Crystal form and salt form of TGF-βRI inhibitor and preparation method therefor

#This application is a 371 National Phase of International Application No. PCT/CN2018/120905, filed Dec. 13, 2018, which claims the benefit of Chinese Patent Application No. CN 201711331447.7, filed Dec. 13, 2017. The entire disclosures of the above applications are incorporated herein by reference.

#The present invention relates to a crystal form and salt form of a TGF-βRI inhibitor, and a preparation method therefor, and further comprises the use of the crystal form and salt form in the preparation of a medicine for treating cancers.

#Transforming growth factor-β (TGF-β) is a multi-functional growth factor superfamily with a wide range of biological activities, involving in early embryonic development, cartilage and bone formation, synthesis of extracellular matrix, inflammation, interstitial fibrosis, regulation of immune and endocrine functions, and tumor formation and development.

#FIG. 1 is the XRPD pattern of the crystal form A of the compound of formula (I).

#FIG. 2 is the DSC pattern of the crystal form A of the compound of formula (I).

#FIG. 3 is the TGA pattern of the crystal form A of the compound of formula (I).

#In order to better understand the content of the present invention, the following specific examples are used for further description, but the specific embodiments do not limit the content of the present invention.

#Step A: Ethyl acetate (291.41 ml, 2.98 mol) was dissolved in toluene (750.00 ml), and then sodium ethoxide (135.06 g, 1.98 mol) was added portionwise at room temperature thereto, and the reaction mixture was stirred at room temperature for 1 hour. 1-1 (150.00 g, 992.33 mmol) was added to the above-mentioned reaction solution at 25° C., and then heated to 95° C. and stirred for 15 hours. The reaction mixture was cooled to about 30° C., adjusted to pH 7 with acetic acid, diluted with water (500 ml), and then extracted with ethyl acetate (500 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column (eluent: petroleum ether/ethyl acetate v/v=50/1) to afford 1-2.

#Step B: 1-2 (120.00 g, 579.07 mmol) was dissolved in pyridine (300 ml), and then p-toluenesulfonate salt (172.01 g, 631.66 mmol) of 1-aminopyrrolidine-2-one was added thereto. The reaction mixture was stirred at 25° C. for 16 hours, and then concentrated under reduced pressure to remove the solvent. The residue was diluted with water (300 ml), and then extracted with ethyl acetate (300 ml×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-3.