A Synthetic Method for a Key Intermediate of Enzalutamide

Abstract

The present invention discloses a synthesis method of a key intermediate of enzalutamide, which relates to the technical field of organic synthesis. Using 4-bromo-2-fluorobenzoic acid as the starting material, 4-bromo-2-fluorobenzoic acid reacts with a sulfuric acid ethanol solution to obtain ethyl 4-bromo-2-fluorobenzoate. Ethyl 4-bromo-2-fluorobenzoate undergoes an Ullmann reaction with ammonium chloride under the action of a ligand, a catalyst and an acid-binding agent to obtain ethyl 4-amino-2-fluorobenzoate. The present invention synthesizes the key intermediate ethyl 4-amino-2-fluorobenzoate of enzalutamide through an esterification reaction and an Ullmann reaction. This synthesis method can not only simplify the operation and reduce the cost, but also improve the yields of the intermediate and the product, thus being applicable to industrial production and providing high-quality intermediates for the preparation of enzalutamide.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing a key intermediate of enzalutamide. Background Art

[0002] The chemical formula of enzalutamide is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methylbenzamide. Its clinical drug was jointly developed by Medivation and Astellas, and was approved by the US Food and Drug Administration (FDA) on August 31, 2012 for the treatment of advanced castration-resistant prostate cancer that has spread or recurred. The trade name is Xtandi, and this drug is an oral preparation. Enzalutamide (MDV 3100) is an androgen receptor antagonist, which can block androgen from binding to the androgen receptor and prevent the nuclear translocation and co-activator recruitment of the ligand-receptor complex. MDV 3100 also has the effect of inducing apoptosis of tumor cells, but has no agonist activity. MDV 3100 is a candidate for the treatment of castration-resistant prostate cancer.

[0003] Ethyl 4-amino-2-fluorobenzoate is widely used in chemical and pharmaceutical research, especially in the production of the raw material drug of enzalutamide in recent years. At present, the synthesis of ethyl 4-amino-2-fluorobenzoate requires reactions such as nitration and palladium-carbon hydrogenation. Not only is the raw material cost relatively high, but the reaction yield is very low, resulting in a consistently very high price for the raw material drug of enzalutamide. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing a key intermediate of enzalutamide, which has the advantages of low raw material cost, high product yield, etc., and is suitable for industrial production.

[0005] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0006] The present invention provides a method for synthesizing a key intermediate of enzalutamide. Using 4-bromo-2-fluorobenzoic acid as the starting material, 4-bromo-2-fluorobenzoic acid reacts with sulfuric acid ethanol solution to obtain ethyl 4-bromo-2-fluorobenzoate, and ethyl 4-bromo-2-fluorobenzoate reacts with ammonium chloride under the action of a ligand, a catalyst and an acid-binding agent to undergo an Ullmann reaction to obtain ethyl 4-amino-2-fluorobenzoate.

[0007] The synthesis route is as follows:

[0008]

[0009] In a further technical solution, the mass concentration of the sulfuric acid ethanol solution is 10-20%. Concentrated sulfuric acid is slowly added to ethanol and mixed evenly to obtain the sulfuric acid ethanol solution. Among them, ethanol undergoes an esterification reaction with 4-bromo-2-fluorobenzoic acid, and concentrated sulfuric acid acts as a dehydrating agent to promote the forward progress of the esterification reaction.

[0010] In a further technical solution, the dosage ratio of 4-bromo-2-fluorobenzoic acid to the sulfuric acid ethanol solution is 1 kg:(5-20) L. Excessive ethanol enables 4-bromo-2-fluorobenzoic acid to react as completely as possible, improving the yield of the esterification reaction.

[0011] In a further technical solution, the dosage of ammonium chloride is 1-1.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate. Ethyl 4-bromo-2-fluorobenzoate undergoes an Ullmann reaction with ammonium chloride to convert the bromo substituent into an amino group.

[0012] In a further technical solution, the catalyst is cuprous halide. The cuprous halide is selected from at least one of cuprous iodide, cuprous chloride, and cuprous bromide. Preferably, the cuprous halide is cuprous iodide.

[0013] In a further technical solution, the ligand is an amino acid. The amino acid is selected from at least one of L-proline, N-methylglycine, N,N-dimethylglycine, N-benzylglycine, N,N-dibenzylglycine, 3-methylaminopropionic acid, and 3-dimethylaminopropionic acid.

[0014] The catalytic mechanism of the Ullmann reaction in the present invention is as follows: First, under the action of the ligand amino acid, cuprous ions undergo oxidative addition with ethyl 4-bromo-2-fluorobenzoate to form a trivalent copper ion complex; second, ammonium chloride releases ammonia under the action of an acid-binding agent, and the nucleophilic ammonia undergoes transmetalation with the above-mentioned trivalent copper ions; finally, the target product is obtained through reductive elimination, and at the same time, the catalyst is recycled and regenerated.

[0015] In a further technical solution, the dosage of the cuprous halide is 0.1-0.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate. Appropriate amount of cuprous halide is added as a catalyst to improve the product yield while controlling the catalyst cost.

[0016] In a further technical solution, the dosage of the amino acid is 0.1-0.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate. Appropriate amount of amino acid is added as a ligand. The chelate ring formed by the amino acid and cuprous ions can, on the one hand, improve the ability of cuprous ions to undergo oxidative addition, and on the other hand, can stabilize the generated trivalent copper ion complex.

[0017] In a further technical solution, the acid-binding agent is one or more of potassium carbonate, sodium carbonate, triethylamine, pyridine, and N,N-diisopropylethylamine. The role of the acid-binding agent is to neutralize the hydrogen bromide generated during the reaction and promote the forward progress of the reaction.

[0018] In a further technical solution, the dosage of the acid-binding agent is 1-1.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate. The acid-binding agent reacts with hydrogen bromide to form a salt, which can be removed by washing with water during post-treatment.

[0019] In a further technical solution, the Ullmann reaction is carried out under nitrogen protection.

[0020] The beneficial effects of the present invention are as follows: The present invention uses 4-bromo-2-fluorobenzoic acid as the starting material, and synthesizes the key intermediate of enzalutamide, ethyl 4-amino-2-fluorobenzoate, through esterification reaction and Ullmann reaction. This synthesis method can not only simplify the operation, reduce the cost, but also improve the yield of the intermediate and the product, so as to be applicable to industrial production and provide high-quality intermediates for the preparation of enzalutamide. Description of the Drawings

[0021] Figure 1 It is the NMR spectrum of the product ethyl 4-amino-2-fluorobenzoate. Detailed Embodiments

[0022] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be further described below in conjunction with specific embodiments and drawings.

[0023] Example 1

[0024] Synthesis of ethyl 4-bromo-2-fluorobenzoate: Weigh 4-bromo-2-fluorobenzoic acid (1.0 kg, 4.56 mol) and dissolve it in 10% sulfuric acid methanol solution (10 L), and heat it to 90 °C for reaction for 12 h. After cooling the reaction solution to room temperature, add it to the ice-water mixture, stir at 5-10 °C for 1 h, filter, wash the filter residue with cold water, and dry it in an oven at 40 °C for 12 h to obtain ethyl 4-bromo-2-fluorobenzoate, with a yield of 88% and a purity of 99%.

[0025] Synthesis of Ethyl 4-amino-2-fluorobenzoate: Ethyl 4-bromo-2-fluorobenzoate (0.994 kg, 4.01 mol, 1.0 eq) was added to a mixed solvent of dimethyl sulfoxide and water (where the volume ratio of dimethyl sulfoxide to water was 20:1). Then, copper(I) iodide (153.0 g, 0.8 mol, 0.2 eq), proline (184.2 g, 1.6 mol, 0.4 eq), potassium carbonate (883.0 g, 6.0 mol, 1.5 eq), and ammonium chloride (280.0 g, 5.2 mol, 1.3 eq) were added. After purging with nitrogen three times, the reaction was carried out at 85 °C overnight. The reaction solution was washed with water, the organic phase was collected, and distilled under reduced pressure. The obtained solid was slurried in n-heptane, filtered, and the filter cake was dried in vacuo at 60 °C to obtain ethyl 4-amino-2-fluorobenzoate with a yield of 61% and a purity of 99%.

[0026] It can be seen from Figure 1 that the target product ethyl 4-amino-2-fluorobenzoate was successfully synthesized in this invention.

[0027] Example 2

[0028] Synthesis of Ethyl 4-bromo-2-fluorobenzoate: 4-Bromo-2-fluorobenzoic acid (1.0 kg, 4.56 mol) was weighed and dissolved in 15% sulfuric acid methanol solution (10 L), and the reaction was carried out at 90 °C for 12 h. After the reaction solution was cooled to room temperature, it was added to an ice-water mixture and stirred at 5 - 10 °C for 1 h. Then it was filtered, and the filter cake was washed with cold water and dried in an oven at 40 °C for 12 h to obtain ethyl 4-bromo-2-fluorobenzoate with a yield of 85% and a purity of 99%.

[0029] Synthesis of Ethyl 4-amino-2-fluorobenzoate: Ethyl 4-bromo-2-fluorobenzoate (0.962 kg, 3.88 mol, 1.0 eq) was added to a mixed solvent of dimethyl sulfoxide and water (where the volume ratio of dimethyl sulfoxide to water was 20:1). Then, copper(I) iodide (220.1 g, 1.16 mol, 0.3 eq), proline (178.5 g, 1.55 mol, 0.4 eq), triethylamine (589.0 g, 5.82 mol, 1.5 eq), and ammonium chloride (331.3 g, 5.82 mol, 1.5 eq) were added. After purging with nitrogen three times, the reaction was carried out at 85 °C overnight. The reaction solution was washed with water, the organic phase was collected, and distilled under reduced pressure. The obtained solid was slurried in n-heptane, filtered, and the filter cake was dried in vacuo at 60 °C to obtain ethyl 4-amino-2-fluorobenzoate with a yield of 51% and a purity of 99%.

[0030] Example 3

[0031] Synthesis of ethyl 4-bromo-2-fluorobenzoate: Weigh 4-bromo-2-fluorobenzoic acid (1.0 kg, 4.56 mol) and dissolve it in 20% sulfuric acid methanol solution (10 L), and heat the solution to 90 °C for reaction for 12 h. After cooling the reaction solution to room temperature, add it to the ice-water mixture, stir at 5 - 10 °C for 1 h, filter, wash the filter cake with cold water, and dry it in an oven at 40 °C for 12 h to obtain ethyl 4-bromo-2-fluorobenzoate, with a yield of 83% and a purity of 95%.

[0032] Synthesis of ethyl 4-amino-2-fluorobenzoate: Add ethyl 4-bromo-2-fluorobenzoate (0.947 kg, 3.78 mol, 1.0 eq) to a mixed solvent of dimethyl sulfoxide and water (where the volume ratio of dimethyl sulfoxide to water is 20:1), then add copper iodide (144.7 g, 0.76 mol, 0.2 eq), proline (130.1 g, 1.13 mol, 0.3 eq), N,N-diisopropylethylamine (586.7 g, 4.54 mol, 1.2 eq) and ammonium chloride (244.7 g, 4.54 mol, 1.2 eq). After displacing with nitrogen three times, react at 85 °C overnight. Wash the reaction solution with water, collect the organic phase, distill under reduced pressure, add the obtained solid to n-heptane for pulping, filter, and vacuum dry the filter cake at 60 °C to obtain ethyl 4-amino-2-fluorobenzoate, with a yield of 57% and a purity of 99%.

[0033] It can be seen from Examples 1 - 3 that the total yield of the product ethyl 4-amino-2-fluorobenzoate is relatively low. The main reason is that the average yield of the Ullmann reaction is less than 60%. Under the condition that the synthesis route remains unchanged, the present invention starts from the catalyst, uses macroporous adsorption resin as the carrier, and loads cuprous halide on its internal pores and surface, thereby increasing the contact area between the catalyst and the substrate, improving the catalytic efficiency, and making the average yield of the Ullmann reaction reach more than 85%.

[0034] In a further technical solution, the catalyst is macroporous adsorption resin supported cuprous halide, and the content of cuprous halide in the catalyst is 20 - 40%.

[0035] The cuprous halide is selected from at least one of copper iodide, copper chloride, and copper bromide. Preferably, the cuprous halide is copper iodide.

[0036] The preparation method of the macroporous adsorption resin includes the following steps: Dissolve a dispersant in water to obtain an aqueous phase; Mix divinylbenzene, N-(2-hydroxyethyl)-N'-2-propenylthiourea, a pore-forming agent, and an initiator to obtain an oil phase; Add the oil phase to the aqueous phase and obtain the macroporous adsorption resin through suspension polymerization reaction.

[0037] Preferably, the mass ratio of the dispersant to water is 100:(1 - 5).

[0038] Preferably, the mass ratio of divinylbenzene, N-(2-hydroxyethyl)-N′-2-propenylthiourea, pore-forming agent, and initiator is (70-80):(20-30):(100-200):(0.5-2).

[0039] Preferably, the volume ratio of the aqueous phase to the oil phase is (1-3):1.

[0040] Preferably, the dispersant is selected from at least one of polyvinyl alcohol, gelatin, sodium chloride, sodium carboxymethyl cellulose, and hydroxyethyl cellulose.

[0041] Preferably, the pore-forming agent is selected from at least one of toluene, xylene, C6-C12 saturated hydrocarbons, and C4-C10 alkanols.

[0042] Preferably, the initiator is an organic peroxide initiator or an azo initiator.

[0043] Example 4

[0044] The synthesis method of ethyl 4-amino-2-fluorobenzoate is the same as that in Example 1, except that the cuprous iodide in Example 1 is replaced with macroporous adsorption resin-supported cuprous iodide. The dosage of macroporous adsorption resin-supported cuprous iodide is calculated based on cuprous iodide and is the same as the dosage of cuprous iodide in Example 1. The yield is 85%, and the purity is 99%.

[0045] Preparation of macroporous adsorption resin: Dissolve 0.5 g of polyvinyl alcohol, 0.5 g of gelatin, and 2.5 g of sodium chloride in 100 g of water to obtain an aqueous phase; mix 70 g of divinylbenzene, 30 g of N-(2-hydroxyethyl)-N′-2-propenylthiourea, 150 g of toluene, and 1.5 g of azobisisobutyronitrile / benzoyl peroxide to obtain an oil phase; add the oil phase to the aqueous phase, with the volume ratio of the aqueous phase to the oil phase being 2:1. Heat to 80 °C and react for 2 h, then continue to heat to 90 °C and react for 3 h, and then heat to 95 °C and react for 4 h. After the reaction, sieve, wash with water, extract toluene with acetone, and dry in vacuo at 60 °C to obtain the macroporous adsorption resin.

[0046] Preparation of macroporous adsorption resin-supported cuprous iodide: Add the above macroporous adsorption resin and cuprous iodide to ethanol, ultrasonically treat for 2 h, and dry in vacuo at 50 °C to obtain macroporous adsorption resin-supported cuprous iodide. Among them, the content of cuprous halide is 30%.

[0047] Example 5

[0048] The synthesis method of ethyl 4-amino-2-fluorobenzoate is the same as that in Example 1, except that the cuprous iodide in Example 1 is replaced with macroporous adsorption resin-supported cuprous iodide. The dosage of macroporous adsorption resin-supported cuprous iodide is calculated based on cuprous iodide and is the same as the dosage of cuprous iodide in Example 1. The yield is 87%, and the purity is 99%.

[0049] Preparation of macroporous adsorption resin: Dissolve 0.5 g of polyvinyl alcohol, 1 g of gelatin, and 2 g of sodium chloride in 100 g of water to obtain an aqueous phase; mix 80 g of divinylbenzene, 20 g of N-(2-hydroxyethyl)-N'-2-propenylthiourea, 200 g of toluene, and 1 g of azobisisobutyronitrile / benzoyl peroxide to obtain an oil phase; add the oil phase to the aqueous phase, with the volume ratio of the aqueous phase to the oil phase being 1:1, heat up to 80 °C and react for 3 h, continue to heat up to 90 °C and react for 3 h, then heat up to 95 °C and react for 4 h, after the reaction is completed, sieve, wash with water, extract toluene with acetone, and dry in vacuum at 60 °C to obtain the macroporous adsorption resin.

[0050] Preparation of macroporous adsorption resin supported with cuprous iodide: Add the above-mentioned macroporous adsorption resin and cuprous iodide to ethanol, perform ultrasonic treatment for 2 h, and dry in vacuum at 50 °C to obtain the macroporous adsorption resin supported with cuprous iodide. Among them, the content of cuprous halide is 35%.

[0051] Example 6

[0052] The synthesis method of ethyl 4-amino-2-fluorobenzoate is the same as that in Example 1, except that cuprous iodide in Example 1 is replaced with macroporous adsorption resin supported with cuprous iodide, and the dosage of macroporous adsorption resin supported with cuprous iodide is calculated based on cuprous iodide, which is the same as the dosage of cuprous iodide in Example 1. The yield is 90%, and the purity is 99%.

[0053] Preparation of macroporous adsorption resin: Dissolve 0.5 g of polyvinyl alcohol, 1 g of gelatin, and 3 g of sodium chloride in 100 g of water to obtain an aqueous phase; mix 75 g of divinylbenzene, 25 g of N-(2-hydroxyethyl)-N'-2-propenylthiourea, 180 g of toluene, and 2 g of azobisisobutyronitrile / benzoyl peroxide to obtain an oil phase; add the oil phase to the aqueous phase, with the volume ratio of the aqueous phase to the oil phase being 3:1, heat up to 80 °C and react for 3 h, continue to heat up to 90 °C and react for 2 h, then heat up to 95 °C and react for 5 h, after the reaction is completed, sieve, wash with water, extract toluene with acetone, and dry in vacuum at 60 °C to obtain the macroporous adsorption resin.

[0054] Preparation of macroporous adsorption resin supported with cuprous iodide: Add the above-mentioned macroporous adsorption resin and cuprous iodide to ethanol, perform ultrasonic treatment for 2 h, and dry in vacuum at 50 °C to obtain the macroporous adsorption resin supported with cuprous iodide. Among them, the content of cuprous halide is 25%.

[0055] Control Example 1

[0056] The synthesis method of ethyl 4-amino-2-fluorobenzoate is the same as that in Example 6, except that N-(2-hydroxyethyl)-N'-2-propenylthiourea, the monomer for preparing the macroporous adsorption resin in Example 6, is replaced with N-hydroxyethylacrylamide. The yield is 78%, and the purity is 99%.

[0057] Comparative Example 2

[0058] The synthesis method of ethyl 4-amino-2-fluorobenzoate was the same as that in Example 6, except that the monomer N-(2-hydroxyethyl)-N'-2-propenylthiourea for preparing the macroporous adsorption resin in Example 6 was replaced with styrene. The yield was 75% and the purity was 99%.

[0059] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of the present invention claimed is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a key intermediate of enzalutamide, characterized in that: Using 4-bromo-2-fluorobenzoic acid as a starting material, 4-bromo-2-fluorobenzoic acid and ethanol sulfuric acid solution undergo esterification reaction to obtain 4-bromo-2-fluorobenzoic acid ethyl ester, and 4-bromo-2-fluorobenzoic acid ethyl ester and ammonium chloride undergo Ullmann reaction under the action of a ligand, a catalyst and an acid binding agent to obtain 4-amino-2-fluorobenzoic acid ethyl ester; The ligand is proline; and the catalyst is cuprous iodide.

2. The method for synthesizing the key intermediate of enzalutamide according to claim 1, characterized in that: The mass concentration of the sulfuric acid ethanol solution is 10-20%.

3. The method for synthesizing the key intermediate of enzalutamide according to claim 2, characterized in that: The usage ratio of the 4-bromo-2-fluorobenzoic acid to the sulfuric acid ethanol solution is 1kg:(5-20)L.

4. The method for synthesizing the key intermediate of enzalutamide according to claim 1, characterized in that: The amount of ammonium chloride used is 1-1.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate.

5. The method for synthesizing the key intermediate of enzalutamide according to claim 1, characterized in that: The amount of cuprous iodide used is 0.1-0.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate.

6. The method for synthesizing the key intermediate of enzalutamide according to claim 1, characterized in that: The amount of proline used is 0.1-0.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate.

7. The method for synthesizing the key intermediate of enzalutamide according to claim 1, characterized in that: The acid binding agent is one or more of potassium carbonate, sodium carbonate, triethylamine, pyridine and N,N-diisopropylethylamine.

8. The method for synthesizing the key intermediate of enzalutamide according to claim 7, characterized in that: The amount of the acid binding agent used is 1-1.5 times the molar amount of ethyl 4-bromo-2-fluorobenzoate.

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