Method for synthesizing enzalutamide

A technology of enzalutamide and compounds, applied in the field of synthesizing enzalutamide, can solve problems such as corrosion, damage, and inhibition of the central nervous system

Pending Publication Date: 2020-12-08
ANLITE SHANGHAI PHARMA TECH CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In fact, the conversion rate of this step reaction is at most only 20%. If the reaction temperature is increased, many by-products will be produced, and the yield cannot be improved; and the second step reaction needs to be carried out in the presence of phenol, which has moderate toxicity , has a strong corrosive effect on the skin and mucous membranes, and can also inhibit the central nervous system or damage the liver and kidney functions

Method used

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  • Method for synthesizing enzalutamide
  • Method for synthesizing enzalutamide
  • Method for synthesizing enzalutamide

Examples

Experimental program
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Effect test

Embodiment 1

[0135] Embodiment 1: Preparation of 2-fluoro-4-bromobenzamide (compound 8)

[0136] Add 4-bromo-2-fluorobenzoic acid (300.0g, 1.4mol), isopropyl acetate (IPAc) 2L, thionyl chloride (228.0g, 1.9mol), DMF (30.0g, 0.4mol) into the reaction flask , slowly raised the temperature to 55°C, and kept the reaction for 3 hours. Cool down to 10-20°C, slowly add a mixture of methylamine aqueous solution (987.0 g, 0.79 mol) and 600 mL of isopropyl acetate dropwise, and control the temperature at 0-10°C. After the dropwise addition, the temperature was raised to 35° C., and stirring was continued for 12 hours. After the reaction was completed, 600 mL of pure water was added and stirred for 10 minutes. The layers were separated, and the aqueous layer was extracted twice with 600 ml of isopropyl acetate. The combined organic layers were dried and concentrated to dryness. Add 1.5 L of n-heptane to the residue to make a slurry, filter, and vacuum-dry at 40° C. for 6 hours to obtain 300.3 g o...

Embodiment 2

[0137] Example 2: Preparation of N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 9):

[0138] Compound 8 (100.0 g, 0.43 mol) prepared in Example 1, methyl aminoisobutyrate hydrochloride (R is -CH 3 ) (99.5g, 0.65mol), K 2 CO 3 (180.0 g, 1.3 mol), CuCl (8.5 g, 85.4 mmol), DMF (600 mL) and water (60 mL), heated to 30°C. Add 2-acetylcyclohexanone (12.0 g, 85.6 mmol), heat to 105° C., and continue stirring for 12 hours. After the reaction, cool down to room temperature, add water (1.2 L) and IPAc (600 mL), and stir for 10 minutes. The separated aqueous layer was extracted twice with IPAc (600 mL). The combined organic layers were acidified with concentrated hydrochloric acid to pH 2-3, and solids were precipitated. It was further cooled to 0-5°C, filtered, and the filter cake was washed with water (300 mL). Add 700mL of absolute ethanol to the wet product, raise the temperature to reflux, and make the solution clear. Cool down to 5-10°C, filter, and v...

Embodiment 3

[0139] Example 3: Preparation of N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 9):

[0140] Compound 8 (5.0 g, 21.6 mmol) prepared in Example 1, benzyl aminoisobutyrate hydrochloride (R is ) (8.9g, 38.8mmol), K 2 CO 3(10.3 g, 74.6 mmol), CuI (0.5 g, 2.6 mmol), DMSO (50 mL) and water (5 mL), heated to 40°C. Add 2-acetylcyclohexanone (0.5 g, 3.6 mmol), heat to 110° C., and continue stirring for 10 hours. After the reaction, cool down to room temperature, add water (60 mL) and IPAc (40 mL), and stir for 10 minutes. The separated aqueous layer was extracted with IPAc (40 mL). The combined organic layers were acidified with concentrated hydrochloric acid to pH 2-3, and solids were precipitated. It was further cooled to 0-5°C, filtered, and the filter cake was washed with water (20 mL). Add 40mL of absolute ethanol to the wet product, raise the temperature to reflux, and make the solution clear. Cool down to 0-5°C, filter, and dry under vacuum at 40°...

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Abstract

The invention provides a method for synthesizing enzalutamide. Specifically, the preparation method comprises the following steps: (1) in a first solvent, in the presence of an inorganic base, a catalyst and a ligand, enabling a compound 8 to react with hydrochloride of a compound shown as a formula I, thereby obtaining a compound 9; wherein the first solvent is composed of an organic solvent 1 and water; and (2) reacting the compound 9 and the compound 7 in a second solvent in the presence of an organic base to obtain enzalutamide. The preparation method has the advantages of short synthesisroute, high yield, mild reaction conditions, simple operation and post-treatment, high product purity, and suitableness for industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthetic chemistry, in particular to a method for synthesizing enzalutamide. Background technique [0002] Enzalutamide (Enzalutamide) was jointly developed by Astellas Pharmaceutical Group and Madison Wesson Medical Company. The trade name is Xtandi and the chemical name is 4-[3-[4-cyano-3-(trifluoromethyl) phenyl]-5,5-dimethyl-4-oxo-2-thione-1-imidazolidinyl]-2-fluoro-N-methylbenzamide. Enzalutamide is a new type of non-steroid androgen receptor antagonist, which can competitively inhibit the binding of androgen to androgen receptor, inhibit the transfer of androgen receptor to the nucleus and the interaction between androgen receptor and DNA interaction to exert anti-prostate cancer efficacy. Enzalutamide was approved by the US FDA on August 31, 2012 for the treatment of diffuse or metastatic castration-resistant prostate cancer. [0003] Currently, the disclosed synthetic techniques of enzalu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor 周吴胡猛
Owner ANLITE SHANGHAI PHARMA TECH CO LTD
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