Novel crystal form of 2-aminopyridine derivative and preparation method thereof

A crystallization, D-type technology, used in organic chemical methods, medical preparations containing active ingredients, separation/purification of carboxylic acid compounds, etc., can solve problems such as low positive rate, and achieve simple preparation methods and good thermal stability. , the effect of good liquidity

Pending Publication Date: 2022-05-06
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

In general non-small cell lung cancer patients, the positive rate of EML4-ALK fusion gene is low, about 3% to 7%.

Method used

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  • Novel crystal form of 2-aminopyridine derivative and preparation method thereof
  • Novel crystal form of 2-aminopyridine derivative and preparation method thereof
  • Novel crystal form of 2-aminopyridine derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0104] The preparation of embodiment 1 formula Ia compound

[0105] Dissolve 0.01mol of the compound of formula I in 90mL of methanol, add 10mL of citric acid-methanol solution with a concentration of 1.1mol / L under reflux and stir, and react for 1 hour, the reaction solution precipitates a solid, and continues to reflux hours, filtered, and the separated solid stirred at reflux in ethanol hour, filtered, and the separated solid was dried with air blast at 85°C under normal pressure to obtain crystals of the compound of formula Ia. The X-ray powder diffraction pattern using CuKa radiation was shown as type A crystals of WO2017016514, such as Figure 11 Shown, the diffraction peak in its X-ray diffraction pattern has following characteristics:

[0106]

[0107]

[0108] 1 H-NMR (500MHz, DMSO-d 6 ): δ=7.83(s, 1H), 7.57(t, J=4.95Hz, 1H), 7.55(d, J=1.45Hz, 1H), 7.46(t, J=8.7Hz, 1H), 6.81(d ,J=1.2Hz,1H),6.38(s,1H),5.98(q,J=6.7Hz,1H),5.73(brs,2H),4.79(brs,1H),4.26(d,J=13...

Embodiment 2

[0109] The preparation of the H type crystal of embodiment 2 formula Ia compound

[0110] Weigh 250 mg of the compound of formula Ia obtained in Example 1 into a 50 mL one-necked flask, add 40 mL of acetonitrile-water mixed solvent (acetonitrile: water (v / v) = 0.25:1) to obtain a suspension, then stir at room temperature for 24 hours, filter , and the separated solid was air-dried at 50° C. for 2 hours to obtain type H crystals of the compound of formula Ia.

[0111] 1 H-NMR (500MHz, DMSO-d 6 ):δ=7.81(s,1H),7.58(dd,J=9.0,4.9Hz,1H),7.53(d,J=1.8Hz,1H),7.47(t,J=8.7Hz,1H),6.78 (d,J=1.9Hz,1H),6.37(s,1H),5.97(q,J=6.7Hz,1H),5.75(s,2H),4.78(d,J=6.3Hz,1H),4.30 –4.19(m,1H),3.69(s,3H),3.30(d,J=12.2Hz,1H),3.23(d,J=12.6Hz,1H),3.18–3.08(m,2H),2.95( td,J=12.4,3.8Hz,1H),2.58(d,J=15.1Hz,2H),2.51(d,J=15.1Hz,2H),1.77(d,J=6.6Hz,3H),1.20( d, J=6.9Hz, 3H).

Embodiment 3

[0112] The preparation of the H type crystal of embodiment 3 formula Ia compound

[0113] Weigh 250 mg of the compound of formula Ia obtained in Example 1 into a 50 mL one-necked flask, add 40 mL of acetonitrile-water mixed solvent (acetonitrile: water (v / v) = 9:1) to obtain a suspension, then stir at room temperature for 24 hours, filter , and the separated solid was air-dried at 50° C. for 2 hours to obtain type H crystals of the compound of formula Ia.

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a novel crystal form of a 2-aminopyridine derivative and a preparation method thereof, in particular to a citrate crystal of 5-((R)-1-(2, 6-dichloro-3-fluorophenyl) ethyoxyl)-4 '-methoxy-6'-((S)-2-methylpiperazine-1-yl)-3, 3 '-bipyridine-6-amine and a preparation method thereof, and more particularly relates to a citrate crystal of 5-((R)-1-(2, 6-dichloro-3-fluorophenyl) ethyoxyl)-4'-methoxy-6 '-((S)-2-methylpiperazine-1-yl)-3, 3'-bipyridine-6-amine and a preparation method thereof. The present invention relates to H-type, NH-type and D-type crystals of a citrate of (2, 6-dichloro-3-fluorophenyl) ethyoxyl)-4 '-methoxy-6'-((S)-2-methylpiperazine-1-yl)-3, 3 '-bipyridine-6-amine, and to a method for preparing the same.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to crystal forms and preparation methods of 2-aminopyridine derivatives, in particular to 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy) Citrate crystal of -4'-methoxy-6'-((S)-2-methylpiperazin-1-yl)-3,3'bipyridin-6-amine and preparation method thereof. Background technique [0002] Protein kinases (PKs) represent a large class of proteins that play an important role in the control of cellular functions and the regulation of various cellular lesions, and can be divided into two categories: protein tyrosine kinases (PTKs) and serine-threonine kinases ( STKs). Protein Tyrosine Kinases (PTKs) are a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on protein substrates, which play a role in normal cell growth. Studies have found that the cell signal transduction pathways of tyrosine kinases also play an extremely important role in the format...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07C59/265C07C51/43A61P35/00A61P35/04A61K31/496
CPCC07D401/14C07C59/265A61P35/00A61P35/04C07B2200/13
Inventor 朱善良刘飞刘彦龙赵锐胡中元李新路臧海山
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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