CN109956938A - Wumei bromine ammonium intermediate crystal form and preparation method thereof and the method that Wumei bromine ammonium is prepared with the intermediate - Google Patents
Wumei bromine ammonium intermediate crystal form and preparation method thereof and the method that Wumei bromine ammonium is prepared with the intermediate Download PDFInfo
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Abstract
The present invention relates to Wumei bromine ammonium intermediate (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorates (II) and preparation method thereof, it is related to a kind of compound (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal form and preparation method thereof of the intermediate (II), also relates to the method using the intermediate (II) as medicinal intermediate raw material preparation Wumei bromine ammonium.Mild condition, simple and easy to do the invention has the benefit that the method that (1) prepares the compounds of this invention (II), yield reaches 90% or more, purity and reaches 99.5% or more;(2) the Wumei bromine ammonium prepared with this compound (II), easy to operate, reaction time is short, and yield reaches 90% or more, purity and reaches 99.4% or more;(3) crystal-form compound (V) stability is good, convenient for storage and uses.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to Wumei bromine ammonium intermediate (1- azabicyclo [2.2.2] octane -4-
Base) (diphenyl) methanol hydrochlorate (II) and preparation method thereof, and be related to one of compound (1- azabicyclo [2.2.2] is pungent
Alkane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal form, and with (1- azabicyclo [2.2.2] octane -4- base) (hexichol
Base) methanol hydrochlorate (II) be starting material prepare Wumei bromine ammonium method.
Background technique
Wumei bromine ammonium (umeclidinium bromide), entitled 4- [hydroxyl (diphenyl) methyl] -1- { 2- of chemistry
[(benzyl) oxygen] ethyl } -1- azabicyclo [2.2.2] octane bromide (I) is researched and developed by GlaxoSmithKline company
The novel long-acting anticholinergic agent of sucking of one kind, can be applied alone or be used in combination with other drugs, be used for chronic obstructive pulmonary disease
The long term maintenance therapy of (Chronic Obstructive Pulmonary Disease, abbreviation COPD) bronchial obstruction in patients.
Wumei bromine ammonium chemical structural formula:
The intermediate of the Wumei bromine ammonium of existing literature report is (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) first
The free alkali (VI) of alcohol, chemical structural formula are as follows:
[1] the compound patent CN1976701A(WO2005104745 of GlaxoSmithKline application),
J.Med.Chem.2009,52,2493-2505, CN104619706A and other correlation preparations patent US7439393,
(1- azabicyclo [2.2.2] octane -4- base) (diphenyl) is reported in US7488827, US7498440 and US7361787
The preparation method of methanol freebase (VI) uses lithium reagent for nucleophilic addition reagent and 1- azabicyclo [2.2.2] octane-
4- Ethyl formate is reacted, and reaction temperature needs -78 DEG C ~ 5 DEG C of control, lithium reagent price is high, hardly possible stores, use condition is harsh,
The cost is relatively high.Wherein reaction equation disclosed in CN104619706A is as follows:
[2] WO2005104745 and J.Med.Chem.2009,52,2493-2505 reports that (1- azabicyclo [2.2.2] is pungent
Alkane -4- base) (diphenyl) methanol freebase (VI) analog synthetic method, phenyl containing substituent group carries out grignard reaction,
It is not required to low temperature, but the reaction time is longer, needs 60 DEG C of reaction 16h, with saturated ammonium chloride quenching reaction, is concentrated again after concentration, extraction
Solid is obtained, post-processing is complicated, and the purity for the product reported is lower.
[3] the immediate prior art be Anhui Dexinjia Bio-Pharmaceutical Co., Ltd. patent CN105461710A in report
Road is reacted with 1- azabicyclo [2.2.2] octane -4- Ethyl formate with Grignard Reagent, the deficiency of the content of the patent disclosure
Be in is to be quenched with water, then (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) is obtained by extraction in: its post-processing approach
Methanol freebase (VI), operation is loaded down with trivial details, and yield is low, and of poor quality, the highest yield of report only has 54.2%.
[4] synthetic route that Wumei bromine ammonium is disclosed in the patent WO2005104745 of GlaxoSmithKline application is
With (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol freebase (VI) for starting material, with benzyl -2- bromine second
Base ether (III) is in solvent C H3CN/CHCl360 DEG C of reaction 16h or for 24 hours in system, not only the reaction time is longer, and yield highest
Only 43.3%.
[5] method for the synthesis Wumei bromine ammonium reported in CN104619706A is with (1- azabicyclo [2.2.2] octane -4-
Base) (diphenyl) methanol freebase (VI) is starting material, it flows back in a solvent 3h or 13h with benzyl -2- bromoethyl ether (III),
Reaction yield is up to 89%.
Summary of the invention
The shortcomings that the purpose of the present invention is overcoming the prior art and deficiency, provide a kind of Wumei bromine ammonium intermediate (1- azepine
Bicyclic [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) and preparation method thereof, and it is related to one of compound (1-
Azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal form, and with (1- azabicyclo [2.2.2]
Octane -4- base) (diphenyl) methanol hydrochlorate be starting material prepare Wumei bromine ammonium (I) method.Compound (II) and compound
(V) structure is shown below.
The contents of the present invention are more particularly to as follows:
In a first aspect, the compound is (1- azabicyclo the present invention provides a kind of intermediate of drug Wumei bromine ammonium
[2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate, structural formula such as formula (II).
HA in compound (II) structural formula is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, formic acid, acetic acid, wherein
The optimal HA of intermediate reaction effect as Wumei bromine ammonium is selected from hydrochloric acid, hydrobromic acid.The compound is not simply by chemical combination
Object (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol freebase (VI) is obtained at salt, but in experimentation
In, in order to solve the problems, such as the practical of the prior art, it may be assumed that 1- azabicyclo [2.2.2] octane -4- Ethyl formate and Grignard Reagent
Reaction, post-processing generate a large amount of magnesium hydroxide gelatinous precipitates after being quenched, and (1- azabicyclo [2.2.2] is pungent with product for these precipitatings
Alkane -4- base) (diphenyl) methanol freebase (VI) mixes, and very big difficulty is brought to subsequent extracting operation, and emulsification is tight
Weight, it is difficult to be layered, leading to extraction, not exclusively extractant dosage is big, and yield is low, and purity difference is not suitable for large-scale production.In order to
The difficulty of the prior art is solved, the present inventor's post-processing approach traditional to grignard reaction is improved, and product (1- nitrogen is utilized
Miscellaneous bicyclic [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) the lesser characteristic of solubility in water, use aqueous acid
Quenching reaction is carried out instead of water or saturated ammonium chloride, makes product (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) first
Alcohol hydrochlorate (II) is precipitated, and does not generate magnesium hydroxide gelatinous precipitate in acid condition, only generates the magnesium salts for being dissolved in water, magnesium ion
It can be removed through subsequent filtering, water-washing process, obtained the compound of the present invention (1- azabicyclo [2.2.2] octane -4-
Base) for (diphenyl) methanol hydrochlorate (II) yield up to 90% or more, purity is up to 99.5% or more, the very good solution prior art
Deficiency.It is cumbersome to eliminate extraction in the prior art, dry, distillation etc. for the compound (II) prepared using method of the invention
Operating process, keep simple process easy, high income is high-quality.Using the compound as the centre of synthetic drug Wumei bromine ammonium
Body better meets and has ensured the quality of Wumei bromine ammonium pharmaceutical product.
Second aspect, it to be compound (1- azepine that the present invention also provides the crystal forms of the intermediate (V) of drug Wumei bromine ammonium
Bicyclic [2.2.2] octane -4- base) for the HA in (diphenyl) methanol hydrochlorate (II) when being hydrochloric acid, i.e., compound is (1- azabicyclo
[2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal form, crystal form feature passes through X-ray powder diffraction
The angle of diffraction (2 θ) is 5.13 ± 0.2,10.25 ± 0.2,14.36 ± 0.2,16.23 ± 0.2,20.62 ± 0.2,31.65 ± 0.2
There is a characteristic absorption peak at place, at the same 2 θ of the angle of diffraction of X-ray powder diffraction 16.34 ± 0.2,18.37 ± 0.2,19.92 ±
0.2,21.13 ± 0.2,22.87 ± 0.2,23.10 ± 0.2,23.25 ± 0.2,26.59 ± 0.2,27.32 ± 0.2,37.25
Also there is characteristic absorption peak at ± 0.2.Compound (V) with the crystal form confirms that stability is good by quality stability research etc.,
Easily stored and use.
The third aspect, the present invention provides (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorates (II)
Preparation method.
Preparation method of the present invention include: 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) with
Grignard Reagent certain solvent, at a temperature of carry out grignard reaction.With sour (HA) at salt after reaction, crystallization is filtered, and washing obtains (1-
Azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II).
Specific reaction equation is as follows:
Specific steps are as follows:
(a) N2Under protection, 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) and Grignard Reagent are certain molten
Agent, at a temperature of react;
(b) TLC(solvent: methanol) monitoring, 0 ~ 5 DEG C is cooled to after fully reacting;
(c) acid HA is added dropwise, adjusts pH about 1~2, crystallization is precipitated;
(d) it filters, washes, it is dry, obtain the compounds of this invention (II).
The method that the present invention uses for use Grignard Reagent carry out (1- azabicyclo [2.2.2] octane -4- base) (hexichol
Base) methanol hydrochlorate (II) preparation.Storage high using lithium reagent price, difficult, use condition harshness, cost are opposite in the prior art
It is higher, it is not suitable for industrialized production.Therefore in (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanolic acid of the invention
Selection Grignard Reagent substitutes lithium reagent in the preparation method of salt (II), and Grignard Reagent is selected from phenyl-magnesium-bromide, phenyl-magnesium-chloride;
The solvent of grignard reaction can be 2- methyltetrahydrofuran, tetrahydrofuran, ether.Commercially available grignard reagent solution, such as: phenyl-bromide
Change the 2- methyltetrahydrofuran solution (2.8M) of magnesium, the tetrahydrofuran solution (1.0M) of phenyl-magnesium-bromide, the second of phenyl-magnesium-bromide
Ethereal solution (3.0M), the tetrahydrofuran solution (2.0M) of phenyl-magnesium-chloride, tetrahydrofuran solution (1.0M) of phenyl-magnesium-chloride etc..
Wherein the 2- methyltetrahydrofuran solution (2.8M) of the phenyl-magnesium-bromide refers to: containing in the 2- methyltetrahydrofuran of 1000ml
There is 2.8 moles of phenyl-magnesium-bromide, can similarly obtain above-mentioned other Grignard Reagent.The solvent of grignard reagent solution is used as lattice again
The solvent of family name's reaction, for example, grignard reagent solution is the 2- methyltetrahydrofuran solution of phenyl-magnesium-bromide, then the grignard reaction
Solvent is 2- methyltetrahydrofuran, can similarly obtain the solvent of other grignard reactions.
Further investigate (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate of the present invention
(II) mole of 1- azabicyclo [2.2.2] described in preparation method octane -4- carboxvlate hvdrochloride and Grignard Reagent
Than.It is obtained by largely testing, raw material 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (II) and grignard are tried
When the molar ratio of agent is 1:3.5 ~ 5, reaction carries out complete and save the cost.
It carries out a series of investigations to reaction temperature in each different action solvent to test, reaction temperature is low, and raw material is molten
Solution is slow, and reaction is incomplete;Reaction temperature is high, and impurity generation is more, has finally been determined that reaction temperature is 30 ~ 80 DEG C, optimal anti-
Answering temperature is 50 ~ 60 DEG C.
Wherein compound is the crystal form of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V)
Preparation method: N2Under protection, the 2- methyltetrahydrofuran solution (2.8M) of phenyl-magnesium-bromide is added in the reaction flask of 250ml
Under stirring, 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) 15.38g is added in 100ml, temperature control in 50~
60 DEG C of reactions, TLC(solvent: methanol) monitoring, react used time about 2h.Reaction solution is cooled to 0 ~ 5 DEG C, dilute hydrochloric acid is added dropwise, is adjusted
PH about 1~2, drop finish, 20 ~ 30 DEG C of stirring 2h of temperature control, then ice-water bath are cooled to -5 ~ 0 DEG C of stirring 1h, filter, filter cake with water 2 ×
100ml mashing is washed 2 times, dry, obtains the crystalline powder of off-white color.
Fourth aspect: the present invention provides one kind with compound (1- azabicyclo [2.2.2] octane -4- base) (diphenyl)
Methanol hydrochlorate (II) is the method that starting material prepares Wumei bromine ammonium.
The method of preparation Wumei bromine ammonium of the present invention includes (1- azabicyclo [2.2.2] octane -4- base) (hexichol
Base) methanol hydrochlorate (II) and benzyl -2- bromoethyl ether (III), back flow reaction, cooling down, crystallization filter in a solvent, are made
Wumei bromine ammonium (I).
Reaction equation are as follows:
(1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol in the method for preparation Wumei bromine ammonium of the present invention
Hydrochlorate (II) and the molar ratio of benzyl -2- bromoethyl ether (III) are investigated, and 1:1.05 ~ 1.2 are ultimately determined to.
It is of the present invention preparation Wumei bromine ammonium method in solvent can choose alcohol, DMF, DMA, DMSO, NMP, acetonitrile,
The single solvents such as tetrahydrofuran, 2- methyltetrahydrofuran, dioxane or any one of the above single solvent mix mixed with water
Bonding solvent.Find that the mixed solvent of single solvent and water goes deimpurity effect more preferable, such as mixes after investigating to Different solution
Solvent normal propyl alcohol and water, DMSO and water, 2- methyltetrahydrofuran and water etc..Raw material (1- azabicyclo [2.2.2] in reaction system
Octane -4- base) (diphenyl) methanol hydrochlorate (II) reflux when can be completely dissolved, can be reacted with benzyl -2- bromoethyl ether, through trying
The ratio for testing determining in the mixed solvent single solvent and water is 1:1 ~ 4(volume ratio), and single solvent effect is most in mixed solvent
Good is alcohol (CnH2nOH, n=2 ~ 5).
The crystal form of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) prepared by the present invention has
There is following feature (X-ray powder diffraction collection is shown in attached drawing 1).
1.X- ray powder diffraction:
Instrument: D/teX Ultra 250 model X-ray diffractometer;
Target: Cu-K-beta, 2 θ scanning ranges: 3-40 °
Step angle: 0.01 DEG C
The calculating time: 0.5 second
Pipe pressure: 40KV
Guan Liu: 40mA
Scanning speed: 10.4018 DEG C/min
Filter disc: graphite monochromator
Detailed description of the invention
Fig. 1 is the X-ray powder of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal form
Last diffracting spectrum.
Fig. 2 is the X-ray powder of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal form
Last diffracting spectrum data.
(1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal prepared by the present invention it is steady
It is qualitative:
Take (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal in weighing bottle, respectively at
It places, is sampled in 5 days, 10 days, high effective liquid chromatography for measuring under 60 DEG C, 4500 ± 500LX illumination and 92.5% relative humidity
Related substance, as a result such as table 1.
The test of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) the crystal influence factor of table 1
Measurement result
Conclusion: (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) crystal 60 DEG C, 4500 ±
It is placed 5,10 days under 500LX illumination and 92.5% relative humidity, related substance, which is showed no, to be substantially change, and powder diffraction has no variation.
The positive effect of the present invention describes in terms of following four, specific as follows:
In a first aspect, the present invention provides Wumei bromine ammonium midbody compounds (1- azabicyclo [2.2.2] octane -4- base) (two
Phenyl) methanol hydrochlorate (II).
Second aspect, the present invention provides drug Wumei bromine ammonium intermediate, compound (1- azabicyclo [2.2.2] octanes-
4- yl) for the HA in (diphenyl) methanol hydrochlorate (II) when being hydrochloric acid, i.e., compound is (1- azabicyclo [2.2.2] octane -4-
Base) (diphenyl) methoxide hydrochlorate (V) crystal form data, i.e., the angle of diffraction (2 θ) of X-ray powder diffraction be located at 5.13 ±
0.2,10.25 ± 0.2,14.36 ± 0.2,16.23 ± 0.2,16.34 ± 0.2,18.37 ± 0.2,19.92 ± 0.2,20.62 ±
0.2,21.13 ± 0.2,22.87 ± 0.2,23.10 ± 0.2,23.25 ± 0.2,26.59 ± 0.2,27.32 ± 0.2,31.65
There is characteristic absorption peak at ± 0.2,37.25 ± 0.2.The crystal form good effect is that quality stability is good, convenient for storage and uses.
The third aspect, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) disclosed by the invention
And preparation method thereof compared with prior art possessed by have the active effect that
1. cost is relatively low for production, starting material 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride, Grignard Reagent
It is commercially available, and price is lower.
2. grignard reaction temperature is 30 ~ 80 DEG C, easily controllable, mild condition, section relative to the low-temp reaction of lithium reagent
About cost.The simultaneous reactions time is shorter, only needs 1.5 ~ 3h energy fully reacting, and the reaction of document report Grignard Reagent needs 60
DEG C, it reacts 16 h or stays overnight.
3. the yield of reaction is higher, the yield of pertinent literature report is up to 54.2%, but its post-processing approach easily wraps up
Inorganic matter etc., purity is not high.And the experiment yield of present patent application can reach 90% or more, purity is higher by 99.5% or more, meets
Requirement as medicinal compound.
4. post-processing is simple, removes the cumbersome operations such as extraction, drying, the distillation of pertinent literature report from, be very suitable to work
Industry metaplasia produces.
5. compound (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) the methanol hydrochlorate (II) is as in medicine
Mesosome stability is good, and quality is easily controllable, and the quality of finished product Wumei bromine ammonium bulk pharmaceutical chemicals is effectively guaranteed.
Fourth aspect, it is disclosed by the invention with (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate
(II) it is had the active effect that for the method for raw material preparation Wumei bromine ammonium is possessed compared with prior art
Reaction dissolvent is preferably the mixed solvent that single solvent is mixed with water, and the ratio of in the mixed solvent single solvent and water
For 1:1 ~ 4(volume ratio).Reaction speed is fast, at most only needs 3h, and product can be precipitated in reaction dissolvent, plays purifying
Effect, product yield reaches 90% or more, purity and reaches 99.4% or more.
The abbreviation involved in the present invention arrived, is described as follows.
DMF: dimethylformamide
DMA: dimethyl acetamide
DMSO: dimethyl sulfoxide
NMP:N- N-methyl-2-2-pyrrolidone N
Specific embodiment
Further illustrate that the present invention, following embodiment are only used for the more specific description present invention preferably below with reference to embodiment
Embodiment, be not used in and technical solution of the present invention limited.
The system of embodiment 1 (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (II, HA=HCl)
It is standby
N2Under protection, 2- methyltetrahydrofuran solution (2.8M) 100ml of phenyl-magnesium-bromide is added in the reaction flask of 250ml,
Under stirring, 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) 15.38g is added, temperature control is anti-in 50~60 DEG C
Answer, TLC(solvent: methanol) monitoring, react used time about 2h.Reaction solution is cooled to 0 ~ 5 DEG C, dilute hydrochloric acid is added dropwise, adjust pH about 1~
2, drop finishes, and stirs, filtering, and 2 × 100ml of filter cake water mashing is washed 2 times, dry, obtains off-white powder 22.59g, yield 97.8%,
Purity 99.73%.1H-NMR(400MHz:DMSO-d6): 7.507 ~ 7.526(4H, m), 7.229 ~ 7.267(4H, m), 7.132 ~
7.168(2H, m), 5.349(1H, s), 2.636 ~ 2.673(6H, m) and, 1.583 ~ 1.619(6H, m).
Embodiment 2 (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrobromate (II, HA=HBr)
Preparation
N2Under protection, 2- methyltetrahydrofuran solution (2.8M) 100ml of phenyl-magnesium-bromide is added in the reaction flask of 250ml,
Under stirring, 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) 13.67g is added, 70~80 DEG C of temperature control are reacted,
TLC(solvent: methanol) monitoring, react used time about 1.5h.Reaction solution is cooled to 0 ~ 5 DEG C, hydrobromic acid is added dropwise, adjust pH about 1~
2, drop finishes, filtering, and 2 × 100ml of filter cake water mashing is washed 2 times, dry, obtains off-white powder 22.48g, yield 96.8%, purity
99.69%。
Embodiment 3 (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol sulphuric acid salt (II, HA=H2SO4)
Preparation
N2Under protection, phenyl-magnesium-bromide tetrahydrofuran solution (1.0M) 100ml is added in the reaction flask of 250ml, under stirring, adds
Enter 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) 6.28g, 40~50 DEG C of reactions, TLC(solvent: first
Alcohol) monitoring, react used time about 2.5h.Reaction solution is cooled to 0 ~ 5 DEG C, dilute sulfuric acid is added dropwise, adjusts pH about 1~2, drop finishes, and filters, filter
2 × 100ml of cake water mashing is washed 2 times, dry, obtains off-white powder 10.44g, yield 93.6%, purity 99.57%.
Embodiment 4 (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol acetate (II, HA=CH3COOH)
Preparation
N2Under protection, tetrahydrofuran solution (1.0M) 100ml of phenyl-magnesium-chloride is added in the reaction flask of 250ml, under stirring,
1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) 4.39g, 30~40 DEG C of temperature control reactions, TLC(expansion is added
Agent: methanol) monitoring, react used time about 3h.Reaction solution is cooled to 0 ~ 5 DEG C, acetic acid is added dropwise, adjusts pH about 1~2, drop finishes, filtering,
2 × 100ml of filter cake water mashing is washed 2 times, dry, obtains off-white powder 6.39g, yield 90.8%, purity 99.52%.
5 4- of embodiment [hydroxyl (diphenyl) methyl] -1- [2- [(benzyl) oxygen] ethyl] -1- azabicyclo [2.2.2]
The preparation of octane bromide
In the four-hole bottle of 250ml, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) is added
4g, benzyl -2- bromoethyl ether (III) 2.87g, reflux is anti-in n-propanol/water (total 32ml) (volume ratio normal propyl alcohol: water=1:1)
2h is answered, cooling down, crystallization, filtering, with normal propyl alcohol: water=1:1 is washed (2 × 4ml), and it is dry, 5.80 g of white solid is obtained, is received
94.01 % of rate, 99.82 % of purity.EM-MS m/z 428(M+); 1H-NMR(400MHz:DMSO-d6): 7.544 ~ 7.563
(4H, d), 7.259 ~ 7.366(9H, m), 7.201 ~ 7.237(2H, t), 5.921(1H, s) and, 4.516(2H, s), 3.831 ~
3.841(2H, m), 3.518 ~ 3.555(6H, t), 3.466(2H, m) and, 1.989~2.025(6H, t).
6 4- of embodiment [hydroxyl (diphenyl) methyl] -1- [2- [(benzyl) oxygen] ethyl] -1- azabicyclo [2.2.2]
The preparation of octane bromide
In the four-hole bottle of 250ml, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrobromate (II is added
) 4 g, benzyl -2- bromoethyl ether (III) 2.42g, in 2- methyltetrahydrofuran/water (total 40ml) (volume ratio 2- methyl tetrahydro furan
Mutter: water=1:4) in back flow reaction 2.5h, cooling down, crystallization, filtering, with 2- methyltetrahydrofuran: water=1:5 wash (2 ×
4ml), dry, obtain white solid 5.08g, 93.25 % of yield, 99.63 % of purity.
7 4- of embodiment [hydroxyl (diphenyl) methyl] -1- [2- [(benzyl) oxygen] ethyl] -1- azabicyclo [2.2.2]
The preparation of octane bromide
In the four-hole bottle of 250ml, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol sulphuric acid salt (II) is added
4g, benzyl -2- bromoethyl ether (III) 2.64g, the back flow reaction 3h in acetonitrile/water (total 44ml) (volume ratio acetonitrile: water=1:2),
Cooling down, crystallization, filtering, with acetonitrile: water=1:3 is washed (2 × 4ml), dry, obtains white solid 4.84g, yield 92.87
%, 99.52 % of purity.
8 4- of embodiment [hydroxyl (diphenyl) methyl] -1- [2- [(benzyl) oxygen] ethyl] -1- azabicyclo [2.2.2]
The preparation of octane bromide
In the four-hole bottle of 250ml, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate (V) is added
4g, benzyl -2- bromoethyl ether (III) 2.87g, the back flow reaction 2h in normal propyl alcohol 36ml, cooling down, crystallization, filtering, with just
Propanol rinse (2 × 4ml), it is dry, obtain white solid 5.71g, 92.75 % of yield, 99.50 % of purity.
9 4- of embodiment [hydroxyl (diphenyl) methyl] -1- [2- [(benzyl) oxygen] ethyl] -1- azabicyclo [2.2.2]
The preparation of octane bromide
In the four-hole bottle of 250ml, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol formates (II) is added
4g, benzyl -2- bromoethyl ether (III) 2.80g, the back flow reaction 2.5h in isopropanol 44ml, cooling down, crystallization filter, and use
Isopropanol washs (2 × 4ml), dry, obtains white solid 5.31g, 92.05 % of yield, 99.48 % of purity.
10 4- of embodiment [hydroxyl (diphenyl) methyl] -1- [2- [(benzyl) oxygen] ethyl] -1- azabicyclo
The preparation of [2.2.2] octane bromide
In the four-hole bottle of 250ml, (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol nitrate (II) is added
4g, benzyl -2- bromoethyl ether (III) 2.66g, the back flow reaction 2h in dioxane 46ml, cooling down, crystallization filter, and use
Dioxane washs (2 × 4ml), dry, obtains white solid 5.19g, yield 90.85%, 99.41 % of purity.
Reference examples (bibliography CN104619706A embodiment 5)
1- azabicyclo [2.2.2] octyl- 4- base (diphenyl) methanol (31.7kg) and benzyl -2- bromoethyl ether (25.7kg) are existed
Solution in normal propyl alcohol (257.5kg) flows back 13 hours.The solution is cooled to 50 ~ 55 DEG C with a no less than hour, stirring
40 minutes, to induce crystallization.Slurries are cooled to 17 ~ 23 DEG C with no less than 1 hour, and are stirred 60 minutes.Then with no less than 1
The slurries are cooled to 0 ~ 5 DEG C, and aging 2 hours by hour.Filter out product, washed twice with normal propyl alcohol (34.8kg and
33.8kg).It is dried in vacuo at 50 DEG C, obtains white solid (47.95kg, 87%).
Claims (10)
1. a kind of intermediate of drug Wumei bromine ammonium, it is characterised in that: the compound is (1- azabicyclo [2.2.2] octane -4-
Base) (diphenyl) methanol hydrochlorate, shown in structural formula such as formula (II):
Wherein HA is acid, is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, formic acid, acetic acid.
2. a kind of drug Wumei bromine ammonium intermediate according to claim 1, it is characterised in that: the HA be selected from hydrochloric acid,
Hydrobromic acid.
The HA in compound 3. (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) is hydrochloric acid, i.e.,
Compound is (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methoxide hydrochlorate, and structural formula such as formula (V) has
Crystal form is characterized in that: 2 θ of the angle of diffraction of X-ray powder diffraction is 5.13 ± 0.2,10.25 ± 0.2,14.36 ± 0.2,16.23
± 0.2,16.34 ± 0.2,18.37 ± 0.2,19.92 ± 0.2,20.62 ± 0.2,21.13 ± 0.2,22.87 ± 0.2,
There is characteristic absorption at 23.10 ± 0.2,23.25 ± 0.2,26.59 ± 0.2,27.32 ± 0.2,31.65 ± 0.2,37.25 ± 0.2
Peak
。
4. a kind of prepare (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) described in claim 1
Method, it is characterised in that: 1- azabicyclo [2.2.2] octane -4- carboxvlate hvdrochloride (IV) and Grignard Reagent are certain
Solvent, at a temperature of carry out grignard reaction;With sour HA at salt after reaction, crystallization is filtered, and washing obtains (1- azabicyclo [2.2.2]
Octane -4- base) (diphenyl) methanol hydrochlorate (II)
Specific reaction equation is as follows:
。
5. the system of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) according to claim 4
Preparation Method, it is characterised in that: the Grignard Reagent is selected from phenyl-magnesium-bromide, phenyl-magnesium-chloride.
6. the system of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) according to claim 4
Preparation Method, it is characterised in that: the solvent of the grignard reaction is 2- methyltetrahydrofuran, tetrahydrofuran, ether.
7. the system of (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) methanol hydrochlorate (II) according to claim 4
Preparation Method, it is characterised in that: the reaction temperature is 30-80 DEG C.
8. (1- azabicyclo [2.2.2] octane -4- base) (diphenyl) first being prepared described in any one of claim 4-7
Alcohol hydrochlorate (II) is the method that starting material prepares Wumei bromine ammonium (I), it is characterised in that: (1- azabicyclo [2.2.2] octane-
4- yl) (diphenyl) methanol hydrochlorate (II) and benzyl -2- bromoethyl ether (III), back flow reaction in a solvent, cooling down, analysis
Wumei bromine ammonium (I) is made in crystalline substance, filtering
Reaction equation are as follows:
。
9. it is according to claim 8 preparation Wumei bromine ammonium (I) method, it is characterised in that: the solvent be alcohol, DMF,
The single solvents such as DMA, DMSO, NMP, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane or any one of the above list
The mixed solvent that one solvent is mixed with water.
10. the method for preparation Wumei bromine ammonium (I) according to claim 9, it is characterised in that: the in the mixed solvent list
The volume ratio of one solvent and water is 1:1-4.
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