CN107304209A - Compound it is unformed and preparation method thereof - Google Patents
Compound it is unformed and preparation method thereof Download PDFInfo
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- CN107304209A CN107304209A CN201610239438.4A CN201610239438A CN107304209A CN 107304209 A CN107304209 A CN 107304209A CN 201610239438 A CN201610239438 A CN 201610239438A CN 107304209 A CN107304209 A CN 107304209A
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- cyclopenta
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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Abstract
The present invention relates to the unformed and preparation method thereof of 3 [(phenyl of 2 cyclopenta, 2 hydroxyl 2) ethyoxyl] 1 methyl bromide 1 azabicyclo [2,2,2] octanes.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically it is to provide selective anticholinergic drug --- 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane is unformed and preparation method thereof.
Background technology
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane is selective anticholinergic drug, there is obvious selectivity to m receptor (to M2 acceptors without obvious effect).It suppresses vagal reflection by the transmitter acetylcholine that antagonism vagus nerve discharges.Pharmacodynamics test shows：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane has obvious antiallergy, anti-inflammatory, itching-relieving action, moreover it is possible to reduce capillary permeability.3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane can suppress airway inflammation, Airway Remodeling and airway hyper-reaction caused by the attack of sensitized mice antigen, and its mechanism of action is relevant with the balance, reduction cell factor and ECF expression that adjust Th1/Th2 cells.
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane is a kind of quaternary ammonium salt, it is minimum through the ability of schneiderian membrane, intestines and stomach and blood-brain barrier, causes systemic anticholinergic effect very low (including spirit, eyes, angiocarpy and intestines and stomach effect).Pharmacological toxicology result of study shows：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane toxicity is very low, and the safety coefficient that clinic is recommended in dosage range is larger.
I, II and III clinical trial phase result show：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane sprays in 90 μ g/, 4 times a day, runny nose, rhiocnesmus, sneeze and nasal obstruction symptom caused by rhinitis after can effectively preventing under the dosage of each 1 spray per side nostril every time and treat continuation allergic rhinitis and catch a cold.Items research shows that subject is preferable for the tolerance of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane, and adverse reaction rate is low, mild degree.
The studies above result shows：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] runny nose, rhiocnesmus, sneeze and nasal obstruction symptom caused by rhinitis, safely and effectively, quality controllable after octane is used to prevent and treats continuation allergic rhinitis and catch a cold.
Up to the present, still document report 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane without disclosed in is unformed both at home and abroad and its prepares.
Summary of the invention
It is unformed and its production and use the present invention relates to the 3- shown in Fig. 1 [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane.
The unformed mixed XRPD characteristic peaks of compound shown in Fig. 1 are disperse peak
Its preparation method is：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane bulk drug is positioned in aluminum sample dish, it is slowly heated to 250 DEG C, take out and be positioned in ice bath immediately, to sample cooling, produced.
Brief description of the drawings
Fig. 1 is the structural formula of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane.
Fig. 2 is the unformed XRPD diagrams of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane.
Fig. 3 is the unformed DSC figures of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane.
Fig. 4 is 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) the ethyoxyl] -1- methyl-unformed microscope figure of bromination -1- azabicyclos [2,2,2] octane, and the image under 200 power microscopes is shown, the crystal formation solid is irregular crystal.
Embodiment
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane that the present invention is obtained it is unformed, it is high in solid-state and solution state stability inferior.So that the presence that 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane can be stablized, is easy to store and transports, it is easy to preparation is made.
By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2, 2, 2] the unformed solid of octane is respectively placed in 25 DEG C/90%RH, 40 DEG C/75%RH, under 60 DEG C/air humidity conditions, in the 0th, sampled at 5 and 10 days, HPLC analyses are changed with the purity for determining laboratory sample, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2, 2, 2] stability result of octane solid is listed in Table 1 below, show 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2 of the present invention, 2, 2] the unformed good solid-state stability of octane.
By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] the unformed solid of octane is soluble in water, sampled when experiment the 0th, 1,3 and 7 days, HPLC analyses are carried out after dilution to determine that purity of the solid in test solvent changes, the results are shown in Table 2 for the stability of solution of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane solid.Purity of the unformed solid of the present invention in water does not have significant change.Show 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) the ethyoxyl] -1- methyl-unformed good stability of solution of bromination -1- azabicyclos [2,2,2] octane of the present invention.
Above result of the test, which illustrates that 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane of the present invention is unformed, has good storage stability.
3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-unformed preparation method of bromination -1- azabicyclos [2,2,2] octane of the present invention is as follows：
A) heated to 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane raw material；
B) take out and be positioned in ice bath immediately；
C) after being cooled down completely to sample, produce.
It is highly preferred that 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-unformed preparation method of bromination -1- azabicyclos [2,2,2] octane of the present invention is as follows：
A) 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane bulk drug is positioned in aluminum sample dish, is slowly heated to 250 DEG C；
B) take out and be positioned in ice bath immediately；
C) after being cooled down to sample, produce.
Illustrate the effect of the present invention with specific embodiment below, but protection scope of the present invention is not limited by the following examples.
Embodiment 1：The unformed preparation example 1 of the present invention
Weigh about 1g 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane bulk drug is placed in aluminum sample dish, 250 DEG C are heated to 10 DEG C per minute of heating rate, take out and be positioned in 0 DEG C of ice bath immediately and cooled down rapidly, after being cooled down completely to sample, produce.
Embodiment 2：The unformed preparation example 2 of the present invention
Weigh about 5g 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane bulk drug is placed in aluminum sample dish, 260 DEG C are heated to 15 DEG C per minute of heating rate, take out and be positioned in 0 DEG C of ice bath immediately and cooled down rapidly, after being cooled down completely to sample, produce.
Embodiment 3：Test
Powder X-ray diffraction approach
Test condition：
Solid sample is detected by using the powder x-ray diffraction (Bruker D8 Advance) equipped with Lynxeye detectors.Sample 120mg is taken to be laid in the middle part of zero Background Samples disk, sample is scanned with 0.1sec/step speed, instrument is scanned since 3o (2 θ) to 40o (2 θ), X-ray light pipe voltage and current is respectively that 40KV and 40mA determines 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2 during scanning, 2,2] the unformed x-ray diffractogram of powder of octane.
Gravitational thermal analysis method
Thermogravimetric analysis test condition：Solid sample carries out thermogravimetric analysis using TA Instrument TGA Q500.About 3.0mg solid sample is placed in Balanced platinum sample disc, sample quality automatic weighing in TGA heating furnaces.Sample is heated to 300 DEG C with 10 DEG C/min speed.In test process, the nitrogen flow in balance room and sample room is 40mL/min and 60mL/min respectively.
Micro- sem observation
Test condition：A small amount of sample is taken to be laid on slide, slide is placed on the microscopical objective table of Nikon Instruments Eclipse 80i types, it is used as polarized light microscopy analyzer in this experiment, it is sent to by DS camera shooting images in computer, and picture is handled with NIS-Elements D3.0 softwares.
Stability
By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] the unformed solid of octane be respectively placed in 25 DEG C/90%RH, 40 DEG C/75%RH, under 60 DEG C/air humidity conditions, in the 0th, 5 and 10 days when sample, HPLC analyses are changed with the purity for determining laboratory sample, refer to table 1,3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] the unformed solid-state stability result of octane.
Table 1：3- [(2- cyclopenta -2- hydroxyl -2- phenyl) the ethyoxyl] -1- methyl-unformed solid-state stability result of bromination -1- azabicyclos [2,2,2] octane
Stability of solution
By 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] the unformed solid of octane is soluble in water, sampled when experiment the 0th, 1,3 and 7 days, HPLC analyses are carried out after dilution to determine that purity of the solid in test solvent changes, 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] the results are shown in Table 2 for the stability of solution of the unformed solid of octane.Purity of the unformed solid of the present invention in water does not have significant change.Refer to the 3- of table 2 [(2- cyclopenta -2- hydroxyl -2- phenyl) the ethyoxyl] -1- methyl-unformed stability of solution test result of bromination -1- azabicyclos [2,2,2] octane bulk drug.
Table 2：The unformed stability of solution test result of 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos [2,2,2] octane bulk drug
It is appreciated that from this professional angle, the change of many details is possible, and this is simultaneously not so limited scope and spirit of the present invention, and the present invention is not limited to above-described embodiment.
Claims (4)
1.3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
[2,2,2] octane it is unformed, its powder is determined through X-ray diffraction method, gained collection of illustrative plates such as the application
Accompanying drawing 2 shown in, in disperse peak.
2. 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- of claim 1
Azabicyclo [2,2,2] octane it is unformed, it is characterized in that, using DSC carry out heat analysis when,
Gained collection of illustrative plates detects the melting peak of sample as shown in the accompanying drawing 3 of the application, not.
3. such as 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethoxies of any one of claim 1 or 2
Base] -1- methyl-bromination -1- azabicyclos [2,2,2] octane unformed preparation method, it is characterised in that
A) to 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
[2,2,2] octane raw material is heated；
B) take out and be positioned in ice bath immediately；
C) after being cooled down completely to sample, produce.
4. method as claimed in claim 3, it is characterised in that
A) by 3- [(2- cyclopenta -2- hydroxyl -2- phenyl) ethyoxyl] -1- methyl-bromination -1- azabicyclos
[2,2,2] octane bulk drug is positioned in aluminum sample dish, is slowly heated to 250-260 DEG C；
B) take out and be positioned in ice bath immediately；
C) after being cooled down to sample, produce.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610239438.4A CN107304209A (en) | 2016-04-18 | 2016-04-18 | Compound it is unformed and preparation method thereof |
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| CN201610239438.4A CN107304209A (en) | 2016-04-18 | 2016-04-18 | Compound it is unformed and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1532196A (en) * | 2003-03-21 | 2004-09-29 | 北京小伙伴医药生物技术有限公司 | Quinic compound containing quaternary ammonium group and its preparation and medicina use |
| CN101585835A (en) * | 2008-05-22 | 2009-11-25 | 北京嘉事联博医药科技有限公司 | Preparation method and application of bencycloquidium bromide optical isomer and composition of bencycloquidium bromide optical isomer |
| CN101856327A (en) * | 2009-04-08 | 2010-10-13 | 北京嘉事堂生物医药有限公司 | Aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof |
-
2016
- 2016-04-18 CN CN201610239438.4A patent/CN107304209A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1532196A (en) * | 2003-03-21 | 2004-09-29 | 北京小伙伴医药生物技术有限公司 | Quinic compound containing quaternary ammonium group and its preparation and medicina use |
| CN101585835A (en) * | 2008-05-22 | 2009-11-25 | 北京嘉事联博医药科技有限公司 | Preparation method and application of bencycloquidium bromide optical isomer and composition of bencycloquidium bromide optical isomer |
| CN101856327A (en) * | 2009-04-08 | 2010-10-13 | 北京嘉事堂生物医药有限公司 | Aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof |
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| CB03 | Change of inventor or designer information |
Inventor after: Zhao Shuqiang Inventor after: Yu Wenzhan Inventor after: Pan Yuanyuan Inventor before: Zhao Shuqiang Inventor before: Yu Wenzhan |
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Application publication date: 20171031 |
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