CN106317188A

CN106317188A - Method for preparing amorphous substance of carfilzomib

Info

Publication number: CN106317188A
Application number: CN201510340809.3A
Authority: CN
Inventors: 刘才平; 周昌兵; 徐立炎; 王兵; 雷皇书; 邓杰
Original assignee: Chongqing Pharmaceutical Research Institute Co Ltd
Current assignee: Chongqing Pharmaceutical Research Institute Co Ltd
Priority date: 2015-06-18
Filing date: 2015-06-18
Publication date: 2017-01-11

Abstract

The invention relates to a method for preparing an amorphous substance of novel peptide compound carfilzomib for the treatment of multiple myeloma, the method comprises the following steps: 1) dissolving the carfilzomib in an organic solvent; 2) adding into a non-water-resist solvent for precipitation of an amorphous solid; and 3) separating the amorphous solid. The method has the advantages of little loss of raw materials and no need of adding of water and concentration, is convenient for mass production under the condition of GMP, is simple and has strong operability.

Description

A kind of method preparing Carfilzomib amorphous article

Technical field

The invention belongs to medicinal chemistry art, relate to the industrialized process for preparing of the amorphous article of a kind of novel peptide type compound Carfilzomib.

Background technology

Carfilzomib is a kind of medicine treating multiple myeloma, trade name Kyprolis, English name is Carfilzomib, this product cures mainly Refractory Multiple Myeloma, it is by the Carfilzomib freeze-dried powder injection of Onyx Pharmaceuticals company research and development the earliest, on July 20th, 2012 by U.S. food Drug Administration (FDA) approval listing.This product is second filial generation proteasome inhibitor, can not injure composing type spheroid protein function and immunoproteasome in Selective depression blood tumor cell, so that cancerous cell is more easy to apoptosis.Because of the selectivity of height, this product has the advantages that untoward reaction is few, sharpest edges are then to overcome the neurotoxicity that some proteasome inhibitor is had, and common adverse reactions is pneumonia, anemia, neutrophils minimizing and thrombocytopenia.

The Carfilzomib crude drug of report exists with unformed and two kinds of forms of specific crystal formation at present.CN101883779A discloses specific crystal formation and the amorphous article of Carfilzomib.

CN101044157A discloses the preparation method of a kind of Carfilzomib amorphous article, will be dissolved in a small amount of methanol by crude product Carfilzomib, then Carfilzomib methanol solution is slowly added in a certain amount of frozen water, quickly obtains Carfilzomib unformed crystal formation solid after stirring a period of time.But this method utilizing water and methanol mixed solvent to prepare Carfilzomib amorphous article, in follow-up dry run, shipwreck, to remove, can increase purifying products difficulty, and the stability of product and quality also can be affected.

CN104402973A discloses a kind of method preparing Carfilzomib amorphous article, the method uses dichloromethane, alcohols, acetone equal solvent uses solvent removed in vacuo after dissolving Ka Feizuo meter again, thus the method obtaining Carfilzomib unformed crystal formation solid, but, Carfilzomib unformed solid show bubble or cotton-shaped and big portion that the method prepares adhere to container bottom, it is difficult to take out from container, and, need the most size-reduced after taking out solid, operation of sieving can obtain pressed powder, operate cumbersome, be unfavorable for large-scale production under the conditions of GMP.

Summary of the invention

Object of the present invention is to provide a kind of method preparing Carfilzomib amorphous article, the method concentrates without heating, directly separates out scattered solid amorphous powder, product does not contains water of crystallization or solvent, easily it is dried and good stability, easy and simple to handle, it is suitable for industrialized production.

For realizing the purpose of the present invention, it is provided that a kind of method preparing Carfilzomib amorphous article, comprise the following steps:

1) Carfilzomib is dissolved in organic solvent；

2) join in non-aqueous solvent resistant, separate out unformed solid；

3) isolated unformed solid.

Preferably, the method for the invention described above, described organic solvent is dichloromethane；Described solvent resistant is selected from normal hexane, hexamethylene, petroleum ether, one or more in normal heptane, step 2) in, temperature when Carfilzomib mixes with solvent resistant is-20 DEG C ~ 50 DEG C, preferably 5 DEG C ~ 40 DEG C.

The method of the invention described above, separates described in step 3), including filtering or centrifugation.

In a particular embodiment, a kind of method preparing Carfilzomib amorphous article, comprise the following steps:

1) Carfilzomib is dissolved in organic solvent dichloromethane；

2) during Carfilzomib dichloromethane solution is added drop-wise to non-aqueous solvent resistant, described non-aqueous solvent resistant be selected from normal hexane, hexamethylene, one or more in petroleum ether and normal heptane,

3) stir 1-3 hour at-20 DEG C ~ 50 DEG C, separate out unformed solid；

4) isolate unformed solid, be drying to obtain.

In above-mentioned specific embodiments, process of the present invention it is preferred that non-aqueous solvent resistant be hexamethylene, the volume mass of organic solvent used and Carfilzomib is than at least 2ml:1g；The volume of non-aqueous solvent resistant is at least 7:1, preferred baking temperature 40 DEG C ~ 50 DEG C with the comparing of volume of organic solvent used.

The preparation method of the Carfilzomib amorphous article of the present invention uses two kinds of mixed organic solvents to carry out recrystallization at normal temperatures, without adding water, product is made to be not likely to produce water of crystallization, and organic solvent used easily removes at follow-up drying course, few residual, makes the Carfilzomib amorphous article prepared have preferable quality and stability.The Carfilzomib amorphous article that this method obtains is scattered white powdery solids, and in preparation process, significant loss is few, it is simple to large-scale production under the conditions of GMP, and method is easy, workable.

Accompanying drawing explanation

Fig. 1 is the HPLC collection of illustrative plates of the unformed solid of Carfilzomib that embodiment 1 prepares；

Fig. 2 is the XRPD collection of illustrative plates of the unformed solid of Carfilzomib that embodiment 1 method obtains；

Fig. 3 is the TGA collection of illustrative plates of the unformed solid of Carfilzomib that embodiment 1 prepares；

Fig. 4 is the DSC collection of illustrative plates of the unformed solid of Carfilzomib that embodiment 1 prepares.

Detailed description of the invention

Embodiment 1

Following example are for being further appreciated by the essence of the present invention, but do not limit the scope of the present invention with this.

After 300g Carfilzomib is dissolved with 750ml dichloromethane, after being filtered to remove mechanical admixture, its filtrate added drop-wise is entered in the there-necked flask equipped with 6000ml hexamethylene, control reaction temperature at 0 DEG C ~ 10 DEG C, a large amount of white solid is produced during dropping, keep 0 DEG C ~ 10 DEG C after dropping and continue stirring 1 ~ 3h, rear sucking filtration, gained white solid washs 2 times with 300ml hexamethylene again, take out gained white solid after 30min, be positioned in porcelain dish, put in vacuum drying oven after sealing, Carfilzomib unformed solid 294.6g, yield: 98.2% is obtained after drying.Gained Carfilzomib is tested through HPLC and XRPD, for amorphous article, as shown in Fig. 1 and Fig. 2.

Embodiment 2

After 100g Carfilzomib is dissolved with 300ml dichloromethane, after being filtered to remove mechanical admixture, its filtrate added drop-wise is entered in the there-necked flask equipped with 2250ml normal heptane, control reaction temperature at 30 DEG C ~ 40 DEG C, a large amount of white solid is produced during dropping, keep 30 DEG C ~ 40 DEG C after dropping and continue stirring 1 ~ 3h, rear sucking filtration, gained white solid washs 2 times with 100ml normal heptane again, take out gained white solid after 30min, be positioned in porcelain dish, put in vacuum drying oven after sealing, Carfilzomib unformed solid 97.8g, yield: 97.8% is obtained after drying.The XRPD figure of gained Carfilzomib amorphous article is essentially identical with Fig. 2.

Embodiment 3

After 100g Carfilzomib is dissolved with 250ml dichloromethane, after being filtered to remove mechanical admixture, its filtrate added drop-wise is entered in the there-necked flask equipped with 2000ml normal hexane, control reaction temperature at-20 DEG C ~ 0 DEG C, a large amount of white solid is produced during dropping, keep-20 DEG C ~ 0 DEG C after dropping and continue stirring 1 ~ 3h, rear sucking filtration, gained white solid washs 2 times with 100ml normal hexane again, take out gained white solid after 30min, be positioned in porcelain dish, put in vacuum drying oven after sealing, Carfilzomib amorphous article solid 98.6g, yield: 98.6% is obtained after drying.The XRPD figure of gained Carfilzomib amorphous article is essentially identical with Fig. 2.

Embodiment 4

After 100g Carfilzomib is dissolved with 400ml dichloromethane, after being filtered to remove mechanical admixture, its filtrate is poured in 3000ml there-necked flask, after be slowly added dropwise into hexamethylene 2800ml, control reaction temperature at 5 DEG C ~ 20 DEG C, a large amount of white solid is produced during dropping, keep 5 DEG C ~ 20 DEG C after dropping and continue stirring 1 ~ 3h, at the bottom of having fraction solids to adhere to bottle, rear sucking filtration, gained white solid washs 2 times with 100ml hexamethylene again, gained white solid is taken out after 30min, it is positioned in porcelain dish, put into after sealing in vacuum drying oven, Carfilzomib unformed solid 94.6g is obtained after drying, yield: 94.6%.Gained Carfilzomib is tested through HPLC and XRPD, and for amorphous article, the XRPD figure of gained Carfilzomib amorphous article is essentially identical with Fig. 2.

Gained Carfilzomib amorphous article does powder x-ray diffraction analysis, and instrument is X^,Pert Pro MPDX-x ray diffractometer x, concrete test method is appropriate, using the copper palladium of 40kv as x-ray radiation source, 2 ~ 40 for taking this product^oIn the range of, the angle of diffraction is with per minute 2^oSpeed make continuously scanning.Knowable to the powder x-ray diffraction figure (XRPD figure) of this product, this product diffraction pattern is disperse shape, does not has any sharp-pointed diffraction maximum, exists with amorphous forms, and the feature of its X-ray powder diagram is unformed consistent with report in CN101883779A.

Conclusion: X-ray powder diffraction experiment shows that this product is unformed is consistent with the X-ray powder diagram feature of patent CN101883779A report.

The Carfilzomib amorphous article solid method of the present invention such as embodiment 1 prepared finds after carrying out subsequent quality research, this product is through thermogravimetric analysis, the TGA figure that detection obtains shows before 220 DEG C substantially without weightless, illustrate that this product does not contains water of crystallization, free water and recrystallisation solvent, by better heat stability before 220 DEG C；About start weightlessness at 220 DEG C, to about 350 DEG C weightlessness about 55%, illustrate that this product starts drastically to decompose, as shown in Figure 3 after 220 DEG C.This product differential scanning calorimetry analysis, the DSC collection of illustrative plates that detection obtains shows that compound is about 180 in one exothermic peak of 160 ~ 200 DEG C of interval appearance^oC has heat absorption peak drastically, should be the exothermic peak of this product crystal conversion, illustrates that this product there occurs in thermal histories and turns crystalline substance；Endothermic peak occur at about 213 DEG C, endothermic peak is sharp-pointed and precipitous, is the feature of melting peak；As shown in Figure 4.

The unformed pressed powder of Carfilzomib prepared by the method for the present invention send HPLC to analyze, purity >=99.80% of the Carfilzomib amorphous article that the method using HPLC to detect records, as shown in Figure 1, the Carfilzomib sterling time in HPLC spectrogram is about at 31.244min, impurity is less, and maximum single impurity content is less than 0.05%.

The unformed solid of Carfilzomib prepared by this method is scattered white powdery solids, compared with the unformed Carfilzomib that the method for other prior art prepares, product characteristics are more preferable, working specification is higher, preparation condition milder is difficult to cause product to go bad, it is easier to large-scale production under gmp conditions, there is preferable economy and practicality.

Claims

1. the method for the amorphous article preparing Carfilzomib: comprise the following steps:

1) Carfilzomib is dissolved in organic solvent；

2) join in non-aqueous solvent resistant, separate out unformed solid；

3) unformed solid is isolated.

2. the method for claim 1, described organic solvent is dichloromethane.

3. the method for claim 1, described solvent resistant is selected from normal hexane, hexamethylene, petroleum ether, one or more in normal heptane.

4. as described in claim 1 method, step 2) in temperature when mixing with solvent resistant be-20 DEG C ~ 50 DEG C.

5. method as claimed in claim 4, temperature when mixing with solvent resistant is 5 DEG C ~ 30 DEG C scopes.

6. the method described in claim 1, separates described in step 3), including filtering or centrifugation.

7. the method as described in claim 1-3 is arbitrary, Carfilzomib is 1:2.0 ~ 1:5g/ml with the mass volume ratio of organic solvent.

8. the method as described in claim 1-3 is arbitrary, Carfilzomib is 1:15 ~ 1:40 with the mass volume ratio of non-aqueous solvent resistant g/ ml。