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 PDF

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CN109956938A
CN109956938A CN201711426410.2A CN201711426410A CN109956938A CN 109956938 A CN109956938 A CN 109956938A CN 201711426410 A CN201711426410 A CN 201711426410A CN 109956938 A CN109956938 A CN 109956938A
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azabicyclo
octane
diphenyl
base
hydrochlorate
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程玉红
王亚江
周永健
苏艳华
张玉
赵平
孟红
候美羽
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Tianjin Jinyao Group Co Ltd
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Tianjin Jinyao Group Co Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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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

Wumei bromine ammonium intermediate crystal form and preparation method thereof and with the intermediate prepare Wumei bromine The method of ammonium
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.
CN201711426410.2A 2017-12-26 2017-12-26 Wumei bromine ammonium intermediate crystal form and preparation method thereof and the method that Wumei bromine ammonium is prepared with the intermediate Pending CN109956938A (en)

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