Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-22
2001-10-16
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06303792
ABSTRACT:
The invention relates to a process for obtaining N-(4-trifluoromethylphenyl)-5-methyl-isoxazole-4-carboxamide in crystalline form, which is essentially free of byproducts. The compound of the formula I
is known per se and is also referred to as N-(4-trifluoromethylphenyl) -5-methyl-isoxazole4-carboxamide or leflunomide (HWA 486). The compound of the formula I can be obtained by the method described in U.S. Pat. No. 4,284,786. In said patents, processes for crystallization from toluene are also described.
The disadvantage of the known processes for obtaining compounds of the formula I is that byproducts such as N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-crotonamide (compound 2 below) essentially cannot be separated by crystallization from solutions containing the compound of the formula I and the compound 2. The compound 2 is described, for example, in U.S. Pat. No. 4,965,276.
The object of the invention is to provide, by modifying the process conditions, a compound of the formula I in high yields which is essentially free of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
The object is achieved by transferring the,compound of the formula 1, containing compound 2 as byproduct, into an organic solvent or into mixtures of organic solvent and water, determining the amount of compound 2 in the solution by an appropriate method of analysis and adding an approximately equimolar amount of a base, for example NaHCO
3
or KHCO
3
, and separating the compound of the formula I by crystallization from the solution obtained.
The invention therefore relates to a process for obtaining the compound of the formula I
from a solution containing water, at least one organic solvent, the compound of the formula I and N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide, which comprises
a) quantitatively determining the amount of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide in the solution,
b) adding the amount of a base which corresponds to from 50 mol % to 150 mol % of the amount determined in a),
c) crystallizing the compound of the formula I and
d) separating the resulting crystals of the compound of the formula I from the solution.
As a result of adding the base, N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide remains in the solution and is not separated off together with the compound of the formula I during the crystallization. Smaller or larger amounts than the amount of added base defined under b) lead to increased byproduct formation and reduce the yield of the compound of the formula I.
For obtaining the compound of formula I, for example, the compound of formula I is dissolved in a solvent. Suitable solvents are, for example, water-miscible solvents, such as (C
1
-C
4
)-alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol or isobutanol, but also ketones, such as acetone or methyl ethyl ketone. Water is then added. Mixtures of organic solvents with water, for example of about 40% to 90% of isopropanol, have also proven useful. The dissolution process is preferably carried out at elevated temperature up to the boiling point of the respective solvent.
In the solution obtained, the amount of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide is determined. Suitable methods of determination are customary quantitative methods of measurement, such as high pressure liquid chromatography (HPLC) or alkalimetric titration. A sample is taken from the solution, and the amount of compound 2 is determined in a standard apparatus. The base is then added to the solution. With the addition of 70 mol % to 130 mol %, based on the determined amount of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide (compound 2), good results are obtained by HPLC. If the amount of compound 2 is determined by alkalimetric titration, amounts of 95 mol % to 105 mol % are advantageous. The quantitatively determined amount of the compound 2 is taken in each case as 100%, and the corresponding molar amount of the base added in each case is determined. It is preferable to add 85 mol % to 120 mol %, particularly preferably 100 mol % to 115 mol %, very particularly preferably 108 mol % to 112 mol %. The base may be added in dissolved or in solid form; the addition in dissolved form is preferred.
The order in which the components water, solvent, compound of the formula I and base are dissolved may also differ from the abovementioned order. For example, the base may be added before the addition of the solvent, water may be added before the addition of the solvent, or the base is not added until the solution has been heated up.
Suitable bases are, for example, organic bases, such as mono-, di- or trialkylamine, e.g. trimethylamine, triethylamine, tripropylamine, tributylamine, triisobutylamine, tripentylamine, trihexylamine, dibutylmethylamine, dimethylamine or diethylamine, the alkylamines being unsubstituted or monosubstituted to trisubstituted by phenyl or benzyl, aromatic amines, such as aniline and substituted anilines, unsubstituted and substituted heterocyclic amines, such as pyridine, piperidine, pyrrole, indole, pyrazine, pyrimidine, morpholine, pyrazole or imidazole, e.g. (C
1
-C
4
)-alkylpyridine. Further suitable bases are inorganic bases, such as sodium bicarbonate (NaHCO
3
), sodium carbonate (Na
2
CO
3
), potassium bicarbonate (KHCO
3
), potassium carbonate (K
2
CO
3
), sodium hydrogen phosphate (Na
2
HPO
4
), sodium dihydrogen phosphate (NaH
2
PO
4
), trisodium phosphate (Na
3
PO
4
), potassium hydrogen phosphate (K
2
HPO
4
), potassium dihydrogenphosphate (KH
2
PO
4
) or tripotassium phosphate (K
3
PO
4
), preferably NaHCO
3
.
The solution or suspension obtained is heated and is kept at the boiling point for some time in order to ensure complete solution of the compound of the formula I.
Thereafter, the optionally filtered solution is cooled so slowly that crystals of the compound of the formula I form. Cooling preferably takes place to the final temperatures of 20° C. to −10° C., in particular to temperatures of 10° C. to −5° C., very particularly preferably to temperatures of 1° C. to 5° C. The crystals are isolated and optionally washed with isopropanol and then with water. The substance is dried at elevated temperature, preferably at 60° C, under reduced pressure or at atmospheric pressure. Other crystallization methods, such as evaporative crystallization or displacement crystallization, are also possible.
A preferred process comprises dissolving the compound of the formula I in 80% strength isopropanol at the boiling point of isopropanol under atmospheric pressure or reduced pressure, carrying out the determination of the amount of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide by HPLC, adding the equimolar amount of base and then cooling the hot solution slowly so that the crystallization takes place at temperatures of more than 40° C., preferably from 40° C. to 85° C., particularly preferably from 45° C. to 80° C., in particular from 50° C. to 70° C. The crystals which have separated out are then washed several times with isopropanol and dried under reduced pressure. The crystallization can be effected without seeding with crystals of the compound of the formula I or preferably in the presence of crystals of the compound of the formula I, which are introduced into the solution by seeding. Seeding can also be effected several times at various temperatures. The amount of the seed material depends on the amount of the solution and can readily be determined by a person skilled in the art.
A particularly preferred process for obtaining the compound of the formula I from a solution containing water, at least one organic solvent, the compound of the formula I and N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide comprises
a) determining the amount of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-crotonamide in the solution by alkalimetric titration,
b) adding the approximately equimolar amount of a base,
c) heating the solution obtained to a temperature from 41° C. up to the boiling point of the organic solvent,
d) diluting th
Faasch Holger
Gappisch Andreas
Hedtmann Udo
Lau Hans-Hermann
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Lambkin Deborah C.
Sackey Ebenezer
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