CN101987858A - New method for preparing decitabine beta-configuration intermediate - Google Patents
New method for preparing decitabine beta-configuration intermediate Download PDFInfo
- Publication number
- CN101987858A CN101987858A CN2009100561113A CN200910056111A CN101987858A CN 101987858 A CN101987858 A CN 101987858A CN 2009100561113 A CN2009100561113 A CN 2009100561113A CN 200910056111 A CN200910056111 A CN 200910056111A CN 101987858 A CN101987858 A CN 101987858A
- Authority
- CN
- China
- Prior art keywords
- reaction
- decitabine
- compound
- temperature
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 C=N/C(/N=C/N1[C@@](C2)OC(C3)(C3O)[C@@]2O)=*\C*C1=O Chemical compound C=N/C(/N=C/N1[C@@](C2)OC(C3)(C3O)[C@@]2O)=*\C*C1=O 0.000 description 2
Images
Abstract
The invention relates to a new method for preparing a decitabine beta-configuration intermediate. The method comprises the following steps of: reacting a decitabine alpha-configuration intermediate used as a raw material with a silanized reagent under an alkaline condition; then preparing the decitabine beta-configuration intermediate in the presence of the action of Lewis acid; and passivating and deprotecting the decitabine beta-configuration intermediate to prepare decitabine. The method can recycle a large quantity of byproducts generated in the process of preparing the decitabine of the traditional method, thereby greatly reducing the material waste, improving the overall yield and reducing the cost, and meanwhile, the method is suitable for industrial production.
Description
Technical field
The invention belongs to chemical field, be specifically related to a kind of novel method for preparing the beta comfiguration intermediate of Decitabine.
Background technology
The chemistry of Decitabine (Decitabine) is by name: 4-amino-1-(2-deoxidation-β-D-erythro form-penta furanoside base)-1,3,5-triazines-2 (1H)-ketone, shown in (IV), call and be 5-azepine-2 '-Deoxyribose cytidine.It is by a kind of antitumor drug of U.S. SuperGen company development, is used for the treatment of myelodysplastic syndrome (MDS), and its commodity are called Dacogen
TM
In the Decitabine of prior art for preparing, containing the Decitabine αYi Gouti usually, shown in (V), also is one of major impurity of Decitabine preparation.
The preparation method the earliest of Decitabine is: construct triazine base fragment in the Decitabine molecular structure by the isocyanate groups on 1 the end group carbon of 3,5 protected 2-deoxyribosyls of hydroxyl; carry out deprotection at last again and prepare Decitabine; referring to document Collect.Czech.Chem.Commun.; 1964; 29, p2576-2578.This method steps is long, productive rate is low, cost is high, lack industrial applicibility.
Another kind of preparation method is with 2-deoxidation-3; two couples of toluyl-α of 5--D-furanoside muriate (VI) is a starting raw material; carry out glycosylation reaction with the 5-azepine cytosine(Cyt) (VII) of silicon ether protection; reaction substrate makes compound (III ') (one of Decitabine beta comfiguration intermediate) through aftertreatment; can make Decitabine through the deprotection base again, reaction formula is as follows.Referring to J.Org.Chem., 1974,39 (25), p3672-3674 and United States Patent (USP) 3817980.
Wherein Tol is to methyl benzoyl; TMS is that front three is silica-based.
This method produces a large amount of by-product compounds (I ') (one of Decitabine α configuration intermediate), content about 50% in the glycosylation reaction process.Compound (I ') behind deprotection, obtain the Decitabine αYi Gouti, Decitabine αYi Gouti parmacodynamics-less activity is one of major impurity of Decitabine product.Because the by-product compounds that this method produces (I ') measure greatly, make that the overall yield of preparation Decitabine is low, thereby cause the production cost height.
So far, also not open report is recycled the method for Decitabine α configuration intermediate preparation Decitabine.Therefore, press for a kind of method of exploitation, utilize Decitabine α configuration intermediate preparation Decitabine beta comfiguration intermediate, and then the preparation Decitabine.By this method, can recycle by product, reduce the material waste, significantly reduce the production cost of Decitabine.
Summary of the invention
In order to solve the problems of the technologies described above, the invention provides a kind of method of utilizing Decitabine α configuration intermediate preparation Decitabine beta comfiguration intermediate.Decitabine beta comfiguration intermediate is carried out promptly obtaining Decitabine behind the deprotection.
Decitabine beta comfiguration intermediate of the present invention is meant the compound represented as following structural formula (III),
Described Decitabine α configuration intermediate is meant the compound represented as following structural formula (I),
Wherein R is selected from C
2-C
4Alkyloyl, substituted C
2-C
4Alkyloyl, carbobenzoxy-(Cbz), benzyl or
R wherein
1Be selected from C
1-C
4Alkyl, halogen atom or nitro.
The invention provides a kind of novel method for preparing Decitabine beta comfiguration intermediate, comprising:
1) compound (I) is reacted with silylating reagent under alkaline condition, preparation compound (II),
2) compound (II) with the step 1) gained acts on down through Louis (Lewis) acid, and reaction makes Decitabine beta comfiguration intermediate.As shown in the formula reaction:
Wherein R is selected from C
2-C
4Alkyloyl, substituted C
2-C
4Alkyloyl, carbobenzoxy-(Cbz), benzyl or
R wherein
1Be selected from C
1-C
4Alkyl, halogen atom or nitro, TMS are that front three is silica-based.
The described R of above-mentioned preparation method base is selected hydroxyl protecting group commonly used, and the protecting group that can leave away by hydrolysis preferably is preferably to methyl benzoyl or ethanoyl, more preferably to methyl benzoyl.
Above-mentioned steps 1) in: described alkaline condition preferably adds organic bases, is selected from C
1-C
4Secondary amine, C that alkyl replaces
1-C
4Tertiary amine, pyridine or 4-Dimethylamino pyridine that alkyl replaces, preferred diethylamine or triethylamine; Described silylating reagent is selected from the mixed of trimethylchlorosilane, Iodotrimethylsilane, bromotrimethylsilane, trimethyl silicane alkanol or above arbitrary reagent and hexamethyldisilazane, and preferably trimethylchlorosilane or trimethylchlorosilane and hexamethyldisilazane is mixed; Reaction solvent is selected from acetonitrile, methylene dichloride, trichloromethane, tetrahydrofuran (THF), 1,4-dioxane, acetone, N, the arbitrary proportion of dinethylformamide or above-mentioned any two kinds of solvents mixed, preferred methylene dichloride; Temperature of reaction is at 0～100 ℃, preferred 20～40 ℃.
Above-mentioned steps 2) described Lewis acid is selected from BF
3.OEt
2, FeCl
3, AlCl
3, SnCl
4, SnCl
2, SbCl
5, ZnCl
2, ZnI
2, EtAlCl
2, SnCl
4/ Sn (OTf)
2/ LiClO
4, Sn (OTf)
2/ BuSn (OAc)
2, TMSOSO
2C
4F
9Or TMSOTf (three silyl triflate), preferred TMSOTf; Reaction solvent is selected from acetonitrile, benzene,toluene,xylene, 1, the arbitrary proportion of 2-ethylene dichloride, methylene dichloride, trichloromethane or above-mentioned any two kinds of solvents mixed, preferred acetonitrile and 1, the mixing of 2-ethylene dichloride; Temperature of reaction is 0～100 ℃, preferred 20～40 ℃.
Utilize aforesaid method to make Decitabine beta comfiguration intermediate, contain by product Decitabine α configuration intermediate, preferably both mol ratios are more than or equal to 1.During purifying Decitabine beta comfiguration intermediate, separablely go out Decitabine α configuration intermediate, it can be used as the starting raw material of the method for the invention, therefore can the recycling by product.
After utilizing the method for the invention to make Decitabine beta comfiguration intermediate to carry out purifying in accordance with known methods, slough the corresponding protection base, make Decitabine.Known purification process is solvent recrystallization method, column chromatography or preparative chromatography partition method etc. for example, and known deprotection based method can use hydride process, hydrolysis method etc.
The invention provides a kind of method for preparing his shore beta comfiguration intermediate of west, may further comprise the steps:
1) compound (I) is dissolved in the organic solvent, adds organic bases, silylating reagent, carry out prepared in reaction compound (II) under 0～100 ℃ of the temperature of reaction;
2) compound (II) is dissolved in the organic solvent, adds Lewis acid, carry out prepared in reaction Decitabine beta comfiguration intermediate under 0～100 ℃ of the temperature of reaction.
Compound (I), (II) as previously mentioned, the described organic solvent of step 1), organic bases, silylating reagent or step 2) described organic solvent, Lewis acid are respectively as previously mentioned.
After the Decitabine beta comfiguration intermediate of method for preparing carried out purifying in accordance with known methods, sloughs the R protecting group, make Decitabine; R as defined above.
The invention provides a kind of concrete method for preparing his shore beta comfiguration intermediate of west, comprising:
1) compound (I ') is dissolved in the methylene dichloride, adds triethylamine, trimethylchlorosilane, hexamethyldisilazane, carry out prepared in reaction compound (II ') under 20～40 ℃ of the temperature of reaction;
2) compound (II ') is dissolved in acetonitrile and 1, the 2-ethylene dichloride adds three silyl triflate, carries out prepared in reaction compound (III ') under 20～40 ℃ of the temperature of reaction,
Reaction formula is as follows.
Wherein Tol is to methyl benzoyl, and TMS is that front three is silica-based.
Compound (III ') behind column chromatography purification, through the hydrolysis deprotection, make Decitabine again.
The method reusable edible for preparing Decitabine beta comfiguration intermediate provided by the invention prepares the by product that produces in the Decitabine process, avoid the material waste, saved the energy, improved whole yield greatly, reduced the production cost of Decitabine, and this method is fit to suitability for industrialized production.
Description of drawings
The HPLC analysis chart of the compound of Fig. 1 embodiment 1 (III ') (one of Decitabine beta comfiguration intermediate) crude product.
Fig. 2 is the HPLC analysis chart of pure compound (I ') (one of Decitabine α configuration intermediate).
The HPLC analysis chart of the Decitabine of Fig. 3 embodiment 3.
Embodiment
The invention will be further described below in conjunction with embodiment, can make this area professional and technical personnel more fully understand the present invention, but not limit the present invention in any way.
Embodiment 1
Reaction formula:
With 0.116g 4-amino-1-[3; 5-two (to toluyl)-2-deoxidation-α-D-furanoside base]-1; 3; 5-triazine-2 (1H)-ketone is that compound (I ') (one of Decitabine α configuration intermediate) is dissolved in the 50ml methylene dichloride; the hexamethyldisilazane that adds 0.18mL triethylamine, 0.12mL trimethylchlorosilane and catalytic amount; react in the room temperature environment; after reaction finishes; reaction substrate decompression be spin-dried for residue; mainly contain compound (II '); do not need purifying, be directly used in next step reaction.
Residue is dissolved in 20mL acetonitrile and 20mL 1, in the 2-ethylene dichloride, adds 0.9mL TMSOTf, reaction is 72 hours in the room temperature environment, adds saturated NaHCO
3The aqueous solution is used CH
2Cl
2Extraction, saturated NaCl solution washing, anhydrous Na
2SO
4Drying, concentrate to remove desolvate after, make compound (III ') (one of Decitabine beta comfiguration intermediate) crude product 0.1g.Analyze through HPLC, contain by-product compounds (I ') in compound (the III ') crude product, both mol ratios are about 3: 2, and as shown in Figure 1, wherein retention time 8.990 is compound (I '), and retention time 9.971 is compound (III '); The HPLC of pure compound (I ') as shown in Figure 2, its retention time is 8.918.
Embodiment 2
The compound that embodiment 1 is made (III ') 0.1g, (eluent is CHCl to carry out column chromatography purification
3: CH
3OH=30: 1v/v) make compound (III ') 0.05g, fusing point: 194～196 ℃.
Embodiment 3
The compound that embodiment 2 is made (III ') 0.05g; make Decitabine 0.015g (yield about 60%) after sloughing protecting group, purifying according to the method for United States Patent (USP) 3817980 embodiment 8; fusing point: 200～201 ℃, HPLC shows that content is 99.2%, as shown in Figure 3.
Claims (19)
1. novel method for preparing Decitabine beta comfiguration intermediate comprises:
1) compound (I) is reacted with silylating reagent under alkaline condition, preparation compound (II),
2) with the compound (II) of step 1) gained under the Lewis acid effect, reaction makes Decitabine beta comfiguration intermediate (III);
Wherein TMS is that front three is silica-based; Wherein R is selected from C
2-C
4Alkyloyl, substituted C
2-C
4Alkyloyl, carbobenzoxy-(Cbz), benzyl or
R wherein
1Be selected from C
1-C
4Alkyl, halogen atom or nitro.
2. method according to claim 1 is characterized in that R is to methyl benzoyl.
3. method according to claim 1 is characterized in that the described alkaline condition of step 1) for adding organic bases, is selected from C
1-C
4Secondary amine, C that alkyl replaces
1-C
4Tertiary amine, pyridine or 4-Dimethylamino pyridine that alkyl replaces.
4. method according to claim 3 is characterized in that organic bases is triethylamine or diethylamine.
5. method according to claim 1 is characterized in that the described silylating reagent of step 1) is selected from the mixed of trimethylchlorosilane, Iodotrimethylsilane, bromotrimethylsilane, trimethyl silicane alkanol or above arbitrary reagent and hexamethyldisilazane.
6. method according to claim 1 is characterized in that step 2) described Lewis acid is selected from BF
3.OEt
2, FeCl
3, AlCl
3, SnCl
4, SnCl
2, SbCl
5, ZnCl
2, ZnI
2, SnCl
4/ Sn (OTf)
2/ LiClO
4, Sn (OTf)
2/ BuSn (OAc)
2, TMSOSO
2C
4F
9Or TMSOTf (three silyl triflate).
7. method according to claim 6 is characterized in that described Lewis acid is three silyl triflate.
8. method according to claim 1, the reaction solvent that it is characterized in that step 1) is selected from acetonitrile, methylene dichloride, trichloromethane, tetrahydrofuran (THF), 1,4-dioxane, acetone, N, the arbitrary proportion of dinethylformamide or above-mentioned any two kinds of solvents mixed.
9. method according to claim 8, the reaction solvent that it is characterized in that step 1) is a methylene dichloride.
10. method according to claim 1, the temperature of reaction that it is characterized in that step 1) is 0～100 ℃.
11. method according to claim 10, the temperature of reaction that it is characterized in that step 1) is 20～40 ℃.
12. method according to claim 1 is characterized in that step 2) reaction solvent be selected from acetonitrile, benzene,toluene,xylene, 1, the arbitrary proportion of 2-ethylene dichloride, methylene dichloride, trichloromethane or above-mentioned any two kinds of solvents mixed.
13. method according to claim 12 is characterized in that step 2) reaction solvent be selected from acetonitrile and 1,2-ethylene dichloride mixed.
14. method according to claim 1 is characterized in that step 2) temperature of reaction be 0～100 ℃.
15. method according to claim 14 is characterized in that step 2) temperature of reaction be 20～40 ℃.
16. method according to claim 1 is characterized in that the Decitabine beta comfiguration intermediate that makes by described method contains Decitabine α configuration intermediate, wherein the mol ratio of beta comfiguration and α configuration is more than or equal to 1.
17. method according to claim 1 also comprises subsequent step, and Decitabine beta comfiguration intermediate is carried out purifying, sloughs the R protecting group and make Decitabine; Wherein R as above defines.
18. method according to claim 1 may further comprise the steps:
1) compound (I) is dissolved in the organic solvent, adds organic bases, silylating reagent, carry out prepared in reaction compound (II) under 0～100 ℃ of the temperature of reaction;
2) compound (II) is dissolved in the organic solvent, adds Lewis acid, carry out prepared in reaction compound (III) under 0～100 ℃ of the temperature of reaction;
Wherein compound (I), (II), (III) as above define.
19. method according to claim 18 may further comprise the steps:
1) compound (I ') is dissolved in the methylene dichloride, adds triethylamine, trimethylchlorosilane, hexamethyldisilazane, carry out prepared in reaction compound (II ') under 20～40 ℃ of the temperature of reaction;
2) compound (II ') is dissolved in acetonitrile and 1, the 2-ethylene dichloride adds three silyl triflate, carries out prepared in reaction compound (III ') under 20～40 ℃ of the temperature of reaction;
Wherein Tol is to methyl benzoyl, and TMS is that front three is silica-based.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910056111A CN101987858B (en) | 2009-08-07 | 2009-08-07 | New method for preparing decitabine beta-configuration intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910056111A CN101987858B (en) | 2009-08-07 | 2009-08-07 | New method for preparing decitabine beta-configuration intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101987858A true CN101987858A (en) | 2011-03-23 |
| CN101987858B CN101987858B (en) | 2012-09-26 |
Family
ID=43744669
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910056111A Active CN101987858B (en) | 2009-08-07 | 2009-08-07 | New method for preparing decitabine beta-configuration intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101987858B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108239128A (en) * | 2016-12-23 | 2018-07-03 | 江苏奥赛康药业股份有限公司 | The preparation method of beta-nucleosides class compound |
| US11187683B2 (en) | 2016-12-13 | 2021-11-30 | Jiangsu Aosaikang Pharmaceutical Co., Ltd. | Dexrazoxane analytical method |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009086687A1 (en) * | 2008-01-03 | 2009-07-16 | Nanjing Zhongshi Chemical Co., Ltd. | The synthesis method of decitabine |
| CN101307084A (en) * | 2008-07-08 | 2008-11-19 | 贵州大学 | Synthetic process of decitabine |
-
2009
- 2009-08-07 CN CN200910056111A patent/CN101987858B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11187683B2 (en) | 2016-12-13 | 2021-11-30 | Jiangsu Aosaikang Pharmaceutical Co., Ltd. | Dexrazoxane analytical method |
| CN108239128A (en) * | 2016-12-23 | 2018-07-03 | 江苏奥赛康药业股份有限公司 | The preparation method of beta-nucleosides class compound |
| CN108239128B (en) * | 2016-12-23 | 2019-03-29 | 江苏奥赛康药业股份有限公司 | The preparation method of beta-nucleosides class compound |
| US10752652B2 (en) | 2016-12-23 | 2020-08-25 | Jiangsu Aosaikang Pharmaceutical Co., Ltd. | Method for preparing a ß-nucleoside compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101987858B (en) | 2012-09-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100457755B1 (en) | Novel 5-O-Desosaminyl 6-O-Methyl Erythronolide A Derivatives, Method for Preparing Same and Application Thereof for Preparing Biologically Active Products | |
| CN102037003B (en) | Method of producing 2'-deoxy-5-azacytidine (decitabine) | |
| CN103121999A (en) | Method for synthesizing tyrosine kinase inhibitor PCI-32765 | |
| EP0260938B1 (en) | Erythromycin a derivatives and method for preparing the same | |
| CN1984898A (en) | Process for production of azulene derivatives and intermediates for the synthesis of the same | |
| CN102933570B (en) | Method for producing (2r)-2-fluoro-2-c-methyl-d-ribono-y-lactone precursor | |
| CN105037363A (en) | Novel synthetic method for entecavir compound | |
| Legorburu et al. | Conversion of uridine into 2′-O-(2-methoxyethyl) uridine and 2′-O-(2-methoxyethyl) cytidine | |
| CN101987858B (en) | New method for preparing decitabine beta-configuration intermediate | |
| CN102516281A (en) | 10-deacetylbaccatin III and method for methoxylation of its derivative | |
| CN114292303A (en) | Preparation method of antiviral drug mupirovir | |
| CN105418681A (en) | Preparation method of tedizolid phosphate | |
| CN111646964B (en) | Novel method for synthesizing 2H-pyran-2-one derivative by base catalysis | |
| CN109970832B (en) | Alkynyl-modified deoxyadenosine phosphoramidite monomer and preparation method thereof | |
| CN102558274B (en) | Synthetic method applicable to industrial production of Abiraterone acetate | |
| Webb | The direct conversion of 5′-O-trityl-3′-keto-2′-deoxythymidine to 1-(2-deoxy-3-methyl-beta-D-xylosyl) thymine | |
| CN105964304A (en) | Method for catalytic synthesis of gamma-propyl chloride trichlorosilane and catalyst thereof | |
| CN102993255B (en) | The preparation of 2 '-O-(2-methoxyethyl)-5-methyl-uridin and 2 '-O-(2-methoxyethyl)-5-methylcytidine and derivative thereof and purification process thereof | |
| CN111269128A (en) | Synthesis method of 1, 1' - (hexa-2, 4-diyne-1, 6-diyl) bis (3-alkyl urea) compound | |
| CN101607963B (en) | Morphinan derivatives and preparation method thereof | |
| CN101343308B (en) | Method for preparing 7 alpha-bromo-sterides | |
| CN111454277A (en) | Synthetic method of eribulin intermediate ER806047 | |
| CN103193570A (en) | High-selectivity protection method of hydroxy | |
| CN117551155B (en) | Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine | |
| CN113880901B (en) | Synthesis method of (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |