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Preparation method of high-purity tolvaptan

A tolvaptan, high-purity technology, applied in the field of drug preparation, can solve the problems of dechlorination impurity residue, inability to completely inhibit dechlorination reaction, and inability to obtain high-purity tolvaptan, and achieve the effect of high yield

Inactive Publication Date: 2018-02-06
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the methods proposed in these two documents cannot completely inhibit the occurrence of dechlorination reaction, and about 0.1% of dechlorination impurities remain in the final product, so that high-purity (≥99.95%) tolvaptan cannot be obtained

Method used

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  • Preparation method of high-purity tolvaptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0031] The preparation method of the high-purity tolvaptan of the present embodiment is as follows:

[0032] Add 5g of the compound of formula II into a 100mL three-neck flask, then add 25mL of tetrahydrofuran, stir to dissolve, cool down to -5~0°C, control the temperature at -5~0°C, and dropwise add 1.73g of dihydrofuran with a concentration of 70wt%. Hydrogen bis(2-methoxyethoxy)sodium aluminate toluene solution, heat up to 10-20°C after addition, and stir for 2 hours.

[0033] After the completion of the reaction monitored by HPLC, the temperature was controlled at 10-20°C, and 50mL of water was added dropwise. Solids were precipitated. Stirring was continued for 1-2h, and suction filtration was performed. The filter cake was recrystallized with methanol aqueous solution, and dried under reduced pressure to obtain white crystals of tolvaptan. 4.73g, the yield was 94.2%, the HPLC purity was 99.97%, and the dechlorinated impurity IV was not detected.

Embodiment 2～ Embodiment 6）

[0035] The preparation method of each embodiment is basically the same as that of Example 1, and the differences are shown in Table 1.

[0036] Table 1

[0037]

Embodiment 7～ Embodiment 10）

[0039] The preparation method of each embodiment is basically the same as that of Example 1, and the differences are shown in Table 2.

[0040] Table 2

[0041]

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PUM

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Abstract

The invention discloses a preparation method of high-purity tolvaptan. The preparation method comprises the step of reducing N-[4-[(5R)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1-benazepine-1-formyl]-3-methyl phenyl]-2-methyl benzamide with sodium bis(2-methoxyethoxy) aluminumhydride, thereby obtaining the high-purity tolvaptan with the purity higher than or equal to 99.95%. The preparation method disclosed by the invention has the advantages that sodium bis(2-methoxyethoxy) aluminumhydride is adopted as a reducing agent for preparing tolvaptan by reducing N-[4-[(5R)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1-benazepine-1-formyl]-3-methyl phenyl]-2-methyl benzamide, the production of a dechlorination impurity IV can be extremely effectively inhibited, and finally the high-purity tolvaptan with the purity higher than or equal to 99.95% can be obtained, and high yield being 90% or above can be obtained while tetrahydrofuran or methyltetrahydrofuran is adopted as a reaction solvent.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of high-purity tolvaptan. Background technique [0002] The chemical name of Tolvaptan is: N-[4-[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1 -Formyl]-3-methylphenyl]-2-methylbenzamide, which was developed by Japan’s Otsuka Pharmaceutical Co. and was approved by the US FDA in 2009. Its trade name is Samsca®. For the treatment of hyponatremia caused by congestive heart failure, liver cirrhosis, and antidiuretic hormone deficiency syndrome. [0003] The structural formula of tolvaptan is shown in formula I: [0004] . [0005] I [0006] At present, the mainstream synthetic route of tolvaptan is to obtain the compound shown in formula II through a series of reactions, and then reduce the 5-ketocarbonyl group of the compound to the 5-hydroxyl group to obtain tolvaptan (see literature 1 ~ document 6). [0007] [...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 胡国宜胡锦平高永清李喜龙奚小金
Owner CHANGZHOU SUNLIGHT PHARMA
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