CN103232512A - Method for preparing beta-enriched Decitabine precursor - Google Patents
Method for preparing beta-enriched Decitabine precursor Download PDFInfo
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- CN103232512A CN103232512A CN2013101269059A CN201310126905A CN103232512A CN 103232512 A CN103232512 A CN 103232512A CN 2013101269059 A CN2013101269059 A CN 2013101269059A CN 201310126905 A CN201310126905 A CN 201310126905A CN 103232512 A CN103232512 A CN 103232512A
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Abstract
The invention discloses a method for preparing beta-enriched decitabine precursor, which comprises the following steps: heating reflux of decitabine precursor crude product at the ratio of isomer alpha to beta being 1 to 0.8-2 in a mixed solvent containing water, organic solvent C1-C3 alcohol, acetone or tetrahydrofuran, cooling and filtering, filtrate condensation, crystallization, filtering, vacuum drying of filter cake, obtaining of the beta-enriched decitabine precursor at the ratio of the isomer alpha to beta being 1 to 7-18. After a protective group of the obtained beta-enriched decitabine precursor is removed, a high-yield and high purity decitabine is obtained.
Description
Technical field
The invention belongs to the medical chemistry technical field, relate to a kind of preparation method of Decitabine precursor, particularly relate to a kind of preparation method of Decitabine precursor of β-enrichment.
Background technology
Decitabine (decitabine) is natural nucleus glycoside 2-Deoxyribose cytidine analogue, the dnmt rna inhibitor, by Supergen company research and development and by MGI Pharma company respectively at going on the market in Europe and the U.S. in April, 2006 and May, go on the market in China in September, 2008, trade(brand)name " Dacogen ", formulation is freeze-dried powder, and specification 50 mg are used for the treatment of primary and Secondary cases myelodysplastic syndrome (MDS).Decitabine is a kind of demethylation medicine, has the treatment mechanism of unique methylated transferase inhibitor.As a kind of neplanocin of 2`-deoxycytidylic acid(dCMP), Decitabine can be converted into 5`-monophosphate Deoxyribose cytidine analogue in vivo, infiltrates under the archaeal dna polymerase effect among the DNA, suppresses the synthetic of DNA and methylates, thereby suppress tumor cell proliferation.Because its unique mechanism of action, Decitabine is being carried out and is being shown good curative effect in the clinical study of 29 more than for the treatment of ovarian cancer, mammary cancer, prostate cancer, cancer of the stomach, lung cancer etc., gets a good chance of becoming the new drug of other cancer for the treatment of.
The chemical name of Decitabine (decitabine) is 4-amino-1-(2'-deoxidation-β-D-erythro form-ribofuranose)-1,3,5-triazine-2 (1H)-ketone, CAS number is 2353-33-5, its chemical structure be beta comfiguration, and the isomer of its α configuration (3) is non-activity as shown in the formula (2), be the major impurity of Decitabine, difficult removal in Decitabine is synthetic.
Decitabine synthetic method commonly used is, in organic solvent, adopts protection 2-deoxy-D-ribose and N, and the 5-azepine cytosine(Cyt) catalyzing and condensing of O-two trimethyl silicon based protections obtains Decitabine precursor crude product (1), wherein isomer α/β=1/0.8 ~ 2.Then in alcoholic solvent; sodium alkoxide or ammonia catalytic eliminating protecting group obtain the Decitabine crude product, are the mixture of beta comfiguration isomer (2) and α configurational isomer (3); at last again with the single or refining active medical thing composition of API(, the bulk drug of obtaining of mixed solvent) the level Decitabine.The patent relevant with aforesaid method is as EP2050757, EP2048151, CN101560232, CN102171195, CN102209467, CN101570559 and WO2010040056.
Because α configurational isomer (3) foreign matter content is very high in the Decitabine crude product, and character is close with Decitabine (beta comfiguration), need repeatedly to make with extra care just can obtain the api class Decitabine.The Decitabine purification yield is low, the purity instability.Therefore his shoreface body crude product (1) of west carries out purifying over the ground, and it is significant to improve the beta isomer ratio.
Patent CN101948493A proposes his shoreface body crude product of land used west and form suspension in the hydrocarbon of C5-C7, stirring, filtration, drying obtain the Decitabine precursor of β-enrichment, but the contriver finds when repeating this patent working example, Decitabine precursor crude product is almost insoluble in the hydrocarbon of C5-C7, do not reach refining purpose, the method for this patent record can't copy.
Patent CN102212097A mentions the Decitabine precursor that can obtain β-enrichment with the Glacial acetic acid crystallization, but does not propose crystallization method.
Patent CN102391338A mentions a Decitabine precursor and is dissolved in the methylene dichloride, slowly drip toluene and separate out solid, then cooling leave standstill, the purification process of crystallization, filtration drying, the ratio of beta isomer behind the purifying is not provided, and this method solvent usage quantity is big, the cost recovery height.
Summary of the invention
The method that the purpose of this invention is to provide the Decitabine precursor of a kind of β of preparation-enrichment, α/β=1/7～18 in the Decitabine precursor of the β-enrichment that wherein obtains; By the follow-up protecting group that removes, can prepare the Decitabine of purity＞99%.
In order to achieve the above object, the present invention is by the following technical solutions: a kind of method for preparing the Decitabine precursor of β-enrichment, with Decitabine precursor crude product (1), reflux in the mixed solvent of water and organic solvent composition, cooling is filtered, filtrate concentrates post crystallization, filter, drying obtains the Decitabine precursor of β-enrichment.
Organic solvent of the present invention is selected from C1-C3 alcohol, acetone or tetrahydrofuran (THF), preferred alcohol or acetone.
In the mixed solvent of the present invention, water and organic solvent ratio (V/V) are preferably 1:4～19.
(mass volume ratio m/V g/ml) is preferably 1/10～25 to the ratio of Decitabine precursor crude product of the present invention and mixed solvent.
The reflux time of the present invention is preferably 0.5～5 hour.
Cooling temperature of the present invention is preferably 15～35 ℃.
Decitabine precursor crude product of the present invention, structure is as follows:
Wherein, R is CH
3, NO
2Or Cl.
As putting down in writing in the background technology; described Decitabine precursor crude product can be according to method preparation of the prior art; a kind of preparation method who adopts in embodiment is; with 2-deoxy-D-ribose and the N of protection, the 5-azepine cytosine(Cyt) of O-two trimethyl silicon based protections is in dichloromethane solvent, with trifluoromethanesulfonic acid trimethylsilyl group catalyzing and condensing; after finishing, reaction adds the alkali termination reaction; washing then, organic layer is washed the thickening filtration drying, obtains Decitabine precursor crude product.
In the described Decitabine precursor crude product, its isomer α/β=1/0.8 ~ 2.
The Decitabine precursor of β-enrichment of the present invention, its isomer α/β=1/7～18.
With the Decitabine precursor of β-enrichment under proper condition, by removing blocking group, obtain the Decitabine of purity＞99%.
The inventive method employing mixed solvent his shoreface body of west over the ground carries out purification process, the Decitabine precursor of preparation β-enrichment, and this method effectively reduces αYi Gouti ratio in the Decitabine precursor.The Decitabine precursor of β-enrichment removes protecting group in methanolic ammonia solution, Decitabine crude product purity＞99% that obtains through simple treating process, is easy to prepare the api class Decitabine, and maximum list is mixed＜0.1%(HPLC area normalization method).The inventive method is applied to Decitabine production, and whole process of production technology is simple, stable operation is controlled, the Decitabine product yield height that obtains, and the purity height is suitable for suitability for industrialized production.
The water that uses among the present invention and the mixed solvent of organic solvent after concentrating recovery, resize ratio, can continue to recycle environmental protection and economy.
Describe the present invention below in conjunction with specific embodiment.Protection scope of the present invention is not limited with embodiment, but is limited by claim.
Description of drawings
The HPLC color atlas of the Decitabine precursor crude product that Fig. 1 embodiment 1 makes.
The HPLC color atlas of the Decitabine precursor of the β enrichment that Fig. 2 embodiment 3 makes.
The HPLC color atlas of the Decitabine that Fig. 3 embodiment 11 makes.
Embodiment
In following examples, at first prepare the Decitabine precursor by method of the prior art, the preparation of relevant Decitabine precursor, concrete technology contents sees EP2050757, EP2048151, CN101560232, CN102171195, CN102209467, CN101570559 and WO2010040056 etc. for details.The Decitabine precursor that makes prepares the Decitabine precursor of β-enrichment by the inventive method, and the Decitabine precursor of β-enrichment that the present invention is made at last is for the preparation of highly purified Decitabine.
The purity of the isomer proportion in the Decitabine precursor and Decitabine finished product and impurity adopt HPLC to analyze, and quantivative approach is area normalization method.Chromatographic condition is: be the chromatographic column (4.6*250mm, 5 μ m) of weighting agent with octadecylsilane chemically bonded silica; Be moving phase with water-acetonitrile-triethylamine-acetic acid (200:800:2:1), flow velocity is 0.6 ml/min; Detecting wavelength is 254 nm.Number of theoretical plate calculates by the beta isomer peak of Decitabine precursor, should be not less than 2000.
Embodiment 1: the preparation of Decitabine precursor crude product
With 600g 5-azepine cytosine(Cyt), 6.0g ammonium sulfate, the 6L hexamethyldisilazane joins in the 10L glass reaction still successively, stir down and obtain settled solution in 120 ℃ ~ 125 ℃ reactions, the unreacted hexamethyldisilazane of concentrating under reduced pressure, add methylene chloride 6L dissolving of the resistates that obtains, be transferred to 50L glass reaction still, 1 ~ 5 ℃ adds trifluoromethanesulfonic acid trimethylsilyl group 1L down, add 2kg 1-chloro-3 then, the 20L dichloromethane solution of two pairs of chlorobenzoyl oxygen base-2-deoxy-D-riboses of 5-, insulation reaction 20h, add an amount of saturated sodium bicarbonate solution termination reaction, add 20L methylene dichloride dilute reaction solution, the purified water washed twice, organic layer is evaporated to a large amount of solids and separates out, filter, drying obtains Decitabine precursor crude product 2.1kg(α/β=1/1.2, as Fig. 1).
Embodiment 2: the preparation of Decitabine precursor crude product
With 600g 5-azepine cytosine(Cyt), 6.0g ammonium sulfate, the 6L hexamethyldisilazane joins in the 10L glass reaction still successively, stir down and react to settled solution in 125 ~ 130 ℃, the unreacted hexamethyldisilazane of concentrating under reduced pressure, add methylene chloride 6L dissolving of the resistates that obtains, be transferred to 50L glass reaction still, 5 ~ 10 ℃ add trifluoromethanesulfonic acid trimethylsilyl group 1L down, add 2kg 1-chloro-3 then, the 20L dichloromethane solution of two pairs of chlorobenzoyl oxygen base-2-deoxy-D-riboses of 5-, insulation reaction 20h adds an amount of saturated sodium bicarbonate solution termination reaction, add 20L methylene dichloride dilute reaction solution, purified water washed twice, organic layer are evaporated to a large amount of solids and separate out, and filtration drying obtains Decitabine precursor crude product 2.1kg(α/β=1/1.0).
Embodiment 3: the Decitabine precursor preparation of β enrichment
The Decitabine precursor crude product 500g that in 20L glass reaction still, adds embodiment 1 preparation, add water/ethanol the mixed solvent 10L of (V/V)=1/10, reflux leaves standstill then, separates out α-enrich body at about 25 ℃ of cooling crystallization 12h(), filter, filtrate decompression is concentrated near doing, and filters filter cake vacuum-drying, obtain Decitabine 254g(α/β=1/11 of β-enrichment, as Fig. 2).
Embodiment 4: the Decitabine precursor preparation of β enrichment
The Decitabine precursor crude product 500g that in 20L glass reaction still, adds embodiment 1 preparation, add water/acetone the mixed solvent 7L of (V/V)=1/10, reflux, leave standstill then, at about 30 ℃ of cooling crystallization 18h, filter, filtrate decompression is concentrated near doing, filter, filter cake vacuum-drying obtains Decitabine 202g(α/β=1/15 of β-enrichment).
Embodiment 5: the Decitabine precursor preparation of β enrichment
The Decitabine precursor crude product 500g that in 20L glass reaction still, adds embodiment 1 preparation, add water/acetone the mixed solvent 10L of (V/V)=1/7, reflux, leave standstill then, at about 20 ℃ of cooling crystallization 10h, filter, filtrate decompression is concentrated near doing, filter, filter cake vacuum-drying obtains Decitabine 237g(α/β=1/9 of β-enrichment).
Embodiment 6: the Decitabine precursor preparation of β enrichment
The Decitabine precursor crude product 500g that in 20L glass reaction still, adds embodiment 1 preparation, add water/methyl alcohol the mixed solvent 7L of (V/V)=1/10, reflux, leave standstill then, at about 25 ℃ of cooling crystallization 18h, filter, filtrate decompression is concentrated near doing, filter, filter cake vacuum-drying obtains Decitabine 212g(α/β=1/14 of β-enrichment).
Embodiment 7: the Decitabine precursor preparation of β enrichment
The Decitabine precursor crude product 500g that in 20L glass reaction still, adds embodiment 2 preparations, add water/acetone the mixed solvent 12.5L of (V/V)=1/10, reflux, leave standstill then, at about 30 ℃ of cooling crystallization 15h, filter, filtrate decompression is concentrated near doing, filter, filter cake vacuum-drying obtains Decitabine 273g(α/β=1/7 of β-enrichment).
Embodiment 8: the Decitabine precursor preparation of β enrichment
The Decitabine precursor crude product 500g that in 20L glass reaction still, adds embodiment 2 preparations, add water/acetone the mixed solvent 10L of (V/V)=1/15, reflux, leave standstill then, at about 25 ℃ of cooling crystallization 15h, filter, filtrate decompression is concentrated near doing, filter, filter cake vacuum-drying obtains Decitabine 214g(α/β=1/10.5 of β-enrichment).
The preparation of embodiment 9 Decitabine crude products
Get β-enrichment Decitabine precursor 250g that embodiment 3 obtains, add in the saturated methanolic ammonia solution of 20L, in 30 ℃ of stirring reaction 15h, be evaporated to about 2.5L, be cooled to room temperature, filtration drying obtains Decitabine crude product 62.0g.
The preparation of embodiment 10 Decitabine crude products
Get β-enrichment Decitabine precursor 200g that embodiment 4 obtains, add in the saturated methanolic ammonia solution of 18L, in 30 ℃ of stirring reaction 12h, be evaporated to about 2L solvent, be cooled to room temperature, filtration drying obtains Decitabine crude product 51.7g.
Embodiment 11 Decitabine are refining
The Decitabine crude product 60.0g that embodiment 9 is obtained moves in the 10L reactor, adds methyl alcohol 6L, and reflux is to molten entirely, add the 3.0g gac and stir decolouring, filter, filtrate decompression is concentrated into 1.5L, crystallization is left standstill in cooling, filter, an amount of methanol wash of gained filter cake, drying obtains Decitabine 51.5g, yield 86%, purity is: 99.92%, maximum single assorted: the 0.06%(HPLC area normalization method, as Fig. 3).
Embodiment 12 Decitabine are refining
The Decitabine crude product 50.0g that embodiment 10 is obtained moves in the 10L reactor, add methyl alcohol 5L, reflux adds the 2.5g gac and stirs decolouring to molten entirely, filters, filtrate decompression is concentrated into 1.3L, crystallization is left standstill in cooling, filters an amount of methanol wash of gained filter cake, drying obtains Decitabine 42.0g, yield 84%: maximum single assorted: the 0.05%(HPLC area normalization method).
The detailed description purpose of the embodiment of the present invention of above embodiment only is to help to understand method of the present invention and core concept thereof; should be understood that; for those skilled in the art; under the prerequisite that does not break away from aim of the present invention or principle; can carry out some improvement and modification to above-mentioned specific embodiment, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (9)
1. method for preparing the Decitabine precursor of β-enrichment is characterized in that: with Decitabine precursor crude product reflux in the mixed solvent that water and organic solvent are formed, described organic solvent is selected from C
1-C
3Alcohol, acetone or tetrahydrofuran (THF), cooling, filter; Filtrate concentrates post crystallization, filters, and drying obtains the Decitabine precursor of β-enrichment.
2. method according to claim 1, it is characterized in that: described Decitabine front body structure is as follows:
Wherein, R is CH
3, NO
2Or Cl.
3. method according to claim 1 and 2, it is characterized in that: described organic solvent is ethanol or acetone.
4. method according to claim 1 and 2, it is characterized in that: in the described mixed solvent, water with the volume of organic solvent ratio is: 1:4～19.
5. method according to claim 1 and 2, it is characterized in that: the mass volume ratio of described Decitabine precursor crude product and mixed solvent is 1:10～25.
6. method according to claim 1 and 2, it is characterized in that: described cooling temperature is 15～35 ℃.
7. method according to claim 1 and 2, it is characterized in that: the described reflux time is 0.5～5 hour.
8. method according to claim 1 and 2, it is characterized in that: described Decitabine precursor crude product isomer proportion is α/β=1/0.8～2.
9. method according to claim 1 and 2 is characterized in that: the Decitabine precursor of described β-enrichment, its isomer α/β=1/7～18.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761605A (en) * | 2014-01-03 | 2015-07-08 | 江苏豪森药业股份有限公司 | Recovery production process for decitabine mother liquor |
| CN112142804A (en) * | 2019-06-28 | 2020-12-29 | 鲁南制药集团股份有限公司 | Preparation method of decitabine |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008101448A2 (en) * | 2007-02-20 | 2008-08-28 | Ustav Organicke Chemie A Biochemie Av Cr, V.V.I. | Method of manufacturing 1-(2-deoxy-alpha-d-erythro-pentofuranosyl)-5-azacytosine |
| CN101497639A (en) * | 2009-03-13 | 2009-08-05 | 济南圣鲁金药物技术开发有限公司 | Preparation of decitabine |
| CN101570559A (en) * | 2008-04-30 | 2009-11-04 | 南京长澳医药科技有限公司 | Methods for preparing 5-Aza-2'-deoxycytidine and intermediate product thereof |
| US20100249394A1 (en) * | 2009-03-26 | 2010-09-30 | Albemarle Corporation | Processes for producing 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 |
| WO2011040984A1 (en) * | 2009-10-02 | 2011-04-07 | Scinopharm Taiwan Ltd. | Synthesis of decitabine |
| CN102391338A (en) * | 2011-09-30 | 2012-03-28 | 重庆泰濠制药有限公司 | Method for purifying decitabine intermediate crude product |
-
2013
- 2013-04-13 CN CN201310126905.9A patent/CN103232512B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008101448A2 (en) * | 2007-02-20 | 2008-08-28 | Ustav Organicke Chemie A Biochemie Av Cr, V.V.I. | Method of manufacturing 1-(2-deoxy-alpha-d-erythro-pentofuranosyl)-5-azacytosine |
| CN101570559A (en) * | 2008-04-30 | 2009-11-04 | 南京长澳医药科技有限公司 | Methods for preparing 5-Aza-2'-deoxycytidine and intermediate product thereof |
| CN101497639A (en) * | 2009-03-13 | 2009-08-05 | 济南圣鲁金药物技术开发有限公司 | Preparation of decitabine |
| US20100249394A1 (en) * | 2009-03-26 | 2010-09-30 | Albemarle Corporation | Processes for producing decitabine |
| WO2011040984A1 (en) * | 2009-10-02 | 2011-04-07 | Scinopharm Taiwan Ltd. | Synthesis 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 |
| CN102391338A (en) * | 2011-09-30 | 2012-03-28 | 重庆泰濠制药有限公司 | Method for purifying decitabine intermediate crude product |
Non-Patent Citations (1)
| Title |
|---|
| U.NIEDBALLA,等: "A Genernal Synthesis of N-Glycosides.V.Synthesis of 5-Azacytidines", 《J.ORG.CHEM.》, vol. 39, no. 25, 31 December 1974 (1974-12-31), pages 3672 - 3674, XP055011604, DOI: doi:10.1021/jo00939a012 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761605A (en) * | 2014-01-03 | 2015-07-08 | 江苏豪森药业股份有限公司 | Recovery production process for decitabine mother liquor |
| CN104761605B (en) * | 2014-01-03 | 2019-03-26 | 江苏豪森药业集团有限公司 | Decitabine disposing mother liquor manufacturing technique method |
| CN112142804A (en) * | 2019-06-28 | 2020-12-29 | 鲁南制药集团股份有限公司 | Preparation method of decitabine |
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