阅读说明：本技术 一种降低醋酸阿比特龙中钯残留的方法 (Method for reducing palladium residue in abiraterone acetate ) 是由 徐宝旺 申新德 孔改兰 李同强 于 2021-01-19 设计创作，主要内容包括：本发明提供了一种降低醋酸阿比特龙中钯残留的方法,包括步骤：将17-碘-雄甾-5,16-二烯-3β-醇与烷基(3-吡啶基)硼烷在钯催化剂作用下反应得到醋酸阿比特龙中间体反应液；向得到的醋酸阿比特龙中间体反应液中加入亚硫酸氢钠溶液,高温搅拌；之后加入活性炭吸附,过滤,将滤液降温析晶,过滤,洗涤、干燥得到醋酸阿比特龙中间体；将醋酸阿比特龙中间体与乙酸酐经酰化反应得到醋酸阿比特龙。本发明的方法工艺简单,对游离的钯离子去除能力较高,可以有效降低醋酸阿比特龙中的钯含量。(The invention provides a method for reducing palladium residue in abiraterone acetate, which comprises the following steps: reacting 17-iodine-androstane-5, 16-diene-3 beta-alcohol with alkyl (3-pyridyl) borane under the action of a palladium catalyst to obtain an abiraterone acetate intermediate reaction liquid; adding a sodium bisulfite solution into the obtained reaction solution of the intermediate of the abiraterone acetate, and stirring at high temperature; then adding activated carbon for adsorption, filtering, cooling the filtrate for crystallization, filtering, washing and drying to obtain an abiraterone acetate intermediate; and (3) carrying out acylation reaction on the intermediate of the abiraterone acetate and acetic anhydride to obtain the abiraterone acetate. The method has simple process and higher capability of removing free palladium ions, and can effectively reduce the palladium content in the abiraterone acetate.)

1. A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

In a solvent A, in the presence of sodium carbonate, carrying out coupling reaction on a compound shown in a formula II and a compound shown in a formula III under the catalysis of bis (triphenylphosphine) palladium dichloride to obtain an abiraterone acetate intermediate reaction liquid;

in the structural formula of the compound shown in the formula III, R is methyl or ethyl;

(2) adding a sodium bisulfite solution into the reaction solution of the abiraterone acetate intermediate obtained in the step (1), and stirring at high temperature; then adding activated carbon for adsorption, filtering, cooling the filtrate for crystallization, filtering, washing and drying to obtain an abiraterone acetate intermediate;

(3) preparation of abiraterone acetate

And (3) carrying out acylation reaction on the intermediate of the abiraterone acetate and acetic anhydride to obtain the abiraterone acetate.

2. The method of claim 1, wherein step (1) comprises one or more of the following conditions:

a. the solvent A is dimethyl sulfoxide; the mass ratio of the compound shown in the formula II to the volume of the dimethyl sulfoxide is 1g:10-20 mL;

b. the mass ratio of the compound shown in the formula II to the sodium carbonate is 1: 0.5-5;

c. the mass ratio of the compound shown in the formula II to the compound shown in the formula III is 1: 0.35-0.75;

d. the mass ratio of the compound shown in the formula II to the bis (triphenylphosphine) palladium dichloride is 100: 0.2-1;

e. the temperature of the coupling reaction is 80-90 ℃, and the reaction time is 3-4 hours;

f. and directly filtering the reaction solution obtained after the coupling reaction is finished while the reaction solution is hot to obtain an abiraterone acetate intermediate reaction solution.

3. The method for reducing palladium residues in abiraterone acetate of claim 1, wherein the mass concentration of the sodium bisulfite solution in step (2) is 25-40%.

4. The method for reducing palladium residue in abiraterone acetate as claimed in claim 1, wherein the volume ratio of the sodium bisulfite solution to the abiraterone acetate intermediate reaction solution in step (2) is 1: 10-20.

5. The method for reducing palladium residue in abiraterone acetate of claim 1, wherein the high temperature stirring in step (2) is at 80-95 ℃ for 1-2 h.

6. The method for reducing palladium residue in abiraterone acetate according to claim 1, wherein the volume ratio of the mass of the activated carbon in the step (2) to the volume of the abiraterone acetate intermediate reaction liquid is 0.005-0.02g:1 mL; adding activated carbon for adsorption for 20-30 min.

7. The method for reducing palladium residues in abiraterone acetate as claimed in claim 1, wherein the temperature-reducing crystallization in step (2) is carried out at a temperature of 0-15 ℃ for 1-3 h.

8. The method for reducing palladium residues in abiraterone acetate of claim 1, wherein the washing in step (2) is 1-3 times with water; the drying in (1) is drying at 70-80 ℃ for 5-15 h.

9. The method for reducing palladium residues in abiraterone acetate as claimed in claim 1, wherein the ratio of the mass of the abiraterone acetate intermediate to the volume of the acetic anhydride in step (3) is 1g: 3-10 mL;

the temperature of the acylation reaction is 60-70 ℃, and the reaction time is 2-3 h;

the post-treatment steps of the obtained reaction liquid are as follows: cooling the reaction liquid obtained after the acylation reaction to 0-10 ℃, filtering, washing a filter cake with purified water until the filtrate is neutral, adding the obtained filter cake into absolute ethyl alcohol, heating to 60-70 ℃ for dissolution, adding activated carbon for decolorization, filtering, cooling the filtrate to 0-10 ℃, keeping the temperature for crystallization for 1-2 hours, filtering, and drying to obtain the abiraterone acetate.

10. The method for reducing palladium residues in abiraterone acetate of claim 9, wherein the ratio of the mass of the abiraterone acetate intermediate to the volume of the absolute ethanol is 1g: 5-10 mL; the mass ratio of the activated carbon to the abiraterone acetate intermediate is 0.01-0.03: 1.

Technical Field

The invention relates to a method for reducing palladium residue in abiraterone acetate, and belongs to the technical field of medicinal chemistry.

Background

Abiraterone acetate is a precursor drug of Abiraterone acetate, is rapidly converted into Abiraterone in vivo, is a selective and irreversible steroid inhibitor of CYP17(17 alpha-hydroxylase and C17, 20-lyase), prevents testosterone synthesis in testis, adrenal gland and tumor by inhibiting enzyme activity, and is used for treating castration-resistant metastatic prostate cancer (mCRPC) of patients who fail androgen ablation therapy and docetaxel chemotherapy in combination with prednisone or prednisolone. The chemical name of the abiraterone acetate is (3 beta) -17- (3-pyridyl) -androstane-5, 16-diene-3-acetate, and the structural formula is shown as the following formula I:

a series of patent documents CN111349138A, US5604213, CN110790809A and CN103965282A report about the synthesis of abiraterone acetate. At present, most of abiraterone acetate preparation processes all use palladium catalytic coupling reaction, but after the reaction is finished, the residual quantity of palladium must be controlled by a certain method. Therefore, how to control the palladium residue in the product to be below the limit (10ppm) required by the regulation and no other substances are generated in the palladium removing process, especially no other harmful substances are introduced, which is a problem of great concern.

The conventional palladium post-treatment methods include column chromatography, separation by 0.22 μm separation membrane, activated carbon adsorption, ligand chelation (tributyl phosphorus, triphenyl phosphorus, 1, 2-bis (diphenyl phosphorus) ethane, etc.), and mercapto precipitation (e.g., 3-mercaptopropyl ethyl sulfide silica, 2-mercaptoethyl sulfide ethyl silica, etc.), etc., but the same reagent has completely different treatment effects on palladium in different valence states and systems. Although the content of palladium can be reduced by the conventional palladium removing agent, organophosphorus reagents such as tributyl phosphorus or triphenyl phosphorus and the like have high toxicity, and sulfydryl belongs to toxic functional groups, so that the conventional palladium removing agent is not suitable for being applied to the production of chemicals, and is not suitable for industrial mass production particularly in the preparation process step close to the finished product medicine; the existing activated carbon adsorption method has an unsatisfactory effect of removing palladium, the activated carbon adsorption method has poor capability of removing palladium ions, the adsorption dosage of activated carbon needs to be increased for ensuring the palladium removal effect, and the increase of the dosage of activated carbon can cause yield loss.

Patent documents report methods for reducing palladium residues in abiraterone acetate. For example: chinese patent document CN107840866A provides a method for preparing abiraterone acetate, which uses a compound shown in formula II to treat abiraterone acetate, but the method still uses an organophosphorus reagent to remove a palladium catalyst, and has larger toxicity.

Therefore, there is a need to develop a method with simple process and capable of effectively reducing the palladium residue in abiraterone acetate. The invention is therefore proposed.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a method for reducing palladium residue in abiraterone acetate. The method has simple process and higher capability of removing free palladium ions, and can effectively reduce the palladium content in the abiraterone acetate.

Description of terms:

a compound of formula I: abiraterone acetate, chemical name is (3 beta) -17- (3-pyridyl) -androstane-5, 16-diene-3-acetic ester.

A compound of formula II: the chemical name is 17-iodine-androstane-5, 16-diene-3 beta-alcohol.

A compound of formula III: the chemical name is R radical (3-pyridyl) borane, wherein R is methyl or ethyl.

A compound of formula IV: the chemical name of the abiraterone acetate intermediate is 17- (3-pyridyl) -androstane-5, 16-diene-3 beta-alcohol.

In the specification, the compound numbers are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.

The technical scheme of the invention is as follows:

a method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

In a solvent A, in the presence of sodium carbonate, carrying out coupling reaction on a compound shown in a formula II and a compound shown in a formula III under the catalysis of bis (triphenylphosphine) palladium dichloride to obtain an abiraterone acetate intermediate reaction liquid;

in the structural formula of the compound shown in the formula III, R is methyl or ethyl;

(2) adding a sodium bisulfite solution into the reaction solution of the abiraterone acetate intermediate obtained in the step (1), and stirring at high temperature; then adding activated carbon for adsorption, filtering, cooling the filtrate for crystallization, filtering, washing and drying to obtain an abiraterone acetate intermediate;

(3) preparation of abiraterone acetate

And (3) carrying out acylation reaction on the intermediate of the abiraterone acetate and acetic anhydride to obtain the abiraterone acetate.

According to the invention, the solvent A in the step (1) is dimethyl sulfoxide; the mass ratio of the compound shown in the formula II to the volume of the dimethyl sulfoxide is 1g:10-20 mL.

According to the invention, the mass ratio of the compound of formula II to sodium carbonate in step (1) is preferably 1: 0.5-5.

Preferably, according to the present invention, the mass ratio of the compound of formula II to the compound of formula III in step (1) is 1: 0.35-0.75.

According to the invention, the mass ratio of the compound shown in the formula II in the step (1) to the bis (triphenylphosphine) palladium dichloride is 100: 0.2-1.

Preferably, according to the invention, the temperature of the coupling reaction in step (1) is between 80 and 90 ℃ and the reaction time is between 3 and 4 hours.

Preferably, in step (1), the reaction solution obtained after the coupling reaction is completed is directly filtered while hot to obtain an abiraterone acetate intermediate reaction solution.

According to the invention, the mass concentration of the sodium bisulfite solution in the step (2) is preferably 25-40%.

According to the invention, the volume ratio of the sodium bisulfite solution to the abiraterone acetate intermediate reaction solution in the step (2) is preferably 1: 10-20.

According to the invention, the high-temperature stirring temperature in the step (2) is 80-95 ℃, and the stirring time is 1-2 h.

According to the invention, the ratio of the mass of the activated carbon in the step (2) to the volume of the abiraterone acetate intermediate reaction liquid is preferably 0.005-0.02g:1 mL; adding activated carbon for adsorption for 20-30 min.

According to the invention, the temperature reduction crystallization in the step (2) is preferably carried out at the temperature of 0-15 ℃ for 1-3 h.

Preferably, according to the present invention, the washing in step (2) is 1 to 3 times with water.

According to the invention, the drying in step (2) is preferably carried out at 70-80 ℃ for 5-15 h.

Preferably, according to the present invention, the ratio of the mass of the abiraterone acetate intermediate to the volume of acetic anhydride in step (3) is 1g: 3-10 mL.

According to the invention, the temperature of the acylation reaction in the step (3) is 60-70 ℃ and the reaction time is 2-3 h.

According to a preferred embodiment of the present invention, in the step (3), the post-treatment step of the obtained reaction solution is: cooling the reaction liquid obtained after the acylation reaction to 0-10 ℃, filtering, washing a filter cake with purified water until the filtrate is neutral, adding the obtained filter cake into absolute ethyl alcohol, heating to 60-70 ℃ for dissolution, adding activated carbon for decolorization, filtering, cooling the filtrate to 0-10 ℃, keeping the temperature for crystallization for 1-2 hours, filtering, and drying to obtain abiraterone acetate;

further preferably, the mass ratio of the abiraterone acetate intermediate to the volume of the absolute ethyl alcohol is 1g: 5-10 mL;

further preferably, the mass ratio of the activated carbon to the abiraterone acetate intermediate is 0.01-0.03: 1.

the reaction route of the invention is as follows:

in the structural formula of the compound shown in the formula III, R is methyl or ethyl.

The invention has the following technical characteristics and beneficial effects:

1. according to the invention, the abiraterone acetate reaction liquid is treated by using the sodium bisulfite solution, and sodium bisulfite can be firstly combined with free palladium ions in the abiraterone acetate reaction liquid to form a sodium bisulfite palladium complex, so that the free palladium ions exist in the feed liquid in the form of the complex, the molecular size of the free palladium ions is increased, and the free palladium ions are easier to be adsorbed by activated carbon; then a small amount of active carbon is used to adsorb and reduce the palladium residue in the abiraterone acetate intermediate; the abiraterone acetate intermediate obtained by preparation is used for preparing the abiraterone acetate, so that the palladium residue in the abiraterone acetate is effectively reduced; meanwhile, the addition amount of the sodium bisulfite solution is critical, the intermediate can be separated out due to the excessively high addition amount, the yield is influenced, and the removal effect of palladium ions can be influenced due to the excessively low addition amount, so that the palladium content in the abiraterone acetate intermediate is excessively high.

2. The method for controlling the palladium residue in abiraterone acetate has the advantages of simple and convenient operation, low cost and higher capability of removing free palladium ions, and is suitable for industrial production.

Detailed Description

The present invention is further illustrated by, but not limited to, the following examples.

Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 1

A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

Adding 20g of 17-iodine-androstane-5, 16-diene-3 beta-alcohol, 10g of methyl (3-pyridyl) borane, 0.2g of bis (triphenylphosphine) palladium dichloride, 40g of sodium carbonate and 200mL of dimethyl sulfoxide into a reaction bottle, heating to 85 ℃, keeping the temperature, reacting for 3 hours, and directly filtering the obtained reaction solution while the reaction solution is hot to obtain an abiraterone acetate intermediate reaction solution.

(2) Adding 15mL of sodium bisulfite solution with the mass concentration of 30% into 200mL of the abiraterone acetate intermediate reaction solution obtained in the step (1), and stirring at 85 ℃ for 2 h; then adding 3g of activated carbon for adsorption for 30 minutes, directly filtering while the solution is hot, cooling the filtrate to 7 ℃, crystallizing for 2 hours, filtering, washing the precipitate obtained by filtering with purified water for 2 times, and drying at 75 ℃ for 12 hours to obtain 12.32g of an abiraterone acetate intermediate, wherein the molar yield is 70.2%.

(3) Preparation of abiraterone acetate

Adding 10g of the abiraterone acetate intermediate prepared in the step (2) and 50mL of acetic anhydride into a reaction bottle, heating to 65 ℃, carrying out heat preservation reaction for 3 hours, cooling to 5 ℃, filtering, washing a filter cake with purified water until the filtrate is neutral, adding the obtained filter cake into 100mL of anhydrous ethanol, heating to 62 ℃, dissolving, adding 0.2g of activated carbon for decolorization, then directly filtering while hot, cooling the filtrate to 7 ℃, carrying out heat preservation and crystallization for 1-2 hours, filtering, and drying to obtain the abiraterone acetate.

And detecting the content of palladium in the prepared abiraterone acetate intermediate to be 34ppm and the content of palladium in the prepared abiraterone acetate to be 5ppm by using an inductively coupled plasma mass spectrometry (ICP-MS).

Example 2

A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

As described in example 1, step (1).

(2) Adding 10mL of sodium bisulfite solution with the mass concentration of 30% into 200mL of the abiraterone acetate intermediate reaction solution obtained in the step (1), and stirring at 83 ℃ for 2 h; then adding 3g of activated carbon for adsorption for 30 minutes, directly filtering while the solution is hot, cooling the filtrate to 6 ℃, crystallizing for 2 hours, filtering, washing the precipitate obtained by filtering with purified water for 2 times, and drying at 75 ℃ for 12 hours to obtain 12.23g of an abiraterone acetate intermediate with a molar yield of 69.7%.

(3) Preparation of abiraterone acetate

As described in example 1, step (3).

And detecting the content of palladium in the prepared abiraterone acetate intermediate to be 37ppm and the content of palladium in the prepared abiraterone acetate to be 5ppm by using an inductively coupled plasma mass spectrometry (ICP-MS).

Example 3

A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

As described in example 1, step (1).

(2) Adding 15mL of sodium bisulfite solution with the mass concentration of 30% into 200mL of the abiraterone acetate intermediate reaction solution obtained in the step (1), and stirring at 83 ℃ for 2 h; then adding 2g of activated carbon for adsorption for 30 minutes, directly filtering while the solution is hot, cooling the filtrate to 6 ℃, crystallizing for 2 hours, filtering, washing the precipitate obtained by filtering with purified water for 2 times, and drying at 75 ℃ for 12 hours to obtain 12.42g of an abiraterone acetate intermediate with a molar yield of 70.8%.

(3) Preparation of abiraterone acetate

As described in example 1, step (3).

And detecting the content of palladium in the prepared abiraterone acetate intermediate to be 40ppm and the content of palladium in the prepared abiraterone acetate to be 6ppm by using an inductively coupled plasma mass spectrometry (ICP-MS).

Comparative example 1

A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

As described in example 1, step (1).

(2) Heating 200mL of abiraterone acetate intermediate reaction liquid obtained in the step (1) to 85 ℃, adding 3g of activated carbon for adsorption for 30 minutes, directly filtering while the reaction liquid is hot, cooling the filtrate to 7 ℃, crystallizing for 2 hours, filtering, washing the precipitate obtained by filtering with purified water for 2 times, drying for 12 hours at 75 ℃ to obtain 12.21g of abiraterone acetate intermediate with the molar yield of 69.6 percent

(3) Preparation of abiraterone acetate

As described in example 1, step (3).

In the comparative example, the reaction solution of the abiraterone acetate intermediate was not treated by adding a sodium bisulfite solution. The content of palladium in the prepared abiraterone acetate intermediate is 135ppm and is obviously higher than that in the embodiment of the invention by using inductively coupled plasma mass spectrometry (ICP-MS) detection, and the content of palladium in the prepared abiraterone acetate is 51ppm and is obviously higher than that in the embodiment of the invention and higher than the limit (10ppm) required by the regulation.

Comparative example 2

A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

As described in example 1, step (1).

(2) Heating 200mL of abiraterone acetate intermediate reaction liquid obtained in the step (1) to 85 ℃, adding 15g of activated carbon for adsorption for 30 minutes, directly filtering while the reaction liquid is hot, cooling the filtrate to 7 ℃, crystallizing for 2 hours, filtering, washing the precipitate obtained by filtering with purified water for 2 times, and drying at 75 ℃ for 12 hours to obtain 10.48g of abiraterone acetate intermediate with the molar yield of 59.7%.

(3) Preparation of abiraterone acetate

As described in example 1, step (3).

Detecting the content of palladium in the prepared abiraterone acetate intermediate by using inductively coupled plasma mass spectrometry (ICP-MS) to be 46 ppm; the palladium content in the prepared abiraterone acetate is 9 ppm.

In the comparative example, sodium bisulfite solution is not added, so that the content of palladium in the abiraterone acetate intermediate is reduced to be similar to that in example 1, the content of activated carbon is increased, but the yield of the abiraterone acetate intermediate is low, and the content of palladium in the abiraterone acetate intermediate and the abiraterone acetate is slightly higher than that in the example of the invention.

Comparative example 3

A method for reducing palladium residue in abiraterone acetate comprises the following steps:

(1) preparation of abiraterone acetate intermediate reaction liquid

As described in example 1, step (1).

(2) Adding 80mL of sodium bisulfite solution with the mass concentration of 30% into 200mL of abiraterone acetate intermediate reaction solution obtained by completing palladium catalytic coupling reaction, and stirring for 2h at 83 ℃ to obtain a white precipitate in the system; then adding 3g of activated carbon for adsorption for 30 minutes, directly filtering while the solution is hot, cooling the filtrate to 6 ℃, crystallizing for 2 hours, filtering, washing the precipitate obtained by filtering with purified water for 2 times, and drying at 75 ℃ for 12 hours to obtain 10.83g of an abiraterone acetate intermediate, wherein the molar yield is only 61.7%.

(3) Preparation of abiraterone acetate

As described in example 1, step (3).

In the preparation of the abiraterone acetate intermediate in the comparative example, the addition amount of sodium bisulfite is too high, so that the intermediate is separated out, and the yield is influenced.