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A kind of crystal form, salt form and preparation method of TGF-βRI inhibitor

一种晶型、化合物的技术，应用在制备治疗癌症药物中的应用领域，能够解决信号转导通路异常等问题

Active Publication Date: 2021-10-29
GENFLEET THERAPEUTICS (SHANGHAI) INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Changes in any link in the TGF-β / Smads signaling pathway will lead to abnormalities in the signal transduction pathway

Method used

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  • A kind of crystal form, salt form and preparation method of TGF-βRI inhibitor
  • A kind of crystal form, salt form and preparation method of TGF-βRI inhibitor
  • A kind of crystal form, salt form and preparation method of TGF-βRI inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] The preparation of embodiment 1 formula (I) compound

[0101]

[0102] Preparation of Intermediates 1-6:

[0103]

[0104] Step A: Ethyl acetate (291.41 mL, 2.98 mol) was dissolved in toluene (750.00 mL), then sodium ethoxide (135.06 g, 1.98 mol) was added in portions at room temperature, 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 reaction solution at 25°C, 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 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 silica gel column (eluent: petroleum ether / ethyl acetate v / v=50 / 1) to obtain 1-2.

[0105]Step B: Dissolve 1-2 (120.00 g, 579.07 mmol) in pyridine (300 mL), then add 1-aminopyrrolidin-2-one p-toluenesu...

Embodiment 2

[0115] The preparation of embodiment 2 formula (II) compound

[0116]

[0117] Add 115 mg of the compound of formula (I) into an 8 ml glass bottle, add 4 ml of tetrahydrofuran, sonicate to help dissolve, and form a suspension; then slowly add 1.05 equivalents of p-toluenesulfonic acid monohydrate. The above suspended sample was placed on a magnetic stirrer (40° C.) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35° C. for 16 hours to obtain the compound of formula (II). 1 H NMR (400MHz, CD 3 OD) δ8.61(s, 1H), 8.14(t, J=8.0Hz, 1H), 8.05(d, J=15.6Hz, 1H), 7.90(d, J=8.8Hz, 1H), 7.70(dd , J=8.4, 15.6Hz, 4H), 7.54(d, J=15.6Hz, 1H), 7.39(d, J=8.0Hz, 1H), 7.20(d, J=7.6Hz, 2H), 4.42(m , 2H), 3.05-2.87 (m, 2H), 2.82 (s, 3H), 2.81-2.74 (m, 2H), 2.35 (s, 3H).

Embodiment 3

[0118] The preparation of embodiment 3 formula (IV) compound

[0119]

[0120] Add 115 mg of the compound of formula (I) into an 8 ml glass bottle, add 4 ml of tetrahydrofuran, sonicate to help dissolve, and form a suspension; then slowly add 1.05 equivalents of hydrochloric acid. The above suspended sample was placed on a magnetic stirrer (40° C.) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35°C for 16 hours. Add appropriate amount of acetone to the obtained solid to form a suspension and stir at 40°C, centrifuge to discard the supernatant, and drain the solid sample with an oil pump at room temperature to obtain the compound of formula (IV).

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Abstract

The invention discloses a crystal form, a salt form of a TGF-βRI inhibitor and a preparation method thereof, and also includes the application of the crystal form and the salt form in preparing medicines for treating cancer.

Description

[0001] This application claims the following priority: [0002] CN201711331447.7, the filing date is December 13, 2017. technical field [0003] The present invention relates to a crystal form, a salt form of a TGF-βRI inhibitor and a preparation method thereof, and also includes the application of the crystal form and the salt form in preparing medicines for treating cancer. Background technique [0004] Transforming growth factor-β (Transforming growth factor-β, TGF-β) is a multifunctional growth factor superfamily with a wide range of biological activities, involved in early embryonic development, cartilage and bone formation, synthesis of extracellular matrix, inflammation, Interstitial fibrosis, regulation of immune and endocrine functions, tumor formation and progression. [0005] The TGF-β superfamily consists of a class of structurally and functionally related polypeptide growth factors, including TGF-βs (i.e. chivalrous TGF-β), activins (axtivins), inhibins (inhibi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D471/04A61K31/4155A61P35/00A61K31/4439
CPCA61P35/00C07D519/00C07D487/04A61K31/444C07D471/04C07B2200/13A61K31/416A61K31/4439C07D401/14
Inventor 吴立方贺辉君陆剑宇丁照中胡利红李卫东施沈一黎健陈曙辉
Owner GENFLEET THERAPEUTICS (SHANGHAI) INC
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