Method for preparing amorphous tolvaptan

Abstract

The invention discloses a method for preparing amorphous tolvaptan. The method comprises the steps of dissolving a tolvaptan crystalline compound into a solvent I, cooling to the temperature of 25-40 DEG C, so as to obtain a tolvaptan solution, then, adding the obtained tolvaptan solution into a rapidly-stirred solvent II, continuing to stir for 5-15 minutes after the adding is completed, then, filtering and drying, thereby obtaining amorphous tolvaptan, wherein the weight / volume ratio of the tolvaptan crystalline compound to the solvent I is 1g: (5-50)mL, solid precipitation exists during adding, the dosage of the solvent II is 0.5-5 times that of the solvent I, and the temperature of the rapidly-stirred solvent II is kept at 0-5 DEG C. According to the method, through using different solvents respectively at a dissolution stage and a precipitation stage and controlling the temperature change and dosage of the solvents, the yield of amorphous tolvaptan can be higher; moreover, the method disclosed by the invention is simple, is easy in operation and has no need of using large-sized equipment, such as a fluidized bed and the like, thereby being capable of playing a more active role in popularizing the drug.

Description

technical field

[0001] Embodiments of the present invention relate to the technical field of organic drug synthesis, and more specifically, embodiments of the present invention relate to a preparation method of amorphous tolvaptan. Background technique

[0002] Tolvaptan is an oral non-peptide vasopressin V2 receptor antagonist developed by Japan’s Otsuka Pharmaceutical Company. It was launched in the United States and Europe in 2009. Hyponatremia in patients with cirrhosis and antidiuretic hormone hyposecretion syndrome.

[0003] Tolvaptan chemical name: N-[4-[(5RS)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-methanol Acyl]-3-methylphenyl]-2-methylbenzamide, its structural formula is as follows:

[0004]

[0005] According to the BCS classification, tolvaptan belongs to category IV, that is, low solubility and low permeability drugs. In the process of preparation research, it was found that the dissolution rate of the amorphous compound was significantl...

Examples

Embodiment 1

[0031] Add 1500mL of acetone and 50g of tolvaptan crystalline compound into a 2L reaction flask, heat and stir until completely dissolved to obtain an acetone-tolvaptan solution, and naturally cool to 25°C under stirring for later use.

[0032] Add 6000mL of pre-cooled n-hexane (temperature 2°C) to the 10L reaction flask, and quickly add the above-mentioned acetone-tolvaptan solution dropwise to n-hexane within 5 minutes under rapid stirring, and a large amount of solids are precipitated immediately. After completion, continue stirring for 15 minutes, filter, and dry under reduced pressure at 60° C. to constant weight to obtain 47.5 g of amorphous tolvaptan, with a yield of 95%.

Embodiment 2

[0034] Add 500mL of methanol and 50g of tolvaptan crystalline compound into a 1L reaction flask, heat and stir until completely dissolved to obtain a methanol-tolvaptan solution, and naturally cool to 35°C under stirring for later use.

[0035] Add 1500mL of pre-cooled water (at a temperature of 5°C) to the 3L reaction bottle, pour it into the above tolvaptan solution under rapid stirring, and immediately precipitate a large amount of solid, after pouring, continue to stir for 5 minutes, filter, 50°C Drying under reduced pressure to constant weight yielded 45.8 g of amorphous tolvaptan, with a yield of 91.6%.

Embodiment 3

[0037] Add 800mL of ethanol and 50g of tolvaptan crystal form compound into a 2L reaction flask, heat and stir until completely dissolved to obtain an ethanol-tolvaptan solution, and naturally cool to 40°C under stirring for later use.

[0038] Add 2000mL of pre-cooled water (at a temperature of 4°C) to the 5L reaction bottle, and quickly add the above ethanol-tolvaptan solution dropwise within 5 minutes under rapid stirring, and a large amount of solids are precipitated immediately. After the dropwise addition, continue to Stir for 15 minutes, filter, and dry under reduced pressure at 60° C. to constant weight to obtain 47 g of amorphous tolvaptan, with a yield of 94%.

technical field

[0001] Embodiments of the present invention relate to the technical field of organic drug synthesis, and more specifically, embodiments of the present invention relate to a preparation method of amorphous tolvaptan. Background technique

[0002] Tolvaptan is an oral non-peptide vasopressin V2 receptor antagonist developed by Japan’s Otsuka Pharmaceutical Company. It was launched in the United States and Europe in 2009. Hyponatremia in patients with cirrhosis and antidiuretic hormone hyposecretion syndrome.

[0003] Tolvaptan chemical name: N-[4-[(5RS)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-methanol Acyl]-3-methylphenyl]-2-methylbenzamide, its structural formula is as follows:

[0004]

[0005] According to the BCS classification, tolvaptan belongs to category IV, that is, low solubility and low permeability drugs. In the process of preparation research, it was found that the dissolution rate of the amorphous compound was significantl...

Examples

Embodiment 1

[0031] Add 1500mL of acetone and 50g of tolvaptan crystalline compound into a 2L reaction flask, heat and stir until completely dissolved to obtain an acetone-tolvaptan solution, and naturally cool to 25°C under stirring for later use.

[0032] Add 6000mL of pre-cooled n-hexane (temperature 2°C) to the 10L reaction flask, and quickly add the above-mentioned acetone-tolvaptan solution dropwise to n-hexane within 5 minutes under rapid stirring, and a large amount of solids are precipitated immediately. After completion, continue stirring for 15 minutes, filter, and dry under reduced pressure at 60° C. to constant weight to obtain 47.5 g of amorphous tolvaptan, with a yield of 95%.

Embodiment 2

[0034] Add 500mL of methanol and 50g of tolvaptan crystalline compound into a 1L reaction flask, heat and stir until completely dissolved to obtain a methanol-tolvaptan solution, and naturally cool to 35°C under stirring for later use.

[0035] Add 1500mL of pre-cooled water (at a temperature of 5°C) to the 3L reaction bottle, pour it into the above tolvaptan solution under rapid stirring, and immediately precipitate a large amount of solid, after pouring, continue to stir for 5 minutes, filter, 50°C Drying under reduced pressure to constant weight yielded 45.8 g of amorphous tolvaptan, with a yield of 91.6%.

Embodiment 3

[0037] Add 800mL of ethanol and 50g of tolvaptan crystal form compound into a 2L reaction flask, heat and stir until completely dissolved to obtain an ethanol-tolvaptan solution, and naturally cool to 40°C under stirring for later use.

[0038] Add 2000mL of pre-cooled water (at a temperature of 4°C) to the 5L reaction bottle, and quickly add the above ethanol-tolvaptan solution dropwise within 5 minutes under rapid stirring, and a large amount of solids are precipitated immediately. After the dropwise addition, continue to Stir for 15 minutes, filter, and dry under reduced pressure at 60° C. to constant weight to obtain 47 g of amorphous tolvaptan, with a yield of 94%.

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