The method for preparing tolvaptan intermediate
A purification method and compound technology, applied in the field of medicine, can solve the problems of cumbersome process, low overall yield of synthetic formula II compound, laborious and laborious cost, etc.
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Embodiment 1
[0041] Example 1: 7-chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-aminobenzoyl)-5H-1-benzazepine-5-one ( Formula III) Preparation
[0042] Add 60kg of methanol, 40kg of tetrahydrofuran and 40kg of concentrated hydrochloric acid into the reaction kettle, stir and add 10.4kg of 7-chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-nitrobenzoyl) -5H-1-Benzazepin-5-one (compound of formula IV). Dissolve 25kg of dihydrate and stannous chloride in 40kg of methanol, add to the above system, heat to 50-60°C, the reaction time is 2-2.5 hours, and the reaction ends. Concentrate under reduced pressure to remove the organic solvent, and put the material into a material bucket to freeze overnight. Shake filter and beat with tetrahydrofuran, shake filter to dryness to obtain the compound of formula III.
Embodiment 2
[0043] Example 2: N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepine-1-yl)carbonyl]-3- Preparation of methylphenyl]-2-methylbenzamide (formula II)
[0044] Add 100 L of dichloromethane and 11.0 kg of pyridine into the reaction kettle, add the compound of formula III under stirring, and then add 7.0 kg of o-toluoyl chloride. After the addition, stir the reaction at 20-30° C., and check that the reaction is complete. 13.9kg crude tolvaptan was obtained by rejection filtration, the purity was 94.79%, and the impurity M was 0.36%.
[0045] Add the solid obtained in the previous step into 57 kg of ethyl acetate / dichloromethane / isopropyl ether (volume ratio 1:5:2) solvent, heat to 50°C-60°C and stir to dissolve, cool and crystallize, and shake off to obtain a white solid 10.1 kg, yield: 71.3%, purity: 99.8%, impurity M content 0.03%.
Embodiment 3
[0047] According to the purification method described in the examples of CN101273017, CN101817783 or CN102060769, the obtained sample yield and purity data are shown in Table 1.
[0048] Table 1
[0049]
[0050] in conclusion:
[0051] 1. The method described in CN101817783 (methanol / petroleum ether) cannot effectively obtain a high-purity compound of formula II, and the appearance of the obtained sample is yellow, and the impurity M in the sample cannot be effectively removed;
[0052] 2. Although the methods described in CN101273017 and CN102060769 can obtain relatively high-purity formula II compounds, the refining yield is low and the production cost is high; meanwhile, the methods of CN101273017 and CN102060769 have poor refining effects on impurities M in the samples, and the obtained samples cannot satisfy Raw material quality standards, the unknown single impurity limit is controlled below 0.1%; in addition, the obtained sample is light yellow or light yellow.
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