The method for preparing pemetrexed disodium 2.5 water crystallizations
Technical field
The present invention relates to pemetrexed disodium crystalline preparation method, be specifically related to a kind of preparation method of 2.5 crystal of hydrate of new pemetrexed disodium.
Background technology
The pemetrexed disodium chemistry is by name: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-disodium glutamate salt, its structural formula is as follows:
Pemetrexed disodium is a kind of antimetabolitas of many target spots; be that multiple folic acid relies on the strong inhibitor that enzyme comprises thymidylate synthetase (TS), Tetrahydrofolate dehydrogenase (DHFR) and glycyl ammonia ribonucleotide transformylase (GARFT); aminooimidazole carboxylic acid amides nucleosides transformylase (AICARFI) is also had certain restraining effect, and clinical trial shows multiple solid tumor effective.More than 70 country's listings such as the U.S., European Union are used for local late period of first-line treatment malignant pleural mesothelioma and second line treatment and transitivity nonsmall-cell lung cancer at present.In the nonsmall-cell lung cancer second line treatment, pemetrexed disodium is compared with Docetaxel (Docetaxel), therapeutic equivalence, but side effect is littler, therefore will become the new selection of nonsmall-cell lung cancer second line treatment.In addition, the tolerance of the clinical use of pemetrexed is good, the utilization of Biological indicators such as homocysteine in plasma can be predicted the generation of untoward reaction, and concomitant medication such as folic acid, VITAMIN, hormone can also further reduce toxicity, thereby make the dose intensity of pemetrexed further to improve, also more flexible with the associating of other chemotherapeutics, this has also enlarged the clinical scope of application of pemetrexed undoubtedly.
Taylor etc. have at first reported pemetrexed and synthetic method thereof in US5248775, the pemetrexed disodium hydrate crystal forms has at present: (the d spacing of characteristic spectral line correspondence is disclosed 2.5 hydrate crystal forms of WO0114379 in its X-ray powder diffraction
), (the d spacing of characteristic spectral line correspondence is disclosed 7 hydrate crystal forms of WO0162760 in its X-ray powder diffraction
), (the d spacing of characteristic spectral line correspondence is disclosed 3 hydrate crystal forms of CN1778802A in its X-ray powder diffraction
Or
).
The inventor discovers, the water absorbability of pemetrexed disodium 2.5 crystal of hydrate that obtain according to the disclosed preparation method of WO0114379 is stronger, in preparation process, be difficult to control its moisture and reach 2.5 crystal water, in addition, also be difficult to obtain 2.5 pure hydrate forms, be mixed with a little 7 hydrate in its crystallization.Though the pemetrexed disodium water absorbability of 3 hydrates than the pemetrexed disodium water absorbability of disclosed 2.5 crystalline hydrates of WO0114379 slightly a little less than, but still have the problem that is difficult to crystallization control water when dry, simultaneously the dissolvent residual in the product also difficulty remove.Though and the pemetrexed disodium no hygroscopicity of 7 hydrates, but dehydration easily takes place and becomes the crystallization water number less than 7 hydrate (existing report in CN1778802) in storage under at comparatively high temps, than low humidity or vacuum condition, in addition, the drying process of 7 hydrates is compared with the drying process of 2.5 crystalline hydrates has also increased process and the corresponding apparatus of handling with wet nitrogen gas stream, has increased production cost.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of pemetrexed disodium 2.5 hydrates, to overcome the above-mentioned defective that prior art exists.
Method of the present invention comprises the steps:
(1) the raw material pemetrexed disodium is soluble in water;
(2) aqueous solution that will obtain pemetrexed disodium is added drop-wise in the organic solvent that can dissolve each other with water, and the dropping time is 0.5~2 hour, is cooled to 0~10 ℃, is incubated 0.5~2 hour and carries out crystallization;
(3) filter, collect filter cake, drying gets target product.
Drying temperature is 40~50 ℃, and time of drying, particular case such as temperature during according to drying, vacuum tightness, thickness of sample was decided, and generalized case drying 20~30 hours can obtain the higher pemetrexed disodium of crystal formation purity 2.5 hydrates.
Said raw material pemetrexed disodium is selected from more than one in pemetrexed disodium 2.5 hydrates, 3 hydrates, 7 hydrates or the amorphous polymorph;
Saidly can be selected from C with the organic solvent that water dissolves each other
1~C
5Alcohol, the C of straight or branched
3~C
5Ketone, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF) or 1, more than one in the 4-dioxane;
Wherein, C
1~C
5The alcohol of straight or branched be meant methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, propyl carbinol or isopropylcarbinol, preferred alcohol;
C
3~C
5Ketone be meant acetone, butanone or pentanone, preferred acetone;
The ratio of raw material pemetrexed disodium and water and organic solvent is: 1: 1~30: 5~300 (g/ml/ml), i.e. 1g raw material, 1~30ml water, 5~300ml organic solvent;
Preferably: 1: 5~10: 40~80 (g/ml/ml);
Preparation method of the present invention, controllability is strong, and is easy and simple to handle, and favorable reproducibility does not need specific installation, the product yield height, stable crystal form is easy to suitability for industrialized production.
Further specify the present invention below by drawings and Examples.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, conceives in the present invention that the simple modifications to preparation method of the present invention all belongs to the scope of protection of present invention under the prerequisite.
Description of drawings
Fig. 1 is the pemetrexed disodium 2.5 hydrate accelerated stability test X-ray powder diffractions contrast figure of the inventive method preparation;
Fig. 2 is the pemetrexed disodium 2.5 hydrates stability long-term experiment X-ray powder diffraction contrast figure of the inventive method preparation;
Fig. 3 is the pemetrexed disodium 2.5 hydrate X-ray powder diffraction patterns of the inventive method preparation.
Embodiment
Embodiment 1
Under argon shield, the 10g pemetrexed disodium is joined in the 60ml water, it is molten clear to stir the system that is warming up to;
Then this aqueous solution at room temperature is added drop-wise in the 480ml dehydrated alcohol, the dropping time is 30 minutes, after dripping off, is cooled to 5 ℃ of insulations 30 minutes.Filter, filter cake places that drying under reduced pressure obtains 9.5g pemetrexed disodium 2.5 hydrates to doing under 50 ℃ of conditions.
According to the method for Chinese Pharmacopoeia regulation, the product that is obtained is quickened and the permanent stability experiment, its water-content of periodic measurement and carry out the crystal formation analysis by the X-ray powder diffraction, concrete data see Table 1, table 2.
Table 1 pemetrexed disodium 2.5 hydrate study on the stability accelerated tests
Table 2 pemetrexed disodium 2.5 hydrate study on the stability long-term experiments
From the experimental result of table 1, table 2 as can be seen, 2.5 hydrates that preparation method provided by the invention obtains (theoretical water content is 8.7%) crystal formation water content and crystal formation under this experiment condition is stable basically.
It is to obtain through Brucker D8 advanceSSS (USA) under envrionment temperature and ambient relative humidity are not more than 70% condition that X-ray powder diffraction of the present invention is analyzed collection of illustrative plates, and radiation is CU K α (40KV, 40mA;
), data under 25 ℃ of conditions from 2 °≤2 θ≤50 ° collections.
The common those of skill in the art in this area should be appreciated that depends on employed measuring condition, may have certain measuring errors in the following X-ray powder diffraction that obtains of different measuring conditions.Especially, the intensity in the common X-ray powder diffraction may the fluctuation to some extent along with the difference of test condition.Will be further understood that relative intensity also may change with the difference of experiment condition, therefore, should not consider the accurate numerical value of intensity.In addition, for conventional X-ray powder diffraction pattern, the measuring error of diffraction angle typical about 5% or still less for above-mentioned diffraction angle, should be considered the measuring error of such degree.
Embodiment 2
Under argon shield the 10g pemetrexed disodium is joined in the 60ml water, it is molten clear to stir the system that is warming up to;
Then this aqueous solution at room temperature is added drop-wise in the 600ml Virahol, the dropping time is 1 hour, is cooled to 10 ℃ of insulations 1 hour after dripping off.Filter, filter cake places that drying under reduced pressure obtains 9.3g pemetrexed disodium 2.5 hydrates to doing under 50 ℃ of conditions.
Adopt the identical method of embodiment 1, quicken and the permanent stability experiment, the result is substantially the same manner as Example 1.
Embodiment 3
Under argon shield the 10g pemetrexed disodium is joined in the 50ml water, it is molten clear to stir the system that is warming up to; Then this aqueous solution at room temperature is added drop-wise in the 650ml acetone, the dropping time is 1 hour, is cooled to 5 ℃ of insulations 1 hour after dripping off.Filter, filter cake places that drying under reduced pressure obtains 9.0g pemetrexed disodium 2.5 hydrates to doing under 50 ℃ of conditions.Adopt the identical method of embodiment 1, quicken and the permanent stability experiment, the result is substantially the same manner as Example 1.
Embodiment 4
Under argon shield the 10g pemetrexed disodium is joined in the 75ml water, it is molten clear to stir the system that is warming up to; Then this aqueous solution at room temperature is added drop-wise in the 750ml tetrahydrofuran (THF), the dropping time is 2 hours, is cooled to 0 ℃ of insulation 2 hours after dripping off.Filter, filter cake places that drying under reduced pressure obtains 9.2g pemetrexed disodium 2.5 hydrates to doing under 50 ℃ of conditions.Adopt the identical method of embodiment 1, quicken and the permanent stability experiment, the result is substantially the same manner as Example 1.
Embodiment 5
Under argon shield the 230.0g pemetrexed disodium is joined in the 1.5L water, it is molten clear to stir the system that is warming up to; Then this aqueous solution at room temperature is added drop-wise in the 1.2L dehydrated alcohol, the dropping time is 1 hour, is cooled to 5 ℃ of insulations 1 hour after dripping off.Filter, filter cake places that drying under reduced pressure obtains 220.8g pemetrexed disodium 2.5 hydrates to doing under 50 ℃ of conditions.Adopt the identical method of embodiment 1, quicken and the permanent stability experiment, the result is substantially the same manner as Example 1.
Embodiment 6
Under argon shield the 1.20kg pemetrexed disodium is joined in the 7.2L water, it is molten clear to stir the system that is warming up to; Then this aqueous solution at room temperature is added drop-wise in the 57.6L dehydrated alcohol, the dropping time is 2 hours, is cooled to 5 ℃ of insulations 2 hours after dripping off.Filter, filter cake places that drying under reduced pressure obtains 1.15kg pemetrexed disodium 2.5 hydrates to doing under 50 ℃ of conditions.Adopt the identical method of embodiment 1, quicken and the permanent stability experiment, the result is substantially the same manner as Example 1.