CN115611765A - A kind of preparation method of enzalutamide intermediate - Google Patents

Abstract

The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of an enzalutamide intermediate. The method comprises the following steps: taking 2-aminoisobutyric acid and 4-bromo-2-fluoro-N-methylbenzamide as raw materials, mixing the raw materials, an acid-binding agent, a catalyst and a ligand in a polar solvent, heating to 80-120 ℃, and reacting for 4 hours; the high-purity enzalutamide intermediate can be obtained through impurity extraction and acidification. The method can improve the reaction conversion rate of the enzalutamide intermediate to more than 85%, shortens the reaction time, reduces the generation of impurities, and has the advantages of simple process, low requirement on equipment and high purity of the obtained product.

Description

A kind of preparation method of enzalutamide intermediate

technical field

The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method of an enzalutamide intermediate.

Background technique

Enzalutamide (enzalutamide, trade name Xtandi), chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo Substitute-2-thione imidazol-1-yl}-2-fluoro-N-methylbenzamide, its structural formula is shown in formula I. Enzalutamide is an oral androgen receptor antagonist, which is a new type of drug targeting the androgen receptor (AR) signaling pathway. It is mainly used to treat asymptomatic or mild symptoms after failure of androgen deprivation therapy (ADT). Treatment of adult patients with symptomatic metastatic castration-resistant prostate cancer (CRPC) not receiving chemotherapy.

The compound of formula II is an important intermediate required in the synthesis process of enzalutamide. This patent study found that the conversion rate of the reaction liquid of the intermediate of enzalutamide is low, and it is easy to produce a compound as shown in formula V in the coupling side reaction. The debrominated impurity shown and the hydrolyzed impurity shown in Formula VI. Moreover, most of the existing synthetic schemes for compounds of formula II have defects such as low yield, expensive ligands, and long reaction times.

For example, the patent of invention with the application number CN201180020668 discloses a preparation method of a compound of formula II, but this invention uses expensive 2-acetylcyclohexanone as a ligand, and the dosage is relatively large (0.2 equivalents), and the reaction time is long Reaching 12～14 hours, not only production cost increases, and reaction time is long, and yield is also relatively low. The invention patent with the application number CN201410264149 discloses a "one-pot method" method for preparing enzalutamide, in which the preparation of the compound of formula II requires a reaction at 120°C for 16 hours, and the reaction time is long. The invention patent with the application number CN201510659222 discloses a preparation method of an intermediate of enzalutamide, which uses proline as a ligand and reacts at 100°C-110°C for 20-24 hours, and the reaction time is relatively long. The invention patent with the application number CN201811588915 discloses a synthesis method of an intermediate of enzalutamide, which uses acetylacetone as a ligand and reacts at 110°C for 24 hours to prepare the compound of formula II. Similarly, the reaction time of this invention Long, the price of the ligand is more expensive, and the yield is lower. The invention patent with the application number CN201880076178 discloses a method for preparing the compound of formula II. The reaction time required for the preparation of the compound of formula II is relatively short, but the invention uses 3-(dimethylamino)cyclohex-2-ene- 1-keto is used as a ligand to prepare the compound of formula II, which is expensive.

In view of this, there is an urgent need for a method with low ligand price, short reaction time, high purity yield, and simple operation to prepare the enzalutamide intermediate shown in formula II, so as to meet the needs of industrial production.

Contents of the invention

One of the objectives of the present invention is to provide a method for preparing an intermediate of enzalutamide, the preparation method has a short reaction time, and the intermediate of enzalutamide can be prepared only after 4 hours of reaction.

To achieve the above object, the present invention adopts the following technical solutions:

The preparation method of the enzalutamide intermediate, the structural formula of the enzalutamide intermediate is shown in formula II; the method is: using the compound of formula III and the compound of formula IV as raw materials, in the process of catalyst, ligand and acid binding The enzalutamide intermediate is obtained through a substitution reaction under the action of an agent and a solvent; the ligands are N-methylglycine, N,N-dimethylglycine, 2,5-hexanedione, 2- Any one or more of aminoisobutyric acid;

Further, the chemical name of the enzalutamide intermediate, that is, the compound of formula II: 2-[3-fluoro-4-(methylcarbamoyl)phenylamino]-2-methylpropionic acid; The chemical name of the compound of formula IV is: 2-aminoisobutyric acid; the chemical name of the compound of formula III is: 4-bromo-2-fluoro-N-methylbenzamide.

The synthesis process is as follows:

Further, the reaction time of the substitution reaction is 4 hours, and the reaction temperature is 80°C-120°C.

Further, the ligand is preferably 2,5-hexanedione.

Further, the amount of the ligand used is 0-0.5 equivalents of the compound of formula III.

Further, the amount of the ligand used is preferably 0.2 equivalents of the compound of formula III.

Further, when 2-aminoisobutyric acid is used as ligand, the amount of ligand used is 0 equivalent.

Further, the catalyst includes any one or more of cuprous chloride and cuprous iodide.

Further, the catalyst is preferably cuprous chloride.

Further, the catalyst is used in an amount of 0.2-1.0 equivalents to the compound of formula III.

Further, the amount of the catalyst used is preferably 0.2 equivalents of the compound of formula III.

Further, the acid-binding agent includes any one or more of sodium carbonate and potassium carbonate.

Further, the acid-binding agent is preferably potassium carbonate.

Further, the amount of the acid-binding agent used is 2.0-3.0 equivalents of the compound of formula III.

Further, the amount of the acid-binding agent is preferably 2.5 equivalents of the compound of formula III.

Further, the solvent includes any one or more of a mixed solution of dimethyl sulfoxide and water, and a mixed solution of N,N-dimethylformamide and water.

Further, the solvent is preferably a mixed solution of N,N-dimethylformamide and water.

Further, after the substitution reaction is completed, the enzalutamide intermediate is prepared by purifying and acidifying.

The second object of the present invention is to provide a production system for preparing the enzalutamide intermediate described in the first object.

To achieve the above object, the present invention adopts the following technical solutions:

A production system for preparing the enzalutamide intermediate, the production system comprising a production unit, an extraction unit, an acidification unit and a drying unit; the production unit, the extraction unit, the acidification unit and the drying unit are connected in sequence; the The compound of formula III and the compound of formula IV are subjected to substitution reaction in the production unit under the action of catalyst, ligand, acid-binding agent and solvent, and the reaction time is 4h; Acidification and drying under reduced pressure in a drying unit to obtain the enzalutamide intermediate; the structural formula of the enzalutamide intermediate is shown in formula II; the ligands are N-methylglycine, N , any one or more of N-dimethylglycine, 2,5-hexanedione, and 2-aminoisobutyric acid.

In this patent, the equivalent ratio means the molar ratio, for example, "the amount of A is 0.2 equivalent of B" means "the molar ratio of A to B is 0.2:1".

The beneficial effects of the present invention are:

The invention provides a method for preparing an intermediate of enzalutamide, which can increase the reaction conversion rate of the intermediate of enzalutamide to more than 85%, shorten the reaction time and reduce the production of impurities. The requirements are not high, and the obtained product has high purity.

Description of drawings

Fig. 1 is the HPLC figure of the enzalutamide intermediate reaction solution of embodiment 1;

Fig. 2 is the HPLC figure of the enzalutamide intermediate of embodiment 1;

Fig. 3 is the HPLC figure of the enzalutamide intermediate of embodiment 2;

Fig. 4 is the HPLC figure of the enzalutamide intermediate of embodiment 3;

Fig. 5 is the HPLC figure of the enzalutamide intermediate reaction solution of comparative example 1;

6 is the HPLC chart of the enzalutamide intermediate in Comparative Example 1.

detailed description

The technical solution of the present invention will be further clearly and completely described in conjunction with specific embodiments below. Apparently, the described embodiments are only some of the embodiments of the present invention, not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative efforts belong to the protection scope of the present invention.

Example 1

Ligand: 2,5-hexanedione.

Preparation method: Take 10g (43.1mmol) of formula III compound, 6.7g (64.6mmol) of formula IV compound, 14.9g (2.5 equivalent) of potassium carbonate, 0.85g (0.2 equivalent) of cuprous chloride, 0.98g (0.2 equivalent) of 2 , 5-hexanedione, 60ml (6 volumes) N,N-dimethylformamide and 1.8ml water, mix and stir, heat up to 100°C ~ 110°C, keep warm for 4 hours, cool down, add 60ml water and 60ml Isopropyl acetate, let stand to separate the liquid, discard the organic layer, adjust the pH value of the water layer to 4 with citric acid solution, filter, wash the filter cake with water, and dry under reduced pressure to obtain the enzalutamide intermediate (Formula II) 8.9 g, yield 81.2%.

Example 2

Ligand: N,N-Dimethylglycine.

Preparation method: Take 10g (43.1mmol) of formula III compound, 6.7g (64.6mmol) of formula IV compound, 14.9g (2.5 equivalent) of potassium carbonate, 0.85g (0.2 equivalent) of cuprous chloride, 0.89ml (0.2 equivalent) of N , N-dimethylglycine, 60ml (6 volumes) N,N-dimethylformamide and 1.8ml water, mix and stir, heat up to 110 ℃ ~ 120 ℃, keep warm for 4 hours, cool down, add 60ml water and 60ml of isopropyl acetate, let stand to separate the liquids, discard the organic layer, adjust the pH value of the water layer to 4 with citric acid solution, filter, wash the filter cake with water, and dry under reduced pressure to obtain the enzalutamide intermediate (formula II) 8.7g, yield 79.4%.

Example 3

Ligand: 2-aminoisobutyric acid.

Preparation method: Take 10g (43.1mmol) of the compound of formula III, 6.7g (64.6mmol) of the compound of formula IV, 14.9g (2.5 equivalents) of potassium carbonate, 0.85g (0.2 equivalents) of cuprous chloride, 60ml (6 volumes) of N, Mix and stir N-dimethylformamide and 1.8ml of water, heat up to 105°C to 110°C, keep the temperature for 4 hours, cool down, add 60ml of water and 60ml of isopropyl acetate, let stand for liquid separation, and discard the organic layer , the water layer was adjusted to pH 4 with citric acid solution, filtered, the filter cake was washed with water, and dried under reduced pressure to obtain 9.0 g of Enzalutamide intermediate (Formula II), with a yield of 82.1%.

Comparative example 1

Ligand: 2-acetylcyclohexanone (refer to CN201180020668 patent).

Preparation method: Take 10g (43.1mmol) of formula III compound, 6.7g (64.6mmol) of formula IV compound, 14.9g (2.5 equivalent) of potassium carbonate, 0.85g (0.2 equivalent) of cuprous chloride, 1.21g (0.2 equivalent) of 2 - Acetylcyclohexanone, 60ml (6 volumes) N,N-dimethylformamide and 1.8ml water, mix and stir, heat up to 105°C, keep warm for 12-14 hours, cool down to room temperature, add 120ml water and 60ml of isopropyl acetate, let stand to separate the liquid, discard the organic layer, add citric acid solution to the water layer to adjust the pH value to 4, filter, wash the filter cake with water, and dry under reduced pressure to obtain the enzalutamide intermediate (formula II) 7.8g, yield 71.2%.

Embodiment 4.HPLC detects

The reaction solution of the enzalutamide intermediate in Examples 1-3 and Comparative Example 1 and/or the prepared compound of formula II were detected by high performance liquid chromatography.

The integration results of the enzalutamide intermediate reaction solution in Example 1 are shown in Table 1, and the chromatogram is shown in Figure 1. The HPLC detection purity of the enzalutamide intermediate reaction solution is 86.46%; The integral result of the formula II compound is as shown in Table 2, and the chromatogram is as shown in Figure 2, and the obtained product HPLC detection purity is 99.93%; The integral result of the formula II compound that embodiment 2 makes is as shown in Table 3, the chromatogram As shown in Figure 3, the HPLC detection purity of the product obtained is 100%; the integral result of the compound of formula II prepared in Example 3 is shown in Table 4, and the chromatogram is shown in Figure 4, and the HPLC detection purity of the product obtained is 99.96%; The integration result of the enzalutamide intermediate reaction solution in Comparative Example 1 is shown in Table 5, and the chromatogram is shown in Figure 5. The HPLC detection purity of the Enzalutamide intermediate reaction solution is 74.73%; The integral result of the compound of formula II is shown in Table 6, and the chromatogram is shown in Figure 6, and the HPLC detection purity of the obtained product is 99.87%.

Table 1. The HPLC integral result table of the enzalutamide intermediate reaction solution of embodiment 1

The integration result table of the formula II compound that table 2. embodiment 1 makes

The integral result table of the formula II compound that table 3. embodiment 2 makes

The integral result table of the formula II compound that table 4. embodiment 3 makes

Table 5. The HPLC integration result table of the reaction solution of Enzalutamide intermediate in comparative example 1

The integral result table of the formula II compound that table 6. comparative example 1 makes

Claims (10)

1. The preparation method of enzalutamide intermediate is characterized in that, the structural formula of described enzalutamide intermediate is as shown in formula II; Described method is: take formula III compound and formula IV compound as raw material, in catalyst , ligand, acid-binding agent, and solvent to obtain the enzalutamide intermediate through substitution reaction; the ligand is N-methylglycine, N,N-dimethylglycine, 2,5- Any one or more of hexanedione and 2-aminoisobutyric acid;

2. The method according to claim 1, characterized in that, the reaction time of the substitution reaction is 4 hours, and the reaction temperature is 80°C-120°C. 3. The method according to claim 1, characterized in that the amount of the ligand used is 0-0.5 equivalents of the compound of formula III. 4. The method according to claim 1, wherein the catalyst comprises any one or more of cuprous chloride and cuprous iodide. 5. The method according to claim 1, characterized in that the catalyst is used in an amount of 0.2-1.0 equivalents to the compound of formula III. 6. The method according to claim 1, wherein the acid-binding agent comprises any one or more of sodium carbonate and potassium carbonate. 7. The method according to claim 1, characterized in that the amount of the acid-binding agent is 2.0-3.0 equivalents of the compound of formula III. 8. The method according to claim 1, wherein the solvent comprises any one of a mixed solution of dimethyl sulfoxide and water, a mixed solution of N,N-dimethylformamide and water, or Various. 9. The method according to claim 1, characterized in that, after the substitution reaction is completed, the enzalutamide intermediate is obtained by extraction and acidification. 10. A production system for preparing the enzalutamide intermediate described in claim 1, characterized in that, the production system comprises a production unit, an extraction unit, an acidification unit and a drying unit; the production unit, the extraction unit, The acidifying unit and the drying unit are connected sequentially; the compound of formula III and the compound of formula IV are subjected to a substitution reaction in the production unit under the action of catalyst, ligand, acid-binding agent and solvent, and the reaction time is 4 hours; then in the extraction unit impurity extraction in the acidification unit, acidification in the acidification unit, and drying under reduced pressure in the drying unit to obtain the enzalutamide intermediate; the structural formula of the enzalutamide intermediate is shown in formula II; the The ligand is any one or more of N-methylglycine, N,N-dimethylglycine, 2,5-hexanedione and 2-aminoisobutyric acid.

Images