CN109134447A - A kind of fumaric acid Lu pa is for fragrant impurity B and preparation method thereof and detection method - Google Patents
A kind of fumaric acid Lu pa is for fragrant impurity B and preparation method thereof and detection method Download PDFInfo
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- CN109134447A CN109134447A CN201811042381.4A CN201811042381A CN109134447A CN 109134447 A CN109134447 A CN 109134447A CN 201811042381 A CN201811042381 A CN 201811042381A CN 109134447 A CN109134447 A CN 109134447A
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Abstract
The present invention provides compound shown in a kind of Formulas I, wherein X—Selected from F—、Cl—、Br—、I—；Preferably, X‑For Br‑.The compound can generate in preparation process of the fumaric acid Lu's pa for sweet smell, due to replacing fragrant structure close with fumaric acid Lu's pa, it is likely that be brought into final product.The present invention also provides the preparation method of compound shown in Formulas I and detection methods.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of fumaric acid Lu pa replaces new impurity and its preparation of sweet smell
Method and detection method.
Background technique
For fumaric acid Lu's pa for sweet smell, structural formula is as indicated with 1, excellent compared with Ketotifen Fumarate (structural formula is as indicated by 10)
Gesture is: (1) eliminating the methyl for leading to sedation on Ketotifen nitrogen-atoms, remain the antihistaminicum and stabilization of its parent nucleus
Mast cell effect；(2) 3- picolyl functional group is introduced, antiplatelet activity factor is facilitated and inhibits acidophil.Cause
This, fumaric acid Lu's pa has multiple anti-allergic effects: antihistamine effect, mast cell stabilization, D-dimer for fragrant
Factor effect, the effect of anti-eosinophil, while the calmness of its maincenter is less side effects.
Fumaric acid Lu's pa replaces sweet smell using Ketotifen as starting material, synthesis route scheme are as follows:
When to the fumaric acid Lu's pa synthesized according to above-mentioned process route for fragrant progress quality testing and related composition detection,
Have found the several impurity having not been reported brought into reaction.Therefore, it is necessary to study the impurity, its knot is specified
Structure establishes detection method, to guarantee fumaric acid Lu's pa for fragrant quality and drug safety.
Summary of the invention
For the above-mentioned problems in the prior art, the present invention provides a kind of new compound.The compound is in richness
Horse acid Lu's pa replaces in fragrant synthesis process, and the tertiary amine position of starting material Ketotifen is further formed with bromo-derivative at quaternization reaction
Quarternary ammonium salt compound, be also referred to as in the present invention " fumaric acid Lu's pa replace fragrant impurity B ".The compound due to fumaric acid Lu
Pa replaces fragrant structure close, may be brought into final product.Inventor is prepared for the compound and establishes its detection side
Method replaces the effective mass control of fragrant bulk pharmaceutical chemicals and its preparation to tamp basis for fumaric acid Lu pa.
In order to achieve the above-mentioned object of the invention, present invention employs the following technical solutions:
Compound shown in a kind of Formulas I,
Wherein, X—Selected from F—、Cl—、Br—、I—；Preferably, X—For Br—。
Compound shown in formula I may occur in which in fumaric acid Lu's pa in fragrant preparation process, it is thus possible to exist as impurity
In final product --- fumaric acid Lu's pa is in sweet smell.
In the present invention, term " compound shown in formula I " and " fumaric acid Lu's pa replaces fragrant impurity B ", " new impurity shown in formula I "
And its similar terms is used interchangeably.
A further object of the invention is to provide the preparation method of compound shown in the Formulas I, include the following steps:
(1) compound shown in Formula II is through basification；
(2) product by alkali process that step (1) obtains reacts shown in production I with Ketotifen in organic solvent A
Compound,
Preferably, the molar ratio of Ketotifen and compound shown in the Formula II is 1:1~6；More preferably 1:1.5~3.
Preferably, the concrete operations of the step (1) are as follows:
Compound shown in the Formula II is dissolved in the water, organic solvent B is added, is cooled to 0~20 DEG C, preferably 0~5
DEG C, the aqueous solution of alkali is added, stirs, adjusts water phase pH=7~8；Separation water phase and organic phase, water phase are extracted with organic solvent B,
Extract liquor merges with organic phase, dries, filters, solution for later use.
Preferably, the alkali is organic base and/or inorganic base.
Preferably, the organic base is in triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide
It is one or more.
Preferably, the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate
One of or it is a variety of.
It is furthermore preferred that the alkali is sodium bicarbonate.
Preferably, the organic solvent B is selected from one of halogenated hydrocarbons, aromatic hydrocarbons, aliphatic ether and aliphatic alcohol ester or a variety of.
Preferably, the halogenated hydrocarbons is selected from one of chloroform, methylene chloride and carbon tetrachloride or a variety of.
Preferably, the aromatic hydrocarbons is toluene and/or dimethylbenzene.
Preferably, the ethers is ether and/or tetrahydrofuran.
Preferably, the esters are ethyl acetate and/or butyl acetate.
Most preferably, the organic solvent B is ethyl acetate.
Preferably, compound shown in the Formula II and the mass volume ratio of the organic solvent B are 1g:1ml~10ml；More
Preferably 1g:2ml~3ml.
As a preferred embodiment, the concrete operations of the step (1) are as follows:
Compound shown in Formula II is added pure water, 60-80 turns/and min stirring and dissolving is to clear；Ethyl acetate, the II is added
The mass volume ratio of shown compound and ethyl acetate is 1g:2ml~3ml；At 5~10 DEG C, mass percent concentration is added
For 5% sodium bicarbonate, stirring adjusts pH=7~8；Separation water phase and organic phase, water phase are extracted with ethyl acetate 1~2 time,
Merge with the organic phase, anhydrous sodium sulfate dries, filters, solution for standby；
Preferably, the concrete operations of the step (2) are as follows:
At room temperature, solution step (1) obtained is added Ketotifen, organic solvent A, is heated to 30~85 DEG C, stirs
It mixes to complete clarification, TLC monitoring reaction to reaction terminates.
Preferably, Ketotifen and the mass volume ratio of the organic solvent A are 1g:3ml~20ml；More preferably 1g:
10ml。
Preferably, the organic solvent A is in halogenated hydrocarbons, aromatic hydrocarbons, aliphatic ether, aliphatic alcohol ester, nitrile, lower aliphatic alcohols
It is one or more.
Preferably, the halogenated hydrocarbons is selected from one of chloroform, methylene chloride and carbon tetrachloride or a variety of.
Preferably, the aromatic hydrocarbons is toluene and/or dimethylbenzene.
Preferably, the aliphatic ether is ether and/or tetrahydrofuran.
Preferably, the aliphatic alcohol ester is butyl acetate and/or ethyl acetate.
Preferably, the nitrile is acetonitrile and/or propionitrile.
Preferential, the lower aliphatic alcohols are dehydrated alcohol and/or anhydrous methanol.
It is furthermore preferred that the organic solvent A is dehydrated alcohol.
Preferential, in the step (2), heating temperature is 55~75 DEG C；
As a preferred embodiment, the concrete operations of the step (2) are as follows:
At room temperature, by solid Ketotifen, dehydrated alcohol according to 1g:3ml~20ml, the quality volume of preferably 1g:10ml
The solution obtained than step (1) is added is heated to 55~75 DEG C, and to complete clarification, TLC monitors reaction to reaction knot for stirring
Beam, reaction solution are spare.
Preferably, the preparation method further include:
(3) reaction solution for obtaining step (2), is naturally cooling to room temperature under stirring, then cools to 0~15 DEG C, stands analysis
Crystalline substance, filtering, oven drying is to get compound shown in the Formulas I.
Preferably, in the step (3), cooling crystallization temperature is 2~6 DEG C.
Preferential, in the step (3), the standing crystallization time is 10~15h.
Preferential, in the step (3), drying temperature is 50~70 DEG C.
As a preferred embodiment, the concrete operations of the step (3) are as follows:
The reaction solution that step (2) is obtained, is naturally cooling to room temperature under stirring, after a large amount of white crystals are precipitated, is further continued for
2~6 DEG C are cooled to, 10~15h of crystallization, filtering are stood, 50~70 DEG C of oven dryings obtain white crystal.
As a preferred embodiment, the preparation method of compound shown in the Formulas I provided by the invention is specific to wrap
Include following operation:
(1) pure water is added in compound shown in Formula II, 60~80 turns/min stirring and dissolving is to clear；Ethyl acetate, institute is added
The mass volume ratio for stating compound and ethyl acetate shown in Formula II is 1g:2ml~3ml, and at 5~10 DEG C, 5% bicarbonate is added
Sodium, stirring adjust pH=7~8；Separation water phase and organic phase, water phase are extracted with ethyl acetate 1~2 time, acetic acid ethyl acetate extract
Merge with the organic phase, anhydrous sodium sulfate dries, filters, solution for standby；
(2) at room temperature, the solution that step (1) obtains, Ketotifen and nothing is added in solid Ketotifen and dehydrated alcohol
The mass volume ratio of water-ethanol is 1g:10ml, is heated to 55~75 DEG C, stirring to complete clarification, TLC monitoring reaction to terminating,
Reaction solution is spare；
(3) reaction solution for obtaining step (2), is naturally cooling to room temperature under stirring, after a large amount of white crystals are precipitated, then
2~6 DEG C are cooled to, 10~15h of crystallization, filtering are stood, 50~70 DEG C of oven dryings obtain white crystal, as described I institute of formula
Show compound.
It is also an object of the present invention to provide compound shown in formula I and the formulas I prepared according to above-mentioned preparation method
The detection method of shown compound, the detection method include using compound shown in high effective liquid chromatography for measuring formula I；
The condition of the high performance liquid chromatography includes:
Chromatographic column: octadecylsilane chemically bonded silica is the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.005mol/L~0.03mol/L, and Mobile phase B is methanol-water
Solution carries out gradient elution；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 58 | 42 |
| 5 | 58 | 42 |
| 20 | 80 | 20 |
| 30 | 80 | 20 |
| 30.01 | 58 | 42 |
| 35 | 58 | 42 |
Flow rate of mobile phase: 0.5~1.5ml/min；Preferably 1.0ml/min；
Chromatographic column column temperature: 15~40 DEG C；Preferably 26 DEG C；
Detection wavelength: 200~400nm；Preferably 270nm.
Preferably, the mobile phase A, the concentration of ammonium acetate methanol solution are 0.01mol/L；
Preferably, the volume ratio of the Mobile phase B, methanol and water is 0~10:100；It is preferred that 0:100.
Preferably, the detection method further includes the preparation of test solution, specific steps are as follows:
Precision weighs test sample 25mg, sets in 25ml volumetric flask, and the methanol aqueous solution of concentration of volume percent 50% is added
Dissolve and be diluted to scale, shake up to get.
It is also preferred that the detection method further includes the preparation of reference substance solution, specific steps are as follows:
Precision weighs compound control product shown in Formulas I, is placed in volumetric flask, and the methanol of concentration of volume percent 50% is added
Aqueous dissolution is simultaneously diluted to scale, be configured to the solution of final concentration of 0.01~1mg/ml to get.
Preferably, the detection method further includes following steps:
Measurement: drawing the test solution and each 20 μ l of the reference substance solution respectively, injects high performance liquid chromatograph,
Chromatogram is recorded, the peak area of each absorption peak on test solution chromatogram is measured, calculates containing for compound shown in impurity Formulas I
Amount.
In addition, it is also an object of the present invention to provide above-mentioned detection method in fumaric acid Lu's pa for fragrant related substance inspection
Application in survey；Wherein, the test sample is that the fumaric acid Lu's pa being prepared via a method which replaces sweet smell:
(a) at room temperature, Ketotifen and dichloroethanes are mixed to clearly, 1- ethyl chloroformate is added dropwise after cooling, adds
After hot back flow reaction, TLC monitoring, reaction terminates, is concentrated to dryness；It adds methanol and carries out alcoholysis, be heated to after reaction, it is dense
Contracting obtains concentrate；
(b) concentrate for obtaining step (a) is through normal phase silicagel column purifies and separates, methanol dichloromethane gradient elution, first
The concentration of volume percent of alcohol is incremented to 5% by 1%, collects principal component, is concentrated to dryness, obtains compound shown in formula 3,
(c) at room temperature, compound shown in the formula 3 step (b) obtained and chloroform are mixed, rear that three second are added
Amine, DMAP continue to stir, and after system temperature no longer increases, feed intake compound shown in Formula II at 15 DEG C, after be stirred to react, liquid phase color
Spectrum monitoring reaction process, after reaction, reaction solution is spare；
(d) at room temperature, reaction solution step (c) obtained respectively through 5% NaHCO3Aqueous solution and water washing, in
Dry at 50~70 DEG C, filtering, concentration, obtain concentrate；
(e) concentrate for obtaining step (d) is through purification on normal-phase silica gel post separation, methanol dichloromethane gradient elution, first
The concentration of volume percent of alcohol is incremented to 5% by 1%, collects principal component, is concentrated to dryness to get compound shown in formula 2 is arrived,
(f) fumaric acid is added in dichloromethane ethanol solution, stirring and dissolving is added step (e) and obtains to clear at 35 DEG C
Shown formula 2 shown in compound, filtering, stirring cooling, after stir 15h at 0~6 DEG C, filter to dry, 70 DEG C of drying obtain
Fumaric acid Lu pa shown in formula 1 replaces sweet smell,
As a preferred embodiment, fumaric acid Lu pa is for the fragrant preparation method system by including the following steps
It is standby to obtain:
(c) at room temperature, it by Ketotifen (SM 19.85g, 64.03mmol), is mixed to dichloroethanes (100ml)
Clearly, 1- ethyl chloroformate (10.4ml, 96.05mmol) is added dropwise after cooling, after heating reflux reaction, TLC monitoring, reaction knot
Beam is concentrated to dryness；Methanolysis is added, heating after reaction, is concentrated to dryness；
(d) concentrate for obtaining step (a) is dissolved through normal phase silicagel column purifies and separates, and methanol dichloromethane gradient is washed
De-, the concentration of volume percent of methanol is incremented to 5% by 1%, collects principal component, is concentrated to dryness, 3 institute of show bubble solid, that is, formula
Show compound, M=14.74g, yield: 78.0%；
(c) at room temperature, compound (14.74g, 49.9mmol) and chloroform shown in the formula 3 step (b) being prepared
(320ml) is mixed, and is stirred under 60~80 turns/min, and triethylamine (34.8ml, 249.6mmol) is added afterwards, DMAP (0.61g,
4.99mmol), continue to stir 30min, observing response system temperature no longer increases, then the compound (5- shown in Formula II that slowly feeds intake
Methyl -3- (bromomethyl) pyridine bromate) (39.8g, 149.7mmol), reaction temperature is more than 25 DEG C and then stops feeding, to temperature
Then continue to feed lower than 25 DEG C, after charging, opens heating device, be warming up to 35 DEG C, the reaction was continued 2~4h, efficient liquid phase
Monitoring response situation to reaction terminates, and reaction solution is spare；
(d) at room temperature, reaction solution step (c) obtained respectively through 5% NaHCO3Solution (320ml) and water
(320ml) washing, dry 5~7h, filtering, concentration, obtain concentrate at 50~70 DEG C；Wherein, the step (c) obtains
Reaction solution, NaHCO3The volume ratio of solution and water is 1:1:1；
(e) concentrate for obtaining step (d) is washed through normal phase silicagel column purifies and separates, methanol dichloromethane solution gradient
De-, the concentration of volume percent of methanol is incremented to 5% by 1%, collects principal component, is concentrated to dryness, 2 institute of show bubble solid, that is, formula
Show compound, M=10.0g, yield: 50.0%；
(f) 2.90g fumaric acid is added in the dichloromethane ethanol solution of 250ml 50%, stirring and dissolving is extremely at 35 DEG C
Clearly, compound shown in the 10.0g formula 2 that step (e) is obtained is added, dissolved clarification filtering is concentrated into the 50~60% of total volume, stirs cold
But to 28 DEG C of heat preservation 0.5h, stirring is cooled to 15 DEG C of heat preservation 0.5h, stirs 15h at 0~6 DEG C, filters to doing, 70 DEG C of drying 5h,
It obtains light yellow solid fumaric acid Lu's pa and replaces fragrant (compound shown in formula 1), weigh m=8.39g, yield: 65.1%.
Commercially available acquisition can be used in heretofore described Ketotifen, and the Formula II compound can be used following synthetic route and obtain
:
Compared with prior art, the invention has the following advantages:
Compound shown in formula I provided by the invention is a kind of fumaric acid Lu's pa having not been reported for fragrant impurity, can will
The new impurity is applied to detection fumaric acid Lu pa and replaces fragrant bulk pharmaceutical chemicals or the related substances content of its formulation samples, to be conducive to matter
Amount control is improved fumaric acid Lu's pa for fragrant or its preparation quality standard, is provided safeguard for clinical application.In addition, I institute of formula
Show that the preparation method of compound without the conditions such as catalyst and atmosphere of inert gases protection, has stable reaction, mild condition, behaviour
Make the advantages that simple, product purity is high.
Detailed description of the invention
With reference to the accompanying drawing, the invention will be further described.
Shown in fig. 1 is the HPLC map of compound shown in the Formulas I of the preparation of embodiment 1, wherein the chromatographic peak marked as 1 is
The absorption peak of compound shown in the Formulas I, retention time 3.622min.
Fig. 2 shows be embodiment 2 prepare Formulas I shown in compound HPLC map, wherein the chromatographic peak marked as 1 is
The absorption peak of compound shown in the Formulas I, retention time 3.620min.
Fig. 3 shows the HPLC map of compound shown in the Formulas I of the preparation of embodiment 3, wherein the chromatographic peak marked as 1 is
The absorption peak of compound shown in the Formulas I, retention time 3.853min.
Fig. 4 shows the HPLC map of the reference substance solution of embodiment 5, wherein being the Formulas I marked as 1 chromatographic peak
The absorption peak of shown compound, retention time 3.667min.
Fig. 5 shows the HPLC map for the test solution that embodiment 5 measures, wherein the chromatographic peak marked as 1 is institute
The absorption peak of compound shown in Formulas I, retention time 3.853min are stated, the chromatographic peak marked as 2 is fumaric acid Lu pa for fragrant suction
Receive peak, retention time 20.697min.
Fig. 6 shows three batches of fumaric acid Lu's pas that embodiment 8 measures for fragrant chromatogram, in which:
6A is first fumaric acid Lu's pa for fragrant chromatogram, is to change shown in the Formulas I marked as 1 chromatographic peak in figure
The absorption peak of object, retention time 3.857min are closed, the chromatographic peak marked as 2 is fumaric acid Lu pa for fragrant absorption peak, is retained
Time is 20.7min；
6B is second batch fumaric acid Lu's pa for fragrant chromatogram, is to change shown in the Formulas I marked as 1 chromatographic peak in figure
The absorption peak of object, retention time 3.86min are closed, the chromatographic peak marked as 2 is fumaric acid Lu pa for fragrant absorption peak, retention time
20.693min；
6C is third batch fumaric acid Lu pa for fragrant chromatogram, is to change shown in the Formulas I marked as 1 chromatographic peak in figure
Close the absorption peak of object, retention time 3.863min, chromatographic peak marked as 2 is fumaric acid Lu pa for fragrant absorption peak, when reservation
Between 20.693min.
Specific embodiment
The present invention is described below with reference to specific embodiments.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, do not limit the scope of the invention in any way.
Experimental method in following embodiments is unless otherwise specified conventional method.Original as used in the following examples
Material, reagent material etc. are commercially available products unless otherwise specified.
Commercially available acquisition can be used in the Ketotifen.
The Formula II compound can be used following synthetic route and obtain:
Other Instruments and reagent:
Instrument: high performance liquid chromatograph (1260 high performance liquid chromatograph of Agilent), constant temperature blender with magnetic force (Great Wall section work
Trade HWCL-5), Rotary Evaporators (IKA), air dry oven (sends out scientific instrument DHG-9070 type in Shanghai three), ball condenser,
Separatory funnel (1000ml), eggplant type bottle (500ml) are several；
Reagent: acetone, THF, HBr, NaBH4、BF3、Et2O。
In following embodiment 1-3, reaction route is as follows:
Embodiment 1: the preparation of compound shown in formula I
(i) pure water (10ml) is added in compound shown in Formula II (4.34g, 16.28mmol), 60-80 turns/min stirring is molten
Xie Zhiqing；It is added ethyl acetate (15ml), at 5~10 DEG C, 5% sodium bicarbonate is added, stirring adjusts water phase pH=7-8；Point
From water phase and organic phase, the water phase with ethyl acetate (15ml) extract 1 time, extract liquor with it is described it is organic mix, anhydrous sulphur
Sour sodium dries, filters, obtained solution for standby；
(ii) at room temperature, step (i) is added in solid Ketotifen (2.01g, 6.51mmol) and dehydrated alcohol (20ml) to obtain
To solution, heating reaction, at 65 DEG C stirring to complete clarification, after white crystal is gradually precipitated, 3-4h is reacted in TLC monitoring reaction,
Reaction terminates, and obtains reaction solution, spare；
(iii) reaction solution for obtaining step (ii), is naturally cooling to room temperature under stirring, wait which a large amount of white crystals are precipitated
Afterwards, then it is cooled to 2-6 DEG C, standing crystallization 10-15h is filtered, and 60 DEG C of oven dryings obtain white crystal, i.e. chemical combination shown in formula I
Object.M=2.93g, yield: 88.2% (fusing point: 206-209 DEG C, ESI-MS (m/s): 415.15)；HPLC map is shown in Fig. 1 (HPLC
Chromatographic condition is shown in embodiment 5).
Embodiment 2: the preparation of compound shown in formula I
(i) pure water (10ml) is added in compound shown in Formula II (3.48g, 13.02mmol), and 60-80 turns/min stirring and dissolving
To clear；It is added ethyl acetate (20ml), at 5~10 DEG C, 5% sodium bicarbonate is added, stirring adjusts water phase pH=7-8；Separation
Water phase and organic phase, the water phase use again ethyl acetate (20ml) extract 2 times, extract liquor with it is described it is organic mix, anhydrous sulphur
Sour sodium dries, filters, obtained solution for standby；
(ii) at room temperature, step (i) is added in solid Ketotifen (2.01g, 6.51mmol) and dehydrated alcohol (20ml) to obtain
To solution in, be heated to 65 DEG C of reactions, stirring to complete clarification, after white crystal gradually is precipitated, TLC monitoring reaction, instead
3-4h is answered, reaction terminates, and obtains reaction solution, spare；
(iii) reaction solution for obtaining step (ii), is naturally cooling to room temperature under stirring, wait which a large amount of white crystals are precipitated
Afterwards, then it is cooled to 2-6 DEG C, standing crystallization 10-15h is filtered, and 70 DEG C of oven dryings obtain white crystal, i.e. chemical combination shown in formula I
Object.M=2.67g, yield: 80.2% (fusing point: 205-208 DEG C, ESI-MS (m/s): 415.15)；HPLC map is shown in Fig. 2 (HPLC
Chromatographic condition is shown in embodiment 5).
Embodiment 3: the preparation of compound shown in formula I
(i) pure water (10ml) is added in compound shown in Formula II (5.21g, 19.51mmol), and 60-80 turns/min stirring and dissolving
To clear；It is added ethyl acetate (20ml), at 5~10 DEG C, 5% sodium bicarbonate is added, stirring adjusts water phase pH=7-8；Separation
Water phase and organic phase, the water phase use again ethyl acetate (20ml) extract 1 time, extract liquor with it is described it is organic mix, anhydrous sulphur
Sour sodium dries, filters, obtained solution for standby.
(ii) at room temperature, solid Ketotifen (2.01g, 6.51mmol) and dehydrated alcohol (20ml) are added to step (i)
In the obtained solution, 65 DEG C are heated to, stirring to complete clarification, after white crystal gradually is precipitated, TLC monitoring is reacted,
3-4h is reacted, reaction terminates, and obtains reaction solution；
(iii) reaction solution for obtaining step (ii) stirs lower nature and is down to room temperature, after a large amount of white crystals are precipitated,
It is cooled to 2-6 DEG C again, stands crystallization 10-15h, filtering, 50 DEG C of oven dryings obtain white crystal, i.e. compound shown in formula I.m
=2.84g, yield: 85.2% (fusing point: 204-208 DEG C, ESI-MS (m/s): 415.15)；HPLC map is shown in Fig. 3 (HPLC chromatogram
Condition is shown in embodiment 5).
4 fumaric acid Lu's pa of embodiment is for fragrant preparation
(a) at room temperature, it by Ketotifen (SM 19.85g, 64.03mmol), is mixed to dichloroethanes (100ml)
Clearly, 1- ethyl chloroformate (10.4ml, 96.05mmol) is added dropwise after cooling, after heating reflux reaction, TLC monitoring, reaction knot
Beam is concentrated to dryness；Methanolysis is added, heating after reaction, is concentrated to dryness；
(b) concentrate for obtaining step (a) is dissolved through normal phase silicagel column purifies and separates, gradient elution (eluant, eluent: first
Alcohol-dichloromethane solution 1%-5%), principal component is collected, is concentrated to dryness, compound shown in show bubble solid, that is, formula 3, M=
14.74g, yield: 78.0%；
(c) at room temperature, compound (14.74g, 49.9mmol) and chloroform shown in the formula 3 step (b) being prepared
(320ml) is mixed, and is stirred under 60~80 turns/min, and triethylamine (34.8ml, 249.6mmol) is added afterwards, DMAP (0.61g,
4.99mmol), continue to stir 30min, observing response system temperature no longer increases, then the compound (5- shown in Formula II that slowly feeds intake
Methyl -3- (bromomethyl) pyridine bromate) (39.8g, 149.7mmol), it is arranged 15 DEG C, reaction temperature is more than 25 DEG C and then stops adding
Material then continues to feed lower than 25 DEG C to temperature, after charging, opens heating device, is warming up to 35 DEG C, the reaction was continued 2-4h,
Efficient liquid phase monitoring response situation to reaction terminates, and reaction solution is spare；
(d) at room temperature, reaction solution step (c) obtained respectively through 5% NaHCO3Solution (320ml) and water
(320ml) washing, dry 5-7h, filtering, concentration, obtain concentrate at 50-70 DEG C；Wherein, what the step (c) obtained is anti-
Answer liquid, NaHCO3The volume ratio of solution and water is 1:1:1；
(e) concentrate for obtaining step (d) is through normal phase silicagel column purifies and separates, gradient elution (eluant, eluent: methanol-two
Chloromethanes solution 1%-5%), principal component is collected, is concentrated to dryness, compound shown in show bubble solid, that is, formula 2, M=10.0g,
Yield: 50.0%；
(f) 2.90g fumaric acid is added in the dichloromethane ethanol solution of 250ml 50%, stirring and dissolving is extremely at 35 DEG C
Clearly, compound shown in the 10.0g formula 2 that step (e) is obtained is added, dissolved clarification filtering is concentrated into the 50-60% of total volume, stirs cold
But to 28 DEG C of heat preservation 0.5h, stirring is cooled to 15 DEG C of heat preservation 0.5h, stirs 15h at 0-6 DEG C, filters to doing, 70 DEG C of drying 5h are obtained
It obtains light yellow solid fumaric acid Lu's pa and replaces fragrant (compound shown in formula 1), weigh m=8.39g, yield: 65.1%.
Embodiment 5: using fumaric acid Lu's pa prepared by high effective liquid chromatography for measuring embodiment 4 for the impurity B (formula in sweet smell
Compound shown in I) content:
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 58 | 42 |
| 5 | 58 | 42 |
| 20 | 80 | 20 |
| 30 | 80 | 20 |
| 30.01 | 58 | 42 |
| 35 | 58 | 42 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 26 DEG C；
Wavelength: 270nm；
Test solution:
Precision weighs fumaric acid Lu's pa of the preparation of embodiment 4 for sweet smell 25mg, sets in 25ml volumetric flask, 50% methanol is added
Water dissolves and is diluted to scale, shake up to get.
Reference substance solution:
Precision weighs the 10mg of compound control product (self-control) shown in formula I, is placed in 100ml volumetric flask, 50% first is added
Alcohol solution dissolves and is diluted to scale, shakes up, and then will pipette 10ml again to 100ml volumetric flask, 50% methanol-water is added
Solution dissolves and is diluted to scale, shake up to get.
Measurement:
20 μ l of test solution and control solution is drawn respectively, injects high performance liquid chromatograph, records chromatogram, control
The HPLC map of product solution is shown in that Fig. 4, the HPLC map of test solution are shown in Fig. 5；It is respectively absorbed on measurement test solution chromatogram
The peak area at peak calculates the content of compound shown in correction factor and formula I according to the following equation.
Correction factor: f=Wr*X/ (Ar*S)
The content of impurity B (compound shown in formula I): T%=Ax*f*/Wx*100%
Wherein:
Ar: reference substance peak area
Wr: the weighing of reference substance
X: labelled amount
S: extension rate
Wx: sample sample weighting amount
S: extension rate
Ax: sample peak area
As a result:
It is detected through above-mentioned analysis method, fumaric acid Lu pa replaces fragrant main peak retention time t=19.8-20.3min, impurity
The opposite main peak retention time RRT=0.18 of B (compound shown in formula I) can accurately calculate in test sample impurity B (shown in formula I
Compound) content, through detecting, the content of impurity B (compound shown in formula I) is 0.62mg/g.
Detection method of the present invention can exclude the interference at other impurities peak, determine that fumaric acid Lu's pa replaces fragrant impurity B (formula
Compound shown in I) position in chromatogram, and accurately calculate fumaric acid Lu pa and replace fragrant impurity B (compound shown in formula I)
Content, and then control effectively to fumaric acid Lu pa for fragrant and its preparation quality.
Embodiment 6: the methodological study of the detection method of compound shown in formula I of the present invention:
1, Precision Experiment
Using with the identical operating procedure of embodiment 5 and condition, precision weighs compound control product 25mg shown in formula I, sets
In 25ml volumetric flask, the methanol-water for being added 50% dissolves and is diluted to scale, shakes up to obtain the final product, in interior continuous sample introduction 5 on the same day
Secondary, 20 μ l, measures the peak area of compound shown in formula I respectively, obtains precision, the results are shown in Table 1 every time.The data of table 1 are shown
This method precision is good.
1 precision experiment result of table
2, stability experiment
Using operating procedure identical with " 1, Precision Experiment " and condition, same reference substance product solution is taken, respectively at matching
0 after system, 2,4,8,12, sample introduction is analyzed for 24 hours, every time 20 μ l, measures the integrating peak areas value of compound shown in formula I, knot respectively
Fruit is shown in Table 2.Compound shown in tables of data Ming Dynasty style I shown in table 2 is stablized in 24 hours.
2 stability experiment result of table
3, repetitive test
Using with the identical operating procedure of embodiment 5 and condition, prepare test solution, respectively measure formula I shown in chemical combination
The average content (mg/g) and RSD of object, the results are shown in Table 3.It is shown in table 3 statistics indicate that this law reproducibility is good.
3 repeated experiment result of table
Embodiment 7: the selection and optimization of the condition of gradient elution of the detection method of compound shown in formula I:
Method 1 (the related substance official method of Ketotifen Fumarate -)
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A be methanol-triethylamine (500:0.175, v/v), Mobile phase B be water-triethylamine (500:
0.175, v/v) gradient elution, is carried out；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 60 | 40 |
| 12 | 60 | 40 |
| 20 | 90 | 10 |
| 25 | 90 | 10 |
| 26 | 60 | 40 |
| 31 | 60 | 40 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 30 DEG C；
Detection wavelength: 297nm.
Method 2
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 50 | 50 |
| 10 | 50 | 50 |
| 15 | 90 | 10 |
| 20 | 90 | 10 |
| 30 | 50 | 50 |
| 35 | 50 | 50 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 30 DEG C；
Detection wavelength: 270nm.
Method 3
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 50 | 50 |
| 18 | 50 | 50 |
| 20 | 90 | 10 |
| 35 | 90 | 10 |
| 40 | 50 | 50 |
| 45 | 50 | 50 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 30 DEG C；
Detection wavelength: 270nm.
Method 4
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 40 | 60 |
| 5 | 40 | 60 |
| 15 | 90 | 10 |
| 25 | 90 | 10 |
| 30 | 40 | 60 |
| 35 | 40 | 60 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 30 DEG C；
Detection wavelength: 270nm.
Method 5
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 58 | 42 |
| 5 | 58 | 42 |
| 15 | 90 | 10 |
| 25 | 90 | 10 |
| 32 | 58 | 42 |
| 37 | 58 | 42 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 30 DEG C；
Detection wavelength: 270nm.
Method 6
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 68 | 32 |
| 5 | 68 | 32 |
| 15 | 90 | 10 |
| 25 | 90 | 10 |
| 32 | 68 | 32 |
| 37 | 68 | 32 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 30 DEG C；
Detection wavelength: 270nm.
Method 7
Chromatographic column: using octadecylsilane chemically bonded silica as the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.01mol/L, and Mobile phase B is aqueous solution, carries out gradient and washes
It is de-；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
| Time (min) | Mobile phase A (v/v%) | Mobile phase B (v/v%) |
| 0 | 58 | 42 |
| 5 | 58 | 42 |
| 20 | 80 | 20 |
| 30 | 80 | 20 |
| 30.01 | 58 | 42 |
| 35 | 58 | 42 |
Flow rate of mobile phase: 1.0ml/min；
Chromatographic column column temperature: 26 DEG C；
Detection wavelength: 270nm.
According to the method and steps of embodiment 5, test solution is prepared, 20 μ L test solutions is drawn respectively, presses respectively
It is measured according to the above method, measurement result and analysis result are shown in Table 4 and table 5 respectively.
4 above method 1-7 Comparative result of table
5 above method of table, 1~7 data comparison conclusion
Embodiment 8: fragrant impurity B (compound shown in formula I) content is replaced to fumaric acid Lu's pa using detection method of the invention
It is measured
3 batches of fumaric acid Lu's pas are prepared for sweet smell, according to the identical operation of embodiment 5 and item according to method as described in example 4
Part prepares test solution and control solution, and measures, and the HPLC map of 3 batches of test samples is shown in Fig. 6 respectively；Content results are shown in
Table 6.Wherein, compound control product sample weighting amount shown in formula I is 10.01mg, and reference substance peak area is 198.
63 batches of fumaric acid Lu's pas of table replace the assay result of impurity B in fragrant sample
In short, specific description of embodiments of the present invention above is not intended to limit the present invention, those skilled in the art can be with
It is variously modified or deforms according to the present invention, as long as it does not depart from the spirit of the invention, should belong to right appended by the present invention and wants
The range asked.
Claims (10)
1. compound shown in a kind of Formulas I,
Wherein, X—Selected from F—、Cl—、Br—、I—；Preferably, X—For Br—。
2. the preparation method of compound shown in Formulas I described in claim 1, includes the following steps:
(1) compound shown in Formula II is through basification；
(2) product by alkali process that step (1) obtains reacts chemical combination shown in production I with Ketotifen in organic solvent A
Object,
Preferably, the molar ratio of Ketotifen and compound shown in the Formula II is 1:1~6；More preferably 1:1.5~3.
3. preparation method according to claim 2, which is characterized in that the concrete operations of the step (1) are as follows:
Compound shown in the Formula II is dissolved in the water, organic solvent B is added, is cooled to 0~20 DEG C, preferably 0~5 DEG C, adds
Enter the aqueous solution of alkali, stir, adjusts water phase pH=7~8；Separation water phase and organic phase, water phase are extracted with organic solvent B, are extracted
Liquid merges with organic phase, dries, filters, solution for later use；
Preferably, the alkali is organic base and/or inorganic base；
It is further preferred that the organic base is in triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide
It is one or more；The inorganic base is in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate
It is one or more；
It is furthermore preferred that the alkali is sodium bicarbonate；
It is also preferred that the organic solvent B is selected from one of halogenated hydrocarbons, aromatic hydrocarbons, aliphatic ether and aliphatic alcohol ester or a variety of；
Preferably, the halogenated hydrocarbons is selected from one of chloroform, methylene chloride and carbon tetrachloride or a variety of；
Preferably, the aromatic hydrocarbons is toluene and/or dimethylbenzene；
Preferably, the ethers is ether and/or tetrahydrofuran；
Preferably, the esters are ethyl acetate and/or butyl acetate；
Most preferably, the organic solvent B is ethyl acetate；
Preferably, compound shown in the Formula II and the mass volume ratio of the organic solvent B are 1g:1ml~10ml；More preferably
For 1g:2ml~3ml.
4. preparation method according to claim 2, which is characterized in that the concrete operations of the step (2) are as follows:
At room temperature, Ketotifen, organic solvent A is added in solution step (1) obtained, is heated to 30~85 DEG C, stirring is extremely
Clarification completely, TLC monitoring reaction to reaction terminate；The molar ratio of compound shown in Ketotifen and the Formula II is 1:1~6；More
Preferably 1:1.5~3；
Preferably, Ketotifen and the mass volume ratio of the organic solvent A are 1g:3ml~20ml；More preferably 1g:10ml；
Preferably, the organic solvent A is selected from one of halogenated hydrocarbons, aromatic hydrocarbons, aliphatic ether, aliphatic alcohol ester, nitrile, lower aliphatic alcohols
Or it is a variety of；
Preferably, the halogenated hydrocarbons is selected from one of chloroform, methylene chloride and carbon tetrachloride or a variety of；
Preferably, the aromatic hydrocarbons is toluene and/or dimethylbenzene；
Preferably, the aliphatic ether is ether and/or tetrahydrofuran；
Preferably, the aliphatic alcohol ester is butyl acetate and/or ethyl acetate；
Preferably, the nitrile is acetonitrile and/or propionitrile；
Preferential, the lower aliphatic alcohols are dehydrated alcohol and/or anhydrous methanol；
It is furthermore preferred that the organic solvent A is dehydrated alcohol；
Preferential, in the step (2), heating temperature is 55~75 DEG C.
5. preparation method according to any one of claim 2 to 4, which is characterized in that the preparation method further include:
(3) reaction solution for obtaining step (2), is naturally cooling to room temperature under stirring, then cools to 0~15 DEG C, stands crystallization, mistake
Filter, oven drying is to get compound shown in the Formulas I；
Preferably, in the step (3), cooling crystallization temperature is 2~6 DEG C；
Preferential, in the step (3), the standing crystallization time is 10~15h；
Preferential, in the step (3), drying temperature is 50~70 DEG C.
6. compound shown in formula I described in claim 1 and according to preparation method described in any one of claim 2 to 5
The detection method of compound shown in the formula I of preparation, including using compound shown in high effective liquid chromatography for measuring formula I；
The condition of the high performance liquid chromatography includes:
Chromatographic column: octadecylsilane chemically bonded silica is the C18 chromatographic column of filler；
Mobile phase: mobile phase A is the ammonium acetate methanol solution of 0.005mol/L~0.03mol/L, and Mobile phase B is that methanol is water-soluble
Liquid carries out gradient elution；
The gradient elution program is as follows, and wherein the ratio of mobile phase is percent by volume:
Flow rate of mobile phase: 0.5~1.5ml/min；Preferably 1.0ml/min；
Chromatographic column column temperature: 15~40 DEG C；Preferably 26 DEG C；
Detection wavelength: 200~400nm；Preferably 270nm.
7. detection method according to claim 1, which is characterized in that the mobile phase A, the concentration of ammonium acetate methanol solution
For 0.01mol/L；
Preferably, the volume ratio of the Mobile phase B, methanol and water is 0~10:100；More preferable 0:100.
8. detection method according to claim 6 or 7, which is characterized in that the detection method further includes that test sample is molten
The preparation of liquid, specific steps are as follows:
Precision weighs test sample 25mg, sets in 25ml volumetric flask, and the methanol aqueous solution dissolution of concentration of volume percent 50% is added
And be diluted to scale, shake up to get；
Preferably, the detection method further includes the preparation of reference substance solution, specific steps are as follows:
Precision weighs compound control product shown in Formulas I, is placed in volumetric flask, and the methanol that concentration of volume percent 50% is added is water-soluble
Liquid dissolves and is diluted to scale, be configured to the solution of final concentration of 0.01~1mg/ml to get；
Preferably, the detection method further includes following steps:
Measurement: drawing the test solution and each 20 μ l of the reference substance solution respectively, injects high performance liquid chromatograph, record
Chromatogram measures the peak area of each absorption peak on test solution chromatogram, calculates the content of compound shown in impurity formula I.
9. detection method described in any one of claim 6 to 8 is in fumaric acid Lu's pa for the application in fragrant related substance detection；
Wherein, the test sample is that the fumaric acid Lu's pa being prepared via a method which replaces sweet smell:
(a) at room temperature, Ketotifen and dichloroethanes are mixed to clearly, 1- ethyl chloroformate is added dropwise after cooling, heats back
After stream reaction, TLC monitoring, reaction terminates, is concentrated to dryness；It adds methanol and carries out alcoholysis, be heated to after reaction, being concentrated to give
To concentrate；
(b) concentrate for obtaining step (a) is through normal phase silicagel column purifies and separates, methanol dichloromethane gradient elution, methanol
Concentration of volume percent is incremented to 5% by 1%, collects principal component, is concentrated to dryness, obtains compound shown in formula 3,
(c) at room temperature, compound shown in the formula 3 step (b) obtained and chloroform are mixed, be added afterwards triethylamine,
DMAP continues to stir, and after system temperature no longer increases, feed intake compound shown in Formula II at 15 DEG C, after be stirred to react, liquid chromatogram
Reaction process is monitored, after reaction, reaction solution is spare；
(d) at room temperature, reaction solution step (c) obtained respectively through 5% NaHCO3Aqueous solution and water washing, in 50~
Dry at 70 DEG C, filtering, concentration, obtain concentrate；
(e) concentrate for obtaining step (d) is through purification on normal-phase silica gel post separation, methanol dichloromethane gradient elution, methanol
Concentration of volume percent is incremented to 5% by 1%, collects principal component, is concentrated to dryness to get compound shown in formula 2 is arrived,
(f) fumaric acid is added in dichloromethane ethanol solution, the institute that step (e) is obtained is added to clear in stirring and dissolving at 35 DEG C
Show compound shown in formula 2, filter, stirring cooling, after stir 15h at 0~6 DEG C, filter to dry, 70 DEG C of drying obtain 1 institute of formula
The fumaric acid Lu's pa shown replaces sweet smell,
10. application according to claim 9, which is characterized in that fumaric acid Lu pa is for fragrant by including the following steps
Preparation method be prepared:
(a) at room temperature, it by 64.03mmol Ketotifen, is mixed to clearly with 100ml dichloroethanes, 1- chloromethane is added dropwise after cooling
Sour chloroethene ester 96.06mmol, after heating reflux reaction, TLC monitoring, reaction terminates, is concentrated to dryness；Methanolysis is added, is added
After thermal response, it is concentrated to dryness；
(b) concentrate for obtaining step (a) is dissolved through normal phase silicagel column purifies and separates, methanol dichloromethane gradient elution, first
The concentration of volume percent of alcohol is incremented to 5% by 1%, collects principal component, is concentrated to dryness, show bubble solid, that is, 3 shownization of formula
Close object, M=14.74g, yield: 78.0%；
(c) at room temperature, compound shown in the 49.9mmol formula 3 step (b) being prepared and the mixing of 320ml chloroform, 60
It is stirred under~80 turns/min, it is rear that 249.6mmol triethylamine and 4.99mmol DMAP is added, continue to stir 30min, observing response
System temperature no longer increases, then the compound 149.7mmol shown in Formula II that slowly feeds intake, and reaction temperature is more than 25 DEG C and then stops adding
Material then continues to feed lower than 25 DEG C to temperature, after charging, opens heating device, is warming up to 35 DEG C, the reaction was continued 2~4h,
Efficient liquid phase monitoring response situation to reaction terminates, and reaction solution is spare；
(d) at room temperature, NaHCO of reaction solution step (c) obtained respectively through 320ml 5%3Solution and 320ml water washing, in
Dry 5~7h, filtering, concentration, obtain concentrate at 50~70 DEG C；Wherein, the step (c) obtains reaction solution, NaHCO3
The volume ratio of solution and water is 1:1:1；
(e) concentrate for obtaining step (d) is through normal phase silicagel column purifies and separates, the elution of methanol dichloromethane solution gradient, first
The concentration of volume percent of alcohol is incremented to 5% by 1%, collects principal component, is concentrated to dryness, show bubble solid, that is, 2 shownization of formula
Close object, M=10.0g, yield: 50.0%；
(f) 2.90g fumaric acid is added in the dichloromethane ethanol solution of 250ml 50%, stirring and dissolving adds to clear at 35 DEG C
Enter compound shown in the 10.0g formula 2 that step (e) obtains, dissolved clarification filtering is concentrated into the 50~60% of total volume, stirring is cooled to
28 DEG C of heat preservation 0.5h, stirring are cooled to 15 DEG C of heat preservation 0.5h, 15h are stirred at 0~6 DEG C, filter to dry, 70 DEG C of drying 5h, acquisition
Light yellow solid fumaric acid Lu's pa is for sweet smell, and weigh m=8.39g, yield: 65.1%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724334A (en) * | 2013-10-02 | 2014-04-16 | 张惠琳 | Novel allergic reaction-resistant benzocyclothiophthene compounds |
| CN103619839B (en) * | 2011-06-28 | 2016-06-01 | 福建省闽东力捷迅药业有限公司 | The Benzocycloheptathiopcompounds derivant of anti-allergy |
| CN107021954A (en) * | 2017-05-09 | 2017-08-08 | 福建省闽东力捷迅药业有限公司 | A kind of fumaric acid Lu handkerchief is for fragrant new impurity and preparation method thereof and detection method |
-
2018
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103619839B (en) * | 2011-06-28 | 2016-06-01 | 福建省闽东力捷迅药业有限公司 | The Benzocycloheptathiopcompounds derivant of anti-allergy |
| CN103724334A (en) * | 2013-10-02 | 2014-04-16 | 张惠琳 | Novel allergic reaction-resistant benzocyclothiophthene compounds |
| CN107021954A (en) * | 2017-05-09 | 2017-08-08 | 福建省闽东力捷迅药业有限公司 | A kind of fumaric acid Lu handkerchief is for fragrant new impurity and preparation method thereof and detection method |
Non-Patent Citations (1)
| Title |
|---|
| COLUMBUS,OHIO,US: "REGISTRY[online]", 《REGISTRY》 * |
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Address after: 355300 No.1 pharmaceutical industry road, Zherong County, Ningde City, Fujian Province Applicant after: Fujian Mindong lijiexin Pharmaceutical Co.,Ltd. Address before: 355300 pharmaceutical industry zone of Zherong County, Fujian, Ningde Applicant before: Fujian Mindong Rejuvenation Pharmaceutical Co.,Ltd. |
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