Method for manufacturing nonsteroidal antiandrogens

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 production of non-steroidal anti-androgen drugs such as 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-[imidazolidinyl]-2-fluoro-N-methyl-benzamide and their intermediates. 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, marketed under the trade name Xtandi(™)) is a non-steroidal anti-androgen (NSAA) drug indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer. It is administered orally.

Chemical formula

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

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

[0005] The first synthetic route of enzalutamide is disclosed in International Publication No. 2006 / 124118. This synthetic approach was considered unsuitable for industrial production purposes due to the poor selectivity of the final coupling step.

Chemical formula

[0006] Numerous synthetic strategies have been proposed over the years for the production of enzalutamide, most of which require a convergent approach. Of particular relevance is the one described in International Publication 2011 / 106570, in which the thiohydantoin ring can be produced through the coupling of two key fragments, hereafter referred to as fragment A and fragment B.

[0007] [ka]

[0008] Experiments have shown that this procedure has a significant drawback: it uses a large excess of fragment B relative to fragment A to obtain the product in an acceptable industrial yield, which affects the overall process cost and the purity of the final product.

[0009] WO2015 / 121768 discloses a method comprising a coupling reaction between fragment B and fragment A', wherein 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 an isothiocyanate with fragment A', where X is an ethyl group. The reaction in the above example was carried out using 2 equivalents of fragment B relative to fragment A', with a total yield of 60.7%.

[0010] [ka]

[0011] WO2015 / 154730 discloses a process in which coupling occurs between acid fragment A and fragment B, 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 the fragment A acid) in order to minimize the formation of impurities shown as "oxo-enzalutamide" which has the structure reported below and is formed by the oxidation of enzalutamide.

[0014] [Chemical formula]

[0015] A major drawback of this method is related to the use of a large amount of phenol which is corrosive, highly irritating and toxic to the human body. Therefore, this method has safety issues and is not suitable for large-scale production.

[0016] Therefore, 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 other objects that will become apparent hereinafter, are achieved by the invention, and according to one aspect, the present invention provides a compound having the structure of formula (I): [Chemical formula] [[ID=##ID=36]] (wherein, - R1 and R2 are independently of each other H, C 1 ~C 8 - alkyl or C6 - C 10 - aryl, optionally substituted with one or more halide, cyano, hydroxy or amino groups; - One or more of R’1 to R’5 and R”1 to R”5 are, independently of each other, selected from the group consisting of R1, cyano, halide, -COOR1, -CONR1R2, -OCOR1, -OCNR1R2, where R1 and R2 are as defined above) A method for producing The method includes a step of coupling a compound of formula (II) and a compound of formula (III) to obtain a compound of formula (I):

Chemical formula

[0018] The meanings of R’1 to R’5 and R”1 to R”5 defined above are clearly applicable to formula (I), (II) and (III), or their derivatives.

[0019] According to another aspect, the present invention relates to a general formula (IIa):

Chemical formula

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

Chemical formula

[0021] According to another aspect, the present invention relates to a method for producing a compound of the above general formula (IIa), which includes a step of esterifying an acid of formula (IV) with a phenol derivative of formula R’’’OH (where R’’’ is as defined above, and preferably R’’’ is 4-nitrophenyl). [ka]

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

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

[0024] The term "approximately" includes a range of experimental error that may normally occur when performing a measurement, such as ±5%, ±2%, or ±1%.

[0025] The term "mass" defines the combination of substrate, reagent, solvent, and product on which a physical or chemical transformation is performed.

[0026] Unless otherwise specified, in the context of this invention, the percentage and amount of a particular component in a composition refer to the weight of that component relative to the total weight of the composition.

[0027] Unless otherwise specified, in the context of this invention, a composition “containing” one or more other components / elements means that the indicated components / elements must be present, and that other components may be present in the composition in addition to those specifically listed, but are not necessarily required. In other words, the statement that a composition “contains” one or more components does not preclude the composition from consisting of, or essentially consisting of, the listed components. Similarly, the statement that a method “contains” one or more steps does not preclude the method from including steps such as synthesis or purification steps in addition to the one or more steps explicitly described.

[0028] As used herein, the expression "completely free" (or "consists of") of compound or composition A, or the term "nd," means that, within the detection range of the instrument or method used, no substances other than those specifically indicated can be detected in A.

[0029] Unless otherwise specified, in the context of this invention, a range of values ​​given for a particular parameter, such as the weight of a component in a mixture, includes an upper and lower limit to the range. For example, if the weight or volume content of a component in a mixture is given as "X~V", the content of A will be X, Y, or an intermediate value.

[0030] According to one embodiment, the present invention relates to a compound having the structure of formula (I): [ka] (In the formula, -R1 and R2 are independent of each other, H, C 1 -C It may be 8-alkyl or aryl, and may be substituted with one or more halides, cyano, hydroxy, or amino groups; -One or more R'1~R'5 and R''1~R''5 are independently selected from the group consisting of R1, cyano, halide, -COOR1, -CONR1R2, -OCOR1, and -OCNR1R2, where R1 and R2 are as defined above.) A method for manufacturing, The process includes the step of coupling the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (I): [ka] (wherein R''' is a phenyl having one or more substituents independently selected from halides and -NO2). Regarding.

[0031] Preferably, in the method according to the present invention, at least one of R"1 to R"5 is a halide or -CONHR1, the halide is a fluorine group, and R1 is as defined above.

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

[0033] The above method is suitable for use in the production 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.

[0034] An analysis of approaches known in the art, particularly those described in International Publications 2011 / 106570 and 2015 / 121768, suggests that coupling fragment A or A' with B can be performed using at least two equivalents of the latter (i.e., the one with the isothiocyanate moiety) to obtain the final product in good and acceptable yields necessary for developing the process on an industrial scale. While not bound by theory, this is likely due to the tendency of methanol produced during the reaction to react with fragment B itself. This forms the corresponding methyl thiocarbamate, an impurity that must be removed from the reaction product, ultimately leading to the removal of fragment B from the reaction mixture. Furthermore, it has been found that the presence of large amounts of fragment B in solution leads to an increase in impurities associated with the side reactions of the aforementioned fragment. The impurities referred to below as thiourea, urea, and trimer guanidine are produced by the side reactions of fragment B. In particular, thiourea is produced by the coupling of fragment B with the corresponding aniline obtained from the hydrolysis of the isothiocyanate moiety, urea is produced by the oxidation of thiourea impurities, and trimer guanidine is a byproduct obtained 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, and its use in the production of thiophosgene (a highly toxic compound requiring special equipment for production and handling) or its derivatives also incurs overall costs. And the feasibility of the procedures in International Publications 2011 / 106570 and 2015 / 121768 has proven to be far from ideal.

[0037] Following the approach outlined in International Publication No. 2015 / 154730, strategies involving the coupling of fragment B with fragment A acid were initially studied. This approach proved to be of little selectivity, both on a small scale and multigram scale, as it led to the formation of a significant amount of at least two impurities associated with Fragment A acid, which were very difficult to remove by crystallization.

[0038] The above impurities were called "ring-opening impurities" (containing 15-20% of the HPLC area relative to enzalutamide) and "oxo-enzalutamide" (containing 2-3% of the HPLC area relative to enzalutamide), which have the structures shown in the following figure.

[0039] [ka]

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

[0041] Oxo-enzalutamide was found to be largely unremovable by crystallization. Furthermore, attempts to inhibit its formation by altering arbitrary reaction parameters failed. Its removal was successfully achieved by crystallization from a methanol / water mixture (Cryst.Growth.Des 2018, 18(7), 3774-3780). However, while approximately 2% of this impurity can be effectively removed in a single crystallization step, the same crystallization conditions are less effective for larger starting amounts, resulting in the need for multiple crystallization steps, which can lead to lower yields and reduced overall process efficiency.

[0042] Furthermore, it was found that using Fragment A-acid significantly reduced the consumption of the most expensive reagent, Fragment B, compared to the amount required in WO2011 / 106570 and WO2015 / 121768, and that adding a large amount of phenol (up to 6 equivalents with respect to Fragment A-acid) reduced the amount of impurity oxo-enzalutamide.

[0043] Next, we investigated the possibility of replacing fragment A with an aromatic ester defined as compound (II) in the coupling reaction to determine whether it was possible to reduce the equivalent amount of fragment B, which has an isothiocyanate moiety, and whether the presence of free phenol, which is produced after the cyclization reaction in a stoichiometric rather than a large amount as taught in WO 2015 / 154730, could prevent the formation of oxoenzalutamide impurities. Thus, we prepared several aromatic esters using a series of phenols and aromatic compounds having OH groups, optionally substituted with electron-withdrawing or electron-donating groups, and tested them in coupling reactions with fragment B.

[0044] Advantageously, in the method according to the present invention, R''' is a phenyl having one or more substituents independently selected from halides and -NO2.

[0045] Preferably, in the method according to the present invention, compound (II) is the following general formula (IIa): [ka] (wherein R''' is a phenyl compound having one or more substituents independently selected from halides and -NO2.) It has.

[0046] The 4-nitrophenol and 4-chlorophenol esters of fragment A are particularly preferred, considering that the esters can be obtained in good yield in a crystalline, easily purifiable form, which leads to obtaining the desired cyclization product (compound I) with high purity and conversion rate.

[0047] Preferably, considering the fact that the corresponding nitrophenol is widely available commercially and has little toxicity to handle for carrying out processes on an industrial scale, the present invention provides compound (II) as follows: [ka] The above method having

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

[0049] Advantageously, the present invention relates to the above method, wherein in a coupling step, a compound of formula (IIb) is coupled with a 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-methylbenzamide, which may be purified by crystallization.

[0050] The advantages of the synthesis according to the present invention were clearly demonstrated by a series of experiments conducted in accordance with the teachings in International Publication No. 2011 / 106570. These teachings were chosen over those described in International Publication No. 2015 / 121768 because, although similar starting materials are involved in both processes, the process leads to obtaining enzalutamide in higher yield.

[0051] Specifically, two sets of experiments were conducted: one relating to the synthesis of the present invention, and the other following the approach of International Publication No. 2011 / 106570, namely, a coupling using methyl ester fragment A, carried out according to the general coupling procedure disclosed in Example 5 of International Publication No. 2011 / 106570. The amount of fragment B (referred to herein as compound (IIIa)) relative to fragment A was varied with the aim of finding the minimum amount of compound (IIIa) required to completely convert fragment A to the final product. The purity profiles and yields obtained in both synthetic approaches were evaluated by titration in the reaction mixture.

[0052] Regarding the procedure of WO2011 / 106570 (coupling using fragment A as a methyl ester), complete conversion of fragment A is achieved only when 2.5 equivalents of compound (IIIa) are used, with a yield of approximately 95%.

[0053] Using -2 equivalents of compound (IIIa) (i.e., the amount reported in Example 5 of WO2011 / 106570), the titration yield is approximately 91%, as reported in Comparative Example 6 of the experimental section. - If the amount of compound (IIIa) is small, the reaction will not proceed to the complete conversion of fragment A. - Methyl thiocarbamate impurities are formed from the start of the reaction. Their formation may explain the large consumption of compound (IIIa).

[0054] The addition of a large excess of compound (IIIa), which allows for the complete conversion of fragment A to the final product, leads to the formation of a large amount of impurities associated with the decomposition of compound (IIIa). The approach according to the present invention was carried out according to the general procedure of Example 5 of International Publication No. 2011 / 106570, using the following 4-nitrophenol ester compound (IIb) as a non-limiting example. [ka]

[0055] The following was observed: -Complete conversion of compound (IIb) is achieved when using 1 to about 1.4 equivalents, preferably 1.2 to 1.3 equivalents, of compound (IIIa) relative to compound (IIb), with a corresponding yield of 90 to about 95%. In Comparative Example 7 of the experimental section, we report the impurity profiles and titration yields obtained using 1.2 and 1.4 equivalents of compound (IIIa). -A slightly higher amount of compound (IIIa) leads to a faster endpoint, but also indicates an increase in impurities associated with compound (IIIa).

[0056] Therefore, the synthetic route according to the present invention enables the production of enzalutamide using about half the amount of compound (IIIa) in a yield comparable to the method disclosed in WO2011 / 106570, and as a result, the amount of byproducts can be reduced and the cost-effectiveness of the process can be improved, as demonstrated by the comparison of 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 clear that using compound IIb as a reactant reduces the level of the aforementioned impurities.

[0058] Preferably, the method of the present invention further includes the step of producing a compound of formula (II) by esterifying the corresponding carboxylic acid with a phenol derivative of formula R'''OH (wherein R''' is a phenyl having one or more substituents independently selected from a halide and -NO2) in the presence of one or more condensing agents.

[0059] In known methods for producing phenol esters, the use of coupling agents has been shown to ensure optimal selectivity and improve the purity of the reaction mixture. Among common coupling agents (such as carbonyldiimidazole), the best results were obtained using N,N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC). Due to several problems associated with post-treatment (DCC forms an insoluble and difficult-to-remove urea), EDAC is preferred as the coupling agent because the corresponding urea exhibits high solubility in water (and therefore can be easily removed by water post-treatment).

[0060] The coupling of the compound of formula (IV) with the phenol derivative of formula R'''OH in the presence of EDAC proceeds even in the absence of the catalyst, but catalytic amounts of strong organic bases, such as 4-dimethylaminopyridine (DMAP), result in a significant increase in the reaction rate, while simultaneously limiting the formation of the corresponding N-acylurea (a known byproduct of this type of reaction) and increasing the yield. [ka]

[0061] In another aspect, the present invention relates to general formula (IIa): (In the formula, R''' is a phenyl having one or more substituents independently selected from halides and -NO2.) Regarding the compounds.

[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] In yet another aspect, the present invention relates to a method for producing the compound of general formula (IIa) described above, comprising the step of esterifying an acid of formula (IV) with a phenol derivative of formula R'''OH (wherein R' is as defined above, preferably 4-nitrophenyl).

[0065] [ka]

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

[0067] The following embodiments are provided to illustrate specific 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-liter jacketed glass reactor, equipped with a mechanical stirrer, thermometer, and reflux condenser, and kept under a nitrogen atmosphere, is filled 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 while stirring.

[0070] In a separate 500 ml jacketed glass reactor equipped with a mechanical stirrer, thermometer, and reflux condenser, and kept under a nitrogen atmosphere, fill with 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (100 g), 4-nitrophenol (60 g), and acetone (200 ml). Cool the suspension to approximately 0°C while stirring, and slowly transfer it little by little over approximately 15 minutes to the reactor containing the suspension of EDAC, DMAP, and acetone.

[0071] Continue stirring the reaction mixture at -10 / -5°C until the reaction is complete. Once the reaction is complete (HPLC), add 900 ml of water dropwise to the mixture, which has been maintained at 0-5°C with stirring, over a period of 30 minutes or more, while maintaining the internal temperature below 15°C. After adding approximately 50% water, a white solid will begin to precipitate.

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

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

[0074] Based on losses due to drying, the corresponding dried product is approximately 135g (91% of the theoretical yield).

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

[0076] Heat the suspension to 50-55°C while stirring until almost all the solids have dissolved and a slight turbidity remains. Filter the solution through a Celite and charcoal pad and mix it with the previous filtrate.

[0077] Add the clean solution (IIb) to the same reactor and, while maintaining the internal temperature at 50-55°C, add water (800 ml) dropwise over a period of 30 minutes or more.

[0078] Approximately 50% of the added substance precipitates as a white solid. Cool the suspension to 0-5°C over approximately 2 hours, stir under these conditions for at least 2 hours, and then filter. Wash the reactor and cake with water.

[0079] The moist product (approximately 150 g) is dried under vacuum at 40-45°C until the residual water content (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, and condenser and kept under a nitrogen atmosphere, is packed with the compound of formula (IIIa) (106 g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, available by the method disclosed in WO2011 / 106570), the compound of formula (IIb) (125 g), isopropyl acetate (250 ml), and DMSO (125 ml).

[0081] Heat the suspension to 73-75°C while stirring, and maintain these conditions for at least 24 hours before sampling for analysis. A solution will be obtained.

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

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

[0084] The washed organic solution is concentrated under vacuum until a concentrated suspension is obtained. Add methanol (250 ml) to the residue and distill the mixture under the same conditions until a concentrated residue is obtained.

[0085] Add methanol (850 ml) to the residue, and heat the mixture under reflux while stirring until a solution is obtained, slowly adding water (170 ml) while maintaining the internal temperature above 55°C.

[0086] Cool the mixture to 40-45°C and continue stirring under these conditions until sufficient crystallization occurs (approximately 30 minutes). Then, stir at 0-5°C and filter.

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

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

[0089] A 5-liter jacketed glass reactor, equipped with a mechanical stirrer, thermometer, and reflux condenser, and kept under a nitrogen atmosphere, is filled with EDAC (211 g), DMAP (12.5 g), and acetone (1200 ml). Cool the suspension to approximately -5°C while stirring.

[0090] In a separate 1 L jacketed glass reactor equipped with a mechanical stirrer, thermometer, and reflux condenser, and kept under a nitrogen atmosphere, fill with 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (200 g), 4-chlorophenol (111.2 g), and acetone (750 ml). Cool the suspension to approximately 0°C while stirring, and slowly add it to the reactor containing the suspension of EDAC, DMAP, and acetone over approximately 15 minutes.

[0091] Continue stirring the reaction mixture at -10 / -5°C until the reaction is complete.

[0092] Once the reaction is complete (HPLC), add 2000 ml of water dropwise to the mixture, which has been maintained at 0-5°C with stirring, over a period of 30 minutes or more, while maintaining the internal temperature below 15°C. After adding approximately 50% water, a white solid will begin to precipitate.

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

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

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

[0096] Heat the suspension to 50-55°C while stirring until almost all the solids have dissolved and a slight turbidity remains. Filter the solution through a Celite and charcoal pad and mix it with the previous filtrate.

[0097] The resulting clean solution is then placed in the same reactor, and water (1200 ml) is added dropwise over a period of 30 minutes or more while maintaining the internal temperature at 50-55°C.

[0098] Approximately 50% of the additive will precipitate as a white solid. Cool the suspension to 0-5°C over approximately 2 hours, continue stirring at this temperature for at least 2 hours, and then filter. Wash the reactor and cake with water.

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

[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, and condenser and kept under a nitrogen atmosphere, is packed with compound (IIIa) (4-isothiocyanato-2-(trifluoromethyl)benzonitrile, 163 g, available by the method disclosed in WO2011 / 106570), 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid 4-chlorophenyl (200 g), isopropyl acetate (400 ml), and DMSO (200 ml).

[0101] Heat the suspension to 60-70°C while stirring, and maintain these conditions for at least 20 hours before sampling for analysis. A solution will be obtained.

[0102] Once the reaction is complete (for example, 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 hour. While maintaining the internal temperature at 40-45°C, add isopropyl acetate (1000 ml) and 5% sodium carbonate aqueous solution (600 ml).

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

[0104] Methanol (1400 ml) was added to the residue, and the mixture was heated under reflux while stirring until a solution was obtained. Crystalline enzalutamide (crystal form R2) seed was added at 38-40°C, and stirring was continued under these conditions until sufficient crystallization occurred (approximately 30 minutes). Then, the mixture was 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 dried enzalutamide as white crystals of crystalline form R1 (molar yield of 79% from 4-chlorophenyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoate). Purity of 99.9% by HPLC analysis.

[0106] Example 5 : The intermediate of the following general formula (IIa) was prepared starting from the corresponding acid (compound IV) according to the procedure reported in Examples 1 and 3 and used in 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 table below.

[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 Using 2 g (7.45 mmol) of fragment A methyl ester obtained by the method disclosed in International Publication No. 2011 / 106570, the reaction was carried out in a jacketed glass reactor equipped with a mechanical stirrer, thermometer, and condenser, and maintained under a nitrogen atmosphere.

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

[0111] Furthermore, all samples were analyzed and impurity profiles were determined using HPLC. In particular, the total amount of isothiocyanate degradation products, i.e., the sum of the area percentages of peaks related to methyl thiocarbamate, thiourea, urea, and trimer guanidine, and the trends throughout all experiments were calculated.

[0112] The measurement of impurities is reported in Table 1 as the area percentage of the HPLC analysis for each sample. The titration yield is comparable to the yield 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 WO2011 / 10657 The reaction was carried out in a jacketed glass reactor equipped with a mechanical stirrer, thermometer, and condenser, and maintained under a nitrogen atmosphere, using 2 g of compound IIb in each test.

[0115] The amounts of compound (IIIa) (fragment B) used in each test were 1.2 equivalents and 1.4 equivalents relative to fragment A. The reagents and solvents (isopropyl acetate (IPAc) and dimethyl sulfoxide (DMSO) were added in 1 and 2 volumes relative to fragment A'', respectively) were added, and the mixture was heated at 83–84°C for 30 hours with stirring. The reaction rate was tracked by sampling the mixture at 10, 24, and 30 hours and analyzing each sample by HPLC. Table 2 below summarizes the yield in solution calculated for each collected sample, and the impurities measured from the HPLC chromatogram, expressed as area percentages.

[0116] [Table 2]

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

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

[0119] HPLC analysis method for in-process control and measurement of intermediate purity

[0120] Equipment: Agilent 1200LC chromatograph 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: Transfer 0.5 ml of trifluoroacetic acid (TFA) to 1000 ml of water (0.05% TFA). Mobile phase B: Acetonitrile Dissolution mode: Gradient [Table 3]

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

[0122] The value of RRt is calculated by applying the following formula, with ENZA-00 as the base.

number

[0123] Here, Rt is the retention time of a specific component, Rt Ref This is the retention time for the reference.

[0124] [Table 4-1] JPEG0007888628000030.jpg157170

Claims

1. Compounds 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 -aryl, or H, C １ ~C ８ alkyl or C ６ ~C １０ -aryl which may be substituted with one or more halide, cyano, hydroxy or amino groups; - One or more R' １ ~R' ５ and R” １ ~R" ５ R is independent of each other. １ cyano, halide, -COOR １ , -CONR １ R ２ Selected from the group consisting of , and -OCOR1, R １ and R ２ (This has the meaning defined above.) A method for manufacturing, A method comprising coupling a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I): 【Chemistry 2】 (In the formula, R''' represents a halide and -NO ２ (A phenyl having one or more substituents independently selected from the above.)

2. R １ and / or R ２ The method according to 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 them is a fluorine group or -CONHR １ It is a base, R １ The method according to claim 1, wherein the property is as defined in claim 1.

4. R" １ ~R" ５ The method according to claim 1, wherein at least one of the groups is a trifluoromethyl group or a cyano group.

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

6. The method according to claim 1, wherein compound (II) has the following formula (IIa): 【Transformation 3】 (In the formula, R''' represents a halide and -NO ２ (A phenyl having one or more substituents independently selected from the above.)

7. The coupling step involves the following compounds: - Compound (II) has the following formula (IIb): 【Chemistry 4】 - Compound (III) has the following formula (IIIa): 【Transformation 5】 The method according to claim 1, wherein the method is carried out using at least one of the following.

8. The method according to 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 the compound of formula (IIb) with the compound of formula (IIIa). 【Transformation 6】

9. The method according to claim 8, wherein the 4-[3-[4-cyano-3-trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methylbenzamide is purified by crystallization.

10. The corresponding carboxylic acid is given by formula R'''OH (wherein R''' is a halogen and -NO ２ The method according to claim 1, further comprising the step of producing a compound of formula (II) by esterification with a phenol derivative of (a phenyl having one or more substituents independently selected from)

11. Compounds of general formula (IIa): 【Transformation 7】 (In the formula, R''' represents a halide and -NO ２ (A phenyl having one or more substituents independently selected from the above.)

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

13. If R''' is 4-nitrophenyl, then the compound of formula (IIa) is the following formula (IIb): 【Transformation 8】 The compound according to claim 11, having the following characteristics.

14. Formula (IV): 【Chemistry 9】 The carboxylic acid is given by formula R'''OH (wherein R''' is a halogen and -NO ２ A method for producing the compound of formula (IIa) according to claim 11, comprising the step of esterifying with a phenol derivative of (a phenyl having one or more substituents independently selected from)

15. A method for producing the 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. Use of the compound of formula (IIa) for the preparation of enzalutamide. 【Chemistry 10】 (wherein R''' is a phenyl having one or more substituents independently selected from the halide and -NO2.)

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

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