Method for synthesizing key intermediate of enzalutamide

Abstract

Provided is a method for synthesizing a key intermediate of enzalutamide, relating to the technical field of organic synthesis. The method comprises: 4-bromo-2-fluorobenzoic acid, as a starting material, undergoing an esterification reaction with an ethanol solution of sulfuric acid to obtain ethyl 4-bromo-2-fluorobenzoate; and ethyl 4-bromo-2-fluorobenzoate and ammonium chloride undergoing an Ullmann reaction under the action of a ligand, a catalyst and an acid-binding agent to obtain ethyl 4-amino-2-fluorobenzoate. By means of an esterification reaction and an Ullmann reaction, the key intermediate of enzalutamide, ethyl 4-amino-2-fluorobenzoate, is synthesized. The synthesis method involves simplified operations, reduced costs, and improved yields of the intermediate and a product, thereby being suitable for industrial production to provide the high-quality intermediate for the preparation of enzalutamide.

Description

Synthesis method of a key intermediate of enzalutamide TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of a key intermediate of enzalutamide. BACKGROUND

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

[0003] 4-amino-2-fluorobenzoic acid ethyl ester is widely used in chemical and pharmaceutical research, especially in recent years for the production of enzalutamide raw drug. The synthesis of 4-amino-2-fluorobenzoic acid ethyl ester currently requires nitration and palladium-carbon hydrogenation reactions, which not only has a high raw material cost, but also has a very low reaction yield, thereby resulting in a very high price of enzalutamide raw drug.

[0004] SUMMARY

[0005] The technical problem to be solved by the present application is to provide a synthesis method of a key intermediate of enzalutamide, which has the advantages of low raw material cost, high product yield, and can be suitable for industrial production.

[0006] The technical problem to be solved by the present application is solved by the following technical scheme:

[0007] The present application provides a synthesis method of a key intermediate of enzalutamide, which takes 4-bromo-2-fluorobenzoic acid as a starting material, and 4-bromo-2-fluorobenzoic acid is subjected to esterification reaction with ethanol sulfate solution to obtain 4-bromo-2-fluorobenzoic acid ethyl ester, and 4-bromo-2-fluorobenzoic acid ethyl ester is subjected to Ullmann reaction with ammonium chloride under the action of a ligand, a catalyst and an acid binding agent to obtain 4-amino-2-fluorobenzoic acid ethyl ester.

[0008] The synthesis route is as follows:

[0009] In a further technical solution, the mass concentration of the ethanol sulfate solution is 10-20%. Concentrated sulfuric acid is slowly added to ethanol to obtain an ethanol sulfate solution. Among them, ethanol and 4-bromo-2-fluorobenzoic acid undergo esterification, 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 amount of 4-bromo-2-fluorobenzoic acid to ethanol sulfate solution is 1 kg:(5-20) L. Excess ethanol makes 4-bromo-2-fluorobenzoic acid react as completely as possible, thereby improving the yield of the esterification reaction.

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

[0012] In a further technical solution, the catalyst is a 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-methyl glycine, N,N-dimethyl glycine, N-benzyl glycine, N,N-dibenzyl glycine, 3-methylamino propionic acid, and 3-dimethylamino propionic acid.

[0014] The catalytic mechanism of the Ullmann reaction in the present application is as follows: first, the cuprous ion, under the action of the ligand amino acid, undergoes oxidative addition with 4-bromo-2-fluorobenzoic acid ethyl ester to form a trivalent copper ion complex; second, ammonium chloride releases ammonia under the action of the acid binding agent, and the nucleophilic ammonia undergoes transmetalation with the above-mentioned trivalent copper ion; finally, the target product is obtained by reductive elimination, and the catalyst is regenerated.

[0015] In a further technical solution, the amount of cuprous halide is 0.1-0.5 times the molar amount of 4-bromo-2-fluorobenzoic acid ethyl ester. An appropriate amount of cuprous halide is added as a catalyst to control the cost of the catalyst while improving the yield of the product.

[0016] In a further technical solution, the amount of amino acid is 0.1-0.5 times the molar amount of 4-bromo-2-fluorobenzoic acid ethyl ester. An appropriate amount of amino acid is added as a ligand. The chelate ring formed by the amino acid and the cuprous ion can improve the ability of the cuprous ion to undergo oxidative addition, and can also stabilize the trivalent copper ion complex produced.

[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 acid-binding agent neutralizes the hydrogen bromide produced in the reaction process, and promotes the forward progress of the reaction.

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

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

[0020] The present application has the following beneficial effects: the present application uses ethyl 4-bromo-2-fluorobenzoate as a starting material, and synthesizes the key intermediate ethyl 4-amino-2-fluorobenzoate of enzalutamide through esterification and Ullmann reaction. This synthesis method can not only simplify the operation and reduce the cost, but also improve the yield of the intermediate and the product, thereby being suitable for industrial production, and providing a high-quality intermediate for the preparation of enzalutamide. BRIEF DESCRIPTION OF DRAWINGS

[0021] Fig. 1 is a nuclear magnetic spectrum of the product ethyl 4-amino-2-fluorobenzoate. DETAILED DESCRIPTION

[0022] In order to make the technical means, creative features, purposes and effects realized by the present application easy to understand, the present application is further described below in combination with specific examples and drawings.

[0023] Example 1

[0024] Synthesis of ethyl 4-bromo-2-fluorobenzoate: 4-bromo-2-fluorobenzoic acid (1.0 kg, 4.56 mol) was dissolved in 10% sulfuric acid methanol solution (10 L), heated to 90℃ and reacted for 12 h. After the reaction liquid was cooled to room temperature, it was added to an ice water mixture, stirred at 5-10℃ for 1 h, filtered, the filter residue was washed with cold water and then dried in a 40℃ oven 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 mixture of dimethyl sulfoxide and water (volume ratio of dimethyl sulfoxide to water was 20:1), then cuprous 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, and the reaction was carried out at 85 °C overnight after nitrogen replacement for three times. The reaction solution was washed with water, and the organic phase was collected and distilled under reduced pressure. The obtained solid was slurried in n-heptane, filtered, and the filter residue was dried under vacuum at 60 °C to obtain ethyl 4-amino-2-fluorobenzoate with a yield of 61% and a purity of 99%.

[0026] As can be seen from FIG. 1, the target product ethyl 4-amino-2-fluorobenzoate is successfully synthesized.

[0027] Example 2

[0028] Synthesis of ethyl 4-bromo-2-fluorobenzoate: 4-bromo-2-fluorobenzoic acid (1.0 kg, 4.56 mol) was dissolved in 15% sulfuric acid methanol solution (10 L), heated to 90 °C and reacted for 12 h. After the reaction solution was cooled to room temperature, it was added to an ice water mixture, stirred at 5-10 °C for 1 h, filtered, and the filter residue 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 mixture of dimethyl sulfoxide and water (volume ratio of dimethyl sulfoxide to water was 20:1), then cuprous 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, and the reaction was carried out at 85 °C overnight after nitrogen replacement for three times. The reaction solution was washed with water, and the organic phase was collected and distilled under reduced pressure. The obtained solid was slurried in n-heptane, filtered, and the filter residue was dried under vacuum 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: 4-bromo-2-fluorobenzoic acid (1.0 kg, 4.56 mol) was dissolved in 20% sulfuric acid methanol solution (10 L) and heated to 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. The filtrate 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 83% and a purity of 95%.

[0032] Synthesis of ethyl 4-amino-2-fluorobenzoate: ethyl 4-bromo-2-fluorobenzoate (0.947 kg, 3.78 mol, 1.0 eq) was added to a mixed solvent of dimethyl sulfoxide and water (volume ratio of dimethyl sulfoxide to water was 20:1), followed by the addition of cuprous 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 nitrogen replacement for three times, the reaction was carried out at 85°C overnight. The reaction solution was washed with water, and the organic phase was collected and distilled under reduced pressure. The obtained solid was slurried in n-heptane, filtered, and the filtrate was dried under vacuum at 60°C to obtain ethyl 4-amino-2-fluorobenzoate with a yield of 57% and a purity of 99%.

[0033] As can be seen from Examples 1-3, the total yield of the product ethyl 4-amino-2-fluorobenzoate is low, mainly because the average yield of the Ullmann reaction is less than 60%. Without changing the synthesis route, the present application starts from the catalyst, uses macroporous adsorption resin as a carrier, and loads halogenated cuprous in the internal pores and on the surface of the carrier, so as to increase the contact area between the catalyst and the substrate, improve the catalytic efficiency, and make the average yield of the Ullmann reaction reach more than 85%.

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

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

[0036] The preparation method of the macroporous adsorption resin comprises the following steps: dissolving a dispersing agent in water to obtain an aqueous phase; mixing divinylbenzene, N-(2-hydroxyethyl)-N'-2-propenyl thiourea, a pore former and an initiator to obtain an oil phase; adding the oil phase into the aqueous phase to obtain the macroporous adsorption resin through a suspension polymerization reaction.

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

[0038] Preferably, the mass ratio of the divinylbenzene, N-(2-hydroxyethyl)-N'-2- propenylthiourea, the porogen, and the 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 dispersing agent is at least one selected from polyvinyl alcohol, gelatin, sodium chloride, sodium carboxymethyl cellulose, and hydroxyethyl cellulose.

[0041] Preferably, the porogen is at least one selected from toluene, xylene, C6-C12 saturated hydrocarbon, and C4-C10 alkanol.

[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 of Example 1, except that the cuprous iodide in Example 1 is replaced by macroporous adsorption resin loaded cuprous iodide, and the amount of macroporous adsorption resin loaded cuprous iodide is the same as that of cuprous iodide in Example 1 in terms of cuprous iodide. The yield is 85%, and the purity is 99%.

[0045] Preparation of macroporous adsorption resin: 0.5 g of polyvinyl alcohol, 0.5 g of gelatin, and 2.5 g of sodium chloride were dissolved in 100 g of water to obtain an aqueous phase; 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 were mixed to obtain an oil phase; the oil phase was added to the aqueous phase, the volume ratio of the aqueous phase to the oil phase was 2:1, the temperature was raised to 80°C and reacted for 2 h, the temperature was then raised to 90°C and reacted for 3 h, and then the temperature was raised to 95°C and reacted for 4 h; after the reaction was completed, sieving, water washing, toluene extraction with acetone, and 60°C vacuum drying were performed to obtain the macroporous adsorption resin.

[0046] Preparation of macroporous adsorption resin loaded cuprous iodide: the above macroporous adsorption resin and cuprous iodide were added to ethanol, ultrasonic treatment was performed for 2 h, and 50°C vacuum drying was performed to obtain the macroporous adsorption resin loaded cuprous iodide. The content of cuprous halide was 30%.

[0047] Example 5

[0048] The synthesis method of ethyl 4-amino-2-fluorobenzoate is the same as that of Example 1, except that the cuprous iodide in Example 1 is replaced by macroporous adsorption resin loaded cuprous iodide, and the amount of macroporous adsorption resin loaded cuprous iodide is the same as that of cuprous iodide in Example 1 in terms of cuprous iodide. The yield is 87%, and the purity is 99%.

[0049] Preparation of macroporous adsorption resin: 0.5 g of polyvinyl alcohol, 1 g of gelatin, 2 g of sodium chloride were dissolved in 100 g of water to obtain an aqueous phase; 80 g of divinylbenzene, 20 g of N-(2-hydroxyethyl)-N'-2-propenyl thiourea, 200 g of toluene and 1 g of azobisisobutyronitrile / benzoyl peroxide were mixed to obtain an oil phase; the oil phase was added to the aqueous phase, the volume ratio of the aqueous phase to the oil phase was 1:1, the temperature was raised to 80°C for 3 h, the temperature was continuously raised to 90°C for 3 h, then the temperature was raised to 95°C for 4 h, after the reaction was completed, sieving, water washing, extraction of toluene with acetone, vacuum drying at 60°C, to obtain the macroporous adsorption resin.

[0050] Preparation of macroporous adsorption resin loaded with cuprous iodide: the above macroporous adsorption resin and cuprous iodide were added to ethanol, ultrasonic treatment was performed for 2 h, vacuum drying was performed at 50°C, to obtain the macroporous adsorption resin loaded with cuprous iodide. The content of cuprous halide was 35%.

[0051] Example 6

[0052] The synthesis method of ethyl 4-amino-2-fluorobenzoate was the same as that in Example 1, except that the cuprous iodide in Example 1 was replaced by the macroporous adsorption resin loaded with cuprous iodide, and the amount of the macroporous adsorption resin loaded with cuprous iodide was the same as that of the cuprous iodide in Example 1. The yield was 90%, and the purity was 99%.

[0053] Preparation of macroporous adsorption resin: 0.5 g of polyvinyl alcohol, 1 g of gelatin, 2 g of sodium chloride were dissolved in 100 g of water to obtain an aqueous phase; 80 g of divinylbenzene, 20 g of N-(2-hydroxyethyl)-N'-2-propenyl thiourea, 200 g of toluene and 1 g of azobisisobutyronitrile / benzoyl peroxide were mixed to obtain an oil phase; the oil phase was added to the aqueous phase, the volume ratio of the aqueous phase to the oil phase was 1:1, the temperature was raised to 80°C for 3 h, the temperature was continuously raised to 90°C for 3 h, then the temperature was raised to 95°C for 4 h, after the reaction was completed, sieving, water washing, extraction of toluene with acetone, vacuum drying at 60°C, to obtain the macroporous adsorption resin.

[0054] Preparation of macroporous adsorption resin loaded with cuprous iodide: the above macroporous adsorption resin and cuprous iodide were added to ethanol, ultrasonic treatment was performed for 2 h, vacuum drying was performed at 50°C, to obtain the macroporous adsorption resin loaded with cuprous iodide. The content of cuprous halide was 25%.

[0055] Comparative Example 1

[0056] 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-propenyl thiourea used to prepare the macroporous adsorption resin in Example 6 was replaced by N-hydroxyethyl acrylamide. The yield was 78%, and the purity was 99%.

[0057] Comparative Example 2

[0058] The synthesis of ethyl 4-amino-2-fluorobenzoate was carried out according to Example 6, except that the monomer N-(2-hydroxyethyl)-N'-2-propenylthiourea used to prepare the macroporous adsorption resin in Example 6 was replaced by styrene. The yield was 75% and the purity was 99%.

[0059] The above shows and describes the basic principles and main features of the present application and the advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A method of synthesis of an enzalutamide key intermediate, characterized by: The 4-bromo-2-fluorobenzoic acid is used as a starting material, the esterification reaction of 4-bromo-2-fluorobenzoic acid and ethanol sulfate solution obtains 4-bromo-2-fluorobenzoic acid ethyl ester, and the Ullmann reaction of 4-bromo-2-fluorobenzoic acid ethyl ester and ammonium chloride under the action of a ligand, a catalyst and an acid binding agent obtains 4-amino-2-fluorobenzoic acid ethyl ester.

2. The process for synthesis of enzalutamide key intermediate as claimed in claim 1, wherein: The mass concentration of the ethanol sulfate solution is 10-20%.

3. The process for synthesis of enzalutamide key intermediate as claimed in claim 2, wherein: The ratio of the amount of 4-bromo-2-fluorobenzoic acid to the amount of ethanol sulfate solution is 1 kg:(5-20) L.

4. The process for synthesis of enzalutamide key intermediate as claimed in claim 1, wherein: The amount of the ammonium chloride is 1-1.5 times the molar amount of 4-bromo-2-fluorobenzoic acid ethyl ester.

5. The process for synthesis of enzalutamide key intermediate as claimed in claim 1, wherein: The catalyst is cuprous halide; preferably, the cuprous halide is at least one selected from cuprous iodide, cuprous chloride and cuprous bromide.

6. The process for synthesis of enzalutamide key intermediate as claimed in claim 1, wherein: The ligand is an amino acid; preferably, the amino acid is at least one selected from L-proline, N-methyl glycine, N,N-dimethyl glycine, N-benzyl glycine, N,N-dibenzyl glycine, 3-methylamino propionic acid and 3-dimethylamino propionic acid.

7. The process for synthesis of enzalutamide key intermediate as claimed in claim 5, wherein: The amount of the cuprous halide is 0.1-0.5 times the molar amount of 4-bromo-2-fluorobenzoic acid ethyl ester.

8. The process for synthesis of enzalutamide key intermediate as claimed in claim 6, wherein: The amount of the amino acid is 0.1-0.5 times the molar amount of 4-bromo-2-fluorobenzoic acid ethyl ester.

9. The process for synthesis of enzalutamide key intermediate as claimed in claim 1, wherein: The acid binding agent is one or more of potassium carbonate, sodium carbonate, triethylamine, pyridine and N,N-diisopropyl ethylamine.

10. The process for synthesis of enzalutamide key intermediate as claimed in claim 9, wherein: The amount of the acid binding agent is 1-1.5 times the molar amount of 4-bromo-2-fluorobenzoic acid ethyl ester.

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