CN102485737B - Method for preparing decitabine - Google Patents
Method for preparing decitabine Download PDFInfo
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- CN102485737B CN102485737B CN201010574317.8A CN201010574317A CN102485737B CN 102485737 B CN102485737 B CN 102485737B CN 201010574317 A CN201010574317 A CN 201010574317A CN 102485737 B CN102485737 B CN 102485737B
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- XAUDJQYHKZQPEU-HSUXUTPPSA-N NC(N=CN1[C@@H](C2)O[C@H](CO)[C@@H]2O)=NC1=O Chemical compound NC(N=CN1[C@@H](C2)O[C@H](CO)[C@@H]2O)=NC1=O XAUDJQYHKZQPEU-HSUXUTPPSA-N 0.000 description 1
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Abstract
The invention provides a method for preparing decitabine, which takes azacitidine as a raw material, the method comprises the following steps: reacting with 1,3-dichloro-1,1,3,3,-tetraisopropyldisiloxane (TPDS-C12) by taking pyridine as a solvent to prepare silane compounds, then reacting with methyl triphenoxyl phosphonium iodide (MTPI) to obtain 2-iodine substituent, reducing by introducing H2 under Pd/C catalysis to obtain the deoxidant, reacting with tetrabutylammonium fluoride (TBAF) and carrying out deprotection to obtain the decitabine. The product purity can reach 99%, the overall yield is 62%, the technology operation is simple and easy for large scale production realization.
Description
Contriver (first rainbow Wang Hao)
Technical field
The preparation method who the present invention relates to a kind of Decitabine, belongs to technical field of pharmaceutical chemistry.
Background technology
Myelodysplastic syndrome (Myelodysplastic syndrome, MDS) is that the abnormal and excessive risk of one group of matter take hemocyte, amount becomes the heterogeneous hemopoietic stem cell disease of acute leukemia as feature.Because the genomic dna of MDS cell exists abnormal methylation, the promoter CpG island of many critical function genes is due to high methylation, the suppressed functionally inactive that causes of transcriptional level.If tumor suppressor gene promoter region occurs new methylating with the gene relevant with maintaining genome stability, these genes, by silence, make cell may obtain growth vigor and paraplasm, become and promote swollen neoplastic principal element.Decitabine is exactly a kind of demethylation medicine, has the treatment mechanism of unique methylated transferase inhibitor.In March, 2004, SuperGen company has completed Decitabine treatment MDS patient's a clinical trial phase.MGI pharmacy and SuperGen company announce that Decitabine is a class hypomethylation reagent.2006, U.S. FDA was ratified the application for quotation of Decitabine (decitabine) injection liquid, and commodity are called Dacogen, the granted myelodysplastic syndrome (MDS) that is used for the treatment of.
The synthetic method of existing Decitabine has several as follows:
1. isocyanic ester method (1978, Wiley, New York, N.Y., 443-449): the method has been used isocyanic acid silver salt, and synthetic route is long, need to carry out isomer separation, without the meaning of industrialization.
The direct glucosides of 2.5-azepine cytosine(Cyt): need to use different protective materials; some protective materials are expensive; and what this method obtained is all α, β-anomeric mixtures, must separate and just can obtain Decitabine through post, the value of large-scale production is little.Also have to obtain by fractional crystallization method, but industrial operation is loaded down with trivial details, is difficult to control.
3. azacitidine deoxidation method (J.A.C.S, 1983,105 (12), 4059-4065): the method need to be used sulfo-phenyl chloroformate and TTMSS, high cost.
Summary of the invention
The object of the invention is to overcome the deficiency that prior art exists, a kind of preparation method of Decitabine is provided, on the basis of aforesaid method 3, improve, first use 1,3-bis-chloro-1,1,3,3 ,-tetra isopropyl disiloxane (TPDS-Cl
2) protect, then take methyl triple phenoxyl phosphonium iodide (MTPI) as iodo reagent, replace 2-OH, and then carry out hydrogenating reduction reduction, finally slough protecting group and obtain Decitabine.The present invention adopts the starting material that are easy to get, and makes finished product with the operation of simplifying.
Object of the present invention is achieved through the following technical solutions:
The preparation method of Decitabine, take azacitidine as raw material, feature is:
First, by I, pyridine, TPDS-Cl
2mix and blend reaction, reacts complete distillation, and residuum is dissolved in solvent, solution washing, and organic layer is dry, the refining II that obtains after filtration, evaporate to dryness.
Then, II is reacted with MTPI, DMF, add a small amount of methyl alcohol, stirring reaction.Be concentrated into after completion of the reaction dryly, residuum is dissolved in chloroform, washing, layering, dry.Be distilled to after dry and obtain III with solvent treatment.
Then III is dissolved in methyl alcohol and triethylamine, adds 10%Pd/C, pass into H
2, carry out reduction reaction.Filter after completion of the reaction, filtrate evaporate to dryness obtains IV.
Finally above-mentioned IV is joined in the THF solution of TBAF, protecting group is sloughed in reaction.React complete be distilled to dry, the refining V that obtains of residuum.
Further, the preparation method of above-mentioned Decitabine, wherein, the described I of step (1) and TPDS-Cl
2mol ratio be 1: (1-1.2).Reaction times is 2-10 hour, and temperature of reaction is 10-40 ℃.
Further, the preparation method of above-mentioned Decitabine, wherein, the solvent that the described residuum of step (1) dissolves is ethyl acetate, the aqueous solution of washing is successively rare HCl, H
2o, NaHCO
3solution, refining solvent is ethanol, methyl alcohol.
Further, the preparation method of above-mentioned Decitabine, wherein, described in step (2), the mol ratio of II and MTPI is 1: (1-2).Reaction times is 20 minutes-2 hours, and temperature of reaction is 20-40 ℃.Refining solvent is ethanol, chloroform-normal hexane.
Further, the preparation method of above-mentioned Decitabine, wherein, III described in step (3): methyl alcohol (m: v)=1: (5-10); III: triethylamine (m: v)=1: (0.5-1).Reaction times is 3-24 hour, and temperature of reaction is 20-50 ℃.
Again further, the preparation method of above-mentioned Decitabine, wherein, described in step (4), the THF concentration of TBAF is: 0.8-1.2mol/L, refining solvent is alcohol-ether, methyl alcohol-ether.Reaction times is 2-10 hour, and temperature of reaction is 50-90 ℃.
The substantive distinguishing features that technical solution of the present invention is outstanding and significant progressive being mainly reflected in:
1. improve existing azacitidine deoxidation method, avoid the starting material that use sulfo-phenyl chloroformate and TTMSS etc. to be not easy to obtain, the method that adopts iodine to replace, starting material are easy to get, and technological operation is easy.
2. avoided column chromatography for separation α, β product, be applicable to large-scale production and amplify.And yield is up to 62%, and product purity reaches 99.0%.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, technical solution of the present invention is described further:
Fig. 1: reaction equation
Embodiment
The present invention proposes a kind of preparation method of new Decitabine, take azacitidine as raw material, first uses TPDS-Cl
2protect, then take MTPI as iodo reagent, replace 2-OH, then carry out hydrogenation reduction, finally slough protecting group and obtain Decitabine.
The preparation of embodiment 1:II
By 12.2g I, 17.8g TPDS-Cl
2, 100ml pyridine is fed in four-necked bottle, opens and stirs, and reacts 5 hours at 25-30 ℃, reaction finishes reactant to be concentrated into dry, slowly adds 100ml ethyl acetate, stirring and dissolving, adds respectively 30ml dilute hydrochloric acid, 30ml water, 30mlNaHCO
3washing, organic layer anhydrous Na
2sO
4dry, dry complete filtration, is distilled to dryly, obtains product I I 20.9g after adding 100ml ethanol refining.
The preparation of embodiment 2:III
The II of 14.6g, 20.3gMTPI are dissolved in 100ml dry DMF, after stirring, add 10ml methyl alcohol, in 25-30 ℃ of reaction 30min.React complete, reactant is distilled to dry, add 100ml chloroform stirring and dissolving, 30ml washing three times, collected organic layer anhydrous Na
2sO
4be dried, dry be completely distilled to dryly, add the refining product I II15.4g of obtaining of ethanol.
The preparation of embodiment 3:III
The II of 14.6g, 16.3gMTPI are dissolved in 100ml dry DMF, after stirring, add 10ml methyl alcohol, in 20-25 ℃ of reaction 1 hour.React complete, reactant is distilled to dry, add 100ml chloroform stirring and dissolving, 30ml washing three times, collected organic layer anhydrous Na
2sO
4be dried, dry be completely distilled to dryly, add the refining product I II16.1g of obtaining of chloroform-normal hexane.
The preparation of embodiment 4:IV
The III of 14.9g is dissolved in 100ml methyl alcohol and 10ml triethylamine, stirs, add 1.5g10%Pd/C, N in reactor
2displaced air three times, H
2displacement N
2three times, pass into H
2, in 40-45 ℃ of reaction 6 hours, reacting complete filtration, filtrate evaporate to dryness obtains IV10.1g.
The preparation of embodiment 5:IV
The III of 14.9g is dissolved in 100ml methyl alcohol and 10ml triethylamine, stirs, add 1.5g10%Pd/C, N in reactor
2displaced air three times, H
2displacement N
2three times, pass into H
2, in 30-35 ℃ of reaction 12 hours, reacting complete filtration, filtrate evaporate to dryness obtains IV10.8g.
The preparation of embodiment 6:V
Above-mentioned IV is joined in the THF solution of 46ml1M TBAF, in 70-75 ℃ of reaction 3 hours, react complete be distilled to dry, by refining 4.56gV, the purity 99.0% of obtaining of alcohol-ether.
Claims (10)
1. a preparation method for Decitabine (V), take azacitidine (I) as raw material, its feature comprises the following steps:
(1), by I, pyridine, 1,3-bis-is chloro-1,1,3,3 ,-tetra isopropyl disiloxane (TPDS-Cl
2) mix and blend reaction, reacting complete distillation, residuum is dissolved in solvent, solution washing, organic layer is dry, the refining II that obtains after filtration, evaporate to dryness;
(2) II is reacted with methyl triple phenoxyl phosphonium iodide (MTPI), DMF, add a small amount of methyl alcohol, stirring reaction; Be concentrated into after completion of the reaction dryly, residuum is dissolved in chloroform, washing, layering, dry; Be distilled to after dry and obtain III with solvent treatment;
(3) III is dissolved in methyl alcohol and triethylamine, adds 10%Pd/C, pass into H
2, carry out reduction reaction; Filter after completion of the reaction, filtrate evaporate to dryness obtains IV;
(4) IV is joined in the THF solution of tetrabutyl ammonium fluoride (TBAF), protecting group is sloughed in reaction; React complete be distilled to dry, the refining V that obtains of residuum.
2. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: I and TPDS-Cl described in step (1)
2mol ratio be 1: (1-1.2).
3. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: the reaction times described in step (1) is 2-10 hour, and temperature of reaction is: 10-40 ℃.
4. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: the solvent that residuum described in step (1) dissolves is ethyl acetate, and the aqueous solution of washing is successively rare HCl, H
2o, NaHCO
3solution, refining solvent is ethanol, methyl alcohol.
5. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: described in step (2), the mol ratio of II and MTPI is 1: (1-2).
6. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: the reaction times described in step (2) is 20 minutes-2 hours, and temperature of reaction is 20-40 ℃; Refining solvent is ethanol, chloroform-normal hexane.
7. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: described in step (3), the mass volume ratio of III and methyl alcohol is 1: (5-10); The mass volume ratio of III and triethylamine is 1: (0.5-1).
8. preparation method's method of a kind of Decitabine according to claim 1, is characterized in that: the reaction times described in step (3) is 3-24 hour, and temperature of reaction is 20-50 ℃.
9. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: described in step (4), the THF concentration of TBAF is: 0.8-1.2mol/L, refining solvent is alcohol-ether, methyl alcohol-ether.
10. the preparation method of a kind of Decitabine according to claim 1, is characterized in that: the reaction times described in step (4) is 2-10 hour, and temperature of reaction is 50-90 ℃.
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| CN201010574317.8A CN102485737B (en) | 2010-12-06 | 2010-12-06 | Method for preparing decitabine |
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| CN201010574317.8A CN102485737B (en) | 2010-12-06 | 2010-12-06 | Method for preparing decitabine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6087490A (en) * | 1996-03-23 | 2000-07-11 | Novartis Ag | Dinucleotide and oligonucleotide analogues |
| WO2004028454A2 (en) * | 2002-09-24 | 2004-04-08 | Koronis Pharmaceuticals, Incorporated | 1, 3, 5-triazines for treatment of viral diseases |
-
2010
- 2010-12-06 CN CN201010574317.8A patent/CN102485737B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6087490A (en) * | 1996-03-23 | 2000-07-11 | Novartis Ag | Dinucleotide and oligonucleotide analogues |
| WO2004028454A2 (en) * | 2002-09-24 | 2004-04-08 | Koronis Pharmaceuticals, Incorporated | 1, 3, 5-triazines for treatment of viral diseases |
Non-Patent Citations (2)
| Title |
|---|
| 地西他滨的合成;季竞竞等;《中国医药工业杂志》;20071231;第38卷(第7期);第468-469页 * |
| 季竞竞等.地西他滨的合成.《中国医药工业杂志》.2007,第38卷(第7期),第468-469页. |
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