CN110981812A - Preparation method of amorphous enzalutamide - Google Patents
Preparation method of amorphous enzalutamide Download PDFInfo
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- CN110981812A CN110981812A CN201911163588.1A CN201911163588A CN110981812A CN 110981812 A CN110981812 A CN 110981812A CN 201911163588 A CN201911163588 A CN 201911163588A CN 110981812 A CN110981812 A CN 110981812A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and provides a preparation method of amorphous enzalutamide, which comprises the following steps: (1) taking the enzalutamide solid, and dissolving the enzalutamide solid by using a first solvent; (2) slowly dripping the solution obtained in the step (1) into a second solvent, and keeping the temperature low in the dripping process; (3) after dripping, stirring, filtering, rinsing with a second solvent, and drying at low temperature. The first solvent is one or a mixture of acetone, DMSO, THF, methanol, dichloromethane or acetonitrile; the second solvent is one or a mixture of water, an alkaline aqueous solution or n-heptane. The method is realized by conventional equipment through separating out the enzalutamide anti-solvent by solvents with different solubilities or different polarities and filtering to obtain an amorphous solid, and the process is high in yield and low in cost and is suitable for industrial scale-up production.
Description
Technical Field
The invention relates to a preparation method of amorphous enzalutamide, belonging to the technical field of pharmaceutical chemicals.
Background
Enzalutamide (Enzalutamide) is an androgen receptor inhibitor that reduces the proliferation and induces the death of prostate cancer cells. The medicament is used for treating the prostate cancer patients who are refractory to metastatic castration and have received docetaxel treatment. The chemical structural formula of enzalutamide is as follows:
the performance characteristics of the medicines expressed by different crystal forms of enzalutamide are different, and the pharmaceutical research is greatly influenced. After multiple explorations of researchers, enzalutamide has multiple crystal forms such as a crystal form R1, a crystal form B1 and an amorphous crystal form, wherein amorphous enzalutamide (i.e., a non-crystalline state) is dissolved more rapidly and to a greater extent than crystalline enzalutamide in an aqueous use environment, such as an aqueous dissolution medium in an in vitro dissolution test (e.g., phosphate buffered saline or model fasted duodenal fluid or simulated gastric fluid) or an in vivo environment of the stomach or small intestine, so that the oral bioavailability of enzalutamide can be greatly improved. Therefore, there is a great need for extensive research on the formulation of amorphous enzalutamide in the market.
The preparation of amorphous enzalutamide is currently concerned with: patent WO2014041487 has preliminarily disclosed that isolating amorphous forms of enzalutamide may include processes such as solvent removal, cooling, rapid cooling, substance concentration, evaporation, flash evaporation, simple evaporation, spin drying, spray drying, membrane drying, agitated suction filter drying, pressure suction filter drying, freeze drying, addition of anti-solvent, extraction with solvent, addition of seed crystals to induce separation, and the like. Although this patent discloses many methods for extracting amorphous enzalutamide, these methods, such as spray drying and film drying, have high equipment requirements and high production cost, and are not suitable for industrial scale-up production; concentration, distillation, rapid evaporation and the like, and specific operating parameters and examples are not disclosed, and the parameters are not well controlled in the operating process, so that crystal transformation is easy to occur, and the method is not suitable for industrial scale-up production.
Chinese patent 201380075784.8 discloses a process for the preparation of amorphous enzalutamide by forming a solution of enzalutamide in a soluble solvent and removing the solvent at a rate of at least 5 ml/min to obtain the amorphous enzalutamide; the soluble solvent is selected from C1-C3Alcohol, C1-C2Halogenated alkanes, C3-C4Ketones, C2-C5Ether, C3-C5Esters, C2-C3A nitrile or a mixture thereof; the concentration of the enzalutamide in the soluble solvent is 0.1-1.0 times of the solubility of the enzalutamide in the soluble solvent at the temperature of the solution; the solvent removing mode comprises rotary evaporation, vacuum evaporation, nitrogen blowing evaporation, freeze drying or spray drying, and mainly removes the solvent of enzalutamide by concentration, so that the concentration process is long, the equipment requirement is high, and the industrial scale-up production is not facilitated.
Therefore, the known preparation method of amorphous enzalutamide has certain defects, and the development of a method more suitable for industrial production is necessary.
Disclosure of Invention
The invention aims to provide a preparation method of amorphous enzalutamide, and solves the problems in the prior art.
A preparation method of amorphous enzalutamide comprises the following steps:
Preferably, the step of
The weight ratio is 1-2 times.
The first solvent is a solvent with better solubility to enzalutamide; preferably one or more of acetone, DMSO, THF, methanol, dichloromethane or acetonitrile.
The second solvent is a less soluble solvent for enzalutamide; preference is given to water, aqueous alkaline solutions and n-heptane. The alkaline aqueous solution is preferably a dilute sodium bicarbonate aqueous solution, and the content of the alkaline aqueous solution is 1-10%.
Preferably, the step of
The low temperature range is-30-10 ℃.
Preferably, the step of
The low temperature range is 0-5 ℃.
Preferably, the weight of the second solvent is 30-500 times that of the enzalutamide solid.
Preferably, the weight of the second solvent is 10-120 times that of the enzalutamide solid.
Further, the low-temperature drying temperature is less than or equal to 45 ℃.
Compared with the reported method for preparing amorphous enzalutamide, the method has the advantages that the enzalutamide anti-solvent is separated out through solvents with different solubilities or different polarities, amorphous solid is obtained through filtration, the method can be realized through conventional equipment, the yield of the process is high, the cost is low, and the method is suitable for industrial scale-up production.
Drawings
FIG. 1 is an XRPD pattern of amorphous enzalutamide obtained in example 1;
FIG. 2 is a DSC of amorphous enzalutamide obtained in example 1.
Detailed Description
The examples given are merely intended to be illustrative of the products or methods of the invention in general terms, and are intended to facilitate a better understanding of the invention, and not to limit the scope of the invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the materials are commercially available, unless otherwise specified.
Example 1
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of enzalutamide solid into a 50mL single-neck flask, and adding 10g of acetone for complete dissolution; adding 700g of water into a 1000mL round-bottom flask, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into the water; after dripping, stirring for 1h at the temperature of 0-5 ℃, filtering, leaching with water, drying at the temperature of 45 ℃ under reduced pressure, and obtaining the yield: 97.9 percent.
The XRPD pattern is shown in figure 1 and is amorphous without any sharp diffraction peaks.
The DSC pattern is shown in figure 2, which shows that the crystal is amorphous and the crystal transformation is generated at 137 ℃. And detecting to form the R1 crystal form after crystal transformation. The results are similar to patent CN201380075784.8 map.
Example 2
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of the crude product of enzalutamide into a 50mL single-neck flask, adding 10g of DMSO, and completely dissolving; adding 100g of water into a 500mL round-bottom flask, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into the water; after dripping, stirring for 1h at the temperature of 0-5 ℃, filtering, leaching with water, and drying at the temperature of 45 ℃ under reduced pressure to obtain amorphous enzalutamide, wherein the yield is as follows: 97.4 percent.
Example 3
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of the crude product of enzalutamide into a 50mL single-neck flask, and adding 20g of THF for complete dissolution; adding 1200g of water into a 3000mL round-bottom flask, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into the water; after dripping, stirring for 30min at the temperature of 0-5 ℃, filtering, leaching with water, and drying at the temperature of 45 ℃ under reduced pressure to obtain amorphous enzalutamide, wherein the yield is as follows: 97.5 percent.
Example 4
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of enzalutamide solid into a 50mL single-neck flask, adding 20g of acetonitrile, and completely dissolving; adding 1000g of water into a 3000mL round-bottom flask, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into the water; after dripping, stirring for 30min at the temperature of 0-5 ℃, filtering, leaching with water, and drying at the temperature of 45 ℃ under reduced pressure to obtain amorphous enzalutamide, wherein the yield is as follows: 97.3 percent.
Example 5
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of enzalutamide solid into a 50mL single-neck flask, and adding 10g of dichloromethane to completely dissolve the enzalutamide solid; adding a 3000mL round-bottom flask into 1200g of n-heptane, cooling to-30 ℃, and slowly dripping the enzalutamide solution into the n-heptane; after dripping, stirring for 15min at the temperature of minus 30 ℃, filtering, leaching with n-heptane, drying at 40 ℃ under reduced pressure, and obtaining the yield: 96.2 percent.
Example 6
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of enzalutamide solid into a 50mL single-neck flask, adding 15g of acetone, and completely dissolving; adding 300g of water into a 1000mL round-bottom flask, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into the water; after dripping, stirring for 20min at the temperature of 0-5 ℃, filtering, leaching with water, drying at the temperature of 45 ℃ under reduced pressure, and obtaining the yield: 98.0 percent.
Example 7
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10g of enzalutamide solid into a 50mL single-neck flask, and adding 10g of acetone for complete dissolution; adding 800g of 5% sodium bicarbonate water solution into a 1000mL round-bottom flask, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into a 5% sodium bicarbonate water solution; after dripping, stirring for 1h at the temperature of 0-5 ℃, filtering, rinsing with 5% sodium bicarbonate aqueous solution, drying at the temperature of 45 ℃ under reduced pressure, and obtaining the following yield: 97.6 percent.
Example 8
A preparation method of amorphous enzalutamide comprises the following steps:
putting 10kg of enzalutamide solid into a reaction kettle, and adding 115kg of acetone to completely dissolve the enzalutamide solid; adding 700kg of water into another reaction kettle, cooling to 0-5 ℃, and slowly dropping the enzalutamide solution into the water; after dripping, stirring for 1h at the temperature of 0-5 ℃, filtering, leaching with water, drying at the temperature of 45 ℃ under reduced pressure, and obtaining the yield: 97.8 percent.
Claims (9)
1. A preparation method of amorphous enzalutamide is characterized by comprising the following steps:
taking the enzalutamide solid, and dissolving the enzalutamide solid by using a first solvent;
slowly dripping the solution obtained in the step (1) into a second solvent, and keeping the temperature low in the dripping process;
after dripping, stirring, filtering, leaching by using a second solvent, and drying at low temperature;
the first solvent is one or a mixture of acetone, DMSO, THF, methanol, dichloromethane or acetonitrile;
the second solvent is one or a mixture of water, an alkaline aqueous solution or n-heptane.
2. The method of claim 1, wherein the weight ratio of the solid enzalutamide to the first solvent in step (1) is 0.5-10.
3. The method for preparing amorphous enzalutamide according to claim 2, wherein the weight ratio of the enzalutamide solid in the step (1) to the first solvent is 1-2 times.
4. The method as claimed in claim 2, wherein the weight of the second solvent is 10-500 times of the weight of the enzalutamide solid.
5. The method as claimed in claim 1, wherein the low temperature in step (2) is in the range of-30-10 ℃.
6. The method for preparing amorphous enzalutamide according to claim 1, wherein the low temperature drying in step (2) is performed at a temperature of 45 ℃ or less.
7. The method as claimed in claim 4, wherein the weight of the second solvent is 10-120 times of the weight of the enzalutamide solid.
8. The method as claimed in claim 1, wherein the alkaline aqueous solution is diluted sodium bicarbonate aqueous solution with a mass concentration of 1-10%.
9. The method for preparing amorphous enzalutamide according to claim 1, wherein the stirring time in step (3) is 10-60 min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104768935A (en) * | 2012-09-11 | 2015-07-08 | 雷迪博士实验室有限公司 | Enzalutamide polymorphic forms and its preparation |
| CN106543085A (en) * | 2013-10-14 | 2017-03-29 | 杭州普晒医药科技有限公司 | Solid-state form of the miscellaneous Shandong amine of grace and its production and use |
| WO2019106691A1 (en) * | 2017-11-28 | 2019-06-06 | Aarti Industries Limited | Process for preparation of enzalutamide using novel intermediate |
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- 2019-11-25 CN CN201911163588.1A patent/CN110981812A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104768935A (en) * | 2012-09-11 | 2015-07-08 | 雷迪博士实验室有限公司 | Enzalutamide polymorphic forms and its preparation |
| CN106543085A (en) * | 2013-10-14 | 2017-03-29 | 杭州普晒医药科技有限公司 | Solid-state form of the miscellaneous Shandong amine of grace and its production and use |
| WO2019106691A1 (en) * | 2017-11-28 | 2019-06-06 | Aarti Industries Limited | Process for preparation of enzalutamide using novel intermediate |
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