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1. (WO2019048974) PROCESS FOR THE PREPARATION OF NINTEDANIB
Nota: Texto obtenido mediante procedimiento automático de reconocimiento óptico de caracteres.
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WE CLAIM:

1. A process for the preparation of nintedanib, a compound of formula I,


or a salt thereof, comprising the steps of:

a) reacting a compound of formula VI,


VI

with acetic anhydride and triethyl rthobenzoate to obtain a compound of formula V,


; and

b) subjecting the compound of formula V to treatment with a solvent system selected from the group consisting of Ci-C6 amide, Ci-C6 ester, Ci-C6 carboxylic acid, C2-C6 carboxylic anhydride, Ci-C6 aliphatic ether, Ci-C6 haloalkane, C6-C12 aromatic hydrocarbon, Ci-C6 alcohol or mixtures thereof, to obtain a compound of formula V, wherein the level of impurity, the compound of formula A,


is less than 0.15% w/w of the compound of formula V, as determined by HPLC.

2. The process as claimed in claim 1, wherein the compound of formula V is obtained in crystalline form.

3. The process as claimed in claim 2, wherein the com ound of formula V,


V

is in crystalline form characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 8.2, 11.2, 16.5 and 25.5±0.2° 2Θ.

4. The process as claimed in claim 1, wherein treatment with a solvent system comprises recrystallizing from a solvent system or slurrying in a solvent system at ambient temperature or at higher temperature.

5. The process as claimed in claim 1, wherein the solvent system is selected from the group consisting of dimethylformamide (DMF), ethyl acetate, methanol, dichloromethane (DCM), acetic acid, acetic anhydride, toluene, methyl t-butyl ether (MTBE) or mixtures thereof.

6. The process as claimed in claim 5, wherein the solvent system is a mixture of toluene and methanol.

7. The process as claimed in claim 2, further comprising the steps of:

i) reacting the compound of formula V with a compound of formula IV,


IV

to obtain a compound of formula ΙΠ,

ii) deprotecting the compound of formula III with piperidine in an alcoholic solvent to obtain nintedanib, the compound of


wherein the level of impurity, the compound of formula B,


is less than 0.15% w/w of nintedanib, the compound of formula I, as determined by HPLC.

8. The process as claimed in claim 7, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, 1,1,-dimethyl-l-propanol or mixture thereof .

9. The process as claimed in claim 8, wherein the alcoholic solvent is methanol.

10. The process as claimed in claim 7, further comprising recrystallizing nintedanib, the compound of formula I, in a solvent system selected from the group consisting of Ci-C6 amine, Ci-C6 ester, Ci-Ce carboxylic acid, Ci-C6 carboxylic anhydride, Ci-C6 aliphatic ether, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, Ci-C6 alcohol, water or mixtures thereof, to obtain nintedanib, the compound of formula I,


11. The process as claimed in claim 10, wherein nintedanib, the compound of formula I is recrystallized from the mixture of methanol and water.

12. The process as claimed in claim 7, wherein nintedanib, the compound of formula I, is further reacted with ethanesulfonic acid to obtain nintedanib esylate hemihydrate, a compound of formula II.


13. A method of assessing the purity of nintedanib or a salt thereof or the pharmaceutical composition containing them, by HPLC comprising the steps of:

a) providing a standard solution of the compound of formula B; and


b) using the solution of step 'a', as a reference marker to determine the level of the compound of formula B.

14. A crystalline compound of formula V


characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 8.2, 11.2, 16.5 and 25.5±0.2° 2Θ.

15. Nintedanib or a salt thereof, a compound of formula I,


wherein the level of impurity, the compound of formula B,


is less than 0.15% of nintedanib, as determined by HPLC.