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A technology of tolvaptan and intermediates, applied in the field of drug synthesis, to achieve the effect of mild conditions
Active Publication Date: 2014-07-02
HUBEI GRAND LIFE SCI & TECH CO LTD
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Embodiment 1
[0024] The synthesis of embodiment 1 compound 4-azepanenone
[0025] N-vinylpyrrolidone (30 g, 0.27 mol) was irradiated in 1600 mL of methanol at 40 °C with a 50-watt low-pressure mercury UV lamp for 45 hours, concentrated under reduced pressure and recrystallized in acetonitrile to obtain 24 g of 4-azepanenone. The yield is 80%. Melting point: 74-76°C. 1 H NMR (400MHz, CDCl 3 ):δ6.90(d,J=10.9Hz,1H),5.14(d,J=10.9Hz,1H),2.99-2.90(m,4H),2.00(s,1H),1.96-1.86(m, 2H).
Embodiment 2
[0026] The preparation of embodiment 2N-p-toluenesulfonyl-4-azepanenone
[0027] Add 24g (0.216mol) of 4-azepanenone, 125ml of dichloromethane, 125ml of pyridine, and 0.3g of 4-dimethylaminopyridine into a 500mL single-necked round bottom flask, and then add 41.18g of p-toluenesulfonyl chloride ( 0.216mol), the mixture was stirred at room temperature for 8 hours. Then add 100mL1N hydrochloric acid, extract with dichloromethane (50mL×3), combine the organic phases, wash with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure to obtain 55.0 g (0.21 mol) of a white solid, with a yield of 96%.
[0029] Example 3 Preparation of N-p-toluenesulfonyl-7-chloro-2,3,4,5,10,11-hexahydro-1H-1-benzazepin-5-one
[0030] Add N-p-toluenesulfonyl-4-azepanenone (265mg, 1.0mmol), 2-chlorobutenal (104mg, 1.0mmol), (S)-diphenyl Trimethylsiloxymethylpyrrolidine (5mg), chloroform (15ml), and p-nitrobenzoic acid (5mg) were reacted at room temperature for 48 hours and separated by column chromatography to obtain 238mg (0.68mmol) of the product, with a yield of 68%.
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Abstract
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a tolvaptan intermediate 7-chloro-2,3,4,5,10,11-hexahydro-1H-1-benzodiazepines-5-one. The method comprises the following steps: by taking N-vinylpyrrolidone as an active ingredient, rearranging under light to obtain 4-azecycloheptatrienone, then protecting nitrogen methyl p-toluenesulfinate, reacting with 2-chloro-2-butenal in the presence of diaryl D-prolinol derivatives to generate 7-chloro-2,3,4,5,10,11-hexahydro-1H-1-benzodiazepines-5-one, dehydrogenizing and aromatizing in the presence of manganese dioxide, and finally removing protection groups to obtain the 7-chloro-2,3,4,5,10,11-hexahydro-1H-1-benzodiazepines-5-one. Due to no Claisen condensation or Friedle-Crafts reaction in the conventional synthesis method, the potassium tert-butanol and aluminum trichloride are omitted, the preparation method is mild in reaction conditions, easily available in raw materials, capable of lowering the cost, and more suitable for industrial production.
Description
technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a preparation method of tolvaptan intermediate 7-chloro-2,3,4,5,10,11-hexahydro-1H-1-benzazepine-5-one . Background technique [0002] Tolvaptan is a specific antagonist of arginine vasopressin and is used for the treatment of hypervolemic or isovolemic hyponatremia with heart failure, liver cirrhosis, and syndrome of abnormal secretion of antidiuretic hormone. Chemical name: N-[4-[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-3-methanol phenyl]-2-methylbenzamide, the molecular formula is as follows: [0003] [0004] The synthesis of tolvaptan has been comprehensively reviewed by the patent literature (CN102093293A), and the typical method is to synthesize according to the following reaction scheme (Drugs of the Future2002,27(4);350-357): [0005] [0006] The Kleiman condensation or Friedle-Crafts reaction in the synthesis method adopts pota...
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