon-based product of 5-azacytosine is directly glycosylated with 2-deoxy-3,5-di-o-p-toluoyl-alpha-D-ribofuranose to be synthesized into an alpha, beta-glucoside mixed isomer, then the fractional crystallization is performed to the mixed isomer by using different organic solvents, firstly, the mixed isomer is recrystallized and separated in an organic solvent to obtain a beta-isomer, then the protecting group is released, and then the mixed isomer is recrystallized in the other organic solvent to obtain the high-purity decitabine.
Description
Technical field
The present invention relates to Decitabine (Decitabine, Dacogen) and 2 '-the synthetic and method for splitting of nucleoside derivative.
Background technology
Decitabine [medicine name: Decitabine; Login name: Decitabine; Trade(brand)name: Dacogen; Medicine another name: 5-azacd, Azadc; Chemical name: 4-amino-1-(2-deoxidation-β-D-erythro ribofuranose)-1,3,5-triazines-2 (1H)-ketone] be synthetic natural nucleus glycoside 2 in 1964 '-analogue of Deoxyribose cytidine, develop into medicine by U.S. SuperGen company.Finished in 2004 the III phase clinical after, development rights are sold in global development and production transfer the MGI drug company.In April, 2006 and May by European EMEA and drugs approved by FDA listing, become the active drug that is used for the treatment of primary and Secondary cases myelodysplastic syndrome (MDS) respectively.Because its unique mechanism of action, the clinical study that Decitabine treatment ovarian cancer, mammary cancer, prostate cancer, cancer of the stomach, lung cancer, carcinoma of the pancreas, leukemia etc. are 29 more than is being carried out and is being shown good curative effect, gets a good chance of becoming the new drug of other cancers of treatment.
Decitabine is dnmt rna inhibitor and DNA synthetic inhibitor, has the clinical effect of treatment myeloproliferative syndrome.Decitabine is directly acted on DNA in vivo after the phosphorylation, suppress dnmt rna, thereby make the DNA hypomethylation, reaches the effect of control cytodifferentiation and propagation, realizes the effect of pharmacological agent.
Decitabine be azacitidine (5-azacytidine/Victor is pricked, 5-azacytidine/Vidaza) 2 '-deoxidation derivative, its antitumor curative effect is far above 5-azacytidine, yet, 2 '-the synthetic difficulty of position Deoxyribose cytidine wants high a lot.The special construction of 5 azacytidines has also brought very big difficulty for it is synthetic.Therefore, up to the present, Decitabine, promptly 5-azepine-2 '-Deoxyribose cytidine remains challenging synthetic, scale operation difficulty especially especially.
The synthetic of Decitabine had many reports, mostly obtains α-and β-mixture of isomers, and chromatographic column is separated and is difficult to enlarge production, and total recovery is low, can not satisfy demand of practical production.It is synthetic that Decitabine mainly contains following several method:
I, isocyanic ester method (referring to A.Piskala, F.Sorm, in Nucleic Acid Chemistry, Ed.L.B.Townsendand R.S.Leroy, 1978, Wiley, New York, N.Y., p443-449), synthetic route is as follows:
This method is used the isocyanate of precious metals silver, and cyclization again is uneconomical after the glucosidesization, and synthetic route is longer, and will carry out the separation of isomer, can't be used for industrial preparation production.
II, azacitidine deoxidation method (referring to M.J, Robins, J.S, Wilson, T.Hansske, J.Am.Chem.Soc.1983,105 (12), be 4059-4065) from 5-azacytidine, slough 2 '-hydroxyl of position and obtain Decitabine.
In the formula: TiPSCh:1,3-two chloro-1,1,3,3-tetra isopropyl disiloxane
TTMSS: three-(trimethyl silicon based) silane
ALBN: Diisopropyl azodicarboxylate
The starting raw material that this route uses is azacitidine, and price is higher, and uses special reagent TiPSCh, sulfo-phenyl chloroformate, and TTMSS etc.Wherein domestic being difficult to of some reagent supplies, and also is unsuitable for industrial production Decitabine anticarcinogen.
The direct glucosidesization of III, 5-azepine cytosine(Cyt): 5-azepine cytosine(Cyt) refluxes together with hexamethyldisilazane, at first generates two silica-basedization products:
Two silica-basedization products both can be with 1,3, the direct glucosidesization of 5-three-O-ethanoyl-2-deoxyribosyl, also can with the direct glucosidesization of 2-deoxyribosyl halogenide of acyl group protection.The glucosides product is sloughed protecting group, can obtain Decitabine through isomer separation.Route is as follows:
Synthetic route 1. usefulness ethanoyl are protected
This synthetic route glucosides product can reach 64% (α, β-isomer mixture), does not separate directly at NH
3-CH
3Deprotection base among the OH is crossed silica gel chromatographic column then and is purified.Crystallization obtains the Decitabine mixture in methyl alcohol, and total recovery 32% (referring to Ji Jingjing, Yang Shouning, Dong Dongyin, Yang Liping, Chinese Journal of Pharmaceuticals 2007,38 (7): 468-469.).
Publication number is that the patent document of CN101307084A has been continued to use above-mentioned similar synthetic method, protects with ethanoyl, synthesizes through five steps to have obtained the target product Decitabine, and overall yield is greater than 18.4%, and product purity is greater than 99.7%.。This patent document not to α-and the fractionation of β-isomer do any explanation.
The different protecting group of usefulness such as synthetic route 2:Robins by the direct glucosidesization of following route obtained Decitabine (M.W.Winkley, R.K.Robins.J.Org.Chem.1970,35 (2), 491-495).
In the synthetic route 2, glucosides halogenide protecting group can be an ethanoyl, also can be to toluyl.When with ethanoyl-2 '-during deoxidation-alpha-chloro ribose, the glucosides product is identical with synthetic route 1, separation can obtain Decitabine through chromatographic column, however yield only has 7%.
When protecting group be during to toluyl (referring to U.Niedballa, H.Vorbriiggen, J.Org.Chem.1974; 39 (25), the glucosides product that 3672-3677) obtains is similarly α, β-anomeric mixture; obtain the β-anomer of wishing through recrystallization, used CDCl
3When making solvent, NMR can observe 6.27 (dd, 1H, H-1 ') characteristic peak.But this article is the deprotection base not, does not also separate obtaining Decitabine.
Synthetic route 3:(is referring to J.Ben-Hattar; J.Jiricny, J.Org.Chem.1986,51 (16), 3211-13) carry out direct glucosidesization as protecting group with Fmoc, also obtained Decitabine:
Yet the glucosides product that obtains is similarly α, β-anomeric mixture, and α, β-anomer ratio is 1:0.9, go protecting group after, the total recovery through the recrystallization products obtained therefrom only has 16.2% again.The Fmoc protecting group reagent costliness of using in this method, and this protecting group stability is low, is unfavorable for the big preparation of producing.
In above-mentioned various synthetic routes, what obtain is α, and β-anomeric mixture needs to separate the monomer that just can obtain Decitabine through post, separates and not too is suitable for industrial preparation yet cross post.
Summary of the invention
At the deficiencies in the prior art, the invention provides a kind of highly purified method for preparing decitabine that is suitable for suitability for industrialized production, comprising the method for splitting of Decitabine isomer.
In view of the deficiencies in the prior art, on the basis of the present invention's synthetic route 2 in background technology, operational path is improved, make it possible to be suitable for the scale operation Decitabine.Technical solution of the present invention is as follows:
Method for preparing decitabine of the present invention; two silica-basedization products 2 with 5-azepine cytosine(Cyt); 4-pair of trimethyl silicon based-S-triazine; with 1-chloro-2-deoxidation-3; 5-two-(O-is to the toluyl)-α-direct glucosidesization of D-ribofuranose; synthesize α; β-glucosides mixed isomers; this mixed isomers is carried out fractional crystallization with different organic solvents; at first mixed isomers recrystallization in a kind of organic solvent acetonitrile or ethyl acetate is separated and obtain β-isomer; then β-isomer is removed the toluyl protecting group, obtain highly purified Decitabine with another kind of organic solvent dehydrated alcohol recrystallization again.Decitabine purity (UV 254nm) can reach more than 98%.
The Decitabine structural formula of the present invention's preparation is as follows:
The present invention adopts following synthetic route to carry out the production of Decitabine:
In the above-mentioned reaction scheme; formula 1 is 1-methoxyl group-2-deoxidation-D-ribofuranose (hereinafter to be referred as compound 1); formula 2 is 1-methoxyl group-2-deoxidation-3; 5-two-(O-is to toluyl)-α; β-D-ribofuranose (hereinafter to be referred as compound 2); formula 3 is 1-chloro-2-deoxidation-3; 5-two-(O-is to toluyl)-α-D-ribofuranose (hereinafter to be referred as compound 3); formula 4 is 2; 4-pair of trimethyl silicon based-S-triazine (hereinafter to be referred as compound 4), formula 5 ' is α, β-two kind of mixture of isomers (hereinafter to be referred as compound 5 '); formula 5 is β-isomer (hereinafter to be referred as compounds 5), and formula 6 is a Decitabine.
2, method for preparing decitabine
Method for preparing decitabine of the present invention comprises the proportioning of reaction conditions and reactant, and step is as follows:
(1) methanol solution with 2-deoxy-D-ribose and hydrogenchloride carries out methylation reaction, obtains 1-methoxyl group-2-deoxidation-D-ribofuranose (compound 1).
(2) 1-methoxyl group-2-deoxidation-D-ribofuranose (formula 1) and Butyltriphenylphosphonium chloride are carried out acylation reaction, get 1-methoxyl group-2-deoxidation-3,5-two-(O-is to toluyl)-α, β-D-ribofuranose (compound 2).
(3) with 1-methoxyl group-2-deoxidation-3; 5-two-(O-is to toluyl)-α; β-D-ribofuranose (compound 2) carries out chlorination reaction in hydrogenchloride-acetum, get 1-chloro-2-deoxidation-3,5-two-(O-is to toluyl)-α-D-ribofuranose (compound 3).
(4) with 1-chloro-2-deoxidation-3; 5-two-(O-is to toluyl)-α-D-ribofuranose (compound 3) and 2; 4-pair of trimethyl silicon based-S-triazine (compound 4) carried out glycosylation reaction in organic solvent; get 1-[2 '-deoxidation-3 '; 5 '-two-(O-is to toluyl)-α, β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5 ') mixed isomers.
(5) mixed isomers (compound 5 ') that step (4) is obtained carries out recrystallization, separates out 1-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5), be β-isomer.
(6) with 1-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5) deprotection base, obtain Decitabine (formula 6).
The preferred scheme of the present invention is as follows:
The described glycosylation reaction of above-mentioned steps (4) is with preferred acetonitrile of organic solvent or chloroform, and most preferably acetonitrile is made solvent.
The described recrystallization of above-mentioned steps (5) is directly to carry out recrystallization with acetonitrile or ethyl acetate.
The described deprotection base of above-mentioned steps (6) is that with the saturated alcoholic solution dissolving β-isomer (compound 5) of ammonia, TLC detects 18-20h and reacts completely in the time of 0 ℃; the solution that gained reacts completely; remove and desolvate, use the dehydrated alcohol recrystallization again, obtain white crystals after the freezing treatment.
The preferred more detailed operation of the present invention is as follows:
The methylation reaction of above-mentioned steps (1) is the 2-deoxy-D-ribose to be dissolved in the methyl alcohol adding 1%wtHCl-methanol solution, stirring at room 30-40min.With the sodium bicarbonate neutralization, removal of solvent under reduced pressure gets yellow dope 1-methoxyl group-2-deoxidation-D-ribofuranose (compound 1).
The acylation reaction of above-mentioned steps (2) is 75mmol1-methoxyl group-2-deoxidation-D-ribofuranose (compound 1) to be dissolved in an amount of pyridine adding Butyltriphenylphosphonium chloride 160mmol under condition of ice bath; reaction is poured in the frozen water after finishing; use dichloromethane extraction, washing, anhydrous Na
2SO
4Drying, decompression is spin-dried for, and gets light yellow oil (compound 2).
The chlorination reaction of above-mentioned steps (3) is; 2 82.5mmol are dissolved in Glacial acetic acid with above-claimed cpd; cooling adds down with the saturated glacial acetic acid solution of hydrogenchloride; then add anhydrous diethyl ether, suction filtration, anhydrous diethyl ether washing; vacuum-drying; get white solid 1-chloro-2-deoxidation-3,5-two-(O-is to toluyl)-α-D-ribofuranose (compound 3), mp.104-106 ℃.
In the glycosylation reaction of above-mentioned steps (4) 2, the preparation method of 4-pair of trimethyl silicon based-S-triazine (compound 4) is, 45mmol mixes with hexamethyldisilazane 100ml with 5-azepine cytosine(Cyt), make catalyzer with ammonium sulfate, carry out silica-basedization reaction, obtain 2,4-pair of trimethyl silicon based-S-triazine (compound 4).
With above-claimed cpd 4 and 1-chloro-2-deoxidation-3; 5-two-(O-is to toluyl)-α-D-ribofuranose (compound 3) 38.6mmol room temperature in organic solvent is carried out glycosylation reaction; treated; obtain 1-[2 '-deoxidation-3 '; 5 '-two-(O-is to toluyl)-α; β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5 '), be α, β-two kind of mixture of isomers.
The described recrystallization of above-mentioned steps (5) is with 1-[2 '-deoxidation-3 '; 5 '-two-(O-is to toluyl)-α; β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5 ') 25.8mmol is dissolved in an amount of acetonitrile; behind the activated carbon decolorizing; place crystallization; get white solid 1-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (5), be β-isomer.
Above-mentioned steps (6) deprotection base is meant that the hydroxyl protecting group that removes on the sugar ring is to toluyl; with 1-[2 '-deoxidation-3 '; 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5) 72mmol; add and use in the saturated methanol solution of ammonia; room temperature reaction is evaporated to driedly, uses the dehydrated alcohol recrystallization; get white solid Decitabine (6), yield 62%.
Technical characterstic of the present invention and excellent results are as follows:
In the synthetic method of the present invention, when compound (4) carries out glucosides with acetonitrile as solvent with the glucosides condensation reaction of compound (3), the α in the gained reaction mixture, the ratio of β-two kind of isomer is α: β=38%:49%, i.e. 1:1.3.And during with the chloroform give solvent, the α in the gained reaction mixture, the ratio of β-two kind of isomer is α: β=47%:43%, i.e. 1:0.9.Up to now, the ratio of resulting β-isomer is higher than the ratio that every other prior art is carried out the resulting β-isomer of glucosidesization among the present invention.
The method for splitting of Decitabine isomer also is provided in the inventive method, to the isomer mixture after the glucosidesization, not having directly to separate β-isomer (compound 5) before the deprotection base, also is one of innovation of the present invention.The α that compound (4) and compound (3) glucosidesization obtain, β-two kind of mixture of isomers is directly carried out the recrystallization separation with acetonitrile or ethyl acetate and is obtained high-purity β-isomer.The purity of β-isomer all reaches more than 95% behind recrystallization, lays a good foundation for accessing highly purified Decitabine behind the deprotection base.
Synthetic method step of the present invention (6) is also innovated the process that the deprotection base prepares Decitabine.Prior art is generally handled with sodium methylate-methanol solution, and the 2h afterreaction is finished substantially.Handle with Zeo-karb, remove sodium ion, again with the methyl p toluate that generates in the reaction of normal hexane flush away, can obtain Decitabine after concentrating with ethyl alcohol recrystallization.Though the reaction of such method is very fast, yield is lower.The present invention handles compound 5 at 0 ℃ with the saturated alcoholic solution of ammonia, and TLC detects about 20h and reacts completely, and removes and desolvates, and uses ethyl alcohol recrystallization again, obtains white crystals after the freezing treatment.Need not silica gel chromatographic column and purify, technology and purge process are easy, and yield is higher, is applicable to the production of Decitabine.
Step in the technology of the present invention (2) adopts makes hydroxyl protecting group on the sugar ring to toluyl and since phenyl ring this as chromophoric group, intermediate carries out TLC easily and detects in the preparation process, is convenient to follow the tracks of reaction process.
Glucosidesization described in the invention, directly the glucosides product of recrystallization decoupled band protecting group become β-isomer and technologies such as deprotection base subsequently also be adapted to synthetic similar 2 '-deoxynucleoside and 2 '-deoxidation-2 '-(as fluorine, difluoro, carbon, β-carbon, beta-hydroxy etc.) nucleoside derivates of replacing.
In sum, operational path of the present invention is selected direct glucosides gained β-isomery height; The direct recrystallization isomer mixture of deprotection base has not just obtained pure β-isomer; Technology and purge process are easy, are suitable for the suitability for industrialized production of Decitabine.
Embodiment
The present invention will be further described below in conjunction with specific embodiment, but be not limited thereto.
Embodiment 1:
1,1-methoxyl group-2-deoxidation-3,5-two-(O-is to toluyl)-α, β's-D-ribofuranose (compound 2) is synthetic
2-deoxyribosyl (74.5mmol) is dissolved in the 120mL methyl alcohol, adds 1% HCl-MeOH solution, room temperature reaction 30min.Add solid NaHCO
3Be neutralized to pH=7, removal of solvent under reduced pressure obtains yellow dope.Compound 1 is added in the 60mL pyridine, and ice bath is cooled to 0 ℃, under agitation add Butyltriphenylphosphonium chloride (23mL, 160mmol), stirred overnight at room temperature.Separate out a large amount of white solids, reaction mixture is poured in the frozen water, uses the dichloromethane extraction secondary, merges organic layer.Washing, anhydrous Na
2SO
4Drying is filtered, and decompression is spin-dried for, and obtains 32g light yellow oil compound 2.Be directly used in next step reaction.
2,1-chloro-2-deoxidation-3,5-two-(O-is to toluyl)-α-D-ribofuranose (compound 3) synthetic
The above-mentioned compound that obtains 2 (83.5mmol) is dissolved in the 40mL glacial acetic acid, under the ice-water bath cooling, slowly adds 63mL HCl-AcOH saturated solution, white solid occurs, to all solidifying, add the 30mL anhydrous diethyl ether, suction filtration, solid washs with cold anhydrous diethyl ether, vacuum-drying obtains 15g white solid 3, and the first two steps total recovery is 51.7%, fusing point 104-106 ℃ (Chen Lili, Cen Junda, Chinese Journal of Pharmaceuticals 2005,36 (7): 387-388; Rolland V., KoteraM., and Lhomme J., Syn.Commun., 1997,27 (20), 3505-3511; Fusing point 108-111 ℃).
3,1 '-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone (compound 5) synthetic
In reaction flask with 5-azepine cytosine(Cyt) (44.6mmol) with after HMDS (100mL) mixes, add a small amount of (NH
4)
2SO
4, reflux is to clarification.With the direct evaporated under reduced pressure of reaction solution, obtain 2-trimethyl silicane aminoalkyl-4-trimethicone-S-triazine (compound 4), be directly used in next step reaction.
The compound 4 that obtains is dissolved in the 40mL acetonitrile, adds compound 3 (38.6mmol), stir under the room temperature and spend the night.The reaction solution evaporated under reduced pressure adds methylene dichloride, washs successively with saturated sodium bicarbonate and saturated aqueous common salt, uses anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains thick liquid (5 '), α, the mixture of two kinds of isomers of β.
With α, mixture (5 ') the acetonitrile recrystallization of two kinds of isomers of β, 4.6g compound 5, LC (UV 254nm) purity is greater than 95%, single configuration β-anomer yield 36.6%.Fusing point 205-208 ℃.LC-MS:m/z 487[M+Na]
+(molecular formula C
24H
24N
4O
6, molecular weight 464).
1H NMR (DMSO-d
6), δ: 8.47 (s, 1H, H-6), 7.92 (d, J=7.8Hz, 2H, Ar-H), 7.72 (d, J=8.4Hz, 2H, Ar-H), 7.55-7.61 (bs, 2H, NH
2), 7.36 (d, J=7.8Hz, 2H, Ar-H), 7.28 (d, J=7.8Hz, 2H, Ar-H), 6.12 (dd, J
12=1.2Hz, J12=7.2Hz, 1H, H-1 ', compound 5 is a beta comfiguration), 5.54 (d, J=6.0Hz, 1H, H-4 '), 5.12 (t, 1H, H-3 '), 4.46 (d, J=4.8Hz, 2H, H-5 '), (2.50 m, 1H, H-2 '), 2.86 (m, 1H, H-2 '), 2.37-2.51 (s+s, 6H).
4, Decitabine (6) is synthetic
Compound 5 (0.72mmol) is dissolved in 0 ℃, 30mL NH
3Among-the MeOH, be stirred under the room temperature and react completely.Use the chromatographic sheet detection reaction.Filter, the filtrate decompression evaporate to dryness is used ethyl alcohol recrystallization.Obtain 101mg white solid product 6, yield 62%.LC-MS:m/z 457.2[2M+H]
+, 479.2[2M+Na]
+(molecular formula C
8H
12N
4O
4, purity (UV 254nm) 98.7%, molecular weight 228).
1H NMR (DMSO-d
6), δ: 8.29 (s, 1H, H-6), 7.42-7.43 (bs, 2H, NH
2), 5.96 (dd, J
12=1.2Hz, J
12=7.2Hz, 1H, H-1 ' compound 6 is a beta comfiguration), 5.21 (d, J=3.0Hz, 1H, H-4 '), 4.86 (t, 1H, H-3 '), 4.21 (m, 2H, H-5 '), 3.39-3.41 (m, 2H, OH), 1.96-2.45 (m, 2H, H-2 ').
Embodiment 2: as described in embodiment 1, different is in the building-up process of step 3, compound 5, replaces acetonitrile to do organic solvent with ethyl acetate, and with α, the mixture (5 ') of two kinds of isomers of β obtains β-isomer with the re-crystallizing in ethyl acetate separation.
Claims (5)
1. method for preparing decitabine; it is characterized in that two silica-basedization products 2 with 5-azepine cytosine(Cyt); 4-pair of trimethyl silicon based-S-triazine; with 1-chloro-2-deoxidation-3; 5-two-(O-is to the toluyl)-α-direct glucosidesization of D-ribofuranose; synthesize α; β-glucosides mixed isomers; this mixed isomers is carried out fractional crystallization with different organic solvents: at first mixed isomers recrystallization in organic solvent acetonitrile or ethyl acetate is separated obtaining β-isomer; then β-isomer is sloughed, obtained Decitabine with the dehydrated alcohol recrystallization again the toluyl protecting group.
2. the described method for preparing decitabine of claim 1 comprises the proportioning of reaction conditions and reactant it is characterized in that synthetic route is as follows:
Corresponding preparation process is as follows:
(1) methanol solution with 2-deoxy-D-ribose and hydrogenchloride carries out methylation reaction, obtains 1-methoxyl group-2-deoxidation-D-ribofuranose;
(2) 1-methoxyl group-2-deoxidation-D-ribofuranose (formula 1) and Butyltriphenylphosphonium chloride are carried out acylation reaction, get 1-methoxyl group-2-deoxidation-3,5-two-(O-is to toluyl)-α, β-D-ribofuranose;
(3) with 1-methoxyl group-2-deoxidation-3,5-two-(O-is to toluyl)-α, β-D-ribofuranose carries out chlorination reaction in hydrogenchloride-acetum, get 1-chloro-2-deoxidation-3,5-two-(O-is to toluyl)-α-D-ribofuranose;
(4) with 1-chloro-2-deoxidation-3,5-two-(O-is to toluyl)-α-D-ribofuranose and 2,4-pair of trimethyl silicon based-S-triazine carried out glycosylation reaction in organic solvent, get 1-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-α, β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone, mixed isomers;
(5) mixed isomers that step (4) is obtained carries out recrystallization, separates out 1-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone, be β-isomer;
(6) with 1-[2 '-deoxidation-3 ', 5 '-two-(O-is to toluyl)-β-D-ribofuranose]-4-amino-S-triazine-2 (1H)-ketone deprotection base, obtain Decitabine.
3. method for preparing decitabine as claimed in claim 2 is characterized in that the described glycosylation reaction organic solvent of step (4) is an acetonitrile.
4. method for preparing decitabine as claimed in claim 2 is characterized in that the described recrystallization of step (5) is directly to carry out recrystallization with acetonitrile or ethyl acetate.
5. method for preparing decitabine as claimed in claim 2 is characterized in that the described deprotection base of step (6) is, with the saturated alcoholic solution dissolving β-isomer of ammonia, TLC detects 18-20h and reacts completely in the time of 0 ℃; The solution that gained reacts completely removes and desolvates, and uses the dehydrated alcohol recrystallization again, obtains the white crystals Decitabine after the freezing treatment.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101948493A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Industrialized production method for high-purity decitabine |
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| CN102010455B (en) * | 2009-09-05 | 2012-07-11 | 山东新时代药业有限公司 | Method for preparing decitabine |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101307084A (en) * | 2008-07-08 | 2008-11-19 | 贵州大学 | Synthetic process of decitabine |
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| CN102010455B (en) * | 2009-09-05 | 2012-07-11 | 山东新时代药业有限公司 | Method for preparing decitabine |
| CN102171195A (en) * | 2009-10-02 | 2011-08-31 | 台湾神隆股份有限公司 | Synthesis of decitabine |
| CN102171195B (en) * | 2009-10-02 | 2015-07-08 | 台湾神隆股份有限公司 | Synthesis 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 |
| CN101948493A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Industrialized production method for high-purity decitabine |
| CN103897008A (en) * | 2012-12-28 | 2014-07-02 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing decitabine and intermediate thereof |
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| CN103242386B (en) * | 2013-04-11 | 2015-11-04 | 中国中化股份有限公司 | A kind of method preparing alpha-1-methoxyl group-2-desoxyribofu-derivative |
| CN103232512A (en) * | 2013-04-13 | 2013-08-07 | 连云港杰瑞药业有限公司 | Method for preparing beta-enriched Decitabine precursor |
| CN103232512B (en) * | 2013-04-13 | 2015-12-09 | 连云港杰瑞药业有限公司 | A kind of method preparing the Decitabine precursor of β-enrichment |
| CN104211743A (en) * | 2013-05-29 | 2014-12-17 | 南京工业大学 | Synthesis of decitabine |
| CN110054654A (en) * | 2019-05-27 | 2019-07-26 | 武汉百科药物开发有限公司 | A kind of synthetic method of Decitabine intermediate alpha-substituted deoxyribose |
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