Preparation method of enzalutamide

A technology of enzalutamide and methylamine, which is applied in the field of prostate cancer drugs, can solve the problems of low total yield, low yield, labor protection and environmental hazards, and achieve convenient and simple post-treatment, mild reaction conditions and low production cost. Reduced effect

Active Publication Date: 2015-07-29
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1) The yield of the target product in the last step reaction is only 25%, so the total yield is very low;
[0008] 2) The purification of each intermediate requires column chromatography, which prolongs the production time and increases the co

Method used

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  • Preparation method of enzalutamide

Examples

Experimental program
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Effect test

Embodiment 1

[0056] Preparation of 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropanoic acid (C)

[0057]

[0058] Add 4-bromo-2-fluoro-benzoic acid methyl ester (A, 100g), 2-aminoisobutyric acid (66g, 1.5 equivalents), cuprous chloride (8.4g, 0.2 equivalents) into a 1L four-neck flask )﹑Potassium carbonate (148g, 2.5 equivalents)﹑DMF (700ml)﹑H 2 O (5.0ml) was heated to 105°C for 14h under nitrogen protection, cooled to room temperature, and isopropyl acetate (600ml) and H 2 O (1.2L), stirred, separated, took the water layer, added 1M citric acid aqueous solution to adjust pH = 4, precipitated solid, cooled to below 5°C, filtered with suction, dried to obtain the product 2-(3-fluoro -4-(Methoxyformyl)phenylamino)-2-methylpropanoic acid (C, 85.9 g, yield 78.5%). MSm / z256[M+H] + ; 1 HNMR (400Hz, DMSO-d 6 )δ7.81-7.79(d,J=8.0Hz,1H),7.52(s,1H),7.47(br,1H),7.40-7.38(d,J=8.0Hz,1H),3.77(s,3H ), 1.59(s,6H).

Embodiment 2

[0060] Preparation of methyl 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropanoate (D)

[0061]

[0062] Add 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropionic acid (C, 100g), MeOH (1.0L), DMF (3.0ml) into a 2L four-neck flask ) after cooling to below 10°C, drop in SOCl 2 (30ml, 1.05 equivalents), reflux reaction for 12h after the dropwise addition, after TCL monitors the reaction, evaporate the solvent to dryness, add H 2 O (400ml) and EtOAc (400ml), stirred, added dropwise sodium carbonate aqueous solution to adjust pH = 8, separated, took the organic layer, evaporated to dryness, added petroleum ether (400ml) and stirred and washed to obtain the white solid product 2-(3 -Methyl fluoro-4-(methoxyformyl)phenylamino)-2-methylpropanoate (D, 101.5 g, yield 96.2%). MSm / z270[M+H] + ; 1 HNMR (400Hz, DMSO-d 6 )δ7.80-7.78(d,J=8.0Hz,1H),7.53(s,1H),7.48(br,1H),7.40-7.38(d,J=8.0Hz,1H),3.77(s,3H ), 3.69(s,3H), 1.58(s,6H).

Embodiment 3

[0064] Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-Fluoro-benzoic acid methyl ester (F)

[0065]

[0066] Add 2-(3-fluoro-4-(methoxyformyl)benzylamino)-2-methylpropionic acid methyl ester (D, 50g)﹑4-isothiocyanato-2 into a 500ml four-necked bottle -(Trifluoromethyl)benzonitrile (E, 84.7g, 2eq), DMSO (50ml) and isopropyl acetate (100ml). Heat the reaction solution to 90°C for 20h, cool to room temperature, add MeOH (15ml), heat to 70°C for 40min, cool to room temperature, add isopropyl acetate (600ml)﹑HO 2 O (300ml) and IPA (100ml), stirred and separated, evaporated the organic phase to remove the solvent to about 450ml, added IPA (1.2L) and heated to 80°C to dissolve completely, then cooled to 10°C, a white solid was precipitated, filtered with suction , dried to give 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1 -yl)-2-fluoro-benzoic acid methyl ester (F, 71.7g, yield 83.0...

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Abstract

The invention provides a preparation method of enzalutamide. The method comprises the following steps: adding a compound with formula F to a solvent; reacting with a methylamine source; and after the reaction, collecting the compound with formula G from the reaction products, so as to obtain the enzalutamide. The invention overcomes the major problems of the prior art, gets rid of the time-consuming and labor-consuming operation such as column chromatography, gets rid of the highly toxic reagent such methyl iodide, and has the advantages of mild reaction conditions, simple and easy post-treatment, increased overall yield, reaction time reduction, production cost reduction, and applicability to industrial scale-up. The reaction general formula is as below.

Description

technical field [0001] The invention relates to a preparation method of Enzalutamide, a drug for treating hormone-refractory prostate cancer. Background technique [0002] Enzalutamide (Enzalutamide) is an androgen receptor antagonist developed by Medivation Corporation of the United States, Medivation and Japan Astek Corporation, and its chemical name is 4-(3-(4-cyano-3-(trifluoromethyl )phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, has divergent castration for treatment Refractory prostate cancer has a special effect. [0003] The methods for preparing enzalutamide in the prior art mainly include: [0004] CN101333922B discloses a method for preparing enzalutamide, as shown in Scheme 1 below: [0005] [0006] This route uses nitrotoluene derivatives as raw materials to prepare the target product through 6-step reactions such as oxidation, amidolysis and reduction, and mainly has the following defects: [0007] 1) The yield of the...

Claims

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Application Information

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IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor 李建其郑永勇邢龙轩吴夏冰施耐燕
Owner SHANGHAI INST OF PHARMA IND
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