CN115124536A - Synthesis method of ibrutinib intermediate - Google Patents

Abstract

The invention provides a preparation method of an ibrutinib intermediate salt, which can obtain high-yield and high-purity ibrutinib and is easy for industrial production.

Description

Synthesis method of ibrutinib intermediate

Technical Field

The invention relates to the field of pharmaceutical chemistry, and particularly relates to a synthesis method of an ibrutinib intermediate.

Background

Ibrutinib (English name is Ibrutinib) is a small molecule BTK inhibitor used for treating mantle cell lymphoma, and has a structural formula shown as the following, and the chemical name is 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one.

Compound patent CN101610676B specification example 1 discloses the preparation of ibrutinib by reacting 4-phenoxybenzoic acid with thionyl chloride, dissolving in toluene and tetrahydrofuran, adding malononitrile to react to 1, 1-dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethylene, which reacts with trimethylsilyldiazomethane to obtain 1, 1-dicyano-2-methoxy-2- (4-phenoxyphenyl) ethylene, reacting with hydrazine hydrate to obtain 3-amino-4-cyano-5- (4-phenoxyphenyl) pyrazole, reacting with formamide to obtain 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine, reacting with 3-hydroxypiperidine-1-tert-butyl formate under the condition that polymer is connected with triphenylphosphine and diisopropyl azodicarboxylate, treating a reaction product with hydrochloric acid/dioxane solution, concentrating, adding triethylamine and acryloyl chloride for reacting, washing, concentrating, and purifying by flash chromatography to obtain ibrutinib. The synthesis process has the advantages of complex steps, low product purity, high impurity content and high cost.

CN105985343A discloses a preparation method of ibrutinib, which comprises the steps of reacting 3-bromo-4-aminopyrazolo [3,4-D ] pyrimidine with 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester, triphenylphosphine and DIAD, adding concentrated hydrochloric acid for deprotection to obtain a hydrochloride product, reacting with 4-phenoxyphenylboronic acid, potassium phosphate and tetrakis (triphenylphosphine) palladium, treating with sodium hydroxide to obtain free alkali of 3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine, salifying with an ethanol solution of hydrochloric acid to obtain a hydrochloride product, and reacting with acryloyl chloride to obtain ibrutinib. When acryloyl chloride reacts with a hydrochloride intermediate product, two nitrogen reaction sites exist, so that dimer impurities are easily generated, and the subsequent purification difficulty is increased.

Wherein, the 3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine is an important intermediate for synthesizing ibrutinib, and the content and purity of the intermediate have important influence on the purity and content of an ibrutinib final product, so that a synthesis process capable of obtaining a high-purity ibrutinib intermediate is urgently needed.

Disclosure of Invention

In order to solve the technical problems, the invention provides a synthesis method of an ibrutinib intermediate salt, which can improve the purity and yield of ibrutinib by using the intermediate to synthesize ibrutinib.

The invention provides a synthesis method of an ibrutinib intermediate salt, in particular to mesylate of 3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine, which comprises the following steps:

1) dissolving 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine in a first organic solvent, and cooling;

2) adding mesylate, and stirring for reaction for a period of time;

3) after the reaction is finished, adding a second organic solvent for extraction, filtering, washing and drying to obtain the mesylate of the 3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine.

Preferably, the ratio of the intermediate to the mesylate is 1: 1-2. When the equivalent of the mesylate is 1, reacting to obtain the mono-mesylate of the intermediate; when the mesylate equivalent is 2, the reaction results in the intermediate bis-mesylate salt.

Preferably, the first organic solvent is dichloromethane.

Preferably, the second organic solvent is methyl tert-butyl ether.

Preferably, the temperature of the reactants in the step 1) is reduced to 0-5 ℃ after the reactants are dissolved.

Further, the intermediate 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine, compound 1, may be prepared by the following reaction,

1) reacting the compound 7 with hydrazine hydrate in an alcohol solvent to obtain a compound 6;

2) reacting the compound 6 with formamide in a ketone solvent to obtain a compound 3;

3) protecting the compound 5 with hydroxyl to obtain a compound 4;

4) carrying out a combination reaction on the compound 4 and the compound 3 to obtain a compound 2;

5) deprotection of compound 2 under acidic conditions affords compound 1.

On the other hand, the invention provides a preparation method of ibrutinib, and ibrutinib is obtained by reacting the intermediate mesylate prepared by the invention with acryloyl chloride.

The ibrutinib is prepared from the 3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine mesylate, so that the impurity content of an ibrutinib dimer can be effectively reduced, the purity and the yield are improved, and the product purity can be improved by improving the purity of an intermediate.

Drawings

FIG. 1 is an HPLC plot of ibrutinib of a comparative example (preferably CN 101610676B);

FIG. 2 is an HPLC profile of ibrutinib prepared according to example 5;

figure 3 is an HPLC profile of ibrutinib intermediate dimesylate prepared according to example 4.

Detailed Description

The invention is described in further detail below with reference to the accompanying examples.

Example 1: comparative example

Compound 3 was prepared as described in International patent application publication No. WO 01/019829. 101mg of Compound 3 and 330mg of polymer-linked triphenylphosphine were mixed together with 5mL of tetrahydrofuran. To the resulting mixture were added 200mg of Compound 5 followed by 0.099mL of diisopropyl azodicarboxylate. The mixture was stirred at room temperature overnight, filtered, concentrated and purified to give compound 2.

48.3mg of Compound 2 was treated with 1mL of 4N HCl/dioxane solution for 1 hour and concentrated to dryness. The residue was dissolved in dichloromethane, and 0.042mL of triethylamine and 0.01mL of acryloyl chloride were added. The reaction was terminated after 2 hours. The reaction mixture was washed with 5% aqueous citric acid and then brine. The organic layer was dried over magnesium sulfate and concentrated. Purification by flash chromatography gave 22mg ibrutinib, 86% pure.

Example 2: preparation of intermediates

Adding 1g of compound 5 into 10mL of dichloromethane at room temperature, cooling to-5 ℃, adding 0.15g of 4-dimethylaminopyridine, 1.5g of p-toluenesulfonyl chloride and 1.5g of triethylamine, stirring for 30 minutes, slowly heating to 25 ℃, and stirring until the reaction is finished. Cooling to 0 ℃, adding water, stirring, standing for layering, taking an organic layer, washing with hydrochloric acid, sodium bicarbonate and water respectively, concentrating the organic layer, removing dichloromethane, adding tert-butyl methyl ether, heating for dissolving, slowly cooling to 0 ℃, stirring for 1h, filtering, washing and drying to obtain a compound 4.

Mixing 1g of compound 4, 10ml of N-methylpyrrolidone and 2.5g of cesium carbonate at room temperature, heating to 75 ℃, stirring for 60 minutes, cooling to 45 ℃, adding 1.5g of compound 3, heating to 75 ℃, and stirring for 8 hours until the reaction is completed. Cooling to room temperature, adding ethyl acetate, stirring, filtering and washing, collecting ethyl acetate filtrate, adding water, stirring, standing for layering, collecting an organic layer, adding sodium carbonate, filtering and washing, collecting ethyl acetate filtrate, and performing vacuum drying to obtain an intermediate 1 with the yield of 89%.

Example 3: preparation of intermediate monomethanesulfonate

Adding 1g of 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine into 20mL of dichloromethane solution, cooling to-5 ℃, dropwise adding 0.25g of methanesulfonic acid, maintaining the temperature, stirring for 30 minutes, slowly heating to 30 ℃, stirring for 16 hours, dropwise adding into 300mL of dichloromethane, stirring for 1 hour, filtering, washing with dichloromethane, and drying to obtain 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine monomethanesulfonate. The yield was 93.5% and the purity was 96%.

Example 4:

under nitrogen atmosphere, 5g of 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine is added into 100mL of dichloromethane solution, the temperature is reduced to 0 ℃, 2.5g of methanesulfonic acid is added, the temperature is maintained, the mixture is stirred for 30 minutes, the temperature is slowly increased to 25 ℃, the mixture is stirred for 16 hours, the dropwise added mixture is added into 300mL of tert-butyl methyl ether, the mixture is stirred for 1 hour, filtered, washed by tert-butyl methyl ether and dried, and 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine disulfonate is obtained. The yield is 92.6 percent, and the purity is 99.9 percent.

Example 5:

adding 100mg of 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine disulfonate into 10mL of dichloromethane at room temperature, stirring for clarification, adding 78mg of diisopropylethylamine, stirring and cooling to 5 ℃, adding 15mg of acryloyl chloride for reaction for 2 hours, adding 10mL of water for stirring after the reaction is finished, adjusting the pH to 3-4 by using 10% citric acid aqueous solution, standing for layering, washing an organic layer by using sodium chloride solution, adding 100mg of sodium sulfate for stirring, filtering, washing by using dichloromethane, collecting the organic layer, and drying in vacuum to obtain ibrutinib, wherein the yield is 98%, and the purity is 99.6%.

Claims (7)

1. A synthesis method of an ibrutinib intermediate salt (mesylate of 3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine) is characterized in that:

1) dissolving 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine in a first organic solvent, and cooling;

2) adding the mesylate and stirring;

3) and dropwise adding a second organic solvent, stirring, filtering, washing and drying to obtain the mesylate of the 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidine-4-amine.

2. The method for synthesizing ibrutinib intermediate salt as claimed in claim 1, wherein the ratio of intermediate to mesylate is 1: 1-2.

3. The method for synthesizing ibrutinib intermediate salt according to claim 1, wherein the first organic solvent is dichloromethane.

4. The process of synthesizing ibrutinib intermediate salt as claimed in claim 1, wherein the second organic solvent is methyl tert-butyl ether.

5. The method for synthesizing ibrutinib intermediate salt according to claim 1, wherein the temperature is reduced to 0-5 ℃ after the reactants are dissolved in the step 1).

6. The synthesis method of ibrutinib intermediate salt according to any one of claims 1-5, characterized in that the intermediate 3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-amine (compound 1) can be prepared by the following reaction:

1) reacting the compound 7 with hydrazine hydrate in an alcohol solvent to obtain a compound 6;

2) reacting the compound 6 with formamide in a ketone solvent to obtain a compound 3;

3) protecting the compound 5 with hydroxyl to obtain a compound 4;

4) carrying out a combination reaction on the compound 4 and the compound 3 to obtain a compound 2;

5) deprotection of compound 2 under acidic conditions affords compound 1.

7. A synthetic method for preparing ibrutinib from an ibrutinib intermediate prepared according to claim 1, wherein an intermediate salt is reacted with acryloyl chloride to obtain ibrutinib.

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