CN103374052B - Capecitabine crystal formation and preparation method thereof - Google Patents
Capecitabine crystal formation and preparation method thereof Download PDFInfo
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- CN103374052B CN103374052B CN201210114935.3A CN201210114935A CN103374052B CN 103374052 B CN103374052 B CN 103374052B CN 201210114935 A CN201210114935 A CN 201210114935A CN 103374052 B CN103374052 B CN 103374052B
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Abstract
The invention belongs to medicinal chemistry art, capecitabine crystal formation relating to structural formula I and preparation method thereof.Capecitabine crude product is joined in the mixed solvent of based organic solvent and ether organic solvent, is warming up to 60 DEG C, molten clear after to lower the temperature crystallization, obtain capecitabine crystal formation.It is high that capecitabine crystal formation provided by the invention has content, and stable crystal form is convenient to the feature of prolonged storage.
Description
Technical field
The present invention relates to capecitabine crystal formation and preparation method thereof, belong to medicinal chemistry art.
Background technology
Capecitabine, the chemistry fluoro-N-of 5 '-deoxidation-5-[(pentyloxy) carbonyl]-cytidine(C by name, as shown in structural formula I:
Capecitabine is a kind of new oral fluorocytidine analogues, no cytotoxicity own, under the effect of enzyme in vivo, metabolism is 5 FU 5 fluorouracil (5-FU), and then plays antitumor action, and clinical being mainly used in treats advanced breast cancer, knot/rectum cancer and other solid tumor.
US2010130734A1 discloses use ethyl acetate, ethyl acetate and normal hexane recrystallization capecitabine, the crystallization of single solvent ethyl acetate is adopted to there is following problem: when ethyl acetate consumption is few (being less than 4 times of crude product amount), during crystallization, the easy thickness of system, is not suitable for industrial operation; And ethyl acetate consumption yield of many times is obviously low.And using ethyl acetate and normal hexane recrystallization, Equations of The Second Kind solvent hexane toxicity is comparatively large, and easily remains, and is not suitable for suitability for industrialized production.
WO2010065586A2 discloses and uses methylene dichloride and re crystallization from toluene capecitabine, and methylene dichloride and toluene are Equations of The Second Kind solvent, and toxicity is comparatively large, easily remains in product, is not suitable for suitability for industrialized production.
Summary of the invention
For the deficiency that prior art exists, the present invention has carried out the experimental study of a large amount of system to capecitabine crystal formation, obtains a kind of capecitabine crystal formation that is stable, that be easy to large-scale production.
The invention provides a kind of capecitabine crystal formation, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles 4.9 ± 0.2,10.4 ± 0.2,18.6 ± 0.2,19.9 ± 0.2 have characteristic peak.
Further, capecitabine crystal formation provided by the invention, uses Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles 4.9 ± 0.2,10.4 ± 0.2,18.6 ± 0.2,19.9 ± 0.2,20.2 ± 0.2,28.2 ± 0.2 have characteristic peak.
Further again, capecitabine crystal formation provided by the invention, uses Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles 4.9 ± 0.2,10.4 ± 0.2,15.1 ± 0.2,17.0 ± 0.2,17.7 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.9 ± 0.2,20.2 ± 0.2,21.1 ± 0.2,21.8 ± 0.2,28.2 ± 0.2 have characteristic peak.
The X-ray powder diffraction of capecitabine crystal formation of the present invention as shown in Figure 1.
As shown in Figure 2, the fusing point of capecitabine crystal formation is 116.80 ~ 120.48 DEG C to capecitabine crystal formation differential scanning calorimeter (DSC-TGA) of the present invention; The imponderability loss before degrading of capecitabine crystal formation, can infer that above-mentioned capecitabine crystal formation is the anhydrate of capecitabine.
The present invention also provides a kind of preparation method of capecitabine crystal formation, and step is as follows:
Capecitabine crude product is joined in the mixed solvent of based organic solvent and ether organic solvent, is warming up to 60 DEG C, molten clear after to lower the temperature crystallization, obtain capecitabine crystal formation.
Wherein, the mass volume ratio of the mixed solvent of capecitabine crude product and based organic solvent and ether organic solvent is 1: 5 ~ 1: 10, and unit is g/ml, preferably 1: 6 ~ 1: 8.
The volume ratio of described based organic solvent and described ether organic solvent is 15: 1 ~ 1: 1, preferably 10: 1 ~ 5: 1.
Wherein, described based organic solvent is the 3rd kind solvent, is selected from one or more in ethyl acetate, ethyl formate, methyl acetate, butylacetate, propyl acetate, isopropyl acetate, isobutyl acetate, ethyl acetate.
Described ether organic solvent is the 3rd kind solvent, is selected from one or more in ether, isopropyl ether, t-butyl methyl ether, preferred isopropyl ether.
The 3rd above-mentioned kind solvent belongs to low-toxic solvent, to the solvent of human body low toxicity, less to the harm of human body and environment.
Preferred further, the preparation method of capecitabine crystal formation of the present invention, step is as follows:
Capecitabine crude product is joined in ester class and ethers mixed organic solvents, is warming up to 60 DEG C, molten clear after add gac and stir, hot suction filtration removing gac, gained filtrate adopts the mode stirring and crystallizing of segmentation cooling, and temperature is progressively down to-10 DEG C, and stirring and crystallizing is complete; Filter, obtain capecitabine crystal formation.
Preferably, the process of the mode stirring and crystallizing of above-mentioned employing segmentation cooling is:
(1) 40 DEG C of insulated and stirred 20 minutes;
(2) be down to 30 DEG C and continue insulated and stirred 40 minutes;
(3) be down to 20 DEG C and continue insulated and stirred 20 minutes;
(4) be down to 10 DEG C and continue insulated and stirred 20 minutes;
(5) be finally cooled to-10 DEG C and continue insulated and stirred 1.5 hours.
Cooling of the present invention can adopt the cooling of Temperature fall, circulating water cooling, frozen water, icy salt solution cooling or other equipment that can lower the temperature.
Recrystallization solvent based organic solvent of the present invention, ether organic solvent select the 3rd kind solvent of low toxicity, and solvent toxicity is little, and drug safety is high, there will not be crystallizing system thickness phenomenon, are more conducive to industrialization amplification and drug manufacture.
The present invention also adopts segmentation cooling method both can avoid because impurity comprises in the product by crystallization speed soon, and getable good crystal formation again, technique favorable reproducibility, purity are high.
The stability of the present invention to capecitabine crystal formation is studied, capecitabine crystal formation is in temperature 25 ± 2 DEG C, keep sample for a long time under humidity 60% ± 10% condition, study on the stability is after 12 months, its content has no obvious reduction, and maximum simple substance and total impurities have no obvious increase, and the sample after above-mentioned investigation is verified this stable crystal form through X-ray powder diffraction, and have the mass uniformity of good guarantee preparation, clinical application is safer.
The present inventor also finds that capecitabine crystal formation of the present invention has good dissolution rate and solubleness, has the property prepared, facilitate suitability for industrialized production at raising gastrointestinal administration preparation such as tablet.
In sum, capecitabine crystal formation provided by the invention has stable crystal form, favorable reproducibility, is convenient to the advantage of prolonged storage.The 3rd kind solvent that its preparation method provided by the invention adopts recrystallization solvent based organic solvent, ether organic solvent selects low toxicity; solvent toxicity is little; drug safety is high; and technological operation is simple, there will not be crystallizing system thickness phenomenon, with low cost; gained capecitabine crystal formation content is high; reach more than 99%, yield more than 90%, be suitable for industrial scale and produce.
Accompanying drawing explanation
Fig. 1 is capecitabine crystal form X-ray powder diffraction.
Fig. 2 is capecitabine crystal formation DSC-TGA collection of illustrative plates.
Fig. 3 is that capecitabine crystal formation keeps sample 12 months X-ray powder diffraction under room temperature.
Embodiment
Following examples only for further illustrating the present invention, but do not limit the present invention.
Preparation example (with reference to prior art as: CN1094056A prepares capecitabine crude product (oily matter))
To 2 ', 3 '-O-diacetyl-5 '-fluoro-N of deoxidation-5-under ice bath cooling and stirring
425ml methyl alcohol is added in the dichloromethane solution (500ml) of-(penta oxygen carbonyl)-cytidine (500g), 1NNaOH (340ml) is dripped at-5 ~ 5 DEG C, stirring reaction 2 hours, add concentrated hydrochloric acid and regulate pH to 6, layering, water layer uses methylene dichloride (500ml × 3) to extract again, merge organic phase, anhydrous sodium sulfate drying organic phase, evaporated under reduced pressure obtains the capecitabine crude product (405g, by 100% yield) of oily.
Embodiment 1
In 500mL flask, add 15g capecitabine crude product, 75mL ethyl acetate, 15ml isopropyl ether, be warming up to 60 DEG C; Until molten clear after add gac and stir; Hot suction filtration, filtrate proceeds in another single port bottle, is inserted by single port bottle in 40 DEG C of hot water baths, insulated and stirred crystallization 20 minutes, be cooled to 30 DEG C of insulated and stirred crystallizatioies 40 minutes, be cooled to 20 DEG C of insulated and stirred crystallizatioies 20 minutes, be cooled to 10 DEG C of insulated and stirred crystallizatioies 20 minutes, be down to-10 DEG C and stir the abundant crystallization of 2h, suction filtration, dry capecitabine crystal formation 13.7g, yield 91.3%, purity 99.92%.
Gained crystal formation measures through X-ray powder diffraction, as shown in figure 1 and table 1, as shown in Figure 2, crystal formation fusing point is 116.80 ~ 120.48 DEG C to DSC-TGA collection of illustrative plates to result, the imponderability loss before degrading of capecitabine crystal formation, can infer the anhydrate for capecitabine.
Keep sample under room temperature 12 menstruation X-ray powder diffraction of gained crystal formation measure, and result as shown in figure 3 and table 2.
Can find out, the capecitabine crystal formation ambient temperatare of gained puts 12 months stable crystal forms, is convenient to prolonged storage.
The position of diffraction peak and intensity in the X-ray powder diffraction of table 1 capecitabine
The position of diffraction peak and intensity in X-ray powder diffraction after table 2 capecitabine room temperature keeps sample 12 months
Embodiment 2
In 100mL flask, add 15g capecitabine crude product, 75mL methyl acetate, 75ml ether, be warming up to 60 DEG C; Until molten clear after add gac and stir; Hot suction filtration, filtrate proceeds in another single port bottle, is inserted by single port bottle in 40 DEG C of hot water baths, insulated and stirred crystallization 20 minutes, be cooled to 30 DEG C of insulated and stirred crystallizatioies 40 minutes, be cooled to 20 DEG C of insulated and stirred crystallizatioies 20 minutes, be cooled to 10 DEG C of insulated and stirred crystallizatioies 20 minutes, be down to-10 DEG C and stir the abundant crystallization of 2h, suction filtration, dry capecitabine crystal formation 13.8g, total recovery 92.0%, purity 99.87%.
According to XPRD data, gained crystal formation is capecitabine crystal formation of the present invention.
Embodiment 3
In 500mL flask, add 25g capecitabine crude product, 150mL ethyl acetate and 50ml ethyl formate, 20ml t-butyl methyl ether, be warming up to 60 DEG C; Until molten clear after add gac and stir; Hot suction filtration, filtrate proceeds in another single port bottle, is inserted by single port bottle in 40 DEG C of hot water baths, insulated and stirred crystallization 20 minutes, be cooled to 30 DEG C of insulated and stirred crystallizatioies 40 minutes, be cooled to 20 DEG C of insulated and stirred crystallizatioies 20 minutes, be cooled to 10 DEG C of insulated and stirred crystallizatioies 20 minutes, be down to-10 DEG C and stir the abundant crystallization of 2h, suction filtration, dry capecitabine crystal formation 22.9g, yield 91.6%, purity 99.93%.
According to XPRD data, gained crystal formation is capecitabine crystal formation of the present invention.
In order to investigate the permanent stability of capecitabine crystal formation of the present invention further, the present invention also for the capecitabine crystal formation of embodiment 1 ~ 3 in temperature 25 ± 2 DEG C, keep sample for a long time under humidity 60% ± 10% condition, study on the stability is after 12 months, and test-results is as shown in table 3.
Table 3 stability test result
Result shows, the capecitabine stable crystal form of gained, favorable reproducibility, and insensitive to temperature, air, light, be convenient to prolonged storage, and have the mass uniformity of good guarantee preparation, clinical application is safer.
Claims (2)
1. a preparation method for capecitabine crystal formation, step is as follows:
Capecitabine crude product is joined in the mixed solvent of based organic solvent and ether organic solvent, is warming up to 60 DEG C, molten clear after add gac and stir, hot suction filtration removing gac, gained filtrate adopts the mode stirring and crystallizing of segmentation cooling, and temperature is progressively down to-10 DEG C, and stirring and crystallizing is complete; Filter, obtain capecitabine crystal formation;
The process of the mode stirring and crystallizing of described segmentation cooling is:
(1) 40 DEG C of insulated and stirred 20 minutes;
(2) be down to 30 DEG C and continue insulated and stirred 40 minutes;
(3) be down to 20 DEG C and continue insulated and stirred 20 minutes;
(4) be down to 10 DEG C and continue insulated and stirred 20 minutes;
(5) be finally cooled to-10 DEG C and continue insulated and stirred 1.5 hours;
The mass volume ratio of described capecitabine crude product and the mixed solvent of based organic solvent and ether organic solvent is 1:5 ~ 1:10, and unit is g/ml, and the volume ratio of described based organic solvent and described ether organic solvent is 15:1 ~ 1:1;
Described based organic solvent is selected from ethyl acetate, and described ether organic solvent is selected from isopropyl ether;
Described capecitabine crystal formation, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles is 4.9 ± 0.2,10.4 ± 0.2,15.1 ± 0.2,17.0 ± 0.2,17.7 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.9 ± 0.2,20.2 ± 0.2,21.1 ± 0.2,21.8 ± 0.2,28.2 ± 0.2 have characteristic peak.
2. the preparation method of capecitabine crystal formation according to claim 1, it is characterized in that, the mass volume ratio of described capecitabine crude product and the mixed solvent of based organic solvent and ether organic solvent is 1:6 ~ 1:8, unit is g/ml, and the volume ratio of described based organic solvent and described ether organic solvent is 10:1 ~ 5:1.
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| RU2393164C1 (en) * | 2008-10-23 | 2010-06-27 | ЗАО "Фарм-Синтез" | α- OR β-CRYSTALLINE MODIFICATIONS OF 5'-DESOXY-N4-CARBOPENTYLOXY-5-FLUOROCYTIDINE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS BASED ON SAID COMPOUNDS |
| CN101861320A (en) * | 2007-11-19 | 2010-10-13 | 韩美药品株式会社 | Methods for preparing capecitabine and beta-anomer-rich trialkyl carbonate compound used therein |
| CN102241721A (en) * | 2011-05-20 | 2011-11-16 | 江南大学 | Method for preparing capecitabine and hydroxyl derivative intermediate thereof |
| CN102260310A (en) * | 2011-05-20 | 2011-11-30 | 江南大学 | New process for preparing Capecitabine from Furtulon |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101861320A (en) * | 2007-11-19 | 2010-10-13 | 韩美药品株式会社 | Methods for preparing capecitabine and beta-anomer-rich trialkyl carbonate compound used therein |
| RU2393164C1 (en) * | 2008-10-23 | 2010-06-27 | ЗАО "Фарм-Синтез" | α- OR β-CRYSTALLINE MODIFICATIONS OF 5'-DESOXY-N4-CARBOPENTYLOXY-5-FLUOROCYTIDINE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS BASED ON SAID COMPOUNDS |
| CN102241721A (en) * | 2011-05-20 | 2011-11-16 | 江南大学 | Method for preparing capecitabine and hydroxyl derivative intermediate thereof |
| CN102260310A (en) * | 2011-05-20 | 2011-11-30 | 江南大学 | New process for preparing Capecitabine from Furtulon |
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