CN109535127A - Rupatadine fumarate derivative, preparation method and intermediate and purposes - Google Patents
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,The preparation method of above-mentioned Rupatadine fumarate derivative L P-3 uses shorter synthetic route, can be improved the yield of Rupatadine fumarate derivative L P-3, while the synthetic route also has side reaction few, high repeatability and other advantages.On this basis, pass through preparation to Rupatadine fumarate derivative L P-3 and Structural Identification, it can provide excellent quality, purity higher reference substance for the qualitative and quantitative analysis of Rupatadine fumarate, so that the preparation and its application to Rupatadine fumarate have good directive significance.And above compound D can use the raw material preparation that source is wide, cheap, therefore reduce the cost of the application preparation method implementation.
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,
The Rupatadine fumarate derivative has following structure Formulas I or its pharmaceutically acceptable salt,
Structural formula I.
Further, above-mentioned preparation method includes: step S3, will have compound D to react with compound E, obtains rich horse
Sour Lu Pata derivative,
The structural formula of compound D isWherein X is halogen atom；
The structural formula of compound E is
Further, in above-mentioned steps S3, the molar ratio of compound E and compound D are 0.5~1.4:1, preferably 0.8:
1；The reaction of preferred steps S3 carries out in the presence of acid binding agent, acid binding agent be organic weak base or inorganic weak bases, preferably triethylamine,
Any one or more in the group of pyridine, potassium carbonate and sodium carbonate composition；The reaction of preferred steps S3 carries out in the first solvent,
First solvent is non-protonic solvent, it is highly preferred that non-protonic solvent is selected from methylene chloride and/or chloroform；It is preferred that walking
The reaction of rapid S3 carries 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 reaction
Temperature be room temperature.
Further, above-mentioned preparation method include the steps that prepare compound D S2, step S2 include: by compound C with
Halogenating agent carries out halogenating reaction, obtains compound D,
The structural formula of compound C is
Further, above-mentioned halogenating agent is selected from phosphorus trihalide, phosphorus pentahalides, halogenation sulfoxide, three oxyhalogen phosphorus, chlorination
Sulfoxide, N- bromo-succinimide, N- chlorosuccinimide, phosgene and solid phosgene composition group in any one or it is more
Kind, it is preferable that phosphorus trihalide be phosphorus trichloride and/or phosphorus tribromide, phosphorus pentahalides be phosphorus pentachloride and/or phosphorus pentabromide, three
Oxyhalogen phosphorus is phosphorus oxychloride and/or tribromo oxygen phosphorus.
Further, the molar ratio of above compound C and halogenating agent is 1:1~5.05, preferably 1:3；Preferred steps
The halogenating reaction of S2 carries out in the second solvent, it is preferable that the second solvent is non-protonic solvent；It is highly preferred that aprotic
Solvent is any one in glycol dimethyl ether, 1,3- dimethyl-2-imidazolinone, ether, tetrahydrofuran and dioxane
Kind is a variety of；The halogenating reaction of preferred steps S2 carries out under room temperature or heating condition, it is preferable that the halogenating reaction temperature of step S2
Degree is room temperature to 50 DEG C, it is preferable that halogenating reaction temperature is room temperature；Halogenating agent, low temperature is added dropwise in preferred steps S2 at low temperature
It is -5~5 DEG C, preferably 0 DEG C.
Further, above-mentioned preparation method include thes steps that prepare compound C S1, step S1 include: to make raw material A and original
Expect B reaction, obtains compound C, raw material A is 5- picoline -3- base methanol or 5- picoline -3- base methoxide, raw material B are
3- ethoxycarbonyl-propen acid, preferably 5- picoline -3- base methoxide are 5- picoline -3- base methanol hydrogen chlorate or 5-
Picoline -3- base methanol hydrobromate.
Further, the reaction of above-mentioned steps S1 carries out under catalysts conditions, and catalyst is selected from alkali and/or aqueous slkali,
It is preferred that alkali is sodium hydroxide, potassium hydroxide and/or triethylamine；The reaction of step S1 is performed under heating conditions, it is preferable that step
The reaction temperature of S1 is 80~150 DEG C, it is highly preferred that reaction temperature is 100~120 DEG C；In preferred steps S1, raw material A, alkali and
The molar ratio of raw material B is 1:0.5~3:0.5~3, preferably 1:0.8~1.4:0.8~1.4, more preferably 1:1.2:0.9；It is excellent
It selects the reaction of step S1 to carry out in a solvent, preferably carries out in water.
According to another aspect of the present invention, a kind of centre for synthesizing above-mentioned Rupatadine fumarate derivative is provided
Body, the intermediate have 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 preparation method of above-mentioned Rupatadine fumarate derivative L P-3 is using shorter
Synthetic route can be improved the yield of Rupatadine fumarate derivative L P-3, while the synthetic route also has side reaction few,
High repeatability and other advantages.It on this basis, can by preparation to Rupatadine fumarate derivative L P-3 and Structural Identification
There is provided excellent quality, purity higher reference substance for the qualitative and quantitative analysis of Rupatadine fumarate, above-mentioned preparation method institute
Purity is all larger than 99% after the product of preparation is purified, so that the preparation and its application to Rupatadine fumarate are with good
Directive significance.And above compound D can use the raw material preparation that source is wide, cheap, therefore reduce the application system
The cost that Preparation Method is implemented.
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 embodiment 1 obtained compound C 1- (2- carboxyl -1- carboxyethyl) -3- methylol -5- methyl pyrrole
The MS of pyridine -1- schemes；
Fig. 2 shows obtained compound D 1- (2- the carboxyethyl) -3- bromomethyl -5- picoline -1- of embodiment 2
MS figure；
Fig. 3 shows the obtained Rupatadine fumarate derivative L P-3's of embodiment 31H-NMR figure；
Fig. 4 shows the obtained Rupatadine fumarate derivative L P-3's of embodiment 313C-NMR figure；And
Fig. 5 shows the MS figure of the obtained Rupatadine fumarate derivative L P-3 of embodiment 3.
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
Lu Pata derivative has following structure Formulas I or its pharmaceutically acceptable salt,
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.
In another typical embodiment of the application, the preparation side of above-mentioned Rupatadine fumarate derivative is provided
Method, the preparation method include: step S3, will have compound D to react with compound E, obtain fumaric acid Lu Pata derivative,
The structural formula of compound D isWherein X is halogen atom；
The structural formula of compound E is
The reaction route of above-mentioned steps S3 is as follows:
The preparation side of above-mentioned Rupatadine fumarate derivative (the application is known as Rupatadine fumarate derivative L P-3)
Method uses shorter synthetic route, can be improved the yield of Rupatadine fumarate derivative L P-3, while the synthetic route is also
It is few with side reaction, high repeatability and other advantages.On this basis, by preparation to Rupatadine fumarate derivative L P-3 and
Structural Identification can provide excellent quality, purity higher reference substance for the qualitative and quantitative analysis of Rupatadine fumarate, on
State product prepared by preparation method it is purified after purity be all larger than 99%, to preparation to Rupatadine fumarate and its answer
With with good directive significance.And above compound D can use the raw material preparation that source is wide, cheap, therefore drop
The cost that low the application preparation method is implemented.
In one embodiment, in above-mentioned steps S3, the molar ratio of compound E and compound D are 1:0.5~1.4, preferably
For 1:0.8.By the control of above-mentioned molar ratio, the conversion ratio of each compound is improved.In order to further speed up above-mentioned reaction, preferably
The reaction of step S3 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.In addition, in order to improve the dispersibility of reactant and then improve anti-
Efficiency is answered, the reaction of preferred steps S3 carries out in the first solvent, and the first solvent is non-protonic solvent, it is highly preferred that non-matter
Sub- property solvent is selected from methylene chloride and/or chloroform.The reaction of above-mentioned steps S3 can carry out under room temperature or heating condition,
But temperature is reacted progress slowly if too low or even can not be carried out, by-product increases if temperature is too high, it is preferable that anti-
The temperature answered is room temperature to 50 DEG C, it is highly preferred that the temperature of reaction is room temperature.
In the application another kind embodiment, above-mentioned preparation method include thes steps that prepare compound D S2, step S2
Include: that compound C and halogenating agent are subjected to halogenating reaction, obtains compound D, the structural formula of compound C is
The route of above-mentioned halogenating reaction is as follows:
Above-mentioned halogenating reaction is conventional reaction route, therefore easily controllable and realize.
For above-mentioned halogenating reaction halogenating agent can there are many, it is preferably above-mentioned in order to avoid introducing excessive impurity
Halogenating agent is selected from phosphorus trihalide, phosphorus pentahalides, halogenation sulfoxide, three oxyhalogen phosphorus, thionyl chloride, N- bromo-succinimide
(NBS), any one or more in the group of N- chlorosuccinimide (NCS), phosgene and solid phosgene composition, it is preferable that
Phosphorus trihalide is phosphorus trichloride and/or phosphorus tribromide, and phosphorus pentahalides is phosphorus pentachloride and/or phosphorus pentabromide, and three oxyhalogen phosphorus are three
Chlorethoxyfos and/or tribromo oxygen phosphorus.
The ratio of two kinds of reactants can be reference with chemical reaction ratio in above-mentioned halogenating reaction, in order to improve halogenated rate,
It is preferred that the molar ratio of above compound C and halogenating agent is 1:1~5, preferably 1:3.Similarly, in order to improve halogenating reaction
The halogenating reaction of activity, preferred steps S2 carries out in the second solvent, it is preferable that the second solvent is non-protonic solvent；It is more excellent
Selection of land, non-protonic solvent are selected from dimethyl ether (DME), 1,3-Dimethyl-2-imidazolidinone (DMI), ether, tetrahydrofuran
(THF) any one or more and in dioxane.In addition, the halogenating reaction of above-mentioned steps S2 is under room temperature or heating condition
It carries out, it is preferable that the halogenating reaction temperature of step S2 is room temperature to 50 DEG C, excellent in order to reduce energy consumption and improve reaction safety
Choosing and stating halogenating reaction temperature is room temperature.In addition, in order to improve reaction safety, halogenated examination is added dropwise in preferred steps S2 at low temperature
Agent, low temperature are -5~5 DEG C, preferably 0 DEG C.
In the application another kind embodiment, above-mentioned preparation method include thes steps that prepare compound C S1, above-mentioned steps
S1 includes: to react raw material A with raw material B, obtains compound C, and raw material A is 5- picoline -3- base methanol or 5- picoline -
3- base methoxide, raw material B are 3- ethoxycarbonyl-propen acid, and preferably 5- picoline -3- base methoxide is 5- picoline -3-
Base methanol hydrogen chlorate or 5- picoline -3- base methanol hydrobromate.5- picoline -3- base methoxide therein is 5- first
Yl pyridines -3- base methanol, which carries out reaction with corresponding acid, can be obtained.
The route of above-mentioned reaction is as follows:
In order to improve reaction efficiency, the preferably reaction of above-mentioned steps S1 carries out under catalysts conditions, and catalyst is selected from alkali
And/or aqueous slkali, preferably alkali is sodium hydroxide, potassium hydroxide and/or triethylamine.The reaction of further preferred above-mentioned steps S1 exists
It is carried out under heating condition, it is preferable that the reaction temperature of step S1 is 80~150 DEG C, it is highly preferred that reaction temperature is 100~120
℃.In order to improve raw material availability, in preferred steps S1, the molar ratio of raw material A, alkali and raw material B is 1:0.5~3:0.5~3,
Preferably 1:0.8~1.4:0.8~1.4, more preferably 1:1.2:0.9；The reaction of preferred steps S1 carries out in a solvent, preferably
It carries out in water.
In the application in another typical embodiment, 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.
The synthetic route of following example 1 to 3 is as follows:
Embodiment 1
150ml water is added in the round-bottomed flask of 500ml, is passed through inert atmosphere N2And keep, then partially add at 0 DEG C
Enter sodium hydroxide (6g, 150.00mmol, 1.00equiv), it is (former to be subsequently added into 5- picoline -3- base methanol hydrogen hydrobromate
Expect A, 30.6g, 149.95mmol, 1.00equiv) and 3- ethoxycarbonyl-propen acid (raw material B, 15.66g,
108.66mmol, 1.00equiv), acquired solution crosses filter solid while hot, filters out liquid cooling back flow reaction 3 days at 110 DEG C of oil bath
But to room temperature, precipitation solid is collected by filtration, washs simultaneously infra-red drying with 1x50ml ice water, obtains 15g (42%) compound C 1-
(2- carboxyl -1- carboxyethyl) -3- methylol -5- picoline -1- white solid.To the substitution product obtained during synthesis
It is tested, test result is shown in Fig. 1.
The MS spectrum data of product are as follows:
LC-MS-PH-JLU-LP-3-1:(ES,m/z):240.0(M+1)。
Embodiment 2
Inert atmosphere N is passed through in the round-bottomed flask of 500ml2And keep, 1- (2- carboxyl -1- carboxyethyl) -3- hydroxyl is added
Methyl -5- picoline -1- (3.3g, 13.79mmol, 1.00equiv) and 60ml glycol dimethyl ether, then at 0 DEG C
Agitation and dropping phosphorus tribromide (6.6ml, 2.00equiv), directly vacuum is dense after acquired solution is stirred to react 5 hours at room temperature
Contracting, acquired solution are diluted with 30ml ACN, and 5ml water quenching reaction is added at 0 DEG C, gained mixture vacuum concentration.It obtains
Crude product purified using Flash-Prep-HPLC, condition is as follows: chromatographic column is C18 filler；Mobile phase, ACN/ water (0.1%
) and acetonitrile NH4OH；Gradient: 0%ACN rises to 5%ACN in 10min；Detector, UV 254&220nm obtain 12g (crude product)
Compound D 1- (2- carboxyethyl) -3- bromomethyl -5- picoline -1-.The substitution product obtained during synthesis is carried out
Test, test result are shown in Fig. 2.
The MS spectrum data of substitution product are as follows:
LC-MS-PH-JLU-LP-3-2:(ES,m/z):302(M+1)；304(M+1).
Embodiment 3
Inert atmosphere N is passed through in the round-bottomed flask of 500ml2And keep, at 0 DEG C, in 1- (2- carboxyethyl) -3- bromine first
Agitation and dropping TEA in methylene chloride (40ml) solution of base -5- picoline -1- (12g, 39.72mmol, 1.00equiv)
4- (chloro- 5, the 6- dihydro -11H- benzo [5,6] of 8- is then added portionwise in (12g, 118.59mmol, 3.00equiv) at 0 DEG C
- 11 alkenyl of cycloheptane [1,2-b] pyridine) and piperidines (compound E, 7.9g, 25.42mmol, 0.60equiv), it is stirred at room temperature
After 2 hours, gained mixture vacuum concentration.Obtained crude product is purified using Prep-HPLC, and condition is as follows: chromatographic column is
C18 filler, 19*150；Mobile phase, ACN/ water (10mmol/mL NH4OH and 5mmol/L NH4CO3)；Gradient: 16% in 9min
ACN rises to 36%ACN；Flow velocity: 25mL/min；Detector, UV 254&220nm obtain 1400mg (yield 7%) fumaric acid Lu
Pa Tading derivative L P-3.The substitution product obtained during synthesis is tested, test result is shown in Fig. 3-5.
1HNMR map, 13CNMR the and MS spectrum data of substitution product are as follows:
1H-NMR-PH-JLU-LP-3-0:(300MHz,DMSO-D6,ppm):δ8.80(s,1H),8.72(s,1H),8.33
(d, J=3.6Hz, 1H), 8.27 (s, 1H), 7.57 (d, J=7.5Hz, 1H), 7.29 (s, 1H), 7.21-7.16 (m, 2H),
7.06 (d, J=8.1Hz, 1H), 5.39 (t, J=6.9Hz, 1H), 3.63 (s, 2H), 3.32-3.08 (m, 3H), 2.91-2.78
(m,3H),2.72-2.63(m,2H),2.46(s,3H),2.39-2.32(m,2H),2.28-2.10(m,4H)；
13C-NMR-PH-JLU-LP-3-0:(300MHz,DMSO-D6,ppm):δ172.44,167.86,157.56,
157.53,146.76,145.59,143.53,142.40,140.52,138.34,138.31,137.86,137.82,137.34,
133.70,132.75,131.96,131.25,129.39,126.09,122.79,72.66,57.91,54.41,54.28,
31.53,30.98,30.82,30.69,18.17；
LC-MS-PH-JLU-LP-3-0:(ES,m/z):532.20(M+H)。
Embodiment 4
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1:1.2, gained compound C
Yield be 41wt%.
Embodiment 5
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1:3, gained compound C's
Yield is 40wt%.
Embodiment 6
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1:0.5, gained compound C
Yield be 38wt%.
Embodiment 7
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1:0.8, gained compound C
Yield be 45wt%.
Embodiment 8
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1:1.4, gained compound C
Yield be 47wt%.
Embodiment 9
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:0.5:0.7, gained compound
The yield of C is 39wt%.
Embodiment 10
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:3:0.7, gained compound C
Yield be 40wt%.
Embodiment 11
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:0.8:0.7, gained compound
The yield of C is 41wt%.
Embodiment 12
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1.4:0.7, gained compound
The yield of C is 43wt%.
Embodiment 13
With the difference of embodiment 1 are as follows: the molar ratio of raw material A, sodium hydroxide and raw material B is 1:1.2:0.9, gained compound
The yield of C is 49wt%.
Embodiment 14
With the difference of embodiment 1 are as follows: raw material A replaces with (5- picoline -3- base) methanol hydrogen chlorate, gained compound
The yield of C is 42wt%.
Embodiment 15
With the difference of embodiment 2 are as follows: phosphorus tribromide is replaced with tribromo oxygen phosphorus, obtains 11g compound D crude product.
Embodiment 16
With the difference of embodiment 2 are as follows: phosphorus tribromide is replaced with thionyl chloride, obtains 11g compound D crude product.
Embodiment 17
With the difference of embodiment 2 are as follows: phosphorus tribromide is replaced with N- bromo-succinimide, 10g compound D is obtained and slightly produces
Product.
Embodiment 18
With the difference of embodiment 2 are as follows: phosphorus tribromide is replaced with phosgene, obtains 12g compound D crude product.
Embodiment 19
With the difference of embodiment 2 are as follows: phosphorus tribromide is replaced with solid phosgene, obtains 11g compound D crude product.
Embodiment 20
With the difference of embodiment 2 are as follows: the molar ratio of compound C and halogenating agent is 1:3, obtains 10g compound D and slightly produces
Product.
Embodiment 21
With the difference of embodiment 2 are as follows: the molar ratio of compound C and halogenating agent is 1:1, obtains 9.7g compound D and slightly produces
Product.
Embodiment 22
With the difference of embodiment 3 are as follows: acid binding agent replaces with sodium carbonate, and the yield of products therefrom is 5wt%.
Embodiment 23
With the difference of embodiment 3 are as follows: the molar ratio of compound E and compound D is 0.8:1, and the yield of products therefrom is
10wt%.
Embodiment 24
With the difference of embodiment 3 are as follows: the molar ratio of compound E and compound D is 0.5:1, and the yield of products therefrom is
8.7wt%.
Embodiment 25
With the difference of embodiment 3 are as follows: the molar ratio of compound E and compound D is 1.4:1, and the yield of products therefrom is
9.2wt%.
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-3 uses shorter synthetic route, can be improved rich horse
The yield of sour Rupatadine derivative L P-3, 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-3 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 the Rupatadine fumarate derivative of claim 1, which is characterized in that the preparation method includes:
Step S3 will have compound D to react with compound E, obtain the fumaric acid Lu Pata derivative,
The structural formula of the compound D isWherein X is halogen atom；
The structural formula of the compound E is
3. preparation method according to claim 2, which is characterized in that in the step S3, the compound E and describedization
The molar ratio for closing object D is 0.5~1.4:1, preferably 0.8:1；It is preferred that the reaction of the step S3 carries out in the presence of acid binding agent,
The acid binding agent is organic weak base or inorganic weak bases, preferably any in the group of triethylamine, pyridine, potassium carbonate and sodium carbonate composition
It is one or more；It is preferred that the reaction of the step S3 carries out in the first solvent, first solvent is non-protonic solvent, more
Preferably, the non-protonic solvent is selected from methylene chloride and/or chloroform；It is preferred that the reaction of the step S3 in room temperature or
It is carried out under heating condition, 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.
4. preparation method according to claim 2, which is characterized in that the preparation method further includes preparing the compound
The step S2, the step S2 of D include:
Compound C and halogenating agent are subjected to halogenating reaction, obtain the compound D,
The structural formula of the compound C is
5. the preparation method according to claim 4, which is characterized in that the halogenating agent is selected from phosphorus trihalide, five
Phosphorus Halides, halogenation sulfoxide, three oxyhalogen phosphorus, thionyl chloride, N- bromo-succinimide, N- chlorosuccinimide, phosgene and solid
Body phosgene composition group in any one or more, it is preferable that phosphorus trihalide be phosphorus trichloride and/or phosphorus tribromide, five halogen
Changing phosphorus is phosphorus pentachloride and/or phosphorus pentabromide, and three oxyhalogen phosphorus are phosphorus oxychloride and/or tribromo oxygen phosphorus.
6. the preparation method according to claim 4, which is characterized in that mole of the compound C and the halogenating agent
Than for 1:1~5.05, preferably 1:3；It is preferred that the halogenating reaction of the step S2 carries out in the second solvent, it is preferable that described
Second solvent is non-protonic solvent；It is highly preferred that the non-protonic solvent is selected from glycol dimethyl ether, 1,3- dimethyl-
Any one or more in 2- imidazolone, ether, tetrahydrofuran and dioxane；It is preferred that the halogenating reaction of the step S2
It is carried out under room temperature or heating condition, it is preferable that the halogenating reaction temperature of the step S2 is room temperature to 50 DEG C, it is preferable that institute
Stating halogenating reaction temperature is room temperature；It is preferred that the halogenating agent is added dropwise in the step S2 at low temperature, the low temperature is -5~5
DEG C, preferably 0 DEG C.
7. the preparation method according to claim 4, which is characterized in that the preparation method further includes preparing the compound
The step S1, the step S1 of C include:
It reacts raw material A with raw material B, obtains the compound C, the raw material A is 5- picoline -3- base methanol or 5- methyl
Pyridin-3-yl methoxide, the raw material B are 3- ethoxycarbonyl-propen acid, and the preferably described 5- picoline -3- base methoxide is
5- picoline -3- base methanol hydrogen chlorate or 5- picoline -3- base methanol hydrobromate.
8. preparation method according to claim 7, which is characterized in that the reaction of the step S1 under catalysts conditions into
Row, the catalyst are selected from alkali and/or aqueous slkali, and the preferably described alkali is sodium hydroxide, potassium hydroxide and/or triethylamine；It is described
The reaction of step S1 is performed under heating conditions, it is preferable that and the reaction temperature of the step S1 is 80~150 DEG C, it is highly preferred that
The reaction temperature is 100~120 DEG C；It is preferred that in the step S1, the molar ratio of the raw material A, the alkali and the raw material B
For 1:0.5~3:0.5~3, preferably 1:0.8~1.4:0.8~1.4, more preferably 1:1.2:0.9；It is preferred that the step S1
Reaction carry out in a solvent, preferably carry out in water.
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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| CN102958926A (en) * | 2010-06-30 | 2013-03-06 | J·乌里亚奇·Y股份有限公司 | Rupatadine salt as an antihistaminic agent |
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| CN109692153A (en) * | 2017-10-24 | 2019-04-30 | 北京睿创康泰医药研究院有限公司 | A kind of aqueous solution preparation of Rupatadine fumarate |
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| CN102958926A (en) * | 2010-06-30 | 2013-03-06 | J·乌里亚奇·Y股份有限公司 | Rupatadine salt as an antihistaminic agent |
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