CN117903138A - A preparation method of larotrectinib and its application - Google Patents

Abstract

The invention relates to the field of drug synthesis, in particular to a preparation method and application of larotinib. The preparation method of the larotinib or the pharmaceutically acceptable salt thereof provided by the invention is characterized in that the compound 3 and the compound 4 react under the action of alkali. The preparation method of the larrotib has the advantages of high yield, controllable reaction time, mild reaction conditions, no pollution, reduced production cost, improved production efficiency, more friendly environment and operators, simple and convenient operation, stable and controllable process, suitability for large-scale industrial production and the like.

Description

A preparation method of larotrectinib and its application

Technical Field

The present invention relates to the field of drug synthesis, and in particular to a preparation method of larotrectinib and application thereof.

Background technique

Larotrectinib was approved by the FDA in 2018 for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors with NTRK gene fusions.

CN107987082A discloses a method for preparing larotrectinib, and the specific route is as follows:

In this route, the p-nitrophenoxy group in compound 5 is a genotoxic warning structure, and the genotoxic impurities that may exist in subsequent products need to be controlled.

CN113307812A discloses a method for preparing larotrectinib, and the route is as follows:

The last step of this route is to reduce pyrrolidone to chiral hydroxyl through chiral reduction, which requires a chiral reducing agent or a chiral inducing agent. The chiral purity of the prepared product is not easy to meet the requirements for pharmaceutical use.

In view of this, the present invention provides a method for preparing larotrectinib, which improves the preparation efficiency of larotrectinib, improves the yield, improves the product quality and is more environmentally friendly.

Summary of the invention

The object of the present invention is to provide a method for preparing larotrectinib, which comprises the following steps:

In the preferred technical scheme of the present invention, in step 4, the molar ratio of compound 3 to compound 2 is 1:1-5.

In the preferred technical scheme of the present invention, in step 4, the molar ratio of compound 3 to compound 2 is 1:1-2.

In a preferred technical solution of the present invention, a base is added in step three, and the base is selected from an organic base or an inorganic base.

In the preferred technical scheme of the present invention, the organic base is selected from any one of triethylamine, pyridine, N,N-dimethylpyridine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine, N-methylpiperidine, trimethylamine, tripropylamine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a combination thereof.

In the preferred technical scheme of the present invention, the inorganic base is selected from any one of potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium methoxide, sodium ethoxide, potassium fluoride/aluminum oxide, potassium phosphate, and sodium phosphate, or a combination thereof.

In the preferred technical scheme of the present invention, in step 4, the molar ratio of compound 3 to the organic base is 1:0.5-3, preferably 1:0.8-1.5.

In the preferred technical scheme of the present invention, the solvent in step 4 is selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, ethylene glycol dimethyl ether, dichloromethane, chloroform, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N.N-dimethylacetamide (DMAc), N-methylpyrrolidone, benzene, toluene, xylene, methanol, ethanol, isopropanol, any one or a combination thereof.

In the preferred technical solution of the present invention, the reaction temperature of step 4 is 20-100°C.

In the preferred technical solution of the present invention, the reaction temperature of step 4 is 30-80°C.

In the preferred technical solution of the present invention, the larotrectinib obtained in step 4 may be separated or not.

In the preferred technical solution of the present invention, the larotrectinib obtained in step 4 is further purified after separation.

In a preferred technical solution of the present invention, the refining is selected from any one of washing, suspension, beating, and recrystallization, or a combination thereof.

In a preferred technical solution of the present invention, the prepared larotrectinib is dried.

In a preferred technical solution of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, and boiling drying, or a combination thereof.

In the preferred technical solution of the present invention, the drying temperature is 20-80°C, preferably 30-70°C, and more preferably 40-60°C.

In the preferred technical solution of the present invention, the larotrectinib prepared in step 4 can be further prepared into a pharmaceutically acceptable salt thereof.

In a preferred technical solution of the present invention, the pharmaceutically acceptable salt is selected from any one of sulfate, toluenesulfonate, methanesulfonate, sulfonate, benzoate, hydrochloride, hydrobromide, phosphate, nitrate, tartrate, fumarate, maleate, citrate, formate, acetate, succinate, malonate, malate, and cinnamate, or a combination thereof.

Another object of the present invention is to provide a high-purity larotrectinib or a pharmaceutically acceptable salt thereof.

In a preferred technical solution of the present invention, the purity of the high-purity larotrectinib or a pharmaceutically acceptable salt thereof is not less than 95.0%.

In a preferred technical solution of the present invention, the purity of the high-purity larotrectinib or a pharmaceutically acceptable salt thereof is not less than 98.0%.

In a preferred technical solution of the present invention, the purity of the high-purity larotrectinib or a pharmaceutically acceptable salt thereof is not less than 99.0%.

In a preferred technical solution of the present invention, the purity of the high-purity larotrectinib or a pharmaceutically acceptable salt thereof is not less than 99.5%.

In a preferred technical solution of the present invention, the purity of the high-purity larotrectinib or a pharmaceutically acceptable salt thereof is not less than 99.9%.

Another object of the present invention is to provide the use of the high-purity larotrectinib or a pharmaceutically acceptable salt thereof for preparing a medicament for treating pain, cancer, inflammation, neurodegenerative diseases or Trypanosoma cruzi infection.

Another object of the present invention is to provide a compound 3, wherein the compound 3 has the following structure:

The present invention also provides a method for preparing compound 3, which comprises reacting compound 4 with N-hydroxysuccinimide to obtain compound 3.

In the preferred technical solution of the present invention, the molar ratio of compound 4 to N-hydroxysuccinimide is 1:1-5.

In the preferred technical solution of the present invention, the molar ratio of compound 4 to N-hydroxysuccinimide is 1:1-3.

In the preferred technical solution of the present invention, a condensation agent is added in step three.

In a preferred technical solution of the present invention, the condensing agent is selected from any one of N,N′-disuccinimidyl carbonate (DSC), carbonyldiimidazole (CDI), isobutyl chloroformate, triphosgene or a combination thereof.

In a preferred technical solution of the present invention, a base is added in step three, and the base is selected from an organic base or an inorganic base.

In the preferred technical scheme of the present invention, the organic base is selected from any one of triethylamine, pyridine, N,N-dimethylpyridine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine, N-methylpiperidine, trimethylamine, tripropylamine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a combination thereof.

In the preferred technical scheme of the present invention, the inorganic base is selected from any one of potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium methoxide, sodium ethoxide, potassium fluoride/aluminum oxide, potassium phosphate, and sodium phosphate, or a combination thereof.

In the preferred technical solution of the present invention, the solvent in step three is an organic solvent.

In the preferred technical scheme of the present invention, the organic solvent is selected from any one of acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, ethylene glycol dimethyl ether, dichloromethane, chloroform, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N.N-dimethylacetamide (DMAc), N-methylpyrrolidone, benzene, toluene, xylene, methanol, ethanol, and isopropanol, or a combination thereof.

In the preferred technical solution of the present invention, the molar ratio of the compound 4 to the condensing agent is 1:1-4, preferably 1:1-2.

In the preferred technical solution of the present invention, the molar ratio of the compound 4 to the base is 1:0.5-5.

In the preferred technical solution of the present invention, the molar ratio of the compound 4 to the base is 1:1-3.

In the preferred technical solution of the present invention, the reaction temperature of step three is 0-60°C, preferably 20-40°C.

In a preferred technical solution of the present invention, the obtained compound 3 is purified.

In a preferred technical solution of the present invention, the refining is selected from any one of washing, suspension, beating, and recrystallization, or a combination thereof.

In a preferred technical solution of the present invention, the prepared compound 3 is dried.

In a preferred technical solution of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, and boiling drying, or a combination thereof.

In the preferred technical solution of the present invention, the drying temperature is 20-80°C, preferably 30-70°C, and more preferably 40-60°C.

Another object of the present invention is to provide a high-purity compound 3.

In the preferred technical solution of the present invention, the purity of the high-purity compound 3 is not less than 95.0%.

In the preferred technical solution of the present invention, the purity of the high-purity compound 3 is not less than 98.0%.

In the preferred technical solution of the present invention, the purity of the high-purity compound 3 is not less than 99.0%.

In the preferred technical solution of the present invention, the purity of the high-purity compound 3 is not less than 99.5%.

In the preferred technical solution of the present invention, the purity of the high-purity compound 3 is not less than 99.9%.

Another object of the present invention is to provide the use of compound 3 for preparing larotrectinib or a pharmaceutically acceptable salt thereof.

Those skilled in the art will appreciate that compound 4 can be obtained by methods known in the art.

Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume/volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume/weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight/volume percentage; the rest are weight/weight percentages.

Compared with the prior art, the present invention has the following beneficial technical effects:

1. The preparation method of larotrectinib provided by the present invention is simple and the raw materials are easily available, which provides a highly feasible option for the preparation of larotrectinib and provides a guarantee for patients to obtain high-quality and low-cost drugs.

2. The preparation method of larotrectinib of the present invention has high yield, controllable reaction time, mild reaction conditions and no pollution, and is more friendly to the environment and operators while reducing production costs and improving production efficiency.

3. The preparation method of the present invention has the advantages of simple operation, stable and controllable process, and suitability for large-scale industrial production.

Detailed ways

The following are some specific embodiments to illustrate the present invention. It is necessary to point out that the following specific embodiments are only used to further illustrate the present invention and do not limit the protection scope of the present invention. Some non-essential modifications and adjustments made by others based on the present invention still fall within the protection scope of the present invention.

Compound 4 in the present invention can be prepared by referring to the methods disclosed in CN107428760A, CN109354578A, CN109414442A, CN110049987A, CN102264736A and the like.

Example 1 Preparation of larotrectinib of the present invention

Compound 3 (1 eq) and compound 2 (1.1 eq) were dissolved in tetrahydrofuran, triethylamine (1.1 eq) was added, and the mixture was reacted at 70°C. The reaction was monitored by TLC until the reaction of compound 3 was complete. The solvent was evaporated, and the mixture was recrystallized from ethyl acetate/petroleum ether and dried to obtain refined larotrectinib as a light yellow powder with a yield of 94.4% and a HPLC purity of 99.96%.

Example 2 Preparation of larotrectinib of the present invention

Compound 3 (1 eq) and compound 2 (1.05 eq) were dissolved in acetonitrile, N,N-diisopropylethylamine (1.2 eq) was added, and the mixture was reacted at 60°C. The reaction was monitored by TLC until the reaction of compound 3 was complete. Methyl tert-butyl ether was added, and the mixture was stirred for crystallization. The mixture was filtered and dried to obtain larotrectinib as a light yellow powder with a yield of 95.1%.

Example 3 Preparation of Compound 3 of the Present Invention

(1) Add 30 mL of tetrahydrofuran, compound 4 (5.0 g, 15.9 mmol, 1.0 eq), N-hydroxysuccinimide (2.2 g, 19 mmol, 1.2 eq) and triethylamine (4.0 g, 39.75 mmol, 2.5 eq) into a three-necked flask, stir magnetically, and cool to 0-10°C in an ice-water bath;

(2) Dissolve trichloromethyl carbonate (triphosgene) (5.0 g, 16.7 mmol, 1.05 eq) in tetrahydrofuran (10 mL) and slowly add dropwise to the system, maintaining the internal temperature at 0-10°C. After the addition is complete, raise the temperature to 20-40°C and react for 2 hours in a nitrogen atmosphere;

(3) 40 mL of purified water was slowly added dropwise to the system, and the mixture was stirred at room temperature for 2-3 h. Crystals gradually precipitated from the system. 40 mL of purified water was slowly added dropwise to the system, and the mixture was stirred at room temperature for 2-3 h. The crystals were collected by filtration, washed with a mixed solvent of water (10 mL) and tetrahydrofuran (5 mL), and dried under reduced pressure (-0.08 to -0.10 MPa) at 45-55°C to obtain compound 3 with a yield of 93.7% and a HPLC purity of 99.95%.

Example 4 Preparation of Compound 3 of the Invention

(1) Add 30 mL of acetonitrile, compound 4 (5.0 g, 15.9 mmol, 1.0 eq), N-hydroxysuccinimide (2.0 g, 17.5 mmol, 1.1 eq) and sodium carbonate (3.4 g, 31.8 mmol, 2.0 eq) into a three-necked flask, stir magnetically, and cool to 0-10°C in an ice-water bath;

(2) Dissolve carbonyldiimidazole (2.8 g, 17.5 mmol, 1.1 eq) in acetonitrile (10 mL) and slowly add dropwise to the system, maintaining the internal temperature at 0-10°C. After the addition is complete, raise the temperature to 30°C and react for 2 hours in a nitrogen atmosphere;

(3) 30 mL of purified water was slowly added dropwise to the system, and the mixture was stirred at room temperature for 2 h. Crystals gradually precipitated from the system. 40 mL of purified water was slowly added dropwise to the system, and the mixture was stirred at room temperature for 2-3 h. The crystals were collected by filtration, washed with acetonitrile, and dried at 60 °C to obtain compound 3 with a yield of 91.5% and a HPLC purity of 99.96%.

Example 5 Preparation of larotrectinib sulfate of the present invention

At room temperature, larotrectinib (5.0 g) was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran solution (10 ml) of sulfuric acid (0.63 ml) was added dropwise with stirring. After the addition was completed, stirring was continued for 30 min, and the mixture was concentrated and recrystallized from ethanol/water to obtain 6.1 g of larotrectinib sulfate with a yield of 98.3% and a HPLC purity of 99.99%.

Example 6 Preparation of larotrectinib sulfate

(1) Tetrahydrofuran (30 mL), compound 4 (5.0 g, 15.9 mmol), N-hydroxysuccinimide (2.2 g, 19 mmol) and triethylamine (5.6 g, 55.7 mmol) were placed in a three-necked flask, stirred magnetically, and cooled to 0-10°C in an ice-water bath;

(2) Dissolve trichloromethyl carbonate (triphosgene) (5.0 g, 17 mmol) in tetrahydrofuran (10 mL) and slowly add dropwise to the system, maintaining the internal temperature at 0-10°C. After the addition is complete, raise the temperature to 20-40°C and react in a nitrogen atmosphere. Monitor by TLC until the reaction of compound 4 is complete;

(3) Compound 2 (1.7 g, 19 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise to the reaction system under stirring at room temperature. After the addition was completed, the temperature was raised to 60° C. and the reaction was continued until the reaction of compound 3 was completed as monitored by TLC, and the temperature was lowered to room temperature.

(4) A solution of sulfuric acid (0.9 ml) in tetrahydrofuran (10 ml) was added dropwise with stirring. After the addition was completed, stirring was continued for 30 min. The mixture was concentrated and recrystallized from ethanol/water to obtain 6.9 g of larotrectinib sulfate. The total yield was 82.4% and the HPLC purity was 99.97%. Hydrogen spectrum: 1H NMR (400 MHz, D2O) (ppm): 2.18-2.33 (m, 7H), 2.68-2.70 (m, 1H), 3.4 3-3.74(m,2H),3.94-4.25(m,2H),4.64-4.71(m,1H),5.46-5.62(m,1H),6.25-6.80(m,1H),7.03(m,1H),7.17-7.20(m,1H),7.25-7.31(m,1H),7.90-8.10(m,1H),8.40-8.65(m,1H).

Claims (10)

1. A method for preparing larotrectinib, comprising the following steps: 2. According to the method of claim 1, in step 4, the molar ratio of compound 3 to compound 2 is 1:1-5, preferably 1:1-2. 3. The method according to claim 1, wherein a base is added in step 3, and the base is selected from an organic base or an inorganic base. 4. The method according to claim 3, wherein the organic base is selected from any one of triethylamine, pyridine, N,N-lutidine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine, N-methylpiperidine, trimethylamine, tripropylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or a combination thereof. 5. The method according to claim 3, wherein the inorganic base is selected from any one or a combination of potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium methoxide, sodium ethoxide, potassium fluoride/aluminum oxide, potassium phosphate, and sodium phosphate. 6. The method according to claim 3, wherein in step 4, the molar ratio of compound 3 to the organic base is 1:0.5-3, preferably 1:0.8-1.5. 7. The method according to claim 1, wherein the solvent in step 4 is selected from any one of acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, ethylene glycol dimethyl ether, dichloromethane, chloroform, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N.N-dimethylacetamide (DMAc), N-methylpyrrolidone, benzene, toluene, xylene, methanol, ethanol, and isopropanol, or a combination thereof. 8. The method according to claim 1, wherein the reaction temperature in step 4 is 20-100°C, preferably 30-80°C. 9. A compound 3 having the following structure: 10. A method for preparing compound 3, comprising reacting compound 4 with N-hydroxysuccinimide to obtain compound 3.