Process for producing enzalutamide crystal form

A technology of enzalutamide and a manufacturing method, applied in the field of manufacturing enzalutamide crystalline form, can solve problems such as unclear details

Active Publication Date: 2018-01-26
ASTELLAS PHARMA INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] As the form of enzalutamide raw material drug, although it is developed in a solvent-free crystal form (hereinafter, sometimes referred to as "type A crystal"), enzalutamide shows that during the crystallization process, it often forms Solvates in the form of solvents, the details of which are still unclear (Patent Documents 1 and 2)

Method used

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  • Process for producing enzalutamide crystal form
  • Process for producing enzalutamide crystal form
  • Process for producing enzalutamide crystal form

Examples

Experimental program
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Effect test

Embodiment 1

[0087] (Example 1) Synthesis of 4-cyano-3-trifluoromethylphenyl isothiocyanate

[0088] Isopropyl acetate (IPAc) (20 mL) / water solution (56 mL) of thiophosgene (14.9 g) was prepared, and 4-cyano-3-trifluoromethylaniline (20 g) was dissolved therein dropwise over 30 minutes. IPAc solution (90 mL). The internal temperature was 4°C. After stirring for 5 minutes at an internal temperature of 4° C. for 5 minutes, the mixture was left to stand for 30 minutes or more to separate the water layer. The obtained organic layer was concentrated under reduced pressure, n-heptane was added to the concentrated residue, and further concentrated under reduced pressure to 80 mL or less. IPAc (1 mL) was added to the obtained concentrated residue, stirred at an internal temperature of 40°C for 5 minutes, then seed crystals (10 mg) were added at 25°C, stirred for 1 hour, stirred at an internal temperature of 4°C, and filtered to obtain 4-Cyano-3-trifluoromethylphenylisothiocyanate (22.1 g) was o...

Embodiment 2

[0089] (Embodiment 2) Synthesis of Enzalutamide Type A Crystal

[0090] In a nitrogen atmosphere, 2-(3-fluoro-4-methylcarbamoyl-phenylamino)-2-methylpropionic acid methyl ester (33.0g) and the 4-cyano- 3-Trifluoromethylphenylisothiocyanate (56.1g) was dissolved in a mixed solvent of dimethylsulfoxide (DMSO) (33mL) / IPAc (66mL), and the temperature was raised to an internal temperature of 75-85°C. The temperature was stirred for more than 12 hours. After the reaction, methanol (4.95 mL) was added dropwise at 55-80° C., and stirred at this temperature for 60-90 minutes. Then, it cooled to 15-25 degreeC, diluted with IPAc (198 mL) and pure water (99 mL), stirred at this temperature for 10-30 minutes, and left still for 30-45 minutes. 2-Propanol (IPA) (49.5 mL) was slowly added dropwise at an internal temperature of 15 to 25° C. to break the emulsion. The obtained organic layer was separated, and the line was washed with IPAc (15 mL).

[0091] The organic layer after liquid sep...

reference example 1-1

[0100] (Reference Example 1-1) Synthesis of Enzalutamide Type B Crystal

[0101] In a nitrogen atmosphere, a solution of purified crystals (10.0 g) of enzalutamide type A crystals in IPA (80 mL) was stirred at room temperature. At 20 to 30° C., a seed crystal (10.2 mg=0.1% by mass) of enzalutamide type B crystal was added, and stirred at this temperature for 4 days. After stirring, the precipitated crystals were collected by filtration. Then, it was washed with IPA (10 mL), and dried under reduced pressure at 55° C. for about 4 hours to obtain 10.3 g of enzalutamide type B crystals of 1 / 2 solvate of IPA. The yield was 96.2%.

[0102] The obtained B-type crystals were respectively 1 The results of H-NMR are shown below, the results of elemental analysis are shown in Table 2, and the results of XRD measurement are shown in figure 2 , and the 2θ values ​​of the peak tops in the XRD pattern are shown below. In addition, in DSC analysis, endothermic peaks were observed from a...

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Abstract

The purpose of the present invention is to provide a new process for producing an enzalutamide crystal form which is reduced in the contents of 2-propanol and B-form crystals, the process including obtaining wet crystals of enzalutamide in a crystallization step during the production of the enzalutamide crystal form and subsequently subjecting the enzalutamide to solvation. The present invention relates to a process for producing an enzalutamide crystal form, characterized by including a crystallization step in which wet crystals of enzalutamide are obtained and a step for drying the wet crystals and by including, after the crystallization step, a cleaning step in which a solvent mixture of a good solvent and a poor solvent is used.

Description

technical field [0001] The present invention relates to a novel process for the manufacture of crystalline forms of enzalutamide. Furthermore, the present invention relates to a novel process for the manufacture of intermediates thereof. Background technique [0002] Enzalutamide (MDV3100) is a very useful oral androgen receptor inhibitor capable of preventing the growth of androgen-promoted castration-resistant prostate cancer (castration-resistant prostate cancer). [0003] As the form of enzalutamide raw material drug, although it is developed in a solvent-free crystal form (hereinafter, sometimes referred to as "type A crystal"), enzalutamide shows that during the crystallization process, it often forms The details of solvates in the form of solvents are still unclear (Patent Documents 1 and 2). [0004] prior art literature [0005] patent documents [0006] Patent Document 1: Japanese PCT Publication No. 2008-540523 [0007] Patent Document 2: Japanese PCT Publica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/86C07C331/28
CPCC07C331/28C07D233/86A61P35/00A61K31/4166C07B2200/13C30B7/00C30B33/00
Inventor 铃木雄介中川秀一北村刚
Owner ASTELLAS PHARMA INC
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