CN104803918B - The preparation method of the miscellaneous Shandong amine of grace - Google Patents

Abstract

The invention provides a preparation method of enzalutamide, comprising the following steps: adding the compound of formula F into a solvent, reacting with a source of methylamine, and collecting the compound of formula G from the reaction product after the reaction, which is the Enzalutamide. The present invention overcomes the main problems existing in the prior art, eliminates time-consuming and laborious operations such as column chromatography, eliminates the use of highly toxic reagents such as methyl iodide, has mild reaction conditions, convenient and simple post-treatment, improves the total yield, and reduces The reaction time is shortened, the production cost is reduced, and it is suitable for industrial scale-up. The general reaction formula is as follows.

Description

The preparation method of enzalutamide

technical field

The invention relates to a preparation method of Enzalutamide, a drug for treating hormone-refractory prostate cancer.

Background technique

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.

The methods for preparing enzalutamide in the prior art mainly include:

CN101333922B discloses a method for preparing enzalutamide, as shown in Scheme 1 below:

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:

1) The yield of the target product in the last step reaction is only 25%, so the total yield is very low;

2) The purification of each intermediate requires column chromatography, which prolongs the production time and increases the cost;

3) The highly toxic reagent acetone cyanohydrin has been used, which has caused great harm to labor protection and the environment.

CN103108549A discloses a method for preparing enzalutamide, as shown in Scheme 2 below:

This route uses p-bromo-o-fluorobenzoic acid as a raw material to prepare the target product through 5-step reaction. This route uses highly toxic reagents such as methyl iodide, which is not conducive to environmental protection and brings great hidden dangers to production safety. .

Another method for preparing enzalutamide is also disclosed in CN103108549A, as shown in Scheme 3 below:

This method yield is extremely low, causes the increase of raw material waste and production cost.

Contents of the invention

The purpose of the present invention is to disclose a method for preparing enzalutamide to overcome the defects in the prior art.

The method for preparing enzalutamide disclosed by the invention comprises the following steps:

The compound of formula F is added into a solvent to react with the source of methylamine. After the reaction, the compound of formula G is collected from the reaction product, which is the enzalutamide.

in:

R ₁ is methyl, ethyl or isopropyl;

The source of methylamine is a methylamine aqueous solution with a weight concentration of 20-40%, a weight concentration of 20-35% methylamine alcohol solution, a weight concentration of 5-10% methylamine tetrahydrofuran solution or methylamine gas, etc. The preferred weight concentration is 30-40% methylamine aqueous solution or methylamine gas;

The amount of methylamine source is 3.0-20.0 equivalents of the compound of formula F, preferably 5.0-15.0 equivalents, more preferably 8.0-10.0 equivalents;

The reaction temperature is 5-50°C, preferably 10-30°C, more preferably 15-25°C;

The reaction time is 0.5 to 20 hours, preferably 3 to 10 hours;

The solvent is one or more of dichloromethane, tetrahydrofuran (THF), alcohols, toluene or ethyl acetate, etc., preferably tetrahydrofuran or alcohols, such as ethanol, isopropanol, n-propanol, n-butanol or isobutanol, more preferably isopropanol or ethanol, and the solvent is more preferably tetrahydrofuran;

The amount of the solvent is 0.5-5.0ml/g intermediate F, preferably 1.0-3.0ml/g intermediate F;

The collection method is solvent recrystallization, and the solvent used is an alcohol solvent, preferably ethanol, isopropanol, n-propanol or n-butanol, more preferably isopropanol or ethanol, and recrystallization is a conventional operation method;

Wherein, the preparation of the compound of formula F comprises the following steps:

R ₁ is methyl, ethyl or isopropyl;

The compound of formula A is mixed with the compound of formula B, in a solvent, in the presence of a copper catalyst, at 80-120°C, preferably 90-110°C, more preferably 100-105°C; react for 6-24 hours, preferably 8-20 hours, more preferably It is preferably 10-16 hours, and then collects compound C from the reaction product;

Where LG is a leaving group such as I, Br, Cl, F;

The solvent is selected from one of dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, isopropyl acetate, isopropanol or water, preferably dimethylsulfoxide or dimethicone One of methyl formamide;

The amount of compound B added is 1.0 to 2.0 equivalents of A, preferably 1.2 to 1.8 equivalents, preferably 1.5 equivalents;

The copper catalyst is selected from cuprous chloride, cuprous iodide or copper powder, etc., preferably cuprous chloride or cuprous iodide; the equivalent of copper catalyst added is 0.02-0.50 equivalent of formula A, preferably 0.10-0.30 equivalent, Preferably 0.20 equivalent;

Both the compound of formula A and the compound of formula B can be commercial products;

R ₁ is methyl, ethyl or isopropyl;

Add the compound of formula C to R ₂ -OH, and react at 40-100°C for 1-24 hours, preferably 10-20 hours, in the presence of a catalytic amount of acid, and then collect the compound D from the reaction product;

Wherein R ₂ -OH is methanol, ethanol, isopropanol and other alcohols;

Described acid is sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid or p-toluenesulfonic acid;

The amount of acid used is 0.05 to 1.00 equivalents of formula C, preferably 0.10 to 0.50 equivalents, more preferably 0.20 to 0.30 equivalents;

Wherein, the amount of R ₂ -OH is 0.5-4.0 L, preferably 1.5-3.0 L, more preferably 2.0-2.5 L, added to 1 mol of the compound of formula C.

or:

After adding the compound of formula C to R ₂ -OH, add thionyl chloride, react under reflux for 1 to 24 hours, preferably 10 to 20 hours, and then collect the compound D from the reaction product;

Wherein, the amount of thionyl chloride is 0.2 to 2.0 equivalents of formula C, preferably 0.5 to 1.5 equivalents, preferably 1.2 equivalents;

R ₁ is methyl, ethyl or isopropyl;

Heat the compound of formula D and compound of formula E in a solvent to 70-120°C, preferably 80-100°C, react for about 2-48h, preferably 10-30h, more preferably 15-24h, then cool to room temperature, add protic Solvent, preferably an alcohol compound, more preferably methanol, heated to 60°C to reflux for 30min to 1h, after the reaction is complete, add one or more of the polar solvents IPAc, IPA or _H2O , and then collect the formula from the reaction product F compound.

The solvent is more than one of DMSO, DMF, IPAc, IPA or _H2O ;

The ratio of the amount of polar solvent IPAc, IPA or H ₂ O to the compound of formula D is 10-20mL/g;

The equivalent of the compound of formula E is 1.0 to 3.0 equivalents of the compound of formula D, preferably 1.5 to 2.5 equivalents, more preferably 2.0 equivalents;

The present invention overcomes the main drawbacks of the prior art, eliminates time-consuming and laborious operations such as column chromatography, avoids the use of highly toxic reagents such as methyl iodide, has mild reaction conditions, convenient and simple post-treatment, increases the total yield, and reduces the reaction time , the preparation cost is reduced, the advantages are environmental protection and suitability for industrial scale-up.

detailed description

Example 1

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

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) heated to 105°C under nitrogen protection for 14 hours, cooled to room temperature, added 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).

Example 2

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

Add 2-(3-fluoro-4-(methoxyformyl)phenylamino)-2-methylpropionic acid (C, 100g), MeOH (1.0L), DMF (3.0ml) into a 2L four-neck flask ), cooled to below 10°C, added dropwise SOCl ₂ (30ml, 1.05 equivalents), and refluxed for 12 hours after the dropwise addition was completed. After the reaction was monitored by TCL, the solvent was evaporated to dryness, and H ₂ O (400ml) and EtOAc (400ml) were added. Stir, add dropwise sodium carbonate aqueous solution to adjust pH = 8, separate the layers, take the organic layer, evaporate the solvent to dryness, add petroleum ether (400ml) and stir and wash to obtain the white solid product 2-(3-fluoro-4-(methoxyformyl )phenylamino)-2-methylpropanoic acid methyl ester (D, 101.5g, 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).

Example 3

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)

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), H ₂ O (300ml) and IPA (100ml ), stirring, and separating the organic phase to remove the solvent to about 450ml, adding IPA (1.2L) and heating to 80°C to completely dissolve, then cooling to 10°C, a white solid precipitated, suction filtered, and dried to obtain 4-(3 -(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro- Methyl benzoate (F, 71.7 g, 83.0% yield). MSm/z466[M+H] ⁺ ; ¹ HNMR(400Hz,DMSO-d ₆ )δ8.41-8.39(d,J=8.0Hz,1H),8.28(s,1H),8.10-8.06(m,2H ),7.52-7.49(dd,J ₁ =11.2Hz,J ₁ =1.6Hz,1H),7.41-7.39(dd,J ₁ =8.4Hz,J ₁ =1.6Hz,1H),3.89(s,3H) ,1.54(s,6H). HPLC content: 98.9%.

Example 4

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and THF (100ml), cool down to 10°C, add dropwise 40% methylamine aqueous solution (100ml, 1.16mol), 10 After reacting at ℃ for 10h, evaporate the solvent to dryness, add IPA (1.2L) and heat to 80℃ to completely dissolve, then cool to 10℃, a white solid precipitates, is suction filtered and dried to give 4-(3-(4-cyano- 3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (G, 43g, 86% yield). MSm/z465[M+H] ⁺ ; ¹ HNMR(400Hz,DMSO-d ₆ )δ8.46(br,1H),8.42-8.40(d,J=8.0Hz,1H),8.29(s,1H), 8.10-8.08(d,J=8.0Hz,1H),7.81-7.77(t,J=8.0Hz,1H),7.45-7.42(dd,J ₁ =8.4Hz,J ₁ =1.6Hz,1H),7.35 -7.32(dd, J ₁ =8.4Hz, J ₁ =1.6Hz, 1H), 2.80-2.79(d, J=8.0Hz, 1H), 1.54(s, 6H). HPLC content: 99.6%.

Example 5

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo Imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and EtOH (250ml), the temperature is controlled at 20°C, 40% methylamine aqueous solution (50ml, 0.58mol) is added dropwise, After reacting at 20°C for 5 hours, evaporate the solvent to dryness, add IPA (1.2L) and heat to 80°C to completely dissolve, then cool to 10°C, a white solid precipitates, suction filters, and dries to give 4-(3-(4-cyano -3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzyl Amide (G, 41 g, 82% yield). HPLC content: 99.7%.

Example 6

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-Fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and CH ₂ Cl ₂ (50ml), control the temperature at 30°C, add dropwise 40% methylamine aqueous solution (150ml, 1.74 mol), reacted at 30°C for 2h, evaporated the solvent, added IPA (1.2L) and heated to 80°C to completely dissolve, then cooled to 10°C, a white solid was precipitated, filtered by suction, and dried to obtain 4-(3-(4 -cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methyl phenylbenzamide (G, 40g, yield 80%). HPLC content: 99.5%.

Example 7

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo Imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and EtOAc (200ml), the temperature was controlled at 40°C, and 20% methylamine aqueous solution (360g, 2.32mol) was added dropwise, After reacting at 40°C for 20 hours, evaporate the solvent to dryness, add IPA (1.2L) and heat to 80°C until completely dissolved, then cool to 10°C, a white solid precipitates, suction filters, and dries to give 4-(3-(4-cyano -3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzyl Amide (G, 42g, 84% yield). HPLC content: 99.7%.

Example 8

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and THF (50ml) and EtOH (50ml), control the temperature at 5 ° C, drop into 30% methylamine aqueous solution (95g , 0.92mol), reacted at 5°C for 20h, evaporated the solvent, added IPA (1.2L) and heated to 80°C to completely dissolve, then cooled to 10°C, a white solid was precipitated, suction filtered, dried to give 4-(3- (4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N - Toluamide (G, 44g, 88% yield). HPLC content: 99.6%.

Example 9

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and THF (100ml), the temperature was controlled at 5°C, methylamine gas was passed through, and after 5°C reaction for 0.5h, evaporation Dry solvent, add IPA (1.2L) and heat to 80°C until completely dissolved, then cool to 10°C, a white solid precipitates, suction filtered, dried to give 4-(3-(4-cyano-3-(trifluoroform base)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (G, 45g, yield rate of 90%). HPLC content: 99.6%.

Example 10

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo imidazolidin-1-yl)-2-fluoro-benzoic acid methyl ester (F, 50g, 0.11mol) and toluene (200ml), the temperature was controlled at 50°C, methylamine gas was passed through, and after 50°C for 0.5h, evaporated Dry solvent, add IPA (1.2L) and heat to 80°C until completely dissolved, then cool to 10°C, a white solid precipitates, suction filtered, dried to give 4-(3-(4-cyano-3-(trifluoroform base)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (G, 45g, yield rate of 90%). HPLC content: 99.5%.

Example 11

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo Imidazolidin-1-yl)-2-fluoro-benzoic acid ethyl ester (F, 50g, 0.10mol) and THF (100ml), cooled to 10°C, drop into 40% methylamine aqueous solution (100ml, 1.16mol), 20 After reacting at ℃ for 10h, evaporate the solvent to dryness, add IPA (1.2L) and heat to 80℃ to completely dissolve, then cool to 10℃, a white solid precipitates, is suction filtered and dried to give 4-(3-(4-cyano- 3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (G, 41 g, 82% yield). HPLC content: 99.8%.

Example 12

Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide (G)

Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo Imidazolidin-1-yl)-2-fluoro-benzoic acid isopropyl ester (F, 50g, 0.10mol) and THF (100ml), cooled to 10°C, and dropped into 40% methylamine aqueous solution (100ml, 1.16mol), After reacting at 20°C for 10 hours, evaporate the solvent to dryness, add IPA (1.2L) and heat to 80°C until it is completely dissolved, then cool to 10°C, a white solid precipitates, is suction filtered and dried to give 4-(3-(4-cyano -3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzyl Amide (G, 40g, 80% yield). HPLC content: 99.6%.

Claims (6)

1. the preparation method of the miscellaneous Shandong amine of grace, it is characterised in that comprise the following steps：Formula F compounds are added in solvent, with first Amine source is reacted, after reaction terminates, the collection type G compounds from reaction product, and the as described miscellaneous Shandong amine of grace；

Wherein：

R₁For methyl, ethyl or isopropyl；The methylamine source is that weight concentration is 20-35% methylamine alcohol solutions, weight concentration 5- 10% methylamine tetrahydrofuran solution or methylamine gas, the dosage in methylamine source are 3.0~20.0 equivalents of formula F compounds.

2. according to the method for claim 1, it is characterised in that reaction temperature is 5~50 DEG C.

3. according to the method for claim 2, it is characterised in that the reaction time is 0.5~20 hour.

4. according to the method for claim 1, it is characterised in that the solvent is dichloromethane, tetrahydrofuran, alcohols, first One or more of benzene or ethyl acetate.

5. according to the method for claim 4, it is characterised in that the dosage of the solvent is 0.5~5.0ml/g formula F chemical combination Thing.

6. according to the method for claim 1, it is characterised in that described collection method is solvent recrystallization, use it is molten Agent is alcohols solvent.