CN116496254A - A kind of preparation method of rupatadine fumarate - Google Patents

Abstract

The invention discloses a preparation method of rupatadine fumarate with a structure shown as a formula (6), which comprises the following steps: the loratadine with the structure shown in the formula (1) is subjected to alkaline hydrolysis to obtain desloratadine with the structure shown in the formula (2); the 5-methylnicotinic acid with the structure shown as the formula (3) is subjected to condensation reaction in the presence of an acid binding agent to obtain rupatamide with the structure shown as the formula (4); the rupatadine with the structure shown as the formula (5) is obtained by reducing the formula (4) under the action of a reducing agent; salifying the rupatadine fumarate with fumaric acid in an organic solvent to obtain rupatadine fumarate; the organic solvent is absolute ethyl alcohol or absolute methyl alcohol. The book is provided withThe preparation method of rupatadine fumarate has the advantages of short synthetic route, mild reaction, good yield, and the purity of the finished product reaching more than 99.0 percent, and is suitable for industrial mass production.

Description

A kind of preparation method of rupatadine fumarate

technical field

The invention relates to a preparation method of rupatadine fumarate.

Background technique

Rupatadine fumarate (Rupatadine fumarate), the chemical name is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piper Pyridylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate is an antiallergic drug with dual blocking effects of histamine and platelet activating factor. The drug was developed by Uriach & Cia SA of Spain, and was first launched in Spain in March 2003 under the trade name Rupafin. Oral therapeutic dose of this product can selectively block _H1 receptors, and has only weak blocking effects on 5-hydroxytryptamine, acetylcholine, prostaglandin _F2a and leukotriene _D4 , and can still interact with platelet activating factor receptors Competitive binding, inhibits degranulation of sensitized cells. This product has no cardiovascular toxicity and potential arrhythmogenic effects, and no central sedative effect.

At present, rupatadine fumarate can be synthesized from 3 synthetic routes using loratadine as the starting material:

The first synthetic route:

The second synthetic route:

The third synthetic route:

From the above three routes, although route 1 has short synthesis steps, the reaction is difficult to control, and it is difficult to obtain a relatively pure product. Carbon tetrachloride needs to be used in the route, which is not scientific and environmentally friendly; route 2 has long synthesis steps, and the intermediate product is difficult to purify Get, the reaction is hard to control.

Route 3 has short synthesis steps, easy purification of the obtained intermediate, mild and controllable reaction, and is suitable for industrial production.

The key synthetic steps in Scheme 3 are the synthesis of luperamide and the reduction of luperamide.

In the published literature reports, the methods for synthesizing luperamide include: in the patent CN 101531654, it is reported that 5-methylnicotinic acid is first reacted with thionyl chloride to obtain 5-methylnicotinyl chloride by acyl chlorination, and then Condensation with desloratadine gives ruperamide. However, according to the experimental verification of this method, the following disadvantages are found: after 1,5-methyl nicotinic acid acid chloride, the residual thionyl chloride will affect the subsequent reaction with desloratadine, resulting in more by-products; 2 1. Since 5-methylnicotinoyl chloride is unstable, effective methods cannot be used to monitor the reaction process, and it is difficult to control the reaction, which is not conducive to large-scale industrial production.

In published literature reports, there are three methods for reducing rupatamide to synthesize rupatadine:

Introduced in U.S. Patent No.5407941 in tetrahydrofuran solution, the reduction method with lithium aluminum hydride as reducing agent, but carry out experimental verification according to this method, find following shortcoming: 1, this reaction yield is low, and product purity is not high 2. Due to the high activity of lithium aluminum hydride, the conditions for storage and use are harsh, and the price is expensive, which is not conducive to large-scale industrial production.

In the Chinese published patent CN1865259, the method of using sodium dihydroaluminate (red aluminum) as a reducing agent in tetrahydrofuran solution is introduced, but according to this method, experimental verification is carried out, and it is found that the yield is low, the product purity is not high and dihydroaluminate Sodium (red aluminum) reagent is expensive and is not conducive to industrialized large-scale production.

In the patent ES2087818, a method for reducing amides using POCl3/NaBH4 as a reducing system was reported. In the method, phosphorus oxychloride is first used to treat luperamide, and then sodium borohydride is used as a reducing agent to reduce the amide. However, the method has harsh operating conditions, and phosphorus oxychloride is highly corrosive, and requires high equipment, which is not conducive to large-scale industrial production.

In view of the medicinal value of rupatadine fumarate, it is necessary to find a synthetic route with simple operation, mild reaction conditions, good yield and satisfactory purity of the product.

Contents of the invention

The purpose of the present invention is to provide a preparation method with mild reaction conditions, simple operation, low requirements on equipment, high product purity and good yield.

The preparation method provided by the invention is as follows:

The first step, a preparation method of desloratadine with a structure as shown in formula (2), is characterized in that described preparation method is as follows: Loratadine, alkaline aqueous solution is added 95% ethanol heating reaction, after reaction is complete Concentrate under reduced pressure to remove ethanol, then add toluene to extract, then add water to wash the organic layer, concentrate the organic layer under reduced pressure, and add ethyl acetate for recrystallization to obtain desloratadine.

The alkali recommended by the present invention is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

The present invention recommends that the molar ratio of loratadine to alkali is 1.0:10.0-30.0, preferably 1.0:20.0-30.0.

The mass ratio of 95 ethanol to loratadine recommended by the present invention is 2.0-10.0:1.0, preferably 4.0-8.0:1.0.

The reaction temperature for preparing desloratadine with the structure shown in formula (2) according to the present invention is preferably 55-85°C.

The ratio of the mass of ethyl acetate to the mass of loratadine in the recrystallization of the present invention is 5.0-30.0:1.0, preferably 8.0-20.0:1.0.

The second step, a preparation method of ruperamide with a structure as shown in formula (4), is characterized in that the preparation method is as follows: desloratadine, 5-methylnicotinic acid, 1-hydroxybenzene Acetyltriazole (HOBT), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and acid-binding agent plus dichloromethane to react at elevated temperature, after the reaction is complete, concentrate under reduced pressure Remove dichloromethane, then add ethyl acetate and alkaline aqueous solution to precipitate a solid, and finally add water to beat the obtained solid to obtain luperamide.

The acid-binding agent recommended in the present invention is triethylamine or N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

The present invention recommends that the amount ratio of the acid-binding agent to desloratadine is 1.0-5.0:1.0, preferably 3.0-5.0:1.0.

The recommended ratio of the amount of 5-methylnicotinic acid to desloratadine feeding material in the present invention is 1.0-2.0:1, preferably 1.2-1.6:1.0.

The reaction temperature for preparing the luperamide with the structure represented by formula (4) in the present invention is preferably 15-35°C.

The alkali aqueous solution recommended by the present invention is an aqueous sodium hydroxide solution, an aqueous sodium carbonate solution or an aqueous potassium carbonate solution, preferably an aqueous sodium carbonate solution.

The third step, a preparation method of rupatadine with a structure as shown in formula (5), is characterized in that the preparation method is as follows: the reduction reaction is carried out by adding rupatamide plus a Lewis acid-activated reducing agent, and the reaction is completed Then add hydrochloric acid solution to adjust the pH value to 1-3, then concentrate under reduced pressure to remove the solvent, then add water to reflux reaction, the temperature of the reaction solution is lowered, and sodium hydroxide aqueous solution is added to adjust the pH value to 9-10, then ethyl acetate is added for extraction, and finally the obtained The crude product was separated by column chromatography to obtain rupatadine.

The Lewis acid recommended by the present invention is acetic acid, trifluoroacetic acid or magnesium chloride, preferably trifluoroacetic acid.

The reducing agent recommended by the present invention is sodium borohydride or potassium borohydride, preferably sodium borohydride.

The present invention recommends that the ratio of reducing agent to ruperamide feed material is 5.0-15.0:1.0, preferably 6.0-12.0:1.0.

The reaction temperature for preparing rupatadine with the structure represented by formula (5) according to the present invention is preferably 15-55°C.

The fourth step, a preparation method of rupatadine fumarate with a structure as shown in formula (6), is characterized in that the preparation method is as follows: the obtained rupatadine and fumaric acid are added with an alcohol solvent The temperature is raised to dissolve, and the temperature of the reaction solution is lowered to precipitate crystals to obtain rupatadine fumarate.

The alcohol solvent recommended by the present invention is ethanol, isopropanol or methanol, preferably ethanol.

The reaction temperature for preparing rupatadine fumarate with the structure shown in formula (6) according to the present invention is preferably 55-85°C.

The cooling crystallization temperature of the rupatadine fumarate having the structure shown in formula (6) for the preparation of the present invention is preferably -15-15°C.

Description of drawings

Figure 1 is a high performance liquid chromatogram of rupatadine

Figure 2 is a high performance liquid chromatogram of rupatadine fumarate

Detailed ways

The present invention will be described below through specific examples, but the present invention is not limited thereto.

Example 1

Add 10.0 g of the compound loratadine of formula (1), 100 ml of 95 ethanol and the prepared aqueous sodium hydroxide solution (15.0 g+50 ml) into the reaction kettle, stir and heat up to reflux reaction, TLC (developing condition DCM: MeOH=30 : 1) Monitor and stop the reaction after the reaction is complete. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to remove ethanol, and 100 ml of toluene and 100 ml of water were added and stirred to dissolve, and the organic layer was collected by liquid separation, and washed once with 100 ml of water. The organic layer was collected and concentrated to dryness, then 150.0 g of ethyl acetate was added to dissolve the above concentrate at elevated temperature, the temperature was lowered to crystallize, filtered by suction, and dried to obtain 6.1 g of desloratadine, a compound of formula (2). Yield: 75.1%.

Example 2

Add 100.0g of the compound loratadine of formula (1), 800ml of 95 ethanol and the prepared aqueous sodium hydroxide solution (250.0g+750ml) into the reaction kettle, stir and heat up to reflux reaction, TLC (developing condition DCM: MeOH=30 : 1) Monitor and stop the reaction after the reaction is complete. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to remove ethanol, and 100 ml of toluene and 100 ml of water were added and stirred to dissolve, and the organic layer was collected by liquid separation, and washed once with 100 ml of water. The organic layer was collected and concentrated to dryness, then 1000.0 g of ethyl acetate was added to dissolve the above-mentioned concentrate at elevated temperature, the temperature was lowered to crystallize, filtered by suction, and dried to obtain 69.6 g of desloratadine, a compound of formula (2). Yield: 85.7%.

Example 3

Add 7.5 g of the compound desloratadine of formula (2) and 150.0 g of dichloromethane into a 500 mL three-necked flask, add 6.0 g of 5-methylnicotinic acid, 6.0 g of HOBT, 7.5 g of EDCI, and 22.0 g of DIPEA , the temperature was raised to 35°C for reaction, the reaction was detected by TLC, and the stirring was stopped after the reaction was complete. Concentrate the reaction solution to remove dichloromethane, heat up and add 75.0 g of ethyl acetate to stir to dissolve, add saturated aqueous sodium carbonate solution to adjust the pH of the system to 8-9, stir, filter with suction, add water to the filter cake, filter with suction, and dry to obtain 8.4g of the compound of formula (3) luperamide. Yield: 81.0%.

Example 4

Add 7.5g of the compound desloratadine of formula (2) and 125.0g of dichloromethane into a 500mL three-necked flask, add 7.5g of 5-methylnicotinic acid, 7.5g of HOBT, 12.5g of EDCI, and 32.0g of DIPEA , the temperature was raised to 35°C for reaction, the reaction was detected by TLC, and the stirring was stopped after the reaction was complete. Concentrate the reaction solution to remove dichloromethane, heat up and add 60.0 g of ethyl acetate to stir to dissolve, add saturated aqueous sodium carbonate solution to adjust the pH of the system to 8-9, stir, filter with suction, add water to the filter cake, filter with suction, and dry to obtain 9.2g of the compound of formula (3) luperamide. Yield: 88.7%.

Example 5

Add 68.0 g of the compound desloratadine of formula (2) and 1000.0 g of dichloromethane into a 2000 mL three-necked flask, add 70.0 g of 5-methylnicotinic acid, 70.0 g of HOBT, 122.5 g of EDCI, and 350.0 g of DIPEA , the temperature was raised to 35°C for reaction, the reaction was detected by TLC, and the stirring was stopped after the reaction was complete. Concentrate the reaction solution to remove dichloromethane, heat up and add 800.0 g of ethyl acetate to stir to dissolve, add saturated aqueous sodium carbonate solution to adjust the pH of the system to 8-9, stir, filter with suction, add water to the filter cake, filter with suction, and dry to obtain 86.8g of the compound of formula (4) luperamide. Yield: 92.3%.

Example 6

Add 8.0g of ruperamide, 60.0g of tetrahydrofuran and 7.0g of sodium borohydride into a 250ml three-necked flask, drop the temperature and add the prepared trifluoroacetic acid tetrahydrofuran solution dropwise, keep the temperature not exceeding 20°C, and detect by TLC After the reaction is complete, stop the dropwise addition, drop the temperature and add 3M hydrochloric acid aqueous solution, adjust the pH to 1-2, concentrate to remove tetrahydrofuran in the system, add water to raise the temperature and reflux for 1 hour, drop the temperature and add 20% NaOH aqueous solution to adjust the pH to 8-9, add acetic acid Ethyl extraction, concentration of ethyl acetate layer to obtain crude product, addition of dichloromethane column chromatography, eluting with dichloromethane: methanol: ammonia water = 30:1:0.02, concentrating the eluent to obtain 3.5g Lupa He decides. Yield: 45.2%.

Example 6

Add 65.0g of ruperamide, 360.0g of tetrahydrofuran and 30.0g of sodium borohydride into a 2000ml three-neck flask of the compound of formula (4), drop the prepared tetrahydrofuran solution of trifluoroacetic acid in the lower temperature, keep the temperature not exceeding 20°C, and detect by TLC After the reaction is completed, drop the temperature and add 3M hydrochloric acid aqueous solution to adjust the pH to 1-2, concentrate to remove tetrahydrofuran in the system, add water to raise the temperature and reflux for 1 hour, drop the temperature and add 20% NaOH aqueous solution to adjust the pH to 8-9, add ethyl acetate to extract, The ethyl acetate layer was concentrated to obtain a crude product, which was separated by column chromatography with dichloromethane, eluted with dichloromethane: methanol: ammonia water = 30:1:0.02, and the eluate was concentrated to obtain 39.0 g of rupatadine. Yield: 62.0%. HPLC purity: 99.819%, as shown in Figure 1.

Example 7

Add 3.0g of rupatadine, 0.8g of fumaric acid and 30.0g of methanol into a 100ml three-neck flask, heat up to dissolve the reaction solution, filter it while it is hot, and place the filtrate in an ice bath at 0°C for 8 hours for crystallization , filtered, and dried to obtain 2.2g rupatadine fumarate. Yield: 57.3%.

Example 8

Add 39.0g rupatadine, 10.9g fumaric acid and 200.0g ethanol of the compound of formula (5) into a 500ml three-necked flask, raise the temperature to dissolve the reaction solution, filter it while it is hot, and place the filtrate in an ice bath at 0°C for 4 hours for crystallization , filtered, and dried to obtain 42.9g rupatadine fumarate. Yield: 86.0%. HPLC purity: 99.960%, as shown in Figure 2.

Claims (13)

1. a kind of preparation method of the rupatadine fumarate shown in formula (6), it is characterized in that described preparation method is as follows: the loratadine shown in structure as formula (1) passes alkaline The hydrolysis reaction obtains desloratadine whose structure is shown in formula (2); formula (2) and the 5-methyl nicotinic acid shown in formula (3), in the presence of acid-binding agent, condensation reaction obtains Structure as the rupatadine shown in formula (4); Formula (4) is reduced under the action of reducing agent to obtain the structure as shown in formula (5) rupatadine; Formula (5) is mixed with fumarate in organic solvent Acid salt formation to obtain rupatadine fumarate. 2. The method for preparing rupatadine fumarate according to claim 1, characterized in that: the alkali in the alkaline hydrolysis reaction is sodium hydroxide or potassium hydroxide. 3 . The method for preparing rupatadine fumarate according to claim 1 or 2 , characterized in that: the molar ratio of loratadine to alkali is 1.0:10.0-30.0. 4. according to claim 1,2 or 3 described preparation methods of rupatadine fumarate, it is characterized in that: described structure is as shown in formula (1) Loratadine is hydrolyzed to obtain structure as shown in formula (2) The reaction of desloratadine is shown as follows: add desloratadine, alkali aqueous solution and 95% ethanol to heat up the reaction, after the reaction is complete, concentrate under reduced pressure to remove ethanol, then add toluene for extraction, then add water to wash the organic layer, and concentrate the organic layer under reduced pressure , plus ethyl acetate recrystallization to obtain desloratadine. 5. The method for preparing rupatadine fumarate according to claim 1, characterized in that: the acid-binding agent is triethylamine or N,N-diisopropylethylamine. 6. The method for preparing rupatadine fumarate according to claim 1 or 5, characterized in that: the molar ratio of the acid-binding agent to desloratadine is 1.0-5.0:1.0. 7. according to claim 1,5 or 6 described preparation methods of rupatadine fumarate, it is characterized in that described structure is as shown in formula (2) and structure is as shown in formula (3) The reaction of 5-methylnicotinic acid condensation to obtain structure as shown in formula (4) ruperamide is as follows: desloratadine, 5-methylnicotinic acid, 1-hydroxybenzotriazole (HOBT), 1- Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and acid-binding agent plus dichloromethane to react at high temperature, after the reaction is complete, concentrate under reduced pressure to remove dichloromethane, then add ethyl acetate The ester and the aqueous alkali solution precipitated a solid, and finally the resulting solid was beaten with water to obtain luperamide. 8. The method for preparing rupatadine fumarate according to claim 1, wherein the reducing agent is sodium borohydride or potassium borohydride. 9. The method for preparing rupatadine fumarate according to claim 1 or 8, characterized in that: the Lewis acid is acetic acid, trifluoroacetic acid or magnesium chloride. 10 . The method for preparing rupatadine fumarate according to claim 1 , 8 or 9, characterized in that: the ratio of the reducing agent to the feed material of rupatamide is 5.0-15.0:1.0. 11. The method for preparing rupatadine fumarate according to claim 1, 8, 9 or 10, characterized in that the structure of rupatadine shown in formula (4) is reduced to obtain the structure of rupatadine fumarate as shown in formula (5) The reaction of rupatadine shown is as follows: add rupatamide plus a reducing agent activated by Lewis acid for reduction reaction, add hydrochloric acid solution to adjust the pH value to 1-3 after the reaction is completed, then concentrate under reduced pressure to remove the solvent, and then add water to reflux the reaction , the temperature of the reaction solution was lowered and sodium hydroxide aqueous solution was added to adjust the pH value to 9-10, and then ethyl acetate was added for extraction, and finally the obtained crude product was separated by column chromatography to obtain rupatadine. 12. The method for preparing rupatadine fumarate according to claim 1, characterized in that: the alcohol solvent is ethanol, isopropanol or methanol. 13. The method for preparing rupatadine fumarate according to claim 1 or 12, characterized in that the structure is as shown in formula (5) rupatadine and fumaric acid are salted to obtain a structure such as formula (6 The reaction of rupatadine fumarate shown in ) is as follows: the obtained rupatadine and fumaric acid plus alcohol solvent are heated and dissolved, and the temperature of the reaction solution is lowered to precipitate crystals to obtain rupatadine fumarate.