CN109678841A - A kind of Rupatadine fumarate derivative, preparation method and intermediate and purposes - Google Patents
A kind of Rupatadine fumarate derivative, preparation method and intermediate and purposes Download PDFInfo
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Abstract
The present invention provides a kind of Rupatadine fumarate derivative, preparation method and intermediate and purposes.The Rupatadine fumarate derivative has following structure Formulas I or its pharmaceutically acceptable salt,Preparation method includes: step S2, and compound B is reacted with compound C, fumaric acid Lu Pata derivative L P-4 is made, wherein the structural formula of compound B isWherein X is halogen atom；The structural formula of compound C isThe above-mentioned Rupatadine fumarate derivative of the application is the impurity in Rupatadine fumarate synthesis, can be used for the standard items of Rupatadine fumarate quality control, provides reference to improve the purity of Rupatadine fumarate.Above-mentioned preparation method uses shorter synthetic route, can be improved the yield of Rupatadine fumarate derivative, while the synthetic route also has side reaction few, high repeatability and other advantages.
Description
Technical field
The present invention relates to drug preparation fields, in particular to a kind of Rupatadine fumarate derivative, its preparation side
Method and intermediate and purposes.
Background technique
A kind of dual antagonist of the Rupatadine fumarate as histamine and platelet aggregation, is mainly used in treatment allergy
The property anaphylactias such as rhinitis and nettle rash.Rupatadine fumarate from March, 2003 in a manner of tablet for the first time in Spain
Since city, the multiple country's listings in the whole world such as Britain, each EU member country, America so far, China had approved state in 2013
Interior pharmacy corporation production Rupatadine fumarate bulk pharmaceutical chemicals and preparation.
During the research of drug, production, supply and clinical use, it is necessary to assure the purity of drug just can guarantee medicine
Object is effectively and safely.Impurity in drug is the principal element for influencing its purity, it is however generally that, impurity, which refers in drug, to be existed
Without therapeutic effect or influence medicine stability and curative effect, or even to the harmful substance of people's health.Impurity source is broadly divided into
Two classes, first is that being brought by production technology and supplementary material；Second is that being influenced in storage by external condition, cause drug physical and chemical
Property changes and generates.The adverse reaction of drug is removed to be had outside the Pass with the physiological activity of active constituent itself, and is deposited in drug
Impurity have close relationship.So specification ground carry out the miscellaneous Quality Research of drug, and by Control of Impurities a safety, rationally
Limits within, the quality and safety of Rupatadine fumarate will be directly related to.
As an important link of drug quality control, in order to preferably control drug quality, it is necessary to be carried out to impurity
Strict inspection and monitoring.By the detection of impurity, the source of impurity, property, detection method and its limitation in drug are understood, it can
It to optimize drug manufacturing process, and then avoids the generation of impurity or impurity is reduced to bottom line, guarantee from many aspects and mention
High drug quality.Great for the preparation method research significance of Rupatadine fumarate impurity, it can be used for fumaric acid Lu's pa
He determine bulk pharmaceutical chemicals and preparation production in impurity quantification and quantitative analysis, so as to improve Rupatadine fumarate bulk pharmaceutical chemicals and
The quality standard of preparation provides guidance for the drug safety of the people.
Up to the present, the preparation of product itself is focused primarily upon for the research of Rupatadine fumarate in the prior art
Technique study, and for there are miscellaneous Quality Research and preparation method are very few in its production process.Applicant is devoted for years to
In the preparation process of research Rupatadine fumarate and the optimization of method for detecting impurities, studies and applied for more than one piece fumaric acid Lu
He customizes Preparation Method and its impurity patent with pa, and more than one piece application at present has been authorized.Such as:
CN104098557A (applying date: 2014.07.02) is related to a kind of Rupatadine fumarate impurity J and its preparation side
Method uses Rupatadine fumarate (2) for raw material, reacts to obtain fumaric acid Lu's pa using the hydrogen peroxide solution of 30%-50%
He determines impurity J crude product (1), and crude product obtains impurity J sterling by purification, and purity can reach 98.5%.
CN108299395A (applying date: 2017.12.08) is related to a kind of Rupatadine fumarate impurity S and its preparation side
Method, impurity structure are(X1 is halogen atom), uses(I) and(II) it is raw material, intermediate is obtained by substitution reaction, halogenating reaction(IV),
Pass through intermediate (IV) and raw material againCondensation reaction occurs, it is miscellaneous that Rupatadine fumarate is finally prepared
Matter S crude product, crude product obtain impurity J sterling by purification, and purity can reach 97% or more, and yield can reach 30%.
However, be still left to be desired for the dopant species research in the presence of production process in the prior art, still there are many
New impurity is undiscovered, and how to meet the huge synthesis demand of contamination levels product, all needs further to be studied.
Based on the above issues the considerations of, the present invention have found a kind of new impurity fumaric acid during production technology optimization
Rupatadine derivative, but do not synthesize the effective ways of the impurity at present, so that the miscellaneous Quality Research and control become
One problem.
Summary of the invention
The main purpose of the present invention is to provide a kind of Rupatadine fumarate derivative, preparation method and intermediate and
Purposes can not be effectively synthesized and cause to solve the impurity Rupatadine fumarate derivative of Rupatadine fumarate in the prior art
It controls more difficult problem.
To achieve the goals above, according to an aspect of the invention, there is provided a kind of Rupatadine fumarate derivative,
Rupatadine fumarate derivative has following structure Formulas I or its pharmaceutically acceptable salt,
Structural formula I.
Further, above-mentioned preparation method includes: step S2, and compound B is reacted with compound C, and fumaric acid Lu is made
His derivative L P-4 of pa, wherein the structural formula of compound B isWherein X is halogen atom；The knot of compound C
Structure formula is
Further, the molar ratio of above compound B and compound C are 1:0.5~1.4, preferably 1:0.8.
Further, the reaction of above-mentioned steps S2 carries out in the presence of acid binding agent, and acid binding agent is organic weak base or inorganic weak
Any one or more in the group that alkali, preferably triethylamine, pyridine, potassium carbonate and sodium carbonate form, further preferred compound B
Molar ratio with acid binding agent is 1:1~5, preferably 1:3；The reaction of preferred steps S2 carries out in the first solvent, the first solvent
For non-protonic solvent, it is highly preferred that non-protonic solvent is selected from methylene chloride and/or chloroform；Preferred steps S2's is anti-
It should be carried out under room temperature or heating condition, it is preferable that the temperature of reaction is room temperature to 50 DEG C, it is highly preferred that the temperature of reaction is
Room temperature.
Further, above-mentioned preparation method include the steps that prepare compound B S1, step S1 include: make compound A with
Oxidant reaction, be made compound B, compound A be 5- first -3- halogenated methyl pyridine or 5- first -3- halogenated methyl pyridiniujm, it is excellent
Selecting 5- first -3- halogenated methyl pyridiniujm is 5- first -3- halogenated methyl pyridine hydrobromide salt or 5- first -3- halogenated methyl pyridine hydrogen chlorine
Hydrochlorate.
Further, the molar ratio of above compound A and oxidant is 1:1~5, more preferably 1:2.
Further, above-mentioned oxidant is selected from m-chloro-benzoic acid peroxide, MnO2, hydrogen peroxide, Peracetic acid, Peracetic acid
Any one in salt and benzoyl hydroperoxide；The reaction of preferred steps S1 carries out under catalysts conditions, catalyst be selected from alkali and/
Or aqueous slkali, catalyst are any in sodium bicarbonate, saleratus, sodium carbonate, potassium carbonate, triethylamine and respective solution
One kind, still more preferably catalyst are sodium bicarbonate aqueous solution；The reaction of step S1 carries out in the second solvent, the second solvent
For non-protonic solvent, it is highly preferred that non-protonic solvent is selected from methylene chloride and/or chloroform；Preferred steps S1's is anti-
It should be carried out under room temperature or heating condition, it is preferable that the temperature of reaction is room temperature to 50 DEG C, it is highly preferred that the temperature of reaction is
Room temperature.
Further, above-mentioned halogen atom is bromine atom.
According to another aspect of the present invention, a kind of intermediate for synthesizing above-mentioned Rupatadine fumarate derivative is provided,
Intermediate has structural formula
According to another aspect of the present invention, above-mentioned Rupatadine fumarate derivative is provided as quality control standard product
Purposes.
It applies the technical scheme of the present invention, the above-mentioned Rupatadine fumarate derivative of the application is Rupatadine fumarate
Impurity in synthesis can be used for the standard items of Rupatadine fumarate quality control, to improve the pure of Rupatadine fumarate
Degree provides reference.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present invention, and of the invention shows
Examples and descriptions thereof are used to explain the present invention for meaning property, does not constitute improper limitations of the present invention.In the accompanying drawings:
Fig. 1 shows compound B 1- (2- carboxyl -1- carboxyethyl) -3- methylol -5- methyl pyrrole that embodiment 1 obtains
The MS of pyridine -1- schemes；
The Rupatadine fumarate derivative L P-4's obtained Fig. 2 shows embodiment 21H-NMR figure；
Fig. 3 shows the Rupatadine fumarate derivative L P-4's that embodiment 2 obtains13C-NMR figure；
Fig. 4 shows the MS figure for the Rupatadine fumarate derivative L P-4 that embodiment 2 obtains.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.The present invention will be described in detail below with reference to the accompanying drawings and embodiments.
As the application background technique is analyzed, the application is optimized in the synthetic route to Rupatadine fumarate
When, it was found that new Rupatadine fumarate derivative, but since its content is very little, can not effectively it be studied and controlled
System, in order to solve this problem, this application provides a kind of preparation method of Rupatadine fumarate derivative and intermediate and use
On the way.
In a kind of typical embodiment of the application, a kind of Rupatadine fumarate derivative, the fumaric acid are provided
Rupatadine derivative has following structure Formulas I or its pharmaceutically acceptable salt,
Structural formula I.
The above-mentioned Rupatadine fumarate derivative of the application (the application is known as Rupatadine fumarate derivative L P-4)
For the impurity in Rupatadine fumarate synthesis, it can be used for the standard items of Rupatadine fumarate quality control, it is rich to improve
The purity of horse acid Rupatadine provides reference.
In another typical embodiment of the application, the preparation side of above-mentioned Rupatadine fumarate derivative is provided
Method, the preparation method include: step S2, and compound B is reacted with compound C, and fumaric acid Lu Pata derivative L P-4 is made,
In, the structural formula of compound B isWherein X is halogen atom；The structural formula of compound C is
The synthetic route of above-mentioned steps S2 is as follows:
Above-mentioned Rupatadine fumarate derivative is Rupatadine fumarate derivative L P-4, and the preparation method use is shorter
Synthetic route, can be improved the yield of Rupatadine fumarate derivative L P-4, while the synthetic route also has side reaction
It is few, high repeatability and other advantages.On this basis, by preparation to Rupatadine fumarate derivative L P-4 and Structural Identification,
It can provide excellent quality, purity higher reference substance for the qualitative and quantitative analysis of Rupatadine fumarate, above-mentioned preparation side
Purity is all larger than 99% after product prepared by method is purified, so that the preparation and its application to Rupatadine fumarate are with good
Good directive significance.And above compound D can use the raw material preparation that source is wide, cheap, therefore reduce this Shen
Please preparation method implement cost.
In one embodiment, the molar ratio of above compound B and compound C are 1:0.5~1.4, preferably 1:0.8.
Guarantee each sufficiently high conversion ratio of raw material by the control of above-mentioned molar ratio.In addition, in order to further speed up above-mentioned reaction, preferably
The reaction of step S2 carries out in the presence of acid binding agent, acid binding agent be organic weak base or inorganic weak bases, preferably triethylamine, pyridine,
Any one or more in the group of potassium carbonate and sodium carbonate composition, the molar ratio of further preferred compound B and acid binding agent is 1:1
~5, preferably 1:3.In addition, the reaction of preferred steps S2 exists in order to improve the dispersibility of reactant and then improve reaction efficiency
Carried out in first solvent, the first solvent be non-protonic solvent, it is highly preferred that non-protonic solvent be selected from methylene chloride and/or
Chloroform.The reaction of above-mentioned steps S2 can carry out under room temperature or heating condition, but temperature reacted if too low into
Row slowly can not even carry out, and by-product increases if temperature is too high, it is preferable that the temperature of reaction is room temperature to 50 DEG C, more
Preferably, the temperature of reaction is room temperature.
In a kind of embodiment of the application, above-mentioned preparation method include thes steps that prepare compound B S1, above-mentioned steps S1
Include: to make compound A and oxidant reaction, compound B is made, compound A is 5- first -3- halogenated methyl pyridine or 5- first -3-
Halogenated methyl pyridiniujm, preferably 5- first -3- halogenated methyl pyridiniujm are 5- first -3- halogenated methyl pyridine hydrobromide salt or 5- first -
3- halogenated methyl pyridine hydrogen chlorate.
In above-mentioned steps S1, when the reaction route that compound A is 5- first -3- halogenated methyl pyridine are as follows:
Above compound A is from a wealth of sources, and price is lower, and the process of above-mentioned oxidation reaction is easily controllable, so that changing
The preparation cost of conjunction object B is lower and yield is higher.
In order to improve the utilization rate of substance, the preferably molar ratio of above compound A and oxidant is 1:1~5, more preferably
1:2。
For above-mentioned reaction oxidant can there are many, preferably above-mentioned oxidant be selected from m-chloro-benzoic acid peroxide (m-
CPBA)、MnO2, hydrogen peroxide, Peracetic acid, any one in Peracetic acid salt and benzoyl hydroperoxide, in favor of point of product
From.In order to accelerate to react, the reaction of preferred steps S1 carries out under catalysts conditions, and catalyst is selected from alkali and/or aqueous slkali, urges
Any one of agent in sodium bicarbonate, saleratus, sodium carbonate, potassium carbonate, triethylamine and respective solution, more into one
Step preferred catalyst is sodium bicarbonate aqueous solution.In addition, in order to improve the dispersibility of reactant and then improve reaction efficiency, preferably
The reaction of above-mentioned steps S1 carries out in the second solvent, and the second solvent is non-protonic solvent, it is highly preferred that non-protonic solvent
Selected from methylene chloride and/or chloroform.The reaction of above-mentioned steps S2 can carry out under room temperature or heating condition, but temperature
Progress is reacted if too low slowly or even can not be carried out, and by-product increases if temperature is too high, it is preferable that above-mentioned reaction
Temperature is room temperature to 50 DEG C, it is highly preferred that the temperature of reaction is room temperature.
Above-mentioned halogen atom can select common chlorine atom, bromine atom or iodine atom, and preferably above-mentioned halogen atom is that bromine is former
Son, to improve product yield.
In another typical embodiment of the application, a kind of above-mentioned Rupatadine fumarate derivative of synthesis is provided
Intermediate, the intermediate have structural formula
In the application in another typical embodiment, provides a kind of above-mentioned Rupatadine fumarate derivative and be used as
The purposes of quality control standard product.Due to the obtained Rupatadine fumarate derivative of the preparation method of the application purity compared with
Height, therefore can be used for the standard items of the quality control of Rupatadine fumarate, it is the preparation of Rupatadine fumarate with good
Good directive significance.
Below with reference to embodiment and comparative example, the beneficial effect of the application is further illustrated.
Embodiment 1
Inert atmosphere N is passed through in the three neck round bottom of 1L2And keep, 3- bromomethyl -5- picoline hydrogen bromine is added
Hydrochlorate (compound A, 20g, 74.92mmol), methylene chloride (200ml) and water (40g), then the agitation and dropping carbon at 0 DEG C
The aqueous solution (40ml) of sour hydrogen sodium (27.1g, 322.58mmol) and the methylene chloride of m-CPBA (37.1g, 214.99mmol) are molten
Liquid (200ml).It is stirred at room temperature 2 hours, acquired solution is extracted with 5x200ml methylene chloride, is merged organic layer, is used anhydrous sodium sulfate
It is dry, vacuum concentration.Silicagel column is eluted with methylene chloride/methanol on residue, obtains 7.5g (50%) compound B3- bromine first
Alkane -5- methylpyridine N oxide faint yellow solid, test result are shown in Fig. 1.
The MS spectrum data of product are as follows:
LC-MS-PH-JLU-LP-4-1:(ES,m/z):202.0(M+1)；204.0(M+1).
Embodiment 2
Inert atmosphere N is passed through in the round-bottomed flask of 250ml2And keep, compound B made from embodiment 1 is added
(7.5g, 37.12mmol), methylene chloride (150ml) and triethylamine (11.2g, 110.68mmol), are added portionwise 4- at 0 DEG C
(chloro- -11 alkenyl of 5,6- dihydro -11H- benzo [5,6] cycloheptane [1,2-b] pyridine of 8-) piperidines (compound C, 11.5g,
37.00mmol) acquired solution is stirred at room temperature overnight, and 20ml water quenching reaction is then added at 0 DEG C, separation organic layer is simultaneously
Vacuum concentration.Obtained crude product is purified using Flash-Prep-HPLC, and condition is as follows: chromatographic column is C18 filler；Mobile phase,
ACN, water (0.1%NH4OH)；Gradient: 20%ACN rises to 50%ACN in 20min；Detector, UV 254&220nm；Crude product
Further purified with Prep-HPLC, condition is as follows: chromatographic column is C18 filler, 19*150nm, mobile phase, ACN and water (0.1%
NH4OH)；Gradient: 38%-39%ACN in 38%ACN in 2min, 8min；Detector, UV 254&220nm, obtains 3.05g
(19%, purity 99.1%) Rupatadine fumarate derivative L P-4 pink solid.To the substitution product obtained during synthesis
It is tested, test result is shown in Fig. 2-4.
1HNMR map, 13CNMR the and MS spectrum data of product are as follows:
1H-NMR:(300MHz, DMSO-D6, ppm) δ 8.33 (d, J=3.3,1H), 8.01 (s, 1H), 7.97 (s, 1H),
7.57 (d, J=6.9Hz, 1H), 7.29 (s, 1H), 7.22-7.16 (m, 2H), 7.12 (s, 1H), 7.06 (d, J=8.4Hz,
1H),3.42(s,1H),3.32-3.23(m,2H),2.85-2.76(m,2H),2.64-2.59(m,2H),2.37-2.30(m,
2H),2.23(s,3H),2.19-2.15(m,4H)；
13C NMR(75MHz,DMSO-D6,ppm)δ157.57,146.79,140.52,138.35,137.97,137.76,
137.61,136.67,136.23,133.65,132.71,131.94,131.23,129.39,127.27,126.07,122.74,
58.45,54.51,40.79,40.51,40.24,39.96,39.68,39.40,39.12,31.52,30.97,30.84,
18.04；
LC-MS-PH-JLU-LP-4-0:(ES,m/z):432.25(M+1)。
Embodiment 3
With the difference of embodiment 1 are as follows: the molar ratio of compound A and m-CPBA are 1:3, and the yield of gained compound B is
45wt%.
Embodiment 4
With the difference of embodiment 1 are as follows: the molar ratio of compound A and m-CPBA are 1:1, and the yield of gained compound B is
41wt%.
Embodiment 5
With the difference of embodiment 1 are as follows: the molar ratio of compound A and m-CPBA are 1:5, and the yield of gained compound B is
40wt%.
Embodiment 6
With the difference of embodiment 1 are as follows: m-CPBA is replaced with H2O2, the yield of gained compound B is 40wt%.
Embodiment 7
With the difference of embodiment 1 are as follows: m-CPBA is replaced with MnO2, the yield of gained compound B is 45wt%.
Embodiment 8
With the difference of embodiment 1 are as follows: sodium bicarbonate is replaced with triethylamine, the yield of gained compound B is 40wt%.
Embodiment 9
With the difference of embodiment 1 are as follows: compound A replaces with -5 picoline hydrogen chlorate of 3- bromomethyl, gained compound B
Yield be 48wt%.
Embodiment 10
With the difference of embodiment 2 are as follows: the molar ratio of compound B and triethylamine is 1:2, and the yield of products therefrom is
12wt%.
Embodiment 11
With the difference of embodiment 2 are as follows: the molar ratio of compound B and triethylamine is 1:1, and the yield of products therefrom is
10wt%.
Embodiment 12
With the difference of embodiment 2 are as follows: the molar ratio of compound B and triethylamine is 1:5, and the yield of products therefrom is
20wt%.
Embodiment 13
With the difference of embodiment 2 are as follows: acid binding agent replaces with sodium carbonate, and the yield of products therefrom is 15wt%.
Embodiment 14
With the difference of embodiment 2 are as follows: the molar ratio of compound C and compound B is 0.8:1, and the yield of products therefrom is
25wt%.
Embodiment 15
With the difference of embodiment 2 are as follows: the molar ratio of compound C and compound B is 0.5:1, and the yield of products therefrom is
16wt%.
Embodiment 16
With the difference of embodiment 2 are as follows: the molar ratio of compound C and compound B is 1.4:1, and the yield of products therefrom is
21wt%.
It can be seen from the above description that the above embodiments of the present invention realized the following chievements:
The above-mentioned Rupatadine fumarate derivative of the application is the impurity in Rupatadine fumarate synthesis, be can be used for
The standard items of Rupatadine fumarate quality control provide reference to improve the purity of Rupatadine fumarate.
The preparation method of above-mentioned Rupatadine fumarate derivative L P-4 uses shorter synthetic route, can be improved rich horse
The yield of sour Rupatadine derivative L P-4, while the synthetic route also has side reaction few, high repeatability and other advantages.In this base
On plinth, by preparation to Rupatadine fumarate derivative L P-4 and Structural Identification, it can determine for Rupatadine fumarate
Property and quantitative analysis excellent quality, the higher reference substance of purity are provided, it is pure after product prepared by above-mentioned preparation method is purified
Degree is all larger than 99%, so that the preparation and its application to Rupatadine fumarate have good directive significance.And above-mentionedization
The raw material preparation that object D can be wide, cheap using source is closed, therefore reduces the cost of the application preparation method implementation.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of Rupatadine fumarate derivative, which is characterized in that the Rupatadine fumarate derivative has following knot
Structure Formulas I or its pharmaceutically acceptable salt,
2. the preparation method of Rupatadine fumarate derivative described in claim 1, which is characterized in that the preparation method packet
It includes:
Step S2 reacts compound B with compound C, and the fumaric acid Lu Pata derivative L P-4 is made, wherein
The structural formula of the compound B isWherein X is halogen atom；
The structural formula of the compound C is
3. preparation method according to claim 2, which is characterized in that the molar ratio of the compound B and the compound C
For 1:0.5~1.4, preferably 1:0.8.
4. preparation method according to claim 2, which is characterized in that the reaction of the step S2 in the presence of acid binding agent into
Row, the acid binding agent is organic weak base or inorganic weak bases, preferably in the group of triethylamine, pyridine, potassium carbonate and sodium carbonate composition
Any one or more, the molar ratio of the further preferred compound B and the acid binding agent is 1:1~5, preferably 1:3；It is excellent
The reaction of the step S2 is selected to carry out in the first solvent, first solvent is non-protonic solvent, it is highly preferred that described non-
Protonic solvent is selected from methylene chloride and/or chloroform；It is preferred that the reaction of the step S2 under room temperature or heating condition into
Row, it is preferable that the temperature of the reaction is room temperature to 50 DEG C, it is highly preferred that the temperature of the reaction is room temperature.
5. preparation method according to claim 2, which is characterized in that the preparation method further includes preparing the compound
The step S1, the step S1 of B include:
Make compound A and oxidant reaction, be made the compound B, the compound A be 5- first -3- halogenated methyl pyridine or
5- first -3- halogenated methyl pyridiniujm, the preferably described 5- first -3- halogenated methyl pyridiniujm are 5- first -3- halogenated methyl pyridine hydrogen bromine
Hydrochlorate or 5- first -3- halogenated methyl pyridine hydrogen chlorate.
6. preparation method according to claim 5, which is characterized in that the molar ratio of the compound A and the oxidant
For 1:1~5, more preferably 1:2.
7. preparation method according to claim 5, which is characterized in that the oxidant be selected from m-chloro-benzoic acid peroxide,
MnO2, hydrogen peroxide, Peracetic acid, any one in Peracetic acid salt and benzoyl hydroperoxide；It is preferred that the reaction of the step S1
It is carried out under catalysts conditions, the catalyst is selected from alkali and/or aqueous slkali, and the catalyst is selected from sodium bicarbonate, bicarbonate
Any one in potassium, sodium carbonate, potassium carbonate, triethylamine and respective solution, the still more preferably described catalyst are carbonic acid
Hydrogen sodium water solution；The reaction of the step S1 carries out in the second solvent, and second solvent is non-protonic solvent, more preferably
Ground, the non-protonic solvent are selected from methylene chloride and/or chloroform；It is preferred that the reaction of the step S1 is in room temperature or heating
Under the conditions of carry out, it is preferable that the temperature of the reaction be room temperature to 50 DEG C, it is highly preferred that the temperature of the reaction be room temperature.
8. the preparation method according to any one of claim 2 to 5, which is characterized in that the halogen atom is bromine atom.
9. a kind of intermediate for synthesizing Rupatadine fumarate derivative described in claim 1, which is characterized in that the centre
Body has structural formula
10. the purposes that the Rupatadine fumarate derivative of claim 1 is used as quality control standard product.
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| CN114133353A (en) * | 2021-12-10 | 2022-03-04 | 重庆华邦制药有限公司 | Rupatadine fumarate intermediate and preparation method of rupatadine fumarate |
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| CN1531537A (en) * | 2001-04-12 | 2004-09-22 | Novel tricyclic pyridyl benzazepine carboxyamides and derivatives their tocolytic oxytocin leceptor antagonists | |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114133353A (en) * | 2021-12-10 | 2022-03-04 | 重庆华邦制药有限公司 | Rupatadine fumarate intermediate and preparation method of rupatadine fumarate |
| CN114133353B (en) * | 2021-12-10 | 2023-12-01 | 重庆华邦制药有限公司 | Rupatadine fumarate intermediate and preparation method of rupatadine fumarate |
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