CN109535127B - Rupatadine fumarate derivative, preparation method, intermediate and application thereof - Google Patents

Rupatadine fumarate derivative, preparation method, intermediate and application thereof Download PDF

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CN109535127B
CN109535127B CN201811482078.6A CN201811482078A CN109535127B CN 109535127 B CN109535127 B CN 109535127B CN 201811482078 A CN201811482078 A CN 201811482078A CN 109535127 B CN109535127 B CN 109535127B
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phosphorus
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CN109535127A (en
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赵志良
狄晓霞
宣燕红
杜双有
郑燕
刘玲
方静
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Hangzhou Qianyuan Baoling Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/30—Oxygen atoms
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    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q

Abstract

The invention provides fumaric acidRupatadine derivatives, methods of preparation, intermediates and uses thereof. The rupatadine fumarate derivative has the following structural formula I or pharmaceutically acceptable salt thereof,
Figure DDA0001893628140000011
the preparation method of the rupatadine fumarate derivative LP-3 adopts a shorter synthetic route, can improve the yield of the rupatadine fumarate derivative LP-3, and meanwhile, the synthetic route also has the advantages of less side reaction, good reproducibility and the like. On the basis, through the preparation and the structure identification of the rupatadine fumarate derivative LP-3, a reference substance with excellent quality and higher purity can be provided for qualitative and quantitative analysis of rupatadine fumarate, so that the method has good guiding significance for the preparation and the application of the rupatadine fumarate. Moreover, the compound D can be prepared from raw materials with wide sources and low price, so that the implementation cost of the preparation method is reduced.

Description

Rupatadine fumarate derivative, preparation method, intermediate and application thereof
Technical Field
The invention relates to the field of medicine preparation, in particular to a rupatadine fumarate derivative, a preparation method, an intermediate and application thereof.
Background
The rupatadine fumarate is used as a dual antagonist of histamine and platelet aggregation, and is mainly applied to treating allergic diseases such as allergic rhinitis and urticaria. The rupatadine fumarate is first marketed in Spain in a tablet mode from 3 months in 2003, is marketed in British countries, member countries of European Union, American countries and other countries in the world so far, and domestic pharmaceutical enterprises are approved to produce rupatadine fumarate bulk drugs and preparations in 2013 in China.
In the research, production, supply and clinical use of the medicine, the purity of the medicine must be ensured so as to ensure the effectiveness and safety of the medicine. Impurities in a drug are the main factors affecting its purity, and in general, impurities refer to substances present in the drug that have no therapeutic effect or affect the stability and efficacy of the drug, even are harmful to human health. The impurity sources can be roughly divided into two types, namely, the impurity sources are brought by the production process and raw and auxiliary materials; secondly, the physicochemical property of the medicine is changed and generated under the influence of external conditions in the storage process. The adverse reaction of the medicine is closely related to the impurities in the medicine besides the physiological activity of the active ingredients. Therefore, the research on the impurities of the medicine is carried out normatively, and the impurities are controlled within a safe and reasonable limit range, which is directly related to the quality and the safety of the rupatadine fumarate.
As an important step in the quality control of pharmaceutical products, impurities must be strictly detected and monitored in order to better control the quality of the pharmaceutical products. The source, the property, the detection method and the limit of the impurities in the medicine are clarified through the detection of the impurities, the medicine manufacturing process can be optimized, the generation of the impurities is avoided or the impurities are reduced to the minimum, and the medicine quality is ensured and improved from multiple aspects. The method has great significance for researching the preparation method of the rupatadine fumarate impurity, and can be used for qualitative and quantitative analysis of the impurity in the production of rupatadine fumarate bulk drug and preparation, thereby improving the quality standard of the rupatadine fumarate bulk drug and preparation and providing guidance for the medication safety of the people.
Until now, the research on rupatadine fumarate in the prior art mainly focuses on the research on the preparation method of the product, and the research on impurities existing in the production process and the preparation method are few. The applicant is dedicated to research on the preparation process of the rupatadine fumarate and optimization of an impurity detection method for a long time, researches and applies for a plurality of rupatadine fumarate preparation methods and impurity patents thereof, and a plurality of applications are granted at present. For example:
CN104098557A (application date: 2014.07.02) relates to rupatadine fumarate impurity J and a preparation method thereof, wherein rupatadine fumarate (2) is used as a raw material, a 30-50% hydrogen peroxide solution is adopted for reaction to obtain crude rupatadine fumarate impurity J (1), the crude rupatadine fumarate impurity J is purified to obtain pure impurity J, and the purity can reach 98.5%.
Figure BDA0001893628120000021
CN108299395A (application date: 2017.12.08) relates to rupatadine fumarate impurity S and a preparation method thereof, and the impurity structure is
Figure BDA0001893628120000022
(X1 is a halogen atom), using
Figure BDA0001893628120000023
(I) And
Figure BDA0001893628120000024
(II) as a raw material, and obtaining an intermediate through substitution reaction and halogenation reaction
Figure BDA0001893628120000025
(IV) and then passing through the Intermediate (IV) and the raw material
Figure BDA0001893628120000026
Condensation reaction is carried out, a crude rupatadine fumarate impurity S product is finally obtained, the crude rupatadine fumarate impurity S product is purified to obtain an impurity J pure product, the purity can reach more than 97%, and the yield can reach 30%.
However, in the prior art, the research on the types of impurities existing in the production process still needs to be perfected, many new impurities are not found, and how to meet the huge synthesis requirement of impurity standards is further researched.
Based on the consideration of the problems, the invention discovers a new impurity rupatadine fumarate derivative in the optimization process of the production process, but no effective method for synthesizing the impurity exists at present, so that the research and control of the impurity become a difficult problem.
Disclosure of Invention
The invention mainly aims to provide a rupatadine fumarate derivative, a preparation method, an intermediate and application thereof, and aims to solve the problem that the rupatadine fumarate derivative serving as an impurity of rupatadine fumarate in the prior art cannot be effectively synthesized, so that the rupatadine fumarate derivative is difficult to control.
To achieve the above objects, according to one aspect of the present invention, there is provided a rupatadine fumarate derivative having the following structural formula I or a pharmaceutically acceptable salt thereof,
Figure BDA0001893628120000031
structural formula I.
Further, the preparation method comprises the following steps: step S3, reacting the compound D with the compound E to obtain the rupatta fumarate derivative,
the structural formula of the compound D is
Figure BDA0001893628120000032
Wherein X is a halogen atom;
the structural formula of the compound E is
Figure BDA0001893628120000033
Further, in the step S3, the molar ratio of the compound E to the compound D is 0.5 to 1.4:1, preferably 0.8: 1; preferably, the reaction of step S3 is performed in the presence of an acid-binding agent, which is an organic or inorganic weak base, preferably one or more of triethylamine, pyridine, potassium carbonate, and sodium carbonate; preferably, the reaction of step S3 is carried out in a first solvent, which is an aprotic solvent, more preferably, the aprotic solvent is selected from dichloromethane and/or chloroform; preferably, the reaction of step S3 is carried out at room temperature or under heating, preferably, the temperature of the reaction is from room temperature to 50 ℃, more preferably, the temperature of the reaction is room temperature.
Further, the above preparation method further includes step S2 of preparing compound D, and step S2 includes: performing halogenation reaction on the compound C and a halogenating reagent to obtain a compound D,
the structural formula of the compound C is
Figure BDA0001893628120000041
Further, the above halogenating agent is selected from any one or more of phosphorus trihalide, phosphorus pentahalide, sulfoxide halide, phosphorus trihalide, sulfoxide chloride, N-bromosuccinimide, N-chlorosuccinimide, phosgene and solid phosgene, preferably, phosphorus trihalide is phosphorus trichloride and/or phosphorus tribromide, phosphorus pentahalide is phosphorus pentachloride and/or phosphorus pentabromide, and phosphorus trihalide is phosphorus oxychloride and/or phosphorus tribromide.
Further, the molar ratio of the compound C to the halogenating agent is 1: 1-5.05, preferably 1: 3; preferably, the halogenation reaction of step S2 is carried out in a second solvent, preferably, the second solvent is an aprotic solvent; more preferably, the aprotic solvent is selected from any one or more of ethylene glycol dimethyl ether, 1, 3-dimethyl-2-imidazolidinone, diethyl ether, tetrahydrofuran and dioxane; preferably, the halogenation reaction of the step S2 is performed at room temperature or under heating, preferably, the halogenation reaction temperature of the step S2 is from room temperature to 50 ℃, preferably, the halogenation reaction temperature is room temperature; preferably, in the step S2, the halogenated reagent is dripped at a low temperature of-5 ℃, and preferably at 0 ℃.
Further, the above preparation method further includes a step S1 of preparing compound C, and step S1 includes: reacting a material A with a material B to obtain a compound C, wherein the material A is 5-methylpyridin-3-yl methanol or 5-methylpyridin-3-yl methoxide, the material B is 3-ethoxycarbonyl-acrylic acid, and preferably the 5-methylpyridin-3-yl methoxide is 5-methylpyridin-3-yl methanol hydrochloride or 5-methylpyridin-3-yl methanol hydrobromide.
Further, the reaction of step S1 is performed under the condition of a catalyst, wherein the catalyst is selected from alkali and/or alkali solution, preferably the alkali is sodium hydroxide, potassium hydroxide and/or triethylamine; the reaction of step S1 is carried out under heating condition, preferably, the reaction temperature of step S1 is 80-150 ℃, more preferably, the reaction temperature is 100-120 ℃; preferably, in step S1, the molar ratio of the raw material a to the base to the raw material B is 1:0.5 to 3, preferably 1:0.8 to 1.4, and more preferably 1:1.2: 0.9; preferably, the reaction of step S1 is carried out in a solvent, preferably in water.
According to another aspect of the present invention, there is provided an intermediate for the synthesis of the rupatadine fumarate derivative as described above, which intermediate has the structural formula
Figure BDA0001893628120000042
According to another aspect of the present invention, there is provided the use of the rupatadine fumarate derivative described above as a quality control standard.
By applying the technical scheme of the invention, the preparation method of the rupatadine fumarate derivative LP-3 adopts a shorter synthetic route, can improve the yield of the rupatadine fumarate derivative LP-3, and meanwhile, the synthetic route also has the advantages of less side reaction, good reproducibility and the like. On the basis, through the preparation and the structure identification of the rupatadine fumarate derivative LP-3, a reference substance with excellent quality and higher purity can be provided for qualitative and quantitative analysis of rupatadine fumarate, and the purity of the product prepared by the preparation method is more than 99% after purification, so that the preparation method has good guiding significance for the preparation and the application of rupatadine fumarate. Moreover, the compound D can be prepared from raw materials with wide sources and low price, so that the implementation cost of the preparation method is reduced.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 shows the MS diagram of the compound C1- (2-carboxy-1-carboxyethyl) -3-hydroxymethyl-5-methylpyridin-1-ium obtained in example 1;
FIG. 2 shows the MS diagram of the compound D1- (2-carboxyethyl) -3-bromomethyl-5-methylpyridin-1-ium obtained in example 2;
FIG. 3 shows the Rupatadine fumarate derivative LP-3 obtained in example 31H-NMR chart;
FIG. 4 shows the Rupatadine fumarate derivative LP-3 obtained in example 313C-NMR chart; and
FIG. 5 shows the MS pattern of rupatadine fumarate derivative LP-3 obtained in example 3.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
As analyzed by the background art of the application, when a synthetic route of rupatadine fumarate is optimized, a novel rupatadine fumarate derivative is found, but the rupatadine fumarate derivative cannot be effectively researched and controlled due to too small content of the rupatadine fumarate derivative, and in order to solve the problem, the application provides a preparation method, an intermediate and application of the rupatadine fumarate derivative.
In a typical embodiment of the present application, there is provided a rupatadine fumarate derivative having the following structural formula I or a pharmaceutically acceptable salt thereof,
Figure BDA0001893628120000061
the rupatadine fumarate derivative is an impurity in the synthesis of rupatadine fumarate, can be used as a standard substance for quality control of rupatadine fumarate, and provides reference for improving the purity of rupatadine fumarate.
In another exemplary embodiment of the present application, there is provided a preparation method of the rupatadine fumarate derivative, the preparation method comprising: step S3, reacting the compound D with the compound E to obtain the rupatta fumarate derivative,
the structural formula of the compound D is
Figure BDA0001893628120000062
Wherein X is a halogen atom;
the structural formula of the compound E is
Figure BDA0001893628120000063
The reaction scheme of the above step S3 is as follows:
Figure BDA0001893628120000064
the preparation method of the rupatadine fumarate derivative (referred to as rupatadine fumarate derivative LP-3 in the application) adopts a shorter synthetic route, can improve the yield of the rupatadine fumarate derivative LP-3, and meanwhile, the synthetic route also has the advantages of less side reaction, good reproducibility and the like. On the basis, through the preparation and the structure identification of the rupatadine fumarate derivative LP-3, a reference substance with excellent quality and higher purity can be provided for qualitative and quantitative analysis of rupatadine fumarate, and the purity of the product prepared by the preparation method is more than 99% after purification, so that the preparation method has good guiding significance for the preparation and the application of rupatadine fumarate. Moreover, the compound D can be prepared from raw materials with wide sources and low price, so that the implementation cost of the preparation method is reduced.
In one embodiment, in the step S3, the molar ratio of the compound E to the compound D is 1:0.5 to 1.4, preferably 1: 0.8. By controlling the above molar ratio, the conversion of each compound is improved. In order to further accelerate the above reaction, it is preferable that the reaction of step S3 is performed in the presence of an acid-binding agent, which is an organic weak base or an inorganic weak base, preferably one or more selected from the group consisting of triethylamine, pyridine, potassium carbonate, and sodium carbonate. In addition, in order to improve the dispersibility of the reactants and thus the reaction efficiency, the reaction of step S3 is preferably carried out in a first solvent, which is an aprotic solvent, more preferably, the aprotic solvent is selected from dichloromethane and/or chloroform. The reaction of the above step S3 can be carried out at room temperature or under heating, but if the temperature is too low, the reaction proceeds slowly or even fails, and if the temperature is too high, the by-products increase, preferably, the temperature of the reaction is from room temperature to 50 ℃, more preferably, the temperature of the reaction is room temperature.
In another embodiment of the present application, the above preparation method further comprises a step S2 of preparing compound D, the step S2 comprising: performing halogenation reaction on the compound C and a halogenating reagent to obtain a compound D, wherein the structural formula of the compound C is shown in the specification
Figure BDA0001893628120000071
The route of the above halogenation reaction is as follows:
Figure BDA0001893628120000072
the above-described halogenation reactions are conventional reaction routes and are therefore easy to control and implement.
The halogenating agent used in the above halogenation reaction may be various, and in order to avoid introduction of excessive impurities, it is preferable that the halogenating agent is selected from any one or more selected from the group consisting of phosphorus trihalide, phosphorus pentahalide, sulfoxide halide, phosphorus oxyhalide, sulfoxide chloride, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), phosgene and solid phosgene, and preferably, the phosphorus trihalide is phosphorus trichloride and/or phosphorus tribromide, the phosphorus pentahalide is phosphorus pentachloride and/or phosphorus pentabromide, and the phosphorus oxyhalide is phosphorus oxychloride and/or phosphorus oxybromide.
The ratio of the two reactants in the halogenation reaction can be referred to as a chemical reaction ratio, and in order to improve the halogenation rate, the molar ratio of the compound C to the halogenating agent is preferably 1:1 to 5, and preferably 1: 3. Likewise, in order to increase the activity of the halogenation reaction, it is preferable that the halogenation reaction of step S2 is carried out in a second solvent, preferably, the second solvent is an aprotic solvent; more preferably, the aprotic solvent is selected from any one or more of dimethyl ether (DME), 1, 3-dimethyl-2-imidazolidinone (DMI), diethyl ether, Tetrahydrofuran (THF), and dioxane. In addition, the halogenation reaction in the step S2 is performed at room temperature or under heating, preferably, the halogenation reaction temperature in the step S2 is from room temperature to 50 ℃, and in order to reduce energy consumption and improve reaction safety, the halogenation reaction temperature is preferably room temperature. In addition, in order to improve the reaction safety, it is preferable that the halogenating agent is added dropwise at a low temperature of-5 to 5 ℃, preferably 0 ℃ in step S2.
In another embodiment of the present application, the above preparation method further comprises a step S1 of preparing compound C, and the above step S1 comprises: reacting a material A with a material B to obtain a compound C, wherein the material A is 5-methylpyridin-3-yl methanol or 5-methylpyridin-3-yl methoxide, the material B is 3-ethoxycarbonyl-acrylic acid, and preferably the 5-methylpyridin-3-yl methoxide is 5-methylpyridin-3-yl methanol hydrochloride or 5-methylpyridin-3-yl methanol hydrobromide. Wherein the 5-methylpyridine-3-yl methoxide is obtained by reacting 5-methylpyridine-3-yl methanol with corresponding acid.
The route of the above reaction is as follows:
Figure BDA0001893628120000081
in order to improve the reaction efficiency, the reaction of step S1 is preferably carried out under the condition of a catalyst selected from alkali and/or alkali solution, preferably the alkali is sodium hydroxide, potassium hydroxide and/or triethylamine. The reaction of step S1 is preferably carried out under heating, and the reaction temperature of step S1 is preferably 80 to 150 ℃, more preferably 100 to 120 ℃. In order to improve the utilization rate of the raw materials, in step S1, the molar ratio of the raw material a to the alkali to the raw material B is preferably 1:0.5 to 3, preferably 1:0.8 to 1.4, and more preferably 1:1.2: 0.9; preferably, the reaction of step S1 is carried out in a solvent, preferably in water.
In still another exemplary embodiment of the present application, there is provided a method for synthesizing the rupatadine fumarate derivative as described aboveBiological intermediates having the formula
Figure BDA0001893628120000091
In still another exemplary embodiment of the present application, there is provided a use of the above rupatadine fumarate derivative as a quality control standard. The rupatadine fumarate derivative obtained by the preparation method has high purity, so that the rupatadine fumarate derivative can be used as a standard substance for quality control of rupatadine fumarate, and has good guiding significance for preparation of rupatadine fumarate.
The advantageous effects of the present application will be further described below with reference to examples and comparative examples.
The synthetic routes for the following examples 1 to 3 are as follows:
Figure BDA0001893628120000092
example 1
150ml of water are placed in a 500ml round bottom flask and an inert atmosphere N is introduced2And held, followed by partial addition of sodium hydroxide (6g, 150.00mmol, 1.00equiv) at 0 ℃, followed by addition of 5-methylpyridin-3-ylmethanol hydrobromide (starting material a, 30.6g, 149.95mmol, 1.00equiv), and 3-ethoxycarbonyl-acrylic acid (starting material B, 15.66g, 108.66mmol, 1.00equiv), the resulting solution was refluxed at 110 ℃ in an oil bath for 3 days, the solid was filtered while hot, the filtrate was cooled to room temperature, the precipitated solid was collected by filtration, washed with 1x50ml ice water and infrared dried to give 15g (42%) of the compound C1- (2-carboxy-1-carboxyethyl) -3-hydroxymethyl-5-methylpyridin-1-ium as a white solid. The substitution products obtained during the synthesis were tested and the results are shown in FIG. 1.
The MS spectrum data of the product were:
LC-MS-PH-JLU-LP-3-1:(ES,m/z):240.0(M+1)。
example 2
Introducing inert atmosphere N into a 500ml round-bottom flask2And maintaining, adding 1- (2-carboxy-1-carboxyethyl) -3-hydroxymethyl-5-methylpyridin-1-ium(3.3g, 13.79mmol, 1.00equiv) and 60ml ethylene glycol dimethyl ether, then phosphorus tribromide (6.6ml, 2.00equiv) is added dropwise with stirring at 0 ℃, the obtained solution is directly concentrated in vacuum after stirring reaction for 5 hours at room temperature, the obtained solution is diluted with 30ml of ACN, 5ml of water is added at 0 ℃ for quenching reaction, and the obtained mixture is concentrated in vacuum. The obtained crude product is purified by Flash-Prep-HPLC, and the conditions are as follows: the chromatographic column is C18 filler; mobile phase, ACN/water (0.1% NH4OH) and acetonitrile; gradient: increasing 0% ACN to 5% ACN within 10 min; detector, UV 254&220nm, 12g (crude) of compound D1- (2-carboxyethyl) -3-bromomethyl-5-methylpyridin-1-ium are obtained. The substitution products obtained during the synthesis were tested and the results are shown in FIG. 2.
The MS spectrum data for the substitution products were:
LC-MS-PH-JLU-LP-3-2:(ES,m/z):302(M+1)；304(M+1)。
example 3
Introducing inert atmosphere N into a 500ml round-bottom flask2While maintaining, TEA (12g, 118.59mmol, 3.00equiv) was added dropwise to a solution of 1- (2-carboxyethyl) -3-bromomethyl-5-methylpyridin-1-ium (12g, 39.72mmol, 1.00equiv) in dichloromethane (40ml) at 0 ℃ with stirring, followed by addition of 4- (8-chloro-5, 6-dihydro-11H-benzo [5,6 ] in portions at 0 DEG C]Cycloheptane [1,2-b ]]Pyridin-11-enyl) piperidine (compound E, 7.9g, 25.42mmol, 0.60equiv) was stirred at room temperature for 2 hours and the resulting mixture was concentrated in vacuo. The crude product obtained was purified by Prep-HPLC under the following conditions: the chromatographic column is C18 packing, 19 x 150; mobile phase, ACN/water (10mmol/mL NH4OH and 5mmol/L NH4CO 3); gradient: increasing the ACN content of 16% to 36% within 9 min; flow rate: 25 mL/min; detector, UV 254&220nm, 1400mg (yield 7%) of rupatadine fumarate derivative LP-3 was obtained. The substitution products obtained during the synthesis were tested and the results are shown in FIGS. 3-5.
The 1HNMR, 13CNMR and MS profile data for the substitution products are:
1H-NMR-PH-JLU-LP-3-0:(300MHz,DMSO-D6,ppm):8.80(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):172.44,167.86,157.56,157.53,146.76,145.59,143.53,142.40,140.52,138.34,138.31,137.86,137.82,137.34,133.70,132.75,131.96,131.25,129.39,126.09,122.79,72.66,57.91,54.41,54.28,31.53,30.98,30.82,30.69,18.17；
LC-MS-PH-JLU-LP-3-0:(ES,m/z):532.20(M+H)。
example 4
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:1:1.2, and the yield of the obtained compound C was 41 wt%.
Example 5
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:1:3, and the yield of the obtained compound C was 40 wt%.
Example 6
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:1:0.5, and the yield of the obtained compound C was 38 wt%.
Example 7
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:1:0.8, and the yield of the obtained compound C was 45 wt%.
Example 8
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:1:1.4, and the yield of the obtained compound C was 47 wt%.
Example 9
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:0.5:0.7, and the yield of the obtained compound C was 39 wt%.
Example 10
The differences from example 1 are: the molar ratio of the raw material A, sodium hydroxide and the raw material B was 1:3:0.7, and the yield of the obtained compound C was 40 wt%.
Example 11
The differences from example 1 are: the molar ratio of the starting material a, sodium hydroxide and starting material B was 1:0.8:0.7, and the yield of the obtained compound C was 41 wt%.
Example 12
The differences from example 1 are: the molar ratio of the starting material A, sodium hydroxide and starting material B was 1:1.4:0.7, and the yield of the obtained compound C was 43 wt%.
Example 13
The differences from example 1 are: the molar ratio of the starting material A, sodium hydroxide and starting material B was 1:1.2:0.9, and the yield of the obtained compound C was 49 wt%.
Example 14
The differences from example 1 are: the starting material A was replaced with (5-methylpyridin-3-yl) methanol hydrochloride, and the yield of the obtained compound C was 42 wt%.
Example 15
The differences from example 2 are: phosphorus tribromide was replaced with phosphorus oxybromide to give 11g of crude compound D.
Example 16
The differences from example 2 are: phosphorus tribromide was replaced with thionyl chloride to give 11g of crude compound D.
Example 17
The differences from example 2 are: phosphorus tribromide was replaced with N-bromosuccinimide to give 10g of a crude compound D.
Example 18
The differences from example 2 are: phosphorus tribromide was replaced with phosgene to give 12g of crude compound D.
Example 19
The differences from example 2 are: phosphorus tribromide was replaced with phosgene to give 11g of crude compound D.
Example 20
The differences from example 2 are: the molar ratio of compound C to halogenating agent was 1:3, yielding 10g of crude compound D.
Example 21
The differences from example 2 are: the molar ratio of compound C to halogenating agent was 1:1, giving 9.7g of crude compound D.
Example 22
The differences from example 3 are: the acid-binding agent was replaced with sodium carbonate and the yield of the product was 5 wt%.
Example 23
The differences from example 3 are: the molar ratio of compound E to compound D was 0.8:1, giving a product yield of 10 wt%.
Example 24
The differences from example 3 are: the molar ratio of compound E to compound D was 0.5:1 and the product yield was 8.7 wt%.
Example 25
The differences from example 3 are: the molar ratio of compound E to compound D was 1.4:1 and the product yield was 9.2 wt%.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the rupatadine fumarate derivative is an impurity in the synthesis of rupatadine fumarate, can be used as a standard substance for quality control of rupatadine fumarate, and provides reference for improving the purity of rupatadine fumarate.
The preparation method of the rupatadine fumarate derivative LP-3 adopts a shorter synthetic route, can improve the yield of the rupatadine fumarate derivative LP-3, and meanwhile, the synthetic route also has the advantages of less side reaction, good reproducibility and the like. On the basis, through the preparation and the structure identification of the rupatadine fumarate derivative LP-3, a reference substance with excellent quality and higher purity can be provided for qualitative and quantitative analysis of rupatadine fumarate, and the purity of the product prepared by the preparation method is more than 99% after purification, so that the preparation method has good guiding significance for the preparation and the application of rupatadine fumarate. Moreover, the compound D can be prepared from raw materials with wide sources and low price, so that the implementation cost of the preparation method is reduced.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (32)

1. A preparation method of rupatadine fumarate derivatives is characterized in that the rupatadine fumarate derivatives have the following structural formula I or pharmaceutically acceptable salts thereof,
Figure FDA0002579456920000011
the preparation method comprises the following steps:
step S3, reacting the compound D with the compound E to obtain the rupatta fumarate derivative,
the structural formula of the compound D is
Figure FDA0002579456920000012
Wherein X is a halogen atom;
the structural formula of the compound E is
Figure FDA0002579456920000013
The preparation method further includes a step S2 of preparing the compound D, the step S2 including:
carrying out halogenation reaction on the compound C and a halogenating reagent to obtain a compound D,
the structural formula of the compound C is
Figure FDA0002579456920000014
The preparation method further includes a step S1 of preparing the compound C, the step S1 including:
reacting a raw material A with a raw material B to obtain the compound C, wherein the raw material A is 5-methylpyridine-3-yl methanol or 5-methylpyridine-3-yl methoxide, and the raw material B is 3-ethoxycarbonyl-acrylic acid.
2. The method according to claim 1, wherein in step S3, the molar ratio of compound E to compound D is 0.5-1.4: 1.
3. The method according to claim 2, wherein the molar ratio of compound E to compound D is 0.8: 1.
4. The method according to claim 1, wherein the reaction of step S3 is carried out in the presence of an acid scavenger which is an organic weak base or an inorganic weak base.
5. The method according to claim 4, wherein the acid-binding agent is one or more selected from the group consisting of triethylamine, pyridine, potassium carbonate, and sodium carbonate.
6. The method according to claim 1, wherein the reaction of step S3 is carried out in a first solvent, and the first solvent is an aprotic solvent.
7. The process according to claim 6, wherein the aprotic solvent is selected from dichloromethane and/or chloroform.
8. The method according to claim 1, wherein the reaction of step S3 is carried out at room temperature or under heating.
9. The method according to claim 8, wherein the reaction temperature is from room temperature to 50 ℃.
10. The method according to claim 9, wherein the reaction temperature is room temperature.
11. The method according to claim 1, wherein the halogenating agent is selected from any one or more selected from the group consisting of phosphorus trihalides, phosphorus pentahalides, sulfoxides halides, phosphorus oxyhalides, sulfoxides chloride, N-bromosuccinimide, N-chlorosuccinimide, phosgene and phosgene in solid form.
12. The method according to claim 11, wherein the phosphorus trihalide is phosphorus trichloride and/or phosphorus tribromide, the phosphorus pentahalide is phosphorus pentachloride and/or phosphorus pentabromide, and the phosphorus oxyhalide is phosphorus oxychloride and/or phosphorus oxybromide.
13. The method according to claim 1, wherein the molar ratio of the compound C to the halogenating agent is 1:1 to 5.05.
14. The method of claim 13, wherein the molar ratio of compound C to the halogenating agent is 1: 3.
15. The method according to claim 1, wherein the halogenation reaction in step S2 is carried out in a second solvent, and wherein the second solvent is an aprotic solvent.
16. The method according to claim 15, wherein the aprotic solvent is selected from any one or more of ethylene glycol dimethyl ether, 1, 3-dimethyl-2-imidazolidinone, diethyl ether, tetrahydrofuran and dioxane.
17. The method according to claim 1, wherein the halogenation reaction in step S2 is carried out at room temperature or under heating.
18. The method according to claim 17, wherein the halogenation reaction temperature in the step S2 is between room temperature and 50 ℃.
19. The method of claim 18, wherein the halogenation temperature is room temperature.
20. The preparation method according to claim 1, wherein the step S2 is to add the halogenating agent dropwise at a low temperature of-5 to 5 ℃.
21. The method of claim 20, wherein the low temperature is 0 ℃.
22. The production method according to claim 1, wherein the 5-methylpyridin-3-ylmethanol salt is 5-methylpyridin-3-ylmethanol hydrochloride or 5-methylpyridin-3-ylmethanol hydrobromide.
23. The method as claimed in claim 22, wherein the step S1 reaction is carried out under the condition of a catalyst selected from alkali and/or alkali solution, and the step S1 reaction is carried out under the heating condition.
24. The method of claim 23, wherein the base is sodium hydroxide, potassium hydroxide and/or triethylamine.
25. The method as claimed in claim 23, wherein the reaction temperature of step S1 is 80-150 ℃.
26. The method according to claim 25, wherein the reaction temperature is 100 to 120 ℃.
27. The method according to claim 23, wherein in step S1, the molar ratio of the raw material A to the base to the raw material B is 1:0.5 to 3.
28. The method according to claim 27, wherein the molar ratio of the raw material a to the base to the raw material B is 1:0.8 to 1.4.
29. The method according to claim 28, wherein the molar ratio of the raw material a to the base to the raw material B is 1:1.2: 0.9.
30. The method according to claim 23, wherein the reaction of step S1 is carried out in a solvent.
31. The method of claim 30, wherein the reaction of step S1 is performed in water.
32. An intermediate, wherein the intermediate has the formula
Figure FDA0002579456920000041
Figure FDA0002579456920000042
Wherein X is a halogen atom.
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