A kind of synthetic method of apalutamide

Abstract

The invention discloses a method for synthesizing apalutamide. The method comprises the following steps: step 1, reacting 6-amino-2-cyano-3-trifluoromethylpyridine (I) and 1-amino-1-cyclobutylcarboxylic acid methyl ester or its salt (II) in a solvent A under the action of TCDI and a base A to obtain an intermediate (III); and step 2, reacting the intermediate (III) with N-methyl-2-fluoro-4-halogenated benzamide (IV) in a solvent B under the action of a catalyst and a base B to obtain apalutamide. The method has cheap and readily available starting materials, avoids the use of highly toxic sodium cyanide and noble metal catalysts, reduces process costs, meets the requirements of green environmental protection, reduces the generation of by-products, improves the yield and purity of the product, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a method for synthesizing apalutamide and an intermediate thereof. Background Art

[0002] Apalutamide is an androgen receptor (AR) inhibitor developed by the University of California, USA. The drug was licensed to Aragon Pharmaceuticals in the United States in 2009. In February 2018, apalutamide was approved by the US FDA for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC) and has been launched in China in 2019. The cultural name 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-methylbenzoyl, and its chemical structure is shown in the following structural formula:

[0003]

[0004] At present, there are mainly the following methods for synthesizing apalutamide:

[0005] (1) Document WO2007126765A2 first reported that compound 1 was used as a raw material to condense with cyclobutanone and sodium cyanide to obtain benzamide intermediate 2; compound 3 was used as a raw material to react with thiophosgene to obtain thioisocyanatopyridine intermediate 4; the last two intermediates were used to obtain apalutamide under microwave assisted reaction. This route requires the use of sodium cyanide and thiophosgene under acidic conditions, and the final cyclization reaction uses microwaves, which makes industrial production difficult.

[0006]

[0007] (2) PCT patent WO2016100645 simplifies the new synthesis method of apalutamide, using the Strecker reaction of 3-fluoro-4-iodoaniline with cyclobutanone and cyanide to obtain cyclobutanamide intermediate 2 and 2-cyano-3-trifluoromethyl-5-aminopyridine compound 3 under the action of thiocarbonyl compound, and then completing the carbonyl insertion reaction catalyzed by precious metal palladium to obtain a carboxylate intermediate or reacting with dry ice after Grignard exchange to obtain a carboxylic acid intermediate, and finally amidation to obtain the final product apalutamide. Although the route has a short number of steps, the palladium-catalyzed carbonyl insertion reaction or Grignard exchange reaction route is costly, and the process production experimental conditions are harsh, which is not suitable for the synthesis of apalutamide by industrial production.

[0008]

[0009] (3) Patent CN104211683A uses TMSCN instead of NaCN, avoiding the use of highly toxic reagents. However, in the last step of the condensation reaction, apalutamide is synthesized in a one-pot method using a highly toxic reagent, thiophosgene. The process production experimental conditions are relatively harsh and it is not suitable for the synthesis of apalutamide by industrial production.

[0010] Summary of the invention

[0011] In view of the deficiencies in the prior art, the present invention provides a novel method for synthesizing apalutamide, which has cheap and readily available raw materials, mild reaction conditions, simple operation, and is suitable for industrial production.

[0012] The present invention provides a method for synthesizing apalutamide, comprising the following steps: step 1, reacting 6-amino-2-cyano-3-trifluoromethylpyridine (I) and 1-amino-1-cyclobutylcarboxylic acid methyl ester or its salt (II) in solvent A under the action of TCDI and base A to obtain an intermediate (III); step 2, reacting the intermediate (III) with N-methyl-2-fluoro-4-halogenated benzamide (IV) in solvent B under the action of a catalyst and base B to obtain apalutamide, which is represented by the following reaction formula:

[0013]

[0014] Wherein, X is fluorine, chlorine, bromine or iodine.

[0015] Preferably, the salt is hydrochloride or sulfate.

[0016] The base A in step 1 is triethylamine, pyridine, diisopropylethylamine or DBU; the solvent A is dichloromethane, THF, toluene or acetonitrile; and the reaction temperature is 20-30°C.

[0017] The molar ratio of compound I to compound II is 1:1, the molar ratio of TCDI to compound 1 is 1.2-1.5:1, and the molar ratio of base A to compound I is 2-5:1.

[0018] The catalyst in step 2 is cuprous chloride, cuprous bromide or cuprous iodide. The catalyst is combined with auxiliary agents such as 2-acetamide cyclohexanone, N1, N2-bis(2,6-dimethylphenyl)oxalamide, N1-benzyl-N2-(2,6-dimethylphenyl)oxalamide or N1-benzyl-N2-(2-methylnaphthalene-1-yl)oxalamide to catalyze the reaction.

[0019] The structural formula of N1, N2-bis(2,6-dimethylphenyl)oxalamide is: .

[0020] The structural formula of N1-benzyl-N2-(2,6-dimethylphenyl)oxalamide is: .

[0021] The structural formula of N1-benzyl-N2-(2-methylnaphthalen-1-yl)oxalamide is: .

[0022] The base B in step 2 is triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate or DBU. The solvent B is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide. The reaction temperature of step 2 is 80-90°C.

[0023] The molar ratio of compound III to compound IV is 1:1.2, the molar ratio of catalyst to auxiliary agent is 1:1, the molar ratio of catalyst to compound III is 0.2-0.3:1, and the molar ratio of base B to compound III is 2-5:1.

[0024] The beneficial effects of the present invention are as follows: the starting raw materials of the method are cheap and easily available, the use of highly toxic sodium cyanide and precious metal catalysts is avoided, the process cost is reduced, the requirements of green environmental protection are met, the generation of by-products is reduced, the yield and purity of the product are improved, and the method is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is compound III 1 H-NMR spectrum.

[0026] Figure 2 It's apalutamide 1 H-NMR spectrum. DETAILED DESCRIPTION

[0027] The present invention is further described below in conjunction with specific embodiments, but the content and scope of protection claimed in the present invention are not limited to the following embodiments.

[0028] Example 1

[0029]

[0030] Add 1g (5.34mmol) of 6-amino-2-cyano-3-trifluoromethylpyridine, 1.4g (8.01mmol) of TCDI and 10mL of toluene to a three-necked flask. Under nitrogen protection, cool to 0-10°C, add 1.1g (10.68mmol) of triethylamine dropwise, raise the temperature to 20-30°C and react for 3-4h, add 0.88g (5.34mmol) of 1-amino-1-cyclobutylcarboxylic acid methyl ester hydrochloride in batches, continue to react at 20-30°C for 1-2h. After the reaction, add 10mL of water and 10mL of ethyl acetate, stir and separate, wash the organic phase twice with water, separate, and concentrate the organic phase under reduced pressure to obtain an oily substance, which is purified by column chromatography to obtain compound III with a yield of 90%. The hydrogen spectrum information of compound III is shown in Figure 1 .

[0031] Example 2

[0032]

[0033] 5 g (26.7 mmol) of 6-amino-2-cyano-3-trifluoromethylpyridine, 5.6 g (32.04 mmol) of TCDI and 50 mL of toluene were added to a three-necked flask. Under nitrogen protection, the temperature was lowered to 0-10°C, 10.5 g (132.7 mmol) of pyridine was added dropwise, and the temperature was raised to 20-30°C for reaction for 5 h. 3.45 g (26.7 mmol) of 1-amino-1-cyclobutylcarboxylic acid methyl ester was added in batches, and the reaction was continued at 20-30°C for 2 h. After the reaction, 60 mL of water and 50 mL of ethyl acetate were added, stirred and separated, and the organic phase was washed twice with water, separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance, which was purified by column chromatography to obtain compound III with a yield of 92%.

[0034] Example 3

[0035]

[0036] Add 10.4 g (32 mmol) of intermediate III, 8.8 g (38 mmol) of N-methyl-2-fluoro-4-bromobenzamide and 50 g of dimethyl sulfoxide to a three-necked flask, add 9.8 g (64 mmol) of DBU, 1.2 g (6.4 mmol) of cuprous iodide and 2 g (6.4 mmol) of N1-benzyl-N2-(2-methylnaphthalene-1-yl)oxalamide under nitrogen protection, stir evenly and heat to 80-90°C for 6 h. After the reaction, add 50 mL of water and 50 g of ethyl acetate, stir and separate the liquids, wash the organic phase twice with saturated brine, separate the layers, collect the organic phase, concentrate and dry, add 50 g of methanol and 150 mL of water for crystallization, filter, and dry the filter cake to obtain apalutamide with a yield of 92%, HPLC purity of 99.62%, and hydrogen spectrum as shown in Figure 2 .

[0037] Example 4

[0038]

[0039] Add 10.4 g (32 mmol) of intermediate III, 6.5 g (38 mmol) of N-methyl-2,4-difluorobenzamide and 50 g of dimethyl sulfoxide to a three-necked flask, add 9.8 g (64 mmol) of DBU, 1.2 g (6.4 mmol) of cuprous iodide and 2 g (6.4 mmol) of N1-benzyl-N2-(2-methylnaphthalene-1-yl)oxalamide under nitrogen protection, stir evenly and heat to 80-90°C for 6 h. After the reaction, add 50 mL of water and 50 g of ethyl acetate, stir and separate, wash the organic phase twice with saturated brine, separate the layers, collect the organic phase, concentrate and dry, add 50 g of methanol and 150 mL of water for crystallization, filter, and dry the filter cake to obtain apalutamide with a yield of 85% and a purity of 99.05%.

Claims

1. A method for synthesizing apalutamide, characterized in that: The method comprises the following steps: step 1, reacting 6-amino-2-cyano-3-trifluoromethylpyridine (I) and 1-amino-1-cyclobutylcarboxylic acid methyl ester or its salt (II) in solvent A under the action of TCDI and base A to obtain an intermediate (III); step 2, reacting the intermediate (III) with N-methyl-2-fluoro-4-halogenated benzamide (IV) in solvent B under the action of a catalyst and base B to obtain apalutamide, which is represented by the following reaction formula: Wherein, X is fluorine, chlorine, bromine or iodine; The base A is triethylamine, pyridine, diisopropylethylamine or DBU; The base B is triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate or DBU; The reaction temperature of step 1 is 20-30°C.

2. The synthesis method according to claim 1, characterized in that The salt is hydrochloride or sulfate.

3. The synthesis method according to claim 1, characterized in that The solvent A is dichloromethane, THF, toluene or acetonitrile.

4. The synthesis method according to claim 1, characterized in that The catalyst is cuprous chloride, cuprous bromide or cuprous iodide.

5. The synthesis method according to claim 4, characterized in that The catalyst is coordinated with auxiliary agents 2-acetamide cyclohexanone, N1, N2-bis(2,6-dimethylphenyl)oxalamide, N1-benzyl-N2-(2,6-dimethylphenyl)oxalamide or N1-benzyl-N2-(2-methylnaphthalene-1-yl)oxalamide to catalyze the reaction.

6. The synthesis method according to claim 1, characterized in that The solvent B is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide.

7. The synthesis method according to claim 1, characterized in that The reaction temperature of step 2 is 80-90°C.

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