CN104327067B - Preparation method of amorphous dasatinib - Google Patents
Preparation method of amorphous dasatinib Download PDFInfo
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- CN104327067B CN104327067B CN201410532533.4A CN201410532533A CN104327067B CN 104327067 B CN104327067 B CN 104327067B CN 201410532533 A CN201410532533 A CN 201410532533A CN 104327067 B CN104327067 B CN 104327067B
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- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to a preparation method of amorphous dasatinib, wherein the preparation method includes the steps: dissolving raw materials of various crystal types of dasatinib in an anhydrous organic solvent at the temperature of 60-100 DEG C, adding a cosolvent for helping dissolution, and thus obtaining a fully-dissolved dasatinib solution; carrying out spray drying on the dasatinib solution, carrying out cyclone isolation, and rapidly precipitating to obtain a dasatinib solid powder; drying the dasatinib solid powder under reduced pressure, removing the solvent, and thus obtaining the dasatinib amorphous product. Through testing, the prepared amorphous dasatinib has the moisture content generally less than 2%, and is nearly anhydrous dasatinib. The method is suitable for converting various crystal types of dasatinib into the dasatinib amorphous product having the residual solvent consistent with Chinese pharmacopoeia, and the preparation yield reaches up to more than 99%. Moreover, the method has the advantages of simple operation, less operation steps, less using solvent, small process pollution, low cost and the like, and is suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to a kind of method for producing amorphous Dasatinib, belongs to pharmaceutical technology field.
Background technology
Dasatinib (BMS-354825, Dasatinib) is a kind of tyrosine kinase inhibitor, for treating Imatinib
(Imatinib) treat the later stage chronic granulocytic leukemia (Chronic Myelogenous Leukemia, CML) and
The acute myeloid leukaemia that Philadelphia chromosome is positive, the current medicine are also proved to treat the cancer of many other types, such as
Prostate cancer of accelerated period etc..
The preparation method of the Dasatinib disclosed by document is concentrated mainly in the synthesis of the various crystal formations of Dasatinib at present,
And rarely have disclosure for how to prepare amorphous Dasatinib.What the CN 1980909 as authorized was protected is that one, band is crystallized
The Dasatinib of water, i.e. its monohydrate crystal form, and the preparation method of the monohydrate crystal form is disclosed, but do not refer to nothing
The preparation of setting Dasatinib.CN103059013 is found that the novel crystal forms of Dasatinib -- the crystal formation of Dasatinib monohydrate
III, and the preparation method of the crystal formation is disclosed, but also it is not directed to amorphous Dasatinib.CN102643275 discloses one kind
The preparation method of Dasatinib N-6 crystal formations, CN102086195 disclose a kind of the polymorph of Dasatinib (mixed crystal) open
Its preparation method and the Pharmaceutical composition comprising the polymorph, these documents are all not related to the system of amorphous Dasatinib
It is standby.
However, Dasatinib crystal formation effect in the production process of Subsequent pharmacological preparation is sometimes unsatisfactory, because up to sand
It is slow for dissolution velocity of Buddhist nun's crystal formation in pharmaceutical auxiliaries such as water or alcohols solvent, the production time of preparation is extended, no
Beneficial to pharmaceutical practice.
It has been investigated that, unbodied Dasatinib, can almost in various pharmacy solvents such as water or alcohols solvent
Enough quick dissolvings, solubility are high, are conducive to pharmaceutical practice, can significantly shorten the production time of preparation, reduce pharmaceutical preparation
The loss of Dasatinib in production process.
CN103408542 discloses a kind of preparation method of highly purified Dasatinib anhydride, and which is by N- (the chloro- 6- of 2-
Aminomethyl phenyl) -2- [(6- chloro-2-methyl -4- pyrimidine radicals) amino] -5- thiazole carboxamides and N- hydroxyethyl piperazines reaction be obtained reach
Husky to replace Buddhist nun's crude product, an one-step refining of going forward side by side is into highly purified Dasatinib anhydride.Wherein mainly include will be obtained for subtractive process
Dasatinib crude product heating for dissolving carries out air-distillation in absolute ethyl alcohol and DMF, then and removes solvent, Jing after filtering cooling,
Methyl tertiary butyl ether(MTBE) or isopropyl ether is added in filtrate, continues cooling crystallization, wash filter cake afterwards with ether solvent, and vacuum is dry
Dry 8-10 hours, obtain Dasatinib anhydride.Although obtained Dasatinib purity is high for the method, and water content is low, but refined
The yield of process is relatively low, and only 70% or so.Because the process for purification is complicated, operating procedure is various, using multi-solvents, therefore easily
Dasatinib is caused to lose.
Therefore, a kind of preparation method of amorphous Dasatinib is found, which can be greatly improved and prepare yield, farthest
The loss of Dasatinib is reduced, is one of Dasatinib preparation field technical problem urgently to be resolved hurrily.
The content of the invention
It is an object of the invention to provide a kind of new method for preparing amorphous Dasatinib, can reaching various crystal formations
Husky simply and rapidly to change into amorphous products for Buddhist nun, product yield is up to more than 99%, and Dasatinib does not almost lose.
2% is generally less than with amorphous solid water content obtained in the method, almost anhydrous Dasatinib, while residual solvent is also closed
The regulation of Chinese Pharmacopoeia.
A kind of one aspect of the present invention, there is provided preparation method of amorphous Dasatinib, including：
Dasatinib various crystal formation raw materials are dissolved in anhydrous organic solvent at 60-100 DEG C, and add cosolvent to help
Dissolving, obtains the Dasatinib solution being completely dissolved；
Dasatinib solution is spray-dried, cyclonic separation, it is quick to separate out Dasatinib pressed powder；
Drying under reduced pressure is carried out to Dasatinib pressed powder, is removed solvent, is obtained Dasatinib amorphous products.
Specifically, the solvent for dissolving the various crystal formation raw materials of Dasatinib is at least one in ethanol, isopropanol and acetone.
One of the invention concrete but non-limiting embodiment, wherein, the various crystal formation raw materials of Dasatinib with
The mass ratio of solvent is 1：5-30.
One of the invention concrete but non-limiting embodiment, wherein, cosolvent is N, N- dimethyl formyls
At least one in amine (DMF) and dimethyl sulfoxide (DMSO) (DMSO).
One of the invention concrete but non-limiting embodiment, wherein, the various crystal formation raw materials of Dasatinib with
The mass ratio of cosolvent is 1：0.005-0.1.
One of the invention concrete but non-limiting embodiment, wherein, is spray-dried and cyclonic separation passes through
Spray-dried instrument is completed.
One of the invention concrete but non-limiting embodiment, wherein, during spray drying, Hot-blast Heating temperature
At 100-150 DEG C, hot-blast outlet temperature is at 80-100 DEG C.
One of the invention concrete but non-limiting embodiment, wherein, during cyclonic separation, control vacuum is little
In -0.095MPa.
One of the invention concrete but non-limiting embodiment, wherein, drying under reduced pressure be under a high vacuum,
60-100 DEG C of heat drying 5-8 hour.
A kind of another aspect of the present invention, there is provided Dasatinib amorphous products prepared by said method, it is aqueous
Less than 2%, residual solvent meets NF regulation to amount.
The beneficial effects are mainly as follows：
1., using being spray-dried, the method for cyclonic separation is quick to separate out Dasatinib pressed powder, then passes through for the present invention
Drying under reduced pressure removes solvent, obtains Dasatinib amorphous products.Dasatinib does not almost lose in the process, high income
Up to more than 99%, have and greatly improve than the yield of existing amorphous Dasatinib preparation method only 70% or so.
2. present invention anhydrous solvent dissolves the various crystal formation raw materials of Dasatinib, it is to avoid introduce extra moisture；The present invention
Add cosolvent to coordinate dissolving Dasatinib raw material, accelerate dissolution velocity, make dissolving more complete, farthest avoid up to sand
Loss for Buddhist nun in course of dissolution, while decreasing the usage amount and the follow-up treating capacity to solvent of solvent, reduces work
Measure, reduce power consumption.
3. the preparation method of the amorphous Dasatinib of the present invention has simple to operate, and operating procedure is few, few using solvent,
Process contamination is little, low cost and other advantages, is adapted to large-scale industrial production.
4. the method for the present invention be adapted to by the Dasatinib of various crystal formations change into water content less than 2%, and residual solvent
In accordance with the Dasatinib amorphous products that Chinese Pharmacopoeia specifies.
Description of the drawings
Fig. 1 is the powder X-ray diffracting spectrum (XRD) of amorphous Dasatinib prepared by the present invention.
Fig. 2 is differential scanning calorimetry (DSC) collection of illustrative plates of amorphous Dasatinib prepared by the present invention.
Fig. 3 is thermogravimetic analysis (TGA) (TGA) collection of illustrative plates of amorphous Dasatinib prepared by the present invention.
Specific embodiment
Provided hereinafter specific embodiment and further illustrate the present invention, but the present invention is not limited only to following enforcement
Mode.
The chemical name of Dasatinib is N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [[6- [4- (2- ethoxys) -1- piperazines
Base] -2- methyl -4- pyrimidine radicals] amino] -5- thiazole carboxamides, molecular formula is C22H28ClN7O2S, molecular weight 488.01, chemistry
Structural formula is as follows：
According to existing Dasatinib preparation method, need to add solvent crystallization in last handling process.According to what is added
Solvent is different, and usually containing the different crystallizations water or the Dasatinib crystal containing different solvents, this has resulted in and has reached the crystal of precipitation
Sand has various different crystal forms for Buddhist nun.Dissolubility of many crystal formations in Subsequent pharmacological formulation manufacturing processes is simultaneously bad, dissolving speed
Degree is slow, and amorphous Dasatinib quickly can be dissolved in the pharmacy solvent such as water or alcohols, it is therefore desirable to by various crystal formations
Dasatinib changes into the amorphous products without the crystallization water and solvent.
The invention provides a kind of preparation method of amorphous Dasatinib, first will be replaced up to sand with anhydrous solvent and cosolvent
The various crystal formation dissolution of raw material of Buddhist nun, then with being spray-dried, the method for cyclonic separation is quick to separate out Dasatinib pressed powder, then
Solvent is removed by drying under reduced pressure, Dasatinib amorphous products of the residual solvent in accordance with Chinese Pharmacopoeia are obtained.Below to this
Bright method is described in detail：
(1) dissolving of the various crystal formation raw materials of Dasatinib
Dasatinib various crystal formation raw materials are added in a certain amount of solvent, and add a certain amount of cosolvent, stirred
And 60-100 DEG C of dissolving is heated to, until Dasatinib raw material is completely dissolved.Solvent should select readily soluble anhydrous of Dasatinib to have
Machine solvent, such as ethanol, isopropanol, acetone etc..The various crystal formation raw materials of Dasatinib can be 1 with the mass ratio of solvent：5-30.
In course of dissolution, it is very important for dissolving Dasatinib raw material to add cosolvent to coordinate dissolving.Hydrotropy
Agent can accelerate the dissolving of Dasatinib raw material, reduce the usage amount of solvent, so as to reduce the follow-up treating capacity to solvent, significantly
Reduction labour intensity simultaneously reduces power consumption.Cosolvent should select to mix with Dasatinib, while can also be dissolved in the nothing of above-mentioned solvent
Water organic solvent, such as DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO) etc..The various crystal formation raw materials of Dasatinib with
The mass ratio of cosolvent can be 1：0.005-0.1.
(2) it is spray-dried, cyclonic separation
The step can be completed in spray-dried instrument.The Dasatinib solution being completely dissolved, while hot into spray-dried instrument, control
Wind heating-up temperature is heated at 100-150 DEG C, at 80-100 DEG C, control vacuum is less than -0.095MPa, flow to hot-blast outlet temperature
Control with cyclonic separation collection to be advisable as pressed powder, it is quick to separate out Dasatinib pressed powder.
(3) drying under reduced pressure
After spray drying terminates, the pressed powder of collection enters decompression baking oven, under a high vacuum, 60-100 DEG C of heat drying
5-8 hours, further dry, and remove solvent, obtain Dasatinib amorphous products.Scheme by X diffracting spectrums and with reference to DSC, TGA
Spectrum is it was determined that obtained product is amorphous Dasatinib.Through karl Fischer water content detection, the amorphous solid water content
Generally less than 2%.Jing Head space gas Chromatographic Determinations, the regulation of the residual solvent of the amorphous products in accordance with Chinese Pharmacopoeia.
The preparation method of above-mentioned amorphous Dasatinib can be processed to the Dasatinib raw material of various crystal formations, and product
High income, more than 99%, Dasatinib almost free of losses.
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.
Experimental technique above and used in following embodiments if no special instructions, is conventional method.
Above and in following embodiments, material used, reagent etc., if no special instructions, commercially obtain.
Dasatinib raw material used in following examples is purchased from Lianyungang Ruizhong Pharmaceutical Co., Ltd. (address：Even
Yun Gang economic and technological development zones great Pu industrial areas Golden Bridge road 16) Chinese medicines quasi-word H20130102 Dasatinib bulk drug (medicine
Product this bit codes is 86909615000088).
Embodiment 1
10g Dasatinib raw materials are added in 100g ethanol, add 0.1gDMF as cosolvent.80 DEG C of heating is molten
Solution, while hot into cloth fine jade B-290 spray-dried instruments, at 100-150 DEG C, hot-blast outlet temperature is in 80- for control Hot-blast Heating temperature
100 DEG C, control vacuum is less than -0.095MPa, and flow controls with cyclonic separation collection to be advisable as pressed powder.It is spray-dried
After end, the pressed powder of collection enters decompression baking oven, and under a high vacuum, 80 DEG C of heat dryings 6 hours are further dried, removed
Solvent is removed, the Dasatinib raw material for obtaining Dasatinib amorphous solid, yield 99.2%, purity and addition is more unchanged,
The X diffracting spectrums of powder are as shown in Figure 1.From from Fig. 1, the peak of the sharp angle of diffraction is not found, it was demonstrated that the product is without fixed
Shape Dasatinib.Through karl Fischer water content detection, moisture is less than 2%.Jing Head space gas Chromatographic Determinations, residual solvent
Specify in accordance with Chinese Pharmacopoeia.
Amorphous Dasatinib to preparing carries out DSC and TGA detections, as a result as follows：
Fig. 2 is differential scanning calorimetry (DSC) collection of illustrative plates of amorphous Dasatinib prepared by embodiment 1.Can from the collection of illustrative plates
To find out at 2 points：One is the fusing point or vitrification point that 164.17 DEG C is amorphous Dasatinib；Two is in 0--164 DEG C of area
Between do not have significantly because crystal formation changes or crystallize the absworption peak that reason is produced, this has also confirmed the thing of the preparation of embodiment 1 indirectly
Matter is amorphous Dasatinib.
Fig. 3 is thermogravimetic analysis (TGA) (TGA) collection of illustrative plates of amorphous Dasatinib prepared by embodiment 1.Can from the collection of illustrative plates
Go out at 2 points：One is that, between 0--164 DEG C (thawing), weightless is only 1.37%, does not reach the weightlessness of 0.5 crystallization water, it was demonstrated that
Amorphous products prepared by embodiment 1 do not contain the crystallization water；Two be the amorphous Dasatinib decomposition temperature be 294.10 DEG C.
Embodiment 2
10g Dasatinib raw materials are added in 150g isopropanols, add 0.1g DMSO as cosolvent.80 DEG C of heating
Dissolving, while hot into cloth fine jade B-290 spray-dried instruments, at 100-150 DEG C, hot-blast outlet temperature exists control Hot-blast Heating temperature
80-100 DEG C, control vacuum is less than -0.095MPa, and flow controls with cyclonic separation collection to be advisable as pressed powder.Spraying
After drying terminates, the pressed powder of collection enters decompression baking oven, and under a high vacuum, 80 DEG C of heat dryings 8 hours further dry
It is dry, solvent is removed, the raw material Dasatinib for obtaining Dasatinib amorphous solid, yield 99.6%, purity and addition compares nothing
Change.By X diffracting spectrums, understand with reference to DSC, TGA collection of illustrative plates, the Dasatinib for preparing is amorphous Dasatinib.Through
Karl Fischer water content detection, moisture are less than 2%.Jing Head space gas Chromatographic Determinations, residual solvent are advised in accordance with Chinese Pharmacopoeia
It is fixed.
Embodiment 3
10g Dasatinib raw materials are added in 200g acetone, add 0.5gDMF as cosolvent.65 DEG C of heating is molten
Solution, while hot into cloth fine jade B-290 spray-dried instruments, at 100-150 DEG C, hot-blast outlet temperature is in 80- for control Hot-blast Heating temperature
100 DEG C, control vacuum is less than -0.095MPa, and flow controls with cyclonic separation collection to be advisable as pressed powder.It is spray-dried
After end, the pressed powder of collection enters decompression baking oven, and under a high vacuum, 80 DEG C of heat dryings 7 hours are further dried, removed
Solvent is removed, the raw material Dasatinib for obtaining Dasatinib amorphous solid, yield 99.7%, purity and addition is more unchanged.
By X diffracting spectrums, understand with reference to DSC, TGA collection of illustrative plates, the Dasatinib for preparing is amorphous Dasatinib.Take through karr
Not water content detection, moisture are less than 2%.Jing Head space gas Chromatographic Determinations, residual solvent specify in accordance with Chinese Pharmacopoeia.
Embodiment 4
10g Dasatinib raw materials are added in 100g ethanol, add 0.7g part DMSO as cosolvent.80 DEG C of heating
Dissolving, while hot into cloth fine jade B-290 spray-dried instruments, at 100-150 DEG C, hot-blast outlet temperature is more than control Hot-blast Heating temperature
80-100 DEG C, control vacuum is less than -0.095MPa, and flow controls with cyclonic separation collection to be advisable as pressed powder.Spraying
After drying terminates, the pressed powder of collection enters decompression baking oven, and under a high vacuum, 80 DEG C of heat dryings 6 hours further dry
It is dry, solvent is removed, the raw material Dasatinib for obtaining Dasatinib amorphous solid, yield 99.7%, purity and addition compares nothing
Change.By X diffracting spectrums, understand with reference to DSC, TGA collection of illustrative plates, the Dasatinib for preparing is amorphous Dasatinib.Through
Karl Fischer water content detection, moisture are less than 2%.Jing Head space gas Chromatographic Determinations, residual solvent are advised in accordance with Chinese Pharmacopoeia
It is fixed.
The above is only the concrete application example of the present invention, protection scope of the present invention is not limited in any way.All employings
Equivalents or equivalence replacement and the technical scheme that formed, all fall within rights protection scope of the present invention.
Claims (7)
1. a kind of preparation method of amorphous Dasatinib, including：
Dasatinib various crystal formation raw materials are dissolved in anhydrous organic solvent at 60-100 DEG C, and it is molten to add cosolvent to help
Solution, obtains the Dasatinib solution being completely dissolved；
Dasatinib solution is spray-dried, cyclonic separation, quick to separate out Dasatinib pressed powder, wherein, spraying is dry
When dry, at 100-150 DEG C, at 80-100 DEG C, cyclonic separation, control vacuum is little for hot-blast outlet temperature for Hot-blast Heating temperature
In -0.095MPa；
Drying under reduced pressure is carried out to Dasatinib pressed powder, is removed solvent, is obtained Dasatinib amorphous products.
2. method according to claim 1, wherein, the solvent for dissolving the various crystal formation raw materials of Dasatinib be ethanol, isopropanol and
At least one in acetone.
3. the method according to claim 1 or 2, wherein, the various crystal formation raw materials of Dasatinib are 1 with the mass ratio of solvent：5-30.
4. method according to claim 1, wherein, cosolvent is at least in DMF and dimethyl sulfoxide (DMSO)
Kind.
5. the method according to claim 1 or 4, wherein, the various crystal formation raw materials of Dasatinib are 1 with the mass ratio of cosolvent：
0.005-0.1。
6. method according to claim 1, wherein, is spray-dried and cyclonic separation is completed by spray-dried instrument.
7. method according to claim 1, wherein, drying under reduced pressure be under a high vacuum, it is little in 60-100 DEG C of heat drying 5-8
When.
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| CN106831710A (en) * | 2015-12-07 | 2017-06-13 | 常州爱诺新睿医药技术有限公司 | A kind of solid dispersions of unformed HKI-272 or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof |
| WO2017108605A1 (en) | 2015-12-22 | 2017-06-29 | Synthon B.V. | Pharmaceutical composition comprising amorphous dasatinib |
| WO2017134617A1 (en) * | 2016-02-03 | 2017-08-10 | Dr. Reddy's Laboratories Limited | Process for the preparation of amorphous dasatinib |
| CN111217807A (en) * | 2018-11-26 | 2020-06-02 | 安礼特（上海）医药科技有限公司 | Dasatinib amorphous form and preparation method thereof |
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| WO2014016848A2 (en) * | 2012-07-24 | 2014-01-30 | Laurus Labs Private Limited | Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof |
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