Method for producing non-steroidal antiandrogen

Abstract

Improved processes for the preparation of nonsteroidal antiandrogens, such as 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-[imidazolidinyl]-2-fluoro-N-methyl-benzamide, and intermediates therefor are disclosed.

Description

[Technical field]

[0001] The present invention relates to the preparation of non-steroidal antiandrogens such as 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-[imidazolidinyl]-2-fluoro-N-methyl-benzamide and intermediates thereof. Background of the Invention

[0002] 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (enzalutamide, commercially available under the trade name Xtandi™) is a nonsteroidal antiandrogen (NSAA) drug indicated for use in the treatment of metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer. It is taken by oral administration. [ka]

[0003] Enzalutamide was first reported in 2006 and introduced for the treatment of prostate cancer in 2012. It was the first second-generation NSAA to enter the market. The drug is widely available worldwide.

[0004] Enzalutamide was approved by the U.S. Food and Drug Administration (FDA) on August 31, 2012, subsequently by the European Medicines Agency (EMA) on June 21, 2013, and by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on March 24, 2014.

[0005] The original synthetic route to enzalutamide was disclosed in WO 2006 / 124118. Due to the poor selectivity of the final coupling step, this synthetic approach was considered unsuitable for industrial production purposes. [ka]

[0006] Numerous synthetic strategies have been proposed over the years to prepare enzalutamide, most of which require a convergent approach. Particularly relevant is the one described in WO 2011 / 106570, in which the thiohydantoin ring can be prepared through the coupling of two key fragments, hereafter referred to as fragment A and fragment B.

[0007] [ka]

[0008] It was experimentally found that this procedure suffers from the important drawback of using a large excess of fragment B with respect to fragment A in order to obtain the product in an acceptable industrial yield, which affects the cost of the entire process and the purity of the final product.

[0009] WO2015 / 121768 discloses a method comprising a coupling reaction between fragment B and fragment A', where fragment X is selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyl. Example 3 of WO2015 / 121768 reports only the coupling of isothiocyanate with fragment A', where X is an ethyl group. The reaction in the above example is carried out using 2 equivalents of fragment B relative to fragment A', with an overall yield of 60.7%.

[0010] [ka]

[0011] WO2015 / 154730 discloses a process in which coupling takes place between a fragment A acid and a fragment B acid, as shown below:

[0012] [ka]

[0013] The above reaction is carried out in the presence of a large excess of phenol (up to 6 equivalents with respect to fragment A acid) to minimize the formation of an impurity designated as "oxo-enzalutamide" having the structure reported below and resulting from oxidation of enzalutamide.

[0014] [ka]

[0015] A significant drawback of this method is related to the use of large amounts of phenol, which is highly corrosive, irritating and toxic to humans, making the method fraught with safety issues and unsuitable for large-scale production.

[0016] Accordingly, one object of the present invention is to provide a synthetic approach for producing enzalutamide and related structures that is cost-effective, has improved safety, is feasible on a large scale, and minimizes or avoids the formation of impurities from side reactions. Summary of the Invention

[0017] These objects, together with others that will become apparent hereinafter, are achieved by the invention, which, according to one aspect, provides a compound having the structure of formula (I): [ka] (In the formula, -R 1 and R 2 are, independently of each other, H, C 6 ~C 10 -Alkyl or C 6 ~C 10 -aryl, optionally substituted with one or more halide, cyano, hydroxy or amino groups; -One or more R' 1 ~R' 5and R.” 1 ~R” 5 are independent of each other, R 1 , Cyano, Halide, -COOR 1 , -CONR 1 R 2 , -OCOR 1 , -OCNR 1 R 2 R 1 and R 2 is as defined above) A method for producing A process comprising the step of coupling a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I): [ka] (wherein R''' represents a halide and -NO 2 and R is phenyl having one or more substituents independently selected from Regarding.

[0018] R' as defined above 1 ~R' 5 and R.” 1 ~R” 5 is expressly applicable to formulae (I), (II) and (III), or derivatives thereof.

[0019] According to another aspect, the present invention relates to a compound of general formula (IIa): [ka] (wherein R''' represents a halide and -NO 2 is phenyl having one or more substituents independently selected from:

[0020] Preferably, R''' is 4-nitrophenyl, referred to herein as compound (IIb), and 4-chlorophenyl, referred to herein as compound (IIe): [ka]

[0021] According to another aspect, the present invention relates to a process for the preparation of a compound of general formula (IIa) as defined above, comprising a step of esterification of an acid of formula (IV) with a phenol derivative of formula R'''OH, where R''' is as defined above, preferably R''' is 4-nitrophenyl. [ka]

[0022] According to one aspect, the present invention relates to the use of a compound of general formula (IIa) or a compound of formula (IIb) or a compound of formula (IIc) for the preparation of enzalutamide.

[0023] All terms used in this application are to be understood in their ordinary sense as known in the art, unless otherwise specified.

[0024] The term "about" includes the range of experimental error that can normally be encountered in performing a measurement, for example, ±5%, or ±2%, or ±1%.

[0025] The term "mass" defines the combination of substrates, reagents, solvents, and products upon which a physical or chemical transformation is carried out.

[0026] Unless otherwise stated, in the context of the present invention, the percentages and amounts of a particular component in a composition are intended to refer to the weight of said component relative to the total weight of the composition.

[0027] Unless otherwise indicated, in the context of the present invention, a composition that "comprises" one or more other components / elements means that the indicated components / elements must be present and that other components may, but need not, be present in the composition in addition to those specifically listed. In other words, a representation that a composition "comprises" one or more components does not exclude that the composition consists or consists essentially of the listed components. Similarly, a representation that a method "comprises" one or more steps does not exclude that the method includes steps, such as synthesis steps or purification steps, in addition to the step or steps explicitly listed.

[0028] As used herein, a statement that a compound or composition A is "completely free" (or "consists of") other substances, or the term "nd", means that there are no detectable substances in A other than those specifically stated, within the detection range of the instrument or method used.

[0029] Unless otherwise indicated, in the context of the present invention, a range of values ​​given for a particular parameter, e.g., the weight of a component in a mixture, includes the upper and lower limits of the range. For example, if the weight or volume content of a component in a mixture is given as "X to V," the content of A can be X, Y, or any intermediate value.

[0030] According to one aspect, the present invention provides a compound having the structure of formula (I): [ka] (In the formula, -R 1 and R 2 are, independently of each other, H, C 6 ~C 10 - may be alkyl or aryl, optionally substituted with one or more halide, cyano, hydroxy or amino groups; -One or more R' 1 ~R' 5 and R.” 1 ~R” 5are independent of each other, R 1 , Cyano, Halide, -COOR 1 , -CONR 1 R 2 , -OCOR 1 , -OCNR 1 R 2 R 1 and R 2 is as defined above) A method for producing coupling a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I): [ka] (wherein R''' represents a halide and -NO 2 is phenyl having one or more substituents independently selected from: Regarding.

[0031] Preferably, in the method according to the invention, R″ 1 ~R” 5 At least one of the groups is a halide or -CONHR 1 where the halide is a fluorine group and R 1 is as defined above.

[0032] Preferably, in the method according to the invention, R' 1 ~R' 5 At least one of is a trifluoromethyl or cyano group.

[0033] The above method is suitable for use in the preparation of 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (enzalutamide) and several analogues thereof.

[0034] Analyzing the approaches known in the art, in particular those of WO 2011 / 106570 and WO 2015 / 121768, it can be seen that for the coupling of fragment A or A' with B, at least two equivalents of the latter (i.e. the one bearing the isothiocyanate moiety) are used to obtain the final product in good and acceptable yields necessary to develop the process on an industrial scale. Without being bound by theory, this is probably due to the tendency of the methanol produced in the course of the reaction to react with fragment B itself. This results in the formation of the corresponding methyl thiocarbamate, an impurity that must be removed from the reaction product, and ultimately the removal of fragment B from the reaction mixture. Furthermore, it was found that the presence of a large amount of fragment B in solution leads to an increase in impurities related to side reactions of the above fragments. The impurities called thiourea, urea and trimer guanidine reported below are generated by side reactions of fragment B. In particular, thiourea is generated from the coupling of fragment B with the corresponding aniline resulting from hydrolysis of the isothiocyanate moiety, urea is generated by oxidation of the thiourea impurity, and trimeric guanidine is a by-product resulting from the self-condensation of fragment B.

[0035] [ka]

[0036] Furthermore, fragment B is the reagent that has the greatest impact on the overall process cost, even when used to prepare thiophosgene (a highly toxic compound that requires special equipment for its manufacture and handling) or its derivatives. And the feasibility of the procedures of WO 2011 / 106570 and WO 2015 / 121768 has proven to be far from ideal.

[0037] Following the approach of WO 2015 / 154730, a strategy involving coupling of fragment B with fragment A acids was first investigated. This approach proved to have little selectivity on both the small and multigram scales, in that it led to significant formation of at least two impurities related to the fragment A acid, which were extremely difficult to remove by crystallization.

[0038] The above impurities were termed the "ring-open impurity" (having an HPLC area of ​​15-20% relative to enzalutamide), which has the structure shown in the diagram below, and "oxo-enzalutamide" (having an HPLC area of ​​2-3% relative to enzalutamide).

[0039] [ka]

[0040] Therefore, a multi-step purification process was developed to reduce their content below acceptable limits, resulting in an overall yield of less than 60% for fragment A-acid (see Production and purification of enzalutamide).

[0041] It was found that oxo-enzalutamide could hardly be removed by crystallization. Moreover, attempts to prevent its formation by modifying any reaction parameters failed. Its removal could be successfully achieved by crystallization from a methanol / water mixture (Cryst.Growth.Des 2018, 18(7), 3774-3780). However, it was found that while the amount of this impurity, about 2%, could be effectively removed in one crystallization procedure, the same crystallization conditions were not as effective when the starting amount was higher, which resulted in the need for multiple crystallizations, which could lead to lower yields and less efficient overall process.

[0042] Furthermore, it was found that the use of fragment A-acids significantly reduces the consumption of the most expensive reagent, fragment B, compared to the amounts required in WO2011 / 106570 and WO2015 / 121768, and the presence of the impurity oxo-enzalutamide is reduced by adding large amounts of phenol (up to 6 equivalents with respect to fragment A-acid).

[0043] Next, the possibility of replacing fragment A with an aromatic ester, defined as compound (II), in the coupling reaction was explored to understand whether it was possible to reduce the equivalent amount of fragment B bearing an isothiocyanate moiety and whether the presence of free phenol formed after the cyclization reaction in stoichiometric amounts rather than in large amounts as taught in WO 2015 / 154730 could prevent the formation of oxoenzalutamide impurity. Thus, several aromatic esters were prepared using a series of phenols and aromatic compounds bearing an OH group, optionally substituted with electron-withdrawing or electron-donating groups, and tested in the coupling reaction with fragment B.

[0044] Advantageously, in the process according to the invention, R''' is selected from the group consisting of halides and -NO 2 and R is 1 or 2.

[0045] Preferably, in the process according to the invention, compound (II) has the following general formula (IIa): [ka] (wherein R''' represents a halide and -NO 2 and R is phenyl having one or more substituents independently selected from has.

[0046] The 4-nitrophenol and 4-chlorophenol esters of fragment A are particularly preferred in view of the fact that said esters are obtained in good yields in a crystalline, easily purifiable form, leading to high purity and conversion of the desired cyclization product (compound I).

[0047] Preferably, the present invention relates to a compound (II) having the following formula (IIb): [ka] The present invention relates to the above method, which has the following structure:

[0048] More preferably, the present invention relates to a compound (III) having the following formula (IIIa): [ka] The present invention relates to the above method, which has the following structure:

[0049] Advantageously, the present invention relates to the above process, wherein in the coupling step, the compound of formula (IIb) is coupled with the compound of formula (IIIa) to obtain 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide, optionally purified by crystallization.

[0050] The advantages of the synthesis according to the invention were clearly demonstrated by a series of experiments carried out according to the teachings of WO 2011 / 106570, which were chosen instead of those described in WO 2015 / 121768, since said process leads to a higher yield of enzalutamide, even though similar starting materials are involved in both processes.

[0051] Specifically, two sets of experiments, one relating to the synthesis of the present invention and one following the approach of WO 2011 / 106570, i.e. coupling using methyl ester fragment A, were carried out according to the general coupling procedure disclosed in Example 5 of WO 2011 / 106570, and the amount of fragment B (herein referred to as compound (IIIa)) relative to fragment A was varied with the aim to find the minimum amount of compound (IIIa) required to completely convert fragment A to the final product. The purity profiles and yields, calculated by titration in the reaction mixture, obtained with both synthetic approaches were evaluated.

[0052] With respect to the procedure of WO2011 / 106570 (coupling using fragment A as a methyl ester), complete conversion of fragment A was only achieved using 2.5 equivalents of compound (IIIa), with a yield of about 95%.

[0053] When −2 equivalents of compound (IIIa) (i.e. the amount reported in Example 5 of WO2011 / 106570) are used, the titration yield is about 91%, as reported in Comparative Example 6 of the experimental part. - If the amount of compound (IIIa) is small, the reaction does not proceed to complete conversion of fragment A. The methyl-thiocarbamate impurity is formed from the beginning of the reaction, which may explain the large consumption of compound (IIIa).

[0054] The addition of a large excess of compound (IIIa) that would allow complete conversion of fragment A to the final product would cause the formation of large amounts of impurities associated with the decomposition of compound (IIIa). The approach according to the invention was carried out according to the general procedure of Example 5 of WO 2011 / 106570, using the 4-nitrophenol ester compound (IIb) shown below as a non-limiting example. [ka]

[0055] The following was observed: Complete conversion of compound (IIb) is achieved when 1 to about 1.4 equivalents, preferably 1.2 to 1.3 equivalents, of compound (IIIa) are used relative to compound (IIb), with a corresponding yield of 90 to about 95%. Comparative Example 7 in the experimental part reports the impurity profile and titration yields obtained using 1.2 and 1.4 equivalents of compound (IIIa). With a slightly higher amount of compound (IIIa), the reaction reaches the end point sooner, but shows an increase in impurities related to compound (IIIa).

[0056] Thus, the synthetic route according to the present invention makes it possible to produce enzalutamide using approximately half the amount of compound (IIIa) with a yield comparable to the method disclosed in WO2011 / 106570, thereby reducing the amount of by-products and improving the cost-effectiveness of the process, as demonstrated by a comparison of the high performance liquid chromatography (HPLC) data described in Comparative Examples 6 and 7.

[0057] Furthermore, by analyzing the amount of oxo-enzalutamide in the final enzalutamide samples obtained in both experiments, it is evident that the use of compound IIb as a reactant reduces the levels of the above impurities.

[0058] Preferably, the process of the present invention comprises the step of converting the corresponding carboxylic acid to a carboxylic acid of formula R'''OH, where R''' is a halide or -NO, optionally in the presence of one or more condensing agents. 2 The method further comprises the step of preparing the compound of formula (II) by esterifying the compound with a phenol derivative of

[0059] In known methods for producing phenolic esters, the methods involving the use of coupling agents have been found to ensure optimal selectivity and improve the purity of the reaction mixture. Among the common coupling agents (such as carbonyldiimidazole), the best results have been obtained with N,N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC). Due to some problems associated with the workup (DCC forms an insoluble and difficult to remove urea), EDAC is preferred as the coupling agent used, since the corresponding urea exhibits high solubility in water (thus allowing easy removal by aqueous workup).

[0060] The coupling of compounds of formula (IV) with phenol derivatives of formula R'''OH in the presence of EDAC also proceeds in the absence of a catalyst, but catalytic amounts of a strong organic base, e.g., 4-dimethylaminopyridine (DMAP), leads to a significant increase in the reaction rate and at the same time limits the formation of the corresponding N-acylurea (a known by-product of this type of reaction) and increases the yield. [ka]

[0061] According to another aspect, the present invention relates to a compound of general formula (IIa): (wherein R''' represents a halide and -NO 2 and wherein the phenyl has one or more substituents independently selected from The present invention relates to a compound of the formula:

[0062] [ka]

[0063] More preferably, R''' is 4-nitrophenyl, 4-chlorophenyl, pentafluorophenyl, 2,4-dichlorophenyl or 2,4-difluorophenyl. Even more preferably, R''' is 4-nitrophenyl or 4-chlorophenyl. Advantageously, in the compound of general formula (IIa), the R''' group is 4-nitrophenyl.

[0064] According to yet another aspect, the present invention relates to a process for the preparation of a compound of general formula (IIa) as defined above, comprising a step of esterifying an acid of formula (IV) with a phenol derivative of formula R'''OH, where R' is as defined above and is preferably 4-nitrophenyl.

[0065] [ka]

[0066] In a further aspect, the present invention relates to the use of a compound of general formula (IIa) or a compound of formula (IIb) or a compound of formula (IIc) for the preparation of enzalutamide. EXAMPLES

[0067] The following examples are provided to illustrate certain embodiments of the present invention and are not intended to limit its scope.

[0068] Example 1: Preparation of methyl 4-nitrophenyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-propanoate, compound of formula (IIb)

[0069] A 2 L jacketed glass reactor equipped with a mechanical stirrer, thermometer, reflux condenser, and maintained under a nitrogen atmosphere is charged with EDAC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 90 g), DMAP (N,N-dimethylaminopyridine, 3.4 g), and acetone (300 ml). The suspension is cooled to approximately -10°C with stirring.

[0070] A separate 500 ml jacketed glass reactor equipped with a mechanical stirrer, thermometer, reflux condenser and kept under a nitrogen atmosphere is charged with 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (100 g), 4-nitrophenol (60 g) and acetone (200 ml). The suspension is cooled to about 0° C. with stirring and slowly transferred in portions to the reactor containing the suspension of EDAC, DMAP and acetone over a period of about 15 minutes.

[0071] The reaction mixture is kept stirred at -10 / -5°C until the reaction is complete. Once the reaction is complete (HPLC), water (900 ml) is added dropwise over 30 minutes to the stirred mixture kept at 0-5° C., while maintaining the internal temperature below 15° C. After approximately 50% of the water has been added, a white solid begins to precipitate.

[0072] The resulting suspension is stirred at 0-5 °C for at least 2 h, filtered, and the reactor and cake are washed with water.

[0073] The wet crude product (IIb) (about 210 g) is used as is in the next purification step.

[0074] Based on losses on drying, the corresponding dry product amounts to about 135 g (91% of the theoretical yield).

[0075] A 2 liter jacketed glass reactor equipped with a mechanical stirrer, thermometer, reflux condenser and kept under nitrogen atmosphere is charged with 210 g of wet crude (IIb) (total amount from previous step), acetone (600 ml) and water (100 ml).

[0076] Heat the suspension to 50-55 °C with stirring until almost all solids are dissolved and a slight turbidity is present. Filter the solution through a pad of Celite and charcoal and combine with the previous filtrate.

[0077] The clean solution of (IIb) is placed in the same reactor and water (800 ml) is added dropwise over 30 minutes while maintaining the internal temperature at 50-55°C.

[0078] After approximately 50% of the addition, precipitation of a white solid occurs. The suspension is cooled to 0-5°C over about 2 hours, left under stirring under these conditions for at least 2 hours and filtered. The reactor and cake are washed with water.

[0079] The wet product (about 150 g) is dried under vacuum at 40-45° C. until the residual water (by KF analysis) is less than 0.2%. 125 g (IIb, 85% yield) is obtained.

[0080] Example 2: Preparation of 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (Enzalutamide) A 2 liter jacketed glass reactor equipped with a mechanical stirrer, thermometer, condenser and maintained under a nitrogen atmosphere is charged with the compound of formula (IIIa) (4-isothiocyanato-2-(trifluoromethyl)benzonitrile, 106 g, obtainable by the method disclosed in WO 2011 / 106570), the compound of formula (IIb) (125 g), isopropyl acetate (250 ml) and DMSO (125 ml).

[0081] The suspension is heated to 73-75 °C with stirring and maintained at these conditions for at least 24 h before sampling for analysis. A solution is obtained.

[0082] Once the reaction is complete (e.g., by HPLC analysis), the reaction solution is cooled to approximately 45-50°C, methanol (25 ml) is added, and the mixture is maintained under these conditions for 1 hour. Add isopropyl acetate (520 ml) and water (250 ml), maintaining the internal temperature at 40-45°C.

[0083] Continue stirring the mixture at 40-45°C for at least 15 minutes, stop stirring and allow the layers to separate. Discard the aqueous layer and wash the organic layer with water (250ml) at 40-45°C.

[0084] The washed organic solution is concentrated in vacuo until a thick suspension is obtained. Methanol (250 ml) is added to the residue and the mixture is distilled under the same conditions until a thick residue is obtained.

[0085] Methanol (850 ml) is added to the residue and the mixture is heated to reflux with stirring until a solution is obtained and water (170 ml) is added slowly whilst maintaining the internal temperature above 55°C.

[0086] The mixture is cooled to 40-45°C and stirred under these conditions until sufficient crystallization has occurred (approximately 30 min), then stirred at 0-5°C and filtered.

[0087] The solid thus obtained can be further crystallized from isopropanol and water to obtain 115 g of dry Enzalutamide as white crystals of crystalline form R1 (75% molar yield from the compound of formula (IIb)). Purity by HPLC analysis: 99.8.

[0088] Example 3: Preparation of 4-chlorophenyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methyl propanoate, a compound of formula (IIc)

[0089] A 5 liter jacketed glass reactor equipped with a mechanical stirrer, thermometer, reflux condenser and maintained under a nitrogen atmosphere is charged with EDAC (211 g), DMAP (12.5 g) and acetone (1200 ml). The suspension is cooled to about -5°C with stirring.

[0090] A separate 1 L jacketed glass reactor equipped with a mechanical stirrer, thermometer, reflux condenser, and kept under a nitrogen atmosphere is charged with 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (200 g), 4-chlorophenol (111.2 g) and acetone (750 ml). The suspension is cooled to about 0° C. with stirring and slowly dosed in portions into the reactor containing the suspension of EDAC, DMAP, and acetone over a period of about 15 minutes.

[0091] The reaction mixture is kept stirred at -10 / -5°C until the reaction is complete.

[0092] Once the reaction is complete (HPLC), water (2000 ml) is added dropwise over 30 minutes to the mixture, kept under stirring at 0-5° C., while maintaining the internal temperature below 15° C. After approximately 50% of the water has been added, a white solid begins to precipitate.

[0093] The resulting suspension is stirred at 0-5 °C for at least 2 h, filtered, and the reactor and cake are washed with water.

[0094] The wet crude product (approximately 400 g) is used as is in the next purification step.

[0095] A 5 liter jacketed glass reactor equipped with a mechanical stirrer, thermometer, reflux condenser and kept under nitrogen atmosphere is charged with 400 g of wet crude (from the previous step), acetone (600 ml) and water (100 ml).

[0096] Heat the suspension to 50-55 °C with stirring until almost all solids are dissolved and a slight turbidity is present. Filter the solution through a pad of Celite and charcoal and combine with the previous filtrate.

[0097] The thus obtained cleaned solution is placed in the same reactor and water (1200 ml) is added dropwise over 30 minutes while maintaining the internal temperature at 50-55°C.

[0098] After about 50% of the addition, precipitation of a white solid occurs. The suspension is cooled to 0-5°C over about 2 hours, kept under stirring at these conditions for at least 2 hours, and filtered. The reactor and cake are washed with water.

[0099] The wet product (about 280 g) is dried under vacuum at 40-45° C. 237 g of tile product is obtained (yield 83%).

[0100] Example 4: Preparation of 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (Enzalutamide) A 5 liter jacketed glass reactor equipped with a mechanical stirrer, thermometer, condenser and kept under a nitrogen atmosphere is charged with the compound of formula (IIIa) (4-isothiocyanato-2-(trifluoromethyl)benzonitrile, 163 g, available by the method disclosed in WO 2011 / 106570), 4-chlorophenyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoate (200 g), isopropyl acetate (400 ml) and DMSO (200 ml).

[0101] The suspension is heated to 60-70 °C with stirring and maintained at these conditions for at least 20 h before sampling for analysis. A solution is obtained.

[0102] Once the reaction is complete (e.g., by HPLC analysis), cool the reaction solution to approximately 45-50°C, add methanol (30 ml), and maintain the mixture under these conditions for 1 h. Add isopropyl acetate (1000 ml) and 5% aqueous sodium carbonate (600 ml), while maintaining the internal temperature at 40-45°C.

[0103] Stir the mixture at 20-25°C for at least 15 minutes, stop stirring and allow the layers to separate. Discard the aqueous layer and concentrate the washed organic solution under vacuum until a thick suspension is obtained. Add methanol (400 ml) to the residue and distill the mixture under the same conditions until a thick residue is obtained.

[0104] Methanol (1400 ml) was added to the residue and the mixture was heated to reflux with stirring until a solution was obtained, seeds of crystalline enzalutamide (crystal form R2) were added at 38-40°C and stirring was continued under these conditions until sufficient crystallization occurred (approximately 30 min), then stirred at 0-5°C and filtered.

[0105] The solid thus obtained can be further crystallized from isopropanol and water to obtain 201 g of dry Enzalutamide as white crystals of crystalline form R1 (79% molar yield from 4-chlorophenyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoate). 99.9% purity by HPLC analysis.

[0106] Example 5 : The following intermediates of general formula (IIa) were prepared starting from the corresponding acid (compound IV) according to the procedures reported in Examples 1 and 3 and used for the preparation of enzalutamide. The overall yield of the preparation of enzalutamide (starting from 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid) is shown in the following table.

[0107] [ka]

[0108] [Table 1-1]

[0109] Example 6: (Comparative Example) Preparation of 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (Enzalutamide) according to the procedure reported in Example 5 of WO2011 / 10657 The reaction was carried out using 2 g (7.45 mmol) of Fragment A methyl ester obtained by the method disclosed in WO 2011 / 106570 in a jacketed glass reactor equipped with a mechanical stirrer, a thermometer, a condenser, and maintained under a nitrogen atmosphere.

[0110] The amount of compound (IIIa) (fragment B) charged was 2.0 equivalents relative to fragment A. After the reagents and solvent (isopropyl acetate (IPAc) and dimethyl sulfoxide (DMSO) were charged in amounts of 2 volumes and 1 volume relative to fragment A, respectively), the mixture was heated at 83-84 °C with stirring for 30 h. The reaction rate was followed by sampling the mixture at 10, 24, and 30 h and analyzing each sample by HPLC method to determine the yield in solution calculated by titrating the reaction mixture with an external standard of enzalutamide, as reported in Table 1.

[0111] All samples were also analyzed to determine the impurity profile using HPLC, specifically calculating the sum of the area percent of the peaks related to the total isothiocyanate degradation products, i.e., methyl thiocarbamate, thiourea, urea, and trimeric guanidine, and the trend across all experiments.

[0112] Impurity measurements are reported in Table 1 as area percent of the HPLC analysis of each sample. The titration yields are comparable to those reported in WO2011 / 10657.

[0113] [Table 1-2]

[0114] Example 7: (Comparative Example) Preparation of 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (enzalutamide) starting from compound (IIa) and following the procedure reported in Example 5 of WO 2011 / 10657 The reactions were carried out in a jacketed glass reactor equipped with mechanical stirrer, thermometer, condenser and kept under nitrogen atmosphere, and 2 g of compound IIb was used in each test.

[0115] The amount of compound (IIIa) (fragment B) used in each test was 1.2 equivalents and 1.4 equivalents relative to fragment A. After charging the reagents and solvent (isopropyl acetate (IPAc) and dimethyl sulfoxide (DMSO) at 1 volume and 2 volumes for fragment A”, respectively), the mixture was heated at 83–84 °C with stirring for 30 h. The reaction rate was followed by sampling the mixture at 10, 24, and 30 h time points and analyzing each sample by HPLC method. Table 2 below summarizes the calculated yield in solution for each sample taken, as well as the impurities measured from the HPLC chromatograms as area percent.

[0116] [Table 2]

[0117] A titration yield comparable to that obtained in Comparative Example 6 was achieved using a smaller amount of compound (IIIa): 1.2 equivalents (instead of 2.0 equivalents).

[0118] Additionally, small amounts of oxo-enzalutamide and impurities related to the decomposition of compound (IIIa) were observed when compared to the values ​​reported in Table 1.

[0119] HPLC analytical methods for in-process control and determining intermediate purity

[0120] Equipment: Agilent 1200LC chromatograph equipped with G1314B VWD detector Software:Chemstation Rev.C.01.07 Column: ACE Excel 5 supeRC18250*4.6mm, 5pm or equivalent Guard column: ACE 5 C18 Column temperature: 35℃ Mobile phase A: 0.5 ml of trifluoroacetic acid (TFA) transferred to 1000 ml with water (0.05% TFA). Mobile phase B: Acetonitrile Elution mode: Gradient [Table 3]

[0121] Sample tray temperature: 25°C Sample concentration: 0.4mg / mL Injection volume: 5μL UV detection: 220 nm Analysis time: 15 minutes Total Run Time: 50 minutes Under these conditions, the retention time (RT) of solution-prepared darolutamide is typically 30.5 minutes.

[0122] The RRt value is calculated using the following formula with ENZA-00 as the standard:

number

[0123] where Rt is the retention time of a particular component, Rt Ref is the retention time of the reference.

[0124] [Table 4-1] JPEG2024523421000030.jpg157170

Claims

1. A compound having the structure of formula (I): 【Chemistry 1】 (In the formula, -R １ and R ２ are, independently of each other, H, C １ ~C ８ -Alkyl or C ６ ~C １０ - may be aryl or may be H, C 1 -C 8 alkyl or C 6 -C 10 aryl substituted with one or more halide, cyano, hydroxy or amino groups; - one or more R' １ ~R' ５ and R. １ ~R” ５ are each independently R １ , cyano, halide, -COOR １ , -CONR １ R ２ , -OCOR １ , and -OCNR １ R ２ R １ and R ２ has the meaning defined above) A method for producing coupling a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I): 【Chemistry 2】 (wherein R''' represents a halide and -NO ２ and R is 1 to 4; and R is 1 to 4.

2. R １ and / or R ２ 2. The method of claim 1, wherein at least one of is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, iodine, trifluoromethyl and trichloromethyl.

3. R” １ ~R” ５ At least one of the groups is a fluorine group or -CONHR １ group, R １ The method of claim 1, wherein:

4. R” １ ~R” ５ The method of claim 1 , wherein at least one of is a trifluoromethyl group or a cyano group.

5. 2. The method of claim 1, wherein the compound of formula (I) is enzalutamide.

6. The method of claim 1, wherein compound (II) has the following formula (IIa): 【Chemistry 3】 where R''' is phenyl having one or more substituents independently selected from halide and -NO2.

7. The coupling step comprises obtaining a compound: Compound (II) has the following formula (IIb): 【Chemistry 4】 Compound (III) has the following formula (IIIa): 【Chemistry 5】 The method of claim 1 , wherein the method is carried out using at least one of the following:

8. The method of claim 1, wherein the compound of formula (I) is 4-[3-[4-cyano-3-trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide, and the method comprises coupling a compound of formula (IIb) with a compound of formula (IIIa). 【Chemistry 6】 9. The method of claim 8, wherein the 4-[3-[4-cyano-3-trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide is purified by crystallization.

10. 2. The process of claim 1, further comprising the step of preparing a compound of formula (II) by esterifying the corresponding carboxylic acid with a phenol derivative of formula R′″OH, where R′″ is phenyl having one or more substituents independently selected from halide and —NO2.

11. Compounds of general formula (IIa): 【Chemistry 7】 (wherein R''' represents a halide and -NO ２ and R is 1 to 4; and R is 1 to 4.

12. The compound of claim 11, wherein R''' is selected from 4-nitrophenyl, pentafluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl and 2,4-difluorophenyl.

13. When R''' is 4-nitrophenyl, the compound of formula (IIa) has the following formula (IIb): 【Chemistry 8】 12. The compound of claim 11 having the formula:

14. Formula (IV): 【Chemistry 9】 of the formula R'''OH, where R''' is a halide or -NO ２ 12. A method for preparing a compound of formula (IIa) according to claim 11, comprising the step of esterifying with a phenol derivative of

15. The process for preparing a compound of formula (IIa) according to claim 14, wherein R''' is selected from 4-nitrophenyl, 4-chlorophenyl, pentafluorophenyl, 2,4-dichlorophenyl and 2,4-difluorophenyl.

16. 13. Use of a compound of formula (IIa) for the preparation of enzalutamide. 【Chemistry 10】

17. 13. Use of a compound of formula (Ib) for the preparation of enzalutamide. 【Chemistry 11】

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