Novel process and intermediates for preparation of apalutamide

Abstract

The present invention relates to a novel efficient and economical process for the large-scale production of apalutamide. The present invention also relates to a novel process for the formation of high purity apalutamide via the novel intermediates. The method avoids the use of expensive and dangerous reagents and solvents. In addition to ease of implementation, the process of the present invention yields high purity end products in high yields. Therefore, the method has high cost effectiveness and time efficiency.

Description

Technical Field

[0001] The present invention relates to a novel, efficient and economical method for large-scale industrial production of apalutamide and its pharmaceutically acceptable salts. The present invention also relates to a novel method for producing high-purity apalutamide by using a novel intermediate. Background Art

[0002] Apalutamide is an androgen receptor (AR) inhibitor that directly binds to the ligand binding domain of AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and blocks AR-mediated transcription.

[0003] A major metabolite, N-desmethyl apalutamide, is a less potent AR inhibitor, exhibiting one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Apalutamide administration results in decreased tumor cell proliferation and increased apoptosis, leading to reduced tumor volume in a mouse xenograft model of prostate cancer. As a result, apalutamide is approved for the treatment of patients with metastatic castration-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer.

[0004] The chemical name of apalutamide (CAS: 956104-40-8) is 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide. Its chemical formula is C 21 H 15 F4N5O2, molecular weight is 477.44 g / mol. The structure of apalutamide is as follows:

[0005]

[0006]

[0007] Apalutamide is a non-hygroscopic white to slightly yellow powder. Apalutamide has no chiral centers. Apalutamide melts at around 194-196°C. Apalutamide is virtually insoluble in aqueous media over a wide pH range and is virtually insoluble to very soluble in organic solvents. The dissociation constant pKa of apalutamide is 9.7 (acidic carboxamide moiety). Solubility experiments have shown that apalutamide is unstable to strong bases (pH>11). Apalutamide exhibits polymorphism.

[0008] Currently, apalutamide has been approved for marketing in the United States under the trade name ERLEADA on February 14, 2018, and has been approved for marketing in the European Union since January 14, 2019. Apalutamide is an oral, immediate-release rectangular green film-coated (FC) tablet containing 60 mg of apalutamide API. The inactive ingredients of this dosage form include colloidal anhydrous silicon dioxide, cross-linked sodium carboxymethyl cellulose, hydroxypropyl methylcellulose acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose.

[0009] WO2006 / 124118 discloses for the first time apalutamide lead compound and a preparation method thereof.

[0010] Indian patent application No. 1920 / DELNP / 2015 (related patents: EP2368550, US8445507, WO2007 / 126765) discloses a method for preparing apalutamide. This patent application discloses the following method for preparing apalutamide, as shown in Scheme-1.

[0011]

[0012] Scheme-1: Method disclosed in 1920 / DELNP / 2015

[0013] The method discloses the reaction of 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile with 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide in dimethylformamide to obtain apalutamide. The main disadvantage of this patent is that the use of dimethylformamide in the reaction makes the handling and post-processing difficult. Therefore, it is necessary to prepare apalutamide that is easy to handle.

[0014] WO2013 / 184681 discloses crystalline forms of apalutamide, namely, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I and crystalline form J of apalutamide and methods for preparing the same. However, the prior art does not report stability studies showing that the polymorphs have poor stability during long-term storage.

[0015] WO2016 / 124149 discloses apalutamide crystalline form I and crystalline form II and a method for preparing the same. The apalutamide obtained by the patent method is agglomerated into solids, with uneven particles and poor fluidity. Therefore, a robust method is needed to produce apalutamide and its polymorphs in a stable and pure form.

[0016] WO2018 / 136001 filed by ScinoPharm Co., Ltd. of Taiwan, China, discloses a method for preparing apalutamide using condensation of the following intermediates shown in Scheme-2. This patent application has been abandoned, thus indicating that the development of the apalutamide process is inefficient.

[0017]

[0018] Scheme-2: Method disclosed in WO2018 / 136001

[0019] US10807965 filed by Cadila Healthcare Limited replaces the methyl group in the carbamoyl intermediate with hydrogen. This intermediate is condensed with an isothiocyanate intermediate to produce apalutamide. The main disadvantage of this patent is that the condensation process must be carried out in the presence of phenol or alcohol, otherwise the expected results cannot be achieved. Scheme-3 describes the preparation method of apalutamide described in this patent.

[0020]

[0021] Scheme-3: Method disclosed in US10807965

[0022] WO2019 / 229625 filed by Olon SPA discloses a similar method in which an intermediate having a carboxyl activating group is condensed with an isothiocyanate intermediate. The patent limits the carboxyl activating group by three groups, including -OMe, -SiOMe3, -OC6H5. Scheme-4 describes one aspect of the patent from three carboxyl activating groups. The main disadvantage of the patent is that it discloses very low yields, ranging from 70-80%, which is considered very low on an industrial scale and therefore not industrially practical.

[0023]

[0024] Scheme-4: Method disclosed in WO2019 / 229625

[0025] Indian Patent Application No. 202021006111 filed by Aarti Industries Limited discloses a method for preparing apalutamide using a novel intermediate. However, a limitation of this Indian patent application is that due to the high steric hindrance of the novel intermediate, the strongest base such as tertiary amine is used in the condensation process. The main disadvantage of this patent application is that the method may not work without the use of expensive strong bases. Therefore, there is still an unmet need for a new method for preparing apalutamide, which is both environmentally friendly and economical and can produce high-purity compounds in high yields. Scheme-5 describes the method disclosed in Aarti Industries' patent application.

[0026]

[0027] Scheme-5: Method disclosed in IN202021006111

[0028] Therefore, as previously mentioned, although various prior arts described above have described methods for preparing apalutamide, there is an increasing need for new and improved methods for manufacturing apalutamide in high yield, with high purity and cost-effectiveness with low time consumption.

[0029] The inventors of the present invention surprisingly developed a new method for manufacturing apalutamide using a novel intermediate, which does not use expensive and dangerous reagents. The method uses very few very cheap solvents and reagents, making the method highly cost-effective and environmentally friendly. In addition to being easy to implement, the method of the present invention also provides a high-purity final product in high yield.

[0030] The novel process according to the invention therefore offers the above-mentioned significant advantages compared to the processes already described in the prior art, which makes the process very suitable for large-scale industrial production. Summary of the invention

[0031] The main object of the present invention is to provide a method for preparing apalutamide to improve any disadvantages of the prior art methods.

[0032] Another object of the present invention is to provide an efficient, improved and industrially advantageous process for preparing apalutamide, which can be conveniently applied on an industrial scale.

[0033] Another object of the present invention is to provide a method for preparing apalutamide with high purity and high yield.

[0034] Another object of the present invention is to provide a novel method for preparing apalutamide via a novel intermediate.

[0035] Yet another object of the present invention is to provide a cost-effective process for preparing apalutamide which avoids the use of expensive reagents.

[0036] Another object of the present invention is to provide an environmentally friendly process for preparing apalutamide, which uses extremely small amounts of solvents and reagents that are easily commercialized.

[0037] Yet another object of the present invention is to provide a process for preparing apalutamide, wherein each intermediate formed during the process is optionally isolated using various techniques known in the art.

[0038] The present invention discloses a novel, efficient and economical large-scale industrial production method of apalutamide. The method of the present invention is a cost-effective method for forming high-purity apalutamide in high yield through a novel intermediate.

[0039] One aspect of the present invention relates to the preparation of apalutamide, which comprises the following reaction:

[0040] a) In the presence of a suitable base, ethyl 2-fluoro-4-aminobenzoate (KSM-1) is condensed with bromocyclobutane-1-carboxylic acid (KSM-2) to form a novel intermediate 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1);

[0041] b) reacting 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1) with 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (KSM-3) in the presence of a suitable base to form 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid ethyl ester (Intermediate-2);

[0042] c) Ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octyl-5-yl)-2-fluorobenzoate (Intermediate-2) is dissolved in a suitable solvent in the presence of a suitable base to form apalutamide. DETAILED DESCRIPTION

[0043] Therefore, the present invention relates to a novel, economical and environmentally friendly method for preparing apalutamide, which is very suitable for large-scale industrial production of apalutamide.

[0044] The invention will now be disclosed by describing certain preferred and alternative embodiments to facilitate its various aspects.

[0045] References to "one," "an," or "multiple" embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate multiple embodiments. The following detailed description should therefore not be taken in a limiting sense, and the scope is limited only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

[0046] One embodiment of the present invention provides a method for preparing apalutamide, wherein apalutamide is formed in a highly pure form via a novel intermediate.

[0047] In one embodiment of the present invention, a novel intermediate 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid is reported for the first time, which is prepared by condensing ethyl 2-fluoro-4-aminobenzoate (KSM-1) with bromocyclobutane-1-carboxylic acid (KSM-2) in a suitable solvent and reagent.

[0048]

[0049] Intermediate-1

[0050] In another embodiment of the present invention, the novel intermediate 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid is then reacted with 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (KSM-3) in a suitable solvent and reagent to form 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid ethyl ester (Intermediate-2) by a novel method.

[0051]

[0052] Intermediate-2

[0053] In yet another embodiment of the present invention, apalutamide is formed by dissolving ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octyl-5-yl)-2-fluorobenzoate (Intermediate-2) in a suitable solvent and reagent.

[0054] In another embodiment of the present invention, the final product formed using the method of the present invention, using appropriate solvents and reagents, provides amorphous apalutamide or crystalline apalutamide; preferably crystalline apalutamide.

[0055] Suitable solvents may include one or more of chloroform, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), ethyl acetate, n-heptane, and combinations thereof.

[0056] Suitable reagents or bases may include one or more of methylamine, triethylamine, diisopropylethylamine, and combinations thereof.

[0057] The method of the present invention can be generally described in Scheme-6 below.

[0058]

[0059] In the method of the present invention, apalutamide is prepared by a novel method, which forms pure apalutamide in high yield. The process is time-saving and economical due to the use of cheap and easily available solvents and reagents.

[0060] According to one embodiment of the present invention, apalutamide can be purified at will to improve purity and / or remove impurities in the product. Any suitable purification method can be used, such as slurry washing, crystallization, alkaline acid treatment, etc.

[0061] Example :

[0062] Having described the present invention with reference to certain preferred embodiments, other aspects will become apparent to those skilled in the art by considering the specification. The present invention is further defined with reference to the following embodiments that describe the preparation of the compounds of this invention in detail. It will be apparent to those skilled in the art that many modifications may be made to materials and methods without departing from the scope of the present invention.

[0063] The following examples are provided for illustrative purposes only, and these examples in no way limit the present invention.

[0064] Embodiment 1:

[0065] Preparation of 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1)

[0066]

[0067] 100 grams of 2-fluoro-4-aminobenzoic acid ethyl ester (KSM-1) and 117.3 grams of 1-bromocyclobutane-1-formic acid (KSM-2) were condensed at 60-65°C for 24 hours in the presence of 1000 milliliters of chloroform and 132.25 milliliters of triethylamine. After the reaction was completed, 100 milliliters of concentrated HCl were added to the reaction mass, and chloroform was completely distilled out under vacuum. The slurry reaction mass was separated with 100 milliliters of toluene. 300 milliliters of toluene were added to the reaction mass, and heated to 65-70°C. The reaction mixture was kept at 65-70°C for 30 minutes. The reaction mass was cooled to 25-30°C and stirred at 25-30°C for 1 hour. The solid was filtered and washed with 100 milliliters of toluene to obtain a wet material. The wet material was placed in a vacuum tray dryer and dried at 50-55°C to obtain 120 g of a novel intermediate, ie, 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1) (purity 98.31%).

[0068] Embodiment 2:

[0069] 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- Preparation of Ethyl Fluorobenzoate (Intermediate-2)

[0070]

[0071] 100 g of 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (intermediate-1) and 97.76 g of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (KSM-3) were condensed at 60-65° C. in the presence of 1600 ml of chloroform and 39.57 g of triethylamine. After the reaction was completed, the reaction mass was cooled to 25-30° C. and filtered to remove salt. The filtrate was taken and the chloroform was completely distilled out under vacuum. The slurry was separated with 100 ml of isopropanol, and then 400 ml of isopropanol was added to the reaction mass. The reaction mass was heated to 50-55° C. and stirred at 50-55° C. for 30 minutes. The reaction mass was cooled to 25-30° C. and stirred at 25-30° C. for 2 hours. The solid was filtered and washed with 100 ml of isopropanol to obtain a wet material. The wet material was placed in a vacuum tray dryer and dried at 50-55°C to produce 110 g of novel ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Intermediate-2) (purity 97.2%).

[0072] Embodiment 3:

[0073] Preparation of Apalutamide

[0074]

[0075] 100 g of ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Intermediate-2) was stirred at 5-10°C for 1 hour in the presence of 200 ml of tetrahydrofuran and 800 ml of monomethylamine. After completion of the reaction, 500 ml of water was added to the reaction mass. The reaction mass was heated to 35°C and the solvent was distilled off below 35°C until a slurry mass was obtained. The reaction mass was cooled to 15-20°C and HCl solution was added to adjust the pH to 8.0-10.0. The reaction mass was stirred at 25-30°C for 1 hour. The solid was filtered and washed with 100 ml of isopropanol to obtain a wet mass. The wet mass was placed in a vacuum tray dryer and dried at 50-55°C to obtain 92.9 g of crude apalutamide (purity 90.72%).

[0076] Embodiment 4:

[0077] Preparation of Apalutamide

[0078]

[0079] 100 g of ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Intermediate-2) was stirred in 1500 ml of monomethylamine at 30-35°C for 1 hour. After completion of the reaction, 500 ml of water was added to the reaction mixture. The reaction mass was distilled off below 35°C to obtain a slurry. The reaction mass was cooled to 15-20°C and HCl solution was added to adjust the pH to 8.0-10.0. The reaction mass was stirred at 25-30°C for 1 hour. The solid was filtered and washed with 100 ml of isopropanol to obtain a wet material. The wet material was placed in a vacuum tray dryer and dried at 50-55°C to obtain 95 g of crude apalutamide (purity 95.53%).

[0080] Embodiment 5:

[0081] Purification of apalutamide

[0082]

[0083] 90 g of crude apalutamide was added to 270 ml of methanol and the reaction mass was heated at 60-65°C to obtain a clear reaction mass. 5% activated carbon treatment was performed at 60-65°C. The reaction mixture was cooled to 20-25°C and then stirred at 20-25°C for 2 hours. The solid was filtered and washed with 50 ml of pre-cooled methanol to obtain a wet mass. The wet mass was placed in a vacuum tray dryer at 50-55°C for drying to obtain 72.5 g of pure apalutamide (purity 99.65%)

[0084] Embodiment 6:

[0085] Preparation of Form B of Apalutamide:

[0086]

[0087] 50 g of apalutamide (obtained in Example 5) was added to 150 ml of ethyl acetate and the reaction mass was heated at 60-65°C to obtain a clear reaction mass. A 5% activated carbon treatment was performed at 60-65°C. The reaction mixture was cooled to 25-30°C and then 400 ml of n-heptane was added. The reaction mass was stirred at 25-30°C for 2 hours. The solid was filtered and washed with 50 ml of n-heptane to obtain a wet material. The wet material was placed in a vacuum tray dryer and dried at 50-55°C to obtain 45.3 g of pure apalutamide Form B (purity 99.78%). Figure 1 shows the powder X-ray diffraction pattern of Form B of apalutamide.

[0088] The invention described herein includes various objects as described above and descriptions thereof with respect to features and processes employed. Although these aspects are emphasized in the present invention, any variation of the above invention should not be considered as departing from the spirit and scope of the invention described.

Claims

1. A new method for preparing apalutamide, characterized in that: The following steps are involved: a) Ethyl 2-fluoro-4-aminobenzoate (KSM-1) reacts with 1-bromocyclobutane-1-carboxylic acid (KSM-2) in the presence of a suitable solvent and a base to obtain 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1); b) In the presence of a suitable solvent and a base, 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1) reacts with 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (KSM-3) to obtain 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid ethyl ester (Intermediate-2); c) 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid ethyl ester (Intermediate-2) reacts with monomethylamine to obtain apalutamide; 2. The method according to claim 1, characterized in that: The suitable solvent is selected from chloroform, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), ethyl acetate, n-heptane and mixtures thereof.

3. The method according to claim 1, characterized in that The suitable base is selected from methylamine, triethylamine, diisopropylethylamine and mixtures thereof.

4. A novel compound, characterized in that The compound is 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid, which has the following structural formula:

5. Use of the compound 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1) for preparing apalutamide.

6. A method for preparing the compound 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1), characterized in that: The method comprises reacting ethyl 2-fluoro-4-aminobenzoate (KSM-1) with 1-bromocyclobutane-1-carboxylic acid (KSM-2) in the presence of a suitable solvent and a base; 7. The method according to claim 6, characterized in that The suitable solvent is selected from chloroform, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), ethyl acetate, n-heptane and a mixture thereof.

8. The method according to claim 6, characterized in that The suitable base is selected from methylamine, triethylamine, diisopropylethylamine and mixtures thereof.

Images