ITUB20151311A1 - PROCEDURE FOR THE PREPARATION OF ENZALUTAMIDE - Google Patents

Description

PROCEDURE FOR THE PREPARATION OF ENZALUTAMIDE

Object of the invention

Object of the invention? a process for the preparation of the active ingredient Enzalutamide and new intermediates used in said process.

State of the art

Enzalutamide, whose chemical name? 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-1-oxo-2-thioxoimidazolidin-1-yl} -2-fluoro-N-methylbenzamide, belongs to a class of compounds capable of binding to androgen hormone receptors used in the treatment of metastatic prostate cancer.

Enzalutamide

AND? It is known that the anti-androgenic drugs used in the treatment of hormone-sensitive prostate tumors can trigger resistance phenomena due to a mechanism of over-expression of the androgen hormone receptors making the drugs ineffective and in some cases even counterproductive. Molecules such as Enzalutamide have shown the ability? to make tumor forms that have become resistant again treatable.

WO2006124118 and WO2007127010 describe a preparation method (Scheme 1) which of enzalutamide provides as the last step the cycloaddition, assisted by microwaves, of isothiocyanate 3 with the cyanoalkylamino derivative 1. The reaction takes place with low yields and? chromatographic purification is required, furthermore the preparation of 1 requires the use of cyanides or cyanhydrins. A more process? efficient for the preparation of Enzalutamide? described in WO2011106570 and provides for the cyclization of the isothiocyanate 3 with the ester 2 or a higher homologue thereof (Scheme 1).

Scheme 1

In the same patent application (WO2011106570)? also claimed a different approach which provides for the formation of the thiohydantoin ring of enzalutamide by reaction of the amide 4 with thiophosgene (Scheme 2). The yields of the cyclization reaction are very low.

Scheme 2

Surprisingly we found Enzalutamide pu? be obtained

with significantly higher yield from amides such as 5 by reaction with isothiocyanate 3

Description of the invention

Object of the present invention? a process for the preparation of Enzalutamide which includes the reaction of isothiocyanate 3 with an amide of formula 5 (Scheme 3), where R1 and R2 can be independently hydrogen, alkyl, arylachyl or aryl, or R1 and R2 together with the atom of nitrogen to which they are bound form a nitrogenous heterocyclic ring.

Scheme 3

Alkyl? preferably C1-C4 alkyl, linear or branched, plus preferably methyl and ethyl.

Arylalkyl? preferably aryl C1-C3 linear or branched alkyl, plus preferably benzyl.

Arile? preferably phenyl or naphthyl, plus preferably phenyl.

The heterocyclic nitrogen ring? preferably a five or six-membered ring, saturated or unsaturated, optionally containing a second heteroatom selected from oxygen, sulfur and nitrogen. Preferably the nitrogenous heterocyclic ring? selected from pyrrolidine, piperidine, morpholine and 4-methylpiperazine.

The above alkyl, aryl and heterocyclic groups can be unsubstituted or substituted by one, two or three groups independently selected in the

group comprising halogen, cyano, nitro, C1-C3-alkyl, trifluoromethyl, methoxy, methylthio, methanesulfonyl, vinyl, phenyl, p-nitrophenyl, p-chlorophenyl and methoxyphenyl.

In one embodiment of the invention, in the compound of formula 5 one of R1 and R2? hydrogen and the other? benzyl.

In another embodiment of the invention, in the compound of formula 5 R1 and R2 are both hydrogen or ethyl.

In still another embodiment of the invention, in the compound of formula 5 R1 and R2 together with the nitrogen atom to which only bonded constitute a piperidine ring.

The condensation between isothiocyanate 3 and a kind of formula 5 to give Enzalutamide? typically carried out in an organic solvent or a mixture of solvents, selected from an ester such as propyl acetate, isopropyl acetate, butyl acetate, an amide such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl pyrrolidone, a carboxylic acid such as acetic acid or propionic acid, an aromatic hydrocarbon such as toluene or xylene, a urea such as 1,3-dimethyl-2-imidazolidinone or N, N? -dimethyl-propylene urea or a sulfur solvent such as dimethylsulfoxide or sulfolane.

Typically the temperature of the reaction? between 50 ° C and 150 ° C, preferably between 70 and 120 ° C; the reaction time between 5 hours and 50 hours, preferably between 10 hours and 30 hours.

The molar ratio between species 5 and isothiocyanate 3? generally between 1: 1 and 1: 4, preferably between 1: 1.5 and 1: 2.5.

The reactions? normally carried out in conditions of high concentration, with a ratio between the weight of the reactants and the volume of the solvents preferably between 1: 1 and 1: 4.

Enzulatamide isolation can be carried out with one of the classical methods, such as for example the precipitation of the crude product by adding antisolvent to the reaction mixture; or the dilution with a suitable solvent, the eventual washing of the organic solution with aqueous solutions, and the obtaining of the crude product by concentrating the organic phase.

The quality of the raw product can? then be increased by treatment with a solvent (slurry) or by crystallization.

The products of formula 5 are new products with the exception of the amide 4 described in WO2011106570.

A further object of the invention? therefore represented by a compound of formula 5 as previously defined, with the exclusion of the compound 4- (1- (4-cyano-3- (trifluoromethyl) phenylamino) -2-methyl-l-oxopropan-2-ylamino) -2 -fluoro-N-methylbenzamide.

In one embodiment of this aspect of the invention, in the compound of formula 5 one of R1 and R2? hydrogen and the other? benzyl.

In another embodiment of this aspect of the invention, in the compound of formula 5 R1 and R2 are both hydrogen or ethyl.

In yet another embodiment of this aspect of the invention, in the compound of formula 5 R1 and R2 together with the nitrogen atom to which only bonded constitute a piperidine ring.

The compounds of formula 5 can be prepared by known methods starting from known products, for example by subjecting the 2- (3-fluoro-4-methylcarbamoyl-phenylamino) -2-methyl-propionic acid 6 to an amidation reaction with an amine R1R2NH of formula 7, wherein R1 and R2 are as defined in the compounds of formula 5 (Scheme 4).

Scheme 4

Acid 6 can for example be prepared, in analogy to general methods described in the literature, starting from aniline 8 (Scheme 5) by alkylation with bromoisobutyric acid or with an ester thereof and subsequent hydrolysis, [see e.g. WO02081453, WO 2011128251, J. Med. Chem. 54, 6254 (2011)] or using 8 as the nucleophilic partner in the Bargellini reaction [see e.g. ARKIVOC 2012 Part (ii) 24-40; Tetrahedron Letters 50, 2497 (2009)] in which chloroethone (1,1,1-trichloro-2-methyl-2-propanol) can? be used as it is or obtained in situ from acetone and chloroform.

OR

Scheme 5

Alternatively, acid 6 can be obtain from bromine derivative 9 (Scheme 5) by nucleophilic substitution with 2-methyl alanine [see e.g. WO2006028226, Tetrahedron Letters 50, 5159 (2009); Bioorganic & Medicinal Chemistry 14, 6789 (2006)].

Isothiocyanate 3? a known product, which is easily obtained by reaction from amine 9, used for the preparation of other active ingredients such as bicalutamide, by reaction with thiocarbonyl dichloride (Scheme 6) [for examples of preparation see e.g. WO 2006133567; Chemical & Pharmaceutical Bulletin 56, 1555 (2008)].

Scheme 6

The invention is now illustrated by the following examples.

EXAMPLES

Example 1

Synthesis of 4- (1-benzylcarbamoyl-1-methyl-ethylamino) -2-fluoro-N-methylbenzamide

A mixture of 2- (3-fluoro-4-methylcarbamoyl-phenylamino) -2-methyl-propionic acid (10g), EDC.HCl (17g) and HOBt (6g) in DMF (100ml)? treated at 25 ° C with benzylamine (13 ml) for 1 hour under stirring. The resulting solution is slowly poured into water (250 ml) with the formation of a precipitate. The suspension is stirred at 25 ° C for 1 hour and filtered on buchner, washing with water. The product is dried under vacuum at 55 ° C for 18 hours. 12 g of benzyl amide are obtained.

Example 2

Synthesis of enzalutamide from 4- (1-benzylcarbamoyl-1-methyl-ethylamino) -2fluoro-N-methyl-benzamide

A mixture of 4- (1-benzylcarbamoyl-1-methyl-ethylamino) -2-fluoro-N-methyl-benzamide (5 g) and 4-isothiocyanate-2-trifluoromethyl-benzonitrile (10 g) in DMSO (4 ml) and isopropyl acetate (8 ml)? heated at 86? 90? C for 24 hours. It is cooled to room temperature and isopropyl acetate, isopropyl alcohol (IPA) and water are added. Is the insoluble removed by filtration, the organic phase and the aqueous phase separated? re-extracted with isopropyl acetate. The combined organic phases are concentrated under vacuum, and the residue is crystallized from IPA. It is filtered on buchner and dried under vacuum for 20 hours at 55 ° C. 3 g of Enzalutamide are obtained.

Example 3

Synthesis of 4- (1,1-dimethyl-2-oxo-2-piperidin-1-yl-ethylamino) -2-fluoro-N-methyl-benzamide

To a mixture of 2- (3-fluoro-4-methylcarbamoyl-phenylamino) -2-methyl-propionic acid (10 g), EDC.HCl (17 g) and HOBt (6 g) in DMF (100 ml) is added morpholine (10 ml) and stirred for 1 hour at 25 ° C. The resulting solution is partitioned between water and dichloromethane. The organic phase is separated and the aqueous phase is re-extracted with dichloromethane. The combined organic phases are washed in sequence with dilute hydrochloric acid and with water. Is it concentrated under vacuum and the residue? treated with n-heptane obtaining a solid which is isolated by filtration. The product is dried under vacuum at 55 ° C for 18 hours. Approx. 10 g of morpholinamide.

Example 4

Synthesis of enzalutamide from 4- (1,1-dimethyl-2-oxo-2-piperidin-1-ylethylamino) -2-fluoro-N-methyl-benzamide

A mixture of 4- (1,1-dimethyl-2-oxo-2-piperidin-1-yl-ethylamino) -2-fluoro-N-methyl-benzamide

(6 g) and 4-isothiocyanate-2-trifluoromethyl-benzonitrile (8 g) in DMSO (5 ml) and isopropyl acetate (10 ml)? heated at 86? 90? C for 24 hours. The reaction mixture is cooled to 25 ° C and isopropyl acetate, water and IPA are added. ? a precipitate is present which is filtered off. The phases are separated and the aqueous phase is re-extracted with isopropyl acetate. The combined organic phases are concentrated under vacuum to an oily residue which is purified by chromatography on silica gel eluting with n-heptane / ethyl acetate mixtures. From the eluate, after concentration under vacuum, filtration and drying, approx. 2 g of Enzalutamide.

Example 5

Synthesis of 4- (1-diethylcarbamoyl-1-methyl-ethylamino) -2-fluoro-N-methylbenzamide

Operating as described in Example 3 and using N, N-diethylamine (12 ml) instead of morpholine, approx. 8 g N, N-diethylamide.

Example 6

Synthesis of enzalutamide from 4- (1-diethylcarbamoyl-1-methyl-ethylamino) -2-fluoro-N-methyl-benzamide

The synthesis? carried out in analogy to what described in example 4 and using 4- (1-diethylcarbamoyl-1-methyl-ethylamino) -2-fluoro-N-methylbenzamide instead of 4- (1,1-dimethyl-2-oxo-2- piperidin-1-yl-ethylamino) -2-fluoro-N-methyl-benzamide.

Claims (9)

CLAIMS 1. Process for the preparation of 4- {3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-1-oxo-2-thioxoimidazolidin-1-yl} -2-fluoro-N- methylbenzamide (Enzalutamide) comprising the reaction of isothiocyanate of formula 3 3 with a compound of formula 5 5 wherein R1 and R2 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, aryl C1-C3 alkyl and aryl; or R1 and R2 together with the nitrogen atom to which they are bound form a 5- or 6-membered nitrogen heterocyclic ring, optionally containing a second heteroatom selected from oxygen, sulfur and nitrogen; wherein said C1-C4 alkyl, aryl C1-C3 alkyl, aryl and said nitrogenous heterocyclic ring are optionally replaced by one, two or three groups independently selected from the group comprising halogen, cyano, nitro, C1-C3-alkyl, trifluoromethyl, methoxy , methylthio, methanesulfonyl, vinyl, phenyl, pnitrophenyl, p-chlorophenyl and p-methoxyphenyl. 2. The process of claim 1 wherein R1 and R2 are independently selected from the group consisting of hydrogen, methyl, ethyl, benzyl, phenyl and naphthyl, or R1 and R2 together with the nitrogen atom to which they are bonded constitute a selected heterocyclic ring between pyrrolidine, piperidine, morpholine and 4-methylpiperazine. 3. The process of claims 1 and 2 wherein R1 and R2 are both hydrogen or ethyl, or one of R1 and R2? hydrogen and the other? benzyl, or R1 and R2 together with the nitrogen atom to which only bonded constitute a piperidine ring. 4. The process according to any one of the preceding claims wherein the reaction between 3 and 5? conducted in an organic solvent or in a mixture of solvents, selected from esters, amides, carboxylic acids, aromatic hydrocarbons, ureas or sulfur solvents, preferably in an organic solvent selected from the group consisting of propyl acetate, isopropyl acetate, butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl pyrrolidone, acetic acid, propionic acid, toluene, xylene, 1,3-dimethyl-2-imidazolidinone, N, N? -Dimethyl-propylene urea, dimethylsulfoxide and sulfolane, or their blends. The process according to any one of the preceding claims, wherein the reaction between 3 and 5? conducted at a temperature of between 50 ° C and 150 ° C, preferably between 70 ° C and 120 ° C and for a reaction time of between 5 hours and 50 hours, preferably between 10 and 30 hours. The process according to any one of the preceding claims, wherein the molar ratio between 5 and 3? between 1: 1 and 1: 4, preferably between 1: 1.5 and 1: 2.5. The process according to any one of the preceding claims, wherein the ratio between the sum of the weights of 5 and 3 and the volume of the solvent or mixture of solvents? between 1: 1 and 1: 4. 8. A compound of formula 5 as defined in claim 1, with the exclusion of the compound 4- (1- (4-cyano-3- (trifluoromethyl) phenylamino) -2-methyl-1-oxopropan-2-ylamino) - 2-fluoro-N-methylbenzamide. 9. A compound according to claim 8 wherein R1 and R2 are both hydrogen or ethyl, or one of R1 and R2? hydrogen and the other? benzyl, or R1 and R2 together with the nitrogen atom to which only bonded constitute a piperidine ring.