ES2311426B1 - A PROCEDURE FOR THE PREPARATION OF RUPATADINA AND ITS SALTS. - Google Patents

Abstract

A procedure for the preparation of Rupatadine and its salts.

Rupatadine is synthesized by the N-alkylation catalyzed by phase transfer of desloratadine in a biphasic solvent system using a aqueous base by the reaction of a compound of formula-A:

one

with desloratadine at a temperature of up to 50 ° C, in which the selected solvent is an organic solvent immiscible in water. Rupatadine also converts to fumarate from rupatadine by the reaction of rupatadine in a ketone solvent with an alcoholic solution of fumaric acid.

Description

A procedure for the preparation of Rupatadine and its salts.

Field of the Invention

The present invention relates to a commercially viable procedure for the preparation of Rupatadine and its salts.

Background and prior art

Rupatadine (formula-I) - chemically referred to as 8-chloro11- [1 - [(5-methyl-3-pyridinyl) methyl] -4-piperidinylidene] -6,11-dihydro-5 H -benzo- [5,6 ] cyclohepta [1,2- b ] pyridine is a potent orally active dual antagonist of platelet activating factor (PAF) and histamine (H1) and which affects its interaction with specific receptors.

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Document ES2042421 [which is equivalent to US 5476856, US5407941, ES2076817T3] describes the preparation of rupatadine, which implies the bromination of 3,5-lutidine in CCl4 using NBS followed by reaction of the product formed with desloratadine using 4- (dimethylamino) pyridine at room temperature for 18 hours followed by extractive work using the solvent dichloromethane and chromatographic purification to give rupatadine with a yield of 40%.

Rupatadine also becomes different salts such as trihydrochloride, hemipenta fumarate, dioxalate and hemicitrate, in which rupatadine in ethyl acetate produces the salts therefrom using the corresponding acid in the solvent; for hemipenta fumarate and citrate salts, acids corresponding used in methanol and for the dioxalate salt, the oxalic acid is used in ethyl acetate, while for Prepare the trihydrochloride salt, diethyl ether saturated with HCl gas.

The main disadvantages of this Procedure in the stage of preparing rupatadine are:

(i)

The long reaction times of the order of 18 hours,

(ii)

The chromatographic purification used to isolate rupatadine

(iii)

He 40% yield makes the procedure commercially non-viable.

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A procedure for the preparation of Rupatadine is described in ES2120899 which comprises react [8-chloro-6.11 dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-one with 3 - [(4-M-piperidine substituted-1-yl) methyl] -5-methylpyridine (where M is MgX or Li; where X is a halogen atom) to give 4- [8-chlorine 6,11-dihydro-11-hydroxy-5H-benzo [5,6] cyclohepta [1,2-b] piperidin-11-yl] -1 - [(5-methyl-3-pyridinyl) methyl] piperidine which, with dehydration, gives rupatadine. The rupatadine is then Transforms into a pharmaceutically acceptable salt.

The main disadvantages of the procedure They are:

(i)

The long reaction times of the order of 18 hours,

(ii)

He reaction product has to be chromatographed on silica gel to get the pure compound,

(iii)

He total yield of 42% [50% for Grignard addition and 84% for dehydration] makes the procedure commercially unfeasible.

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U.S. Pat. . 6803468 describes a procedure for the preparation of N- (5-methylnicotinoyl) -4-hydroxypiperidine, a key intermediate of rupatadine in which the acid reaction 5-methylnicotinic with alkyl chloroformate or pivaloyl chloride in a suitable solvent in the presence of a organic base gives the corresponding mixed anhydride that reacts with 4-hydroxypiperidine to give N- (5-methylnicotinoyl) -4-hydroxypiperidine.

The defect of this procedure is that it implies a multi-stage extractive work that do Commercially unattractive.

Document ES 2087818 A1 describes the Preparation of rupatadine that involves bromination of 3,5-lutidine in CCl4 using NBS followed by reaction of the product formed with desloratadine using 4- (dimethylamino) pyridine at room temperature for 18 hours followed by extractive work using the solvent dichloromethane and chromatographic purification to give rupatadine in a yield of 40%. In addition, rupatadine is converted to rupatadine fumarate using the solvent ethanol with a 70% yield.

The main disadvantages of this procedure are:

(i)

The long reaction times of the order of 18 hours,

(ii)

The chromatographic purification used to isolate rupatadine

(iii)

He 40% yield makes the procedure commercially non-viable.

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It is desirable to minimize the number of reaction steps including chromatographic separations for make the procedure commercially operable. The present invention provides a process for the preparation of rupatadine and in relation to its salts without intermediate stages of purification / isolation.

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Summary of the invention

The main object of the invention is provide a commercially viable procedure for rupatadine preparation

Another object of the invention is to provide a procedure for the preparation of rupatadine with times of lower reaction.

Another object of the invention is to provide a procedure for the preparation of rupatadine without a job extensive.

Another object is to prepare rupatadine by adding a solution of 3-bromomethyl 5-methyl-pyridine (prepared from of 3,5-dimethyl-pyridine without 3-bromomethyl insulation 5-methyl-pyridine) and make it react with desloratadine using a catalyst phase transfer and an aqueous base in a biphasic system.

The procedure to prepare rupatadine involves N-alkylation of desloratadine with 3-bromomethyl-5-methyl-pyridine using a base and a phase transfer catalyst in a biphasic solvent system. The process of this invention describes a method to prepare rupatadine fumarate from rupatadine reacting rupatadine in ketone solvents with a methanolic solution of fumaric acid. This procedure It has short reaction times, gives high yields and prevents extensive work of reaction products.

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Detailed description of the invention

The process of the invention is illustrated in Scheme 1:

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Scheme one

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Rupatadine is prepared from desloratadine by N-alkylation of desloratadine with compounds of 5-methyl-3-pyridinyl methyl of structure A

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Thus according to this invention:

(a) a solution of a compound of Formula-A in an organic solvent is treated with desloratadine using an aqueous base and a catalyst of phase transfer at a temperature of up to 50 ° C,

(b) The organic and aqueous layers are separated, the aqueous layer is discarded and the organic layer is distilled at reduced pressure to provide rupatadine,

(c) Rupatadine is dissolved in a solvent ketone and reacted with an alcoholic acid solution fumaric to give rupatadine fumarate.

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For stage (a):

The base used in the reaction is selected at from alkali metal bases and hydroxides, carbonates, bicarbonates such as NaOH, KOH, LiOH, Ca (OH) 2,  Ba (OH) 2; Na 2 CO 3, K 2 CO 3, Li 2 CO 3, CaCO 3, KHCO 3, NaHCO 3 and the like, more preferably NaOH.

The reaction medium for the reaction of the step (a) comprises a biphasic solvent system comprising water and a second organic solvent immiscible in water. He Organic solvent is selected from:

- Aromatic hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene or mixtures thereof;

- Ethers such as diethyl ether, diisopropyl ether, dibutyl ether, etc. or their mixtures;

- Ketone solvents such as MIBK.

- Halogenated solvents such as CCl4, CHCl 3, CH 2 Cl 2, chlorobenzene, trichlorethylene, tetrachlorethylene or mixtures thereof,

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The preferred solvent for the N-alkylation is CCl4, trichlorethylene, tetrachloro-ethylene, dichloromethane.

The phase transfer catalyst used for the reaction step (a) it is selected from a group of Quaternary ammonium salts of general formula: N (R1R2R3R4) X where R1, R2, R3, and R4 is a group C1 to C13 alkyl or aralkyl, cycloalkyl, aryl, or heterocyclyl. X is a monovalent anion. The preferred catalyst is:

- chloride triethyl benzyl ammonium, or bromide tetrabutyl ammonium, or hydrogen sulfate tetrabutyl ammonium

- Quaternary phosphonium salts

- PEG ethers such as PEG-400, PEG-600 and the like.

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The preferred PTC is bromide of tetrabutyl ammonium

The temperature for the reaction of step (a) it varies between 0 and 50 ° C, preferably, the ambient temperature.

The procedure described in step (c) for prepare rupatadine fumarate can also be extended to prepare other pharmaceutically acceptable salts such as hydrochloride, hydrobromide, maleate, mesylate, besylate, citrate, tartrate, sulfate, phosphate.

The present invention is illustrated with the following examples, without limiting the scope of the invention.

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Example 1 Preparation of hydrochloride 3-bromomethyl-5-methylpyridine

A mixture of carbon tetrachloride (4000 ml), azobisisobutyronitrile (45.96 g, 0.299 moles), 3,5-lutidine (150 g, 1,399 moles) and N-Bromosuccinamide (299.4 g, 1.682 mol) is subjected at reflux for 2 hours. The reaction mixture is cooled to room temperature and the solid is filtered. HCI gas is passed through the filtered and the solid obtained is separated and filtered. Performance It is 196 g. The yield is 67.66%.

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Example 2 Rupatadine Preparation

A mixture of desloratadine (5.0 g, 0.016 moles), methylene chloride (15 ml), tetrabutylammonium bromide (0.575 g, 0.0018 mol) and a solution of sodium hydroxide (2.5 g, 0.064 mol in 8 ml of water) is cooled to 0 to 50 ° C. Is added to the previous hydrochloride mixture of 3-bromomethyl-5-methylpyridine (7.18 g, 0.032 mol) in methylene chloride (35 ml). The mixture of reaction is stirred at 0 to 50 ° C for 1 hour and at temperature environment for 12 hours. The layers are separated and the organic layer Wash with a dilute solution of HCI and water. Chloride Methylene is distilled. Yield = 9.5 g,% Yield = 67.66%.

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Example 3 Preparation of rupatadine fumarate

A solution of fumaric acid (3.3 g) in methanol (46 ml) is added to rupatadine solution (4.5 g) in ethyl acetate (30 ml) at room temperature. The mass of The reaction is cooled to -5 to 0 ° C for 4 hours. The fumarate of Rupatadine is separated from the filtrate and washed with ethyl acetate. Yield = 5.5 g.

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Example 4 Preparation of 3-bromomethyl-5-methylpyridine

(a) It takes 3,5-Lutidine (100 g) to a 5.0L round bottom flask with a capacity of four mouths equipped with a head shaker, reflux condenser, thermometer, with a nitrogen gas passage device. Later loading with 3500 ml of carbon tetrachloride followed by (133 g) of N-Bromosuccinimide and (15.38 g) of AlBN, that is, 2,2'-azobisisobutyronitrile. Heats up slowly reaction mass at 70 ° C. The temperature is maintained for 4 hours. The reaction mass is cooled to room temperature (20-30 ° C). The reaction mass is filtered and the Filtering is used as such for the next stage.

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Rupatadine Preparation

(b) 3.7 L of the product solution of the Example 4 (a) is stirred with 60 g of desloratadine, 7.6 g of bromide of tetrabutyl ammonium. To this is added a solution aqueous sodium hydroxide (18.66 g of sodium hydroxide in 100 ml of water) at room temperature. And the reaction mass is stirred for 6-8 hours at room temperature. The stirring is stopped and the reaction mass is allowed to settle and The layers are separated. The organic layer is loaded into the flask of round bottom and 500 ml of water are added. The reaction mass is Stir for 15 to 20 minutes and allow to settle. The layers are separate The aqueous layer is discarded. The organic phase is dried in anhydrous sodium sulfate. The organic phase is filtered and the solvent it is distilled under vacuum at 35-40 ° C. The weight of residue is 110 g. To this 560 ml of acetone is added to room temperature and stir to dissolve. 160 g of gel Silica are added and stirred for one hour at room temperature. The silica gel is filtered off and washed with acetone and The solvent is removed to give rupatadine.

Weight of rupatadine obtained = 60 g.

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Preparation of rupatadine fumarate

(c) A solution of 60.0 g of rupatadine in 300 ml of acetone is loaded into a 1.0 L round bottom flask of capacity under a nitrogen atmosphere at room temperature (20-30 ° C). A solution of fumaric acid (17.0 g) in methanol (255 ml) then it is loaded with stirring. The mass of reaction is stirred at room temperature for 8-10 hours. Rupatadine fumarate solid salt precipitates The solid is filtered and washed with acetone (2 x 60 ml). He product is dried in a vacuum oven at 50-55 ° C for 8 to 10 hours.

Rupatadine fumarate weight = 36 g.

Purity> 99% of the area by HPLC.

P.F. = 196-99 ° C.

Although the present invention has been described in terms of their specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and will requires that they be included in the scope of this invention.

Claims (8)

1. A procedure for the preparation of rupatadine fumarate comprising: (a) react a solution of a compound of formula-A: 5 with desloratadine in a solvent water immiscible organic using an aqueous base and a catalyst phase transfer at a temperature of up to 50 ° C, (b) separate the organic and aqueous layers, (c) remove the organic solvent from the layer organic, dissolve the residue in an organic solvent and treat with silica gel or alumina followed by removal of solvent to provide rupatadine and convert rupatadine into rupatadine fumarate reacting a solution of rupatadine in a ketone solvent with an acid solution fumaric in an alcoholic solvent. 2. A procedure for the preparation of rupatadine fumarate as claimed in claim 1, wherein compound A is 3-bromomethyl 5-methyl-pyridine. 3. A procedure for the preparation of rupatadine fumarate as claimed in claim 1, in which the solvent used for N-alkylation phase transfer catalyzed is a solvent system biphasic comprising water and a second organic solvent immiscible in water, which is selected from: - Aromatic hydrocarbon solvents such such as benzene, toluene, xylene, ethylbenzene or optionally its mixtures; - Ethers such as diethyl ether, diisopropyl ether, dibutyl ether, etc. or optionally their mixtures; - Ketone solvents such as MIBK. - Halogenated solvents such as CCl4, CHCl 3, CH 2 Cl 2, chlorobenzene, trichlorethylene, tetrachlorethylene or optionally mixtures thereof, The preferred solvent for the N-alkylation is CCl4, CH2Cl2, trichlorethylene, tetrachlorethylene. 4. A process for the preparation of rupatadine fumarate as claimed in claim 1, wherein the base used for N-alkylation catalyzed by desloratadine phase transfer is selected from alkali metal bases and hydroxides, carbonates , bicarbonates such as NaOH, KOH, LiOH, Ca (OH) 2, Ba (OH) 2;
Na 2 CO 3, K 2 CO 3, Li 2 CO 3, CaCO 3, KHCO 3, NaHCO 3 and the like, with NaOH being more preferable. 5. A procedure for the preparation of rupatadine fumarate as claimed in claim (1) wherein the phase transfer catalyst used for the N-alkylation is selected from: [a] quaternary ammonium salts of formula general: N (R1R2R3R4) X where R1, R2, R3, and R4 is a C1 to C13 alkyl or aralkyl, cycloalkyl group, aryl, or heterocyclyl. X is a monovalent anion. Catalyst preferred is chloride triethyl benzyl ammonium, or bromide tetrabutyl ammonium, or hydrogen sulfate tetrabutyl ammonium [b] Quaternary phosphonium salts [c] PEG ethers such as PEG-400, PEG-600, etc. The most preferred PTC is the bromide of tetrabutyl ammonium 6. A procedure for the preparation of rupatadine fumarate as claimed in claim (1) in which the temperature for the reaction of N-alkylation catalyzed by phase transfer varies between 0 and 50 ° C, preferably it is the temperature ambient. 7. A procedure for the preparation of rupatadine fumarate according to claim 1, wherein said ketone solvent is acetone and where said alcohol solvent It is methanol. 8. A procedure for the preparation of a pharmaceutically acceptable salt of rupatadine such as hydrochloride, hydrobromide, maleate, mesylate, besylate, citrate, tartrate, sulfate, phosphate; which comprises mixing a solution Rupatadine ketone with an alcoholic acid solution correspondent.