阅读说明：本技术 一种恩杂鲁胺的合成方法 (Synthetic method of enzalutamide ) 是由 朱义胜 杨铎 张�杰 于 2020-12-29 设计创作，主要内容包括：本发明公开了一种恩杂鲁胺的合成方法。该方法采用4-氨基-2-三氟甲基苯甲腈为起始原料,依次与苯甲酰异硫氰酸酯(硫氰酸铵与苯甲酰氯的反应产物)、2-甲基-2-氯丙酸甲酯、N-甲基-4-溴-2-氟代苯甲酰胺经多步取代反应得到恩杂鲁胺。该合成方法不仅可以保证产率和产品质量,而且可以保护人员健康安全,生产安全,适宜于工业化生产。(The invention discloses a synthesis method of enzalutamide. The method adopts 4-amino-2-trifluoromethyl benzonitrile as a starting material, and sequentially carries out multi-step substitution reaction with benzoyl isothiocyanate (a reaction product of ammonium thiocyanate and benzoyl chloride), 2-methyl-2-methyl chloropropionate and N-methyl-4-bromo-2-fluorobenzamide to obtain enzalutamide. The synthesis method can not only ensure the yield and the product quality, but also protect the health and safety of personnel, ensure the production safety and be suitable for industrial production.)

1. The synthesis method of enzalutamide is characterized by comprising the following steps:

1) firstly, reacting ammonium thiocyanate with benzoyl chloride to generate benzoyl isothiocyanate, then reacting with 4-amino-2-trifluoromethyl benzonitrile, and removing benzoyl under an alkaline condition to obtain a compound A;

2) under the action of triethylamine, carrying out cyclization on the compound A and 2-methyl-2-methyl chloropropionate to obtain a compound B;

3) under the action of inorganic base, cuprous iodide and 2-acetyl cyclohexanone, the compound B reacts with N-methyl-4-bromo-2-fluorobenzamide to obtain enzalutamide;

the compound A is 1- (4-cyano-3- (trifluoromethyl) phenyl) thiourea;

the compound B is 2- (trifluoromethyl) -4- (4, 4-dimethyl-5-oxo-2-thioimidazoline-1-yl) benzonitrile.

2. The method for synthesizing enzalutamide according to claim 1, wherein the reaction temperature in the step 1) is as follows: 30-60 ℃.

3. The method for synthesizing enzalutamide according to claim 1, wherein the reaction temperature in the step 2) is as follows: 70-100 ℃.

4. The method for synthesizing enzalutamide as claimed in claim 1, wherein the reaction temperature in the step 3) is: 100 to 130 ℃.

5. The synthesis method of enzalutamide as claimed in any one of claims 1-4, characterized by comprising the following steps:

1) adding ammonium thiocyanate, an organic solvent 1 and benzoyl chloride into a reaction container, heating to 40-45 ℃, dropwise adding a 4-amino-2-trifluoromethyl benzonitrile solution, and continuing to perform heat preservation reaction for 0.5-2 hours after dropwise adding; after the reaction is finished, pouring the reaction solution into ice water, separating out a precipitate, dissolving the precipitate in a NaOH solution, adjusting the pH value to 1.5-2.5, and performing post-treatment to obtain a compound A;

2) adding the compound A, 2-methyl-2-methyl chloropropionate and triethylamine into the organic solvent 2 under stirring, heating to 80-90 ℃, reacting for 3-8 h, and carrying out post-treatment to obtain a compound B;

3) under the protection of inert gas, adding N-methyl-4-bromo-2-fluorobenzamide, a compound B, solid inorganic base and cuprous iodide into a reaction vessel, adding an organic solvent 3, fully stirring, adding 2-acetyl cyclohexanone, heating to 110-115 ℃, reacting for 20-25 hours, and performing post-treatment to obtain enzalutamide.

6. The method for synthesizing enzalutamide as claimed in claim 5, wherein the organic solvent 1 is: acetone, tetrahydrofuran or n-hexane; the organic solvent 2 is tetrahydrofuran, dioxane or DMF; the organic solvent 3 is: toluene, dioxane or DMF.

7. The method for synthesizing enzalutamide according to claim 5, wherein the inorganic base in the step 3) is: potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

8. The method for synthesizing enzalutamide according to claim 5, wherein the post-treatment in the step 1) is as follows: adjusting pH to 7.5-8.5 with alkali solution, filtering, washing with water, and oven drying to obtain compound A; the alkali liquor is as follows: potassium hydroxide solution, sodium hydroxide solution, or ammonia water.

9. The method for synthesizing enzalutamide according to claim 5, wherein the post-treatment in the step 2) is as follows: and cooling to room temperature, adding the reaction solution into ice water, filtering, and drying a filter cake to obtain a compound B.

10. The synthesis method of enzalutamide as claimed in claim 5, wherein the post-treatment of the step 3) is: cooling the reaction solution to room temperature, adding water and ethyl acetate, standing, concentrating the organic layer under reduced pressure to dryness, adding a refined solvent, heating for dissolving, and cooling for crystallization to obtain enzalutamide; the refined solvent is as follows: methanol, ethanol or isopropanol.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of enzalutamide.

Background

Enzalutamide (enzalutamide) is a co-developed androgen receptor inhibitor by anslatide and Medivation, which was initially approved by the FDA at 8 months of 2012 for the treatment of advanced castration resistant prostate cancer under the trade name Xtandi. At 8 months 2016, fevered purchases meditation at $ 140 million to keep this drug under capsule. In vitro experimental studies show that enzalutamide can inhibit the proliferation of prostate cancer cells and induce the death of the prostate cancer cells, and enzalutamide can reduce the tumor volume in a mouse prostate cancer xenograft model experiment. The major metabolite of enzalutamide is N-demethylenzalutamide, which exhibits similar inhibitory activity in vitro as enzalutamide.

Enzalutamide, compound name: 4- [3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thione-1-imidazolidinyl ] -2-fluoro-N-methylbenzamide, molecular weight: 464. the structural formula is as follows:

to date, the synthetic patents for enzalutamide can be briefly summarized in two categories: one is a synthetic method taking a compound 4-isothiocyanato-2- (trifluoromethyl) benzonitrile as a raw material or an intermediate, the compound has high sensitivity to human bodies and can cause harm to operators who use and produce, and most patents belong to the same class; the other method does not adopt the compound 4-isothiocyanato-2- (trifluoromethyl) benzonitrile as a raw material or an intermediate for synthesis, but uses dangerous materials with potential safety hazards.

Patent CN103108549A discloses a synthesis method of enzalutamide, which uses 4-bromo-2-fluoro-N-methylbenzamide and 2-amino-2-methylpropanoic acid as starting materials, firstly performs substitution reaction, then performs esterification reaction with methyl iodide, and then performs reaction cyclization with 4-isothiocyanato-2- (trifluoromethyl) benzonitrile to obtain enzalutamide, wherein the synthetic route is shown in the following. In the synthetic method, expensive and toxic raw material methyl iodide is used, and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile is used as an intermediate to synthesize the enzalutamide, so that the synthetic method is dangerous, unfavorable for production and high in raw material cost.

CN104844520A discloses a method for synthesizing enzalutamide, which comprises the steps of firstly reacting thiourea with an isobutyric acid derivative to obtain a key parent nucleus 5, 5-dimethyl-2-thioketone imidazole-4-ketone, then reacting with a compound 4 under the action of alkali (such as sodium hydride) to obtain a compound 5, and reacting with a compound 6 under the action of alkali (such as sodium hydride) to obtain the enzalutamide, wherein the synthetic route is shown as follows. In the synthesis method, sodium hydride is used in two steps, the substance is strong in alkalinity, but the substance is active in property, flammable and explosive, difficult to store and brings great potential safety hazard to production operation and use, and the method is not suitable for large-scale production.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a synthesis method of enzalutamide. The method adopts 4-amino-2-trifluoromethyl benzonitrile as a starting material, and the enzoyl isothiocyanate, 2-methyl-2-methyl chloropropionate and N-methyl-4-bromo-2-fluorobenzamide are subjected to multi-step substitution reaction in sequence to obtain enzalutamide. The synthesis method can not only ensure the yield and the product quality, but also protect the health and safety of personnel, ensure the production safety and be suitable for industrial production.

The technical scheme of the invention is as follows: a method for synthesizing enzalutamide, which is characterized in that,

1) firstly, reacting ammonium thiocyanate with benzoyl chloride to generate benzoyl isothiocyanate, then reacting with 4-amino-2-trifluoromethyl benzonitrile, and removing benzoyl under an alkaline condition to obtain a compound A (1- (4-cyano-3- (trifluoromethyl) phenyl) thiourea);

2) under the action of triethylamine, the compound A and 2-methyl-2-methyl chloropropionate are subjected to cyclization to obtain a compound B (2- (trifluoromethyl) -4- (4, 4-dimethyl-5-oxo-2-thioimidazoline-1-yl) benzonitrile);

3) under the action of inorganic base, cuprous iodide and 2-acetyl cyclohexanone, the compound B reacts with N-methyl-4-bromo-2-fluorobenzamide to obtain enzalutamide.

The reaction temperature of the step 1) is as follows: 30-60 ℃, preferably 40-45 ℃.

The reaction temperature of the step 2) is as follows: 70-100 ℃, preferably 80-90 ℃.

The reaction temperature of the step 3) is as follows: 100 to 130 ℃, preferably 110 to 115 ℃.

The reaction equation is as follows.

The method specifically comprises the following steps:

1) adding ammonium thiocyanate, an organic solvent 1 and benzoyl chloride into a reaction container, heating to 40-45 ℃, dropwise adding a 4-amino-2-trifluoromethyl benzonitrile solution, continuing to perform heat preservation reaction for 0.5-2 hours after dropwise adding, pouring a reaction solution into ice water, separating out a precipitate, dissolving the precipitate in a NaOH solution, adjusting the pH value to 1.5-2.5, and performing post-treatment to obtain a compound A;

2) adding the compound A, 2-methyl-2-methyl chloropropionate and triethylamine into the organic solvent 2 in turn under stirring, heating to 80-90 ℃, reacting for 3-8 h, and carrying out post-treatment to obtain a compound B;

3) under the protection of inert gas, adding N-methyl-4-bromo-2-fluorobenzamide, a compound B, solid inorganic base and cuprous iodide into a reaction vessel, adding an organic solvent 3, fully stirring, adding 2-acetyl cyclohexanone, heating to 110-115 ℃, reacting for 20-25 hours, and performing post-treatment to obtain enzalutamide.

Wherein, the organic solvent 1 is: acetone, tetrahydrofuran, n-hexane, etc., preferably acetone. The organic solvent 2 is tetrahydrofuran, dioxane, DMF, etc, preferably DMF. The organic solvent 3 is: toluene, dioxane, DMF, etc., preferably DMF.

The molar ratio of the 4-amino-2-trifluoromethyl benzonitrile, the benzoyl chloride and the ammonium thiocyanate in the step 1) is 1: 1-1.2: 1-1.1, preferably 1:1.1: 1.

The molar ratio of the compound A in the step 2), methyl 2-methyl-2-chloropropionate and triethylamine is 1: 1-1.2, preferably 1:1.05: 1.1.

The compound B, N-methyl-4-bromo-2-fluorobenzamide in the step 3), the inorganic base, the cuprous iodide and the 2-acetyl cyclohexanone are in a molar ratio of 1: 0.9-1.1: 1.5-3.0: 0.1-0.5, preferably 1:1:2:0.2: 0.1-0.5. The inorganic base is as follows: potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like, preferably potassium carbonate.

The post-treatment of the step 1) comprises the following steps: adjusting pH to 7.5-8.5 with alkali solution, filtering, washing with water, and oven drying to obtain compound A; the alkali liquor is as follows: potassium hydroxide solution, sodium hydroxide solution, ammonia water, etc., preferably ammonia water.

The post-treatment of the step 2) comprises the following steps: and cooling to room temperature, adding the reaction solution into ice water, filtering, and drying a filter cake to obtain a compound B.

The post-treatment of the step 3) comprises the following steps: and cooling the reaction solution to room temperature, adding water and ethyl acetate, standing, concentrating the organic layer under reduced pressure to dryness, adding a refined solvent, heating for dissolving, and cooling for crystallization to obtain enzalutamide. The refined solvent is as follows: methanol, ethanol, isopropanol, etc., preferably isopropanol.

The invention has the beneficial effects that: most of the existing enzalutamide synthesis methods use raw materials or intermediates which can cause allergy to users or producers, and great potential safety hazards exist in the actual operation and production of the process. The enzalutamide is obtained by taking 4-amino-2-trifluoromethyl benzonitrile as a starting material through a multi-step substitution reaction. The synthesis method of the invention not only can ensure the yield and the product quality, but also can protect the health and safety of operators, has safe production and is suitable for industrial production.

Detailed Description

The present invention is described in detail below with reference to examples, which are intended to be illustrative only and not limiting.

Example 1: synthesis of intermediate A

Adding 9g of ammonium thiocyanate, 100ml of anhydrous acetone and 15.1g of benzoyl chloride into a three-mouth glass reaction bottle at room temperature, heating the solution to 40-45 ℃, dropwise adding a mixture of 20g of 4-amino-2-trifluoromethyl benzonitrile and 100ml of acetone solution, and continuing to perform heat preservation reaction for 1h after dropwise adding. The reaction solution was poured into ice water, and the precipitate was separated out and filtered. The filter cake was dissolved in 2M NaOH solution, adjusted to pH 2 with concentrated HCl and adjusted to pH8 with ammonia. The product was filtered, washed with copious amounts of water and dried to yield 21.8g of compound a in 83.0%.

Example 2: synthesis of intermediate B

Adding 160ml of DMF into a three-opening glass reaction bottle, adding 20g of compound A, 11.7g of 2-methyl-2-chloropropionate and 9g of triethylamine in turn under stirring, heating to the temperature of 80-90 ℃, reacting for 5 hours, and monitoring by TLC to complete the reaction. And cooling to room temperature, adding the reaction solution into ice water, filtering, and drying a filter cake to obtain 22.7g of a compound B, wherein the yield is 88.9%.

Example 3: synthesis of enzalutamide

14.8g of N-methyl-4-bromo-2-fluorobenzamide, 20g of compound B, 22g of potassium carbonate and 2.4g of cuprous iodide are added into a three-neck reaction flask under the protection of inert gas, DMF160ml is added, the mixture is fully stirred, 1.8g of 2-acetyl cyclohexanone is added, and the mixture is heated to 110 ℃ to react for 22 hours. After completion of the reaction, the reaction solution was cooled to room temperature, purified water (500ml) and ethyl acetate (150ml) were added, the mixture was allowed to stand, the layers were separated, the aqueous ethyl acetate was extracted twice, and the organic layers were combined. Drying with anhydrous magnesium sulfate, concentrating under reduced pressure to dryness, adding isopropanol, heating to dissolve, stirring at 0-5 deg.C to crystallize, filtering, and oven drying the filter cake to obtain 26.3g of enzalutamide with yield of 88.7 and purity of 98.2%.