A crystal form of a spirocyclic dihydroisoquinoline carboxamide derivative and a preparation method thereof

A crystal form and drug technology, applied in the crystal form of spirocyclic dihydroisoquinoline carboxamide derivatives and its preparation field, can solve the problems of poor product stability, poor fluidity, fine crystallization, etc., and achieve stable production process , HPLC purity change is small, the effect of high crystal form purity

Active Publication Date: 2022-04-12
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • A crystal form of a spirocyclic dihydroisoquinoline carboxamide derivative and a preparation method thereof
  • A crystal form of a spirocyclic dihydroisoquinoline carboxamide derivative and a preparation method thereof
  • A crystal form of a spirocyclic dihydroisoquinoline carboxamide derivative and a preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] N-(4-(ethylsulfonyl)benzyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1, Preparation of 4'-isoquinoline]-7'-carboxamide

[0060]

[0061] first step

[0062] 1-(7'-Bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-2,2,2-trifluoroethanone 1b

[0063] N-((1-(4-bromophenyl)cyclopropyl)methyl)-2,2,2-trifluoroacetamide 1a (22g, 68.3mmol, prepared by the method disclosed in the patent application "WO2011124093" (obtained) was dissolved in 150 mL of pre-made mixed solvent of acetic acid and sulfuric acid (V / V=2:3), added paraformaldehyde (7.96 g, 264.99 mmol), and stirred for 12 hours. The reaction solution was poured into 500mL ice water, extracted with ethyl acetate (500mL×2), the organic phases were combined, washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Concentration gave the crude title c...

Embodiment 2

[0082] The compound represented by formula (I) (100 mg, 0.2 mmol) was added into 5 mL of ethyl acetate, heated to reflux, stirred to dissolve, and slowly cooled to room temperature. The reaction solution was filtered, the filter cake was collected, and vacuum-dried to obtain the A crystal form of the compound represented by formula (I). Its X-ray diffraction pattern is shown in figure 1 , whose DSC spectrum is shown in figure 2 , see the TGA spectrum image 3 , and its characteristic peak positions are shown in the table below:

[0083]

Embodiment 3

[0085] The compound represented by formula (I) (100 mg, 0.2 mmol) was added into 5 mL of methanol, heated to reflux, stirred to dissolve, and slowly cooled to room temperature. The reaction solution was filtered, the filter cake was collected, and vacuum-dried to obtain the A crystal form of the compound represented by the formula (I).

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Abstract

The invention relates to a crystal form of a spirocyclic dihydroisoquinoline carboxamide derivative and a preparation method thereof. Specifically, the present invention relates to the crystal form A of the compound represented by formula (I), which has good stability and can be better used in clinical treatment.

Description

technical field [0001] The invention relates to a crystal form of a spirocyclic dihydroisoquinoline carboxamide derivative and a preparation method thereof. Background technique [0002] Retinoic acid-related orphan nuclear receptor (ROR) is a member of the nuclear receptor family, which can regulate a variety of physiological and life processes. The ROR family includes three types RORα, RORβ and RORγ. Three different RORs can be expressed in different tissues and control different physiological processes. RORα is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain. RORβ has a small range of action and mainly acts on In the central nervous system, RORγ can be expressed in many tissues, including liver, animal fat and skeletal muscle. Mammals lacking RORγ exhibit reduced blood glucose. [0003] RORγ, especially the RORγt type, has been identified as an important transcriptional regulator of Th17 cell differentiation. In 2006,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/20A61P29/00A61P37/02A61P35/00A61K31/4747
CPCC07D221/20A61P29/00A61P37/02A61P35/00C07B2200/13
Inventor 陆伟栋曹笑立邵启云李心
Owner JIANGSU HENGRUI MEDICINE CO LTD
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