Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
A polymorph (A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 15.75° in a powder X-ray diffraction; and a polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 21.75° in a powder X-ray diffraction.
1 . A polymorph (A) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 15.75° in a powder X-ray diffraction.
2 . The polymorph (A) according to claim 1 , wherein the polymorph further has diffraction peaks at diffraction angles (2θ±0.2°) of 9.98° and 11.01° in a powder X-ray diffraction.
3 . (canceled)
4 . The polymorph (A) according to claim 1 or 2 , wherein the polymorph has an absorption band at a wavenumber of 3452.3±2.5 cm −1 in an infrared absorption spectrum in potassium bromide.
5 . The polymorph (A) according to claim 1 or 2 , wherein the polymorph further has an absorption band at a wavenumber of 1712.2±1.0 cm −1 .
6 . A polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 21.75° in a powder X-ray diffraction.
7 . The polymorph (B) according to claim 6 , wherein the polymorph further has diffraction peaks at diffraction angles (2θ±0.2°) of 12.430° and 16.56° in a powder X-ray diffraction.
8 . (canceled)
9 . The polymorph (B) according to claim 6 or 7 , wherein the polymorph has an absorption band at a wavenumber of 1557.6±1.0 cm −1 in an infrared absorption spectrum in potassium bromide.
10 . The polymorph (B) according to claim 6 or 7 , wherein the polymorph further has an absorption band at a wavenumber of 1464.4±1.0 cm −1 .
11 . A process for the preparation of the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 1 , comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a good organic solvent, followed by rapid admixing with a poor solvent.
12 . A process for the preparation of the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 1 , comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a good organic solvent with stirring, followed by admixing with a poor solvent in such a way that the resultant crystals precipitate when the stirring is stopped.
13 . A process for the preparation of the polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 1 , comprising a step of reacting 7-methoxy-4-chloro-quinoline-6-carboxamide with 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea in the presence of a base in a good organic solvent for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, followed by rapid admixing with a poor solvent for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide.
14 . The process for the preparation according to any one of claims 11 to 13 , wherein the poor solvent is admixed rapidly within 10 minutes.
15 . A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 6 , comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a good organic solvent, followed by slow admixing with a poor solvent.
16 . A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 6 , comprising a step of dissolving 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide in a good organic solvent while stirring, followed by admixing with a poor solvent in such a way that the resultant crystals diffuse when the stirring is stopped.
17 . A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 6 , comprising a step of reacting 7-methoxy-4-chloro-quinoline-6-carboxamide with 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea in the presence of a base in a good organic solvent for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, followed by slow admixing with a poor solvent for 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide.
18 . The process for the preparation according to any one of claims 15 to 17 , wherein the poor solvent is admixed slowly in 1 hour or more.
19 . A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 6 , comprising a step of heating a polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having a diffraction peak at a diffraction angle (2θ±0.2°) of 15.75° in a powder X-ray diffraction, in suspension in a mixed solvent of a good organic solvent for the polymorph and a poor solvent for the polymorph.
20 . The process for the preparation according to claim 19 , wherein the polymorph (A) is a polymorph further having diffraction peaks at diffraction angles (2θ±0.2°) of 9.98° and 11.01° in a powder X-ray diffraction.
21 . A process for the preparation of the polymorph (B) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide according to claim 6 , comprising a step of heating a polymorph (A) of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, having an absorption band at a wavenumber of 3452.3±2.5 cm −1 in an infrared absorption spectrum in potassium bromide, in suspension in a mixed solvent of a good organic solvent for the polymorph and a poor solvent for the polymorph.
22 . The process for the preparation according to claim 19 or 20 , wherein the polymorph (A) is a polymorph having an absorption band at a wavenumber of 3452.3±2.5 cm −1 in an infrared absorption spectrum in potassium bromide.
23 . The process for the preparation according to claim 22 , wherein the polymorph (A) is a polymorph further having an absorption band at a wavenumber of 1712.2±1.0 cm −1 .
24 . The process for the preparation according to any one of claims 11 to 13 , 15 to 17 or 19 to 21 , wherein the good organic solvent is dimethylsulfoxide, dimethylimidazolidinone, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, acetic acid, sulforane, or a mixed solvent of at least two of the foregoing.
25 . The process for the preparation according to any one of claims 11 to 13 , 15 to 17 or 19 to 21 , wherein the poor solvent is water, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropanol, or a mixed solvent of at least two of the foregoing.
26 . The process for the preparation according to claim 13 or 17 , wherein the base is potassium t-butoxide, cesium carbonate or potassium carbonate.
27 - 55 . (canceled)