A kind of substitute of glycopyrronium bromide and its preparation method and medical application
A technology of glycopyrronium bromide and substitutes, applied in the preparation of sulfate, sulfonate, antipyretic, etc., can solve problems such as identification difficulty, and achieve the effects of not easy to absorb moisture, suitable solubility, and excellent stability
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Embodiment 1
[0032]Embodiment 1: the preparation of formula (I) 3-[(cyclopentyl hydroxyphenylacetyl) oxygen]-1,1-dimethylpyrrolidine methyl sulfate
[0033] a. In a dry 5L reaction kettle, add 400g (1.82mol) of cyclopentylmandelic acid and 2000ml of N,N-dimethylformamide, cool to 20±5°C, add 360g of N'N-carbonyldiimidazole ( 2.22mol), stirred for 20min, added 228g (2.25mol) of 3-hydroxy-1-methyltetrahydropyrrole, heated to 60±5°C within 50-60min, reacted for 22h, after the reaction was identified by TLC, cooled to 20°C , pumped into a 10L separator, added 2.8L of purified water and stirred, added 3.2L of toluene, stirred for 10 minutes, separated, the organic layer was washed with purified water 1440ml×5, concentrated to dryness under reduced pressure at 50°C, and an oily substance of about 580 g, used directly in the next step.
[0034] b. Add 580g (1.91mol) of the above product, add 3000ml of acetone, cool to 0-5°C, add 241g (1.91mol) of dimethyl sulfate, stir for 1h, filter, wash the s...
Embodiment 2
[0039] Embodiment 2: Preparation of formula (II) 3-[(cyclopentyl hydroxyphenylacetyl) oxygen]-1,1-dimethylpyrrolidine taurate
[0040] Preparation: In a dry 1000ml reactor, add 40g (0.182mol) of cyclopentylmandelic acid and 200ml of N,N-dimethylformamide, cool to 20±5°C, add 36g of N'N-carbonyldiimidazole ( 0.222mol), stirred for 20min, added 22.8g (0.225mol) of 3-hydroxy-1-methyltetrahydropyrrole, heated to 60±5°C within 50~60min, reacted for 24h, after TLC identified the reaction, cooled to 20 ℃, pump into a 5L liquid separator, add 280ml of purified water, stir, add 320ml of toluene, stir for 10 minutes, separate the liquids, wash the organic layer with 144ml of purified water x 5, concentrate to dryness at 50℃ under reduced pressure, and obtain about 59.2 grams of oily substance , used directly in the next step.
[0041] a. Add 59g (0.194mol) of the above product, 33g (0.194mol) methyl benzenesulfonate, and 450ml acetone into a 1000ml reactor, cool to 0°C, stir for 5 hour...
Embodiment 3
[0047] Embodiment 3: physicochemical property comparison
[0048] According to the four routine tests of the Chinese Pharmacopoeia 2015 edition.
[0049]
[0050]
[0051] Conclusion: The compounds of formula (I) and formula (II) of the present invention have suitable solubility and fluidity, and are not hygroscopic.
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