TWI636052B - Method for preparing amorphous carfilzomib (i) - Google Patents

Abstract

The invention provides a preparation method of amorphous amorphous carfilzomib (I) suitable for process amplification. The solvent for the precipitation of carfilzomib (I) is divided into two series: 1. The solvent for precipitation is water, and the solvent for the dissolution of carfilzomib (I) can be an alcohol solvent of methanol, ethanol or isopropanol when dissolved. Then, it is added dropwise to water, followed by filtration and drying to obtain amorphous carfilzomib (I), and the yield is as high as 90% or more. 2. The solvent for precipitation is a series of alkane, and the solvent for the dissolution of carfilzomib (I) may be dichloromethane, ethyl acetate or acetone. When dissolved, it is directly added dropwise to hexane or heptane, followed by filtration. Drying can obtain amorphous carfilzomib (I), and the yield is also as high as 90% or more. The process of the invention is relatively simple to operate, and is superior to the prior art and is also quite suitable for industrial production.

Description

Method for preparing amorphous carfilzomib (I)

The present invention provides a method for preparing a compound, in particular, a method for preparing amorphous amorphous Carfilzomib (I) suitable for process amplification.

Multiple Myeloma (MM, myeloma, plasma cell myeloma, or Kahler's disease) is a malignant tumor that causes abnormal proliferation of plasma cells and causes invasion of the bone marrow. If a malignant tumor is produced, it will cause the activation of the osteoclasts, accompanied by the destruction of the hard bone outside the bone, causing symptoms of bone pain. Carfilzomib (shown below in Formula I) of Onyx Pharmaceuticals: (I) On July 20, 2012, the US Food and Drug Administration (FDA) approved a proteasome inhibitor to treat patients with multiple myeloma.

The conventional technique is to dissolve carfilzomib (I) in isopropyl alcohol. After it is completely dissolved, water is quickly added to precipitate carfilzomib (I). Previous researchers have published a crystalline form of Carfilzomib (I), which is based on carfilzomib (I), added to methanol, and heated to an oil bath with an oil bath temperature of 80 ° C. After completely dissolving, 4 ml of pure water was slowly added, and the reaction was cooled to room temperature, and concentrated under a reduced pressure concentrator to remove 10 ml, filtered, and washed with 8 ml of pure water: methanol (1:1). After drying, 0.9 g of crystalline Carfilzomib (I) is obtained, which has a specific characteristic peak in the X-ray powder diffraction pattern, and the X-ray powder diffraction pattern of the compound crystal is on the following 2θ. There are peaks: 6.10, 8.10, 9.32, 10.10, 11.00, 12.14, 12.50, 13.64, 13.94, 17.14, 17.52, 18.44, 20.38, 21.00, 22.26, 23.30, 24.66, 25.98, 26.02, 27.84, 28.00, 28.16, 29.98, 30.46, 32.98, 33.22, 34.52 and 39.46.

Another method for preparing amorphous Amorphous Carfilzomib (I) is roughly as follows.

It is a crystalline compound of carfilzomib (I), added with isopropanol, and heated to an oil bath with an oil bath temperature of 80 ° C, completely dissolved, and then concentrated using a vacuum concentrator, and then quickly Add pure water, stir for 1 hour, filter, wash with pure water, and dry to obtain amorphous carfilzomib (I). However, in addition to the problem of experimental reproducibility, these methods, in addition to the step of precipitating carfilzomib (I) and the step of rapidly adding water, tend to cause a large amount of precipitation, resulting in a block shape, and at the same time, because of the need to quickly add pure water. It takes a long time to expand the experiment, which is less easy to control and difficult to industrialize.

In order to solve the above problems, the present invention provides a high-yield preparation method of amorphous carfilzomib (I) to shorten the processing time, improve the agglomeration phenomenon, simplify complicated manufacturing steps, and improve the feasibility of industrial production.

The method for preparing amorphous Amorphous Carfilzomib according to the present invention has the following steps: First, the alcohol or ketone having a carbon number of less than 10 is used as the first solvent to dissolve the card. Rice (Carfilzomib, I) dissolves to form a first solution; then the first solution is added dropwise to water to form a second solution, wherein the temperature of the water and the dropping process is controlled below 30 ° C; and then the first The two solutions were solid after solid filtration.

Another method for preparing amorphous Amorphous Carfilzomib (I) having the structural formula of the present invention comprises the steps of: first dissolving carfilzomib (I) with a second solvent; Forming a third solution, wherein the second solvent is a polar organic solvent having a carbon number of less than 15; then the third solution solution is added dropwise to a precipitation solvent to form a fourth solution, wherein the precipitation solvent and the solution The dropping process temperature is controlled at -10 ° C to 40 ° C, and the precipitation solvent is hexane, heptane, or a mixture thereof; and then the fourth solution is filtered and dried after filtration.

The first dissolution solvent of the present invention is preferably an alcohol or a ketone having a carbon number of less than 5, and more preferably methanol, ethanol, isopropanol, or a combination thereof. The second solubilizing solvent of the present invention is a polar solvent, preferably dichloromethane, ethyl acetate, acetone, or a combination thereof. In the present invention, the temperature of the water and the dropping process is preferably controlled below 10 °C.

The invention firstly modifies the preparation step of carfilzomib (I), and the conventional technology needs to be heated to 80 ° C for high temperature dissolution and reaction, and the present invention changes it to carfilzomib (I) at 60 ° C to 70 ° C. In propanol, the concentration is increased after complete dissolution, and the solution of carfilzomib (I) in isopropanol is added dropwise to the water of the stirring solvent in the stirring to precipitate carfilzomib (I). Since the above-mentioned experimental isopropyl alcohol is a solvent in which carfilzomib (I) is dissolved, isopropyl alcohol is defined as a solvent for dissolution, and water is a solvent for depositing carfilzomib (I). Therefore, water is defined as a solvent for precipitation. The present invention further changes the type of solvent to be dissolved and the solvent to be precipitated, and divides it into two series by a solvent system in which carfilzomib (I) is precipitated: 1. A solvent for the precipitation of carfilzomib (I) The solvent which is a series of water and 2. Carfilzomib (I) is a series of hexane and heptane.

The present invention can be illustrated by the following examples, but the scope of the present invention is not limited to the embodiments described below:

Example 1-1

Firstly, the solvent of carfilzomib (I) is discussed as a series of water. Referring to the previous experiment, carfilzomib (I) is added to the solvent isopropanol, dissolved by heating, concentrated, and then added to the stirring. In the water, so refer to the previous experiment, the carfilzomib (I) is in 10 times the volume of isopropanol as a solvent, heated to 60 ° C ~ 70 ° C to completely dissolve the reaction, after it is completely dissolved, use reduced pressure concentration to reduce The amount of the solvent is such that the total weight is 4.0 to 6.0 times that of carfilzomib (I), and the solution is added dropwise to the solvent water which precipitates carfilzomib (I), and the dropping process controls the temperature and continues. Stirring, until the end of the dropwise addition, the filter can be used to filter at room temperature, and after drying, amorphous carfilzomib (I) can be obtained, and the results are shown in Table 1.

Table 1 Results of precipitation of carfilzomib (I) dissolved in isopropanol

As shown in the results in Table 1, the carfilzomib (I) used in the precipitation experiments in the first to third experiments was used in an amount of about 27.59 g to 30.28 g, and the solvent was heated to 60 ° C in 10 times the volume of isopropanol. The reaction was completely dissolved at ~70 ° C, concentrated to a total weight of 4.0 to 4.5 times that of carfilzomib (I), and the solution was added dropwise to 50 times the volume of water, and the temperature was controlled to be less than 10 ° C during the dropwise addition. After the completion of the dropwise addition, the mixture was filtered to obtain amorphous carfilzomib (I) (the X-ray powder diffraction pattern is shown in Fig. 2), the yield was 88% to 91%, and the product purity was 99.87%. To 99.94% (area percentage, area%). In the 4th to 5th experiments, the amount of carfilzomib (I) was increased by 10g, which was 40.3g to 41.27g respectively. The same amount of isopropanol was used and heated to 60°C~70°C to completely dissolve the reaction. After concentration, the reaction was completely dissolved. The total weight was 4.8 times and 5.0 times that of carfilzomib (I), respectively, because the solution was observed to have a misty appearance during the concentration process, and then the solution was added dropwise to 50 times the volume of water while changing the drop. The temperature control was 10 ° C ~ 15 ° C, the final results were able to obtain amorphous carfilzomib (I), the yield was 90.7% and 92%, respectively, and the purity of the product by HPLC analysis was 99.92% and 99.91%, respectively. (area percentage, area%). According to the above experiment, the experimental conditions for preparing amorphous carfilzomib (I) can be summarized as the solvent is isopropanol 10 times volume multiple, the heating dissolution temperature is 60 ° C ~ 70 ° C, and the total weight is carfilzomib. (I) 4.0 to 5.0 times, the amount of solvent water precipitated by carfilzomib (I) is 50 times the volume multiple, the temperature is controlled at 10 ° C ~ 15 ° C during the dropwise addition, and filtered at room temperature, set at 10 ° C The vacuum oven is dried, and finally an amorphous carfilzomib (I) can be obtained.

Analytical method for high pressure liquid chromatography (chromatography system I): Column: Waters Symmetry C18 column, 250 × 4.6 mm ID 5 μm, column temperature: 25 ° C; eluent A: 1 mL of TFA in 1000 mL of DIW Eluent B: 1mL of TFA in 1000mL of AN; Gradient program: Retention time (RT): Compound I was 23.7 min.

In addition, the solvent precipitated from carfilzomib (I) is a series of pure water, and the modification is carried out in the step of increasing the concentration, and when the carfilzomib (I) is completely dissolved in the dissolved solvent, it is directly added thereto. The precipitated solvent water in the stirring causes the carfilzomib (I) to be precipitated, which makes the process operation easier and reduces the variation of the process. In addition to the original dissolved solvent isopropanol, the solvent to be dissolved may be changed, which includes a solvent such as methanol and ethanol, and a solvent such as acetone, and the results are shown in Table 2.

Table 2 shows the results of precipitation experiments for changing dissolved solvents

As shown in the results of Table 2, the carbozomib (I) used in the precipitation experiment in the first experiment was heated to 60 ° C to 70 ° C in 14 times the volume of isopropanol to completely dissolve the reaction. The solution was added dropwise to 182 times the volume of water. Since the amount of isopropanol used was increased, the amount of the precipitated solvent water was increased to 13 times the volume of isopropanol, and the temperature was controlled at 15 ° C to 20 ° C during the dropwise addition. After the dropwise addition, the mixture was filtered, and after drying, the amorphous carfilzomib (I) was obtained, but the filtration time was high, and the purity of the product was analyzed by HPLC to be 99.78% (area%, area%). The steps that were previously unsuitable for industrial production have been improved. The second to fourth experiments changed the solvent to be dissolved, respectively, the alcohol solvent methanol and ethanol and the common solvent acetone, and reduced the amount of solvent water used to 50 times the volume of carfilzomib (I), the experiment is in At room temperature, the solvents dissolved in the third and fourth experiments were ethanol and acetone, respectively, in 10 times volume, and heated to 50 ° C ~ 55 ° C, carfilzomib (I) will be completely dissolved, and then The solution was added dropwise to water, and in the third experiment, amorphous carfilzomib (I) was obtained, and the purity of the product was analyzed by HPLC to be 99.86% (area%, area%), but the fourth experimental solvent was acetone. Then, an amorphous crystallized form containing a crystal form is obtained (the X-ray powder diffraction pattern is shown in FIG. 3); finally, the solvent dissolved in the second experiment is methanol, and methanol is used for carfilzomib ( The solubility of I) is very good. It can be completely dissolved by using 10 times the volume multiple at room temperature. The temperature is controlled at 25 ° C to 30 ° C during the dropwise addition. After the addition, the filtration can be carried out after drying. Obtaining the amorphous carfilzomib (I) while the filtration takes a short time and analyzes it by HPLC The purity of the product was 99.93% (area%, area%).

It has been confirmed by the above experiments that the present invention has improved the steps previously unsuitable for industrial production. In the present invention, the solvent dissolving isopropanol is further tested in detail, and the amount of the dissolved solvent and the precipitated solvent used in the pure water is changed, and the experimental combination of the temperature control change at the time of dropping is shown in Table 3.

Table 3 Results of precipitation of isopropanol as solvent for dissolution

As shown in the results in Table 3, the first to fifth experiments have reduced the amount of dissolved carfilzomib (I) solvent isopropanol to 10 times the volume multiple of carfilzomib (I), and heated to 62 ° C ~ After completely dissolving the reaction at 65 ° C, the solution was directly added dropwise to the precipitation solvent water, and the amount of the precipitation solvent used in the first to third experiments was also reduced to 130 times the volume multiple of carfilzomib (I), and the solution was added dropwise. The temperature control to the precipitation solvent is 20 ° C ~ 25 ° C, 15 ° C ~ 20 ° C and < 5 ° C, respectively, after filtration can obtain amorphous carfilzomib (I), and the purity of the product by HPLC analysis is 99.80 %~99.85% (area percentage, area%); while in the 4th and 5th experiments, the temperature of the solution added to the precipitation solvent was controlled at 15 °C ~ 20 °C, but the amount of precipitation solvent was reduced to carfilzomib ( 100 times and 50 times the volume multiple of I), the same obtained carfilzomib (I), the purity of the product was 99.80% and 99.63% (area%, area%).

In addition, when the dissolving solvent is methanol, the solubility of carbozomib (I) in methanol is good, and the time required for the filtration process is short, the same is the change in the amount of the solvent and the solvent water used for the dissolution, and the drop The experimental combination of the temperature control changes of the overtime was further carried out, and the results are shown in Table 4.

Table 4 Results of precipitation of methanol as solvent

As shown in the results in Table 4, since the solubility of methanol to carfilzomib (I) is very good, the carbozomib (I) of the first to third experiments to be subjected to the precipitation test uses 10 times the volume of methanol. The room temperature can be completely dissolved, and the amount of precipitation solvent is also 100 times, 115 times and reduced to 50 times the volume multiple of carfilzomib (I). All three experiments are carried out at room temperature. Zomi (I) solution dissolved in methanol, directly added to the precipitation solvent water, the temperature will rise to nearly 30 ° C when added dropwise, filtered after the end of the addition, after drying, can obtain amorphous carfilzomib (I) The filtration was completed in a short time, and the purity of the product was analyzed by HPLC to be 99.85% to 99.93% (area percentage, area%) (the X-ray powder diffraction pattern is shown in Fig. 4). In addition, in the fourth experiment, carfilzomib (I) was dissolved at room temperature with 12 times the volume of methanol, and the amount of precipitation solvent was also 60 times the volume multiple of carfilzomib (I), and the dropping was controlled. The temperature is between 15 ° C and 20 ° C, and the result of amorphous carfilzomib (I) can also be obtained, and filtration can be completed in a short time, and the purity of the product is 99.93% (area percentage, area%). It is proved by the above experiments that there are two major characteristics when the dissolved solvent is methanol: 1. It can be completely dissolved at room temperature in the case of carfilzomib (I) with methanol as a solvent; 2. The time required for filtration is also short. It proves that the invention is quite suitable for industrial production.

Example 1-2

Next, the solvent to be precipitated is a series of hexane and heptane. According to the previous experiment, carfilzomib (I) (10g) was added, and 10 times the volume of methanol (100 ml) was added to dissolve at room temperature. The solvent which was added dropwise to the precipitate after dissolution was hexane (1600 ml), and no solid precipitated. Will change the type of solvent dissolved, the solubility of dichloromethane and ethyl acetate is also very good, in addition to the dissolved solvent acetone used in the previous experiments, heating to 45 ° C ~ 50 ° C can make carfilzomib (I) completely Soluble, so these solvents will be selected as a solvent for dissolving carfilzomib (I). After completely dissolved, it is added dropwise to the precipitated solvent of hexane or heptane, and finally filtered and dried. The results are shown in Table 5. Shown.

The experimental results of the solvents listed in Table 5 are hexane and heptane.

As shown in the results in Table 5, the carbozomib (I) of the first and second experiments to be subjected to the precipitation test was completely dissolved at room temperature using 4 times and 5 times the volume of methylene chloride respectively, respectively. Up to 71 times the volume of n-heptane and 84 times the volume of n-hexane, after the end of the addition of filtration, the filtration time is also very short, after drying can obtain amorphous carfilzomib (I) (X-ray powder diffraction The spectrum is shown in Figure 5), and the purity of the product was 99.93% and 99.79% (area%, area%) by HPLC, and the yield was >95%. In the third experiment, the carfilzomib (I) to be subjected to the precipitation test was completely dissolved at room temperature using 10 times the volume of ethyl acetate, and then added dropwise to 160 times the volume of n-hexane, and filtered after the dropwise addition. The filtration time was also very short. After drying, the amorphous carfilzomib (I) was obtained, and the purity of the product was 99.92% (area%, area%) by HPLC analysis, and the yield was 90%. Finally, the fourth experiment used carfilzomib (I) using 10 times the volume of acetone, heating to 46 ° C can both completely dissolve carfilzomib (I), and then add dropwise to 178 times the volume of n-hexane After filtration at the end of the dropwise addition, the filtration time is also very short. After drying, amorphous carfilzomib (I) can be obtained, and the purity of the product by HPLC analysis is 99.81% (area%, area%), and the yield is 89. %. Thus, it is known that the dissolved solvent is dichloromethane, ethyl acetate and acetone, and the solvent to be precipitated is hexane and heptane, and all of the amorphous carfilzomib (I) can be obtained, which overcomes the previous steps which are not suitable for industrial production. And the filtration time is also shortened. These two characteristics indicate that the process is also quite suitable for industrial production.

In the experimental combination of the two series of the invention, the solvent selected for precipitation is a series of water precipitation, and the solvent selected for dissolution is methanol, because the combination has the following characteristics: 1. The organic solvent is used in a small amount; Carfilzomib (I) can be completely dissolved at room temperature with methanol as a dissolution solvent and 3. The time required for filtration is also short. Therefore, the process is amplified by using methanol as a solvent to a level of more than 100 grams, and the results are shown in Table 6.

Table 6 Results of precipitation experiments with more than 100 grams of methanol as solvent

As shown in the results in Table 6, the carbozomib (I) of the first to fifth experiments to be subjected to the precipitation test was completely dissolved at room temperature using 12 times the volume of methanol, and the solution temperature of the completely dissolved solution was 22 °C, and the amount of precipitation solvent used was 60 times the volume multiple of carfilzomib (I). As a result, it was found that the experimental conditions of amplification to 100 g or more, the temperature of the precipitation solvent and the temperature at the time of dropping were equivalent. The important process parameters were carried out in the first experiment at room temperature, the temperature of the precipitation solvent was 24 ° C, and the temperature of the solution of the carfilzomib (I) solution was added to the precipitation solution at <30 ° C. A crystalline form of Crystal+Amorphous Form; therefore, in the second experiment, the temperature is lowered, the temperature of the precipitation solvent is 14 ° C, and the methanol solution of carfilzomib (I) is added dropwise to the precipitation solution. The temperature control temperature is <20 ° C, and as a result, an amorphous crystal + Amorphous Form containing a crystal form is obtained; therefore, in the experiments of 3 and 4, the temperature is lowered, and the temperature of the precipitation solvent is about 3.5 ° C. And the methanol solution of carfilzomib (I) is added dropwise to the precipitation solution. The temperature control temperature is <10 °C, and the temperature at the end of the recording process is about 8.8 °C. The result is an amorphous Amorphous Form. Finally, the carbofizomib (I) is taken in the fifth experiment. The amount is 155 g, 1800 ml of methanol is added, and the temperature is 22 ° C after stirring at room temperature, the temperature of the precipitation solvent is 3.4 ° C, and the methanol solution of carfilzomib (I) is added dropwise to the temperature of the precipitation solution. The temperature control is <10 ° C, and the actual temperature at the end of the addition is 8.3 ° C. After the completion of the dropwise addition, the filtration is completed in only 1.5 hours, and after drying, the amorphous carfilzomib (I) (146 g) can be obtained. The purity of the product was analyzed by HPLC to be 99.93% (area%, area%), and the yield was 93.9%. Therefore, it is known that the temperature at which the solution is added to the precipitation solution is a critical process parameter, and the temperature of the process parameter is that the methanol solution of carfilzomib (I) is added dropwise to the temperature at which the precipitation solution is water is less than 10 ° C. Three experiments in the third, fourth and fifth experiments proved that the experiment was reproducible and quite suitable for industrial production.

The invention provides a preparation method of two series of amorphous Carfilzomib (I), wherein the solvent is water, and the dissolved solvent may be methanol, ethanol or isopropanol, respectively. The rice (I) is completely dissolved in the dissolved solvent, and is directly added dropwise to the pure water. After the dropwise addition, the mixture is filtered, and dried to obtain amorphous carfilzomib (I), and the yield is 90% or more. In addition, in the series of hexane and heptane, the dissolved solvent may be dichloromethane, ethyl acetate or acetone, respectively. When the carfilzomib (I) is completely dissolved in the dissolved solvent, it is directly added to the hexane or the heptane. In the alkane, after the dropwise addition, the mixture was filtered, and dried to obtain amorphous carfilzomib (I), and the yield was 90% or more. Therefore, the preparation method of the present invention is superior to the prior art, and the process operation is quite easy.

The invention can further enlarge the process to a level of more than 100 grams of the carfilzomib (I) batch, wherein the solvent selected for dissolution is 12 times the volume multiple of methanol, and the solvent to be precipitated is 60 times the volume multiple of the pure water. The methanol solution of carfilzomib (I) is added dropwise to the temperature at which the precipitation solution is water and the temperature is controlled at <30 ° C or < 20 ° C. As a result, an amorphous form of carfilzomib (Crystal+Amorphous Form) is obtained. ). The methanol solution of carfilzomib (I) is added dropwise to the temperature at which the precipitation solution is water and the temperature is controlled at <10 ° C. As a result, amorphous carfilzomib (I) is obtained, thereby knowing the temperature. Control is a very critical process parameter, and it also proves that the experiment is reproducible. This experiment proves once again that the invention has less organic solvent and can be completely dissolved and filtered in carfilzomib (I) at room temperature. The required time is also short, indicating that the invention is quite suitable for industrial production.

Example 2-1

The precipitation of carfilzomib (I) dissolved in isopropanol and then increased to a concentration

Take carbazole (I) (30.28 g) in a round bottom bottle, add isopropanol (330 ml), heat to 60 ° C ~ 70 ° C, the reaction is completely dissolved, and then concentrated under reduced pressure, concentrated to the reaction The total weight of the liquid is 135 grams. Then add the reaction droplets to a stirred water bath (1500 ml), add the process and control the temperature at less than 10 ° C, filter at room temperature, dry in a vacuum oven, and finally obtain amorphous carfilzomib (I) 27.474 g, purity 99.92%, yield 90.7%. (X-ray powder diffraction pattern is shown in Figure 2)

Example 2-2

Precipitation experiment of carfilzomib (I) dissolved in water after being dissolved in isopropanol

Carfilzolamide (I) (9.0 g) was placed in a round bottom flask, isopropanol (90 ml) was added, and the mixture was heated to 60 ° C to 70 ° C to completely dissolve the reaction. Then add the reaction droplets to the stirring water bath (1170 ml), add the process and control the temperature at 20 ° C ~ 25 ° C, filter at room temperature, the wet product is amorphous carfilzomib (I), two After dissolving methyl chloride (150 ml), it was concentrated and dried to give 8.2 g of carfilzomib (I) with a purity of 99.8% and a recovery of 92%.

Example 2-3

Precipitation experiment of carfilzomib (I) dissolved in water after adding to methanol

Carfilzomib (I) (26 g) was placed in a 0.5 L four-necked round bottom flask, and methanol (260 ml) was added and stirred at room temperature to dissolve the reaction completely. Then add the reaction droplets to the stirring water bath (3000 ml), add the process and control the temperature at 25 ° C ~ 30 ° C, filter at room temperature, filter at room temperature, dry in a vacuum oven set at 10 ° C, and finally Obtained 24.47 g of amorphous carfilzomib (I) with a purity of 99.91% and a yield of 94%. (X-ray powder diffraction pattern is shown in Figure 4)

Example 2-4

Precipitation experiment of carfilzomib (I) dissolved in ethanol and added to pure water

Carfilzomib (I) (14 g) was placed in a 0.25 L round bottom flask, and ethanol (140 ml) was added and heated to 50 ° C to 55 ° C to completely dissolve the reaction. Then add the reaction droplets to the stirring water bath (700 ml), add the process and control the temperature at 20 ° C ~ 30 ° C, filter at room temperature, dry in a vacuum oven set at 10 ° C, and finally get an amorphous card Non-zomi (I) 13.98 g, purity 99.86%, yield >98%.

Example 2-5

Precipitation experiment of carfilzomib (I) dissolved in acetone and added to pure water

Carfilzomib (I) (10 g) was placed in a 0.25 L round bottom flask, acetone (100 ml) was added, and heated to 50 ° C to 60 ° C to completely dissolve the reaction. Then, the reaction liquid was added to a stirring water bath (500 ml), and the dropping process was carried out at a temperature of 20 ° C to 25 ° C. The wet product was a crystalline form and an amorphous carfilzomib (I), which was dichloromethane. (150 ml) was dissolved, concentrated and dried to give 10.5 g of carfilzomib (I) with a purity of 99.85% and a recovery of >100%. (X-ray powder diffraction pattern is shown in Figure 3)

Example 2-6

Precipitation experiment of carfilzomib (I) dissolved in dichloromethane and added to n-heptane

The carfilzomib (I) (14 g) was placed in a 0.25 L round bottom flask, dichloromethane (50 ml) was added, and the reaction was completely dissolved by stirring at room temperature. The reaction solution was further added to a stirred n-Heptane (1000 ml), filtered at room temperature, and dried in a vacuum oven set at 10 ° C to finally obtain an amorphous carfilzomib (I). 14 g, purity 99.93%, yield > 98%.

Example 2-7

Precipitation experiment of carfilzomib (I) dissolved in dichloromethane and added dropwise to n-hexane

Carfilzomib (I) (9.5 g) was placed in a 0.25 L round bottom flask, dichloromethane (50 ml) was added, and the reaction was completely dissolved by stirring at room temperature. The reaction solution was added dropwise to a stirred portion of n-Hexane (800 ml), filtered at room temperature, and dried in a vacuum oven set at 10 ° C to finally obtain amorphous carfilzomib (I). 8.764 g, purity 99.79%, yield 92.3%. (X-ray powder diffraction pattern is shown in Figure 5)

Example 2-8

Precipitation experiment of carfilzomib (I) dissolved in ethyl acetate and added dropwise to n-hexane

Carfilzomib (I) (10 g) was placed in a 0.25 L round bottom flask, ethyl acetate (100 ml) was added, and the reaction was completely dissolved by stirring at room temperature. The reaction solution was added dropwise to a stirred portion of n-Hexane (1600 ml), and filtered at room temperature. After drying, an amorphous carfilzomib (I) of 9.01 g was obtained, and the purity was 99.92%. The yield was 90%.

Example 2-9

Precipitation experiment of carfilzomib (I) dissolved in acetone and added to n-hexane

Carfilzomib (I) (9 g) was placed in a 0.25 L round bottom flask, acetone (90 ml) was added, and the mixture was heated to 40 ° C to 50 ° C to completely dissolve the reaction. Stir at room temperature to completely dissolve the reaction. The reaction solution was added dropwise to a stirred portion of n-Hexane (1600 ml), and filtered at room temperature. After drying, an amorphous carfilzomib (I) 8.03 g was obtained, and the purity was 99.81%. The yield was 89%.

Example 2-10

A 100-gram preparative precipitation experiment of carfilzomib (I) dissolved in methanol and added to water

The carfilzomib (I) (155.47 g) was placed in a 2 L four-necked round bottom flask, methanol (1500 ml) was added, and the reaction was completely dissolved by stirring at room temperature, filtered through a filter, and then methanol (300 ml). washing. Then, the reaction liquid was added to a stirring water bath (9000 ml), the dropping process was carried out and the temperature was controlled to be less than 10 ° C, filtered, and dried in a vacuum oven set at 10 ° C, and finally an amorphous carfilzomib (I was obtained). 146 g, purity 99.93%, yield 93.9%. (X-ray powder diffraction pattern is shown in Figure 6)

Comparative example 1

Take carbazole (I) (3.5 g), add isopropanol (178 ml), and heat to an oil bath at an oil bath temperature of 80 ° C to completely dissolve it, then concentrate to a vacuum condenser. (10.1 g), quickly add water (231 ml), stir for 1 hour, filter, water 100 ml wash, but the filtration time is nearly 4 hours, the filtration time is quite long, and after drying, amorphous carfilzomib will be obtained. I) is (2.8 grams).

Comparative example 2

Take carbazole (I) (2 g), add isopropanol (100 ml), and heat to an oil bath at an oil bath temperature of 80 ° C to completely dissolve it, then concentrate to a vacuum condenser. (7.1 g), then quickly add water (132 ml), stir for 1 hour, filter, water 100 ml wash, but the filtration time is nearly 4 hours, the filtration time is quite long, and after drying, you will get amorphous carfilzomib ( I) are (1.876 grams) respectively.

Comparative example 3

Take calofazol (I) (3.1g), add isopropanol (150 ml), and heat to an oil bath. The oil bath temperature is 80 ° C, completely dissolve it, and then concentrate to a vacuum condenser. (35.9g), water (198 ml) was added quickly, stirred for 1 hour, filtered, and dried to obtain crystalline Carfilzomib (I) (2.89 g) (X-ray powder diffraction pattern as shown in Figure 1 Shown).

Comparative example 4

Take carbazole (I) (2.6 g), add isopropanol (125 ml), and heat to an oil bath. The temperature of the oil bath is 80 ° C, completely dissolve, and then concentrated to a reduced pressure concentrator. (34.1 g), respectively, water (165 ml) was added quickly, stirred for 1 hour, filtered, and dried to give crystalline carfilzomib (I) (2.5 g).

The method for preparing amorphous Amorphous Carfilzomib (I) of the invention has a yield of more than 90%, and the preparation method is superior to the prior art (such as a comparative example), and the process operation is relatively easy, and the time required for filtration is also relatively high. The short characteristics indicate that the invention is quite suitable for industrial production.

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Figure 1 is a diffraction diagram of an X-ray powder having a crystalline form of carfilzomib (I) of Comparative Example 3. Figure 2 is an X-ray powder diffraction pattern of the amorphous carfilzomib (I) of Examples 1-1, 2-1. Figure 3 is a diffraction pattern of the X-ray powder of the amorphous form of carfilzomib containing the crystalline form of Examples 1-1 and 2-5. Figure 4 is an X-ray powder diffraction pattern of the amorphous carfilzomib (I) of Examples 1-1, 2-3. Figure 5 is an X-ray powder diffraction pattern of the amorphous carfilzomib (I) of Examples 1-1, 2-7. Figure 6 is an X-ray powder diffraction pattern of the amorphous carfilzomib (I) of Examples 2-10.

Claims (2)

A method for preparing amorphous Amorphous Carfilzomib (I) having the formula: The steps include: a. dissolving carfilzomib (I) in a first dissolved solvent to form a first solution; b. adding the first solution to water to form a second solution, wherein the water and the The temperature of the dropping process is controlled below 30 ° C, wherein the volume ratio of the first dissolved solvent to the water is 1:4.54, 1:5, 1:10 or 1:13; and c. filtering the second solution and drying The solid obtained after filtration; wherein the first dissolution solvent is isopropyl alcohol. The method of claim 1, wherein the water of the step b and the temperature of the dropping process are controlled below 10 °C.