CN104402973A - Method for preparing carfilzomib amorphous crystal - Google Patents
Method for preparing carfilzomib amorphous crystal Download PDFInfo
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- CN104402973A CN104402973A CN201410680314.0A CN201410680314A CN104402973A CN 104402973 A CN104402973 A CN 104402973A CN 201410680314 A CN201410680314 A CN 201410680314A CN 104402973 A CN104402973 A CN 104402973A
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Abstract
The invention provides a method for preparing a carfilzomib amorphous crystal. The method comprises the following steps: dissolving carfilzomib in an organic solvent to obtain a carfilzomib solution; concentrating the carfilzomib solution to obtain the carfilzomib amorphous crystal. The method has the advantages that as the solvent is organic, no water is needed, and the organic solvent is easy to remove during concentration, no residual can be generated in the product, the moisture content is extremely low, no crystal water is formed, and the obtained carfilzomib amorphous crystal is relatively high in stability. The carfilzomib amorphous crystal is prepared by dissolving carfilzomib and directly concentrating and drying the carfilzomib solution, that is, the processes of crystal growth and devitrification are not avoided, so that the obtained carfilzomib crystal is amorphous. Therefore, the method is simple, high in operability, and suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, particularly relate to the preparation method of the unformed crystalline substance of a kind of Ka Feizuo meter.
Background technology
Ka Feizuo meter (Carfilzomib); chemical name is (2S)-N-((S)-1-((S)-4-methyl isophthalic acid-((R)-2-methyl oxirane-2-base)-1-oxo-pentane-2-base formamyl)-2-styroyl)-2 – ((S)-2-(2-morpholine acetamido)-4-phenylbutanamides base)-4-methylpentanamide; commodity are called Kyprolis, and molecular formula is C
40h
57n
5o
7, there is structure shown in formula I:
Ka Feizuo meter is the Ka Feizuo meter freeze-dried powder injection produced by Onyx Pharmaceuticals company the earliest, listing is ratified by U.S. food Drug Administration (FD) on July 20th, 2012, accept at least 2 kinds of medicines before being used for the treatment of, comprise the multiple myeloma patients of Velcade and immunomodulator treatment.Carfilzomib's is granted, is the multiple myeloma patients of those recurrences after current therapy treatment, provides a kind of therapeutic choice.In the clinical trial of Carfilzomib medicine, have 266 patients and receive test, researchist represents, patient, after the treatment accepting this medicine, wherein has neoplastic conditions in the patient body of 23% to improve.Claim according to Onyx drugmaker, compared with current leukemia medicine, the advantage of Carfilzomib is to reduce nervous lesion.Carfilzomib is played a role by a kind of albumen composition in optionally T suppression cell, thus makes cancer cell more easily dead.The II phase clinical research data display that Onyx drugmaker announces, to the unfruitful patient of other treatment, has 24% to have certain curative effect at least after taking Carfilzomib.
Ka Feizuo meter is the same with many medicinal compounds, also there is polymorphism.The crystal formation of Ka Feizuo meter can remarkably influenced drug quality, security and validity, in numerous crystal formations of many Ka Feizuo meter, the amorphous crystalline substance of Ka Feizuo meter has certain advantage in solvability and bioavailability.US Patent No. 7232818 discloses the preparation method of the unformed crystalline substance of a kind of Ka Feizuo meter, by Ka Feizuo meter dissolving crude product in a small amount of methyl alcohol, then slowly add in a certain amount of frozen water by the methanol solution of the Ka Feizuo meter crude product obtained, rapid stirring obtains Ka Feizuo meter amorphous forms.But the method for the unformed crystalline substance of this Ka Feizuo meter of preparation has used water, in drying process, the more difficult removing of water, can affect material stability.
Summary of the invention
The object of the present invention is to provide the preparation method of the amorphous crystalline substance of a kind of Ka Feizuo meter, not containing water in the amorphous crystalline substance of the Ka Feizuo meter that method provided by the invention obtains, good stability.
The invention provides the preparation method of the amorphous crystalline substance of a kind of Ka Feizuo meter, comprise the following steps:
Ka Feizuo meter is dissolved in organic solvent, obtains Ka Feizuo meter solution;
Described Ka Feizuo meter solution is concentrated, obtains the amorphous crystalline substance of Ka Feizuo meter.
Preferably, described organic solvent comprises one or more in methylene dichloride, alcohol compound and acetone.
Preferably, described organic solvent comprises one or more in methylene dichloride, methyl alcohol, ethanol and acetone.
Preferably, the quality of described Ka Feizuo meter and the volume ratio of organic solvent are 1g:(5 ~ 30) mL.
Preferably, described simmer down to concentrating under reduced pressure.
Preferably, the vacuum tightness of described concentrating under reduced pressure is 0.03 ~ 0.1.
Preferably, the temperature of described concentrating under reduced pressure is 20 DEG C ~ 80 DEG C.
Preferably, described drying is drying under reduced pressure.
Preferably, the vacuum tightness of described drying under reduced pressure is more than 0.08.
Preferably, the temperature of described drying under reduced pressure is 30 DEG C ~ 80 DEG C.
The invention provides the preparation method of the amorphous crystalline substance of a kind of Ka Feizuo meter, comprise the following steps: Ka Feizuo meter is dissolved in organic solvent, obtain Ka Feizuo meter solution; Described Ka Feizuo meter solution is concentrated, obtains the amorphous crystalline substance of Ka Feizuo meter.What the preparation method of amorphous crystalline substance provided by the invention adopted is organic solvent, without the need to adding water, organic solvent is easy to removing in concentration process, can not produce residual in the product, and moisture content is low in the unformed crystalline substance of the Ka Feizuo meter obtained, can not crystal water be formed, thus make the amorphous crystalline substance of Ka Feizuo meter obtained have higher stability.And the preparation method of the amorphous crystalline substance of Ka Feizuo meter provided by the invention is after dissolving Ka Feizuo meter, directly by concentrated and dry for the Ka Feizuo meter solution obtained, do not experience the process of long crystalline substance, crystallization, the Ka Feizuo meter crystal obtained is amorphous crystalline substance; Make method provided by the invention simple, workable, be applicable to large-scale industrial production.Moreover the preparation method of the unformed crystalline substance of Ka Feizuo meter provided by the invention, without the need to specific installation, is beneficial to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of the Ka Feizuo meter sterling that the embodiment of the present invention 1 prepares;
Fig. 2 is the XRPD collection of illustrative plates of the Ka Feizuo meter crystal that the embodiment of the present invention 1 obtains;
Fig. 3 is the XRPD collection of illustrative plates of the Ka Feizuo meter crystal that the embodiment of the present invention 2 obtains;
Fig. 4 is the XRPD collection of illustrative plates of the Ka Feizuo meter crystal that the embodiment of the present invention 3 obtains.
Embodiment
The invention provides the preparation method of the amorphous crystalline substance of a kind of Ka Feizuo meter, comprise the following steps:
Ka Feizuo meter is dissolved in organic solvent, obtains Ka Feizuo meter solution;
Described Ka Feizuo meter solution is concentrated, obtains the amorphous crystalline substance of Ka Feizuo meter.
What the preparation method of amorphous crystalline substance provided by the invention adopted is organic solvent, and without the need to adding water, organic solvent is easy to removing in concentration process, can not produce residual in the product, and moisture content is low, can not crystal water be formed, make the amorphous crystalline substance of Ka Feizuo meter obtained have higher stability.And the preparation method of the amorphous crystalline substance of Ka Feizuo meter provided by the invention is after dissolving Ka Feizuo meter, directly by concentrated and dry for the Ka Feizuo meter solution obtained, do not experience the process of long crystalline substance, crystallization, the Ka Feizuo meter crystal obtained is amorphous crystalline substance; Make method provided by the invention simple, workable, be applicable to large-scale industrial production.Moreover the preparation method of the unformed crystalline substance of Ka Feizuo meter provided by the invention, without the need to specific installation, is beneficial to suitability for industrialized production.
Ka Feizuo meter is dissolved in organic solvent by the present invention, obtains Ka Feizuo meter solution.The purity of the present invention to described Ka Feizuo meter does not have special restriction, adopts Ka Feizuo meter well known to those skilled in the art; In an embodiment of the present invention, described Ka Feizuo meter can Ka Feizuo meter sterling, also Ke Yi Wei Ka Feizuo meter crude product.The source of the present invention to described Ka Feizuo meter does not have special restriction, in an embodiment of the present invention, the commercial goods of Ka Feizuo meter sterling or Ka Feizuo meter crude product can be adopted, also the preparation method of Ka Feizuo meter well known to those skilled in the art can be adopted to prepare voluntarily, prepare voluntarily as publication number Ka Feizuo metric system Preparation Method disclosed in the Chinese patent of CN103641890A can be adopted.
When described Ka Feizuo meter is Ka Feizuo meter sterling, the present invention, preferably according to following purification process, prepares Ka Feizuo meter sterling:
The solution of Ka Feizuo meter crude product is carried out silica gel column chromatography separation, obtains chromatographic solution; The moving phase that described silica gel column chromatography is separated comprises mobile phase A and Mobile phase B, and described mobile phase A comprises one or more in ethyl acetate, acetone and methylene dichloride, and described Mobile phase B comprises the alkane that carbonatoms is 5 ~ 10;
Described chromatographic solution is carried out recrystallization, obtains Ka Feizuo meter sterling.
Ka Feizuo meter crude product is carried out silica gel column chromatography and recrystallization by method provided by the invention successively, with one or more in ethyl acetate, acetone and methylene dichloride in column chromatography procedure, and carbonatoms be 5 ~ 10 alkane be moving phase, be conducive to being separated of impurity and Ka Feizuo meter in Ka Feizuo meter crude product, carry out recrystallization again, improve the purity of Ka Feizuo meter.And method provided by the invention is simple, workable, is beneficial to large-scale commercial production.
The solution of Ka Feizuo meter crude product is carried out silica gel column chromatography separation by method provided by the invention, obtains chromatographic solution.The source of the present invention to described Ka Feizuo meter crude product does not have special restriction, adopt Ka Feizuo meter well known to those skilled in the art, as the commercial goods that Ke Yi is Ka Feizuo meter, prepare voluntarily not purified of the preparation method that also can be Ka Feizuo meter well known to those skilled in the art or the Ka Feizuo meter crude product that purity is lower.Concrete, in an embodiment of the present invention, described Ka Feizuo meter crude product can be prepared by publication number Ka Feizuo metric system Preparation Method disclosed in the Chinese patent of CN103641890A.
In the present invention, the solvent in the solution of described Ka Feizuo meter crude product is preferably moving phase described in technique scheme; The mass concentration of the solution of described Ka Feizuo meter crude product is preferably 0.1g/mL ~ 0.6g/mL, is more preferably 0.3g/mL ~ 0.4g/mL.
In the present invention, the moving phase that described silica gel column chromatography is separated comprises mobile phase A and Mobile phase B, and described mobile phase A comprises one or more in ethyl acetate, acetone and methylene dichloride, and described Mobile phase B comprises the alkane that carbonatoms is 5 ~ 10.Method provided by the invention is with one or more in ethyl acetate, acetone and methylene dichloride, and carbonatoms be 5 ~ 10 alkane be moving phase, the solution of Ka Feizuo meter crude product is carried out column chromatography, above-mentioned moving phase is beneficial to being separated of the impurity that Ka Feizuo meter coexists with it, is conducive to the purity improving Ka Feizuo meter.In the present invention, described mobile phase A preferably includes ethyl acetate; Described Mobile phase B preferably includes normal hexane and/or normal heptane, most preferably is normal hexane.In the present invention, the volume ratio of described mobile phase A and described Mobile phase B is preferably (1 ~ 10): 1, is more preferably (2 ~ 8): 1, most preferably is (2 ~ 5): 1.In an embodiment of the present invention, the volume ratio of described mobile phase A and Mobile phase B can be specially 2:1,3:1,4:1 or 5:1.In the present invention, the flow velocity of described moving phase is preferably 5mL/min ~ 25mL/min, is more preferably 10mL/min ~ 20mL/min.
In the present invention, in described silicagel column, the granularity of filling gel is preferably 160 order ~ 300 orders, is more preferably 180 order ~ 280 orders, most preferably is 200 order ~ 250 orders; The dress post amount of described silica gel in silicagel column is preferably (5 ~ 80) g Ka Feizuo meter /kg silica gel, is more preferably (10 ~ 50) g Ka Feizuo meter /kg silica gel, most preferably is (15 ~ 35) g Ka Feizuo meter /kg silica gel.The method of silicagel column dress post of the present invention does not have special restriction, adopts column packing technique scheme well known to those skilled in the art, as being dry column-packing or wet method dress post; In the present invention, the method for described dress post is preferably wet method dress post.
In the process that the present invention is separated at described silica gel column chromatography, preferably adopt the composition of thin-layer chromatography or high performance liquid chromatography (HPLC) tracking monitor chromatographic solution, to collect the chromatographic solution containing Ka Feizuo meter sterling.The present invention does not have special restriction to the method that described thin-layer chromatography and high performance liquid chromatography detect, and adopts the technical scheme that thin-layer chromatography well known to those skilled in the art and high performance liquid chromatography detect.In an embodiment of the present invention, HPLC is preferably adopted to carry out tracking monitor to chromatography process; Chromatographic column during described HPLC detects be preferably Agilent Extend-C18150mm × 4.6mm, 3.5 μm; The column temperature of described chromatographic column is preferably 30 DEG C; Sample size during described HPLC detects is preferably 10 μ L; Flow velocity during described HPLC detects is preferably 1mL/min; Moving phase during described HPLC detects preferably includes solution A and solution B, and solution A is preferably the dipotassium hydrogen phosphate buffered soln that volumetric molar concentration is 0.02mol/L, pH value is 6.5, and solution B is preferably acetonitrile;
Gradient elution program during described HPLC detects is preferably:
In 20min, the volume ratio of described mobile phase A and described Mobile phase B is preferably 50:50;
In 20min ~ 40min, the volume ratio of described mobile phase A and described Mobile phase B is preferably 30:70;
In 40min ~ 50min, the volume ratio of described mobile phase A and described Mobile phase B is preferably 30:70;
Starting time during described HPLC detects is preferably 5min; In the present invention, when described tracking sample is chromatographic solution, described chromatographic solution direct injection detects, and concentrates without the need to carrying out or dilutes; ; Determined wavelength during described HPLC detects is preferably 210nm.
After completing the separation of described silica gel column chromatography, the chromatographic solution obtained is carried out recrystallization by the present invention, obtains Ka Feizuo meter sterling.In the present invention, described recrystallization is preferably specially:
Described chromatographic solution is concentrated, obtains Ka Feizuo meter solid;
Be dissolved in the first solvent by described Ka Feizuo meter solid, obtain Ka Feizuo meter solution, described first solvent comprises one or more in acetone, methylene dichloride and ethyl acetate;
By described Ka Feizuo meter solution and the second solvent, crystallization, obtains Ka Feizuo meter sterling, and described second solvent comprises one or more in normal hexane, normal heptane and methyl alcohol.
Described chromatographic solution, after obtaining chromatographic solution, preferably concentrates by the present invention, obtains Ka Feizuo meter solid.The present invention does not have special restriction to described concentrated method, can obtain Ka Feizuo meter solid except desolventizing.In the present invention, described concentrated preferably concentrating under reduced pressure; The vacuum tightness of described concentrating under reduced pressure is preferably 0.03 ~ 0.1, is more preferably 0.05 ~ 0.08; The temperature of described underpressure distillation is preferably 20 DEG C ~ 80 DEG C, is more preferably 25 DEG C ~ 60 DEG C, most preferably is 30 DEG C ~ 50 DEG C.In an embodiment of the present invention, at room temperature can carry out described underpressure distillation, without the need to heating or cooling in described vacuum distillation process.
After obtaining described Ka Feizuo meter solid, described Ka Feizuo meter solid is preferably dissolved in the first solvent by the present invention, obtains Ka Feizuo meter solution, and described first solvent comprises one or more in acetone, methylene dichloride and ethyl acetate.The present invention does not have special restriction to the method that described Ka Feizuo meter solid dissolves in the first solvent, can by described Ka Feizuo meter dissolution of solid.Described Ka Feizuo meter solid preferably, under the condition stirred, is dissolved in the first solvent by the present invention; The method of the present invention to described stirring does not have special restriction, adopts the technical scheme of stirring well known to those skilled in the art.In an embodiment of the present invention, can be different according to the kind of the first solvent, select stirring at normal temperature or heated and stirred, can by described Ka Feizuo meter dissolution of solid in described first solvent; The method of the present invention to described heating does not have special restriction, adopts the technical scheme of heating for dissolving well known to those skilled in the art.In the present invention, the temperature of described heated and stirred is preferably 30 DEG C ~ 60 DEG C, is more preferably 35 DEG C ~ 55 DEG C, most preferably is 40 DEG C ~ 50 DEG C; In the present invention, the mass concentration of described Ka Feizuo meter solid in described first solvent is preferably (0.05 ~ 0.1) g/mL, is more preferably (0.06 ~ 0.08) g/mL.
After obtaining Ka Feizuo meter solution, the present invention is preferably by described Ka Feizuo meter solution and the second solvent, and crystallization, obtains Ka Feizuo meter sterling, and described second solvent comprises one or more in normal hexane, normal heptane and methyl alcohol.The present invention preferably adds described second solvent, crystallization in described Ka Feizuo meter solution, obtains Ka Feizuo meter sterling.The volume ratio of described first solvent and described second solvent is preferably 1:(1 ~ 5 in the present invention); In an embodiment of the present invention, the volume ratio of described first solvent and described second solvent can be specially 1:1,1:2,1:3,1:4 or 1:5.
In the present invention, when described first solvent comprises acetone, described second solvent preferably includes normal hexane and/or normal heptane; When described first solvent comprises methylene dichloride, described second solvent preferably includes methyl alcohol and/or normal hexane; When described first solvent comprises ethyl acetate, described second solvent preferably includes normal hexane.
In the present invention, described crystallization can for leaving standstill crystallization, and can be stirring and crystallizing, the present invention have special restriction to this yet.In the present invention, the temperature of described crystallization is preferably 0 DEG C ~ 60 DEG C, is more preferably 5 DEG C ~ 50 DEG C, most preferably is 10 DEG C ~ 30 DEG C; The time of described crystallization is preferably 0.5h ~ 24h, most preferably is 1h ~ 12h, most preferably is 2h ~ 6h.In an embodiment of the present invention, described crystallization can carry out at normal temperatures, in the process of described crystallization, without the need to heating crystallization system or lowering the temperature.
After completing described Crystallization Process, the system after crystallization is preferably filtered by the present invention, by the filtration cakes torrefaction obtained, obtains Ka Feizuo meter sterling.The present invention does not have special restriction to described filtration and dry technical scheme, adopts filtration well known to those skilled in the art and dry technical scheme.In the present invention, described filtration is preferably suction filtration; Described drying is preferably drying under reduced pressure; The vacuum tightness of described high-pressure drying, preferably more than 0.08, is more preferably 0.08 ~ 0.1; The temperature of described drying under reduced pressure is preferably 30 DEG C ~ 80 DEG C, is more preferably 40 DEG C ~ 60 DEG C, most preferably is 45 DEG C ~ 55 DEG C.
After obtaining Ka Feizuo meter sterling, the present invention adopts the purity of the detection method of HPLC described in technique scheme to described Ka Feizuo meter sterling to detect, when detecting described Ka Feizuo meter sterling, moving phase during Ka Feizuo meter sterling preferably adopts HPLC to detect is dissolved, the Ka Feizuo meter HPLC obtained is detected sample detect, the mass concentration that described Ka Feizuo meter HPLC detects sample is preferably 0.5mg/mL ~ 2mg/mL, is more preferably 1mg/mL.Result shows, and the purity of the Ka Feizuo meter sterling that method provided by the invention obtains is more than 99.5%, and maximum single foreign matter content is less than 0.1%.
In the present invention, described organic solvent is preferably one or more in methylene dichloride, alcohol compound and acetone, is more preferably one or more in methylene dichloride, methyl alcohol, ethanol and acetone.In the present invention, the quality of described Ka Feizuo meter and the volume ratio of described organic solvent are preferably 1g:(5 ~ 30) mL, be more preferably 1g:(8 ~ 25) mL, and most preferably be 1g:(10 ~ 20) mL; In an embodiment of the present invention, the quality of described Ka Feizuo meter and the volume ratio of described organic solvent can be specially 1g:10mL, 1g:15mL or 1g:20mL.
The present invention does not have special restriction to the method that described Ka Feizuo meter dissolves in organic solvent, described Ka Feizuo meter can be dissolved with organic solvent; In an embodiment of the present invention, the mode of stirring can be specifically adopted to promote Ka Feizuo meter dissolving in organic solvent; The method of the present invention to described stirring does not have special restriction, adopts the technical scheme of stirring well known to those skilled in the art.
After obtaining Ka Feizuo meter solution, described Ka Feizuo meter solution concentrates by the present invention, obtains the amorphous crystalline substance of Ka Feizuo meter.Described Ka Feizuo meter solution, before being concentrated by described Ka Feizuo meter solution, preferably filters by the present invention, removing insoluble impurity wherein.
After filtration, the filtrate that described filtration obtains preferably is concentrated into dry by the present invention, obtains the amorphous crystalline substance of Ka Feizuo meter.In the present invention, described concentrated preferably concentrating under reduced pressure; The vacuum tightness of described concentrating under reduced pressure is preferably 0.03 ~ 0.1, is more preferably 0.05 ~ 0.08; The temperature of described concentrating under reduced pressure is preferably 20 DEG C ~ 80 DEG C, is more preferably 25 DEG C ~ 60 DEG C, most preferably is 30 DEG C ~ 50 DEG C.In an embodiment of the present invention, the vacuum tightness of described concentrating under reduced pressure can be specially 0.03,0.04,0.05,0.06,0.07,0.08,0.09 or 0.1; The temperature of described concentrating under reduced pressure can be specially 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C or 50 DEG C; In other embodiment of the present invention, described concentrating under reduced pressure can specifically at room temperature carry out, without the need to heating concentrating under reduced pressure process or lowering the temperature.
After completing described concentrating, the present invention preferably by the solid drying after described concentrating, obtains the amorphous crystalline substance of Ka Feizuo meter.The method of the present invention to described drying does not have special restriction, adopts the technical scheme of drying well known to those skilled in the art; As being forced air drying, drying under reduced pressure or bipyramid drying; In the present invention, described drying is preferably drying under reduced pressure, can improve the stability obtaining product.In the present invention, the vacuum tightness of described drying under reduced pressure, preferably more than 0.08, is more preferably 0.08 ~ 0.1; The temperature of described drying under reduced pressure is preferably 30 DEG C ~ 80 DEG C, is more preferably 35 DEG C ~ 70 DEG C, most preferably is 40 DEG C ~ 60 DEG C.In an embodiment of the present invention, the vacuum tightness of described drying under reduced pressure can be specially 0.08,0.09 or 0.1; The temperature of described drying under reduced pressure can be specially 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C or 60 DEG C; In other examples, described drying under reduced pressure can specifically at room temperature carry out, without the need to heating drying process or lowering the temperature; The time of described drying under reduced pressure is preferably 6h ~ 24h, is more preferably 9h ~ 21h, most preferably is 12h ~ 18h.
The present invention adopts X powder diffraction method (XRPD) to measure the crystal formation of the product obtained, and result shows, and the Ka Feizuo meter crystal that method provided by the invention obtains is amorphous crystalline substance.
The invention provides the preparation method of the amorphous crystalline substance of a kind of Ka Feizuo meter, comprise the following steps: Ka Feizuo meter is dissolved in organic solvent, obtain Ka Feizuo meter solution; Described Ka Feizuo meter solution is concentrated, obtains the amorphous crystalline substance of Ka Feizuo meter.What the preparation method of amorphous crystalline substance provided by the invention adopted is organic solvent, without the need to adding water, organic solvent is easy to removing in concentration process, can not produce residual in the product, and moisture content is low in the unformed crystalline substance of the Ka Feizuo meter obtained, can not crystal water be formed, thus make the amorphous crystalline substance of Ka Feizuo meter obtained have higher stability.And the preparation method of the amorphous crystalline substance of Ka Feizuo meter provided by the invention is after dissolving Ka Feizuo meter, directly by concentrated and dry for the Ka Feizuo meter solution obtained, do not experience the process of long crystalline substance, crystallization, the Ka Feizuo meter crystal obtained is amorphous crystalline substance; Make method provided by the invention simple, workable, be applicable to large-scale industrial production.Moreover the preparation method of the unformed crystalline substance of Ka Feizuo meter provided by the invention, without the need to specific installation, is beneficial to suitability for industrialized production.
In order to further illustrate the present invention, below in conjunction with embodiment, the preparation method to the amorphous crystalline substance of Ka Feizuo meter provided by the invention is described in detail, but they can not be interpreted as limiting the scope of the present invention.
Each raw material in following embodiment is commercial goods.
Embodiment 1
1g Ka Feizuo meter crude product being dissolved in volume ratio is in the ethyl acetate of 2:1 and the mixing solutions of normal hexane, be that the Ka Feizuo meter crude product solution of 0.5g/mL joins on silicagel column by the concentration obtained, in silicagel column, the granularity of filling gel is 200 order ~ 250 orders, wet method dress post controling parameters is 15g Ka Feizuo meter /kg silica gel, be that the ethyl acetate of 2:1 and the mixing solutions of normal hexane make moving phase by volume ratio, carry out column chromatography for separation, in column chromatography for separation, the flow velocity of moving phase is 5mL/min, follow the tracks of with HPLC, the parameter that HPLC detects is:
Chromatographic column be Agilent Extend-C18150mm × 4.6mm, 3.5 μm; Column temperature is 30 DEG C; Sample size is 10 μ L; Flow velocity is 1mL/min; Moving phase comprises solution A and solution B, the dipotassium hydrogen phosphate buffered soln that solution A is volumetric molar concentration is 0.02mol/L, pH value is 6.5, and solution B is acetonitrile; Gradient elution program:
| Time (min) | A(％) | B(％) |
| 0 | 50 | 50 |
| 20 | 50 | 50 |
| 40 | 30 | 70 |
| 50 | 30 | 70 |
Starting time is 5min; Chromatographic solution direct injection carries out HPLC tracking monitor; Determined wavelength is 210nm;
Collect chromatographic solution, under vacuum tightness is 0.03 and temperature is the condition of 30 DEG C, vacuum concentration, obtains Ka Feizuo meter solid.
The Ka Feizuo meter solid obtained heated and stirred at 40 DEG C be dissolved in 10mL acetone, then add 50mL normal hexane wherein and mix, left at room temperature crystallization 2h, suction filtration, filter cake drying under reduced pressure, obtains Ka Feizuo meter sterling.
The method that the present invention adopts above-mentioned HPLC to detect monitors the purity of the Ka Feizuo meter sterling obtained, Ka Feizuo meter sterling HPLC detect the mass concentration of sample be 1mg/mL result as shown in Figure 1, Fig. 1 is the HPLC collection of illustrative plates of the Ka Feizuo meter sterling that the embodiment of the present invention 1 obtains, as seen from Figure 1, Ka Feizuo meter sterling go out peak position at 13.785min, impurity is less, purity >=99.71% of the Ka Feizuo meter sterling that the present embodiment obtains, and maximum single foreign matter content is less than 0.1%.
Under agitation, to obtain Ka Feizuo meter sterling 1g 10mL methylene dichloride dissolve, cross filter insoluble impurity, filtrate vacuum tightness be 0.03 and room temperature condition under be evaporated to dry, again vacuum tightness be 0.08 and room temperature condition under drying under reduced pressure 12h, obtain Ka Feizuo meter crystal.
The present invention adopts X-powder diffraction method to detect the Ka Feizuo meter crystal obtained, result as shown in Figure 2, Fig. 2 is the XRPD collection of illustrative plates of the Ka Feizuo meter crystal that the embodiment of the present invention 1 obtains, and as seen from Figure 2, the Ka Feizuo meter crystal that the present embodiment obtains is the amorphous crystalline substance of Ka Feizuo meter;
The present invention detects the moisture content of the unformed crystalline substance of Ka Feizuo meter obtained, and result shows, and the moisture content of the unformed crystalline substance of the Ka Feizuo meter that the present embodiment method obtains is 0.20wt%;
The present invention detects the stability of the unformed crystalline substance of Ka Feizuo meter obtained, and result is as shown in table 1, the Detection of Stability result of the unformed crystalline substance of Ka Feizuo meter that table 1 obtains for the embodiment of the present invention;
The Detection of Stability result of the unformed crystalline substance of the Ka Feizuo meter that table 1 embodiment of the present invention obtains
| Storage time (moon) | Moisture (%) | Maximum single foreign matter content (%) | Total impurities content (%) | Indicate content (%) |
| 0 | 0.20 | 0.07 | 0.22 | 99.2 |
| 1 | 0.22 | 0.07 | 0.23 | 99.2 |
| 2 | 0.19 | 0.07 | 0.25 | 99.1 |
| 3 | 0.23 | 0.07 | 0.26 | 99.2 |
| 6 | 0.23 | 0.07 | 0.26 | 99.1 |
As can be seen from Table 1, the unformed crystalline substance of the Ka Feizuo meter that method provided by the invention prepares is in storage process, and foreign matter content, moisture content are almost unchanged, have satisfactory stability.
Embodiment 2
Under the condition stirred, by 1g Ka Feizuo meter crude product 15mL dissolve with methanol, cross and filter insoluble impurity, filtrate is under vacuum tightness is 0.1 and temperature is the condition of 40 DEG C, be evaporated to dry, again under vacuum tightness is 0.1 and temperature is the condition of 50 DEG C, drying under reduced pressure 12h, obtains Ka Feizuo meter crystal.
The present invention adopts X-powder diffraction method to detect the Ka Feizuo meter crystal obtained, result as shown in Figure 3, Fig. 3 is the XRPD collection of illustrative plates of the Ka Feizuo meter crystal that the embodiment of the present invention 2 arrives, and as seen from Figure 3, the Ka Feizuo meter crystal that the present embodiment obtains is the amorphous crystalline substance of Ka Feizuo meter.
The present invention detects the moisture content of the unformed crystalline substance of Ka Feizuo meter obtained, and result shows, and the moisture content of the unformed crystalline substance of the Ka Feizuo meter that the present embodiment method obtains is 0.14wt%;
The present invention detects the stability of the unformed crystalline substance of Ka Feizuo meter obtained, and result shows, and the unformed crystalline substance of the Ka Feizuo meter that method provided by the invention prepares is in storage process, and foreign matter content, moisture content are almost unchanged, have satisfactory stability.
Embodiment 3
Under agitation, 1g type Ka Feizuo meter crude product is dissolved in 20mL acetone, crosses and filter insoluble impurity, filter vacuum degree be 0.05 and temperature be under the condition of 60 DEG C, be evaporated to dry, then under vacuum tightness is 0.1 and temperature is the condition of 40 DEG C, drying under reduced pressure 12h, obtains Ka Feizuo meter crystal.
The present invention adopts X-powder diffraction method to detect the Ka Feizuo meter crystal obtained, result as shown in Figure 4, Fig. 4 is the XRPD collection of illustrative plates of the Ka Feizuo meter that the embodiment of the present invention 3 obtains, and as seen from Figure 4, the Ka Feizuo meter crystal that the present embodiment obtains is the amorphous crystalline substance of Ka Feizuo meter.
The present invention detects the moisture content of the unformed crystalline substance of Ka Feizuo meter obtained, and result shows, and the moisture content of the unformed crystalline substance of the Ka Feizuo meter that the present embodiment method obtains is 0.24wt%;
The present invention detects the stability of the unformed crystalline substance of Ka Feizuo meter obtained, and result shows, and the unformed crystalline substance of the Ka Feizuo meter that method provided by the invention prepares is in storage process, and foreign matter content, moisture content are almost unchanged, have satisfactory stability.
As seen from the above embodiment, what the preparation method of amorphous crystalline substance provided by the invention adopted is organic solvent, without the need to adding water, organic solvent is easy to removing in concentration process, can not produce residual in the product, and moisture content is low in the unformed crystalline substance of the Ka Feizuo meter obtained, and can not form crystal water, thus the amorphous crystalline substance of Ka Feizuo meter obtained is made to have higher stability.And the preparation method of the amorphous crystalline substance of Ka Feizuo meter provided by the invention is after dissolving Ka Feizuo meter, directly by concentrated and dry for the Ka Feizuo meter solution obtained, do not experience the process of long crystalline substance, crystallization, the Ka Feizuo meter crystal obtained is amorphous crystalline substance; Make method provided by the invention simple, workable, be applicable to large-scale industrial production.Moreover the preparation method of the unformed crystalline substance of Ka Feizuo meter provided by the invention, without the need to specific installation, is beneficial to suitability for industrialized production.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. the preparation method of the amorphous crystalline substance of Yi Zhong Ka Feizuo meter, comprises the following steps:
Ka Feizuo meter is dissolved in organic solvent, obtains Ka Feizuo meter solution;
Described Ka Feizuo meter solution is concentrated, obtains the amorphous crystalline substance of Ka Feizuo meter.
2. preparation method according to claim 1, is characterized in that, described organic solvent comprises one or more in methylene dichloride, alcohol compound and acetone.
3. preparation method according to claim 2, is characterized in that, described organic solvent comprises one or more in methylene dichloride, methyl alcohol, ethanol and acetone.
4. the preparation method according to claims 1 to 3 any one, is characterized in that, the quality of described Ka Feizuo meter and the volume ratio of organic solvent are 1g:(5 ~ 30) mL.
5. preparation method according to claim 1, is characterized in that, described simmer down to concentrating under reduced pressure.
6. preparation method according to claim 5, is characterized in that, the vacuum tightness of described concentrating under reduced pressure is 0.03 ~ 0.1.
7. preparation method according to claim 5, is characterized in that, the temperature of described concentrating under reduced pressure is 20 DEG C ~ 80 DEG C.
8. preparation method according to claim 1, is characterized in that, described drying is drying under reduced pressure.
9. preparation method according to claim 8, is characterized in that, the vacuum tightness of described drying under reduced pressure is more than 0.08.
10. preparation method according to claim 8, is characterized in that, the temperature of described drying under reduced pressure is 30 DEG C ~ 80 DEG C.
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| CN105938123A (en) * | 2015-12-18 | 2016-09-14 | 重庆两江药物研发中心有限公司 | Detection method of impurity in carfilzomib intermediate |
| WO2017098532A1 (en) * | 2015-12-11 | 2017-06-15 | Mylan Laboratories Limited | Crystalline and amorphous forms of carfilzomib |
| TWI636052B (en) * | 2015-12-31 | 2018-09-21 | 中化合成生技股份有限公司 | Method for preparing amorphous carfilzomib (i) |
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| CN104961799A (en) * | 2015-06-19 | 2015-10-07 | 重庆医药工业研究院有限责任公司 | Kyprolis crystal form A and method for preparing same |
| CN104961799B (en) * | 2015-06-19 | 2021-05-11 | 重庆医药工业研究院有限责任公司 | Carfilzomib crystal form A and preparation method thereof |
| WO2017098532A1 (en) * | 2015-12-11 | 2017-06-15 | Mylan Laboratories Limited | Crystalline and amorphous forms of carfilzomib |
| CN105938123A (en) * | 2015-12-18 | 2016-09-14 | 重庆两江药物研发中心有限公司 | Detection method of impurity in carfilzomib intermediate |
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| TWI636052B (en) * | 2015-12-31 | 2018-09-21 | 中化合成生技股份有限公司 | Method for preparing amorphous carfilzomib (i) |
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Application publication date: 20150311 |