HK1181379B - Process for the preparation of 4- {4-[({[4 -chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate - Google Patents

Description

Preparation of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl)]Amino } carbonyl) amino]-3-fluorophenoxy-NProcess for preparing (2-methyl pyridine) -carboxamide, its salt and monohydrate

Technical Field

The invention relates to a method for preparing 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl)]Amino } carbonyl) amino]-3-fluorophenoxy-N-picoline-2-carboxamide (carboxamide), salts and monohydrate thereof.

Background

4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl group)]Amino } carbonyl) amino]-3-fluorophenoxy-N-methylpyridine-2-carboxamides mentioned in WO05/009961 and corresponding to the compounds of formula (I):

the monohydrate of the compound of formula (I) is mentioned in WO 08/043446. Furthermore, salts of the compounds of formula (I), such as their hydrochloride, mesylate and phenylsulfonate salts, are mentioned in WO05/009961 and may be formed by treating the compounds of formula (I) with the corresponding acids. Compounds of formula (I) are described for use in the treatment of hyperproliferative diseases, such as cancers, tumors, lymphomas, sarcomas and leukemias.

WO05/009961 describes a process for the preparation of compounds of formula (I) which is illustrated in the following scheme:

in the first step, 4-amino-3-fluorophenol is treated with potassium tert-butoxide and a solution of 4-chloro-N-methyl-2-pyridinecarboxamide in N, N-dimethylacetamide is added to form 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide, which is finally treated after extraction with a solution of (4-chloro-3- (trifluoromethyl) phenyl) isocyanate in toluene to form 4{4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido ] -3-fluorophenoxy } -pyridine-2-carboxylic acid methylamide, which is a compound of formula (I).

Although the processes disclosed in the prior art are effective per se for the preparation of the compounds of formula (I), their monohydrate, hydrochloride, mesylate and phenylsulfonate salts, factors such as purity, product yield, process efficiency, safety and economy are very important for processes for pharmaceutical products on an industrial scale.

Disclosure of Invention

It is an object of the present invention to provide an industrial scale (kilogram to metric ton range) process for the preparation of compounds of formula (I), salts and monohydrate thereof, which meets the criteria of application in production and provides improvements in purity, environmental suitability, industrial applicability, safety and volumetric yield. In particular, purity and safety aspects are to be considered for the preparation of the drug. This object is achieved by the present invention.

The preparation of the compounds of formula (I) of the present invention is shown in the following scheme:

preparation of a compound of formula (I), a monohydrate or a salt thereof

The present invention comprises a process for preparing a compound of formula (I), a salt or monohydrate thereof:

by reacting in a reaction mixture a compound of formula (IV) which is 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide

Treatment with a compound of formula (V) which is (4-chloro-3-trifluoromethyl-phenyl) isocyanate,

the dissolved compound of formula (I) is then treated with an acid to form a salt of the compound of formula (I) which precipitates from the solution containing the dissolved compound of formula (I), then optionally the salt of the compound of formula (I) is treated with an aqueous base solution to precipitate a monohydrate of the compound of formula (I), and optionally the monohydrate is dried under reduced pressure until the compound of formula (I) is formed.

Salts of the compounds of formula (I) may be prepared by the following steps: treating the compound of formula (IV) with a compound of formula (V) in a reaction mixture, and then treating the dissolved compound of formula (I) with an acid to form a salt of the compound of formula (I), which precipitates from the solution containing the dissolved compound of formula (I).

The monohydrate of the compound of formula (I) may be prepared by the following steps: treating a compound of formula (IV) with a compound of formula (V) in a reaction mixture, then treating the dissolved compound of formula (I) with an acid to form a salt of the compound of formula (I) which precipitates from the solution containing the dissolved compound of formula (I), and then treating the salt of the compound of formula (I) with an aqueous base solution preferably at a temperature of from 35 ℃ to 45 ℃, most preferably from 38 ℃ to 42 ℃ to precipitate the monohydrate of the compound of formula (I).

The compounds of formula (I) may be prepared by the following steps: treating a compound of formula (IV) with a compound of formula (V) in a reaction mixture, then treating the dissolved compound of formula (I) with an acid to form a salt of the compound of formula (I) which precipitates from the solution containing the dissolved compound of formula (I), then treating the salt of the compound of formula (I) with an aqueous base solution to precipitate a monohydrate of the compound of formula (I), and drying the monohydrate under reduced pressure, preferably at a temperature of from 85 ℃ to 120 ℃, and preferably at a pressure of less than 30 mbar, until the compound of formula (I) is formed.

The solution containing the dissolved compound of formula (I) and the substance precipitated from the salt of the compound of formula (I) may preferably be a reaction mixture, or may be a separate solution containing the compound of formula (I), according to the method described above. The separate solution may be prepared after isolation of the compound of formula (I) from the reaction mixture, for example by following standard work-up procedures as described in, for example, WO05/009961 and dissolving the compound of formula (I) in a suitable organic solvent.

In a preferred embodiment of the process for the preparation of a compound of formula (I), a monohydrate or a salt thereof as described above, the acid is generated in situ in a solution containing the dissolved compound of formula (I) by adding a protic substance and an acid precursor to the reaction mixture.

In a more preferred embodiment of the process for preparing the compound of formula (I), its monohydrate or salt, the acid is generated in situ in the reaction mixture after the compound of formula (I) is produced by adding an alcohol and an acid precursor to the reaction mixture.

In the most preferred embodiment of the process for preparing the compound of formula (I), its monohydrate or salt, the acid is generated in situ in the reaction mixture after the compound of formula (I) is formed by adding an alcohol and an acid chloride, preferably acetyl chloride, to the reaction mixture.

In a process for the preparation of a compound of formula (I), a monohydrate or a salt thereof, the reaction of a compound of formula (IV) with a compound of formula (V) takes place in a suitable organic solvent, for example in tetrahydrofuran, at a temperature above 15 ℃ and below 70 ℃ (preferably at a temperature of from 15 ℃ to 60 ℃, more preferably from 15 ℃ to 50 ℃, most preferably at room temperature). Preferably the compound of formula (IV) is first added to a suitable organic solvent (e.g. in tetrahydrofuran) and mixed with the compound of formula (V) for 30 to 300 minutes, preferably 60 to 150 minutes, most preferably 80 to 100 minutes, preferably dissolved or suspended in a suitable organic solvent (e.g. toluene), which may be different from the first suitable organic solvent. After the compound of formula (I) is formed, an acid is added to the reaction mixture. Preferably the acid is generated in situ in the reaction mixture by adding a protic substance (e.g. water and/or an alcohol, preferably an alcohol) and an acid precursor (preferably an acid chloride) to form the corresponding acid in situ, for example over a period of from 5 to 60 minutes, preferably from 10 to 30 minutes. Preferably, the protic substance is added first. Salts of the compounds of formula (I) may be isolated by precipitation.

To prepare the monohydrate of the compound of formula (I), the salt of the compound of formula (I) is further treated with an aqueous alkaline solution, preferably with a mixture of an organic solvent and an aqueous alkaline solution. The monohydrate of the compound of formula (I) may be isolated by precipitation, preferably at a temperature of from 35 ℃ to 45 ℃, most preferably from 38 ℃ to 42 ℃.

To prepare the compound of formula (I), the monohydrate of the compound of formula (I) is dried, preferably at a temperature of from 85 ℃ to 120 ℃ and under reduced pressure, more preferably at a pressure of less than 30 mbar.

Suitable acids in the process for preparing the compound of formula (I), its monohydrate or salt include, but are not limited to, inorganic acids, carboxylic acids and sulfonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Preferred are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid and naphthalenedisulfonic acid, more preferred are hydrochloric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid, and most preferred is hydrochloric acid.

Salts of compounds of formula (I), which are pharmaceutically acceptable salts, include, but are not limited to, acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid and naphthalenedisulfonic acid are preferred, salts of hydrochloric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid are more preferred, and the hydrochloride salt is most preferred.

According to the invention, alcohols are organic substances which carry at least one hydroxyl group. Alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol, or mixtures thereof. Methanol, ethanol and isopropanol are preferably used as the alcohol in the process.

For the in situ preparation of the acid, suitable acid precursors include, but are not limited to, organic acid halides, preferably acid halides such as acid chlorides and acid bromides, more preferably acetyl chloride, acetyl bromide, propionyl chloride or propionyl bromide, most preferably acetyl chloride.

Preference is given to the process described above in which the acid is prepared in situ in the absence of water.

Suitable organic solvents in the process for preparing the compound of formula (I), its monohydrate or salt include, but are not limited to, tetrahydrofuran, toluene, ethyl acetate, dioxane, methyl tert-butyl ether, dimethoxyethane, dimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone or mixtures of the above solvents. More preferably, tetrahydrofuran, toluene and mixtures thereof are used.

Suitable aqueous alkaline solutions in the process for preparing the monohydrate of the compound of formula (I) include, but are not limited to, aqueous solutions of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, alkaline earth metal alkoxides, organic amines, and ammonia, preferably aqueous solutions of sodium hydroxide and potassium hydroxide, more preferably aqueous solutions of sodium hydroxide. The aqueous alkaline solution may be mixed with an organic solvent such as acetone, ethyl acetate, tetrahydrofuran, preferably acetone.

According to the process of the present invention, potential by-products, in particular aniline (anilic) by-products, such as the starting compound 4-amino-3-fluorophenol and the compound of formula (IV), can be very efficiently separated from the salt, preferably the hydrochloride, of the compound of formula (I), since the salt of the aniline by-products, in particular the salt of the compound of formula (IV), preferably the hydrochloride of the compound of formula (IV), does not precipitate under the conditions of the process according to the present invention and remains in the filtrate. Furthermore, in case the acid is generated in situ (by using an acid halide), the corresponding acylated derivative of the aniline by-product, in particular the compound of formula (IV), can be easily separated from the salt, preferably the hydrochloride, of the compound of formula (I), since the acylated derivative does not precipitate under the conditions of the process according to the invention and remains in the filtrate. Accordingly, the compound of formula (I), its salt and its monohydrate can be prepared in very high purity.

Another embodiment of the invention is a compound of formula (I), a monohydrate or a salt thereof, of very high purity, containing or contaminated with one or more anilines, preferably in an amount of 0.05 wt% or less (i.e., from 0.0001 wt% to maximum 0.05 wt%) per aniline, preferably in an amount of 0.025 wt% or less (i.e., from 0.0001 wt% to maximum 0.025 wt%) per aniline, and most preferably in an amount of 0.01 wt% or less (i.e., from 0.0001 wt% to maximum 0.01 wt%) per aniline, based on the amount of the compound of formula (I). In other words, another embodiment is a mixture of a compound of formula (I), a monohydrate or a salt thereof, and one or more anilines, each anilines being in an amount equal to or less than 0.05% (i.e., from 0.0001% to maximum 0.05% by weight), preferably in an amount equal to or less than 0.025% (i.e., from 0.0001% to maximum 0.025% by weight), and most preferably in an amount equal to or less than 0.01% (i.e., from 0.0001% to maximum 0.01% by weight), based on the amount of the compound of formula (I).

Anilines include, but are not limited to, 4-amino-3-fluorophenol, 4-chloro-3-trifluoromethylaniline, 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide, which is a compound of formula (IV).

Preferably, the compound of formula (I), the monohydrate or the salt thereof contains or is contaminated with 4-amino-3-fluorophenol and/or 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide in an amount of equal to or less than 0.05 wt% of each of the above aniline species (i.e. from 0.0001 wt% to maximum 0.05 wt%), preferably in an amount of equal to or less than 0.025 wt% of each of the aniline species (i.e. from 0.0001 wt% to maximum 0.025 wt%), most preferably in an amount of equal to or less than 0.01 wt% of each of the aniline species (i.e. from 0.0001 wt% to maximum 0.01 wt%), based on the amount of the compound of formula (I). In other words, mixtures of the compound of formula (I), its monohydrate or salt with 4-amino-3-fluorophenol and/or 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide are preferred, the amount of each of the above mentioned aniline species being equal to or less than 0.05 wt.% (i.e. from 0.0001 wt.% to maximum 0.05 wt.%), preferably the amount of each aniline species being equal to or less than 0.025 wt.% (i.e. from 0.0001 wt.% to maximum 0.025 wt.%), most preferably the amount of each aniline species being equal to or less than 0.01 wt.% (i.e. from 0.0001 wt.% to maximum 0.01 wt.%), based on the amount of the compound of formula (I).

Preparation of a Compound of formula (IV):

the invention likewise comprises a process for preparing compounds of the formula (IV) by reacting compounds of the formula (III)

Wherein R is¹And R²Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,

or

R¹And R²Are linked and, together with the carbon atom to which they are attached, form a 4-to 7-membered cycloalkyl ring,

with a compound of formula (II) which is 4-chloro-N-methyl-2-pyridinecarboxamide in the presence of a base,

followed by the addition of an acid to produce the compound of formula (IV).

In a preferred embodiment of the process for preparing the compound of formula (IV), the compound of formula (III) is used in solution in a suitable organic solvent and is formed by reacting 4-amino-3-fluorophenol with a compound of formula (VI),

wherein R is¹And R²Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,

or

R¹And R²Are linked and, together with the carbon atom to which they are attached, form a 4-to 7-membered cycloalkyl ring.

In a further preferred embodiment of the process for preparing the compound of formula (IV), the compound of formula (II) is used in a solution of a suitable organic solvent prepared by neutralizing the hydrochloride salt of the compound of formula (II) with a base, preferably with sodium hydroxide, more preferably with an aqueous solution of sodium hydroxide.

In the process for the preparation of the compound of formula (IV), 4-amino-3-fluorophenol is reacted with the compound of formula (VI), which may be used in excess and as a solvent, at a temperature of from 20 ℃ up to the reflux temperature, preferably at a temperature of from 50 ℃ up to the reflux temperature, most preferably at the reflux temperature of the compound of formula (VI). Optionally, additional different solvents may be added, such as toluene, ethyl acetate, cyclohexane, or mixtures thereof. The volatile reaction components can be removed by azeotropic distillation, optionally under reduced pressure. The compound of formula (III) formed may be used in solution in a suitable organic solvent, preferably in 1-methyl-2-pyrrolidone solution, and treated with 4-chloro-N-methyl-2-pyridinecarboxamide in the presence of a base, preferably in solution with a suitable organic solvent, more preferably in 1-methyl-2-pyrrolidone solution. The reaction mixture is heated to a temperature of from 50 ℃ up to 150 ℃, preferably from 80 ℃ up to 120 ℃. After 1 to 5 h, preferably 2 to 4 h, the temperature is adjusted to 50 ℃ up to 90 ℃, preferably 70 ℃ up to 90 ℃, and an acid (preferably acetic acid in water) is added. After cooling, preferably to a temperature of 0 ℃ to 10 ℃, and optionally seeding with crystals of the compound of formula (IV), the compound of formula (IV) can be isolated by precipitation.

Preference is given to compounds of the formula (VI) in which R¹And R²Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or R¹And R²Are linked and, together with the carbon atom to which they are attached, form a 4-to 7-membered cycloalkyl ring. More preferably, the compound of formula (VI) is selected fromFrom 4-methyl-2-pentanone, 3-methyl-2-butanone, 2-pentanone, 4-heptanone, 2, 4-dimethyl-3-pentanone, and cyclohexanone.

Suitable organic solvents in the process for preparing the compound of formula (IV) include, but are not limited to, 1-methyl-2-pyrrolidone, dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, sulfolane or mixtures of the mentioned solvents. Preference is given to using 1-methyl-2-pyrrolidone and/or dimethylformamide.

Suitable bases in the process for preparing the compounds of the formula (IV) are alkali metal hydroxides and alkali metal alkoxides. Potassium tert-butoxide is preferred. The potassium tert-butoxide is preferably used in solution, more preferably in tetrahydrofuran solution.

To provide the compound of formula (II) in high purity form, it is dissolved in a suitable organic solvent, treated with an acid generated in situ by the addition of a protic substance and an acid precursor, precipitated as a salt of the compound of formula (II) (preferably the hydrochloride salt of the compound of formula (II)), and neutralized by the addition of an aqueous base.

For this purpose, the starting compound 4-chloro-N-methyl-2-pyridinecarboxamide is dissolved in a suitable organic solvent, preferably in toluene, and treated with the acid generated in situ (by adding a protic substance, for example water and/or an alcohol, preferably an alcohol, and an acid precursor, preferably an acid chloride, for example in 5 to 60 minutes, preferably in 10 to 30 minutes, so that the corresponding acid is generated in situ). Preferably, the protic substance is added first. The salt of 4-chloro-N-methyl-2-pyridinecarboxamide, preferably the hydrochloride salt of 4-chloro-N-methyl-2-pyridinecarboxamide, may be isolated by precipitation. Such purified salts of 4-chloro-N-methyl-2-pyridinecarboxamide are dissolved in a suitable organic solvent, preferably in toluene, and neutralized by addition of an aqueous solution of a base, preferably an aqueous solution of sodium hydroxide. After separation of the phases, the organic phase is optionally concentrated under reduced pressure and a suitable organic solvent (preferably 1-methyl-2-pyrrolidone) is added to prepare a solution which can be used directly for the preparation of the compound of formula (IV) (as described above).

Suitable organic solvents in the process for the preparation of 4-chloro-N-methyl-2-pyridinecarboxamide include, but are not limited to, tetrahydrofuran, toluene, ethyl acetate, dioxane, methyl tert-butyl ether, dimethoxyethane, dimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone or mixtures of the mentioned solvents. More preferably, tetrahydrofuran, toluene and mixtures thereof are used.

According to the invention, alcohols are organic substances which carry at least one hydroxyl group. Alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol, or mixtures thereof. Methanol, ethanol and isopropanol are preferably used as alcohols in the process of the invention.

For the in situ preparation of the acid, suitable precursors include, but are not limited to, organic acid halides, preferably acid halides such as acid chlorides and acid bromides, more preferably acetyl chloride, acetyl bromide, propionyl chloride or propionyl bromide, most preferably acetyl chloride.

The acid is preferably prepared in situ in the absence of water.

Alternatively, the compounds of formula (II) and their hydrochloride salts may be prepared according to the methods described in WO05/009961 or Bank ston et al (Organic Process Research & Development, 2002, 6, 777-781). .

The compound of formula (V), which is (4-chloro-3-trifluoromethyl-phenyl) isocyanate, may be prepared according to the method described in WO 00/42012.

Abbreviations:

DCI direct chemical ionization (in MS)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

EI Electron bombardment ionization (in MS)

ESI electrospray ionization (in MS)

h hours (hours)

min minute (minutes)

m.p. melting Point

MS Mass Spectrometry

NMR nuclear magnetic resonance spectroscopy

THF tetrahydrofuran.

Detailed Description

Working examples

Recording at room temperature using a spectrometer from Bruker¹H-NMR spectrum. Deuterated dimethyl sulfoxide (deuteriumdimethylulfoxide) was used as a solvent, which included tetramethylsilane as an internal standard if not mentioned otherwise.

MS spectra were recorded using spectrometers from Waters and Applied Biosystems. Relative signal intensities (expressed as a percentage based on the main peak) are given.

HPLC was performed using HP 1100 from Hewlett Packard. The determined conditions are given in connection with the respective working examples.

4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl)]Amino } carbonyl) amino]-3-fluorophenoxy } -N-methylpyridine Preparation of pyridine-2-carboxamides, their hydrochloride and their monohydrate

Stage 1:

4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride salt:

420 g of a solution of 4-chloro-N-methylpyridine-2-carboxamide (prepared according to WO 2006/034796) in toluene (approx. 30% w/w) and 48.8 g of ethanol were added to the reaction flask. 67.2 g of acetyl chloride were added with stirring to the extent that the temperature of the reaction mixture did not exceed 30 ℃. After further stirring at room temperature for 1.5 h, the product is filtered off, washed with toluene (212 g) and dried under reduced pressure (30 ℃, 80 mbar). In this way 156 g (quantitative yield) of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride are obtained.

MS [DCI, NH3]: m/e = 171 [M+H]⁺(M = free base).

HPLC: stationary phase: nucleodur Gravity C18 (150 mm long, 3 mm ID, 3.0 μm particle size); mobile phase A: 1.15 g diammonium phosphate + 0.68 mL ortho-phosphoric acid (85% solution in water)/l L water; mobile phase B: acetonitrile; and (4) UV detection: at 254 nm; oven temperature: 45 ℃, injection volume: 3 μ l, flow rate: 0.5 mL/min; linear gradient: 5% B- >80% B (20 min.), 10 min retention time at 80% B; purity: >98% (Rt = 17.9 min.).

And (2) stage:

4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide

Method 2 a:

to a reaction flask with stirrer was added 41.4 g of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g of toluene as solvent. After the addition of 68.4 g of water and 19.6 g of aqueous sodium hydroxide solution (45% w/w), the reaction mixture was stirred for 30 minutes. The two phases were separated and the aqueous layer was discarded. The organic layer was concentrated by vacuum distillation and toluene was substituted with 1-methyl-2-pyrrolidone (70 g) to give a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone.

To a second reaction flask with stirrer were added 26.7 g of 4-amino-3-fluorophenol and 100 g of 4-methyl-2-pentanone. Water was removed by azeotropic distillation by heating to reflux and stirring for an additional 1 hour. Then, excess 4-methyl-2-pentanone was removed by vacuum distillation and substituted with 1-methyl-2-pyrrolidone (70 g) to prepare a solution containing the imine compound according to formula (III). To the resulting reaction mixture was added a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone. The reaction mixture was heated to about 100 ℃. A solution of 123.2 g of potassium tert-butoxide in tetrahydrofuran (20% w/w) was added dropwise (over about 70 minutes) while the tetrahydrofuran was distilled off. Thereafter, the reaction mixture was stirred at 100 ℃ for an additional 3 hours to complete the reaction. After adjustment to 80 ℃ 350 ml of toluene, 392 ml of water and 8 g of acetic acid were added. The mixture was stirred at 80 ℃ for 10 minutes, cooled to 50 ℃ and seeded with crystals of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide. After cooling to 0 ℃, the suspension was stirred for about 30 minutes. The product was filtered off, washed with methanol/water (1:3v/v, 144 ml) and dried under reduced pressure (30 ℃, 80 mbar). In this way, 40.7 g (78% of theory) of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide are obtained as brown crystals.

HPLC: stationary phase: agilent Zorbax SB-AQ (150 mm long, 3 mm ID, 3.5 μm particle size); mobile phase A: 1.40 g dipotassium hydrogen phosphate + 5.8 ml o-phosphoric acid (8.5% solution in water)/l L water; mobile phase B: acetonitrile; and (4) UV detection: at 268 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 0.8 mL/min; linear gradient in two steps: 10% B- >37% B (10 min.), 37% B- >80% B (10 min.), 10 min retention time at 80% B; purity: >97% (Rt = 9.2 min.).

Method 2 b:

to a reaction flask with stirrer was added 41.4 g of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g of toluene as solvent. After the addition of 68.4 g of water and 19.6 g of aqueous sodium hydroxide solution (45% w/w), the reaction mixture was stirred for 30 minutes. The two phases were separated and the aqueous layer was discarded. The organic layer was concentrated by vacuum distillation and toluene was substituted with 1-methyl-2-pyrrolidone (70 g) to give a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone.

To a second reaction flask with stirrer were added 26.7 g of 4-amino-3-fluorophenol and 100 g of 3-methyl-2-butanone. Water was removed by azeotropic distillation by heating to reflux and stirring for an additional 3 hours. Then, excess 3-methyl-2-butanone was removed by vacuum distillation and substituted with 1-methyl-2-pyrrolidone (70 g) to prepare a solution containing the imine compound according to formula (III). To the resulting reaction mixture was added a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone. The reaction mixture was heated to about 100 ℃. A solution of 123.2 g of potassium tert-butoxide in tetrahydrofuran (20% w/w) was added dropwise (over about 3 hours) while the tetrahydrofuran was distilled off. Thereafter, the reaction mixture was stirred at 100 ℃ for an additional 2.5 hours to complete the reaction. After adjustment to 80 ℃ 350 ml of toluene, 392 ml of water and 8 g of acetic acid were added. The mixture was stirred at 80 ℃ for 10 minutes, cooled to 50 ℃ and seeded with crystals of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide. After cooling to 0 ℃, the suspension was stirred for about 30 minutes. The product was filtered off, washed with methanol/water (1:3v/v, 144 ml) and dried under reduced pressure (30 ℃, 80 mbar). In this way, 44.4 g (84% of theory) of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide are obtained as light brown crystals.

HPLC: stationary phase: agilent Zorbax SB-AQ (150 mm long, 3 mm ID, 3.5 μm particle size); mobile phase A: 1.40 g dipotassium hydrogen phosphate + 5.8 ml o-phosphoric acid (8.5% solution in water)/l L water; mobile phase B: acetonitrile; and (4) UV detection: at 268 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 0.8 mL/min; linear gradient in two steps: 10% B- >37% B (10 min.), 37% B- >80% B (10 min.), 10 min retention time at 80% B; purity: 99% (Rt = 9.1 min.).

Method 2 c:

to a reaction flask with stirrer was added 41.4 g of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g of toluene as solvent. After the addition of 68.4 g of water and 19.6 g of aqueous sodium hydroxide solution (45% w/w), the reaction mixture was stirred for 30 minutes. The two phases were separated and the aqueous layer was discarded. The organic layer was concentrated by vacuum distillation and toluene was substituted with 1-methyl-2-pyrrolidone (70 g) to give a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone.

To a second reaction flask with stirrer were added 26.7 g of 4-amino-3-fluorophenol, 73 g of cyclohexane and 20.6 g of cyclohexanone. Water was removed by azeotropic distillation by heating to reflux and stirring for an additional 3 hours. The solvent cyclohexane and excess cyclohexanone were then removed by vacuum distillation and replaced with 1-methyl-2-pyrrolidone (70 g) to prepare a solution containing the imine compound according to formula (III). To the resulting reaction mixture was added a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone. The reaction mixture was heated to about 100 ℃. 126 g of a solution of potassium tert-butoxide in tetrahydrofuran (20% w/w) were added dropwise (over about 40 minutes) while the tetrahydrofuran was distilled off. Thereafter, the reaction mixture was stirred at 100 ℃ for an additional 3 hours to complete the reaction. After adjusting to 80 ℃ 350 ml of toluene, 392 ml of water and 8 g of acetic acid were added. The mixture was stirred at 80 ℃ for 10 minutes, cooled to 50 ℃ and seeded with crystals of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide. After cooling to 3 ℃, the suspension was stirred for about 30 minutes. The product was filtered off, washed with methanol/water (1:3v/v, 144 ml) and dried under reduced pressure (30 ℃, 80 mbar). In this way, 40.2 g (76% of theory) of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide are obtained as light brown crystals.

HPLC: stationary phase: agilent Zorbax SB-AQ (150 mm long, 3 mm ID, 3.5 μm particle size); mobile phase A: 1.40 g dipotassium hydrogen phosphate + 5.8 ml o-phosphoric acid (8.5% solution in water)/l L water; mobile phase B: acetonitrile; and (4) UV detection: at 268 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 0.8 mL/min; linear gradient in two steps: 10% B- >37% B (10 min.), 37% B- >80% B (10 min.), 10 min retention time at 80% B; purity: >98% (Rt = 9.1 min.).

And (3) stage:

4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl)]Amino } carbonyl) amino]-3-fluorophenoxy } -N-methylpyridine Pyridine-2-carboxamide monohydrate

To a reaction flask with stirrer was added 20.0 g of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide and 180 g of tetrahydrofuran as solvent. A solution of 18.7 g of (4-chloro-3-trifluoromethyl-phenyl) isocyanate and 21.1 g of toluene was added dropwise at room temperature over a period of about 90 minutes. The resulting solution was stirred for 3 hours to complete the reaction. Then 30g of tetrahydrofuran and 7.8 g of methanol were added to the reaction mixture. 9.0 g of acetyl chloride was then added dropwise to the reaction mixture over 15 minutes. After stirring for an additional about 2 hours, the suspension was filtered and the solid was washed with tetrahydrofuran (18.2 g) and acetone (136.4 g). The solid was added to a mixture of acetone (268.6 g), water (55.8 g) and aqueous sodium hydroxide (8.2 g, 45% w/w) at 40 ℃. The mixture was stirred for an additional 30 minutes. Crystallization was then initiated by seeding with crystals of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl ] amino } carbonyl) amino ] -3-fluorophenoxy } -N-methylpyridine-2-carboxamide monohydrate. After cooling to 20 ℃, 31.6 g of water were added. The suspension was cooled to about 3 ℃ and stirred for 30 minutes. The product was filtered off, washed with a cold mixture of acetone (106 g) and water (44 g) and dried under reduced pressure (30 ℃, 80 mbar). In this way, 31.8 g (83% of theory) of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl ] amino } carbonyl) amino ] -3-fluorophenoxy } -N-methylpyridine-2-carboxamide monohydrate were obtained as white crystals.

HPLC: stationary phase: eclipse XDB-C8 (150 mm long, 2.1 mm ID, 3.5 μm particle size); mobile phase A: 1.0g Hexane-1-sulfonic acid sodium salt + 1.0 mL trifluoroacetic acid/1L water; mobile phase B: acetonitrile; and (4) UV detection: at 232 nm; oven temperature: 43 ℃, injection volume: 3 μ l, flow rate: 0.5 mL/min; linear gradient over 3 steps: 5% B- >36% B (14.5 min.), 36% B- >44% B (6 min.), 44% B- >80% B (9.5 min.), 10 minutes retention time at 80% B; purity: 99.5% (Rt = 25.7 min.), the relevant potential by-products: RRT (relative retention time) 0.10 (4-amino-3-fluorophenol): typically <0.01% (2.6 min.), RRT 0.37(4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide): typically <0.01% (9.5 min.); RRT 0.46 (4- (3-fluoro-4- { [2- (methylcarbamoyl) pyridin-4-yl ] amino } phenoxy) -N-methylpyridine-2-carboxamide): typically <0.15% (11.7 min.); RRT 0.69 (4- (3-fluoro-4- { [ (2-fluoro-4- { [2- (methylcarbamoyl) pyridin-4-yl ] oxy } phenyl) carbamoyl ] amino } phenoxy) -N-methylpyridine-2-carboxamide): typically <0.15% (17.7 min.).

HPLC (Trace analysis method for quantification of 4-amino-3-fluorophenol): stationary phase: X-Bridge Shield dC18 (150 mm long, 3.0 mm ID, 3.5 μm particle size); mobile phase A: 1.5 g of monopotassium phosphate + 0.5 g of dipotassium hydrogen phosphate 1L of water; mobile phase B: acetonitrile; and (4) UV detection: at 228 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 1.0 mL/min; 5 minute retention time: linear gradient in 1 step at 5% B: 5% B- >80% B (10 min.), RT of 4-amino-3-fluorophenol: 1.7min., quantification based on external standard 4-amino-3-fluorophenol.

HPLC (trace analytical method for quantification of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide): stationary phase: X-Bridge Shield C18 (150 mm long, 3.0 mm ID, 3.5 μm particle size); mobile phase A: 1.5 g of monopotassium phosphate + 0.5 g of dipotassium hydrogen phosphate 1L of water; mobile phase B: acetonitrile; and (4) UV detection: at 228 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 1.0 mL/min; linear gradient in 1 step: 8% B- >80% B (15 min.), RT of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide: 7.0 min, quantification based on external standard 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.

And (4) stage:

4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl)]Amino } carbonyl) amino]-3-fluorophenoxy } -N-methylpyridine Pyridine-2-carboxamides

10.2 g of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl ] amino } carbonyl) amino ] -3-fluorophenoxy } -N-methylpyridine-2-carboxamide monohydrate were dried at 90 ℃ under reduced pressure (21 mbar) for 3 hours in this way to give 9.8 g of 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) -phenyl ] amino } carbonyl) -amino ] -3-fluorophenoxy } -N-methylpyridine-2-carboxamide as white crystals.

HPLC: stationary phase: eclipse XDB-C8 (150 mm long, 2.1 mm ID, 3.5 μm particle size); mobile phase A: 1.0g Hexane-1-sulfonic acid sodium salt + 1.0 mL trifluoroacetic acid/1L water; mobile phase B: acetonitrile; and (4) UV detection: at 232 nm; oven temperature: 43 ℃, injection volume: 3 μ l, flow rate: 0.5 mL/min; linear gradient over 3 steps: 5% B- >36% B (14.5 min.), 36% B- >44% B (6 min.), 44% B- >80% B (9.5 min.), 10 minutes retention time at 80% B; purity: 99.5% (Rt = 25.2 min.), the relevant potential by-products: RRT (relative retention time) 0.10 (4-amino-3-fluorophenol): typically <0.01% (2.5 min.), RRT 0.36 (4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide): typically <0.01% (9.1 min.); RRT 0.46 (4- (3-fluoro-4- { [2- (methylcarbamoyl) pyridin-4-yl ] amino } phenoxy) -N-methylpyridine-2-carboxamide): typically <0.15% (11.3 min.); RRT 0.69 (4- (3-fluoro-4- { [ (2-fluoro-4- { [2- (methylcarbamoyl) pyridin-4-yl ] oxy } phenyl) carbamoyl ] amino } phenoxy) -N-methylpyridine-2-carboxamide): typically <0.15% (17.2 min.).

HPLC (Trace analysis method for quantification of 4-amino-3-fluorophenol): stationary phase: X-Bridge Shield dC18 (150 mm long, 3.0 mm ID, 3.5 μm particle size); mobile phase A: 1.5 g of monopotassium phosphate + 0.5 g of dipotassium hydrogen phosphate 1L of water; mobile phase B: acetonitrile; and (4) UV detection: at 228 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 1.0 mL/min; 5 minute retention time: linear gradient over 1 step at 5% B: 5% B- >80% B (10 min.), RT of 4-amino-3-fluorophenol: 1.7min., quantification based on external standard 4-amino-3-fluorophenol.

HPLC (trace analytical method for quantification of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide): stationary phase: X-Bridge Shield C18 (150 mm long, 3.0 mm ID, 3.5 μm particle size); mobile phase A: 1.5 g of monopotassium phosphate + 0.5 g of dipotassium hydrogen phosphate 1L of water; mobile phase B: acetonitrile; and (4) UV detection: at 228 nm; oven temperature: 50 ℃, injection volume: 3 μ l, flow rate: 1.0 mL/min; linear gradient in 1 step: 8% B- >80% B (15 min.), RT of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide: 7.0 min., quantification based on external standard 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.

Claims (10)

1. A process for preparing a monohydrate of a compound of formula (I)

The process is carried out by reacting a compound of formula (IV)

Treatment with a compound of formula (V),

the dissolved compound of formula (I) is then treated with an acid to form a salt of the compound of formula (I) which precipitates from the solution containing the dissolved compound of formula (I), the acid being generated in situ in the reaction mixture after formation of the compound of formula (I) by addition of an alcohol and an acid halide to the reaction mixture, and the salt of the compound of formula (I) is then treated with an aqueous base to precipitate a monohydrate of the compound of formula (I).

2. The process of claim 1, wherein the monohydrate of the compound of formula (I) precipitates at a temperature of from 35 ℃ to 45 ℃.

3. The process for the preparation of the compound of formula (I) according to claim 1 or 2, wherein the monohydrate is dried under reduced pressure until the compound of formula (I) is formed.

4. The process of claim 1, wherein the acid is generated in situ in the reaction mixture after formation of the compound of formula (I) by adding an alcohol and an acid chloride to the reaction mixture.

5. The method of claim 4, wherein the alcohol is ethanol and the acid chloride is acetyl chloride.

6. The process of any one of claims 1 to 5, wherein the compound of formula (IV) is prepared by: reacting a compound of formula (III)

Wherein R is¹And R²Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,

or

R¹And R²Are linked and, together with the carbon atom to which they are attached, form a 4-to 7-membered cycloalkyl ring,

with a compound of formula (II) in the presence of a base,

followed by the addition of an acid to produce the compound of formula (IV).

7. The process of claim 6, wherein the compound of formula (III) is used in solution in a suitable organic solvent and is produced by reacting 4-amino-3-fluorophenol with a compound of formula (VI)

Wherein R is¹And R²Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,

or

R¹And R²Are linked and, together with the carbon atom to which they are attached, form a 4-to 7-membered cycloalkyl ring.

8. The process of claim 6 or 7, wherein the compound of formula (II) is used in a solution in a suitable organic solvent, said solution being prepared by neutralizing the hydrochloride salt of the compound of formula (II) with a base.

9. A process according to any one of claims 6 to 7, wherein the compound of formula (II) is dissolved in a suitable organic solvent, treated with an acid generated in situ by the addition of a protic substance and an acid precursor, precipitated as a salt of the compound of formula (II), and neutralised by the addition of an aqueous base.

10. The method of claim 9, wherein the protic substance is an alcohol and the acid precursor is an acid chloride.