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Preparation method of enzalutamide intermediate F

A technology for enzalutamide and intermediates is applied in the field of preparing enzalutamide (Enzalutamide) intermediates, which can solve the problems of labor protection and environmental hazards, unreported synthesis methods, and prolong production time, so as to reduce labor insurance risks. , the post-processing is simple, and the effect of improving the total yield

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

AI Technical Summary

Problems solved by technology

[0008] 1) The yield of the target product in the last step reaction is only 25%, so the total yield is very low;
[0009] 2) The purification of each intermediate requires column chromatography, which prolongs the production time and increases the cost;
[0010] 3) The highly toxic reagent acetone cyanohydrin was used, which caused great harm to labor protection and the environment
[0020] Patent CN101333922B reports the structure of compound F, but no report of its synthetic method

Method used

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  • Preparation method of enzalutamide intermediate F
  • Preparation method of enzalutamide intermediate F
  • Preparation method of enzalutamide intermediate F

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropanoic acid (C)

[0055]

[0056] 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 1.0L four-neck flask )﹑Potassium carbonate (148g, 2.5 equivalents)﹑DMF (700ml)﹑H 2 O (5ml) was heated to 105°C for 14h under the protection of nitrogen, cooled to room temperature, and added with IPAc (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%). MS m / 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

[0058] Preparation of methyl 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropanoate (D)

[0059]

[0060] Add 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropionic acid (C, 100g), MeOH (1.0L), DMF (3.0 ml) and cool to below 10°C, add SOCl2 (30ml, 1.05 equivalent) dropwise, reflux for 12 hours after the dropwise addition, monitor the reaction with TCL, evaporate the solvent to dryness, add H2 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

[0062] 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)

[0063] 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 IPAc (100ml). Heat the reaction solution to 90°C for 20h, cool to room temperature, add MeOH (15ml), heat to 60°C for 60min, cool to room temperature, add IPAc (600ml)﹑HO 2 O (300ml) and IPA (100ml), stirred, separated, evaporated the organic phase to remove the solvent to about 450ml, added IPA (750mL) and heated to 80°C to completely dissolve, then cooled to 10°C, a white solid precipitated, suction filtered, Dry to give 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1- base)-2-fluoro-benzoic acid methyl ester (F, 71.7g, yield 83.0%). MS m / z466[M+H] + ; 1 HNMR (400Hz, DMSO-d 6...

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Abstract

The invention provides a preparation method of an enzalutamide intermediate F. The method comprises the steps of: (1) reacting a compound with a formula D and a compound with a Formula E in a solvent; (2) after the reaction, cooling to room temperature and adding a protic solvent; and (3) adding a polar solvent, and then collecting the compound with the formula F from the reaction products. The preparation process has the advantages of easily available raw materials, easy reaction operation, simple post-treatment and no usage of hazardous reagent in the preparation method, and is applicable to industrial production. The reaction general formula is as below.

Description

technical field [0001] The invention relates to a preparation method for the preparation of Enzalutamide (Enzalutamide) intermediates, in particular to 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl The preparation method of -4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-benzoic acid ester (F). [0002] Background technique [0003] 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. [0004] The methods for preparing enzalutamide in the prior art mainly include: [0005] The method for preparing such compounds in CN101333922B is shown in Scheme 1 below: [0006] [0007] This route uses nitrotoluene derivatives as raw materials t...

Claims

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Application Information

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