Preparation method of rupatadine fumarate and intermediate compound

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly discloses a preparation method of rupatadine fumarate and an intermediate compound. The preparation method comprises the following steps: S1, dissolving 4-piperidone hydrochloride and 3-(chloromethyl)-5-methylpyridine hydrochloride in an organic solvent, and performing N-alkylation reaction under the action of alkali to obtain a compound shown as a formula III; s2, the compound shown in the formula III and tricyclic ketone are subjected to a McMurry coupling reaction in an organic solvent under the action of a coupling agent system, and rupatadine is obtained; s3, enabling rupatadine and fumaric acid to react in an organic solvent to obtain rupatadine fumarate. By preparing the compound shown in the formula III, the raw material cost for preparing rupatadine by taking loratadine as a raw material is greatly reduced, the process route is shorter, the conditions are milder, the economy of the rupatadine fumarate preparation process is improved while the operation difficulty is reduced, and the preparation method has great market prospects and popularization value.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of rupatadine fumarate and an intermediate compound. Background Art

[0002] Rupatadine fumarate, chemically named 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidinyl]-5H-benzo[5,6]cycloheptan[1,2-b]pyridine fumarate, is an antiallergic drug developed by Uriach of Spain with dual blocking effects on histamine and platelet activating factor. Since its launch in March 2003, it has been mainly used to treat urticaria and allergic rhinitis. This product not only has no cardiovascular toxicity, arrhythmogenic effects, and central sedative effects, but also can bind to platelet activating factor receptors non-competitively and inhibit the degranulation of sensitized cells, and has broad market application prospects.

[0003] At present, the preparation routes of rupatadine fumarate are mainly divided into two types, one is to use loratadine as the starting material, which has been reported in a large number of documents and patents; the other is to use tricyclic ketone and Grignard reagent as the starting materials. When loratadine is used as the starting material, the shorter route needs to be reduced by rupatadine amide. The document with the publication number CN1865259A uses red aluminum as a reducing agent, and the yield is low, which is not suitable for large-scale industrial production; the document with the publication number ES2087818A1 uses POCl3 / NaBH4 to reduce amide, the operating conditions are harsh, the reagent corrodes the equipment seriously, and it is difficult to industrialize production; the document with the publication number US5407941A uses lithium aluminum hydride as a reducing agent, the reaction yield is low, the product purity is low, and it is not conducive to industrial production. When tricyclic ketone and Grignard reagent are used as starting materials, the preparation and storage of Grignard reagent are difficult, and the potential safety risks in the industrial production process are high.

[0004] In view of the high value and potential large market of rupatadine fumarate, it is necessary to develop a synthetic route with simple operation, high yield and mild reaction conditions. Summary of the invention

[0005] In view of the shortcomings in the current synthesis process of rupatadine fumarate, the technical problem to be solved by the present invention is to provide a preparation method of rupatadine fumarate, which has mild reaction conditions and is easy to operate. A new intermediate compound in the synthesis process of rupatadine is prepared by the method, which greatly reduces the cost of synthesizing rupatadine using loratadine as a starting material, and improves the problems of difficulty in operating the reaction involving a Grignard reagent and difficulty in preparing the Grignard reagent.

[0006] In order to solve the above technical problems, the technical solution of the present invention is: A method for preparing rupatadine fumarate, characterized in that it comprises the following steps: S1. Dissolve the compound 4-piperidone hydrochloride of formula I and the compound 3-(chloromethyl)-5-methylpyridine hydrochloride of formula II in an organic solvent, and subject them to N-alkylation reaction under the action of a base to obtain the compound 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone of formula III; the structural formula of the compound of formula III is: ; S2, subjecting the compound of formula III and tricyclic ketone to a McMurry coupling reaction in an organic solvent under the action of a coupling agent system to obtain a compound of formula IV, rupatadine; S3, reacting rupatadine and fumaric acid in an organic solvent to obtain rupatadine fumarate, a compound of formula V; Its synthetic route is as follows: .

[0007] Preferably, in step S1, the organic solvent is one of N,N-dimethylformamide and N,N-dimethylacetamide, and N,N-dimethylformamide is most preferred.

[0008] Preferably, in step S1, after the N-alkylation reaction is completed, three extraction processes are required to obtain the compound of formula III; the three extraction processes are as follows: After the N-alkylation reaction was completed and before the first extraction, 20% potassium dihydrogen phosphate solution was added; The first extraction is with ethyl acetate to remove N, N-dimethylformamide or N, N-dimethylacetamide; The organic phase after the first extraction is extracted with a hydrochloric acid solution to salt the product and remove the by-products; After the second extraction, sodium hydroxide solution was added to the system to adjust the pH value, and then extraction was performed with ethyl acetate; The organic phase after the third extraction was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound of formula III.

[0009] Preferably, before the first extraction, the volume ratio of the added potassium dihydrogen phosphate solution to N,N-dimethylformamide is 1 to 5:1, and the optimal ratio is 2:1.

[0010] Preferably, the molar concentration of the hydrochloric acid solution used in the second extraction is 1 mol / L to 5 mol / L, and optimally 2 mol / L.

[0011] Preferably, the mass concentration of the sodium hydroxide solution added to the system after the second extraction is 10% to 30%.

[0012] Preferably, sodium hydroxide solution is added to the system after the second extraction to adjust the pH value to 8-12.

[0013] Preferably, in step S1, the base is one of triethylamine, sodium carbonate and potassium carbonate.

[0014] Preferably, in step S1, the mass ratio of 4-piperidone hydrochloride, 3-(chloromethyl)-5-methylpyridine hydrochloride and the alkaline substance is 1-2:1:2-5, and the optimal ratio is 1.3:1:4.5.

[0015] Preferably, in step S2, the preparation method of rupatadine with a structural formula as shown in formula IV is as follows: adding the compound of formula III, tricyclic ketone and coupling agent to an organic solvent at low temperature, reflux reaction under nitrogen protection, cooling after the reaction is completed, adding a terminator to quench the reaction and filtering, extracting the filtrate with dichloromethane, drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain rupatadine.

[0016] Preferably, in step S2, the organic solvent is one of tetrahydrofuran, ethylene glycol dimethyl ether and toluene.

[0017] Preferably, in step S2, the coupling agent system is one of the titanium reagent systems TiCl3 / LiAlH4, Zn / TiCl4, and Zn-Cu / TiCl4, with Zn / TiCl4 being the most preferred.

[0018] Preferably, in step S2, the mass ratio of the compound of formula III, tricyclic ketone and zinc powder is 1:1-1.5:5-10.

[0019] Preferably, the mass ratio of zinc powder to titanium tetrachloride in the coupling agent system Zn / TiCl4 is 2 to 2.5:1.

[0020] Preferably, the terminator is one of saturated potassium carbonate solution, saturated ammonium chloride solution, and saturated sodium bicarbonate solution, and the most preferred is saturated potassium carbonate solution.

[0021] Preferably, in step S3, the organic solvent is one of methanol, ethanol and isopropanol.

[0022] Preferably, in step S3, rupatadine and fumaric acid are added to an organic solvent, the temperature is raised to dissolve, and then the temperature is lowered to precipitate crystals, the filter cake is collected by filtration, and the filter cake is recrystallized from a methanol / ethyl acetate mixture to obtain rupatadine fumarate.

[0023] Preferably, in step S3, the mass ratio of rupatadine to fumaric acid is 1:0.31-0.33.

[0024] Preferably, in step S3, the volume ratio of methanol to ethyl acetate in the methanol / ethyl acetate mixture is 1:1-5.

[0025] Compared with the prior art, the present invention has at least the following beneficial effects: (1) The present invention uses 4-piperidone hydrochloride and 3-(chloromethyl)-5-methylpyridine hydrochloride to N-alkylate to prepare a compound represented by formula III. The reaction can be carried out at room temperature, and the operation is simple, the yield is high, and the atom economy is good.

[0026] (2) Due to the use of N-alkylation reaction, the potential safety risks in the preparation of the Grignard reagent are avoided. The compound of formula III does not contain solvent after treatment, which has little effect on the next step reaction, greatly improving the flexibility of the synthesis process and making the subsequent process optimization more operable.

[0027] (3) The present invention greatly reduces the raw material cost of preparing rupatadine using loratadine as the raw material by preparing the compound of formula III, and the process route is shorter and the conditions are milder.

[0028] (4) The method of the present invention has mild reaction conditions and is easy to operate. While reducing the difficulty of operation, it improves the economic efficiency of the preparation process of rupatadine fumarate and has great market prospects and promotion value. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The following drawings are intended only to illustrate and explain the present invention, and are not intended to limit the scope of the present invention. Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound of formula III in Example 1 of the present invention; Figure 2 is the carbon NMR spectrum of the compound of formula III in Example 1 of the present invention; Figure 3 is the hydrogen nuclear magnetic resonance spectrum of rupatadine fumarate synthesized in Example 1 of the present invention; Figure 4 This is the carbon nuclear magnetic resonance spectrum of rupatadine fumarate synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0030] The present invention will be further specifically described below in conjunction with the embodiments. In the following detailed description, some exemplary embodiments of the present invention are described only by way of illustration. Needless to say, those of ordinary skill in the art will appreciate that the described embodiments may be modified in various ways without departing from the spirit and scope of the present invention. Therefore, the description in the embodiments is illustrative in nature and is not intended to limit the scope of protection of the claims.

[0031] Example 1 10.0 g of 4-piperidone hydrochloride, 8.9 g of 3-(chloromethyl)-5-methylpyridine hydrochloride, 31.8 g of potassium carbonate and 180 ml of N,N-dimethylformamide were added to a reaction bottle, and the reaction was stirred at room temperature. After the reaction was completed, 360 ml of 20% potassium dihydrogen phosphate solution was added, and the mixture was extracted with 360 ml of ethyl acetate. The organic phase was collected and extracted with 180 ml of 2 mol / L hydrochloric acid. The pH of the hydrochloric acid was adjusted to 10 with 30% sodium hydroxide solution, and then the mixture was extracted with 360 ml of ethyl acetate. After the extraction, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 8.9 g of compound III 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone with a yield of 86.2%.

[0032] 7.2 g of the compound of formula III, 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone, 8.0 g of tricyclic ketone, 19.2 g of zinc powder and 80 ml of tetrahydrofuran were added to a reaction bottle, and 24.8 g of titanium tetrachloride was added dropwise at 0-5°C in a nitrogen atmosphere. After the addition was completed, the temperature was raised to reflux and monitored by TLC (development conditions: petroleum ether: ethyl acetate = 1:1). After the reaction was complete, the mixture was cooled to room temperature, 320 ml of saturated potassium carbonate solution was added, and the mixture was filtered and extracted with 800 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 12.9 g of the compound rupatadine with a yield of 94.5%.

[0033] Add 10 g of rupatadine, 3.1 g of fumaric acid and 50 ml of ethanol to a reaction bottle, heat to 70°C to dissolve, cool to crystallize, filter after crystallization, recrystallize the filter cake with 100 ml of a mixture of ethyl acetate and methanol (the volume ratio of ethyl acetate to methanol is 2:1), filter and dry to obtain 11.5 g of rupatadine fumarate, with a yield of 87.8%.

[0034] Example 2 10.0 g of 4-piperidone hydrochloride, 8.9 g of 3-(chloromethyl)-5-methylpyridine hydrochloride, 31.8 g of potassium carbonate and 180 ml of N,N-dimethylacetamide were added to a reaction bottle, and the reaction was stirred at room temperature. After the reaction was completed, 360 ml of 20% potassium dihydrogen phosphate solution was added, and the mixture was extracted with 360 ml of ethyl acetate. The organic phase was collected and extracted with 180 ml of 2 mol / L hydrochloric acid. The pH of the hydrochloric acid was adjusted to 10 with 30% sodium hydroxide solution, and then the mixture was extracted with 360 ml of ethyl acetate. After the extraction, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 7.9 g of compound III 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone with a yield of 76.3%.

[0035] 7.2 g of the compound of formula III, 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone, 8.0 g of tricyclic ketone, 38.1 g of zinc copper couple and 80 ml of ethylene glycol dimethyl ether were added to a 250 ml reaction bottle, and 24.8 g of titanium trichloride was added dropwise at 0-5°C in a nitrogen atmosphere. After the addition was completed, the temperature was raised to reflux and monitored by TLC (development conditions: petroleum ether: ethyl acetate = 1:1). After the reaction was complete, the mixture was cooled to room temperature, 320 ml of saturated potassium carbonate solution was added, and the mixture was filtered and extracted with 800 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10.6 g of the compound rupatadine with a yield of 77.7%.

[0036] Add 10.6 g of rupatadine, 3.3 g of fumaric acid and 53 ml of methanol to a reaction bottle, heat to 60°C to dissolve, cool to crystallize, filter after crystallization, recrystallize the filter cake with 106 ml of a mixture of ethyl acetate and methanol (the volume ratio of ethyl acetate to methanol is 3:1), filter and dry to obtain 11.2 g of rupatadine fumarate, with a yield of 82.6%.

[0037] Example 3 10.0 g of 4-piperidone hydrochloride, 8.9 g of 3-(chloromethyl)-5-methylpyridine hydrochloride, 24.3 g of sodium carbonate and 180 ml of N,N-dimethylformamide were added to a reaction bottle, and the reaction was stirred at room temperature. After the reaction was completed, 360 ml of 20% potassium dihydrogen phosphate solution was added, and the mixture was extracted with 360 ml of ethyl acetate. The organic phase was collected and extracted with 180 ml of 2 mol / L hydrochloric acid. The pH of the hydrochloric acid was adjusted to 10 with 30% sodium hydroxide solution, and then the mixture was extracted with 360 ml of ethyl acetate. After the extraction, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 8.1 g of compound III 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone with a yield of 78.2%.

[0038] 7.2 g of compound III 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone, 8.0 g of tricyclic ketone, 11.2 g of lithium aluminum hydride and 80 ml of tetrahydrofuran were added to a reaction bottle, and 24.8 g of titanium trichloride was added dropwise at 0-5°C in a nitrogen atmosphere. After the addition was completed, the temperature was raised to reflux and monitored by TLC (development conditions: petroleum ether: ethyl acetate = 1:1). After the reaction was complete, the mixture was cooled to room temperature, 320 ml of saturated potassium carbonate solution was added, and the mixture was filtered and extracted with 800 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 11.8 g of compound IV rupatadine with a yield of 86.5%.

[0039] Add 11.8 g of rupatadine, 3.7 g of fumaric acid and 59 ml of isopropanol into a reaction bottle, heat to 70°C to dissolve, cool to crystallize, filter after crystallization, recrystallize the filter cake with 118 ml of a mixture of ethyl acetate and methanol (the volume ratio of ethyl acetate to methanol is 2:1), filter and dry to obtain 12.1 g of rupatadine fumarate, with a yield of 80.2%.

[0040] The present invention prepares a new intermediate compound for synthesizing rupatadine (compound shown in formula III), thereby avoiding the disadvantages of expensive raw materials, long reaction route, harsh reaction conditions, and difficult operation in preparing rupatadine using loratadine as the starting raw material, and at the same time avoids the disadvantages of difficult preparation of Grignard reagent and difficult storage in preparing rupatadine by reacting tricyclic ketone with Grignard reagent. The intermediate compound prepared by the present invention has a simple synthesis process, convenient operation, and easy storage, and can directly prepare rupatadine with tricyclic ketone through McMurry coupling reaction, unlike the need for a concentrated sulfuric acid dehydration reaction after the reaction of Grignard reagent and tricyclic ketone. The process route of the present invention is shorter, which can make the synthesis process of rupatadine fumarate simpler, greener, and more suitable for large-scale industrialization needs.

[0041] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for preparing rupatadine fumarate, characterized in that: The steps include: S1, dissolving the compound 4-piperidone hydrochloride of formula I and the compound 3-(chloromethyl)-5-methylpyridine hydrochloride of formula II in an organic solvent, and subjecting them to N-alkylation reaction under the action of a base to obtain a compound of formula III; S2, subjecting the compound of formula III and tricyclic ketone to a McMurry coupling reaction in an organic solvent under the action of a coupling agent system to obtain a compound of formula IV, rupatadine; S3, reacting rupatadine and fumaric acid in an organic solvent to obtain rupatadine fumarate, a compound of formula V; Its synthetic route is as follows: 。 2. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S1, the organic solvent is one of N,N-dimethylformamide and N,N-dimethylacetamide.

3. The method for preparing rupatadine fumarate according to claim 2, characterized in that: In step S1, after the N-alkylation reaction is completed, three extraction processes are required to obtain the compound of formula III; the three extraction processes are as follows: After the N-alkylation reaction is completed and before the first extraction, potassium dihydrogen phosphate solution is added; The first extraction is with ethyl acetate to remove N, N-dimethylformamide or N, N-dimethylacetamide; The organic phase after the first extraction is extracted with a hydrochloric acid solution to salt the product and remove the by-products; After the second extraction, sodium hydroxide solution was added to the system to adjust the pH value, and then extraction was performed with ethyl acetate; The organic phase after the third extraction was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound of formula III.

4. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S1, the base is one of triethylamine, sodium carbonate and potassium carbonate.

5. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S1, the mass ratio of the 4-piperidone hydrochloride, 3-(chloromethyl)-5-methylpyridine hydrochloride and the alkaline substance is 1-2:1:2-5.

6. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S2, the organic solvent is one of tetrahydrofuran, ethylene glycol dimethyl ether and toluene.

7. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S2, the coupling agent system is one of TiCl3 / LiAlH4, Zn / TiCl4, and Zn-Cu / TiCl4 in the titanium reagent system.

8. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S3, the organic solvent is one of methanol, ethanol and isopropanol.

9. The method for preparing rupatadine fumarate according to claim 1, characterized in that: In step S3, rupatadine and fumaric acid are added to an organic solvent, the temperature is raised to dissolve, and then the temperature is lowered to precipitate crystals, the filter cake is collected by filtration, and the filter cake is recrystallized from a methanol / ethyl acetate mixture to obtain rupatadine fumarate.

10. An intermediate compound, characterized in that The structural formula is: 。

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