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A kind of crystal form of inhibitor and its preparation method and use

A technology of crystal form and solvent, applied in the field of medicinal chemistry crystallization, can solve problems such as poor stability of crystal form I

Active Publication Date: 2016-09-21
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventors of the present invention found that the crystal form I has the following defects: the weight change is about 0.95% in the range of 20-80% relative humidity, and it has certain hygroscopicity; the stability of the crystal form I is relatively poor

Method used

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  • A kind of crystal form of inhibitor and its preparation method and use
  • A kind of crystal form of inhibitor and its preparation method and use
  • A kind of crystal form of inhibitor and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0201] Referring to the method of Example 9 in the patent document WO2005113556A1 to prepare the crystal form I of Idelalisib, the specific operation is: at 80°C, (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl- 3H-quinazolin-4-one (65.6 mmol, 1 equiv), 6-bromopurine (14.6 g, 73.4 mmol, 1.1 equiv) and diisopropylethylamine (24.3 ml, 140 mmol, 2 equiv ) in tert-butanol (40 mL) was stirred for 24 hours. The reaction mixture was concentrated in vacuo and treated with water to give a solid crude product which was collected by concentration in vacuo, washed with water and dried in the air. Half of the crude solid obtained was dissolved in 600 mL methanol, concentrated onto silica gel (300 mL dry), purified by flash chromatography (7.5 x 36 mm, eluted with 10 L 4% methanol / dichloromethane), and concentrated to give a solid. The solid product was then dissolved in 250 mL of ethanol and concentrated in vacuo to obtain a pale yellow solid compound, which was shown by elemental analysis to be...

Embodiment 2

[0209] Take 102.8mg of the crystal form I of Idelalisib in a 10mL glass vial, add 5mL of toluene, ultrasonicate for 5 minutes to obtain a suspension, stir at room temperature for 8 days to crystallize, filter the obtained solid, and vacuum dry at 60°C for 10 hours to obtain the compound of the present invention. The above-mentioned crystal form II. The yield was 94.3 mg; the molar yield was 95.8%.

[0210] X-ray powder diffraction spectrum as Figure 5 shown.

[0211] IR spectrum such as Figure 6 shown.

[0212] DSC spectrum such as Figure 7 shown. Display: The melting range is 244-249°C.

[0213] TGA spectrum as Figure 8 shown. It shows that there is about 0.41% weight loss (anhydrous matter) before 150°C, and the decomposition temperature is 271°C.

[0214] DVS shows: 0.46% weight change in the range of 20%-80% relative humidity.

Embodiment 3

[0216] Take 102.8mg of Idelalisib crystal form I in a 15mL glass vial, add 5mL of water and 5mL of tetrahydrofuran, sonicate for 5 minutes to obtain a suspension, stir at 40°C for 1 day to crystallize, filter the obtained solid, and dry under vacuum at 40°C for 24 hours to obtain this Said crystalline form II was invented. The yield was 80.2 mg; the molar yield was 81.5%.

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Abstract

The present invention relates to a kind of inhibitor 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one New crystalline forms having one or more improved properties compared to known crystalline forms. The present invention also relates to a new crystal form of 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one The preparation method, its pharmaceutical composition and its use in the preparation of medicines for treating and / or preventing diseases such as chronic lymphocytic leukemia and inert non-Hodgkin's lymphoma.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical crystallization. Specifically, a PI3Kδ inhibitor, 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazoline-4 - A new crystal form of ketone (Idelalisib), a preparation method and use thereof, and a pharmaceutical composition comprising the new crystal form. Background technique [0002] Idelalisib is a phosphatidylinositol 3-kinase δ inhibitor (referred to as PI3Kδ inhibitor) developed by Gilead Sciences of the United States, which is used for chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large For the treatment of B-cell lymphoma, Hodgkin's lymphoma, multiple myeloma, acute myeloid leukemia and hematological malignancies, the oral preparations are capsules with specifications of 100 mg, 150 mg and 300 mg. In 2012, it entered the clinical phase III study for the treatment of chronic lymphocytic leukemia. [0003] The chemic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/34A61K31/52A61P35/00A61P35/02
CPCC07B2200/13C07D473/34A61P35/00A61P35/02
Inventor 章中华盛晓霞盛晓红
Owner SOLIPHARMA
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