CN104356205A - Method applied to purification of kyprolis - Google Patents
Method applied to purification of kyprolis Download PDFInfo
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- CN104356205A CN104356205A CN201410680367.2A CN201410680367A CN104356205A CN 104356205 A CN104356205 A CN 104356205A CN 201410680367 A CN201410680367 A CN 201410680367A CN 104356205 A CN104356205 A CN 104356205A
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Abstract
The invention provides a method applied to purification of kyprolis. The method comprises the following steps: carrying out silica gel column chromatographic separation on a solution of crude kyprolis to obtain a chromatographic solution; and re-crystallizing the chromatographic solution to obtain pure kyprolis, wherein mobile phases of the silica gel column chromatographic separation comprise a mobile phase A and a mobile phase B; the mobile phase A comprises one or several of ethyl acetate, acetone and dichloromethane; the mobile phase B comprises alkane with 5-10 carbon atoms. By virtue of the method, the silica-gel column chromatography and re-crystallization are sequentially carried out on the crude kyprolis; one or several of ethyl acetate, acetone and dichloromethane and alkane with 5-10 carbon atoms are used as the mobile phases in the chromatographic process, so that the separation of impurities and kyprolis in the crude kyprolis is facilitated; then the crude kyprolis is re-crystallized, so that the purity of the kyprolis is improved. The method is simple, and is high in operability and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, particularly relate to the purification process 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.
Since FDA in 2012 ratifies Ka Feizuo meter listing, the imitated research of the synthesis of Ka Feizuo meter is just progressively launched.Medicine is special commodity, medicine research and development, copy, declare with preparation process in the control of foreign matter content, residual solvent etc. is even more important.Therefore, exploitation residual solvent is low, foreign matter content is low and be conducive to the purification process of suitability for industrialized production, and the Ka Feizuo meter bulk drug obtaining meeting medicinal standard has great importance.But still less about the report of the purification process of Ka Feizuo meter at present, report that the purity of the Ka Feizuo meter sterling that the purification process of Ka Feizuo meter out obtains is still lower.
Summary of the invention
The object of the present invention is to provide the purification process of a kind of Ka Feizuo meter, the Ka Feizuo meter sterling that method provided by the invention obtains has higher purity.
The invention provides the purification process of a kind of Ka Feizuo meter, comprise the following steps:
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.
Preferably, described Mobile phase B comprises normal hexane and/or normal heptane.
Preferably, the volume ratio of described mobile phase A and described Mobile phase B is (1 ~ 10): 1.
Preferably, in described silicagel column, the granularity of filling gel is 160 order ~ 300 orders.
Preferably, in described silicagel column, the dress post amount of silica gel is (5 ~ 80) g Ka Feizuo meter /kg silica gel.
Preferably, described recrystallization is 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.
Preferably, the mass concentration of described Ka Feizuo meter solution is (0.05 ~ 0.1) g/mL.
Preferably, the volume ratio of described first solvent and the second solvent is 1:(1 ~ 5).
Preferably, the temperature of described crystallization is 0 DEG C ~ 60 DEG C;
The time of described crystallization is 0.5h ~ 2h.
The invention provides the purification process of a kind of Ka Feizuo meter, comprise the following steps: 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.Experimental result shows, the purity of the Ka Feizuo meter sterling that the present invention prepares is greater than 99.5%, and maximum single foreign matter content is less than 0.1%.
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 obtains;
Fig. 2 is the HPLC collection of illustrative plates of the Ka Feizuo meter sterling that the embodiment of the present invention 2 obtains;
Fig. 3 is the HPLC collection of illustrative plates of the Ka Feizuo meter sterling that the embodiment of the present invention 3 obtains.
Embodiment
The invention provides the purification process of a kind of Ka Feizuo meter, comprise the following steps:
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 ~ 0.8g/mL, is more preferably 0.3g/mL ~ 0.5g/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%, meets medicinal standard.
The invention provides the purification process of a kind of Ka Feizuo meter, comprise the following steps: 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.Experimental result shows, the purity of the Ka Feizuo meter sterling that the present invention prepares is greater than 99.5%, and maximum single foreign matter content is less than 0.1%.
In order to further illustrate the present invention, being described in detail below in conjunction with the purification process of embodiment to Ka Feizuo meter provided by the invention, but they can not being interpreted as limiting the scope of the present invention.
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 0.4g/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, 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 detects; 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 present invention adopts HPLC to detect the purity of the Ka Feizuo meter sterling obtained, the mass concentration that Ka Feizuo meter sterling HPLC detects sample is 1mg/mL, detected 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, maximum single foreign matter content is less than 0.1%.
Embodiment 2
1g Ka Feizuo meter crude product is dissolved in the ethyl acetate and normal hexane mixing solutions that volume ratio is 4:1, be that the Ka Feizuo meter crude product solution of 0.3g/mL joins on silicagel column by the concentration obtained, in silicagel column, the granularity of filling gel is 200 order ~ 300 orders, wet method dress post controling parameters is 20g Ka Feizuo meter /kg silica gel, be that the use ethyl acetate of 4:1 and normal hexane mixing solutions make moving phase by volume ratio, carry out column chromatography for separation, in column chromatography for separation, the flow velocity of moving phase is 10mL/min, follow the tracks of with HPLC, the parameter of HPLC tracking monitor is consistent with embodiment 1;
Collect chromatographic solution, under vacuum tightness is 0.1 and temperature is the condition of 40 DEG C, vacuum concentration, obtains Ka Feizuo meter solid.
At room temperature, by the Ka Feizuo meter solid stirring and dissolving that obtains in 18mL acetone, then add 20mL normal hexane wherein and mix, left at room temperature crystallization 4h, suction filtration, filter cake drying under reduced pressure, obtains Ka Feizuo meter sterling.
The HPLC detect parameters in embodiment 1 is adopted to detect the Ka Feizuo meter sterling obtained, result as shown in Figure 2, Fig. 2 is the HPLC collection of illustrative plates of the Ka Feizuo meter sterling that the embodiment of the present invention 2 obtains, as seen from Figure 2, Ka Feizuo meter sterling go out peak position at 14.060min, impurity is less, purity >=99.78% of the Ka Feizuo meter sterling that the present embodiment obtains, and maximum single foreign matter content is less than 0.1%.
Embodiment 3
1g Ka Feizuo meter crude product is dissolved in the ethyl acetate and normal hexane mixing solutions that volume ratio is 5:1, 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 250 order ~ 300 orders, wet method dress post controling parameters is 35g Ka Feizuo meter /kg silica gel, be that the ethyl acetate of 5:1 and normal hexane mixing solutions make moving phase by volume ratio, carry out column chromatography for separation, in column chromatography for separation, the flow velocity of moving phase is 25mL/min, follow the tracks of with HPLC, the parameter of HPLC tracking monitor is consistent with embodiment 1;
Collect chromatographic solution, under vacuum tightness is 0.05 and temperature is the condition of 50 DEG C, vacuum concentration, obtains Ka Feizuo meter solid.
At ambient temperature, by the Ka Feizuo meter solid stirring and dissolving that obtains in 15mL acetone, then add 45mL normal hexane wherein and mix, the mixing solutions obtained is cooled to 0 DEG C of standing crystallization 6h, suction filtration, filter cake drying under reduced pressure, obtains Ka Feizuo meter sterling.
The HPLC detect parameters in embodiment 1 is adopted to detect the Ka Feizuo meter sterling obtained, result as shown in Figure 3, Fig. 3 is the HPLC collection of illustrative plates of the Ka Feizuo meter sterling that the embodiment of the present invention 3 obtains, as seen from Figure 3, Ka Feizuo meter sterling go out peak position at 14.180min, impurity is less, purity >=99.83% of the Ka Feizuo meter sterling that the present embodiment obtains, and maximum single foreign matter content is less than 0.1%.
As seen from the above embodiment, the invention provides the purification process of a kind of Ka Feizuo meter, comprise the following steps: 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.Experimental result shows, the purity of the Ka Feizuo meter sterling that the present invention prepares is greater than 99.5%, and maximum single foreign matter content is less than 0.1%.
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 purification process of Yi Zhong Ka Feizuo meter, comprises the following steps:
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.
2. purification process according to claim 1, is characterized in that, described Mobile phase B comprises normal hexane and/or normal heptane.
3. purification process according to claim 1 and 2, is characterized in that, the volume ratio of described mobile phase A and described Mobile phase B is (1 ~ 10): 1.
4. purification process according to claim 1 and 2, is characterized in that, in described silicagel column, the granularity of filling gel is 160 order ~ 300 orders.
5. purification process according to claim 1 and 2, is characterized in that, in described silicagel column, the dress post amount of silica gel is (5 ~ 80) g Ka Feizuo meter /kg silica gel.
6. purification process according to claim 1 and 2, is characterized in that, described recrystallization is 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.
7. purification process according to claim 6, is characterized in that, the mass concentration of described Ka Feizuo meter solution is (0.05 ~ 0.1) g/mL.
8. purification process according to claim 6, is characterized in that, the volume ratio of described first solvent and the second solvent is 1:(1 ~ 5).
9. purification process according to claim 6, is characterized in that, the temperature of described crystallization is 0 DEG C ~ 60 DEG C.
10. purification process according to claim 6, is characterized in that, the time of described crystallization is 0.5h ~ 2h.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104650193A (en) * | 2015-01-28 | 2015-05-27 | 南京新百药业有限公司 | Oxytocin recrystallization method |
| CN105524137A (en) * | 2015-12-24 | 2016-04-27 | 利穗科技(苏州)有限公司 | Method for purifying carfilzomib with macromolecular amino polymer-bonded silica gel |
| 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 |
| CN107402259A (en) * | 2016-05-18 | 2017-11-28 | 石药集团中奇制药技术（石家庄）有限公司 | The detection method of chiral isomer in Carfilzomib |
| CN111153964A (en) * | 2020-01-20 | 2020-05-15 | 安礼特（上海）医药科技有限公司 | Carfilzomib crystal form, preparation method and application thereof |
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Cited By (9)
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| CN104650193A (en) * | 2015-01-28 | 2015-05-27 | 南京新百药业有限公司 | Oxytocin recrystallization method |
| CN104650193B (en) * | 2015-01-28 | 2017-12-12 | 南京新百药业有限公司 | A kind of oxytocin recrystallization method |
| 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 |
| CN105938123B (en) * | 2015-12-18 | 2018-09-14 | 重庆两江药物研发中心有限公司 | The detection method of impurity in a kind of Carfilzomib intermediate |
| CN105524137A (en) * | 2015-12-24 | 2016-04-27 | 利穗科技(苏州)有限公司 | Method for purifying carfilzomib with macromolecular amino polymer-bonded silica gel |
| CN107402259A (en) * | 2016-05-18 | 2017-11-28 | 石药集团中奇制药技术（石家庄）有限公司 | The detection method of chiral isomer in Carfilzomib |
| CN107402259B (en) * | 2016-05-18 | 2020-10-13 | 石药集团中奇制药技术（石家庄）有限公司 | Method for detecting chiral isomer in carfilzomib |
| CN111153964A (en) * | 2020-01-20 | 2020-05-15 | 安礼特（上海）医药科技有限公司 | Carfilzomib crystal form, preparation method and application thereof |
| CN111153964B (en) * | 2020-01-20 | 2023-12-19 | 江苏希迪制药有限公司 | Carfilzomib crystal form, preparation method and application thereof |
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