A highly efficient method for the preparation of apalutamide

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a high-efficiency preparation method of apalutamide. The application uses 2-cyano-3-trifluoromethyl-5-isothiocyanatopyridine and 1-aminocyclobutane-1-carboxylate hydrochloride as starting materials to prepare a diazaspirocyclic intermediate 4-(8-oxo-6-thioxooxy-5,7-diazaspiro[3.4]oct-5-yl)-2-fluoro-N-methylbenzamide, and the intermediate is reacted with 4-bromo-2-fluoro-N-methylbenzamide under the action of alkali to obtain apalutamide. The method for preparing apalutamide provided by the application has mild reaction conditions, simple post-reaction treatment, easy operation, avoids the use of highly toxic reagents such as sodium cyanide, reduces waste discharge, is environmentally friendly, and is suitable for industrialized production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to an efficient method for preparing apalutamide. Background Technology

[0002] Apalutamide, developed by Johnson & Johnson, is an androgen receptor (AR) antagonist approved by the FDA in February 2018. Apalutamide selectively binds to AR, blocking the binding of AR to androgens and inhibiting AR nuclear translocation. It is an effective androgen receptor antagonist used to treat castration-resistant prostate cancer (CRPC) and early-stage disease, including localized prostate cancer (Pca) and metastatic hormone-sensitive prostate cancer. Apalutamide was the first drug approved by the FDA for the treatment of non-metastatic castration-resistant prostate cancer and has broad development prospects. Its structural formula is as follows:

[0003]

[0004] According to existing literature, the main difficulty in preparing apalutamide lies in the preparation of the diazaspirocyclic ring, which includes the following processes depending on the ring-locking method:

[0005] Potassium thiocyanate method: Chinese patent application CN108383749 uses intermediate compound 4 obtained by esterification as a starting material, reacts it with thiocyanate salt to cyclize it to obtain compound 5, and finally couples compound 5 with compound 6 to obtain apalutamide. The synthetic route is shown below:

[0006]

[0007] This route uses highly toxic potassium thiocyanate as a raw material for cyclization, posing significant safety hazards in industrial production.

[0008] Thioisocyanate method: US patent application US2015 / 0191449A and Chinese patent application CN104211683 describe the synthesis of apalutamide by reacting N-methyl-2-fluoro-4-aminobenzamide with sodium cyanide (or trimethylcyanosilane) and cyclobutanone via a Strecker reaction to obtain a cyclobutanenitrile intermediate. This intermediate is then condensed and cyclized with a thioisocyanate intermediate under microwave conditions, followed by hydrolysis under hydrochloric acid-methanol conditions. The synthetic route is shown below:

[0009]

[0010] Although this method has a short reaction route, it requires microwave conditions and sophisticated equipment. The preparation of cyanide requires the use of highly toxic sodium cyanide (or trimethylcyanosilane), which is extremely toxic when inhaled or through skin contact, posing safety hazards in industrial production.

[0011] Phenyl thiochloroformate method: Chinese patent application CN107108507 and patent WO2016100652: Using APAL-007 and 1-Boc-aminocyclobutane-1-carboxylic acid as raw materials, compound 24, after a multi-step reaction, reacts with phenyl thiochloroformate under DMAP catalysis to obtain apalutamide. The synthetic route is shown below:

[0012]

[0013] Diazaspirocyclic compounds can be obtained by ring closure of phenyl thiochloroformate as a raw material, but this method has a low yield and is not suitable for large-scale industrial production.

[0014] Amine-cyanide reaction: Patent WO2016100645: The cyclobutanenitrile intermediate obtained by the Strecker reaction of 3-fluoro-4-iodoaniline with cyclobutanone and cyanide is condensed and cyclized with 2-cyano-3-trifluoromethyl-5-aminopyridine under the action of a thiocarbonyl compound, followed by carbonyl insertion reaction catalyzed by the noble metal palladium to obtain a carboxylic acid ester intermediate, or reacting with dry ice after Grignard exchange to obtain a carboxylic acid (ester) intermediate, and finally amidation to obtain the final product apalutamide. The synthetic route is shown below. This route not only uses highly toxic sodium cyanide, but also uses the noble metal palladium catalysis, resulting in high cost for scale-up production.

[0015]

[0016] Thioreagent method: Using 3-fluoro-4-iodoaniline as a raw material, it is first reacted with sodium cyanide and cyclobutanone via the Strecker reaction to obtain intermediate 31. 31 then reacts with intermediate 6 and 1,1'-thiocarbonylbis-2(1H)-pyridone to obtain a diazaspirocyclic intermediate. This method requires nitrogen protection, is relatively complex to operate, and uses highly toxic sodium cyanide, posing safety hazards in industrial production.

[0017]

[0018] Therefore, in view of the shortcomings of the existing diazaspirocyclic ring-locking reaction, there is an urgent need for a simple, industrially suitable, high-yield, and low-cost method for the synthesis of apalutamide to meet market demand. Summary of the Invention

[0019] To address the above shortcomings, this invention aims to provide a synthetic route and method suitable for the industrial production of apalutamide. This route successfully avoids the use of highly toxic cyanides and heavy metal catalysts, reducing process costs. It is simple to operate, with mild reaction conditions, high safety, and low pollution, yielding high-yield products, making it more suitable for industrial scale-up.

[0020] This invention is specifically achieved through the following technical solution:

[0021]

[0022] Compound I, namely 2-cyano-3-trifluoromethyl-5-isothiocyanopyridine, reacts with 1-aminocyclobutane-1-carboxylic acid hydrochloride under alkaline conditions to yield 4-(8-oxo-6-thiooxy-5,7-diazaspiro[3.4]oct-5-yl)-2-fluoro-N-methylbenzamide, an important intermediate for apalutamide; this intermediate reacts with 4-bromo-2-fluoro-N-methylbenzamide under alkaline conditions to yield apalutamide.

[0023] Preferably, the above steps will be described in detail in the following sections:

[0024] Preparation of Compound III

[0025] Compound I and Compound II were added to organic solvent A at room temperature, and base A was added at low temperature. After the addition was complete, the temperature was raised to T1 and the mixture was stirred until the reaction was finished to obtain compound III.

[0026] Preferably, the organic solvent A is selected from one or a combination of toluene, 1,4-dioxane, ethyl acetate, isopropyl acetate, and acetonitrile.

[0027] Preferably, the base A is selected from triethylamine, N-methylmorpholine, and N,N-diisopropylethylamine.

[0028] Preferably, the molar ratio of compound I, compound II, and base A is 1:1.0 to 2.0:2.0 to 3.0, and particularly preferably 1:1.5:2.5.

[0029] Preferably, the reaction temperature is controlled at -5 to 5°C when alkali A is added.

[0030] Preferably, the reaction temperature T1 is 75-100℃, more preferably 95-100℃.

[0031] In a preferred embodiment, the reaction requires post-treatment, specifically as follows: cooling the reaction solution, adding ethyl acetate to dilute the reaction solution, washing successively with purified water, dilute hydrochloric acid, and alkali, drying and concentrating under reduced pressure to remove the organic solvent, and finally recrystallizing from ethyl acetate / petroleum ether to obtain the target product.

[0032] Preparation of apalutamide

[0033] Compounds III and IV were added to organic solvent B, and sodium hydride was added at low temperature. After the addition was complete, the mixture was brought to room temperature to react. The reaction was then post-treated to obtain apalutamide.

[0034] Preferably, the molar ratio of compound III, compound IV and sodium hydride is 1.0:1.0-2.0:1.2-2.0, and particularly preferably 1:1.2:1.5.

[0035] Preferably, the organic solvent B is selected from DMF, 1,4-dioxane, acetonitrile, and tetrahydrofuran.

[0036] Preferably, the temperature controlled during the addition of sodium hydride is -5 to 5°C.

[0037] In a preferred embodiment, the reaction requires post-treatment, specifically as follows: purified water is added to the reaction solution, filtered, and the filter cake is added to isopropanol, heated under reflux, then cooled to room temperature and stirred to precipitate a large amount of solid, which is then filtered, dried, and apalutamide is obtained.

[0038] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0039] 1. The method for preparing apalutamide provided by this invention has mild reaction conditions, simple post-reaction processing, and easy operation. It avoids the use of highly toxic reagents such as sodium cyanide, reduces waste emissions, is environmentally friendly, and is suitable for industrial production.

[0040] 2. This patent uses 2-cyano-3-trifluoromethyl-5-isothiocyanopyridine and 1-aminocyclobutane-1-carboxylic acid hydrochloride as starting materials to prepare the diazaspirocyclic intermediate 4-(8-oxo-6-thiooxy-5,7-diazaspiro[3.4]oct-5-yl)-2-fluoro-N-methylbenzamide. The starting materials are inexpensive and readily available, no expensive catalysts are required, conventional operation is sufficient, and the yield is high. Detailed Implementation

[0041] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0042] Confirmation of the structure of the compound obtained in this invention:

[0043] Structural characterization of compound III

[0044]

[0045] ESI-MS (m / z): 327.08 [M+H]+ ; 1 H NMR (400MHz, CDCl3) δ = 9.09 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 2.76 (m, 4H), 1.88 (m, 2H).

[0046] Structural characterization of compound V

[0047]

[0048] ESI-MS (m / z): 478.13 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 9.10 (d, J = 2.1Hz, 1H), 8.36 (d, J = 2.1Hz, 1H), 8.34 (m, 1H), 7.28 (m, 1H), 7.1 8(m,1H),6.75(m,1H),3.09(d,J=4.6Hz,3H),2.73(m,2H),2.57(m,2H),2.27(m,1H),1.71(m,1H).

[0049] Preparation of Compound III

[0050] Example 1

[0051] Compound I (22.9 g, 100 mmol) and Compound II (22.7 g, 150 mmol) were added to toluene (250 mL). Triethylamine (25.3 g, 250 mmol) was added at 0–5 °C. After the addition was complete, the temperature was raised to 95–100 °C and the reaction mixture was stirred for 0.5–1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). It was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The product was dried and concentrated under reduced pressure to remove the organic solvent. Finally, it was recrystallized from petroleum ether / ethyl acetate (200 mL, 1:1 v / v) to give an off-white solid product with a yield of 97.5% and an HPLC purity of 99.92%.

[0052] Example 2

[0053] Compound I (22.9 g, 100 mmol) and Compound II (11.6 g, 100 mmol) were added to 1,4-dioxane (250 mL), and N,N-diisopropylethylamine (32.3 g, 250 mmol) was added at 0–5 °C. After the addition was complete, the temperature was raised to 95–100 °C and the reaction mixture was stirred for 0.5–1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). It was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The mixture was dried and concentrated under reduced pressure to remove the organic solvent. Finally, it was recrystallized from petroleum ether / ethyl acetate (200 mL, 1:1 v / v) to give an off-white solid product with a yield of 94.6% and an HPLC purity of 99.61%.

[0054] Example 3

[0055] Compound I (22.9 g, 100 mmol) and Compound II (23.2 g, 200 mmol) were added to acetonitrile (250 mL). N-methylmorpholine (25.3 g, 250 mmol) was added at 0–5 °C. After the addition was complete, the temperature was raised to 81–82 °C and the reaction mixture was stirred for 0.5–1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). It was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The product was dried and concentrated under reduced pressure to remove the organic solvent. Finally, recrystallization from petroleum ether / ethyl acetate (200 mL, 1:1 v / v) yielded a white solid product with a yield of 95.1% and an HPLC purity of 99.54%.

[0056] Example 4

[0057] Compound I (22.9 g, 100 mmol) and Compound II (22.7 g, 100 mmol) were added to isopropyl acetate (250 mL), and triethylamine (20.3 g, 200 mmol) was added at -5 to 0 °C. After the addition was complete, the temperature was raised to 75 to 78 °C and the reaction was stirred for 0.5 to 1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). The solution was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The solution was dried and concentrated under reduced pressure to remove the organic solvent. Finally, the product was recrystallized from petroleum ether / ethyl acetate (200 mL, 1:1 volume ratio) to give an off-white solid product with a yield of 93.5% and an HPLC purity of 99.71%.

[0058] Example 5

[0059] Compound I (22.9 g, 100 mmol) and Compound II (22.7 g, 100 mmol) were added to 1,4-dioxane (250 mL), and triethylamine (30.4 g, 300 mmol) was added at 0–5 °C. After the addition was complete, the temperature was raised to 95–100 °C and the reaction mixture was stirred for 0.5–1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). It was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The product was dried and concentrated under reduced pressure to remove the organic solvent. Finally, it was recrystallized from petroleum ether / ethyl acetate (200 mL, 1:1 v / v) to give an off-white solid product with a yield of 94.9% and an HPLC purity of 99.55%.

[0060] Example 6

[0061] Compound I (22.9 g, 100 mmol) and Compound II (22.7 g, 100 mmol) were added to ethyl acetate (250 mL). Triethylamine (18.2 g, 180 mmol) was added at -10 to -5 °C. After the addition was complete, the temperature was raised to 70–75 °C and the reaction was stirred for 0.5–1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). It was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The product was dried and concentrated under reduced pressure to remove the organic solvent. Finally, it was recrystallized from petroleum ether / ethyl acetate (200 mL, 1:1 volume ratio) to give an off-white solid product with a yield of 88.6% and an HPLC purity of 98.65%.

[0062] Example 7

[0063] Compound I (22.9 g, 100 mmol) and Compound II (25.3 g, 220 mmol) were added to toluene (250 mL). N,N-diisopropylethylamine (41.2 g, 320 mmol) was added at 5–10 °C. After the addition was complete, the temperature was raised to 100–105 °C and the reaction mixture was stirred for 0.5–1 hour. The mixture was cooled and diluted with ethyl acetate (200 mL). It was washed successively with purified water (250 mL), 1N HCl (200 mL), and 20% NaHCO3 (200 mL). The product was dried and concentrated under reduced pressure to remove the organic solvent. Finally, recrystallization from petroleum ether / ethyl acetate (200 mL, 1:1 v / v) yielded a white solid product with a yield of 89.8% and an HPLC purity of 98.43%.

[0064] Preparation of apalutamide

[0065] Example 8

[0066] Compound III (16.3 g, 50 mmol) and compound IV (13.9 g, 60 mmol) were added to DMF (100 mL). Sodium hydride (1.8 g, 75 mmol) was added in portions at 0–5 °C. After the addition was complete, the mixture was stirred at 0–5 °C for 0.5 hours, then allowed to return to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 96.8% and an HPLC purity of 99.93%.

[0067] Example 9

[0068] Compound III (16.3 g, 50 mmol) and Compound IV (11.6 g, 50 mmol) were added to DMF (100 mL). Sodium hydride (1.8 g, 75 mmol) was added in portions at 0–5 °C. After the addition was complete, the mixture was stirred at 0–5 °C for 0.5 hours, then allowed to return to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 93.2% and an HPLC purity of 99.65%.

[0069] Example 10

[0070] Compound III (16.3 g, 50 mmol) and compound IV (23.2 g, 100 mmol) were added to DMF (100 mL). Sodium hydride (1.8 g, 75 mmol) was added in portions at 0–5 °C. After the addition was complete, the mixture was stirred at 0–5 °C for 0.5 hours, then allowed to return to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 94.5% and an HPLC purity of 99.61%.

[0071] Example 11

[0072] Compound III (16.3 g, 50 mmol) and compound IV (13.9 g, 60 mmol) were added to 1,4-dioxane (100 mL). Sodium hydride (1.5 g, 60 mmol) was added in portions at -5 to 0 °C. After the addition was complete, the mixture was stirred at -5 to 0 °C for 0.5 hours, then allowed to return to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 93.0% and an HPLC purity of 99.58%.

[0073] Example 12

[0074] Compound III (16.3 g, 50 mmol) and compound IV (13.9 g, 60 mmol) were added to acetonitrile (100 mL). Sodium hydride (2.4 g, 100 mmol) was added in portions at 0–5 °C. After the addition was complete, the mixture was stirred at 0–5 °C for 0.5 hours, then allowed to return to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 93.8% and an HPLC purity of 99.52%.

[0075] Example 13

[0076] Compound III (16.3 g, 50 mmol) and Compound IV (11.6 g, 50 mmol) were added to tetrahydrofuran (100 mL). Sodium hydride (1.2 g, 50 mmol) was added in portions at -10 to -5 °C. After the addition was complete, the mixture was stirred at -10 to -5 °C for 0.5 hours, then allowed to return to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 87.8% and an HPLC purity of 98.93%.

[0077] Example 14

[0078] Compound III (16.3 g, 50 mmol) and compound IV (25.4 g, 110 mmol) were added to tetrahydrofuran (100 mL). Sodium hydride (2.6 g, 110 mmol) was added in portions at 5–10 °C. After the addition was complete, the mixture was stirred at 5–10 °C for 0.5 hours, then cooled to room temperature and stirred for another 6 hours. Purified water (500 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was added to isopropanol (100 mL), heated under reflux for 10 minutes, and then cooled to room temperature with stirring. A large amount of solid precipitated. The solid was filtered, dried, and apalutamide was obtained with a yield of 88.9% and an HPLC purity of 98.45%.

Claims

1. A method for preparing apalutamide, characterized in that, The preparation method is as follows: 1) Take 22.9 g of compound I and 22.7 g of compound II in 250 mL of toluene, add 25.3 g of triethylamine at 0~5℃, after which heat to 95~100℃ and stir for 0.5~1 hour; cool and dilute the reaction solution with 200 mL of ethyl acetate, wash successively with 250 mL of purified water, 200 mL of 1 N HCl and 200 mL of 20% NaHCO3, dry and concentrate under reduced pressure to remove organic solvent, and finally recrystallize from 200 mL of petroleum ether / ethyl acetate at a volume ratio of 1:1 to obtain a white solid product, namely compound III; 2) Take 16.3 g of compound III and 13.9 g of compound IV in 100 mL of DMF, add 1.8 g of sodium hydride in portions at 0~5℃. After the addition is complete, continue stirring at 0~5℃ for 0.5 hours, then restore to room temperature and continue stirring for 6 hours. Add 500 mL of purified water to the reaction solution, filter, and add the filter cake to 100 mL of isopropanol. Heat under reflux for 10 minutes, then cool to room temperature and stir. A large amount of solid precipitates. Filter, dry, and obtain compound V, i.e., apalutamide. The synthesis route is as follows: 。

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