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Method for preparation of compound shown as formula (IV) of enzalutamide synthesis intermediate

A technology of enzalutamide and compounds, which is applied in the field of chemical drug synthesis, can solve the problems of difficult removal of by-products and low yield of target products, and achieve the effects of simple post-treatment operation, high conversion rate and mild reaction conditions

Pending Publication Date: 2020-07-28
令灏远(苏州)科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In order to overcome the deficiencies in the prior art, the embodiment of the present invention provides a method for preparing the enzalutamide intermediate compound of formula (IV), which is used to overcome the low yield of the target product in the method for preparing formula IV in the prior art, The disadvantage that the by-product introduced by the condensing agent EDCI is not easy to remove

Method used

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  • Method for preparation of compound shown as formula (IV) of enzalutamide synthesis intermediate
  • Method for preparation of compound shown as formula (IV) of enzalutamide synthesis intermediate
  • Method for preparation of compound shown as formula (IV) of enzalutamide synthesis intermediate

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Embodiment 1

[0022] Under the protection of nitrogen, add compound I (50g, 0.150mol), sodium iodide (67.5g, 0.450mol) and 500mL of acetone to a 1000mL three-necked flask at room temperature, magnetically stir, and heat to reflux, react for 16h, stop the reaction , Concentrated to an appropriate volume to precipitate a solid, filtered with suction, washed with water, and dried to obtain an off-white solid, dried to obtain 45.8 g of the compound of formula II, with a yield of 80.0%.

Embodiment 2

[0024] Under the protection of nitrogen, into a 100mL three-necked flask, add compound II (2.67g, 0.007mol), compound III (X=OCH 3 ) (1.39g, 0.008mol), potassium carbonate (2.85g, 0.021mol) and acetonitrile (30mL), magnetically stirred and heated to reflux, react for 16h, stop the reaction, cool to room temperature, concentrate to 10mL, add 30mL of water After suction filtration and drying, 2.22 g of off-white solid was obtained, with a yield of 75.0%. 1 H-NMR(400M,DMSO-d6): 10.576(s,1H),8.324-8.319(d,1H,J=2.0Hz),8.220-8.193(dd,1H,J=8.8Hz,2.0Hz), 8.082 -8.061(d,1H,J=8.4Hz),7.652-7.608(t,1H,J=8.8Hz),7.065(s,1H),6.396-6.369(dd,1H,J=8.8Hz,2.0Hz) ,6.293-6.252(m,1H),3.721(s,3H),1.529(s,6H)

Embodiment 3

[0026] Under the protection of nitrogen, into a 100mL three-necked flask, add compound II (2.67g, 0.007mol), compound III (X=OCH 3 ) (1.39g, 0.008mol), diisopropylethylamine (2.66g, 0.021mol) and acetonitrile (30mL), magnetically stirred, and heated to reflux, react overnight, stop the reaction, cool to room temperature, concentrate to 10mL, 30 mL of citric acid aqueous solution was added, suction filtered and dried to obtain a crude brown solid. Petroleum ether / ethyl acetate column chromatography was used to obtain 1.67 g of off-white solid, with a yield of 56.3%.

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Abstract

The invention discloses a method for preparing a compound shown as a formula (IV) of an enzalutamide synthesis intermediate. The compound shown as the formula (IV) is an important intermediate for preparing an anti-prostate cancer drug enzalutamide. The method comprises the following steps of: taking a compound as shown in a formula (I) as a starting material, performing iodination to obtain a compound as shown in a formula (II), and performing a nucleophilic substitution reaction on the compound as shown in the formula (II) and a compound as shown in a formula (III) to obtain the compound asshown in the formula (IV). The method is high in yield, mild in reaction condition, simple and convenient to operate and suitable for large-scale industrial production.

Description

Technical field [0001] The invention belongs to the field of chemical drug synthesis, and specifically is a method for preparing a compound of formula (IV) as an intermediate for the synthesis of enzalutamide. Background technique [0002] Enzalutamide (MDV3100) is a new generation of androgen receptor antagonist jointly developed by Medivation and Astellas. It can block androgen from binding to the androgen receptor and prevent the core of the ligand-receptor complex. Relocation and recruitment of co-activators. Enzalutamide has been shown to induce tumor cell apoptosis and has no agonist activity. In 2012, the U.S. Food and Drug Administration (FDA) approved for the treatment of advanced male castration-resistant prostate cancer that has spread or relapsed (castration-resistantprostatecancer), the trade name is Xtandi, and the drug is an oral preparation. [0003] Enzalutamide (MDV3100), the structural formula is as follows: [0004] [0005] Synthetic intermediate of enzalutami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/60C07C253/30
CPCC07C253/30C07C255/60
Inventor 孟祥国邱诗汪硕闻
Owner 令灏远(苏州)科技有限公司
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